WO2023012817A1 - A pharmaceutical composition comprising combination of dapagliflozin and sitagliptin - Google Patents

Abstract

The present invention relates to a stable pharmaceutical composition comprising combination of a therapeutically effective amount of SGLT2 inhibitor and a therapeutically effective amount of DPP-IV inhibitor for reducing blood glucose level in patients with diabetes. The present invention specifically relates to a stable pharmaceutical composition comprising Dapagliflozin or a pharmaceutically acceptable salts thereof, and Sitagliptin or a pharmaceutically acceptable salts thereof in presence of one or more pharmaceutically acceptable excipients. Moreover, the present invention relates to a stable pharmaceutical composition comprising Dapagliflozin or a pharmaceutically acceptable salts thereof, Sitagliptin or a pharmaceutically acceptable salts thereof, at least one stabilizer and one or more pharmaceutically acceptable excipients.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING COMBINATION OF DAPAGLIFLOZIN AND SITAGLIPTIN

PRIORITY APPLICATION

This application claims the benefit of priority of our Indian patent application 202121034536 filed on July 31, 2021 which is incorporated herein by reference and disclosures of which is incorporated in the instant application.

FIELD OF INVENTION

The present invention relates to a stable pharmaceutical composition comprising combination of a therapeutically effective amount of Sodium-glucose co- transporter-2 (SGLT2) inhibitor and a therapeutically effective amount of Dipeptidyl peptidase-4 (DPP4) inhibitor for reducing blood glucose level in patients with diabetes. The present invention specifically relates to a stable pharmaceutical composition comprising Dapagliflozin or a pharmaceutically acceptable salts or hydrates thereof and Sitagliptin or a pharmaceutically acceptable salts or solvates or hydrates thereof in the presence of one or more pharmaceutically acceptable excipients. Further, the invention relates to a stable pharmaceutical composition comprising Sitagliptin and Dapagliflozin present in a ratio in the range from about 40: 1 to about 2.5:1. Moreover, the present invention relates to a stable pharmaceutical composition comprising Sitagliptin Phosphate Monohydrate, Dapagliflozin Propanediol Hydrate and one or more pharmaceutically acceptable excipients with high content uniformity and reduced degradation impurities.

BACKGROUND OF THE INVENTION

Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. The treatment of Type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy. For many patients, these regimens do not sufficiently control glycaemia during long-term treatment, leading to a requirement for combination therapy within several years following diagnosis. However, co-prescription of two or more oral antidiabetic drugs may result in treatment regimens that are complex and difficult for many patients to follow. Combining two or more oral antidiabetic agents into a single tablet provides a potential means of delivering combination therapy without adding to the complexity of patients' daily regimens. Such formulations have been well accepted in other disease indications, such as hypertension (HYZAAR™ which is a combination of losartan potassium and hydrochlorothiazide) and cholesterol lowering (VYTORIN™ which is a combination of simvastatin and ezetimibe). The selection of effective and well-tolerated treatments is a key step in the design of a combination tablet.

Two novel classes of glucose-lowering agents that meet these criteria are the dipeptidyl peptidase-4 (DPP-4) inhibitors and the sodium glucose cotransporter-2 (SGLT2) inhibitors. SGLT2 inhibitor is associated with glucosuria, an increase in the rate of endogenous glucose production (EGP), which offsets the glucose- lowering effect by approximately 50%. In contrast, DPP-4 inhibitor inhibits glucagon secretion and reduce EGP. This combination of DPP-4 inhibitor plus SGLT2 inhibitor would prevent the increase in EGP following SGLT2 inhibition and produce an additive and synergistic effect to reduce HbAlc.

Sitagliptin is a novel Dipeptidyl peptidase-4 (DPP-IV) inhibitor represented by following chemical structure

Fig. 1 : Chemical structure of Sitagliptin

The chemical name for 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 phosphate (1:1) monohydrate. It was developed by Merck & Co. Ltd and is approved as Januvia® in the United States of America and in Europe. Sitagliptin is approved as 25 mg, 50 mg and 100 mg immediate release tablet dosage form for once daily administration for adult patients with type 2 diabetes mellitus, Januvia is indicated to improve glycaemic control as monotherapy, as dual therapy in combination with Metformin, a sulphonyl urea, or a thiazolidinedione and as a triple therapy in combination with a sulphonyl urea and metformin or a thiazolidinedione and metformin. Januvia is also indicated as add-on to insulin (with or without metformin).

US 7,326,708 discloses a dihydrogenphosphate salt of Sitagliptin or a hydrate thereof, a crystalline monohydrate with specific XRD, NMR, Mass characteristics, its pharmaceutical composition, process for preparation and method of treatment of type 2 diabetes using the same. It also discloses specific pharmaceutical composition comprising Sitagliptin phosphate monohydrate and dibasic calcium phosphate (or mannitol), microcrystalline cellulose, croscarmellose, magnesium Stearate and coating agent prepared using direct compression or using roller compaction process.

Dapagliflozin is a novel Sodium-glucose co-transporter-2 (SGLT2) inhibitor represented by following chemical structure.

Fig. 2: Chemical structure of Dapagliflozin

The chemical name for Dapagliflozin is (lS)-l,5-Anhydro-l-[4-chloro-3-(4- methoxybenzyl)phenyl]-D-glucitol. It was developed by Bristol-Myers Squibb in partnership with AstraZeneca and is approved under different brand names for example, Forxiga®, Edistride® in Europe and Farxiga® in United States of America. Dapagliflozin is approved as 5 mg and 10 mg immediate release tablet dosage form for once daily administration for the treatment of insufficiently controlled type 2 diabetes mellitus, type 1 diabetes mellitus and heart failure. It is also under priority review for Chronic Kidney Disease (CKD) indication by USFDA. US 8,221,786 discloses an immediate release pharmaceutical composition of Dapagliflozin in the form of capsule or tablet or stock granules for loading in capsules or forming tablets containing one or more bulking agents, binders, disintegrants, glidants/anti-adherents and lubricants.

In addition to the main effects of Sitagliptin and Dapagliflozin of lowering blood sugar without risk of hypoglycaemia, Sitagliptin has a protective effect on pancreatic beta-cells and increases GLP-1, and Dapagliflozin has a weight loss effect. However, it has been introduced as a clinical result that the combination of the two active ingredients shows a synergistic effect because it has a blood pressure lowering effect. In addition, as diabetes progresses in diabetic patients, it is difficult to control blood sugar, resulting in complications. In particular, elderly diabetic patients are more likely to suffer from hypertension, obesity, and hyperlipidaemia. Due to the characteristics of these diabetic patients, medication adherence is a very important factor, and a decrease in medication compliance may not only lower the patient's quality of life, but also reduce the patient's treatment rate, increase personal medical expenses, and worsen insurance finances. Therefore, it is necessary to develop a combination formulation containing Sitagliptin and Dapagliflozin.

Andre" J. Scheen et al. (Clin Pharmacokinet, Springer International Publishing Switzerland 2016) studied Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes and has concluded that the combination of an SGLT2I and DPP-41 is an attractive therapeutic strategy because the complementary modes of action of the two medications contribute to improve blood glucose control in patients with T2D, without deteriorating the safety/tolerance profile of each compound.

W02009091082 Al discloses use of combination of DPP-IV inhibitor and SGLT2 inhibitor and optionally a third diabetic agent for the treatment of conditions such as type 2 diabetes and diseases related to diabetes. It discloses combination of Sitagliptin (10 to 200 mg) and Dapagliflozin (1 to 100 mg). However, it does not disclose or exemplify any pharmaceutical fixed dose combination for these two drugs.

WO2021/133023 Al discloses combination preparation comprising Sitagliptin Phosphate Monohydrate and Dapagliflozin L-Proline along with specific excipients comprising sodium stearyl fumerate and magnesium stearate. However, it does not disclose anything about in-vivo synergistic or additive effect of this combination.

The above prior arts only disclose concomitant product administration of Sitagliptin and Dapagliflozin for the patients suffering from diabetes mellitus. None of the prior arts discuss about potential generation of impurities when Sitagliptin phosphate monohydrate and Dapagliflozin propanediol hydrate are combined together in a single formulation and to prevention or reduction of the generation of impurities by using a stabilizer.

In attempts to prepare pharmaceutical compositions of selected DPP-4 inhibitors it has been observed, that the DPP-4 inhibitors with a primary or secondary amino group show incompatibilities, degradation problems, or extraction problems with a number of customary excipients such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose, maltodextrines. Though the compounds themselves are very stable, they react with incompatible partner drug, or its impurity product, and/or 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. Thus, pharmaceutical compositions are required to solve these technical problems, which may be associated with the unexpected potency of selected DPP-4 inhibitor compounds.

However, the development of a combination formulation comprising a fixed dose combination of Sitagliptin phosphate monohydrate and Dapagliflozin propanediol hydrate is very challenging and has not yet been attempted due to numerous problems such as completely different physical properties of each API and the size of the tablet. In the case of Sitagliptin, although it is having appreciable flow properties, it has a problem in that the amount per tablet is large and is liable to punch sticking because as it is sticky in nature. Whereas, in the case of Dapagliflozin, its density is low and thus the volume of the Dapagliflozin is large despite a small amount. Thus due to different physical properties of both the API’s, they also tend to agglomerate or there is a high possibility of layer separation with other main components and excipients, and hence it is difficult to ensure content uniformity in the formulation.

The inventors of the present invention have overcome the problems associated with the currently marketed products and have developed patient compliant and stable pharmaceutical compositions containing combination of Sitagliptin or a pharmaceutically acceptable salts thereof and Dapagliflozin or a pharmaceutically acceptable salts thereof in single product with reduced amount of impurities and high content uniformity.

The Sitagliptin and Dapagliflozin fixed dose combination product would facilitate long unmet need of a simplified dosage regimen wherein the patients can be treated with only a single product. This will also lead to increase in patient compliance and adherence considering long period of treatment associated with chronic disease and will reduce the pill burden. Further, the fixed dose combination product can also produce synergistic effects and provide superior efficacy in comparison to monotherapy.

Moreover, the still unaddressed issue of potential increase in impurity in such composition, has also been overcome by the composition of present invention.

SUMMARY OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising combination of a therapeutically effective amount of DPP-IV inhibitor and a therapeutically effective amount of SGLT-2 inhibitor for the treatment of diabetes mellitus. In one aspect of the invention, there is provided a pharmaceutical composition comprising a fixed dose combination of DPP-IV inhibitor or salt thereof and SGLT2 inhibitor and one or more pharmaceutically acceptable excipients.

The present invention specifically relates to a stable pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In one aspect, the present invention relates to a stable pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable stabilizers.

In another aspect of the invention, there is provided a pharmaceutical composition comprising about 1 mg to about 200 mg, even more preferably from about 1 mg to 100 mg, even more preferably from about 25 mg to about 100 mg of Sitagliptin or a pharmaceutically acceptable salt thereof and about 1 mg to 100 mg, even more preferably from about 1 mg to 50 mg, most preferably from about 1 mg to 10 mg of Dapagliflozin or a pharmaceutically acceptable salt thereof wherein Sitagliptin and Dapagliflozin present in a ratio in the range from about 40:1 to about 2.5:1.

In another aspect of the invention, there is provided a pharmaceutical composition comprising a fixed dose combination of about 25 mg/50 mg/100 mg Sitagliptin or equivalent amount of its salt or hydrate thereof and about 2.5 mg/5 mg/10 mg of Dapagliflozin or equivalent amount of its salt or solvate thereof.

In another embodiment, the pharmaceutical composition of the present invention comprises one or more stabilizer along with Sitagliptin part of the composition to limit the generation of impurity.

In particular, use of acidic compound, basic compound, amino acid, antioxidant and the likes as stabilizer in this composition helped to minimize the reaction of free amino group with reducing sugars or with reactive carbonyl or carboxylic acid functional group associated with partner drug or its impurities or with many excipients and provided composition with improved stability and reduced impurities. The present invention specifically relates to a stable pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient which shows optimum content uniformity despite the difference in the physical properties of each API and the differing dose.

The present invention further relates to pharmaceutical composition for oral administration for treatment of diabetes mellitus comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the composition remains stable at 40°C + 2°C/75% RH + 5% RH conditions for a time period of at least 6 months. Moreover, the present invention relates to pharmaceutical composition for oral administration for treatment of diabetes mellitus comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the composition retains at least 90% of amount of Sitagliptin and/or Dapagliflozin initially present in the composition and wherein any of the known or unknown individual impurity of Sitagliptin and Dapagliflozin is not more than 0.2 % w/w and the total impurity is not more than 2 % w/w.

More particularly in alternative embodiment, the present invention relates to an oral dosage form comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof, and optionally, one or more pharmaceutically acceptable excipients. More preferably, a core comprising a therapeutically effective amount of Sitagliptin and a surrounding part comprising a therapeutically effective amount of Dapagliflozin with minimum contact between Sitagliptin and Dapagliflozin which provides unexpected increase in stability relative to unknown individual impurity.

In a preferred embodiment, the present invention relates to a pharmaceutical composition comprising a first portion comprising Sitagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients and a second portion comprising Dapagliflozin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients, which provides an increase in dissolution, reduction in impurities and improvement in stability.

The present invention is directed to a solid pharmaceutical composition for oral administration comprising Sitagliptin or a pharmaceutically acceptable salt thereof and Dapagliflozin or a pharmaceutically acceptable salt thereof, in admixture with one or more excipients, more preferably a stabilizer, in a pharmacokinetically effective ratio such that said Sitagliptin and said Dapagliflozin are released in a bioequivalent manner.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising Sitagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients and (b) an extra-granular portion comprising Dapagliflozin or a pharmaceutically acceptable salt thereof or vice versa and a pharmaceutically acceptable excipients. Alternatively, Dapagliflozin or a pharmaceutically acceptable salt thereof and Sitagliptin or a pharmaceutically acceptable salt thereof can be either in extragranular part compressed with inert core.

The present invention further relates to a process of preparing pharmaceutical composition comprising a fixed dose formulation of Sitagliptin or a pharmaceutically acceptable salt, solvate, hydrate thereof and Dapagliflozin or a pharmaceutically acceptable salt, solvate, hydrate thereof by direct compression or by dry granulation or by wet granulation.

In further aspect of the invention, the pharmaceutical composition according to present invention is used for prevention, treatment or prophylaxis of diabetes. Further, there is provided a use of kit comprising the pharmaceutical composition according to present invention, for prevention, treatment or prophylaxis of diabetes.

DETAILED DESCRIPTION

The present invention relates to a stable pharmaceutical composition comprising combination of a therapeutically effective amount of DPP-IV inhibitor and a therapeutically effective amount of SGLT-2 inhibitor for the treatment of diabetes mellitus. Specifically, the present invention relates to a stable pharmaceutical composition comprising a therapeutically effective amount of Sitagliptin or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of Dapagliflozin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention more specifically relates to a stable pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable stabilizers.

As used herein, the term "Sitagliptin" refers to compound which may be present in its base form or any of its pharmaceutically acceptable salt or solvate or prodrug or metabolite or analog or isomer or like thereof.

As used herein, the term "Dapagliflozin" refers to compound which may be present in base form or in the form of the pharmaceutically acceptable salt or solvate or prodrug or metabolite or analog or isomer or like thereof.

As used herein, the term "pharmaceutically acceptable salts" include, but are not limited to mineral or organic salts of basic residues such as amines, alkali or mineral or organic salts of acidic residues such as carboxylic acids and the like thereof. Further, the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts. The conventional non-toxic salts include inorganic or organic acids, for example those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like thereof; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like thereof.

As used herein, the term "therapeutically effective amount of Sitagliptin” is an amount of Sitagliptin or its pharmaceutically acceptable salt which eliminates, alleviates, or provides relief in diabetes mellitus. As used herein, the term ' therapeutically effective amount of Dapaghflozin is an amount of Dapagliflozin or its pharmaceutically acceptable salt which eliminates, alleviates, or provides relief in diabetes mellitus.

The terms "solid oral dosage form", "oral dosage form", "unit dose form", "dosage form for oral administration" and the like are used interchangeably, and refer to a pharmaceutical composition in the form of a mini-tablets, pellets, pills, granules, beads, sachets, tablets in tablets, tablets in capsules, capsules, caplets, capsule, gelcap, geltab, pill, dry syrup, suspension or the like dosage forms.

The term “stable” means a drug substance and/or pharmaceutical composition for pharmaceutical use which remains stable as per ICH guidelines. The term “ICH guidelines” means drug substance and composition remains stable for longer period of time at 25°C + 2°C/60% RH + 5% RH, 30°C + 2°C/65% RH + 5% RH, and 40°C + 2°C/75% RH + 5% RH conditions for a period of at least 6 months.

As used herein, the terms “about” and “approximately” should be understood to mean within an acceptable range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 30%, preferably up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.

As used herein, the terms "bioequivalence" is defined as a pharmacokinetic (PK) comparison of the present pharmaceutical composition to that of the approved formulation. The pharmaceutical composition of the present invention must display drug pharmacokinetics that fall within a range of 80-125% (0.8-1.25) when one computes the ratio of the drug PK of the present invention composition with respect to approved marketed formulation. The PK parameters that are used for this comparison are the maximum concentration achieved in the blood (Cmax) and the area-under-the-curve (AUC). The AUC is determined by plotting the concentration of the active ingredient in the blood over time. It is accepted as bioequivalent if the present invention composition PK falls within the 80 - 125% range when compared to the approved marketed drug formulation PK. As used herein, the term “impurity” include total impurities or individual impurities.

In another embodiment, the DPP-IV inhibitor compound is selected from the group consisting Alogliptin, Vildagliptin, Saxagliptin, Linagliptin, Sitagliptin, Gemigliptin, Anagliptin, Teneligliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Dutagliptin, Melogliptin, Denagliptin or a like thereof.

In one embodiment, the SGLT-2 inhibitor compound is selected from the group consisting of Dapagliflozin, Empagliflozin, Canagliflozin, Ertugliflozin, Sotagliflozin, Luseogliflozin, Tofogliflozin, Remogliflozin Etabonate, Ipragliflozin, or a like thereof.

According to one aspect, there is provided a stable pharmaceutical composition comprising Sitagliptin and Dapagliflozin wherein Sitagliptin and Dapagliflozin are present in a ratio in the range from about 40:1 to about 2.5:1. In a preferred embodiment, the pharmaceutical composition comprising Sitagliptin and Dapagliflozin is present invention is in a ratio of about 10:1.

According to second aspect, the Sitagliptin or its pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in the range from about 1 mg to about 200 mg, preferably from about 1 mg to about 100 mg and more preferably from about 25 mg to about 100 mg.

According to third aspect, the Dapagliflozin or its pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in the range from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg and more preferably from about 1 mg to about 10 mg.

According to fourth aspect, the present invention is directed to a solid pharmaceutical composition for oral administration which comprises Sitagliptin or a pharmaceutically acceptable salt thereof and Dapagliflozin or a pharmaceutically acceptable salt thereof, in admixture with one or more excipients, in a pharmacokinetically effective ratio such that said Sitagliptin and said Dapagliflozin are released in a bioequivalent manner. In a particular embodiment, the Sitagliptin and Dapagliflozin are released from said formulation simultaneously, at a rate and in a ratio providing each in a therapeutically effective and non-toxic amount.

In one embodiment, the present invention relates to pharmaceutical composition comprising Sitagliptin, Dapagliflozin and one or more pharmaceutically acceptable excipients. In another embodiment, the method for administration of pharmaceutical composition comprising Sitagliptin, Dapagliflozin and one or more pharmaceutically acceptable excipients by administering in once daily oral dosage form.

The pharmaceutical compositions are present in any one of the unit dose form such as tablets, mini-tablets, pellets, pills, granules, beads, sachets, tablets in tablets, tablets in capsules, capsules, caplets, dry syrup, suspension or a like thereof.

The present invention specifically relates to a stable pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof, Dapagliflozin or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient which shows optimum content uniformity despite the difference in the physical properties of each API and the differing dose.

In another embodiment, the pharmaceutical compositions comprising Sitagliptin having a particle size D90 less than about 200 pm, preferably less than about 150 pm.

In one embodiment, the pharmaceutical compositions comprising Dapagliflozin having a particle size D90 less than about 200 pm. The particle size D90 preferred for use in the present invention is less than about 150 pm, more preferably less than 100 pm and even more preferably less than about 50 pm.

The active pharmaceutical ingredient in the present invention composition may present in any one polymorphic form selected from crystalline, amorphous, a solvate, a hydrate, or an anhydrous or a like thereof.

In another embodiment, the pharmaceutical composition comprising Sitagliptin, Dapagliflozin and one or more pharmaceutically acceptable excipient wherein the composition remains stable at 25°C + 2°C/60% RH + 5% RH, 30°C + 2°C/65% RH + 5% RH, and 40°C + 2°C/75% RH + 5% RH conditions for a time period of at least 6 months.

In another embodiment, there is no significant change in content level of Sitagliptin and Dapagliflozin in the said pharmaceutical composition after 6 months storage stability conditions at 40°C + 2°C/75% RH + 5% RH, wherein total known and unknown impurities level remain in the limit as per the defined criteria of ICH & USP/EP monographs.

In another embodiment, there is no significant change in content level of Sitagliptin and Dapagliflozin in the said pharmaceutical composition after 6 months storage stability conditions at 40°C + 2°C/75% RH + 5% RH, wherein any of the known and unknown individual impurity of Sitagliptin and Dapagliflozin is not more than 0.2 % w/w and the total impurity is not more than 2 % w/w, preferably not more than 1 % w/w.

In a preferred embodiment, the present invention relates to a pharmaceutical composition comprising a first portion comprising Sitagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients and a second portion comprising Dapagliflozin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients.

In one aspect of the invention, the present invention relates to an oral dosage form comprising a fixed dose combination of Sitagliptin or a pharmaceutically acceptable salt thereof and Dapagliflozin or a pharmaceutically acceptable salt thereof in form of a single layer tablet, wherein the Sitagliptin is present intra- granularly along with pharmaceutically acceptable excipients and wherein the Dapagliflozin is present extra-granularly along with pharmaceutically acceptable excipients which provides unexpected increase in the rate of dissolution of both drugs.

In one another aspect of the invention, the present invention relates to an oral dosage form comprising a fixed dose combination of Sitagliptin or a pharmaceutically acceptable salt thereof and Dapagliflozin or a pharmaceutically acceptable salt thereof in form of a single layer tablet, wherein the Sitagliptin is present intra-granularly optionally with a stabilizer along with pharmaceutically acceptable excipients and wherein the Dapaghflozin is present extra-granularly, which provides unexpected increase in stability relative to any known or unknown individual or total impurity.

In one another aspect of the invention, the FDC can be in form of a bilayer tablet comprising one layer of Sitagliptin or a pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipients, a second layer of Dapagliflozin or a pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipients, wherein the tablet provides optimum dissolution of both drugs and is stable.

In one embodiment, the pharmaceutical composition comprising from about 10 % to about 50 % w/w of Sitagliptin, from about 1 % to about 10 % w/w Dapagliflozin, and one or more pharmaceutically acceptable excipients.

In another embodiment, the pharmaceutical composition of the invention may include one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants/superdisintegrants, lubricants, glidants, coloring agents, stabilizers, solvents, suitable film-forming agents or a like thereof.

The diluents according to the present invention include, but are not limited to, starch (maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, partially Pregelatinized starch and others), lactose (e.g., lactose monohydrate, such as Fast Flo® 316, lactose anhydrous and others), cellulose derivatives includes crystalline celluloses such as microcrystalline cellulose, kaolin and powdered celluloses, confectioner's sugar, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, dicalcium phosphate, calcium sulfate, carmellose, sugar alcohols such as mannitol, sorbitol, xylitol, inositol sucrose, inositol, polysaccharides polymers such as pullulan and mixtures thereof. Preferably, the diluent in present invention is Pregelatinized starch, microcrystalline cellulose, lactose and dibasic calcium phosphate. The diluent may present in an amount from about 10% to about 90% w/w of the composition, preferably from about 20% to about 80% w/w of the composition and more preferably from about 25% to about 65% w/w of the composition. The binders according to the present invention include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone and its derivatives in various grades such as povidone, copovidone and others, methyl cellulose, pre-gelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose in various grades, microcrystalline cellulose and mixtures thereof. The binder may present in an amount from about 0% to about 10% w/w of the composition, preferably from about 0% to about 5% w/w of the composition and more preferably from about 0% to about 4% of the composition. The disintegrants/superdisintegrants according to the present invention include, but are not limited to, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, alginic acid, calcium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, maize, potato or tapioca starch, pregelatinized starch, partially Pregelatinized starch and mixtures thereof. The disintegrant present either alone or in combination with other disintegrants and the preferred disintegrant is croscarmellose sodium and low-substituted hydroxypropyl cellulose. The disintegrant may present in amount from about 1 to about 10% w/w of the composition, preferably from about 1 to about 5% w/w of the composition and more preferably about 3% w/w of the composition.

The lubricants according to the present invention include, but are not limited to, magnesium stearate, glyceryl monostearates, glyceryl behenate, palmitic acid, talc, carnauba wax, calcium stearate, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, sodium stearyl fumarate, sodium lauryl sulphate and mixtures thereof. Preferably, the lubricant in present invention is zinc stearate &/or sodium stearyl fumerate. The lubricants may present in an amount from about 0.01 to about 5% w/w of the composition, preferably from about 0.5 to about 2% w/w of the composition and more preferably about 1.5% w/w of the composition. The glidants according to the present invention include, but are not limited to, silica such as colloidal silicon dioxide or kaolin, talc and mixtures thereof. Preferably, the glidant in present invention is colloidal silicone dioxide. The glidants may present in amount from about 0.01% to about 5%w/w of the composition, preferably from about 0.1% to about 1% w/w of the composition.

The coloring agents according to the present invention include, but are not limited to, natural colorants, synthetic colorants or like thereof. Examples of natural colorants include pigments and dyes obtained from mineral, plant, and animal sources like red ferric oxide, titanium dioxide, yellow ferric oxide, zinc oxide, indigo and synthetic colorants include FD&C or D&C dye, an azo dye or a like thereof. The colouring agents may be present in the composition as per the quantity sufficient requirement, preferably from about 0.1% to about 1.0 w/w of the composition.

The stabilizers may be included in the compositions of the present invention depending upon the requirement which include, but are not limited to acidic compound selected from the group comprising acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, benzoic acid, sodium benzoate and the like or basic compound selected from the group comprising basic amino acids such as L-arginine, L-lysine, L-histidine, L-citrulline, cysteine, 6-amino caproic acid and the like or basic/alkalizing agents selected from the group comprising ammonium carbonate, sodium carbonate, monoethanolamine, diethanolamine, potassium hydroxide, sodium hydroxide, potassium carbonate and the like or buffering agents selected from the group comprising acetic acid, adipic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, potassium phosphate monobasic, potassium phosphate dibasic, sodium acetate, sodium citrate, sodium lactate, sodium phosphate monobasic, sodium phosphate dibasic, succinic acid and the likes. The stabilizer may further include antioxidant substances which is present in amounts effective to retard decomposition of a drug that is susceptible to oxidation. The antioxidants according to the present application include, but are not limited to include one or more of ascorbic acid and its salts, tocopherols, sulfite salts such as sodium metabisulfite or sodium sulfite, sodium sulfide, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, propyl gallate and mixtures thereof. Any other category excipient may be included in the stabilizer list in the present invention pharmaceutical composition. The stabilizers may be present in amount from about 0.001 to about 10%w/w of the composition.

The solvents according to the present invention, but are not limited to, for the purpose of film coating/granulation includes water, methanol, ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, and any mixtures thereof.

The compositions of the present invention may be coated with one or more film forming materials as known in the art. These coatings may be sugar coatings, film coatings, color coatings, drug coating or the like thereof. The film-forming agents according to the present invention includes, but are not limited to, a water- soluble/water-insoluble film forming polymers, such as hydroxpropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose, povidone, polydextrose, lactose, maltodextrin, acrylic polymer such as ammonium ethacrylate copolymers, polyvinyl derivative, polyvinyl acetate, Poly (ethylene oxide), Poly (ethylene glycol) and mixtures thereof. The film coating may optionally contain a plasticizer, such as castor oil, polyethylene glycol, propylene glycol or glycerine, and a coloring or pacifying agent. The film coating may also contain a flavoring and/or sweetening agent to improve palatability.

According to one embodiment, the pharmaceutical composition is present in any one of the form selected from single layer composition, bi-layer composition, multi-layer composition or any other alternative modification in the composition as accompanied in the present invention. The dosage forms herein, e.g., fixed dose combination tablets, can be of any suitable size and shape and the invention is not limited in this regard. For example, the dosage forms may be of triangular, round, rectangular, square, capsule, almond, oval, diamond, biconvex, multi-layered, or have an irregular shape. There may also be letters or characters embossed or printed on the dosage form surface.

In one embodiment of the present invention, the pharmaceutical composition is in form of a single layer tablet comprising Sitagliptin or a pharmaceutically acceptable salt thereof in amount from about 20% to about 40% w/w, Dapagliflozin or a pharmaceutically acceptable salt thereof in amount from about 1.0% to about 10% w/w, one or more diluents, each in amount from about 10 % to about 60 %, with the total diluent in the composition from about 30 % to about 80% w/w, disintegrant in amount from about 1% to 10% w/w, optionally a binder in an amount from about 1% to about 10% w/w, optionally a stabilizer in an amount from about 0.5 to 10 % w/w, one or more lubricants in an amount from about 0.1% to about 5 % w/w, glidant in an amount from about 0.1 to about 5 % and optionally film forming substance in an amount from about 1.0% to about 10% w/w of the composition.

In an aspect of the embodiment, the composition comprises Sitagliptin phosphate monohydrate, Dapagliflozin propanediol hydrate, one or more diluents selected from microcrystalline cellulose, anhydrous lactose, Calcium hydrogen phosphate anhydrous, silicified microcrystalline cellulose, optionally one or more binder selected from Povidone and hydroxypropyl cellulose, one or more disintegrant selected from croscarmellose sodium, and hydroxypropyl cellulose, optionally one or more stabilizer selected from L-cysteine and L-arginine, one or more lubricant selected from sodium stearyl fumerate, zinc stearate and magnesium stearate, colloidal anhydrous silica as a glidant and polyvinyl alcohol based coating material.

In one another aspect of the embodiment, the composition comprises 27.72 % w/w Sitagliptin phosphate monohydrate, 2.65 % w/w Dapagliflozin propanediol hydrate, 40.77 % w/w microcrystalline cellulose, 15.1 % w/w anhydrous lactose, 2.59 % w/w Povidone, 0.97 % w/w L-argmme, 2.91 % w/w croscarmellose sodium, 1.94 % w/w sodium stearyl fumerate, 1.46 % w/w zinc stearate, 0.97 % w/w colloidal anhydrous silica and 2.91 % w/w polyvinyl alcohol based coating material.

In one another aspect of the embodiment, the composition comprises 128.5 mg Sitagliptin phosphate monohydrate, 12.3 mg Dapagliflozin propanediol hydrate, 188.85 mg microcrystalline cellulose, 70 mg anhydrous lactose, 12 mg Povidone, 4.5 mg L-arginine, 13.5 mg croscarmellose sodium, 9 mg sodium stearyl fumerate, 6.75 mg zinc stearate, 4.5 mg colloidal anhydrous silica and 13.5 mg polyvinyl alcohol based coating material.

According to another embodiment of the invention, the pharmaceutical composition is in form of a bilayer tablet comprising Sitagliptin or a pharmaceutically acceptable salt thereof in amount from about 15% to about 40% w/w, Dapagliflozin or a pharmaceutically acceptable salt thereof in amount from about 1.0% to about 10% w/w, one or more diluents, each in amount from about 10 % to about 60 %, with the total diluent in the composition from about 30 % to about 80% w/w, disintegrant in amount from about 1% to 10% w/w, optionally a binder in an amount from about 1% to about 10% w/w, one or more lubricants in an amount from about 0.1% to about 5 % w/w, glidant in an amount from about 0.1 to about 5 % and optionally film forming substance in an amount from about 1.0% to about 10% w/w of the total weight of the composition.

In an aspect of the embodiment, the composition comprises a first layer comprising Sitagliptin phosphate monohydrate, microcrystalline cellulose, and calcium hydrogen phosphate anhydrous as diluents, Povidone as a binder, croscarmellose sodium as a disintegrant, sodium stearyl fumerate and magnesium stearate as lubricants, and a second layer comprising Dapagliflozin propanediol hydrate, microcrystalline cellulose and lactose anhydrous as diluents, hydroxypropyl cellulose as a disintegrant, zinc stearate as a lubricant, colloidal anhydrous silica as a glidant and polyvinyl alcohol based coating material.

The pharmaceutical composition of the present invention can be obtained by a known conventional methods like direct compression, wet granulation, dry granulation, roller compaction or slugging, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion or like thereof. The wet granulation process may involve shear granulators (such as planetary mixers), high shear mixer granulators (such as Fielder or Diosna), twin screw granulators (such as ConsiGma) and Fluid Bed Granulators (such as Aeromatic or Glatt).

According to one embodiment, the pharmaceutical compositions can be prepared by a direct compression process comprising the steps of: (i) blending Dapagliflozin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; (ii) blending Sitagliptin or a pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (iii) blending the mixture obtained in step (i) with the mixture obtained in step (ii) and at least one pharmaceutically acceptable excipient; (iv) finally compressing the mixture obtained in step (iii) into tablets which can be then optionally coated.

According to another embodiment, the pharmaceutical compositions can be prepared by wet granulation method comprising the steps of: i) Co-sifting followed by blending Sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient to form a dry mix ii) preparing binder solution by dissolving a binder and optionally a stabilizer in a granulation liquid, iii) granulating the dry mix obtained in step (i) with binder solution of step (ii) to form a wet granulate, iv) drying & sizing the wet granulate obtained in step (iii) to form dried granules v) Co-sifting and blending Dapagliflozin or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient vi) mixing the dried granulate obtained in step (iv) with powder mix of step (v) vii) lubricating the powder mix of step (vi) and viii) compression of powder mix of step (vii) to obtain the tablet, ix) coating the tablets.

According to an alternate aspect of the embodiment, Dapagliflozin is present intra-granularly and Sitagliptin is present extra-granularly. In another alternate aspect, both Sitagliptin and Dapagliflozin are present intra-granularly. In yet another alternate aspect both Sitagliptin and Dapagliflozin are present extra- granularly. According to one another aspect of the invention, wet granulation can be earned out in rapid mixer granulator or can be carried out in fluidized bed granulator, wherein either Sitagliptin or Dapagliflozin or both can either be present in the dry mix or can be dissolved in the binder solution.

According to another alternate aspect of the embodiment, either Sitagliptin or Dapagliflozin or both can also be added in coating dispersion and coated over inert core tablets.

According to another embodiment, the pharmaceutical compositions can be prepared by dry granulation method comprising the steps of: i) preparing a powder mixture containing Dapagliflozin or a pharmaceutically acceptable salt thereof, Sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient, ii) compacting the powder mixture obtained in step (i) to form a compact/slug/ribbon, iii) converting the compact/slug/ribbon obtained in step (ii) into a granulate, iv) optionally mixing the granulate obtained in step (iii) with a pharmaceutical excipient, and v) subjecting the granulate obtained in step (iii) or the mixture obtained in step (iv) to compression to obtain the tablet.

According to another embodiment, the bi-layer pharmaceutical compositions can be prepared by direct compression or granulation methods such as wet or dry granulation comprising the steps of: i) preparing a granules containing Sitagliptin or a pharmaceutically acceptable salt thereof and pharmaceutical excipients by dry granulation or wet granulation methods, and ii) preparing a powder mixture containing Dapagliflozin or a pharmaceutically acceptable salt thereof and pharmaceutical excipients iii) subjecting the granules obtained in step (i) and step (ii) to compression to obtain the tablet. Alternatively, the Sitagliptin layer and Dapagliflozin layer prepared different techniques can also be compressed into tablet.

The pharmaceutical composition of the present invention can be preferably packed into blisters or bottles or a like thereof. Preferred blisters are made of material or laminate, which ensures high protection against humidity, oxygen and UV radiation. It is preferred that blisters are made of PVC, OPA (oriented polyamide), aluminium foil, PCTFE (e.g. Aclar), PVDC (polyvinylidene chloride), PVDC-coated PVC, PVC/PE/PCTFE laminate, CFF (Cold-Form Foil), COC (Cyclic Olefin Copolymer) or combination thereof.

According to one embodiment, the combination pharmaceutical composition of Sitagliptin and Dapagliflozin exhibits bioequivalent plasma profile in comparison to marketed individual products of Sitagliptin and Dapagliflozin. The pharmaceutical composition of the present invention can be used in the treatment of diabetes mellitus by administering effective amount of pharmaceutical compositions to the patient.

The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLES

Example 1: Single layer tablets of Sitagliptin and Dapagliflozin by direct compression

Single layer tablets of fixed dose combination of Sitagliptin and Dapagliflozin were first prepared by direct compression method using routinely used excipients.

Tablet 1: Composition of single layer tablets prepared by direct compression

Manufacturing Process (DC-1): i. Sitagliptin phosphate monohydrate, calcium hydrogen phosphate, cysteine and part quantity of microcrystalline cellulose were sifted together through a suitable sieve, Dapagliflozin propanediol monohydrate, part quantity of microcrystalline cellulose were sifted together through a suitable sieve, both the materials were mixed in a blender for suitable time. ii. Croscarmellose sodium and remaining quantity of microcrystalline cellulose were sifted together and were mixed with the material of step I in a blender. iii. Zinc stearate and magnesium stearate were sifted through a suitable sieve and were mixed with material of step ii in a blender for suitable time. iv. Tablets were compressed using lubricated blend of step iii. v. Coating dispersion was prepared by dispersing opadry in purified water and the compressed tablets of step vii were coated in an auto coater.

• Tablets of batches DC-2 and DC-3 were similarly prepared using direct compression method.

• Excessive rat-holing, poor flow and sticking was observed for all batches and thus direct compression method was not found to be suitable for formulation of FDC containing Sitagliptin and Dapagliflozin.

Example 2: Single layer tablets of Sitagliptin and Dapagliflozin by wet granulation

The manufacturing problems observed with direct compression method were overcome by using wet granulation method. Tablet 2: Composition of single layer tablets prepared by wet granulation

Manufacturing Process (WG-8): i. Sitagliptin phosphate monohydrate, microcrystalline cellulose (dry mix part) were co-sifted through suitable sieve and were loaded in Fluid bed processor. ii. Binder solution was prepared by dissolving Povidone in water, the dry mix part of step i was then granulated with prepared binder solution in a fluid bed processor, the granules were then dried to desire LOD and were sifted. iii. Dapagliflozin, part of anhydrous lactose, and colloidal anhydrous silica were co-sifted through suitable sieve and were collected in a polybag. iv. Powder material of step iii was co-sifted with croscarmellose sodium and part of anhydrous lactose and was then mixed it with dried granules of step ii in a blender for suitable time. v. Remaining part of anhydrous lactose, microcrystalline cellulose was co-sifted and was mixed with blend of step iv in a blender for suitable time. vi. Sodium stearyl fumerate and zinc stearate were sifted through suitable sieve and were mixed with material of step v in a blender for suitable time. vii. Tablets were compressed using lubricated blend of step vi. viii. Coating dispersion was prepared by dispersing opadry in purified water and the compressed tablets of step vii were coated with prepared coating dispersion in an auto coater.

• Tablets of WG-4, WG-6 and WG-7 batches were similarly prepared using wet-granulation method. Example 3: In-vitro dissolution study of batch WG-4, WG-6, WG-7 & WG-8 The tablets of batch WG-4, WG-6, WG-7 and WG-8 were evaluated for in-vitro dissolution using USP paddle type apparatus in 900 ml of 0.1 N HC1 & pH 6.8 phosphate buffer at 50 RPM. The tablets of batch WG-4, and WG-6 showed slower dissolution for the Dapagliflozin part, which could be attributed to the presence of calcium hydrogen phosphate in the formulation. The concentration of calcium hydrogen phosphate anhydrous was reduced in batch WG-7, but still the dissolution of Dapagliflozin was slower. The dissolution of Dapagliflozin was improved and was much faster in batch WG-8, wherein anhydrous lactose was used as a diluent in place of calcium hydrogen phosphate anhydrous.

Table 3: In-vitro dissolution of WG-4, 6, 7 & 8 in 0.1 N HC1

Tablet 4: In-vitro dissolution of WG-4, 6, 7 & 8 in pH 6.8 phosphate buffer

Example 4: Bilayer Tablets of Sitagliptin and Dapagliflozin (WG-9)

Bilayer tablets were prepared in batch WG-9 as per below table. Table 5: Composition of bilayer tablets

Manufacturing Process:

A. Sitagliptin Blend Preparation: i. Sitagliptin phosphate monohydrate, calcium hydrogen phosphate and microcrystalline Cellulose (dry mix part) were co-sifted through suitable sieve and were loaded in fluidized bed processor. ii. Binder solution was prepared by dissolving Povidone in water, the dry mix part of step i was granulated with the binder solution in the fluid bed processor, the prepared granules were dried to desire LOD and were sifted through suitable sieve. iii. Microcrystalline cellulose and croscarmellose sodium were co-sifted through suitable sieve and were mixed with granules of step ii. iv. Sodium stearyl fumerate and magnesium stearate were sifted through suitable sieve and were mixed with blend of step iii to prepare lubricated blend.

B. Dapagliflozin Blend Preparation: i. Dapagliflozin propanediol monohydrate, part quantity of anhydrous lactose and colloidal anhydrous silica were co-sifted through suitable sieve. ii. Remaining quantity of anhydrous lactose, microcrystalline cellulose and L- HPC LH-11 were co-sifted through suitable sieve. iii. Powder of step i & ii were mixed in a blender for suitable time. iv. Zinc stearate was sifted through a suitable sieve and was mixed with the blend of step iii in a blender for a suitable time.

C. Tablet Compression: Bi-layer tablets were compressed using first layer of Sitagliptin blend and second layer of Dapagliflozin blend in a bilayer compression machine.

D. Film-coating: A homogenous coating dispersion was prepared by dissolving PVA based Opadry in purified water, the bi-layer tablets were then coated using the prepared dispersion in an auto coater.

Table 6: In-vitro dissolution study of Batch WG-9 in 0.1 N HC1

Example 5: Single layer tablets of Sitagliptin and Dapagliflozin with stabilizer (WG-10):

Based on results of in-vitro dissolution, batch WG-8 was selected for further study and was formulated with a stabilizer to increase the stability of the formulation & reduce the generation of impurities. The tablets of batch WG-10 were formulated by wet granulation method using similar process as WG-8.

Table 7: Composition of single layer tablets with stabilizer

Example 6: Evaluation of batch WG-10

The tablets of batch WG-10 were evaluated for content uniformity and for in-vitro dissolution using USP paddle type apparatus in 900 ml of 0.1 N HC1 & pH 6.8 phosphate buffer at 50 RPM. The results of content uniformity study clearly indicate that despite the difference between dose, flow properties, density and other physic-chemical properties between Sitagliptin and Dapagliflozin, optimum content uniformity was achieved suggesting robustness of manufacturing process.

Table 8: Results of content uniformity of batch WG-10

The results of in-vitro dissolution study clearly shows optimum drug dissolution of both Sitagliptin and Dapagliflozin in 0.1 N HC1 as well as in pH 6.8 phosphate buffer. More than 85 % Sitagliptin and about same % of Dapagliflozin was released from the tablet within 15 minutes, whereas more than 90 % Sitagliptin and about the same % of Dapagliflozin were released from the tablets at the end of 45 minutes.

Table 9: Results of in-vitro dissolution study of batch WG-10

Example 7: Accelerated stability studies of batch WG-10

The optimized batch WG-10 was exposed to accelerated stability analysis. The tablets were packaged in Alu-Alu packaging and were stored at 40 °C/75 % RH. The tablets were evaluated at initial and after 1 month for any increase in any known, unknown and total impurities for both Sitagliptin and Dapagliflozin. The tablets were also characterized for assay and in-vitro dissolution in 0.1 N HC1.

Table 10: Accelerated stability studies of WG-10

There was no increase in any of the known or unknown or the total impurities of Sitagliptin and Dapagliflozin despite the inherent incompatibilities, degradation problems, or extraction problems observed in case of DPP-IV inhibitors with primary or secondary amino group when formulated along with another drugs or number of customary excipients. The assay and in-vitro drug dissolution was also unchanged for both Sitagliptin and Dapagliflozin after 1 month.

Claims

We claim:

1. A stable pharmaceutical composition comprising combination of Sitagliptin or pharmaceutically acceptable salt or solvate thereof with Dapagliflozin or pharmaceutically acceptable salt or solvate thereof and at least one or more pharmaceutically acceptable excipients.

2. The stable pharmaceutical composition as claimed claim 1, wherein the pharmaceutical composition comprises a first portion and a second portion wherein the first portion comprises Sitagliptin or pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient; the second portion comprises Dapagliflozin or pharmaceutically acceptable salt or solvate thereof and at least one or more pharmaceutically acceptable excipients.

3. The stable pharmaceutical composition as claimed in claim 1 or 2, wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluent, binder, disintegrant, stabilizer, lubricant, glidant, coloring agent, flavoring agent, film coating agent or a combination thereof.

4. The stable pharmaceutical composition as claimed in claimed 3, wherein the composition comprises Sitagliptin or pharmaceutically acceptable salt or solvate thereof with Dapagliflozin or pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable stabilizer.

5. The stable pharmaceutical composition as claimed in claim 4, wherein the stabilizer is selected from the group consisting of acidic agent, alkalizing agent, buffering agent, amino acid, anti-oxidant or a combination thereof.

32 The stable pharmaceutical composition as claimed in claim 5, wherein the stabilizer is an amino acid selected from L-cysteine and L- arginine. The stable pharmaceutical composition according to any of the previous claims, wherein the composition is in the form of single layer or bilayer tablet. The stable pharmaceutical composition according to any of the previous claims, wherein the composition when stored at 40°C and 75% relative humidity has not more than 0.2 % of any known or unknown individual impurity and has not more than 2% of total impurity. The stable pharmaceutical composition according to any of the previous claims, wherein at least 75% of Sitagliptin and Dapagliflozin are released within 30 minutes. The stable pharmaceutical composition according to any of the previous claims, wherein the composition comprises 20-40 % w/w Sitagliptin, 1-10 % w/w Dapagliflozin, 30-80 % w/w of diluent, 1-10 % w/w of disintegrant, 1-10 % w/w binder, 0-10 % w/w stabilizer, 0.1-5 % lubricant, 0.1-5 % w/w glidant, 1-10 % w/w of film former of the total weight of the composition.

33