WO2010111264A2

WO2010111264A2 - Rasagiline formulations

Info

Publication number: WO2010111264A2
Application number: PCT/US2010/028314
Authority: WO
Inventors: Deepak Gupta; Nagesh Nagaraju; Sanjay Tripathi; M. Pavan Kumar; Shrikant Vitthalrao Dhoke; Suryakumar Jayanthi
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories Inc.
Priority date: 2009-03-24
Filing date: 2010-03-23
Publication date: 2010-09-30
Also published as: WO2010111264A3

Abstract

The present invention relates to pharmaceutical formulations comprising rasagiline, or a pharmaceutically acceptable salt thereof. Aspects relate to formulations prepared using rasagiline or a salt with a particle size distribution wherein about 90% of the particles have particle sizes smaller than 1000 μm, and having content uniformity such that the formulation contains 90% to 110% of the label content of rasagiline or its salt. Further aspects relate to stable pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein the formulations are substantially free of a sugar alcohol.

Description

RASAGILINE FORMULATIONS

INTRODUCTION

Aspects of the present invention relate to pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof. Further aspects of the invention relate to processes for making pharmaceutical formulations and to methods of using pharmaceutical formulations for the management of diseases, such as for the treatment of Parkinson's disease.

The drug compound having the adopted name "rasagiline mesylate" has chemical names: (1 R)-N-prop-2-ynyl-2,3-dihydro-1 H-inden-1 -amine methanesulfonate; or 1 H-inden-1 -amine, 2,3-dihydro-N-2-propynyl-, (1 R)-, methanesulfonate; and has structural Formula I.

Formula I Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. Rasagiline mesylate is the active ingredient in AZI LECT^® tablets from Teva Neuroscience, Inc., intended for oral administration and containing 0.5 mg and 1 mg of rasagiline free base equivalent. Each AZILECT^® tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid, and talc. Rasagiline mesylate is prescribed for the treatment of idiopathic Parkinson's disease, as initial monotherapy and as adjuvant therapy with levodopa.

U.S. Patent No. 5,457,133 discloses rasagiline and its pharmaceutically acceptable salts, and U. S. Patent No. 5,532,415 discloses the mesylate salt of rasagiline.

U. S. Patent Nos. 5,387,612 and 5,453,446 relate to methods of treating Parkinson's disease using rasagiline or a pharmaceutically acceptable salt. Various other patent documents relate to pharmaceutical formulations containing rasagiline or pharmaceutically acceptable salts.

U. S. Patent No. 5,786,390 discloses pharmaceutical formulations of rasagiline or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

U. S. Patent No. 6,126,968 relates to pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof and at least one alcohol selected from the group consisting of pentahydric and hexahydric alcohols. According to the patent, the presence of certain alcohols significantly improves stability of pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salts. Formulations disclosed include alcohols selected from mannitol, xylitol and sorbitol.

Several other publications, including International Application Publication No. WO 2006/057912 and U.S. Patent Application Publication No. 2008/0107729, relate to pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salts, wherein the formulations contain at least two sugar alcohols.

Especially for low-dose active ingredients like rasagiline, it is important to achieve content uniformity of active ingredient blends with pharmaceutical excipients, since drug content and bioavailability are dependent on the content uniformity. Poor content uniformity of the blend may lead to variable quantities of the drug in doses of a pharmaceutical formulation.

U.S. Patent Application Publication No. 2006/0188581 describes pharmaceutical preparations of rasagiline or salts having enhanced content uniformity of the active agent. The publication teaches that a homogeneous distribution of the drug substance can be achieved by certain particle size distributions that can be obtained by milling or other methods for altering particle sizes. The publication discloses a mixture of particles of a pharmaceutically acceptable salt of rasagiline having reduced particle sizes less than 250 μm.

There remains a need to develop stable formulations comprising rasagiline which are easy to manufacture using conventional techniques and equipment.

SUMMARY

Aspects of the present invention relate to pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof. In embodiments, the present invention provides pharmaceutical formulations comprising rasagiline mesylate.

In embodiments, formulations of the present invention comprise rasagiline mesylate in crystalline form, amorphous form, or mixtures of such forms. In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are smaller than about 1000 μm.

In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles have particle sizes from about 0.1 μm to about 1000 μm, or about 1 μm to about 500 μm, or about 10 μm to about 250 μm, or about 100 μm to about 150 μm.

In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are smaller than about 6 μm. In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are larger than about 200 μm, or larger than about 250 μm.

In embodiments, formulations of the present invention comprise rasagiline mesylate having particle surface areas about 0.01 to about 100 m²/g. In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are smaller than about 250 μm, the particle sizes being obtained without using a procedure for alteration of particle size such as milling, or any other technique.

In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein 90% of the particles have particle sizes from about 10 μm to about 250 μm, or from about 100 μm to about 150 μm, said particle sizes being obtained without using any procedure for alteration of particle sizes such as milling, or any other technique.

In embodiments, pharmaceutical compositions of the present invention have a content uniformity of a lubricated blend ranging from about 90% to about 1 10% of the label content of rasagiline mesylate, and a relative standard deviation not more than about 5%, or not more than about 2%.

In an aspect, the present invention includes stable pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. In embodiments, the present invention relates to stable formulations comprising rasagiline mesylate and at least one pharmaceutically acceptable carrier.

In embodiments, stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable carrier, free of a sugar alcohol.

In embodiments, stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable carrier, free of a pentahydric or hexahydric sugar alcohol. In embodiments, stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable carrier, free of mannitol, xylitol, and sorbitol.

In embodiments, stable pharmaceutical formulations of the present invention have total amounts of drug-related impurities less than about 5%, or less than about 2%, of the label rasagiline content after storage in a closed HDPE container at accelerated stability testing conditions of 4O⁰C and 75% relative humidity (RH), for at least 3 months.

In an aspect, the present invention provides processes for preparing pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof. In embodiments, pharmaceutical formulations of the present invention can be prepared using any of techniques including wet granulation, dry granulation, spray granulation, direct compression, and the like.

In an aspect, pharmaceutical formulations of the present invention provide in vitro drug release profiles such that more than 20%, or more than 50%, or more than 90%, of contained rasagiline mesylate is dissolved in less than 15 minutes, following immersion into an aqueous fluid.

The present invention provides methods of using pharmaceutical formulations comprising rasagiline or a salt thereof for the management of diseases or disorders, comprising administering a formulation containing an effective amount of the active agent.

In an aspect, the present invention provides methods of treatment of Parkinson's disease using pharmaceutical formulations comprising rasagiline or its pharmaceutically acceptable salt. In an aspect, the present invention provides methods of treatment of Parkinson's disease using pharmaceutical formulations comprising rasagiline or its pharmaceutically acceptable salt, wherein the formulations are used as a monotherapy. In an aspect, the present invention provides methods of treatment of

Parkinson's disease using pharmaceutical formulations comprising rasagiline or its pharmaceutically acceptable salt, wherein the formulations are used as an adjuvant to therapy with levodopa.

DETAILED DESCRIPTION

Aspects of the present invention provide pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof. In embodiments, rasagiline is in the form of its mesylate salt.

The term "rasagiline" wherever it appears includes rasagiline in the form of the free base, in the form of a pharmaceutically acceptable salt thereof, or any isomer, derivative, hydrate, solvate, or prodrug thereof.

The particle size distribution of a material can be described in terms of Di₀, D₅O, D₉₀, and D[4,3], used routinely to describe the particle sizes or size distributions. It is expressed as a volume, weight or surface percentage. D_x values, as used herein, are the sizes of particles for which x volume or weight percentage of the particles have sizes less than the value given. D[4,3] is the volume mean diameter of the particles. D₉₀, for example, means that 90% of the particles are below the specified particle size. Particle sizes or particle size distributions of the pharmaceutical formulations of rasagiline of the present invention can be determined using any techniques that are known to the person skilled in the art, including but not limited to microscopy, sieve analysis, size analysis by laser light diffraction, such as using a Malvern particle size analyzer (Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom), use of a Coulter counter, and the like. As used herein, the term "mean particle size" refers to the distribution of particles wherein about 50 volume percent of all particles measured have particle sizes less than the defined mean particle size value, and about 50 volume percent of all measurable particles measured have particle sizes greater than the defined mean particle size value; this can be identified by the term "D₅₀." Similarly, a particle size distribution where 90 volume percent of the particles have sizes less than a specified size is referred to as "D90" and a distribution where 10 volume percent of particles have sizes less than a specified size is referred to as "D₁₀."

In embodiments of the present invention, the formulations comprise rasagiline mesylate having particle size distributions such that D₉₀ is less than about 1000 μm.

In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle size distributions where D₉₀ is in the range of from about 0.1 μm to about 1000 μm, or about 1 μm to about 500 μm, or from about 10 μm to about 250 μm, or from about 100 μm to about 150 μm.

In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle size distributions where about 90% of the particles are smaller than about 6 μm.

In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle size distributions where about 90% of the particles are larger than about 200 μm, or larger than about 250 μm.

In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle surface areas of about 0.01 to about 100 m²/g.

In embodiments of the present invention, the formulations comprise rasagiline mesylate having particle size distributions where D₅₀ is less than about 800 μm, or less than about 500 μm.

In embodiments of the present invention, the formulations comprise rasagiline mesylate having particle size distributions where D₁0 is less than about 400 μm, or less than about 200 μm. In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle size distributions where D₉₀ Of rasagiline mesylate is smaller than about 250 μm, said particles being obtained without using any process for alteration of particle size. In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle size distributions where D₉₀ is in the range of from about 10 μm to about 250 μm, or from about 100 μm to about 150 μm, wherein the rasagiline mesylate is obtained without using any process for alteration of particle size.

It is recognized that finished pharmaceutical formulations, prepared using techniques such as granulation, compression, etc., frequently do not permit measurements of the particles sizes of their components. Therefore, a formulation is considered as "comprising" an ingredient having a specified particle size distribution, if that ingredient was added in the form of a solid during preparation of the formulation. In an aspect, the present invention includes stable pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In an aspect, the present invention includes stable formulations comprising rasagiline mesylate and at least one pharmaceutically acceptable carrier. In an aspect, the present invention includes stable formulations comprising rasagiline mesylate and at least one pharmaceutically acceptable carrier, wherein any rasagiline-related impurities, such as degradants formed during processing or storage, are not present at more than about 5% by weight of the label rasagiline content. In embodiments, formulations of the present invention include rasagiline or its pharmaceutically acceptable salt, present in crystalline form.

In embodiments, the formulations of the present invention include rasagiline or its pharmaceutically acceptable salt, which is substantially free from the amorphous form. The term "substantially free" of amorphous form means not more than about 5%, or not more than about 10%, by weight of the amorphous form of the rasagiline is present.

It is especially important for a low-dose drugs like rasagiline to maintain a uniformity of their blends with excipients. Lack of content uniformity may lead to higher or lower concentrations of the active in units of a dosage form prepared from a blend. While higher concentrations of an active in a dosage form unit may lead to toxicity, lower concentrations of the active may fail to provide adequate in vivo drug levels and thereby adversely affect bioavailability. In embodiments of the present invention, content uniformity of the compositions is achieved by using appropriate particle sizes of the drug particles and making a homogeneous mixture of drug and the excipients. The particle sizes play a role in forming such homogeneous mixtures. The particle sizes of the drug particles should be appropriate to provide a desired uniformity of content to the blends, so as to ensure that an optimum quantity of drug is present in a unit dosage form prepared using the blends. Content uniformity can be determined using test 905 "Uniformity of Dosage Units," in United States Pharmacopeia 29, United States Pharmacopeial Convention, Rockville, Maryland 2005.

Useful techniques of altering particle sizes according to the present invention include techniques such as, without limitation thereto, pulverizing, air jet milling (using compressed air or an inert gas), ball milling, homogenization using, for example, a high speed homogenizer, a high pressure homogenizer, an EmulsiFlex™ homogenizer (Avestin Inc., Ottawa, Canada), etc., colloid milling, microfluidizing, bead milling, and the like.

In embodiments, the particle sizes of rasagiline mesylate are adequate to maintain acceptable content uniformity of the blend that is used to make the pharmaceutical formulations of the present invention.

In embodiments, the particle sizes of rasagiline mesylate are adequate to maintain content uniformity of blends with excipients that are used to make pharmaceutical formulations of the present invention, such particle sizes being obtained inherently in a synthetic process for preparing rasagiline mesylate and without using any techniques to alter the particle sizes.

The content uniformity of a composition, such as a lubricated blend of drug and excipients, before the blend is compressed into tablets or made into other formulations, can be determined by random sampling of 300 mg to 500 mg portions of the blend. In embodiments, pharmaceutical compositions of the present invention have a content uniformity of a lubricated blend ranging from about 90% to about 110% of the theoretical content of rasagiline or a salt thereof, and a relative standard deviation value not more than about 5%, or not more than about 2%. Finished pharmaceutical formulations of the present invention have similar content uniformity and standard deviation values.

Pharmaceutical compositions of the present invention can be made into solid dosage forms such as solid dispersions, tablets, capsules, granules, pellets, beads, particles, mini-tablets, or orally disintegrating tablets, as well as liquid dosage forms such as solutions, suspensions, syrups, and the like. A solid dispersion is a dispersion of one or more active ingredients in an inert carrier or matrix, in a solid state, prepared by melting (fusion), solvent, or melting-solvent methods. Dispersions obtained through the fusion process are often called melts, and those obtained by the solvent method are frequently referred to as coprecipitates or coevaporates. Chiou and Riegelman classified solid dispersions into the following six representative types: simple eutectic mixtures, solid solutions, glass solutions and glass suspensions, amorphous precipitations in a crystalline carrier, compound or complex formation, and combinations thereof. In a solid solution the two components form a homogeneous one-phase system. These dispersions differ from simple mixtures of solid components, since their individual component particles cannot be distinguished using techniques such as optical microscopy.

Pharmaceutically acceptable excipients include any one or more of fillers, binders, diluents, disintegrants, glidants, lubricants, antioxidants, pH modifiers, buffering agents, organic acids, basifying agents, complexing agents, plasticizers, sweetners, flavors, colorants, film coating polymers, and the like.

Various useful fillers or diluents include, but are not limited to, different varieties and grades of starches like pregelatinized starch and maize starch, sugars such as lactose, sucrose, and trehalose, cellulose derivatives such as microcrystalline celluloses, and the like. Other useful diluents include but are not limited to carmelloses; calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and thbasic calcium phosphate.

Various useful binders include, but are not limited to, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones, copovidones, powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol™ products), methylcelluloses, polymethacrylates, and starches.

Various useful disintegrants include natural starches such as maize starch and potato starch; directly compressible starches such as starch 1500, modified starches such as carboxymethyl starch and sodium starch glycolate, starch derivatives such as amylase, various grades of crospovidones, croscarmellose sodium, alginic acid and sodium alginate, microcrystalline celluloses, cross-linked polymers, cross-linked starches, and the like.

Various useful glidants or anti-adherents include, but are not limited to, talc, silica derivatives, colloidal silicon dioxide, and the like, and mixtures thereof. Various plasticizers that can be used include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, and thethyl citrate.

Various lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, zinc stearate, castor oils, and waxes.

Other excipients particularly useful in making orally disintegrating dosage forms according to the present invention include sweetners, flavors, colors, and the like.

Various useful sweeteners include, but are not limited to, natural sweeteners such as sucrose, dextrose, fructose, and invert sugar, and synthetic sweeteners such as saccharin, aspartame, acesulfame potassium, cyclamates, and the like. Various useful flavoring agents include, but are not limited to, various fruit flavors, mint flavors, and other natural or synthetic flavors.

Various useful coloring agents include, but are not limited to, iron oxides, which can be red, yellow, black, or blends thereof, as well as other synthetic and natural agents that are used in pharmaceutical products. Various film-forming agents that are useful include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses (HPMC or hypromellose, different grades such as HPMC 6 cps, HPMC 15 cps, HPMC 50 cps being available), sodium carboxymethyl celluloses, etc., acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate thmellitates and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc., insoluble cellulose derivatives such as ethyl celluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acids, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (e.g., Eudragit™ products), chitosan and derivatives thereof, shellac and derivatives thereof, waxes, and fat substances. The poor permeability of rasagiline, leading to poor delivery characteristics, poses a tremendous challenge to the pharmaceutical formulation scientist in providing for its delivery in adequate concentrations into the systemic circulation. Some of the known approaches to improve permeability and/or solubility include salt formation, particle size reduction, pH adjustment, use of surfactants, emulsifiers, solubilizers, inclusion complexes with cyclodextrins, use of oily formulations, use of self-emulsifying drug delivery systems, formation of co- precipitates with hydrophilic polymers, and co-milling with hydrophilic excipients, to name a few. Surfactants improve the wettability of the active agent. According to an aspect of the present invention, various useful surfactants include, but are not limited to, sodium lauryl sulfate, cetrimide, polysorbates such as polysorbate 80, poloxamers such as poloxamer 188 and poloxamer 407, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycehdes available commercially such as GELUCIRE^®40/14, GELUCIRE^® 42/12, and GELUCIRE^® 50/13, vitamin E TGPS, TWEEN^® surfactants, SPAN^® surfactants, and mixtures thereof.

Emulsifying agents can include any of a wide variety of cationic, anionic, zwittehonic, and amphoteric surfactants, many of which are known in the art. Non- limiting examples of anionic emulsifying agents include the alkoyl isothionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, alkyl methyl taurates, and alkali metal salts including sodium or potassium salts of long chain fatty acids. Examples of amphoteric and zwitterionic emulsifying agents include, but are not limited to, carboxy, sulfonate, sulfate, phosphate, or phosphonate compounds. Examples are alkylimino acetates and iminodialkanoates and aminoalkanoates, imidazolinium and ammonium derivatives betaines, sultaines, hydroxysultaines, alkyl sarcosinates and alkanoyl sarcosinates, and the like. Examples of suitable emulsifying agents include disodium cocoampho diacetate, oxyethylenated glyceryl cocoate (7 EO), PEG-20 hexadecenyl succinate, PEG-15 stearyl ether, the ricinoleic monoethanolamide monosulfosuccinate salts, oxyethylenated hydrogenated ricinoleic triglyceride, poloxamers, non-solid fatty substances such as sesame oil, almond oil, apricot stone oil, sunflower oil, octoxyglyceryl palmitate (or 2-ethylhexyl glyceryl ether palmitate), octoxyglyceryl behenate (or 2-ethylhexyl glyceryl ether behenate), dioctyl adipate, tartrates of branched dialcohols, and the like. Other useful non- ionic emulsifying agents include alkylene oxide esters of fatty acids, alkylene oxide diesters of fatty acids, alkylene oxide ethers of fatty alcohols, alkylene oxide esters, and the like.

In embodiments, stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable excipient, free from a sugar alcohol.

In embodiments, stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable excipient, free from a pentahydric or hexahydhc sugar alcohol.

In embodiments, stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable excipient, free from mannitol, xylitol, and sorbitol.

"Free from" means that the ingredient is not intentionally added as a major ingredient during preparation of a composition; the composition can contain trace amounts of the ingredient, such as less than about 2%, or 1 %, or 0.5%, by weight. "Substantially free from" is similar, but with an upper concentration limit of about 5% by weight.

In an aspect, the present invention provides processes for preparing pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salt. The pharmaceutical formulations may be prepared using any of process operations such as wet granulation, dry granulation, spray granulation, direct compression, spheronization, and the like.

Pharmaceutical formulations of the present invention can be subjected to in vitro dissolution evaluations as described in Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Rockville, Maryland, 2005 ("USP"), to determine the release of drug from the dosage forms, and drug content can conveniently be determined in solutions using techniques such as high performance liquid chromatography.

The in vitro dissolution studies can be carried out using USP type Il apparatus and 500 ml_ of 0.1 N hydrochloric acid, pH 4.5 acetate buffer, or pH 6.8 phosphate buffer, as a dissolution medium, with a 50 rpm stirring speed. In embodiments, pharmaceutical formulations of the present invention provide in vitro dissolution profiles of rasagiline wherein more than about 20%, or more than about 50%, or more than about 90%, of the contained drug is dissolved within about 15 minutes after immersion of a dosage form into an aqueous medium. In certain embodiments of the invention, tablets prepared according to the invention and containing rasagiline mesylate equivalent to 1 mg of rasagiline provide comparable bioavailability to that of AZILECT^® 1 mg tablets, after oral administration of single doses to healthy humans. Comparable bioavailability is shown by pharmacokinetic parameters for a test product being 80% to 125% of the values for a reference product.

In embodiments, administration of a dose containing 1 mg of rasagiline produces maximum fasting state plasma concentrations (C_maχ) about 5000 to about 8000 pg/mL, and maximum fed state plasma concentrations (C_maχ) about 2000 to about 5000 pg/mL.

In embodiments, administration of a dose containing 1 mg of rasagiline produces areas under the fasting state plasma concentration vs. time curve (AUCo-t) about 3000 to about 7000 pg hour/mL, and areas under the fed state plasma concentration vs. time curve (AUCo-t) about 2000 to about 5000 pg-hour/mL

The present invention provides methods of using pharmaceutical formulations of rasagiline or its salt for the management of diseases or disorders, comprising administering a formulation containing an effective amount of the active agent. The formulations of the present invention are useful for prophylaxis, amelioration, or treatment of a disease state in a subject in need thereof.

The present invention also provides methods of treating Parkinson's disease using pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salt, comprising administering to a subject in need thereof a required quantity of rasagiline or a pharmaceutically acceptable salt thereof. The present invention also provides methods of treatment of Parkinson's disease, using pharmaceutical formulations of rasagiline mesylate, which comprise administering to a subject in need thereof a required quantity of rasagiline mesylate.

The present invention also provides methods of treatment of Parkinson's disease using the pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salts, wherein a pharmaceutical formulation can be used as a monotherapy.

The present invention also provides methods of treatment of Parkinson's disease using the pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salt, wherein a pharmaceutical formulation can be used as as adjuvant therapy together with levodopa.

In embodiments, the present invention includes the use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, and blisters or strips composed of aluminum, high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc. which are useful in packing the pharmaceutical formulations of the present invention. The described packaging materials are only representative, as many other materials will be suitable.

Certain specific aspects and embodiments of the invention will be further described in the following examples, which are provided only for purposes of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1 : Pharmaceutical formulations of rasagiline.

^*Prosolv is silicified microcrystalline cellulose, from JRS Pharma.

# 1.56 mg of rasagiline mesylate is equivalent to 1.0 mg of rasagiline base. t Evaporates during processing. Manufacturing process:

1. Sift powder blend ingredients through a #20 mesh sieve and blend together for 10 minutes in a fluidized bed processor.

2. Dissolve rasagiline mesylate and citric acid in water.

3. Granulate the mixture of step 1 by spraying the solution of step 2 in the fluidized bed processor, then dry the granules.

4. Sift the dried granules of step 3 through a #40 mesh sieve.

5. Sift croscarmellose sodium and colloidal silicon dioxide through a #40 mesh sieve.

6. Blend the granules of step 4 with the mixture of step 5.

7. Sift stearic acid through a #60 mesh sieve.

8. Blend the mixture of step 6 with stearic acid of step 7.

9. Compress the blend of step 8 into tablets.

EXAMPLE 2: Pharmaceutical formulation of rasagiline.

$ Evaporates during processing. Manufacturing process: 1 . Sift powder blend colloidal silicon dioxide and dicalcium phosphate through a #40 mesh sieve and mix.

2. Mix rasagiline mesylate in a geometric manner with the material of step 1 to achieve a homogeneous mixture.

3. Sift starch through a #30 mesh sieve and blend with the mixture of step 2, using a rapid mixer granulator.

4. Prepare a binder by dispersing starch in water at 60⁰C with stirring and add citric acid.

5. Granulate the mixture of step 3 using binder of step 4 and dry the granules.

6. Sift the dried granules through a #40 mesh sieve.

7. Sift extra-granular croscarmellose sodium and colloidal silicon dioxide through a #40 mesh sieve.

8. Blend the granules of step 6 with the mixture of step 7.

9. Sift stearic acid through a #60 mesh sieve.

10. Blend the mixture of step 8 with stearic acid of step 9.

1 1 . Compress the blend of step 10 into tablets.

EXAMPLE 3: Pharmaceutical formulation of rasagiline.

Manufacturing process:

1 . Mix rasagiline mesylate and dicalcium phosphate in a geometric manner to achieve a homogeneous mixture.

2. Sift povidone, colloidal silicon dioxide, and starch through a #30 mesh sieve and blend with the mixture of step 1 . 3. Sift stearic acid through a #60 mesh sieve.

4. Blend the mixture of step 2 with stearic acid of step 3.

5. Compress the blend of step 4 into tablets.

EXAMPLE 4: Pharmaceutical formulations of rasagiline.

t Evaporates during processing. Manufacturing process:

1. Dissolve rasagiline mesylate and the permeability enhancer in water.

2. Sift the diluent, corn starch and pregelatinized starch through a #20 mesh sieve and transfer to a fluid bed processor.

3. Granulate blend of step 2 by spraying the solution of step 1 onto the powder bed.

4. Dry the granules of step 3 at about 50⁰C until the loss on drying obtained is less than 3%.

5. Sift the dried granules of step 4 through a #30 mesh sieve.

6. Sift colloidal silicon dioxide and stearic acid through a #60 mesh sieve and blend with the granules of step 5.

7. Compress the blend of step 6 into tablets. EXAMPLE 5: Pharmaceutical formulations of rasagiline.

^* MicroceLac 100 is a commercially available spray-dried composition containing 75% alpha-lactose monohydrate and 25% microcrystalline cellulose. t Evaporates during processing. Manufacturing process:

1. Dissolve rasagiline mesylate in water.

3. Granulate the blend of step 2 by spraying the solution of step 1 , and dry the granules.

4. Sift the dried granules of step 3 through a #24 mesh sieve.

5. Sift colloidal silicon dioxide and lubricant through a #60 mesh sieve and blend with the granules of step 4.

6. Compress the blend of step 5 into tablets.

EXAMPLE 6: Pharmaceutical formulations of rasagiline.

Opadry White includes hypromellose, titanium dioxide and polyethylene glycol.

Manufacturing process:

1. Sift the diluent, corn starch and pregelatinized starch through a #20 mesh sieve.

2. Mix rasagiline mesylate with the blend of step 1 in a geometric manner.

3. Sift the blend of step 2 through a #20 mesh sieve and mix in a blender.

4. Sift colloidal silicon dioxide and lubricant through a #40 mesh sieve and blend with the granules of step 3.

5. Compress the blend of step 4 into tablets.

6. Coat the tablets of step 5 with a dispersion of Opadry White in water, and dry.

EXAMPLE 7: Pharmaceutical formulations of rasagiline.

Manufacturing process:

1. Sift the diluent, pregelatinized starch and disintegrant through a #20 mesh sieve.

2. Mix rasagiline mesylate with the blend of step 1.

3. Sift the blend of step 2 through a #20 mesh sieve.

4. Mix half the quantity of magnesium stearate with the blend of step 3 in a blender.

5. Roller-compact the blend of step 4.

6. Sift the compacted material through an oscillating granulator having a #30 mesh sieve.

7. Sift the remaining quantity of magnesium stearate through a #60 mesh sieve and blend with the granules of step 6.

8. Compress the blend of step 7 into tablets.

EXAMPLE 8: Pharmaceutical formulations of rasagiline.

$ Evaporates during processing. Manufacturing process:

1. Sift powder blend ingredients through a #20 mesh sieve and blend together for 10 minutes in a top spray fluidized bed processor.

2. Dissolve rasagiline mesylate acid in water.

3. Granulate the mixture of step 1 by spraying with the solution of 2 in the fluidized bed processor, and dry the granules.

4. Sift the dried granules through a #30 mesh sieve.

5. Sift extra-granular ingredients through a #60 mesh sieve and blend with the granules of step 4.

6. Compress the blend of step 5 into tablets.

For determination of content uniformity, samples are withdrawn from a double cone blender (after blending of granules with extra-granular excipients), from a stainless steel vessel (used for containing the blend immediately before tablet compression), and from the compressed 8A tablets. The content uniformity is compared with that of commercial AZILECT tablets. The content uniformity data are shown below, where the drug assay is expressed as a percentage of the label rasagiline content.

Samples of the 8A formulation are packaged in closed HDPE containers and stored at the accelerated stability testing conditions of 40⁰C and 75% RH. The impurity content is analyzed by HPLC at intervals and results are shown below, where values are percentages of the label rasagiline content.

Tablets prepared in 8A ("Test") are subjected to dissolution testing, using the USP procedure and the following dissolution conditions:

Medium: 50O mL of 0.1 N HCI. Stirring speed: 50 rpm.

Apparatus: USP Il paddle type. Standard = AZILECT^® 1 mg tablets. Results are as shown below:

A randomized, two-way crossover, open-label, single-dose, fasting state and fed state clinical study involves administration of single doses of the product 8A ("T") and the commercial product AZILECT 1 mg tablets ("R") to 18 healthy human volunteers, and plasma rasagiline concentrations are determined at intervals after dosing.

The following parameters are calculated:

AUCo-_t = the area under plasma concentration versus time curve, from the time of administration to the last measurable concentration, expressed in pg-hour/mL units.

Cmax = maximum plasma concentration following administration, expressed in pg/mL units.

Results are as shown below.

Claims

CLAIMS:

1. A pharmaceutical composition comprising rasagiline or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the composition: is free from sugar alcohols; and has content uniformity from about 90% to about 110% of the label content of rasagiline or its pharmaceutically acceptable salt, and a relative standard deviation not more than about 5%.

2. The pharmaceutical composition of claim 1 , wherein a sugar alcohol is a pentahydhc or hexahydhc alcohol.

3. A pharmaceutical composition of claim 1 , wherein a sugar alcohol is mannitol, xylitol, or sorbitol.

4. The pharmaceutical composition of claim 1 , wherein rasagiline or a pharmaceutically acceptable salt thereof is rasagiline mesylate.

5. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles in the range from about 0.1 μm to about 1000 μm.

6. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles in the range from about 1 μm to about 500 μm.

7. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles in the range from about 10 μm to about 250 μm.

8. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles in the range from about 100 μm to about 150 μm.

9. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles smaller than about 6 μm.

10. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles larger than about 200 μm

11. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles larger than about 250 μm.

12. The pharmaceutical composition of claim 4, wherein a rasagiline mesylate ingredient has a specific surface area about 0.01 m²/g to about 100 m²/g.

13. The pharmaceutical composition of claim 4, having total drug-related impurities in concentrations less than about 5% of the label rasagiline content, after storage at 40⁰C and 75% relative humidity for at least 3 months.

14. The pharmaceutical composition of claim 4, having total drug-related impurities in concentrations less than about 2% of the label rasagiline content, after storage at 40⁰C and 75% relative humidity for at least 3 months.

15. The pharmaceutical composition of claim 4, having a content uniformity of a lubricated powder blend immediately before compression, or of compressed tablets, ranging from about 95% to about 105% of the label content of rasagiline, and a relative standard deviation not more than about 5%.

16. The pharmaceutical composition of claim 4, providing a dissolution profile wherein more than about 20% of contained rasagiline mesylate is dissolved within 15 minutes after immersion into an aqueous fluid.

17. The pharmaceutical composition of claim 4, providing a dissolution profile wherein more than about 50% of contained rasagiline mesylate is dissolved within 15 minutes after immersion into an aqueous fluid.

18. The pharmaceutical composition of claim 4, providing a dissolution profile wherein more than about 90% of contained rasagiline mesylate is dissolved within 15 minutes after immersion into an aqueous fluid.

19. The pharmaceutical composition of claim 4 providing, after oral administration to healthy humans: a maximum fasting state plasma concentration (Cmax) about 5000 to about 8000 pg/mL; a maximum fed state plasma concentration (C_max) about 2000 to about 5000 pg/mL; an area under the fasting state plasma concentration vs. time curve (AUCo-t) about 3000 to about 7000 pg-hour/mL; and an area under the fed state plasma concentration vs. time curve (AUCo-t) about 2000 to about 5000 pg hour/mL.

20. A process for preparing a pharmaceutical composition comprising rasagiline, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, comprising using any of wet granulation, dry granulation, spray granulation, and direct compression, wherein the composition: is substantially free from sugar alcohols; and has content uniformity from about 90% to about 110% of the label content of rasagiline or its pharmaceutically acceptable salt, and a relative standard deviation value not more than about 5%.

21. The process of claim 20, wherein rasagiline or a pharmaceutically acceptable salt thereof is rasagiline mesylate.

22. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with 90% of the particles in the range from about 0.1 μm to about 1000 μm.

23. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with 90% of the particles in the range from about 1 μm to about 500 μm.

24. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with 90% of the particles in the range from about 10 μm to about 250 μm.

25. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with 90% of the particles in the range from about 100 μm to about 150 μm.

26. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles smaller than about 6 μm.

27. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles larger than about 200 μm.

28. The process of claim 21 , wherein a rasagiline mesylate ingredient has a particle size distribution with about 90% of the particles larger than about 250 μm.

29. A method of treating Parkinson's disease, comprising orally administering a pharmaceutical formulation comprising rasagiline, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the composition: is substantially free from sugar alcohols; and has content uniformity from about 90% to about 110% of the label content of rasagiline or its pharmaceutically acceptable salt, and a relative standard deviation not more than about 5%.

30. The method of claim 29, wherein a sugar alcohol is a pentahydhc or hexahydric sugar alcohol.

31. A method of treating Parkinson's disease, comprising orally administering a pharmaceutical formulation comprising rasagiline mesylate and at least one pharmaceutically acceptable excipient, wherein the formulation is substantially free from sugar alcohols.

32. The method of claim 31 , wherein a sugar alcohol is mannitol, xylitol, or sorbitol.

33. The method of claim 31 , wherein the pharmaceutical formulation is administered as a monotherapy.

34. The method of claim 31 , wherein the pharmaceutical formulation is administered as an adjuvant therapy with levodopa.