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WO2025022362A1 - Compositions et méthodes de traitement de la dyskinésie - Google Patents

Compositions et méthodes de traitement de la dyskinésie Download PDF

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Publication number
WO2025022362A1
WO2025022362A1 PCT/IB2024/057253 IB2024057253W WO2025022362A1 WO 2025022362 A1 WO2025022362 A1 WO 2025022362A1 IB 2024057253 W IB2024057253 W IB 2024057253W WO 2025022362 A1 WO2025022362 A1 WO 2025022362A1
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composition
pharmaceutically acceptable
acceptable salt
acylethanolamine
pharmaceutical composition
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Adi Zuloff-Shani
Ezekiel Golan
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Clearmind Medicine Inc
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Clearmind Medicine Inc
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/0043—Nose
    • 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

Definitions

  • Dyskinesias are characterized by the development in a subject of abnormal involuntary movements and may manifest as chorea (irregular, involuntary movements of the body, especially the face and extremities) or dystonia (disorder or lack of muscle tonicity). Dyskinesia can be tardive or acute.
  • Tardive dyskinesia is a chronic disorder of the nervous system, characterized by involuntary, irregular rhythmic movements of the mouth, tongue, and facial muscles. The upper extremities also may be involved. These movements may be accompanied, to a variable extent, by other involuntary movements and movement disorders.
  • TD cases include rocking, writhing, or twisting movements of the trunk (tardive dystonia), forcible eye closure (tardive blepharospasm), an irresistible impulse to move continually (tardive akathisia), jerking movements of the neck (tardive spasmodic torticollis), and disrupted respiratory movements (respiratory dyskinesia).
  • antipsychotic drugs neuroroleptics
  • metoclopramide that, like neuroleptics, block dopamine receptors. TD often manifests or worsens in severity after neuroleptic drug therapy is discontinued.
  • TD affects approximately 15-20% of patients treated with neuroleptic drugs (Khot et al., Neuroleptics and Classic Tardive Dyskinesia, in Lang A E, Weiner W J (eds.): Drug Induced Movement Disorders, Futura Publishing Co., 1992, pp.121-166).
  • the cumulative incidence of TD is substantially higher in women, in older people, and in those being treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (see, e.g., Hayashi et al., Clin. Neuropharmacol, 19:390, 1996; Jeste et al., Arch. Gen.
  • TD does not respond in general to antiparkinsonian drugs (Decker et al., New Eng. J. Med., October 7, p.861, 1971).
  • TD is also associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol. Med.26:681, 1996; Swartz, Neuropsychobiology, 32:115, 1995).
  • the cognitive impairment associated with TD usually is seen as a marker of underlying differences in brain function that predispose the patient to TD. However, it may also be due to the TD itself, and may be either irreversible, or partially reversible if the TD is successfully treated. [7]
  • the pathophysiology of TD has not been established definitively. It is well known that blockade of dopamine receptors will lead to an increased number of dopamine receptors, and therefore to an increased sensitivity to dopamine of striatal neurons (see, e.g., Andrews, Can J Psych 39:576, 1994; Casey, in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995).
  • TD was the result of this hypersensitivity of striatal neurons to dopamine.
  • dopamine supersensitivity it is noted that dopamine agonists can aggravate the disorder (Bezchibnyk-Butler & Remington, Can J. Psych., 39:74, 1994).
  • the dopamine supersensitivity hypothesis is not compatible with the observation that TD and Parkinsonism (a dopamine deficiency state) infrequently exist together in the same patient.
  • Other studies have suggested that irreversible cases of TD may be related to excitotoxic damage to the basal ganglia (Andreassen & Jorgensen, Pharmacol. Biochem.
  • TD patients with TD can show chorea (quick, irregular movements of the extremities) indistinguishable from that seen in cases of Huntington's disease. Neck, trunk and limb movements of TD can be indistinguishable from those of the “peak-dose dyskinesia” associated with prolonged treatment of Parkinson’s disease with levodopa.
  • Vitamin E can reduce symptoms of TD modestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri et al. Am. J. Psychiatry, June, 151(6):925-926, 1994).
  • GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD, probably because their low toxicity justifies their use despite their limited efficacy.
  • GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD, probably because their low toxicity justifies their use despite their limited efficacy.
  • This review only cited reports of variable benefits associated with other agents including propranolol, clonidine, cholinergic agonists, buspirone and calcium-channel antagonists. However, none of these has become a generally accepted treatment for either the movement or cognitive disorders associated with TD. [12] U.S. Pat.
  • No.5,602,150 proposes that co-administration of taurine or taurine derivatives together with neuroleptics, might prevent the emergence of tardive movement disorders, on the theory that the latter are due to excitotoxic damage against which taurine would protect.
  • the recommendation of taurine is based on studies in a single animal model. The experiments reported do not deal with any therapeutic effects of taurine on established movements, either in the presence of continued neuroleptic therapy or otherwise. Neither the patent nor the experiments cited in it predict or imply that taurine or derivatives will be beneficial for established movement disorders.
  • Medications for treating tardive dyskinesia such as Valbenazine, have been known to have side effects including sleepiness and depression. These in turn have been observed to frequently cause more patients to discontinue treatment.
  • 3-Methylmethcathinone (3MMC) inhibits norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters.
  • NET norepinephrine
  • SERT serotonin
  • DAT dopamine
  • the chemical structure of 3MMC is: of , appreciation of music and awareness of senses. Higher doses of 3-MMC may cause anxiety, altered vision, sweating, insomnia, dizziness, confusion, loss of coordination, and convulsions.
  • these side-effects may surprisingly be reduced and/or controlled when selected doses and regimens disclosed herein for treating patients with symptoms associated with dyskinesia.
  • N-acylethanolamines are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is linked to the nitrogen atom of ethanolamine.
  • Examples of N-acylethanolamines include anandamide (the amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-Palmitoylethanolamine (the amide of palmitic acid (16:0) and ethanolamine), N-Oleoylethanolamine (the amide of oleic acid (18:1) and ethanolamine), N-Stearoylethanolamine (the amide of stearic acid (18:0) and ethanolamine) and N-Docosahexaenoylethanolamine (the amide of docosahexaenoic acid (22:6) and ethanolamine).
  • anandamide the amide of arachidonic acid (20:4 omega-6) and ethanolamine
  • N-Palmitoylethanolamine the amide of palmitic acid (16:0) and ethanolamine
  • Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl) hexadecanamide; Hydroxyethylpalmitamide; palmidrol; N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists.
  • the chemical structure of PEA is: .
  • PEA has been demonstrated to bind to a receptor in the and exerts a variety of biological functions related to chronic pain and inflammation. Studies have shown that PEA interacts with distinct non- CB1/CB2 receptors, suggesting that PEA utilizes a unique “parallel” endocannabinoid signaling system.
  • PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation.
  • Much of the biological effects of PEA on cells can be attributed to its affinity to peroxisome proliferator-activated receptor (PPAR), particularly PPAR-alpha and Attorney Docket No.: 15691.0016-00304 PPAR-gamma.
  • PPAR peroxisome proliferator-activated receptor
  • TRPV1 transient receptor potential vanilloid type 1 receptor
  • PEA has been shown to have anti-inflammatory, anti-nociceptive, neuro-protective, and anti-convulsant properties.
  • the present disclosure provides for using safe and effective specific dosages and dose ranges of 3-MMC or salts thereof to prevent and/or treat dyskinesia or one or more symptoms of dyskinesia, either alone or in conjunction with one or more additional therapeutic agent such as PEA or a salt thereof.
  • the disclosure also encompasses using safe and effective combinations with N-acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”), to prevent and/or treat dyskinesia or one or more symptoms of dyskinesia.
  • PDA palmitoylethanolamide
  • the present disclosure provides pharmaceutical compositions comprising 3MMC, or pharmaceutically acceptable salts thereof, and their use in preventing and/or treating dyskinesia, or for reducing one or more symptoms of dyskinesia.
  • the disclosure further provides pharmaceutical compositions comprising 3MMC, or pharmaceutically acceptable salts thereof, or combinations of 3MMC, or pharmaceutically acceptable salts thereof and N- acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”) for use in the same treatments.
  • PDA palmitoylethanolamide
  • the present disclosure relates to methods for corrective prevention and/or treatment of antipsychotic-induced dyskinesia or any other indication amenable to treatment of dyskinesia, including, but not limited to tardive dyskinesia [19]
  • the present disclosure relates, in part, to compositions and methods for potentiating therapeutic effects and/or reducing side-effects of 3-MMC or pharmaceutically acceptable salts thereof.
  • the present disclosure provides pharmaceutical compositions comprising 3-MMC, or pharmaceutically acceptable salts thereof, or combinations of 3-MMC, or pharmaceutically acceptable salts thereof, for example, PEA and methods for their use in a variety of indications amenable to treatment, including, but not limited to treating dyskinesias such as tardive dyskinesia.
  • the present disclosure encompasses pharmaceutical compositions comprising combinations of 3MMC, or salts thereof, and N-acylethanolamines, or salts thereof for use in a method for preventing and/or treating dyskinesia, or for reducing one or more symptoms of dyskinesia.
  • the N-acylethanolamine or salt Attorney Docket No.: 15691.0016-00304 thereof is PEA or a salt thereof.
  • these compositions comprise therapeutically effective dosages and may be employed in a variety of methods.
  • the present disclosure provides methods for preventing and/or treating dyskinesia. Particularly, the present disclosure provides methods for treating tardive dyskinesia.
  • the present disclosure provides, in one aspect, a composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier, for use in preventing tardive dyskinesia in a subject in need, or for treating, preventing and/or reducing one or more symptoms of tardive dyskinesia.
  • a composition comprising a therapeutically effective amount of 3MMC or a salt thereof, a therapeutically effective amount of PEA, or a salt thereof, and at least one pharmaceutically acceptable carrier, for use in treating tardive dyskinesia in a subject in need, or for treating and/or reducing one or more symptoms of tardive dyskinesia.
  • the present disclosure provides, in another aspect, a nasal spray formulation comprising a therapeutically effective amount of 3MMC or a salt thereof and at least one pharmaceutically acceptable carrier for use in treating tardive dyskinesia in a subject in need thereof.
  • the nasal spray formulation may be self-delivered by the patient.
  • the spray further comprises an N-acylethanolamine such as PEA, or a salt thereof.
  • the present disclosure provides, in one aspect, a composition comprising 3MMC, or salts thereof, and N-acylethanolamines, or salts thereof for use in preventing tardive dyskinesia in a subject in need, or for preventing and/or reducing one or more symptoms of tardive dyskinesia.
  • the present disclosure provides, in one aspect, a composition comprising combinations of 3MMC, or salts thereof, and N-acylethanolamines, or salts thereof, for use in treating tardive dyskinesia in a subject in need, or for treating and/or reducing one or more symptoms of tardive dyskinesia.
  • the present disclosure provides, in one aspect, a method of treating or improving at least one symptom associated with dyskinesia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof.
  • 3-MMC 3-Methylmethcathinone
  • the present disclosure provides, in one aspect, a method of treating or improving at least one symptom associated with dyskinesia, comprising administering to a subject Attorney Docket No.: 15691.0016-00304 in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides pharmaceutical compositions comprising 3MMC, or pharmaceutically acceptable salts thereof, e.g., for compositions for preventing and/or treating dyskinesia, or for reducing one or more symptoms of dyskinesia.
  • the present disclosure relates to methods of using the pharmaceutical compositions for corrective treatment of medication-induced dyskinesia. In some embodiments, the present disclosure relates to methods of using the pharmaceutical compositions for corrective treatment of antipsychotic-induced dyskinesia.
  • the formulations and compositions disclosed herein may comprise 3MMC or any pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the salt is 2- (methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride.
  • the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt.
  • pharmaceutical compositions of the present disclosure comprising 3MMC or a salt thereof is formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, intravenous, topical, and/or aerosol administration.
  • the present disclosure provides the composition in the form of a nasal spray comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof.
  • the nasal spray may be self-delivered by the patient.
  • the present disclosure provides an oral composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof.
  • the present disclosure provides an intravenous composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof.
  • the present disclosure provides a topical composition
  • a topical composition comprising a therapeutically Attorney Docket No.: 15691.0016-00304 effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof.
  • 3MMC or a pharmaceutically acceptable salt thereof is present in a composition (e.g., one that is administered to a subject) in an amount of about 0.1 mg to about 150 mg.
  • the 3MMC or the pharmaceutically acceptable salt thereof is administered to said subject in an amount (a dose) of about 0.5 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, or 270 mg.
  • a dose of about 0.5 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3 mg, 5 mg, 10
  • the dose is 50 mg. In some embodiments, the dose ranges from about 60 mg to 260 mg.
  • the pharmaceutical composition comprises a unit dose of 3MMC or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutical composition is a solid form composition. In some embodiments, the pharmaceutical composition is a gel. In still other embodiments, the pharmaceutical composition is a liquid form composition. [35] In additional embodiments, the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses. In some embodiments, the unit dose is in a composition formulated for nasal or oral administration. In certain embodiments, the dosage unit is formulated as a gel, a powder or a spray.
  • the dosage unit is formulated as a liquid. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray. [36] In some embodiments, the pharmaceutical composition is present in a unit dosage form ranging from 20 mg to 1000 mg of 3MMC or pharmaceutically acceptable salt thereof. In some embodiments, the amount of 3MMC, or pharmaceutically acceptable salt thereof, in the unit dosage form ranges from about 20 mg to about 300 mg. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 to about 1000 mg 3MMC or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a unit dose of about 20 mg 3MMC or a pharmaceutically acceptable salt thereof.
  • the Attorney Docket No.: 15691.0016-00304 3MMC or pharmaceutically acceptable salt thereof is in a unit dosage form of 50 mg.
  • the pharmaceutical composition comprises a unit dose of about 25 mg, about 35 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg 3MMC or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg to about 10 mg/kg body weight.
  • the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 to about 0.5 mg/kg, about 0.5 to about 1.0 mg/kg, about 1.0 to about 1.5 mg/kg, about 1.5 to about 2.0 mg/kg, about 2.0 mg/kg to about 2.5 mg/kg, about 2.5 mg/kg to about 3.0 mg/kg, about 3.5 mg/kg to about 4.0 mg/kg, about 4.0 mg/kg to about 4.5 mg/kg, about 4.5 mg/kg to about 5.0 mg/kg, about 5.0 mg/kg to about 5.5 mg/kg body weight, about 5.5 mg/kg to about 6.0 mg/kg, about 6.5 mg/kg to about 7.0 mg/kg, about 7.0 mg/kg to about 7.5 mg/kg, about 7.5 mg/kg
  • the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 mg/kg, about 4.5 mg/kg, or about 5.0 mg/kg bodyweight.
  • the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.5 mg/kg, less than about 0.5 mg/kg, less than about 1.0 mg/kg, less than about 1.5 mg/kg, less than about 2.0 mg/kg, less than about 2.5 mg/kg, less than about 3.0 mg/kg, less than about 3.5 mg/kg, less than about 4.0 mg/kg, less than about 4.5 mg/kg, less than about 5.0 mg/kg, less than about 5.5 mg/kg, less than about 6.0 mg/kg, less than about 6.5 mg/kg, less than about 7.0 mg/kg, less than about 7.5 mg/kg, less than about 8.0 mg/kg, less than about 8.5 Attorney Docket No.: 15691.0016-00304 mg/kg, less than about 9.0 mg/kg, less than about 9.5 mg/kg, or about 10.0 mg/kg bodyweight.
  • the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg to about 0.5 mg/kg, about 0.2 mg/kg to about 1.0 mg/kg, about 0.2 mg/kg to about 1.5 mg/kg, about 0.2 mg to about 2.0 mg/kg, about 0.2 mg/kg to about 2.5 mg/kg, about 0.2 mg/kg to about 3.0 mg/kg, about 0.2 mg/kg to about 3.5 mg/kg, about 0.2 mg/kg to about 4.0 mg/kg, about 0.2 mg/kg to about 4.5 mg/kg, about 0.2 mg/kg to about 5.0 mg/kg, about 0.2 mg/kg to about 5.5 mg/kg, about 0.2 mg/kg to about 6.0 mg/kg, about 0.2 mg/kg to about 6.5 mg/kg, about 0.2 mg/kg to about 7.0 mg/kg, about 0.2 mg/kg to about 7.5 mg/kg, about
  • the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg to 0.5 mg/kg, 0.2 mg/kg to 1.0 mg/kg, 0.2 mg/kg to 1.5 mg/kg, 0.2 mg/kg to 2.0 mg/kg, 0.2 mg/kg to 2.5 mg/kg, 0.2 mg/kg to 3.0 mg/kg, 0.2 mg/kg to 3.5 mg/kg, 0.2 mg/kg to 4.0 mg/kg, 0.2 mg/kg to 4.5 mg/kg, 0.2 mg/kg to 5.0 mg/kg, 0.2 mg/kg to 5.5 mg/kg, 0.2 mg/kg to 6.0 mg/kg, 0.2 mg/kg to 6.5 mg/kg, 0.2 mg/kg to 7.0 mg/kg, 0.2 mg/kg to 7.5 mg/kg, 0.2 mg/kg to 8.0 mg/kg, 0.2 mg/kg to 8.5 mg/kg, 0.2 mg/kg
  • the composition is suitable for administration orally. In some embodiments, the composition is suitable for administration in a nasal spray. In some embodiments, the pharmaceutical composition comprising 3MMC or a pharmaceutically acceptable salt thereof is a solid or liquid form composition. In some embodiments, the pharmaceutical composition comprising 3MMC or a pharmaceutically acceptable salt thereof is a nasal spray composition. [41] In some embodiments, 3MMC or a pharmaceutically acceptable salt thereof forms a part of a composition which further comprises a pharmaceutically acceptable carrier. Any pharmaceutically suitable carrier may be used. In some Attorney Docket No.: 15691.0016-00304 embodiments, the composition comprises the 3MMC dissolved in saline.
  • the saline comprises a 0.9 wt % aqueous sodium chloride solution.
  • the 3MMC dissolved in a pharmaceutically acceptable carrier, e.g., saline is in a concentration of 5 x 10 5 nM to 20 x 10 5 nM. In some embodiments, the 3MMC is in a concentration of 7.22 x 10 5 nM to 19.26 x 10 5 nM. In some embodiments, the 3MMC is in a concentration of 14.43 x 105 nM.
  • a nasal spray is provided, which is capable of providing sprayed droplets with a size distribution measured by D10, D50, and D90 volume diameter percentiles, wherein D(x) represents that x% of particles in the size distribution are smaller than a specific particle size.
  • the D values may be expressed as 10%, 50% and 90% of the cumulative volume in a sample respectively.
  • the size distribution of the spray droplets may also be measured by a SPAN number, which is reported as (D90 ⁇ D10)/D50).
  • the nasal spray is capable of providing sprayed droplets with a size distribution having a D10 ranging from about 0.5 ⁇ m to about 6 ⁇ m.
  • the nasal spray may provide sprayed droplets with a size distribution having a D10 of 0.6 ⁇ m, a D50 of 2.3 ⁇ m, a D90 of 5.2 ⁇ m, a SPAN of not more than 2.0, and a % Volume of ⁇ 5.2 ⁇ m of less than 25 V%, said formulation having a viscosity of 1.1 cps.
  • the droplets are produced by a nasal spray device capable of providing a droplet having a size distribution D50 between 30-70 ⁇ m, and a D90 ⁇ 200 ⁇ m.
  • the droplet size distribution has a D90 >10 ⁇ m in diameter during administration.
  • the droplet size distribution has a D10 from about 5 ⁇ m to about 40 ⁇ m during administration. In some embodiments, the droplet size distribution has a D50 from about 20 ⁇ m to 80 ⁇ m during administration. In some embodiments, the droplet size distribution has a D90 from about 50 ⁇ m to 700 ⁇ m during administration.
  • the nasal spray device has a spray plume that has an ovality ratio from about 1.0 to 2.5, wherein the ovality ratio is defined as the ratio of D max (i.e., the longest diameter that passes through the center of gravity (COG) of the spray pattern and extends to the perimeter of the true shape of the spray pattern) to D min (i.e., the shortest diameter that passes through the COG and extends to the perimeter of the true shape of the spray pattern.)
  • the nasal spray device has a spray plume width from about 25 to about 70 mm during administration, wherein the spray plume width is measured as the width of the plume at a given distance (e.g., 3cm) from the spray nozzle, and a spray plume angle from about 15 to about 70 degrees during administration, wherein the spray plume angle is Attorney Docket No.: 15691.0016-00304 measured as the angle of the emitted plume measured from the vertex of the spray cone and spray nozzle.
  • the device may comprise a reservoir and means for expelling the pharmaceutical dose in the form of a spray, wherein a quantity of the pharmaceutical composition is contained within the reservoir.
  • the device comprises a pump spray device in which the means for expelling a single or multiple doses comprises a metering pump, or a sterile single dose disposable device.
  • the dose to be delivered is metered by the spray pump, which is preferably finger or hand-actuated.
  • the device is programmed to dispense one or more pharmaceutical doses.
  • the nasal spray may be designed for discharge of multiple spray doses, e.g., 1 to 10 or more.
  • the spray device may improve penetration of the active into the body without creating undue discomfort.
  • the dimension(s) of the emission hole(s) at the tip of the device spout are such that the liquid emitted comes out in a diffuse spray of small droplets.
  • larger or concentrated droplets may contain enough active to induce an unwanted burning sensation in the inner nose which may lead to an interruption of the treatment.
  • the nasal spray dosing of 3MMC may range from 20 mg/ml to 300 mg/ml. In some embodiments, the nasal spray 3MMC dosing may range from 3 to 10 doses per day. In some embodiments, the nasal spray 3MMC may be administered after an initial oral dose of 3MMC at an earlier point in time during the day.
  • the pharmaceutical compositions discussed above may further comprise one or more additional active agent such as an N- acylethanolamine, or salts thereof. In some embodiments, the 3MMC or a salt thereof and at least one N-acylethanolamine or a salt thereof are packaged in separate units, e.g., vials, within a kit.
  • the 3MMC or a salt thereof and at least one N-acylethanolamine or a salt thereof are in a single vial (e.g., in a single formulation).
  • the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me- PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), salts thereof and any Attorney Docket No.: 15691.0016-00304 combination thereof.
  • the N-acylethanolamine is PEA or a salt thereof.
  • the N-acylethanolamine consists of PEA or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the N- acylethanolamine, e.g., of the PEA is a hydrochloride salt.
  • the salt is 2-(methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride.
  • the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt.
  • a pharmaceutical composition comprising 3MMC comprises about 200-1800 mg of an N-acylethanolamine (e.g., PEA) or a salt thereof.
  • the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N-acylethanolamine or a salt thereof.
  • PEA N-acylethanolamine
  • the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N-acylethanolamine or a salt thereof.
  • the pharmaceutical composition comprises at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg or at least about 1800 mg N-acylethanolamine or a salt thereof.
  • the pharmaceutical composition comprises about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg or about 1800 mg N-acylethanolamine or a salt thereof.
  • Each possibility represents a separate embodiment of the present disclosure.
  • the N-acylethanolamine or pharmaceutically Attorney Docket No.: 15691.0016-00304 acceptable salt thereof, is administered at a dose ranging from about 2.5 mg/kg to 36.0 mg/kg body weight N-acylethanolamine.
  • a pharmaceutical composition disclosed herein comprises a therapeutically-effective amount of 3MMC or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:1 to about 1:120.
  • the N-acylethanolamine is PEA or a salt thereof.
  • the molar ratio between the 3MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof is between about 1:1 to about 1:5. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:7 to about 1:10, about 1:10 to about 1:20, between about 1:15 to about 1:30, between about 1:20 to about 1:40, between about 1:25 to about 1:50, between about 1:30 to about 1:60, between about 1:40 to about 1:75, between about 1:50 to about 1:80, between about 1:60 to about 1:100, between about 1:50 to about 1:100, between about 1:50 to about 1:110, or between about 1:50 to about 1:120.
  • the N-acylethanolamine is PEA or a salt thereof.
  • the molar ratio between the 3MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof is between about 1:7 to about 1:120.
  • the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:7 to about 1:110, about 1:7 to about 1:100, about 1:7 to about 1:90, about 1:7 to about 1:80, about 1:7 to about 1:70, about 1:7 to about 1:60, about 1:7 to about 1:50, about 1:7 to about 1:40, about 1:7 to about 1:30, about 1:7 to about 1:20, about 1:5 to about 1:20, about 1:1 to about 1:20, or about 1:1 to about 1:10.
  • Each possibility represents a separate embodiment of the present disclosure.
  • the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:25 to about 1:120. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:25 to about 1:150, about 1:25 to about 1:140, about 1:25 to about 1:130, about 1:25 to about 1:120, 1:25 to about 1:110, about 1:25 to about 1:100, about 1:25 to about 1:90, about 1:25 to about 1:80, about 1:25 to about 1:70, about 1:25 to about 1:60, about 1:25 to about 1:50, about 1:25 to about 1:40, about 1:25 to about 1:30.
  • the molar ratio between Attorney Docket No.: 15691.0016-00304 the 3MMC and the N-acylethanolamine is between 1:50 to about 1:150, about 1:50 to about 1:140, about 1:50 to about 1:130, about 1:50 to about 1:120, 1:50 to about 1:110, about 1:50 to about 1:100, about 1:50 to about 1:90, about 1:50 to about 1:80, about 1:50 to about 1:70, or about 1:50 to about 1:60.
  • the molar ratio between the 3MMC and the N-acylethanolamine is about 1:75 to about 1:150, about 1:75 to about 1:140, about 1:75 to about 1:130, about 1:75 to about 1:120, 1:75 to about 1:110, about 1:75 to about 1:100, about 1:75 to about 1:90, about 1:75 to about 1:80. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:100 to about 1:150, about 1:100 to about 1:140, about 1:100 to about 1:130, about 1:100 to about 1:120, or 1:100 to about 1:110.
  • the molar ratio between the 3MMC and the N-acylethanolamine is about 1:110 to about 1:150, about 1:110 to about 1:140, about 1:110 to about 1:130, about 1:110 to about 1:120. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:90 to about 1:150, about 1:90 to about 1:140, about 1:90 to about 1:130, about 1:90 to about 1:120, 1:90 to about 1:110, about 1:90 to about 1:100.
  • the molar ratio between the 3MMC and the N-acylethanolamine is about 1:80 to about 1:150, about 1:80 to about 1:140, about 1:80 to about 1:130, about 1:80 to about 1:120, 1:80 to about 1:110, about 1:80 to about 1:100, or about 1:80 to about 1:90.
  • the molar ratio between the 3MMC and the N- acylethanolamine is about 1:40 to about 1:150, about 1:40 to about 1:140, about 1:40 to about 1:130, about 1:40 to about 1:120, 1:40 to about 1:110, about 1:40 to about 1:100, about 1:40 to about 1:90, about 1:40 to about 1:80, about 1:40 to about 1:70, about 1:40 to about 1:60, or about 1:40 to about 1:50.
  • the N- acylethanolamine is PEA or a salt thereof.
  • the N- acylethanolamine increases the therapeutic potency of the 3MMC compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine decreases the required therapeutic dosage of the 3MMC compared to the same pharmaceutical composition without the N- acylethanolamine. In certain embodiments, the N-acylethanolamine expands the therapeutic window of the 3MMC compared to the same pharmaceutical composition without the N-acylethanolamine.
  • formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, vials, syringes, or tablets, each containing a predetermined amount of a compound of the present disclosure as a solid such as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • the formulations of the present disclosure may be prepared by any known techniques of pharmacy for admixing the components. [56]
  • the composition is in the form of a powder, tablet, capsule, lozenge, liquid, concentrate, syrup, hydrogel, aerosol, spray, micelle, nasal spray, or liposome.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • formulations may be prepared by uniformly admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least Attorney Docket No.: 15691.0016-00304 one compound of the present disclosure is moistened with an inert liquid diluent.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such carriers and procedures include those described in the following references: Powell, M.F.
  • Formulations suitable for aerosol administration comprising the pharmaceutical composition disclosed herein include, for example, aqueous and non- aqueous, isotonic sterile solutions, which can contain anti-oxidants, buffers, bacteriostats, and/or solutes, as well as aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and/or preservatives, alone or in combination with other suitable components, which can be made into aerosol formulations to be administered via inhalation.
  • These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • a nasal preparation comprising any of the compositions described in the preceding embodiments can take a variety of forms for administration in nasal drops, nasal spray, gel, ointment, cream, powder or suspension, using a dispenser or other device as needed.
  • dispensers and delivery vehicles are known in the art, including single-dose ampoules, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like. More generally, the preparation can take a solid, semi-solid, or liquid form.
  • a liquid preparation may be administered as a nasal spray or as nasal drops, using devices known in the art, including nebulizers capable of delivering selected volumes of formulations as liquid-droplet aerosols.
  • nebulizers capable of delivering selected volumes of formulations as liquid-droplet aerosols.
  • a commercially available spray pump with a delivery volume of 50 or 100 ⁇ L is available from, for example, Valois (Congers, N.Y.) with spray tips in adult size and pediatric size.
  • the composition comprised of 3MMC via an aerosol spray in a daily volume of between about 10 ml to 100mL.
  • the liquid preparation can be produced by known procedures.
  • an aqueous preparation for nasal administration can be produced by dissolving, suspending, or emulsifying the polypeptide and the steroid compounds in water, buffer, or other aqueous medium, or in an oleaginous base, such as a pharmaceutically-acceptable oil like olive oil, lanoline, silicone oil, glycerin, fatty acids, and the like. It will be appreciated that excipients necessary for formulation, stability, and/or bioavailability can be included in the preparation.
  • excipients include sugars (glucose, sorbitol, mannitol, sucrose), uptake enhancers (chitosan), thickening agents and stability enhancers (celluloses, polyvinyl pyrrolidone, starch, etc.), buffers, preservatives, and/or acids and bases to adjust the pH.
  • the pharmaceutical composition is formulated for systemic administration.
  • the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration.
  • the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of the present disclosure.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for oral mucosal administration.
  • the pharmaceutical composition is formulated for nasal administration.
  • the pharmaceutical composition is formulated for sublingual administration. [63]
  • the formulation comprises a pharmaceutically acceptable salt of a compound disclosed herein.
  • the salt may be an acid addition salt comprising at least one basic (e.g., amine) group of the compound which is in a positively charged form (e.g., an ammonium ion), in combination with at least one counter-ion, derived from the selected acid, that forms a pharmaceutically acceptable salt.
  • a basic (e.g., amine) group of the compound which is in a positively charged form e.g., an ammonium ion
  • at least one counter-ion derived from the selected acid, that forms a pharmaceutically acceptable salt.
  • the acid addition salts may include a variety of organic and inorganic acids, such as, but not limited to, hydrochloric acid which affords a hydrochloric acid addition salt, hydrobromic acid which affords a hydrobromic acid addition salt, acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzenesulfonic acid which affords a besylate addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, citric acid which affords a citric acid addition salt, maleic acid which affords a maleic acid addition Attorney Docket No.: 15691.0016-00304 salt, malic acid which affords a malic acid addition salt, methanesulfonic acid which affords a methanesulfonic acid (mesylate) addition salt, naphthalenesulfonic acid which affords a naphthalenesulfonic acid addition salt, ox
  • a pharmaceutically acceptable salt of a compound disclosed herein may optionally be a base addition salt comprising at least one group of the compound which is in a form of an anion, in combination with at least one counter ion (i.e., cation) that forms a pharmaceutically acceptable salt.
  • suitable cations include metal cations of metals such as, but not limited to, sodium, potassium, magnesium, and calcium or ammonium.
  • Each of these base addition salts can be either a mono-addition salt or a poly-addition salt, as these terms are defined herein.
  • the acid or base additions salts can be either mono-addition salts or poly-addition salts.
  • the phrase “mono-addition salt”, as used herein, refers to a salt in which the stoichiometric ratio between the counter-ion and charged form of the compound is 1:1, such that the addition salt includes one molar equivalent of the counter-ion per one molar equivalent of the compound.
  • poly-addition salt refers to a salt in which the stoichiometric ratio between the counter-ion and the charged form of the compound is greater than 1:1 and is, for example, 2:1, 3:1, 4:1 and so on, such that the addition salt includes two or more molar equivalents of the counter- ion per one molar equivalent of the compound.
  • a compound disclosed herein, including a salt thereof may be in a form of a solvate or a hydrate thereof.
  • solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the 2-aminoindan derivatives described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute.
  • solute the 2-aminoindan derivatives described herein
  • hydrate refers to a solvate where the solvent is water.
  • compositions of the present disclosure may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions that can be used orally include stiff or soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Formulations for oral administration may be in dosages suitable for the chosen route of administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner or in adhesive carriers.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., a sterile, pyrogen-free, water-based solution, before use.
  • Therapeutic Uses [71]
  • the present disclosure provides methods for treating dyskinesia by administering any one or more of the compositions and formulations discussed above.
  • dyskinesia may include tremor, chorea, dystonia, myoclonus, and/or torticollis. In some embodiments, dyskinesia may include dyskinesia associated with Parkinson’s disease. In some embodiments, the dyskinesia is tardive dyskinesia. In some embodiments, dyskinesia may include dyskinesia associated with myoclonus. In some embodiments, dyskinesia may include dyskinesia associated with Tourette syndrome. [72] In some embodiments, the tardive dyskinesia is a result of one or more antipsychotic medicines (i.e. neuroleptics), e.g., used to treat mental illnesses.
  • antipsychotic medicines i.e. neuroleptics
  • the pharmaceutical composition comprising 3MMC or pharmaceutically acceptable salt thereof is administered twice, three times, four times, or five times daily.
  • a treatment disclosed above is administered on demand, e.g., self-administered, based on the patient’s experience of TD symptoms.
  • a chosen dosage at any given administration may vary depending upon the requirements of the patient and the severity of the condition being treated.
  • the amount of 3MMC administered may be dependent on the subject being treated, the subject’s weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration at a perceived dosage of about 16 mg to 128 mg.
  • the 3MMC is administered intermittently, such as on a monthly or yearly basis. In some embodiments, the 3MMC is administered as needed to treat the TD as determined by the subject. In some embodiments, the 3MMC is administered for a period of time sufficient to treat dyskinesia, which may range from within one day to one or more years, depending on the severity of the symptoms and responsiveness to treatment. In some embodiments, a nasal spray dosage of 3MMC may be administered after the administration of an oral dosage. For instance, after an initial oral dose of 3MMC has been administered at a patient’s rising, a nasal spray dosage of 3MMC may be administered to the patient at a later point of time during the day.
  • nasal spray dosing may comprise 3 to 10 doses per day.
  • the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, e.g., any of those discussed above, for use in preventing dyskinesia, e.g., tardive dyskinesia, in a subject in need, or for preventing and/or reducing one or more symptoms of dyskinesia, e.g., tardive dyskinesia.
  • the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, e.g., any of those discussed above, for use in treating tardive dyskinesia in a subject in need, or for treating and/or reducing one or more symptoms of tardive dyskinesia.
  • the present disclosure provides a method of treating tardive dyskinesia comprising administering to a subject in need thereof a therapeutically effective amount Attorney Docket No.: 15691.0016-00304 of a pharmaceutical composition comprising 3-MMC or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier, in combination with N-acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”), e.g., any of those discussed above, to treat dyskinesia, or treat and/or reduce or one or more symptoms of dyskinesia.
  • PDA palmitoylethanolamide
  • the present disclosure provides methods for treating tardive dyskinesia or for reducing one or more symptoms of dyskinesia by administering a composition disclosed herein.
  • the composition comprises 3MMC or a pharmaceutically acceptable salt thereof.
  • the composition comprises 3MMC or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof.
  • the N-acylethanolamine or a pharmaceutically acceptable salt thereof is PEA or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the salt is 2-(methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride.
  • the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt.
  • the N- acylethanolamine consists of PEA.
  • the present disclosure relates to methods of using any of the pharmaceutical compositions disclosed above for corrective treatment of medication-induced dyskinesia. In some embodiments, the present disclosure relates to methods of using the pharmaceutical compositions for corrective treatment of antipsychotic-induced dyskinesia. [81] In some embodiments, the methods disclosed herein further comprise administering one or more additional therapeutic agents. In some embodiments, the one Attorney Docket No.: 15691.0016-00304 or more additional therapeutic agents may comprise taurine or taurine derivatives, memantine or a similar NMDA receptor blocker, and/or acamprostate.
  • the methods disclosed herein comprise delivering a nasal spray formulation for treating tardive dyskinesia in a subject in need, comprising the steps of: providing a spray of 3MMC having a saline solution formulation in a concentration of 0.003M to 0.009MM, delivering a spray of said formulation to a subject’s nose having a spray characteristic comprising droplets with a size distribution having a D10 of X ⁇ m, a D50 of Y ⁇ m, a D90 of Z ⁇ m, a SPAN of not more than W, and a % volume of ⁇ P ⁇ m of less than V%, said formulation having a viscosity of Q cps; wherein the nasal spray formulation comprises a therapeutically effective amount of 3MMC or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • the methods disclosed herein reduce tardive dyskinesia, e.g., as measured by a change in the Abnormal Involuntary Movement Scale (AIMS), e.g., by at least 1-3 points.
  • AIMS Abnormal Involuntary Movement Scale
  • the present disclosure provides a method of reducing tardive dyskinesia as measured by a standardized mean difference for a change in the Abnormal Involuntary Movement Scale (AIMS), e.g., by at least 1-3 points.
  • the AIMS test has a total of twelve items rating involuntary movements of various areas of the patient's body. These items are rated on a five-point scale of severity from 0–4.
  • the scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). A rating of 2 or higher on the AIMS scale may provide evidence of tardive dyskinesia.
  • chronic means that the length of time of the diseases or conditions of the disclosure can be weeks, months, or possibly years. The intensity of the diseases or conditions can differ according to various factors such as patient age, temperature, season, type of disease, etc. Symptoms of the diseases or conditions may worsen over time.
  • dystonia means the development in a subject of abnormal involuntary movements. These movements may manifest as chorea (irregular, involuntary movements of the body, especially the face and extremities) or dystonia (disorder or lack of muscle tonicity).
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent being administered which will relieve to some extent one or more of the signs, symptoms, or side effects of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses may be the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • excipients include calcium carbonate, povidone K-30, crospovidone, silicon dioxide, magnesium stearate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar toxicity when administered to an individual.
  • pharmaceutically acceptable may mean approved by a regulatory agency (for example, the U.S. Food and Drug Agency) or listed in a generally recognized pharmacopeia for use in animals (e.g., the U.S. Pharmacopeia).
  • the term “preventing” as used herein, encompasses: stopping the onset of one or more symptoms or side effects of a diseases or condition, or delaying or lessening or reducing the severity of one or more symptoms or side effects of the diseases or conditions once they do onset.
  • salt refers to any form of an active ingredient in which the active ingredient assumes an ionic form and is coupled to a counter ion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed by ion interaction.
  • the term "subject” refers to a warm-blooded animal, such as a human that would benefit biologically, medically or in quality of life from a treatment.
  • the term “treating” as used herein includes, but is not limited to, any one or more of the following: abrogating, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, halting, alleviating or preventing a disease or at least one or more symptoms or side effects of the disease or condition.
  • unit dose refers to a fixed amount, i.e., a unit of a compound within a composition that is to be administered to or taken by a subject.
  • a range of values is listed, it is intended to encompass each value and sub-range within the range.
  • the dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "10 ⁇ m” is intended to mean "about 10 ⁇ m”.
  • Toxicity and therapeutic efficacy may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferable.
  • Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans.
  • Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the following Table for Equivalent Surface Area Dosage Factors).
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • Example 1 [109] Patient 1 is a 45-year-old male in psychiatric treatment for 8 years. Tardive dyskinesia occurred following 2 days of sleep deprivation and excessive alcohol and cocaine use. TD presented as uncontrollable shaking of the right hand. Attorney Docket No.: 15691.0016-00304 [110] A single oral dose of 50 mg of 3MMC resulted in rapid alleviation of the symptoms of TD, as well as a sense of calmness and introspection. Further administration of 3MMC was not documented.
  • Example 2 [111] Patient 2 is a 31 year old male in psychiatric treatment for 5 years. Patient 2 was diagnosed with bipolar disorder I as well as addiction to cannabis and cocaine. Patient 2 noted severe, moderate and mild involuntary movements of the facial muscles including jaw clenching and tongue sucking as well as neck and hand tremors over the period of 3 months which occurred in response to periods of insomnia, in states of “daydreaming” (absence of concentrated awareness), combined cannabis use and stressful situations, reflecting on past traumas and withdrawal from antipsychotics as well as during treatment by antipsychotics. [112] Following withdrawal of catecholaminergic medication, Patient 2 followed a regimen of self-administered initial doses of 3MMC ranging from 64mg to 256 mg.
  • This treatment regimen resulted in effective and swift reduction of his symptoms of TD from moderate and severe to minimal and mild involuntary movements of the arms and neck.
  • Patient 2 noted that 3MMC was most effective for him when administered after morning meal and exercise (e.g. cycling).
  • Patient 2 typically took an initial dose of 128 mg-256 mg orally after rising, and used a nasal spray with 25.6 mg/ml 3MMC in water every 0.5-1.5 hours, which provided greatest relief for Patient 2.
  • Patient 2 noted that exceeding this regimen had little effect in improving his symptoms, and that higher doses may even reduce the potency of the 3MMC for addressing the symptoms of TD.
  • Example 3 [114] Patient 3 is a 60-year-old male who has been diagnosed with Schizophrenia, and abusive drug use (including amphetamines, cannabis, and cocaine). Patient 3 was treated for the Schizophrenia with various medications over the course of 12 years, resulting in dependency on antipsychotics including Olanzapine, Trevecta, Risperidal, Paliperidone, Aripropazol and Haldol. Patient 3 suffers from TD symptoms including tongue protrusions, grimacing of the face and involuntary neck movements. [115] Patient 3 typically took an initial oral dose of 128mg of 3MMC following rising, and then used 3MMC nasal spray for maintenance.
  • patient 3 administered the 3MMC in a nasal spray consisting of 256mg in 10ml (25.6mg/ml) every 0.5-1.5 hours, resulting in anywhere from 3 to 10 doses nasally per day.
  • Attorney Docket No.: 15691.0016-00304 [116] Patient 3 noted that 3MMC treatments facilitate coping with symptoms stemming from the use of and withdrawal from prescribed antipsychotics, and most importantly, alleviated the tendency towards suicidal thoughts.
  • Example 4 [117] Patient 4 is a 67-year-old female in psychiatric treatment for more than 10 years.
  • Tardive Dyskinesia occurred in Patient 4 following administration and during the course of treatment through depot which releases a small amount of anti-psychotic medication every day during the month (Trevecta, 100mg), manifesting in shaking of the hands and uncontrollable jaw movements, along with excessive salivation and labored breathing.
  • Revecta 100mg
  • 3MMC suspension 12.8 mg/ml
  • Example 5 [119] Patient 5 is a 28-year-old female in psychiatric treatment for 6 years. Patient 5 was diagnosed as Bipolar Disorder type I and suffered bouts of over 3 months of depression. Tardive Dyskinesia occurred in Patient 5 following administration of a monthly depot of antipsychotic medication, including most recently Olanzapine and historically antipsychotics including Trivecta and Citalopram. In Patient 5 TD manifested in severe shaking of the arms and head.
  • Example 6 [121] Patient 6 is a 24-year-old female in psychiatric treatment for 8 years. Tardive Dyskinesia occurred in Patient 6 following years of treatment with dopamine blockers and traditional antipsychotics of which the most recent is Haldol and is often Attorney Docket No.: 15691.0016-00304 triggered by appearing in public and/or returning to locations or situations that have triggered TD in the past.
  • Patient 6 has been treated for her schizophrenia by other antipsychotics and neuroleptics including Zuclopenthixol and Prozac. [122] Patient 6 also noticed that her symptoms of moderate bouts of involuntary movements over the course of 3 months went from a scale of 4 to 1 on the Abnormal Involuntary Movement Scale (AIMS) with administration of 30-50 mg/day of 3MMC in a nasal spray, over the course of 3 months. Patient 6 was given the choice of up to 5 nasal spray medication moments a day, each comprising of 10mg. Patient 6 sprays approximately 4mg in each nostril every 30 minutes throughout the first part of the day, stopping approximately 3 hours before retiring at bedtime.
  • AIMS Abnormal Involuntary Movement Scale
  • Example 7 [124] Patient 7 is a 26-year-old female in psychiatric treatment for Schizophrenia for 1.5 years. Tardive Dyskinesia occurred in Patient 7 following elevated doses of, or extended treatment with medications including Lithium, Depakine, Diazepam, Seroquel and Risperidone. Patient 7 experienced severe shaking of arms, legs and head, as well as uncontrollable jaw, tongue and lip movements.
  • Patient 7 also reported using approx.1 gram of cocaine/day (“to maintain sociability”), withdrawal of which leads to anxiety and panic attacks, exacerbating her TD symptoms. These resulted in involuntary movements that cause severe, moderate and mild distress and involuntary movement. These also occurred during sleep and lead to insomnia.
  • Oral administration of 50-80 mg of 3MMC was effective in relieving the TD symptoms for Patient 7. After initial oral administration, Patient 7 self-administered occasional nasal insufflations (8 mg) as needed (in response to recurrence of the TD symptoms). Patient 7 also noted that the 3-MMC boosts his self-confidence and rendered the “voices I experience[d]” from the Schizophrenia more bearable.
  • Example 8 [126] Patient 8 is a 53-year-old male out-patient in psychiatric treatment for 16 years. Tardive Dyskinesia occurred in Patient 8 following administration of antipsychotic medication (e.g. Cicordinon), resulting in uncontrollable shaking of the head and neck as well as jaw, lips and tongue. Attorney Docket No.: 15691.0016-00304 [127] Administration of Akineton (biperiden) was ineffective in controlling TD symptoms. In contrast, nasal administration of 3MMC was effective in relieving the TD symptoms for Patient 8.
  • antipsychotic medication e.g. Cicordinon
  • Patient 8 begins the day with an orally administered initial dose of 128 mg of 3MMC and maintenance for recurrence of TD symptoms via 3MMC nasal spray, and further re-dosing, as per need, with nasal spray of 25.6mg/ml 3MMC in suspension.
  • 3MMC 3MMC nasal spray
  • nasal spray 25.6mg/ml 3MMC in suspension.
  • these data show the clinical efficacy of 3MMC administration for Tardive Dyskinesia.
  • patients who have adopted a regimen of initial oral administration of relatively larger doses (64-256 mg) followed by occasional nasal administration of smaller doses (4-25 mg) through the remainder of the day and in response to perceived TD triggers have reported significant relief of the TD symptoms, and reduced dependence on traditional pharmacological anti-psychotic and psychotropic medication.

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Abstract

La présente invention concerne des compositions et des méthodes de traitement de la dyskinésie à l'aide de compositions pharmaceutiques comprenant de la 3-méthylméthcathinone (3MMC), ou un sel pharmaceutiquement acceptable de celle-ci.
PCT/IB2024/057253 2023-07-27 2024-07-26 Compositions et méthodes de traitement de la dyskinésie Pending WO2025022362A1 (fr)

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WO2019145773A1 (fr) * 2017-12-15 2019-08-01 Nos Life Sciences Corporation Formulations encapsulées dans des liposomes
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US5602150A (en) 1992-10-02 1997-02-11 Research Foundation For Mental Hygiene, Inc. Treatment of central nervous system disorders associated with psychotic behavior and dementia with a combination of neuroleptic drugs and taurine, or derivatives thereof, to prevent the development of tardive dyskinesia
WO2019145773A1 (fr) * 2017-12-15 2019-08-01 Nos Life Sciences Corporation Formulations encapsulées dans des liposomes
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