WO2013175493A1

WO2013175493A1 - Stable oral pharmaceutical compositions

Info

Publication number: WO2013175493A1
Application number: PCT/IN2013/000234
Authority: WO
Inventors: Sunilendu Bhushan Roy; Sushrut Krishnaji Kulkarni; Maulik Kiritkumar Panchal
Original assignee: Cadila Healthcare Limited
Priority date: 2012-04-09
Filing date: 2013-04-09
Publication date: 2013-11-28

Abstract

The present invention relates to pharmaceutical compositions of rasagiline, its enantiomer or salts thereof. In particular, the invention relates to stable pharmaceutical compositions of rasagiline, its enantiomer or salts thereof, process of preparation of such compositions.

Description

STABLE ORAL PHARMACEUTICAL COMPOSITIONS

FIELD OF THE INVENTION:

The present invention relates to pharmaceutical compositions of rasagiline, its enantiomer or salts thereof. In particular, the invention relates to stable pharmaceutical compositions of rasagiline, its enantiomer or salts thereof, process of preparation of such compositions and use thereof for treatment of Parkinson's disease, Dementia and Alzheimer's disease. BACKGROUND OF THE INVENTION:

Rasagiline is a selective irreversible inhibitor of monoamine oxidase enzyme Type-B (MAO-B) and has the chemical name N-propargyl-l (R)-aminoindan ("(R)-PAI"). Its structural formula is:

Rasagiline is an active MAO-B inhibitor while the corresponding S-enantiomer

("(S)-Rasagiline") shows extremely low MAO-B inhibitory activity (U.S. Patent No. 6,316,504). It has also been found that (R)-Rasagiline has a degree of selectivity for MAO-B inhibition surprisingly higher than that of the corresponding racemic form (U.S. Patent No. 6,316,504). The fact that (R)-Rasagiline is more active than the racemic mixture for the inhibition of MAO-B is a reflection of the extremely low activity of (S)- Rasagiline for inhibition of MAO-B (U.S. Patent No. 6,316,504).

Rasagiline, its salts, preparation and use for the treatment of Parkinson's disease, Alzheimer's disease, memory disorders, stroke and other disorders have been the subject of numerous patents, including U.S. Patent Nos. 5,387,612, 5,453,446, 5,457, 133, 5,668,181, 5,576,353, 5,532,415, 5,599,991 , 5,786,390, 5,519,061, 5,891 ,923, 5,744,500 and 6,316,504, the contents of which are hereby incorporated by reference.

Rasagiline is currently marketed in US in the form of film coated tablets under trade name Azilect® by Teva Pharmaceuticals. PCT publication No. WO 95/1 1016 discloses pharmaceutical formulations of rasagiline.

U.S. Patent No. 6, 126,968 subsequently disclosed that the formulations of PCT Publication No. 95/1 1016 were of unacceptable stability. U.S. Patent No. 6,126,968 then proceeds to offer certain alternative formulations of rasagiline intended to provide improved stability relative to the formulations of PCT Publication No. 95/1 1016. The tablet of R(+)-N-propargyl-l -aminoindane or pharmaceutical acceptable salt thereof disclosed in the patent comprises at least one alcohol selected from the group consisting of pentahydric and hexahydric alcohols such as mannitol, xylitol and sorbitol.

European Patent No. EP 0814789 discloses formulations of MAO-B inhibitors which attempt to address some of the known problems. However, the European patent relies on lyophilization of the MAO-B inhibitor formulations which is a costly process and results in high friability of the product, further increasing cost by necessitating costly special blister-pack packaging.

PCT Publication No. WO 2010/1 1 1264 discloses pharmaceutical formulations comprising rasagiline, or a pharmaceutically acceptable salt thereof with a particle size distribution wherein about 90% of the particles have particle sizes smaller than 1000 μηι, and having content uniformity such that the formulation contains 90% to 1 10% of the label content of rasagiline or its salt, wherein the formulations are substantially free of a sugar alcohol.

PCT publication No. WO 201 1/010324 discloses stable rasagiline compositions comprising rasagiline or its salts and a carrier selected from poly hydric alcohol, disaccharide(s) and poly saccharide(s) or mixtures thereof, and wherein the said composition is free of pentahydric or hexa hydric alcohols.

European Patent Application No. EP 1892233 discloses polymorphic forms of rasagiline oxalate and rasagiline edisilate. The patent application also discloses that mesylate, hydrochloride and phosphate salts of rasagiline show agglomerates after storage even in a closed glass bottle and can also display a slight discoloration and when stored under humid conditions (40°C, 75% relative humidity in an open glass bottle), a sticky powder which is difficult to process forms from said salts of rasagiline.

Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, chemical reactivity, stability etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. Polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice.

Moreover, poor physico-chemical and formulation characteristics of many salts of rasagiline possess limitations and challenge in developing a stable formulation.

Thus, there exists a need to provide a stable formulation of rasagiline which are suitable for all patient population and also such formulations, remain stable over the storage period.

SUMMARY OF THE INVENTION:

In a first general aspect, there is provided a stable pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and atleast one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols.

In another general aspect, there is provided a stable pharmaceutical composition comprising rasagiline besylate or its enantiomer and atleast one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols.

In another general aspect, there is provided a stable pharmaceutical composition comprising rasagiline hydrogen phosphate or its enantiomer and atleast one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols.

In another general aspect, there is provided a stable pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and atleast one antioxidant.

In another general aspect, there is provided a stable pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and atleast one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols, wherein said composition retains at least 80% of the potency of rasagiline, its enantiomer or salts thereof in the pharmaceutical composition after storage for three months at 40° C and 75% relative humidity.

In a further general aspect, there is provided a pharmaceutical packaging kit comprising a sealed oxygen impermeable container comprising a pharmaceutical composition comprising rasagiline„Hs enantiomer or salts thereof and at least one pharmaceutically acceptable stabilizer selected from the group consisting of an oxygen absorber, a moisture absorber or a combination thereof.

In a further general aspect, there is provided a pharmaceutical kit comprising a container having deposited therein rasagiline, its enantiomer or salts thereof in a solid unit dosage form and at least one oxygen absorber (preferably a self-activated absorber).

The oxygen absorber may be provided in a sachet, cartridge, canister or any other means of containing the absorber such that the absorber is physically separated from the solid dosage forms deposited in the container and has sufficient oxygen permeability to remove at least a portion of the oxygen in the air within the container.

The sealed oxygen permeable container may also include a desiccant.

In a further general aspect, there is provided a stable pharmaceutical composition comprising a pharmaceutical formulation comprising rasagiline„its enantiomer or salts thereof and at least one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols, and a packing not permeable to gas exchange, wherein the formulation is enveloped in the packaging under an inert gas atmosphere, said composition produced by the process of-

(i) packing said pharmaceutical formulation into the packing under an inert gas atmosphere; and

(ii) enveloping the formulation in the packaging under an inert gas atmosphere.

In a further general aspect, there is provided a method of stablization of pharmaceutical composition comprising a pharmaceutical formulation comprising rasagiline„its enantiomer or salts thereof and atleast one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols, the method comprising packing the pharmaceutical formulation into packing not permeable to gas exchange, wherein the packaging step is carried out in an inert gas atmosphere, and enveloping the formulation in the inert gas atmosphere.

In another general aspect, there is provided a stable pharmaceutical composition of rasagiline, its enantiomer or salt thereof comprising at least one stabilizer, at least one water soluble and/or water insoluble polymer and pharmaceutical excipients comprising disintegrating agents, diluents, fillers, binders, lubricants, glidants, sweeteners and flavors, wherein said composition is free of sugar alcohols or polyols. Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients. The pharmaceutical acceptable excipients may include fillers/diluents, binders, polymers, disintegrants, stabilizers, lubricants, glidants, sweeteners, taste masking agents and flavors.

In another general aspect, there is provided a pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and at least one stabilizer, wherein rasagiline, its enantiomer or salts thereof have 90th volume percentile particle size (D90) greater than about 250 μηι, or any combination thereof.

Alternatively, rasagiline, its enantiomer or salts thereof may have particle size distribution wherein 10th volume percentile particle size (D10) is greater than about 20 μιη, the 50th volume percentile particle size (D50) is greater than about 100 μιη, D(90) is greater than about 250 μηι, or any combination thereof.

In another general aspect, there is provided a method of treating Parkinson's disease, dementia and Alzheimer's disease in patient comprising administering to said subject a pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof comprising atleast one pharmaceutically acceptable stabilizer, and one or more pharmaceutical excipients, wherein said composition is free of sugar alcohols or polyols.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAIL DESCRIPTION OF THE INVENTION:

The inventors of the present invention have found that the stability of formulations comprising rasagiline, its enantiomer or salts thereof can be significantly improved by the incorporation of one or more pharmaceutically acceptable stabilizers other than amino sugars or polyols. Additionally, the inventors have found that formulations containing besylate and hydrogen phosphate salt of rasagiline may exhibit significant stability and in particular, possess good formulation characteristics. In accordance with the present invention, there is provided a stable pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and atleast one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols.

The composition retains at least 80% of the potency of rasagiline, its enantiomer or salts thereof in the pharmaceutical composition after storage for three months at 40° C and 75% relative humidity.

The term 'rasagiline' is used in broad sense to include not only the rasagiline per se but also its: pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and their crystalline and amorphous forms. Racemic, S(-) or R(+) enantiomers of rasagiline, and especially the enantiomer R(+) of rasagiline is particularly preferred. Particularly preferred salts of rasagiline or its enantiomer are besylate, hydrogen phosphate, mesylate, maleate, fumarate, tartrate, hydrobromide, esylate, tosylate, benzoate, oxalate, edisilate, phosphate, hydrochloride, acetate, sulphate.

In accordance with the present invention, there is provided a stable pharmaceutical composition of rasagiline comprising rasagiline, its enantiomer or salts thereof and atleast one antioxidant.

The inventors of the present invention have also found that the stability of pharmaceutical composition of rasagiline comprising rasagiline, its enantiomer or salts thereof can be significantly improved by packing the formulation with oxygen absorber or using a packing not permeable to gas exchange, or envelpoing the composition in the packaging under an inert gas atmosphere, without employing any sugar alcohols or polyols.

Accordingly, there is provided a pharmaceutical kit comprising a container having deposited therein rasagiline, its enantiomer or salts thereof in a solid unit dosage form and at least one oxygen absorber (preferably a self-activated absorber), moisture absorber or combinations thereof.

The term "oxygen absorbers" as used herein, means agents used to trap oxygen that is present in the overhead space of closed container. Concerning the chemical and physical mechanisms of active oxygen absorbers* they can be classified into the following categories:

• inorganic, metal based oxygen absorber

• ascorbic acid based absorber:

· enzymatic absorber

• polymer based oxygen absorber

Inorganic, metal-based oxygen absorbers are inexpensive, available with different 0₂- scavenging capacities in sachets and are commonly used in foods and beverages. The broadest range of iron-based products are offered by Mitsubishi Gas Chemicals Ageless™.

Similar products are also offered by Multisorb under the trade name Fresh Pax™. The reaction is based on the well-known corrosion of iron. Another variant for oxygen absorbers is self-activated oxygen absorbers which involve combining moisture-retaining additives to metals such as iron. Another modification of metal absorbers is "stealth absorbers", which is also based on corrosion of iron but the metal is embedded in an extendable plastic. Ascorbic acid is a well-known preserving agent and may also be used as one of the options. There are also available enzymatic oxygen absorber which are based on glucose/glucose oxidase.

Polymer based scavengers are suitable for moisture protected applications.

Polymer-based compounds consist of high molecular weight, ethylenically-unsaturated hydrocarbons. An activation step often enables the user to start the oxygen scavenging when desired.

Commercially available sachets include D Series FreshPax™ (available from Multisorb Technologies Inc), Ageless™ Z (Ageless-Z is designated as Z-IOO, Z-1000, etc., to indicate the milliliters of oxygen with which a single packet will react), StabilOx D (available from Multisorb Technologies Inc) and ZPTJ™ sachets (both available from Mitsubishi Gas Corporation), O-Buster™ (available from Hsiao Sung Non-Oxygen Chemical Co., Ltd), Bioka™ Oxygen Absorber (available from Bioka Ltd) and the like.

The moisture absorbers include activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth. The particular moisture - retaining materials used will depend upon the humidity level of the environment. For example, in a very low-humidity environment, a moisture-carrying material such as a hydrogel that partially binds water may be preferred. The moisture absorber can be supplied in the form of a sachet, cartridge or canister. A preferred form is a canister of silica gel, such as SorBit™ (commercially supplied by Sud-Chemie Corporation). Multisorb provides variety of moisture absorbers under trade name of Natrasorb M, Natrasorb S, Natrasorb C, and Hi-dry, which comprise diatomaceous earth, silica gel, calcium oxide and molecular sieve, respectively.

Further, there are certain commercially available packets or sachets which comprise a combination of oxygen absorber and moisture absorber such as Pharmakeep oxygen- and moisture-absorbing packets (PharmaKeep KD or KC) (distributed jointly by Sud-Chemie and Mitsubishi Gas Chemical Company).

In addition, combination of oxygen absorber and moisture absorber can be used together in a packaging kit. Oxygen absorbers usually lead to an increase in moisture levels, hence a combination of moisture absorber and oxygen absorber will regulate moisture levels as well as oxygen levels.

The moisture/oxygen absorber may be in the form of packet, sachet, strips or canisters. The packet, sachet, strips or canisters may additionally comprise a moisture- indicating card. ^

In an embodiment, the pharmaceutical kit comprising a sealed oxygen permeable container (preferably sealed with a heat-induction seal (HIS)) having deposited therein rasagiline, its enantiomer or salts thereof in a solid unit dosage form and at least one oxygen absorber (preferably a self-activated absorber).

The oxygen absorber may be provided in a sachet, cartridge, canister (preferably a cartridge) or any other means of containing the absorber such that the absorber is physically separated from the solid dosage forms deposited in the container and has sufficient oxygen permeability to remove at least a portion of the oxygen in the air within the container. The sealed oxygen permeable container may also include a desiccant.

The desiccant for use in the practice of the invention can be any available desiccants; however, preferred desiccants include those commonly used in the pharmaceutical industry which have adequate capacity to handle the combination of moisture ingress through the container (e.g. glass or plastic bottle) and moisture given off by the self-activating oxygen absorber. Suitable desiccant are discussed in R. L. Dobson, J. Packaging Technol., 1 , 127-131 (1987). A preferred desiccant is silica gel. The desiccant can be supplied in the form of a sachet, cartridge or canister. A preferred form for the practice of the current invention is a canister of silica gel, such as that commercially supplied under the trade name, SorBit.TM. (Sud-Chemie Corporation, Albuquerque, N.Mex.).

In further embodiment, the inventions provides a stable pharmaceutical composition comprising a pharmaceutical formulation comprising rasagiline, its enantiomer or salts thereof and at least one pharmaceutically acceptable stabilizer other than sugar alcohols or polyols, and a packing not permeable to gas exchange, wherein the formulation is enveloped in the packaging under an inert gas atmosphere, said composition produced by the process of -

(ii) enveloping the formulation in the packaging under an inert gas atmosphere.

The stabilizers of the present invention can be any available pharmaceutically acceptable stabilizer other than sugar alcohols or polyols, preferably antioxidant.

Suitable antioxidants are, but not limited to ascorbic acid, fumaric acid, citric acid, malic acid, gallic acid and its salts and esters, sodium metabisulphite, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E acetate, vitamin E PEG 1000 succinate, mixtures thereof and the like and the like.

The amount of antioxidant in the composition may range between about 0.1% w/w to about 10% w/w of the composition or between about 0.5% w/w to about 5% w/w of the composition.

The inventors of the present invention have also found that particle size distributions have a beneficial effect on the uniformity of the solid pharmaceutical composition of Rasagiline. In contrast to the finer particle size of Rasagiline and its pharmaceutically acceptable salts, the larger particle size i.e. coarser particle size still provide the better uniformity, flowability and suitable for pharmaceutical formulations.

In accordance with the present invention, there is provided a pharmaceutical composition of rasagiline, its enantiomer or salts thereof comprising atleast one pharmaceutically acceptable stabilizer, wherein rasagiline, its enantiomer or salts thereof have 90th volume percentile particle size (D90) greater than about 250 μηι, or any combination thereof. In an embodiment, rasagiline, its enantiomer or salts thereof may have particle size distribution, wherein 10th volume percentile particle size (D10) is greater than about 20 μτη, the 50th volume percentile particle size (D50) is greater than about 100 μπι, and D(90) is greater than about 250 μιη, or any combination thereof.

In a further embodiment, rasagiline, its enantiomer or salts thereof may have particle size D(90) greater than 250 microns, and D(50) greater than 150 microns.

The term 'sugar alcohols' used hereinbefore and throughout the description hereinafter refers to polyhydric sugar and its derivatives e.g. lactose, mannitol, xylitol, fructose, maltitol, isomaltitol, erythritol, lactitol and Sorbitol and the term 'polyols' used hereinbefore and throughout the description hereinafter refers to excipients containing more that four alcohol (-OH) groups.

The pharmaceutical composition of rasagiline, its enantiomer or salts thereof can be prepared by any suitable method known in the art such as direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation. Typically, direct compression is preferred when formulations of phosphate salt of rasagiline is developed.

In an embodiment, the process of preparing the pharmaceutical composition of rasagiline, its enantiomer or salts thereof comprises admixing the rasagiline, its enantiomer or salts thereof and stabilizer with water soluble and/or water insoluble polymer together with one or more pharmaceutical excipient and compressing into suitable dosage form, particularly solid dosage form such as tablets.

The pharmaceutical composition may be formulated into orally disintegrating tablets, pellets, wafers, granules, micro-granules, powders, capsules, tablets, lozenges, films, chewables, pellets in capsule, granules in capsule or any other dosage form suitable for oral administration.

In an embodiment, the pharmaceutical composition's provided as a tablet, which can be film coated with one or more coating agents. Usable coating agents are hypromellose, polyvinyl alcohol, sodium carboxymethyl cellulose and various methacrylic acid polymers. The coating may also contain further such as plasticizers, pigments, pore forming materials or suspension stabilizers, such as polyethylene glycol, talcum or titanium dioxide. In another embodiment, the composition of rasagiline, its enantiomer or salts thereof can be developed into fast-releasing and delayed-releasing compositions by methods known to the person skilled in the art.

Pharmaceutically acceptable excipients for use in the pharmaceutical composition of rasagiline comprise one or more diluents, fillers/bulking agents, binders, disintegrants, lubricants, glidants, sweeteners/taste masking agents, colorants and flavors.

In a preferred embodiment, the pharmaceutically acceptable excipients for use in the pharmaceutical composition of rasagiline contains less than five alcohol (-OH) groups.

Suitable diluents/fillers or bulking agents which includes, but are not limited to, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols having less than five alcohol (-OH) groups, dibasic calcium phosphate and other bulking agents such as powdered cellulose and derivatives thereof.

Suitable binders which includes, but are not limited to, cellulose derivatives, starch, polyvinyl pyrrolidone (PVP), gelatin, gum Arabic, polyvinyl alcohol, tragacanth, sodium alginate and equivalents thereof.

Suitable disintegrants which includes, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch and modified starches, calcium silicates, low substituted hydroxy- propylcellulose.

Suitable lubricants and glidants which may include, but are not limited to, stearic acid and its derivatives or esters like sodium stearate, magnesium stearate and calcium stearate and the corresponding esters such as sodium stearyl fumarate; talc and colloidal silicon dioxide.

Suitable taste masking agents may include one or more of polymers, surfactants, sweeteners and flavors. Examples of polymers include one or more of cellulose acetate, polymethacrylates, cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose; and the like. Examples of sweeteners include but not limiting to one or more of aspartame, saccharin, sucralose, glycyrrhizin; and the like.

Suitable sweeteners that may be used, comprises saccharides such as aspartame, sugar derivatives having less than five alcohol (-OH) groups. Other examples of sweeteners comprise sodium saccharin; aspartame; sugarless sweeteners including glycerol, hydrogenated starch hydrolysates, alone or in combination.

Suitable flavors that may be used, comprise citric acid, cinnamon, wintergreen, eucalyptus, spearmint, peppermint, menthol, anise as well as fruit flavors such as apple, pear, peach, vanilla, strawberry, cherry, apricot, orange, watermelon, banana and the like; bean-derived flavors, such as coffee, cocoa and the like or mixtures thereof.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1:

Table 1

Process: Drug solution was prepared by dissolving drug in Isopropyl Alcohol. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate anhydrous, Microcrystalline Cellulose & Pregelatinized Starch in rapid mixture granulator following by drying in fluidized bed dryer at temperature of about 60 °C. Dried granules were sized through suitable screen following by blending with extra-granular Colloidal silicon dioxide and lubricating with stearic acid. Finally lubricated blend was compressed to form tablets and packed in Alu-Alu Blisters and charged for stability study. Example 2:

Table 2

Process: Drug solution was prepared by dissolving drug, ascorbic acid and Butylated Hydroxy Anisole in Isopropyl Alcohol. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate anhydrous & Pregelatinized Starch in rapid mixture granulator following by drying in fluidized bed dryer at temperature of about 60 °C. Dried granules were sized through suitable screen following by blending with extra- granular Colloidal silicon dioxide and lubricating with stearic acid. Finally lubricated blend was compressed to form tablets and packed in Alu-Alu Blisters and charged for stability study.

Example 3:

Table 3

Process: Drug solution was prepared by dissolving drug in Isopropyl Alcohol. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate anhydrous, Pregelatinized Starch & Microcrystailine Cellulose in rapid mixture granulator following by drying in fluidized bed dryer at temperature of about 60 °C. Dried granules were sized through suitable screen following by blending with extra-granular Colloidal silicon dioxide and lubricating with stearic acid. Finally lubricated blend was compressed to form tablets and packed in Alu-Alu Blisters and charged for stability study.

Example 4:

Table 4

Process: Drug solution was prepared by dissolving drug in purified water. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate dihydrate, Pregelatinized Starch & Microcrystailine Cellulose in rapid mixture granulator following by drying in fluidized bed dryer at temperature of about 60 °C. Dried granules were sized through suitable screen following by blending with extra-granular Colloidal silicon dioxide and lubricating with stearic acid. Finally lubricated blend was compressed to form tablets and packed in Alu-Alu Blisters and charged for stability study.

Example 5:

Table 5

3 Pregeiatinized Starch 20.00

4 Butylated Hydroxy Tolune 0.52

5 Ascorbic Acid 2.50

6 Collodal silicon dioxide 1.00

7 Stearic acid 3.00

8 Dehydrated alcohol qs

Total 200.00

Process; Drug solution was prepared by dissolving drug, ascorbic acid and Butylated Hydroxy toluene in Isopropyl Alcohol. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate anhydrous & Pregeiatinized Starch in rapid mixture granulator following by drying in fluidized bed dryer at temperature of about 60 °C. Dried granules were sized through suitable screen following by blending with extra- granular Colloidal silicon dioxide and lubricating with stearic acid. Finally lubricated blend was compressed to form tablets and packed in Alu-Alu Blisters and charged for stability study.

Stability Data:

Samples of the formulation are packed in Alu-Alu Blisters and stored at the accelerated stability testing conditions of 40°C and 75% RH. The impurity content is analyzed by HPLC at intervals and results are show below, where values are percentages of the rasagiline label content.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention

Claims

A stable pharmaceutical composition of rasagiline comprising rasagiline, its enantiomers or salts thereof and one or more of a pharmaceutically acceptable stabilizer other than sugar alcohol or a polyol.

The stable pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable stabilizer comprises atleast one antioxidant.

The stable pharmaceutical composition of claim 2, wherein the antioxidant comprises one or more of ascorbic acid, fumaric acid, citric acid, malic acid, gallic acid and its salts and esters, sodium metabisulphite, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E acetate, vitamin E PEG 1000 succinate, or mixtures thereof.

The stable pharmaceutical composition of claim 2, wherein the antioxidant is present in the range of about 0.1 % w/w to about 10% w/w of the composition.

The stable pharmaceutical composition of claim 1 , wherein the rasagiline is rasagiline besylate.

The stable pharmaceutical composition of claim 1, wherein the rasagiline is rasagiline hydrogen phosphate.

The stable pharmaceutical composition of claim 1 , wherein the rasgiline has a particle size (d90) greater than about 250 μιη.

The stable pharmaceutical composition of claim 7,\wherein the rasgiline has a particle size (d90) in the range of about 300 μιτι to about 1000 μχη. The stable pharmaceutical composition of claim 1, wherein the composition retains at least about 80% of the potency of rasagiline, its enantiomers or salts thereof in the pharmaceutical composition after storage for three months at 40° C and 75% relative humidity.

The stable pharmaceutical composition of claim 1, further comprising one or more pharmaceutically acceptable excipients comprising one or more of diluents, fillers, binders, disintegrants, lubricants, glidants, sweeteners/taste masking agents, colorants and flavors. 1. The stable pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in the form of an orally disintegrating tablet, pellets, wafers, granules, micro-granules, a powder, a tablet, a capsule, lozenges, films, a chewable tablet, pellets in a capsule, granules in a capsule, or any other dosage form suitable for oral administration.

The stable pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is an immediate release, delayed release, or a sustained release dosage form.