Solid compositions comprising imeglimin

Abstract

The present invention relates to pharmaceutical composition comprises imeglimin or pharmaceutically acceptable salts thereof.

Description

[0001] DESCRIPTION

[0002] SOLID COMPOSITIONS COMPRISING IMEGLIMIN

[0003] Field of Invention

[0004] The present invention relates to pharmaceutical composition comprises imeglimin or pharmaceutically acceptable salts thereof.

[0005] Background of the Invention

[0006] The eradication of Type 2 Diabetes Mellitus (T2DM) represents a therapeutic strategy aimed at completely eliminating this condition, which poses a significant global public health concern. T2DM is associated with serious metabolic complications, including hyperglycemia, insulin resistance, and an increased risk of cardiovascular disease. The primary objective of eradication therapy is to alleviate symptoms and prevent related long-term consequences. Current treatment protocols typically involve the administration of two or three pharmacological agents in combination with lifestyle modifications. The success of eradication depends heavily on selecting the optimal therapeutic regimen and ensuring patient adherence to the treatment plan, which may include monitoring blood glucose levels and adjustments to dietary and physical activity habits

[0007] Imeglimin is a novel oral anti-diabetic agent that targets mitochondrial bioenergetics to improve glycemic control in patients with Type 2 Diabetes Mellitus (T2DM). Unlike traditional medications, Imeglimin acts on multiple organs — primarily the liver, muscle, and pancreas — to enhance insulin sensitivity, increase insulin secretion, and reduce hepatic glucose production. This multifaceted mechanism makes it particularly effective in addressing both insulin resistance and beta-cell dysfunction, which are core defects in T2DM. It is used for managing hyperglycemia and has shown promise in improving overall metabolic parameters in patients. Its unique pharmacokinetics and mode of action provide better glycemic control, especially in patients requiring comprehensive management of their diabetic condition. The molecular structure of imeglimin hydrochloride is shown below.

[0008]

[0009] Imeglimin Hydrochloride

[0010] JP4926357B2 discloses imeglimin or pharmaceutically acceptable salts thereof, use compound imeglimin or pharmaceutically acceptable salts thereof for manufacturing medicament intended for the treatment diabetes.

[0011] US12036226B2 discloses a method of treating prediabetes or type 1 or type 2 diabetes mellitus comprising administering to a subject in need thereof an effective amount of imeglimin, wherein the subject has chronic kidney disease.

[0012] One key challenge is that the decrease in production efficiency and the complication of the process are due to the use of a very high amount of the active substance. Given these challenges, the invention described herein aims to provide a novel pharmaceutical composition that comprise imeglimin or pharmaceutically acceptable salts thereof This specific formulation approach addresses the stability requirements ultimately enhancing the therapeutic efficacy. These solutions will be described in detail.

[0013] Summary of the Invention

[0014] A solid pharmaceutical composition comprising non-micronized imeglimin or pharmaceutically acceptable salts thereof and vinylpyrrolidone polymer derivatives.

[0015] The solid pharmaceutical composition in present invention comprises vinylpyrrolidone based derivatives amount is between 2.00 - 8.00% (w / wj.

[0016] The solid pharmaceutical composition in present invention, wherein the viscosity value of vinylpyrrolidone derivative polymer is between 1.0 and 5.2 cps.The solid pharmaceutical composition comprising vinylpyrrolidone based derivatives can be selected from polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyvinylpyrrolidone-Vinyl acetate copolymer, crospovidone or mixtures thereof.

[0017] The solid pharmaceutical composition can be in the form of a film coated tablet.

[0018] In other aspect of the present invention a process for preparing solid pharmaceutical compositions, comprising the steps of

[0019] a. Sieving and mixing Imeglimin or pharmaceutically acceptable salts thereof and one or more disintegrant,

[0020] b. Obtaining granulation solution with purified water and one or more vinylpyrrolidone - vinyl acetate copolymer,

[0021] c. Spraying granulation solution onto step a,

[0022] d. Obtaining and drying granules with fluid bed dryer,

[0023] e. Grinding the obtained granules,

[0024] f. Adding and mixing granules with one or more glidant and one or more lubricant,

[0025] g. Obtaining core tablets,

[0026] h. Coating with a film coating solution.

[0027] Detailed Description of the Invention

[0028] The aspects and disclosures according to the present invention, in particular solid pharmaceutical composition comprises non-micronized imeglimin or pharmaceutically acceptable salts, vinylpyrrolidone polymer derivative and one or more pharmaceutically acceptable excipients.

[0029] In preferred embodiment, imeglimin or pharmaceutically acceptable salts thereof can be imeglimin hydrochloride.

[0030] In preferred embodiment amount of imeglimin hydrochloride can be between 75.0 - 98.0 % (w / w). Preferably, amount of imeglimin hydrochloride can be between 85.0 - 95.0 % (w / w).Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0031] Lubricants are crucial excipients in pharmaceutical compositions, primarily used to reduce friction during the tablet manufacturing process. They help prevent the tablet blend from sticking to the equipment, ensuring a smooth and efficient production process. Lubricants improve the flow of the tablet mixture through the machinery, enhancing the uniformity and consistency of the final product. Additionally, they aid in the ejection of tablets from the die cavity, preventing damage and ensuring the integrity of the tablets.

[0032] Commonly used lubricants in pharmaceutical compositions include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, colloidal silicon dioxide, and polyethylene glycol (PEG). In preferred embodiment in the present invention amount of lubricant can be between 0.1-3.5% (w / w). Preferably, amount of lubricant can be between 0.5 - 2.0 % (w / w)

[0033] In preferred embodiment in present invention lubricant can be sodium stearyl fumarate. In the preferred embodiment, the present invention amount of sodium stearyl fumarate can be between 0.1-3.5% (w / w). Preferably, the amount of sodium stearyl fumarate can be between 0.50 - 2.00 (w / w).

[0034] Commonly used binders in pharmaceutical compositions include polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyvinylpyrrolidone-Vinyl acetate copolymer, crospovidone and starch.

[0035] The solid pharmaceutical composition in present invention comprises vinylpyrrolidone based derivatives amount is between 2.00 - 8.00% (w / w).

[0036] The solid pharmaceutical composition in present invention, wherein the viscosity value of vinylpyrrolidone derivative polymer is between 1.0 and 5.2 cps (1% solution, 25°C).The solid pharmaceutical composition comprising vinylpyrrolidone based derivatives can be selected from polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyvinylpyrrolidone-Vinyl acetate copolymer, crospovidone or mixtures thereof.

[0037] In a preferred embodiment of the present invention, the binder can be polyvinylpyrrolidone-Vinyl acetate copolymer. In a preferred embodiment of the present invention, the amount of polyvinylpyrrolidone-Vinyl acetate copolymer can be between 0.10-10.00% (w / w). In preferred embodiment present invention amount of polyvinylpyrrolidone-Vinyl acetate copolymer can be between 0.5-5.00% (w / w).

[0038] In a preferred embodiment of the present invention, the binder can be polyvinylpyrrolidone-Vinyl acetate copolymer. It is an excipient consisting of a copolymer of polyfvinyl pyrrolidone) (PVP) and vinyl acetate, widely used in pharmaceutical formulations. It shows partial water solubility and is soluble in both water and organic solvents. It does not have a high-water absorption capacity, which is advantageous in formulations with low hygroscopicity. Because of its polymer structure, it can increase the dissolution of low solubility APIs.

[0039] Commonly used disintegrants in pharmaceutical compositions include croscarmellose sodium, sodium starch glycolate, and crospovidone.

[0040] In a preferred embodiment of the present invention, the amount of disintegrant can be between 1.00-10.00 % (w / w). In a preferred embodiment of the present invention, the amount of disintegrant can be between 3.00-6.00 % (w / w). In a preferred embodiment of the present invention, the disintegrant can be crospovidone.

[0041] In preferred embodiment pharmaceutical composition in present invention comprise a glidant. Preferably, the amount of glidant can be between 0.10 - 1.0 % (w / w).

[0042] In preferred embodiment pharmaceutical composition in present invention further comprise coating. Preferably, the amount of coating can be between 3.0 - 5.0 % (w / w).

[0043] The use of imeglimin or pharmaceutically acceptable salts thereof in very high amounts within a composition poses significant challenges in maintaining stability. Such elevated concentrations may lead to issues such as degradation of the active ingredient,undesirable interactions with excipients, or reduced shelf-life of the formulation. Addressing these stability concerns requires careful selection of excipients, optimization of formulation parameters, and the potential application of stabilizing agents or protective packaging systems. These measures are critical to ensuring the efficacy and safety of the final pharmaceutical product over its intended storage period.

[0044] The inventors surprisingly have found that the pharmaceutical composition comprising imeglimin or pharmaceutically acceptable salts thereof and vinylpyrrolidone - vinyl acetate copolymer, represent a significant advancement in chemical stability with providing a viable alternative formulation.

[0045] The inventors surprisingly have found that the pharmaceutical composition comprising imeglimin or pharmaceutically acceptable salts thereof and vinylpyrrolidone based derivatives represent both ideal powder flow and tablet compactibility are ensured and the desired bioavailability is achieved with the specified nonmicronised particle size.

[0046] The inventors surprisingly have found that the pharmaceutical composition comprising imeglimin or pharmaceutically acceptable salts thereof and vinylpyrrolidone - vinyl acetate copolymer represent both ideal powder flow and tablet compactibility are ensured and the desired bioavailability is achieved with the specified nonmicronised particle size.

[0047] Preferably the pharmaceutical composition according to the present invention may be in the form of a tablet, capsule, caplet, film-coated tablet, enteric tablet, controlled-release tablet and any similar solid oral dosage forms. The preferred dosage form according to the present invention is film-coated tablet form. Commonly available coating materials may be used for coating tablets.

[0048] The solid pharmaceutical composition of the present invention comprises below:

[0049] • 85.00% - 95.00% by weight imeglimin or pharmaceutical acceptable salts thereof, • 2.00% - 8.00% by weight binder

[0050] • 3.00% -6.00% by weight disintegrant,

[0051] • 0.10-1.50% by weight glidant,

[0052] • 0.50-2.00 % by weight lubricant.The film coated tablet composition of the present invention comprises below:

[0053] • 85.00% - 95.00% by weight imeglimin hydrochloride,

[0054] • 2.00% - 8.00% by weight vinylpyrrolidone - vinyl acetate copolymer,

[0055] • 3.00% -6.00% by weight crospovidone,

[0056] • 0.10-1.00% by weight glidant,

[0057] • 0.50-2.00 % by weight sodium stearyl fumarate,

[0058] • 2.0 - 4.0 % (w / wj by weight coating agents.

[0059] In other aspect of the present invention a process for preparing solid pharmaceutical compositions, comprising the steps of

[0060] a. Sieving and mixing Imeglimin or pharmaceutically acceptable salts thereof and one or more disintegrant,

[0061] b. Obtaining granulation solution with purified water and one or more vinylpyrrolidone - vinyl acetate copolymer,

[0062] c. Spraying granulation solution onto step a,

[0063] d. Obtaining and drying granules with fluid bed dryer,

[0064] e. Grinding the obtained granules,

[0065] f. Adding and mixing granules with one or more glidant and one or more lubricant,

[0066] g. Obtaining core tablets,

[0067] h. Coating with a film coating solution.

[0068] In other aspect of the present invention a process for preparing solid pharmaceutical compositions, comprising the steps of

[0069] a. Sieving and mixing Imeglimin or pharmaceutically acceptable salts thereof and one or more disintegrant,

[0070] b. Obtaining granulation solution with purified water and one or more vinylpyrrolidone - vinyl acetate copolymer,

[0071] c. Spraying granulation solution onto step a,

[0072] d. Obtaining and drying granules with fluid bed dryer,

[0073] e. Grinding the obtained granules,f. Adding and mixing granules with one or more glidant and sodium stearyl fumarate,

[0074] g. Obtaining core tablets,

[0075] h. Coating with a film coating solution.

[0076] In other aspect of a pharmaceutical composition of the present invention for use in the treatment of type 2 diabetes.

[0077] EXAMPLES

[0078] Example 1

[0079]

[0080] Imeglimin HC1 and one or more disintegrant were sieved and mixed. Granulation solution with purified water and polyvinylpyrrolidone K30 is obtained. This solution sprayed onto mixing of imeglimin HC1 and one or more disintegrant. Granules were dried with fluid bed dryer. At least one glidant and at least one lubricant was added to granules. Compressing tablet was performed. Tablets were coated with a film coating solution.

[0081] Example 2

[0082]

[0083] Imeglimin HCI and one or more disintegrant were sieved and mixed. Granulation solution with purified water and polyvinylpyrrolidone K90 is obtained. This solution sprayed onto mixing of imeglimin HCI and one or more disintegrant. Granules were dried with fluid bed dryer. At least one glidant and at least one lubricant was added to granules. Compressing tablet was performed. Tablets were coated with a film coating solution.

[0084] Example 3

[0085]

[0086] Imeglimin HCI and one or more disintegrant were sieved and mixed. Granulation solution with purified water and vinylpyrrolidone - vinyl acetate copolymer is obtained. This solution sprayed onto mixing of imeglimin HCI and one or more disintegrant. Granules were dried with fluid bed dryer. At least one glidant and at least one lubricant was added to granules. Compressing tablet was performed. Tablets were coated with a film coating solution.

Claims

CLAIMS1. A solid pharmaceutical composition comprises non-micronized imeglimin or pharmaceutically acceptable salts, vinylpyrrolidone polymer derivative and one or more pharmaceutically acceptable excipients.

2. The solid pharmaceutical composition according to claim 1, wherein the vinylpyrrolidone polymer derivative amount is between %2 (w / wj and %8 (w / w).

3. The solid pharmaceutical composition according to claim 1 or claim 2, wherein the viscosity value of vinylpyrrolidone derivative polymer is between 1.0 and 5.2 cps.

4. The solid pharmaceutical composition according to preceding claims, wherein the vinylpyrrolidone derivative polymer is vinylpyrrolidone - vinyl acetate copolymer.

5. The solid pharmaceutical composition according to preceding claims, wherein said composition is in the form of film coated tablet.

6. A process for preparing film coated tablet compositions according to claim 5, comprising the steps of;a. Sieving and mixing Imeglimin or pharmaceutically acceptable salts thereof and one or more disintegrant,b. Obtaining granulation solution with purified water and one or more vinylpyrrolidone - vinyl acetate copolymer,c. Spraying granulation solution onto step a,d. Obtaining and drying granules with fluid bed dryer,e. Grinding the obtained granules,f. Adding and mixing granules with one or more glidant and one or more lubricant,g. Obtaining core tablets,h. Coating with a film coating solution.

7. A pharmaceutical composition according to any one of the proceeding claims for use in the treatment of type 2 diabetes.

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