CN110753540A

CN110753540A - Oral pharmaceutical formulation of regagliflozin

Info

Publication number: CN110753540A
Application number: CN201880038198.9A
Authority: CN
Inventors: U·杜帕德; 尼廷·德许姆克; 克里许纳·撒达法
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2017-06-08
Filing date: 2018-06-07
Publication date: 2020-02-04
Also published as: KR20200013719A; MX2019014687A; BR112019026029A2; WO2018198102A1

Abstract

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

Description

Oral pharmaceutical formulation of regagliflozin

Priority file

This patent application claims priority to indian provisional patent application 201721020166 (filed on 8/6/2017), the contents of which are incorporated herein by reference.

Technical Field

The invention relates to the technical field of pharmaceutical preparations. In particular, the present invention relates to an immediate release formulation of remogliflozin for oral administration. The invention also relates to a pharmaceutical formulation comprising a synergistic combination of remogliflozin and metformin.

Background

Type II diabetes is characterized by insulin resistance and impaired glucose-stimulated insulin secretion by pancreatic cells, and its incidence increases with a shift to lifestyles that lead to weight gain and obesity. When a restricted lifestyle cannot be maintained, chronic hyperglycemia leads to progressive impairment of insulin secretion and insulin resistance of peripheral tissues, a phenomenon commonly referred to as glucotoxicity, which further worsens blood glucose levels.

The present invention relates to a method for treating diabetes mellitus, and in particular to a method for treating diabetes mellitus, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising metformin (metformin), a sulfonylurea, a thiazolidinedione and an α -glucosidase inhibitor, wherein the pharmaceutical composition is formulated as monotherapy, and wherein the therapeutic composition is formulated for combined therapy, wherein metformin is the preferred agent for treating diabetes mellitus in overweight and obese humans.

Regagliflozin (Remogliflozin) is another antidiabetic drug used in the treatment of type II diabetes mellitus, regagliflozin is a highly selective sodium glucose co-transporter 2(SGLT2) inhibitor-low affinity sodium glucose co-transporter (SGLT2) plays an important role in renal glucose reabsorption, being an excellent transporter as a molecular target for the treatment of diabetes mellitus-regagliflozin acts by inhibiting the sodium-glucose transporter (SGLT) protein responsible for glucose reabsorption in the kidney (fujimmorizin et al, Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268- & gt 276. & Remogliflozin etabonate (Remogliflozin etabonate) is a prodrug of regagliflozin etabonate-is chemically referred to as 5-methyl-4- [4- (1-methylethoxy) benzyl ] -1- (1-methylethyl) -1H-3-6-pyrazole-based-furozin (Remogliflozin-carbonyl) -1H-11-carbonyl-carboxylate-is also disclosed as a prodrug which is excreted in a selective fashion after administration of mouse-glucose transporter and glucose-uptake in animals — 9, 327, 18, 76, and No. 11-ethoxy-pyrazole-carboxylate (Remogliflozin-carboxylate) is also disclosed in patent publication EP-11-2, EP-11-folate-2, et al.

Remogliflozin etabonate has the potential to be used as a 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, WO2012006398a2 relates to a biphasic formulation comprising remogliflozin etabonate in an immediate release phase and a controlled release phase, US8951976 relates to a method of treating NAFL, NASH, hyperalimentation fatty liver, alcoholic fatty liver disease, diabetic fatty liver and acute fatty liver using remogliflozin etabonate, WO2010092125 relates to a composition comprising (a) an SGLT2 inhibitor and (b) a DPPIV inhibitor and (c) a third antidiabetic agent.

Although several approaches have been reported in the art for formulations comprising remogliflozin, there remains a substantial need in the art for new and improved remogliflozin pharmaceutical formulations that will exhibit beneficial effects for the treatment of type II diabetes.

The present invention satisfies this need, as well as others, and generally overcomes the deficiencies in the prior art.

All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was 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 not the definition of that term in the reference.

Groupings of optional elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be recited 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 may be included in or deleted from the group for convenience and/or patentability reasons.

Summary of The Invention

According to one aspect of the present invention, there is provided a solid oral pharmaceutical formulation comprising remogliflozin in combination with one or more pharmaceutically acceptable excipients. The disclosed formulation of regexedin provides immediate release of the drug and is effective in controlling plasma glucose levels in a mammalian subject having abnormal plasma glucose levels.

In one embodiment of the invention, an immediate release formulation of remogliflozin can include an intragranular portion and an extragranular portion. The intragranular portion may include an amount of remogliflozin in combination with at least one disintegrant and at least one binder. The extra-granular fraction may comprise at least one disintegrant and at least one lubricant.

According to an embodiment of the invention, the immediate release formulation of remogliflozin may further comprise a coating, preferably a film coating.

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

According to another aspect of the present invention, there is provided a combined preparation comprising a synergistic combination of remogliflozin and metformin. The combined preparation can show synergistic effect on blood sugar control of diabetic subjects, thereby enhancing therapeutic effect.

In one embodiment, the combined preparation disclosed herein may be in the form of a solid dosage form, which may include (a) a first layer comprising metformin or a pharmaceutically acceptable salt thereof in a sustained release formulation; and (b) a second layer comprising remogliflozin in an immediate release formulation.

In a preferred embodiment, the combined preparation may comprise 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 may be in the form of a fixed dose bilayer tablet for oral administration.

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

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

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

In a preferred embodiment, the immediate release layer contains remogliflozin etabonate in an amount of about 100mg or 250mg, and the extended release layer contains metformin hydrochloride in an amount of about 500mg or 850mg or 1000mg, and one or more pharmaceutically acceptable excipients.

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

According to an embodiment of the present invention, the pharmaceutical formulations disclosed herein may be administered to a mammalian subject, preferably a human, 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 present 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 invention, and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the invention and, together with the description, serve to explain the principles of the invention.

Fig. 1 is a flow diagram showing an exemplary process for preparing an immediate release tablet of remogliflozin etabonate.

Fig. 2 is a flow diagram showing an exemplary process for preparing a bilayer tablet comprising a fixed dose combination of remogliflozin etabonate and metformin hydrochloride.

Detailed Description

As used in the description herein and in the appended claims, the meaning of "a", "an", and "the" includes plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

Throughout this specification, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be construed in an open, inclusive sense, i.e., "including but not limited to". "

In some embodiments, numbers expressing quantities of ingredients, properties such as concentrations, processing 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". Thus, in some embodiments, the numerical parameters set forth in the written description are approximations that may vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, 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 possible.

As used herein, the term "about" is used synonymously with the term "about", e.g., in reference to a therapeutically effective drug dose, the use of the term "about" denotes a value that deviates slightly from the cited value, e.g., plus or minus 0.1% to 10%, which is also effective and safe.

Recitation of ranges of values herein are 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 any 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 as essential to the practice of the invention.

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

The term "treating" and grammatical variations thereof (e.g., "treat," "treatment," and "treatment") refers to administering remogliflozin etabonate to a patient with the aim of ameliorating one or more symptoms or reducing the incidence of a disorder or disease state in the patient. Such symptoms may be chronic or acute; and this improvement 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 an 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 a synergistic combination of regagliflozin and another antidiabetic agent, and in which regagliflozin is used in an immediate release dosage form.

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

The term regorazin refers to regorazin, salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complexes, co-crystals, symbionts (cogeners) and prodrugs thereof. Remogliflozin etabonate or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, 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, complexes, co-crystals, symbionts and prodrugs thereof.

The term "combination" includes the administration of one or more active pharmaceutical ingredients in a single dosage form or in separate dosage forms; administered alone in fixed dose combinations or as adjuvant therapy.

The term "immediate release" as used herein refers to the characteristic of a pharmaceutical formulation in which the pharmaceutically active agent in the formulation is made bioavailable without significant delay.

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

According to an embodiment of the invention, an immediate release formulation of remogliflozin may be in the form of a solid dosage form for oral administration. In a more preferred embodiment, the disclosed regexed formulations may be in the form of an immediate release tablet for oral administration.

The immediate release tablet may further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, one or more diluents, disintegrants, glidants and lubricants, preservatives, buffers, chelating agents, polymers, opacifiers, colorants, gelling/viscosity modifiers, antioxidants, solvents, co-solvents, and combinations thereof. The formulation may contain polymeric excipients for delayed drug release.

Non-limiting examples of diluents include one or more of microcrystalline cellulose, silicified microcrystalline cellulose (e.g., microcrystalline cellulose

) Fine 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 diluent of the present invention is present in an amount of 5-30% w/w.

Non-limiting examples of disintegrants suitable for use in the invention include povidone, croscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and other known disintegrants. Several specific types of disintegrants are suitable for use in the formulations described herein. For example, any grade of crospovidone may be used, including, for example, crospovidone XL-10, and including 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 raw granulation is sodium starch glycolate, croscarmellose sodium, and/or crospovidone. These materials are also known as insoluble povidone, insoluble PVP, crosslinked PVP and PVPP. Crospovidone may be replaced by croscarmellose sodium, sodium starch glycolate. The disintegrant according to the invention is present in an amount of 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 of the present invention is present in an amount of 0.1 to 5% w/w.

Non-limiting examples of binders include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidone, and polyvinyl alcohol. The binder according to the invention is present in an amount of 0.5-10% w/w.

Non-limiting examples of preservatives include one or more of phenoxyethanol, parabens such as methyl and propyl parabens and their sodium salts, propylene glycol, sorbates, urea derivatives such as diazolidinyl urea (diazolidinyl 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 ethylenediaminetetraacetic acid ("EDTA") and disodium ethylenediaminetetraacetate and EDTA derivatives. The binder according to the invention is present in an amount of 0.1-2% w/w.

Non-limiting examples of polymers include one or more of gum arabic, guar gum, sodium lignosulfonates, polyethylene oxide, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate, and cellulosic polymers including hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose.

The solvent includes one or more aqueous or non-aqueous solvents, including alcoholic solvents and oils. Non-limiting examples include water, tetrahydrofuran, methanol, ethanol, isopropanol, and higher alcohols; hydrogenated castor oil, alkanes such as pentane, hexane and heptane; ketones such as acetone and methyl ethyl ketone; chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, dichloromethane and dichloroethane acetates, such as ethyl acetate.

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

In one illustrative embodiment, an immediate release formulation of remogliflozin disclosed herein can comprise (a) an intragranular portion comprising remogliflozin, at least one disintegrant, and at least one binder; (b) an extra-granular fraction comprising at least one disintegrant and at least one lubricant; and (c) coating.

In a more preferred embodiment, the intragranular portion of the immediate release formulation may comprise (by weight): 31.25% remogliflozin etabonate, 1.5% croscarmellose sodium, 6.46% microcrystalline cellulose and 2.08% K29/32. The extra-granular fraction may comprise (by weight): 2.1% croscarmellose sodium, 55.71% microcrystalline cellulose and 0.90% magnesium stearate. The coating may comprise from 2.0 to 3.0 wt% opadry white (opadry white).

In another aspect, the invention provides methods for treating type II diabetes in a mammalian subject having diabetes. The method may comprise administering to the mammalian subject a therapeutically effective amount of an immediate release formulation of remogliflozin disclosed herein.

In a preferred embodiment, the immediate release layer contains remogliflozin etabonate in an amount of about 100mg or 250mg, and the sustained release layer contains metformin hydrochloride in an amount of about 500mg or 850mg or 1000mg, and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a combined preparation comprising remogliflozin in combination with metformin or a pharmaceutically acceptable salt thereof.

The term "sustained release" as used herein refers to a pharmaceutical formulation designed to maintain a level of gradual and continuous release of metformin or a pharmaceutically acceptable salt thereof for a prolonged period of time of therapeutic or prophylactic effect.

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

The amount of metformin in the present combined preparation may be in the range of 30 to 90% by weight based on the total weight of the combined preparation, and the amount of remogliflozin may be in the range of 5 to 60% by weight based on the total weight of the combined preparation.

The present invention relates to remogliflozin etabonate in daily doses of 100mg, 200mg, 250mg and 500mg, in single or divided doses, and to be administered to patients with insufficient glycemic control. The total daily dose of remogliflozin etabonate does not exceed 500 mg. The formulations of the present invention may be administered once or twice daily.

The present invention relates to metformin hydrochloride in a daily dose of 500mg, 750, 800mg and 1000mg, in single or divided doses, and administered to patients with insufficient glycemic control. The total daily dosage of metformin hydrochloride does not exceed 2000 mg. The formulation of the present invention relates to a synergistic combination of remogliflozin etabonate and metformin hydrochloride, which can be administered once or twice daily.

In a preferred embodiment, a first layer of the combined preparation may contain 500mg of metformin hydrochloride in a sustained release formulation and a second layer of the combined preparation may contain 100mg of remogliflozin etabonate in an immediate release formulation.

In another preferred embodiment, the first layer may contain 500mg of metformin hydrochloride in a sustained release formulation and the second layer may contain 250mg of remogliflozin etabonate in an immediate release formulation.

In another preferred embodiment, the first layer may contain 1000mg of metformin hydrochloride in a sustained release formulation and the second layer may contain 100mg of remogliflozin etabonate in an immediate release formulation.

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

According to embodiments of the present invention, both the metformin sustained release layer and the remogliflozin immediate release layer may comprise one or more pharmaceutically acceptable excipients.

The present invention relates to a stable bilayer tablet composition comprising an immediate release layer of remogliflozin etabonate and a sustained release layer comprising metformin or a pharmaceutically acceptable salt, solvate, prodrug, ester thereof, wherein the composition exhibits no less than 75% remogliflozin etabonate dissolution in 45 minutes, no less than 20% metformin or a salt thereof dissolution in 60 minutes and no less than 80% metformin or a salt thereof dissolution in 10 hours.

The present invention also relates to a stable remogliflozin etabonate composition, wherein remogliflozin etabonate is present in an 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 an immediate release layer and metformin hydrochloride is present in a sustained release layer.

The immediate release tablet formulation of remogliflozin and the bilayer formulation of remogliflozin and metformin are stable at 25 ℃ ± 20 ℃ and 60% RH ± 5% RH. Other formulations are also stable at 30 ℃. + -. 20 ℃ and 75% RH. + -. 5% RH as well as 40 ℃. + -. 20 ℃ and 75% RH. + -. 5% RH

In another aspect, the invention provides a method of treating type II diabetes in a mammalian subject having diabetes. The method may comprise administering to a mammalian subject a therapeutically effective amount of a combination preparation in the form of a solid dosage form comprising (a) a first layer comprising metformin or a pharmaceutically acceptable salt thereof in a sustained release formulation; and (b) a second layer comprising remogliflozin in an immediate release formulation.

According to embodiments of the present invention, immediate release formulations of remogliflozin and combined formulations of remogliflozin and metformin may be administered to a mammalian subject (preferably a human) for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance and diabetic complications (e.g. hyperglycemia, hyperinsulinemia and obesity).

While the foregoing is directed to various embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. The invention is not limited to the embodiments, versions or examples described, 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 invention is further illustrated in the form of the following examples. It should be understood, however, that the foregoing examples are illustrative only and are not to be construed as limiting 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 can be made without departing from the scope of the present invention.

Example 1: the formulation ingredients and amounts for a 100mg immediate release tablet of remogliflozin are listed in table 1 below.

TABLE-1

The processing steps shown in the flow chart of fig. 1 were used to manufacture a 100mg immediate release tablet of remogliflozin.

Example 2: the formulation ingredients and amounts for a 250mg immediate release tablet of remogliflozin are listed in table 2 below.

TABLE-2

The processing steps shown in the flow chart of fig. 1 were used to manufacture 250mg immediate release tablets of remogliflozin.

Example 3: table 3 below lists the ingredients and amounts used to prepare bilayer tablets containing a sustained release formulation of metformin hydrochloride (500mg) and an immediate release formulation of remogliflozin etabonate (100 mg).

TABLE-3

Bilayer tablets were prepared according to the method shown in the flow chart of figure 2.

Example 4: table 4 below lists the ingredients and amounts used to prepare bilayer tablets containing a sustained release formulation of metformin hydrochloride (500mg) and an immediate release formulation of remogliflozin etabonate (250 mg).

TABLE-4

Example 5: table 5 below lists the ingredients and amounts used to prepare bilayer tablets containing a sustained release formulation of metformin hydrochloride (1000mg) and an immediate release formulation of remogliflozin etabonate (100 mg).

TABLE-5

Example 6: table 6 below lists the ingredients and amounts used to prepare bilayer tablets containing a sustained release formulation of metformin hydrochloride (1000mg) and an immediate release formulation of remogliflozin etabonate (250 mg).

TABLE-6

Example 7

Dissolution data for bilayer tablets as described in examples 3-6

Example 8:

stability data for bilayer tablet formulations described in examples 3-7

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 applications of the present invention. Thus, it should be understood that many modifications may be made to the exemplary 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 were specifically and individually indicated to be incorporated by reference.

Claims

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

2. The solid oral dosage form of claim 1, which is a tablet or capsule.

3. The solid oral dosage form of claim 2, wherein the tablet is further coated with a film coating.

4. The solid oral dosage form of claim 1, wherein the pharmaceutically acceptable excipient comprises one or more diluents, binders, disintegrants, lubricants, or glidants.

5. The solid oral dosage form of claim 1, wherein the pharmaceutically acceptable excipients comprise croscarmellose sodium, microcrystalline sodium, magnesium stearate, and povidone.

6. A fixed dose solid oral dosage form comprising remogliflozin or a pharmaceutically acceptable salt thereof in an immediate release form and metformin or a pharmaceutically acceptable salt thereof in a sustained release form, and one or more pharmaceutically acceptable excipients.

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

8. The fixed-dose solid oral dosage form according to claim 6, wherein the solid oral dosage form comprises regagliflozin etabonate in an immediate release form in an amount of 100-250mg and metformin or a pharmaceutically acceptable salt thereof in a sustained release form in an amount of 500-1000 mg.

9. The fixed-dose solid oral dosage form of claim 6, wherein the dosage form comprises an immediate release layer comprising remogliflozin etabonate and a sustained release layer comprising metformin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. The fixed-dose solid oral dosage form of claim 9, wherein the immediate release layer comprises remogliflozin etabonate and one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, lubricants and glidants, and the sustained release layer comprises metformin hydrochloride and one or more pharmaceutically acceptable excipients selected from diluents, binders, controlled release polymers, disintegrants, lubricants and glidants.

11. The fixed-dose solid oral dosage form of claim 9, wherein the immediate release layer comprises remogliflozin etabonate and a pharmaceutically acceptable excipient selected from croscarmellose sodium, microcrystalline sodium, magnesium stearate, and povidone, and the sustained release layer comprises metformin hydrochloride and a pharmaceutically acceptable excipient selected from guar gum, polyethylene oxide, carboxymethylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, hydrogenated castor oil, magnesium stearate, and a preservative.

12. The fixed-dose solid oral dosage form of claim 9, wherein remogliflozin etabonate is present at about 5% to 50% by weight based on the total weight of the formulation and dimethylbiguanide is present at about 30% to 90% by weight based on the total weight of the formulation.

13. The fixed dose solid oral dosage form of claim 9, wherein the dosage form is stable at 25 ℃ ± 2 ℃ and 60% RH ± 5% RH, 30 ℃ ± 2 ℃ and 75% RH ± 5% RH, and 40 ℃ ± 2 ℃ and 75% RH ± 5% RH.

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

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

16. Use of a fixed-dose solid oral dosage form comprising remogliflozin etabonate and metformin hydrochloride, wherein remogliflozin etabonate is present in an immediate release form and metformin hydrochloride is present in a sustained release form, for the treatment of diabetes.

17. A method of treating diabetes by administering to a patient in need thereof a fixed dose solid oral dosage form comprising remogliflozin etabonate in immediate release form and metformin hydrochloride in sustained release form.

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

19. The bilayer tablet according to claim 18 wherein the total daily dosage of remogliflozin or a pharmaceutically acceptable salt does not exceed 500mg and the total daily dosage of metformin or a pharmaceutically acceptable salt does not exceed 2000 mg.

20. The bilayer tablet according to claim 18, wherein the immediate release layer comprises remogliflozin etabonate in an amount of about 100mg or 250mg and the extended release layer comprises metformin hydrochloride in an amount of about 500mg or 850mg or 1000mg, and one or more pharmaceutically acceptable excipients.

21. The bilayer tablet according to claim 18 wherein said tablet is further coated with a film coating.

22. The bilayer tablet of claim 18 wherein said tablet is administered in a patient in need thereof for the treatment of diabetes.