PHARMACUTICAL COMPOSITION COMPRISING REMOGLIFLOZIN ETABONATE, METFORMIN HYDROCHLORIDE AND VILDAGLIPTIN

RELATED APPLICATION

This application claims the benefit of Indian Provisional Patent Application No. 202121026505 filed on June 14, 2021, the entire disclosure of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical composition comprising Remogliflozin or pharmaceutically acceptable salt, ester or derivatives thereof in combination with one or more anti-hyperglycemic agent or anti-diabetic agent. Particularly the present invention relates to pharmaceutical composition comprising combination of Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin for the treatment of diabetes mellitus. The invention also provides processes of preparation of the said compositions and methods of use thereof.

BACKGROUND OF THE INVENTION

Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type 1 diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type 2 diabetes). Type 1 diabetes is also called insulin-dependent diabetes. It used to be called juvenile-onset diabetes, because it often begins in childhood. By far, the most common form of diabetes is type 2 diabetes, accounting for 95% of diabetes cases in adults. Type 2 diabetes is often a milder form of diabetes than type 1. Nevertheless, type 2 diabetes can still cause major health complications, particularly in the smallest blood vessels in the body that nourish the kidneys, nerves, and eyes. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Management concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications. Oral therapeutic options for the treatment of type 2 diabetes mellitus include agents known as: biguanides (Metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate.

Sodium-glucose cotransporter-2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. Sodium-glucose Cotransporter-2 is the major cotransporter involved in glucose reabsorption in the kidney. Sodium-glucose cotransporter-2 inhibitors lead to a reduction in blood glucose levels. Therefore, Sodium-glucose cotransporter-2 inhibitors have potential use in the treatment of type 2 diabetes.

Remogliflozin etabonate is the pro-drug of Remogliflozin. Remogliflozin etabonate also known as 5-methyl-4-[4-(l -methyl ethoxy )benzyl]-l-(l -methyl ethyl)- lH-pyrazol-3-yl-6-0-(ethoxycarbonyl )-b -D-glucopyranoside has the following formula

Also known as 3-(6-0-ethoxycarbonyl-.p.-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl) methyl]- l-isopropyl-5-methylpyrazole. Salts of compounds of formula are useful as the active ingredient in the pharmaceutical presentation of the invention. Such salts may be as described in U.S Patent 7,084,123, herein incorporated by reference. Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of diabetes mellitus type 2. Remogliflozin etabonate or a salt thereof may be used in combination with another antihyperglycemic agent and/or a hypolipidemic agent and/or antiobesity agent which may be administered orally in the same dosage form in accordance with the invention. The other antihyperglycemic agent may be an oral antihyperglycemic agent including biguanides, sulfonylureas, thiazolidinediones, Dipeptidyl peptidase IV inhibitors (DPPIV inhibitor) and alpha-glucosidase inhibitors Particularly the combination comprises a biguanide such as Metformin or other known biguanides that improve hyperglycemia primarily through suppression of hepatic glucose production.

Metformin is known as N,N-Dimethylimidodicarbonimidic diamide represented by formula

Dipeptidyl peptidase IV inhibitors, also known as gliptins, are a class of oral diabetes drugs that inhibit the enzyme dipeptidyl peptidase IV inhibitors which destroys hormone incretin. Incretin helps the body - to regulate insulin secretion and glucose metabolism. Gliptins inhibit the

inactivation of glucagon-like peptide 1 and gastric inhibitory polypeptide by dipeptidyl peptidase IV inhibitors, allowing glucagon-like peptide 1 and gastric inhibitory polypeptide to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. The use of dipeptidyl peptidase IV inhibitors is very well known in the art, however recently it has been found that some dipeptidyl peptidase IV inhibitors were also able to provide benefit for refractory cases of abnormal accumulation of liver lipids.

Vildagliptin is an oral anti-hyperglycemic agent (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin is known as (S)-l-[N-(3 -hydroxy- 1-adamantyl)glycyl] pyrrolidine-2-carbonitrile and represented by formula:

International Patent Application No. W02001016147 discloses the Remogliflozin base whereas W02002053573 discloses the Remogliflozin etabonate.

Furthermore, U.S. Patent No. 6,166,063 discloses Vildagliptin;

The international patent application W02020089760 discloses the fixed dose pharmaceutical composition comprising combination of Remogliflozin or salt or ester thereof and Vildagliptin or salt thereof in a weight ratio of 1 :0.1 to 1 : 10 for the treatment of diabetes.

International patent application W02020089761 discloses the stable pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises Remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises Vildagliptin or salt thereof and a pharmaceutically acceptable excipient

International patent application W02018/198102 discloses the fixed dose solid oral dosage form comprising Remogliflozin or pharmaceutically acceptable salts thereof in immediate release form and Metformin or its pharmaceutically acceptable salts thereof in an extended release form_with one or more pharmaceutically acceptable excipients.

International patent application W02019/162800 discloses the immediate release pharmaceutical composition comprising Remogliflozin or pharmaceutically acceptable salt or ester thereof and Metformin or pharmaceutically acceptable salt thereof.

None of the prior arts discloses a composition comprising combination of Remogliflozin or its salt or ester, Vildagliptin or its salt or ester and Metformin. Further the prior art doesn’t disclose a bilayer tablets comprising first layer of Remogliflozin or salt or ester thereof and Metformin hydrochloride and second layer of Vildagliptin or its salt or ester.

The management of diabetes and associated complications often requires combining drugs with supplemental mechanisms of action. The advanced therapy using a combination of two or more drugs having different pharmacological actions makes it possible to improve preventive or therapeutic effects, while lowering side effects arising from the long term administration of a single drug. Therefore, a need for further development of methods of treatment, combination, and pharmaceutical compositions clearly exists. It is further much more user friendly for the patients to take just one a fixed-dose combination product comprising all three active pharmaceutical ingredients: (i) Remogliflozin etabonate or a salt thereof, (ii) a Metformin HC1 and (iii) a Vildagliptin in comparison with separate single-dosed products.

Metformin Additionally, a fixed dose combination of Remogliflozin, Vildagliptin and Metformin will help to simplify the treatment of type 2 diabetes mellitus, reduce the pill burden and consequently improve compliance.

Remogliflozin, Vildagliptin and Metformin have different glycemic reduce parameters e.g. Remogliflozin which is a stable, competitive, reversible and selective inhibitor of sodium-glucose cotransporter-2 inhibits renal glucose reabsorption, promotes urinary glucose excretion and lowers hyperglycemia independently of insulin secretion or action (Remogliflozin summary of product characteristics), Metformin acts by inhibiting gluconeogenesis and glycogenolysis, increase insulin sensitivity in muscles, and delays intestinal glucose absorption (Glucophage summary of product characteristics), whereas Vildagliptin acts by rapid and complete inhibition of dipeptidyl peptidase IV inhibitors activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (Galvus summary of product characteristics). In addition, Remogliflozin, Vildagliptin and Metformin have low potential for hypoglycaemia, allowing for maximizing glucose lowering benefits without fear of hypoglycaemia. The combination also has potential for moderate weight loss.

While combining two or more antidiabetic drugs in a single composition provides patient compliance, but on the other end it is also highly challenging for a formulator, because each drug has different physical and chemical properties, and hence maintaining the in-process parameters as well as avoiding manufacturing problems like sticking and clogging is always challenging for a formulator. Moreover, maintaining drugs’ properties in the finished product like dissolution, stability, impurity profile, etc. are also highly challenging. Combining three drugs is even more challenging than combination of two drugs. Inventors of the present patent application has surprisingly and unexpectedly developed a versatile and robust formulation and manufacturing process that is suitable to overcome such problems and maintain the stability of each drugs in the composition comprising triple combination of Remogliflozin etabonate, Vildagliptin and Metformin.

SUMMARY OF THE INVENTION

The present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin or a pharmaceutically acceptable salts, solvate, ester thereof in combination with Vildagliptin or a pharmaceutically acceptable salts thereof and Metformin or a pharmaceutically acceptable salts thereof for the treatment of diabetes mellitus.

In one aspect, the present invention relates to a solid oral pharmaceutical composition comprising combination of therapeutically effective amount of Remogliflozin or salts or prodrugs thereof with Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof for the treatment of type 2 diabetes mellitus.

In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof wherein the Remogliflozin etabonate is present in an amount of about 10 mg to about 1000 mg.

In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof, wherein the Metformin is present in an amount of about 100 mg to about 2500 mg.

In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof, wherein Vildagliptin is present in an amount of about 5 mg to about 500 mg.

In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin wherein the Remogliflozin etabonate is present in an amount of 100 mg or 250 mg, Vildagliptin is present in an amount of about 25 mg or about 50 mg and metformin hydrochloride is present in an amount of 500 mg or 1000 mg.

In another aspect, the solid oral pharmaceutical composition can be a tablet or capsule. Particularly the triple combination as per the invention is available in the form of bilayer tablet, wherein the first layer comprises Remogliflozin etabonate and Metformin HC1 and second layer comprises vildagliptin. The composition can be administered in single or divided doses.

The bilayer tablets comprising the combination 3 actives as per the invention, the first layer comprising Remogliflozin etabonate and Metformin hydrochloride prepared by wet granulation method and the second layer comprising Vildagliptin is prepared by using dry granulation or direct compression method.

In another aspect, the solid oral pharmaceutical composition is administered once or twice daily in a single or divided doses to achieve the glycemic control in patient suffering from type 2 diabetes mellitus.

In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and vildagliptin, present in immediate release or controlled release composition.

Further the composition comprises blend of granules of active ingredients with pharmaceutically acceptable excipients filled in capsule or compressed into a tablets.

In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and vildagliptin, wherein the composition is a bilayer tablet.

The triple combination product of the present invention has surprisingly similar properties of the original mono or dual combination reference product with reference to dissolution rates and stability. The combination formulation prevents an excessive degradation of the mono components and therefore contributes to a better stability of the final triple combination product. Therefore, it is not necessary to somehow adjust the storage limits of the triple combination product. Composition of the present invention has not only overcome the manufacturing process difficulties encountered while developing a combination formulation, the manufacturing process of the present invention is also simple and cost-effective which allows easy laboratory testing and that limits the potential of interactions of one drug with other or with one or more excipients used in the formulation.

In another aspect, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and vildagliptin, wherein the composition is stable at 30°C ± 2°C & 75% RH ± 5 % RH.

In another aspect, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and vildagliptin, wherein the composition is stable at 40°C ± 2°C & 75% RH ± 5 % RH.

According to embodiments of the present invention, the pharmaceutical compositions disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of type 2 diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.

DETAILED DESCRIPTION OF THE INVENTION

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.

The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.

The term Remogliflozin refers to Remogliflozin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof. Remogliflozin etabonate or a pharmaceutically acceptable salt thereof such as the hydrochloride, all of which are collectively referred to as Remogliflozin etabonate.

The term Metformin refers to Metformin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof, all of which are collectively referred to as Metformin.

The term Vildagliptin refers to Vildagliptin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof, all of which are collectively referred to as Vildagliptin.

The term "immediate release (IR)" used throughout the specification means the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging dissolution or absorption of drug.

The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating metabolic disorders, produces an intended therapeutic benefit in a subject.

The term “active ingredient” (used interchangeably with “active” or “active substance” or “drug”) as used herein includes Remogliflozin etabonate and Metformin or pharmaceutically acceptable salts thereof.

The term “treating” or “treatment” as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by Remogliflozin etabonate and Metformin in a mammal.

The term "patient" includes mammals like human and other animals. Preferably, the patient is a human.

By “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

The term “combination” includes administration of one or more active pharmaceutical ingredients either in a single dosage form or in separate dosage forms; in fixed dose combination or administered separately as adjuvant therapy.

Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise.

Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type 1 diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type 2 diabetes). The term "diabetes" as employed herein refers to type 2 diabetes and type 1 diabetes, usually type 2 diabetes. Management of diabetes concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications. Oral therapeutic options for the treatment of type 2 diabetes mellitus include agents known as: sodium -glucose cotransporter-2 inhibitors, dipeptidyl peptidase IV inhibitors, biguanides (Metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors.

The use of the Remogliflozin etabonate or salt thereof in combination with another anti-hyperglycemic agent may be of particular use in achieving anti-hyperglycemic results compared to each of these medicaments alone and greater than the combined additive anti-hyperglycemic effects produced by these medicaments.

The present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin or a pharmaceutically acceptable salts, solvate, ester thereof in combination with Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof for the treatment of diabetes mellitus.

In another embodiment, the solid oral pharmaceutical composition comprising combination of therapeutically effective amount of Remogliflozin or salts or prodrugs thereof with Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof for the treatment of type 2 diabetes mellitus.

In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof, wherein the Remogliflozin etabonate is present in an amount of about 10 mg to about 1000 mg.

In still another embodiment, the Remogliflozin etabonate is present in an amount of about 100 mg or about 250 mg, more preferably in an amount of about 100 mg.

In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin or a pharmaceutically acceptable salts thereof and Vildagliptin or a pharmaceutically acceptable salts thereof, wherein the Metformin ormin is present in an amount of about 100 mg to about 2500 mg.

In still another embodiment, Metformin or a pharmaceutically acceptable salts thereof is Metformin hydrochloride.

In still another embodiment, Metformin hydrochloride is present in an amount of about 500 mg or about 1000 mg.

In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin or a pharmaceutically acceptable salts thereof, wherein the Vildagliptin is present in an amount of about 5 mg to about 500 mg.

In still another embodiment, Vildagliptin or a pharmaceutically acceptable salts thereof is Vildagliptin base.

In still another embodiment, Vildagliptin is present in an amount of about 25 mg or about 100 mg, more preferably in an amount of about 50 mg.

In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein the Remogliflozin etabonate is present in an amount of about 100 mg, wherein the

Metformin hydrochloride is present in an amount of about 500 mg, and wherein the Vildagliptin is present in an amount of about 50 mg.

In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein the Remogliflozin etabonate is present in an amount of about 100 mg, wherein the Metformin hydrochloride is present in an amount of about 1000 mg, and wherein the Vildagliptin is present in an amount of about 50 mg.

In another embodiment, a weight ratio of Remogliflozin etabonate and Metformin hydrochloride ranges from about 1 : 1 to about 1 : 15. In still another embodiment, the weight ratio of Remogliflozin etabonate and Metformin hydrochloride is about 1:5 or about 1:10.

In another embodiment, a weight ratio of Remogliflozin etabonate and Vildagliptin ranges from about 1:0.1 to about 1:1. In still another embodiment, the weight ratio of Remogliflozin etabonate and Vildagliptin is about 1:0.25 or about 1:0.5.

In another embodiment, a weight ratio of Vildagliptin and Metformin hydrochloride ranges from about 1 : 10 to about 1 :30. In still another embodiment, the weight ratio of Vildagliptin and Metformin hydrochloride is about 1:10 or about 1:20.

In preferred embodiment, the weight ratio of Remogliflozin etabonate: Vildagliptin: Metformin hydrochloride is about 1:0.5:5 or about 1:0.5:10.

The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result. In still another embodiment, the composition can be administered in single or divided doses. The dosage form of the present invention may be in form of a tablet, capsule, granules, tablet in tablet, pellets, beads, tablets in capsule, granules/pellets in capsule, bilayer tablet, trilayer tablet, inlay tablet, caplet, dry syrup or suspension.

In still another embodiment, the solid oral pharmaceutical composition is tablet or capsule, particularly is the tablet, wherein the tablet can be coated or uncoated.

The triple combination as per the invention may available in the form of capsule wherein a capsule may comprise coated or uncoated granules or pellets of three active ingredients.

In still another embodiment, the solid oral pharmaceutical composition is administered once or twice daily in a single or divided doses to achieve the glycemic control in patient suffering from type 2 diabetes mellitus.

Further the composition comprises blend of granules of active ingredients with pharmaceutically acceptable excipients filled in capsule or compressed in tablets.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and vildagliptin, wherein the composition is tablet and Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin are mixed together and present in core of the compressed tablet.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein the composition is a multilayer tablet.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein Remogliflozin etabonate and Vildagliptin present in different layers.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein metformin hydrochloride is present in the layer comprising Remogliflozin etabonate. In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein Metformin hydrochloride is present in the layer comprising vildagliptin.

In still another embodiment, the said pharmaceutical composition is the immediate release bilayer tablets composition comprising Remogliflozin or pharmaceutically acceptable salt or ester thereof, Metformin or pharmaceutically acceptable salt thereof, Vildagliptin and pharmaceutical acceptable excipients.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein Remogliflozin etabonate and Metformin hydrochloride are mixed together in one layer and Vildagliptin is present in second layer.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein granules of Remogliflozin etabonate and Metformin hydrochloride comprising layer is prepared using wet granulation or dry granulation or direct compression method.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein granules of Vildagliptin comprising layer is prepared using dry granulation or direct compression method.

In still another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein granules of Remogliflozin etabonate and Metformin hydrochloride comprising layer is prepared using wet granulation method and granules of Vildagliptin comprising layer is prepared using direct compression method.

In another embodiment, the solid oral pharmaceutical composition is the trilayer tablet and Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin are present in each layer of the tablet.

In still another embodiment, the solid oral pharmaceutical composition is the trilayer tablet, wherein Remogliflozin etabonate and Metformin hydrochloride are present in same layer, Vildagliptin is present in separate layer and third layer is drug free layer.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release or controlled release composition.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release composition.

The tablets can be coated or uncoated wherein the coating can be functional or film coating. Alternatively there may present the barrier layer between two layers comprising active ingredients.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release composition, wherein the composition is coated with aqueous or non-aqueous film coating.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release composition, wherein the composition is coated with aqueous film coating.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release composition, wherein the composition is coated with non-aqueous film coating.

In still another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release composition, wherein Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin release not less than 70 % of the labeled amount within 45 minutes.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is immediate release composition, wherein Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin release not less than 90 % of the labeled amount within 45 minutes.

In still another embodiment, the solid oral pharmaceutical composition comprising

Remogliflozin etabonate, metformin hydrochloride and Vildagliptin is immediate release composition, wherein Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin release not less than 95 % of the labeled amount within 45 minutes.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein the composition comprises one or more excipients.

The excipients may include rate controlling polymers or non-polymers, diluents, disintegrants, binders, bulking agents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents such as opadry white, anti-tacking agents, emulsifiers, surfactants, plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents and the like used either alone or in combination thereof.

Further the composition comprises blend of granules of active ingredients with pharmaceutically acceptable excipients filled in capsule or compressed in tablets.

Non-limiting examples of diluents include anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv®), microfme cellulose, hydroxy propyl cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, low substituted hydroxy propyl cellulose, sorbitol, or sucrose and combinations thereof. The diluents according to current invention are present in an amount 5-50% w/w.

Non limiting examples of disintegrants suitable for use herein include, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Several specific types of disintegrant are suitable for use in the compositions described herein. For example, any grade of crospovidone can be used, including for example crospovidone XL- 10, and includes members selected from the group consisting of Kollidon CL.RTM., Polyplasdone XL.RTM., Kollidon CL-M.RTM., Polyplasdone XL-10.RTM., and Polyplasdone INF-10.RTM. In one embodiment, the disintegrant, if present, of the stock granulation is sodium

starch glycolate, croscarmellose sodium and/or crospovidone. These materials are also referred to as insoluble polyvidone, insoluble polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and polyvinylpyrrolidone-P. The crospovidone can be substituted with croscarmellose sodium, sodium starch glycolate. The disintegrant according to current invention are present in an amount 1-30% w/w.

Non-limiting examples of glidants and lubricants include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate. The glidant according to current invention are present in an amount 0.05-5% w/w.

Non limiting examples of binder include low substituted hydroxy propyl cellulose, Hydroxy propyl cellulose, starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, hydroxypropyl methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and starch. The binder according to current invention are present in an amount 0.1-20% w/w.

Non-limiting examples of preservatives include one or more of phenoxy ethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and mixtures thereof. Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof. Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives. The preservatives according to current invention are present in an amount 0.1-10% w/w.

Suitable plasticizers include, but are not limited to, one or more of diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, and polyethylene glycol. The solvents comprise one or more of dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water or mixture thereof.

Suitable rate controlling polymers are selected from, but not limited to, methacrylic acid copolymer dispersion, polyvinylpyrrolidone (PVP) and its derivatives such as copolyvidone, mixtures of PVP and polyvinylacetates, such as Kollidon SR; cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose; vinyl acetate copolymers; polysaccharides (such as alginate, xanthan gum, guar gum etc.), starch and starch-based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.

Suitable rate controlling non-polymers includes, but not limited to fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester or any combinations thereof.

Non-limiting examples of solvents include one or more of water; tetrahydrofuran; alcohols, e.g., methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons, e.g., chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, e.g., ethyl acetate.

Examples of suitable lubricants include stearic acid, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, zinc stearate, calcium stearate, silica, talc, polyethylene glycol, paraffin or the mixtures thereof. The lubricant according to current invention are present in an amount 0.1-10% w/w.

Suitable anti-tacking agents may be selected from stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; sodium benzoate; sodium acetate and the like.

The surfactants and emulsifiers may be ionic or nonionic. Specific examples of surfactants and emulsifiers are such as poloxamers, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil, etc.

Moreover, the composition of the present invention may include stabilizers like gums, agar; taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications.

In some embodiments, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin is the bilayer tablet, wherein granules of Remogliflozin etabonate and Metformin hydrochloride comprising layer is prepared using wet granulation method and granules of Vildagliptin comprising layer is prepared using dry granulation method.

In some embodiments, granules of Remogliflozin etabonate and Metformin hydrochloride comprising layer is prepared using following steps:

i. Mix Remogliflozin etabonate, Metformin, diluent & disntigrant

ii. Separately prepared binder solution.

iii. Granulate mixture of step (i) using binder solution of step (ii).

iv. Dry the wet granules of step (iii).

v. Mix the extra-granular excipients i.e. disintegrant and lubricant with dry granules of step

(iv).

In some embodiments, granules of Remogliflozin etabonate and Metformin hydrochloride comprising layer is prepared using following steps:

i. Mix Remogliflozin etabonate, Metformin and L- hydroxypropyl cellulose.

ii. Separately prepared binder solution by mixing hydroxyl propyl cellulose with water. iii. Granulate mixture of step (i) using binder solution of step (ii).

iv. Dry the wet granules of step (iii).

v. Mix L- hydroxypropyl cellulose extra granularly with dry granules of step (iv) and finally add magnesium stearate.

In some embodiments, granules of Vildagliptin comprising layer is prepared using roller compaction process.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein composition is packed in Alu-Alu blister pack.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein the composition is stable at 30°C ± 2°C & 75% RH ± 5 % RH.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and vildagliptin, wherein the composition is stable at 40°C ± 2°C & 75% RH ± 5 % RH.

In another embodiment, the solid oral pharmaceutical composition comprising Remogliflozin etabonate, Metformin hydrochloride and Vildagliptin, wherein composition exhibits a synergistic effect.

The pharmaceutical compositions disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of type 2 diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.

EXAMPLES

EXAMPLE 1: Fixed dose combination of Remogliflozin etabonate, Vildagliptin and Metformin hydrochloride.

Part I: Remogliflozin etabonate and Metformin HC1 Part

Part II: Vildagliptin Part

Part III: Coating Part

Manufacturing Process for Example 1 & 2:

I) Manufacturing process for Remogliflozin etabonate & Metformin hydrochloride blend:

1. Milling of Metformin Hydrochloride:

1.1 Mill the Metformin HC1 through multimil using 0.5 mm screen.

1.2 Mix Remogliflozin Etabonate (A), L- Hydroxy propyl cellulose & Metformin HC1 approximately one fourth quantity from step no 1.1 & Sift through # 30 mesh SS sieve

1.3 Co-Sift step 1.2 & remaining quantity of Metformin Hydrochloride through # 30 mesh SS sieve

2. Preparation of binder Solution:

2.1 Dissolve under stirring Hydroxy propyl cellulose (Klucel LF) in water and continue the stirring for 45 minute till the clear is solution obtained

3. Top spray granulation in FBP:

3.1 Load the blend from step 1.3 in to FBP bowl.

3.2 Commence spray of binder solution once bed temperature 33°C ± 5°C is achieved & perform the granulation process

4. Drying:

4.1 Dry the granules of step no. 3.2

4.2 Dry the granules till LOD is within target of 0.9 to 1.3% w/w

5.0 Diminution:

5.1 Sift dried granules through 18 # sieve using vibratory sifter

5.2 Mill the oversized granules through Cad mill /Multimill using 3.0/1.5/1.0 mm sieve/screen and sift through # 18 mesh screen using vibratory sifter.

6.0 Blending & Lubrication:

6.1 Sift using vibratory sifter, L-hydroxy propyl cellullose-through # 40 sieve

6.2 Remove granules of step 6.1 and Mix manually in polybag with sifted L-hydroxy propyl cellullose from step no 6.1 and sift through # 16

6.3 Load the Granules from step 6.1 and Premix blend from step 6.2 into Blender and Mix for 12 minutes at 12 rpm.

6.4 Sift Magnesium stearate through # 60 sieve and collect it in a double polyethylene bag.

6.5 Remove blend from blender (Step 6.3) and Mix manually in double polybag with sifted magnesium stearate (Step 6.4) & Sift through # 16 sieve and add to blender (of step 6.4) and Mix for 3 minutes at 12 rpm.

II) Manufacturing of Vildagliptin Blend

1.0 Sifting:

1.1 Remove approximately half quantity of anhydrous Lactose by sifting suitable quantity through #100 sieve

1.2 Co-Sift through 40 # sieve, Vildagliptin Remaining quantity of anhydrous Lactose and Sodium starch Glycol ate

1.3 Mix Ferric oxide yellow and fines of anhydrous Lactose from step 1.1 and Sift through 100 # sieve

1.4 Co-sift step no 1.2 and 1.3 through #40 sieve

1.5 Sift Magnesium stearate (0.385 kg) through #60 sieve

2.0 Blending and Lubrication for roll compaction:

2.1 Load above sifted ingredient from step 1.4 in to a blender and Mix for 15 minutes at 12 rpm

3.0 Roll Compaction & Sizing:

3.1 Fill the hopper of the Roll Compactor with blend of step 2.2 Compact the blend with the following

Settings and continue with manual feeding of blend.

Appearance of flakes: Pale yellow to yellow

3.2 After completion of compaction cycle, Pass the flakes/ compacts/ granules/ through ASTM # 30 sieve and take the un-compacted blend for compaction and compacts for sizing.

3.3 Pass the flakes through cad mill / multimill using 6.0 mm sieve/screen & then sift the obtained granules through #30 sieve using vibratory sifter, Collect the oversized & undersized granules separately. Record the speed of Cad mill / multimill.

3.4 Pass the oversized granules if any of step 3.3 through cad mill / multimill using 3.0 mm/1.5/1.0/0.5 sieve/screen & sift the obtained granules through #30 sieve using vibratory sifter.

3.5 In case retention over # 30 sieve is observed, mill the retention through cad mill / multi mill using 0.5 mm sieve/screen and sift through # 30 sieve. Record the speed of cad mill / multimill. Repeat the milling process through 0.5 mm screen till no retention on #30 sieve.

3.6 Check the fine and granules percentages using #60 mesh i.e. above and below 60 mesh.

If Granules quantity is more than 70% of practical weight then proceed for Lubrication, if granules quantity is less than 70% proceed for next roll compaction cycle & sizing using fines.

3.7 Repeat the above roll compaction cycle & sizing till required percent granules are achieved.

4.0 Blending & Lubrication:

4.1 Load granules and fines from step 3.0 in to the blender and mix for 5 minutes at 12 rpm,

4.2 Sift Magnesium stearate through #60 sieve and collect in a double polyethylene bag

4.3 Remove blend from step 4.1 and Mix with sifted magnesium stearate from step 4.2 and Sift through #30 sieve and Load to blender (step 4.1) and Mix for 3 minute.

III) Compression of Bilayer Tablets:

1. Set the Bilayer compression machine using punches.

2. Transfer the both the drugs granules in the separate hopper and adjust machine to set the average weight for Remogliflozin Etabonate and Metformin Hydrochloride layer and Vildagliptin layer as desired

IV) Film Coating of Bilayer Tablets:

1.1 Place Methylene chloride and Isopropyl alcohol in suitable SS vessel equipped with mechanical stirrer and stir the mixture for approximately 2 to 5 minutes.

1.2 Remove Methylene chloride and Isopropyl alcohol mixture from step 1.1, to it add Ferric oxide yellow under stirring and mix approximately for 2 to 5 minutes.

1.3 Pass the color dispersion from step 1.2 through colloid mill for approximately 5 to 15 minutes. Rinse the colloid mill using Methylene chloride and Isopropyl alcohol mixture from step 1.1 and filter it through #200 mesh Nylon cloth.

1.4 Add under stirring Opadry White YS-1- 18202 A into remaining quantity of Methylene chloride and Isopropyl alcohol mixture from step 1.1 and mix it for approximately 5 minutes.

1.5 Add under stirring filtered color dispersion from step 1.3 into Opadry White YS-1-18202 A dispersion at step 1.4 and continue the stirring for 45 minutes.

1.6 Filter the above coating dispersion from step 1.5 through 200# Nylon cloth and collect in a SS vessel.

2.0 Film coating process:

2.1 Load the tablets in the coating pan

2.2 Carry out the pre warming of tablets for 2 to 5 minutes

2.3 Once the product bed temperature attains 30°C to 35°C, start spraying of coating solution

2.4 Continue the spraying of coating dispersion till the film coverage & target weight gain of 2.0% (Limit 1.5 to 2.5 %) per tablet of pre warmed tablets is achieved by taking average weight of 100 tablets.

2.5 Commence the drying of the tablets in same machine

Example 3: Dissolution data of composition of examples 1 & 2

I) Dissolution data for Remogliflozin etabonate and Vildagliptin:

Dissolution Conditions:

Dissolution data:

II) Dissolution data for Metformin Hydrochloride:

Dissolution Conditions:

Dissolution data:

Stability Analysis:

Stability test was performed for the combined tablet obtained in the above Example 1 & 2 under the following conditions

Example 4: Stability data of composition of Example 1 Condition: 30°C ± 2°C & 75% RH ± 5 % RH

Condition: 40°C ± 2°C & 75% RH ± 5 % RH

Example 5: Stability data of composition of example 2 Storage condition: 30°C ± 2°C & 75% RH ± 5 % RH

Storage condition: 40°C ± 2°C & 75% RH ± 5 % RH

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
We Claims:

1. A pharmaceutical composition comprising:

a) Remogliflozin etabonate in an amount of lOOmg to 250mg

b) Metformin hydrochloride in amount of 500mg to lOOOmg,

c) Vildagliptin in amount of 50mg to lOOmg, and

d) a pharmaceutical acceptable excipient

2. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient comprises a diluent, a binder, a lubricant, a disintegrant and a glidant.

3. A pharmaceutical composition according to claim 2, wherein

- diluent is selected from the group comprising anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfme cellulose, lactose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol

- binder is selected from group comprising low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, starche, pregelatinize starche, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose

- lubricant is selected from the group comprising stearic acid, magnesium stearate, sodium stearyl fumarate, silica and talc

- disintegrant is selected from the group comprising crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose

- glidant is selected from group comprising stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.

4. A pharmaceutical composition according to claim 1, wherein the composition provides a dissolution of at least 75% within 45 minute of Remogliflozin etabonate and Vildagliptin in a dissolution media comprising phosphate buffer pH 3.0 and 0.5 % w/w cetyltrimethylammonium bromide and at least 75 % within 45 minute of Metformin hydrochloride in a dissolution media comprising phosphate buffer pH 6.8.

5. A bilayer tablet comprising:

a) Remogliflozin etabonate

b) Metformin hydrochloride

c) Vildagliptin, and

d) a pharmaceutical acceptable excipient

wherein first layer of the tablet comprises Remogliflozin etabonate and Metformin hydrochloride and the second layer comprises vildagliptin.

6. A bilayer tablet according to claim 5, wherein the first layer of the tablet comprising Remogliflozin etabonate and Metformin is prepared by wet granulation process and the second layer comprising Vildagliptin is prepared by roller compaction process.

7. A bilayer tablet according to claim 5, wherein the composition provides a dissolution of at least 75 % within 45 minute of Remogliflozin etabonate and Vildagliptin in a dissolution media comprising phosphate buffer pH 3.0 and 0.5 % w/w cetyl trimethyl ammonium bromide and at least 75 % within 45 minute of Metformin hydrochloride in a dissolution media comprising phosphate buffer pH 6.8.

8. A bilayer tablet according to claim 5, wherein the total amount of impurity is not more than 2 % when stored at 30 °C ± 2°C & 75% RH ± 5 % RH & 40°C ± 2°C & 75% RH ± 5 % RH.

9. A bilayer tablet comprising:

a first layer of Remogliflozin etabonate and Metformin hydrochloride, a second layer of Vildagliptin and one or more pharmaceutically acceptable excipient comprising

- a diluent in an amount of 5-50% w/w,

- a binder in an amount of 0.1-20% w/w,

- a disintegrant in an amount of 1-30% w/w,

- a lubricant in an amount of 0.1-10% w/w,

- a glidant in an amount of 0.05-5% w/w, wherein the amount of excipient is based on % w/w of the tablet weight.

10. The bilayer tablet according to claim 9, wherein

- the diluent is selected from group comprising anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfme cellulose, lactose, starch, pregelatinized starch, mannitol, low substituted hydroxy propyl cellulose

- the binder is selected from group comprising low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, starches, pregelatinize starches, gelatin,

polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose

- the lubricant is selected from group comprising stearic acid, magnesium stearate, sodium stearyl fumarate, silica, talc

- the disintegrant is selected from group comprising crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose

- the glidant is selected from group comprising stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.