DESC:
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

“INJECTABLE COMPOSITIONS OF LIRAGLUTIDE”

BIOCON PHARMA LIMITED, an Indian Company of Special Economic zone, Plot Nos. 2, 3, 4 & 5, Phase - IV, Bommasandra-Jigani Link Road, Bommasandra Post, Bengaluru – 560099, State of Karnataka, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The invention relates to long acting injectable liraglutide compositions, methods of making them and use of such composition in the treatment of metabolic diseases.

BACKGROUND OF THE INVENTION

Diabetic mellitus is a disease of metabolic dysregulation, most notably abnormal glucose metabolism, accompanied by characteristic long term complications. It's a chronic disease requiring long term medications. Various parenteral anti-diabetic medications are available in market including human insulin and different GLP-1 agonists.

The natural GLP-1 is a gut hormone with therapeutic potential in the treatment of Type 1 and Type 2 diabetes and the treatment of obesity. The natural GLP-1 has a short half-life of only few minutes in the body as it is rapidly degraded by dipeptidyl peptidase-4 enzyme.

Many GLP-1 agonists were developed by modifications to natural GLP-1 to overcome the problem of its short half-life. One of the approaches used was substitution of one or more amino acids of the GLP-1 polypeptide and attachment of a lipophilic substituent to these peptides. These lipophilic substituted GLP-1 agonists showed protracted action when injected.

U.S. Pat. No. 6,268,343 discloses such fatty acid acylated GLP-1 agonists. One particular example includes liraglutide. Liraglutide is (Arg34, Lys26 (N?-(?-GLu(N-hexadecanoyl)))-GLP-1(7-37).

In United States, Liraglutide is approved as a once daily subcutaneous injection to improve glycemic control in adults with type 2 diabetes mellitus under the trade name VICTOZA™. VICTOZA™ is a 6 mg/mL injectable solution of liraglutide in a pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg. The approved dosage of VICTOZA™ starts with 0.6 mg daily for one week and then increase to 1.2 mg daily, if additional glycemic control is required, the dose increased to 1.8 mg daily after one week of treatment with the 1.2 mg daily dose.Liraglutide is also approved as a once daily subcutaneous injection forchronic weight management in adult patients under the trade name SAXENDA™. SAXENDA™ is a 6 mg/mL injectable solution of liraglutide in a pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg.

US20180221451 discloses a long acting liraglutide composition of microspheres, wherein said microspheres comprises Poly(lactide-co-glycolide) polymer; therapeutically effective amount of liraglutide or a pharmaceutically acceptable salt thereof; and a hydrophilic particle size modulating agent.

Yipei Chen et al. publication inScientific Reports 6:31593 (DOI: 10.1038/srep31593), discloses a long acting subcutaneously administrable controlled release composition of Liraglutide using thermogelling polymers like poly(e-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(e-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) and poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-coglycolic acid) (PLGA-PEG-PLGA).

Liraglutide is used as long-term medications for glycemic control. Hence it needs to be administered subcutaneously daily for long time.However, in spite of the available therapies, there is still a need to lower the frequency of injections for the patients to provide patient compliance and adherence. The present invention provides a long acting composition of liraglutide, which reduces the dosing frequency and improves patient compliance and adherence with lower diabetes-related medical costs.

SUMMARY OF THE INVENTION

In accordance with one aspect, the present invention provides long acting injectable compositions of Liraglutide.

According to one embodiment, the present invention provides an injectable composition comprising:(a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and(c) a biocompatible solvent.

According to another embodiment, the present invention provides an injectable composition comprising:(a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and(c) a biocompatible solvent,

wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

According to another embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or pharmaceutically acceptable salt thereof; (b) poly (D,L-lactic-co-glycolic acid)or poly (D, L-lactic acid) and(c) N-methyl-2-pyrrolidone.

According to another embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or pharmaceutically acceptable salt thereof; (b) poly (D,L-lactic-co-glycolic acid) or poly (D, L-lactic acid) and (c) N-methyl-2-pyrrolidone, wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

According to another embodiment, the present invention provides an injectable composition comprising:(a) 0.5% w/w to about 50% w/w of liraglutide or pharmaceutically acceptable salt thereof; (b) poly (D,L-lactic-co-glycolic acid)orpoly (D, L-lactic acid)and(c) N-methyl-2-pyrrolidone.

According to another embodiment, the present invention provides an injectable composition comprising:(a) 4% w/w to about 20% w/w of liraglutide or pharmaceutically acceptable salt thereof; (b) poly (D,L-lactic-co-glycolic acid)orpoly (D, L-lactic acid)and (c) N-methyl-2-pyrrolidone.

According to another embodiment, the present invention provides an injectable composition comprising:(a) 10% w/w to about 20% w/w of liraglutide or pharmaceutically acceptable salt thereof; (b) poly (D,L-lactic-co-glycolic acid)orpoly (D, L-lactic acid)and (c) N-methyl-2-pyrrolidone.

According to another embodiment, the present invention provides an injectable composition comprising: (a) 8.4mg to 162mg of liraglutide or pharmaceutically acceptable salt thereof; (b) poly (D, L-lactic-co-glycolic acid) or poly (D, L-lactic acid) and (c) N-methyl-2-pyrrolidone.

According to another embodiment, the amount of liraglutide in injectable composition of the present invention is 50mg.

According to another embodiment, the amount of liraglutide in injectable composition of the present invention is 25mg.

According to another embodiment, the amount of liraglutide in injectable composition of the present invention is 12.5mg.

According to another embodiment, the amount of liraglutide in injectable composition of the present invention is 18mg.

According to another embodiment, the amount of liraglutide in injectable composition of the present invention is 36mg.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and (c) a biocompatible solvent, wherein the biodegradable carrier is selected from polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids) and copolymers,or combinations thereof.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and(c) a biocompatible solvent, wherein the biodegradable carrier is selected from poly (D, L-lactic acid), poly (D,L-lactic-co-glycolic acid), polycaprolactone, linear polyhydroxyalkanoate, polybutylene succinate, polybutylene succinate adipate, polybutylene adipate, polybutylene adipate terephthalate, ethylene-vinyl acetate, polyurethane, or combination thereof.

According to another embodiment, the biodegradable carrier of the injectable composition of the present invention ispoly (D,L-lactic-co-glycolic acid) or poly (D, L-lactic acid).

According to another embodiment, the biodegradable carrier of the injectable composition of the present invention ispoly (D,L-lactic-co-glycolic acid) or poly (D, L-lactic acid) having average molecular weight ranging from 4000 to 250000 daltons.

According to another embodiment, the biodegradable carrier of the injectable composition of the present invention is poly (D,L-lactic-co-glycolic acid) having lactic acid:glycolic acid ratio 95:5 to 5:95.

According to another embodiment, the biodegradable carrier of the injectable composition of the present invention is poly (D, L-lactic-co-glycolic acid) having lacticacid:glycolic acid ratio80:20 to 20:80.

According to another embodiment, the biodegradable carrier of the injectable composition of the present invention ispoly (D,L-lactic-co-glycolic acid) having lacticacid:glycolic acid ratio 75:25.

According to another embodiment, the biodegradable carrier of the injectable composition of the present invention is poly (D,L-lactic-co-glycolic acid) having lacticacid:glycolic acid ratio 50:50.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and(c) a biocompatible solvent, wherein the biocompatible solvent is selected from N-methyl-2-pyrrolidone, benzyl alcohol, benzyl benzoate, ethyl benzoate, ethyl hydroxide, dimethylsulfoxide, or mixtures thereof.

According to another embodiment, the biocompatible solventof the injectable composition of the present invention is N-methyl-2-pyrrolidone or dimethylsulfoxide.

According to one embodiment, the present invention providesan injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and(c) a biocompatible solvent, wherein the weight ratio of liraglutide or a pharmaceutically acceptable salt thereof to biodegradable carrier is 1:1 to 1:10.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and (c) a biocompatible solvent, wherein the weight ratio of liraglutide or a pharmaceutically acceptable salt thereof to biocompatible solvent is 1:1 to 1:15.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and(c) a biocompatible solvent, wherein the weight ratio of biodegradable carrier to biocompatible solvent is 1:0.5 to 1:10.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and (c) a biocompatible solvent, wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium, wherein the injectable composition is administered once monthly.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and (c) a biocompatible solvent, wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium, wherein the injectable composition is administered once in two weeks.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and (c) a biocompatible solvent, wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium, wherein the injectable composition is administered once in two months.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) a biodegradable carrier; and (c) a biocompatible solvent, wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium, wherein the injectable composition is administered once in three months.

According to one embodiment, the present invention provides an injectable composition comprising: (a) liraglutide or a pharmaceutically acceptable salt thereof; (b) poly (D,L-lactic-co-glycolic acid) or poly (D, L-lactic acid) and (c) N-methyl-2-pyrrolidone, wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium, wherein the injectable composition is administered once monthly.

Another aspect of the present invention, provides a kit comprising long acting, injectable compositions of Liraglutide or a pharmaceutically acceptable salt thereof.

According to one embodiment, the present invention provides a kit comprising;
(a) syringe comprising liraglutide or a pharmaceutically acceptable salt thereof;
(b)syringe comprising a biodegradable carrier and biocompatible solvent.

According to another embodiment, the present invention provides a kit comprising;
(a) syringe comprising liraglutide or a pharmaceutically acceptable salt thereof;
(b) syringe comprising a biodegradable carrier and biocompatible solvent,

wherein the biodegradable carrier is selected from polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids) and copolymers or combinations thereof, and
wherein the biocompatible solvent is selected from N-methyl-2-pyrrolidone, benzyl alcohol, benzyl benzoate, ethyl benzoate, ethyl hydroxide, dimethylsulfoxide or mixtures thereof.

According to another embodiment, the present invention provides a kit comprising;
(a) syringe comprising 8.4mg to 162mg of liraglutide or a pharmaceutically acceptable salt thereof;
(b) syringe comprising a biodegradable carrier and biocompatible solvent,

wherein the biodegradable carrier is poly (D, L-lactic acid) or poly (D, L-lactic-co-glycolic acid) and biocompatible solvent is N-methyl-2-pyrrolidone.

According to one embodiment, the present invention provides a kit comprising: a prefilled syringe comprising of liraglutide or a pharmaceutically acceptable salt thereof, a biodegradable carrier and biocompatible solvent.

According to another embodiment, the present invention provides a kit comprising: a prefilled syringe comprising of liraglutide or a pharmaceutically acceptable salt thereof, a biodegradable carrier and biocompatible solvent, wherein the biodegradable carrier is poly (D, L-lactic acid) or poly (D, L-lactic-co-glycolic acid) and biocompatible solvent is N-methyl-2-pyrrolidone.

Another aspect of the present invention, provides a method for treating type 2 diabetes mellitus, the method comprising administering to the patient an injectable composition comprising:
(a) liraglutide or a pharmaceutically acceptable salt thereof;
(b) a biodegradable carrier; and
(c) a biocompatible solvent;

wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

According to one embodiment the present invention provides a method for treating type 2 diabetes mellitus, the method comprising administering to the patient, an injectable composition comprising:
(a) 8.4mg to 162mg liraglutide or a pharmaceutically acceptable salt thereof;
(b) a biodegradable carrier; and
(c) a biocompatible solvent;

wherein the biodegradable carrier is poly (D, L-lactic acid) or poly (D, L-lactic-co-glycolic acid) and wherein the biocompatible solvent is N-methyl-2-pyrrolidone;

wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

According to one embodiment the present invention provides a method for treating type 2 diabetes mellitus, the method comprising administering to the patient, an injectable composition,whereinsaid injectable composition is administered subcutaneously or intramuscularly.

According to another embodiment the present invention provides a method for treating type 2 diabetes mellitus, the method comprising administering to the patient, an injectable composition, wherein said injectable composition is administered subcutaneously.

According to one embodiment the present invention provides a method for treating type 2 diabetes mellitus, the method comprising subcutaneously administering to the patient once per month, an injectable composition comprising:
(a) 18mg to 54mg liraglutide or a pharmaceutically acceptable salt thereof;
(b) a biodegradable carrier; and
(c) a biocompatible solvent;

wherein the biodegradable carrier is poly (D, L-lactic acid) or poly (D, L-lactic-co-glycolic acid) and wherein the biocompatible solvent is N-methyl-2-pyrrolidone;

wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

Another aspect of the present invention, provides a process of preparation of injectable composition comprising:(a) liraglutide or a pharmaceutically acceptable salt thereof;(b) a biodegradable carrier; and(c) a biocompatible solvent.

According to one embodiment the present invention provides a process of preparation of injectable composition comprising:(a) liraglutide or a pharmaceutically acceptable salt thereof;(b) a biodegradable carrier; and(c) a biocompatible solvent, wherein the process comprises following steps:
(i) preparation of a polymer solution by dissolving biodegradable carrier in a biocompatible solvent;
mixing of dry sterile powder of liraglutide or a pharmaceutically acceptable salt thereof with the polymer solution obtained from step-(i).

DESCRIPTION OF THE FIGURES

Figure. 1 depicts pharmacokinetic profile of VICTOZA Injection (Group-1) in male sprague dawley rats.
Figure. 2 depictspharmacokinetic profileof Example-1 (Group-6) in male sprague dawley rats.
Figure. 3 depicts pharmacokinetic profileof Example-2 (Group-5)in male sprague dawley rats.
Figure. 4 depicts pharmacokinetic profileof Example-3 (Group-4)in male sprague dawley rats.
Figure. 5 depicts pharmacokinetic profileof Example-4 (Group-3)in male sprague dawley rats.
Figure. 6 depicts pharmacokinetic profileof Example-5 (Group-2)in male spraguedawley rats.

DEFINITIONS

As used herein, the term "biocompatible" means that the material, substance, compound, molecule, polymer, or system to which it applies should not cause severe toxicity, severe adverse biological reaction, or lethality in an animal to which it is administered at reasonable doses and rates.

As used herein, the term "biodegradable" means that the material, substance, compound, molecule, polymer, or system is cleaved, oxidized, hydrolyzed, or otherwise broken down by hydrolytic, enzymatic, or another mammalian biological process for metabolism to chemical units that can be assimilated or eliminated by the mammalian body.

The term "long acting" as used herein, refers to the duration of action of composition of the liraglutide as disclosed herein. More specifically, it refers to the period of time after administration of a dose of liraglutide composition of the present invention for which blood glucose levels are controlled. The composition of the present invention can be suitably formulated to provide effective blood glucose control over a period of about 14 days when administered as once biweekly formulation to a period of about 90 days after single administration of a three months dose to a patient in need thereof. Preferably, the composition of the present invention may be suitably formulated to obtain the desired blood levels of liraglutide such that it provides effective blood glucose control over an intended dosage interval which may be for about two weeks to about three months after a single administration. In a more preferred embodiment, the composition of the present invention provides effective blood glucose control for about a month after single administration such that the composition may be administered as once a month injection.

As used herein, the term "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

As used herein, average molecular weight is the weight average molecular weight of a polymer as determined by gel permeation chromatography (GPC) or gel permeation chromatography-refractive index (GPC-RI) or size exclusion chromatography (SEC) or size exclusion chromatography-refractive index(SEC-RI) using tetrahydrofuran (THF) as the solvent and using a molecular weight calibration curve using polystyrene standards.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a long acting injectable composition of liraglutide. The composition of the present invention can be used in the treatment of metabolic diseases such as type 2 diabetes mellitus. The composition of the invention provides a long acting composition of liraglutide for once biweekly or once monthly or once in two months or once in three months of administration.

The composition of the present invention transformed in situ into a gel by contact with water, body fluid or other aqueous medium.The injectable composition is a combination of a biodegradable carrier, a biocompatible solvent and liraglutide or a pharmaceutically acceptable salt thereof.

The specific and preferred biodegradable carrier and biocompatible solvent; the concentration of biodegradable carrier, biocompatible solvent and liraglutide or a pharmaceutically acceptable salt thereof; the molecular weights of the biodegradable carrier polymers; and the weight or mole ranges of components of the injectable composition herein are exemplary. They do not exclude other carriers and biocompatible solvents; other concentrations of biodegradable carrier, biocompatible solvent and liraglutide or a pharmaceutically acceptable salt thereof; other molecular weights of the biodegradable carrier polymers; and other components within the composition.

Liraglutide

Liraglutide is (Arg34, Lys26 (N?-(?-GLu(N-hexadecanoyl)))-GLP-1(7-37). In United States, Liraglutide is approved as a once daily subcutaneous injections under the trade names VICTOZA™ and SAXENDA™. Liraglutide may be present in the composition in the form of base or in the form of its salts or mixtures thereof. Representative example of salts includes salts with suitable inorganic acids such as hydrochloric, hydrobromic, and the like. Representative examples of salts also includes salts with organic acids such as formic acid, acetic acid, propionic acid, lactic acid, tartaric acid, ascorbic acid and the like. Representative examples of salts also includes salt with base such as triethanolamine, diethylamine, meglumine, arginine, alanine, leucine, histidine, diethylethanolamine, olamine, triethylamine, tromethamine, choline, trimethylamine, taurine, benzamine, methylamine, dimethylamine, trimethylamine, methylethanolamine, propylamine, isopropylamine, adenine, guanine, cytosine, thymine, uracil, thymine, xanthine, hypoxanthine and like. In a preferred embodiment, liraglutide is present as liraglutide free base. In another preferred embodiment, liraglutide is present as a Liraglutide-protamine-zinc complex. In another preferred embodiment, liraglutide is present as a tromethamine salt.

In one embodiment, liraglutide used in the composition may be in the form of a lyophilized form of liraglutide or a pharmaceutically acceptable salt thereof. The lyophilized form of liraglutide may be prepared by mixing liraglutide or a pharmaceutically acceptable salt thereof in water for injection to form a solution and lyophilizing the solution to form the lyophilized form. In another embodiment, liraglutide used in the composition may be in the form of a lyophilized mixture comprising liraglutide with parenterally acceptable amine base. The lyophilized mixture may be prepared by mixing liraglutide or a pharmaceutically acceptable salt thereof and a parenterally acceptable amine base in water for injection to form a solution and lyophilizing the solution to form the lyophilized mixture. The parenterally acceptable amine base may be selected from triethanolamine, diethylamine, meglumine, ornithine, lysine, arginine, alanine, leucine, histidine, diethylethanolamine, olamine, triethylamine, tromethamine, glucosamine, choline, trimethylamine, taurine, benzamine, trimethyl ammonium hydroxide, ammonium hydroxide, epolamine methylamine, dimethylamine, methylethanolamine, propylamine, isopropylamine and the like. Preferably, the parenterally acceptable amine base is selected from tromethamine, ammonium hydroxide, histidine, lysine and arginine.

The amount of Liraglutide present in the composition may be from 0.5% w/w to 50% w/w of the total weight of the composition. In preferred embodiment the amount of liraglutide in a given composition may be from 5% w/w to 20% w/w of the total weight of the composition. In another preferred embodiment, the amount of liraglutide may be 8% w/w to 15% w/w of the total weight of the composition. The amount is calculated in terms of equivalent of liraglutide base.

According to one embodiment, the amount of liraglutide present in the injectable composition of the present invention is in the range of 8.4mg to 162mg.

According to another embodiment, the amount of liraglutide present in the injectable composition of the present invention is in the range of 18mg to 54mg.

According to another embodiment, the amount of liraglutide present in the injectable composition of the present invention is selected from 12.5mg, 18mg, 25mg, 36mg and 50mg.

Liraglutide used in the present invention may be prepared by a chemical synthesis or by using recombinant DNA technology.

Biodegradable carrier

The injectable composition of the present invention is prepared by combining a biodegradable carrier, liraglutide or pharmaceutically acceptable salt thereof and a biocompatible solvent. Any suitable biodegradable carrier can be employed, provided that the biodegradable carrier is at least substantially insoluble in body fluid. The biodegradable carrier can be made from a variety of polymers. The polymers made from a variety of monomers which form polymer chains or monomeric units joined together by linking groups. The polymer is composed of a polymer chain or backbone containing monomeric units joined by such linking groups as ester, amide, urethane, anhydride, carbonate, urea, esteramide, acetal, ketal, or orthocarbonate groups as well as any other organic functional group that can be hydrolyzed by enzymatic or hydrolytic reaction. The polymer is typically formed by reaction of starting monomers containing the reactant groups that should form the backbone linking groups. For example, alcohols and carboxylic acids should form ester linking groups. Isocyanates and amines or alcohols should respectively form urea or urethane linking groups.

Any aliphatic, aromatic, or arylalkyl starting monomer having the specified functional groups can be used to make the polymers, provided that the polymers and their degradation products are biocompatible. The monomer or monomers used in forming the polymer may be of a single or multiple identity. The resultant polymer should be a homopolymer formed from one monomer, or one set of monomers such as when a diol and diacid are used, or a copolymer, or multi-polymer formed from two or more, or three or more, or more than three monomers or sets of monomers. The biocompatiblity specifications of such starting monomers are known in the art. The polymers are substantially insoluble in aqueous media and body fluids, preferably completely insoluble in such media and fluids. They are also capable of dissolving or dispersing in selected organic liquids having a water solubility ranging from completely soluble in all proportions to water insoluble. The polymers also are biocompatible.

In one embodiment, the biodegradablecarrier can be a linear polymer, it can be a branched polymer, or it can be a combination thereof.

The monomers used to make the biodegradable carriers should produce polymers or copolymers that are biocompatible, and biodegradable. Suitable biocompatible, biodegradable polymers include, for example, polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), and copolymers, combinations, or mixtures of the above materials. Suitable examples of such biocompatible, biodegradable polymers are disclosed, e.g., in U.S. Pat. Nos. 4,938,763, 5,278,201, 5,324,519, 5,702,716, 5,744,153, 5,990,194, 6,461,631, and 6,565,874.

In a preferred embodiment, the biodegradable carrier is selected from poly (D, L-lactic acid), poly (D, L-lactic-co-glycolic acid), polycaprolactone, linear polyhydroxyalkanoate, polybutylene succinate, polybutylene succinate adipate, polybutylene adipate, polybutylene adipate terephthalate, ethylene-vinyl acetate, polyurethane or combination thereof. In another most preferred embodiment the biodegradable carrier is or poly (D,L-lactic-co-glycolic acid) or poly (D,L-lactic acid).

The molecular weight of the polymer can affect the rate of release of liraglutide or a pharmaceutically acceptable salt thereof from the gel. Therefore, the selection of polymer with an optimum molecular weight range plays a major role in the development of injectable composition with desired release profile. The control of molecular weight and/or inherent viscosity of the polymer is a factor involved in the formation of gel and release profile of drug from the gel. In general, polymers with higher molecular weight and higher inherent viscosity should provide a gel with a slower release rate and therefore a longer duration. Changes of the molecular weight of the polymer following the compounding of the delivery system should result in the formation of a gel that shows a release rate and duration substantially different from the release rate and duration desired or predicted.

The polymers used in the present invention may have average molecular weights ranging from about 4000 Daltons to about 250000 Daltons. In preferred embodiment, the polymersused in the present invention may have an average molecular weight of about 4000 Daltons to about 60,000 Daltons.

In another most preferred embodiment the biodegradable carrier used in the present invention is poly (D, L-lactic-co-glycolic acid).

Poly (D,L-lactic-co-glycolic acid) (PLGA) is a copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA). Depending on the ratio of lactide to glycolide used for the polymerization, different forms of PLGA can be obtained. PLGA copolymer undergoes degradation by hydrolysis or biodegradation through cleavage of its backbone ester linkages into oligomers and, finally monomers. The degradation of PLGA copolymer is the collective process of bulk diffusion, surface diffusion, bulk erosion and surface erosion. The rate of drug release from the composition depends on the biodegradation rate of the polymer. The factors which affect the biodegradation rate of the PLGA copolymers are the molar ratio of the lactic and glycolic acids in the polymer chain, molecular weight of the polymer, the degree of crystallinity, the nature of end-group of the polymer (acid/ester) and the glass transition temperature (Tg) of the polymer.

According to one embodiment, the poly (D, L-lactic-co-glycolic acid) used in the present invention is having a lactic acid:glycolicacid ratio 95:5 to 5:95. According to another embodiment, the poly (D, L-lactic-co-glycolic acid) used in the present invention is having a lacticacid:glycolic acid ratio 75:25 to 25:75. In a most preferred embodiment, the poly (D, L-lactic-co-glycolic acid) used in the present invention is having a lacticacid:glycolic acid ratio 50:50. In another most preferred embodiment, the poly (D, L-lactic-co-glycolic acid) used in the present invention is having a lacticacid:glycolic acid ratio 75:25.

According to one embodiment, the poly (D,L-lactic-co-glycolic acid) used in the present invention is having average molecular weight ranging from 4000 Daltons to 250000 Daltons. According to another embodiment, the poly (D, L-lactic-co-glycolic acid) used in the present invention is having average molecular weight ranging from 4000 Daltons to 60000 Daltons.

The poly (D,L-lactic-co-glycolic acid) polymers are either synthesized by ringopening polymerization of the respective lactic acid dimers (lactiderings) and glycolic acid dimers (glycolide rings), or by poly condensation of lactic acid and glycolic acid monomers. There are many limitations of poly condensation, a sit does not allow for well controlled synthesis of high molecular weight polymers. For this reason, ringopeningpolymerization is a more popular technique. In thistechnique, polymerization is typically initiated by either water orby an alkyl alcohol, such as dodecanol, to yield a PLGA which is eitheracid or ester end-capped, respectively. Thenature of end-group has an effectonpolymerproperties including degradation and drug release.

According to one embodiment, the poly (D,L-lactic-co-glycolic acid) used in the present invention is having ester end groups or acidend groups.

In another preferred embodiment, the poly (D,L-lactic-co-glycolic acid) used in the present invention is having acidend groups.

In another preferred embodiment, the poly (D,L-lactic-co-glycolic acid) used in the present invention is having esterend groups.

In another preferred embodiment the biodegradable carrier used in the present invention is poly (D, L-lactic acid). Poly (D, L-lactic acid) is a polymer of D/L-lactic acid monomer units. According to one embodiment, the poly (D, L-lactic acid) used in the present invention is having L-lactic acid: D-lactic acid ratio 0:100 to 100:0.

Biocompatible solvent

The biocompatible solvents suitable for use in the injectable composition of the present invention are biocompatible and display a range of solubilities in aqueous medium, body fluid, or water. That range includes complete insolubility at all concentrations upon initial contact, to complete solubility at all concentrations upon initial contact between the solvent and the aqueous medium, body fluid, or water.

The biocompatible solvents used in the injectable composition of the present invention include, for example, aliphatic, aryl, and arylalkyl; linear, cyclic, and branched organic compounds that are liquid or at least flowable at ambient and physiological temperature and contain such functional groups as alcohols, alkoxylated alcohols, ketones, ethers, polymeric ethers, amides, esters, carbonates, sulfoxides, sulfones, any other functional group that is compatible with living tissue, or any combination thereof.

Preferred biocompatible solvents that are at least slightly soluble in aqueous or body fluid include, for example, N-methyl-2-pyrrolidone, 2-pyrrolidone; (C1-C15) alcohols, diols, triols, and tetraols such as ethyl hydroxide, glycerin, propylene glycol, and butanol; (C3-C15) esters and alkyl esters of mono-, di-, and tricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, and glyceryl triacetate; (C3-C20) ethers such as tetrahydrofuran or solketal; tweens, triacetin, decylmethylsulfoxide, dimethyl sulfoxide, oleic acid, I-dodecylazacycloheptan-2-one, esters of carbonic acid and alkyl alcohols such as propylene carbonate, ethylene carbonate, and dimethyl carbonate; alcohols such as benzyl alcohol, solketal, glycerol formal, and glycofurol; esters such as benzyl benzoate and ethyl benzoate; dialkylamides such as dimethylformamide and dimethylacetamide; lactones such as epsilon-caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; triacetin and diacetin; aromatic amides such as N,N-dimethyl-m-toluamide; and mixtures thereof.

In a preferred embodiment, the biocompatible solvent used in the present invention is selected from N-methyl-2-pyrrolidone, benzyl alcohol, benzyl benzoate, ethyl benzoate, ethyl hydroxide, dimethylsulfoxide, or mixtures thereof.

In a most preferred embodiment, the biocompatible solvent used in the present invention is N-methyl-2-pyrrolidone.

In a most preferred embodiment, the biocompatible solvent used in the present invention is N-methyl-2-pyrrolidone and may preferably present in about 30 wt. % to about 80 wt. % of the composition.

In situ gel

When the injectable composition of the present invention injected in to the body, it is transformed in situ into a gel by contact with water or a bodily fluid. The formed gel has the physical state of a semi-solid and can act as a depot system, capable of consistently releasing liraglutide or pharmaceutically acceptable salts thereof, over an extended period of time i.e., from several days to several months.

Because all of the components of the gel are biodegradable or can be swept away from the injected site by body fluid and eliminated from the body, the gel eventually disappears. The gel components may complete their biodegradation or disappearance before, after or at the same time as the liraglutide or pharmaceutically acceptable salts thereof has been typically completely released.

Methods of treatment

The present invention also provides use of the long-acting injectable composition for treatment of metabolic diseases. In a preferred embodiment, the long-acting injectable composition of the invention is suitable for use in the treatment of type-2 diabetes mellitus.

In another embodiment, the injectable composition of the invention is suitable for use in reducing blood glucose levels in a patient in need thereof for a period of at least two weeks or at least one month or at least two months or at least three months. The injectable composition of the present invention provides for maintenance of therapeutic levels of liraglutide after single administration over an extended period of time which may be for two weeks or for a month or for two months or for three months. The injectable composition is used for the treatment of type-2 diabetes mellitus by administration of composition once biweekly or once monthly or once in two months or once in three months. In a most preferred embodiment, the composition is used for the treatment of type-2 diabetes mellitus by administration of composition once monthly.

In one embodiment, the present invention provides a method for treating type 2 diabetes mellitus in a patient, the method comprising administering to the patient an injectable composition comprising:
(a) liraglutide or a pharmaceutically acceptable salt thereof;
(b) a biodegradable carrier; and
(c) a biocompatible solvent;

wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

Preferably, the injectable composition of the invention may be administered by subcutaneous or intramuscular route. More preferably, the composition of the invention may be administered by subcutaneous route.

In another embodiment, the injectable composition of the present invention comprising liraglutide in the range of 8.4mg to 162mg is suitable for use in the treatment of type-2 diabetes mellitus.

EXAMPLES

The compositions of the present invention are illustrated as examples herein under. However, it is to be noted that the present disclosure is not limited to the illustrative examples but can be practiced in various other ways.
Component Example-1 Example-2 Example-3 Example-4 Example-5
Liraglutide 50mg 50mg 50mg 50mg 50mg
N-methyl-2-pyrrolidone 330mg 258.5mg 258.5mg 258.5mg 258.5mg
poly(D,L- lactic-co-glycolic acid) 100mg 150mg 110mg 150mg 110mg
Features of poly(D,L- lactic-co-glycolic acid)
Ratio of Lactic acid : Glycolic acid 50:50 75:25 75:25 75:25 75:25
End group Acid Acid Acid Ester Ester
Average Molecular Weight 38,000- 54,000 Daltons 4,000-15,000Daltons 4,000-15,000 Daltons 4,000-15,000 Daltons 4,000-15,000 Daltons

Process of preparation of Examples:

The process of preparation injectable compositions as exemplified in the above examples includes following steps:

Step-1: Preparation of a prefilled syringe-A with Liraglutide powder

Step-1 can be carried out by two different methods, Method-A and Method-B.
Method-A: A measured quantity of liraglutide was dissolved in water for injection in a compounding vessel, the obtained solution was transferred in to a syringe -A and lyophilize the filled syringe-A to obtain a dry cake of liraglutide in a pre-filled syringe-A.
Method-B: In this method, the measured quantity of dry and sterile Liraglutide was filled directly in to syringe-A.
Step-2: preparation of prefilled syringe-B with polymer solution

The measured quantity of biodegradable polymer (eg. PLGA or PLA) was dissolved in a measured quantity of biocompatible solvent (eg. N-Methyl-2-pyrrolidone) in a compounding vessel, the obtained polymer solution was filled in to a syringe -B and was inserted the plunger stopper to the syringe-B.

Step-3: Mixing of contents of the Syringe-A and Syringe-B

Just before administration of the composition in to a subject, both the syringes-A&B shall be connected to each other with the luer fittings and the contents of both the syringes should be mixed to obtain a homogenous suspension.

Example-6 to Example-21 are prepared using similar procedure as mentioned above for the Examples-1 to 5.
Component Example-6 Example-7 Example-8 Example-9
Liraglutide 12.5mg 25mg 37.5mg 50mg
N-methyl-2-pyrrolidone 175 mg 225 mg 250 mg 350 mg
poly(D,L- lactic-co-glycolic acid) 100 mg 150 mg 200 mg 250 mg
Features of poly(D,L- lactic-co-glycolic acid)
Ratio of Lactic acid : Glycolic acid 85:15 45:55 75:25 90:10
End group Acid Acid Acid Acid
Average Molecular Weight 50-150 kDa 15-85 kDa 5-150 kDa 30-100 kDa

Component Example-10 Example-11 Example-12 Example-13
Liraglutide 12.5mg 25mg 37.5mg 50mg
N-methyl-2-pyrrolidone 175 mg 225 mg 250 mg 350 mg
poly(D,L- lactic-co-glycolic acid) 100 mg 150 mg 200 mg 250 mg
Features of poly(D,L- lactic-co-glycolic acid)
Ratio of Lactic acid : Glycolic acid 85:15 45:55 75:25 90:10
End group Ester Ester Ester Ester
Average Molecular Weight 50-150 kDa 15-85 kDa 5-150 kDa 30-100 kDa

Component Example-14 Example-15 Example-16 Example-17
Liraglutide 12.5mg 25mg 37.5mg 50mg
N-methyl-2-pyrrolidone 150 mg 175 mg 250 mg 300 mg
poly (D, L-lactic acid) 80 mg 100 mg 180 mg 200 mg
Features of poly (D, L-lactic acid)
End group Acid Acid Acid Acid
Average Molecular Weight 5-25 kDa 40-90 kDa 70-100 kDa 100-250 kDa

Component Example-18 Example-19 Example-20 Example-21
Liraglutide 12.5mg 25mg 37.5mg 50mg
N-methyl-2-pyrrolidone 150 mg 175 mg 250 mg 300 mg
poly (D, L-lactic acid) 80 mg 100 mg 180 mg 200 mg
Features of poly (D, L-lactic acid)
End group Ester Ester Ester Ester
Average Molecular Weight 5-25 kDa 40-90 kDa 70-100 kDa 100-250 kDa

Example-22-Pharmacokinetic evaluation of long-acting injectable compositions:

A single subcutaneous dose pharmacokinetic study of Liraglutide injectable compositions was studied in male sprague dawley rats to evaluate pharmacokinetics and to determine relative bioavailability of test Liraglutide injectable compositions in comparison with reference Product i.e. Victoza™ Injection. The test compositions and reference drug product were injected through dorsal scapular region of the male sprague dawley rats and blood was collected into K2EDTA coated tubes via retro-orbital plexus puncture under mild isoflurane anesthesia as per time points:1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, 30 hrs, 36 hrs, 48 hrs, 72 hrs, 120 hrs, 168 hrs, 216 hrs, 264 hrs, 336 hrs, 408 hrs, 552 hrs, 624 hrs, 696 hrs, 936 hrs, 1176 hrs and 1416 hrs (± 5 minutes up to 72 h of blood collection and Day 6 onwards ± 15 minutes). 0.3 mL blood was collected at each time point. Plasma was separated by centrifuging the whole blood sample at 5000 rpm for 10 minutes at 2-8°C and transferred into labelled tubes and stored at <- 60°C until bioanalysis. LC-MS/MS method was used for sample analysis.

Pharmacokinetic (PK) evaluation of five examples (Example-1 to 5) was performed by validated Phoenix®WinNonlin®software (6.3 version) from Pharsight Corporation, USA. The PK parameters such as area under the concentration time curve (AUCall and AUCINF_obs), peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), half-life, Clast and Tlastare reported. The relative and comparative bioavailability was calculated and represented in graphical presentation. Descriptive statistics [N (No. of observations used in calculations), mean, standard deviation and CV%] were used to summarize plasma concentrations.

A total of 36 male Sprague Dawley rats with serial sampling study design were used in this study for the pharmacokinetics evaluation as shown below:
Group No. Group Description Dose / rat (mg) Dose Volume (mL) No. of rats
G1 Victoza® (Liraglutide) 1.8 ~0.3 mL* 6
G2 Example-5 50 Entire volume
of syringe 6
G3 Example-4 50 Entire volume
of syringe 6
G4 Example-3 50 Entire volume
of syringe 6
G5 Example-2 50 Entire volume
of syringe 6
G6 Example-1 50 Entire volume
of syringe 6
*approx. volume delivered by PEN device after setting 1.8 mg dose

Pharmacokinetics of Victoza Injection (Group-1) (Figure. 1):

Following single subcutaneous administration of Victoza®(Liraglutide) Injection, the mean peak concentration (Cmax) of 3.679 µg/mLwas observed at 2 hours post dose. Plasma concentrations decreased with half-life of 7 hours and last concentration (Tlast) observed at 48 hours (Day 2). Overall exposure (AUCall) was 55.114 h*µg/mL.

Pharmacokinetics of Liraglutide composition described in Example-1 (Group-6) (Figure. 2):

Following single subcutaneous administration of composition mentioned in Example-1, the mean peak concentration (Cmax) of 55.507 µg/mL was observed at 30 hours post dose. Plasma concentrations decreased with half-life of 72 hours and last concentration (Tlast) observed at 696 hours (Day 30). Overall exposure (AUCall) was 1708.251 h*µg/ mL.

Pharmacokinetics of Liraglutide composition described in Example-2 (Group-5) (Figure. 3):

Following single subcutaneous administration of composition mentioned in Example-2, the mean peak concentration (Cmax) of 21.094 µg/mL was observed at 30 hours post dose. Plasma concentrations decreased with half-life of 76 hours and last concentration (Tlast) observed at 696 hours (Day 30). Overall exposure (AUCall) was 911.284 h*µg/mL.

Pharmacokinetics of Liraglutide composition described in Example-3 (Group-4) (Figure. 4):

Following single subcutaneous administration of composition mentioned in Example-3, the mean peak concentration (Cmax) of 49.022 µg/mL was observed at 36 hours post dose. Plasma concentrations decreased with half-life of 60 hours and last concentration (Tlast) observed at 696 hours (Day 30). Overall exposure (AUCall) was 2019.508 h*µg/mL.

Pharmacokinetics of Liraglutide composition described in Example-4 (Group-3) (Figure. 5):

Following single subcutaneous administration of composition mentioned in Example-4, the mean peak concentration (Cmax) of 29.490 µg/mL was observed at 36 hours post dose. Plasma concentrations decreased with half-life of 68 hours and last concentration (Tlast) observed at 696 hours (Day 30). Overall exposure (AUCall) was 1035.165 h*µg/ mL.

Pharmacokinetics of Liraglutide composition described in Example-5 (Group-2) (Figure. 6):

Following single subcutaneous administration of composition mentioned in Example-4, the mean peak concentration (Cmax) of 19.222 µg/mL was observed at 24 hours post dose. Plasma concentrations decreased with half-life of 48 hours (2 days) and last concentration (Tlast) observed at 696 hours (Day 30). Overall exposure (AUCall) was 912.999 h*µg/mL.

Pharmacokinetic parameters of Victoza® and Liraglutide compositions -Example-1 to 5 in Male Sprague Dawley Rats
Group No. Dose / Rat (mg) Dose (mg/Kg) Test Item Tmax (h) Cmax (µg/ mL) AUCall
(h*µg/mL) Tlast (h) Clast (µg/mL) T1/2
(h) AUCINF obs(h*µg/mL)
G1 1.8 5 Victoza 2 3.679 55.114 48 0.154 7 54.801
G2 50 137 Example-5 24 19.222 912.999 696 0.014 48 912.315
G3 50 138 Example-4 36 29.490 1035.165 696 0.023 68 1037.387
G4 50 138 Example-3 36 49.022 2019.508 696 0.016 60 2020.856
G5 50 137 Example-2 30 21.094 911.284 696 0.018 76 911.086
G6 50 137 Example-1 30 55.507 1708.251 696 0.012 72 1709.539

Following single dose subcutaneous administration of Liraglutide compositions described in Example-1 to 5, Tmax was observed at 24 to 36 hours as compared to 2 hours in Victoza® Injection. Liraglutide depot concentrations eliminated slowly with half-life of 48 to 76 hours (2 to 3 days) and detected up to 696 hours (30 days). Victoza® (Liraglutide) concentrations eliminated relatively rapidly with half-life of 7 hours and detected up to 48 hours. The selected polymers were able to deliver liraglutide for longer time, thereby, it offers advantage over Victoza® in terms of reduction in dosing frequency. Further, the reduced dosing frequency may improve convenience to patients and thereby increasing patient compliance and adherence.
,CLAIMS:We Claim:

1. An injectable composition comprising:
(a) liraglutide or a pharmaceutically acceptable salt thereof;
(b) a biodegradable carrier; and
(c) a biocompatible solvent;
wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

2. The injectable composition according to claim 1, wherein the injectable composition is administered once monthly.

3. The injectable composition according to claim 1, wherein the biodegradable carrier is selected from polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids) and copolymers, or combinations thereof.

4. The injectable composition according to claim 1, wherein the biodegradable carrier is selected from poly (D, L-lactic acid), poly (D,L-lactic-co-glycolic acid), polycaprolactone, linear polyhydroxyalkanoate, polybutylene succinate, polybutylene succinate adipate, polybutylene adipate, polybutylene adipate terephthalate, ethylene-vinyl acetate, polyurethane or combination thereof.

5. The injectable composition according to claim 4, wherein the poly (D, L-lactic-co-glycolic acid) is having average molecular weight ranging from 4000 to 250000 daltons.

6. The injectable composition according to claim 4, wherein the poly (D, L-lactic acid) is having average molecular weight ranging from 4000 to 250000 daltons.

7. The injectable composition according to claim 4, wherein the poly (D, L-lactic-co-glycolic acid) is having lactic acid:glycolic acid ratio 95:5 to 5:95.

8. The injectable composition according to claim 1, wherein the biocompatible solvent is selected from N-methyl-2-pyrrolidone, benzyl alcohol, benzyl benzoate, ethyl benzoate, ethyl hydroxide, dimethylsulfoxide or mixtures thereof.

9. The injectable composition according to claim 1, wherein the weight ratio of liraglutide or a pharmaceutically acceptable salt thereof to biodegradable carrier is1:1 to 1:10.

10. The injectable composition according to claim 1, wherein the weight ratio of liraglutide or a pharmaceutically acceptable salt thereof to biocompatible solvent is 1:1 to 1:15.

11. The injectable composition according to claim 1, wherein the weight ratio of biodegradable carrier to biocompatible solvent is 1:0.5 to 1:10.

12. The injectable composition according to claim 1, wherein liraglutide is in the range of 8.4mg to 162mg.

13. The injectable composition according to claim 1, wherein liraglutide is in the range of 0.5% w/w to 50% w/w.

14. The injectable composition according to claim 1, wherein liraglutide is in the range of 8.4mg to 162mg, biodegradable carrier is poly (D, L-lactic acid) or poly (D, L-lactic-co-glycolic acid) and biocompatible solvent is N-methyl-2-pyrrolidone.

15. An injectable kit comprising:
(a) syringe comprising liraglutide or a pharmaceutically acceptable salt thereof;
(b) syringe comprising a biodegradable carrier and a biocompatible solvent.

16. A method for treating type 2 diabetes mellitus, the method comprising administering to the patient an injectable composition comprising:
(a) liraglutide or a pharmaceutically acceptable salt thereof;
(b) a biodegradable carrier; and
(c) a biocompatible solvent;
wherein the composition is transformed in situ into a gel by contact with water, body fluid or other aqueous medium.

17. The method according to claim 16, wherein the injectable composition is administered subcutaneously.

18. The method according to claim 16, wherein liraglutide is in the range of 8.4mg to 162mg.

19. The method according to claim 16, wherein the method comprising administering the injectable composition once in two weeks, once in a month, once in two months or once in three months.

20. The method according to claim 16, wherein the method comprising administering the injectable composition once per month by subcutaneous injection, wherein liraglutide is in the range of 18mg to 54mg; biodegradable carrier is poly (D, L-lactic acid) or poly (D, L-lactic-co-glycolic acid); biocompatible solvent is N-methyl-2-pyrrolidone.

21. A process for preparing a composition according to claim 1 comprising the steps of: (i) preparation of a polymer solution by dissolving biodegradable carrier in a biocompatible solvent; (ii) mixing liraglutide or a pharmaceutically acceptable salt thereof with the polymer solution obtained from step-(i).