WO2014192022A1

WO2014192022A1 - Pharmaceutical compositions of rasagiline

Info

Publication number: WO2014192022A1
Application number: PCT/IN2014/000336
Authority: WO
Inventors: Sushrut Krishnaji Kulkarni; Pavak Rajnikanth Mehta; Ritesh Kapoor
Original assignee: Cadila Healthcare Limited
Priority date: 2013-05-20
Filing date: 2014-05-20
Publication date: 2014-12-04
Also published as: IN2013MU01782A

Abstract

The present invention provides pharmaceutical compositions of rasagiline, its enantiomer or salts thereof. In particular, the invention relates to stabilizer free 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.

Description

PHARMACEUTICAL COMPOSITIONS OF RASAGILINE FIELD OF INVENTION

The present invention relates to pharmaceutical compositions of rasagiline, its enantiomer or salts thereof. In particular, the invention relates to stabilizer free 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.

A formulation of rasagiline mesylate is currently marketed in US in the form of film coated tablets for the treatment of Parkinson's disease either as monotherapy or as an adjunct with other treatments under trade name Azilect® by Teva Pharmaceuticals.

PCT publication No. 95/11016 discloses pharmaceutical formulations of rasagiline.

U.S. Patent No. 6,126,968 subsequently disclosed that the formulations of

PCT Publication No. 95/11016 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. 95/11016. 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.

PCT publication No. 2010/085354 discloses the delayed release composition of rasagiline, wherein the core comprises atleast one antioxidant, preferably citric acid and malic acid.

European Patent No. 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.

European Patent Application No. 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.

Prior art formulations suggest that use of sugar alcohols or polyols is required in order to develop stable formulations of rasagiline. However, when consumed in relatively large amount, sugar alcohols such as lactose, mannitol, are known to cause gastro-intestinal disturbances. The most common side effect is the possibility of bloating and diarrhea when sugar alcohols are eaten in excessive amounts. There is also some evidence that sugar alcohols, much like fructose can cause a 'laxative effect' and weight gain has also been seen when these products are overeaten. The American Diabetes Association claims that sugar alcohols are acceptable in a moderate amount but should not be eaten in excess. Some people with diabetes, especially Type I diabetics have found that their blood sugars rise if sugar alcohols are eaten in uncontrolled amounts. Moreover, the 'lactose- intolerant' patient group having inability to digest lactose may result in aggravation of gastro-intestinal symptoms.

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 formulation of rasagiline which are suitable for all patient population and also such formulations, without employing any stabilizer, ought to remain stable over the storage period.

OBJECTS OF THE INVENTION

Accordingly, it is the primary object of the invention to provide for a pharmaceutical composition of rasagiline, its enantiomer or salts thereof comprising one or more pharmaceutical excipients, wherein said composition is free of stabilizer.

It is a further object of the invention to provide for a pharmaceutical composition of rasagiline, its enantiomer or salts thereof, wherein said composition is free of stabilizer and it 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.

It is another object of the invention to provide for a pharmaceutical composition of rasagiline besylate, its enantiomer thereof, wherein said composition is free of stabilizer and it 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. It is another object of the invention to provide for a pharmaceutical composition of rasagiline, its enantiomer or salts thereof, wherein the composition is prepared by dissolving rasagiline, its enantiomer or salts thereof alone or in combination with atleast one polymer in suitable solvent and adsorbing the resultant solution on to atleast one pharmaceutically acceptable excipient and formulated in to suitable dosage forms by methods known in the art.

A yet another object of the invention is to provide for embodiments of the invention which may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include fillers/diluents, binders, polymers, disintegrants, lubricants, glidants, sweeteners, taste masking agents and flavors.

It is a further object of the invention to provide for a pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof have 90th volume percentile particle size (D₉₀) greater than about 250 μιη.

An alternative object of the invention is to provide for, rasagiline, its enantiomer or salts thereof which may have particle size distribution wherein 10th volume percentile particle size (D₁₀) is greater than about 20 μηι, the 50th volume percentile particle size (D₅₀) is greater than about 100 μιη, 90th volume percentile particle size (D₉₀) is greater than about 250 μιη, or any combination thereof.

A yet another object of the invention is to provide for a pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof having water content less than 6%.

It is another object of the invention to provide for a method of treating Parkinson's disease, dementia and Alzheimer's disease in patient comprising administering to said subject a pharmaceutical composition of rasagiline, its enantiomer or salts thereof comprising one or more pharmaceutical excipients, wherein said composition is free stabilizer. SUMMARY OF THE INVENTION

The present invention provides for a pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and at least one pharmaceutically acceptable excipient, wherein said composition is free of stabilizer.

A preferred embodiment of the present invention provides for a pharmaceutical composition as described above, wherein said pharmaceutically acceptable excipient is selected from diluent, binder, disintegrant, lubricant and/or a combination thereof.

Another preferred embodiment of the present invention provides for a pharmaceutical composition as described above, wherein said composition comprises 15-95 % of diluent, 1-15% disintegrant, 0-15% binder, 0.1-5% lubricant.

Yet another preferred embodiment of the present invention provides for a pharmaceutical composition as described above, wherein said rasagiline is rasagiline besylate.

Yet another preferred embodiment of the present invention provides for a pharmaceutical composition as described above, wherein said rasagiline is rasagiline hydrogen phosphate.

A further preferred embodiment of the present invention provides for a pharmaceutical composition as described above, wherein the particle size (D90) of rasagiline is greater than 250 μηι.

The present invention provides for a process of preparing the pharmaceutical composition of claim 1 comprising the steps of:

i) mixing rasagiline, its enantiomer or salts and optionally one or more pharmaceutically acceptable polymer in a suitable solvent; ii) granulating the mixture of step i) with one or more filler, disintegrant, binder;

iii) drying said granulate followed by sizing;

iv) blending said granulate of step (iii) with one or more pharmaceutically acceptable excipient; v) formulating the blended granulate of step (iv) into a suitable dosage form.

In a preferred embodiment, in the process of preparing pharmaceutical composition as described above, said solvent is aqueous and/or organic solvent.

In a further embodiment, the pharmaceutical composition of the invention is in the form of tablet, capsule, lozenge, powder, film or sachet.

In a still further embodiment the pharmaceutical composition of the invention is free of stabilizer and it 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 yet another embodiment the pharmaceutical composition of the invention is administered to a patient in need thereof for the treatment of Parkinson's disease, dementia or alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have formulated stable formulations of rasagiline without any stabilizer and such formulation 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. Additionally, the inventors have found that formulations containing besylate salt of rasagiline exhibits significant stability and in particular, possess good formulation characteristics.

In accordance with the present invention, there is provided a pharmaceutical composition of rasagiline, its enantiomer or salts thereof comprising one or more pharmaceutical excipients, wherein the composition is free stabilizer.

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.

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, mesylate, maleate, fumarate, tartrate, hydrobromide, esylate, tosylate, benzoate, oxalate, edisilate, phosphate, hydrochloride, acetate, sulphate.

The term 'stabilizers' used hereinbefore and throughout the description hereinafter refers to lactose, mannitol, xylitol, fructose, maltitol, isomaltitol, erythritol, lactitol and Sorbitol, citric acid, tartaric acid, lactic acid, butyl hydroxyl toluene, butyl hydroxyl anisole, EDTA and the like.

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. Coarser particle size of rasagiline, its enantiomer or salts thereof provides better uniformity, flowability compared to the finer particle size and suitable for pharmaceutical formulations.

In accordance with the present invention, there is provided a pharmaceutical composition of rasagiline, its enantiomer or salts thereof have 90th volume percentile particle size (D90) greater than about 250 μιη. 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 μπι, the 50th volume percentile particle size (D50) is greater than about 100 μηι, 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. In an embodiment, the pharmaceutical composition of rasagiline, its enantiomer or salts thereof have water content less than 6%, preferably less than 4%.

In accordance with the present invention, there is provided a process for the preparation of pharmaceutical composition of rasagiline, its enantiomer or salts thereof, wherein said, process comprises the steps of dissolving rasagiline, its enantiomer or salts thereof alone or in combination with atleast one polymer in suitable solvent (s) and adsorbing the resultant solution on atleast one pharmaceutically acceptable excipient and formulated in to suitable dosage forms by methods known in the art.

In an embodiment of the invention, the process for the preparation of pharmaceutical composition of rasagiline, its enantiomer or salts thereof, comprises the steps of i) . Preparing granulate comprising rasagiline dispersion along with at least one filler and optionally other excipients, by wet granulation; ii) . Drying said granulate; iii) . Blending said granulate of step (ii) with extra-granular excipient; iv) . Compressing said blended granulate of step (iii) to get the tablet; and v). Optionally coating said tablet with a film coating material.

Suitable solvents that may be used for preparing the dispersion include organic, aqueous, or a mixture thereof. Organic solvents may be aliphatic alcohols such as methanol, ethanol, n-propanol, and isopropanol; aliphatic ketones such as acetone and methyl ethyl ketone; aliphatic carboxylic esters such as ethyl acetate; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile; chlorinated hydrocarbons such as dichloromethane; aliphatic sulfoxides such as dimethyl sulfoxide; and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Aqueous solvents include solvent comprising water and/or a water-miscible organic solvent such as a lower alcohol, acetonitrile, tetrahydrofuran, dimethylacetamide, dimethyl formamide, and the like. Combination of various solvents can also be used.

The polymer that may be used for preparing drug dispersion includes water soluble and/or water insoluble polymer.

Suitable polymers that may be used for preparing the dispersion include, but are not limited to, copovidone, ethylcellulose, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl alcohol, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and the like.

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 granulation or wet granulation using aqueous and/or nonaqueous solvents, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation.

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

In an embodiment, the pharmaceutical composition is 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. In another embodiment, the composition containing 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, and other bulking agents such as dibasic calcium phosphate and powdered cellulose and derivatives thereof and combinations thereof, preferably dibasic calcium phosphate and/or microcrystalline cellulose. The diluent/filler may be present in an amount from about 1% w/w to about 99% w/w of the total weight of the composition.

Suitable binders which includes, but are not limited to, acacia, alginic acid, carbomer copolymer, carbomer interpolymer, copovidone, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, polyvinyl alcohol, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and the like. The binder may be present in an amount from about 0% w/w to about 15% w/w of the total weight of the composition.

Suitable disintegrants which includes, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch, pregelatinized starch and modified starches, calcium silicates, low substituted hydroxy- propylcellulose. The disintegrant may be present in an amount from about 0.1% w/w to about 15% w/w of the total weight of the composition.

Suitable lubricants and glidants which may include, but are not limited to, stearic acid and its derivatives or esters like sodium stearate, magnesium stearate, calcium stearate and sodium stearyl fumarate; talc and colloidal silicon dioxide. The lubricant may be present in an amount from about 0.1 % w/w to about 10% w/w of the total weight of the composition.

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. The taste masking agent may be present in an amount from about 0% w/w to about 5% w/w of the total weight of the composition.

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 flavor may be present in an amount from about 0% w/w to about 5% w/w of the total weight of the composition. 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, Pregelatinized Starch & Microcrystalline 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 arid 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 in purified water. 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 3 Table 3

Process: Drug solution was prepared by dissolving drug and povidone in Isopropyl Alcohol. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate anhydrous, Pregelatinized Starch & Microcrystalline 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 Isopropyl alcohol. The drug solution was adsorbed onto mixture of Dibasic calcium phosphate anhydrous, Pregelatinized Starch and part of microcrystalline 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 microcrystalline cellulose and 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.

Claims

A pharmaceutical composition comprising rasagiline, its enantiomer or salts thereof and at least one pharmaceutically acceptable excipient, wherein said composition is free of stabilizer.

The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable excipient is selected from diluent, binder, disintegrant, lubricant and/or a combination thereof.

The pharmaceutical composition of claim 1, wherein said composition comprises 15-95 % of diluent, 1-15% disintegrant, 0-15% binder, 0.1-5% lubricant.

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

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

The pharmaceutical composition of claim 1, wherein the particle size (D90) of rasagiline is greater than 250 μπι.

A process of preparing the pharmaceutical composition of claim 1 comprising the steps of:

iii) drying said granulate followed by sizing;

iv) blending said granulate of step (iii) with one or more pharmaceutically acceptable excipient;

v) formulating the blended granulate of step (iv) into a suitable dosage form.

The process of preparing pharmaceutical composition of claim 7, wherein said solvent is aqueous and/or organic solvent.

The pharmaceutical composition of claim 1, wherein said composition is tablet, capsule, lozenge, powder, film or sachet.

10. The pharmaceutical composition of claim 1, wherein said composition is free of stabilizer and it 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.

11. The pharmaceutical composition of claim 1 , wherein said composition is administered to a patient in need thereof for the treatment of parkinson's disease, dementia or alzheimer's disease.