DESC:FORM 2

THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003

COMPLETE SPECIFICATION
(Section 10 and rule 13)

PHARMACUTICAL COMPOSITION COMPRISING REMOGLIFLOZIN ETABONATE, METFORMIN HYDROCHLORIDE AND TENELIGLIPTIN

APPLICANT
GLENMARK PHARMACEUTICALS LTD
B/12 Mahalaxmi Chambers 22
Bhulabhai Desai Road, Mumbai
Maharashtra, India - 400026

The following specification particularly describes the invention and the manner in which is to be performed.

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 teneligliptin hydrobromide or oxalate 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.
SGLT2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibitors lead to a reduction in blood glucose levels. Therefore, SGLT2 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-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß -D-glucopyranoside has the following formula

Also known as 3-(6-O-ethoxycarbonyl-.ß.-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl) methyl]-1-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 US 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 DPP IV which destroys hormone incretin. Incretin helps the body to regulate insulin secretion and glucose metabolism. Gliptins inhibit the inactivation of GLP-1and GIP by DPP-4, allowing GLP-1 and GIP 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.
3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (INN teneligliptin) is a potent pharmaceutical drug used for the treatment of type 2 diabetes mellitus. Teneligliptin hydrobromide is a DPP-IV inhibitor available in the form of 20 mg tablets in Japan by the trade name Tenelia®. It is indicated in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea or thiazolidine class drugs. Teneligliptin therapy in individuals with type 2 diabetes has been found to significantly reduce hemoglobin A1c (HbA1c) levels with a minimum of adverse side effects such as weight gain or hypoglycemia.
Teneligliptin is represented by formula:

International Patent Application Publication No. WO2001016147 and WO2002053573 relate to remogliflozin base and remogliflozin etabonate respectively.
U.S. Patent No. 7,074,794 discloses teneligliptin and trihydrochloride salt thereof;
Below applications discloses certain combination of SGLT2 inhibitors with other antidiabetic drugs, however none of them provides the specific triple combination of remogliflozin etabonate, teneligliptin and metformin as disclosed in the instant application. WO2001052825, WO2001097808 and WO2009022010 generically disclose combinations of DPP-IV inhibitor or SGLT2 inhibitor with other antidiabetic compounds. WO2010092125, similarly, discloses the combination, however, there is no disclosure for the triple combination of remogliflozin etabonate, teneligliptin and metformin.
The management of diabetes and associated complications often requires combining drugs with supplemental mechanisms of action. Lack of adherence to the multidrug therapy, possibly due to greater number of pills, higher administration frequency and poor tolerability, may lead to deficiency in the clinical outcomes. One way of addressing these problems is through a use of fixed-dose combinations that improve the medication compliance by reducing the pill burden of the patients thus proving more effective than the monotherapy.
There are always challenges to combine two or more drugs within one composition. Due to different physical and chemical properties of each drugs, maintaining in-process parameters and avoiding problems like sticking and clogging is always concern for the formulator. Moreover, maintaining drugs’ properties in finished product like dissolution, stability, impurity profile, etc. are also concern, while formulating fixed dose composition. Combination three drugs may even create more hurdles than combination of two drugs. Inventors of this patent application come up with versatile formulation and manufacturing process to tackle such problems and maintaining stability of each drug in triple combination of remogliflozin etabonate, teneligliptin 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 metformin or a pharmaceutically acceptable salts thereof and teneligliptin 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 teneligliptin 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 teneligliptin 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 teneligliptin 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 teneligliptin or a pharmaceutically acceptable salts thereof, wherein the teneligliptin is present in an amount of about 5 mg to about 50 mg.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, wherein the Remogliflozin etabonate is present in an amount of 100 mg or 250 mg, wherein the metformin hydrochloride is present in an amount of 500 mg or 1000 mg, and wherein the Teneligliptin is present in an amount of about 5 mg or about 20 mg.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, wherein the remogliflozin etabonate is present in an amount of 100 mg or 250 mg, wherein the Metformin hydrochloride is present in an amount of 500 mg or 1000 mg, and wherein the teneligliptin is present in an amount of about 10 mg or about 20 mg.
The composition can be administered in single or divided doses.
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 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 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 teneligliptin hydrobromide present in immediate release.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin oxalate, present in immediate release
Further the composition comprises blend of granules of active ingredients with pharmaceutically acceptable excipients filled in capsule or compressed in tablets.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, wherein the composition is a multilayer tablet.
In another aspect, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, wherein the composition is stable at 25°C ± 2°C & 60% RH ± 5 % RH.
In another aspect, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, 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 teneligliptin hydrobromide, 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. The preferred form of remogliflozin is 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. The preferred form of metformin is metformin hydrochloride.
The term “teneligliptin” as employed herein refers to teneligliptin or its pharmaceutically acceptable salts or ester or prodrug thereof. Examples of salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like, and salts with inorganic bases such as a sodium salt, a potassium salt and the like. Preferred is teneligliptin hydrobromide or teneligliptin oxalate salt. Teneligliptin oxalate used may be either teneligliptin 2.5 or or 3.5 or 4.0 oxalate
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, teneligliptin or pharmaceutically acceptable salts thereof 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 “intra-granular” refers to a composition of actives and/or other pharmaceutical excipients present within a granule of tablet composition.
The term “extra-granular” refers to a composition of active/or other pharmaceutical excipients present outside the granule of tablet composition.
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. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
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: SGLT2 inhibitors, DPP IV inhibitor, 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 prior art publication such as Indian patent application 201921037338 discloses composition of remogliflozin etabonate and teneligliptin and WO2019162800 discloses a composition comprising remogliflozin and metformin.
None of the prior arts discloses a composition comprising combination of remogliflozin or its salt or ester, teneligliptin 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 teneligliptin or its salt or ester.
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 teneligliptin 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 teneligliptin 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 teneligliptin 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 teneligliptin or a pharmaceutically acceptable salts thereof, wherein the metformin 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 teneligliptin or a pharmaceutically acceptable salts thereof, wherein the teneligliptin is present in an amount of about 5 mg to about 50 mg.
In still another embodiment, teneligliptin or a pharmaceutically acceptable salts thereof is teneligliptin hydrobromide.
In still another embodiment, teneligliptin or a pharmaceutically acceptable salts thereof is teneligliptin oxalate.
In still another embodiment, teneligliptin hydrobromide is present in an amount of about 5 mg to about 20 mg equivalent teneligliptin base, more preferably in an amount of about 10 mg equivalent Teneligliptin base. (i.e. 14. 74 mg teneligliptin hydrobromide is equivalent to 10 mg teneligliptin base)
In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, 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 teneligliptin is present in an amount of about 10 mg.
In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, 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 teneligliptin base is present in an amount of about 10 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 teneligliptin ranges from about 1:0.1 to about 1:1. In still another embodiment, the weight ratio of remogliflozin etabonate and teneligliptin is about 1:0.1 or about 1:0.2.
In another embodiment, a weight ratio of teneligliptin and metformin hydrochloride ranges from about 1:50 to about 1:300. In still another embodiment, the weight ratio of teneligliptin and metformin hydrochloride is about 1:50 or about 1:100.
In preferred embodiment, the weight ratio of remogliflozin etabonate: teneligliptin: metformin hydrochloride is about 1:0.1:5 or about 1:0.1:10.
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, tablet/s 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 teneligliptin, wherein the composition is tablet and remogliflozin etabonate, metformin hydrochloride and teneligliptin are mixed together to form a core of the compressed tablet.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin, wherein the composition is a multilayer tablet.
In still another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide is the bilayer tablet.
In still another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide is the bilayer tablet, wherein remogliflozin etabonate and teneligliptin hydrobromide present in different layers.
In still another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide is the bilayer tablet, wherein metformin hydrochloride is present in the layer comprising remogliflozin etabonate.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide is the bilayer tablet, wherein metformin hydrochloride is present in the layer comprising teneligliptin hydrobromide.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide in the form a bilayer tablet, wherein remogliflozin etabonate and metformin hydrochloride are mixed together in one layer and teneligliptin hydrobromide is present in second layer.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide in the form a 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 another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide in the form a bilayer tablet, wherein granules of teneligliptin hydrobromide 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 teneligliptin hydrobromide in the form a bilayer tablet, wherein granules of remogliflozin etabonate and metformin hydrochloride comprising layer is prepared using wet granulation method and granules of teneligliptin hydrobromide comprising layer is prepared using wet granulation method.
In another embodiment, the solid oral pharmaceutical composition is the trilayer tablet wherein remogliflozin etabonate, metformin hydrochloride and teneligliptin 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 first layer, teneligliptin hydrobromide is present in second layer and third layer is drug free layer.
In another embodiment, the drug free layer is present in middle layer of a trilayer tablet composition, wherein remogliflozin etabonate and metformin hydrochloride are present in first layer, teneligliptin hydrobromide is present in third layer.
In still another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide is immediate release composition.
In still another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide 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 teneligliptin hydrobromide 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 teneligliptin hydrobromide 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 teneligliptin hydrobromide 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 teneligliptin hydrobromide is immediate release composition, wherein remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide 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 teneligliptin hydrobromide is immediate release composition, wherein remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide 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 teneligliptin hydrobromide is immediate release composition, wherein remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide 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 teneligliptin hydrobromide, wherein the composition comprises one or more excipients.
The excipients may include rate controlling polymers or non-polymers, diluents, disintegrant, binders, bulking agents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, 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 one or more of anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv®), microfine 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, sorbitol, or sucrose, low substituted hydroxy propyl cellulose 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 PVP, crosslinked PVP, and PVPP. 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 0.01-5% w/w.
Non limiting examples of binder include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, hydroxypropyl methylcellulose, hydroxy propyl cellulose, 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 phenoxyethanol, 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. The buffering agent according to current invention are present in an amount 0.1-5% w/w.
Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives. The chelating agent according to current invention are present in an amount 0.1-5% 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.
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 or mixture thereof.
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 lubricants 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 teneligliptin hydrobromide is the bilayer tablet, wherein granules of remogliflozin etabonate and metformin hydrochloride comprising layer is prepared by wet granulation method and granules of teneligliptin hydrobromide comprising layer is also prepared by wet granulation method.
In some embodiments, remogliflozin etabonate and metformin hydrochloride comprising layer comprises intra-granular and extra-granular excipients.
In some embodiments, remogliflozin etabonate and metformin hydrochloride comprising layer comprises diluent and disintegrating agent as intra-granular excipients.
In some embodiments, remogliflozin etabonate and metformin hydrochloride comprising layer comprises microcrystalline cellulose and croscarmellose sodium as intra-granular excipients.
In some embodiments, remogliflozin etabonate and metformin hydrochloride comprising layer comprises disintegrating agent and lubricant as extra-granular excipients.
In some embodiments, remogliflozin etabonate and metformin hydrochloride comprising layer comprises croscarmellose sodium and magnesium stearate as extra-granular excipients.
In some embodiments, teneligliptin hydrobromide comprising layer comprises intra-granular and extra-granular excipients.
In some embodiments, teneligliptin comprising layer comprises diluent and disintegrating agent and optionally colorant as intra-granular excipients.
In some embodiments, teneligliptin hydrobromide comprising layer comprises microcrystalline cellulose, L- hydroxy propyl cellulose and optionally ferric oxide yellow as intra-granular excipients.
In some embodiments, teneligliptin hydrobromide comprising layer comprises disintegrating agent, diluent, glidant and lubricant as extra-granular excipients.
In some embodiments, remogliflozin etabonate and metformin hydrochloride comprising layer comprises L- hydroxy propyl cellulose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate as extra-granular excipients.
In some embodiments, granules of remogliflozin etabonate and metformin hydrochloride comprising layer is prepared using following steps:
i. Mix remogliflozin etabonate and metformin hydrochloride with diluent and disintegrating agent.
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 and metformin with microcrystalline cellulose and croscarmellose sodium
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 croscarmellose sodium extra granularly with dry granules of step (iv) and finally add magnesium stearate.
In some embodiments, granules of teneligliptin hydrobromide comprising layer is prepared using following steps:
i. Mix teneligliptin hydrobromide with diluent, disintegrating agent and optionally colourant.
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. diluent, disintegrant, glidant and lubricant with dry granules of step (iv).
In some embodiments, granules of teneligliptin hydrobromide comprising layer is prepared using following steps:
i. Mix teneligliptin with microcrystalline cellulose, L- hydroxy propyl cellulose and ferric oxide yellow.
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- hydroxy propyl cellulose, microcrystalline cellulose and colloidal silicon dioxide extra granularly with dry granules of step (iv) and finally add magnesium stearate.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, wherein composition is packed in Alu-Alu blister pack.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, wherein the composition is stable at 25°C ± 2°C & 60% RH ± 5 % RH.
In another embodiment, the solid oral pharmaceutical composition comprising remogliflozin etabonate, metformin hydrochloride and teneligliptin hydrobromide, 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 teneligliptin hydrobromide, 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 teneligliptin hydrobromide, 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 & 2: Fixed dose combination of remogliflozin etabonate, teneligliptin hydrobromide and metformin hydrochloride.
Ingredients Example 1 Example 2
A) Remogliflozin + Metformin Part: mg/tab mg/tab
Intragranular Part
1 Remogliflozin Etabonate 100.00 100.000
2 Metformin Hydrochloride 1000.00 500.000
3 Croscarmellose sodium 25.00 13.650
4 Hydroxy Propyl Cellulose 25.00 13.650
5 Purified water QS QS
Extragranular Part
6 Microcrystalline Cellulose 22.90 12.450
7 Croscarmellose sodium 25.00 13.650
8 Magnesium Stearate 12.100 6.60
Average weight= 1210.00 660.00
B) Teneligliptin Part:
Intragranular Part
1 Teneligliptin Hydrobromide Hydrate 14.742 14.742
2 Microcrystalline Cellulose 195.00 195.00
3 L- Hydroxy Propyl Cellulose 10.000 10.000
4 Ferric oxide yellow 0.280 0.280
5 Hydroxy propyl cellulose 3.30 3.30
6 Purified Water# QS QS
Extragranular Part
7 L- Hydroxy Propyl Cellulose 10.000 10.000
8 Microcrystalline Cellulose 37.908 37.908
9 Colloidal Silicon Dioxide 1.500 1.500
10 Magnesium Stearate 2.200 2.200
Average weight= 275.00 275.00
Bilayer Compression and Film Coating
C) Blend Compression
1 Blend of Remogliflozin etabonate and Metformin HCl 1210.00 660.00
2 Blend of Teneligliptin 275.0 275.00
Average weight of Bilayer core Tablet = 1485.00 935.00
D ) Film Coating
1. Opadry White 03K580004 29.20 18.490
2. Ferric oxide yellow 0.80 0.510
3. Purified Water# QS QS
Average weight= 1515.0 954.0

Manufacturing process for example 1 & 2:
Manufacturing of remogliflozin etabonate & metformin hydrochloride blend
1.0 Milling of metformin HCl
1.1 Mill the metformin hydrochloride through multi mil using 0.5mm screen and collect in double polybag line container.
1.2 Mix the remogliflozin etabonate, metformin hydrochloride (1/3 quantity), and Croscarmellose sodium sift through # 30 mesh sieve using vibratory sifter and collect in polybag lined container.
1.3 Co-sift step 1.2 & remaining quantity of metformin HCl through #30 mesh sieve using vibratory sifter and collect in polybag lined container.
2. Preparation of binder solution:
2.1 Place desired quantity of water in suitable vessel
2.2 Add and dissolve under stirring hydroxyl propyl cellulose and continue stirring for 45 minutes till clear solution obtained
3. Top spray granulation in FBP:
3.1 Set the all parameter and place the container containing binder solution over weighing balance
3.2 Load the blend from step 1.3 in to a FBP bowl
3.3 start the FBP and commence spray of binder solution once bed temperature 33°C±5°C is achieved. After completion of spraying, check the LOD at 70°C
4. Drying:
4.1 Dry the granules of step no. 3.2
4.2 Dry the granules till LOD is NMT 1.75%w/w at 70°C @ auto mode, checked using moisture balance
4.3 Unload the dried granules in suitable polylined container
5. Diminution
5.1 sift dried granules through 18# sieve using vibratory sifter. Collect the undersize and oversize granules separately in container
5.2 Mill the oversized granules through co-mill using 3.0mm screen and sift through#18 mesh sieve using vibratory sifter
5.3 Mill the oversized granules if any through co-mill using 1.6 mm screen and sift through#18 mesh sieve using vibratory sifter
5.4 collect the above material in double polyethylene bag lined container and check the weight of diminuted granules
6. Blending and Lubrication:
6.1 Co-sift the dried granules through #16 mesh using vibratory sifter and collect in container
6.2 Sift using vibratory sifter, calculated quantity of microcrystalline cellulose, Croscarmellose sodium through #40 sieve and collect in container
6.3 sift the magnesium stearate and collect in a polybag
6.4 Mix the blend from step 6.2 and magnesium stearate in step 6.3
6.5 collect the lubricated granules in the container

Manufacturing of Teneligliptin blend
a. Co-sift calculated quantity of teneligliptin hydrobromide hydrate, microcrystalline cellulose, L- hydroxy propyl cellulose and ferric oxide yellow though # 20 sieve
b. Load sifted blend from step (a) in to RMG and Mix for 15 minutes at slow speed
c. Prepare binder solution using purified water and hydroxy propyl cellulose
d. Granulate the content of RMG with binder solution
e. Dry wet sifted material of at inlet temperature of 40°C to 50°C till the required LOD is achieved.
f. Sift dried granules through 20 # sieve using vibratory sifter
g. Mill the oversized granules through Co-mill using suitable screen and sift through # 20 mesh sieves using vibratory sifter
h. Sift using vibratory sifter, L- hydroxy propyl cellulose, microcrystalline cellulose and colloidal silicon dioxide and mix with dried granules
i. Sift magnesium stearate through # 60 sieve and add to (step i) and mix for 3 minutes at 12 rpm
j. Collect the lubricated granules in suitable container
COMPRESSION: Compress the granules of remogliflozin etabonate and metformin HCl as well as of teneligliptin hydrobromide in to bilayer tablet punching machine.
Film Coating: Coat the bilayer tablet using opadry based coating solution.
Dissolution Data for Example 1 & 2:
Dissolution conditions:
• Remogliflozin etabonate & teneligliptin hydrobromide: Volume: 900 ml Apparatus-Paddle; 75 RPM;
• Metformin HCl: Volume 900 ml; Apparatus Basket; 100 RPM
Dissolution data for Example 1:
Remogliflozin
Etabonate 100 mg Metformin
HCl 1000 mg Teneligliptin
10 mg
Dissolution media Phosphate Buffer pH 3.0 with 0.5 % w/w CTAB Phosphate Buffer
pH 6.8 Phosphate Buffer pH 3.0
with 0.5 % w/w CTAB
10 min 76.0 84.8 99.6
15 min 90.1 93.4 101.2
30 min 93.5 97.9 102.4
45min 96.0 98.9 102.5

Dissolution data for Example 2:
Remogliflozin
Etabonate 100 mg Metformin
hydrochloride 500 mg Teneligliptin
10 mg
Dissolution media Phosphate Buffer pH 3.0 with 0.5 % w/w CTAB Phosphate Buffer
pH 6.8 Phosphate Buffer pH 3.0
with 0.5 % w/w CTAB
10 min 80.0 91.6 97.3
15 min 92.4 95.7 101.9
30 min 98.8 97.5 103.3
45min 101.4 98.2 103.2

Stability Data:
Stability data for example 1:
A) 30°C ± 2°C & 75% RH ± 5 % RH
Tests Initial analysis Analysis After
1 Month 3 Months 6 Months 9 Months
Description Complies Complies Complies Complies Complies
Average weight of tablet
1515.0 mg (± 5%) 1549.5 1557.2 1562.9 1558.4 1561.6
Disintegration Time (Lt : Not more than 30 minutes) 6 mins,
40 sec’s 6 mins,
30 sec’s 6 mins,
48 sec’s 6 mins,
52 sec’s 7 mins,
10 sec’s
Dissolution (in %) for Remogliflozin Etabonate
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 minutes) 94.3 95.2 96.6 104.9 93.9
Dissolution (in %) for Teneligliptin
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 minutes) 102.1 102.0 100.3 103.3 96.4
Dissolution (in %) for Metformin Hydrochloride
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 minutes) 100.9 101.2 95.4 100.0 99.3
Related Substances (in %)for Remogliflozin Etabonate
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.04 0.05 0.05 0.05 0.05
ii) Single Max. Unknown Impurity
(Lt: NMT 0.5 %) 0.08 0.10 0.14 0.10 0.10
iii) Total impurities (Lt: NMT 2.0%) 0.31 0.36 0.39 0.38 0.29
Related Substances (in%) for Teneligliptin
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.12 0.11 0.11 0.27 0.20
ii) Single Max. Unknown Impurity
(Lt: NMT 0.5 %) 0.32 0.17 0.17 0.21 0.17
iii) Total impurities (Lt: NMT 2.0%) 0.58 0.45 0.76 0.96 0.82
Related Substances (in%) for Metformin Hydrochloride
i) Single Max. Unknown Impurity
(Lt: NMT 0.2 %) 0.034 0.007 0.016 0.017 0.012
ii) Total impurities (Lt: NMT 0.5%) 0.055 0.017 0.027 0.037 0.040
Assay (in %) for Remogliflozin Etabonate
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 98.7 96.2 99.0 99.3 97.0
Assay (in %) for Teneligliptin
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 103.5 104.7 100.6 95.4 102.3
Assay (in %) for Metformin Hydrochloride
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 102.6 99.9 107.1 102.0 95.2
Microbiological Examination Test
A) Microbial Enumeration Tests
a) Total Aerobic Microbial Count (Lt: NMT 103 cfu/g)
b) Total combined yeast and moulds count (Lt: NMT 102 cfu/g)
B) Test For Specified Micro-organisms
Escherichia coli (Limit: should be Absent/ g)

< 10 cfu/g
< 10 cfu/g

Absent ---

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B) 40°C ± 2°C & 75% RH ± 5 % RH
Tests Initial analysis Analysis After
1 Month 3 Months 6 Months
Description Complies Complies Complies Complies
Average weight of tablet
1515.0 mg (± 5%) 1549.5 1559.2 1550.9 1561.4
Disintegration Time
(Lt : Not more than 30 min) 6 mins,
40 sec’s 6 mins,
18 sec’s 6 mins,
40 sec’s 6 mins,
48 sec’s
Dissolution (in %) for Remogliflozin Etabonate
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 min) 94.3 95.4 95.7 102.5
Dissolution (in %) for Teneligliptin
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 min) 102.1 101.8 97.0 93.7
Dissolution (in %) for Metformin Hydrochloride
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 min) 100.9 102.5 95.4 99.4
Related Substances (in %)for Remogliflozin Etabonate
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.04 0.05 0.05 0.06
ii) Single Max. Unknown Impurity (Lt: NMT 0.5 %) 0.08 0.09 0.10 0.09
iii) Total impurities
(Lt: NMT 2.0%) 0.31 0.40 0.38 0.46
Related Substances (in%) for Teneligliptin
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.12 0.13 0.24 0.33
ii) Single Max. Unknown Impurity (Lt: NMT 0.5 %) 0.32 0.17 0.11 0.30
iii) Total impurities (Lt: NMT 2.0%) 0.58 0.52 0.86 1.62
Related Substances (in%) for Metformin Hydrochloride
i) Single Max. Unknown Impurity (Lt: NMT 0.2 %) 0.034 0.007 0.021 0.026
ii) Total impurities (Lt: NMT 0.5%) 0.055 0.021 0.038 0.049
Assay (in %) for Remogliflozin Etabonate
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 98.7 98.0 97.7 97.6
Assay (in %) for Teneligliptin
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 103.5 102.6 99.4 93.3
Assay (in %) for Metformin Hydrochloride
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 102.6 98.8 103.5 97.1
Microbiological Examination Test
A) Microbial Enumeration Tests
a) Total Aerobic Microbial Count (Lt: NMT 103 cfu/g)
b) Total combined yeast and moulds count (Lt: NMT 102 cfu/g)
B) Test For Specified Micro-organisms
Escherichia coli (Limit: should be Absent/ g)

< 10 cfu/g
< 10 cfu/g

Absent

---
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---

< 10 cfu/g
< 10 cfu/g

Absent

Stability data for example 2:
A) 30°C ± 2°C & 75% RH ± 5 % RH
Tests Initial analysis Analysis After
1 Month 3 Months 6 Months 9 Months
Description Complies Complies Complies Complies Complies
Average weight of tablet
954.0 mg (± 5%) 951.6 961.7 947.1 953.8 944.9
Disintegration Time
(Lt : Not more than 30 min) 6 mins,
07 sec’s 6 mins,
15 sec’s 6 mins,
25 sec’s 6 mins,
30 sec’s 6 mins,
42 sec’s
Dissolution (in %) for Remogliflozin Etabonate
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 min) 96.8 98.0 98.4 100.6 95.6
Dissolution (in %) for Teneligliptin
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 min) 97.7 99.1 94.8 99.1 92.9
Dissolution (in %) for Metformin HCl
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 min) 101.2 101.9 102.6 101.6 98.5
Related Substances (in %)for Remogliflozin Etabonate
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.05 0.05 0.06 0.06 0.05
ii) Single Max. Unknown Impurity
(Lt: NMT 0.5 %) 0.08 0.12 0.13 0.10 0.10
iii) Total impurities (Lt: NMT 2.0%) 0.35 0.44 0.43 0.37 0.31
Related Substances (in%) for Teneligliptin
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.10 0.10 0.11 0.22 0.14
ii) Single Max. Unknown Impurity
(Lt: NMT 0.5 %) 0.10 0.15 0.11 0.25 0.17
iii) Total impurities (Lt: NMT 2.0%) 0.33 0.46 0.59 0.98 0.62
Related Substances (in%) for Metformin Hydrochloride
i) Single Max. Unknown Impurity
(Lt: NMT 0.2 %) 0.036 0.018 0.004 0.022 0.009
ii) Total impurities (Lt: NMT 0.5%) 0.059 0.044 0.012 0.045 0.037
Assay (in %) for Remogliflozin Etabonate
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 99.8 100.2 99.7 100.3 100.1
Assay (in %) for Teneligliptin
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 99.8 97.1 97.0 99.5 95.2
Assay (in %) for Metformin Hydrochloride
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 94.7 103.2 109.4 99.0 98.8
Microbiological Examination Test
A) Microbial Enumeration Tests
a) Total Aerobic Microbial Count
(Lt: NMT 103 cfu/g)
b) Total combined yeast and moulds count
(Lt: NMT 102 cfu/g)
B) Test For Specified Micro-organisms
Escherichia coli (Limit: should be Absent/ g)

< 10 cfu/g
< 10 cfu/g

Absent ---

---

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--

--
---

--

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--

--

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B) 40°C ± 2°C & 75% RH ± 5 % RH
Tests Initial analysis Analysis After
1 Month 3 Months 6 Months
Description Complies Complies Complies Complies
Average weight of tablet
954.0 mg (± 5%) 951.6 947.2 945.6 955.4
Disintegration Time (Lt : Not more than 30 minutes) 6 mins,
07 sec’s 6 mins,
42 sec’s 6 mins,
50 sec’s 6 mins,
45 sec’s
Dissolution (in %) for Remogliflozin Etabonate
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 minutes) 96.8 95.5 96.1 100.3
Dissolution (in %) for Teneligliptin
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 minutes) 97.7 97.2 93.8 98.6
Dissolution (in %) for Metformin Hydrochloride
(Lt : NLT 70%(D) of the L.A of drug is dissolved in 45 minutes) 101.2 101.9 103.7 99.1
Related Substances (in %)for Remogliflozin Etabonate
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.05 0.05 0.06 0.06
ii) Single Max. Unknown Impurity (Lt: NMT 0.5 %) 0.08 0.11 0.12 0.10
iii) Total impurities (Lt: NMT 2.0%) 0.35 0.35 0.45 0.39
Related Substances (in%) for Teneligliptin
i) Identified (known) impurity, Impurity-A (Lt : NMT 1.0 %) 0.10 0.09 0.18 0.23
ii) Single Max. Unknown Impurity
(Lt: NMT 0.5 %) 0.10 0.10 0.19 0.24
iii) Total impurities (Lt: NMT 2.0%) 0.33 0.36 1.09 1.02
Related Substances (in%) for Metformin Hydrochloride
i) Single Max. Unknown Impurity
(Lt: NMT 0.2 %) 0.036 0.021 0.008 0.028
ii) Total impurities (Lt: NMT 0.5%) 0.059 0.049 0.020 0.057
Assay (in %) for Remogliflozin Etabonate
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 99.8 98.1 100.3 100.5
Assay (in %) for Teneligliptin
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 99.8 97.7 96.0 97.0
Assay (in %) for Metformin Hydrochloride
(Lt: NLT 90.0 % to NMT 110.0 % of L.A) 94.7 103.7 103.3 97.5
Microbiological Examination Test
A) Microbial Enumeration Tests
a) Total Aerobic Microbial Count
(Lt: NMT 103 cfu/g)
b) Total combined yeast and moulds count (Lt: NMT 102 cfu/g)
B) Test For Specified Micro-organisms
Escherichia coli (Limit: should be Absent/ g)

< 10 cfu/g

< 10 cfu/g

Absent --

---

--

--

---

--

< 10 cfu/g

< 10 cfu/g

Absent

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.
,CLAIMS:We claims
1. A pharmaceutical composition comprising:
a) remogliflozin etabonate in an amount of 100mg to 250mg
b) metformin hydrochloride in amount of 500mg to 1000mg,
c) teneligliptin or pharmaceutically acceptable salt thereof in amount of 5 mg to 20mg, 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, microfine 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 teneligliptin 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) teneligliptin or pharmaceutically acceptable salt thereof, and
d) a pharmaceutical acceptable excipient
wherein first layer of the tablet comprises remogliflozin etabonate and metformin hydrochloride and the second layer comprises teneligliptin or its salt.
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 teneligliptin is prepared by wet granulation process.
7. A bilayer tablet according to claim 5, wherein the total amount of impurity for remogliflozin etabonate is not more than 2 % when stored at 30 °C ± 2°C & 75% RH ± 5 % RH & 40°C ± 2°C & 75% RH ± 5 % RH.
8. A bilayer tablet according to claim 5, wherein the total amount of impurity for teneligliptin 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 according to claim 5, wherein the total amount of impurity for metformin is not more than 1 % when stored at 30 °C ± 2°C & 75% RH ± 5 % RH & 40°C ± 2°C & 75% RH ± 5 % RH.
10. A bilayer tablet comprising:
a first layer of remogliflozin etabonate and metformin hydrochloride, a second layer of teneligliptin or pharmaceutically acceptable salt thereof 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 0.01-5% w/w, wherein the amount of excipient is based on % w/w of the tablet weight.