FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification [See Sections 10 and rule 13]
Title: Novel composition of Rasagiline mesylate
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Nationality: Indian
(c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad - 380009. Gujarat. India.
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel composition of Rasagiline or. its pharmaceutically acceptable salts and methods for preparing the same.
BACKGROUND OF THE INVENTION
Rasagiline mesylate, a propargylamine-based drug is indicated for the treatment of idiopathic Parkinson's disease. It is designated chemically as 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-( 1R)-methanesulfonate having the following structural formula:

Rasagiline mesylate is an irreversible monoamine oxidase (MAO) inhibitor. MAO, a flavin-containing enzyme, is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. MAO-B is the major form in the human brain. In ex vivo animal studies in brain, liver and intestinal tissues Rasagiline was shown to be a potent, irreversible monoamine oxidase type B (MAO-B) selective inhibitor.

US 5457133 discloses Rasagiline and its acid addition salt and composition made thereof. US 5532415 disclose mesylate salt of Rasagiline and its acid addition salt. US 6126968 disclose formulation of Rasagiline or its salt comprising pentahydric or hexahydric alcohols. According to this reference, incorporation of pentahydric and hexahydric alcohols along-with Rasagiline mesylate significantly improves the stability of pharmaceutical composition of Rasagiline mesylate.
US 5786390 claim a pharmaceutical composition consisting essentially of pharmaceutically acceptable salt of Rasagiline and a pharmaceutically acceptable carrier. However, the patent does not disclose the pharmaceutically acceptable carriers or any specific compositions of Rasagiline or its pharmaceutically acceptable salt.
US 20060188581 discloses mixture of particles of a pharmaceutically acceptable salt of R(+)-N-propargyl-l-aminoindan, wherein more than 90% of the total amount by volume of R(+)-N-propargyl-l -aminoindan salt particles have a size of greater than 6 microns and less than 250 microns. This reference patent application has identified poor content uniformity as a source for marked decrease in bioavailability. Hence, milling, as well as other methods, can be used to alter the particle size distribution in order to provide the content uniformity of solid pharmaceutical compositions of Rasagiline to increase bioavailability and safety of composition.

According to the available back-ground art, Rasagiline mesylate having particle size uniformity in between 6 microns and 250 microns in a pharmaceutical composition would increase the bioavailability of the composition. Hence, there is a need to develop a pharmaceutical composition of Rasagiline mesylate which does not depend on the uniformity of Rasagiline mesylate particle size of less than 250 microns and affects the bioavailability of the drug.
The inventors of the present invention have surprisingly found that bioavailability of pharmaceutical composition having Rasagiline mesylate with particle size of more than 250 microns can be attained by incorporating isomalt in the Rasagiline mesylate composition.
OBJECTS OF THE INVENTION
An object of the invention is to provide novel pharmaceutical composition of Rasagiline mesylate wherein the composition comprises Rasagiline mesylate of particle size more than 250 microns along with isomalt in formulation for attaining desired bioavailability.
Another object of the invention is to provide a process for preparing the said novel pharmaceutical composition of Rasagiline mesylate.

SUMMARY OF THE INVENTION
Present invention relates to novel pharmaceutical formulation of Rasagiline mesylate wherein the composition comprises Rasagiline mesylate of particle size more than 250 microns along with isomalt. The said Rasagiline mesylate composition may further comprise of conventional pharmaceutically acceptable excipients comprising of a diluent, binder, disintegrant, lubricant, and glidant or mixtures thereof.
Further, the present invention describes a process for preparing the said novel pharmaceutical composition of Rasagiline mesylate wherein the composition comprises Rasagiline mesylate of particle size more than 250 microns along with isomalt.
DESCRIPTION OF THE INVENTION
According to the back-ground art, Rasagiline mesylate having uniform particle size of less than 250 microns would help in attaining the desired bioavailability of the Rasagiline mesylate composition. In this context back-ground art discloses that in order to obtain Rasagiline mesylate having uniform particle size of less than 250 microns, the drug was milled after preparation. Size reduction of Rasagiline mesylate through milling or any other method would be undesirable as it would increase the cost and time required for the preparation of Rasagiline mesylate.

In accordance with the present invention, there is provided a pharmaceutical composition comprising Rasagiline mesylate having a particles size of more than 250 microns and isomalt. The composition disclosed in the present invention further comprises of conventional pharmaceutically acceptable excipients comprising of a diluent, binder, disintegrant, lubricant, and glidant or mixtures thereof.
"Isomalt" is a sugar substitute and a sugar alcohol (polyol) that is processed from real sugar made from beets. Isomalt occurs as a white or almost white powder or granular or crystalline substance. It has been allotted GRAS (Generally Recognized as Safe) status by FDA. Isomalt is a mixture of two stereoisomers: 6-O-a-D-glucopyranosyl-D-sorbitol (1,6-GPS) and 1-O-a-D-glucopyranosyl-D-mannitol dihydrate(1,1-GPM).
"Bioavailability" is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation.
"Desired bioavailability" describes the bioavailability which would be similar to that of innovator's marketed product Azilect® (Rasagiline mesylate).
"Tmax" refers to the time to reach maximum concentration of drug in serum.
"Cmax" refers to maximum concentration of drug in serum.

"AUC" refers to area under the concentration-time curve
"AUCo-t" refers to area under the plasma concentration-time curve from time zero to the last measurable concentration.
Details of bioavailability of innovator's marketed product Azilect® (Rasagiline mesylate) is as under:

Parameter T max (hr) C max (pg/mL) AUC0-t
(pg.h/mL)
Reference Formulation 0.348 5292.926 3698.264
The pharmaceutical composition of the present invention comprises a tablet or capsule as the solid oral dosage form.
Rasagiline mesylate used in the composition according to present invention is having particle size more than 250 microns.
Preferably, the composition of the present invention comprises upto 0.5-5 wt% of Rasagiline mesylate and 30-90 wt% of isomalt. Further, the composition according to the claimed invention may comprise of 1-25 wt% of binder, 0.25-3 wt% of glidant,

0.25-5 wt% of lubricant, upto 20 wt% of disintegrant, 0.01-0.5wt% of stabilizers and optionally additional diluent other than isomalt.
Additional diluents can be selected from the group comprising of but not limited to calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, cellulose, cellulose powdered, cellulose silicified microcrystalline, corn starch and pregelatinized starch, lactose anhydrous, lactose monohydrate and corn starch, lactose monohydrate and microcrystalline cellulose, lactose spray dried, microcrystalline cellulose, starch pregelatinized, trehalose, and the likes thereof.
Binder can be selected from the group comprising of but not limited to carboxymethylcellulose sodium, co-povidone, corn starch, pregelatinized starch, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose low-substituted, hypromellose, lactose, povidone, starch pregelatinized sucrose and the likes thereof.
Glidants can be selected from the group comprising of but not limited to talc, sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate and the likes thereof.

Lubricant can be selected from the group comprising of but not limited to magnesium stearate, stearic acid, talc, calcium stearate, zinc stearate, sodium stearyl fumerate and the likes thereof.
Disintegrants can be selected from the group comprising of carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose powdered, corn starch, pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate, starch pregelatinized and the likes thereof.
Stabilizers can be selected from the group comprising of citric acid and the likes thereof.
The dosage form of the present invention is preferably based on dry granulation, wet granulation method, direct compression or pellet based technology. The granules or pellets are compressed into tablets or filled into the capsule. More preferred process used herein is top spray granulation and direct compression.
Procedure for Granulation
Part of diluent and dry binder is sifted and dry mixed for 10 minutes. Drug-binder solution is prepared by dissolving binder, stabilizer and drug in purified water and stirring until a clear solution is formed. The dry mixed material is granulated using the drug-binder solution. The granules are dried to desired LOD and size reduced.

The size reduced granules are mixed with remaining quantity of diluent, disintegrant and glidant using blender. Then sifted lubricant is added, blended and then compressed to form a tablet or filled into capsule.
Procedure for Direct compression
Drug and a part of the diluent is sifted together and collected. Now, remaining quantity of diluent & binder are mixed and collected. The drug-diluent mixture is mixed with remaining quantity of diluent-binder mixture and blended for 25 minutes. Required quantities of disintegrant, glidant and lubricant are mixed and sifted together. Now, the drug-diluent-binder mixture and disintegrant-glidant-lubricant mixture are blended together in a blender for 5 minutes then compressed to form a tablet.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of the

appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.
The above said invention can be illustrated by but not limited to following example(s):
Examples:
Example 1: Granulation

Sr. No Ingredient Function % (w/w)
Dry Mixing:
1 Pregelatinised starch Binder 9.524
2 Maize Starch Disintegrant 12.459
3 Isomalt Diluent 52.381
Granulation:
4 Rasagiline Mesylate API 0.743
5 Hydroxypropyl cellulose Binder 0.250
6 Citric acid anhydrous Stabilizer 0.286
7 Purified Water Solvent q.s.
Blending:
8 Croscarmellose sodium Disintegrant 10.000
9 Pregelatinised starch Binder 11.857
10 Stearic acid Lubricant 2.000
11 Colloidal anhydrous silica Glidant 0.500
Total 100

Procedure:
1. Co-Sift dry mixed materials and collect the sifted materials.
2. Transfer the materials of step no.l to Blender and mix.
3. Preparation of Drug solution:
Take purified water and dissolve the required quantity of Hydroxypropylcellulose
(LF) and Citric acid anhydrous.
Add Rasagiline Mesylate and stir till clear solution is formed.
4. Granulate the dry mix of step 2 using solution of step 3 using Fluid bed processor.
5. Dry the granules to achieve the desired LOD.
6. Sift the granules though the sieve and retains to be milled and sifted
7. Blend the dried granules and add the extra-granular materials and mix using the Blender.
8. Lubricate the step 7 materials using stearic acid in blender.
9. Compress to form a tablet or fill in the capsule

Example 2: Direct Compression

Sr.No Ingredient Function % (w/w)
1 Maize Starch Disintegrant 9.524
2 Isomalt Diluent 75.828
3 Rasagiline Mesylate API 0.743
4 Pregelatinised starch Binder 9.524
5 Stearic acid Lubricant 1.905
6 Colloidal anhydrous silica Glidant 0.571
7 Talc Glidant 1.905
Total 100
Procedure: Sifting:
1.1 Co-Sift rasagiline mesylate and some quantity of isomalt.
1.2 Co-Sift remaining quantity of isomalt, Pregelatinized starch and Maize starch. Mixing:
2.1 Transfer the materials of step no. 1.1 and 1.2 to Blender and mix.
Sifting:
3.1 Co-Sift extra-granular ingredients and collect the sifted materials.
Blending:
4.1 Add presifted materials of step No. 3.1 to step 2,1 and mix.
Compression
5.1 Compress the above mixture to form a tablet

RESULT:
Following results were obtained after performing bioavailability studies for product obtained according to the present invention (Test formulation) and comparing the result obtained with innovator's product (Reference formulation)
Table 1: Comparison of Rasagiline Tablets 1 mg - Fasting Study

Parameter Tmax (hr) Cmax (pg/mL) AUCO-t (pg.h/mL)
Test Formulation 0.449 5103.350 3799.567
Reference Formulation 0.348 5292.926 3698.264
According to the results obtained as per table 1, the parameters for accessing bio-availability of test formulation prepared according to present invention are similar to the reference formulation. Hence, composition comprising Rasagiline mesylate having particle size of more than 250 microns can be prepared having desired bioavailability by incorporating Isomalt in the composition.

We claim:
1. Novel pharmaceutical composition of Rasagiline mesylate comprising Rasagiline mesylate along with isomalt.
2. Pharmaceutical composition according to claim 1, wherein the particle size of Rasagiline mesylate is more than 250 microns.
3. Pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition further comprises of conventional pharmaceutically acceptable excipients comprising of binder, disintegrant, lubricant, glidant, stabilizer and optionally an additional diluent other than isomalt.
4. Pharmaceutical composition as claimed in any of the preceding claims which comprises of a tablet or capsule as the solid oral dosage form.
5. Pharmaceutical composition as claimed in any of the preceding claims, which comprises of 0.5-5 wt% of Rasagiline mesylate, 30-90 wt% of isomalt, 1-25 wt% of binder, upto 20 wt% of disintegrant, 0.25-5 wt% of lubricant, 0.25-3 wt% of glidant, 0.01 to 0.5 wt% of stabilizer, and optionally 30-90 wt% of an additional diluent other than isomalt.

6. Pharmaceutical composition as claimed in preceding claims, wherein the optional
additional diluents can be selected from the group comprising of calcium phosphate
dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic,
cellulose, cellulose powdered, cellulose silicified microcrystalline, corn starch and
pregelatinized starch, lactose anhydrous, lactose monohydrate and corn starch, lactose
monohydrate and microcrystalline cellulose, lactose spray dried, microcrystalline
cellulose, starch pregelatinized and trehalose.
7. Pharmaceutical composition as claimed in claims 1 and 4, wherein the
pharmaceutical composition is prepared by a method selected from a group
comprising of dry granulation, wet granulation method, direct compression or pellet
based technology.
8. Novel pharmaceutical composition of Rasagiline mesylate as herein described with
foregoing description and example.