FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Pharmaceutical Compositions Comprising Rasagiline
2. APPLICANT
NAME : Micro Labs Limited
NATIONALITY : Indian
ADDRESS : CTS No. 73, Saki Estate, Off Chandivali Road, Chandivali, Kurla (W),
Mumbai- 400 072, India.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical compositions comprising Rasagiline or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable antioxidant(s), wherein the said composition is free of sugar alcohols. The present invention also provides process for the preparation of such compositions which are used for the treatment of Parkinson's disease, memory disorders and dementia of the Alzheimer type (DAT), depression and hyperactive syndrome in children or a disease or condition associated with these, optionally with one or more pharmaceutically acceptable excipient(s).
BACKGROUND OF THE INVENTION

US 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.
Rasagiline is a propargylamine-based drug which is a selective irreversible inhibitor of the enzyme monoamine oxidase (hereinafter MAO) and provides the R(+) enantiomer of N-propargyl-1-aminoindan which is a selective irreversible inhibitor of the B-form of monoamine oxidase enzyme (hereinafter MAO-B). Rasagiline is used as a monotherapy in early Parkinson's disease or as an adjunct therapy with levodopa. Rasagiline is currently administered orally in the form of a conventional tablet and is presently marketed in US as Azilect® by Teva Pharma. The drug compound having the adopted name "Rasagiline mesylate" has chemical names (1 R)-N-prop-2-ynyl-2,3-dihydro-l H-inden-1 -amine methanesulfonate; or 1 H-inden-1 -amine, 2,3-dihydro-N-2-propynyl-, (1 R)-, methanesulfonate; and has structural formula as below.

US Patent no. 5,387,612 and 5,453,446 relate to methods of treating Parkinson's disease using Rasagiline or a pharmaceutically acceptable salt.
US Patent No. 6,126,968 assigned to Teva Pharmaceuticals discloses a 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 publication no. WO 2006/057912 and U.S. Patent application no. 2008/0107729 relates to pharmaceutical formulations of Rasagiline or its pharmaceutically acceptable salts, wherein the formulations contain at least two sugar alcohols.
US application No. US20100189791 discloses a stable oral dosage form comprising a core having Rasagiline malate and at least one pharmaceutically acceptable excipient; and an acid resistant pharmaceutically acceptable coating.
US application no US20100189790 discloses a stable oral dosage form comprising a core having a production process-resulting form of Rasagiline and at least one pharmaceutically acceptable excipient; and an acid resistant pharmaceutically acceptable coating, the production process comprising a) preparing the core by admixing Rasagiline base, citric acid and/or malic acid, and a pharmaceutically acceptable excipient; and b) coating the core with the acid resistant pharmaceutically acceptable coating.
International publication no WO2011010324 discloses a stable oral pharmaceutical composition comprising Rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, wherein the carrier is selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof, and wherein the said composition is free of pentahydric or hexahydric alcohols

International publication no WO2010111264 discloses 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%.
International publication no WO2010070090 discloses a solid composition comprising at least one pharmaceutically acceptable excipient and as an active ingredient Rasagiline or a pharmaceutically acceptable salt thereof, characterized in that auxiliary and active substance is present in a homogeneous, molecularly disperse mixture.
International publication No WO2011050728 discloses a stable Rasagiline composition containing acceptable salt of Rasagiline or drugs and drug acceptable antioxidants. It further discloses the composition specifically used for transdermal or mucosal administration.
However, none of the above listed prior art documents hereinabove disclose about a stable oral pharmaceutical composition comprising Rasagiline or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable antioxidant(s), wherein the said composition is free of sugar alcohols. Inventor of the instant invention surprisingly found that oral pharmaceutical compositions are equally stable by using antioxidants without having any added sugar alcohols as used in commercially available innovator formulation.
Moreover, a review of the prior art reveals that there still exists an unmet medical need for development of a stable pharmaceutical composition to provide a therapy for Parkinson's disease, memory disorders and dementia of the Alzheimer type (DAT), depression and hyperactive syndrome in children or a disease or condition associated with these without using any sugar alcohol in the composition.

The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to develop a stable pharmaceutical composition of Rasagiline or a pharmaceutically acceptable salt thereof without using sugar alcohol. The present invention also provides safe and effective compositions for the management of Parkinson's disease which are particularly devoid of the associated side effects and therefore provides a significant advancement in the said field.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide a stable oral pharmaceutical composition comprising Rasagiline or its pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable antioxidant(s) and optionally with one or more pharmaceutically acceptable excipient(s), wherein the said composition is free of sugar alcohols.
It is an objective of the present invention to provide a stable oral pharmaceutical composition comprising Rasagiline mesylate with at least one pharmaceutically acceptable antioxidant(s) and optionally with one or more pharmaceutically acceptable excipient(s), wherein the said composition is free of sugar alcohols.
It is an objective of the present invention to provide a stable oral pharmaceutical
composition comprising Rasagiline mesylate with at least one pharmaceutically
acceptable antioxidant(s) selected from the group but not limited to ascorbic acid and
their esters, alpha-tocopherol, ethylenediaminetetraacetic acid, sodium metabisulfite ,
sodium bisulfite , Butylated Hydroxy Toluene (BHT), Hydroxy propyl p -cyclodextrin, p
-cyclodextrin, Propyl gallate, Butylated Hydroxy Anisole (BHA),
fumaric acid or salt, propionic acid or salt, erythorbic acid or salt, citric acid or salt and tartaric acid or salt and the like optionally with one or more pharmaceutically acceptable excipient(s).
It is another objective of the present invention; the composition is devoid of any sugar alcohols i.e. pentahydric alcohols or hexahydric alcohols or polyhydric alcohols.

It is another objective of the present invention to provide a pharmaceutical compositions and preparation which is administrated by oral route.
It is further an objective of the present invention to provide pharmaceutical compositions can be formulated as but not limited to tablets, pellets ,capsules, suspensions, syrups, sachets, ointments, creams, gels and transdermal patches optionally with one or more pharmaceutically acceptable excipient(s).
It is further an objective of the present invention to prepare oral tablet composition which can be given either as immediate release, sustained release, extended release, delayed release or in combination there of.
It is yet another objective of the present invention to provide a process for the preparation of such pharmaceutical combination(s) and compositions thereof.
The compositions of the present invention provide effective prophylactic or therapeutic concentrations of active agent(s) for immediate release of the composition.
The present invention provides pharmaceutical formulations comprising Rasagiline or a salt thereof which are used for the management of diseases or disorders, comprising administering a formulation containing an effective amount of the active agent.
DETAILED DESCRIPTION OF THE INVENTION:
It is believed that one skilled in the art can based upon the description herein; utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
The present invention provides 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 pro drug thereof.
In an embodiment the present invention provides a stable oral pharmaceutical composition comprising Rasagiline or its pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient(s), wherein the said composition is free of sugar alcohols.
The term 'stable' as used herein refers to chemical stability of Rasagiline or its salts in solid dosage forms wherein there is no significant change in impurities percentages and dissolution profile when kept at accelerated temperature and humidity conditions.
It would be note worthy that prior arts relate to pharmaceutical compositions of Rasagiline and its salts having in corporation of relatively larger amount of sugar alcohols to improve the stability of formulation. Sugar alcohols specifically mannitol, xylitol and sorbitol in an amount of at least 70% weight of the composition are being used for this purpose. However, these compositions may further comprise acids for added advantages w.r.t. stability of the compositions.
In an embodiment of the present invention stable oral pharmaceutical composition comprises Rasagiline mesylate with at least one pharmaceutically acceptable antioxidant(s) and optionally one or more pharmaceutically acceptable excipient(s), wherein the said composition is free of sugar alcohols.
Inventor of the instant invention surprisingly found that oral pharmaceutical compositions are equally stable by using only antioxidants without using any added sugar alcohols as used in commercially available innovator formulation.
In an embodiment of the present invention the antioxidant(s) used in the invention are selected from the group but not limited to ascorbic acid and their esters, alpha-tocopherol, ethylenediaminetetraacetic acid, sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT), Hydroxy propyl β -cyclodextrin, β -cyclodextrin,

Propyl gallate, Butylated Hydroxy Anisole (BHA), fumaric acid or salt, propionic acid or salt, erythorbic acid or salt, citric acid or salt and tartaric acid or salt and the like.
In further an embodiment present invention uses the antioxidant specifically ascorbic acid esters or ascorbic acid and/or citric acid either alone or combination thereof.
In further an embodiment the particle sizes of Rasagiline mesylate are adequate to maintain acceptable content uniformity of the blend that is used to make the pharmaceutical compositions of the present invention.
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 or well within the limit. In embodiments, formulations of the present invention include Rasagiline or its pharmaceutically acceptable salt thereof.
In a further aspect, present invention uses active ingredient in binder solution, which in turn nullify influence of particle size on the in-vitro performance of the formulation.
In an embodiment of the present invention the pharmaceutical compositions can be formulated as but not limited to tablets, pellets, capsules, suspensions, syrups, sachets, ointments, creams, gels and transdermal patches.
In the embodiment of the present invention to prepare oral tablet composition which can be given either as immediate release, sustain release, extended release, delay release or in combination there of.
In further an embodiment of the present invention is formulated specifically as tablet dosage form.
In another embodiment of the present invention, the pharmaceutically acceptable excipient(s) of the present invention are selected from but not limited to a group comprising diluents, lubricants, binders, surfactants, anti-oxidants, colorants, glidants,

complexing agents and the like known to the art used either alone or in combination thereof.
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as Avicel® PH101, Avicel® PH102, Avicel® PHI 12, Avicel® PH200, Avicel® PH301 and Avicel® PH302; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress®; starch; sucrose; glucose, and the like used either alone or in combination thereof.
Suitable lubricants are selected from but not limited to a group comprising talc; stearic acid, magnesium stearate, calcium stearate, colloidal silicon dioxide such as Aerosil® 200; sodium stearyl fumarate, hydrogenated vegetable oil and the like used either alone or in combination thereof.
Suitable binder useful in the present invention is selected from but not limited to a group comprising polyvinylpyrrolidone (e.g. PVP K-90 or PVP K-30), copovidone (e.g. Plasdone® S630), cellulosic polymers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or the like), gums such as xanthan, alginates such as sodium alginate, polyvinylacetate, and the like used either alone or in combination thereof. More preferably, copovidone (e.g. Plasdone® S630) is useful as a binder.
Suitable antioxidant is selected from but not limited to a group comprising ascorbic acid
and their esters, alpha-tocopherol, ethylenediaminetetraacetic acid, sodium metabisulfite,
sodium bisulfite, Butylated Hydroxy Toluene (BHT), Hydroxy propyl (3 -cyclodextrin, p
-cyclodextrin, Propyl gallate, Butylated Hydroxy Anisole (BHA),
fumaric acid or salt, propionic acid or salt, erythorbic acid or salt, citric acid or salt and tartaric acid or salt and the like. Suitable glidant is selected from but not limited to a group comprising talc, magnesium stearate, stearic acid, calcium stearate or hydrogenated castor oil and the like used either alone or in combination thereof.

The present invention provides pharmaceutical formulations of Rasagiline or its salt which is used for the management of Parkinson's disease, memory disorders and dementia of the Alzheimer type (DAT), depression and hyperactive syndrome in children or a disease or condition associated with these, comprising administering a formulation containing an effective amount of Rasagiline or a pharmaceutically acceptable salt thereof.
The present invention provides pharmaceutical formulations of Rasagiline or its salt which are used for the management of Parkinson's disease or disorders either alone as a monotherapy as well as adjuvant therapy together with levodopa.
Table 1

Batch Stage Condition/ Pack % total impurity
Example 1
(without sugar alcohol) Initial — 0.02

Stability 40°C/75%RH/ Bulk pack 0.07

40°C/75%RH/ Blister pack 0.07
Example 2 Initial — 0.38
(With sugar alcohol) Stability 40°C/75%RH/ Bulk pack 0.54

40°C/75%RH/ Blister pack 0.48
Innovator formulation Initial — 0.48

Stability 40°C/75%RH/ Blister pack 0.52
Above Table 1 represents the % total impurity of different compositions under accelereted temperature and humidity conditions. It would be note worthy that % total impurity formed during initial and stability stage of the composition of example 1

(without having sugar alcohol) are equally stable when compare to the composition of example 2 (with sugar alcohols) and the innovator formulation.
The examples given below serve to illustrate embodiments of the present invention. However, they do not intend to limit the scope of present invention in any manner whatsoever.
The term 'q.s.' wherever appears in the examples is an abbreviation for 'quantity sufficient' which is the amount of the excipient in such quantities that is just sufficient for its use in the composition of the present invention.
Example -1
Table-2: Pharmaceutical composition of the invention (Rasagiline mesylate Tablet):

SN. Ingredients Quantity/tab (mg)
Dry mix
1. Microcrystalline cellulose 91.94
2. Pregelatinized Starch 16.00
3. Maize Strach 85.00
Binder solution
4. Rasagiline mesylate 1.56
5. Citric acid monohydrate 1.50
6. Purified Water q.s
Prelubrication
7. Colloidal silicon dioxide 1.00
8. Talc 2.00
Lubrication
9. Stearic Acid 1.00
Procedure:
i) Microcrystalline cellulose, pregelatinized starch and maize strach were weighed and
passoud through #40 sieve, ii) Sifted material of step 1 were mixed in RMG for 10 minutes at low speed

iii) Binder solution was prepared by adding Rasagiline mesylate, citric acid
monohydrate to purified water under constant stirring, iv) Binder solution of step 3 was added to step 2 in RMG
v) Granules of step 4 were dryed at 60° C inlet temperature to get the desired LOD vi) Colloidal silicon dioxide and talc were sifted through #40 sieve and blended with
the granules of step 5 for 10 minutes at slow speed vii) Stearic acid was sifted and passed through #40 sieve and mixed with prelubricated
blend of step 6 followed by compression.
Example -2
Table-3: Pharmaceutical composition of the invention (Rasagiline mesylate Tablet):

SN. Ingredients Quantity/tab (mg)
Dry mix
1. Mannitol 140.24
2. Pregelatinized Starch 20.00
Binder solution
3. Rasagiline mesylate 1.56
4. Hydroxy propyl β -cyclodextrin 9.00
5. Purified Water q.s
Prelu prication
6. Maize starch 20.00
7. Colloidal silicon dioxide 1.20
8. Talc 4.00
Lubrication
9. Stearic Acid 4.00
Procedure:
i) Mannitol and Pregelatinized starch were weighed and passoud through #40 sieve. ii) Sifted material of step 1 were mixed in RMG for 10 minutes at low speed iii) Binder solution was prepared by adding Rasagiline mesylate, hydroxy propyl p -cyclodextrin to purified water under constant stirring.

iv) Binder solution of step 3 was added to step 2 in RMG
v) Granules of step 4 were dryed at 60° C inlet temperature to get the desired LOD
vi) Maize starch, colloidal silicon dioxide and talc were sifted through #40 sieve and
blended with the granules of step 5 for 10 minutes at slow speed vii) Stearic acid was passed through #40 sieve and mixed with prelubricated blend of
step 6 followed by compression.
Example -3
Table-4: Pharmaceutical composition of the invention (Rasagiline mesylate Tablet):

SN. Ingredients Quantity/tab (mg)
Dry mix
1. Microcrystalline cellulose 176.94
2. Pregelatinized Starch 16.00
Binder solution
3. Rasagiline mesylate 1.56
4. Citric acid monohydrate 1.50
5. Purified Water q.s
Prelu mcation
6. Colloidal silicon dioxide 1.00
7. Talc 2.00
Lubrication
8. Stearic Acid 1.00
Procedure:
i) Microcrystalline cellulose and Pregelatinized starch were weighed and passed
through #40 sieve, ii) Sifted material of step 1 were mixed in RMG for 10 minutes at low speed iii) Binder solution was prepared by adding Rasagiline mesylate, citric acid
monohydrate to purified water under constant stirring, iv) Binder solution of step 3 was added to step 2 in RMG v) Granules of step 4 were dried at 60° C inlet temperature to get the desired LOD

vi) Colloidal silicon dioxide and talc were sifted through #40 sieve and blended with
the granules of step 5 for 10 minutes at slow speed vii) Stearic acid was sifted and passed through #40 sieve and mixed with prelubricated
blend of step 6 followed by compression.
Example -4
Table-5: Pharmaceutical composition of the invention (Rasagiline mesylate Tablet):

SN. Ingredients Quantity/tab (mg)
Dry mix
1. Mannitol 142.62
2. Pregelatinized Starch 20.00
Binder solution
3. Rasagiline mesylate 1.56
4. β -cyclodextrin 6.62
5. Purified Water q.s
Prelu brication
6. Maize starch 20.00
7. Colloidal silicon dioxide 1.20
8. Talc 4.00
Lubrication
9. Stearic Acid 4.00
Procedure:
i) Mannitol and Pregelatinized starch were weighed and passoud through #40 sieve.
ii) Sifted material of step 1 were mixed in RMG for 10 minutes at low speed
iii) Binder solution was prepared by adding Rasagiline mesylate, β -cyclodextrin to
purified water under constant stirring. iv) Binder solution of step 3 was added to step 2 in RMG
v) Granules of step 4 were dried at 60° C inlet temperature to get the desired LOD vi) Maize starch, colloidal silicon dioxide and talc were sifted through #40 sieve and
blended with the granules of step 5 for 10 minutes at slow speed

vii) Stearic acid was passed through #40 sieve and mixed with prelubricated blend of step 6 followed by compression.
Example -5
Table-6: Pharmaceutical composition of the invention (Rasagiline mesylate Tablet):

SN. Ingredients Quantity/tab (mg)
Dry mix
1. Rasagiline mesylate 1.56
2. Microcrystalline cellulose 91.94
3. Pregelatinized Starch 16.00
4. Maize Strach 85.00
Binder solution
5. Citric acid monohydrate 1.50
6. Purified Water q.s
Prelu brication
7. Colloidal silicon dioxide 1.00
8. Talc 2.00
Lubrication
9. Stearic Acid 1.00
Procedure:
i) Rasagiline mesylate, microcrystalline cellulose, Pregelatinized starch and maize
strach were weighed and passoud through #40 sieve, ii) Sifted material of step 1 were mixed in RMG for 10 minutes at low speed iii) Binder solution was prepared by adding citric acid monohydrate to purified water
under constant stirring. iv) Binder solution of step 3 was added to step 2 in RMG
v) Granules of step 4 were dried at 60° C inlet temperature to get the desired LOD vi) Colloidal silicon dioxide and talc were sifted through #40 sieve and blended with
the granules of step 5 for 10 minutes at slow speed

vii) Stearic acid was sifted and passed through #40 sieve and mixed with prelubricated blend of step 6 followed by compression.

WE CLAIM:
1. A stable oral pharmaceutical composition comprising Rasagiline or its pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable antioxidant(s), and wherein the said composition is free of sugar alcohols.
2. The pharmaceutical composition according to claim 1, wherein sugar alcohol is Mannitol, xylitol or sorbitol.
3. The pharmaceutical composition according to claim 1, wherein Rasagiline or its pharmaceutically acceptable salt thereof is Rasagiline mesylate.
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable antioxidant(s) selected from the group ascorbic acid esters or ascorbic acid and/or citric acid either alone or combination thereof.
5. The pharmaceutical composition according to claim 4, wherein the
pharmaceutically acceptable antioxidant(s) is citric acid.
6. The pharmaceutical compositions for the preparation of pharmaceutical
compositions substantially as herein described and illustrated by the examples.