Fixed-dose combination formulations with low level of impurity profile

Abstract

The present invention relates to a stable, fixed-dose combination formulation comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof in combination with metformin hydrochloride and one or more pharmaceutically acceptable excipient manufactured by wet granulation method in monolayer dosage form.

Description

[0001] FIXED-DOSE COMBINATION FORMULATIONS WITH LOW LEVEL OF IMPURITY PROFILE

[0002] Technical Field

[0003] The present invention relates to a stable, fixed-dose combination formulation in monolayer dosage form comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof in combination with metformin hydrochloride and one or more pharmaceutically acceptable excipient manufactured by wet granulation method.

[0004] Background Of The Invention

[0005] Sitagliptin is an orally administered, well-tolerated compound that acts as a potent and selective inhibitor of dipeptidyl peptidase IV (DPP -4). It enhances glycemic control by elevating the levels of incretin hormones, notably glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretin hormones work to reduce blood glucose levels by stimulating the production and release of insulin while also suppressing the secretion of glucagon.

[0006] Sitagliptin is currently approved for the treatment of adults with Type 2 Diabetes Mellitus (T2DM). It can be used as a monotherapy or in combination with metformin, sulfonylurea, PPAR-y agonists, and as part of triple combination therapy with metformin plus sulfonylurea or metformin plus PPAR-y agonists. In addition to that it has also approval for use in conjunction with insulin.

[0007] The chemical name of sitagliptin is “7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine,” and it has an empirical formula of CieHisFeNso. Its relative molecular mass is 407.3 g / mol as a free base, 443.77 g / mol as the hydrochloride salt and 461.77 g / mole hydrochloride monohydrate salt. The chemical structure of sitagliptin is shown in the Formula I.

[0008] Fonnida I Sitagliptin is a white to off-powder with aqueous solubility that depends on pH. It readily dissolves in water and N,N-dimethylformamide, shows slight solubility in methanol, and is soluble in ethanol, acetone, and acetonitrile.

[0009] Sitagliptin monohydrate phosphate received its first commercial authorization in the EU from the European Medicines Agency on March 20, 2007 under the brand name Januvia®. The film- coated tablet dosage form of Januvia® is available in the strengths of 25 mg, 50 mg, 100 mg and 200 mg per tablet.

[0010] A combination therapy of sitagliptin with the well-established diabetes management metformin HC1 results in a more effective treatment for Type II diabetes. As a result, a combination product containing sitagliptin phosphate monohydrate and metformin HCI that received its commercial authorization in the EU from the European Medicines Agency on July 16, 2008. This combined medication is marketed as film-coated tablets under the trade name Janumet®, and it is available in strengths of 50 mg / 500 mg, 50 mg / 850 mg, and 50 mg / 1000 mg per tablet.

[0011] The chemical structure of metformin is shown in Formula II.

[0012] Formula II

[0013] The state of art including patents / patent applications is summarized below.

[0014] EP2477660 discloses pharmaceutical compositions comprising sitagliptin in a pharmaceutically acceptable salt and metformin hydrochloride in combination with polyethylene glycol or mixtures of polyethylene glycol with one or more other excipients as lubricant(s) in concentration of more than 10% w / w of the total composition.

[0015] W02020013777 discloses pharmaceutical compositions comprising sitagliptin and metformin by declaring that these drug substances are incompatible. To overcome the compatibility problem, the formulation is designed by inhibition of these two drugs each other such as multi compartment formulation design.

[0016] WO2015114152 relates to stable pharmaceutical composition in the form of immediate release tablets comprising sitagliptin hydrochloride monohydrate wherein the pharmaceutical composition is prepared by dry granulation. TR2011 / 08763 relates to a pharmaceutical formulation comprising DPP -IV inhibitor and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer manufactured by using hot-melt granulation method.

[0017] W02012131005 relates to stable pharmaceutical compositions comprising amorphous sitagliptin prepared from a solution comprising sitagliptin, a crystallization inhibitor which is polyvinylpyrrolidone and microcrystalline cellulose.

[0018] EP2578208 discloses a formulation comprising DPP -IV inhibitor with at least one binding dry granulation excipient polycarbophil along with performing dry granulation through briquette pressing or compression between rollers.

[0019] EP 1852108 declares solid pharmaceutical compositions comprising as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant by using wet granulation manufacturing method.

[0020] W02006078593 relates to a compressed pharmaceutical tablet comprising DPP-IV inhibitor formulations manufactured by using direct compression method. The amount of DPP-IV inhibitor in free base form or in acid addition salt form is between at least 60% or 80%, and the particle size distribution in the tablet is less than 250 pm.

[0021] W02014170770 relates to a solid oral pharmaceutical composition comprising sitagliptin or a salt thereof, metformin or a salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is devoid of glidant and / or surface active agent.

[0022] Therefore, there is a need to develop a stable fixed-dose combination composition comprising sitagliptin or pharmaceutically acceptable salt thereof and metformin hydrochloride in combination with at least one pharmaceutically acceptable excipient in a monolayer dosage form manufactured by using wet granulation process.

[0023] Summary Of The Invention

[0024] The object of this invention relates to stable pharmaceutical composition comprising sitagliptin or pharmaceutically acceptable salt thereof; metformin hydrochloride and at least one pharmaceutically acceptable excipient manufactured using wet granulation process.

[0025] The present object of the present invention is to provide a pharmaceutical composition comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof and metformin in combination in a solid dosage form such as tablet, sachet, granule, powder, capsule.

[0026] The present object of the present invention is to provide a pharmaceutical composition comprising sitagliptin and metformin in combination in an immediate-release solid dosage form.

[0027] Also, the present invention particularly relates to a process for the preparation of a pharmaceutical composition manufactured by using wet granulation method by employing spray granulation process.

[0028] Another objective of this invention is to provide a pharmaceutical composition that exhibits enhanced stability and mitigates the presence of related substances due to in compatibility between sitagliptin or pharmaceutically acceptable salts or derivatives thereof and metformin.

[0029] Another objective of this invention is to provide a pharmaceutical composition that exhibits enhanced stability and mitigates the presence of related substances due to in compatibility between sitagliptin or pharmaceutically acceptable salts or derivatives thereof and metformin without employing an antioxidant.

[0030] Another objective of this invention is to provide a pharmaceutical composition comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof and metformin hydrochloride that exhibits enhanced stability although the formulation is in monolayer tablet design and comprises excipients to cause oxidation phenomenon which trigger impurity levels in drug product.

[0031] Detailed Description Of The Invention

[0032] The present invention provides a stable immediate-release pharmaceutical composition comprising a therapeutically effective amount of sitagliptin or pharmaceutically acceptable salt thereof, metformin hydrochloride and at least one pharmaceutically acceptable excipient manufactured by using wet granulation method without using any antioxidant.

[0033] In the present invention, sitagliptin is in crystalline form.

[0034] In the present invention, sitagliptin is present as a low-dose drug that is constituted between 4% to 5% w / w by the total weight of the composition. Most of the prior art documents related to fixed-dose combination of sitagliptin and / or pharmaceutically acceptable salt thereof and metformin hydrochloride declared the manufacturing method as direct compression or dry granulation.

[0035] The common important property of these two manufacturing methods is being avoided from any solvent. Besides, there would be no drying process to remove the solvent from the environment.

[0036] The purity of the pharmaceutical compositions relates to either compatibility between the excipients and the active substances in the formulation or being exposed to many processes that could lead to degradation during manufacturing or both.

[0037] In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof and metformin hydrochloride by using wet granulation method wherein provided for the manufacture of tablets containing the active ingredient, diluents, binder, surfactant and lubricant selected as to be the most suitable ones with respect to the intended form of administration.

[0038] In a preferred embodiment, the pharmaceutical composition comprises at least one diluent can be selected from the group consisting of dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, the diluent is microcrystalline cellulose.

[0039] In the patent document numbered as EP2023902B1 declares that in attempts to prepare pharmaceutical compositions of selected DPP -IV inhibitors it has been observed, that the DPP- IV inhibitors with a primary or secondary amino group such as sitagliptin show incompatibilities, degradation problems, or extraction problems with a number of customary excipients such as microcrystalline cellulose.

[0040] In a preferred embodiment, the pharmaceutical composition comprises binder can be selected from the group consisting of hypromellose, low- substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is povidone. In a preferred embodiment, the pharmaceutical composition comprises surfactant can be selected from the group consisting of polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, sugar esters of fatty acids and glycerides of fatty acids, or mixtures thereof. Preferably, the binder is sodium lauryl sulfate.

[0041] In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant can be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof. Preferably, the lubricant is sodium stearyl fumarate.

[0042] However, in the present invention, the inventors have surprisingly found that a developed pharmaceutical composition comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof, metformin hydrochloride and in a specified processing ratio of microcr stalline cellulose in a monolayer dosage form is obtained with a suitable impurity profile although the composition is free of antioxidant.

[0043] Table 1: Unit Formula of Example

[0044] In a preferred embodiment, the process for the preparation of a pharmaceutical composition manufactured by using wet granulation method, including the steps of: a) Microcrystalline cellulose in 50-55% quantity of the total amount and Metformin hydrochloride are screened through a proper sieve and stirred, b) Povidone, Sodium lauryl sulfate are dissolved in water and stirred, c) The solution in step (b) is sprayed on the powder mixture in step (a) during stirring (granulation), d) The granule obtained in step (c) is dried till to get loss of drying level between 1-2% in fluid-bed dryer and sifted, e) The 45-50% amount of microcrystalline cellulose and Sitagliptin or pharmaceutically acceptable salts or derivatives thereof are screened together and added to the powder blend in step (d), mixed, f) Sodium stearyl fumarate is added on to the powder blend in step (e), mixed g) Tablet compression is performed with the powder blend in step (f).

[0045] Both active substances; sitagliptin or pharmaceutically acceptable salts or derivatives thereof and metformin hydrochloride, are diluted with a specified quantities of microcrystalline cellulose amount individually before processing any other excipient.

[0046] Related substances test was performed to analyze the embodiment regarding impurity that could be formed due to compatibility between two active substances, in comparison with the reference product.

[0047] The related substances test was carried out with a validated method via the HPLC device.

[0048] Table 2. Comparative related substances results of reference drug product with the Example

[0049] Further, the obtained tablets were subjected to the stability chamber adjusted to the conditions of 40°C±0.5°C, 75%±5% RH. The conditions are identified as the accelerated conditions and 6th-month period is the last period of this stability study to stimulate shelf-life of 24-month for the drug product.

[0050] Table 3: Comparative related substances results of reference drug product with the Example stored under the accelerated stability conditions till to 6-month period

[0051] According to EP2023902B1, DPP-IV inhibitors comprise secondary or primary amines. In close look into sitagliptin chemical structure, there is also a primary amine group. Based on this, as it is stated in the patent document; Though the compounds themselves are very stable, they react with many excipients used in solid dosage forms and with impurities of excipients, especially in tight contact provided in tablets and at high excipient / drug ratios. The amino group appears to react with reducing sugars and with other reactive carbonyl groups and with carboxylic acid functional groups formed for example at the surface of microcrystalline cellulose by oxidation. These unforeseen difficulties are primarily observed in low dosage ranges which are required due to the surprising potency of the selected inhibitors. Thus, pharmaceutical compositions are required so solve these technical problems associated with the unexpected potency of selected DPP-IV inhibitor compounds.

[0052] As a result of a detailed research;

[0053] Recently, The Food and Drug Administration (FDA) has reported that the presence of Nitroso- STG-19, also known as NTTP, has been detected in sitagliptin comprising products. NTTP belongs to the nitrosamine class of compounds that is present as an impurity with the name 7- Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo-[4,3-a]pyrazine.

[0054] Nitrosamines are a group of compounds commonly found in low levels in our daily lives, including water, foods, or even some drugs. However, some nitrosamines are classified as increasing the risk of the cancer when people are exposed to them over a prolonged period above acceptable levels.

[0055] As a response; the marketing authorization holder of reference product, Merck, has presented a declaration to the authorities by confirming the findings of nitrosamine impurity concerning Januvia® and Janumet®. A root-cause analysis has been conducted and it was provided that the impurity is formed during manufacturing and subsequent storage of the drug product.

[0056] In addition, a scientific method was published for analysing nitrosamines in sitagliptin— metformin combinations like Janumet® on April 2021. That was because metformin, a nitrogenrich compound like sitagliptin, was one of the first drugs to show nitrosamine contamination, rather than them previously seeing any obvious problem with sitagliptin.

[0057] Based on above information, nitrosamine impurity analysis was also carried out by using validated analytical methods to identify and quantify both NTTP regarding sitagliptin and nitrosamine contamination regarding metformin in the Example which was stored under longterm stability conditions of 25°C±0.5°C, 60%±5% RH for 24-month period. Table 4: Nitrosamine impurity profile of the Example at 24rdmonth period

[0058] According to all results of the impurity analysis, in the embodiment of the present invention, a stable fixed-dose combination formulation comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof, metformin hydrochloride and at least one pharmaceutically acceptable excipient is manufactured by using wet granulation method in a monolayer dosage form, wherein;

[0059] - the composition is free of antioxidant in a monolayer dosage form, and

[0060] - the composition comprises microcrystalline cellulose, o 45-50% w / w of the amount of microcrystalline cellulose in the total formulation used to dilute metformin hydrochloride, o 50-55% w / w of the amount of microcrystalline cellulose in the total formulation used to dilute sitagliptin or pharmaceutically acceptable salts or derivatives thereof.

[0061] While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

CLAIMS1. A stable fixed-dose combination formulation in monolayer dosage form comprising sitagliptin or pharmaceutically acceptable salts or derivatives thereof, metformin hydrochloride and at least one pharmaceutically acceptable excipient manufactured by using wet granulation method, wherein;- the composition is free of antioxidant, and- the composition comprises microcrystalline cellulose, 45-50% of the amount of microcrystalline cellulose used to dilute metformin hydrochloride, 50-55% of the amount of microcrystalline cellulose used to dilute sitagliptin or pharmaceutically acceptable salts or derivatives thereof.

2. A stable fixed-dose combination formulation according to claim 1, wherein the composition comprises at least one further pharmaceutically acceptable excipient selected from binder, lubricant, surfactant and mixtures thereof.

3. A stable fixed-dose combination formulation according to claim 2, wherein the binder is selected from hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol and mixtures thereof.

4. A stable fixed-dose combination formulation according to claim 3, wherein the binder is povidone.

5. A stable fixed-dose combination formulation according to claim 2, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof.

6. A stable fixed-dose combination formulation according to claim 5, wherein the lubricant is magnesium stearate.

7. A stable fixed-dose combination formulation according to claim 2, wherein the surfactant is selected from polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, sugar esters of fatty acids and glycerides of fatty acids and mixtures thereof.

8. A stable fixed-dose combination formulation according to claim 7, wherein the surfactant is sodium lauryl sulfate.

9. A wet granulation method for the manufacturing of a pharmaceutical composition according to any one of the preceding claims, wherein the process comprises the steps of; a) The Microcrystalline cellulose in 50-55% quantity of the total amount and Metformin hydrochloride are screened through a proper sieve and stirred, b) Povidone, Sodium lauryl sulfate are dissolved in water and stirred, c) The solution in step (b) is sprayed on the powder mixture in step (a) during stirring (granulation), d) The granule obtained in step (c) is dried till to get loss of drying level between 1-2% in fluid-bed dryer and sifted, e) The 45-50% amount of Microcrystalline cellulose and Sitagliptin or pharmaceutically acceptable salts or derivatives thereof are screened together and added to the powder blend in step (d), mixed, f) Sodium stearyl fumarate is added on to the powder blend in step (e), mixed g) Tablet compression is performed with the powder blend in step (f).

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