WO2018198102A1

WO2018198102A1 - Oral pharmaceutical formulations of remogliflozin

Info

Publication number: WO2018198102A1
Application number: PCT/IB2018/054091
Authority: WO
Inventors: Ulhas Dhuppad; Nitin Deshmukh; Krishna SADAPHAL
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2017-06-08
Filing date: 2018-06-07
Publication date: 2018-11-01
Anticipated expiration: 2019-12-08
Also published as: PH12019502767A1; MX2019014687A; KR20200013719A; CN110753540A; BR112019026029A2

Abstract

The present invention relates to an immediate release oral formulation of remogliflozin or pharmaceutically acceptable salts thereof administered in patients in need thereof, for the treatment of diabetes mellitus. The present invention further relates to a pharmaceutical formulation comprising synergistic combination of remogliflozin etabonate and metformin hydrochloride. In a preferred embodiment, the invention relates to a bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin etabonate or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salt thereof.

Description

ORAL PHARMACEUTICAL FORMULATIONS OF REMOGLIFLOZIN

PRIORITY DOCUMENTS

This patent application claims priority to Indian Provisional Patent Application number 201721020166 (filed on June 8, 2017) the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present disclosure relates to technical field of pharmaceutical formulations. In particular, the present disclosure relates to immediate release formulation of remogliflozin for oral administration. The present disclosure further relates to pharmaceutical formulation that includes a synergistic combination of remogliflozin and metformin.

BACKGROUND OF THE INVENTION

Type II diabetes is characterized by insulin resistance and impaired glucose- stimulated insulin secretion by the pancreatic-cells, and it has increased in incidence with changes in lifestyles that lead to weight gain and obesity. When a restricted lifestyle is not maintained, chronic hyperglycemia leads to progressive impairment of insulin secretion and to insulin resistance of peripheral tissues, a phenomenon often referred to as glucose toxicity, which further worsens the blood glucose level.

The treatment of type II diabetes usually begins with dietary changes and exercise, followed by oral antidiabetic therapy. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in blood. Oral therapeutic options for the treatment of type II 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. Among the oral antidiabetic agents, only metformin is regarded as the first-line drug of choice for the treatment of type II diabetes in overweight and obese people. Metformin is usually administered orally, and it improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. However, the United Kingdom Prospective Diabetes Study demonstrated that intensive treatment of type II diabetes with metformin resulted in only a limited improvement of glycemic control. Further, the use of conventional combination therapies, e.g. combination of metformin with sulfonylurea may show an increased risk for side effects, such as hypoglycemia or weight gain, which may limit their safety and efficacy.

Remogliflozin is another class of antidiabetic agent useful for the treatment of type

II diabetes. Remogliflozin is a highly selective sodium glucose co-transporter 2 (SGLT2) inhibitor. The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. Remogliflozin works by inhibiting the sodium-glucose transport (SGLT) proteins which are responsible for glucose reabsorption in the kidney (Fujimori et al., Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268-276). Remogliflozin etabonate is a prodrug of remogliflozin. Remogliflozin etabonate is chemically known as 5 -methyl-4-[4-(l -methylethoxy)benzyl]-l-(l -methyl ethyl)- 1H- pyrazol-3-yl 6-0-(ethoxycarbonyl)- -D-glucopyranoside. Remogliflozin etabonate is also known as GSK 189075 or KGT-1681. Upon administration and absorption, the prodrug is converted to its active form remogliflozin and acts selectively on the SGLT2. It has been shown that oral administration of remogliflozin etabonate increases urinary glucose excretion in a dose-dependent manner in both rodents and humans (Fujimori et al., Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268-276). Remogliflozin etabonate is described in patent publications EP 1354888 Al and EP 1213296 Al .

Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type II diabetes in human subjects suffering from diabetes. Efforts have been made to develop oral formulations of remogliflozin for the treatment of type II diabetes.

WO2001016147 relates to remogliflozin base, WO02053573_relates to remogliflozin etabonate, WO2012006398 A2_relates to biphasic formulation comprising remogliflozin etabonate in immediate and controlled release phases, US8951976 relates to method of treatment for NAFL, NASH, hypernutritive fatty liver, alcoholic fatty liver disease, diabetic fatty liver and acute fatty liver using remogliflozin etabonate, WO2010092125 relates to composition comprising (a) an SGLT2 inhibitor, and (b) a DPPIV inhibitor, and (c) a third anti-diabetic agent

Although several approaches have been reported in the art with respect to formulations comprising remogliflozin, there remains a substantial need in the art for new and improved pharmaceutical formulations of remogliflozin which exhibit advantageous effect on the treatment of type II diabetes mellitus.

The present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability.

SUMMARY OF THE INVENTION

According to one aspect of the present disclosure there is provided a solid oral pharmaceutical formulation that includes remogliflozin in combination with one or more pharmaceutically acceptable excipients. The disclosed formulation of remogliflozin can provide immediate release of the drug, and can effectively control plasma glucose level in a mammalian subject having abnormal levels of plasma glucose.

In an embodiment of the present disclosure, the immediate release formulation of remogliflozin can include an intragranular portion and an extragranular portion. The intragranular portion can include a quantity of remogliflozin in combination with at least one disintegrant and at least one binder. The extragranular portion can include at least one disintegrant and at least one lubricant. According to embodiments of the present disclosure, the immediate release formulation of remogliflozin can further include a coating, preferably film coating.

In preferred embodiment, the formulation of remogliflozin is in the form of an immediate-release tablet for oral administration.

According to another aspect of the present disclosure there is provided a combination formulation that includes a synergistic combination of remogliflozin and metformin. The combination formulation can exhibit a synergist effect on glycemic control in subjects with diabetes, thereby enhancing the treatment effectiveness.

In an embodiment, the combination formulation disclosed herein can be in the form of a solid dosage form which can include (a) a first layer including metformin or a pharmaceutically acceptable salt thereof in an extended release formulation; and (b) a second layer including remogliflozin in an immediate release formulation.

In a preferred embodiment, the combination formulation can include remogliflozin in the form of remogliflozin etabonate, and metformin in the form of metformin hydrochloride.

In a more preferred embodiment, the combination formulation disclosed herein can be in the form of a fixed dose bilayer tablet for oral administration.

In an embodiment, the present invention relates to the use of fixed dose solid oral dosage form comprising remogliflozin etabonate and metformin hydrochloride for the treatment of diabetes mellitus wherein remogliflozin etabonate is present in an immediate release form and metformin hydrochloride is present in an extended release form.

In another embodiment, the present invention relates to method of treating diabetes mellitus by administering a patient in need thereof, a fixed dose solid oral dosage form comprising remogliflozin etabonate in an immediate release form and metformin hydrochloride in an extended release form.

Further in an embodiment, the present invention relates to a bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the tablet may comprise one or more pharmaceutically acceptable excipients. In the preferred embodiment, the immediate release layer comprises remogliflozin etabonate in an amount of about lOOmg or 250mg and the extended release layer comprises metformin hydrochloride in an amount of about 500mg or 850mg or 1000 mg with one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention relates to bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the total daily dose of remogliflozin or pharmaceutically acceptable salts does not exceed 500mg and total daily dose of metformin or pharmaceutically acceptable salts does not exceed 2000mg.

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

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.

FIG.l is a flow chart showing an exemplary process for producing remogliflozin etabonate immediate release tablets.

FIG.2 is a flow chart showing an exemplary process for producing bilayer tablets comprising a fixed dose combination of remogliflozin etabonate and metformin hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

As used in the description herein and throughout the claims that follow, the meaning of "a," "an," and "the" includes plural reference 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.

Unless the context requires otherwise, throughout the specification which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense that is as "including, but not limited to."

In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, process conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

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 recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

The term "treating" and its grammatical variants (e.g. "to treat," "treating," and

"treatment") refer to administration of remogliflozin etabonate to a patient with the purpose of ameliorating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. Such symptoms may be chronic or acute; and such amelioration may be partial or complete.

Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

The present invention relates to immediate release oral formulation of remogliflozin for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity. The invention also relates to synergistic combination of remogliflozin and other anti diabetic agent wherein remogliflozin is available in immediate release dosage form.

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

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

The term metformin refers to metformin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof. 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.

As used herein, the term "immediate release" refers to a feature of a pharmaceutical formulation wherein the pharmaceutically active agent in the formulation is made bioavailable without substantial delay.

As used herein, the term "intragranular" refers to the ingredients incorporated prior to granulation and "extragranular" refers to incorporation of the ingredie ts after granulation.

In an embodiment of the present disclosure, the immediate release formulation of remogliflozin can include an intragranular portion and an extragranular portion. The intragranular portion can include a quantity of remogliflozin in combination with at least one disintegrant and at least one binder. The extragranular portion can include at least one disintegrant and at least one lubricant.

According to embodiments of the present disclosure, the immediate release formulation of remogliflozin can further include a coating, preferably film coating.

According to embodiments of the present disclosure, the immediate release formulation of remogliflozin can be in the form of a solid dosage form for oral administration. In a more preferred embodiment, the disclosed formulation of remogliflozin can be in the form of an immediate -release tablet for oral administration.

Immediate release tablets may further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to one or more of diluents, disintegrant, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, opacifiers, colorants, gelling agents / viscosity modifying agents, antioxidants, solvents, co-solvents, and combinations thereof. Formulations may comprise polymeric excipients for extended release of the drug.

Non-limiting examples of diluents include one or more of 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 and combinations thereof. The diluents according to current invention are present in an amount 5-30% w/w.

Non limiting examples of disintegrants suitable for use herein include, povidone, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, pregelatinised starch, micro crystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Several specific types of disintegrant are suitable for use in the formulations 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 0.1-5% w/w.

Non limiting examples of binder include starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols. The binder according to current invention are present in an amount 0.5-10% 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. Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid ("EDTA"), and disodium edetate and EDTA derivatives. The binder according to current invention are present in an amount 0.1-2% w/w. Non-limiting examples of polymers include one or more of gum arabic, guar gum, sodium based lignosulfonate, polyethylene oxide, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate and cellulosic polymers including hydroxyl propyl cellulose, carboxy methyl cellulose, hydroxyl propyl methyl cellulose,.

Solvents include one or more of aqueous or non-aqueous solvents including alcoholic solvents and oils. Non-limiting examples include water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol and higher alcohols; hydrogenated castor oil, 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.

The immediate release tablet according to present invention comprises combination of remogliflozin etabonate and metformin further comprising crosscarmellose sodium, microcrystalline cellulose, magnesium stearate and povidone.

In an illustrative embodiment, the remogliflozin immediate release formulation disclosed herein can include (a) an intragranular portion including remogliflozin, at least one disintegrant and at least one binder; (b) an extragranular portion including at least one disintegrant and at least one lubricant; and (c) a coating.

In a more preferred embodiment, the intragranular portion of the immediate release formulation can include (by weight): 31.25% remogliflozin etabonate, 1.5% croscarmellose sodium, 6.46% microcrystalline cellulose, and 2.08% K 29/32. The extragranular portion can include (by weight): 2.1% croscarmellose sodium, 55.71% microcrystalline cellulose, and 0.90% magnesium stearate. The coating can include 2.0-3.0% by weight of opadry white.

In another aspect, the present disclosure provides a method for treating type II diabetes in a mammalian subject suffering from diabetes. The method can include administering to the mammalian subject a therapeutically effective amount of the immediate release formulation of remogliflozin disclosed herein.

Further in an embodiment, the present invention relates to a bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the tablet may comprise one or more pharmaceutically acceptable excipients.

In the preferred embodiment, the immediate release layer comprises remogliflozin etabonate in an amount of about lOOmg or 250mg and the extended release layer comprises metformin hydrochloride in an amount of about 500mg or 850mg or 1000 mg with one or more pharmaceutically acceptable excipients.

In another aspect, the present disclosure provides a combination formulation that includes remogliflozin in combination with metformin or a pharmaceutically acceptable salt thereof.

In an embodiment, the combination formulation disclosed herein can be in the form of a solid dosage form which can include (a) a first layer including metformin or a pharmaceutically acceptable salt thereof in an extended release formulation; and (b) a second layer including remogliflozin in an immediate release formulation. As used herein, the term "extended release" means a pharmaceutical formulation designed to gradually and continually release amounts of metformin or its pharmaceutically acceptable salt to maintain a level of therapeutic or prophylactic effect over an extended period of time.

In a more preferred embodiment, the combination formulation disclosed herein can be in the form of a fixed dose bilayer tablet for oral administration. The bilayer tablet can include metformin hydrochloride extended release formulation as the first layer, and remogliflozin etabonate immediate release formulation as the second layer.

The amount of metformin in the present combination formulation can range from 30% to 90% by weight based on the total weight of the combination formulation, and the amount of remogliflozin can range from 5% to 60% by weight based on the total weight of the combination formulation.

The present invention relates to remogliflozin etabonate in daily dose of lOOmg, 200mg, 250mg and 500mg in single or divided doses and is administered to patients who have inadequate glycemic control. The total daily dose of remogliflozin etabonate does not exceed 500mg. the current formulation can be administered once or twice daily.

The present invention relates to metformin hydrochloride in daily dose of 500mg, 750, 800mg and lOOOmg in single or divided doses and is administered to patients who have inadequate glycemic control. The total daily dose of metformin hydrochloride does not exceed 2000mg. The current formulation relates to the synergistic combination of remogliflozin etabonate and metformin hydrochloride which can be administered once or twice daily.

In a preferred embodiment, the first layer of the combination formulation can contain 500 mg of metformin hydrochloride in an extended release formulation, and the second layer of the combination formulation can contain 100 mg of remogliflozin etabonate in an immediate release formulation.

In another preferred embodiment, the first layer can contain 500 mg of metformin hydrochloride in an extended release formulation, and the second layer can contain 250 mg of remogliflozin etabonate in an immediate release formulation. In another preferred embodiment, the first layer can contain 1000 mg of metformin hydrochloride in an extended release formulation, and the second layer can contain 100 mg of remogliflozin etabonate in an immediate release formulation.

In yet another preferred embodiment, the first layer can contain 1000 mg of metformin hydrochloride in an extended release formulation, and the second layer can contain 250 mg of remogliflozin etabonate in an immediate release formulation.

According to embodiments of the present disclosure, both the extended release metformin layer and the immediate release remogliflozin layer can include one or more pharmaceutically acceptable excipients.

Present invention relates to a stable bilayer tablet composition comprising immediate release remogliflozin etabonate layer and extended release layer comprising metformin or pharmaceutically acceptable salt, solvate, prodrugs, esters thereof, wherein the composition exhibits dissolution of not less than 75% remogliflozin etabonate in 45min, not less than 20% metformin or salts thereof in 60min and not less than 80% metformin or salts thereof in lOhrs.

The present invention also relates to a stable composition of remogliflozin etabomate wherein remogliflozin etabonate is present in immediate release form.

In another embodiment, the present invention relates to a stable bilayer composition of remogliflozin etabonate and metformin hydrochloride wherein, remogliflozin etabonate is present in immediate release layer whereas metformin hydrochloride is present in an extended release layer.

Immediate release Remogliflozin tablet formulation as well as bilayer formulation of remogliflozin and metformin are stable at 25°C ± 20C & 60% RH ± 5 % RH. Further formulations are also stable at 30°C ± 20C & 75% RH ± 5 % RH and at 40°C ± 20C & 75% RH ± 5 % RH

In yet another aspect, the present disclosure provides a method for treating type II diabetes in a mammalian subject suffering from diabetes. The method can include administering to the mammalian subject a therapeutically effective amount of a combination formulation in the form of a solid dosage form which includes (a) a first layer including metformin or a pharmaceutically acceptable salt thereof in an extended release formulation; and (b) a second layer including remogliflozin in an immediate release formulation.

According to embodiments of the present disclosure, the immediate release formulation of remogliflozin and the combination formulation of remogliflozin and metformin can be administered to mammalian subjects, preferably humans, for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.

While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.

EXAMPLES

The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

EXAMPLE 1: Table- 1 below lists the ingredients and amount for the formulation of remogliflozin 100 mg immediate -release tablets.

Table-1

Binder

Povidone K 29/32 6.665 2.08

Purified Water q.s -

Extragranular Portion

Croscarmellose Sodium 6.720 2.10

Microcrystalline cellulose 178.267 55.71

Magnesium Stearate 2.880 0.90

320

Film Coating

Opadry White YS- 1 - 18202A 8.000 2.50

Total Film Coated Tablet 328

The processing steps as shown in the flow chart of FIG. 1 were used to manufacture remogliflozin 100 mg immediate-release tablets. EXAMPLE 2: Table-2 below lists the ingredients and amount for the formulation of remogliflozin 250 mg immediate-release tablets.

Table-2

Microcrystalline cellulose 445.667 55.71

Magnesium Stearate 7.200 0.90

800

Film Coating

Opadry White YS- 1 - 18202A 16.000 2.00

Total Film Coated Tablet 816

The processing steps as shown in the flow chart of FIG. 1 were used to manufacture 250 mg immediate -release tablets of remogliflozin. EXAMPLE 3: Table-3 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HC1 (500 mg) extended release formulation and remogliflozin etabonate (100 mg) immediate release formulation.

Table-3

Remoglifloziii Eiabcmate immediate release layer

Ifitragramilar Portion

Remoglifiozm Etabonate 100.000 31.25

Croscarmellose Sodium 4.800 1.50

Microcrystalline cellulose 20.668 6.46

Binder

Po vidone K 29/32 6.665 2.08

Purified Water q.s -

Extragranular Portion

Croscarmellose Sodium 6.720 2.10

Ferric oxide Yellow 0.1 0.1

Microcrystalline cellulose 177.947 55.61

Magnesium Stearate 2.880 0.90

Total Remoglifiozin Etabonate 320

immediate release

Total Core Bilayer 1075

Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2. EXAMPLE 4: Table-4 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HC1 (500 mg) extended release formulation and remoglifiozin etabonate (250 mg) immediate release formulation.

Table-4

Carboxy Methyl Cellulose 41 ,000 5.430

Methyl Paraben 1.500 0.199

Propyl Paraben 0.150 0.020

Purified Water q.s -

Blending and Lubrication

Hydroxy Propyl Methyl Cellulose 87.350 11.570

Pre-Gelatinised Starch 9.000 1.192

Polyethylene oxide 40.000 5.298

Hydrogenated Caster Oil 5.000 0.662

Magnesium Stearate 5.000 0.662

Total Metformin extended release 755

Remogliflezin Etabonate immediate release layer

Intragramtlar Portion

Remogliflozin Etabonate 250.000 31.25

Croscarmellose Sodium 12.000 1.50

Microcrystalline cellulose 51.670 6.46

Binder

Povidone K 29/32 16.663 2.08

Purified Water q.s -

Extragranular Portion

Croscarmellose Sodium 16.800 2.10

Ferric oxide Red 0.5 0.2

Microcrystalline cellulose 444.067 55.51

Magnesium Stearate 7.200 0.90

Total Remogliflozin Etabonate 800

immediate release

Total Core Bilayer 1555 Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2.

EXAMPLE 5: Table-5 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HCl (1000 mg) extended release formulation and remogliflozin etabonate (100 mg) immediate release formulation.

Table-5

Macrocrystalline cellulose 177.947 55.61

Magnesium Stearate 2.880 0.90

Total Remogliflozin Etabonate 320

immediate release

Total Core Bilayer 1545

Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2. EXAMPLE 6: Table-6 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HC1 (1000 mg) extended release formulation and remogliflozin etabonate (250 mg) immediate release formulation.

Table-6

Mi crocrys tailine cellul ose 51.670 6.46

Binder

Povidone K 29/32 16.663 2.08

Purified Water q.s -

Extragranular Portion

Croscarmellose Sodium 16.800 2.10

Ferric oxide yellow 0.5 0.2

Macrocrystalline cellulose 444.067 55.51

Magnesium Stearate 7.200 0.90

Total Remogliflozin Etahonate 801

immediate release

Total Core Bilayer 2026

Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2.

EXAMPLE 7

Dissolution data of bilayer tablet formulation described in example 3 to 6

EXAMPLE 8:

Stability data for bilayer tablet formulations described in example 3-7

RS Remogliflozin

0.10 0.10

i) Imp A 0.11 0.11

ii) Single Max 0.18 0.18 0.19 0.18

iii) Total Imp 0.60 0.60 0.59 0.66

RS of Metformin

0.006 0.006 0.002 0.002

i)Dicyandiamide

ii) Single Max.

0.004 0.004 0.007 0.007

impurity

iii) Total impurities 0.010 0.010 0.009 0.008

Assay

103.7 103.7 107.2 106.1

a) Remogliflozin

b) Metformin HC1 97.3 97.3 98.9 99.7

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 application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments.

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

Claims

WE CLAIM:

1. An immediate release solid oral dosage form comprising Remogliflozin or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients for the treatment of diabetes mellitus, wherein remogliflozin etabonate is present in an amount of 100-250 mg.

2. The solid oral dosage form as claimed in claim 1 is a tablet or capsule.

3. The solid oral dosage form as claimed in claim 2, wherein the tablet can further be coated with a film coating layer.

4. The solid oral dosage form as claimed in claim 1 , wherein the pharmaceutically acceptable excipients comprise one or more diluent, binder, disintegrant, lubricant or glidant.

5. The solid oral dosage form as claimed in claim 1, wherein pharmaceutically acceptable excipients comprises croscarmellose sodium, microcrystalline sodium, magnesium stearate and povidone.

6. A fixed dose solid oral dosage form comprising remogliflozin or pharmaceutically acceptable salts thereof in immediate release form and metformin or its pharmaceutically acceptable salts thereof in an extended release form with one or more pharmaceutically acceptable excipients.

7. The fixed dose solid oral dosage form as claimed in claim 6, wherein remogliflozin etabonate is present in an amount of 100-250 mg and metformin or its pharmaceutically acceptable salt is present in an amount of 500-1000 mg

8. The fixed dose solid oral dosage form as claimed in claim 6, wherein the solid oral dosage form comprises remogliflozin etabonate in an amount 100-250mg in immediate release form and metformin or its pharmaceutically acceptable salt in an amount 500-1000 mg in an extended release form.

9. The fixed dose solid oral dosage form as claimed in claim 6, wherein the dosage form comprises an immediate release layer comprising remogliflozin etabonate and an extended release layer comprises metformin or a pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.

10. The fixed dose solid oral dosage form as claimed in claim 9, wherein the immediate release layer comprising remogliflozin etabonate with one or more pharmaceutically acceptable excipients selected from the group comprising of diluent, binder, disintegrant, lubricant and glidant and the extended release layer comprises metformin hydrochloride with one or more pharmaceutically acceptable excipients selected from the group comprising of diluent, binder, release controlling polymer, disintegrant, lubricant and glidant.

11. The fixed dose solid oral dosage form as claimed in claim 9, wherein the immediate release layer comprises remogliflozin etabonate with pharmaceutically acceptable excipients selected from the group comprising of croscarmellose sodium, microcrystalline sodium, magnesium stearate and povidone and the extended release layer comprises metformin hydrochloride with pharmaceutically acceptable excipients selected from the group comprising of guar gum, polyethylene oxide, carboxy methyl cellulose, hydroxypropyl methyl cellulose, pre-gelatinized Starch, hydrogenated castor oil, magnesium stearate and preservatives.

12. The fixed dose solid oral dosage form as claimed in claim 9, wherein remogliflozin etabonate is present in the range of about 5% to 50% by weight based on the total weight of the formulation and metformin is present in the range of about 30% to 90% by weight based on the total weight of the formuklation.

13. The fixed dose solid oral dosage form as claimed in claim 9, wherein the dosage form is stable at 25°C ± 2°C & 60% RH ± 5 % RH, 30°C ± 2°C & 75% RH ± 5 % RH and at 40°C ± 2°C & 75% RH ± 5 % RH.

14. The fixed dose solid oral dosage form as claimed in claim 9, wherein not less than 75% of remogliflozin etabonate is released in 45 minutes and not less than 20% of metformin is released in 60 minutes.

15. The fixed dose solid oral dosage form as claimed in claim 14, wherein not less than 80% of metformin is released in 10 hours.

16. The use of fixed dose solid oral dosage form comprising remogliflozin etabonate and metformin hydrochloride for the treatment of diabetes mellitus wherein remogliflozin etabonate is present in an immediate release form and metformin hydrochloride is present in an extended release form.

17. Method of treating diabetes mellitus by administering a patient in need thereof, a fixed dose solid oral dosage form comprising remogliflozin etabonate in an immediate release form and metformin hydrochloride in an extended release form.

18. A bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the tablet may comprise one or more pharmaceutically acceptable excipients.

19. The bilayer tablet as claimed in claim 18, wherein the total daily dose of remogliflozin or pharmaceutically acceptable salts does not exceed 500mg and total daily dose of metformin or pharmaceutically acceptable salts does not exceed 2000mg.

20. The bilayer tablet as claimed in claim 18, wherein the immediate release layer comprises remogliflozin etabonate in an amount of about lOOmg or 250mg and the extended release layer comprises metformin hydrochloride in an amount of about 500mg or 850mg or 1000 mg with one or more pharmaceutically acceptable excipients.

21. The bilayer tablet as claimed in claim 18, wherein the tablet can further be coated with film coating layer.

22. The bilayer tablet as claimed in claim 18, wherein the tablet is administered to the patients in need thereof, for the treatment of diabetes mellitus.