WO2016038521A1

WO2016038521A1 - Pharmaceutical compositions of liraglutide

Info

Publication number: WO2016038521A1
Application number: PCT/IB2015/056775
Authority: WO
Inventors: Ravindra Agarwal; Bhaskar Chauhan; Ravi Kochhar
Original assignee: Sun Pharmaceutical Industries Limited
Priority date: 2014-09-08
Filing date: 2015-09-04
Publication date: 2016-03-17
Also published as: WO2016038521A8

Abstract

The present invention relates to pharmaceutical compositions comprising: (i) liraglutide; (ii) a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; (iii) propylene glycol; and (iv) a preservative. The compositions of the present invention remain stable after exposure to 5 multiple freeze-thaw cycles or after being subjected to elevated temperature. It also relates to processes for the preparation of said pharmaceutical compositions.

Description

PHARMACEUTICAL COMPOSITIONS OF LIRAGLUTIDE

Field of the Invention

The present invention relates to pharmaceutical compositions comprising: (i) liraglutide; (ii) a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; (iii) propylene glycol; and (iv) a preservative. The compositions of the present invention remain stable after exposure to multiple freeze-thaw cycles or after being subjected to elevated temperature. It also relates to processes for the preparation of said pharmaceutical compositions.

Background of the Invention

Liraglutide is an analog of human GLP-1 and acts as a GLP-1 receptor agonist. It is indicated for the treatment of patients with type 2 diabetes to improve glycemic control.

U.S. Patent No. 6,268,343 discloses liraglutide and its formulations.

Several attempts have been made in the prior art to provide optimal and stable injection compositions of liraglutide.

U.S. Patent No. 8,114,833 discloses a pharmaceutical formulation comprising a GLP-1 agonist, a disodium phosphate dihydrate buffer, and propylene glycol, wherein said propylene glycol is present in said formulation in a final concentration of from about 1 mg/mL to about 100 mg/mL, and wherein said formulation has a pH of from about 7.0 to about 10.0.

U.S. Publication No. 2010/0234299 relates to a pharmaceutical formulation comprising a GLP-1 compound, an isotonic agent, a buffer, and a preservative, wherein said pharmaceutical formulation has a pH of from 7.0 to 10.0, and provides that if an isotonic agent is present and the pH of the formulation is 7.4, then mannitol or NaCl is not the isotonic agent.

There remains a need to develop alternative pharmaceutical compositions of liraglutide that are simple, easy to manufacture, and stable. Therefore, the inventors of the present invention have developed pharmaceutical compositions of liraglutide using alternative buffers. The compositions of the present invention are stable and easy to manufacture. Summary of the Invention

Detailed Description of the Invention

A first aspect of the present invention provides a pharmaceutical composition comprising: (i) liraglutide; (ii) a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; (iii) propylene glycol; and (iv) a preservative.

According to one embodiment of this aspect, the preservative is selected from the group consisting of phenol, ra-cresol, thiomerosal, methyl paraben, propyl paraben, butyl paraben, chlorobutanol, and phenoxyethanol.

In a preferred embodiment, the preservative is phenol.

In a further embodiment of the above aspect, the pharmaceutical composition remains stable after exposure to multiple freeze-thaw cycles or after being subjected to elevated temperature.

A second aspect of the present invention provides a process for the preparation of the pharmaceutical composition of liraglutide comprising:

(i) dissolving in water a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous;

propylene glycol; and a preservative;

(ii) dissolving liraglutide in the solution of step (i);

(iii) adjusting the pH of the solution of step (ii) with a pH-adjusting agent to a pH range from about 7.0 to about 11.0.

According to one embodiment of the above aspect, the pH-adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, hydrochloric acid, and N-methyl glucamine. The term "liraglutide," as used herein, includes liraglutide as well as its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chelates, and complexes.

The term "buffer," as used herein, refers to a chemical compound added to a liraglutide composition to prevent the pH from changing with time. Suitable buffers are selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous.

Propylene glycol is preferably used as an isotonic agent in the pharmaceutical compositions of the present invention. However, it can be replaced or used in combination with sodium chloride, potassium chloride, mannitol, sorbitol, trehalose, lactitol, xylitol, glycerol, sucrose, glycine, lactose, glucose, maltose, lysine, isoleucine, aspartic acid, L- glycine, L-histidine, arginine, myo-inositol, polyethylene glycol, or combinations thereof.

Suitable preservatives are selected from the group consisting of phenol, m-cresol, thiomerosal, methyl paraben, propyl paraben, butyl paraben, chlorobutanol,

phenoxyethanol, and mixtures thereof. Preferably, the preservative is phenol.

The term "pH-adjusting agent," as used herein, refers to an agent used to maintain the pH in the desired range. Suitable examples of pH-adjusting agents include sodium hydroxide, potassium hydroxide, hydrochloric acid, and N-methyl glucamine. The pH of the solution is adjusted to about 7.0 to about 11.0. Preferably, the pH is adjusted to about 7.0 to about 10.0. More preferably the pH is adjusted to about one of the following values, i.e., 7.0, 7.2, 8.1, 8.2, 8.3, or 9.8. The term "about" as used herein in relation to pH means ±0.1 pH units from the specified value.

The compositions of the present invention may further comprise a stabilizer, a surfactant, and a chelating agent.

Suitable examples of stabilizers include polyethylene glycol or its derivatives, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, sodium chloride, L- glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, or mixtures thereof.

Suitable examples of surfactants include polysorbate, poloxamers,

ethylene/polypropylene block polymers, lecithins, alcohols, sodium lauryl sulfate, bile acids and salts thereof, polymeric surfactants, long-chain fatty acids, phospholipids, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, monoglycerides, diglycerides, glycerol, glycerophospholipids, glyceroglycolipids, sphingophospholipids,

sphingoglycolipids, docusate sodium, docusate calcium, docusate potassium, and mixtures thereof.

Suitable examples of chelating agents include ethylenediaminetetraacetic acid or its salts, and mixtures thereof.

The compositions of the invention are prepared by conventional processes, involving dissolving and mixing the ingredients to give the desired composition.

The compositions of the present inventions were surprisingly found to be stable after exposure to multiple freeze-thaw cycles. The compositions also remained stable after being subjected to elevated temperature.

The term "freeze-thaw," as used herein, refers to the exposure of the

pharmaceutical composition to a temperature of 2°C to -8°C for 24 hours, then at 25°C for 24 hours and subsequently at -10°C for 24 hours. Samples subjected to this freeze-thaw cycle two or more times according to this procedure are said to have undergone multiple freeze-thaw cycles.

Stability can be measured in any way, including visually inspecting the compositions in daylight with a dark background for any signs of turbidity, changes in color or clarity, or any other visible precipitates. Assay studies were carried out to determine liraglutide content in the compositions of the present invention. The results were compared with the commercially available liraglutide composition available under the brand name Victoza^®. Each mL of Victoza^® solution contains 6 mg of liraglutide, 1.42 mg of disodium phosphate dihydrate, 14 mg of propylene glycol, 5.5 mg of phenol, and water for injection.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. EXAMPLES

EXAMPLES 1-4

Procedure:

(i) Propylene glycol, buffer, and phenol were dissolved in water and the pH was adjusted to about 8.0 with sodium hydroxide.

(ii) Liraglutide was dissolved in the solution of step (i).

(iii) The pH of the solution obtained in step (ii) was adjusted to a final value using sodium hydroxide.

Stability studies:

The compositions prepared according to Examples 1-4 were exposed to fireeze- thaw cycles and to elevated temperature. The compositions were visually inspected for any signs of turbidity, changes in color or clarity, or any other visible precipitate. These results are presented in Table 1 below. Assay studies were also carried out to determine liraglutide content and the results are presented in Table 2 below. Table 1: Visual Observations and pH Values of the Compositions Prepared as per Examples 1-4 After Being Subjected to Freeze-Thaw Cycles

As evident from the above data, the compositions prepared with alternative buffers were found to be physically stable after exposure to multiple freeze-thaw cycles. All of the compositions remained clear and did not show signs of any precipitate or turbidity.

Table 2: Assay Values of Liraglutide in the Compositions Prepared as per Examples 1-4

The above assay results demonstrate that the compositions were stable after exposure to multiple freeze-thaw cycles as well as to elevated temperature. Acceptable assay values were obtained for compositions having pH values 7.0, 8.15, and 9.8, respectively.

Claims

We claim:

1. A pharmaceutical composition comprising: (i) liraglutide; (ii) a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; (iii) propylene glycol; and (iv) a preservative.

2. The pharmaceutical composition of claim 1, wherein the preservative is selected from the group consisting of phenol, ra-cresol, thiomerosal, methyl paraben, propyl paraben, butyl paraben, chlorobutanol, and phenoxyethanol.

3. The pharmaceutical composition of claim 2, wherein the preservative is phenol.

4. The pharmaceutical composition of claim 1, wherein the composition remains stable after exposure to multiple freeze-thaw cycles or after being subjected to elevated temperature.

5. A process for the preparation of the pharmaceutical composition of claim 1 , wherein the process comprises:

(i) dissolving in water a buffer selected from the group consisting of

dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; propylene glycol; and a preservative;

(ii) dissolving liraglutide in the solution of step (i);

(iii) adjusting the pH of the solution of step (ii) with a pH-adjusting agent to a pH range from about 7.0 to about 1 1.0.

6. The process of claim 4, wherein the pH-adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, hydrochloric acid, and N-methyl glucamine.