Composition comprising dapagliflozin and sitagliptin, and method of preparation thereof

Abstract

The present disclosure relates to a pharmaceutical composition comprising dapagliflozin and sitagliptin, and method of preparation thereof. More particularly, dapagliflozin is present as dapagliflozin propanediol monohydrate, and sitagliptin is present as sitagliptin phosphate monohydrate. Furthermore, the present disclosure provides methods including wet granulation, dry granulation and direct compression for preparing fixed dose composition(s). The fixed dose composition is available in solid oral dosage forms, such as a tablet, capsule or sachet, wherein the tablet can be monolayer or bilayer tablet. The said composition is uniform, effective, stable to simplify management regimens, enhance subject adherence, and provide sustained glycaemic control in management of Type 2 Diabetes Mellitus.

Description

[0001] COMPOSITION COMPRISING DAPAGLIFLOZIN AND SITAGLIPTIN, AND METHOD OF PREPARATION THEREOF

[0002] PRIORITY CLAIM

[0003] The instant patent application is related to and claims priority from the Indian provisional patent application entitled, “COMPOSITION COMPRISING DAPAGLIFLOZIN AND SITAGLIPTIN, AND METHOD OF PREPARATION THEREOF”, Patent Application no: 202441066732, Filed on: September 4th, 2024, which is incorporated in its entirety herewith.

[0004] TECHNICAL FIELD OF THE DISCLOSURE

[0005]

[0001] The present disclosure is in the technical field of a pharmaceutical composition comprising a SGLT2 inhibitor, DPPIV inhibitor and one or more pharmaceutically acceptable excipients. More particularly, the SGLT2 inhibitor is dapagliflozin and DPPIV inhibitor is sitagliptin. Furthermore, the present disclosure provides a method for preparing a fixed-dose combination (FDC) comprising dapagliflozin and sitagliptin and one or more pharmaceutically acceptable excipients.

[0006] BACKGROUND OF THE DISCLOSURE

[0007]

[0002] Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder characterized by insulin resistance, impaired insulin secretion, and increased hepatic glucose production, resulting in elevated blood glucose levels. The global prevalence of T2DM has increased significantly in recent decades, posing a substantial burden on healthcare systems worldwide. Effective glycaemic control is crucial to prevent long-term complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy.

[0008]

[0003] Diabetes requires more than one drug to manage it effectively. Generally, subjects with diabetes are often prescribed two to three different drugs to achieve adequate glycaemic control. Managing multiple medications can be challenging, often resulting in missed doses.

[0009]

[0004] As diabetes progresses, managing the blood glucose levels with a single medication becomes difficult which may result in serious complications. Specifically, elderly diabetic subjects are more prone to serious complications like high blood pressure, obesity, and hyperlipidaemia.

[0005] Monotherapy is often insufficient to achieve and maintain target glycaemic levels in many subjects with T2DM due to the complex nature of the disease. As such, combination therapy targeting different pathophysiological mechanisms is commonly employed to enhance treatment efficacy. Among various pharmacological classes, sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors are important therapeutic agents for the management of T2DM due to their complementary mechanisms of action and favourable safety profiles.

[0010]

[0006] Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor that lowers plasma glucose by inhibiting glucose reabsorption in the proximal tubules of the kidneys, resulting in increased urinary glucose excretion.

[0011]

[0007] Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that works by increasing endogenous levels of incretin hormones such as GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), enhancing insulin secretion and decreasing glucagon release in a glucose-dependent manner.

[0012]

[0008] EP4162929 Al discloses a composite formulation, wherein said formulation comprises dry granules of sitagliptin and dapagliflozin along with sodium stearyl fumarate as a lubricant in an amount ranging from 1 wt% to 5 wt% of sodium stearyl fumarate, based on the total weight of the composite formulation. The prior art discloses dry granulation of both dapagliflozin and sitagliptin. It does not teach about separate preparations of the active ingredients to obtain a stable formulation.

[0013]

[0009] WO2023012817A1 discloses a 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. The prior art discloses formulations that rely on stabilizers such as L-arginine or L-cysteine to ensure dapagliflozin stability, as well as approaches where dapagliflozin is processed in the extra-granular portion or subjected to dry granulation.

[0014]

[0010] WO2023113488A1 discloses a pharmaceutical combination comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amount ranging from 35% to 50% by weight based on the total weight of the whole pharmaceutical combination. The prior art describes wet granulation of dapagliflozin in the presence of a binder solution. Binder-mediated granulation usually requires longer processing time, solvent handling, and potential stability concerns.

[0015] [OH] The prior art documents disclose combination formulation of dapagliflozin and sitagliptin. Further, the prior art also discloses that the combination of dapagliflozin and sitagliptin offers synergistic approach to T2DM management by targeting renal and hormonal pathways to achieve better glycaemic control without significantly increasing the risk of adverse effects. The clinical studies have also shown that co-administration of dapagliflozin and sitagliptin leads to superior glycaemic control compared to either agent alone and may improve adherence and convenience when formulated into a fixed-dose combination.

[0016]

[0012] Despite the known therapeutic advantages, there are technical challenges in developing a stable fixed-dose combination (FDC) of dapagliflozin and sitagliptin, including differences in their physicochemical properties, stability profiles, and processing requirements. Dapagliflozin is known to be sensitive to humidity and may require protection against degradation, while sitagliptin may have specific formulation and compatibility concerns when co-formulated.

[0017]

[0013] Moreover, existing methods for producing compositions comprising dapagliflozin and sitagliptin exhibit batch-to-batch variations. Since dapagliflozin is present in a very small dose, its uniform distribution is often difficult to achieve, leading to poor reproducibility and inconsistency in the final product. While such variations may appear negligible at a small scale, they become significant during large-scale manufacturing, resulting in substantial differences between compositions.

[0018]

[0014] Making a composite formulation that meets all the desired parameters such as commercial productivity, drug dissolution, stability during shelf life and bioequivalence to marketed products is the challenging task.

[0019]

[0015] Therefore, there is a pressing need for developing a uniform, effective, stable fixed- dose pharmaceutical composition meeting the parameters including commercial productivity, drug dissolution, stability during shelf life and bioequivalence to commercial products for simplifying management regimens, enhancing subject adherence, and exhibiting sustained glycaemic control in management of Type 2 Diabetes Mellitus. OBJECTIVES OF THE PRESENT DISCLOSURE

[0020]

[0016] The primary objective of the present disclosure is to provide a fixed-dose combination (FDC) pharmaceutical composition comprising dapagliflozin and sitagliptin for the effective management of type 2 diabetes mellitus.

[0021]

[0017] Another objective of the present disclosure is to provide a process for preparing the fixed-dose combination pharmaceutical composition in solid oral dosage forms, such as tablets, capsule or sachet.

[0022]

[0018] Yet another objective of the present disclosure is to provide physically and chemically stable fixed-dose combination of dapagliflozin and sitagliptin.

[0023]

[0019] Still another object of the present disclosure is to provide fixed dose combination for enhanced subject compliance and convenience by reducing pill burden through a single oral dosage form containing both dapagliflozin and sitagliptin.

[0024] SUMMARY OF THE DISCLOSURE

[0025]

[0020] According to one embodiment, a pharmaceutical composition comprising, dapagliflozin or a pharmaceutically acceptable salt thereof; and sitagliptin or a pharmaceutically acceptable salt thereof; wherein the composition is formulated as a solid dosage form for oral administration.

[0026]

[0021] According to another embodiment, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from diluents, disintegrant, lubricants, glidants and coating agents.

[0027]

[0022] According to yet another embodiment, wherein the diluents are selected from mannitol, microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate; preferably, mannitol, microcrystalline cellulose and dibasic calcium phosphate.

[0028]

[0023] According to another embodiment, wherein the disintegrants are selected from croscarmellose sodium, sodium starch glycolate, crospovidone; preferably, croscarmellose sodium and crospovidone.

[0029]

[0024] According to yet another embodiment, wherein the lubricants are selected from magnesium stearate, sodium stearyl fumarate, stearic acid; preferably, sodium stearyl fumarate and magnesium stearate.

[0030]

[0025] According to one embodiment, wherein the glidants are selected from colloidal silicon dioxide, talc; preferably, colloidal silicon dioxide.

[0026] According to another embodiment, wherein the coating agents are selected from polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, hydroxypropyl methylcellulose (HPMC), iron oxide etc., or combination thereof.

[0031]

[0027] According to yet another embodiment, wherein the dapagliflozin is present as dapagliflozin propanediol monohydrate, and wherein the sitagliptin is present as sitagliptin phosphate monohydrate.

[0032]

[0028] According to another embodiment, wherein the weight ratio of dapagliflozin to sitagliptin is in the range of 1 :5 to 1 :40.

[0033]

[0029] According to yet another embodiment, wherein the solid dosage form is selected from a tablet, capsule or sachet.

[0034]

[0030] According to another embodiment, wherein the tablet is monolayer tablet or bilayer tablet.

[0035]

[0031] According to yet another embodiment, wherein the composition is prepared by wet granulation or direct compression, dry granulation or roller compaction or slugging. According to another embodiment, a method for preparing a pharmaceutical composition comprising a fixed dose combination of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof, wherein the method comprises steps of a) dissolving dapagliflozin propanediol monohydrate in an organic solvent; b) adsorbing dissolved drug solution from step (a) onto microcrystalline cellulose or mannitol or colloidal silicon dioxide or combinations thereof; c) obtaining a blend ‘A’; drying the blend from step (b) to remove the organic solvent; d) transferring the blend in a blender with a disintegrant and a lubricant to obtain granules ‘A’, e) sifting sitagliptin phosphate monohydrate, microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate; f) subjecting the mixture from step (e) to roller compaction to obtain granules ‘B’; g) mixing blend ‘A’ obtained in step (c) and granules ‘B’ obtained from step (f); compressing to obtain a monolayer tablet; and / or h) compressing the granules ‘A’ obtained in step (d) and granules ‘B’ obtained from step (f) into a bilayer tablet; i) coating the tablet with a coating material selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide, and colourant such as iron oxide; and j) packing the tablets in packaging material selected from blister foil or bottle.

[0036]

[0032] According to yet another embodiment, wherein the organic solvent is selected from ethanol, isopropyl alcohol, dimethylsulfoxide (DMSO), and dimethylformamide, preferably, isopropyl alcohol.

[0037]

[0033] According to another embodiment, the monolayer tablet, comprising: a) the dapagliflozin propanediol monohydrate as dapagliflozin is present in doses of 2.5 mg,

[0038] 5 mg, or 10 mg comprising mannitol or microcrystalline cellulose; and b) the sitagliptin phosphate monohydrate as sitagliptin is present in doses of 25mg, 50mg or lOOmg comprising microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; c) croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate; wherein the monolayer tablet is coated with coating material and packed in blister foil or bottle; wherein the monolayer tablet provides immediate release of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof; wherein (a), (b) and (c) are present within a single layer.

[0039]

[0034] According to yet another embodiment, the bilayer, comprising: a) a layer comprising the granules of dapagliflozin or a pharmaceutically acceptable salt thereof; b) another layer comprising the granules of sitagliptin or a pharmaceutically acceptable salt thereof; and c) one or more pharmaceutically acceptable excipients in each layer; wherein the bilayer tablet provides immediate release of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof; wherein both layers are physically separated from each other.

[0040]

[0035] According to another embodiment, the bilayer tablet, comprising: a) the granules of dapagliflozin propanediol monohydrate as dapagliflozin is present in doses of 2.5 mg, 5 mg, or 10 mg in a one layer comprising mannitol or microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and b) the granules of sitagliptin phosphate monohydrate as sitagliptin is present in doses of 25mg, 50mg or lOOmg in another layer comprising microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; wherein the bilayer tablet is coated with coating material and packed in blister foil or bottle.

[0036] According to yet another embodiment, wherein the composition is in the form of a capsule, comprising: a) the dapagliflozin propanediol monohydrate, b) the sitagliptin phosphate monohydrate, and c) one or more pharmaceutically acceptable excipients, wherein the capsule is for oral administration and provides a fixed-dose combination of dapagliflozin and sitagliptin.

[0041]

[0037] According to another embodiment, wherein the capsule comprises of the pharmaceutically acceptable excipients; wherein the excipients are diluents selected from mannitol, microcrystalline cellulose and dibasic calcium phosphate; disintegrants selected from croscarmellose sodium and crospovidone; lubricants selected from sodium stearyl fumarate and magnesium stearate; glidant selected from colloidal silicon dioxide.

[0042]

[0038] According to yet another embodiment, wherein the capsule is a hard gelatine capsule or non-gelatine capsule.

[0043]

[0039] According to another embodiment, wherein the capsule comprises the combination of granules, blend, powder, beads, mini tablets or tablet of dapagliflozin propanediol monohydrate and sitagliptin phosphate monohydrate.

[0044]

[0040] According to yet another embodiment, wherein the pharmaceutical composition exhibits a dissolution profile, wherein at least 50% w / w of dapagliflozin and at least 70% w / w of sitagliptin is dissolved within 10 minutes.

[0045]

[0041] According to another embodiment, wherein the pharmaceutical composition release at least 80% each of dapagliflozin and sitagliptin within 30 minutes.

[0046]

[0042] According to yet another embodiment, a method of managing a condition in a subject; wherein the said condition is Type 2 Diabetes Mellitus; wherein the said method comprising act of administering composition comprising dapagliflozin or a pharmaceutically acceptable salt thereof, sitagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients to the subject in need thereof.

[0043] According to another embodiment, wherein the subject is an animal or a human being.

[0047]

[0044] According to yet another embodiment, wherein administration of a single oral dose of the composition in human subjects exhibits a maximum plasma concentration Cmax of dapagliflozin of 91.639 ± 22.8558 pg / mL, and a Cmax of sitagliptin of 308.194 ± 59.4823 pg / mL, under fasting conditions.

[0048]

[0045] According to another embodiment, wherein the composition when administered orally to a human subject in a fasting state, provides a pharmacokinetic profile characterized by an AUCo-tof dapagliflozin of 571.571 ± 151.3448 hr. pg / mL; and an AUCo-t of sitagliptin is 3703.920 ± 484.1193 hr. pg / mL.

[0049]

[0046] According to yet another embodiment, wherein the composition when administered orally to a human subject in a fasting state, provides a pharmacokinetic profile that is bioequivalent to the co-administration of separate immediate-release formulations (reference products) of dapagliflozin and sitagliptin, as determined by the ratio of the geometric means of AUCo-co for dapagliflozin is 604.134 ± 152.3982 hr. pg / mL; and the ratio of the geometric means of AUCo-co for sitagliptin is 3765.609 ± 478.6945 hr. pg / mL.

[0047] Several aspects of the disclosed embodiment are described below with reference to examples for illustration. However, one skilled in the relevant art will recognize that the disclosed embodiment can be practiced without one or more of the specific details or with other methods, components, materials and so forth. In other instances, well-known structures, materials, or operations are not shown in detail to avoid obscuring the features of the disclosed embodiment. Furthermore, the features / aspects described can be practiced in various combinations, though only some of the combinations are described herein for conciseness.

[0050] BRIEF DESCRIPTION OF THE DRAWINGS

[0051]

[0048] Example embodiments of the disclosed embodiment will be described with reference to the accompanying drawings briefly described below.

[0052]

[0049] FIG.l illustrates a method for preparation of a tablet comprising dapagliflozin and sitagliptin by direct compression, according to the aspects of the present disclosure.

[0053]

[0050] FIG.2 illustrates a method for preparation of tablet comprising dapagliflozin and sitagliptin by wet granulation and dry granulation, according to the aspects of the present disclosure.

[0051] FIG.3 illustrates a method for preparation of capsules comprising dapagliflozin and sitagliptin, according to the aspects of the present disclosure.

[0054]

[0052] FIG.4A illustrates the pharmacokinetics profile comprising Cmax, AUCo-t and AUCo- co values for dapagliflozin in Example formulation 3, according to the aspects of the present disclosure.

[0055]

[0053] FIG.4B illustrates the plasma concentration time curve (mean vs time curve) obtained for dapagliflozin in Example formulation 3, according to the aspects of the present disclosure.

[0056]

[0054] FIG .5A illustrates the pharmacokinetics profile comprising Cmax, AUCo-t and AUCo- co values for sitagliptin in Example formulation 3, according to the aspects of the present disclosure.

[0057]

[0055] FIG.5B illustrates the plasma concentration time curve (mean vs time curve) obtained for sitagliptin in Example formulation 3, according to the aspects of the present disclosure.

[0058]

[0056] In the drawings, like reference numbers generally indicate identical, functionally similar, and / or structurally similar elements. The drawing in which an element first appears is indicated by the leftmost digit(s) in the corresponding reference number.

[0059] DETAILED DESCRIPTION OF THE DISCLOSURE

[0060]

[0057] It is to be understood that the present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0061]

[0058] The use of “including”, “comprising” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. Further, the use of terms “first”, “second”, and “third”, and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. Further, the terms “comprising,” “including,” “having,” and the like, as used with respect to embodiments of the present disclosure, are synonymous. As used herein, the terms “agent,” “component,” or “ingredient” are used interchangeably and refer to a particular item that includes one or more chemical compounds (e.g., a food item from one or more plants that comprise one or more naturally occurring chemical compounds).

[0062]

[0059] The term “component” or “ingredient” as used herein, refers to a particular item that includes one or more chemical compounds, i.e., edible compounds sourced from plants, fungi or algae that comprise one or more naturally occurring chemical compounds.

[0063]

[0060] Alternative embodiments of the present disclosure and their equivalents may be devised without parting from the spirit or scope of the present disclosure. It should be noted that any discussion herein regarding “one embodiment”, “an embodiment”, “an exemplary embodiment”, and the like indicate that the embodiment described may include a particular feature, structure, or characteristic and that such particular feature, structure, or characteristic may not necessarily be included in every embodiment. In addition, references to the foregoing do not necessarily comprise a reference to the same embodiment. Finally, irrespective of whether it is explicitly described, one of ordinary skill in the art would readily appreciate that each of the particular features, structures, or characteristics of the given embodiments may be utilized in connection or combination with those of any other embodiment discussed herein.

[0064]

[0061] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise. By way of example, “a dosage” refers to one or more than one dosage.

[0065]

[0062] The terms “comprising”, “comprises” and “comprised of’ as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps.

[0063] All documents cited in the present specification are hereby incorporated by reference in their totality. In particular, the teachings of all documents herein specifically referred to are incorporated by reference.

[0066]

[0064] Example embodiments of the disclosed embodiments are described with reference to the accompanying figures.

[0067]

[0065] In the drawings, like reference numbers generally indicate identical, functionally similar, and / or structurally similar elements. The drawing in which an element first appears is indicated by the leftmost digit(s) in the corresponding reference number.

[0068]

[0066] DEFINITIONS

[0069]

[0067] The term “Dapagliflozin” refers to an oral medication used to manage Type 2 diabetes mellitus. It belongs to a class of drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors.

[0068] The term “Sitagliptin” refers to an oral medication used to manage Type 2 diabetes mellitus. It belongs to a class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors.

[0069] The term “Sodium glucose cotransporter-2 (SGLT2) inhibitors” refers to a class of inhibitors used primarily to manage type 2 diabetes. They work by inhibiting the SGLT2 protein in the kidneys, which is responsible for reabsorbing glucose back into the bloodstream.

[0070]

[0070] The term “Dipeptidyl peptidase-4 (DPP-4) inhibitors” refers to a class of inhibitors that works by increasing endogenous levels of incretin hormones such as GLP-1 (glucagon- like peptide- 1) and GIP (glucose-dependent insulinotropic polypeptide), enhancing insulin secretion and decreasing glucagon release in a glucose-dependent manner.

[0071]

[0071] The term “Pancreatic beta cells” refers to a specialized cells located in the islets of Langerhans in the pancreas.

[0072]

[0072] The term “GLP-1” refers to an incretin hormone produced in the intestines. It plays a key role in regulating blood glucose levels through several mechanisms.

[0073]

[0073] The term “Hyperlipidemia” refers to a condition characterized by elevated levels of lipids (fats) in the blood, including cholesterol and triglycerides.

[0074]

[0074] The terms “composition” and “formulation” are interchangeably used in the disclosure.

[0075]

[0075] The term “Active pharmaceutical ingredients (API)” refers to the component of a drug that is biologically active and responsible for the intended therapeutic effect. In pharmaceutical formulations, the API is combined with excipients (inactive substances) to make the final product.

[0076]

[0076] The term “excipient” refers to an inactive substance used in pharmaceutical formulations to support the delivery of the active ingredient.

[0077]

[0077] The term “direct compression” refers to a method used in pharmaceutical manufacturing to produce tablets or other dosage forms directly from powdered ingredients without the need for granulation.

[0078]

[0078] The term “roller compaction” refers to a process used in pharmaceutical manufacturing to produce granules or powders through a roller compactor without the need for liquid binders. It is a dry granulation process.

[0079]

[0079] The term “wet granulation” refers to a process used in pharmaceutical manufacturing to produce granules with liquid binders for obtaining a uniform and stable composition.

[0080] The term “blend” refers to a mixture of powders (API + excipients) to achieve content uniformity.

[0080]

[0081] The term “granule” refers to agglomerates of powder particles prepared to improve flowability, compressibility, and reduce segregation. They are typically formed during granulation processes (wet granulation, dry granulation, or melt granulation etc.).

[0081]

[0082] The term “commercial productivity” refers to the efficiency and effectiveness with which a company can produce and bring its products to market in pharmaceutical industry.

[0082]

[0083] The term “synergistic effect” refers when two or more substances or factors work together to produce an effect that is greater than the sum of their individual effects. This concept is commonly observed in pharmacology, where the combined effect of two drugs can be more potent or beneficial than each drug taken alone.

[0083]

[0084] The term “%w / w” refers percentage weight / weight, it is a way of expressing the concentration of a component in a mixture or solution.

[0084]

[0085] The term “monolayer tablet” refers to a single layer tablet comprising granules of dapagliflozin or a pharmaceutically acceptable salt, sitagliptin or a pharmaceutically acceptable salt along with pharmaceutically acceptable excipients.

[0085]

[0086] The term “bilayer tablet” refers to a tablet comprising two layers wherein one layer comprises dapagliflozin or a pharmaceutically acceptable salt and pharmaceutically acceptable excipients and another layer comprises sitagliptin or a pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the two layers are physically separated from each other.

[0086]

[0087] The term “stability study” refers to a study conducted to determine the quality, safety and efficacy throughout the shelf life of a pharmaceutical product.

[0087]

[0088] The term “dissolution study” refers to an in vitro study conducted to evaluate the rate of release of a drug substance from the dosage form. The study provides information to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, and to predict in vivo drug release profile.

[0088]

[0089] The term “pharmacokinetics” refers to a study of how the body interacts with administered substances for the entire duration of exposure.

[0089]

[0090] The term “subject” refers to a patient or human being or animal. The term subject is basically used for individual participated in studies. While the term patient is used for an individual already diagnosed for disease and recommended the specific drug for the treatment of said diseases.

[0091] The term “AUCo-t” refers to the area under the plasma concentration versus time curve from time zero to the last measurable concentration. This parameter quantifies drug exposure from administration up to the last measurable time point.

[0090]

[0092] The term “AUCo-co” refers to the area under the plasma concentration-time curve from zero to infinity. AUCo-co reflects theoretical total systemic exposure, integrating observed exposure (AUCo-t) plus an extrapolated component that accounts for elimination beyond the last measured point.

[0091]

[0093] The term “Cmax” refers to maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. Cmax reflects the highest measured concentration post-dosing. It is a crucial parameter for predicting onset of therapeutic effect and potential toxicity.

[0092]

[0094] The term “Bioequivalence” refers to a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug, assuming that they will provide the same therapeutic effect or that they are therapeutically equivalent.

[0095] The term “plasma concentration time curve (mean vs time curve)” refers to the graphical representation of the plasma concentration of a drug over time, which displays distinct phases: an initial rapid increase during the absorption phase, a rapid decline during the distribution phase, and a slower decline during the elimination phase.

[0093]

[0096] The term “blend uniformity” refers to assessment of uniform distribution of an active pharmaceutical ingredient (API) within the powder blend / mixture prior to manufacturing dosage forms. It's a critical factor to determine problems such as poor mixing and inconsistent dosing in the final product.

[0094]

[0097] The term “content uniformity” refers to a measure of the consistency of API content in individual dosage units (e.g., tablets / capsules). It ensures each unit delivers the intended dose within pharmacopeial limits.

[0095]

[0098] The term “RSD” refers to Relative Standard Deviation expressed as a percentage of the mean. It quantifies variability relative to the mean or average. RSD helps determine how uniformly the active pharmaceutical ingredient (API) is distributed within a powder blend and ensures each tablet or capsule contains the right amount of drug.

[0096]

[0099] The term “Reference Product 1” refers to the commercially available Dapagliflozin.

[0097]

[0100] The term “Reference Product 2” refers to the commercially available Sitagliptin. 1) EMBODIMENTS OF THE DISCLOSURE

[0098]

[0101] The present disclosure provides a fixed-dose combination (FDC) pharmaceutical composition comprising dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof, for oral administration in the management of type 2 diabetes mellitus (T2DM).

[0099]

[0102] The present disclosure provides different formulation strategies to co-formulate dapagliflozin and sitagliptin in a single dosage form, to obtain a stable, pharmaceutically acceptable, and subject-compliant formulation.

[0100]

[0103] The pharmaceutical composition is formulated as a solid dosage form for oral administration.

[0101]

[0104] The present disclosure further provides fixed dose combination in solid dosage forms, including but not limited to tablets, capsules or sachet which offer a stable and effective option for delivery of both active pharmaceutical ingredients (APIs) to subjects, thereby improving glycaemic control, enhancing subject compliance, and reducing the pill burden.

[0102]

[0105] In another embodiment, the present disclosure provides a pharmaceutical composition comprising the granules of dapagliflozin or a pharmaceutically acceptable salt thereof; and the granules of sitagliptin or a pharmaceutically acceptable salt thereof; wherein the composition is formulated as a solid dosage form for oral administration, wherein the dapagliflozin is present as dapagliflozin propanediol monohydrate; and wherein the sitagliptin is present as sitagliptin phosphate monohydrate.

[0103]

[0106] (I) PHARMACEUTICAL COMPOSITION

[0104]

[0107] A pharmaceutical composition comprising, a) dapagliflozin or a pharmaceutically acceptable salt thereof; and b) sitagliptin or a pharmaceutically acceptable salt thereof;

[0105]

[0108] wherein the composition is formulated as a solid dosage form for oral administration.

[0106]

[0109] The composition further comprises one or more pharmaceutically acceptable excipients selected from diluents, disintegrant, lubricants, glidants and coating agents.

[0107] [HO] The afore mentioned composition is detailed in the following:

[0108]

[0111] a) Dapagliflozin or pharmaceutically acceptable salt thereof

[0109]

[0112] Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor that lowers plasma glucose by inhibiting glucose reabsorption in the proximal tubules of the kidneys, resulting in increased urinary glucose excretion. Dapagliflozin is chemically known as (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-

[0110] (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. It is generally used in the form of dapagliflozin propanediol monohydrate. Dapagliflozin is sensitive to hydrolytic degradation under humid conditions and requires formulation strategies that limit moisture exposure.

[0111]

[0113] b) Sitagliptin or pharmaceutically acceptable salt thereof

[0112]

[0114] Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that works by increasing endogenous levels of incretin hormones such as GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), enhancing insulin secretion and decreasing glucagon release in a glucose-dependent manner. This mechanism helps regulate postprandial glucose levels with minimal risk of hypoglycemia. Sitagliptin is chemically known as (3R)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3- a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one. It is generally used in the form of sitagliptin phosphate monohydrate. Sitagliptin is more stable than dapagliflozin under ambient conditions but is hygroscopic and may interact with certain excipients.

[0113]

[0115] c) Pharmaceutically acceptable excipients

[0114]

[0116] i) Diluents

[0115]

[0117] Diluents play a crucial role in increasing the bulk of the tablet and addressing potential issues associated with the API, such as inadequate flowability, poor compaction properties, and capping. Diluents are selected from but not limited to mannitol, microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate (also referred as dicalcium phosphate). Preferably, the diluent is microcrystalline cellulose, mannitol and dicalcium phosphate.

[0116]

[0118] ii) Binders

[0117]

[0119] Binder or an adhesive is added to a powder blend to impart mechanical strength and cohesion to granules or tablets. Binders are selected from but not limited to povidone K30, hydroxypropyl cellulose, starch.

[0118]

[0120] iii) Disintegrants

[0119]

[0121] Disintegrants facilitate rapid break-up of a tablet into smaller fragments upon contact with aqueous fluids, promoting drug release for absorption. Disintegrants are selected from but not limited to croscarmellose sodium, sodium starch glycolate, crospovidone. Preferably, the disintegrant is croscarmellose sodium, crospovidone.

[0120]

[0122] iv) Lubricants

[0121]

[0123] Lubricants are the agents added to tablet and capsule formulations in a very small quantity to enhance the powder processing properties of formulations. Lubricants are selected from but not limited to magnesium stearate, sodium stearyl fumarate stearic acid. Preferably, the lubricant is sodium stearyl fumarate, magnesium stearate.

[0124] v) Glidants

[0122]

[0125] Glidants enhance the flow characteristics of powders or granules by reducing interparticle friction and cohesion. Glidants are selected from but not limited to colloidal silicon dioxide, talc. Preferably, the glidant is colloidal silicon dioxide.

[0123]

[0126] vi) Coating agents and colourants

[0124]

[0127] Coating agents are excipients used to protect the drug from moisture and light, masking unpleasant tastes and odours, and improving swallowability. Coating agents are selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide, and colourants such as but not limited to iron oxide.

[0125]

[0128] FORMS OF THE PHARMACEUTICAL COMPOSITION

[0126]

[0129] The fixed-dose combination of pharmaceutical composition may be presented in any of the following solid oral dosage forms such as monolayer tablet, bilayer tablet, capsule containing powder, beads, blend, tablet or mini-tablets, pellets, or granules, multiparticulate system with distinct compartments for each API, sachet containing the powder of fixed dose combination and one or more pharmaceutically acceptable excipients.

[0127]

[0130] According to embodiments of the disclosure, the pharmaceutical composition can be a monolayer or bilayer tablet:

[0128]

[0131] A) Monolayer Tablet

[0129]

[0132] In a preferred embodiment, the present disclosure provides a monolayer tablet comprising the blend or granules of dapagliflozin or a pharmaceutically acceptable salt thereof; the blend or granules of sitagliptin or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients; wherein the monolayer tablet provides immediate release of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof, wherein the weight ratio of the dapagliflozin to sitagliptin is in the range of 1 :5 to 1 :40.

[0130]

[0133] The pharmaceutically acceptable excipients are selected based on the stability, compressibility, flow properties, and compatibility with the APIs. The excipients used are selected from but not limited to diluents selected from but not limited to mannitol, microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate (dicalcium phosphate), disintegrants selected from but not limited to croscarmellose sodium, sodium starch glycolate, crospovidone, lubricants selected from but not limited to magnesium stearate, stearic acid, glidants selected from but not limited to colloidal silicon dioxide, talc, binders selected from but not limited to povidone K30, hydroxypropyl cellulose, starch, and coating agents selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide etc and colourants such as but not limited to iron oxide.

[0131]

[0134] In another embodiment, the present disclosure provides a monolayer tablet comprising the granules of dapagliflozin propanediol monohydrate as dapagliflozin in unit doses of 2.5mg, 5 mg, or 10 mg comprising mannitol or microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and the granules of sitagliptin phosphate monohydrate as sitagliptin in unit doses of 25mg, 50mg and lOOmg comprising microcrystalline cellulose, calcium dicalcium phosphate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; wherein the monolayer tablet is coated with coating material and colourants such as but not limited to iron oxide.

[0132]

[0135] In a few embodiments, the monolayer tablet comprising dapagliflozin propanediol monohydrate as dapagliflozin can be of 2.5 mg, 5 mg, or 10 mg and sitagliptin phosphate monohydrate as sitagliptin can be of 25 mg, 50 mg or 100 mg dosage.

[0133]

[0136] The total tablet weight is in the range of 100 mg to 800 mg. In another embodiment, the tablet weight is in the range of lOOmg to 700 mg. In another embodiment, the tablet weight is in the range of lOOmg to 600 mg. In another embodiment, the tablet weight is in the range of 200mg to 600 mg. In another embodiment, the tablet weight is in the range of 300mg to 600 mg.

[0134]

[0137] In another embodiment, the monolayer tablet comprises the granules or blend of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 1-15% w / w comprising mannitol in an amount ranging from 50-90 % w / w or microcrystalline cellulose in an amount ranging from 50-90 % w / w; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 10-50 % w / w comprising microcrystalline cellulose in an amount ranging from 3-20 % w / w, dicalcium phosphate in an amount ranging from 3-20 % w / w, croscarmellose sodium in an amount ranging from 1- 25 % w / w, colloidal silicon dioxide in an amount ranging from 1-10 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; croscarmellose sodium in an amount ranging from 1-10 % w / w, colloidal silicon dioxide in an amount ranging from 1-5 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; magnesium stearate 0.1-3 % w / w wherein the monolayer tablet is coated with coating material in an amount ranging from 1-10 % w / w. The concentration of the excipients used can be changed based on dosage amount of dapagliflozin and sitagliptin.

[0135]

[0138] In another embodiment, the monolayer tablet comprising the granules or blend of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 1-15% w / w comprising mannitol in an amount ranging from 25-45 % w / w or microcrystalline cellulose in an amount ranging from 25-45 % w / w or colloidal silicon dioxide in an amount ranging from 25-45 % w / w, and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 10-50 % w / w comprising microcrystalline cellulose in an amount ranging from 3-20 % w / w, dicalcium phosphate in an amount ranging from 3- 20 % w / w, croscarmellose sodium in an amount ranging from 1-25 % w / w, colloidal silicon dioxide in an amount ranging from 1-10 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; croscarmellose sodium in an amount ranging from 1-10 % w / w, colloidal silicon dioxide in an amount ranging from 1-5 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; magnesium stearate 0.1-3 % w / w wherein the monolayer tablet is coated with coating material in an amount ranging from 1-10 % w / w. The concentration of the excipients used can be changed based on dosage amount of dapagliflozin and sitagliptin.

[0136]

[0139] In another embodiment, the monolayer tablet comprising the granules or blend of dapagliflozin propanediol monohydrate as dapagliflozin in an amount of 1.69% w / w comprising mannitol in an amount of 22.73% w / w or microcrystalline cellulose in an amount of 22.73% w / w or colloidal silicon dioxide in an amount of 22.73% w / w, and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount of 36.71% w / w comprising microcrystalline cellulose in an amount of 11.00% w / w, dicalcium phosphate in an amount of 11.07 % w / w, croscarmellose sodium in an amount of 4.29 % w / w, colloidal silicon dioxide in an amount of 2.14 % w / w, and sodium stearyl fumarate in an amount of 1.43% w / w; and croscarmellose sodium in an amount of 4.86 % w / w, colloidal silicon dioxide in an amount of 0.71% w / w, and sodium stearyl fumarate in an amount of 2.5% w / w, magnesium stearate in an amount of 0.86%, wherein the monolayer tablet is coated with coating material in an amount ranging from 1-10 % w / w, The concentration of the excipients used can be change based on dosage amount of dapagliflozin and sitagliptin.

[0137]

[0140] In another embodiment, the monolayer tablet comprising the granules or blend of dapagliflozin propanediol monohydrate as dapagliflozin in an amount of 2.64% w / w comprising mannitol in an amount of 35.36% w / w or microcrystalline cellulose in an amount of 35.36% w / w or colloidal silicon dioxide in an amount of 35.36% w / w, and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount of 28.56% w / w comprising microcrystalline cellulose in an amount of 8.56% w / w, dicalcium phosphate in an amount of 8.61 % w / w, croscarmellose sodium in an amount of 3.33 % w / w, colloidal silicon dioxide in an amount of 1.67 % w / w, and sodium stearyl fumarate in an amount of 1.11% w / w; and croscarmellose sodium in an amount of 6.44 % w / w, colloidal silicon dioxide in an amount of 0.56% w / w, and sodium stearyl fumarate in an amount of 2.5% w / w, magnesium stearate in an amount of 0.67%, wherein the monolayer tablet is coated with coating material in an amount ranging from 1-10 % w / w, The concentration of the excipients used can be change based on dosage amount of dapagliflozin and sitagliptin.

[0138]

[0141] In another embodiment, the monolayer tablet comprising the granules or blend of dapagliflozin propanediol monohydrate as dapagliflozin in an amount of 3.65% w / w comprising mannitol in an amount of 48.97% w / w or microcrystalline cellulose in an amount of 48.97% w / w or colloidal silicon dioxide in an amount of 48.97% w / w, and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount of 19.77% w / w comprising microcrystalline cellulose in an amount of 5.92% w / w, dicalcium phosphate in an amount of 5.96 % w / w, croscarmellose sodium in an amount of 2.31 % w / w, colloidal silicon dioxide in an amount of 1.15 % w / w, and sodium stearyl fumarate in an amount of 0.77% w / w; and croscarmellose sodium in an amount of 8.15 % w / w, colloidal silicon dioxide in an amount of 0.38% w / w, and sodium stearyl fumarate in an amount of 2.5% w / w, magnesium stearate in an amount of 0.46%, wherein the monolayer tablet is coated with coating material in an amount ranging from 1-10 % w / w, The concentration of the excipients used can be change based on dosage amount of dapagliflozin and sitagliptin.

[0139]

[0142] In another embodiment the monolayer tablet comprising the granules or blend of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 2.5-10 mg comprising mannitol in an amount ranging from 30-180 mg or microcrystalline cellulose in an amount ranging from 30-180 mg or colloidal silicon dioxide in an amount ranging from 30-180 mg; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 25-100 mg comprising microcrystalline cellulose in an amount ranging from 5-50mg, dicalcium phosphate in an amount ranging from 5-50mg, croscarmellose sodium in an amount ranging from 2-50mg, colloidal silicon dioxide in an amount ranging from 1-10 mg, and sodium stearyl fumarate in an amount ranging from 1-20 mg, and croscarmellose sodium in an amount ranging from 5-40mg, colloidal silicon dioxide in an amount ranging from 0.5-10 mg, and sodium stearyl fumarate in an amount ranging from 2- 20 mg; magnesium stearate 0.1-5 mg; wherein the monolayer tablet is coated with coating material in an amount ranging from l-20mg. The concentration of the excipients used can be change based on dosage amount of dapagliflozin and sitagliptin.

[0143] In another embodiment, the monolayer tablet can be administered orally in once-daily oral dose or in twice-daily oral dose.

[0140]

[0144] B) Bilayer Tablet

[0141]

[0145] In a preferred embodiment, the present disclosure provides a bilayer tablet comprising a one layer comprising the granules of dapagliflozin or a pharmaceutically acceptable salt thereof; another layer comprising the granules of sitagliptin or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients in each layer.

[0142]

[0146] In a preferred embodiment, the present disclosure provides a bilayer tablet comprising a one layer comprising the granules of dapagliflozin or a pharmaceutically acceptable salt thereof; another layer comprising the granules of sitagliptin or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients in each layer; wherein the dapagliflozin is present as dapagliflozin propanediol monohydrate; and wherein the sitagliptin is present as sitagliptin phosphate monohydrate.

[0143]

[0147] The pharmaceutically acceptable excipients are selected based on the stability, compressibility, flow properties, and compatibility with the APIs. The following excipients can be used in one or both layers such as diluents selected from but not limited to mannitol, microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate (dicalcium phosphate), binders selected from but not limited to povidone K30, hydroxypropyl cellulose, starch, disintegrants selected from but not limited to croscarmellose sodium, sodium starch glycolate, crospovidone, lubricants selected from but not limited to magnesium stearate, sodium stearyl fumarate, stearic acid, glidants selected from but not limited to colloidal silicon dioxide, talc, coating agents selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide etc colourants such as but not limited to iron oxide.

[0144]

[0148] In a preferred embodiment, the bilayer tablet comprises the granules of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 2.5 mg to 10 mg in a one layer comprising microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 25 mg to 100 mg in a another layer comprising microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; wherein the bilayer tablet is coated with coating material.

[0145]

[0149] The fixed-dose combination includes dapagliflozin 2.5 mg, 5 mg or 10 mg with sitagliptin 25 mg, 50 mg or 100 mg.

[0150] The total tablet weight is in the range of 100 mg to 800 mg. In another embodiment, the tablet weight is in the range of lOOmg to 700 mg. In another embodiment, the tablet weight is in the range of lOOmg to 600 mg. In another embodiment, the tablet weight is in the range of 200mg to 600 mg. In another embodiment, the tablet weight is in the range of 300mg to 600 mg.

[0146]

[0151] In another embodiment, the bilayer tablet comprising dapagliflozin propanediol monohydrate can be of 2.5 mg, 5 mg, or 10 mg and sitagliptin phosphate monohydrate can be of 25 mg, 50 mg and 100 mg dosage.

[0147]

[0152] In another embodiment, the bilayer tablet comprising the granules of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 1-15% w / w comprising mannitol in an amount ranging from 50-90 % w / w or microcrystalline cellulose in an amount ranging from 50-90 % w / w, croscarmellose sodium in an amount ranging from 1-10 % w / w, crospovidone in an amount ranging from 5-15 % w / w, colloidal silicon dioxide in an amount ranging from 1-5 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 10-60 % w / w comprising microcrystalline cellulose in an amount ranging from 3-20 % w / w, dicalcium phosphate in an amount ranging from 3-20 % w / w, croscarmellose sodium in an amount ranging from 1-25 % w / w, colloidal silicon dioxide in an amount ranging from 1-10 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; magnesium stearate 0.1-3 % w / w wherein the bilayer tablet is coated with coating material in an amount ranging from 1-10 % w / w. The concentration of the excipients used can be changed based on dosage amount of dapagliflozin and sitagliptin.

[0148]

[0153] In another embodiment, the bilayer tablet comprising the granules of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 1-15% w / w comprising mannitol in an amount ranging from 25-45 % w / w or microcrystalline cellulose in an amount ranging from 25-45 % w / w or colloidal silicon dioxide in an amount ranging from 25-45 % w / w, croscarmellose sodium in an amount ranging from 1-10 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 10-60 % w / w comprising microcrystalline cellulose in an amount ranging from 3-20 % w / w, dicalcium phosphate in an amount ranging from 3-20 % w / w, croscarmellose sodium in an amount ranging from 1-25 % w / w, colloidal silicon dioxide in an amount ranging from 1-10 % w / w, and sodium stearyl fumarate in an amount ranging from 0.1-3 % w / w; magnesium stearate 0.1-3 % w / w wherein the bilayer tablet is coated with coating material in an amount ranging from 1-10 % w / w. The concentration of the excipients used can be changed based on dosage amount of dapagliflozin and sitagliptin.

[0149]

[0154] In preferred embodiment the bilayer tablet comprising the granules of dapagliflozin propanediol monohydrate as dapagliflozin in an amount of 5.93% w / w comprising mannitol in an amount of 79.57 % w / w or microcrystalline cellulose in an amount ranging from 79.57 % w / w or colloidal silicon dioxide in an amount ranging from 79.57 % w / w, croscarmellose sodium in an amount ranging from 12 % w / w, sodium stearyl fumarate in an amount 2.5 % w / w; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 51.40 % w / w comprising microcrystalline cellulose in an amount ranging from 15.40% w / w, dicalcium phosphate in an amount of 15.50 % w / w, croscarmellose sodium in an amount of 6.00 % w / w, colloidal silicon dioxide in an amount of 3.0 % w / w, and sodium stearyl fumarate in an amount of 2.0 % w / w; and Croscarmellose sodium 2.00%, colloidal silicon dioxide 1.00%, sodium stearyl fumarate 2.50%, magnesium Stearate 1.20%; wherein the bilayer tablet is coated with coating material in an amount ranging from 1-10 % w / w. The concentration of the excipients used can be changed based on dosage amount of dapagliflozin and sitagliptin.

[0150]

[0155] In another embodiment the bilayer tablet comprising the granules of dapagliflozin propanediol monohydrate as dapagliflozin in an amount ranging from 2.5-10 mg comprising mannitol in an amount ranging from 30-180 mg or microcrystalline cellulose in an amount ranging from 30-180 mg or colloidal silicon dioxide in an amount ranging from 30-180 mg, croscarmellose sodium in an amount ranging from 5-40mg, and sodium stearyl fumarate in an amount ranging from 2-20 mg; and the granules of sitagliptin phosphate monohydrate as sitagliptin in an amount ranging from 25-100 mg comprising microcrystalline cellulose in an amount ranging from 5-50mg, dicalcium phosphate in an amount ranging from 5-50mg, croscarmellose sodium in an amount ranging from 2-50mg, colloidal silicon dioxide in an amount ranging from 1-10 mg, and sodium stearyl fumarate in an amount ranging from 1- 20 mg, and Croscarmellose sodium 1-5.0 mg, colloidal silicon dioxide 0.1.2 mg, sodium stearyl fumarate 1.0-5 mg, magnesium stearate 0.1-5 mg; wherein the bilayer tablet is coated with coating material in an amount ranging from l-20mg. The concentration of the excipients used can be changed based on dosage amount of dapagliflozin and sitagliptin.

[0151]

[0156] In another embodiment, the bilayer tablet comprises of two layers, wherein both layers are prepared separately and compressed into bilayer tablet which allows for the physical separation of dapagliflozin and sitagliptin to minimize drug-drug and drug-excipient interactions, thereby enhancing chemical stability.

[0152]

[0157] In another embodiment present disclosure provides a bilayer tablet, wherein both layers are prepared separately and compressed into bilayer tablet, wherein the tablet is coated with coating material.

[0153]

[0158] In another embodiment, the bilayer tablet can be administered orally in once-daily oral dose or twice-daily oral dose.

[0154]

[0159] These formulations are suitable for once-daily administration or twice daily administration, with or without food, and may be used as monotherapy or in combination with other antidiabetic agents such as but not limited to metformin, sulfonylureas, insulin, GLP-1.

[0155]

[0160] C) Powder

[0156]

[0161] In another embodiment the present disclosure provides pharmaceutical composition wherein the composition is in the form of a powder comprising the granules of dapagliflozin or a pharmaceutically acceptable salt thereof; the granules of sitagliptin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is suitable for oral administration.

[0157]

[0162] The composition in the form of a powder can be packaged in a unit dose sachet, wherein the composition can be reconstituted into an aqueous oral suspension prior to administration.

[0158]

[0163] D) Capsule

[0159]

[0164] In another embodiment, the pharmaceutical composition is in the form of a capsule, comprising the granules of dapagliflozin propanediol monohydrate, the granules of sitagliptin phosphate monohydrate, and one or more pharmaceutically acceptable excipients, wherein the capsule is designed for oral administration and provides a fixed-dose combination of dapagliflozin and sitagliptin.

[0160]

[0165] In another embodiment, the pharmaceutical composition is in the form of a capsule comprising the powder, beads, blend, tablet or mini-tablets, pellets, or granules, multiparticulate system with distinct compartments for each API and one or more pharmaceutically acceptable excipients.

[0166] In another embodiment, the pharmaceutical composition is in the form of a capsule, wherein the capsule is hard gelatine capsule or non-gelatine capsule. The hard capsules or non-gelatine capsules are two-piece structures comprising of a cap and a body filled with solid dosage forms selected from but not limited to powder, beads, blend, tablet or mini- tablets, pellets, or granules, multiparticulate system with distinct compartments for each API.

[0161]

[0167] In another embodiment, the pharmaceutical composition is in the form of a capsule, comprising the granules of dapagliflozin propanediol monohydrate, the granules of sitagliptin phosphate monohydrate, and one or more pharmaceutically acceptable excipients, wherein the capsule is a hard gelatine capsule or non-gelatine capsule.

[0162]

[0168] In another embodiment, the pharmaceutical composition is in the form of a capsule, comprising the blend of dapagliflozin propanediol monohydrate, the granules of sitagliptin phosphate monohydrate, and one or more pharmaceutically acceptable excipients, wherein the capsule is a hard gelatine capsule or non-gelatine capsule.

[0163]

[0169] In another embodiment, the pharmaceutical composition is in the form of a capsule, comprising the tablet of dapagliflozin propanediol monohydrate, the granules of sitagliptin phosphate monohydrate, and one or more pharmaceutically acceptable excipients, wherein the capsule is a hard gelatine capsule or non-gelatine capsule.

[0164]

[0170] In another embodiment, the pharmaceutical composition is in the form of a capsule, comprising the tablet of dapagliflozin propanediol monohydrate, the powder of sitagliptin phosphate monohydrate, and one or more pharmaceutically acceptable excipients, wherein the capsule is a hard gelatine capsule or non-gelatine capsule.

[0165]

[0171] The monolayer and bilayer tablets or capsules can be packed in aluminium-aluminium blister packs or bottle, which helps to minimize exposure to humidity and maintain product integrity during storage and transport.

[0166]

[0172] II) METHODS FOR PREPARATION OF PHARMACEUTICAL COMPOSITION

[0167]

[0173] The present disclosure further provides methods for the preparation of such fixed-dose combinations using pharmaceutical manufacturing techniques adapted to ensure the chemical and physical stability of both active ingredients. Processes include direct compression, dry granulation, wet granulation, roller compaction or slugging and bilayer compression, with suitable in-process controls to ensure uniformity, stability, and performance of the final product.

[0168]

[0174] In another embodiment, the present disclosure provides a process for preparing the granules of sitagliptin phosphate monohydrate, wherein the granules of sitagliptin phosphate monohydrate are manufactured using dry granulation or roller compaction or slugging.

[0169]

[0175] In another embodiment, the present disclosure provides a process for preparing the granules of dapagliflozin propanediol monohydrate, wherein the granules of dapagliflozin propanediol monohydrate can be manufactured using wet granulation or direct compression, roller compaction or slugging.

[0170]

[0176] A method for preparing a pharmaceutical composition comprising a fixed dose combination of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof, wherein the method comprises steps of a) dissolving dapagliflozin propanediol monohydrate in an organic solvent; b) adsorbing dissolved drug solution from step (a) onto microcrystalline cellulose or mannitol or colloidal silicon dioxide or combinations thereof; c) obtaining a blend ‘A’; drying the blend from step (b) to remove the organic solvent; d) transferring the blend in a blender with a disintegrant and a lubricant to obtain granules ‘A’, e) sifting sitagliptin phosphate monohydrate, microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate; f) subjecting the mixture from step (e) to roller compaction to obtain granules ‘B’; g) mixing blend ‘A’ obtained in step (c) and granules ‘B’ obtained from step (f); compressing to obtain a monolayer tablet; and / or h) compressing the granules ‘A’ obtained in step (d) and granules ‘B’ obtained from step (f) into a bilayer tablet; i) coating the tablet with a coating material selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide, and colourant such as iron oxide; and j) packing the tablets in packaging material selected from blister foil or bottle.

[0171]

[0177] The methods as illustrated in FIG.l, FIG.2 and FIG.3 are described in the following:

[0172]

[0178] Method for preparation of tablet by direct compression

[0179] The method as illustrated in FIG.l comprises of the steps: a) sifting and blending of dapagliflozin propanediol monohydrate and microcrystalline cellulose or mannitol, or combinations thereof (102); b) combining the blend with crospovidone, colloidal silicon dioxide and sodium stearyl fumarate (104) to obtain granules ‘A’ (106); c) sifting and blending of sitagliptin phosphate monohydrate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate (108); d) subjecting the blend to roller compaction (110) to obtain granules ‘B’ (112); e) mixing granules ‘A’ and granules ‘B’ and compressing into monolayer tablets

[0173] (OR) compressing granules ‘A’ and granules ‘B’ into bi-layer tablets (114); f) coating the tablets with coating materials selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide and colourant such as iron oxide (116); and g) packing the tablets in aluminium-aluminium blister foil or bottle (118).

[0174]

[0180] Method for preparation of tablet by wet granulation and dry granulation

[0175]

[0181] The method as illustrated in FIG.2 comprises of the steps: a) dissolving dapagliflozin propanediol monohydrate in isopropyl alcohol (202); b) adsorbing onto microcrystalline cellulose, mannitol, colloidal dioxide or combinations thereof (204); c) drying the blend to remove excess of isopropyl alcohol (206) to obtain blend ‘A’; d) combining the blend with croscarmellose sodium, and sodium stearyl fumarate; and compressing the blend (208) to obtain granules ‘A’ (210); e) sifting and blending of sitagliptin phosphate monohydrate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate (212); f) subjecting the blend to roller compaction and compressing the blend (214) to obtain granules ‘B’ (216); g) mixing blend ‘A’ obtained in step (c) and granules ‘B’ obtained in step (f) and compressing into monolayer tablets

[0176] (OR) compressing granules ‘A’ obtained in step (d) and granules ‘B’ obtained in step (f) individually into bi-layer tablets (218); h) coating the tablets with coating materials selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide and colourant such as iron oxide (220); and i) packing the tablets in aluminium-aluminium blister foil or bottle (222)

[0177]

[0182] Method for preparation of capsule

[0178]

[0183] The method as illustrated in FIG.3 comprises of the steps: a) sifting and blending of dapagliflozin propanediol monohydrate and microcrystalline cellulose or mannitol, or combinations thereof (302); b) combining the blend with colloidal silicon dioxide and sodium stearyl fumarate (304) to obtain granules ‘A’ (306); c) sifting and blending of sitagliptin phosphate monohydrate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate (308); d) subjecting the blend to roller compaction (310) to obtain blend or granules ‘B’ (312); e) mixing blend or granules ‘A’ and granules ‘B’ filling into hard gelatine capsules or nongelatine capsules (314); f) preparing capsules with combination of granules, obtained according to wet granulation or dry granulation, blend obtained according to wet granulation, powder, beads, mini tablets or tablet of dapagliflozin propanediol monohydrate and sitagliptin phosphate monohydrate (316); and g) packing the capsules in aluminium-aluminium blister foil or bottle (318).

[0179]

[0184] III) METHOD FOR MANAGEMENT OF DIABETES MELLITUS

[0180]

[0185] A method of managing a condition in a subject; wherein the said condition is Type 2 Diabetes Mellitus; wherein the said method comprising act of administering composition comprising dapagliflozin or a pharmaceutically acceptable salt, sitagliptin or a pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients to the subject in need thereof.

[0181]

[0186] The said method may be used in Drug-naive subjects requiring dual therapy; subjects inadequately controlled on dapagliflozin or sitagliptin monotherapy; subjects on triple therapy with agents such as but not limited to metformin, sulfonylureas, insulin, GLP-1 etc. The FDC may improve treatment adherence, simplify dosing regimens, and lead to better glycaemic control and overall outcomes.

[0187] The present disclosure provides a pharmaceutical composition for use in the manufacture of the medicament for the management of type 2 diabetes mellitus in a subject in need thereof; wherein the pharmaceutical composition is administered in therapeutically effective amount of fixed dose combination.

[0182]

[0188] The present disclosure provides a pharmaceutical composition for use in the manufacture of the medicament such as tablet or capsule, wherein the tablet can be monolayer tablet and / or bilayer tablet for the management of type 2 diabetes mellitus in a subject in need thereof; wherein the pharmaceutical composition is administered in therapeutically effective amount of fixed dose combination.

[0183]

[0189] The present disclosure provides a stable, therapeutically effective, and subject-friendly fixed-dose combination of dapagliflozin and sitagliptin for the treatment of type 2 diabetes mellitus. The present disclosure overcomes technical problem associated with coformulation and provide clinical benefits in a simplified dosage form. The composition, methods, and manufacturing processes disclosed herein contribute to the advancement in diabetes therapy.

[0184]

[0190] 2) EXAMPLE EMBODIMENTS

[0185]

[0191] The disclosed embodiment will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosed embodiment in any manner.

[0186]

[0192] The fixed dose combination pharmaceutical composition comprising dapagliflozin and sitagliptin has been developed with an aim to achieve better production capability, bioequivalence, ideal dissolution rate and stability during shelf life. To meet these desired product profiles, several formulation trials have been attempted.

[0187]

[0193] EXAMPLE 1-8: PREPARATION OF MONOLAYER TABLET FORMULATION

[0188]

[0194] TABLE 1: MONOLAYER TABLET FORMULATION

[0189]

[0190]

[0195] QS stands for "quantum satis" refers to an amount which is enough or as much as needed.

[0191]

[0196] Preparation of dapagliflozin granules (granules ‘A’) or blend (blend ‘A’) according to Table 1 of Examples 1-8:

[0192]

[0197] Example 1: In direct compression method, the dapagliflozin propanediol monohydrate and microcrystalline cellulose were sifted and blended in a pharmaceutically acceptable manner to obtain blend ‘A’.

[0193]

[0198] Example 2: In direct compression method, the dapagliflozin propanediol monohydrate and mannitol were sifted and blended in a pharmaceutically acceptable manner to obtain blend ‘A’.

[0194]

[0199] Example 3: In direct compression method, the dapagliflozin propanediol monohydrate and mixture of microcrystalline cellulose and mannitol were sifted and blended in a pharmaceutically acceptable manner to obtain blend ‘A’.

[0195]

[0200] Example 4: In wet granulation method, the dapagliflozin propanediol monohydrate was dissolved in isopropyl alcohol and adsorbed on to microcrystalline cellulose. This blend was dried to remove the isopropyl alcohol to obtain blend ‘A’.

[0196]

[0201] Example 5: In wet granulation method, the dapagliflozin propanediol monohydrate was dissolved in isopropyl alcohol and adsorbed on to mannitol. This blend was dried to remove the isopropyl alcohol to obtain blend ‘A’.

[0202] Example 6: In wet granulation method, the dapagliflozin propanediol monohydrate was dissolved in isopropyl alcohol and adsorbed on to microcrystalline cellulose and mannitol mixture. This blend was dried to remove the isopropyl alcohol to obtain blend ‘A’.

[0197]

[0203] Example 7: In wet granulation method, the dapagliflozin propanediol monohydrate was dissolved in isopropyl alcohol and adsorbed on to microcrystalline cellulose and colloidal silicon dioxide. This blend was dried to remove the isopropyl alcohol to obtain blend ‘A’.

[0198]

[0204] Example 8: In wet granulation method, the dapagliflozin propanediol monohydrate was dissolved in isopropyl alcohol and adsorbed onto mannitol and colloidal silicon dioxide. This blend was dried to remove the isopropyl alcohol to obtain blend ‘A’.

[0199]

[0205] Preparation of Granules (B) according to Table 1 of Examples 1-8:

[0200]

[0206] The sitagliptin phosphate monohydrate and excipients were sifted. The sifted material was blended in a pharmaceutically acceptable manner. The blend was transferred to roller compactor to carry out the roller compaction process to obtain sitagliptin phosphate monohydrate granules (granules B) with ideal flow characteristics.

[0201]

[0207] Preparation of monolayer tablet:

[0202]

[0208] The dapagliflozin propanediol monohydrate blend (blend A) obtained by wet granulation method or granules ‘A’ obtained by dry granulation method disclosed above was mixed with sitagliptin phosphate monohydrate granules (granule B) and blended with croscarmellose sodium, crospovidone, colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate and compressed together to obtain a monolayer tablet. In final step, the monolayer tablets were coated with coating material. The tablets were then packed in aluminium-aluminium (Alu-Alu) blister foil or bottle.

[0203]

[0209] EXAMPLE 9-10: PREPARATION OF MONOLAYER TABLET

[0204] FORMULATION USING DIRECT COMPRESSION METHOD

[0205]

[0210] TABLE 2: MONOLAYER TABLET FORMULATION

[0206]

[0207]

[0211] In direct compression method as illustrated in Table 2, the dapagliflozin propanediol monohydrate and excipients were sifted and blended in a pharmaceutically acceptable manner. In next step, sitagliptin phosphate monohydrate and excipients were sifted and blended in a pharmaceutically acceptable manner. Further, the blend of dapagliflozin propanediol monohydrate and sitagliptin phosphate monohydrate were mixed and compressed to obtain mono or single layer tablets. The tablets were then coated with coating material.

[0208]

[0212] EXAMPLE 11: DISSOLUTION STUDY FOR MONOLAYER TABLET

[0209]

[0213] A dissolution study was conducted to evaluate the release profile of dapagliflozin and sitagliptin from a fixed-dose combination tablet using USP Apparatus I (Basket method). The study employed 500 mL of 0.1 N hydrochloric acid (HC1) as the dissolution medium, maintained at 37.0 ± 0.5°C to simulate gastric conditions. The basket was rotated at 100 RPM, and samples were withdrawn at predetermined intervals of 5, 10, 15, 30, 45, and 60 minutes. Each sample was filtered and analyzed using a validated HPLC method capable of quantifying both active pharmaceutical ingredients separately. The study aimed to ensure that at least 80% of each drug was released within 30 minutes, in line with pharmacopeial or in-house specifications. All critical parameters such as bath temperature, rotation speed, and pH of the medium were closely monitored and documented throughout the procedure to ensure consistency and reliability of results.

[0210]

[0214] TABLE 3: DISSOLUTION STUDY FOR MONOLAYER TABLET OBTAINED BY DIRECT COMPRESSION METHOD

[0211]

[0215] TABLE 4: DISSOLUTION STUDY FOR MONOLAYER TABLET OBTAINED

[0212] BY WET GRANULATION METHOD

[0213]

[0216] TABLE: 5 DISSOLUTION STUDY FOR MONOLAYER TABLET OBTAINED BY WET GRANULATION METHOD (MICROCRYSTALLINE CELLULOSE + COLLOIDAL SILICON DIOXIDE COMBINATION)

[0214]

[0217] The monolayer tablet exhibits a dissolution profile, wherein at least 50% w / w of dapagliflozin and at least 70% w / w of sitagliptin is dissolved within 10 minutes, using 500 ml 0.1N HC1, stirring at 100 revolutions per minute.

[0215]

[0218] The composition preferably releases at least 80% of each API within 30 minutes.

[0216]

[0219] The monolayer tablet exhibits stability for at least 6 months long-term storage conditions.

[0217]

[0220] EXAMPLE 12: STABILITY STUDIES FOR MONOLAYER TABLET

[0218]

[0221] These monolayer tablets were packed in aluminium-aluminium (alu-alu) blisters or bottle and subjected to accelerated stability studies. An accelerated stability study was conducted to evaluate the stability profile of the product under stress conditions of 40°C ± 2°C and 75% RH ± 5% RH, in accordance with ICH guidelines. Samples were stored in aluminium-aluminium (alu-alu) blisters or bottle and placed in stability chambers with continuous monitoring of temperature and humidity. Testing was performed at three time points: initial (0 month), 3 months, and 6 months. At each interval, the samples were evaluated for impurities (related substance of dapagliflozin and sitagliptin). All analytical methods used were validated and results were compared against established specifications. The data collected helped assess any significant changes in the product’s quality attributes over time. If the product remained within acceptable limits throughout the 6-month period, the results could support a longer shelf life under recommended storage conditions. All observations and results were documented in detailed stability reports for regulatory and internal review. The results are presented in Table 6.

[0219]

[0222] TABLE 6: ACCELERATED STABILITY STUDIES FOR MONOLAYER

[0220] TABLET

[0221]

[0222]

[0223]

[0223] ND- Not detected; BDL- Below detection limit; BQL- Below quantitation limit.

[0224]

[0224] TABLE: 7: ACCELERATED STABILITY STUDIES FOR MONOLAYER

[0225] TABLET

[0226]

[0227]

[0225] The results provided in Tables 6 and 7 for accelerated stability studies clearly indicate that tablet formulations are stable at accelerated conditions.

[0228]

[0226] The accelerated stability studies (40°C / 75% RH) and long-term studies (25°C / 60% RH) are conducted to assess the chemical integrity of the APIs and the physical appearance of the dosage form over time. The tablet remains stable for at least 6 months.

[0229]

[0227] EXAMPLE 13: PHARMACOKINETIC STUDIES

[0230]

[0228] The pharmacokinetic study was performed for dapagliflozin and sitagliptin tablet formulation. The pharmacokinetic study in healthy volunteers demonstrate that the FDC is bioequivalent to the separate administration of dapagliflozin and sitagliptin reference products. The tablet exhibits comparable maximum plasma concentration (Cmax) and area under the curve (AUC) for both active ingredients under fasting conditions. The results are depicted in Tables 8 and 9.

[0231]

[0229] An open label, balanced, randomized, two -treatment, two-period, two-sequence, single-dose, crossover, oral bioequivalence study of Dapagliflozin / Sitagliptin tablets lOmg / lOOmg fixed dose combination of Test product (Example formulation 3 disclosed in the present disclosure) compared with Reference product (R=R1+R2) Rl: Commercially available Dapagliflozin 10 mg film-coated tablets and R2: Commercially available Sitagliptin 100 mg film-coated tablets in healthy, adult, human subjects under fasting conditions. A total of 18 healthy, adult, human subjects were enrolled for the study. Subjects were instructed not to chew or crush the drug product and asked to swallow the drug product as a whole with specified quantity of 20 % glucose solution in water. Blood samples were collected through an indwelling cannula placed in a forearm vein till 24.00 hours post-dose samples. Bioequivalence of the test product (T) with that of the reference products (R) under fasting conditions were concluded if the 90% confidence intervals of geometric least square mean ratio of the test to reference product falls within the acceptance range of 80.00%- 125.00% for Cmax and AUCo-t of Dapagliflozin and Sitagliptin.

[0232]

[0230] TABLE 8: PHARMACOKINETIC STUDY FOR DAPAGLIFLOZIN

[0233] PREPARED ACCORDING TO EXAMPLE 3 FORMULATION

[0234]

[0231] TABLE 9: PHARMACOKINETIC STUDY FOR SITAGLIPTIN PREPARED

[0235] ACCORDING TO EXAMPLE 3 FORMULATION

[0236]

[0232] In one embodiment, the pharmacokinetic study in healthy volunteers demonstrate that the fixed dose combination (FDC) is bioequivalent to the separate administration of dapagliflozin and sitagliptin reference products. The tablet exhibits comparable maximum plasma concentration (Cmax) and area under the curve (AUC) for both active ingredients under fasting conditions.

[0237]

[0233] The fixed-dose combination of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof, wherein administration of a single oral dose of the composition in human subjects results in a (Cmax) of dapagliflozin exhibits a maximum plasma concentration (Cmax) of 91.639 ± 22.8558 pg / mL, and a (Cmax) of sitagliptin, exhibits a maximum plasma concentration (Cmax) of 308.194 ± 59.4823 pg / mL, under fasting conditions.

[0238]

[0234] The pharmaceutical composition comprising dapagliflozin and sitagliptin, wherein the composition, when administered orally to a human subject in a fasting state, provides a pharmacokinetic profile characterized by a) an AUCo-tof dapagliflozin is 571.571 ± 151.3448 hr. pg / mL; and b) an AUCo-tof sitagliptin is 3703.920 ± 484.1193 hr. pg / mL.

[0239]

[0235] The pharmaceutical composition comprising dapagliflozin and sitagliptin, wherein upon oral administration to a human subject under fasting conditions, the composition exhibits a pharmacokinetic profile that is bioequivalent to the co-administration of separate immediate-release formulations of dapagliflozin and sitagliptin, as determined by the ratio of the geometric means of AUCo-co for dapagliflozin is 604.134 ± 152.3982 hr. pg / mL; and the ratio of the geometric means of AUCo-co for sitagliptin is 3765.609 ± 478.6945 hr. pg / mL.

[0240]

[0236] It can be confirmed from the Test / Reference (T / R) ratio % as provided in Table 8 for test sample (pharmaceutical composition comprising dapagliflozin and sitagliptin according to present disclosure) that the LnCmax for dapagliflozin is 102.24% and LnAUCt for reference product (commercially available dapagliflozin) is 98.14%, obtained for dapagliflozin of present disclosure vs individual reference product.

[0241]

[0237] It can be confirmed from the T / R ratio% as provided in Table 8 for test sample (pharmaceutical composition comprising dapagliflozin and sitagliptin according to present disclosure) that the Ln Cmax for sitagliptin is 98.08% and LnAUCt for reference product (commercially available sitagliptin) is of 99.19%, obtained for sitagliptin of present disclosure vs individual reference product.

[0242]

[0238] FIG.4A illustrates the pharmacokinetics profile comprising Cmax, AUCo-t and AUCo- co values for dapagliflozin in Example formulation 3, according to the aspects of the present disclosure.

[0243]

[0239] FIG.4B illustrates the plasma concentration time curve (mean vs time curve) obtained for dapagliflozin in Example formulation 3, according to the aspects of the present disclosure.

[0244]

[0240] FIG .5A illustrates the pharmacokinetics profile comprising Cmax, AUCo-t and AUCo- co values for sitagliptin in Example formulation 3, according to the aspects of the present disclosure.

[0245]

[0241] FIG.5B illustrates the mean vs time curve obtained for sitagliptin in Example formulation 3, according to the aspects of the present disclosure.

[0246]

[0242] EXAMPLE 14-21 : PREPARATION OF BILAYER TABLET FORMULATION

[0247]

[0243] TABLE 10: BILAYER TABLET FORMULATION

[0248]

[0249]

[0250]

[0244] Preparation of dapagliflozin granules (A) according to Table 10 of Examples 14- 21:

[0251]

[0245] Example 14: In direct compression method, the dapagliflozin propanediol monohydrate and microcrystalline cellulose were sifted and blended in a pharmaceutically acceptable manner. The blend was mixed with crospovidone, colloidal silicon dioxide and sodium stearyl fumarate and compressed to obtain (granules ‘A’).

[0252]

[0246] Example 15: In direct compression method, the dapagliflozin propanediol monohydrate and mannitol were sifted and blended in a pharmaceutically acceptable manner. The blend was mixed with crospovidone, colloidal silicon dioxide and sodium stearyl fumarate and compressed to obtain (granules ‘A’).

[0253]

[0247] Example 16: In direct compression method, the dapagliflozin propanediol monohydrate and mixture of microcrystalline cellulose and mannitol were sifted and blended in a pharmaceutically acceptable manner. The blend was mixed with crospovidone, colloidal silicon dioxide and sodium stearyl fumarate and compressed to obtain (granules ‘A’).

[0254]

[0248] Example 17: In wet granulation method, the dapagliflozin API was dissolved in isopropyl alcohol and adsorbed on to microcrystalline cellulose. This blend was dried to remove the isopropyl alcohol and then mixed with croscarmellose sodium and sodium stearyl fumarate (granules ‘A’).

[0255]

[0249] Example 18: In wet granulation method, the Dapagliflozin API was dissolved in isopropyl alcohol and adsorbed on to mannitol. This blend was dried to remove the isopropyl alcohol and then mixed with croscarmellose sodium and sodium stearyl fumarate (granules ‘A’).

[0256]

[0250] Example 19: In wet granulation method, the Dapagliflozin API was dissolved in isopropyl alcohol and adsorbed on to microcrystalline cellulose and mannitol mixture. This blend was dried to remove the isopropyl alcohol and then mixed with croscarmellose sodium and sodium stearyl fumarate (granules ‘A’).

[0257]

[0251] Example 20: In wet granulation method, the dapagliflozin API was dissolved in isopropyl alcohol and adsorbed on to microcrystalline cellulose and colloidal silicon dioxide. This blend was dried to remove the isopropyl alcohol and then mixed with croscarmellose sodium and sodium stearyl fumarate (granules ‘A’).

[0258]

[0252] Example 21: In wet granulation method, the dapagliflozin API was dissolved in isopropyl alcohol and adsorbed on to mannitol and colloidal silicon dioxide. This blend was dried to remove the isopropyl alcohol and then mixed with croscarmellose sodium and sodium stearyl fumarate (granules ‘A’).

[0259]

[0253] Preparation of Granules (B) according to Table 8 of Examples 14-21:

[0260]

[0254] The sitagliptin phosphate monohydrate and excipients were sifted. The sifted material was blended in a pharmaceutically acceptable manner. The blend was transferred to roller compactor to carry out the roller compaction process to obtain sitagliptin phosphate monohydrate granules (granules B) with ideal flow characteristics.

[0261]

[0255] Preparation of Bilayer Tablet:

[0262]

[0256] The granules A and B were individually compressed into bi-layer tablets of dapagliflozin propanediol monohydrate and sitagliptin phosphate monohydrate. In final step, the monolayer tablets were coated with coated with coating material. The tablets were then packed in aluminium-aluminium (Ahi- Ahi) blister foil or bottle.

[0263]

[0257] EXAMPLE 22: DISSOLUTION STUDY FOR BILAYER TABLET

[0264]

[0258] A dissolution study was conducted to evaluate the release profile of dapagliflozin and sitagliptin from a fixed-dose combination tablet using USP Apparatus I (Basket method). The study employed 500 mL of 0.1 N hydrochloric acid (HC1) as the dissolution medium, maintained at 37.0 ± 0.5°C to simulate gastric conditions. The basket was rotated at 100 RPM, and samples were withdrawn at predetermined intervals of 5, 10, 15, 30, 45, and 60 minutes. Each sample was filtered and analyzed using a validated HPLC method capable of quantifying both active pharmaceutical ingredients separately. The study aimed to ensure that at least 80% of each drug was released within 30 minutes, in line with pharmacopeial or in-house specifications. All critical parameters such as bath temperature, rotation speed, and pH of the medium were closely monitored and documented throughout the procedure to ensure consistency and reliability of results.

[0265]

[0259] In vitro dissolution data of bilayer tablets is represented in Table 11 which shows the similarity with individual tablets of Reference Product 1 and 2.

[0266]

[0260] TABLE 11 : DISSOLUTION STUDY FOR BILAYER TABLET OBTAINED BY

[0267] DIRECT COMPRESSION METHOD

[0268]

[0261] TABLE 12: DISSOLUTION STUDY FOR BILAYER TABLET OBTAINED BY

[0269] WET GRANULATION METHOD TABLE 13: DISSOLUTION STUDY FOR BILAYER TABLET OBTAINED BY WET

[0270] GRANULATION METHOD (MICROCRYSTALLINE CELLULOSE +

[0271] COLLOIDAL SILICON DIOXIDE COMBINATION)

[0272]

[0262] The bilayer tablet exhibits a dissolution profile, wherein at least 50% w / w of dapagliflozin and at least 70% w / w of sitagliptin is dissolved within 10 minutes, using 500 ml 0.1N HC1, stirring at 100 revolutions per minute.

[0273]

[0263] The bilayer tablet tested using USP apparatus II in media such as 0.1N HC1. The composition preferably releases at least 80% of each API within 30 minutes.

[0274]

[0264] EXAMPLE 23: STABILITY STUDIES FOR BILAYER TABLET

[0275]

[0265] The bilayer tablets were packed in aluminium-aluminium (alu-alu) blisters or bottle and subjected to accelerated stability studies. An accelerated stability study was conducted to evaluate the stability profile of the product under stress conditions of 40°C ± 2°C and 75% RH ± 5% RH, in accordance with ICH guidelines. Samples were stored in aluminium-aluminium (alu-alu) blisters or bottle and placed in stability chambers with continuous monitoring of temperature and humidity. Testing was performed at three time points: initial (0 month), 3 months, and 6 months. At each interval, the samples were evaluated for impurities (related substance of dapagliflozin and sitagliptin). All analytical methods used were validated and results were compared against established specifications. The data collected helped assess any significant changes in the product’s quality attributes over time. If the product remained within acceptable limits throughout the 6-month period, the results could support a longer shelf life under recommended storage conditions. All observations and results were documented in detailed stability reports for regulatory and internal review. The results are presented below:

[0276]

[0266] TABLE: 14: ACCELERATED STABILITY STUDIES FOR BILAYER

[0277] TABLET

[0278] ND- Not detected; BDL- Below detection limit; BQL- Below quantitation limit.

[0279]

[0267] The results provided in Table 14 for accelerated stability studies clearly indicate that tablet formulations are stable at accelerated conditions.

[0280]

[0268] The bilayer tablet exhibits stability for at least 6 months long-term storage conditions.

[0281]

[0269] The accelerated stability studies (40°C / 75% RH) and long-term studies (25°C / 60% RH) are conducted to assess the chemical integrity of the APIs and the physical appearance of the dosage form over time. The tablet remains stable for at least 6 months.

[0282]

[0270] EXAMPLE 24-25: PREPARATION OF CAPSULE FORMULATION:

[0283]

[0271] TABLE 15: CAPSULE FORMULATION

[0284]

[0272] In direct compression method, the dapagliflozin propanediol monohydrate and excipients were sifted and blended in a pharmaceutically acceptable manner. In next step, sitagliptin phosphate monohydrate and excipients were sifted and blended in a pharmaceutically acceptable manner. In next step, the above blend of dapagliflozin propanediol monohydrate and sitagliptin phosphate monohydrate were mixed and compressed to obtain granules. The granules were filled in to hard gelatine capsules or nongelatine capsules.

[0273] EXAMPLE 26-29: PREPARATION OF CAPSULE FORMULATION:

[0285]

[0274] TABLE 16: CAPSULE FORMULATION

[0286]

[0275] The granules A and B obtained according to above process were mixed and filled in to hard gelatine capsules or non-gelatine capsule.

[0287]

[0276] The blend of dapagliflozin propanediol monohydrate and granules B obtained according to above process were mixed and filled in to hard gelatine capsules or non-gelatine capsule.

[0288]

[0277] The blend of dapagliflozin propanediol monohydrate and granules B obtained according to above process were compressed into tablets and filled in to hard gelatine capsules or non-gelatine capsules comprising the blend of dapagliflozin and tablet of sitagliptin.

[0289]

[0278] The granules of dapagliflozin propanediol monohydrate were compressed into tablets and granules B obtained according to above process filled in to hard gelatine capsules or non-gelatine capsules comprising the tablet of dapagliflozin and granules of sitagliptin.

[0290]

[0279] The capsules are filled with tablet of dapagliflozin, and blend of sitagliptin and one or more pharmaceutically acceptable excipients. Alternatively, the capsule can also be filled with blend of dapagliflozin and tablet of sitagliptin. The tablet and the blend are filled within a single capsule shell to provide a fixed-dose combination.

[0291]

[0280] EXAMPLE 30: DISSOLUTION STUDY FOR BLEND IN CAPSULE

[0292]

[0281] A dissolution study was conducted to evaluate the release profile of dapagliflozin and sitagliptin from a fixed-dose combination tablet using USP Apparatus I (Basket method). The study employed 500 mL of 0.1 N hydrochloric acid (HC1) as the dissolution medium, maintained at 37.0 ± 0.5°C to simulate gastric conditions. The basket was rotated at 100 RPM, and samples were withdrawn at predetermined intervals of 5, 10, 15, 30, 45, and 60 minutes. Each sample was filtered and analyzed using a validated HPLC method capable of quantifying both active pharmaceutical ingredients separately. The study aimed to ensure that at least 80% of each drug was released within 30 minutes, in line with pharmacopeial or in-house specifications. All critical parameters such as bath temperature, rotation speed, and pH of the medium were closely monitored and documented throughout the procedure to ensure consistency and reliability of results.

[0293]

[0282] In vitro dissolution data is represented in Table 17 given below which shows the similarity with individual marketed reference formulations 1 and 2.

[0294]

[0283] TABLE 17: DISSOLUTION STUDY FOR BLEND IN CAPSULE

[0295]

[0284] TABLE: 18: DISSOLUTION STUDY FOR TABLET AND BLEND IN

[0296] CAPSULES

[0297]

[0285] The fixed dose combination of dapagliflozin and sitagliptin tablets prepared by following above mentioned approaches and their dissolution profiles were found to be similar with the marketed individual tablets. Thus, the fixed dose combination of dapagliflozin and sitagliptin tablets would offer an advantage in terms of convenience and compliance aspects.

[0298]

[0286] EXAMPLE 31: STABILITY STUDIES FOR CAPSULE FORMULATION

[0299]

[0287] The capsules were packed in aluminium-aluminium (alu-alu) blisters or bottle and subjected to accelerated stability studies. An accelerated stability study was conducted to evaluate the stability profile of the product under stress conditions of 40°C ± 2°C and 75% RH ± 5% RH, in accordance with ICH guidelines. Samples were stored in aluminiumaluminium (alu-alu) blisters or bottle and placed in stability chambers with continuous monitoring of temperature and humidity. Testing was performed at three time points: initial (0 month), 3 months, and 6 months. At each interval, the samples were evaluated for impurities (related substance of dapagliflozin and sitagliptin). All analytical methods used were validated and results were compared against established specifications. The data collected helped assess any significant changes in the product’s quality attributes over time. If the product remained within acceptable limits throughout the 6-month period, the results could support a longer shelf life under recommended storage conditions. All observations and results were documented in detailed stability reports for regulatory and internal review.

[0300] The results are presented below:

[0301]

[0288] TABLE 19: ACCELERATED STABILITY STUDIES FOR CAPSULE

[0302] FORMULATION

[0303]

[0289] TABLE 20: ACCELERATED STABILITY STUDIES FOR CAPSULE

[0304] FORMULATION

[0305] ND- Not detected; BDL- Below detection limit; BQL- Below quantitation limit.

[0306]

[0290] The results provided in Tables 19-20 for accelerated stability studies clearly indicate that capsule formulations are stable at accelerated conditions.

[0307]

[0291] From the above results, it was confirmed that all the discussed approaches were suitable for the fixed dose combination of Dapagliflozin and Sitagliptin tablets.

[0308]

[0292] Dapagliflozin and sitagliptin tablets were developed using different techniques and combinations for meeting the desired dissolution criteria stability and bioavailability with individual reference products and also the manufacturing process was simple, robust and reproducible. Stability results of the drug product were well within the acceptable limits. Hence these methods of developing fixed dose combination of dapagliflozin and sitagliptin tablets were found to be very promising.

[0309]

[0293] EXAMPLE 32: BLEND UNIFORMITY AND CONTENT UNIFORMITY ASSAYS

[0310]

[0294] The dapagliflozin granulation process of the present disclosure allows uniform drug distribution and superior compressibility and dissolution. The dapagliflozin drug is used at relatively lower concentration in the formulation. The step of dissolving dapagliflozin in non-aqueous solvent such as isopropyl alcohol helps to obtain better distribution of dapagliflozin which is observed from blend uniformity results. Table 21 depicts the results for blend uniformity test and content uniformity test.

[0311]

[0295] TABLE 21 : BLEND UNIFORMITY AND CONTENT UNIFORMITY ASSAYS

[0312]

[0313]

[0296] It can be observed that the dissolved and adsorbed form of dapagliflozin exhibits a relative standard deviation (RSD) of 0.48%, which is substantially lower compared to the RSD of 3.63% observed for dapagliflozin in powder form within granules. Nevertheless, the RSD of 3.63% remains well within the acceptable range.

[0314]

[0297] Furthermore, the content uniformity test results of tablet formulation indicate that the dissolved and adsorbed form of dapagliflozin exhibits a relative standard deviation (RSD) relatively lower. However, the RSD values of 1.35% and 2.21% also fall well within the acceptable limits.

[0315]

[0298] Although the wet granulation approach helps to improve blend uniformity, the present disclosure is not limited to wet granulation of dapagliflozin. The granules obtained using direct compression or dry granulation are equally providing a stable formulation and exhibiting dissolution profile like those of individual marketed drugs.

[0316]

[0299] 3) INVENTIVE STEP OF THE PRESENT DISCLOSURE

[0317]

[0300] The present disclosure avoids the use of binder-based wet granulation. By employing alternative processing approaches, the formulation overcomes drawbacks associated with binder-mediated granulation such as longer processing time, solvent handling, and potential stability concerns.

[0318]

[0301] The present disclosure does not require stabilizers for achieving a stable formulation. The specific excipient selection and granulation method employed in the present disclosure confers improved manufacturability and stability without reliance on stabilizers.

[0319]

[0302] The present disclosure differs significantly by employing wet granulation and direct compression for dapagliflozin, while sitagliptin is processed by direct compression. Furthermore, granules of each active are prepared separately and subsequently combined during tableting. This selective application of granulation techniques developed to the physicochemical properties of each active ingredient results in an optimized fixed-dose composition with enhanced stability and compressibility.

[0320]

[0303] 4) USES, APPLICATIONS AND BENEFITS OF THE PRESENT DISCLOSURE

[0321]

[0304] The disclosed fixed-dose combination of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof contributes to subject convenience and adherence by reducing pill burden and simplifying treatment regimens.

[0322]

[0305] The disclosed pharmaceutical composition exhibits proper flow of granules, to overcome stickiness of the active ingredients and to ensure uniform distribution of drug in the blend.

[0323]

[0306] The present disclosure provides a pharmaceutical composition comprising dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof in a single dosage form, addressing clinical, technical, and manufacturing challenges associated with their co-formulation.

[0324]

[0307] The present disclosure offers an improved therapeutic option for subjects with type 2 diabetes mellitus and supports long-term disease management with better outcomes, reduced side effects, and increased subject adherence.

[0325]

[0308] The present disclosure provides methods of treating or managing type 2 diabetes mellitus in a subject in need thereof, by administering an effective amount of the fixed-dose combination as disclosed. The treatment may be initiated in subjects who are inadequately controlled on monotherapy or who require multiple agents to achieve glycaemic targets. The present disclosure can also be used as part of a triple therapy regimen with agents selected from but not limited to metformin, sulfonylureas, insulin, GLP-1 etc.

[0326]

[0309] The said composition reduces blood sugar by inhibiting the breakdown of gastrointestinal hormones called incretins to enable the incretins, which regulate insulin and glucagon, to function well in the body. Dapagliflozin selectively inhibits SGLT2 in the kidneys and increases the excretion of glucose in the urine, thereby normalizing plasma glucose levels. In addition, sitagliptin protects pancreatic beta cells and increases GLP-1.

[0327]

[0310] 5) BEST MODE TO PRACTICE

[0311] Best mode to practice the present disclosure is by commercializing the pharmaceutical composition in the form of monolayered tablet, bilayered tablet, capsule or a sachet for management of Type 2 Diabetes Mellitus.

[0328]

[0312] Merely for illustration, only representative number / type of graph, chart, block, and sub-block diagrams were shown. Many environments often contain many more block and sub-block diagrams or systems and sub-systems, both in number and type, depending on the purpose for which the environment is designed.

[0329]

[0313] While specific embodiments of the disclosure have been shown and described in detail to illustrate the inventive principles, it will be understood that the disclosed embodiment may be embodied otherwise without departing from such principles.

[0330]

[0314] Reference throughout this specification to “one embodiment”, “an embodiment”, or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, appearances of the phrases “in one embodiment”, “in an embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0331]

[0315] It should be understood that the figures and / or screen shots illustrated in the attachments highlighting the functionality and advantages of the disclosed embodiment are presented for example purposes only. The disclosed embodiment is sufficiently flexible and configurable, such that it may be utilized in ways other than that shown in the accompanying figures.

[0332]

[0316] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

I / We claim:1) A pharmaceutical composition comprising,(a) dapagliflozin or a pharmaceutically acceptable salt thereof; and(b) sitagliptin or a pharmaceutically acceptable salt thereof; wherein the composition is formulated as a solid dosage form for oral administration.2) The composition as claimed in claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from diluents, disintegrant, lubricants, glidants and coating agents.3) The composition as claimed in claim 2, wherein the diluents are selected from mannitol, microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate; preferably, mannitol, microcrystalline cellulose and dibasic calcium phosphate.4) The composition as claimed in claim 2, wherein the disintegrants are selected from croscarmellose sodium, sodium starch glycolate, crospovidone; preferably, croscarmellose sodium and crospovidone.5) The composition as claimed in claim 2, wherein the lubricants are selected from magnesium stearate, sodium stearyl fumarate, stearic acid; preferably, sodium stearyl fumarate and magnesium stearate.6) The composition as claimed in claim 2, wherein the glidants are selected from colloidal silicon dioxide, talc; preferably, colloidal silicon dioxide.7) The composition as claimed in claim 2, wherein the coating agents are selected from polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, hydroxypropyl methylcellulose (HPMC), iron oxide etc., or combination thereof.8) The composition as claimed in claim 1, wherein the dapagliflozin is present as dapagliflozin propanediol monohydrate, and wherein the sitagliptin is present as sitagliptin phosphate monohydrate.9) The composition as claimed in claim 1, wherein the weight ratio of dapagliflozin to sitagliptin is in the range of 1 :5 to 1 :40.10) The composition as claimed in claim 1, wherein the solid dosage form is selected from a tablet, capsule or sachet.11) The composition as claimed in claim 10, wherein the tablet is monolayer tablet or bilayer tablet.12) The composition as claimed in claim 1, wherein the composition is prepared by wet granulation or direct compression, dry granulation or roller compaction or slugging.13) A method for preparing a pharmaceutical composition comprising a fixed dose combination of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof, wherein the method comprises steps of: a) dissolving dapagliflozin propanediol monohydrate in an organic solvent; b) adsorbing dissolved drug solution from step (a) onto microcrystalline cellulose or mannitol or colloidal silicon dioxide or combinations thereof; c) obtaining a blend ‘A’ ; drying the blend from step (b) to remove the organic solvent; d) transferring the blend in a blender with a disintegrant and a lubricant to obtain granules ‘A’, e) sifting sitagliptin phosphate monohydrate, microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate; f) subjecting the mixture from step (e) to roller compaction to obtain granules ‘B’; g) mixing blend ‘A’ obtained in step (c) and granules ‘B’ obtained from step (f); compressing to obtain a monolayer tablet; and / or h) compressing the granules ‘A’ obtained in step (d) and granules ‘B’ obtained from step (f) into a bilayer tablet; i) coating the tablet with a coating material selected from polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, titanium dioxide, and colourant such as iron oxide; and j) packing the tablets in packaging material selected from blister foil or bottle.14) The method as claimed in claim 13, wherein the organic solvent is selected from ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), and dimethylformamide, preferably, isopropyl alcohol.15) The monolayer tablet as claimed in claim 13, comprising:(a) the dapagliflozin propanediol monohydrate as dapagliflozin is present in doses of 2.5 mg, 5 mg, or 10 mg comprising mannitol or microcrystalline cellulose; and(b) the sitagliptin phosphate monohydrate as sitagliptin is present in doses of 25mg, 50mg or lOOmg comprising microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate;(c) croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate; wherein the monolayer tablet is coated with coating material and packed in blister foil or bottle; wherein the monolayer tablet provides immediate release of dapagliflozin or apharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof; wherein (a), (b) and (c) are present within a single layer.16) The bilayer tablet as claimed in claim 13, comprising:(a) a layer comprising the granules of dapagliflozin or a pharmaceutically acceptable salt thereof;(b) another layer comprising the granules of sitagliptin or a pharmaceutically acceptable salt thereof; and(c) one or more pharmaceutically acceptable excipients in each layer; wherein the bilayer tablet provides immediate release of dapagliflozin or a pharmaceutically acceptable salt thereof and sitagliptin or a pharmaceutically acceptable salt thereof; wherein both layers are physically separated from each other.17) The method as claimed in claim 13, wherein the monolayer and bilayer tablets exhibit a dissolution profile, wherein at least 50% w / w of dapagliflozin and at least 70% w / w of sitagliptin is dissolved within 10 minutes.18) The method as claimed in claim 13, wherein the composition releases at least 80% each of dapagliflozin and sitagliptin within 30 minutes.19) The bilayer tablet as claimed in claims 13 and 16, comprising: a) the granules of dapagliflozin propanediol monohydrate as dapagliflozin is present in doses of 2.5 mg, 5 mg, or 10 mg in a one layer comprising mannitol or microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and b) the granules of sitagliptin phosphate monohydrate as sitagliptin is present in doses of 25mg, 50mg or lOOmg in another layer comprising microcrystalline cellulose, calcium dihydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; wherein the bilayer tablet is coated with coating material and packed in blister foil or bottle.20) The pharmaceutical composition as claimed in claim 13, wherein the composition is in the form of a capsule, comprising: a) the dapagliflozin propanediol monohydrate, b) the sitagliptin phosphate monohydrate, and c) one or more pharmaceutically acceptable excipients, wherein the capsule is for oral administration and provides a fixed-dose combination of dapagliflozin and sitagliptin.21) The pharmaceutical composition as claimed in claim 20, wherein the pharmaceutically acceptable excipients are diluents selected from mannitol, microcrystalline cellulose and dibasic calcium phosphate; disintegrants selected from croscarmellose sodium and crospovidone; lubricants selected from sodium stearyl fumarate and magnesium stearate; glidant selected from colloidal silicon dioxide.22) The pharmaceutical composition as claimed in claim 20, wherein the capsule is a hard gelatine capsule or non-gelatine capsule.23) The pharmaceutical capsule as claimed in claim 20, wherein the capsule comprises the combination of granules, blend, powder, beads, mini tablets or tablet of dapagliflozin propanediol monohydrate and sitagliptin phosphate monohydrate.24) A method of managing a condition in a subject; wherein the said condition is Type 2 Diabetes Mellitus; wherein the said method comprising act of administering composition comprising dapagliflozin or a pharmaceutically acceptable salt thereof, sitagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients to the subject in need thereof.25) The method of managing a condition in a subject of claim 24, wherein the subject is an animal or a human being.26) The method as claimed in claim 24, wherein administration of a single oral dose of the composition in human subjects exhibits a maximum plasma concentration Cmax of dapagliflozin of 91.639 ± 22.8558 pg / mL, and a Cmax of sitagliptin of 308.194 ± 59.4823 pg / mL, under fasting conditions.27) The method as claimed in claim 24, wherein the composition when administered orally to a human subject in a fasting state, provides a pharmacokinetic profile characterized by an AUCo-t of dapagliflozin of 571.571 ± 151.3448 hr. pg / mL; and an AUCo-tof sitagliptin is 3703.920 ± 484.1193 hr. pg / mL.28) The method as claimed in claim 24, wherein the composition when administered orally to a human subject in a fasting state, provides a pharmacokinetic profile that is bioequivalent to the co-administration of separate immediate-release formulations (reference products) of dapagliflozin and sitagliptin, as determined by the ratio of the geometric means of AUCo-co for dapagliflozin is 604.134 ± 152.3982 hr. pg / mL; and the ratio of the geometric means of AUCo-co for sitagliptin is 3765.609 ± 478.6945 hr. pg / mL.

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