DESC:
FORM 2

THE PATENTS ACTS, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See Section 10; rule 13)

“PHARMACEUTICAL COMPOSITION COMPRISING REMOGLIFLOZIN OR SALT OR ESTER THEREOF AND TENELIGLIPTIN OR SALT THEREOF”

Glenmark Pharmaceuticals Limited, an Indian Company of B/12 Mahalaxmi Chambers 22, Bhulabhai Desai Road, Mumbai- 400026, Maharashtra, India

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

TECHNICAL FIELD OF THE INVENTION

The invention relates to a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and DPP-IV inhibitor or pharmaceutically acceptable salt thereof. In particular, the invention relates to a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, teneligliptin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

BACKGROUND OF THE INVENTION

Diabetes is becoming an increasing concern across the world as in 2007, approximately 246 million people were affected by the disease, with an additional 7 million people developing the disease each year. As per the one prediction in 2025, around 380 million people will have diabetes. 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). Diabetes is associated with macro and micro complications such as retinopathy, nephropathy, and neuropathy. It highly desirable to adopt a healthier lifestyle, failing of which calls for chronic therapy with medicinal agents.

U.S. Patent No. 7,056,892 is directed to remogliflozin or pharmaceutically acceptable salt or ester thereof. U.S. Patent No. 7,084,123 is directed to remogliflozin etabonate or pharmaceutically acceptable salt thereof. These patents also disclose the use of the drugs for prevention or treatment of disease associated with hyperglycemia. Another U.S. Patent No. 8,951,976 is directed to the use of remogliflozin or remogliflozin etabonate for treating disease associated with 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. US patent 7,074,794 discloses teneligliptin trihydrochloride salt, the entire content of which is incorporated herein by reference. US patent 8,003,790 describes teneligliptin 2.5 hydrobromide salt and the hydrate form thereof, the entire content of which is incorporated herein by reference. Chinese patent application 104650065 discloses the trihydrate form of teneligliptin hydrobromide. The Indian patent application No 201817006680 discloses teneligliptin oxalate salt and its composition thereof, the entire content of which is incorporated herein by reference.

International Patent Publication No. WO2012/006398 discloses a combination immediate and delayed release delivery system for remogliflozin etabonate. The U.S. Patent No. 8,853,385 (Mitzubishi Tanabe) discloses method for increasing plasma active GLP-1 levels using combination of DPP-IV inhibitor and SGLT-2 inhibitors. The invention does not disclose etabonate salt of remogliflozin. International Patent Publication No. WO 2009/022008 & WO 2009/022009 discloses composition comprising a pyrazole-O-glucoside derivative in combination with a DPP-IV inhibitor. U.S. Patent Application No. 2011/0046076 discloses combination of SGLT2 inhibitor and DPP-IV inhibitor broadly. None of these prior art discloses combination of remogliflozin or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof.

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. The inventors of present invention have invented a fixed dose combinations of remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof for treatment of diabetes and associated complications.

SUMMARY OF INVENTION

In general aspect of the invention, provided is a combination of remogliflozin or pharmaceutically acceptable salt or ester thereof and DPP-IV inhibitor or pharmaceutically acceptable salt thereof. In particular, a combination of remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof. This combination is fixed dose combination suitable for twice a day administration.

In one aspect of the invention, there is provided a pharmaceutical composition comprising a combination of remogliflozin etabonate and teneligliptin hydrobromide or oxalate salt.

In another aspect of the invention, there is provided a pharmaceutical composition comprising a combination of remogliflozin etabonate, teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising about 0.5 mg to 500 mg, even more preferably from about 1 to 300 mg, most preferably from about 1 to 270 mg of remogliflozin or pharmaceutically acceptable salt or ester thereof, and about 5mg to about 500mg, even more preferably from about 10mg to 300mg, even more preferably from about 10 to about 100mg teneligliptin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, there is provided a fixed dose combination of about 50mg, or about 100mg, or about 250 mg of remogliflozin or pharmaceutically acceptable salt or ester thereof and about 10mg or about 20mg, or about 40mg, or about 80mg of teneligliptin or pharmaceutically acceptable salt thereof.

In still another aspect of the invention, the composition is a monolayer tablet or a bilayer tablet.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and (b) a second layer comprising teneligliptin or pharmaceutically acceptable salt thereof.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and (b) a second layer comprising teneligliptin or pharmaceutically acceptable salt thereof, wherein the composition is in the form of a bilayer tablet.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, and teneligliptin or pharmaceutically acceptable salt thereof and (b) a second layer comprising at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, the composition is bilayer tablet comprising (a) a first layer comprising remogliflozin etabonate and at least one pharmaceutically acceptable excipient and (b) a second layer comprising teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, the composition is bilayer tablet comprising (a) a first layer comprising an intra-granular portion comprising remogliflozin etabonate, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant; and (b) a second layer comprising an intra-granular portion comprising teneligliptin hydrobromide or oxalate, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant.

In still another aspect of the invention, the composition is bilayer tablet comprising(a) a first layer comprising an intra-granular portion comprising remogliflozinetabonate, crosscarmellose sodium, microcrystalline cellulose, and povidone; and (b) an extra-granular portion comprising crosscarmellose sodium, microcrystalline cellulose and magnesium stearate; and (b) a second layer comprising an intra-granular portion comprising teneligliptin hydrobromide or oxalate, maize starch, microcrystalline cellulose, and hydroxypropyl cellulose; and (b) an extra-granular portion comprising L-hydroxypropyl cellulose and magnesium stearate.

In still another aspect of the invention, there is provided a pharmaceutical composition in the form of a mono-layer tablet comprising: (a) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, the composition is monolayer tablet comprising (a) an intra-granular portion comprising remogliflozin etabonate and teneligliptin hydrobromide or oxalate and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, there is provided a pharmaceutical composition in the form of monolayer tablet comprising: (a) an intra-granular portion comprising remogliflozin etabonate, teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

In still another aspect of the invention, the composition is in the form of monolayer tablet comprising (a) an intra-granular portion comprising remogliflozin etabonate and teneligliptin hydrobromide or oxalate, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant and a lubricant.

In still another aspect of the invention, the composition is in the form of monolayer tablet comprising (a) an intra-granular portion comprising remogliflozin etabonate and teneligliptin hydrobromide or oxalate, crosscarmellose sodium, microcrystalline cellulose, povidone and water and (b) an extra-granular portion comprising crosscarmellose sodium, microcrystalline cellulose and magnesium stearate.

In an embodiment of the invention, a weight ratio of remogliflozin etabonate and teneligliptin is in the range of 2:1 to 15, particularly 2:1 to 13:1 and more particularly in the range of 2.5:1 to 10:1.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof, wherein the composition exhibits dissolution of not less than 75% remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof in 45min.

In still another aspect of the invention, there is provided a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof, wherein the composition is stable at 250C ± 20C & 60% RH ± 5 % RH after 6 months of stability period. Further the composition is also stable at 300C ± 20C & 75% RH ± 5 % RH and at 400C ± 20C & 75% RH ± 5 % RH after 6 months of stability period.

In still another embodiment of the invention, the composition is further coated with film coating layer.

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

In still another aspect, the pharmaceutical composition of the present invention on administration reduces Hb1Ac level and body weight of patient without causing hypoglycemia. Further the composition of the present invention complies with the in-vitro parameters and in-vivo parameters shown by the individual drugs.

BREIF DESCRIPTION OF FIGURES
Figure 1: Antihyperglycemic effects of remogliflozin etabonate and teneligliptin hydrobromide hydrate alone and in combination using healthy SD Male rats. Blood glucose concentrations (mg/ml) were measured from 0min to 120min in OGTT test and AUC0-120min was calculated for group A (Control), group B (Remogliflozin etabonate 1mg/kg), group C (Teneligliptin hydrobromide 10mg/kg) and group D (Remogliflozin 1mg/kg and Teneligliptin hydrobromide 10mg/kg).

Figure 2: Antihyperglycemic effects of remogliflozin etabonate and teneligliptin hydrobromide hydrate alone and in combination using healthy SD Male rats. Blood glucose concentrations (mg/ml) were measured from 0min to 120min in OGTT test and AUC0-120min was calculated for group A (Control), group B (Remogliflozin etabonate 3mg/kg), group C (Teneligliptin hydrobromide 1mg/kg), group D (Teneligliptin hydrobromide 10mg/kg), and group E (Remogliflozin 3mg/kg and Teneligliptin hydrobromide 1mg/kg) and group F (Remogliflozin 3mg/kg and Teneligliptin hydrobromide 10mg/kg).

DETAIL DESCRIPTION OF INVENTION
In one aspect of the invention, there is provided a combination of remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof. In particular, there is provided a combination of remogliflozin etabonate and teneligliptin hydrobromide or oxalate. This combination is a fixed dose combination suitable for twice a day administration.

The terms used herein are defined as follows.

The term “diabetes” used herein refers to Type 1 diabetes or Type 2 diabetes.

The term "remogliflozin" as employed herein refers to remogliflozin, prodrug and salts thereof, in particular ester such as remogliflozin etabonate, including hydrates and solvates thereof, amorphous and crystalline forms 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 remogliflozin etabonate.

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 teneliglptin 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 invention composition can be prepared by methods known in art such as wet granulation, dry granulation or direct compression. In granulation, there is formation of granules (microstructures) having active and pharmaceutically acceptable excipients such as binder, disintegrant, diluent, lubricant and kneeded together to obtain a granule. These granules then lubricated with other pharmaceutically acceptable excipients and finally compressed to obtain a dosage form such as tablet.

The term “intra-granular” refers to a composition of actives and/or at least one pharmaceutically acceptable excipient present within a granule of tablet composition.

The term “extra-granular” refers to a composition of active/or at least one pharmaceutically acceptable excipient present outside the granule of tablet composition.

The term “first layer” refers to a layer or compartment separated from second layer or compartment. This first layer could be a composition having intra-granular part and extra-granular part compressed together to obtain such a first layer.

The term “second layer” refers to a layer or compartment separated from first layer or compartment. This second layer could be a composition having intra-granular part and extra-granular part compressed together to obtain such a first layer.

The term "extended release (ER or DR)" means the drug is formulated to make it available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form). The term extended release and delayed release has been used inter-changingly.

The term “excipient” used throughout the specification refers to a substance with which the drug may be combined to achieve a specific dosage form, formulation or composition for delivery to humans.

In an embodiment, the invention provides a combination of remoglifozin etabonate and teneligliptin hydrobromide or oxalate which is superior in efficacy as compared to monotherapies for treatment of diabetes.

The combination of remogliflozin etabonate and teneligliptin hydrobromide or oxalate provides synergistic effects in reducing the blood glucose levels in patients with diabetes when compared to remogliflozin etabonate alone or teneligliptin hydrobromide or oxalate alone.

In another aspect of the invention, there is provided a pharmaceutical composition comprising a combination of remogliflozin or pharmaceutically acceptable salt or ester thereof, teneligliptin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The combination is in the form of a fixed dose combination.

In an embodiment, the combination of remogliflozin and teneligliptin or pharmaceutically acceptable salt thereof of the present invention is administered in the form of oral dosage form. The dosage form of the present invention may be in form of a tablet, tablet in tablet, bilayer tablet, trilayer tablet, inlay tablet, capsule, capsule in capsule, tablet/s in capsule, granules and/or pellets in capsule, caplet, granules, pellets, pellets and tablet in capsules, dry syrup or suspension.

In still another embodiment, there is provided a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof, wherein the composition exhibits dissolution of not less than 75% remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof in 45min.

In still another embodiment, there is provided a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof, wherein the composition is stable at 250C ± 20C & 60% RH ± 5 % RH after 6 months of stability period. Further the composition is also stable at 300C ± 20C & 75% RH ± 5 % RH and at 400C ± 20C & 75% RH ± 5 % RH after 6 months of stability period.

The disclosed immediate release formulation of remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof can exhibit desired drug dissolution profile, and can effectively control plasma glucose level in a mammalian subject having abnormal levels of plasma glucose.

In an embodiment, the composition is suitable for twice a day administration or once a day administration.

In an embodiment, the remogliflozin or ester or pharmaceutically acceptable salt thereof and teneligliptin or pharmaceutically acceptable salt thereof are administered in same dosage form or administered in separate dosage form.

In one embodiment, the remogliflozin is present as remogliflozin etabonate.

In another embodiment, teneligliptin is present as base or teneligliptin hydorbromide hydrate or teneligliptin oxalate.

In still another embodiment, there is provided a pharmaceutical composition comprising remogliflozin etabonate and teneligliptin hydorbromide or oxalate, wherein the composition exhibits dissolution of not less than 75% remogliflozin etabonate and teneligliptin hydorbromide or oxalate in 45min.

In still another embodiment, there is provided a pharmaceutical composition comprising remogliflozin etabonate and teneligliptin hydorbromide or oxalate, wherein the composition is stable at 250C ± 20C & 60% RH ± 5 % RH after 6 months of stability period. Further the composition is also stable at 300C ± 20C & 75% RH ± 5 % RH and at 400C ± 20C & 75% RH ± 5 % RH after 6 months of stability period.

In still another embodiment, the remogliflozin etabonate is present in the concentration from about 0.5 mg to 500 mg, even more preferably from about 1 to 300 mg, most preferably from about 1 to 270 mg. In still another embodiment, the remogliflozin etabonate is present in the concentration from about 250mg, or 200mg, or 150mg, or 100mg or 50mg.

In still another embodiment, the concentration of teneligliptin or pharmaceutically acceptable salt thereof is ranges from about 5mg to about 500mg, even more preferably from about 10mg to 300mg, even more preferably from about 10mg to about 100mg. Alternatively, teneligliptin or pharmaceutically acceptable salt thereof is present in amount of 10mg or 20mg or 30mg or 40mg or 50mg or 60mg or 70mg or 80mg.

In further embodiment, a weight ratio of remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof ranges from about 1:0.1 to about 15:1. In still another embodiment, a weight ratio of remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof ranges from about 1:0.1 to 13:1.

In a first embodiment of the invention, weight ratio of Remogliflozin and Teneligliptin is in the range of 2:1 to 15:1. In particular, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2:1 to 13:1. More particularly, weight ratio of Remogliflozin and Teneligliptin is in the range of 2.5: 1 to 13:1. Furthermore particularly, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.5:1 to 10:1

In a second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2:1 to 3.5:1. In accordance with a first aspect of the second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2:1 to 3.25:1. In accordance with a second aspect of the second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2:1 to 3:1. In accordance with a third aspect of the second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.25:1 to 3.5:1. In accordance with a fourth aspect of the second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.25:1 to 3.25:1. In accordance with a fifth aspect of the second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.25:1 to 3:1. In accordance with a sixth aspect of the second embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.5:1 to 3.5:1. In accordance with a seventh aspect of the second embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.5:1 to 3.25:1. In accordance with a eighth aspect of the second embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.5:1 to 3:1. In accordance with a ninth aspect of the second embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.75:1 to 3.5:1. In accordance with a tenth aspect of the second embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.75:1 to 3.25:1. In accordance with an eleventh seventh aspect of the second embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 2.75:1 to 3:1. In accordance with a twelfth aspect of the second embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is about 2.5:1.

In a third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4:1 to 6:1. In accordance with a first aspect of the third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4:1 to 5.5:1. In accordance with a second aspect of the third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4:1 to 5.25:1. In accordance with a third aspect of the third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4:1 to 5:1. In accordance with a fourth aspect of the third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.25:1 to 6:1. In accordance with a fifth aspect of the third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.25:1 to 5.5:1. In accordance with a sixth aspect of the third embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.25:1 to 5.25:1. In accordance with a seventh aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.25:1 to 5:1. In accordance with a eighth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.5:1 to 6:1. In accordance with a ninth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.5:1 to 5.5:1. In accordance with a tenth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.5:1 to 5.25:1. In accordance with an eleventh seventh aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.5:1 to 5:1. In accordance with a twelfth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.75:1 to 6:1. In accordance with a thirteenth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.75:1 to 5.5:1. In accordance with a fourteenth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.75:1 to 5.25:1. In accordance with a fifteenth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 4.75:1 to 5:1. In accordance with a sixteenth aspect of the third embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is about 5:1.

In a forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9:1 to 11:1. In accordance with a first aspect of the forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9:1 to 10.5:1. In accordance with a second aspect of the forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9:1 to 10.25:1. In accordance with a third aspect of the forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9:1 to 10:1. In accordance with a fourth aspect of the forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.25:1 to 11:1. In accordance with a fifth aspect of the forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.25:1 to 10.5:1. In accordance with a sixth aspect of the forth embodiment of the invention, the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.25:1 to 10.25:1. In accordance with a seventh aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.25:1 to 10:1. In accordance with an eighth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.5:1 to 11:1. In accordance with a ninth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.5:1 to 10.5:1. In accordance with a tenth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.5:1 to 10.25:1. In accordance with an eleventh seventh aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.5:1 to 10:1. In accordance with a twelfth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.75:1 to 11:1. In accordance with a thirteenth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.75:1 to 10.5:1. In accordance with a fourteenth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.75:1 to 10.25:1. In accordance with a fifteenth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is in the range of 9.75:1 to 10:1. In accordance with a sixteenth aspect of the forth embodiment of the invention the weight ratio of Remogliflozin and Teneligliptin is about 10:1.

In another aspect of invention, there is provide a pharmaceutical composition comprising about 50mg or about 100mg or about 250 mg of remogliflozin etabonate and about 10mg or 20mg or 30mg or 40mg or 50mg or 60mg or 70mg or 80mg of teneligliptin hydrobromide or oxalate.

In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutical composition comprising a combination of remogliflozin etabonate together with teneligliptin or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein remogliflozin etabonate is in the amount of 100 mg or 250 mg and wherein teneligliptin or its pharmaceutically acceptable salts thereof is in the amount of 10 mg or 20 mg.

In another embodiment, there is provided a pharmaceutical composition comprising a combination of remogliflozin etabonate together with teneligliptin or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein remogliflozin etabonate is in the amount of 100 mg or 250 mg, wherein teneligliptin or its pharmaceutically acceptable salts thereof is in the amount of 10 mg or 20 mg, and wherein combination of remogliflozin etabonate and teneligliptin or its pharmaceutically acceptable salts thereof shows synergistic effect in decreasing blood glucose level as compared to their individual effects.

In another embodiment, there is provided a pharmaceutical composition comprising a combination of remogliflozin etabonate together with teneligliptin or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein remogliflozin etabonate is in the amount of 100 mg or 250 mg, wherein teneligliptin or its pharmaceutically acceptable salts thereof is in the amount of 10 mg or 20 mg, wherein at least 75% of remogliflozin etabonate and teneligliptin or its pharmaceutically acceptable salts thereof are released within 45 minutes, and wherein combination of remogliflozin etabonate and teneligliptin or its pharmaceutically acceptable salts thereof shows synergistic effect in decreasing blood glucose level as compared to their individual effects.

The pharmaceutical composition of this invention comprises at least one pharmaceutically acceptable excipient such as one or more of rate controlling polymers or non-polymers, diluents, disintegrants, binders, bulking agents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, anti-tacking agents, emulsifiers, surfactants, plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents.

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. The concentration of polymer ranges from about 1-40% by weight of composition.

Suitable binders are selected from, but not limited to, polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone with other vinylderivatives, hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and starch. The concentration of binder ranges from about 1-30% by weight of composition.

Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide and magnesium aluminum silicate. The concentration of diluent ranges from about 1-35% by weight of composition.

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 concentration of lubricant ranges from about 1-25% by weight of composition.

Example of suitable glidants include, but are not limited to, colloidal silicon dioxide, stearic acid, talk, aluminium silicate or the mixtures thereof. The concentration of glidant ranges from about 1-25% by weight of composition.

Suitable disintegrants are selected from microcrystalline cellulose, low-substituted hydroxypropyl cellulose, maize starch, alginic acid and alginates, modified starches, Sodium starch glycolate, sodium carboxy methyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, docusate sodium, guar gum or the mixtures thereof. The concentration of disintegrant ranges from about 1-45% by weight of composition.

Suitable buffering agents may include, but are not limited to, one or more of a bicarbonate salt of alkali earth metal, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing.

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 sweeteners include aspartame, neotame, sucralose, sodium saccharine and the like.

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.

The present invention relates to a stable fix dose combination of remogliflozin etabomate and teneligliptin or pharmaceutically acceptable salt thereof.

In one embodiment of the invention, there is provided a pharmaceutical composition comprising a combination of remogliflozin etabonate together with teneligliptin or its pharmaceutically acceptable salts thereof, wherein the composition is monolayer tablet or bilayer tablet.

In one embodiment of the invention, there is provided a pharmaceutical composition comprising a combination of remogliflozin etabonate together with teneligliptin or its pharmaceutically acceptable salts thereof, wherein the composition is suitable for twice a day administration or once a day administration, and for the treatment of diabetes mellitus.

Alternatively, the invention composition is present in the form of a monolayer tablets having intra-granular and extragranular portion compressed together and coated.

In one embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and teneligliptin or pharmaceutically acceptable salt thereof and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin etabonate, teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin etabonate, teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient, wherein the composition exhibits dissolution of not less than 75% remogliflozin etabonate and teneligliptin hydrobromide or oxalate in 45min.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin etabonate, teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient, wherein the composition is stable at 250C ± 20C & 60% RH ± 5 % RH after 6 months of stability period. Further the composition is also stable at 300C ± 20C & 75% RH ± 5 % RH and at 400C ± 20C & 75% RH ± 5 % RH after 6 months of stability period.

In another embodiment of invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, teneligliptin or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

In another embodiment of invention, there is provided a use of a pharmaceutical composition according to any of the claim, for prevention, treatment or prophylaxis of diabetes.

In another embodiment of invention, there is provided a use of kit comprising a pharmaceutical composition according to any of the claim, treatment or prophylaxis of diabetes.

In another embodiment of invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, teneligliptin or pharmaceutically acceptable salt thereof, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant.

In another embodiment of invention, there is provided a pharmaceutical composition comprising: (a) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, teneligliptin or pharmaceutically acceptable salt thereof, crosscarmellose sodium, microcrystalline cellulose, povidone and water and (b) an extra-granular portion comprising crosscarmellose sodium, microcrystalline cellulose and magnesium stearate.

Alternatively, the invention composition are present as a bilayer composition having first layer or layer having one active and second layer or layer having second active.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and (b) a second layer comprising teneligliptin or pharmaceutically acceptable salt thereof.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient and (b) a second layer comprising teneligliptin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and (b) a second layer comprising teneligliptin or pharmaceutically acceptable salt thereof, wherein the composition is in the form of a bilayer tablet.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin etabonate and at least one pharmaceutically acceptable excipient and (b) a second layer comprising teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient, wherein the composition is in the form of a bilayer tablet.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant; and (b) a second layer comprising an intra-granular portion comprising teneligliptin or pharmaceutically acceptable salt thereof, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant; wherein the composition is a bilayer tablet.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising an intra-granular portion comprising remogliflozin etabonate, crosscarmellose sodium, microcrystalline cellulose, and povidone; and (b) an extra-granular portion comprising crosscarmellose sodium, microcrystalline cellulose and magnesium stearate; and (b) a second layer comprising an intra-granular portion comprising teneligliptin hydrobromide or oxalate, maize starch, microcrystalline cellulose, and hydroxypropyl cellulose; and (b) an extra-granular portion comprising L-hydroxypropyl cellulose and magnesium stearate; wherein the composition is a bilayer tablet.

In another embodiment, the bilayer tablet is coated with suitable coating such as film coating.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin etabonate and at least one pharmaceutically acceptable excipient and (b) a second layer comprising teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient, wherein the composition exhibits dissolution of not less than 75% remogliflozin etabonate and teneligliptin hydrobromide or oxalate in 45min.

In still another embodiment of the invention, there is provided a pharmaceutical composition comprising: (a) a first layer comprising remogliflozin etabonate and at least a pharmaceutically acceptable excipient and (b) a second layer comprising teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient, wherein the composition is stable at 250C ± 20C & 60% RH ± 5 % RH after 6 months of stability period. Further the composition is also stable at 300C ± 20C & 75% RH ± 5 % RH and at 400C ± 20C & 75% RH ± 5 % RH after 6 months of stability period.

The tablet dosage form of the present invention may be a bilayer tablet in which remogliflozin is present in a first layer and teneligliptin or pharmaceutically acceptable salt thereof is present in the second layer. Alternatively, the formulation may be a film-coated tablet in which remogliflozin is present in the core tablet and teneligliptin or pharmaceutically acceptable salt thereof is present in the film-coating layer. Alternatively, the tablet may be a trilayer tablet in which the two layers containing only remogliflozin and teneligliptin or pharmaceutically acceptable salt thereof are separated by a third layer which does not contain any active ingredient. Alternatively, the tablet may be a press-coated tablet, i.e. a tablet in which remogliflozin is contained in small tablets and the teneligliptin or pharmaceutically acceptable salt thereof is contained in a second granulation or blend and compressed together with one small tablet to one large press-coated tablet. All types of the herein before mentioned tablets may be without a coating or may have one or more coatings, in particular film-coatings.

The tablet-in-tablet dosage form of the invention may be prepared by compressing remogliflozin with one or more rate controlling polymer or non-polymer to form a core extended release tablet; and compressing remogliflozin and teneligliptin or pharmaceutically acceptable salt thereof optionally along with one or more pharmaceutically acceptable excipient onto said core tablet to form compressed outer tablet that causes immediate release.

In another aspect of the present invention, the pharmaceutical composition is formulated as an inlay tablet. Inlay tablets according to the present invention are tablets wherein inner tablet is positioned within a comparatively larger “outer” tablet in such a way that at least one surface of the inner tablet is not in contact with outer tablet. Inlay tablet dosage form of present invention comprises: (a) an inner inlayed tablet comprising remogliflozin and excipient(s) that causes extended release; and (b) an outer tablet comprising remogliflozin and teneligliptin or pharmaceutically acceptable salt thereof along with excipient(s) to cause immediate release.

In another aspect, this invention embraces capsule- in- capsule formulations wherein smaller size capsule is encapsulated into a larger capsule. Capsule-in-capsule consists of an external capsule and internal capsule (inner capsule) located therein. It is preferred that smaller size capsule is filled with remogliflozin and excipients so as to cause extended release while larger capsule is filled with remogliflozin and teneligliptin or pharmaceutically acceptable salt thereof along with excipients for immediate release.

In still another aspect, the pharmaceutical composition of the present invention on administration reduces Hb1Ac level and body weight of patient without causing hypoglycemia. Further the composition of the present invention complies with the in-vitro parameters and in-vivo parameters shown by the individual drugs.

EXAMPLES

EXAMPLE 1: A tablet composition of remogliflozin etabonate and teneligliptin hydrobromide.

Sr. No Ingredients Ex-1.1
Mg/tab Ex-1.2
Mg/tab Ex-1.3
Mg/tab Ex-1.4
Mg/tab Ex-1.5
Mg/tab
Intragranular Part
1 Remogliflozin Etabonate 100.00 100.00 100.00 200.00 200.00
2 Teneligliptin Hydrobromide hydrate 14.74 29.48 58.96 29.48 58.96
3 Croscarmellose Sodium 4.80 4.80 4.80 4.80 4.80
4 Microcrystalline Cellulose (Avicel PH 101) 20.67 20.67 20.67 20.67 20.67
Binder solution
5 Povidone K 30 (Plasdone K 29/32) 6.67 6.67 6.67 6.67 6.67
6 Purified Water q.s. q.s. q.s. q.s. q.s.
Intragranular part Total 146.88 161.62 191.10 261.61 291.10
Extra granular Part
7 Croscarmellose Sodium 6.72 6.72 6.72 6.72 6.72
8 Microcrystalline Cellulose (Avicel PH 102) 163.52 148.78 119.30 48.78 19.30
9 Magnesium Stearate 2.88 2.88 2.88 2.88 2.88
Core Tablet weight 320.00 320.00 320.00 320.00 320.00
Coating
10 Opadry White YS – 1 – 18202A 8.00 8.00 8.00 8.00 8.00
11 Purified Water q.s. q.s. q.s. q.s. q.s.
Coated Tablet weight 328.00 328.00 328.00 328.00 328.00

* Teneligliptin hydrobromide 14.74 mg, 29.48 mg and 58.96 mg correspond to Teneligliptin base 10 mg, 20 mg and 40 mg respectively

Manufacturing process for formulations of example 1:
S. No. Step Process
1 Sifting • Intragranular excipients are sifted through # 20 sieves.
2 Binder solution preparation • Povidone K 30 is added in purified water.
3 Granulation • Step no. 1 is granulated using step 2 binder solution.
4 Drying & sizing • Drying is done in FBD at 70° till LOD is around 2 % w/w.
• Sizing of granules is done using #30 sieve.
5 Sifting of extra granular material • Extragranular excipients are sifted using #40 sieve and Magnesium stearate using #60 sieve.
6 Blending & Lubrication • Above sifted blend (except Magnesium stearate) and Aerosil are mixed in a suitable blender for 12 min at 12 RPM.
• Then Magnesium stearate is added to it & mixed for another 3 min at 12 RPM.
7 Compression • Compress the tablets using suitable punches.
8 Packing • Blister packing (Alu-Alu blisters)

EXAMPLE 2: A tablet composition of remogliflozin etabonate and teneligliptin hydrobromide.

Sr. No Ingredients Ex-2.1
Mg/tab Ex-2.2
Mg/tab Ex-2.3
Mg/tab Ex-2.4
Mg/tab Ex-2.5
Mg/tab
Intragranular Part
1 Remogliflozin Etabonate 100.00 100.00 100.00 200.00 200.00
2 Teneligliptin Hydrobromide hydrate 14.74 29.48 58.96 29.48 58.96
3 Maize starch 46.00 46.00 46.00 46.00 46.00
4 Microcrystalline Cellulose (Avicel PH 101) 242.26 227.52 198.04 127.52 98.04
Binder solution
5 Hydroxy propyl cellulose (Klucel LF) 6.00 6.00 6.00 6.00 6.00
6 Purified Water q.s. q.s. q.s. q.s. q.s.
Intragranular part Total 409.00 409.00 409.00 409.00 409.00
Extra granular Part
7 L-Hydroxy propyl cellulose (L-HPC Type 11) 32.00 32.00 32.00 32.00 32.00
8 Colloidal silicone dioxide 4.50 4.50 4.50 4.50 4.50
9 Magnesium Stearate 4.50 4.50 4.50 4.50 4.50
Core Tablet weight 450.00 450.00 450.00 450.00 450.00
Coating
10 Opadry White YS – 1 – 18202A 14.00 14.00 14.00 14.00 14.00
11 Purified Water q.s. q.s. q.s. q.s. q.s.
Coated Tablet weight 464.00 464.00 464.00 464.00 464.00

* Teneligliptin hydrobromide 14.74 mg, 29.48 mg and 58.96 mg correspond to Teneligliptin base 10 mg, 20 mg and 40 mg respectively

Manufacturing process for formulations of example 2:
S. No. Step Process
1 Sifting • Intragranular excipients are sifted through # 20 sieves.
2 Binder solution preparation • Hydroxy propyl cellulose (Klucel LF) is added in purified water.
3 Granulation • Step no. 1 is granulated using step 2 binder solution.
4 Drying & sizing • Drying is done in FBD at 60° till LOD is around 2 % w/w.
• Sizing of granules is done using #30 sieve.
5 Sifting of extra granular material • Extragranular excipients are sifted using #40 sieve and Magnesium stearate using #60 sieve.
6 Blending & Lubrication • Above sifted blend (except Magnesium stearate) and Aerosil are mixed in a suitable blender for 12 min at 12 RPM.
• Then Magnesium stearate is added to it & mixed for another 3 min at 12 RPM.
7 Compression • Compress the tablets using suitable punches.
8 Packing • Blister packing (Alu-Alu blisters)

EXAMPLE 3: A bilayer tablet composition of remogliflozin etabonate and teneligliptin hydrobromide.

Remogliflozin Etabonate layer
Ingredients Ex-3.1
Mg/tab Ex-3.2
Mg/tab Ex-3.3
Mg/tab Ex-3.4
Mg/tab Ex-3.5
Mg/tab
Intragranular Part
Remogliflozin Etabonate 100.00 100.00 100.00 200.00 200.00
Croscarmellose Sodium 4.80 4.80 4.80 4.80 4.80
Microcrystalline Cellulose (Avicel PH 101) 20.67 20.67 20.67 20.67 20.67
Binder solution
Povidone K 30 (Plasdone K 29/32) 6.67 6.67 6.67 6.67 6.67
Purified Water q.s. q.s. q.s. q.s. q.s.
Intragranular part Total 132.14 132.14 132.14 232.14 232.14
Extra granular Part
Croscarmellose Sodium 6.72 6.72 6.72 6.72 6.72
Microcrystalline Cellulose (Avicel PH 102) 178.26 178.26 178.26 78.26 78.26
Magnesium Stearate 2.88 2.88 2.88 2.88 2.88
Weight of Remogliflozin Etabonate layer 320.00 320.00 320.00 320.00 320.00

Teneligliptin Layer
Ingredients Ex-3.1
Mg/tab Ex-3.2
Mg/tab Ex-3.3
Mg/tab Ex-3.4
Mg/tab Ex-3.5
Mg/tab
Intragranular Part
Teneligliptin Hydrobromide hydrate 14.74 29.48 58.96 29.48 58.96
Maize starch 23.00 23.00 23.00 23.00 23.00
Microcrystalline Cellulose (Avicel PH 101) 116.01 101.27 71.79 101.27 71.79
Binder solution
Hydroxy propyl cellulose (Klucel LF) 3.00 3.00 3.00 3.00 3.00
Purified Water q.s. q.s. q.s. q.s. q.s.
Intragranular part Total 156.75 156.75 156.75 156.75 156.75
Extra granular Part
L-Hydroxy propyl cellulose (L-HPC Type 11) 16.25 16.25 16.25 16.25 16.25
Colloidal silicone dioxide 1.00 1.00 1.00 1.00 1.00
Magnesium Stearate 1.00 1.00 1.00 1.00 1.00
Weight of Teneligliptin Layer 175.00 175.00 175.00 175.00 175.00
Bilayer Tablet weight 495.00 495.00 495.00 495.00 495.00
Coating
Opadry White YS – 1 – 18202A 15.00 15.00 15.00 15.00 15.00
Purified Water q.s. q.s. q.s. q.s. q.s.
Coated Tablet weight 510.00 510.00 510.00 510.00 510.00

* Teneligliptin hydrobromide 14.74 mg, 29.48 mg and 58.96 mg correspond to Teneligliptin base 10 mg, 20 mg and 40 mg respectively

Manufacturing process for formulations of example 3:
S. No. Step Process
Remogliflozin Etabonate layer
1 Sifting • Intragranular excipients are sifted through # 20 sieves.
2 Binder solution preparation • Povidone is added in purified water.
3 Granulation • Step no. 1 is granulated using step 2 binder solution.
4 Drying & sizing • Drying is done in FBD at 60° till LOD is around 2 % w/w.
• Sizing of granules is done using #30 sieve.
5 Sifting of extra granular material • Extragranular excipients are sifted using #40 sieve and Magnesium stearate using #60 sieve.
6 Blending & Lubrication • Above sifted blend (except Magnesium stearate) and Aerosil are mixed in a suitable blender for 12 min at 12 RPM.
• Then Magnesium stearate is added to it & mixed for another 3 min at 12 RPM.
Teneligliptin layer
1 Sifting • Intragranular excipients are sifted through # 20 sieves.
2 Binder solution preparation • Hydroxy propyl cellulose (Klucel LF) is added in purified water.
3 Granulation • Step no. 1 is granulated using step 2 binder solution.
4 Drying & sizing • Drying is done in FBD at 60° till LOD is around 2 % w/w.
• Sizing of granules is done using #30 sieve.
5 Sifting of extra granular material • Extragranular excipients are sifted using #40 sieve and Magnesium stearate using #60 sieve.
6 Blending & Lubrication • Above sifted blend (except Magnesium stearate) and Aerosil are mixed in a suitable blender for 12 min at 12 RPM.
• Then Magnesium stearate is added to it & mixed for another 3 min at 12 RPM.
7 Compression of bilayer tablets • Compress the tablets using suitable punches with Remogliflozin layer & Teneligliptin layer.
8 Packing • Blister packing (Alu-Alu blisters)

EXAMPLE 4: Dissolution data of formulation of examples 1, 2 and 3:

Dissolution study of the formulations described in examples 1, 2 and 3 are performed in various dissolution mediums like phosphate buffer pH 3.0, 0.1M HCl, acetate Buffer pH 4.5 and phosphate Buffer pH 6.8 using 900 ml volume at 75 RPM. In all these dissolution mediums, both remogliflozin etabonate & teneligliptin hydrobromide hydrate release not less than (NLT) 75% in 45 minutes.

Example 5: Stability data of bilayer tablet of composition of example 3.1

250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Specification Initial 6M 6M 6M
RS Remogliflozin
i) Impurity A NMT 1.0% 0.09 0.09 0.09 0.09
ii) Single Max. NMT 0.5% 0.11 0.10 0.11 0.12
iii)Total Imp NMT 2.0% 0.52 0.60 0.11 0.12
RS for Teneligliptin
i) Impurity-A NMT 1.0% 0.22 0.26 0.30 0.47
ii) Single Max NMT 0.5% 0.27 0.27 0.30 0.35
iii) Total impurities NMT 2.0% 0.63 0.75 0.93 1.80
Assay
a) Remogliflozin 90.0 % to 110.0 % LA 97.4 100.9 101.8 101.7
b) Teneligliptin 90.0 % to 110.0 % LA 102.7 103.2 105.5 99.5

EXAMPLE 6: Effect of remogliflozin etabonate & teneligliptin hydrobromide hydrate on blood glucose using Oral Glucose Tolerance Test (OGTT) in healthy SD Rats.

METHODOLOGY: Oral glucose tolerance test (OGTT) was performed in Sprague Dawley healthy male rats (6 to 8 weeks old). Rats were divided into different treatment groups based on overnight-fasting whole-blood-glucose (WBG). Rats in control groups were orally dosed with glucose, whereas the treatment groups received a dose of glucose as well as respective treatment. After glucose challenge, WBG was measured at 15, 30, 60 and 120 minutes by tail-cut method using glucose meter. Journal of Endocrinology (2014) 222, G13–G25. European Journal of Pharmacology 729 (2014) 59–66.

RESULTS: As shown in Figure 1, Remogliflozin 1mg/kg alone did not show anti-hyperglycemic effect (decrease in blood glucose AUC). Teneligliptin alone 10mg/kg decreased blood glucose AUC by 15%. The combination of remogliflozin and teneligliptin significantly decreased blood glucose (27%).

As shown in Figure 2, Remogliflozin 3mg/kg, teneligliptin 1mg/kg or 10mg/kg decreased blood glucose by 9%, 11% and 12%, respectively. Combination of remogliflozin 3mg/kg and teneligliptin 1mg/kg, lowered blood glucose AUC by 31%. Combination of remogliflozin 3mg/kg and teneligliptin 10mg/kg, reduced the blood glucose AUC by 30%.

CONCLUSIONS: Combination of remogliflozin etabonate and teneligliptin hydrobromide hydrate showed synergistic effect in decreasing blood glucose compared to their individual effects. For the combination, a 3-fold increase in the dose of remogliflozin favored a 10-fold decrease in the dose of teneligliptin required to achieve maximal synergism.

Example 7: Comparison of Remogliflozin and Teneligliptin free drug concentration combination ratio in rat and human

Table below shows the free drug Cmax concentrations of Remogliflozin and Teneligliptin in both rat and human species. The ratio of fold over Ki/IC50 values (Remogliflozin : Teneligliptin :: ~1:1) approximate to be similar in both species.
Species Treatment Plasma Cmax conc. (ng/mL) Plasma Cmax conc (nmol)* Free drug Cmax conc. (nM)# Fold Over Ki/IC50
(Biochemical)% Dose Ratio Fold Over Ratio
Rat Remogliflozin 3 mg/kg 252.7 544.1 288.4 11 3:1 ~1:1


Teneligliptin 1 mg/kg 152.4 357.1 50.0 17


Human Remogliflozin 100 mg 536.2 1154.3 404.0 34 10:1 ~1:1


Teneligliptin 10 mg 116.0 271.7 59.8 30

*Molecular weight (Remogliflozin=464.5); Teneligliptin=426.8)
# Rat PPB (Remogliflozin=47%); Teneligliptin=86%)
Human PPB (Remogliflozin=65%); (Teneligliptin=78%)
% Rat Ki (Remogliflozin=26 nM); Rat IC50 (Teneligliptin=3 nM)
Human Ki (Remogliflozin=12 nM); Rat IC50 (Teneligliptin=2 nM)

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 Claim:

1. A pharmaceutical composition comprising a combination of remogliflozin etabonate together with teneligliptin or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

2. The composition as claimed in claim 1, wherein remogliflozin etabonate is in the amount of 100 mg or 250 mg.

3. The composition as claimed in claim 1, wherein teneligliptin or its pharmaceutically acceptable salts thereof is in the amount of 10 mg or 20 mg or 40 mg.

4. The composition as claimed in claim 1, wherein pharmaceutically acceptable salt of teneligliptin is hydrobromide salt or an oxalate salt.

5. The composition as claimed in claim 1, wherein a weight ratio of remogliflozin etabonate and teneligliptin is in the range of 2:1 to 15:1, particularly 2:1 to 13:1.

6. The composition as claimed in claim 1, wherein a weight ratio of remogliflozin etabonate and teneligliptin is in the range of 2.5:1 to 10:1

7. The composition as claimed in claim 1, wherein the composition is monolayer tablet or bilayer tablet.

8. The composition as claimed in claim 5, wherein the composition is monolayer tablet comprising (a) an intra-granular portion comprising remogliflozin etabonate and teneligliptin hydrobromide or oxalate and (b) an extra-granular portion comprising at least one pharmaceutically acceptable excipient.

9. The composition as claimed in claim 6, wherein the composition comprising (a) an intra-granular portion comprising remogliflozin etabonate and teneligliptin hydrobromide or oxalate, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant and a lubricant.

10. The composition as claimed in claim 7, wherein the composition comprising (a) an intra-granular portion comprising remogliflozin etabonate and teneligliptin hydrobromide or oxalate, crosscarmellose sodium, microcrystalline cellulose, and povidone and (b) an extra-granular portion comprising crosscarmellose sodium, microcrystalline cellulose and magnesium stearate.

11. The composition as claimed in claim 5, wherein the composition is bilayer tablet comprising (a) a first layer comprising remogliflozin etabonate and at least one pharmaceutically acceptable excipient and (b) a second layer comprising teneligliptin hydrobromide or oxalate and at least one pharmaceutically acceptable excipient.

12. The composition as claimed in claim 9, wherein the composition is bilayer tablet comprising (a) a first layer comprising an intra-granular portion comprising remogliflozin etabonate, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant; and (b) a second layer comprising an intra-granular portion comprising teneligliptin hydrobromide or oxalate, a disintegrant, a diluent, and a binder; and (b) an extra-granular portion comprising a disintegrant, a diluent and a lubricant.

13. The composition as claimed in claim 10, wherein the composition is bilayer tablet comprising(a) a first layer comprising an intra-granular portion comprising remogliflozinetabonate, crosscarmellose sodium, microcrystalline cellulose, and povidone; and (b) an extra-granular portion comprising crosscarmellose sodium, microcrystalline cellulose and magnesium stearate; and (b) a second layer comprising an intra-granular portion comprising teneligliptin hydrobromide or oxalate, maize starch, microcrystalline cellulose, and hydroxypropyl cellulose; and (b) an extra-granular portion comprising L-hydroxypropyl cellulose and magnesium stearate.

14. The composition as claimed in claim 5, wherein the composition is further coated with film coating layer.

15. The composition as claimed in claim 1, wherein the at least one pharmaceutically acceptable excipient is such that at least 75% of remogliflozin etabonate and teneligliptin hydrobromide or oxalate are released within 45 minutes.

16. The composition as claimed in claim 1, wherein the composition is stable after 6 months of stability condition of 250C ± 20C & 60% relative humidity ± 5 % relative humidity, 300C ± 20C & 75 % relative humidity ± 5 % relative humidity and 400C ± 20C & 75 % relative humidity ± 5 % relative humidity.