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WO2015136515A1 - Procédés, compositions et dispositifs destinés au traitement des symptômes moteurs et dépressifs associés à la maladie de parkinson - Google Patents

Procédés, compositions et dispositifs destinés au traitement des symptômes moteurs et dépressifs associés à la maladie de parkinson Download PDF

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Publication number
WO2015136515A1
WO2015136515A1 PCT/IL2014/050282 IL2014050282W WO2015136515A1 WO 2015136515 A1 WO2015136515 A1 WO 2015136515A1 IL 2014050282 W IL2014050282 W IL 2014050282W WO 2015136515 A1 WO2015136515 A1 WO 2015136515A1
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Prior art keywords
mao
rasagiline
subject
brain
salt
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Moussa B.H. Youdim
Orly Weinreb
Tamar Amit
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ABITAL PHARMA PIPELINES Ltd
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ABITAL PHARMA PIPELINES Ltd
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Priority to PCT/IL2014/050282 priority Critical patent/WO2015136515A1/fr
Priority to PCT/IL2015/050267 priority patent/WO2015136543A1/fr
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to compositions, methods and devices useful for the treatment of neuropsychiatry conditions or symptoms such as depression and/or neurodegenerative conditions such as Parkinson's disease and/or motor and neuropsychiatric symptoms associated therewith.
  • MAO monoamine oxygen oxidoreductase
  • MAO monoamine oxygen oxidoreductase
  • EC NUMBER EC 1.4.3.4 This enzyme is known as oxidizing primary aliphatic and aromatic amines and some secondary and tertiary amines.
  • the reaction catalyzed by MAO can be represented by the following generalized equation:
  • MAO- A and MAO-B Two isoenzymes of monoamine oxidase are present in most mammalian tissues. These isoenzymes, denoted in the art as MAO- A and MAO-B, were originally distinguished by their sensitivities to inhibition by the acetylenic inhibitors clorgyline and deprenyl and by their substrate specificities.
  • MAO-A catalyzes the oxidative deamination of 5 -hydroxy tryptamine (5-HT)
  • MAO-B is active toward benzylamine and 2-phenylethylamine (PEA)
  • PEO 2-phenylethylamine
  • tyramine and dopamine are substrates for both enzymes in the brain, and the role of MAO enzymes is recognized as regulating the metabolism of catecholamine neurotransmitters (e.g., dopamine and noradrenaline) and serotonin.
  • catecholamine neurotransmitters e.g., dopamine and noradrenaline
  • MAO-A and/or MAO-B A list of exemplary substrates of MAO-A and/or MAO-B is presented, for example, in Tipton et al., "Monoamine oxidase: functions in the central nervous system", In Encyclopedia of Neuroscience, Adelman, G; B. Smith, B, Eds:. Elsevier Science BV, Amsterdam, 3rd Edition, 2004.].
  • MAO-A and/or MAO-B in peripheral tissues such as the intestine, liver, lung, and placenta appear to play a protective role in the body by oxidizing vasoactive amines from blood or preventing their entry into the circulation.
  • intraneuronal MAO-A and MAO-B have been suggested to protect neurons from exogenous amines and/or to regulate levels of neurotransmitter amines synthesized within a neuron.
  • non selective MAO and selective MAO-A inhibitors were primarily considered as anti-depressants.
  • more than 80 % inhibition of MAO-A is required for increasing the concentration of 5- HT and noradrenaline in the brain and thus to exhibit antidepressant effects [See, for example, Tipton et al., 2004, supra].
  • MAO-A selective or nonselective irreversible MAO inhibitors has been limited because individuals taking these drugs become susceptible to amines, such as tyramine, in the diet. These amines are normally degraded by MAO in peripheral tissues. When MAO is inhibited, ingested tyramine can enter the blood, from which it is taken up by adrenergic nerve terminals releasing stored noradrenaline and resulting in a hypertensive response (hypertensive crises). On the basis of the high concentrations of tyramine in some cheeses, this hypertensive response to dietary amines is widely known as the "cheese reaction" or "cheese effect”. Tyramine is found in high concentration also in other food nutrients.
  • MAO-A inhibitory drugs due to side effects of the MAO-A inhibitory drugs, e.g., hypertension ("cheese effect"), these drugs are often replaced by other antidepressants [Youdim et al., Journal of neural transmission, 1987, 25, 27-33; Youdim, Journal of neural transmission, 1980, 16, 157-161].
  • MAO inhibitors were found to be highly potent protectors against MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) neurotoxicity, which gives rise to a condition resembling idiopathic Parkinson's disease. Inhibitors of MAO are therefore considered to prolong the actions of dopamine in Parkinson's disease.
  • MPTP l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine
  • Parkinson's disease is a slowly progressive neurodegenerative disorder. It is characterized by motor symptoms, such as bradykinesia, rigidity, tremor at rest and postural instability, which are associated with degeneration of the nigrostriatal dopaminergic projection originating in the substantia nigra (SN). In addition to these motor symptoms, non-motor symptoms, such as olfactory dysfunction, can be observed even prior to the manifestation of motor symptoms in PD patients.
  • Depression is a common psychiatric comorbidity in PD, affecting more than 60 % of the patients.
  • Pharmacotherapy for depression in PD entails special concerns related to different side effects of the various anti-depressants and great potential for drug-drug interaction.
  • Selective serotonin reuptake inhibitors (SSRIs) are typically prescribed, however with often insufficient results.
  • Selegiline also referred to in the art as Anipryl, (-)-deprenyl, L-deprenyl, Eldepryl, Emsam, Zelapar
  • Rasagiline N-propargyl-l-(R)-aminoindan; Marketed as Azilect®
  • PD Parkinson's disease
  • MDD Major Depressive Disorder
  • Both drugs are orally- administered drugs, and are subject to extensive first pass hepatic metabolism, resulting in poor and highly variable oral bioavailability (35 % for Rasagiline and 4-10 % for Selegiline).
  • Rasagiline and Selegiline are preferential MAO-B inhibitors, their selectivity is dose-dependent; While Selegiline is approved for the treatment of depression, the dose is 3- to 6-fold higher than that for the treatment of PD, causing loss of MAO-B selectivity and requiring precautions to prevent hypertensive crises due to "cheese reaction".
  • Rasagiline is a new MAO-B inhibitor, introduced in 2006, that has 3- to 16-fold greater potency than Selegiline. Similarly to Selegiline, Rasagiline is generally devoid of potential to cause hypertensive crises, the "cheese reaction", unless administered at high concentrations that are sufficient to inhibit MAO-A [Youdim and Bakhle, 2006, Br J Pharmacol, 2006, 147 Suppl 1, S287-296].
  • the recommended dose of rasagiline for humans is 1 mg once daily when used alone (monotherapy), and 0.5-1 mg once daily when combined with 1-DOPA. Patients with mild liver disease should not use more than 0.5 mg daily.
  • patients administered with Rasagiline are typically cautioned to avoid tyramine rich food, as well as administration of anti-depressants of the selective serotonin uptake inhibitors family, serotonin-norepinephrine uptake inhibitors family and other MAO inhibitors.
  • Rasagiline is primarily metabolized by hepatic cytochrome P-450 to form its major metabolite, l-(R)-aminoindan, a non-amphetamine, weak reversible MAO-B inhibitor compound.
  • one of the Selegiline principal metabolites is 1-methamphetamine which can be converted to 1- amphetamine. See, for example, Bar Am et al., Journal of Neurochemistry, 2010, Vol. 11, pp. 1131-1137; Weinreb et al, Antioxidants & Redox Signaling, Volume 14, Number 5, 2011, page 767.
  • Intranasal administration is a noninvasive means for targeting the brain bypassing the blood-brain barrier (BBB), minimizing systemic absorption, and limiting potential peripheral side effects [Vyas et al., Current drug delivery, 2005, 2, 165-175; Ilium, 2004, The Journal of pharmacy and pharmacology, 2004, 56, 3-17].
  • BBB blood-brain barrier
  • MAO-B inhibitors such as Rasagiline are useful in the treatment of Parkinson's disease, particularly in alleviating motor symptoms associated with Parkinson's disease, a need still remains to treat depression symptoms associated with this disease. Such a need becomes even more pronounced due to adverse drug-drug interactions between Rasagiline and commonly used anti-depressants such as SSRIs, and while considering the depression symptoms associated with a majority of Parkinsonian patients.
  • MAO-B inhibitors such as, for example, Rasagiline and Selegiline, may act also as anti-depressants at higher doses, due to MAO-A inhibition, administration of these drugs at doses effective in treating MAO-A inhibition is limited by the "cheese reaction" (hypertensive crisis) associated with such high doses.
  • Rasagiline and Selegiline are prescribed for the treatment of Parkinson's disease at doses which are selective to MAO-B inhibition and are therefore ineffective in treating depression symptoms in Parkinsonian patients.
  • a MAO-B inhibitor such as Rasagiline is administered into the brain at a range of doses, which are capable of treating neuropsychiatric conditions such as depression and/or alleviating neuropsychiatric (e.g., depression) symptoms (e.g., symptoms associated with Parkinson's disease).
  • administering a MAO-B inhibitor such as Rasagiline to the brain of a subject results in alleviating or treating both motor and depression symptoms associated with Parkinson's disease.
  • This methodology is effected while utilizing Rasagiline or any other MAO-B inhibitor, at doses sufficient to inhibit MAO-A in the brain, possibly without potentiation of sympathetic cardiovascular activity (e.g., "cheese reaction").
  • Such a methodology allows using drugs such as Rasagiline for exhibiting anti- depressant activity (e.g., due to MAO-A inhibition), and particularly, for exhibiting a dual effect of MAO-A and MAO-B inhibition, thereby improving the effect of the drug in patients suffering from Parkinson's disease by alleviating both motor and depression symptoms associated with the disease.
  • the present inventors have demonstrated that intranasal administration of Rasagiline at a range of doses, results in both MAO-A and MAO-B inhibition in the brain, whereby similar doses, when administered intraperitoneally (IP) or orally, are inefficient in inhibiting MAO-A in the brain.
  • IP intraperitoneally
  • the present inventors have further demonstrated that intranasal administration of Rasagiline at a range of doses, results in efficient inhibition of MAO-A and MAO-B in the brain, yet in inefficient inhibition of MAO-A in the periphery (e.g., liver and small intestine).
  • the methodology described herein can therefore be utilized optionally for administering to a subject in need thereof a therapeutically effective amount of a MAO-B inhibitor such as Rasagiline such that a ratio between inhibition of MAO-A in the brain and inhibition of MAO-A in the periphery is higher than the respective ratio that is obtained by oral administration of Rasagiline.
  • a MAO-B inhibitor such as Rasagiline
  • a method of treating motor and neuropsychiatric symptoms associated with Parkinson's disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Rasagiline or a pharmaceutically acceptable salt thereof, wherein the administering is effected by intranasal administration.
  • a method of treating a neuropsychiatric condition such as depression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Rasagiline or a pharmaceutically acceptable salt thereof, wherein the administering is effected by intranasal administration.
  • the depression is associated with Parkinson's disease.
  • a method of treating a neuropsychiatric condition and/or a neurodegenerative condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Rasagiline or a pharmaceutically acceptable salt thereof, wherein the administering is effected by intranasal administration.
  • the condition is treatable by l-(R)-aminoindan.
  • the amount of Rasagiline or a salt thereof is such that inhibits at least 50 % of an activity of MAO-A in the brain of the subject.
  • the amount of Rasagiline or a salt thereof is such that inhibits at least 80 % of an activity of MAO-A in the brain of the subject.
  • the amount of Rasagiline or a salt thereof is such that a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A is higher than 1.
  • the Rasagiline or a salt thereof is administered as a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier.
  • the composition is in a form of a powder.
  • composition and/or a mode of the intranasal administration are configured such that following the administering, an amount of rasagiline in the brain of the subject is such that inhibits at least 50 % or at least 80 % of an activity of MAO-A in the brain.
  • composition and/or a mode of the intranasal administration are configured such that following the administering, an amount of rasagiline in the brain of the subject is such that a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A is higher than 1.
  • the amount of rasagiline or a salt thereof ranges from an amount equivalent to 0.2 mg/kg per day to 6 mg/kg per day in rats.
  • the subject is a human and the amount of rasagiline or a salt thereof is higher than 2 mg per day.
  • a pharmaceutical composition comprising Rasagiline or a pharmaceutically acceptable salt thereof, the composition being formulated for intranasal administration.
  • the composition is in a form of a powder.
  • the composition is identified for use in treating or alleviation any one of the conditions and/or symptoms as described herein.
  • Rasagiline or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition (medicament) for treating or alleviation any one of the conditions and/or symptoms as described herein.
  • a system for intranasal administration of Rasagiline or a pharmaceutically acceptable salt thereof to a subject in need thereof comprising means for dispensing a pre-determined dose of Rasagiline or the salt thereof and for intranasally delivering the dose, the pre-determined dose being effective for alleviating neuropsychiatric and motor symptoms associated with Parkinson's disease.
  • a system for intranasal administration of Rasagiline or a pharmaceutically acceptable salt thereof to a subject in need thereof comprising means for dispensing a pre-determined dose of Rasagiline or the salt thereof and for intranasally delivering the dose, the pre-determined dose being effective for treating neuropsychiatric and/or neurodegenerative conditions in a subject in need thereof, as described herein (e.g., depression).
  • the pre-determined dose is effective for treating depression.
  • a method of treating a neuropsychiatric and/or neurodegenerative condition is a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Rasagiline or a pharmaceutically acceptable salt thereof, wherein the administering is effected at a dose and/or a mode of administration selected such that a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A in the subject is higher than 1.
  • a system configured for administering Rasagiline or a pharmaceutically acceptable salt thereof to a subject in need thereof, the system comprising means for delivering Rasagiline or the salt thereof to the subject, wherein the means are such that upon delivering Rasagiline or the salt thereof, a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A in the subject is higher than 1.
  • the method and system are for use in treating or alleviating any one of the conditions and/or symptoms described herein.
  • FIG. 7 is a bar graph showing the effect of intranasal administration of rasagiline, given in liquid or powder formulations, on the ratio of striatal/small intestinal MAO- A inhibition in acute-treated adult male Sprague Dawley rats. Rats were intranasally administered either with rasagiline in dextrose powder formulation (0.24,
  • the present invention in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to compositions, methods and devices useful for the treatment of neuropsychiatry conditions or symptoms such as depression and/or neurodegenerative conditions such as Parkinson' s disease and/or motor and neuropsychiatric symptoms associated therewith.
  • Parkinson's disease is the second most common neurodegenerative disorder, affecting 1-3 percent of people older than 50 years. Parkinson's disease is characterized by motor symptoms, such as bradykinesia, rigidity, tremor at rest and postural instability, which are associated with degeneration of the nigrostriatal dopaminergic projection.
  • Depression is a common and potentially debilitating aspect of Parkinson's disease, affecting 50-70 percent of Parkinsonian patients. Depression in Parkinson's disease is demonstrably different from ordinary major depression in terms of gender ratio, age, symptom profile, comorbidity, and chronicity. Treatment of depression in Parkinson's disease entails special concerns related to side effects and drug-drug interactions.
  • the currently most common drugs for the treatment of Parkinson' s disease are the irreversible selective MAO-B inhibitors (e.g., Rasagiline and Selegiline). These drugs are assumed to exert their primary effect in Parkinson' s disease (PD) by MAO-B inhibition which results in a slower metabolism of endogenous and exogenous dopamine (DA), thus providing symptomatic benefits (Finberg et al. 1996, 1998, supra).
  • MAO-B inhibitors e.g., Rasagiline and Selegiline
  • Irreversible nonselective MAO-AB and selective MAO-A inhibitors are known as anti-depressants.
  • Such drugs can potentiate the cardiovascular effect of the sympathomimetic amine, tyramine, present in many foods. Since tyramine is metabolized by MAO, the inhibition of MAO-A results in uptake of tyramine from circulatory system, which results in hypertensive crisis, known as the "cheese effect", as a consequence of noradrenaline release from peripheral adrenergic neurons by tyramine.
  • Parkinson' s disease at doses in which MAO-B inhibition is exerted may also exhibit MAO-A inhibition, however, at doses which are at least 3-fold higher that those required for exhibiting MAO-B inhibition.
  • Rasagiline when given orally or IP, does not cause a "cheese reaction" at its selective MAO-B inhibitory activity dosage. However, at higher dosage it loses its selectivity and consequently further inhibits MAO-A, thus causing a "cheese reaction”.
  • Rasagiline is also contraindicated with several families of anti-depressants, including for example, the SSRIs. Thus, while treatment of Parkinsonian patients with Rasagiline results in alleviation of motor symptoms associated with the dopaminergic system, such a treatment limits the possibilities of alleviating depression symptoms associated with Parkinson's disease.
  • the present inventors have conceived administering a MAO-B inhibitor such as Rasagiline directly into the brain, at a dose that would affect depression in a subject in need thereof, and hence would affect both motor and depression symptoms associated with Parkinson's disease.
  • a MAO-B inhibitor such as Rasagiline
  • the present invention have envisioned administering a MAO-B inhibitor such as rasagiline at a dose which would inhibit both MAO-A and MAO-B in the brain, yet would not inhibit systemic (peripheral) MAO-A.
  • Such a methodology provides for an efficient treatment of depression and particularly, for an efficient treatment of both motor symptoms and depression symptoms associated with Parkinson's disease, presumably due to MAO-A and MAO-B inhibition in the brain, and avoids inhibition of MAO-A in the periphery and the consequent adverse "cheese reaction".
  • intranasal delivery of rasagiline in e.g., a powder formulation resulted in inhibition of monoamine oxidase (MAO)-A, in rat striatum and hippocampus, following acute treatment.
  • a powder formulation was shown to exhibit a greater efficacy compared to a liquid formulation.
  • the intranasal delivery of rasagiline (0.6 mg/kg in rats) in powder formulation showed a significantly low peripheral MAO- A inhibition (expressed as the striatum/intestine MAO-A inhibitory ratio).
  • the present inventors have further uncovered that intranasal delivery of rasagiline in powder formulation (0.24-6 mg/kg in rats) resulted in a dose-dependent MAO-A inhibition in the striatum and hippocampus (up to about 97 % and about 95 %, respectively) in rats.
  • MAO-B was almost completely inhibited (about 98%) in the striatum and hippocampus, at all rasagiline doses analyzed.
  • Intranasal delivery of rasagiline (0.24 and 0.6 mg/kg) in powder formulation resulted in significantly reduced peripheral MAO-A inhibitor, compared to respective doses of oral administration of Rasagiline.
  • intranasal delivery of rasagiline e.g., as a mesylate salt thereof
  • can attain high drug concentrations in the brain that could also inhibit brain MAO-A activity and cause only limited potentiation to induce hypertensive crises ("cheese reaction").
  • intranasal delivery of rasagiline may exert overall beneficial effects of the drug via its active potent neuroprotective/neurorestorative metabolites (propargylamine and 1-R-aminoindan) without periphery side effects.
  • a method of treatment which is effected by administering to the brain of subject a therapeutically effective amount of a MAO-B inhibitor such as Rasagiline.
  • the method is effected by administering to the brain of a subject a MAO-B inhibitor is an amount that is capable of treating a neuropsychiatric condition or symptom in a subject in need thereof.
  • a method as described herein is effected by administering to the brain of a subject a MAO-B inhibitor in an amount that is capable of treating (or alleviating) both motor and neuropsychiatric (e.g., depression) symptoms associated with Parkinson's disease.
  • a MAO-B inhibitor in an amount that is capable of treating (or alleviating) both motor and neuropsychiatric (e.g., depression) symptoms associated with Parkinson's disease.
  • the amount of the MAO-B inhibitor is sufficient to inhibit MAO-A in the brain of the subject.
  • administering to the brain of a subject a MAO-B inhibitor is an amount that is sufficient to inhibit MAO-A in the brain of the subject results in inhibition of both, MAO-A and MAO-B in the brain.
  • a method as described herein can be used for treating neuropsychiatric conditions such as depression, e.g., by means of inhibiting MAO-A in the brain.
  • a method as described herein can particularly be used for treating Parkinson's disease, and, in some embodiments, for treating motor symptoms and neuropsychiatric (e.g., depression) symptoms associated with Parkinson's disease in a subject in need thereof.
  • motor symptoms and neuropsychiatric e.g., depression
  • a "subject in need thereof is a subject suffering from a neuropsychiatric condition or symptom, such as depression.
  • the subject suffers from Parkinson's disease.
  • Such subjects are also referred to herein and in the art as “Parkinsonian" subjects or patients.
  • the subject is a Parkinsonian subject who suffers, in addition to motor symptoms associated with Parkinson's disease, from neuropsychiatric symptoms (e.g., depression) associated with Parkinson's disease.
  • neuropsychiatric symptoms e.g., depression
  • a method of treating motor and neuropsychiatric symptoms associated with Parkinson's disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Rasagiline or a pharmaceutically acceptable salt thereof, wherein said administering is effected by intranasal administration.
  • neuropsychiatric conditions are conditions that result from imbalanced brain activity and include, for example, depression, psychosis, impulse control disorders, cognitive impairment, anxiety, dementia and sleep disturbances.
  • Neuropsychiatric symptoms result from a disease or disorder such as Parkinson's disease, and are used herein to define non-motor symptoms such as, for example, depression, drug-induced psychosis and impulse control disorders, cognitive impairment, anxiety, dementia and sleep disturbances, which may result for the disease's etiology and/or treatment.
  • depression is interchangeable to the term “depressive illness” and encompasses psychiatric (or mental) conditions known as major depressive disorder, major depression, clinical depression, or simply depression. Such conditions are characterized, for example, by episodes of all-encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities.
  • Depression, or depressive illness is characterized, for example, by the presence of some or all of following symptoms: (i) depressed mood most of the day, nearly every day, as indicated by either subjective report or observation made by others; (ii) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day; (iii) significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day; (iv) insomnia or hypersomnia nearly every day; (v) psychomotor agitation or retardation nearly every day; (vi) fatigue or loss of energy nearly every day; (vii) feelings of worthlessness or excessive or inappropriate guilt nearly every day; (viii) diminished ability to think or concentrate, or indecisiveness, nearly every day; and (ix) recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
  • depression can be determined either behaviorally, according to the above-indicated symptoms, or by well-known tests, such as, but not limited to, according to DSM-IV diagnostic criteria.
  • treatment or alleviation of depression can be determined behaviorally, according to the above-indicated symptoms, or by well-known tests, such as, but not limited to, according to DSM-IV diagnostic criteria.
  • depression or “depressive illness” refers to both depression as a neuropsychiatric condition per se, and depression symptoms associated with Parkinson's disease.
  • motor symptoms associated with Parkinson's disease include, for example, bradykinesia, rigidity, tremor at rest and postural instability.
  • a method of treating Parkinson's disease in a subject in need thereof comprising administering to the brain of the subject a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof).
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof).
  • a method of treating motor symptoms and neuropsychiatric symptoms e.g., depression
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof).
  • a method of treating a neuropsychiatric condition comprising administering to the brain of the subject a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof).
  • a neuropsychiatric condition e.g., depression
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof).
  • the depression is associated with Parkinson's disease and the subject is a Parkinsonian subject, as defined herein.
  • the MAO-B inhibitor e.g., Rasagiline or a salt thereof
  • a pharmaceutical composition comprising the same, as described herein.
  • a MAO-B inhibitor Rosagiline or a salt thereof
  • a pharmaceutical composition for the treatment of Parkinson's disease in a subject in need thereof, the pharmaceutical composition being formulated for administration into the brain of the subject (e.g., intranasal administration).
  • a MAO-B inhibitor Rosagiline or a salt thereof
  • a pharmaceutical composition for the treatment of motor symptoms and neuropsychiatric symptoms, such as depression, associated with Parkinson's disease in a subject in need thereof, the pharmaceutical composition being formulated for administration into the brain of the subject (e.g., intranasal administration).
  • a MAO-B inhibitor Rosagiline or a salt thereof
  • a pharmaceutical composition for the treatment of a neuropsychiatric condition (e.g., depression) in a subject in need thereof, the pharmaceutical composition being formulated for administration into the brain of the subject (e.g., intranasal administration).
  • the neuropsychiatric condition is associated with Parkinson's disease and the subject is a Parkinsonian subject, as defined herein.
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof), for use in the treatment of Parkinson's disease in a subject in need thereof, the pharmaceutical composition being formulated for administration into the brain of the subject (e.g., intranasal administration).
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof), for use in the treatment of motor symptoms and neuropsychiatric symptoms (e.g., depression) associated with Parkinson's disease in a subject in need thereof, the pharmaceutical composition being formulated for administration into the brain of the subject (e.g., intranasal administration).
  • a MAO-B inhibitor Rosagiline or a salt thereof
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof), for use in the treatment of a neuropsychiatric (e.g., depression) and/or neurodegenerative condition (e.g., Parkinson's disease) in a subject in need thereof, the pharmaceutical composition being formulated for administration into the brain of the subject (e.g., intranasal administration).
  • a neuropsychiatric e.g., depression
  • neurodegenerative condition e.g., Parkinson's disease
  • the neuropsychiatric and/or neurodegenerative condition is associated with Parkinson's disease and the subject is a Parkinsonian subject, as defined herein.
  • the MAO-B inhibitor (Rasagiline or a salt thereof) is used in an amount that is capable of treating or alleviating depression and/or depressive illness symptoms, or any other neuropsychiatric symptom condition as defined herein, and any combination thereof, including neuropsychiatric symptoms associated with Parkinson's disease.
  • the MAO-B inhibitor (Rasagiline or a salt thereof) is used in an amount that is sufficient to inhibit MAO-A inhibition in the brain of the subject.
  • the MAO-B inhibitor (Rasagiline or a salt thereof) is administered in a therapeutically effective amount, and the therapeutically effective amount is as an amount sufficient to treat or alleviate a neuropsychiatry (e.g., depression and/or depressive illness) symptoms associated with Parkinson's disease.
  • a neuropsychiatry e.g., depression and/or depressive illness
  • the MAO-B inhibitor (Rasagiline or a salt thereof) is administered in a therapeutically effective amount, and the therapeutically effective amount is as an amount sufficient to inhibit MAO-A in the brain of the subject.
  • the composition is used such that an amount of the MAO-B inhibitor (Rasagiline or a salt thereof) administered to the brain of the subject is a therapeutically effective amount as described herein.
  • the composition is used such that an amount of the MAO-B inhibitor (Rasagiline or a salt thereof) sufficient to inhibit MAO-A in the brain of the subject.
  • the MAO-B inhibitor Rosagiline or a salt thereof
  • the composition comprises a therapeutically effective amount of the MAO-B inhibitor (Rasagiline or a salt thereof), as described herein.
  • the composition comprises an amount of the MAO-B inhibitor (Rasagiline or a salt thereof) which is sufficient to inhibit MAO-A in the brain of the subject.
  • the MAO-B inhibitor Rosagiline or a salt thereof
  • terapéuticaally effective amount it is generally meant herein an amount effective to treat, alleviate or ameliorate a disorder or a symptom, or prolong the survival of the subject being treated.
  • therapeutically effective amount describes an amount of a MAO-B inhibitor (Rasagiline or a salt thereof) which is sufficient to alleviate the neuropsychiatric symptom or condition.
  • a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof) as described herein comprises an amount of the MAO-B inhibitor (Rasagiline or a salt thereof) which, when administered, inhibits MAO-A in the brain.
  • the amount is sufficient to inhibit at least 50 % of the activity of MAO- A in the brain and is some embodiments, the amount is sufficient to inhibit at least 60 5, at least 70 %, at least 80 % or at least 85 % of the activity of MAO- A in the brain of the subject, including higher inhibition values.
  • the pharmaceutical composition is used at doses and regimens which provide a therapeutically effective amount of the MAO-B inhibitor (Rasagiline or a salt thereof) in the brain of the subject, and in some embodiments, such a therapeutically effective amount causes inhibition of MAO-A in the brain, as is described herein.
  • the MAO-B inhibitor Rosagiline or a salt thereof
  • the therapeutically effective amount of the MAO-B inhibitor is such that inhibits MAO- A in the brain, and administering the composition does not cause "cheese reaction", as described herein.
  • administering the composition does not result in inhibition of systemic MAO-A (MAO-A in the periphery) or results in reduced inhibition of systemic MAO-A.
  • the composition is used such that inhibition of MAO-A in the brain is effected yet, "cheese reaction" is not caused.
  • administering the composition does not result in inhibition of systemic MAO-A (MAO-A in the periphery) or results in reduced inhibition of systemic MAO-A.
  • MAO-B inhibitor Rosagiline or a salt thereof
  • intranasal administration allows using wide range of dosing, wherein high doses of the drug will inhibit MAO-A (and MAO-B) in the brain without potentiation of sympathetic cardiovascular activity, i.e., without the side effect resulting from MAO-A inhibition and produced by said MAO-B inhibitor (Rasagiline or a salt thereof) when administered at high doses to the periphery and ingested together with a high tyramine content food (e.g., "cheese reaction").
  • Rasagiline or a salt thereof is such that a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A is higher than 1.
  • a ratio can be 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2, and even higher.
  • Such a ratio means, for example, that when the Rasagiline or any other MAO- inhibitor is administered to the subject and exhibits, for example, inhibition of 50 % of the MAO-A activity in the brain, the inhibition of peripheral MAO-A is lower than 50 %, and can be, for example, 40 %, 30 %, 20 % and even lower. Similarly, for inhibition of 80 % of MAO-A activity in the brain, inhibition of peripheral MAO-A is lower than 80 %, or lower than 70 %, or lower than 40 %, or lower than 30 %.
  • the above-described ratio is higher than the same ratio when Rasagiline or a salt thereof is administered orally or intraperitoneally. In some embodiments, the ratio is higher by 10 5, 20%, 30 %, 40 %, 50 % and even more compared to the same ratio when oral or IP administration is effected.
  • the pharmaceutical composition and/or the mode of administration are configured such that the above-indicated amount of the MAO-B inhibitor (e.g., Rasagiline or a salt thereof) is present in a brain of a subject following the administration.
  • the MAO-B inhibitor e.g., Rasagiline or a salt thereof
  • composition and/or a mode of the intranasal administration are configured such that following the administration, an amount of rasagiline in the brain of the subject is such that inhibits at least 50 % or at least 80 % of an activity of MAO-A in the brain.
  • composition and/or a mode of the intranasal administration are configured such that following the administration, an amount of Rasagiline in the brain of the subject is such that a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A is higher than 1, as described herein.
  • the method and pharmaceutical composition as described herein result in inhibition of both MAO-B and MAO-A in the brain.
  • the concentration of the pharmaceutically active agent, i.e., the MAO-B inhibitor as defined herein (Rasagiline or a salt thereof), in a pharmaceutical composition is determined in accordance with the particular agent chosen; its efficacy; a comparison of its bioavailability by the particular mode of administration used, e.g., intranasal administration, and by other routes of administration, e.g., parenteral injection or oral administration; and the desired frequency of administration combined with the desired single dosage of the formulation.
  • Such pharmacological data can routinely be obtained by the skilled artisan from animal experiments, e.g., in terms of index values. Exemplary animal experiments are provided in the Examples section that follows.
  • the dosage administered, for example, to a particular Parkinsonian patient will depend on the state of that patient, and will be determined as deemed appropriate by the practitioner.
  • the pharmaceutical composition is formulated and used (administered to the brain at a certain regimen) so as to deliver to the brain a MAO-B inhibitor (Rasagiline or a salt thereof) as described herein in an amount as described herein.
  • a MAO-B inhibitor Rosagiline or a salt thereof
  • such an amount inhibits MAO- A in the brain and may optionally also inhibit MAO-B in the brain.
  • the pharmaceutical composition is formulated and used (administered to the brain at a certain regimen) so as to deliver to the brain a MAO-B inhibitor as described herein in an amount that does not substantially inhibit systemic MAO-A, namely, MAO-A present in the periphery, for example, in liver and small intestine.
  • any one of the compositions, uses and methods as described herein, the MAO-B inhibitor used (or a composition comprising the MAO-B inhibitor) is administered intranasally and hence directly into the brain.
  • administering bypasses the circulation and in particular the liver and small intestine thus avoiding the undesired side effect produced by inhibition of the MAO-A enzyme in these tissues.
  • Intranasal administration is a noninvasive means for targeting the brain by passing the BBB, minimizing systemic absorption, and limiting potential peripheral side effects. Intranasal administration allows the drug administered to travel through the roof of the nose, along the fibers of the olfactory and trigeminal nerves found in the mucosa of the nose, directly to the extracellular space of the neurons of the brain and spinal cord without having to cross the BBB or access the blood stream, and consequently, without exposing the other organs of the body to the drug, thus reducing its side effects and required dosage.
  • modes of administrations include, for example, local administration to the brain, for example, by intrastriatal administration, i.e., directly to the corpus striatum of the individual treated, ocular administration, and the like.
  • modes of administration typically utilize liquid compositions.
  • intranasal administration can be replaced by local, ocular or other modes for directly administering the MAO-B inhibitor to the brain.
  • Administration of the composition as described herein can be effected once daily, or twice daily, or once every two days. In some embodiments, administration is effected so as to maintain an amount of the MAO-B inhibitor (e.g., Rasagiline) in the brain of the subject, which inhibits MAO-A in the brain, as described herein.
  • the MAO-B inhibitor e.g., Rasagiline
  • a "pharmaceutical composition” refers to a preparation of an active compound (e.g., a MAO-B inhibitor such as Rasagiline or a salt thereof), with other chemical components such as pharmaceutically acceptable and suitable carriers and excipients.
  • an active compound e.g., a MAO-B inhibitor such as Rasagiline or a salt thereof
  • suitable carriers and excipients e.g., a pharmaceutically acceptable and suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, i.e., to the brain of the subject, as described herein.
  • the term "pharmaceutically acceptable carrier” refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water, as well as solid (e.g., powdered) and gaseous carriers.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars (e.g., dextrose) and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the pharmaceutical composition is identified for administration once per day (e.g., as described herein).
  • the pharmaceutical composition comprises a unit dosage form, comprising a therapeutically effective amount of a MAO-B inhibitor, as described herein.
  • unit dosage form describes physically discrete units, each unit containing a predetermined quantity of MAO-B inhibitor calculated to produce the desired therapeutic effect, in association with at least one pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
  • the amount of MAO-B inhibitor in the unit dosage form may optionally be a daily dosage of the MAO-B inhibitor, as described herein, such that a method or treatment such as described herein may be effected by administration of one unit dosage form per day.
  • the amount of the MAO-B inhibitor in the unit dosage form may be, for example, half a daily dosage described herein, such that a method or treatment described herein may be effected by administration of two unit dosage forms per day; or a third or a quarter of a daily dosage described herein, such that a method or treatment described herein may be effected by administration of three or four unit dosage forms per day, respectively.
  • the pharmaceutical composition is formulated such that a single dosage of the composition contains a desired amount of the MAO-B inhibitor, as described herein, or can be formulated into a device or a delivery system that dispenses or releases a desired amount of the MAO-B inhibitor as described herein into the brain of a subject.
  • compositions comprising the MAO-B inhibitor according to any one of the embodiments relating to the methods, uses and compositions, as described herein, can be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the MAO-B inhibitor (Rasagiline or a salt thereof) into preparations which can be used pharmaceutically and administered to the brain of a subject. Proper formulation is dependent upon the route of administration chosen.
  • compositions can be prepared, e.g., by uniformly and intimately bringing the active agent, i.e., a MAO-B inhibitor (Rasagiline or a salt thereof), as defined above, into association with a pharmaceutically acceptable carrier, such as a liquid carrier, a (e.g., finely divided) solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.
  • a pharmaceutically acceptable carrier such as a liquid carrier, a (e.g., finely divided) solid carrier, or both.
  • the composition may be in liquid, solid or semisolid form and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients.
  • the pharmaceutical composition of the present invention is formulated in a solid form, e.g., as a powder and/or as nanoparticles.
  • the pharmaceutical composition can be formulated for any suitable route of administration that may deliver the active agent directly into the brain, as described herein, and is preferably formulated for intranasal administration.
  • a pharmaceutical composition formulated for intranasal administration may be liquid, e.g., adapted for administration as a spray or drops.
  • Liquid preparations such as those based on aqueous formulations, may include ancillary agents, e.g., a pH-buffering system, for example, a buffer such as phosphate, borate, citrate or acetate buffers, a preservative, and an osmotic pressure controlling agent, e.g., glycerol or sodium chloride.
  • ancillary agents e.g., a pH-buffering system, for example, a buffer such as phosphate, borate, citrate or acetate buffers, a preservative, and an osmotic pressure controlling agent, e.g., glycerol or sodium chloride.
  • Non limiting examples of buffering agents/systems include boric acid, sodium bicarbonate, sodium citrate, sodium acetate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate dibasic heptahydrate, potassium dihydrogen phosphate, and combinations thereof such as combinations of boric acid and sodium bicarbonate, sodium phosphate monobasic and sodium phosphate dibasic, or sodium citrate and citric acid. If a buffering agent is employed, it is chosen in quantities that preferably do not irritate the nasal mucosa.
  • the carrier is an aqueous carrier, e.g., water.
  • aqueous carrier e.g., water.
  • Such preparations may be prepared by dispersing the active agent, i.e., the MAO-B inhibitor as defined herein (Rasagiline or a salt thereof), and ancillary agents, utilizing any method usually employed for suspension or emulsification, e.g., ultrasonic treatment. Adjustment of the aqueous phase to neutrality, i.e., to pH in the range from about 6.5 to about 8, may be accomplished in any of the preparatory steps.
  • microemulsions for intranasal administration are prepared in which the size of the dispersed particles or droplets is of the order of 10 nm, thereby facilitating their passage across the nasal mucosa.
  • Such microemulsions may be sterilized by filtration.
  • the pharmaceutical composition includes one or more agents that increase viscosity, chosen in quantities that preferably do not irritate the nasal mucosa and increase nasal retention time.
  • agents that increase viscosity include, without being limited to, methylcellulose, carboxymethylcellulose sodium, ethylcellulose, carrageenan, carbopol, and combinations thereof.
  • the pharmaceutical composition may contain aqueous diluents, e.g., saline, water, dextrose, and combinations thereof, and/or non-aqueous, e.g., alcohols, particularly polyhydroxy alcohols such as propylene glycol, polyethylene glycol, and glycerol, vegetable oils and mineral oils.
  • aqueous diluents e.g., saline, water, dextrose, and combinations thereof
  • non-aqueous e.g., alcohols, particularly polyhydroxy alcohols such as propylene glycol, polyethylene glycol, and glycerol, vegetable oils and mineral oils.
  • the pH of the compositions may be adjusted to the desired value using any suitable organic or inorganic acid or organic or inorganic base.
  • suitable organic acids include, without limiting, acetic acid, citric acid, glutamic acid and methane sulfonic acid.
  • Suitable inorganic acids include, but are not limited to, hydrochloric acid and sulphuric acid.
  • Suitable organic bases include, without limiting, meglumine, lysine and tromethamine.
  • Suitable inorganic bases include, without being limited to, sodium hydroxide and potassium hydroxide.
  • Solvents that may be used to prepare the pharmaceutical compositions of the invention include, without being limited to, water, ethanol, propylene glycol, polyethylene glycol, glycerin, phenol, glycofurol, benzyl benzoate and polyoxyethylene castor oil derivatives.
  • the pharmaceutical composition is in a solid form, and comprises pharmaceutically acceptable solid carrier.
  • Suitable carriers and/or excipients include, for example, fillers such as sugars, including dextrose, lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the MAO-B inhibitor can be conveniently delivered in the form of an aerosol spray presentation (which typically includes powdered, liquefied and/or gaseous carrier) from a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of MAO-B inhibitor (Rasagiline or a salt thereof) and a suitable powder base such as, but not limited to, lactose or starch.
  • MAO-B inhibitor Rosagiline or a salt thereof
  • suitable powder base such as, but not limited to, lactose or starch.
  • compositions of the invention may contain excipients such as antioxidants, chemical preservatives, buffering agents, agents that increase viscosity, diluents, pH adjusters, and solvents.
  • Antioxidants are substances that prevent oxidation of the formulations.
  • Suitable antioxidants for use in the compositions of the invention include, without being limited to, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, and the like.
  • the pharmaceutical composition of the present embodiments contains a preservative chosen in quantities that preserve the composition but do not cause irritation of the nasal mucosa.
  • suitable preservatives include, without limiting, benzalkonium chloride, methyl, ethyl, propyl- or butylparaben, benzyl alcohol, phenylethyl alcohol, benzethonium, and combinations thereof.
  • compositions of the present embodiments may contain other pharmaceutically acceptable ingredients well known in the art.
  • excipients include, without limiting, chelating agents such as edetic acid or a salt thereof, flavors, sweeteners, thickening, adhesive or gelling agents, e.g., celluloses such as methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxyl cellulose and microcrystalline cellulose, poloxomers, polyethylene glycols, carbomers or polyethylene oxide.
  • compositions of the present invention when formulated for intranasal administration, may be used in any dosage dispensing device adapted for intranasal administration.
  • the device should be constructed with a view to ascertaining optimum metering accuracy and compatibility of its constructive elements.
  • a device configured for intranasal administration of a pharmaceutical composition comprising a MAO-B inhibitor (Rasagiline or a salt thereof) as described herein to a subject.
  • a MAO-B inhibitor Rosagiline or a salt thereof
  • the device is configured for dispensing the composition, from a container comprising the composition, and may comprise means for dispensing a pre-determined dose of the composition from the container and delivering said dose intranasally.
  • the pre-determined dose is such that when administered intranasally, results in an amount of the MAO-B inhibitor in the brain which is a therapeutically effective amount, as described herein, and/or is sufficient to inhibit MAO-A in the brain, as described herein.
  • a system for intranasal administration of Rasagiline or a pharmaceutically acceptable salt thereof as described herein comprises means for dispensing a pre-determined dose of Rasagiline or a salt thereof and for intranasally delivering the pre-determined dose, which is effective for alleviating neuropsychiatric and motor symptoms associated with Parkinson's disease, as described herein.
  • a system for intranasal administration of Rasagiline or a pharmaceutically acceptable salt thereof as described herein comprises means for dispensing a pre-determined dose of Rasagiline or said salt thereof and for intranasally delivering the pre-determined dose, which is g effective for treating neuropsychiatric and/or neurodegenerative conditions in a subject in need thereof, as described herein.
  • compositions may be administered as drops, sprays, aerosols or by any other intranasal dosage form or a dosage form for administering into the brain, as described herein.
  • the delivery system may be a unit dose delivery system.
  • the volume of solution, powder or suspension delivered per dose may be anywhere from 10 to 10000 ⁇ and preferably 1000-5000 ⁇ .
  • Delivery systems for these various dosage forms may be dropper bottles, plastic squeeze units, atomizers, nebulizers, metered nasal sprayers, metered-occular sprays, or pharmaceutical aerosols in either unit dose or multiple dose packages.
  • Aerosol systems require a propellant to be inert towards the formulation.
  • Suitable propellants may be selected among such gases as fluorocarbons, hydrocarbons, nitrogen and dinitrogen oxide or mixtures thereof.
  • the device is configured for dispensing a composition, as described herein, wherein the composition is a solid compotation (e.g., in a powder form).
  • the MAO-B inhibitor is Rasagiline (N-propargyl-l-(R)-aminoindan) or a salt thereof.
  • the MAO-B inhibitor is Rasagiline or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of pharmaceutically acceptable salts of Rasagiline include the mesylate salt; the esylate salt; the maleate salt; the fumarate salt; the tartrate salt; the sulfate salt; the hydrochloride salt; the hydro bromide salt; the p- toluenesulfonate salt; the benzoate salt; the acetate salt; or the phosphate salt of rasagiline.
  • Pharmaceutically acceptable salts of rasagiline may be prepared according to any suitable technique known in the art, e.g., as described in detail in US 5,532,415.
  • the Rasagiline is used as a mesylate salt of Rasagiline.
  • the MAO-B inhibitor e.g., aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-a)-2-N-B inhibitor
  • Rasagiline can be in any of the possible stereoisomers or enantiomers, or as a mixture of two or more stereoisomer sot enantiomers, or as a racemic mixture.
  • an amount of Rasagiline or a salt thereof administered to the brain of the subject is lower than an amount equivalent to 10 mk/kg per day in rats, that is, lower than the amount required for inhibiting MAO- A in the brain when Rasagiline or a salt thereof is administered orally or IP.
  • an amount of Rasagiline or a salt thereof administered to the brain of the subject is higher than an amount equivalent to 1 mg per day in humans.
  • An amount of 1 mg in humans is equivalent to about 0.1 mg/kg in rats.
  • the amount is higher than 2 mg, and in come embodiments, the amount is 1.1, 1.5,1.8, 2, 2.5, 3, 3.5, 4, 4.5, 5 or higher, including any intermediate value or subranges between said values.
  • an amount of Rasagiline or a salt thereof administered to the brain of the subject is higher than an amount equivalent to 0.1 mg/kg in rats, and can range, for example, from an amount equivalent to 0.2 mg/kg in rats to 6 mg/kg in rats, including any value and subrange therebetween.
  • MAO-B inhibitors such as selegiline (( ?)-N-methyl-N-(l-phenylpropan- 2-yl)prop-l-yn-3-amine; L-depreny; Eldepryl), and optionally safinamide (V2- ⁇ 4-[(3- fluorobenzyl)oxy]benzyl ⁇ -L-alaninamide), or a pharmaceutically acceptable salt thereof, can be used instead of Rasagiline.
  • a methodology can be used for improving the ratio of inhibiting an activity of MAO-A such that inhibition of brain MAO-A is higher than inhibition of peripheral (e.g., liver and/or intestine) MAO-A, namely that the ratio between inhibition of brain and peripheral MAO-A is higher than 1.
  • Such an improvement when compared, for example, to the ratio obtained when Rasagiline or a salt thereof is administered orally or IP, is advantageous, for example, as it reduced the side effects associated with inhibiting peripheral MAO-A, yet allows to obtain higher amount of the drug in the brain and thus benefit from additional therapeutic effect such as alleviation or treatment of neuropsychiatric symptoms and/or conditions, as described herein.
  • Such a methodology can be used by mode of administrations other than intranasal administration, or any other administration to the brain, as described herein.
  • a method of treating a neuropsychiatric and/or neurodegenerative condition is a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of Rasagiline or a pharmaceutically acceptable salt thereof, wherein administration is effected at a dose and/or a mode of administration selected such that a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A in the subject is higher than 1, as described in any one of the respective embodiments herein.
  • a system configured for administering Rasagiline or a pharmaceutically acceptable salt thereof to a subject in need thereof, the system comprising means for delivering Rasagiline or a salt thereof to the subject, wherein the means are such that upon delivering Rasagiline or said salt thereof, a ratio of the inhibition of an activity of brain MAO-A to inhibition of an activity of peripheral MAO-A in the subject is higher than 1, according to any one of the respective embodiments described herein.
  • Exemplary modes of administration and corresponding systems include, without limitation, transdermal administration, e.g., via a patch; topical administration; local administration to the brain by, e.g., injection or by guided therapy; and intranasal administration and corresponding systems as described herein.
  • any of the methods and systems and compositions as described herein can be utilized for improving the efficacy of Rasagiline or a salt thereof by means of activities exerted by its metabolites, particularly by the l-(R)-amino indan.
  • this metabolite may exhibit additional therapeutic effects such as neuroprotective and neurorestorative effects in the brain.
  • Using the compositions, methods and systems as described herein should result in enhanced concentration of this metabolite in the brain and thus by additional therapeutic effects of a composition comprising Rasagiline or a salt thereof, as described herein.
  • the methods, compositions and systems as described herein which account for a relatively high amount of Rasagiline in the brain, and hence, presumably for a relatively high amount of its metabolites in the brain, can be beneficially used for treating various neurodegenerative and neuropsychiatric conditions that can be treated by the aminoindan metabolite, and, for example, by its neuroprotective and neurorestorative effect.
  • These conditions include any one of the conditions listed in the Examples section hereinbelow and those which have been previously described, including Parkinson's disease per se and a neuropsychiatric condition.
  • the MAO-B inhibitor can be used in combination with an additional active agent or drug, for example, an anti-Parkinsonian drug such as 1-DOPA.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • Rasagiline (mesylate salt), was used.
  • Rasagiline (0.1 and 0.3 mg/kg) and vehicle were administered intraperitonealy
  • IP intranasally
  • NAS intranasally
  • Figure 1 demonstrates that rasagiline (0.3 mg/kg) significantly inhibited brain MAO-A inhibition by using NAS delivery compared to IP administration.
  • Figure 2 demonstrates that no significant difference in brain MAO-B inhibition is observed between the two modes of drug administration
  • Figure 3 demonstrates that rasagiline (0.3 mg/kg) significantly inhibited liver
  • Rasagiline as a mesylate salt
  • a mesylate salt of Rasagiline was used in all experiments.
  • Powder formulation of rasagiline was prepared using a dextrose filler.
  • Liquid formulation of rasagiline was prepared in water as a vehicle. Control liquid formulations included vehicle only.
  • intranasal (I.N.) delivery of rasagiline in powder formulation at 0.6 mg/kg caused a significant higher inhibition of striatal MAO- A activity, compared to the same dose of rasagiline delivered in liquid formulation in rats.
  • Table 2 presents the data obtained for MAO-B inhibition.
  • Rasagiline at doses ranging from 0.24 to 6 mg/kg
  • significantly inhibited about 98 %; p ⁇ 0.05
  • MAO-B activity in the striatum and hippocampus of drug-treated rats compared to respective vehicle-treated animals (not shown).
  • Table 2 (MAO-B Inhibition)
  • Table 3 below, and Figure 7, present the ratio of MAO-A inhibition in the CNS vs. the periphery, represented by the ratio of MAO-A inhibition in striatum/ Hippocampus and intestines or striatum/Hippocampus and liver, upon intranasal (I.N.) delivery of rasagiline, at variables doses in powder formulation.
  • a dose of 0.6 mg/kg intranasally delivered Rasagiline resulted in the highest ratio of % MAO-A inhibition in the striatum vs. small intestine.
  • Liquid oral formulation of rasagiline was prepared in water as a vehicle.
  • Control liquid formulations included vehicle only.
  • Figures 8 A and 8B present the effects of acute intranasal delivery vs. oral administration of rasagiline on rat striatal and hippocampal MAO-A and MAO-B, respectively, and the ratio of striatal/small intestinal MAO-A inhibition, respectively.
  • Figure 9 presents the ratio of % MAO-A inhibition in the striatum/small intestine, and shows that Rasagiline exerted significantly lower MAO-A inhibition in the periphery (small intestine) following intranasal delivery, compared to P.O. administration.
  • the tail suspension test is one of the most widely used models for assessing antidepressant- like activity in mice, based on the fact that animals that are subjected to short-term, inescapable stress by being suspended by their tail, will develop an immobile posture [Cryan, et al. Neurosci Biobehav Rev, 2005. 29: 571-625].
  • the TST was assayed using Rasagiline (0.2 mg/kg) and its metabolite l-(R)-aminoindan (5 mg/kg), vs. control, and the results are presented in Figure 10. It is shown that the duration of immobility of vehicle-treated aged rats was higher than vehicle-treated young animals. It is further shown that both rasagiline and l-(R)-aminoindan reduced the duration of immobility of drug-treated aged rats, compared to vehicle-aged group.

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Abstract

L'invention concerne des compositions, procédés et dispositifs pour l'administration de Rasagiline ou d'un sel pharmaceutiquement acceptable de cette dernière. Les compositions, dispositifs et procédés peuvent être utilisés pour traiter des affections telles que des symptômes ou affections neuropsychiatriques (par exemple, la dépression), des affections neurodégénératives telles que la maladie de Parkinson et/ou des symptômes moteurs et neuropsychiatriques associés à la maladie de Parkinson.
PCT/IL2014/050282 2014-03-13 2014-03-13 Procédés, compositions et dispositifs destinés au traitement des symptômes moteurs et dépressifs associés à la maladie de parkinson Ceased WO2015136515A1 (fr)

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PCT/IL2015/050267 WO2015136543A1 (fr) 2014-03-13 2015-03-12 Procedes, compositions et dispositifs pour le traitement de symptômes moteurs et de depression associes a la maladie de parkinson

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PCT/IL2015/050267 Ceased WO2015136543A1 (fr) 2014-03-13 2015-03-12 Procedes, compositions et dispositifs pour le traitement de symptômes moteurs et de depression associes a la maladie de parkinson

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113924086A (zh) * 2019-04-17 2022-01-11 维奇健康科学有限责任公司 液体药物组合物
EP3886612A4 (fr) * 2018-11-26 2022-08-17 Roar Holding LLC Procédés d'amélioration de la qualité d'une boisson
WO2023133463A1 (fr) * 2022-01-06 2023-07-13 Cyrano Therapeutics, Inc. Administration nasale améliorée d'agents thérapeutiques contre parkinson
US11774458B2 (en) 2014-02-18 2023-10-03 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US12241048B2 (en) 2014-09-16 2025-03-04 Roar Holding Llc Energy drinks and other nutritional aids derived from agave-based spirits
US12329753B2 (en) 2008-07-23 2025-06-17 Cyrano Therapeutics, Inc. Phosphodiesterase inhibitor treatment

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US5891923A (en) * 1990-01-03 1999-04-06 Teva Pharmaceutical Industries Ltd. R-enantiomer of N-propargyl-1-aminoindan for the treatment of dementia
WO2009003147A1 (fr) * 2007-06-26 2008-12-31 Parkinson's Institute Procédés et compositions destinés au traitement d'affections neurologiques

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US5891923A (en) * 1990-01-03 1999-04-06 Teva Pharmaceutical Industries Ltd. R-enantiomer of N-propargyl-1-aminoindan for the treatment of dementia
WO2009003147A1 (fr) * 2007-06-26 2008-12-31 Parkinson's Institute Procédés et compositions destinés au traitement d'affections neurologiques

Non-Patent Citations (1)

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Title
RAVI PR ET AL.: "Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization.", DRUG DELIV., 29 November 2013 (2013-11-29) *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12329753B2 (en) 2008-07-23 2025-06-17 Cyrano Therapeutics, Inc. Phosphodiesterase inhibitor treatment
US11774458B2 (en) 2014-02-18 2023-10-03 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US12298316B2 (en) 2014-02-18 2025-05-13 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US12241048B2 (en) 2014-09-16 2025-03-04 Roar Holding Llc Energy drinks and other nutritional aids derived from agave-based spirits
EP3886612A4 (fr) * 2018-11-26 2022-08-17 Roar Holding LLC Procédés d'amélioration de la qualité d'une boisson
CN113924086A (zh) * 2019-04-17 2022-01-11 维奇健康科学有限责任公司 液体药物组合物
WO2023133463A1 (fr) * 2022-01-06 2023-07-13 Cyrano Therapeutics, Inc. Administration nasale améliorée d'agents thérapeutiques contre parkinson

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