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  • 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
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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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
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  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
• • 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
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• rasagiline is a selective inhibitor of the B-form of the enzyme monoamine oxidase ("MAO-B") and is useful in treating Parkinson's disease and various other conditions by inhibition of MAO-B in the brain.
• MAO-B monoamine oxidase
• AZILECT is a commercially available rasagiline mesylate immediate release formulation indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.
• the current marketed formulation of rasagiline (Azilect®) is rapidly absorbed, reaching peak plasma concentration (t max ) in approximately 1 hour.
• the absolute bioavailability of rasagiline is about 36%.
• MAO monoamine oxidase
• a concern in using monoamine oxidase (“MAO”) inhibitors is the risk of hypertensive crises, often called the "cheese effect.” (Simpson, G.M. and White K.
• Rasagiline is a nonspecific inhibitor of MAOA, and has been shown to inhibit MAOA activity in the brain and liver of rats.
• This invention provides a method of preferentially inhibiting monoamine oxidase A (MAOA) in the brain of a subject relative to in the intestine of the subject comprising parenterally administering to the subject a formulation comprising a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof .
• MAOA monoamine oxidase A
• This invention also provides a method of method of treating a subject in need of rasagiline therapy comprising parenterally administering to the subject a formulation comprising a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
• This invention also provides the use of a controlled release formulation of rasagiline or a pharmaceutically acceptable salt thereof for the preparation of a medicament to preferentially inhibit MAOA in the brain of a subject relative to in the intestine of the subject, or to treat a subject in need of rasagiline therapy.
• This invention also provides a controlled release formulation of rasagiline or a pharmaceutically acceptable salt thereof for use in preferentially inhibiting MAOA in the brain of a subject relative to in the intestine of the subject, or to treat a subject in need of rasagiline therapy.
• ALZET® pumps groups were weighed on the first and last day of the study.
• the oral administered groups were weighed on the first day and also on day 6 and 13 of the study.
• Figure 2 shows that all groups gained about 6- 9% except the group of 0.8 mg/kg/day delivered by ALZET® pumps, in which the weight gain was lower (1.3%) .
• R ( + ) -N-propargyl-l-aminoindan (R-PAI) , also known as rasagiline, is a small molecule having the following chemical structure:
• Rasagiline has been reported to be a selective inhibitor of the B-form of the enzyme monoamine oxidase ("MAO-B”) and is useful in treating Parkinson's disease and various other conditions by inhibition of MAO-B in the brain.
• MAO-B monoamine oxidase
• This invention provides a method of preferentially inhibiting monoamine oxidase A (MAOA) in the brain of a subject relative to in the intestine of the subject comprising parenterally administering to the subject a formulation comprising a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof .
• MAOA monoamine oxidase A
• the therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof is delivered substantially entirely into the bloodstream of the subject so as to reduce or avoid intestinal inhibition of MAOA while enhancing MAOA inhibition in the brain of the subject.
• the subject is in need of rasagiline therapy.
• the formulation is a controlled release formulation.
• rasagiline is rasagiline base.
• the pharmaceutically acceptable salt is citrate, tannate, malate, mesylate, maleate, fumarate, tartrate, esylate, p-toluenesulfonate, benzoate, acetate, phosphate or sulfate.
• This invention also provides a method of treating a subject in need of rasagiline therapy comprising parenterally administering to the subject a formulation comprising a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
• the formulation is a controlled release formulation.
• rasagiline is rasagiline base.
• the pharmaceutically acceptable salt is citrate, tannate, malate, mesylate, maleate, fumarate, tartrate, esylate, p-toluenesulfonate, benzoate, acetate, phosphate or sulfate.
• the subject in need of rasagiline therapy is a subject afflicted with Parkinson's Disease.
• the subject in need of rasagiline therapy is a subject afflicted with premotor Parkinson's Disease.
• the subject in need of rasagiline therapy is a subject afflicted with attention deficit hyperactivity disorder (ADHD) , bipolar disorder, depression, post-traumatic stress disorder (PTSD) , multiple system atrophy (MSA) , Progressive Supranuclear Palsy (PSP) or amyotrophic lateral sclerosis (ALS) .
• ADHD attention deficit hyperactivity disorder
• PTSD post-traumatic stress disorder
• MSA multiple system atrophy
• PSP Progressive Supranuclear Palsy
• ALS amyotrophic lateral sclerosis
• the subject in need of rasagiline therapy is a subject afflicted with restless legs syndrome, hearing loss, glaucoma, or olfactory dysfunction.
• the subject in need of rasagiline therapy is a subject afflicted with Parkinson's Disease, Multiple Sclerosis (MS), Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS) or Huntington's Disease (HD) .
• the subject in need of rasagiline therapy is a subject afflicted with depression.
• the percentage of MAOA inhibition in the brain is at least 5% higher than for a corresponding oral dose. In another embodiment, the percentage of MAOA inhibition in the brain is at least 6% higher than for a corresponding oral dose. In another embodiment, the percentage of MAOA inhibition in the brain is at least 7% higher than for a corresponding oral dose. In one embodiment, the percentage of MAOA inhibition in the brain is at least 10% higher than the percentage of MAOA inhibition in the intestine. In another embodiment, the percentage of MAOA inhibition in the brain is at least 20% higher than the percentage of MAOA inhibition in the intestine. In another embodiment, the percentage of MAOA inhibition in the brain is at least 30% higher than the percentage of MAOA inhibition in the intestine. In another embodiment, the percentage of MAOA inhibition in the brain is at least 40% higher than the percentage of MAOA inhibition in the intestine.
• the controlled release formulation is a subcutaneous osmotic pump.
• the controlled release formulation releases rasagiline or a pharmaceutically acceptable salt thereof at a rate of 0.25 yl/hr-10.0 ⁇ /hr. In another embodiment, the controlled release formulation releases rasagiline or a pharmaceutically acceptable salt thereof at a rate of about 0.5 ⁇ /hr. In one embodiment, the controlled release formulation comprises rasagiline at a daily dosage of 0.003 mg/kg- 0.13 mg/kg. In another embodiment, the controlled release formulation releases rasagiline at a daily dosage of about 0.016 mg/kg. In one embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week to 6 months.
• the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week. In one embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week to 6 months. In another embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 2 weeks. In one embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week to 6 months. In another embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 4 weeks. In one embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week to 6 months.
• the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 2 months. In one embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week to 6 months. In another embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 4 months. In one embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 1 week to 6 months. In another embodiment, the controlled release formulation contains a total amount of rasagiline for a course of therapy lasting 6 months.
• the subject is human.
• This invention also provides a controlled release parenteral formulation comprising rasagiline or a pharmaceutically acceptable salt thereof.
• the controlled release parenteral formulation is an osmotic pump. In one embodiment, the controlled release parenteral formulation is a subcutaneous osmotic pump, vaginal ring, or vaginal cream.
• This invention also provides the use of a controlled release formulation of rasagiline or a pharmaceutically acceptable salt thereof for the preparation of a medicament to preferentially inhibit MAOA in the brain of a subject relative to in the intestine of the subject, or to treat a subject in need of rasagiline therapy.
• This invention also provides a controlled release formulation of rasagiline or a pharmaceutically acceptable salt thereof for use in preferentially inhibiting MAOA in the brain of a subject relative to in the intestine of the subject, or to treat a subject in need of rasagiline therapy.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
• a "controlled release" of an agent refers to the release of the agent at a predetermined rate over time .
• an osmotic pump refers to a drug form or formulation which releases an agent at a controlled, and usually predetermined, rate using osmotic pressure.
• a "subject in need of rasagiline therapy” means a subject suffering from any condition for which rasagiline has a therapeutic benefit.
• Such conditions include, but are not limited to, Parkinson's Disease, premotor Parkinson's Disease, amyotrophic lateral sclerosis, restless legs syndrome (RLS) , multiple system atrophy (MSA) , hearing loss, glaucoma, olfactory dysfunction, Progressive Supranuclear Palsy (PSP) , attention deficit hyperactivity disorder (ADHD) , bipolar disorder, depression, or post-traumatic stress disorder (PTSD) .
• Parkinson's Disease premotor Parkinson's Disease
• Amyotrophic lateral sclerosis restless legs syndrome
• MSA multiple system atrophy
• PSP Progressive Supranuclear Palsy
• ADHD attention deficit hyperactivity disorder
• bipolar disorder depression
• post-traumatic stress disorder PTSD
• rasagiline means rasagiline base or a pharmaceutically acceptable salt thereof.
• a “salt” is salt of the instant compounds which have been modified by making acid or base salts of the compounds.
• pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.
• a “pharmaceutically acceptable salt” of rasagiline includes citrate, tannate, malate, mesylate, maleate, fumarate, tartrate, esylate, p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts.
• the free base can be reacted with the desired acids in the presence of a suitable solvent by conventional methods.
• Rasagiline can also be used in its free base form.
• a process of manufacture of the rasagiline free base is described in U.S. Patent Nos. 7,750,051 and 7,968,749, the contents of which are hereby incorporated by reference.
• administering to the subject means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject to relieve or cure a pathological condition.
• Oral administration is one way of administering the instant compounds to the subject.
• an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this disclosure.
• an amount effective to treat a symptom of a disorder or disease without causing undue adverse side effects is administered to the patient.
• the specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compounds or its derivatives.
• drug substance refers to the active ingredient in a drug product, which provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
• drug product refers to the finished dosage form containing the drug substance as well as at least one pharmaceutically acceptable carrier.
• a dosage unit may comprise a single compound or mixtures of compounds thereof.
• a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, and granules.
• a "pharmaceutically acceptable" carrier or excipient is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
• to "treat” or “treating” encompasses, e.g., inducing inhibition, regression, or stasis of the disorder and/or disease.
• inhibittion of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
• MAOA is the natural barrier to indirect sympathomimetic amines such as tyramine, which act by releasing norepinephrine (NE) from nerve endings, which may cause a malignant increase in blood pressure (the "cheese effect") .
• NE norepinephrine
• MAOA is important for the catabolism of tyramine which is ingested in certain foods.
• Tyramine at lmg injected systematically, causes an increase of 59 mmHg in blood pressure.
• M.J. Rand, J. Wilson Mechanisms of the pressor and depressor actions of St 155 (2- (2, 6-dichlorophenylamino) -2-imidazoline hydrochloride, catapres®) , European Journal of Pharmacology, Volume 3, Issue 1, April 1968, Pages 27-33, ISSN 0014-2999, 10.1016/0014-2999(68)90044-7. This is due to the fact that most of the tyramine is catabolized by the liver MAO enzymes.
• Rasagiline was administered to male Sprague Dawely rats, 6 in a group, using ALZET® osmotic minipumps model 2002 (DURECT Corporation, Cupertino, CA 95014) .
• ALZET® osmotic minipumps are described in Perkins L, Peer C, and Murphy-hackley P. "Chapter 21: The use of mini-osmotic pumps in continuous infusion studies" in Handbook of Pre-Clinical Continuous Intravenous Infusion, (Smith & healing, eds . , Taylor and Francis, 2000), the contents of which are incorporated herein by reference.
• Rasagiline concentrations in the pumps were calculated in order to deliver daily doses of 0, 0.02, 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg rasagiline salt (0, 0.013, 0.032, 0.064, 0.13, 0.26 and 0.52 base) .
• Similar daily doses of rasagiline were given by oral administration (2 ml/kg) Each route of administration had its own control (saline) group .
• Rats were anesthetized in a chamber with 4% Isoflurane. During surgical procedure anesthesia was maintained by a homemade nose cone with 1.5% Isoflurane.
• the osmotic minipumps were inserted subcutaneously with a single surgical procedure: after clipping the fur from the dorsal area and cleaning the skin with antiseptic skin preparation, about 1 cm long incision was made on the dorsum of the animal, midway between both scappulae.
• the pump was placed along the axis of the body to one side of the backbone. The incision was positioned about
• a pair of hemostats was inserted through the incision under the skin in a cranial direction and the jaws of the hemostats opened to make a subcutaneous pocket for the minipump.
• the pump was inserted into the subcutaneous pocket and the skin sutured.
• Tissue homogenates were pre incubated (37°C) in the presence of clorgyline or deprenyl to inhibit the activity of MAO-A or MAO-B respectively.
• MAO-B determination samples were incubated for 20 minutes with C 14 PEA ⁇ and for MAO-A determination samples were incubated 30 minutes with C 14 ⁇ 5HT ⁇ as substrate Termination of the reaction was done by acidification.
• the labeled metabolites were extracted into toluene: ethyl acetate, and counted in a ⁇ counter. Percent of inhibition was calculated using the average dpm of the control group as 100% activity, by the formula:
• ALZET® pumps groups were weighed on the first and last day of the study.
• the oral administered groups were weighed on the first day and also on day 6 and 13 of the study.
• the percent weight changes is presented in Figure 2, which shows that all groups gained about 6 9 ⁇ 6 in weight except the group of 0.8 mg/kg/day delivered by ALZET® pumps, in which the weight gain was lower (1.3%) .
• a level of 48% inhibition was observed with a dose of 0.2 mg/kg/day (salt, equivalent to 0.13 mg/kg/day base) when administered orally and 12% inhibition when administered with the pumps.
• the highest dose of 0.8 mg/kg/day reached a level of 42% inhibition with the ALZET® pumps and 79% by the oral administration.
• MAO-A inhibition in the brain was higher than the inhibition caused by oral administration.
• a dose of 0.2 mg/kg/day given orally caused 37% brain MAO-A inhibition when given orally and 57% inhibition when given by the pumps.
• the dose of 0.8 mg/kg/day caused 78% by oral administration and 88% by the pumps.
• Doses of 0.4 and 0.8 mg/kg/day caused full inhibition when given by pumps while only 54 and 70% respectively when administered per os (p.o.) .
• Table 1 MAO-B and MAO-A activity in different tissues, two weeks after rasagiline administration continuous sc ALZET® pumps or by oral administration (dpm +/- sd)
• Table 2 Percent of MAO-B and MAO-A inhibition in different tissues, two weeks after rasagiline administration continuously by sc ALZET® pumps or by oral administration.
• the inhibition levels of MAO-A in the intestine were lower when rasagiline was administered continuously with the subcutaneous pumps compared with oral administration, Administration of rasagiline by systemic subcutaneous ALZET® osmotic pumps, for 14 days, reduced the amount of Rasagiline reaching the gut, a fact which was expressed in reduced values of MAOA inhibition in this organ, as compared to values of MAOA inhibition obtained by oral administration. These differences were statistically significant.
• the lower MAOA inhibition in the intestine in the ALZET® pump group indicates a diminished danger for tyramine induced hypertension.
• MAO inhibition by rasagiline administered by the subcutaneous ALZET® osmotic pumps was higher than that exerted by oral administration. Inhibition of MAOA in the brain to levels over 50% may cause in addition to some benefits in depression and other CNS functions, serotonin syndrome in depressed parkinsonian patients being treated concomitantly with selective serotonin uptake inhibitors (SSRIs) .
• One treatment for serotonin syndrome is the administration of serotonin antagonists.
• controlled release parenteral formulations of rasagiline are effective to treat diseases such as premotor Parkinson's Disease.
• Patients with Parkinson' s disease often experience symptoms such as autonomic dysfunction and impaired olfaction before the onset of motor symptoms. This stage of Parkinson' s is also known as premotor Parkinson' s Disease.
• the best results were observed at 0.1 mg/kg rasagiline which corresponds to 1 mg clinical human dose.
• the MAOA inhibition in the brain reaches 57% and is increased further to 76% and 88% with the higher doses of 0.4 and 0.8 mg/kg rasagiline, respectively. As mentioned previously, this may cause serotonin syndrome in patients receiving SSRIs. Higher doses of rasagiline administered parenterally could also potentially lead to excess rasagiline in the liver. MAOA inhibition in the liver reached 71%, 99% and 100% at 0.2, 0.4 and 0.8 mg/kg dosages of rasagiline, respectively.

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