CN110753540A - Oral pharmaceutical formulation of regagliflozin - Google Patents

Abstract

The present invention relates to an immediate-release oral formulation of repagliflozin or a pharmaceutically acceptable salt thereof for administration in a patient in need thereof for the treatment of diabetes. The present invention further relates to a pharmaceutical formulation comprising a synergistic combination of Repagliflozin 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 Repagliflozin, or a pharmaceutically acceptable salt thereof, and the sustained-release layer comprises metformin or a pharmaceutically acceptable salt thereof.

Description

Oral pharmaceutical preparations of repagliptin

priority document

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

technical field

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

Background technique

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 a lifestyle that leads to weight gain and obesity. When a restrictive 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 exacerbates blood glucose levels.

Treatment of type 2 diabetes usually begins with dietary changes and exercise, followed by oral antidiabetic therapy. The goal of current diabetes treatment is to achieve and maintain blood sugar as close to normal as possible to prevent long-term microvascular and macrovascular complications associated with elevated glucose in the blood. Oral treatment options for the treatment of type II diabetes include the following drugs: biguanides (metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. These drugs are all indicated as monotherapy, and some are designated for combination therapy, often after monotherapy is found to be insufficient. Among oral antidiabetic drugs, only metformin is considered the drug of choice for the treatment of type 2 diabetes in overweight and obese populations. Metformin is usually administered orally, and it improves glycemic control by improving insulin sensitivity and reducing intestinal absorption of glucose. However, the UK Diabetes Prospective Study showed that intensive treatment of type 2 diabetes with metformin resulted in only limited improvements in glycemic control. In addition, the use of conventional combination therapies, such as metformin in combination with sulfonylureas, may show an increased risk of side effects, such as hypoglycemia or weight gain, which may limit their safety and efficacy.

Remogliflozin is another class of antidiabetic drugs used to treat type 2 diabetes. Repagliflozin is a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor. The low-affinity sodium-glucose co-transporter (SGLT2) plays an important role in renal glucose reabsorption and is an excellent transporter as a molecular target for the treatment of diabetes. Repagliflozin acts by inhibiting the sodium-glucose transport (SGLT) protein 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 Repagliflozin. Repagliflozin is chemically known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazole -3-yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside. Repagliflozin is also known as GSK189075 or KGT-1681. Following administration and absorption, the prodrug is converted to its active form repagliptin and selectively acts on SGLT2. Oral administration of repagliflozin has been shown to increase urinary glucose excretion in rodents and humans in a dose-dependent manner (Fujimori et al., Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268-276). Repagliflozin is described in patent publications EP1354888A1 and EP1213296A1.

Repagliflozin has potential as a monotherapy for the treatment of type II diabetes in human subjects with diabetes. Efforts have been made to develop oral formulations of repagliflozin for the treatment of type II diabetes. WO2001016147 relates to Repagliflozin Base, WO02053573 relates to Repagliflozin Ecarbonate, WO2012006398A2 relates to a biphasic formulation comprising Repagliflozin etabonate in immediate release phase and controlled release phase, US8951976 relates to treatment with Repagliflozin etabonate Methods for NAFL, NASH, hypertrophic fatty liver, alcoholic fatty liver disease, diabetic fatty liver and acute fatty liver, WO2010092125 relates to a method comprising (a) an SGLT2 inhibitor and (b) a DPPIV inhibitor and (c) a third antidiabetic agent Compositions.

Although several approaches have been reported in the art for formulations comprising repagliptin, there remains a substantial need in the art for new and improved pharmaceutical formulations of repagliflozin that The formulation will show a beneficial effect on the treatment of type II diabetes.

The present invention satisfies existing needs as well as other needs, and generally overcomes the deficiencies of the prior art.

All publications herein are incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. To the extent that the definition or use of a term in an incorporated reference is inconsistent with or contrary to the definition of that term provided herein, the definition of that term provided herein shall control, rather than the term's definition in the reference definition.

The grouping of optional elements or embodiments of the invention disclosed herein should not be construed as limiting. Each group member may be stated and claimed alone 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 a group for reasons of convenience and/or patentability.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided a solid oral pharmaceutical formulation comprising repagliflozin in combination with one or more pharmaceutically acceptable excipients. The disclosed Repagliflozin formulations provide immediate release of the drug and are effective in controlling plasma glucose levels in mammalian subjects with abnormal plasma glucose levels.

In one embodiment of the present invention, the immediate release formulation of repagliptin may include an intragranular portion and an extragranular portion. The intragranular portion may include an amount of repagliflozin in combination with at least one disintegrant and at least one binder. The extragranular portion may include at least one disintegrant and at least one lubricant.

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

In a preferred embodiment, the repagliflozin 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 combination formulation comprising a synergistic combination of repagliptin and metformin. The combined preparation can exhibit a synergistic effect on glycemic control in diabetic subjects, thereby enhancing the therapeutic effect.

In one embodiment, the combination formulations 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 first layer Two-layer, containing Repagliflozin in an immediate release formulation.

In a preferred embodiment, the combined preparation may comprise repagliptin in the form of 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 repagliflozin etabonate and metformin hydrochloride for the treatment of diabetes, wherein repagliflozin etabonate is in immediate release form and metformin hydrochloride is in slow release form Exist in the form of interpretation.

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 an immediate release form of etabonate and a sustained release form of metformin hydrochloride.

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 Repagliflozin or a pharmaceutically acceptable salt thereof, and the sustained release layer comprises metformin or a pharmaceutically acceptable salt thereof An acceptable salt, wherein the tablet may contain one or more pharmaceutically acceptable excipients.

In a preferred embodiment, the immediate release layer comprises repagliptin in an amount of about 100 mg or 250 mg, the extended release layer comprises metformin hydrochloride in an amount of about 500 mg or 850 mg or 1000 mg, and one or more pharmaceutically acceptable Accepted 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 Repagliflozin or a pharmaceutically acceptable salt thereof, and the sustained release layer comprises metformin or a pharmaceutically acceptable salt thereof The above acceptable salts, wherein the total daily dose of repagliflozin or a pharmaceutically acceptable salt thereof does not exceed 500 mg, and the total daily dose of metformin or a pharmaceutically acceptable salt thereof does not exceed 2000 mg.

According to embodiments of the present invention, 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 Hyperemia and obesity.

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

Brief Description of Drawings

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

FIG. 1 is a flow chart showing an exemplary method for preparing an immediate release tablet of Repagliflozin etabonate.

2 is a flow chart showing an exemplary method for preparing a bilayer tablet comprising a fixed dose combination of repagliptin etabonate and metformin hydrochloride.

Detailed ways

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

Unless the context otherwise requires, throughout this specification, the word "including" and variations thereof, such as "comprising" and "containing", should be construed in an open, inclusive sense, ie, "including but not limited to". "

In some embodiments, numbers representing amounts, properties, such as concentrations, process conditions, etc. of ingredients used to describe and claim certain embodiments of the invention should be understood to be modified in some cases 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, numerical parameters should be construed in light of reported numbers of significant digits and by applying ordinary rounding techniques. Notwithstanding that the broad numerical ranges and parameters setting forth 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 "approximately", eg, with respect to a certain therapeutically effective drug dosage, the use of the term "about" means a value that deviates slightly from the recited value, eg, plus or minus 0.1% to 10%, which is also effective and safe.

The 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 a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (eg, "such as") provided with respect to certain embodiments herein is intended only to better clarify the invention, and not to limit the scope of the invention (which is otherwise claimed). No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

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

The term "treatment" and grammatical variations thereof (e.g., "treatment", "treatment" and "treatment") refer to the administration of repagliptin to a patient for the purpose of ameliorating one or more symptoms of the patient's disorder or disease state or reduce its incidence. Such symptoms may be chronic or acute; and the improvement may be partial or complete.

Various terms are used here. To the extent a term used in a claim is not defined below, it should be given to those skilled in the relevant art to the broadest definition it has given the term as reflected in the printed publication and issued patent at the time of filing.

The present invention relates to immediate-release oral formulations of repagliflozin for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance and diabetic complications such as hyperglycemia, hyperinsulinemia and obesity. The present invention also relates to synergistic combinations of Repagliflozin and other antidiabetic agents in which Repagliflozin is used in an immediate release dosage form.

The disclosed immediate release formulations of repagliflozin can exhibit a desired drug dissolution profile and can effectively control plasma glucose levels in mammalian subjects with abnormal plasma glucose levels.

The term Repagliflozin refers to Repagliflozin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complexes, co-crystals, cogeners and its prodrug. Repagliflozin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, all of which are collectively referred to as Repagliflozin.

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 administration of one or more active pharmaceutical ingredients in a single dosage form or in separate dosage forms; in fixed dose combination or alone as adjunctive therapy.

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

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

In one embodiment of the present invention, the immediate release formulation of repagliptin may include an intragranular portion and an extragranular portion. The intragranular portion may include an amount of repagliflozin in combination with at least one disintegrant and at least one binder. The extragranular portion may include at least one disintegrant and at least one lubricant.

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

According to an embodiment of the present invention, the immediate release formulation of Repagliflozin may be in the form of a solid dosage form for oral administration. In a more preferred embodiment, the disclosed Repagliflozin formulations may be in the form of immediate release tablets 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 diluents, disintegrants, glidants and lubricants, preservatives, buffers, chelating agents, polymers, opacifiers, colorants , gelling agents/viscosity modifiers, antioxidants, solvents, cosolvents, and combinations thereof. The formulations may contain polymeric excipients for delayed drug release.

)、微细纤维素、乳糖、淀粉、预胶化淀粉、甘露醇、山梨醇、葡萄糖结合剂、糊精、麦芽糖糊精、右旋糖、碳酸钙、硫酸钙、磷酸氢钙二水合物、磷酸三钙、碳酸镁、氧化镁、糖如右旋糖、甘露醇、山梨醇或蔗糖及其组合。本发明的稀释剂以5-30％w/w的量存在。Non-limiting examples of diluents include one or more of microcrystalline cellulose, silicified microcrystalline cellulose (eg

), microcellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, glucose binder, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, calcium hydrogen phosphate dihydrate, phosphoric acid Tricalcium, 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 present 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 includes a member 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 raw material granulated disintegrant, if present, is sodium starch glycolate, croscarmellose sodium and/or crospovidone. These substances are also known as insoluble povidone, insoluble PVP, cross-linked PVP and PVPP. Crospovidone can be replaced by croscarmellose sodium and sodium starch glycolate. The disintegrant according to the present 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 0.1-5% w/w.

Non-limiting examples of binders include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyl oxalate oxazolidone (polyvinyloxoazolidone) and polyvinyl alcohol. The binder according to the present 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 diazolindinyl urea and mixtures thereof. Non-limiting examples of buffers include sodium hydroxide, potassium hydroxide, ammonium hydroxide, and mixtures thereof. Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid ("EDTA") and disodium EDTA and EDTA derivatives. The binder according to the present invention is present in an amount of 0.1-2% w/w.

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

Solvents include 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, Examples are chloroform, carbon tetrachloride, dichloromethane and dichloroethane acetates such as ethyl acetate.

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

In an illustrative embodiment, the immediate release formulations of repagliflozin disclosed herein may comprise (a) an intragranular portion comprising repagliflozin, at least one disintegrant, and at least one binder; (b) ) an extragranular portion comprising 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 may comprise (by weight): 31.25% Repagliflozin Ecarbonate, 1.5% Croscarmellose Sodium, 6.46% Microcrystalline Cellulose and 2.08% K29/32. The extragranular fraction may include (by weight): 2.1% croscarmellose sodium, 55.71% microcrystalline cellulose, and 0.90% magnesium stearate. The coating may comprise 2.0-3.0 wt% opadry white.

In another aspect, the present invention provides methods for treating Type II diabetes in a mammalian subject having diabetes. The method can include administering to the mammalian subject a therapeutically effective amount of an immediate release formulation of repagliptin disclosed herein.

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

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 an immediate release form of etabonate and a sustained release form of metformin hydrochloride.

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 Repagliflozin or a pharmaceutically acceptable salt thereof, and the sustained release layer comprises metformin or a pharmaceutically acceptable salt thereof An acceptable salt, wherein the tablet may contain one or more pharmaceutically acceptable excipients.

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

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 Repagliflozin or a pharmaceutically acceptable salt thereof, and the sustained release layer comprises metformin or a pharmaceutically acceptable salt thereof The above acceptable salts, wherein the total daily dose of repagliflozin or a pharmaceutically acceptable salt thereof does not exceed 500 mg, and the total daily dose of metformin or a pharmaceutically acceptable salt thereof does not exceed 2000 mg.

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

In one embodiment, the combination formulations 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 first layer Two-layer, containing Repagliflozin in an immediate release formulation.

As used herein, the term "sustained release" refers to a pharmaceutical formulation designed to be a gradual and continuous release amount of metformin or a pharmaceutically acceptable salt thereof 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 may be in the form of a fixed dose bilayer tablet for oral administration. The bilayer tablet may include a metformin hydrochloride extended-release formulation as a first layer, and a repagliflozin etabonate immediate-release formulation as a second layer.

The amount of metformin in the present combination formulation may be in the range of 30% to 90% by weight based on the total weight of the combination formulation, and the amount of repagliflozin may be in the range of 5% to 60% by weight based on the total weight of the combination formulation Inside.

The present invention relates to repaggliflozin in daily doses of 100 mg, 200 mg, 250 mg and 500 mg, in single or divided doses, and administered to patients with insufficient glycemic control. The total daily dose of repagliflozin should 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 daily doses of 500 mg, 750, 800 mg and 1000 mg in single or divided doses and administered to patients with insufficient glycemic control. The total daily dose of metformin hydrochloride should not exceed 2000 mg. The formulations of the present invention involve a synergistic combination of Repagliflozin and Metformin hydrochloride, which may be administered once or twice daily.

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

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

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

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

According to embodiments of the present invention, both the metformin extended-release layer and the repagliflozin immediate-release layer may include one or more pharmaceutically acceptable excipients.

The present invention relates to a stable bilayer tablet composition comprising an immediate-release layer of repagliptin etabonate and a sustained-release layer, the sustained-release layer comprising metformin or a pharmaceutically acceptable salt, solvate, pro- Drugs, esters, wherein the composition exhibits not less than 75% dissolution of repagliptin etabonate within 45 minutes, not less than 20% dissolution of metformin or a salt thereof within 60 minutes and no dissolution within 10 hours Less than 80% of metformin or its salts dissolved.

The present invention also relates to stabilized repagliptin etabonate compositions wherein the repagliptin etabonate is present in immediate release form.

In another embodiment, the present invention is directed to a stable bilayer composition of repagliflozin etabonate and metformin hydrochloride, wherein repagliflozin etabonate is present in the immediate release layer and metformin hydrochloride is present in the slow release layer.

Repagliflozin immediate release tablet formulations and bilayer formulations of repagliflozin and metformin were stable at 25°C ± 20°C and 60% RH ± 5% RH. Other formulations are also stable at 30°C±20°C and 75%RH±5%RH and 40°C±20°C and 75%RH±5%RH

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

According to an embodiment of the present invention, immediate release formulations of repagliflozin and combined formulations of repagliflozin and metformin can be administered to mammalian subjects, preferably humans, for the treatment of type II diabetes, impaired glucose tolerance, insulin Resistance and complications of diabetes (eg, hyperglycemia, hyperinsulinemia, and obesity).

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

Example

The content of the invention is further explained in the form of the following examples. It should be understood, however, that the foregoing embodiments are illustrative only and should not be construed as limiting the scope of the present 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 present invention.

Example 1: Table 1 below lists the formulation ingredients and amounts for 100 mg Repagliflozin immediate release tablets.

Table 1

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

Example 2: Table 2 below lists the formulation ingredients and amounts for 250 mg Repagliflozin immediate release tablets.

Table 2

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

Example 3: Table 3 below lists the ingredients and amounts used to prepare bilayer tablets containing metformin hydrochloride (500 mg) extended-release formulation and repagliflozin etabonate (100 mg) immediate-release formulation.

table 3

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

Example 4: Table 4 below lists the ingredients and amounts used to prepare bilayer tablets containing metformin hydrochloride (500 mg) extended-release formulation and repagliflozin (250 mg) immediate-release formulation.

Table 4

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

Example 5: Table 5 below lists the ingredients and amounts used to prepare bilayer tablets containing metformin hydrochloride (1000 mg) extended-release formulation and repagliflozin (100 mg) immediate-release formulation.

table 5

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

Example 6: Table 6 below lists the ingredients and amounts used to prepare bilayer tablets containing metformin hydrochloride (1000 mg) extended release formulation and etabonate (250 mg) immediate release formulation.

Table-6

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

Example 7

Dissolution data for bilayer tablets described in Examples 3-6

Example 8:

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

Although the invention has been described herein with reference to specific embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the invention. Therefore, it should be understood that many modifications are possible to the exemplary embodiments.

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

Claims (22)

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.

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