FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10 and Rule 13]
Title
LONG ACTING PHARMACEUTICAL COMPOSITION OF
RASAGILINE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention and the manner in which it is to performed:

LONG ACTING PHARMACEUTICAL, COMPOSITION OF RASAGILINE
FIELD OF THE INVENTION
The present invention relates to a novel long acting pharmaceutical composition of rasagiline or its pharmaceuticallly acceptable salts or its ion pair complex to provide prolong release of rasagiline for extended period of time. The present invention also provides a process for the preparation and use of the said composition for the treatment of Parkinson's disease.
BACKGROUND OF THE INVENTION
Rasagiline has a chemical name (R (+) n-propargyl-1-aminoindane). The empirical formula of rasagiline is C12H13N. Its structural formula is as follow;

EP 0812190 disclose R(+)-N-propargyl-l-aminoindan ("R-PAI"), also known as rasagiline. Rasagiline has been reported to be a selective inhibitor of the B-form of the enzyme monoamine oxidase ("MAO-B") and is useful in treating Parkinson's disease and various other conditions by inhibition of MA0-B in the brain.
Currently Rasagiline is only available in immediate release oral form. AZILECT® is a commercially available rasagiline mesylate immediate release composition indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.

US 6126968 discloses pharmaceutical composition comprising rasagiline or pharmaceutically acceptable salts 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.
The treatment of Parkinson's disease is very sensitive to drug levels. Low levels of dopamine results in Parkinson's symptoms, while high levels produce motor response complications or, in extreme cases, psychosis. Inconsistent (pulsatile) stimulation of the dopamine receptor may hasten disease progression.
There are several concerns associated with the commercially available form of rasagiline mesylate. For example, due to first pass metabolism, oral bioavailability of the current marketed composition of rasagiline mesylate is very low (~36%).
Another concern in using monoamine oxidase ("MAO") inhibitors is the risk of hypertensive crisis, often called the "cheese effect." This effect is caused by inhibition of peripheral MAO. A high concentration of peripheral MAO is found in the stomach. Further concern in Parkinson's disease patients is that many patients suffer from delayed gastric emptying, which can be a cause of increased inhibition of peripheral MAO, and can contribute to the cheese effect. Rasagiline was shown to be a potent, irreversible MAO-B selective inhibitor, largely devoid of the potential to cause cheese effect. However, the possibilities exists that delayed gastric emptying of rasagiline contribute to the cheese effect.
Efforts to address such concerns and to improve the commercially available form of rasagiline mesylate are described in literature. For example, EP 2218444 A2, US 20090181086 discloses delayed release formulation of rasagiline to minimize the release the active ingredient in the duodenum and the jejunum, past the stomach to achieve above mentioned objective.

WO2007/101400 discloses the rasagiline transdermal patch comprising rasagiline or pharmaceutically acceptable salts thereof, and said patch formulation can either be manufactured according to the standard hot melt technique or according to the standard solvent/casting/drying process.
WO2011029598 also disclose the pharmaceutical patch formulation containing rasagiline or derivatives or analogues thereof comprises the incubation of the volatile active ingredient in retaining means before admixing the active ingredient into the polymer matrix of the patch formulation.
According to WO2011029598, the techniques for the manufacture of a patch formulation disclosed in WO2007/101400, containing the free base of rasagiline inevitably leads to a substantial loss of the active ingredient, which can even be up to 90 or 95% of the originally introduced amount of the active ingredients.
Further these transdermal patches have some disadvantages like local irritation at the site of application, erythema, itching and local edema caused by the drug, the adhesive or other excipient in the patch formulation.
There is increasing evidence that maintaining continuous and stable blood levels of the dopamine agonists may minimize the motor fluctuations and dyskinesias (involuntary movements) that are a debilitating side effect of the frequent oral administration of current dopamine replacement therapies.
However, there is still need to address the non motor features of Parkinsonism disease like depression in 2.7 to 70% of patients, anxiety in 66% patients and dementia in approximately 30% patient, which leads to lower patient compliance to the therapy (Charles et. al. Movement Disorders, 2005, vol 20, S23-S29). Moreover, the majority of Parkinson patients have difficulties in walking and taking medication by oral route; it is desirable to formulate rasagiline in a long acting form so that rasagiline may be administered less frequently than daily administration.

There is still need to develop long acting pharmaceutical composition of rasagiline which provides consistent and sustained levels of rasagiline.
The inventors of the present application found long acting pharmaceutical composition of rasagiline which not only provides consistent levels of drug in plasma but also decreases the possibility of hypertensive crisis caused by peripheral MAO inhibition in stomach.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure shows comparative pharmacokinetic profile of in situ implant of Rasagiline mesylate in wistar rats.
Fig. 2: This figure shows comparative pharmacokinetic profile of in situ implant and micrpparticles of Rasagiline mesylate in wistar rats.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to long acting injectable composition of rasagiline or pharmaceutically acceptable salts or ion pair complexes thereof, which provides prolong release of the rasagiline for extended period of time.
In another aspect, the present invention relates to long acting injectable composition of rasagiline or pharmaceutically acceptable salts or ion pair complexes thereof, which provides prolong release of the rasagiline for extended period of about one week to about one month, up to about two months, up to about three months, up to about four months, up to about five months, or up to about six months.
In another aspect, the present invention relates to long acting injectable composition comprises rasagiline or its pharmaceutically acceptable salts or ion pair complexes

thereof and one or more pharmaceutically acceptable excipient(s), which is capable of forming in-situ implant in human body.
In another aspect, the present invention relates to long acting injectable composition comprises rasagiline or its pharmaceutically acceptable salts or ion pair complexes thereof, at least one biodegradable polymer(s) and optionally at least one biocompatible solvent(s).
In another aspect, the present invention relates to long acting injectable composition comprises rasagiline or its pharmaceutically acceptable salts or ion pair complexes thereof and one or more pharmaceutically acceptable excipient(s), which is capable of forming insitu microparticles in human body.
In another aspect, the present invention relates to long acting injectable composition comprises rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof, at least one biodegradable polymer(s) and optionally at least one biocompatible solvent(s), which is capable of forming insitu microparticles in human body.
In another aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof, which is capable of forming in situ implant in human body comprises:
a) Biodegradable polymer is dissolved in suitable solvent and sterilized by membrane filtration and lyophilized in bulk;
b) Rasagiline or its pharmaceutically acceptable salts is dissolved and/ or dispersed in biocompatible solvent followed by sterilizing it by membrane filtration;
c) Mixing lyophilized biodegradable polymer and rasagiline or its pharmaceutically acceptable salt solution of step a & b aseptically; and
d) optionally adding one or more rate retarding agents.

Rasagiline or its pharmaceutically acceptable salts can also be added to polymer solution
at the time of use.
In another aspect, the present invention relates to a process for the preparation of long
acting injectable composition of rasagiline or it pharmaceutically acceptable salts or ion
pair complexes thereof, which is capable of forming in situ microparticles in human body
comprises:
a) biodegradable polymer is dissolved in biocompatible solvent;
b) rasagiline or its pharmaceutically acceptable salts is dissolved and /or dispersed in above polymeric solution;
c) solution or dispersion obtained in step (b) added to oil phase containing suitable stabilizer; and
d) mixture obtained in step (c) is subjected to homogenization to obtain an emulsion ready for injection.
In yet another aspect, the present inventions relates to long acting injectable composition of rasagiline comprises the ion pair complex of rasagiline, alternatively dispersed in aqueous phase or in polymer solution.
In another aspect, the present invention relates to long acting injectable composition of rasagiline or it pharmaceutically acceptable salts or ion pair complexes in the form of solid implant, which is prepared by low temperature extrusion, hot melt extrusion or other suitable techniques like injection moulding.
In another aspect, the present invention relates to long acting injectable composition of rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof in the form of microparticles, which is prepared by spray drying, spray congealing or supercritical fluid technology.
In another aspect, the present invention relates to a long acting injectable composition rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof, which is in the form of lipid/non ionic surfactant based vesicles.

In yet another aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof, which is in the form of lipid/non ionic surfactant based vesicles comprises:
a) dissolve lipids /non ionic surfactant in suitable organic solvent or combination of organic solvents;
b) dissolve rasagiline or its pharmaceutically acceptable salts in suitable aqueous buffer; and
c) Prepare lipid/non ionic surfactant based vesicles by any suitable method.
In another aspect, the present invention relates to long acting injectable composition comprises rasagiline or pharmaceutically acceptable salts or ion pair complexes thereof, provides rasagiline bioavailability of more than 45% upon parenteral administration.
In yet another aspect, the present invention relates to the use of long acting injectable composition for the treatment of Parkinson's disease.
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
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.

In one aspect the present inventions relates to the novel long acting pharmaceutical composition of rasagiline which may provide consistent and sustained levels of Rasagiline. It is often desirable to administer drugs using controlled or sustained release injectable compositions that can maintain therapeutic blood levels of the active agent (drug) over extended period of time. These sustained release injectable compositions reduce the frequency of dosing for enhanced patient convenience and compliance, and also reduce the severity and frequency of side effects. By maintaining substantially constant blood levels and avoiding blood level fluctuations of the drug particularly associated with conventional immediate release compositions that are administered several times a day, long acting injectable compositions can provide a better therapeutic profile than is obtainable with conventional immediate release compositions. It is also often desirable to extend the release time of an injected drug to increase its duration of action, or to reduce its toxic effects.
In one aspect, the present invention relates to a long acting injectable composition comprising rasagiline or pharmaceutically acceptable salts or ion pair complexes thereof provides rasagiline more than bioavailability of 45% upon parenteral administration.
The term "Long acting pharmaceutical composition" or "Long acting injectable composition" as used herein means specifically composition to provide a sustained release of the medicament over an extended period of one week to about one month, up to about two months, up to about three months, up to about four months, up to about five months, or up to about six months.
The term "pharmaceutically acceptable salt", as used herein means salts of rasagiline suitable for use in the treatment of mammals without undue toxicity, irritation, allergic response and exerts pharmacological response similar to Rasagiline.
The term "Bioavailability", as used herein means the extent to which or rate at which a drug or other substance is absorbed or becomes available systemically after administration.

The term "Extended period of time", as used herein means shall have different meanings with respect to the various drug delivery systems and its application. Normally, it includes one week to about one month, up to about two months, up to about three months, up to about four months, up to about five months, or up to about six months.
The term "biodegradable", as used herein means a material that gradually decomposes, dissolves, hydrolyzes and/or erodes in vivo. Generally, the "biodegradable polymers" herein are, polymers that are hydrolysable, and/or bioerodable in-situ primarily through hydrolysis and/or enzymolysis. The term "biodegradable polymer" as used herein is meant to include any biocompatible and/or biodegradable synthetic and natural polymers that can be used in vivo.
The term "biocompatible solvent", as used herein means such solvents generally do not react,or cause any untoward interaction with the biological tissues.
In another aspect, the pharmaceutical composition is long acting injectable composition which provides prolong release of the rasagiline for extended period of the time.
In another aspect, the present invention relates to long acting injectable composition comprises rasagiline or pharmaceutically acceptable salts or ion pair complexes thereof comprises at least one biodegradable polymer(s) and optionally at least one biocompatible solvent(s).
Insiiu implant
In general aspect, the present invention relates to long acting injectable composition comprises rasagiline or its pharmaceutically acceptable salts or ion pair complexes thereof, at least one biodegradable polymer(s) and optionally at least one biocompatible solvent(s); wherein the said composition is capable of forming insitu implant in human

body when administered to a patient, and provide prolong release of rasagiline for extended period of time.
The term "in situ implant", as used herein means the biodegradable delivery systems are generally liquid composition that form gel, semi-solid or solid depot after injection. The drug is dissolved or dispersed in a concentrated solution of water insoluble biodegradable polymer in a water miscible biocompatible solvent. Upon injection into aqueous body fluids, the solvent diffuses into the surroundings aqueous environment while water diffuses into the polymer matrix leading to the formation of solid insitu implant.
In one aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or it pharmaceutically acceptable salts, which is capable of forming insitu implant in human body comprises:
a) Biodegradable polymer is dissolved in suitable solvent and sterilized by membrane filtration and lyophilized in bulk;
b) Rasagiline or its pharmaceutically acceptable salts is dissolved and/ or dispersed in biocompatible solvent followed by sterilizing it by membrane filtration;

c) Mixing lyophilized biodegradable polymer and rasagiline or its pharmaceutically acceptable salt solution of step a & b aseptically; and
d) optionally adding one or more rate retarding agents.
Rasagiline or its pharmaceutically acceptable salts can also be added to polymer solution at the time of use
Biodegradable polymer is selected from but not limited to a group comprising lactic acid-based polymers such as polylactides e.g. poly (D,L-lactide) i.e. PLA; glycolic acid-based polymers such as polyglycolides (PGA) e.g. Lactel® from Durect; poly (D,L-lactide-co-glycolide) i.e. PLGA, (Resomer® RG-504, Resomer® RG-502, Resomer® RG-504H, Resomer® RG- 502H, Resomer® RG-504S, Resomer® RG-502S, from Boehringer, Lactel® from Durect); polycaprolactones such as Poly(e-caprolactone) i.e. PCL (Lactel®

from Durect); polyanhydrides; poly(Sebacic acid) SA; poly(Ricenolic acid) RA; poly(Fumaric acid), FA; poly(Fatty acid dimmer), FAD; poly(terephthalic acid), TA; poly(isophthalic acid), IPA; poIy(p-{carboxyphenoxy}methane), CPM; poly(p-{carboxyphenoxy} propane), CPP; poly(p-{carboxyphenoxy}hexane)s CPH; polyamines, polyurethanes, polyesteramides, polyorthoesters {CHDM: Cis/trans- cyclohexyl dimethanol, HD:l,6-hexanediol. DETOU: (3,9-diethylidene-2,4,8,10- tetraoxaspiro undecane)}; polydioxanones; polyhydroxybutyrates; polyalkysne oxalates; polyamides; polyesteramides; polyurethanes; polyacetals; polyketals; polycarbonates; polyorthocarbonates; polysiloxanes; polyphosphazenes; succinates; hyaluronic acid; poly(malic acid); poly(amino acids); polyhydroxyvalerates; polyalkylene succinates; polyvinylpyrrolidone; polystyrene; synthetic celluloses; polyacrylic acids; polybutyric acid; triblock copolymers (PLGA-PEG-PLGA), triblock copolymers (PEG-PLGA-PEG), poly (N-isopropylacrylamide) (PNIPAAm), poly (ethylene oxide)- poly (propylene oxide)- poly (ethylene oxide) tri-block copolymers (PEO-PPO-PEO), poly valeric acid; polyethylene glycol; polypropylene glycol; polyhydroxycellulose; chitin; chitosan; polyorthoesters and copolymers, terpolymers; lipids such as cholesterol, lecithin; poly(glutamic acid-co-ethyl glutamate) and the like, or mixtures thereof.
The biodegradable polymer can be present in any suitable amount. The suitable biodegradable polymer is preferably present in an about 20 wt. % to about 80 wt. % of the composition, more preferably present in about 30 wt. % to about 60 wt. % of the composition.
Specifically, the biocompatible organic solvent can be used in the present invention are N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, propylene carbonate, ethylene carbonate, dimethyl carbonate, 2-ethyoxylyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dichloromethane (DCM) dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, glyceryl triacetate, acetone, methyl ethyl ketone, solketal, glycerol formal, glycofurol, dimethylformamide, dimethylacetamide, dimethylsulfoxide (DMSO), dimethylsulfone;

tetrahydrofiiran; epsilon-caprolactone, butyrolactone, caprolactam, N,N-dimethyI-m-toluamide, l-dodecylazacycloheptan-2-one, benzyl alcohol, benzyl benzoate, poly vinyl alcohol (PVA) benzyl benzoate, triacetin or mixtures thereof.
Rate retarding agents can also be added in the composition. Such retarding agents can be selected from the group comprising of ester of a mono, di or tricarboxylic acid, a polyhydroxy alcohol, a fatty acid, a fatty, acid ester, epoxidized oil, a sterol, a higher alkyl alcohol, and any mixture thereof.
In situ Microparticles:
In one aspect, the present invention relates to long acting injectable composition comprises rasagiline or its pharmaceutically acceptable salts or ion pair complexes thereof, at least one biodegradable polymer(s) and optionally at least one biocompatible solvent(s); wherein the said composition is capable of forming In situ microparticles in human body when administered to a patient, and provide prolong release of rasagiline for extended period of time
The term "Microparticles" as used herein means particles that comprise a polymer that serves as a matrix or binder of the particle. The microparticles contain an active agent or other substance dispersed or dissolved within the polymeric matrix. The polymer is preferably biodegradable and biocompatible.
In one aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or it pharmaceutically acceptable salts, which is capable of forming an insitu microparticles in human body comprises:
a) biodegradable polymer is dissolved in biocompatible solvent;
b) rasagiline or its pharmaceutically acceptable salts is dissolved and /or dispersed in above polymeric solution;

c) solution or dispersion obtained in step (b) added to oil phase containing suitable stabilizer; and
d) mixture obtained in step (c) is subjected to homogenization to obtain an emulsion ready for injection.
The biodegradable polymer and biocompatible solvent are as described herein above.
The stabilizer includes but not limited to poloxamer, polysorbate 20, polysorbate 80 and sorbitan oleate.
The oil phase selected from Ethyl oleate, Medium Chain Triglyceride (Miglyol 812), peanut oil, sesame oil, soybean oil, safflower bean oil, ethyl oleate and castor oil.
Ion Pair complexes:
In one aspect, the present invention relates to long acting injectable composition of rasagiline comprises the ion pair complex of rasagiline, alternatively dispersed in aqueous phase or in polymer solution.
The term uion pair complex", as used herein means an ionic interaction that occurs between two opposite charged compounds. In the instant case, Rasagiline is basic in nature and the other ionic compounds are acidic in nature. Ionic interaction of rasagiline with compound of opposite charge (acidic) results in formation of ionic pair complex which may retard the release of rasagiline with or without incorporation into biodegradable polymer/ lipid vesicles.
Examples of ionic compounds which can be used for complex formation are Cholesteryl sulfate, distearoyl phosphatidylglycerole and the like.
The biodegradable polymers are as described herein above.

In one aspect, the present invention relates to long acting injectable composition of
-» *
rasagiiine or it pharmaceutically acceptable salts or ion pair complexes thereof in the
form of solid implant, which is prepared by low temperature extrusion or other suitable
techniques like injection moulding.
In one aspect, the present invention relates to long acting injectable composition of rasagiiine or it pharmaceutically acceptable salts or ion pair complexes thereof in the form of solid implant, prepared by hot melt extrusion which provide prolong release of rasagiiine for extended period of time.
The term "Hot melt extrusion", as used herein means a process whereby a blended composition is heated and/or compressed to a molten (or softened) state and subsequently forced through an orifice where the extruded product (extrudate) is formed into its final shape in which it solidifies upon cooling.
In one aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiiine or its pharmaceutically acceptable salts in the form of solid implant, comprises:
a) prepare the mixture of rasagiiine or its pharmaceutically acceptable salts and polymer;
b) feed the above mixture through the hot melt extruder to obtain extrudate;
c) cool the extrudate to room temperature and the cut into appropriate length to form
. an implant;
In one aspect, the present invention relates to long acting injectable composition of rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof in the form of microparticles, which is prepared by spray drying, spray congealing or supercritical fluid technology.

The term "spray drying" as used herein means transformation of feed from fluid state into dried form by spraying the feed into a hot drying medium. The process is one step continuous operation. The feed can be a solution or suspensions.
In one aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or its pharmaceutically acceptable salts or ion pair complexes thereof in the form of microparticles, comprises:
a) dissolve and /or disperse rasagiline or its pharmaceutically acceptable salts and polymer into organic solvent to prepare spray solution/dispersion;
b) spraying the solution/dispersion of step a) through atomizer into chamber to form droplets; and
c) drying the droplets to form microparticles containing rasagiline in polymer matrix.
The above said polymer can be biodegradable polymer and solvent can be biocompatible solvent, which are as described herein above.
The term "spray congealing", as used herein means the transition of a melt from a soft or fluid state to a rigid or solid state by cooling is called congealing. The various droplet formation techniques and the efficient droplet / air contact make the spray drying concept ideal for making spherical particle powder by congealing of melts. During the spray cooling /spray congealing process a melt is formed into particles of spherical shape by spraying the melt into a cooling chamber.
In one aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or its pharmaceutically acceptable salts in the form of microparticle comprises:
a) dissolve and /or disperse the drug in melted polymer;

b) spraying the solution/dispersion of step a) through atomizer into chamber to form droplets; and
c) cooling the droplets to form solid dispersion containing rasagiline or its pharmaceutically acceptable salts in polymer matrix.
The above said polymer can be biodegradable polymer, which is as described herein above.
The term "Super critical fluid technology", as used herein means extraction of solvent with the help of super critical fluid e.g. Carbon dioxide, di-nitrogen oxide, carbon disulphide etc. Supercritical fluid is any substance at a temperature and pressure above its critical point. It can effuse through solids like a gas, and dissolve materials like a liquid. The advantages of supercritical fluid extraction (compared with liquid extraction) are that it is relatively rapid because of the low viscosities and high diffusivities associated with supercritical fluids.
In one aspect, the present invention relates to a long acting injectable composition rasagiline or it pharmaceutically acceptable salts or ion pair complexes thereof in the form of lipid/non ionic surfactant based vesicles.
In one aspect, the present invention relates to a process for the preparation of long acting injectable composition of rasagiline or it pharmaceutically acceptable salts in the form of lipid/non ionic surfactant based vesicles comprises:
a) dissolve lipids /non ionic surfactant and optionally rasagiline in suitable organic solvent or combination of organic solvents;
b) dissolve rasagiline or its pharmaceutically acceptable salts in suitable aqueous buffer; and
c) Prepare lipid/non ionic surfactant based vesicles by any suitable method.

Lipid is selected from but not limited to a group comprising synthetic or semi-synthetic origin. Examples of lipids include but not limited to phosphatidylcholines, phosphatidylglycerol, cholesterol and the like or mixture thereof. Phosphatidylcholines is selected from hydrogenated soybean phosphatidylcholine (HSPC), dimyristoylphosphatidylcholine (DMPC), Dipalmitoylphosphatidylcholine (DPPC), Disteroylphosphatidylcholine (DSPC) and the like. Phosphatidylglycerol is selected from distearoyl- phosphatidylglycerol (DSPG), Dipalmitoylphosphatidylglycerol (DPPG) and the like.
The non ionic surfactant include but not limited to cetyl alcohol, cocamide DEA, cocamide MEA, poloxamer, poloxamer 407, polyglycerol, polysorbate, spans, tween and their mixture thereof.
The organic solvent include but not limited to Chloroform, methanol, ethanol, isopropyl alcohol, isobutanol, n- butanol, ethers.
In one aspect, the present invention relates to the use of long acting injectable composition for the treatment of Parkinson's disease.
In one aspect, the long acting injectable formulation of the present invention can be administered to a subject, animals or humans, preferably via intramuscular, intradermal, cutaneous or subcutaneous routes. In a preferred aspect, the long acting injectable formulation is in the form of parenteral composition, which may be administered via intramuscular or subcutaneous route.
The various embodiments of the invention having thus been generally described and the following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.

Examples:
A. In situ implants
Example 1: In situ implants of Rasagiline base/salt using PLGA as biodegradable polymer

No Ingredients Quantity
1 Rasagiline 0.5-25%
2 PLGA 20-60%
3 NMP 20-80%
Step 1:" Dissolve polymer in solvent
Step 2: Dissolve or disperse Rasagiline base/salt in step one solution.
Example 2: In situ implants of Rasagiline base/salt using PLGA as biodegradable polymer

No Ingredients Quantity
1 Rasagiline 0.5-25%
2 PLGA 20-60%
3- Benzyl benzoate 0.5-30%
4 NMP 20-70%
Step 1; Dissolve polymer in solvent.
Step 2: Dissolve or disperse Rasagiline base/salt in step one solution.
B. In situ microparticles:
Example 3: In situ microparticles of Rasagiline base/salt using PLGA as biodegradable polymer

No Ingredients Quantity
1 Rasagiline 2-25%
2 PLGA 5-30%
3 NMP 10-30%
4 Span 20 1-5%
5 Miglyol 812 25-50%

Step .1: Preparation of PLGA solution: Dissolve PLGA in biocompatible solvent such as
N-methyl pyrrolidone, Polyethylene glycol, DMSO, benzyl benzoate, benzyl alcohol,
ethyl lactate, 2-pyrrolidone, triacetin, propylene carbonate, triethyl citrate.
Step 2: Dissolve Rasagiline base/salt in same solvent used in step 1 or any other
biocompatible solvent miscible with solvent used in step 1.
Step 3: Mix both the solution of step 1 and step 2.
Step 4: Homogenize the step 3 solution in oil (Miglyol 812) containing stabilizer (Span
80).
Example 4: In situ microparticles of Rasagiline base/salt using PLGA-PEG as biodegradable polymer

No Ingredients Quantity
1 Rasagiline 2-25%
2 PLGA-PEG 5-30%
3 NMP 10-30%
4 Span 20 1-5%
5 Miglyol 812 25-50%
Step 1: Preparation of PLGA-PEG solution: Dissolve PLGA-PEG in biocompatible
solvent such as N-methyl pyrrolidone, Polyethylene glycol, DMSO, benzyl benzoate,
benzyl alcohol, ethyl lactate, 2-pyrrolidone, triacetin, propylene carbonate, triethyl
citrate.
Step 2: Dissolve Rasagiline base in same solvent used in step 1 or any other
biocompatible solvent miscible with solvent used in step 1.
Step 3: Mix both the solution of step 1 and step 2.
Step 4: Homogenize the step 3 solution in oil (Medium chain triglycerides (Miglyol 812),
Castor oil, peanut oil, safflower seed oil, sesame oil, soybean oil, Ethyl oleate) containing
suitable stabilizer (Tween 80, Tween 20, Span 80).

C. Solid implant of rasagiline base/salt Example 5: Solid implants Rasagiline base/salt

No Ingredients Quantity
1 Rasagiline 2-50%
2 PLGA 50-95%
Step"1. Mix Rasagiline base/salt with PLGA.
Step 2"; Extrude at 70-80°C.
Step 3. Cut the extrudate in appropriate size.
Example 6: Mill the extrudate from example 5 and suspend in diluents.
D. Ion pair complex:
Example 7: Preparation of ion pair complex

No Ingredients Quantity
1 Rasagiline 2-50%
2 Cholesteryl sulphate 50-95%
3. ' PLGA 20-60%
4. DCM q.s.
5 PVA 0.5-10%
6 Water q.s.
Step 1: Prepare ion pair complex as described in example 9
Step 2: Dissolve PLGA in DCM.
Step 3: Dissolve or disperse step 1 complex in PLGA solution.
Step 4: Add step 3 mixes into aqueous solution under homogenization to form
microparticles.
Example 8: Preparation of ion pair complex

No Ingredients Quantity
1 Rasagiline mesylate 268.5 mg

2 distearoyl phosphatidylglycerol sodium 800 mg
3 Chloroform 6.25 ml
4 Methanol 8.25 ml
5 Glacial acetic acid q.s.
Manufacturing process:
1. Distearoyl phosphatidylglycerol sodium was dissolved in 12.5 ml chloroform: methanol (1:1) mixture by heating at 65°C in closed vessel.
2. pH of step 1 solution was adjusted to 3.0 using glacial acetic acid.
3. Rasagiline mesylate was dissolved separately in methanol.
4,. Both the solution were mixed in a round bottom flask and stirred to get clear
solution at 60°C. 5. Solvent from step 4 solution was removed using rotavapor to obtain precipitates.
Example 9: Microparticles of Rasagiline using spray drying technique

No ingredients Quantity
1 Rasagiline 2-50%>
2. PLGA 5-70%
3. Ethyl acetate q.s.
Step 1: Dissolve PLGA in ethyl acetate.
Step 2: Dissolve or disperse Rasagiline in step 1 solution.
Step 3: Spray dry step 2 solution or dispersion
E. Multilamellar Liposome of Rasagiline Example 10:

No Ingredients Quantity
1 Rasagiline 2-50%
2. DSPG 2-40%
3. HSPC 10-90%
4. Cholesterol 5-50%
5. ■■';■ Chloroform q.s.
6. Methanol q.s.
Step 1: Dissolve Lipids in mixture of Chloroform and methanol.
Step 2: Prepare dry thin film of step 1 solution using Rotavapour .
Step 3: Hydrate step 2 lipid film using drug solution to get multilamellar liposome.

Step 4; Lyophillize the liposomal suspension.
Example 11: In-Situ Implant of Rasagiline Mesylate Formulation composition

Formulation
No. Polymer solution Composition Label claim
I 7525DLG3A 40% 60% Each 0.3 ml formulation contains Rasagiline mesylate equivalent to 10 mg Rasagiline base

NMP

II 100DL2.5A 10% 35% 55% Each 0.3 ml formulation contains Rasagiline mesylate equivalent to 10 mg Rasagiline base
7525DLG3A

NMP

III 100DL2.5A 10%
35%
...55%o Each 0.3 ml formulation contains Rasagiline mesylate equivalent to 15 mg Rasagiline base

7525DLG3A

NMP

Process:
1. Biodegradable polymer was dissolved in acetic acid and sterilized by membrane filtration and lyophilized in bulk;
2. Prepared Rasagiline mesylate solution in a NMP followed by sterilizing it by membrane filtration; and
3. Lyophilized polymer and Rasagiline mesylate solution (step 1 & 2) were mixed aseptically and filling in a suitable container closure system
In vivo study of Rasagiline Mesylate
A comparative evaluation of pharmacokinetic profile of three different Rasagiline in situ implant formulation of was carried out in male wistar rats. Formulations were administered through subcutaneous route. Each group (N=5) was administered a single dose. Blood samples were withdrawn at predefined time interval for measurement rasagiline in plasma using LC-MS/MS detection.

Group Formulation Dose Dose volume
I Formulation I 30 mg/kg 0.3 ml/site
II Formulation II 30 mg/kg 0.3 ml/site
III Formulation III 45 mg/kg 0.3 ml/site
The comparison of Mean Plasma concentration of Rasagiline of above three Formulations i.e. I, II & III is provided in Figure-1.
Example 12: Long acting injectable composition of Rasagiline Mesylate
Formulation composition

Formulation Composition Label claim
No
V Rasagiline mesylate eq to 10 mg Rasagiline base. Each 0.3 ml formulation
Polymer solution q.s. to 0.3 ml
Composition of Polymer solution
7525 DLG 3A 45% contains 10.0 mg eq Rasagiline base

NMP 55%

VI Rasagiline mesylate eq to 10 mg Rasagiline base. Each 0.3 ml formulation
Polymer solution q.s. to 0.3 ml
Composition of Polymer solution
100DL2.5A 10% contains 10.0 mg eq Rasagiline base

7525 DLG 3A 35%

PG 10%

NMP 45%
VII Rasagiline Mesylate microparticles of Each 0.3 ml formulation contains 2.0 mg eq
7525 DLG 3A '. 268 mg
Diluent composition
Na CMC (Blanose 7 LF) 30 mg
NaCl 9mg
WFI...q.s to 1ml Rasagiline base
VIII Rasagiline Mesylate microparticles of Each 0.3 ml formulation

Formulation No Composition Label claim
5050 DLG 2A 91.56 mg contains 2.0 mg eq Rasagiline base

7525 DLG 3A 161.24 mg

Diluent composition
Na CMC (Blanose 7 LF) 30 mg
NaCl 9mg
WFI...q.s to 1ml
Process for the preparation of Formulation V & VI:
1. Biodegradable polymer was dissolved in acetic acid and sterilized by membrane filtration and lyophilized in bulk;
2. Prepared Rasagiline mesylate solution in a NMP followed by sterilizing it by membrane filtration; and
3. Lyophilized polymer and Rasagiline mesylate solution (step 1 & 2) were mixed aseptic-ally and filling in a suitable container closure system
Process for the preparation of Formulation VII & VIII:
Preparation of Microparticles
1. Microspheres were prepared by oil-water (O/W) solvent evaporation method. Briefly, organic phase was prepared by dissolving PLGA in CH2Cl2. Rasagiline mesylate was then dispersed in PLGA solution using vortex mixer.
2. Organic phase was added to precooled 50 ml aqueous phase (2.5% w/v PVA, pH 10) under stirring and both phases were emulsified with a Polytron® system (Kinematica) for 60 s at 8000 rpm under cooling at about 5±2°C to get o/w emulsion.
3. The resulting O/W emulsion was immediately poured into 1000 ml PVA solution (1% w/v, pH 10) with 5% NaCl and continuously stirred for 3 h at room temperature with an overhead mechanical stirrer (700 rpm) to allow complete evaporation of the organic solvent
4. The microspheres were vacuum-filtered through 25-μ filter followed by 0.8 μ membrane filters. Collected microparticles were vacuum dried at room temperature.

In vivo study of Rasagiline Long Acting Composition
A comparative evaluation of pharmacokinetic profile of four different Rasagiline long acting injectable formulation of was carried out in male wistar rats. Formulations were administered through subcutaneous route. Each group (N=5) was administered a single dose. Blood samples were withdrawn at predefined time interval for measurement rasagiline in plasma using LC-MS/MS detection.

Group Formulation Dose Dose volume
I Formulation V 30 mg/kg 0.3 ml/site
II Formulation VI 30 mg/kg 0.3 ml/site
III Formulation VII 6 mg/kg 0.3 ml/site
IV Formulation VIII 6 mg/kg 0.3 ml/site
The comparison of Mean Plasma concentration of Rasagiline of above four Formulation V, VI, VII ■& VIII is provided in figure-2.

Figure -1


Figure - 2


We Claim:
1. A long acting injectable composition of rasagiline or pharmaceutically acceptable salts or ion pair complexes thereof, which provides prolong release of the rasagiline for extended period of time.
2. The long acting injectable composition according to claim 1, which is capable of forming insitu implant in human body.
3. The long acting injectable composition according to claim 1, which is capable of forming insitu microparticles in human body.
4. The long acting injectable composition according to claim 1, which is in the form of lipid/non ionic surfactant based vesicles.
5. The long acting injectable composition according to claim 1, which is in the form of solid implant.
6. The long acting injectable composition according to claim 2 comprises at least one biodegradable polymer and optionally at least one biocompatible solvent.
7. A process for the preparation of long acting injectable composition according to claim 2, which comprises:

a) Biodegradable polymer is dissolved in suitable solvent and sterilized by membrane filtration and lyophilized in bulk;
b) Rasagiline or its pharmaceutically acceptable salts is dissolved and/or dispersed in biocompatible solvent followed by sterilizing it by membrane filtration;
c) Mixing lyophilized biodegradable polymer and rasagiline or its pharmaceutically acceptable salt solution of step a & b aseptically; and
d) optionally adding one or more rate retarding agents.

8. A process for the preparation of long acting injectable composition according to claim
3, which comprises:
a) biodegradable polymer is dissolved in biocompatible solvent;
b) rasagiline or its pharmaceutically acceptable salts is dissolved and /or dispersed in above polymeric solution;
c) solution or dispersion obtained in step (b) added to oil phase containing suitable stabilizer; and
d) mixture obtained in step (c) is subjected to homogenization to obtain an emulsion ready for injection.
9. The long acting injectable composition according to claim 1, wherein the duration of
drug release is from one week to about six months.
10. A long acting injectable composition of rasagiline or pharmaceutically acceptable
salts or ion pair complexes thereof, as herein described, particularly with reference to the
foregoing examples.