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CN120936350A - Methods and compositions for alleviating symptoms of parkinson's disease - Google Patents

Methods and compositions for alleviating symptoms of parkinson's disease

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Publication number
CN120936350A
CN120936350A CN202480025472.4A CN202480025472A CN120936350A CN 120936350 A CN120936350 A CN 120936350A CN 202480025472 A CN202480025472 A CN 202480025472A CN 120936350 A CN120936350 A CN 120936350A
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daily
baseline
hours
relative
dyskinesia
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Inventor
里埃·艾达
尼尔森·菲力克斯·洛普斯
罗伦斯·萨林
塔玛·亚迪尼
尼辛·萨松
席拉·欧伦
遣田光
日水幹夫
娜塔莉亚·沃斯托寇瓦
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Neuroderm Ltd
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Neuroderm Ltd
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Publication of CN120936350A publication Critical patent/CN120936350A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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  • Pharmacology & Pharmacy (AREA)
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  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Psychology (AREA)
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Abstract

公开了一种用于治疗有相应需要的患者的神经系统障碍或运动障碍例如帕金森病的方法，所述方法通过肠胃外施用左旋多巴和多巴脱羧酶抑制剂(DDCI)诸如卡比多巴、苄丝肼或其任何组合。A method for treating neurological or motor disorders, such as Parkinson's disease, in patients with corresponding needs is disclosed, the method being administered parenterally with levodopa and a dopa decarboxylase inhibitor (DDCI) such as carbidopa, benserazide, or any combination thereof.

Description

Methods and compositions for alleviating symptoms of parkinson's disease
Cross Reference to Related Applications
The present application claims the benefits and priorities of U.S. provisional patent application Ser. No. 63/459,438 filed on day 4 and 14, U.S. provisional patent application Ser. No. 63/508,634 filed on day 6 and 16, 2023, U.S. application Ser. No. 18/234,232 filed on day 8 and 15, 2023, and U.S. provisional patent application Ser. No. 63/564,464 filed on day 3 and 12, 2024, the respective disclosures of which are incorporated herein by reference in their entirety.
Technical Field
The present invention provides a method for treating neurological disorders or movement disorders such as parkinson's disease by parenterally administering levodopa and a dopa decarboxylase inhibitor (DDCI) such as carbidopa, benserazide, or any combination thereof.
Background
Parkinson's disease is a degenerative condition characterized by a decrease in the concentration of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or L-3, 4-dihydroxyphenylalanine) is a direct metabolic precursor of dopamine, which, unlike dopamine, is able to cross the blood brain barrier and is most commonly used to restore dopamine concentration in the brain. Levodopa has been the most effective therapy for the treatment of parkinson's disease throughout the last 40 years.
However, levodopa has a short half-life in plasma, leading to pulsatile dopaminergic stimulation (pulsatile dopaminergic stimulation), even under the best current common standard of care. Thus, long-term therapy is complicated by motor fluctuations and dyskinesias, which may represent a cause of severe disability in certain patients. Therapeutic strategies that can ultimately deliver levodopa/dopamine to the brain in a more continuous and physiological manner would provide the benefits of standard levodopa, with reduced motor complications, and are highly desirable for patients suffering from parkinson's disease and other neurological or movement disorders.
Summary of The Invention
Provided herein are, inter alia, methods and pharmaceutical compositions for treating neurological disorders or dyskinesias, including parenteral administration of levodopa or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as well as compositions comprising them (e.g., a pharmaceutically acceptable composition, such as a liquid pharmaceutical composition) and a dopa decarboxylase inhibitor (DDCI) or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and compositions comprising them (e.g., a pharmaceutically acceptable composition, such as a liquid pharmaceutical composition).
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily Good open time (day Good ON-time) relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day and for about 2 or 3 days,
Wherein the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day and for about 2 or 3 days,
Wherein the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day, and for about 2 or 3 days,
Wherein the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day, and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Based on the improvement in subject global change impression (SGI-C) scores over baseline,
Based on the improvement of clinical global change impression (CGI-C) scores over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Based on the improvement in the overall patient improvement impression (PGI-I) score over baseline,
Based on the improvement of the clinical overall improvement impression (CGI-I) score relative to baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Based on the improvement in subject global change impression (SGI-C) scores over baseline,
Based on the improvement of clinical global change impression (CGI-C) scores over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Based on the improvement in the overall patient improvement impression (PGI-I) score over baseline,
Based on the improvement of the clinical overall improvement impression (CGI-I) score relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Based on the improvement in subject global change impression (SGI-C) scores over baseline,
Based on the improvement of clinical global change impression (CGI-C) scores over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Based on the improvement in the overall patient improvement impression (PGI-I) score over baseline,
Based on the improvement of the clinical overall improvement impression (CGI-I) score relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily OFF-time relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day,
Wherein after 2 or 3 days of administration, administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day and for about 2 to 3 days,
Wherein the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day and for about 2 days to 3 days,
Wherein the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day, and for about 2 days to 3 days,
Wherein the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method of treating a patient suffering from Parkinson's disease comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day, and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
A decrease in daily off-period relative to baseline,
Without an increase in the daily open period with respect to baseline for dyskinesias,
A reduction of daily gross troublesome dyskinesias relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score over baseline,
Or any combination thereof.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline. According to some embodiments, the administration results in the patient having a decrease in the daily open period with moderate-severe movement disorder relative to baseline. According to some embodiments, the administration results in the patient having an improvement in overall change impression (SGI-C) score over baseline based on the subject. According to some embodiments, the administration results in the patient having an improvement based on the patient's overall improvement impression (PGI-I) score relative to baseline. According to some embodiments, the administration results in the patient having an improvement over baseline based on clinical global change impression (CGI-C) scores. According to some embodiments, the administration results in the patient having an improvement based on a clinical overall improvement impression (CGI-I) score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline and a decrease in the daily open period relative to baseline with moderate-severe dyskinesia. According to some embodiments, the administration results in the patient having an increase in daily good open time relative to baseline and an improvement in overall change impression (SGI-C) score relative to baseline based on the subject. According to some embodiments, the administration results in the patient having an increase in the daily good open time relative to baseline and an improvement based on the patient's overall improvement impression (PGI-I) score relative to baseline. According to some embodiments, administration results in patients with an increase in daily good open-term versus baseline and an improvement in clinical global change impression (CGI-C) based scores versus baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline and an improvement based on the subject's overall change impression (SGI-C) score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline and an improvement based on the patient's overall improvement impression (PGI-I) score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline and an improvement based on clinical global change impression (CGI-C) scores relative to baseline. According to some embodiments, the administration results in the patient having an improvement based on the subject global change impression (SGI-C) score over baseline and an improvement based on the clinical global change impression (CGI-C) score over baseline. According to some embodiments, the administration results in the patient having an improvement based on the patient's overall change impression (PGI-C) score relative to baseline and an improvement based on the clinical overall improvement impression (PGI-I) score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, and an improvement in the overall change impression (SGI-C) score relative to baseline based on the subject. According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, and an improvement relative to baseline based on the patient's overall improvement impression (PGI-I) score. According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, and an improvement based on clinical global change impression (CGI-C) scores relative to baseline. According to some embodiments, the administration results in the patient having an increase in daily good open-term over baseline, an improvement based on the subject's overall change impression (SGI-C) score over baseline, and an improvement based on the clinical overall change impression (CGI-C) score over baseline. According to some embodiments, the administration results in the patient having an increase in daily good open time relative to baseline, an improvement based on the patient's overall improvement impression (PGI-I) score relative to baseline, and an improvement based on the clinical overall improvement impression (CGI-I) score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline, an improvement based on the subject global change impression (SGI-C) score relative to baseline, and an improvement based on the clinical global change impression (CGI-C) score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline, an improvement based on the patient overall improvement impression (PGI-I) score relative to baseline, and an improvement based on the clinical overall improvement impression (CGI-I) score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, an improvement based on the subject's global change impression (SGI-C) score relative to baseline, and an improvement based on the clinical global change impression (CGI-C) score relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, an improvement based on the patient's overall improvement impression (PGI-I) score relative to baseline, and an improvement based on the clinical overall improvement impression (CGI-I) score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline. According to some embodiments, the administration results in the patient having a decrease in the daily open period with moderate-severe movement disorder relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily off-period from baseline. According to some embodiments, the administration results in the patient having an increase in the daily open period over baseline without movement disorder. According to some embodiments, administration results in a patient with a reduction of daily overall troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline and a decrease in the daily open period relative to baseline with moderate-severe dyskinesia. According to some embodiments, the administration results in the patient having an increase in daily good open time relative to baseline and a decrease in daily closed time relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline and an increase in the daily open period relative to baseline without concomitant movement disorder. According to some embodiments, administration results in patients with an increase in daily good open time relative to baseline and a decrease in daily overall troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an increase in daily good onset relative to baseline and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe movement disorder relative to baseline and a decrease in daily closed period relative to baseline. According to some embodiments, the administration results in the patient having a decrease in the daily open period with moderate-severe movement disorder relative to baseline and an increase in the daily open period without movement disorder relative to baseline. According to some embodiments, the administration results in the patient having a reduction in daily open period with moderate-severe dyskinesia relative to baseline and a reduction in movement disorder of daily total trouble relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily off-period relative to baseline and an increase in daily on-period relative to baseline without dyskinesia. According to some embodiments, the administration results in the patient having a reduction in daily deadlines relative to baseline and a reduction in daily overall troublesome dyskinesias relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily deadlines relative to baseline and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily open period relative to baseline that is not accompanied by dyskinesia and a decrease in dyskinesia relative to baseline that is generally troublesome per day. According to some embodiments, the administration results in the patient having an increase in daily opening period over baseline that is not accompanied by dyskinesia and an improvement in daily life exercise experience over baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score over baseline. According to some embodiments, the administration results in the patient having a daily overall troublesome reduction in dyskinesia relative to baseline and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a reduction in UPDRS part III score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, and a decrease in the daily closed period relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, and an increase in the daily open period relative to baseline without dyskinesia. According to some embodiments, the administration results in the patient having an increase in the daily good open time relative to baseline, a decrease in the daily open time relative to baseline with moderate-severe dyskinesia, and a decrease in the daily overall troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good onset relative to baseline, with a decrease in the daily onset relative to baseline of moderate-severe dyskinesia, and an improvement in the daily life exercise experience relative to baseline, resulting in a decrease in the UPDRS part III score relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having an increase in daily good open time relative to baseline, a decrease in daily open time relative to baseline, and an increase in daily open time relative to baseline without dyskinesia. According to some embodiments, the administration results in the patient having an increase in daily good open time relative to baseline, a decrease in daily closed time relative to baseline, and a decrease in daily overall troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an increase in daily good onset relative to baseline, a decrease in daily off relative to baseline, and an improvement in daily life exercise experience relative to baseline, resulting in a decrease in UPDRS part III score relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having an increase in the daily good open time relative to baseline, an increase in the daily open time relative to baseline without concomitant dyskinesia, and a decrease in total daily troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good onset relative to baseline, without an increase in the daily onset of dyskinesia relative to baseline, and an improvement in the daily life exercise experience relative to baseline, resulting in a decrease in the UPDRS part III score relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having an increase in daily good onset relative to baseline, a decrease in daily overall troublesome dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe movement disorder relative to baseline, a decrease in daily closed period relative to baseline, and an increase in daily open period without movement disorder relative to baseline. according to some embodiments, the administration results in the patient having a decrease in daily open period relative to baseline with moderate-severe dyskinesia, a decrease in daily closed period relative to baseline, and a decrease in movement disorder relative to baseline of daily total trouble. According to some embodiments, the administration results in the patient having a decrease in daily open time with moderate-severe dyskinesia relative to baseline, a decrease in daily closed time relative to baseline, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. according to some embodiments, the administration results in the patient having a decrease in the daily open period with moderate-severe dyskinesia relative to baseline, an increase in the daily open period without dyskinesia relative to baseline, and a decrease in overall daily troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open time with moderate-severe dyskinesia relative to baseline, an increase in daily open time without dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline, resulting in a decrease in UPDRS part III score relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having a reduction in daily open period with moderate-severe dyskinesia relative to baseline, a reduction in daily overall troublesome dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a reduction in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily deadlines relative to baseline, an increase in daily open periods relative to baseline without dyskinesias, and a decrease in dyskinesias relative to baseline that is generally troublesome per day. According to some embodiments, the administration results in the patient having a decrease in daily deadlines relative to baseline, without an increase in daily open time relative to baseline of dyskinesias, and an improvement in daily life exercise experience relative to baseline, resulting in a decrease in UPDRS part III score relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having a reduction in daily deadlines relative to baseline, a reduction in daily overall troublesome dyskinesias relative to baseline, and an improvement in daily life exercise experience relative to baseline, resulting in a reduction in UPDRS part III score relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having an increase in daily open time without dyskinesia relative to baseline, a decrease in daily overall troublesome dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline, a decrease in the daily open period relative to baseline with moderate-severe dyskinesia, a decrease in the daily open period relative to baseline, and an increase in the daily open period relative to baseline without dyskinesia. According to some embodiments, the administration results in the patient having an increase in the daily good open time relative to baseline, a decrease in the daily open time relative to baseline with moderate-severe dyskinesia, a decrease in the daily closed time relative to baseline, and a decrease in the daily gross troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good onset relative to baseline, with a decrease in the daily onset relative to baseline of moderate-severe dyskinesia, a decrease in the daily off-period relative to baseline, and an improvement in the daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in the UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having an increase in daily good open time relative to baseline, a decrease in daily closed time relative to baseline, an increase in daily open time relative to baseline without dyskinesia, and a decrease in movement disorder relative to baseline that is generally troublesome per day. According to some embodiments, the administration results in the patient having an increase in daily good onset relative to baseline, a decrease in daily off relative to baseline, without an increase in daily onset of dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline, as assessed by the unified parkinson's disease assessment scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. according to some embodiments, the administration results in the patient having an increase in the daily good onset relative to baseline, without an increase in the daily onset relative to baseline of dyskinesia, a decrease in the daily overall troublesome dyskinesia relative to baseline, and an improvement in the daily life exercise experience relative to baseline, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision, advocated by the dyskinesia association, resulting in a decrease in the UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open period with moderate-severe dyskinesia relative to baseline, a decrease in daily closed period relative to baseline, an increase in daily open period without dyskinesia relative to baseline, and a decrease in dyskinesia with daily total trouble relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open time relative to baseline with moderate-severe dyskinesia, a decrease in daily closed time relative to baseline, no increase in daily open time relative to baseline with dyskinesia, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease assessment scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open time relative to baseline with moderate-severe dyskinesia, an increase in daily open time relative to baseline without dyskinesia, a decrease in daily overall troublesome dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease assessment scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily deadlines relative to baseline, an increase in daily open time relative to baseline without a concomitant increase in daily overall troublesome dyskinesia relative to baseline, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good open time relative to baseline, a decrease in the daily open time relative to baseline with moderate-severe dyskinesia, a decrease in the daily open time relative to baseline, an increase in the daily open time relative to baseline without dyskinesia, and a decrease in the daily gross troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an increase in the daily good onset relative to baseline, a decrease in the daily onset relative to baseline with moderate-severe dyskinesia, a decrease in the daily off-period relative to baseline, an increase in the daily onset not with dyskinesia relative to baseline, and an improvement in the daily life exercise experience relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in the UPDRS part III score relative to baseline. According to some embodiments, the administration results in the patient having a decrease in daily open time relative to baseline with moderate-severe dyskinesia, a decrease in daily closed time relative to baseline without an increase in daily open time relative to baseline with daily overall troublesome dyskinesia, and an improvement in daily life exercise experience relative to baseline as assessed by the unified parkinson's disease assessment scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in UPDRS part III score relative to baseline.
According to some embodiments, the administration results in the patient having an increase in the daily good onset relative to baseline, a decrease in the daily onset relative to baseline with moderate-severe dyskinesia, a decrease in the daily off relative to baseline, an increase in the daily onset relative to baseline without dyskinesia, a decrease in the daily overall troublesome dyskinesia relative to baseline, and an improvement in the daily life movement experience relative to baseline as assessed by the unified parkinson's disease assessment scale part III (UPDRS part III) score revision advocated by the dyskinesia association, resulting in a decrease in the UPDRS part III score relative to baseline.
Some embodiments of the invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, and arginine for substantially continuous periods of about 24 hours/day,
Wherein the pharmaceutically acceptable liquid composition comprises about 60 mg/mL of levodopa and 7.5. 7.5 mg/mL of carbidopa, and wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg of levodopa and about 90 mg of carbidopa to a patient over a period of about 24 hours,
Wherein after 2 or 3 days of administration, the patient has at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of at least about 0.3 hours to 3.5 hours, and the decrease in daily open time relative to baseline with moderate-severe movement disorder is a decrease in daily open time relative to baseline with moderate-severe movement disorder of at least about 0.3 hours to 2.5 hours.
According to some embodiments, the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours. According to some embodiments, the low active night rate is administered for about 6 hours or about 8 hours, and the high active daytime rate is administered for about 18 hours or about 16 hours, respectively. According to some embodiments, the low activity night time rate is about 0.08 mL/hour. According to some embodiments, the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
Some embodiments of the invention relate to a method of increasing the good onset of a patient suffering from parkinson's disease, the method comprising
Substantially continuously for about 24 hours/day for about 2 to 3 consecutive days, subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w,
Wherein by the third consecutive day, administration results in an increase in the daily good open period of at least about 0.3 hours to 3.5 hours relative to baseline.
According to some embodiments, administration results in an increase in the daily good open period from baseline of about 1.8 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition further comprises arginine. According to some embodiments, the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
According to some embodiments, the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours. According to some embodiments, the low active night rate is administered for about 6 hours and the high active daytime rate is administered for about 18 hours. According to some embodiments, the low activity night time rate is about 0.08 mL/hour. According to some embodiments, the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
without the troublesome increase of the daily opening period of dyskinesia,
A decrease in the daily period of closure,
As assessed by the unified parkinsonism rating scale (UPDRS) part II score revision, improvement in the exercise experience of everyday life, resulting in a decrease in UPDRS part II score,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof,
Wherein the improvement in said patient is measured as compared to a patient treated with an immediate release oral dosage form of levodopa, and
Wherein the patient is improved in:
The improvement in the daily open period without troublesome dyskinesia is an increase of about 1.7 hours in the daily open period without troublesome dyskinesia,
The improvement in daily off-period is a reduction of about 1.4 hours per daily off-period,
The improvement in daily exercise experience as assessed by UPDRS part II score was a drop of about 3.0,
The improvement in patient global change impression (PGI-C) score was a ratio of about 5.3, and
The improvement in clinical overall improvement impression (CGI-I) score was a ratio of ratios of about 7.2.
According to some embodiments, the pharmaceutically acceptable liquid composition further comprises arginine. According to some embodiments, the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa. According to some embodiments, the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours. According to some embodiments, the low active night rate is administered for about 6 hours or about 8 hours and the high active daytime rate is administered for about 18 hours or about 16 hours, respectively, wherein the low active night rate is about 0.08 mL/hour, and wherein the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
Some embodiments of the invention relate to a method of treating a patient suffering from parkinson's disease, said method comprising subcutaneously administering to said patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, and further comprising arginine, substantially continuously for about 24 hours/day, and for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline of at least about 0.3 to 3.5,
A decrease in the daily open period associated with moderate-to-severe movement disorders from baseline of at least about 0.3 hours to 2.5 hours,
A decrease in daily off period from baseline of at least 0.1 to 2.0,
An increase in the daily open period relative to baseline of at least about 0.1 to 3.5 without concomitant movement disorder,
A reduction of the daily total troublesome dyskinesia by at least 0.1 to 3.2 relative to baseline,
The UPDRS part III score decreases from about 2 points to 13 points relative to baseline,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient via a device comprising a control station, a reusable component, and a disposable component.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa. According to some embodiments, the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours. According to some embodiments, the low active night rate is administered for about 6 hours and the high active daytime rate is administered for about 18 hours. According to some embodiments, the low activity night time rate is about 0.08 mL/hour and the high activity day time rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
According to some embodiments, the patient is fully open after about 5 hours of administration at the first flow rate.
According to some embodiments, the patient has an improvement in sleep quality over baseline after two days of treatment. According to some embodiments, the patient has a change in sleep quality from baseline after two days of treatment.
Some embodiments of the invention relate to a method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, and arginine substantially continuously for about 24 hours/day, and for about 2 to 3 consecutive days,
Wherein the pharmaceutically acceptable liquid composition comprises about 60 mg/mL of levodopa and 7.5. 7.5 mg/mL of carbidopa, and wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg of levodopa and about 90 mg of carbidopa to a patient over a period of about 24 hours,
Wherein by the third consecutive day, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline of at least about 0.3 to 3.5,
A decrease in the daily open period associated with moderate-to-severe movement disorders from baseline of at least about 0.3 hours to 2.5 hours,
A decrease in daily off period from baseline of at least 0.1 to 2.0,
An increase in the daily open period relative to baseline of at least about 0.1 to 3.5 without concomitant movement disorder,
A reduction of the daily total troublesome dyskinesia by at least 0.1 to 3.2 relative to baseline,
The UPDRS part III score decreases from about 2 points to 13 points relative to baseline,
Or any combination thereof.
According to some embodiments, the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient via a device comprising a control station, a reusable component, and a disposable component.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours. According to some embodiments, the low active night rate is administered for about 6 hours or about 8 hours, and the high active daytime rate is administered for about 18 hours or about 16 hours, respectively. According to some embodiments, the low activity night time rate is about 0.08 mL/hour and the high activity day time rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
According to some embodiments, the patient is fully open after about 5 hours of administration at the first flow rate.
According to some embodiments, the patient has an improvement in sleep quality over baseline after two days of treatment. According to some embodiments, the patient has a change in sleep quality from baseline after two days of treatment.
Some embodiments of the invention relate to a method of increasing the good onset of a patient suffering from parkinson's disease, the method comprising
Subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w and further comprising arginine, substantially continuously for about 24 hours/day for about 2 to 3 consecutive days,
Wherein by the third consecutive day, administration results in an increase in the daily good open period of at least about 0.3 hours to 3.5 hours relative to baseline.
According to some embodiments, administration results in an increase in the daily good open period from baseline of about 1.8 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient via a device comprising a control station, a reusable component, and a disposable component.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa. According to some embodiments, the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
According to some embodiments, the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours. According to some embodiments, the low active night rate is administered for about 6 hours and the high active daytime rate is administered for about 18 hours. According to some embodiments, the low activity night time rate is about 0.08 mL/hour. According to some embodiments, the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
According to some embodiments, the patient is fully open after about 5 hours of administration at the first flow rate.
According to some embodiments, the patient has an improvement in sleep quality over baseline after two days of treatment. According to some embodiments, the patient has a change in sleep quality from baseline after two days of treatment.
According to any of the embodiments described herein, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of at least about 0.1 hour to 3.5 hours.
According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.1 hour. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.11 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.12 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.13 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.14 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.15 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.16 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.17 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.18 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.19 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.20 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.22 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.24 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period of about 0.26 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period of about 0.28 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.3 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.32 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.34 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.36 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.38 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.4 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.42 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.44 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.46 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.48 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.5 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.55 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.6 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.65 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.7 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.75 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.8 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.85 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.9 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 0.95 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.0 hour. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.1 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.2 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.3 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.4 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.5 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.6 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.7 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.8 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.8 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 1.9 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.0 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.1 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.2 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.25 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.3 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.4 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.5 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.6 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.7 hours. according to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.75 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.8 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 2.9 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.0 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.1 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.2 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.25 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.3 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.4 hours. According to some embodiments, the increase in daily good open time relative to baseline is an increase in daily good open time relative to baseline of about 3.5 hours.
According to any of the embodiments described herein, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of at least about 0.3 hours to 2.5 hours.
According to some embodiments, the decrease in daily open period with moderate-severe movement disorder relative to baseline is a decrease in daily open period relative to baseline of about 0.3 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.32 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.34 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.36 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.38 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.4 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.42 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.44 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.46 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.48 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.5 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.55 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.6 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.65 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.7 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.75 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.8 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.85 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.9 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 0.95 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1 hour. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.1 hour. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.2 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.3 hours. according to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.4 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.5 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.6 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.7 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.8 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 1.9 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 2 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 2.1 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 2.1 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 2.3 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 2.4 hours. According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-severe movement disorder relative to baseline of about 2.5 hours.
According to any of the embodiments described herein, the decrease in daily off-period from baseline is a decrease in daily off-period from about 0.1 hour to 2.0 hours from baseline.
According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.1 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.11 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.12 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.13 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.14 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.15 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.16 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.17 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.18 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.19 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.20 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.22 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.24 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase of about 0.26 hours of daily total closed period. According to some embodiments, the increase in daily good open period relative to baseline is an increase of about 0.28 hours of daily total closed period. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.3 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.32 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.34 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.36 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.38 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.4 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.42 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.44 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.46 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.48 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.5 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.55 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.6 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.65 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.7 hours. according to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.75 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.8 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.85 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.9 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 0.95 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.0 hour. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.1 hour. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.2 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.3 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.4 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.5 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.6 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.7 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.8 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.8 hours. according to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 1.9 hours. According to some embodiments, the decrease in daily off period from baseline is a decrease in daily overall off period from baseline of about 2.0 hours.
It should be noted that daily off periods and daily total off periods are interchangeable herein unless specifically mentioned otherwise or unless otherwise understood by one of skill in the art.
According to any of the embodiments described herein, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline without dyskinesia of at least about 0.1 hour to 3.5 hours.
According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 0.1 hour without dyskinesia. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.11 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.12 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.13 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.14 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.15 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.16 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.17 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.18 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.19 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.20 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.22 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.24 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase of about 0.26 hours in the daily open period without dyskinesia. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase of about 0.28 hours in the daily open period without dyskinesia. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.3 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.32 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.34 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.36 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.38 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.4 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.42 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.44 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.46 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.48 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.5 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.55 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.6 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.65 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.7 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.75 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.8 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.85 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.9 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 0.95 hours. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.0 hour without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.1 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.2 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.3 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.4 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.5 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.6 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.7 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.8 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.8 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 1.9 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.0 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.1 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.2 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.25 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.3 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.4 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.5 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.6 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.7 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.75 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.8 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 2.9 hours without dyskinesia. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 3.0 hours. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 3.1 hours without dyskinesia. According to some embodiments, the increase in the daily open period over baseline without dyskinesia is an increase in the daily open period over baseline of about 3.2 hours without dyskinesia. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 3.25 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 3.3 hours. According to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 3.4 hours. according to some embodiments, the increase in the daily open period without dyskinesia relative to baseline is an increase in the daily open period without dyskinesia relative to baseline of about 3.5 hours.
According to any of the embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia from about 0.1 hour to 3.2 hours relative to baseline.
According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.1 hour. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.11 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.12 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.13 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.14 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.15 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.16 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.17 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.18 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.19 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.20 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.22 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.24 hours. According to some embodiments, the increase in daily good onset relative to baseline is an increase of about 0.26 hours of daily total troublesome dyskinesia. According to some embodiments, the increase in daily good onset relative to baseline is an increase of about 0.28 hours of daily total troublesome dyskinesia. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.3 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.32 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.34 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.36 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.38 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.4 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.42 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.44 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.46 hours. according to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.48 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.5 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.55 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.6 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.65 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.7 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.75 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.8 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.85 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.9 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 0.95 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.0 hour. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.1 hour. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.2 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.3 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.4 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.5 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.6 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.7 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.8 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.8 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 1.9 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.0 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.1 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.2 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.3 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.4 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.5 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.6 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.7 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.8 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 2.9 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 3.0 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 3.1 hours. According to some embodiments described herein, the decrease in daily gross troublesome dyskinesia relative to baseline is a decrease in daily gross troublesome dyskinesia relative to baseline of about 3.2 hours.
According to any of the embodiments described herein, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 2 to 13 points relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association.
According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 2 to 3 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 3 to 4 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 4 to 5 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 5 to 6 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 6 to 7 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 7 to 8 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 8 to 9 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 9 to 10 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 10 points to about 11 points relative to baseline as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 11 to 12 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association. According to some embodiments, the improvement in the daily exercise experience over baseline results in a reduction in UPDRS part III score from about 12 to 13 points relative to baseline as assessed by the unified parkinson's disease rating scale part III score revision advocated by the dyskinesia association.
According to some embodiments, the increase in daily good open period relative to baseline lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the decrease in the daily open period with moderate-severe movement disorder from baseline lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the decrease in daily off period from baseline lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the increase in daily open period over baseline without dyskinesia lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the decrease in daily total troublesome dyskinesia from baseline lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement in the daily exercise experience relative to baseline, as assessed by the unified parkinsonism rating scale part III score revision advocated by the dyskinesia association (UPDRS part III), results in a decrease in UPDRS part III score relative to baseline for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement in subject global change impression (SGI-C) score lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement in clinical global change impression (CGI-C) score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement in the patient's overall improvement impression (PGI-I) score lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement in clinical overall improvement impression (CGI-I) score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
As assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision, advocated by the dyskinesia association, improvement of the daily locomotor experience,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
As assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision, advocated by the dyskinesia association, improvement of the daily locomotor experience,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
In some embodiments, administration also results in a reduction of movement disorders in patients with daily trouble.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
As assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision, advocated by the dyskinesia association, improvement of the daily locomotor experience,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
A reduction of daily troublesome dyskinesias,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa or a pharmaceutically acceptable salt thereof and optionally carbidopa or a pharmaceutically acceptable salt thereof, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
As assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision, advocated by the dyskinesia association, improvement of the daily locomotor experience,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
A reduction of daily troublesome dyskinesias,
Or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof and carbidopa or a pharmaceutically acceptable salt thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
A reduction of daily troublesome dyskinesias,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
A reduction of daily troublesome dyskinesias,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
A reduction of daily troublesome dyskinesias,
Or any combination thereof.
A further embodiment of the invention relates to a method of ameliorating at least one symptom of parkinson's disease in a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day,
Wherein the administration results in the patient having at least one of:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
Improvement of the exercise experience of everyday life as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
A reduction of daily troublesome dyskinesias,
Or any combination thereof.
According to some embodiments, administration results in a reduction in daily off-periods. According to some embodiments, the administration results in an increase in the daily open period without concomitant dyskinesia. According to some embodiments, the administration results in an improvement in the exercise experience of daily living as assessed by a revised version of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association. According to some embodiments, the administration results in an improvement in the score based on the overall change impression (PGI-C) of the patient. According to some embodiments, the administration results in an improvement based on a clinical overall improvement impression (CGI-I) score. According to some embodiments, the administration results in an improvement based on clinical global change impression (CGI-C) scores. According to some embodiments, administration results in a reduction of daily troublesome dyskinesias.
According to some embodiments, administration results in a decrease in daily off-period and an increase in daily on-period without concomitant troublesome dyskinesia. According to some embodiments, administration results in a reduction of daily deadlines, as well as an improvement in the exercise experience of daily living as assessed by a revised version of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association. According to some embodiments, administration results in a reduction in daily off-period and an improvement in the score based on patient overall change impression (PGI-C). According to some embodiments, administration results in a reduction in daily deadlines and an improvement in the impression of improvement based on clinical population (CGI-I) score. According to some embodiments, the administration results in an improvement based on clinical global change impression (CGI-C) scores. According to some embodiments, administration results in a reduction of daily off-periods and a reduction of daily troublesome dyskinesias. According to some embodiments, the administration results in an increase in daily opening without troublesome dyskinesias, and a daily life exercise experience as assessed by a revised version of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, advocated by the dyskinesia association. According to some embodiments, administration results in an increase in the daily open period without concomitant dyskinesia and an improvement in the patient's overall change impression (PGI-C) based score. According to some embodiments, administration results in an increase in the daily open period without concomitant dyskinesia and an improvement based on clinical global improvement impression (CGI-I) scores. According to some embodiments, the administration results in an increase in the daily open period without concomitant dyskinesia and a decrease in daily dyskinesia. According to some embodiments, administration results in an increase in the daily open period without concomitant dyskinesia and an improvement in clinical global change impression (CGI-C) based scores. According to some embodiments, the administration results in an improvement in the daily life exercise experience as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, as advocated by the dyskinesia association, as well as an improvement in the overall change impression (PGI-C) score based on the patient. According to some embodiments, the administration results in an improvement in the daily locomotor experience as assessed by a revised version of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, as advocated by the dyskinesia association, as well as an improvement in the clinical global improvement impression (CGI-I) score. According to some embodiments, the administration results in an improvement in the exercise experience of daily life as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score revision, as well as an improvement in the clinical global change impression (CGI-C) based score, advocated by the dyskinesia association. According to some embodiments, administration results in an improvement in the daily locomotor experience, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, as advocated by the dyskinesia association, and a reduction in daily bothersome dyskinesias. According to some embodiments, the administration results in an improvement based on patient global change impression (PGI-C) scores and an improvement based on clinical global improvement impression (CGI-I) scores. According to some embodiments, the administration results in an improvement based on patient global change impression (PGI-C) score and an improvement based on clinical global change impression (CGI-C) score. According to some embodiments, administration results in a reduction of patient global change impression (PGI-C) scores and daily troublesome dyskinesias. According to some embodiments, administration results in an improvement in clinical global change impression (CGI-C) based scores and a reduction in daily troublesome dyskinesias. According to some embodiments, administration results in an improvement based on clinical overall improvement impression (CGI-I) scores and a reduction in daily troublesome dyskinesias.
According to some embodiments, administration results in a reduction of daily deadlines, daily open-term without concomitant trouble movement disorders, and improvement of the daily life movement experience as assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the movement disorder association. According to some embodiments, administration results in a reduction of daily off-period, daily on-period without troublesome dyskinesia, and an improvement based on patient global change impression (PGI-C) scores. According to some embodiments, administration results in a reduction of daily off-period, daily on-period without troublesome dyskinesia, and improvement of the clinical-based overall improvement impression (CGI-I) score. According to some embodiments, administration results in a reduction of daily off-period, daily on-period without troublesome dyskinesia, and an improvement based on clinical global change impression (CGI-C) scores. According to some embodiments, administration results in a reduction of daily off-period, daily on-period without concomitant troublesome dyskinesia, and a reduction of daily troublesome dyskinesia. According to some embodiments, administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, as advocated by the dyskinesia association, an improvement in the exercise experience of daily life, and an improvement in the overall change impression (PGI-C) score based on the patient. According to some embodiments, administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, as advocated by the dyskinesia association, an improvement in the exercise experience of daily life, and an improvement based on the clinical overall improvement impression (CGI-I) score. According to some embodiments, administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinsonian rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement of the daily life exercise experience, and a reduction of daily troublesome dyskinesias advocated by the dyskinesia society. According to some embodiments, administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, as advocated by the dyskinesia association, an improvement in the exercise experience of daily life, and an improvement in the clinical global change impression (CGI-C) score. According to some embodiments, administration results in a reduction in daily deadlines, an improvement based on patient global change impression (PGI-C) scores, and an improvement based on clinical global improvement impression (CGI-I) scores. According to some embodiments, administration results in a reduction of daily off-period, an improvement in patient global change impression (PGI-C) score, and a reduction of daily troublesome dyskinesia. According to some embodiments, the administration results in a reduction in daily deadlines, an improvement based on patient global change impression (PGI-C) scores, and an improvement based on clinical global change impression (CGI-C) scores. According to some embodiments, the administration results in an increase in daily opening without troublesome dyskinesias, as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and an improvement based on the patient's overall change impression (PGI-C) score. According to some embodiments, the administration results in an increase in daily opening without troublesome dyskinesias, as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and an improvement based on a clinical overall improvement impression (CGI-I) score. According to some embodiments, the administration results in an increase in daily opening without troublesome dyskinesias, as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and an improvement based on clinical global change impression (CGI-C) score. according to some embodiments, the administration results in an increase in daily open period without troublesome dyskinesias, as assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and a decrease in daily troublesome dyskinesias advocated by the dyskinesia society. According to some embodiments, the administration results in an improvement in the daily life exercise experience, an improvement in the patient population change impression (PGI-C) score, and an improvement in the clinical population improvement impression (CGI-I) score as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association. According to some embodiments, the administration results in an improvement in the daily life exercise experience, an improvement in the patient population change impression (PGI-C) score, and an improvement in the clinical population change impression (CGI-C) score as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association.
According to some embodiments, administration results in a reduction of daily deadlines, without an increase in daily opening with troublesome dyskinesias, as assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and an improvement based on the patient's overall change impression (PGI-C) score. According to some embodiments, administration results in a reduction of daily deadlines, without an increase in daily opening with troublesome dyskinesias, as assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and an improvement based on a clinical overall improvement impression (CGI-I) score, advocated by the dyskinesia society. According to some embodiments, administration results in a reduction of daily off period, an increase in daily on period without troublesome dyskinesias assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and a reduction in daily troublesome dyskinesias advocated by the dyskinesia society. According to some embodiments, administration results in a reduction of daily off-period, an increase in daily on-period without troublesome dyskinesias assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, and an improvement based on clinical global change impression (CGI-C) score. According to some embodiments, the administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in the daily life exercise experience, an improvement in the patient population change impression (PGI-C) score, and an improvement in the clinical population improvement impression (CGI-I) score, advocated by the dyskinesia association. According to some embodiments, administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement of the daily life exercise experience, an improvement of the patient's overall change impression (PGI-C) score, and a reduction of daily troublesome dyskinesias advocates. According to some embodiments, the administration results in a reduction of daily deadlines, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score advocated by the dyskinesia association, an improvement in the exercise experience of daily life, an improvement in the patient population change impression (PGI-C) score, and an improvement in the clinical population change impression (CGI-C) score. According to some embodiments, the administration results in an increase in the daily opening period without troublesome dyskinesias, as assessed by the unified parkinson's disease rating scale part II score revision advocated by the dyskinesia association, an improvement in the daily life exercise experience, an improvement in the patient population change impression (PGI-C) score, and an improvement in the clinical population improvement impression (CGI-I) score. According to some embodiments, the administration results in an increase in daily opening without troublesome dyskinesias, as assessed by revisions of the unified parkinson's disease rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, an improvement in patient population change impression (PGI-C) score, and an improvement in clinical population change impression (CGI-C) score, advocated by the dyskinesia association. According to some embodiments, the administration results in an increase in daily opening without troublesome dyskinesias, as assessed by revisions of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, an improvement in patient overall change impression (PGI-C) score, and a reduction in daily troublesome dyskinesias, advocated by the dyskinesia society.
According to some embodiments, the administration results in a reduction of daily off-period, without an increase in daily on-period with troublesome dyskinesias, as assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life exercise experience, an improvement in patient population change impression (PGI-C) score, and an improvement in clinical population improvement impression (CGI-I) score, advocated by the dyskinesia association. According to some embodiments, administration results in a reduction of daily off-period, an increase in daily on-period without troublesome dyskinesias, as assessed by the unified parkinsonism rating scale part II score revision advocated by the dyskinesia association, an improvement in daily life exercise experience, an improvement in patient global change impression (PGI-C) score, and an improvement in clinical global change impression (CGI-C) score. According to some embodiments, administration results in a reduction of daily deadlines, an increase in daily opening without concomitant trouble movement disorders, as assessed by a revised version of the unified parkinsonism rating scale part II (UPDRS part II) score or part III (UPDRS part III) score, an improvement in daily life movement experience, an improvement in patient overall change impression (PGI-C) score, and a reduction in daily trouble movement disorders.
According to any of the embodiments described above, the decrease in daily off-period is a decrease in daily off-period of at least about ≡25% from baseline.
According to some embodiments, the decrease in daily off-period is a decrease of about ≡25% per day off-period from baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡30% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡35% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡40% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡45% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡50% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡55% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡60% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡65% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡70% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡75% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡80% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡85% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡90% in daily deadlines of the patient relative to baseline. According to some embodiments, the decrease in daily deadlines is a decrease of about ≡95% in daily deadlines of the patient relative to baseline. According to some embodiments, the reduction in daily off-period is elimination of daily off-period.
According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period relative to baseline.
According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period relative to an immediate release oral formulation to which levodopa is administered.
According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period of at least about 0.1 hours to 3.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of at least about 0.1 hours to 6 hours.
According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period from baseline of at least about 0.1 hours to 3.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period from baseline of at least about 0.1 hours to 6 hours.
According to any of the embodiments described herein, the reduction in daily off period is a reduction in daily off period of at least about 0.1 hour to 3.5 hours, as compared to a patient treated with an immediate release oral formulation of levodopa. According to any of the embodiments described herein, the decrease in daily off period is a decrease of at least about 0.1 to 6 hours per day compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period of at least about 0.1 hour to 3.5 hours relative to an immediate release oral formulation for administration of levodopa. According to any of the embodiments described herein, the decrease in daily off-period is a decrease in daily off-period of at least about 0.1 hour to 6 hours relative to an immediate release oral formulation for administration of levodopa.
According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.1 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.15 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.2 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.25 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.35 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.4 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.45 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.55 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.6 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.65 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.7 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.75 hours. According to some embodiments, the decrease in daily off-period is a decrease of about 1 hour per daily off-period. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.8 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.85 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.9 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 0.95 hours. According to some embodiments, the decrease in daily off-period is a decrease of about 1 hour per daily off-period. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.1 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.2 hours. According to some embodiments, the decrease in daily off period is a decrease in the number of hours per day of daily off period of about 1.3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.4 hours. According to some embodiments, the decrease in daily off-period is a decrease of about 1.5 hours per daily off-period. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.6 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.7 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.8 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 1.9 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.1 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.2 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.4 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.6 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.7 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.8 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 2.9 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.1 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.2 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.4 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.6 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.7 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.8 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 3.9 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.1 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.2 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.4 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.6 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.7 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.8 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 4.9 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.1 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.2 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.3 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.4 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.5 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.6 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.7 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.8 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 5.9 hours. According to some embodiments, the decrease in daily off period is a decrease in daily off period of about 6 hours.
According to some embodiments, the decrease in daily off period lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to any of the embodiments described herein, the increase in the daily open period without concomitant dyskinesia is an increase in the daily open period without concomitant dyskinesia relative to baseline.
According to any of the embodiments described herein, the increase in the daily open period without concomitant liability of movement disorders is an increase in the daily open period without concomitant liability of movement disorders compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the increase in the daily open period without concomitant dyskinesia is an increase in the daily open period without concomitant dyskinesia relative to an immediate release oral formulation of administration of levodopa.
According to any of the embodiments described herein, the increase in the daily open period without concomitant dyskinesia is an increase in the daily open period without concomitant dyskinesia of at least about 0.1 hour to 3.5 hours. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase in the daily open period without concomitant dyskinesia of at least about 0.1 hour to 6 hours.
According to any of the embodiments described herein, the increase in the daily open period without concomitant dyskinesia is an increase in the daily open period without concomitant dyskinesia of at least about 0.1 hours to 3.5 hours relative to baseline. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase in the daily open period without concomitant dyskinesia of at least about 0.1 hour to 6 hours relative to baseline.
According to any of the embodiments described herein, the increase in the daily open period without concomitant liability of movement disorder is an increase of at least about 1 hour to 3.5 hours in the daily open period without concomitant liability of movement disorder compared to a patient treated with an immediate release oral formulation of levodopa. According to any of the embodiments described herein, the increase in the daily open period without concomitant liability of movement disorder is an increase of at least about 1 hour to 6 hours in the daily open period without concomitant liability of movement disorder compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the increase in the daily open period without concomitant dyskinesia is an increase of at least about 1 hour to 3.5 hours in the daily open period without concomitant dyskinesia relative to an immediate release oral formulation to which levodopa is administered. According to any of the embodiments described herein, the increase in the daily open period without concomitant dyskinesia is an increase of at least about 1 hour to 6 hours in the daily open period without concomitant dyskinesia relative to an immediate release oral formulation to which levodopa is administered.
According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1 hour in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.1 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.2 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.3 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the improvement in the patient's daily open period without concomitant dyskinesia is an increase in the daily open period of about 1.4 hours without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.5 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.6 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.7 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.72 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.8 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 1.9 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.1 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.2 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.3 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.4 hours in the daily open period without concomitant dyskinesia. according to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.5 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.6 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.7 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.8 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 2.9 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.1 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.2 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.3 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.4 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.5 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.6 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.7 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.8 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 3.9 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.1 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.2 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.3 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.4 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.5 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.6 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.7 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.8 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 4.9 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.1 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.2 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.3 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.4 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.5 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.6 hours in the daily open period without concomitant dyskinesia. according to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.7 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.8 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 5.9 hours in the daily open period without concomitant dyskinesia. According to some embodiments, the increase in the daily open period without concomitant dyskinesia is an increase of about 6 hours in the daily open period without concomitant dyskinesia.
According to some embodiments, the increase in daily open period without concomitant dyskinesia lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months or 36 months.
According to any of the embodiments described herein, the reduction in daily dyskinesia is a reduction in daily dyskinesia relative to baseline.
According to any of the embodiments described herein, the reduction of daily troublesome dyskinesia is a reduction of daily troublesome dyskinesia compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the reduction of daily troublesome dyskinesia is a reduction of daily troublesome dyskinesia relative to an immediate release oral formulation of administered levodopa.
According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of at least about 0.1 hours to 3.5 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of at least about 0.1 hours to 6 hours.
According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of at least about 0.1 hours to 3.5 hours relative to baseline. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of at least about 0.1 hours to 6 hours relative to baseline.
According to some embodiments, the reduction in daily troublesome dyskinesia is a reduction of at least about 0.1 hour to 3.5 hours of daily troublesome dyskinesia as compared to a patient treated with an immediate release oral formulation of levodopa. According to some embodiments, the reduction in daily troublesome dyskinesia is a reduction of at least about 0.1 hour to 6 hours of daily troublesome dyskinesia as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, the reduction in daily troublesome dyskinesia is a reduction of at least about 0.1 to 3.5 hours relative to an immediate release oral formulation to which levodopa is administered. According to some embodiments, the reduction in daily troublesome dyskinesia is a reduction of at least about 0.1 to 6 hours relative to administration of an immediate release oral formulation of levodopa.
According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.1 hour. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.15 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.2 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia for about 0.25 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.3 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of about 0.35 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.4 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of about 0.45 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.5 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.55 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.6 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.65 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.7 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia of about 0.75 hours. According to some embodiments, the reduction in daily bothersome movement disorder is a reduction in daily bothersome movement disorder for about 1 hour. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.8 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia for about 0.85 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.9 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 0.95 hours. According to some embodiments, the reduction in daily bothersome movement disorder is a reduction in daily bothersome movement disorder for about 1 hour. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.1 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.2 hours. According to some embodiments, the reduction in daily troublesome dyskinesia is a reduction in the number of daily hours of daily troublesome dyskinesia of about 1.3 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.4 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.5 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.6 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.7 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.8 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 1.9 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia for about 2 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.1 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.2 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.3 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.4 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.5 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.6 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.7 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.8 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 2.9 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.1 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.2 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.3 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.4 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.5 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.6 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.7 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.8 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 3.9 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.1 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.2 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.3 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.4 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.5 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.6 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.7 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.8 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 4.9 hours. According to some embodiments, the reduction in daily bothersome movement disorder is a reduction in daily bothersome movement disorder for about 5 hours. according to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.1 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.2 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.3 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.4 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.5 hours. according to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.6 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.7 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.8 hours. According to some embodiments, the reduction in daily bothersome dyskinesia is a reduction in daily bothersome dyskinesia for about 5.9 hours. According to some embodiments, the reduction in daily dyskinesia is a reduction in daily dyskinesia for about 6 hours.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a decrease in UPDRS part II score relative to baseline.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a decrease in UPDRS part II score compared to patients treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the improvement in the exercise experience in daily life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a decrease in UPDRS part II score relative to administration of an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of at least about 1.5 to about 4.5.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a decrease in the UPDRS part II score from baseline of at least about 1.5 to about 4.5.
According to some embodiments, the improvement in the exercise experience of daily life, as assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a decrease in UPDRS part II score of at least about 1.5 to about 4.5 compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a decrease in UPDRS part II score of at least about 1.5 to about 4.5 relative to administration of an immediate release oral formulation of levodopa.
According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 1.5. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 1.6. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 1.7. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 1.8. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 1.9. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 2.0. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 2.2. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 2.4. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 2.6. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 2.8. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 3.0. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 3.2. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 3.4. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 3.6. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 3.8. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 4.0. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 4.2. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 4.4. according to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association, is a reduction in UPDRS part II score of about 4.5.
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According to some embodiments, the improvement in the exercise experience of daily life lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months or 36 months as assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score relative to baseline.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score compared to patients treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the improvement in the exercise experience in daily life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score relative to administration of an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of at least about 2 to about 50.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score from baseline of at least about 2 to about 50.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score of at least about 2 to about 50 compared to a patient treated with an immediate release oral formulation of levodopa.
According to any of the embodiments described herein, the improvement in the exercise experience of daily life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score of at least about 2 to about 50 relative to administration of an immediate release oral formulation of levodopa.
According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 2 to about 3. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 3 to about 4. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 4 to about 5. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 5 to about 7.5. According to some embodiments, the improvement in the exercise experience of daily life, as assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 7.5 to about 10. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 10 to about 15. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 15 to about 20. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 20 to about 30. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a decrease in UPDRS part III score of about 30 to about 40. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 40 to about 50. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 7. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 8. according to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 8. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 9. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 10. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 11. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 12. According to some embodiments, the improvement in the exercise experience of everyday life, as assessed by the unified parkinson's disease rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, is a reduction in UPDRS part III score of about 13.
According to some embodiments, the improvement in the exercise experience of daily life lasts for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months or 36 months as assessed by the unified parkinsonism rating scale part III score revision advocated by the dyskinesia association.
According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios relative to baseline.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score is a ratio of ratios compared to patients treated with an immediate release oral formulation of levodopa.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score is the ratio of ratios relative to an immediate release oral formulation to which levodopa is administered.
According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of at least about 2.4 to about 11.0.
According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of at least about 2.4 to about 11.0 relative to baseline.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score is a ratio of ratios of at least about 2.4 to about 11.0, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, the improvement in the overall patient change impression (PGI-C) score relative to an immediate release oral formulation administered levodopa is a ratio of at least about 2.4 to about 11.0.
According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of about 2.4. According to some embodiments, the improvement based on the patient overall change impression (PGI-C) score is a ratio of about 2.6. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of about 2.8. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 3.0. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 3.2. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 3.4. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 3.6. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of 3.8. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 4.0. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 4.4. According to some embodiments, the improvement based on the patient overall change impression (PGI-C) score is a ratio of about 4.8. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 5.0. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 5.3. According to some embodiments, the improvement based on the patient overall change impression (PGI-C) score is a ratio of ratios of about 5.5. According to some embodiments, the improvement based on the patient overall change impression (PGI-C) score is a ratio of ratios of about 6.0. According to some embodiments, the improvement based on the patient overall change impression (PGI-C) score is a ratio of ratios of about 6.5. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 7.0. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of about 7.5. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 8.0. According to some embodiments, the improvement based on the patient overall change impression (PGI-C) score is a ratio of about 8.5. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 9.0. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of about 9.5. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 10.0. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of about 10.5. According to some embodiments, the improvement based on the patient global change impression (PGI-C) score is a ratio of ratios of about 11.0.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement based on the patient overall improvement impression (PGI-I) score is a ratio of ratios relative to baseline.
According to some embodiments, the improvement based on the patient overall improvement impression (PGI-I) score is a ratio of ratios compared to patients treated with an immediate release oral formulation of levodopa.
According to some embodiments, the improvement based on the patient's overall improvement impression (PGI-I) score is the ratio of ratios relative to an immediate release oral formulation to which levodopa is administered.
According to some embodiments, the improvement based on the patient overall improvement impression (PGI-I) score is a ratio of at least about 2.0 to about 11.0.
According to some embodiments, the improvement based on the patient overall improvement impression (PGI-I) score is a ratio of at least about 2.0 to about 11.0 relative to baseline.
According to some embodiments, the improvement based on the overall patient improvement impression (PGI-I) score is a ratio of ratios of at least about 2.0 to about 11.0, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, the improvement based on the patient's overall improvement impression (PGI-I) score relative to an immediate release oral formulation of administration of levodopa is a ratio of at least about 2.0 to about 11.0.
According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 2.4. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 2.6. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 2.8. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 3.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 3.2. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 3.4. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 3.6. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of 3.8. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 4.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 4.4. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 4.8. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 5.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 5.3. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 5.5. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 6.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 6.5. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 7.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 7.5. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 8.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 8.5. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 9.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 9.5. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 10.0. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 10.5. According to some embodiments, the improvement based on the patient global impression (PGI-I) score is a ratio of ratios of about 11.0.
According to some embodiments, the improvement based on the patient overall improvement impression (PGI-I) score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of ratios relative to baseline.
According to some embodiments, the improvement based on clinical global change impression (CGI-C) score is the ratio of ratios compared to patients treated with immediate release oral formulations of levodopa.
According to some embodiments, the improvement based on clinical global change impression (CGI-C) score is the ratio of ratios relative to an immediate release oral formulation administered levodopa.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.0 to about 15.0.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.0 to about 15.0 relative to baseline.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of ratios of at least about 3.0 to about 15.0, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of ratios of at least about 3.0 to about 15.0 relative to an immediate release oral formulation to which levodopa is administered.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.2. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.4. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.6. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 3.8. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 4.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 4.4. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 4.8. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 5.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 5.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 6.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 6.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 7.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 7.2. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 7.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 8.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 8.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 9.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 9.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 10.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 10.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 11.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 11.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 12.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 12.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 13.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 13.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 14.0. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 14.5. According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score is a ratio of at least about 15.0.
According to some embodiments, the improvement based on the clinical global change impression (CGI-C) score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to any of the embodiments described herein, the administration results in the patient having an improvement in sleep quality as assessed by parkinson's disease sleep scale 2 (PDSS-2) score.
According to some embodiments, the improvement in sleep quality is a decrease in the PDSS-2 score as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score.
According to some embodiments, the improvement in sleep quality is a decrease in the PDSS-2 score relative to baseline as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score.
According to some embodiments, the improvement in sleep quality is a decrease in the PDSS-2 score as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, the improvement in sleep quality relative to an immediate release oral formulation administered levodopa, as assessed by a parkinson's disease sleep scale 2 (PDSS-2) score, is a decrease in PDSS-2 score.
According to some embodiments, the sleep improvement is a decrease in the PDSS-2 score of at least about 1 to about 30 as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score.
According to some embodiments, the sleep improvement is a decrease in the PDSS-2 score from baseline of at least about 1 to about 30 as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score.
According to some embodiments, the sleep improvement as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score is a decrease in PDSS-2 score of at least about 1 to about 30, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, the sleep improvement as assessed by the parkinson's disease sleep scale 2 (PDSS-2) score relative to an immediate release oral formulation of levodopa administration is a decrease in PDSS-2 score of at least about 1 to about 30.
According to some embodiments, the sleep improvement as assessed by a parkinson's disease sleep scale 2 (PDSS-2) score is a decrease in PDSS-2 score of at least about 1 to about 30.
According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 1 to about 2. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 2 to about 3. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 3 to about 4. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 4 to about 5. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 5 to about 10. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 10 to about 15. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 15 to about 20. According to some embodiments, the sleep improvement as assessed by PDSS-2 score is a decrease in PDSS-2 score of at least about 20 to about 30.
According to some embodiments, sleep improvement as assessed by PDSS-2 score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
According to any of the embodiments described herein, the administration results in the patient having an improvement in sleep. According to some embodiments, substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein improves sleep in a patient. According to some embodiments, about 10% to about 75% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 10% to about 20% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 20% to about 30% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 30% to about 40% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 40% to about 50% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 50% to about 60% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 60% to about 75% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of a pharmaceutically acceptable liquid composition as detailed herein. According to some embodiments, about 50% of patients benefit from sleep improvement in view of the substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition as detailed herein.
According to some embodiments, the patient's sleep quality has an improvement over baseline after one day of treatment. According to some embodiments, the patient's sleep quality has an improvement over baseline after two days of treatment. According to some embodiments, the patient's sleep quality has an improvement over baseline after three days of treatment.
According to some embodiments, administration results in patients having an improvement in quality of life (QoL) as assessed by parkinson's disease questionnaire (PDQ-39) score.
According to some embodiments, the administration results in the patient having an improvement in quality of life (QoL) relative to baseline as assessed by parkinson's disease questionnaire (PDQ-39) score.
According to some embodiments, administration results in a patient having an improvement in quality of life (QoL) as assessed by a parkinson's disease questionnaire (PDQ-39) score, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, administration results in a patient having an improvement in quality of life (QoL) as assessed by a parkinson's disease questionnaire (PDQ-39) score relative to an immediate release oral formulation of administration of levodopa.
According to some embodiments, administration results in a patient having an improvement in quality of life (QoL) as assessed by a parkinson's disease questionnaire (PDQ-39) score, which improvement is a decrease in PDQ-39 score of at least about 1 to about 30.
According to some embodiments, the administration results in the patient having an improvement in quality of life (QoL) as assessed by a parkinson's disease questionnaire (PDQ-39) score relative to baseline, which improvement is a decrease in PDQ-39 score of at least about 1 to about 30.
According to some embodiments, administration results in a patient having an improvement in quality of life (QoL) as assessed by a parkinson's disease questionnaire (PDQ-39) score, which improvement is a decrease in PDQ-39 score of at least about 1 to about 30, as compared to a patient treated with an immediate release oral formulation of levodopa.
According to some embodiments, administration results in a patient having an improvement in quality of life (QoL) as assessed by a parkinson's disease questionnaire (PDQ-39) score, which improvement is a decrease in PDQ-39 score of at least about 1 to about 30, relative to an immediate release oral formulation of levodopa.
According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 1 to about 2. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 2 to about 3. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 3 to about 4. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 4 to about 5. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 5 to about 10. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 10 to about 15. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 15 to about 20. According to some embodiments, the improvement in QoL as assessed by PDQ-39 score is a decrease in PDQ-39 score of at least about 20 to about 30.
According to some embodiments, the improvement in QoL as assessed by PDQ-39 score lasts at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa for a substantially continuous duration of about 24 hours/day, for about 2 or 3 days,
Wherein the administration results in an increase in the daily good open period from baseline of at least about 0.3 hours to about 3.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day for at least about 28 days
Wherein the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 6.0 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa for a period of substantially continuous duration of about 24 hours/day for at least about 28 days,
Wherein the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 8.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for about 2 or 3 days substantially continuously for about 24 hours/day,
Wherein the administration results in an increase in the daily good open period from baseline of at least about 0.3 hours to about 3.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day for at least about 28 days,
Wherein the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 6.0 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day for at least about 28 days,
Wherein the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 8.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in an increase in the daily good open period from baseline of at least about 0.3 hours to about 3.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day for at least about 28 consecutive days,
Wherein by day 28 of the succession, the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 6.0 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa substantially continuously for about 24 hours/day for at least about 28 consecutive days,
Wherein by day 28 of the succession, the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 8.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day for about 2 to 3 consecutive days,
Wherein by the third consecutive day, the administration results in an increase in the daily good open period from baseline of at least about 0.3 hours to about 3.5 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day for at least about 28 consecutive days,
Wherein by day 28 of the succession, the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 6.0 hours.
A further embodiment of the invention relates to a method of increasing the good onset of a patient suffering from parkinson's disease, said method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w, substantially continuously for about 24 hours/day for at least about 28 consecutive days,
Wherein by day 28 of the succession, the administration results in an increase in the daily good open period from baseline of at least about 1.5 hours to about 8.5 hours.
According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period of at least about 0.3 hours to 6.0 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period of at least about 0.3 hours to 3.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period of at least about 1.5 hours to about 8.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period of at least about 1.5 hours to about 6.0 hours.
According to some embodiments, an increase in daily good open time relative to baseline is achieved after 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, or longer of treatment. According to some embodiments, the daily good open period increase from baseline is at least about 2.0 hours, at least about 2.1 hours, at least about 2.2 hours, at least about 2.3 hours, at least about 2.4 hours, or at least about 2.5 hours after treatment for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, or 36 months. According to some embodiments, the daily good open period increase from baseline is at least about 2.5 hours, at least about 2.6 hours, at least about 2.7 hours, at least about 2.8 hours, at least about 2.9 hours, or at least about 3 hours after treatment for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, or 36 months. According to some embodiments, the increase in daily good open time relative to baseline is an increase of at least about 4 hours, at least about 4.1 hours, at least about 4.2 hours, at least about 4.3 hours, at least about 4.4 hours, or at least about 4.5 hours after treatment for about 1 month, 2 months, 3 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, or 36 months. According to some embodiments, the daily good open period increase from baseline is at least about 7.5 hours, at least about 7.6 hours, at least about 7.7 hours, at least about 7.8 hours, at least about 7.9 hours, or at least about 8 hours increase after treatment for about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, or 36 months.
According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.32 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.34 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.36 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.38 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.42 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.44 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.46 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.48 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.55 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.65 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.75 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.85 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 0.95 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1 hour. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.1 hour. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 1.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.25 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.75 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 2.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.0 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.25 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 3.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.0 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 4.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.0 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 5.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.0 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 6.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.5 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.6 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.7 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 7.9 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 8 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 8.1 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 8.2 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 8.3 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 8.4 hours. According to some embodiments, the increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of about 8.5 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered for a period of time of more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered for a period of at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years.
According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 2 years results in an improvement in the adverse events (TREATMENT EMERGENT ADVERSE EVENT, TEAE) occurring in the treatment as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 3 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 4 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 5 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 6 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 7 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 8 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 9 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year. According to some embodiments, substantially continuous subcutaneous administration of the pharmaceutically acceptable liquid composition for a period of at least about 10 years results in an improvement in adverse events (TEAE) occurring in the treatment, as compared to administration of the pharmaceutically acceptable liquid composition for a period of about 1 year.
According to some embodiments, adverse events (TEAE) occurring in the treatment are severe (severe). According to some embodiments, the adverse event (TEAE) occurring in the treatment is severe (serious).
According to some embodiments, the adverse event (TEAE) occurring in the treatment is a drug-related TEAE. According to some embodiments, the drug-related TEAE is an infusion site reaction. According to some embodiments, the adverse event (TEAE) occurring in the treatment is an infusion site reaction.
According to some embodiments, the patient's daily wake time is normalized to about 14 hours to 18 hours. According to some embodiments, the patient's daily wake time is normalized to about 14 hours. According to some embodiments, the patient's daily wake time is normalized to about 15 hours. According to some embodiments, the patient's daily wake time is normalized to about 16 hours. According to some embodiments, the patient's daily wake time is normalized to about 17 hours. According to some embodiments, the patient's daily wake time is normalized to about 18 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition further comprises arginine.
According to some embodiments, the pharmaceutically acceptable liquid composition further comprises at least one antioxidant.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises about 7.5 mg/mL carbidopa and about 60 mg/mL levodopa.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered to deliver about 370 mg, about 420 mg, about 470 mg, about 520 mg, about 570 mg, about 620 mg, about 670 mg, or about 720 mg levodopa to the patient over the course of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is subcutaneously administered to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
According to some embodiments, the low active night rate is administered for about 8 hours and the high active daytime rate is administered for about 16 hours. According to some embodiments, the low active night rate is administered for about 6 hours and the high active daytime rate is administered for about 18 hours.
According to some embodiments, the low activity night time rate is about 0.08 mL/hour. According to some embodiments, the low activity night time rate is about 0.04 mL/hour.
According to some embodiments, the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour. According to some embodiments, the high active daytime rate is about 0.32 mL/hour, about 0.295 mL/hour, about 0.275 mL/hour, about 0.25 mL/hour, about 0.225 mL/hour, about 0.205 mL/hour, about 0.18 mL/hour, or about 0.16 mL/hour.
According to some embodiments, the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
According to some embodiments, the pharmaceutically acceptable oral composition comprises one of 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.
According to some embodiments, the pharmaceutically acceptable oral composition is a morning dose of oral levodopa.
In some embodiments, neurological disorders or dyskinesias associated with the methods described herein include parkinson's disease, secondary parkinsonism such as drug-induced secondary parkinsonism, nerve-blocker-induced parkinsonism, postencephalitis parkinsonism, and vascular parkinsonism, motor fluctuations, neurodegenerative disorders, dyskinesias, reduced dopamine levels in the brain, levodopa-induced dyskinesias, rapid eye movement sleep disorder (RBD), dystonia, morning motor failure, tremor symptoms such as essential tremor and drug-induced tremor, myoclonus, chorea such as drug-induced chorea, tics such as drug-induced tics and organic tics, drug-induced dyskinesia, drug-induced akathisia, restless Leg Syndrome (RLS), stiff person syndrome, benign tremor attacks, nerve-blocker malignant syndrome, huntington's disease, sham-Drager's syndrome, brain injury-induced tremor conditions such as carbon monoxide or any combination thereof, for example, and methods of treating a patient suffering from the conditions provided herein.
Typically, doctors use, for example, multiple scales to assess the severity of parkinson's disease patients based on objective and subjective signs and symptoms, and prescribe levodopa dosing accordingly. One of the well known and widely used scales for diagnosing and measuring the severity of parkinson's disease is the Unified Parkinson's Disease Rating Scale (UPDRS). Modifications of the UPDRS may also be used to classify parkinson's disease patients (e.g., the UPDRS part I revision (MDS-UPDRS part I) advocated by the dyskinesia association, the UPDRS part II revision advocated by the dyskinesia association, the UPDRS part III revision advocated by the dyskinesia association, or the UPDRS part IV revision advocated by the dyskinesia association). Parts I and II measure the impact of non-exercise experience and exercise experience on daily life, and both parts I and II are the results of patient reporting. Part III measures the motor exam and part IV measures the motor complications.
Another known method for measuring the severity of Parkinson's disease is to stage according to Hoehn and Yahr (H & Y), which includes a 5-stage scale, where stages 1-2 are considered to be mild or early stage Parkinson's disease patients, stage 3 are considered to be moderate or mid-stage Parkinson's disease patients, and stages 4-5 are considered to be late stage Parkinson's disease patients. Additional stages 0, 1.5 and 2.5 have been added to the scale and are widely used.
The scale used to measure changes in parkinson's disease or its symptoms is according to the overall improvement impression scale (also known as the overall change impression scale), where a score of 1 is completely free of disease and a score of 7 is the most severe disease. The global change impression score is assessed by both the clinician and the subject as a clinical global improvement impression (CGI-I) and a subject global improvement impression (SGI-I) (also referred to as patient global change impression (PGI-C)). It should be noted that generally in the art, the terms subject global change impression (SGI-C), subject global improvement impression (SGI-I), patient global change impression (PGI-C), and patient global improvement impression (PGI-I) are interchangeable, unless those skilled in the art will understand otherwise. Similarly, the clinician global change impression (CGI-C) and the clinician global improvement impression (CGI-I) are also interchangeable unless those skilled in the art will understand otherwise. Another term known in the art is clinical global impression severity (CGI-S) and may also be improved according to the methods of the present invention. Any other interchangeable terms used in the art are also relevant herein and are encompassed by the present disclosure. In this regard, it should be noted that the definitions used in the art sometimes refer to "clinic" and sometimes refer to "clinician" or the like. In this context, these are also interchangeable. For example, "clinical global change impression (CGI-C)" is used interchangeably with "clinician global change impression (CGI-C)". Similarly, "clinical global improvement impression (CGI-I)" is used interchangeably with "clinician global improvement impression (CGI-I)".
The daily levodopa dose may be determined and varied by the physician from time to time, for example, according to clinical findings and "trial and error" methods, according to the condition of a particular patient, the patient's response to treatment, and the like. Furthermore, depending on the sign and symptoms, different daily doses may be administered to the patient on different days, wherein the range of daily doses administered may be set by the physician, allowing flexibility in the patient's treatment. It should be noted that physicians often refer to signs as objective measurements and symptoms as subjective measurements.
According to some embodiments, provided herein are methods of treating patients with advanced parkinson's disease. According to some embodiments, provided herein are methods of treating patients with advanced stage and/or moderate parkinson's disease. According to some embodiments, provided herein are methods for treating a patient having motor fluctuations. According to some embodiments, provided herein are methods for treating parkinson's disease patients with motor fluctuations.
According to some embodiments, provided herein are methods of treating parkinson's disease patients in need of a dose of greater than about 300 mg levodopa/day, greater than about 400 mg levodopa/day, greater than about 500 mg levodopa/day, greater than about 600 mg levodopa/day, greater than about 700 mg levodopa/day, greater than about 800 mg levodopa/day, greater than about 900 mg levodopa/day, greater than about 1000 mg levodopa/day.
According to some embodiments, provided herein are methods of treating parkinson's disease patients in need of elevated doses of levodopa at specific time points, e.g., in the morning, e.g., near the end of the low activity/night period (about the last hour), e.g., at the beginning of the high activity/day period (about the first hour). For example, according to some embodiments, there may be a certain rate for high activity/daytime hours and a different rate for low activity/nighttime hours, wherein elevated doses of levodopa may be administered near the end of low activity/nighttime hours, at the beginning of high activity/daytime hours, etc. Such elevated doses may be provided by administration of an oral dose of a pharmaceutically acceptable oral composition, for example at the times mentioned above, concomitantly with a substantially continuous pharmaceutically acceptable liquid composition.
According to some embodiments, provided herein are methods of treating a patient suffering from parkinson's disease for a period of time of more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.
According to some embodiments, provided herein are methods of treating parkinson's disease patients suffering from a daily off period of at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours. According to some embodiments, provided herein are methods of treating parkinson's disease patients having improved Hoehn and Yahr scales in the "open-time (ON)" state of 2, 2.5, 3, 4.
Brief Description of Drawings
Fig. 1A is a graph showing an increase in good open time on days 3 and 28 and a decrease in open time with moderate/severe dyskinesia as described in example 1. Fig. 1B is a graph showing changes from baseline in the off period (decrease), the open period without movement disorder (increase), the good open period or the open period with or with mild movement disorder (increase), and the open period with moderate or severe movement disorder (decrease) as described in example 1.
Fig. 1C is a graph showing the improved UPDRS part III score as described in example 1.
Fig. 2 is a diagram showing improvement of patient overall change impression and clinician overall change impression as described in example 1.
Fig. 3 is a graph showing the proportion of patients reporting a full ON period (full ON) at 9 am ON day 7 as described in example 1.
Fig. 4 is a graph showing drug-related TEAE reported in the first three years of continuous subcutaneous levodopa/carbidopa infusion for parkinson's disease described in example 2.
Fig. 5 is a graph showing the increase in open period and decrease in closed period observed at month 36 without troublesome dyskinesia for continuous subcutaneous levodopa/carbidopa infusion for parkinson's disease described in example 2. The wake time was normalized to 16 hours.
Figure 6 provides a flow chart depicting patient flow through a study with an open label introduction period and randomized, double blind, double simulated comparison period of active control.
Fig. 7 is a graph showing the open period with ND0612 treatment providing an additional 1.72 h of non-troublesome dyskinesia compared to immediate release levodopa/carbidopa (IR-LD/CD; p < 0.0001).
Fig. 8 provides a graph showing mean plasma levodopa concentrations of five test groups versus time in hours after the start of subcutaneous infusion.
Figure 9 provides a graph showing C max carbidopa values, C max carbidopa values obtained from subcutaneously administering three different administered carbidopa concentrations.
FIG. 10 provides a graph showing PGI-C and CGI-I evaluations of ND0612 with respect to IR-LD/CD.
Fig. 11 is a table describing the results from the open label study and the double blind double simulation study described in example 6.
Detailed Description
Features and other details of the present disclosure will now be described more particularly. Certain terms used throughout the description, examples, and appended claims are collected here. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Definition of the definition
The term "about" as used herein is considered to encompass a range of ±10% of the listed values unless specifically mentioned otherwise or unless the person skilled in the art would understand otherwise. It should also be noted that any value provided may be considered to encompass a range of + -10% of that value, even without the use of the term "about". This includes the values in the examples section, which may vary depending on the apparatus and machine used, the purity of the compound, etc.
The term "concomitant" as used herein refers to any type of combined administration of two or more active ingredients in the same composition, as well as simultaneous administration of the active ingredients in different compositions, and sequential, consecutive administration of two or more active ingredients on the same day, wherein a predetermined period of time separates the administration of the active ingredients from each other, and so forth, unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art. The term "concomitant" may also be used herein to refer to any type of combined administration of two separate pharmaceutical compositions, wherein each composition may be administered by a different route of administration, at different time intervals, doses, etc. For example, as detailed herein, one composition may be administered substantially continuously parenterally, e.g., subcutaneously, while a second composition is administered in a discontinuous manner by oral administration concomitantly with the first composition. Furthermore, concomitant administration of two or more separate compositions may be dependent or independent of each other.
The terms "continuously" and "substantially continuously" as used herein refer to a period of time during which the composition is administered throughout the period of time, wherein the interval is less than about 24 hours, about 12 hours, about 5 hours, about 3 hours, about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or about 1 minute, unless specifically mentioned otherwise or unless otherwise understood by those of skill in the art. The composition may be administered for a period of time of at least about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, three days, seven days, two weeks, one month, three months, six months, one year, two years, three years, five years, ten years, etc.
The term "dopa decarboxylase inhibitor" as used herein refers to agents capable of inhibiting the peripheral metabolism of levodopa to dopamine by aromatic L-amino acid decarboxylases, such as carbidopa and benserazide.
"Individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or non-human primates, and humans. In some embodiments, the mammal treated in the methods of the invention is a human suffering from a neurodegenerative condition such as parkinson's disease.
The term "levodopa moiety" as used herein includes any moiety comprising levodopa, including, for example, levodopa itself and levodopa salts, unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art. Similarly, the term "carbidopa moiety" as used herein includes any moiety comprising carbidopa, including, for example, carbidopa itself and a carbidopa salt, unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art.
The term "liquid" as used herein refers to any type of fluid, including gels, aqueous compositions, non-aqueous compositions, and the like, unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art.
The terms "morning dose" and "morning oral dose" as used herein are interchangeable unless specifically mentioned otherwise or unless otherwise understood by those of skill in the art and refer to an oral composition (e.g., oral dosage form) comprising levodopa that is administered specifically within the morning time, such as within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours of the patient's wakefulness. According to some embodiments, the morning dose refers to an oral composition (e.g., oral dosage form) comprising levodopa that is administered within 1, 5, 10, 15, 20, or 30 minutes of the patient's wake time.
A neurological disorder is a disorder of the nervous system of the body, and the term "dyskinesia" as used herein refers to a neurological condition that causes abnormal autonomous or involuntary movement or slow, reduced movement. According to some embodiments, the neurological disorder or movement disorder is parkinson's disease, secondary parkinsonism such as drug-induced secondary parkinsonism, nerve-blocker-induced parkinsonism, postencephalitis parkinsonism and vascular parkinsonism, movement fluctuations, neurodegenerative disorders, movement disorders, reduced levels of dopamine in the brain, levodopa-induced movement disorders, rapid eye movement sleep disorder (RBD), dystonia, morning movement failure, tremor symptoms such as essential tremor and drug-induced tremor, myoclonus, chorea such as drug-induced chorea, tics such as drug-induced tics and organic tics, drug-induced movement disorders, drug-induced akathisia, restless Leg Syndrome (RLS), stiff person syndrome, benign tremor attacks, nerve-blocker malignancy syndrome, huntington's disease, chard's syndrome, brain injury-induced conditions such as carbon monoxide or manganese poisoning, or any combination thereof. According to some embodiments, the method involves treating parkinson's disease and/or motor fluctuations, including motor fluctuations derived from parkinson's disease, motor fluctuations in patients suffering from parkinson's disease, and the like.
The term "off-period" as used herein refers to a period of time when a patient experiences symptoms (e.g., motor symptoms or non-motor symptoms) associated with parkinson's disease that are unresponsive or significant to treatment. In some embodiments, the off-phase is a recurrence of parkinson's disease between doses of the drug.
The term "open-term" as used herein refers to a period of time when a patient experiences a good response to a drug and few symptoms associated with parkinson's disease (e.g., motor symptoms or non-motor symptoms). The patient may or may not experience movement disorders during the open period.
The term "open period without movement disorder" as used herein refers to a period of time when a patient experiences an open period and does not have movement disorder (e.g., levodopa-induced movement disorder).
The term "open period with non-troublesome dyskinesia" as used herein refers to a period of time when the patient experiences open period and has mild dyskinesia (e.g., mild levodopa-induced dyskinesia).
The term "open-term with troublesome dyskinesia" refers to a period of time when a patient experiences open-term and has moderate to severe dyskinesia (e.g., moderate to severe levodopa-induced dyskinesia).
The term "good open period" as used herein refers to the sum of an open period without a movement disorder plus an open period with a non-troublesome movement disorder.
Depending on the context or as will be appreciated by the person skilled in the art, an improvement, an increase, a decrease, etc. of any of the parameters mentioned herein (including an open period, an off period, an open period without dyskinesia, an open period with non-troublesome dyskinesia, an open period with moderate-severe dyskinesia, a good open period) compared to an immediate release dosage form comprising levodopa and/or relative to baseline is measured as a therapeutic effect of a subcutaneous formulation administered according to the invention.
The term "baseline" as used herein is defined as the first measurement of any of the variables mentioned, as measured prior to administration of the therapy under study.
The term "day 3" or "third day" or "third consecutive day" as used herein is defined as the third consecutive day of treatment, followed by two consecutive days of treatment.
The term "Change From Baseline (CFB)" as used herein is defined as the change in measured value from before treatment with the therapy under study to the point in time of measurement. If the point in time measured is a particular day of treatment, such as day three or day 3, the measurement may be made at any time during that day, unless specifically mentioned otherwise. The measurement may be made in the morning, e.g., 8 am, or a certain number of hours after the patient wakes up.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein interchangeably refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
The terms "pharmaceutical composition" and "pharmaceutical formulation" as used herein refer to a composition or formulation comprising at least one biologically active compound, such as levodopa or carbidopa, or a pharmaceutically acceptable salt thereof, formulated with one or more pharmaceutically acceptable excipients.
The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic groups or basic groups that may be formed with the conjugates used in the compositions disclosed herein.
The term "physiologically acceptable pH" and similar terms as used herein refer to a pH in the range between about 4.5 and about 10 unless specifically mentioned otherwise or unless otherwise understood by those of skill in the art. It should also be noted that when pH values are provided, including in the examples, these values may be within about ± 0.1% and/or ± 10% of the listed values, such that if the measured pH is 8.1, the same formulation may be prepared to provide a pH of about 8.0 or 8.2. Such differences may be due to temperature variations, various measuring devices, etc.
"Preventing" includes delaying the onset of a clinical symptom, complication, or biochemical sign of a state, disorder, disease, or condition that develops in a subject who is likely to suffer from or is susceptible to the state, disorder, disease, or condition but has not experienced or exhibited a clinical or subclinical symptom of the state, disorder, disease, or condition. "preventing" includes the prophylactic treatment of a state, disorder, disease, or condition in or developing in a subject, including the prophylactic treatment of a clinical symptom, complication, or biochemical sign of a state, disorder, disease, or condition in or developing in a subject.
In any of the embodiments provided herein, the change in value (e.g., increase, decrease, or improvement) can be a significant change. The term "significant" as used herein refers to a statistically significant (e.g., increased, decreased, or improved) change (e.g., p-value < 0.05) in value (e.g., an open period without movement disorder, an open period with non-troublesome movement disorder, an open period with moderate-severe movement disorder, e.g., an open period without daily movement disorder, an open period with daily non-troublesome movement disorder, an open period with daily troublesome movement disorder, or an open period with daily moderate-severe movement disorder), a closed period (e.g., a daily closed period), a subject global change impression (SGI-C) score, a clinical global change impression (CGI-C) score, a patient global change impression (PGI-C) score, or a unified parkinson's disease assessment scale part II (MDS-UPDRS part II) version advocated by the movement disorder association). In certain embodiments, the statistically significant change is the difference between the average value from a patient group receiving a treatment as described herein (e.g., a substantially continuous administration of a levodopa composition as described herein for 24 hours) and the average value from a patient group receiving a control treatment (e.g., an oral levodopa composition).
Unless specifically mentioned otherwise or unless understood otherwise by those skilled in the art, the terms patient global change impression (PGI-C), subject global improvement impression (SGI-I), and patient global improvement impression (PGI-I) are interchangeable. Similarly, clinical global improvement impression (CGI-I) and clinical global change impression (CGI-C) are interchangeable herein.
The terms "treatment", "treatment" and the like are generally used herein to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in partially or completely curing the disease and/or adverse effects due to the disease. The term "treatment" as used herein includes any treatment of a disease in a mammal, particularly a human, and includes (a) inhibiting the disease, i.e., preventing an increase in the severity or extent of the disease, (b) alleviating the disease, i.e., causing a partial or complete amelioration of the disease, or (c) preventing recurrence of the disease, i.e., preventing the disease from returning to an active state after a previous successful treatment of a symptom of the disease or treatment of the disease.
The term "occurrence in treatment" as used herein refers to an event that occurs after administration of a dose (e.g., a first dose) of a therapy (e.g., a subcutaneous formulation administered according to the present invention). For example, an "adverse event occurring in treatment" is an event identified at or after a dose (e.g., a first dose) of therapy in a clinical study. Examples of Adverse Events (TEAEs) that occur in treatment include, but are not limited to, drug-related TEAEs (e.g., infusion site reactions). In some embodiments, adverse events (TEAEs) that occur in treatment are severe. In some embodiments, adverse events (TEAEs) that occur in treatment are severe.
The term "up to" as used herein when occurring as part of a range is defined such that the range does not include "none", "0", unless specifically mentioned otherwise or unless otherwise understood by those of skill in the art. That is, if the amount of the component is up to a certain amount, e.g., 720 mg, then 0mg is not considered to be part of this range. Thus, if a composition comprises, for example, up to 360 mg, up to 370 mg, up to 720 mg, for example, levodopa, the composition must comprise more than 0 levodopa. Similarly, if the composition comprises, for example, carbidopa, for example, up to 45 mg, up to 46 mg, up to 90 mg, the composition must comprise more than 0 carbidopa.
Therapeutic method
Disclosed herein are methods for treating a patient suffering from a neurological disorder or movement disorder, the methods comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitor (DDCI), DDCI salts or any combination thereof.
Embodiments of the present invention relate to a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein after 2 or 3 days of administration, administration results in the patient having:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein after 2 or 3 days of administration, administration results in the patient having:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
Embodiments of the present invention relate to a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein after 2 or 3 days of administration, administration results in the patient having:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Improvement over baseline based on subject global change impression (SGI-C) scores,
Improvement over baseline based on clinical global change impression (CGI-C) scores,
Or any combination thereof.
Embodiments of the present invention relate to a method for treating a patient suffering from a neurological or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein after 2 or 3 days of administration, administration results in the patient having:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Improvement over baseline based on patient overall improvement impression (PGI-I) scores,
Improvement over baseline based on clinical global improvement impression (CGI-I) scores,
Or any combination thereof.
According to some embodiments, the administration results in the patient having an increase in the daily good open period relative to baseline. According to some embodiments, the administration results in the patient having a decrease in the daily open period with troublesome dyskinesia relative to baseline. According to some embodiments, the administration results in the patient having an improvement over baseline based on the subject's overall change impression (SGI-C) score. According to some embodiments, the administration results in the patient having an improvement over baseline based on the patient's overall improvement impression (PGI-I) score. According to some embodiments, the administration results in the patient having an improvement over baseline based on clinical global change impression (CGI-C) scores. According to some embodiments, the administration results in the patient having an improvement over baseline based on a clinical overall improvement impression (CGI-I) score.
A further embodiment of the invention relates to a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein administration results in an increase in the patient's good open time over the course of about 24 hours of at least about 0.3 hours to about 3.5 hours after the treatment lasts at least about 2 or 3 days.
A further embodiment of the invention relates to a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein administration results in an increase in the patient's good open period over the course of about 24 hours of at least about 1.5 hours to about 6 hours after the treatment has continued for at least about 28 days.
A further embodiment of the invention relates to a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising parenterally administering to the patient a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein administration results in the patient having:
a decrease in the daily period of closure,
Without the troublesome increase of the daily opening period of dyskinesia,
As assessed by the unified parkinsonism rating scale part II (UPDRS part II) score revision, advocated by the dyskinesia association, improvement of the daily locomotor experience,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof.
According to some embodiments, the decrease in daily off-period is measured compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the increase in the daily open period without concomitant dyskinesia is measured compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the improvement in the exercise experience of daily life is measured as compared to patients treated with immediate release oral levodopa as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score is measured compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the improvement based on the clinical global improvement impression (CGI-I) score is measured compared to patients treated with immediate release oral levodopa.
According to some embodiments, the administration results in a patient having a reduction in daily off-periods. According to some embodiments, the administration results in an increase in the daily open period of the patient with no concomitant dyskinesia. According to some embodiments, the administration results in an improvement in the patient's exercise experience in daily life as assessed by the unified parkinson's disease rating scale part II score revision advocated by the dyskinesia association. According to some embodiments, the administration results in the patient having an improvement based on the patient's overall change impression (PGI-C) score. According to some embodiments, the administration results in the patient having an improvement based on a clinical overall improvement impression (CGI-I) score.
According to some embodiments, the decrease in daily off-period is compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the increase in the daily open period without concomitant dyskinesia is compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the improvement in the exercise experience of daily life is compared to patients treated with immediate release oral levodopa as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score is compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the improvement based on the clinical global improvement impression (CGI-I) score is compared to a patient treated with immediate release oral levodopa.
According to some embodiments, the decrease in daily off-period is relative to an immediate release oral dosage form for administration of levodopa.
According to some embodiments, the increase in the daily open period without concomitant dyskinesia is relative to an immediate release oral dosage form of administration of levodopa.
According to some embodiments, the improvement in the exercise experience of daily life is relative to an immediate release oral dosage form of levodopa administration as assessed by the unified parkinson's disease rating scale part II (UPDRS part II) score revision advocated by the dyskinesia association.
According to some embodiments, the improvement based on the patient's overall change impression (PGI-C) score is relative to an immediate release oral dosage form administered levodopa.
According to some embodiments, the improvement based on the clinical global improvement impression (CGI-I) score is relative to an immediate release oral dosage form administered levodopa. According to some embodiments, the pharmaceutically acceptable liquid composition comprises (1) levodopa and/or a salt of levodopa and (2) carbidopa and/or a salt of carbidopa.
According to some embodiments, DDCI is carbidopa, a carbidopa salt, benserazide, a benserazide salt, or any combination thereof. According to some embodiments, DDCI is carbidopa.
In some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa.
In some embodiments, the pharmaceutically acceptable liquid composition comprises DDCI or a pharmaceutically acceptable salt thereof. In some embodiments DDCI is carbidopa.
In some embodiments, the pharmaceutically acceptable liquid composition comprises carbidopa or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable liquid composition comprises carbidopa.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises levodopa and carbidopa.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered by any parenteral route of administration, e.g., subcutaneous, transdermal, intradermal, intravenous, intramuscular, intratracheal, intranasal, intrathecal, intragastric or intraduodenal administration. According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously. According to some embodiments, the pharmaceutically acceptable liquid composition is a liquid. According to some embodiments, the pharmaceutically acceptable liquid composition is aqueous.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered substantially continuously. According to some embodiments, the pharmaceutically acceptable liquid composition is administered subcutaneously via a designated pump device.
The embodiments of the devices specified may be any of the device embodiments disclosed, for example, in US 62/529,784、US 62/576,362、US 63/341,090、 PCT/IB2018/054962、PCT/IL2023/050147、PCT/IL2023/050577、US 16/027,804、US 16/027,710、US 10,463,787、US 10,463,572、US 10,603,430、US 11,554,210、US 18/065,373、US 11,779,697、US 16/838,384、US 2020/0368448、US 17/691,857、US 2022/0288312、US 18/086,401、US D887,577、US D921,187、US D921,188、US D865,665、US D868,689、US D921,189、US D921,190、US D935,478、US D960,905、US D960,906、US D960,907、US D960,908、US D960,909、US D960910、US D960,911、USD 29/779,154、USD 29/779,153、USD 29/811,491、USD 29/842,699、USD 29/842,700、USD 29/842,701、USD 29/842,702、USD 29/842,703、USD 29/842,704、USD 29/846,963、USD 29/861,832、USD 29/655,583、USD 29/655,587、USD 29/655,589、USD 29/655,591、USD 29/655,592、USD 29/655,594 and USD 29/655,597, all of which are incorporated herein by reference in their entirety.
According to some embodiments, the dedicated device comprises a control station. According to some embodiments, the special device comprises a disposable part, such as a cartridge, and a reusable part, such as a pump element.
According to some embodiments, the methods of the invention comprise administering the pharmaceutically acceptable liquid composition at one site, two sites, or three or more sites, wherein the positions of the sites may be changed at any suitable, possibly predetermined, interval. According to some embodiments, once administered via a particular site, administration via the same site or in the vicinity of the site may be only after a possibly predetermined period of time. According to some embodiments, the location of any one of the sites is changed after about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours. According to some embodiments, the location of the site is changed after about 4 days, about 5 days, about 6 days, or about 7 days. According to some embodiments, the location of the site is changed after about two weeks, about three weeks, or about four weeks. According to some embodiments, the location of the site is changed when needed or desired, e.g., based on subjective data received from the patient and/or based on objective data received, e.g., from a sensor located at or near the injection site.
According to some embodiments, the volume and/or rate of administration is the same in all or at least two sites. According to other embodiments, the rate of administration and/or the volume of administration varies from site to site. Each site may be controlled independently or otherwise, and all sites may be controlled dependent on each other.
According to some embodiments, the methods of the invention comprise subcutaneously administering the pharmaceutically acceptable liquid compositions of the invention over the course of about 5 hours to about 24 hours or more, such as from about 5 hours to about 12 hours or more, from about 7 hours to about 10 hours or more, or such as about 8 hours or about 24 hours.
According to some embodiments, the dose of carbidopa moiety in a pharmaceutically acceptable liquid composition is between about 10 mg and about 25 mg per administration, between about 10 mg and about 50 mg per administration, between about 10 mg and about 75 mg per administration, between about 12 mg and about 25 mg per administration, between about 12 mg and about 50 mg per administration, between about 12 mg and about 75 mg per administration, between about 15 mg and about 25 mg per administration, between about 15 mg and about 50 mg per administration, between about 15 mg and about 75 mg per administration, between about 25 mg and about 50 mg per administration, between about 25 mg and about 75 mg per administration, and between about 50 mg and about 75 mg per administration. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable liquid composition is about 90 mg, e.g., administered over a course of about 5 hours to about 24 hours or more. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable liquid composition is between about 46 mg and about 90 mg per administration. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable liquid composition is about 90 mg, e.g., administered over the course of about 24 hours. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable liquid composition is between about 46 mg and about 90 mg, for example, administered over the course of about 24 hours.
According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable liquid composition is between about 10 mg and about 800 mg per administration, between about 10 mg and about 25 mg per administration, between about 25 mg and about 50 mg per administration, between about 50 mg and about 75 mg per administration, between about 75 mg and about 100 mg per administration, between about 100 mg and about 150 mg per administration, between about 150 mg and about 200 mg per administration, between about 200 mg and about 250 mg per administration, between about 250 mg and about 300 mg per administration, between about 300 mg and about 350 mg per administration, between about 350 mg and about 400 2 per administration, between about 400 2 and about 450 mg per administration, between about 450 and about mg per administration, between about mg and about 800, between about 600 and about mg per administration, or between about mg and about 720 each administration. In certain embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable liquid composition is between about 370 mg to about 720 mg. In certain embodiments, the dose is administered over the course of about 5 hours to about 24 hours (e.g., about 7 hours to about 10 hours, or about 8 hours, or about 24 hours) or longer. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable liquid composition is about 720 mg, e.g., administered over the course of about 24 hours. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable liquid composition is between about 370 mg to about 720 mg, for example, administered over the course of about 24 hours. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable liquid composition is between about 360 mg to about 720 mg, for example, administered over the course of about 24 hours. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable liquid composition is up to about 720 mg.
In certain embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers to the patient a levodopa fraction of from about 100 mg to about 200 mg and a carbidopa fraction of from about 12 mg to about 50 mg. In certain embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers to the patient a levodopa fraction of from about 140 mg to about 170 mg and a carbidopa fraction of from about 16 mg to about 24 mg.
In certain embodiments, the dose is administered over a course of about 5 hours to about 24 hours (e.g., about 7 hours to about 10 hours) or longer.
In certain embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers to the patient a levodopa fraction of from about 650 mg to about 800 mg, e.g., about 720 mg, and a carbidopa fraction of from about 80 mg to about 100mg, e.g., about 90 mg, over a course of about 24 hours. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable liquid composition is between about 46 mg and about 90 mg, for example, administered over the course of about 24 hours. According to some embodiments, the dose of carbidopa moiety in a pharmaceutically acceptable liquid composition is between about 45 mg to about 90 mg, e.g., administered over the course of about 24 hours. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable liquid composition is up to about 90 mg.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of about 8:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers about 720 mg levodopa portion and about 90 mg carbidopa portion per day, about 360 mg levodopa portion and about 45 mg carbidopa portion per day, about 370 mg levodopa portion and about 46 mg carbidopa portion per day, wherein the ratio of levodopa portion to carbidopa portion is about 8:1 w/w.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers more than 0 mg and up to about 720 mg levodopa moieties and more than 0 mg and up to about 90 mg carbidopa moieties per day, wherein the ratio of levodopa moieties administered/carbidopa moieties (e.g., LD/CD) is about 8:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers between about 8 mg to about 720 mg of levodopa moieties and between about 1 mg to about 90 mg of carbidopa moieties per day, the ratio of levodopa moieties/carbidopa moieties (e.g., LD/CD) being about 8:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers between about 360 mg to about 720 mg of levodopa moieties and between about 45 mg to about 90 mg of carbidopa moieties per day, the ratio of levodopa moieties/carbidopa moieties (e.g., LD/CD) being about 8:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers between about 370 mg to about 720 mg of levodopa moieties and between about 46 mg to about 90 mg of carbidopa moieties per day, the ratio of levodopa moieties/carbidopa moieties (e.g., LD/CD) being about 8:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers between about 370 mg to about 720 mg of levodopa moieties and between about 46 mg to about 90 mg of carbidopa moieties per day, the ratio of levodopa moieties/carbidopa moieties (e.g., LD/CD) being about 8:1 w/w.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises up to about 720 mg levodopa. According to some embodiments, the pharmaceutically acceptable liquid composition comprises up to about 90 mg carbidopa. According to some embodiments, the pharmaceutically acceptable liquid composition comprises up to about 720 mg levodopa and up to about 90 mg carbidopa, wherein the ratio of levodopa to carbidopa is about 8:1 w/w.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount to deliver about 720 mg, about 660 mg-670 mg, about 620 mg-630 mg, about 560 mg-570 mg, about 510 mg-520 mg, about 470 mg-480 mg, about 410 mg-420 mg, or about 370 mg-380 mg levodopa per day. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount to deliver about 90 mg, about 85 mg-90 mg, about 80 mg-85 mg, about 75 mg-80 mg, about 70 mg-75 mg, about 65 mg-70 mg, about 60 mg-65 mg, about 55 mg-60 mg, about 50 mg-55 mg, or about 45 mg-50 mg carbidopa per day. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount to deliver about 720 mg levodopa and about 90 mg carbidopa, about 660 mg-670 mg levodopa and about 80 mg-85 mg carbidopa, about 610 mg-620 mg levodopa and about 75 mg-80 mg carbidopa, about 560 mg-570 mg levodopa and about 70 mg-75 mg carbidopa, about 510 mg-520 mg levodopa and about 60 mg-70 mg carbidopa, about 470 mg-480 mg levodopa and about 55 mg-60 mg carbidopa, about 410 mg-420 mg levodopa and about 50 mg-55 mg carbidopa, or about 370 mg-380 mg levodopa and about 45 mg-50 mg carbidopa, wherein the levodopa and the carbidopa are administered at a ratio of about 8:1 w/w.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 2:1 w/w to about 40:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 2:1 w/w to about 4:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 4:1 w/w to about 6:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 6:1 w/w to about 8:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 8:1 w/w to about 10:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 10:1 w/w to about 15:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 15:1 w/w to about 20:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 20:1 w/w to about 25:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 25:1 w/w to about 30:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 30:1 w/w to about 35:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of between about 35:1 w/w to about 40:1 w/w. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a ratio of levodopa moieties to carbidopa moieties of about 20:1 w/w.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers the levodopa moiety of about 100 mg, about 200 mg, about 240 mg, about 480 mg, about 720 mg, about 960 mg, about 1200 mg, about 1440 mg, about 1680 mg, about 1920 mg, about 2160 mg, about 2400 mg, about 2640 mg, about 2880 mg, about 3120 mg, about 3360 mg, about 3600 mg, about 3830 mg, about 4080 mg, about 4320 mg, about 4560 mg, about 4800 mg, about 5040 mg, about 5280 mg, about 5520 mg, about 5760 mg, about 6000 mg over a period of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a fraction of levodopa of between about 100 mg to about 6000 mg over a course of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a levodopa moiety of between about 240 mg to about 4800 mg over the course of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a levodopa moiety of between about 8 mg to about 1600 mg over a course of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a levodopa moiety of between about 8 mg to about 3200 mg over the course of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a levodopa moiety of between about 8 mg to about 3440 mg over the course of about 24 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers the carbidopa moiety of about 5 mg, about 6 mg, about 10 mg, about 12 mg, about 24 mg, about 36 mg, about 48 mg, about 60mg, about 72 mg, about 84 mg, about 90 mg, about 96 mg, about 108 mg, about 120 mg, about 132 mg, about 144 mg, about 156 mg, about 168 mg, about 180 mg, about 192 mg, about 204 mg, about 216 mg, about 228 mg, about 240 mg, about 252 mg, about 264 mg, about 276 mg, about 288 mg, or about 300 mg over a period of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a carbidopa moiety of between about 12 mg to about 240 mg over a course of about 24 hours. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers a carbidopa moiety of between about 1 mg to about 300 mg over a period of about 24 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered in an amount that delivers between about 240 mg to about 4800 mg of levodopa and between about 12 mg to about 240 mg of carbidopa over the course of about 24 hours.
According to some embodiments, the methods of the invention comprise subcutaneously administering between about 1 mL to about 30 mL of the pharmaceutically acceptable liquid composition of the invention over a 24 hour period. According to some embodiments, the methods of the invention comprise subcutaneously administering the pharmaceutically acceptable liquid compositions of the invention between about 1 mL to about 120 mL over a 24 hour period. According to some embodiments, the methods of the invention comprise subcutaneously administering between about 1 mL and about 2mL, between about 2mL and about 3mL, between about 3mL and about 4 mL, between about 4 mL and about 5mL, between about 5mL and about 6 mL, between about 6 mL and about 7 mL, between about 7 mL and about 8mL, between about 8mL and about 9 mL, between about 9 mL and about 10mL, between about 10mL and about 11 mL, between about 11 mL and about 12 mL, between about 12 mL and about 13 mL over a 24 hour period, Between about 13 mL and about 14 mL, between about 14 mL and about 15 mL, between about 15 mL and about 16 mL, between about 16 mL and about 17 mL, between about 17 mL and about 18 mL, between about 18 mL and about 19 mL, between about 19 mL and about 20 mL, between about 20 mL and about 21 mL, between about 21 mL and about 22 mL, between about 22 mL and about 23 mL, between about 23 mL and about 24 mL, between about 24 mL and about 25 mL, Between about 25 mL and about 26 mL, between about 26 mL and about 27 mL, between about 27 mL and about 28 mL, between about 28 mL and about 29 mL, between about 29 mL and about 30 mL, between about 30 mL and about 40 mL, between about 40 mL and about 50 mL, between about 50 mL and about 60mL, between about 60mL and about 70 mL, between about 70 mL and about 80 mL, between about 80 mL and about 90 mL, between about 90 mL and about 100mL, A pharmaceutically acceptable liquid composition between about 100 mL and about 110 mL, between about 110 mL and about 120 mL. According to some embodiments, the methods of the invention comprise subcutaneously administering about 12 mL of the pharmaceutically acceptable liquid compositions of the invention over the course of about 24 hours. According to some embodiments, the methods of the invention comprise subcutaneously administering about 20mL of the pharmaceutically acceptable liquid compositions of the invention over the course of about 24 hours. According to some embodiments, the methods of the invention comprise subcutaneously administering the pharmaceutically acceptable liquid compositions of the invention up to about 12 mL over the course of about 24 hours. According to some embodiments, the methods of the invention comprise subcutaneously administering the pharmaceutically acceptable liquid compositions of the invention up to about 20mL over the course of about 24 hours. According to some embodiments, the methods of the invention comprise subcutaneously administering the pharmaceutically acceptable liquid compositions of the invention up to about 120 mL over the course of about 24 hours.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered in a volume of between about 1mL to about 30 mL per site per day, between about 2 mL to about 20 mL per site per day, between about 3 mL to about 10 mL per site per day, between about 5 mL to about 7 mL per site per day, or about 6 mL per site per day. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in a volume of between about 1mL and about 2.5 mL per day, between about 2.5 mL and about 5.0 mL per day, between about 5.0 mL and about 7.5 mL per day, between about 7.5 mL and about 10 mL per day, between about 10 mL and about 12.5 mL per day, between about 12.5 mL and about 15 mL per day, between about 15 mL and about 17.5 mL per day, between about 17.5 mL and about 20 mL per day, between about 20 mL and about 22.5 mL per day, between about 22.5 mL and about 25 mL per day, between about 25 mL and about 27.5 mL per day, and between about 27.5 mL and about 30 mL per day. According to some embodiments, the pharmaceutically acceptable liquid composition is administered in a volume of about 6 mL per site per day.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises about 5.5 mg/mL, about 6.0 mg/mL, about 6.5 mg/mL, about 7.0 mg/mL, about 7.5 mg/mL, about 8.0 mg/mL, about 8.5 mg/mL, about 9.0 mg/mL, or about 9.5 mg/mL of carbidopa moiety. According to some embodiments, the pharmaceutically acceptable liquid composition comprises a levodopa moiety of 44 mg/mL, about 48 mg/mL, about 52 mg/mL, about 56 mg/mL, about 60 mg/mL, about 64 mg/mL, about 68 mg/mL, about 72 mg/mL, or about 76 mg/mL. According to some embodiments, the pharmaceutically acceptable liquid composition comprises about 7.5 mg/mL carbidopa and 60 mg/mL levodopa.
It should be noted that the rate of administration may remain unchanged over the course of 24 hours, or may change over the course of 24 hours. For example, according to some embodiments, there may be a certain rate for high activity/daytime hours and a different rate for low activity/nighttime hours. The high activity/daytime time may be, for example, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 19 hours, and the low activity/nighttime time may be about 9 hours, about 8 hours, about 7 hours, about 6 hours, or about 5 hours, respectively. According to some embodiments, the high activity/daytime rate is performed for about 18 hours, and the low activity/nighttime rate is performed for about 6 hours. According to some embodiments, the high activity/daytime rate is performed for about 16 hours, while the low activity nighttime rate is performed for about 8 hours. According to some embodiments, the rate of administration is determined at least in part by input received from the patient, caregiver, at least one sensor, or the like. According to some embodiments, the rate of administration may be increased if necessary or decreased if necessary according to a predetermined pattern that may be set periodically, for example, by a caregiver or patient. According to other embodiments, the rate of administration may be changed in an on-line fashion, e.g., increased or decreased, e.g., based on input received from the patient, caregiver, or at least one sensor indicating that a change in the rate of administration is desired or beneficial. For example, if the patient wishes to rest at some point during the day, the rate may be reduced from the daytime rate to the nighttime rate, for example, by a command provided by the patient. In addition, caregivers may consider that patients give systematic commands, for example, rest during daytime. In addition, the sensor may alert the system patient that he has fallen asleep (or falls asleep) and reduce the administration rate accordingly. The sensor may also provide sleep pattern data allowing the system to be notified before the patient wakes up from sleep and, in response, for example, to increase the rate of administration. The monitored condition of the patient may also cause a change in the rate of administration, such as a "closing period" (off episode), etc., which may cause an increase in the rate of administration.
The rate of administration may be between about 0.01 mL/site/hour to about 1 mL/site/hour. According to some embodiments, the rate of administration is between about 0.01 mL/site/hour and 0.02 mL/site/hour. According to some embodiments, the rate of administration is between about 0.02 mL/site/hour and 0.03 mL/site/hour. According to some embodiments, the rate of administration is between about 0.03 mL/site/hour and 0.04 mL/site/hour. According to some embodiments, the rate of administration is between about 0.04 mL/site/hour and 0.05 mL/site/hour. According to some embodiments, the rate of administration is between about 0.05 mL/site/hour and 0.06 mL/site/hour. According to some embodiments, the rate of administration is between about 0.06 mL/site/hour and 0.07 mL/site/hour. According to some embodiments, the rate of administration is between about 0.07 mL/site/hour and 0.08 mL/site/hour. According to some embodiments, the rate of administration is between about 0.08 mL/site/hour and 0.09 mL/site/hour. According to some embodiments, the rate of administration is between about 0.09 mL/site/hour and 0.1 mL/site/hour. According to some embodiments, the rate of administration is between about 0.1 mL/site/hour and 0.15 mL/site/hour. According to some embodiments, the rate of administration is between about 0.15 mL/site/hour and 0.2 mL/site/hour. According to some embodiments, the rate of administration is between about 0.2 mL/site/hour and 0.25 mL/site/hour. According to some embodiments, the rate of administration is between about 0.25 mL/site/hour and 0.3 mL/site/hour. According to some embodiments, the rate of administration is between about 0.3 mL/site/hour and 0.35 mL/site/hour. According to some embodiments, the rate of administration is between about 0.35 mL/site/hour and 0.4 mL/site/hour. According to some embodiments, the rate of administration is between about 0.4 mL/site/hour and 0.45 mL/site/hour. According to some embodiments, the rate of administration is between about 0.45 mL/site/hour and 0.5 mL/site/hour. According to some embodiments, the rate of administration is between about 0.5 mL/site/hour and 0.55 mL/site/hour. According to some embodiments, the rate of administration is between about 0.55 mL/site/hour and 0.6 mL/site/hour. According to some embodiments, the rate of administration is between about 0.6 mL/site/hour and 0.65 mL/site/hour. According to some embodiments, the rate of administration is between about 0.65 mL/site/hour and 0.7 mL/site/hour. According to some embodiments, the rate of administration is between about 0.7 mL/site/hour and 0.75 mL/site/hour. According to some embodiments, the rate of administration is between about 0.75 mL/site/hour and 0.8 mL/site/hour. According to some embodiments, the rate of administration is between about 0.8 mL/site/hour and 0.85 mL/site/hour. according to some embodiments, the rate of administration is between about 0.85 mL/site/hour and 0.9 mL/site/hour. According to some embodiments, the rate of administration is between about 0.9 mL/site/hour and 0.95 mL/site/hour. According to some embodiments, the rate of administration is between about 0.95 mL/site/hour and 1.0 mL/site/hour.
According to some embodiments, the rate of administration during low activity/night time is between about 0.01 mL/site/hour and 0.15 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.01 mL/site/hour and 0.02 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.02 mL/site/hour and 0.03 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.03 mL/site/hour and 0.04 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.04 mL/site/hour and 0.05 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.05 mL/site/hour and 0.06 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.06 mL/site/hour and 0.07 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.07 mL/site/hour and 0.08 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.08 mL/site/hour and 0.09 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.09 mL/site/hour and 0.1 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.1 mL/site/hour and 0.11 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.11 mL/site/hour and 0.12 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.12 mL/site/hour and 0.13 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.13 mL/site/hour and 0.14 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.14 mL/site/hour and 0.15 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is about 0.04 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is about 0.08 mL/site/hour.
According to some embodiments, the rate of administration during high activity/daytime is between about 0.15 mL/site/hour and 1.0 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.15 mL/site/hour and 0.2 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.2 mL/site/hour and 0.25 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.25 mL/site/hour and 0.3 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.3 mL/site/hour and 0.35 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.35 mL/site/hour and 0.4 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.4 mL/site/hour and 0.45 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.45 mL/site/hour and 0.5 mL/site/hour. according to some embodiments, the rate of administration during high activity/daytime is between about 0.5 mL/site/hour and 0.55 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.55 mL/site/hour and 0.6 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.6 mL/site/hour and 0.65 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.65 mL/site/hour and 0.7 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.7 mL/site/hour and 0.75 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.75 mL/site/hour and 0.8 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.8 mL/site/hour and 0.85 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.85 mL/site/hour and 0.9 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.9 mL/site/hour and 0.95 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.95 mL/site/hour and 1.0 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is about 0.32 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.32 mL/hour and about 0.64 mL/hour. According to some embodiments, the rate of administration during high activity/daytime is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.5 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour. According to some embodiments, the rate of administration during high activity/daytime is about 0.32 mL/site/hour, about 0.295 mL/site/hour, about 0.275 mL/site/hour, about 0.25 mL/site/hour, about 0.225 mL/site/hour, about 0.205 mL/site/hour, about 0.18 mL/site/hour, or about 0.16 mL/site/hour.
As mentioned above, although the low rate and the high rate are referred to as a night rate and a daytime rate, respectively, they may be used regardless of the time of day, but instead, in consideration of the condition of a patient or the like, for example, low activity and high activity. Furthermore, the rate may be gradually changed and may be set at any suitable value, not necessarily tied to one particular high rate and one particular low rate.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered at a high activity rate over a course of about 12 hours to about 20 hours (e.g., about 18 hours) and at a low activity rate over a course of about 4 hours to about 12 hours (e.g., about 6 hours), wherein about 500 mg to about 800 mg (e.g., about 700 mg or about 691.2 mg) of levodopa and about 60 mg to about 100 mg (e.g., about 80 mg or about 86.4 mg) of carbidopa are administered over a course of high activity, and about 20 mg to about 40 mg (e.g., about 30 mg or about 28.8 mg) of levodopa and about 2mg to about 5mg (e.g., about 3 mg or about 3.6 mg) of carbidopa are administered over a course of low activity. According to some embodiments, the high activity rate and/or the low activity rate may be a continuous period of time in the course of 24 hours. According to other embodiments, the high activity rate and/or the low activity rate may be administered over a 24 hour period in several discrete time periods.
It should also be noted that the volume and/or rate of administration may remain unchanged throughout the treatment, or may vary during different times of the day, between different treatment days, weeks or months of treatment, etc. According to some embodiments, the patient is monitored, e.g., by an administrator independently, or electronically, e.g., by sensors, patch-like sensors, administration pumps, etc., that may be found in a dedicated device (e.g., a wristwatch-like device). According to such embodiments, the application volume and/or rate is determined from data received from such monitoring.
Some embodiments relate to methods for bolus subcutaneous injection of the pharmaceutically acceptable liquid compositions of the present invention. According to some embodiments, the bolus injection comprises between about 0.5 mL/Kg to about 2.0 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 0.5 mL/Kg to about 0.75 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 0.75 mL/Kg to about 1.0 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 1.0 mL/Kg to about 1.25 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 1.25 mL/Kg to about 1.5 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 1.5 mL/Kg to about 1.75 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 1.75 mL/Kg to about 2.0 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises between about 0.75 mL/Kg to about 1.25 mL/Kg of the pharmaceutically acceptable liquid composition. According to some embodiments, the bolus injection comprises about 1.0 mL/Kg of the pharmaceutically acceptable liquid composition.
Bolus subcutaneous injections may be administered at any point in time associated with any possible continuous subcutaneous administration, e.g., before, during, or after continuous administration. Bolus subcutaneous injections may be administered at any point during the day. Bolus injections may be administered once daily, once every two days, once every three days, once every four days, once every five days, or once every six days, once a week, or longer. Bolus subcutaneous injections may be administered as needed/desired based on feedback received from the patient, administrator, doctor, sensor, etc., and/or according to a predetermined regimen. Bolus subcutaneous injections may be administered over between about 5 minutes and about 40 minutes, between about 5 minutes and about 10 minutes, between about 10 minutes and 15 minutes, between about 15 minutes and 20 minutes, between about 20 minutes and 25 minutes, between about 25 minutes and 30 minutes, between about 30 minutes and 35 minutes, between about 35 minutes and 40 minutes.
According to some embodiments, by using more than one pump, more than one injection site per pump, etc., the dose administered may be doubled, tripled, or more.
According to some embodiments, the pharmaceutically acceptable liquid composition is administered for a defined period of time, e.g., days, weeks, months or years. According to some embodiments, the pharmaceutically acceptable liquid composition is administered indefinitely for the treatment of chronic conditions.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 1% w/v and about 40% w/v of levodopa, a salt of levodopa, or any combination thereof. According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 1% w/v and about 5% w/v, between about 5% w/v and about 10% w/v, between about 10% w/v and about 15% w/v, between about 15% w/v and about 20% w/v, between about 20% w/v and about 25% w/v, between about 25% w/v and about 30% w/v, between about 30% w/v and about 35% w/v, between about 35% w/v and about 40% w/v, between about 2% w/v and about 10% w/v, between about 4% w/v and about 8% w/v, between about 5% w/v and about 7% w/v, about 6% w/v levodopa, levodopa salts, or any combination thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 0.5% w/v and about 10% w/v carbidopa, a carbidopa salt, or any combination thereof. According to some embodiments, the pharmaceutically acceptable liquid composition comprises any combination of between about 0.5% w/v and about 1% w/v, between about 1% w/v and about 1.5% w/v, between about 1.5% w/v and about 2% w/v, between about 2% w/v and about 2.5% w/v, between about 2.5% w/v and about 3% w/v, between about 3% w/v and about 3.5% w/v, between about 3.5% w/v and about 4% w/v, between about 4% w/v and about 4.5% w/v, between about 4.5% w/v and about 5% w/v, between about 5% w/v and about 5.5% w/v, between about 5.5% w/v and about 6% w/v, between about 6.5% w/v and about 3% w/v, between about 3.5% w/v and about 7% w/v, between about 7% w/v and about 7% w/v, between about 8% w/v, between about 4.5% w/v and about 5% w/v, between about 5% w/v and about 8.5% w/v, between about 8% w/v and about 9% w/v.
For example, provided herein are pharmaceutically acceptable liquid compositions suitable for parenteral (e.g., subcutaneous) administration comprising about 4% -10% by weight of levodopa, about 0.5% to about 2% by weight of carbidopa, and about 10% to about 20% by weight of arginine. Another exemplary pharmaceutically acceptable liquid composition provided herein comprises about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 10% to about 20% by weight arginine.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 0.05% w/v and about 2.0% w/v, between about 0.05% w/v and about 0.1% w/v, between about 0.1% w/v and about 0.2% w/v, between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v and about 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.6% w/v and about 0.7% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1.1% w/v and about 1.5% w/v, between about 0.5% w/v and about 1.6% w/v, between about 0.6% w/v and about 0.7% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.9% w/v and about 1.9% w/v, between about 1.1.1% w/v and about 1.1.5% w/v, between about 1.6% w/v and about 1.6% w/v, between about 1.7% w/v and about 0.8% w/v and about 1.8% w/v and about 1.5% w/v Between about 0.75% w/v and about 1.25% w/v, about 0.75% w/v, about 0.8% w/v, about 0.85% w/v, about 0.9% w/v, about 0.95% w/v, about 1.0% w/v of an antioxidant or a combination of antioxidants.
According to some embodiments, the antioxidant is selected from the group consisting of ascorbic acid or a salt thereof, a cysteine such as N-acetylcysteine, an acid sulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a divalent cation, butylated Hydroxytoluene (BHT), beta Hydroxy Acid (BHA) tocopherol, gentisic acid, tocopherol, a tocopherol derivative, thioglycerol, and any combination thereof. According to some embodiments, the antioxidant is ascorbic acid. According to some embodiments, the antioxidant is N-acetylcysteine (NAC). According to some embodiments, the pharmaceutically acceptable liquid composition comprises a combination of ascorbic acid and NAC. For example, provided herein are pharmaceutically acceptable liquid compositions suitable for, e.g., subcutaneous administration, comprising from about 0.1% to about 10% by weight of ascorbic acid or a pharmaceutically acceptable salt thereof, from about 0.01% to about 1% by weight of a component selected from the group consisting of NAC, L-cysteine, and pharmaceutically acceptable salts thereof, from about 2% to about 16% by weight of levodopa or an ester thereof, and from about 0.6% to about 2% by weight of carbidopa or an ester thereof.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises a base. According to some embodiments, the base is selected from the group consisting of arginine, naOH, TRIS (hydroxymethyl) aminomethane (TRIS), NH 4 OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. According to some embodiments, the base is arginine.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 5% w/v and about 30% w/v of the base. According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 5% w/v and about 10% w/v, between about 10% w/v and about 15% w/v, between about 15% w/v and about 20% w/v, between about 20% w/v and about 25% w/v, between about 25% w/v and about 30% w/v, between about 12.5% w/v and 17.5% w/v, or about 15% w/v, or about 15.2% w/v of the base.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises a surfactant. According to some embodiments, the surfactant is selected from tween-80, tween-60, tween-40, tween-20, tween-65, tween-85, span 20, span 40, span 60, span 80, span 85, polyoxyethylene 35 castor oil (Cremophor EL), polyoxyethylene-660-hydroxystearate (macrogol 660), or poloxamer 188 (Pluronic F-68), or any combination thereof. The pharmaceutically acceptable liquid composition of the present invention may comprise between about 0.1% w/v to about 3.0% w/v surfactant or a combination of two or more surfactants. According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 0.1% w/v and about 0.2% w/v, between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v and about 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.6% w/v and about 0.7% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.5% w/v, between about 1.5% w/v and about 2.0% w/v, between about 2.7% w/v and about 0.8% w/v, between about 0.2% w/v, between about 2.5% w/v, or between about 2.5% w/v and about 2.2% of the surfactant.
The pharmaceutically acceptable liquid composition may further comprise additional pharmaceutically acceptable excipients such as N-methyl pyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, preservatives, pharmaceutically acceptable vehicles, stabilizers, dispersants, suspending agents, amino sugars, calcium chelators, protease inhibitors, or any combination thereof. The pharmaceutically acceptable liquid composition of the invention may comprise between about 5.0% w/v to about 80.0% w/v of an additional pharmaceutically acceptable excipient, for example, a solvent such as NMP or a buffer or any other co-solvent. For example, provided herein are pharmaceutically acceptable liquid compositions comprising about 6% by weight of levodopa, about 0.75% by weight of carbidopa, about 10% to about 20% by weight of arginine, about 0.5% by weight of L-cysteine or NAC, and/or about 0.5% by weight of ascorbic acid or a salt thereof. An exemplary pharmaceutically acceptable liquid composition may comprise about 6% levodopa by weight, about 0.75% carbidopa by weight, and about 14% to about 16% arginine by weight. Another exemplary pharmaceutical composition may comprise about 6% levodopa by weight, about 0.75% carbidopa by weight, about 14% to about 16% arginine by weight, about 0.5% ascorbic acid, and about 0.5% NAC.
According to some embodiments, the pharmaceutically acceptable liquid composition of the present invention comprises between about 5.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 15.0% w/v, between about 15.0% w/v and about 20.0% w/v, between about 20.0% w/v and about 25.0% w/v, between about 25.0% w/v and about 30.0% w/v, between about 30.0% w/v and about 35.0% w/v, between about 35.0% w/v and about 40.0% w/v, between about 40.0% w/v and about 45.0% w/v, between about 45.0% w/v and about 50.0% w/v, between about 50.0% w/v and about 55.0% w/v, between about 55.0% w/v and about 60.0% w/v, between about 60.0% w/v and about 75.0% w/v, between any other solvents, such as a co-solvent.
According to some embodiments, the pharmaceutically acceptable liquid composition further comprises a buffer. According to some embodiments, the buffer is selected from citrate buffer, sodium acetate buffer, tartrate buffer, phosphate buffer, succinate buffer, tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium citrate tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, tromethamine (Tris), or any combination thereof. The pharmaceutically acceptable liquid composition may comprise between about 0.1% w/v to about 30.0% w/v buffer. According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 0.1% w/v and about 1.0% w/v, between about 1.0% w/v and about 2.0% w/v, between about 2.0% w/v and about 3.0% w/v, between about 3.0% w/v and about 4.0% w/v, between about 4.0% w/v and about 5.0% w/v, between about 5.0% w/v and about 6.0% w/v, between about 6.0% w/v and about 7.0% w/v, between about 8.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 15.0% w/v, between about 15.0% w/v and about 20.0% w/v, between about 20.0% w/v and about 25.0% w/v, between about 25% w/v and about 0.0% w/v.
According to some embodiments, the pharmaceutically acceptable liquid composition further comprises an acid or base, e.g., to provide the composition with a predetermined pH. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. According to some embodiments, the base is selected from NaOH, ca (OH) 2, ammonium hydroxide, arginine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, diisopropylethylamine, diazabicycloundecene, or any combination thereof. The pharmaceutically acceptable liquid composition may comprise between about 0.1% w/v to about 30.0% w/v of a base or acid. According to some embodiments, the pharmaceutically acceptable liquid composition comprises between about 0.1% w/v and about 1.0% w/v, between about 1.0% w/v and about 2.0% w/v, between about 2.0% w/v and about 3.0% w/v, between about 3.0% w/v and about 4.0% w/v, between about 4.0% w/v and about 5.0% w/v, between about 5.0% w/v and about 6.0% w/v, between about 6.0% w/v and about 7.0% w/v, between about 8.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 11.0% w/v, between about 11.0% w/v and about 12.0% w/v, between about 12.0% w/v and about 12.0% w/v, between about 16.0% w/v and about 18.0% w/v, between about 18.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 10.0% w/v, between about 12.0% w/v and about 19.0% w/v, A base or acid between about 22.0% w/v and about 23.0% w/v, between about 23.0% w/v and about 24.0% w/v, between about 24.0% w/v and about 25.0% w/v, between about 25.0% w/v and about 26.0% w/v, between about 26.0% w/v and about 27.0% w/v, between about 27.0% w/v and about 28.0% w/v, between about 28.0% w/v and about 29.0% w/v, between about 29.0% w/v and about 30.0% w/v.
The pH of the pharmaceutically acceptable liquid composition of the present invention may be between about 4.5 and about 10 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 4.5 and about 5 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 5 and about 6 at about 25 ℃. According to some embodiments, the pharmaceutically acceptable liquid composition has a pH between about 6 and about 7 at about 25 ℃. According to some embodiments, the pharmaceutically acceptable liquid composition has a pH between about 7 and about 8 at about 25 ℃. According to some embodiments, the pharmaceutically acceptable liquid composition has a pH between about 8 and about 9 at about 25 ℃. According to some embodiments, the pharmaceutically acceptable liquid composition has a pH between about 9 and about 10 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 4.5 and about 5.5 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 5.5 and about 6.5 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 6.5 and about 7.5 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 7.5 and about 8.5 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is between about 8.5 and about 9.5 at about 25 ℃. According to some embodiments, the pharmaceutically acceptable liquid composition has a pH between about 9.5 and about 10 at about 25 ℃. According to some embodiments, the pH of the pharmaceutically acceptable liquid composition is about 9.5 at about 25 ℃. According to some embodiments, an acid or base is added to the pharmaceutically acceptable liquid composition in order to provide the composition with a predetermined pH value. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. According to some embodiments, the base is selected from NaOH, arginine, amine bases, any of the bases mentioned herein, and any combination thereof.
In some embodiments, the method further comprises concomitantly administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitor (DDCI), DDCI salts or any combination thereof.
As described herein, the present disclosure provides a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising:
parenterally administering a pharmaceutically acceptable liquid composition to the patient, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitor (DDCI), DDCI salts or any combination thereof.
Disclosed herein is a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising:
parenterally administering a pharmaceutically acceptable liquid composition to the patient, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein after 2 or 3 days of administration, the patient has:
an increase in the daily good open period relative to baseline,
With a decrease in the onset of moderate-severe dyskinesia relative to baseline,
Improvement over baseline based on subject global change impression (SGI-C) scores,
Improvement over baseline based on clinical global change impression (CGI-C) scores,
Or any combination thereof.
Disclosed herein is a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising:
parenterally administering a pharmaceutically acceptable liquid composition to the patient, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein after 2 or 3 days of administration, the patient has:
an increase in the daily good open period relative to baseline,
With a decrease in the onset of moderate-severe dyskinesia relative to baseline,
Improvement over baseline based on patient overall improvement impression (PGI-I) scores,
Improvement over baseline based on clinical global improvement impression (CGI-I) scores,
Or any combination thereof.
Also disclosed herein is a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising:
parenterally administering a pharmaceutically acceptable liquid composition to the patient, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein administration results in an increase in the patient's good open period over the course of about 24 hours of at least about 0.3 hours to about 3.5 hours after the treatment has been continued for about 2 or 3 days.
Also disclosed herein is a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising:
parenterally administering a pharmaceutically acceptable liquid composition to the patient, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein administration results in an increase in the patient's good open period over the course of about 24 hours of at least about 1.5 hours to about 6.0 hours after the treatment has continued for at least about 28 days.
Also disclosed herein is a method for treating a patient suffering from a neurological disorder or movement disorder, the method comprising:
parenterally administering a pharmaceutically acceptable liquid composition to the patient, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering to the patient a pharmaceutically acceptable oral composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
Wherein administration results in an improvement in the patient in terms of:
In the closing period of each day,
Without troublesome daily open-phase dyskinesias,
As assessed by the unified parkinsonism rating scale part II scoring revision, advocated by the dyskinesia association, the daily life exercise experience,
Patient global change impression (PGI-C),
The clinical overall improvement impression (CGI-I),
Or any combination thereof.
According to some embodiments, the improvement in the patient is measured compared to a patient treated with an immediate release oral dosage form of levodopa. According to some embodiments, the improvement in the patient is relative to an immediate release oral dosage form for administration of levodopa.
According to some embodiments, concomitant administration of the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition provides a synergistic effect such that the blood level of levodopa obtained by concomitant administration is higher than the additive effect expected when the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition are provided non-concomitantly. According to some embodiments, the synergy between the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition provides an increase in blood level of levodopa of between about 5% and about 50% compared to the expected additive value. According to some embodiments, the synergy between the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition provides an increase in blood level of levodopa of between about 10% and 40%, an increase in blood level of levodopa of between about 15% and 35%, an increase in blood level of levodopa of between about 20% and 40%, an increase in blood level of levodopa of between about 25% and 35%, or an increase in blood level of levodopa of about 20%, 25% or 30% compared to the expected additive value.
According to some embodiments, the pharmaceutically acceptable liquid composition comprises (1) levodopa and/or a salt of levodopa, and/or (2) carbidopa and/or a salt of carbidopa.
According to some embodiments, DDCI is carbidopa, a carbidopa salt, benserazide, a benserazide salt, or any combination thereof. According to some embodiments, DDCI is carbidopa.
In some embodiments, the pharmaceutically acceptable oral composition comprises levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable oral composition comprises levodopa.
In some embodiments, the pharmaceutically acceptable oral composition comprises DDCI or a pharmaceutically acceptable salt thereof. In some embodiments DDCI is carbidopa.
In some embodiments, the pharmaceutically acceptable oral composition comprises carbidopa or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable oral composition comprises carbidopa.
According to some embodiments, the pharmaceutically acceptable oral composition comprises levodopa and carbidopa.
According to some embodiments, the pharmaceutically acceptable oral composition comprises levodopa and carbidopa. According to some embodiments, the pharmaceutically acceptable oral composition comprises only levodopa as an active ingredient. According to some embodiments, the pharmaceutically acceptable oral composition further comprises a catechol o-methyltransferase (COMT) inhibitor, such as entacapone or tolcapone.
DDCI in the pharmaceutically acceptable liquid composition may be the same as or different from DDCI in the pharmaceutically acceptable oral composition.
Furthermore, the levodopa moiety in each of the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition may be the same or different. That is, while both the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition comprise levodopa according to some embodiments, according to other embodiments, the pharmaceutically acceptable liquid composition may comprise one type of levodopa moiety, such as a levodopa salt, while the pharmaceutically acceptable oral composition comprises a different type of levodopa moiety, such as levodopa. It should also be noted that the concentration or amount of each moiety in the pharmaceutically acceptable liquid composition may be different from the concentration or amount of that moiety in the pharmaceutically acceptable oral composition.
According to some embodiments, the pharmaceutically acceptable oral composition is administered when desired and/or needed, e.g., when symptoms from the neurological disorder or dyskinesia require such administration, or according to a predetermined therapeutic regimen. The evaluation of the timing of administration of the pharmaceutically acceptable oral composition may be performed by an administrator, a physician, a patient to whom the composition is administered, or any combination thereof, resulting from consultation and/or joint decisions, etc. According to some embodiments, the system supported by any type of sensor may provide data for determining the need to administer a pharmaceutically acceptable oral composition. The data may be delivered to an administrator, doctor, patient, or any combination thereof via any means, such as via an electronic device, e.g., a smart phone, dedicated console, tablet, email, dedicated or known application, etc.
According to some embodiments, the pharmaceutically acceptable oral composition is administered at predetermined times, predetermined intervals, or both, e.g., according to a treatment regimen or according to data received from a patient, caregiver, doctor, sensor, etc. The predetermined time and/or interval may be reset at any point in time, for example, in view of data received from a patient, administrator, sensor, doctor evaluation, etc.
According to some embodiments, the pharmaceutically acceptable oral composition is administered orally substantially simultaneously with the beginning of the infusion time course. According to some embodiments, the pharmaceutically acceptable oral composition is administered orally about 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours after the start of the infusion time course. It should be noted that the "start of infusion time course" may be the time of day in which the infusion cycle starts, e.g. when a new vial is introduced into the system, when a cartridge is replaced, when an infusion device is replaced, etc.
According to some embodiments, the orally administered pharmaceutically acceptable oral composition is a morning oral dose. According to some embodiments, the morning oral dose comprises levodopa, a levodopa salt, or any combination thereof. According to some embodiments, the morning oral dose comprises one of 25 mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.
According to some embodiments, the morning oral dose comprises (a) levodopa, a salt of levodopa, (b) a salt of dopa decarboxylase inhibitor (DDCI), DDCI, or (c) any combination thereof.
According to some embodiments, the pharmaceutically acceptable oral composition is administered up to 20 times a day. According to some embodiments, the pharmaceutically acceptable oral composition is administered about 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 times a day. In some embodiments, the methods described herein comprise administering a pharmaceutically acceptable oral composition 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 times a day. According to some embodiments, the pharmaceutically acceptable oral composition is administered between about 3 and 7 times a day. According to some embodiments, the pharmaceutically acceptable oral composition is administered between about 4 and 6 times a day. According to some embodiments, the pharmaceutically acceptable oral composition is administered at a frequency of between about 30 minutes to about 24 hours. According to some embodiments, the pharmaceutically acceptable oral composition is administered at a frequency of between about 30 minutes and about 1 hour, between about 1 hour and about 2 hours, between about 2 hours and about 3 hours, between about 3 hours and about 4 hours, between about 4 hours and about 5 hours, between about 5 hours and about 6 hours, between about 6 hours and about 7 hours, between about 7 hours and about 8 hours, between about 8 hours and about 9 hours, between about 9 hours and about 10 hours, between about 10 hours and about 11 hours, between about 11 hours and about 12 hours, between about 12 hours and about 13 hours, between about 13 hours and about 14 hours, between about 14 hours and about 15 hours, between about 15 hours and about 16 hours, between about 16 hours and about 17 hours, between about 17 hours and about 18 hours, between about 18 hours and about 19 hours, between about 19 hours and about 21 hours and about 22 hours, between about 21 hours and about 22 hours.
The interval between one administration and the next may also vary, e.g., depending on patient/administrator/physician observations and evaluations, data received from any type of appropriate sensor, predetermined treatment regimen, any combination thereof, and so forth.
According to some embodiments, the dose of levodopa moiety administered in a pharmaceutically acceptable oral composition is the same at each administration thereof. According to some embodiments, the dose of the levodopa moiety in a pharmaceutically acceptable oral composition may vary between administrations. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable oral composition is between about 10 and about 3000 a day, between about 10 and about 50 a day, between about 50 a day and about 100 a day, between about 100 a day and about 150 a day, between about 150 a day and about 250 a day, between about 250 a day and about 350 a day, between about 350 a day and about 500 a day, between about 500 a day and about 750 a day, between about 750 a day and about 1000 a day, between about 1000 a day and about 1250 a day, between about 1250 a day and about 1500 a day, between about 1500 a day and about 1750 a day, between about 1750 a day and about 2000 a day, between about 2000 a day and about 2250 a day, between about 2250 a day and about 2500 a day, between about 2500 a day and about 2750 a day, or between about 2750 a day and about 3000 a day. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable oral composition is between about 100 mg a day to about 1800 a day mg a day. According to some embodiments, the dose of the levodopa moiety in the pharmaceutically acceptable oral composition is between about 350 mg a day to about 700 a day mg a day.
It should be noted that the dose administered is determined according to the time at which the composition is administered to the patient, and thus, if several tablets, for example, 4 tablets each comprising 100 mg levodopa are administered to the patient at approximately the same time, in such a case the administered dose of levodopa in a pharmaceutically acceptable oral composition would be considered 400 mg. Furthermore, the daily dose may consist of several doses administered, which are not necessarily identical to each other, e.g. the patient may administer 100 mg at 8 a.m., 200 mg at 10 a.m., 100 mg at 3 a.m., and 75 mg at 7 a.m., such that the dose of the levodopa portion of a pharmaceutically acceptable oral composition would be considered 475 mg a day.
According to some embodiments, the dose of levodopa moiety in a pharmaceutically acceptable oral composition is between about 10mg and about 500 mg per administration, between about 10mg and about 25 mg per administration, between about 25 mg and about 50mg per administration, between about 50mg and about 75 mg per administration, between about 75 mg and about 100 mg per administration, between about 100 mg and about 150 mg per administration, between about 150 mg and about 200 mg per administration, between about 200 mg and about 250 mg per administration, between about 250 mg and about 300 mg per administration, between about 300 mg and about 350 mg per administration, between about 350 mg and about 400 mg per administration, between about 400 mg and about 450 mg per administration, and between about mg and about 500 mg per administration. According to some embodiments, the dose varies between administrations. According to other embodiments, the dose is maintained for at least two administrations, e.g., over the course of 24 hours, three days, one week, etc.
In certain embodiments, the dose of the levodopa moiety in a pharmaceutically acceptable oral composition is about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200mg, or 250 mg levodopa, e.g., in an immediate release tablet or capsule. According to some embodiments, the dose of the levodopa moiety in a pharmaceutically acceptable oral composition is about 95 mg, about 145 mg, about 195 mg, or about 245 mg levodopa, e.g., in an extended release form, e.g., a tablet or capsule.
As mentioned above, the levodopa moiety in a pharmaceutically acceptable oral composition is a levodopa salt. According to some embodiments, the levodopa moiety is levodopa.
According to some embodiments, the dose of carbidopa in a pharmaceutically acceptable oral composition is between about 2.5 mg and about 50mg per application, between about 2.5 mg and about 20 mg per application, between about 2.5 mg and about 25 mg per application, between about 2.5 mg and about 35 mg per application, between about 2.5 mg and about 40 mg per application, between about 15 mg and about 20 mg per application, between about 15 mg and about 25 mg per application, between about 15 mg and about 35 mg per application, between about 15 mg and about 40 mg per application, between about 15 mg and about 50mg per application, between about 20 mg and about mg per application, between about 20 and mg per application, between about mg and about mg per application, between about 20.5 mg and about 40 mg per application, between about 20 and about mg per application, between about mg and about 50 and about mg per application, between about 2 and about mg and about 50 per application, between about mg and about 50 and about mg per application. According to some embodiments, the dose of carbidopa portion in a pharmaceutically acceptable oral composition comprises 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg, or 50mg carbidopa.
The pharmaceutically acceptable oral compositions may be in any suitable oral form, such as pills, hard or soft capsules, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixirs. The pharmaceutically acceptable oral composition may be in an immediate release form, or any type of controlled release form, such as sustained release, extended release, delayed release, extended release (prolonged release), and the like. As mentioned above, a pharmaceutically acceptable oral composition may comprise at least two active ingredients, such as levodopa and carbidopa. It should be noted that each of the active ingredients in the pharmaceutically acceptable oral compositions may be formulated in a different release form, e.g. levodopa may be in a controlled release form while carbidopa is in an immediate release form and vice versa.
According to some embodiments, the pharmaceutically acceptable oral composition is administered only during the high activity/wake time, e.g., during the daytime, such that the interval of administration during the high activity/wake time is smaller than during other parts of the day (e.g., low activity/night time). According to further embodiments, the pharmaceutically acceptable oral composition is provided at a higher dose during the high activity/wake time than is administered during other parts of the day (e.g., low activity/night time). According to some embodiments, a 24 hour dosing regimen is designed and may remain unchanged for a certain number of days, while the regimen may differ based on wakefulness, activity, etc. during the same day. According to some embodiments, the dosing regimen may vary between different days, and may vary within the same day.
In some embodiments, the methods described herein comprise administering a pharmaceutically acceptable oral composition when symptoms from the neurological disorder or dyskinesia require the administration.
In some embodiments, the methods described herein comprise administering a pharmaceutically acceptable oral composition at predetermined times, predetermined intervals, or both.
In some embodiments, the methods described herein comprise administering a pharmaceutically acceptable oral composition more than once, wherein the dosage administered is the same throughout the administration.
In some embodiments, the methods described herein comprise administering a pharmaceutically acceptable oral composition more than once, wherein the dose administered differs in at least two administrations.
In some embodiments, the methods described herein comprise administering a pharmaceutically acceptable oral composition at a dose of between about 25 mg and about 400 mg of levodopa or a salt thereof in each administration.
In some embodiments, the methods described herein comprise levodopa, carbidopa, and arginine, or any salt thereof, as a pharmaceutically acceptable liquid combination.
In some embodiments, the methods described herein comprise levodopa, carbidopa, arginine, or any salt thereof, and at least one antioxidant as a pharmaceutically acceptable liquid composition.
In some embodiments, the methods described herein comprise levodopa, carbidopa, arginine, or any salt thereof, and at least two antioxidants as a pharmaceutically acceptable liquid composition.
In some embodiments, the methods described herein comprise a composition comprising levodopa, carbidopa, or any salt thereof, and a base selected from the group consisting of arginine, naOH, TRIS (hydroxymethyl) aminomethane (TRIS), and any combination thereof, as a pharmaceutically acceptable liquid composition.
In some embodiments, the methods described herein include the composition as a pharmaceutically acceptable liquid composition having a pH in the range of between about 6 and about 10, in the range of between about 8 and about 10, in the range of between about 9 and about 10, in the range of between about 9.1 and about 9.8, or about 9.5.
In some embodiments, the methods described herein comprise a composition comprising levodopa, a levodopa salt, or any combination thereof, between about 1% w/v and about 40% w/v, between about 1% w/v and about 20% w/v, between about 1% w/v and about 10% w/v, between about 2% w/v and about 8% w/v, between about 4% w/v and about 8% w/v, between about 5% w/v and about 7% w/v, or about 6% w/v, as a pharmaceutically acceptable liquid composition.
In some embodiments, the methods described herein comprise a composition comprising carbidopa, carbidopa salt, or any combination thereof, between about 0.5% w/v and about 10% w/v, between about 0.5% w/v and about 6% w/v, between about 0.5% w/v and about 4% w/v, between about 0.5% w/v and about 2% w/v, between about 0.5% w/v and about 1% w/v, about 0.75% w/v, as a pharmaceutically acceptable liquid composition.
In some embodiments, the methods described herein comprise an antioxidant selected from the group consisting of ascorbic acid or a salt thereof, a cysteine such as N-acetylcysteine, an acid sulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a divalent cation, butylated Hydroxytoluene (BHT), beta Hydroxy Acid (BHA) tocopherol, gentisic acid, tocopherol, a tocopherol derivative, thioglycerol, and any combination thereof.
Embodiments of the present invention also relate to a method for treating a neurological disorder or movement disorder such as parkinson's disease in a patient in need thereof, wherein the method comprises:
A pharmaceutically acceptable liquid composition is administered parenterally, the pharmaceutically acceptable liquid composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitors (DDCI), DDCI salts or any combination thereof,
And concomitantly, administering a pharmaceutically acceptable oral composition, the pharmaceutically acceptable oral composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) Dopa decarboxylase inhibitor (DDCI), DDCI salts or any combination thereof.
Further embodiments of the present invention relate to a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) A dopa decarboxylase inhibitor (DDCI), DDCI salt, or any combination thereof;
a pharmaceutically acceptable oral composition, the pharmaceutically acceptable oral composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) A dopa decarboxylase inhibitor (DDCI), DDCI salt, or any combination thereof;
as a combination for the treatment of neurological disorders or movement disorders such as parkinson's disease, wherein the pharmaceutically acceptable liquid composition is formulated as a parenteral composition and the pharmaceutically acceptable oral composition is formulated as an oral composition.
Further embodiments of the present invention relate to a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) A dopa decarboxylase inhibitor (DDCI), DDCI salt, or any combination thereof;
a pharmaceutically acceptable composition for oral administration, which comprises, the pharmaceutically acceptable oral composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) A dopa decarboxylase inhibitor (DDCI), DDCI salt, or any combination thereof;
And instructions for concomitant administration of a pharmaceutically acceptable liquid composition and a pharmaceutically acceptable oral composition for treating neurological disorders or dyskinesia such as parkinson's disease.
Further embodiments of the present invention relate to a pharmaceutically acceptable liquid composition comprising:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) A dopa decarboxylase inhibitor (DDCI), DDCI salt, or any combination thereof;
a pharmaceutically acceptable composition for oral administration, which comprises, the pharmaceutically acceptable oral composition comprises:
(a) Levodopa, levodopa salts or any combination thereof, and
(B) A dopa decarboxylase inhibitor (DDCI), DDCI salt, or any combination thereof;
and instructions for concomitant administration of a pharmaceutically acceptable liquid composition and a pharmaceutically acceptable oral composition for treating a neurological disorder or movement disorder such as parkinson's disease, wherein the pharmaceutically acceptable oral composition is provided separately.
A further embodiment of the invention relates to a method of treating parkinson's disease in a patient in need thereof, wherein said patient was previously administered previous forms of levodopa other than immediate release carbidopa-levodopa tablets in a 1:4 ratio, and wherein said method comprises:
Converting the patient from the previous form of levodopa to an oral immediate release levodopa-carbidopa 100/25 mg tablet;
subcutaneously administering a pharmaceutically acceptable liquid composition comprising levodopa to a patient over a period of time of at least about 24 hours or more, and
At least one pharmaceutically acceptable oral composition comprising levodopa is administered to a patient prior to or during the subcutaneous infusion time course.
A further embodiment of the invention relates to a method of treating parkinson's disease in a patient in need thereof, wherein said patient was previously administered previous forms of levodopa other than immediate release carbidopa-levodopa tablets in a 1:4 ratio, and wherein said method comprises:
converting the patient from the previous form of levodopa to the oral immediate release form of levodopa-carbidopa;
Subcutaneously administering a pharmaceutically acceptable liquid composition comprising levodopa to a patient over a subcutaneous infusion time course of at least about 24 hours or more after said converting, and
At least one pharmaceutically acceptable oral composition comprising levodopa is administered to a patient prior to or during the subcutaneous infusion time course.
A further embodiment of the invention relates to a method of treating parkinson's disease in a patient in need thereof, wherein said patient was previously administered previous forms of levodopa other than immediate release carbidopa-levodopa tablets in a 1:4 ratio, and wherein said method comprises:
Converting a patient from a previous form of levodopa to an oral immediate release form of levodopa, whereby an amount of oral immediate release levodopa is administered to the patient;
Subcutaneously administering a pharmaceutically acceptable liquid composition comprising a subcutaneous amount of levodopa to a patient over a subcutaneous infusion time period of at least about 24 hours or more after said converting, wherein if the amount of oral immediate release form of levodopa is greater than the subcutaneous amount of levodopa, the amount of oral immediate release form of levodopa is reduced to about the subcutaneous amount of levodopa and the remaining amount of oral immediate release levodopa is administered to the patient, and
If the amount of oral immediate release form of levodopa is lower than the subcutaneous amount of levodopa, then the oral immediate release form of levodopa is not administered to the patient except for the early morning dose of oral immediate release levodopa administered prior to or during the subcutaneous infusion time course.
A further embodiment of the invention relates to a method of treating parkinson's disease in a patient in need thereof, wherein said patient was previously administered previous forms of levodopa other than immediate release carbidopa-levodopa tablets in a 1:4 ratio, and wherein said method comprises:
Converting the patient from the previous form of levodopa to the oral immediate release form of levodopa, whereby an initial daily amount of oral immediate release levodopa is administered to said patient;
Subcutaneously administering to the patient, after the conversion, a pharmaceutically acceptable liquid composition in an amount that delivers about 720 mg of levodopa to the patient over a period of at least about 24 hours or more over a period of at least about 24 hours, wherein if the initial daily amount of oral immediate release form of levodopa is greater than about 700 mg, the amount of oral immediate release form of levodopa is reduced to about 700 mg and a remaining amount of oral immediate release levodopa equal to the initial daily amount of oral immediate release levodopa minus 700 mg is administered to the patient, and
If the initial daily amount of levodopa in the form of oral immediate release is less than about 700 mg, then only a morning dose of oral immediate release levodopa is administered to the patient, either before or during the subcutaneous infusion time course.
In certain embodiments of the methods described herein, concomitant administration of a pharmaceutically acceptable liquid composition (parenteral, e.g., subcutaneous administration) and a pharmaceutically acceptable oral composition (e.g., oral tablet) to a patient results in an area under the curve (AUC) of levodopa from time 0 to the end of parenteral (e.g., subcutaneous) infusion that is higher than the AUC of the combination of levodopa in the patient when the pharmaceutically acceptable liquid composition and the pharmaceutically acceptable oral composition are administered non-concomitantly, wherein the total amount of levodopa administered is the same, whether administered concomitantly or non-concomitantly.
Unless explicitly stated, the method embodiments described herein are not limited to a particular order or sequence. In addition, some of the described method embodiments or elements thereof may occur or be performed simultaneously, at the same point in time, or synchronously.
It is appreciated that certain features of the invention may also be provided in combination in a single embodiment. Conversely, various elements of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as appropriate in any other described embodiment of the invention. Furthermore, certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments are not practical without those elements.
Various embodiments and aspects of the invention as described above and as claimed in the following claims section may be supported by the following examples, however, they are not limited by the examples.
Examples
Example 1-onset of efficacy with continuous subcutaneous L-dopa/carbidopa infusion in patients with PD experiencing motor fluctuations
Purpose this study evaluated the onset of efficacy of a continuous 24 hour subcutaneous infusion of liquid levodopa/carbidopa (LD/CD) with ND0612, a LD/CD liquid formulation comprising 60 mg/ml LD and 7.5 mg/ml CD.
Background the main results from the previous study demonstrate that in patients with PD experiencing motor fluctuations, 28 days of treatment with 24-hour ND0612 infusion reduced the off period by 2.8 < -4.6 > -0.9] hours (P < 0.0004), increased the on period without/with mild dyskinesia (good on period) by 3.7 [95% CI: 1.9, 5.6] hours (P < 0.001), and decreased the on period with moderate/severe dyskinesia by 1.2 < -2.1 > -0.3] hours (p≤0.01).
Methods data from a secondary analysis of patients treated with 24 hour ND0612 infusion protocol (n=19) are described herein. The patient received an infusion at a rate of 0.64 mL/hour from 4 am to 10 pm and 0.08 mL/hour between 10 pm and 4 am to a total LD/CD dose of 720 mg/90 mg. The state of motion was determined by a blind assessor (blinded-rater) at 30-minute intervals for 8 hours. The patient also assessed the time of the full open period in the diary every morning. Efficacy evaluation after the first baseline was performed on day 3. Day 3 is the third consecutive day of treatment, followed by two consecutive days of treatment. Unless specifically mentioned otherwise, baseline evaluations were performed on day 1 of treatment, prior to the initiation of treatment, and on day 3 during day 3, perhaps at 8 am, after a high rate of 4 hours, and perhaps on day 3 at another time point during day 3. The "change from baseline" for any data on day 3 is the difference between the day 3 measurement and the baseline measurement on day 1, where at least 48 hours of treatment has ended.
Model results patients treated with ND0612 infusion for two consecutive daily 24 hours showed a significant increase in the mean change adjusted (adjusted MEAN CHANGE) of the good phase from baseline (+1.83 [95% CI: 0.30, 3.35] hours, p=0.02) and a significant decrease in the mean change adjusted from baseline with moderate-severe dyskinesia (-1.36 [95% CI: -2.29, -0.42] hours, p=0.006) on day 3 (fig. 1A).
On day 3, patients treated with ND0612 infusion for two consecutive daily 24 hours also showed a decrease in the mean change of the off period adjusted from baseline (-0.66 [95% CI: -1.98, 0.67] hours, p=0.319) and an increase in the mean change of the on period adjusted from baseline without dyskinesia (+1.47 [95% CI: -0.32, 3.27] hours, p=0.105) (fig. 1B). * The values provided are calculated according to the following model. The mixed model for repeated measurements included as dependent variables the observed changes from day 3 and day 28 to baseline for the overall "on" or "off" period of each day. The model included randomized treatment regimen, planned study day, interactions between randomized treatment regimen and planned study day, and region as fixed factors, and "on" phase/"off phase at baseline (day 1) as covariates. Unstructured covariance structures were assumed and the denominator degrees of freedom were calculated using the Kenward-Roger method.
Results based on raw data (descriptive statistics) on day 3, patients treated with ND0612 infusion for two consecutive daily 24 hours showed a decrease in both off-period and troublesome dyskinesia, as well as an increase in good on-period. The UPDRS part III score also improved significantly (fig. 1C), as does the sleep quality in 50% of patients. See the following table:
TABLE 1
N=19 (MITT set, observed case), open/closed period diary normalized to 16 h wake time
The improvement on day 3 was also evident in terms of patient global change impression and clinician global change impression, PGI improvement and CGI improvement were reported for 73.7% and 52.6% of patients, respectively (fig. 2). By the end of the first week of treatment, the proportion of patients reported to achieve a full open period at 9 am increased from 31.6% at baseline to 72.2% (fig. 3).
Conclusion the results of this analysis demonstrate that patients experience a statistically significant and clinically relevant improvement on day 3 after initiation of treatment with 24 hours subcutaneous infusion with ND0612, which improves further by day 28 (primary endpoint).
Example 2 safety and efficacy of continuous subcutaneous L-dopa/carbidopa infusion for Parkinson's disease reduction of the period of closure for patients suffering from Parkinson's disease who experience motor fluctuations
Purpose this study evaluated the efficacy of 24 hour continuous subcutaneous infusion of liquid levodopa/carbidopa with ND0612 in reducing the off period of persons suffering from Parkinson's disease (PwP) experiencing motor fluctuations.
Background previous studies demonstrated that one year treatment with ND0612 infusion was safe and well tolerated. The adjusted average daily good open period (i.e., the sum of the open period without movement disorder + the open period with non-troublesome movement disorder) was increased by 2.3 hours at month 3 relative to baseline and maintained for at least 12 months.
Method this open label study of ND0612 treatment was performed in PD patients (n=214) aged 30 years and having a Hoehn & Yahr score of 3 during the open period, who experienced a daily off period of 2 hours or more, despite 4 or more levodopa doses and other PD medications per day. Patients received 16 hours/day or 24 hours/day of LD/CD subcutaneous infusion with a total daily LD/CD dose of 720 mg/90 mg.
In this analysis of daily deadlines (patient home diaries), responders are conservatively defined as patients who achieved an adjusted average daily deadline reduction of 50% or more relative to baseline.
As a result, 44.0% of patients were classified as treatment responders using continued final observations, and this response level was maintained over a 12 month follow-up. In addition, 63.5% of patients achieved >25% reduction in the off period from baseline, and 26.9% of patients achieved >75% reduction in the off period. In addition, in 12.8% of patients, the off phase was completely eliminated. Using only the observed cases (i.e., non-LOCF), the percentage of ND0612 treatment responders increased from 44.0% (n=150) at month 1 to 53.3% (n=107) at month 6 and 56.7% (n=90) at month 12.
Extension study of 214 patients entering the study 114 patients entered the extension study. Baseline demographics and disease characteristics of 114 patients entering the extension study are shown in the table below.
TABLE 2
At baseline, most patients still have Hoehn and Yahr scores of less than 2 to 2.5, but the average time from fluctuation is 4.7 years. The patient has taken levodopa and at least one adjuvant drug when entering the study. About one third of patients take less levodopa than 720 mg provided by ND0612, while 2/3 of patients take higher doses. Baseline drug data shows that patients who continue to treat for more than one year enter the trial with a wide range of baseline severity.
94 Patients completed 2 years of treatment. 76 patients completed the treatment for 3 years. Although infusion skin reactions occur in most patients, they often become very accustomed to these medications, and only 4 patients have a discontinuation (discontinuation) cause in the third year. Adverse events are summarized in the table below.
TABLE 3 Table 3
* First year n=114, relative to second year n=112:2 patients completed 1 year but did not complete 365 days, so they were not included in the second year dataset.
The favorable safety profile seen over the year persists throughout the study. Drug-related TEAEs reflect mainly infusion site reactions, and over time these drug-related TEAEs are often less reported as adverse events (fig. 4). Otherwise, the systemic safety of the levodopa product is as expected. Notably, dyskinesias are rarely reported as TEAE.
Improvement in open and closed phase remains clinically relevant at 3 years and is generally similar to the improvement in open and closed phase that has been reported at 1 year, showing good efficacy maintenance as would be expected for levodopa (fig. 5).
Conclusion this open label study provides support for the 12 month and 36 month efficacy of treatment with ND0612 in reducing the period of closure in patients with PD experiencing motor fluctuations.
ND0612 treatment shows a favorable safety profile and is well tolerated over a longer period in patients with PD experiencing motor fluctuations. The general safety profile of ND0612 is a typical general safety profile of known oral LDs/CDs. Infusion site reactions are common, mostly mild, and rarely cause discontinuation. Of the patients who continued OLE (open label extension), ISR (infusion site reaction) caused 4 patients (3.5%) to discontinue within 3 years. The patient achieves a clinically relevant increase in the open phase and decrease in the closed phase without concomitant dyskinesia.
Example 3 safety and efficacy of continuous subcutaneous levodopa/carbidopa infusion for parkinson's disease case study
Case study this example describes four case studies from the test described in example 2 above.
Case 1
Patients were male, aged 67.9 years old and BMI 32.5, 12 years from PD diagnosis, H & Y stage 3, movement fluctuations without dyskinesia for 7 years, daily levodopa (ER) doses 800 mg, 4 divided doses, amantadine 300 mg/day and selegiline 5 mg/day.
ND0612 treatment A daily dose of 720 mg/90 mg of levodopa/carbidopa was provided with an auxiliary oral Extended Release (ER) of levodopa (625 per day mg) for 4.5 years with ND0612 treatment.
Safety and tolerability there were nodules of moderate intensity that persisted for 4.5 years from the first month starting with ND0612, mild/moderate infusion site reactions (eschar, erosion, edema, erythema), 3 infection events (cellulitis/abscess), all resolved without discontinuation of treatment (1 abscess reported as severe), moderate constipation and vitamin B6 deficiency.
As a result, the baseline for the good open period was 10.2 hours and the baseline daily closed period was 5.8 hours for this patient. After 36 months of treatment, the good open period increased by 2.2 hours and the daily closed period decreased by 2.2 hours. Note that the state of motion is normalized to the 16 hour wake time.
Case 2
Patients were females aged 63.9 and BMI 23.4 for 11 years from PD diagnosis, H & Y stage 2, movement fluctuations and dyskinesias for 3 years, daily dose of levodopa (ER) 2200 mg divided into 5 doses, amantadine 200 mg/day.
ND0612 treatment-treatment with ND0612 for 4.5 years, a daily dose of 720 mg/90 mg of levodopa/carbidopa was provided with an auxiliary oral Extended Release (ER) of levodopa (780 mg daily) and amantadine (200 mg/day).
Safety and tolerability within 4.5 years, there were mild to moderate infusion site reactions (nodules, hematomas, exfoliation (excoriation), eschar), 5 infection events (cellulitis/abscess), all resolved by oral antibiotics, no systemic AEs reported.
As a result, the baseline for the good open period was 13.3 hours and the baseline daily closed period was 2.7 hours for this patient. After 36 months of treatment, the good open period was increased by 2.7 hours and the daily off period was eliminated. Note that the state of motion is normalized to the 16 hour wake time.
Case 3
Patients were females aged 65.8 and BMI 22.8, H & Y stage 2.5, movement fluctuations for 5 years, movement disorders for 4 years, daily doses of L-dopa (ER) 900 mg divided into 5 doses, ropinirole 4 mg/day.
ND0612 treatment A daily dose of 720 mg/90 mg of levodopa/carbidopa was provided with an auxiliary oral Extended Release (ER) of levodopa (350 mg daily) for 4.7 years with ND0612 treatment.
Safety and tolerability within 4.7 years, there was moderate bruising and mild pain at the infusion site, which resolved over time, moderate nodules, one of which had lasted about 19 months, no systemic AE reported.
As a result, the baseline for the good open period was 5.4 hours and the baseline daily closed period was 8.5 hours for this patient. After 36 months of treatment, the good open period increased by 7.7 hours and the daily closed period decreased by 5.5 hours. The patient also had an open period of 2 hours at baseline with troublesome dyskinesia, and she did not have an open period with troublesome dyskinesia at visit 36 months. Note that the state of motion is normalized to the 16 hour wake time.
Case 4
Patients were male, aged 60.7 years old and BMI 22.9, H & Y stage 2.5, exercise fluctuation for 1 year, daily dose of levodopa (ER) 750 mg divided into 5 doses, rasagiline 1 mg/day.
ND0612 treatment A daily dose of 720 mg/90 mg of levodopa/carbidopa was provided with an auxiliary oral Extended Release (ER) of levodopa (1000 mg daily) for 4.25 years with ND0612 treatment.
Safety and tolerability within 4.25 years, there were mild nodules and moderate erythema at the infusion site, 1 mild infection event at the infusion site that had resolved, mild urticaria response that resolved without any corrective treatment and discontinuation of study medication.
As a result, the baseline for the good open period was 7.6 hours and the baseline daily closed period was 8.3 h for this patient. After 36 months of treatment, the good open period increased by 4.1 hours and the daily closed period decreased by 4.6 hours. Note that the state of motion is normalized to the 16 hour wake time.
Example 4-efficacy of continuous subcutaneous levodopa/carbidopa infusion (ND 0612) on motor signs of PD and daily life experience
The objective was to evaluate the impact of research ND0612 on the motor signs of PD and the daily life motor experience (m-EDL), as assessed using MDS-UPDRS.
The BouNDless study demonstrated the superiority of ND0612 over immediate release levodopa/carbidopa (IR-LD/CD) in reducing motor fluctuations and improving m-EDL (MDS-UPDRS section II).
Design/method in BouNDless study, MDS-UPDRS part II and part III (in the off state) sub-scores were evaluated at the beginning of ND0612 (i.e., in the lead-in period) and at weeks 8 and 12 of the double-blind period. A descriptive analysis of the change from ND0612 to each double-blind visit is presented here. In addition, posterior analysis was performed on items related to group symptoms of tremor, rigidity, bradykinesia, dysposture instability gait disorder (PIGD), speech and oral health, and self care (according to part II and part III) using a mixed model for repeated measurements. The P value is shown in nominal form without adjustment.
As a result, a therapeutic difference of ND0612 over IR-LD/CD (ND 0612 relative to IR-LD/CD) was observed in the fraction II sub-scores at both week 8 (average [95% CI ] difference: -2.4 [ -3.5, -1.3 ]) and week 12 (-3.1 [ -4.3, -1.8 ]). Similarly, the difference in treatment for the part III sub-scores was-4.2 [ -6.7, -1.7] at week 8 and-2.4 [ -5.2, 0.4] at week 12. Differences were observed in PIGD (-0.26 versus 0.02, p=0.0012), speech and oral health (-0.11 versus 0.05, p=0.0140), tremors (-0.15 versus-0.05, p= 0.0992), and self-care (-0.08 versus 0.09, p= 0.0528) ND0612 over IR-LD/CD. No relevant differences in rigidity and bradykinesia were observed.
Conclusion in addition to reducing motor fluctuations, our results support the clinical benefits of ND0612 24 hours continuous subcutaneous therapy in the different symptomatic areas of MDS-UPDRS II and MDS-UPDRS III.
EXAMPLE 5 dose ratio
Example 5a
The dose ratio of subcutaneously administered Levodopa (LD) and Carbidopa (CD) was demonstrated in a clinical trial (ND 0612-001, a single dose, single-center, randomized, double-blind, placebo-controlled, dose-escalation study) in healthy male subjects.
Compositions comprising LD (6% w/w)/CD (1.4% w/w) were administered to subjects by continuous infusion at different infusion rates for 24 hours:
group 1 80. Mu.l/h
Group 2 120. Mu.l/h
Group 3 160. Mu.l/h
Group 4 200. Mu.l/h
Group 5 240. Mu.l/h
In dose scale assessment, several PK parameters were obtained for both LD and CD, including AUC (hr ng/mL), C max(ng/mL)、C15 (ng/mL) and C 24 (ng/mL).
All analyses performed on all PK parameters studied demonstrated dose ratios for both LD and CD. Referring to fig. 8, the mean plasma levodopa concentrations of five test groups are presented with respect to time (in hours) after the start of subcutaneous infusion. As clearly shown in fig. 8, the levodopa plasma levels depend on the administered levodopa dose and are proportional to each other. Similar results were obtained for carbidopa.
Example 5b
In a separate clinical trial (ND 0612-005a and ND0612-005b, open-label design studies), plasma carbidopa levels were tested based on subcutaneous administration of several carbidopa doses. Three formulations comprising 60 mg/ml of levodopa and (a) 7.5 mg/ml, (b) 6 mg/ml, or 4 mg/ml of carbidopa were administered to three groups of subjects over a 24 hour period, providing a total of 17.9 mg/24h of carbidopa to each subject in the first group, providing 26.9 mg/24h of carbidopa to each subject in the second group, and providing 33.6 mg/24h of carbidopa to each subject in the third group. The obtained carbidopa C max values show a well-defined dose scale (see fig. 9).
Example 6-comparison of continuous subcutaneous levodopa-carbidopa infusion (ND 0612) with oral immediate release levodopa in the treatment of parkinson's disease with motor fluctuations. Phase 3 randomization, double blind, double simulation test (BouNDless)
This is a randomized, double-blind, double-simulated, active control study at 117 academic and community neurological sites spanning the united states, europe, and israel. Patients with PD who experience a period of ≡2.5 h/day off experience an open label lead-in period (up to 12 weeks) during which their optimal oral IR-LD/CD regimen is established and then their optimal ND0612 (together with supplemental oral levodopa/carbidopa) regimen is established. The participants were then randomized (layered in region 1:1 using a block randomization table (permuted block schedule)) to a 12 week double-blind, double-analogue treatment with their optimized ND0612 regimen or oral levodopa/carbidopa regimen. The primary efficacy endpoint was the change in daily overall opening period from randomization to the end of the double blind period without troublesome dyskinesia.
Design/method A phase 3, double blind, double simulation, active (IR-LD/CD) control, multicenter key trial of ND0612 was performed at 117 academic and community neurological sites in 16 countries spanning the United states, europe and Israel. The study included a screening period (1-4 weeks), an open label introduction period (8-12 weeks) to establish an optimized clinical status and experimental treatment regimen for fair comparison (first 4-6 weeks for optimized IR-LD/CD dosing followed by 4-6 weeks for optimized ND 0612), and a randomized, double blind, double simulated, active control period (12 weeks) (fig. 6). At the end of the double blind period, the participants may choose to continue using ND0612 therapy in an optional open-label extension study (the results will be reported separately).
Qualified participants were men and women (as identified by medical history) aged 30 years or older and diagnosed with parkinson's disease (Hoehn and Yahr stages of stage No.3 in the open state). The participants were asked to take at least 4 doses per day of oral levodopa/decarboxylase therapy or 3 doses per day of extended release LD/CD capsules (Rytary-unit), and a total of at least 400 mg equivalent dose of levodopa per day. Participants underwent training on self-completed home diaries, capturing their responses to the medications every 30 minutes. Participants were eligible if they experienced an average off period of > 2.5 h/day over 3 consecutive days (2 h/day) that could not be further improved by adjustment of antiparkinsonian drugs (as determined by the treating physician). Qualification is confirmed by the independent committee of inclusion at the end of the screening period, which operates according to pre-specified rules. Critical exclusion criteria are atypical or acquired parkinsonism, acute psychosis or troublesome hallucinations within the first 6 months, past surgical treatment of PD, use of apomorphine or inhaled levodopa, severe disabling dyskinesia, or any unstable medical condition, surgical condition or mental condition or laboratory abnormality that may represent a safety risk or prevent participation in a comprehensive study.
Randomization and masking randomization (referred to as baseline/randomization visit) was performed at the beginning of the double-blind, double-simulation period. Participants completing the open label lead-in period are randomly assigned by the interactive network response system (Suvoda LLC) in a 1:1 ratio to accept the optimized ND0612 or IR-LD/CD scheme they achieve during the lead-in period. Randomization was layered by region using a granule randomization table.
To ensure that treatment assignments remain masked during the double blind period, a double simulation approach was employed in which participants randomized to ND0612 also received oral placebo for their IR-LD/CD treatment regimen (i.e., patients received the same number of capsules at the same time of day) and participants randomized to IR-LD/CD also received placebo infusion for their ND0612 treatment regimen. ND0612 and matched placebo solutions were supplied in the same vials and packages. The active IR-LD/CD capsule (supplied as a 100/25 mg encapsulated tablet) is also identical in packaging to and has a similar appearance to its placebo counterpart. The study site has three distinct individuals with non-overlapping roles, a efficacy assessor, a safety assessor, and a designated staff member for performing the medication inventory procedure and managing potential accidental blind uncovering. Planned schedules were made so that the participants did not meet each other and the participants were advised not to discuss any adverse reactions with the efficacy assessors at the beginning of each study visit.
Procedure-open label importation period consists of two parts. The enrolled patients initially underwent an oral IR-LD/CD optimization period (4-6 weeks, including at least 2 weeks of stable dosing) in which the participants' current oral levodopa formulation (including COMT inhibitors) was converted to an equivalent dose of 16 (100 mg increments) of supplied IR-LD/CD and adjusted until the dose was optimized (judgment of the investigator). Any other levodopa preparation or COMT inhibitor is then prohibited until the end of the double blind period. Other antiparkinsonian drugs remained stable throughout the study. Once the appropriate IR-LD/CD regimen is determined and eligibility is again confirmed, the participants enter an open label ND0612 optimization period (4-6 weeks, including steady dosing of ≡2 weeks) during which treatment is initiated with ND0612 (replacing oral IR-LD/CD up to 700 mg) and supplemented with oral IR-LD/CD (including at least one morning dose) as needed. The pump system was preprogrammed to deliver a fixed night rate and a flexible daytime rate of 6 h and 18 h, respectively. The night time rate was fixed at 0.08 mL/h, providing approximately 30 mg levodopa during the period of 6 h. The investigator can adjust the flexible daytime rate to a maximum rate of 0.64 mL/h, providing approximately 690 mg levodopa within 18 h, for a total of up to 720 mg/day. If the patient requires less levodopa than 720 mg from ND0612, the daytime pump flow rate is reduced until optimized.
The participants who completed the open label lead-in period were then randomized to maintain their optimized ND0612 regimen (i.e., ND0612 plus supplemental IR-LD/CD) and either add placebo IR-LD/CD or switch back to their optimized IR-LD/CD plus placebo for the ND0612 regimen for an additional 12 weeks of double-blind, double-simulated treatment. Throughout the trial, ND0612 and matched placebo infusions were self-administered via 2 subcutaneous sites (up to 6 mL per site in 24 h) connected to a single portable pump system. Infusion sets and syringes are replaced at the same time each day and the importance of participants and their care partners in their home for proper operation of the pump system and for maintaining good skin hygiene is trained.
Endpoint the primary efficacy endpoint is the change from baseline/randomization to the end of the double blind period for the average number of hours of the daily open period without troublesome movement disorder (sum of open period without movement disorder and open period with non-troublesome movement disorder) as assessed by the patient's home diary within 3 consecutive days prior to visit. Nine secondary efficacy endpoints are pre-specified in a hierarchical order, (1) normalized daily deadlines (key secondary endpoints) as assessed by a family diary over 3 consecutive days, (2) daily life exercise experience as assessed by a unified PD rating scale of the motion impairment society (MDS-UPDRS) part II score, (3) patient global change impression (PGIC), (4) clinical global improvement impression (CGI-I), (5) exercise symptoms (during the deadline state) as assessed by a MDS-UPDRS part III score, (6) normalized daily open periods without motion impairment, (7) proportion of closed period responders (response defined as reduction of > 50% of the deadline), (8) PD questionnaire-39 (PDQ-39) summary index score, and (9) PD sleep scale-2 (PDSS-2) total score. Patient diaries and rating scale scores were evaluated for change between randomization and double-blind end, while the frame of reference for PGIC, CGI-I and response rate (response rate) was from the start of open label ND0612 treatment to the end of double-blind. The daily open and daily closed periods were normalized to the typical wake day (16 h) to account for the different sleep patterns in the participants. In addition, the change in diary movement status from the time of study enrollment to the end of the open label and double blind period was analyzed as an exploratory endpoint.
Safety and tolerability were assessed by incidence of Adverse Events (AE), changes in vital signs, clinical laboratory parameters, electrocardiogram, columbia suicide severity rating scale (Columbia-Suicide SEVERITY RATING SCALE, C-SSRS), PD impulse-compulsive disorder questionnaire rating scale (QUIP-RS), and Epworth Sleepiness Scale (ESS). The AE of particular interest is pre-defined as Infusion Site Response (ISR), hypersensitivity and polyneuropathy (polyneuropathy), and blind independent arbitration procedure is performed on the AE of hypersensitivity and polyneuropathy (adjudication process). Researchers have received training regarding the identification, management and reporting of ISRs, including pain assessment (visual analog scale [ VAS ]), and assessment of local skin response load by patients and clinicians. All ISRs are reported regardless of severity or burden.
The independent data security monitoring committee (including a neurologist, a dermatologist, and a collectist, all not otherwise involved in the trial) reviews the security data every six months. At the end of the study, the participants completed a blind questionnaire asking them why they considered themselves to have received treatment during the double blind, double simulation period.
As a result, 557 participants were screened, and 381 participants were enrolled (FIG. 6). Of these, 259 completed the open label introduction period and was randomly assigned to the double-blind, double-simulation period, and 243 completed the study. The main reason for the exit in the open label lead-in period was to withdraw consent (7.9% during oral IR-LD/CD optimization and 6.8% during ND0612 optimization) followed by AE (4.2% during oral IR-LD/CD optimization and 8.1% during ND0612 optimization). During the double blind period, the discontinuation rates were similar for both treatment groups (ND 0612.3% versus IR-LD/CD 6.1%). The following table shows the key demographic and clinical characteristics of ITT sets at screening and enrollment. Average (SD) daily overall levodopa doses increased from 1079 (487) mg at enroll to 1237 (447) mg at randomization (including 534 [427] mg from adjuvant oral levodopa) in ND0612 group and from 981 (450) mg at enroll to 1065 (409) mg at randomization in IR-LD/CD group.
TABLE 4 participant characteristics
Unless otherwise indicated, data are mean (SD). * Data were normalized to 16h, levodopa dose, including COMT. BMI = body mass index, COMT = catechol o-methyltransferase, MAO-B = type B monoamine oxidase.
In the ND0612 open label lead-in period, when the open label ND0612 was accepted, the normalized average was not accompanied by a troublesome movement disorder with an opening period increased from 9.4 h (two groups) at the time of enrollment to 11.8 h at the time of randomization in the ND0612 group and to 12.1 h in the IR-LD/CD group. During the 12 week double-blind treatment, an increase in the open period without troublesome dyskinesia was maintained in the ND0612 group (11.47 h at the study endpoint) and decreased in the IR-LD/CD group (9.75 h at the study endpoint). Thus, the test is consistent with the primary efficacy endpoint of ND0612, providing an open period (p < 0.0001) at week 12 (Table; FIG. 7) of 1.72 h [95% CI:1.08 h to 2.36 h ] in addition to IR-LD/CD without troublesome dyskinesias.
TABLE 5 summary of primary efficacy and secondary efficacy surveys
Unless otherwise stated, data were LS mean (SE) [95% confidence interval ] changes from baseline to study endpoint (week 12 of double blind, double simulation period). The treatment difference is the difference between the least squares mean changes (SE) and the ratio is expressed as ND0612 versus IR-LD/CD. * Diary data was normalized to 16h, classification data based on the change from the start of open label treatment with ND0612 to the end of study. MDS-UPDRS = dyskinesia association unified parkinson's disease rating scale, PDSS-2 = parkinson's sleep scale-2, pdq-39 = 39 parkinsonian questionnaires. IR-LD/CD n=122 for PGIC, n=119 for CGI-C and n=126 for off-phase responders, n=121 for PGIC and CGI-C and n=126 for off-phase responders.
Significant treatment differences with respect to IR-LD/CD were also observed in the first four graded secondary endpoints (table 4). The critical secondary endpoint, i.e., the decrease in normalized daily off period, showed a therapeutic difference of ND0612 over IR-LD/CD-1.4 h [95% CI: -1.99 to-0.80 ] (p < 0.0001). ND0612 infusion also significantly improved MDS-UPDRS fraction II scores (-3.05 [95% CI: -4.28 to-1.81 ] scores, p < 0.0001) compared to IR-LD/CD. The PGI-C and CGI-I assessments were consistent at week 12, with significantly higher proportions of ND0612 relative to both the IR-LD/CD improving participants and clinicians (fig. 10) (both p < 0.0001). The change in MDS-UPDRS part III scores (during the off period) showed a numerical difference that favors ND0612, but did not reach significance. Although the formal grading test terminated at this comparison, analysis of normalized open-phase, closed-phase responder ratios and PDQ-39 scores without dyskinesia supported ND0612 to be superior to IR-LD/CD (table 4), with nominal p-values <0.05, and no difference in PDSS-2 scores between treatment groups. Furthermore, analysis of diary movement status from enrollment to end of double blind period indicated that a decrease in period of closure and a decrease in period of opening with no movement disorder (troublesome or non-troublesome) were observed with ND0612, whereas no decrease in period of closure and a decrease in period of opening with movement disorder (troublesome or non-troublesome) were observed with IR-LD/CD regimen and an increase in period of opening with no movement disorder.
One participant died during open-label IR-LD/CD optimization due to COVID-19 infection. During open label ND0612 optimization 287 (89%) participants reported AEs, most of which (n= 167,58%) were rated mild by the treatment investigator (fig. 11).
6 Participants (2%) experienced severe AEs, of which 3 had severe AEs (nausea and visual hallucinations; infusion site cellulitis; and infusion site abscesses) assessed as relevant to study treatment. 266 (83%) participants reported ISR, most of which were rated as mild (76%) or moderate (22%) and 5 (2%) participants experienced events rated as severe.
AE were reported by 103 (81%) participants in ND0612 group and 97 (74%) participants in IR-LD/CD group during double-blind, double-simulation period (fig. 11). The incidence of serious adverse events was similar between treatment groups. Serious AEs in 4 of the 7 participants treated with ND0612 were relevant to study treatment (infusion site abscess and infusion site ulcer; infusion site cellulitis [2 participants ]; paresthesia and peripheral sensorimotor neuropathy). One participant in the ND0612 group caused death during the double-blind period due to AE assessed as not relevant to study treatment (traumatic brain injury due to falls).
The rate of discontinuation due to AE was highest during open label ND0612 period (8.1%, n=26), with the most common causes being infusion site nodules (4%), infusion site pain (3%) and infusion site hematomas (3%). During the double blind period, AE caused the discontinuation of 7 (6%) participants in ND0612 group (including 3 causal ISR) and 4 (3%) participants in IR-LD/CD group. In total, 15 participants treated with ND0612 and 1 participant treated with placebo infusion (infusion site abscess) were transferred to the dermatologist throughout the study. 4 (1.2%) participants had polyneuropathy AE adjudicated as ND 0612. Only 1 participant reported severe/severe multiple neuropathy events, and no participant needed discontinuation of treatment due to multiple neuropathy. One participant had a non-severe hypersensitivity event during the open label ND0612 treatment that resolved with antihistamine treatment and ND0612 discontinuation.
No clinically significant changes were observed in laboratory results, vital signs or electrocardiograms for either treatment group. Positive responses based on C-SSRS indicating suicidal ideation or behavior were reported with low and similar incidence throughout the treatment group (6 [5% ] participants in ND0612 group and 6 [5% ] participants in IR-LD/CD group). Based on QUIP-RS data, there was no evidence of impulse control disorder, and one participant reported a tendency to compulsive shopping with ND0612 (fading without treatment modification). The daytime sleepiness rate as assessed by ESS remained low throughout the study and was comparable between treatment groups, and the average score of related sleepiness never exceeded a 10 point threshold. Similarly, the incidence of somnolence in the double blind period reported as AE was 0 in ND0612 group and 2 (1.5%) in the IR-LD/CD group.
Overall, the percentage of patients in the IR-LD/CD group that correctly guessed their treatment assignment (85/131,65%) was higher than the percentage of patients in the ND0612 group that correctly guessed their treatment assignment (63/128,49%), with the most common reasons for correct guessing being related to efficacy (IR-LD/CD, 49/85 [58% ] and ND0612, 53/63 [84% ]). Because of the safety, one participant in the ND0612 group and none of the participants in the IR-LD/CD group correctly guessed their treatment assignments.
Conclusion 381 participants enrolled, of which 259 were randomized in the double blind period (nd0612n=128, ir-LD/cdn=131), and 243 completed the study. At the end of the 12-week double-blind period, treatment with optimized ND0612 provided an additional 1.72 h [95% CI: 1.08, 2.36] open period (p < 0.0001) without troublesome dyskinesias compared to IR-LD/CD. Significant therapeutic differences in favor of ND0612 were also found in graded minor endpoints of daily off-period (-1.4 h < -1.99, -0.80 ]), unified Parkinson disease rating scale II part score (-3.05 < -4.28, -1.81 ]), patient overall change impression (ratio [ OR ]:5.31 [2.67, 10.58 ]) and clinical overall improvement impression (OR: 7.23 [3.57, 14.64 ]). The most adverse events reported were infusion site reactions (82.6% during open label ND0612 optimization and 57.0% for ND0612 during double blind period, 42.7% relative to oral IR-LD/CD), most of which were mild.
Example 7-quality of life with 24 hours subcutaneous L-dopa/carbidopa infusion (ND 0612) PDQ-39 results from a phase 3 randomization, activity control study
The objective was to evaluate quality of life (QoL) data from a phase 3 randomization, active control BouNDless study.
Background key data from the BouNDless study show that treatment with investigational ND0612 provides an additional 1.72h [95% CI: 1.08h, 2.36h ] of open period without troublesome dyskinesia (p < 0.0001) for patients with Parkinson's Disease (PD) and motor fluctuations compared to IR-LD/CD.
Design/method patients with PD who took ≡4 oral LD/CD doses/day (. Gtoreq.400 mg/day LD) and experienced a daily off period of ≡2.5 hours underwent 4-6 weeks of open label IR-LD/CD dose adjustment followed by 4-6 weeks of open label ND0612 conversion (+IR-LD/CD). Patients were then randomized (1:1) to 12 week double-blind treatment with their optimized ND0612 regimen or IR-LD/CD regimen. The change in QoL from the start of the open label ND0612 transition to the end of double-blind treatment was evaluated using PD questionnaire-39 (PDQ-39) and analyzed using ANCOVA after multiple interpolation.
The result is that at the end of the double blind period, the adjusted mean [95% CI ] change in PDQ-39 index score shows an improvement (-2.1 (-3.7, -0.6 ]) with ND0612 treatment compared to no change (+0.6 (-0.9, 2.1 ]) in the IR-LD/CD group, resulting in a treatment difference of-2.7 (-4.8, -0.6] (nominal p=0.014). PDQ-39 Domain analysis supports ND0612 treatment in most domains, average changes (ND 0612 versus IR-LD/CD) are motor capacity (-0.2 versus +2.4), physical discomfort (-4.3 versus-2.3), cognition (-0.9 versus-0.3), daily activities (-0.6 versus-0.1), photophobia (-2.6 versus-2.4), social support (0.4 versus 0.7), communication (2.3 versus-0.4), and emotional well-being (0.6 versus-1.3).
Note that the data in example 7 was from the first dose ND0612 (V7, exploratory analysis from ND0612 open tag transition start to end of DBDD periods), while the data in example 6 was from randomization (V13) to end of DBDD periods. Thus, although the treatment differences were the same (-2.7) in the two examples, the results were different.
Conclusion ND0612 improves the quality of life as measured by PDQ-39 compared to IR-LD/CD, further supporting the clinical significance of reduced motor fluctuations observed from the PD patient perspective.
EXAMPLE 8-24 Long term efficacy of subcutaneous L-dopa/carbidopa infusion (ND 0612) on motor fluctuations in Parkinson's disease BouNDless open tag expansion
The objective is to describe the 1 year efficacy results from the on-going Open Label Extension (OLE) phase of the subcutaneous levodopa/carbidopa infusion (ND 0612) for the BouNDless study of fluctuating PD patients.
Background it has been previously reported that open label treatment with ND0612 correlates with an increase in the daily open period (good open period) for > 2 hours and a decrease in the closed period without troublesome dyskinesia relative to baseline. The double blind period of the BouNDless study demonstrated that treatment with investigational ND0612 provided patients with a good open period (p < 0.0001) of another 1.72 h compared to immediate release levodopa/carbidopa (IR-LD/CD). Method patients in the double blind phase who completed BouNDless study were eligible to enter the on-going OLE phase (up to 54 months). The patient received ND0612 and adjusted all anti-PD drugs (including ND 0612) based on the individual response. The analysis was performed 6 months and 1 year after the last patient entered OLE. The change in the off period measured from the ND0612 in the key study lead-in period to the 6 th and 12 th months of the OLE period, the open period without movement disorder, the open period with non-troublesome movement disorder and the open period with troublesome movement disorder was normalized to 16 h and analyzed without interpolation. The subgroup analysis for patients with troublesome dyskinesia at the beginning of treatment with a change in the period of onset of troublesome dyskinesia was accompanied by ≡1 h.
As a result, of the 232 participants entering OLE (n=113 were previously randomized to ND0612, n=119 were previously randomized to IR-LD/CD), 167 (72%) completed ND0612 treatment for 1 year in OLE. By month 6, the patient had mean ± SE changes with a period of-2.2 ± 0.2h and a good period of +2.4 ± 0.2h (an period of +2.7 ± 0.2h without dyskinesia and an period of-0.3 ± 0.2h with non-troublesome dyskinesia). Efficacy benefits persist until month 12, where the change in off period is-2.1±0.2 hours, and the change in good on period is +2.2±0.2 hours (the change in on period without dyskinesia is +2.3±0.3 hours and the change in on period with non-troublesome dyskinesia is-0.2±0.2 hours). Patients with an open period with troublesome dyskinesia of ≡1h at the beginning of ND0612 (n=45) showed a change of-1.2±0.3h at month 6 and-1.5±0.3h at month 12.
Conclusion the results confirm previously published data on the long term efficacy of ND0612 on PD patients experiencing motor fluctuations.
Example 9-24 hours influence of subcutaneous Levodopa/carbidopa infusion (ND 0612) on the transition of the motion state throughout the day
The objective was to evaluate the effect of a study ND0612 infusion on the number of daily PD motor states, duration of PD motor states and transitions between PD motor states, as assessed by a home diary.
Background major efficacy analysis (without troublesome dyskinesia open period) demonstrated that ND0612 was superior to immediate release levodopa/carbidopa (IR-LD/CD), with a significant difference of 1.72h (p < 0.0001).
Design/methods post hoc analysis of diary data from BouNDless studies. The number and duration of episodes (episode) spent in the off-state, the open period without movement disorder, the open period with non-troublesome movement disorder, and the open period with troublesome movement disorder (collected the last day before each visit) were descriptive analyzed. Episodes are defined as the time spent in the PD-diary state before transitioning to any other state. The total number of transitions between any motion states is analyzed by poisson regression (Poisson Regression) with baseline adjustment.
As a result, the state of motion characteristics between the ND0612 group and the IR-LD/CD group are balanced before the ND0612 starts (i.e., during the lead-in period). At the end of the double blind period, the ND0612 group experienced an average of 2.4 versus 3.3 off-period episodes per day relative to the patients in the IR-LD/CD group, with a daily overall off-period duration of 3.8 h versus 5.2 h. Participants (ND 0612 versus IR-LD/CD) experienced 2.7 versus 3.1 open episodes with no dyskinesia (total duration 9.4 h versus 7.4 h), 1.2 versus 1.4 open episodes with non-troublesome dyskinesia (total duration 2.2 h versus 2.7 h), and 0.3 versus 0.5 open episodes with troublesome dyskinesia (total duration 0.4 h versus 0.7 h). The average daily number of transitions between exercise states with ND0612 was lower compared to IR-LD/CD treatment (5.7 versus 7.3, p < 0.0001).
It was concluded that treatment with ND0612 resulted in more stable motor control relative to IR-LD/CD, as evidenced by fewer daily transitions between motor states and by more time of open-phase states without any motor impairment.
Example 10-dopaminergic adverse events with 24 hour subcutaneous infusion of ND0612
The objective was to characterize adverse events (TEAE) occurring in dopaminergic treatments reported in clinical studies with 24h ND0612 treatment.
Background dopaminergic adverse events are typically reported throughout the range of available dopaminergic therapies for PD. ND0612 is a investigational continuous 24h subcutaneous infusion of levodopa/carbidopa (720 mg/90 mg daily maximum dose) developed to manage PD movement fluctuations.
Method A comprehensive safety analysis was performed on the reported dopaminergic TEAE in PD patients treated with ND0612 for 24h regimen and supplemented immediate release levodopa/carbidopa from both phase 2 and one phase 3 study. Selected dopaminergic TEAEs of interest to the population include dizziness, nausea, vomiting, dyskinesia, hallucinations (group term), impulse control disorders (ICD, group term), orthostatic hypotension, sleep disorders and somnolence. The incidence of Exposure Adjustment (EAIR) is calculated as the total number of patients experiencing TEAE divided by the total time (person-year) that the patient is at risk for the event.
As a result, a total of 419 patients (528.8 person-year, median exposure of ND0612 of 346 days [ up to 6.6 years ]) were included in the analysis. The most common dopaminergic TEAE (% patient; EAIR) is dyskinesia (13.1%; 0.114). Other dopaminergic TEAEs were reported in less than 5% of patients for dizziness (4.3%; 0.035), hallucinations (3.8%; 0.031), orthostatic hypotension (3.6%; 0.029), nausea (2.9%; 0.023), somnolence (1.4%; 0.011), unspecified sleep disorders (1.2%; 0.010), and ICD (1.2%; 0.010). Vomiting, nightmare and REM sleep disturbance (less than or equal to 0.7%; 0.006) were reported in less than or equal to 3 patients, respectively.
Conclusion 24 hours continuous subcutaneous administration of ND0612 demonstrated overall tolerability and low incidence of dopaminergic adverse events.
Equivalent(s)
While specific embodiments of the subject invention have been discussed, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification and such variations.
Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". It should be noted that where a particular value is described in the specification and claims, unless otherwise indicated, the term "about" means an acceptable range of error, e.g., up to 5% or 10%, that should be assumed for the particular value.
Incorporated by reference
The entire contents of all patents, published patent applications, websites, and other references cited herein are hereby expressly incorporated by reference in their entirety.

Claims (52)

1. A method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa, carbidopa and arginine substantially continuously for about 24 hours/day,
Wherein the pharmaceutically acceptable liquid composition comprises about 60 mg/mL of levodopa and 7.5. 7.5 mg/mL of carbidopa, and wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over a course of about 24 hours,
Wherein after 2 or 3 days of administration, the patient has at least one of:
an increase in the daily good open period relative to baseline,
A decrease in the daily open period with moderate-severe dyskinesia relative to baseline,
Or any combination thereof.
2. The method according to claim 1, wherein:
The increase in daily good open period relative to baseline is an increase in daily good open period relative to baseline of at least about 0.3 hours to 3.5 hours, and
The decrease in the daily open period with moderate-to-severe movement disorder relative to baseline is a decrease in the daily open period with moderate-to-severe movement disorder relative to baseline of at least about 0.3 hours to 2.5 hours.
3. The method of claim 1, wherein the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
4. The method of claim 1, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
5. The method of claim 4, wherein the low active night rate is administered for about 6 hours or about 8 hours and the high active daytime rate is administered for about 18 hours or about 16 hours, respectively.
6. The method of claim 4, wherein the low activity night time rate is about 0.08 mL/hour.
7. The method of claim 4, wherein the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
8. A method of increasing the good onset of a patient suffering from parkinson's disease, the method comprising
Substantially continuously for about 24 hours/day for about 2 to 3 consecutive days, subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w,
Wherein by the third consecutive day, the administration results in an increase in the daily good open period of at least about 0.3 hours to 3.5 hours relative to baseline.
9. The method of claim 8, wherein the administration results in an increase in daily good open time relative to baseline of about 1.8 hours.
10. The method of claim 8, wherein the pharmaceutically acceptable liquid composition further comprises arginine.
11. The method of claim 8, wherein the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa.
12. The method of claim 8, wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
13. The method of claim 8, wherein the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
14. The method of claim 8, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
15. The method of claim 14, wherein the low active night rate is administered for about 6 hours and the high active daytime rate is administered for about 18 hours.
16. The method of claim 14, wherein the low activity night time rate is about 0.08 mL/hour.
17. The method of claim 14, wherein the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
18. A method of ameliorating at least one symptom of Parkinson's disease in a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w for a substantially continuous period of about 24 hours/day,
Wherein the administration results in the patient having at least one of:
without the troublesome increase of the daily opening period of dyskinesia,
A decrease in the daily period of closure,
As assessed by the unified parkinsonism rating scale (UPDRS) part II score revision, improvement in the exercise experience of everyday life, resulting in a decrease in UPDRS part II score,
Based on the improvement in patient global change impression (PGI-C) scores,
Based on the improvement of the clinical overall improvement impression (CGI-I) score,
Or any combination thereof,
Wherein the improvement in said patient is measured as compared to a patient treated with an immediate release oral dosage form of levodopa, and
Wherein the patient is improved in:
The improvement in the daily open period without troublesome dyskinesia is an increase of about 1.7 hours in the daily open period without troublesome dyskinesia,
The improvement in daily off-period is a reduction of about 1.4 hours per daily off-period,
The improvement in daily exercise experience as assessed by UPDRS part II score was a drop of about 3.0,
The improvement in patient global change impression (PGI-C) score was a ratio of about 5.3, and
The improvement in clinical overall improvement impression (CGI-I) score was a ratio of ratios of about 7.2.
19. The method of claim 18, wherein the pharmaceutically acceptable liquid composition further comprises arginine.
20. The method of claim 18, wherein the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa.
21. The method of claim 18, wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
22. The method of claim 18, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
23. The method of claim 22, wherein the low active night rate is administered for about 6 hours or about 8 hours and the high active daytime rate is administered for about 18 hours or about 16 hours, respectively,
Wherein the low activity night time rate is about 0.08 mL/hour, and
Wherein the high active daytime rate is about 0.64 mL/hr, about 0.59 mL/hr, about 0.55 mL/hr, about 0.50 mL/hr, about 0.45 mL/hr, about 0.41 mL/hr, about 0.36 mL/hr, or about 0.32 mL/hr.
24. A method of treating a patient suffering from parkinson's disease, said method comprising subcutaneously administering to said patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w and further comprising arginine, substantially continuously for about 24 hours/day and for about 2 to 3 consecutive days,
Wherein by day 3, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline of at least about 0.3 to 3.5,
A decrease in the daily open period associated with moderate-to-severe movement disorders from baseline of at least about 0.3 hours to 2.5 hours,
A decrease in daily off period from baseline of at least 0.1 to 2.0,
An increase in the daily open period relative to baseline of at least about 0.1 to 3.5 without concomitant movement disorder,
A reduction of the daily total troublesome dyskinesia by at least 0.1 to 3.2 relative to baseline,
As assessed by the unified parkinsonism rating scale part III (UPDRS part III) score revision advocated by the dyskinesia association, improvement in daily life exercise experience over baseline, resulting in a decrease in UPDRS part III score of about 2 to 13 points relative to baseline,
Or any combination thereof.
25. The method of claim 24, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient via a device comprising a control station, a reusable component, and a disposable component.
26. The method of claim 24, wherein the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa.
27. The method of claim 24, wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
28. The method of claim 24, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over the course of 24 hours at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
29. The method of claim 28, wherein the low active night rate is administered for about 6 hours and the high active daytime rate is administered for about 18 hours.
30. The method of claim 28, wherein the low active night time rate is about 0.08 mL/hour, and wherein the high active day rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
31. The method of claim 28, wherein the patient is fully open after about 5 hours of administration at the first flow rate.
32. The method of claim 24, wherein the patient has an improvement in sleep quality over baseline after two days of treatment.
33. A method of treating a patient suffering from Parkinson's disease, the method comprising subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, and arginine substantially continuously for about 24 hours/day and for about 2 to 3 consecutive days,
Wherein the pharmaceutically acceptable liquid composition comprises about 60 mg/mL of levodopa and 7.5. 7.5 mg/mL of carbidopa, and wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over a course of about 24 hours,
Wherein by day 3, the administration results in the patient having at least one of:
an increase in the daily good open period relative to baseline of at least about 0.3 to 3.5,
A decrease in the daily open period associated with moderate-to-severe movement disorders from baseline of at least about 0.3 hours to 2.5 hours,
A decrease in daily off period from baseline of at least 0.1 to 2.0,
An increase in the daily open period relative to baseline of at least about 0.1 to 3.5 without concomitant movement disorder,
A reduction of the daily total troublesome dyskinesia by at least 0.1 to 3.2 relative to baseline,
The UPDRS part III score decreases from about 2 points to 13 points relative to baseline,
Or any combination thereof.
34. The method of claim 33, wherein the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
35. The method of claim 33, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient via a device comprising a control station, a reusable component, and a disposable component.
36. The method of claim 33, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
37. The method of claim 33, wherein the low active night rate is administered for about 6 hours or about 8 hours and the high active daytime rate is administered for about 18 hours or about 16 hours, respectively.
38. The method of claim 37, wherein the low active night time rate is about 0.08 mL/hour, and wherein the high active day rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
39. The method of claim 37, wherein the patient is fully open after about 5 hours of administration at the first flow rate.
40. The method of claim 33, wherein the patient has an improvement in sleep quality over baseline after two days of treatment.
41. A method of increasing the good onset of a patient suffering from parkinson's disease, the method comprising
Subcutaneously administering to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in a ratio of about 8:1 w/w and further comprising arginine, substantially continuously for about 24 hours/day for about 2 to 3 consecutive days,
Wherein by day 3, the administration results in an increase in the daily good open period of at least about 0.3 hours to 3.5 hours relative to baseline.
42. The method of claim 41, wherein the administration results in an increase in daily good open time relative to baseline of about 1.8 hours.
43. The method of claim 41, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient via a device comprising a control station, a reusable component, and a disposable component.
44. The method of claim 41, wherein the pharmaceutically acceptable liquid composition comprises 7.5 mg/mL carbidopa and 60 mg/mL levodopa.
45. The method of claim 41, wherein the pharmaceutically acceptable liquid composition is administered to deliver about 720 mg levodopa and about 90 mg carbidopa to the patient over the course of about 24 hours.
46. The method of claim 41, wherein the method further comprises administering to the patient at least one pharmaceutically acceptable oral composition comprising levodopa prior to or during the subcutaneous infusion time course.
47. The method of claim 41, wherein the pharmaceutically acceptable liquid composition is administered subcutaneously to the patient over a 24 hour period at a first flow rate and a second flow rate, wherein the first flow rate is a high activity rate for daytime hours and the second flow rate is a low activity rate for nighttime hours.
48. The method of claim 47, wherein the low active night time rate is administered for about 6 hours and the high active day rate is administered for about 18 hours.
49. The method of claim 47, wherein the low activity night time rate is about 0.08 mL/hour.
50. The method of claim 47, wherein the high active daytime rate is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55 mL/hour, about 0.50 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour, about 0.36 mL/hour, or about 0.32 mL/hour.
51. The method of claim 47, wherein the patient is fully open after about 5 hours of administration at the first flow rate.
52. The method of claim 41, wherein the patient has an improvement in sleep quality over baseline after two days of treatment.
CN202480025472.4A 2023-04-14 2024-04-14 Methods and compositions for alleviating symptoms of parkinson's disease Pending CN120936350A (en)

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