FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
PHARMACUTICAL COMPOSITION COMPRISING REMOGLIFLOZIN AND ANTIDIABETIC AGENT
APPLICANT
GLENMARK PHARMACEUTICALS LTD
B/12 Mahalaxmi Chambers
22, Bhulabhai Desai Road,
Mumbai 400026
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
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Technical Field of the Invention
The invention relates to a pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof. In particular, it relates to an immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient.
Background of the Invention
Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type 1 diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type 2 diabetes). Type 1 diabetes is also called insulin-dependent diabetes. By far, the most common form of diabetes is type 2 diabetes, accounting for 95% of diabetes cases in adults. The chronic hyperglycemia in type 2 diabetes can cause major health complications, particularly in the smallest blood vessels in the body that nourish the kidneys, nerves, and eyes. The chronic hyperglycemia of diabetes is also associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Management of diabetes concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications. Oral therapeutic options for the treatment of type 2 diabetes mellitus include agents known as: biguanides (metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors.
SGLT2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibitors lead to a reduction in blood
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glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type 2 diabetes.
Remogliflozin (base) has been disclosed in PCT publication WO2001/016147 A1.
Remogliflozin etabonate is the pro-drug of remogliflozin. Remogliflozin etabonate also known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-β -D-glucopyranoside has the following formula
US Patent 7,084,123 discloses Remogliflozin etabonate and its salts. Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes mellitus. The other antihyperglycemic agent may be an oral antihyperglycemic agent including biguanides, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. Particularly the biguanide such as metformin or other known biguanides improves hyperglycemia primarily through suppression of hepatic glucose production.
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In general monotherapy has been used as the initial treatment in diabetic patients. If monotherapy fails it may be supplemented with other drugs. The addition of a second drug, e.g., biguanides, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors to the concurrent treatment can provide a balance of stimulated release of insulin while ameliorating insulin resistance. This can provide an optimal level of glycemic control that is unattainable using monotherapy. However, requiring a patient to take multiple medications for the prophylaxis or treatment of diseases can result in patient inconvenience and lead to non-compliance of the prescribed dosage regimen. The ease of using single composition for multiple medications as opposed to separate administration of the individual medications has long been recognized in the practice of medicine. Such a composition can provide a therapeutic advantage for the benefit of the patient and the clinician. Further, such a composition can provide both increased convenience and improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness. PCT publication WO2012/006398A2 relates to a biphasic composition comprising remogliflozin etabonate delayed release portions dispersed in remogliflozin immediate release portions. PCT publication WO2009/022010A1 relates to a pharmaceutical composition comprising combination of SGLT2 inhibitor and DPP-IV inhibitor. The US patent 8,951,976 relates to a method of treatment for NAFL, NASH, hypernutritive fatty liver, alcoholic fatty liver disease, diabetic fatty liver and acute fatty liver using remogliflozin etabonate. PCT publication WO2010/092125A1 relates to a composition comprising (a) an SGLT2 inhibitor, and (b) a DPPIV inhibitor, and (c) a third anti-diabetic agent. PCT publication. However, there still exists a need for stable immediate release formulation of remogliflozin or pharmaceutically acceptable salt or ester thereof in combination with biguanide such as metformin used for treatment of type 2 diabetes mellitus.
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Summary of the Invention
In one general embodiment of the invention, there is provided an immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient.
In one embodiment, the remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate.
In one embodiment, the excipients are one or more of a diluent, a disintegrant, a binder, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof.
In one embodiment, the remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof present in a weight ratio of about 1:1 to about 1:15.
In another embodiment, the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.1 to about 1:10.
In another embodiment of the invention, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient.
In still another embodiment of the invention, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a
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glidant, a binder, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof.
In yet another embodiment of the invention, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) an extra-granular portion comprising a disintegrant and a lubricant. In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) an extra-granular portion comprising a crosscarmellose sodium and magnesium stearate.
In yet another embodiment of the invention, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 10mg to about 1000mg of remogliflozin etabonate, (b) about 10mg to 1500mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate.
In yet another embodiment of the invention, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) a
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second layer comprising a pharmaceutically acceptable excipient, and wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15.
In yet another embodiment of the invention, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) a second layer comprising a disintegrant and a lubricant.
In one embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) a second layer comprising crosscarmellose sodium and magnesium stearate.
In yet another embodiment of the invention, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and wherein the said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, metformin or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipients to obtain a granule, (ii) mixing said granules of step (i) with the pharmaceutically acceptable excipients and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.
In yet another embodiment of the invention, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein said process comprises steps of:
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(i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, metformin or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipients to obtain a granule, (ii) mixing said granules of step (i) with the pharmaceutically acceptable excipients and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.
In yet another embodiment of the invention, there is provided a method of treating diabetes using an immediate release pharmaceutical composition of this invention.
Brief Description to Figures
Figure 1A & 2A: Figure 1A & 2A shows anti-hyperglycemic effect measured as AUC0-120min in remogliflozin etabonate treated, metformin hydrochloride treated, combination of remogliflozin etabonate and metformin hydrochloride treated in comparison with control (untreated) groups.
Detail Description of the Invention
In one general embodiment of the invention, there is provided an immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient.
Surprisingly, the inventors of the invention found an immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof present in a weight ratio of about 1:1 to about 1:15. Further, inventors have also found a stable immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin or
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pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient. Inventors have observed that the invention composition comprising the combination of remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof shows synergy in terms of reducing the hyperglycemia when compared with standalone treatments.
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth in a non-provisional application claiming priority from the provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.
The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.
The term remogliflozin refers to remogliflozin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof. Specifically term remogliflozin refers to remogliflozin etabonate.
The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating metabolic disorders, produces an intended therapeutic benefit in a subject.
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The term “active ingredient” (used interchangeably with “active” or “active substance” or “drug”) as used herein includes remogliflozin etabonate and metformin hydrochloride.
The term “treating” or “treatment” as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by remogliflozin etabonate and metformin in a mammal.
The term "patient" includes mammals like human and other animals. Preferably, the patient is a human.
By “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
The term “combination” includes administration of one or more active pharmaceutical ingredients either in a single dosage form or in separate dosage forms; in fixed dose combination or administered separately as adjuvant therapy.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The invention composition comprises remogliflozin or pharmaceutically acceptable salt or ester thereof as remogliflozin etabonate. The remogliflozin etabonate is present in an amount of about 10mg to about 1000mg. Alternatively, the remogliflozin etabonate is present in an amount of 20mg, or about 30mg, or about 40mg, or about 50mg, or about 60mg, or about 70mg, or about 80mg, or about 90mg, or about 100mg, about 150mg, or about 200mg, or about 250mg, or about 300mg, or about 400mg, or about 500mg, or about 600mg, or about 700mg, or about 800mg, or about 900mg. Alternatively, the invention composition comprises about 50mg, or about 100mg or about 250mg of remogliflozin etabonate.
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The remogliflozin or pharmaceutically acceptable salt or ester thereof is administered orally as once a day or twice a day or thrice a day. Preferred dosing is twice a day.
The invention composition comprises the metformin or pharmaceutically acceptable salt thereof as metformin hydrochloride. The metformin hydrochloride is present in an amount of about 10mg to 1500mg. Alternatively, the metformin hydrochloride is present in about 100mg, or about 200mg, or about 300mg, or about 400mg, or about 500mg, or about 600mg, or about 700mg, or about 800mg, or about 900mg, or about 1000mg, or about 1100mg, or about 1200mg, or about 1300mg, or about 1400mg. Alternatively, the invention composition comprises about 500mg, or 800mg, or 1000mg of metformin hydrochloride.
The pharmaceutical composition comprising remogliflozin etabonate and metformin hydrochloride exhibit a synergistic effect in reducing the hyperglycemia and glycated hemoglobin as compared to alone remogliflozin etabonate or alone metformin hydrochloride.
The pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof are present in a weight ratio of about 1:1 to about 1:15. Alternatively, the remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof present in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10.
The pharmaceutical composition can be present in the form of a tablet, capsule, tablets in capsule, bilayer tablet, soft gelatin capsule, pill, oral suspension or solution. The compositions of the invention can be prepared by using known formulation methods such as direct compaction, wet granulation, dry granulation, hot melt granulation, granulation using spheronization etc.
The pharmaceutical composition of this invention comprises a pharmaceutically acceptable excipient. The excipients are one or more of a diluent, a disintegrant, a
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binder, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, or combinations thereof.
The diluent is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, micro 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, sucrose and combinations thereof. The diluent is present in a concentration of about 5-30% w/w by weight of composition. Alternatively, the diluent is present in a concentration of about 8-25% w/w, or about 12-20% w/w, or about 14- 18% w/w by weight of composition.
The disintegrant is selected from the group consisting of crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combination thereof. The disintegrant is present in a concentration of about 1-30% w/w by weight of composition. Alternatively, the disintegrant is present in a concentration of about 1.5-25% w/w, or about 1.5-20% w/w, or about 1.5-15% w/w, or about 1.5-10% w/w, or about 1.5-5% w/w by weight of composition.
The glidant is selected from the group consisting of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate and combination thereof. The glidant is present in a concentration of about 0.1-5% w/w by weight of composition. Alternatively, the glidant is present in a concentration of about 0.2-4% w/w, or about 0.5-3.5% w/w, or about 0.7-3% w/w, or about 0.9-2% w/w by weight of composition.
The binder is selected from the group consisting of starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium
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carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols and combination thereof. The binder is present in a concentration of about 0.1-10% w/w by weight of composition. Alternatively, the binder is present in a concentration of about 0.5-8% w/w, or about 1-6% w/w, or about 1.2-4% w/w, or about 1.5-3% w/w, or about 2-3% w/w by weight of composition.
The preservative is selected from the group consisting 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. The preservative is present in a concentration of about 0.1-30% w/w by weight of composition. Alternatively, the preservative is present in a concentration of about 0.1-30% w/w, or about 0.5-25% w/w, or about 1-20% w/w, or about 2-15% w/w, or about 3-10% w/w by weight of composition.
The buffering agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof.
The chelating agent is selected from the group consisting of ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives.
The polymer is selected from the group consisting of gum arabic, sodium based lignosulfonate, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate and combination thereof.
The solvent is selected from the group consisting of water; tetrahydrofuran; alcohols, such as methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes such as pentane, hexane and heptane; ketones, such as acetone and methyl ethyl ketone; chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, such as ethyl acetate and combination thereof.
In preferred embodiment, the diluent is microcrystalline cellulose. In preferred embodiment, the disintegrant is crosscarmellose sodium. In preferred embodiment, the
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glidant is magnesium stearate. In preferred embodiment, the binder is polyvinylpyrrolidone.
In an embodiment, there is provided a composition wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.1 to about 1:10. Alternatively, there is provided a composition wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.08, or about 1:0.2, or about 1:0.3. In most preferred embodiment, the disintegrant is crosscarmellose sodium.
There is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient.
In one embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient.
In another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a glidant, a binder, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a glidant, a lubricant, a preservative, a buffering agent, a
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chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof.
In still another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the remogliflozin etabonate is present in an amount of about 10mg to about 1000mg or about 100mg or 250mg and the metformin hydrochloride is present in an amount of about 10mg to 1500mg or about 500mg or 800mg or 1000mg.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15 or in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a glidant, a binder, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of
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about 1:0.1 to about 1:10 or the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1:0.08 or about 1:0.2 or about 1:0.3.
In yet another embodiment, the disintegrant is crosscarmellose sodium. In yet another embodiment, the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 or the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.08, or about 1:0.2, or about 1:0.3. In yet another embodiment, the disintegrant is present in either intra-granular portion or extra-granular portion or both.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) an extra-granular portion comprising a disintegrant and a lubricant.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) an extra-granular portion comprising a crosscarmellose sodium and magnesium stearate.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 10mg to about 1000mg of remogliflozin etabonate, (b) about 10mg to 1500mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 100mg or
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250mg of remogliflozin etabonate, (b) about 500mg or 800mg or 1000mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) an extra-granular portion comprising a disintegrant and a lubricant,
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wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion or extra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) an extra-granular portion comprising a crosscarmellose sodium and magnesium stearate, wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) an extra-granular portion comprising a crosscarmellose sodium and magnesium stearate, wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra or extra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 10mg to about 1000mg of remogliflozin etabonate, (b) about 10mg to 1500mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion.
19
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 100mg or 250mg of remogliflozin etabonate, (b) about 500mg or 800mg or 1000mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15, and wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about
20
1:15, and wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the extra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10, and wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10, and wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the extra-granular portion.
There is provided a bilayer tablet dosage form comprising: (A) a first layer comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) a second layer comprising a pharmaceutically acceptable excipiens, and wherein the remogliflozin etabonate, and metformin hydrochloride
21
present in a weight ratio of about 1:1 to about 1:15, or the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:2 or about 1:4 or about 1:5 or about 1:10.
In one embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) a second layer comprising a disintegrant and a lubricant.
In another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) a second layer comprising crosscarmellose sodium and magnesium stearate.
In still another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) about 10mg to about 1000mg of remogliflozin etabonate, (b) about 10mg to 1500mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) a second layer comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate.
In yet another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) about 100mg or 250mg of remogliflozin etabonate, (b) about 500mg or 800mg or 1000mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) a second layer comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate.
In yet another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride,
22
(c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) a second layer comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15.
In yet another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) a second layer comprising: about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate, wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10.
In yet another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) a second layer comprising a disintegrant and a lubricant, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion or extra-granular portion.
In yet another embodiment, there is provided a bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) a second layer comprising crosscarmellose sodium and magnesium stearate, and wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion or extra-granular portion.
23
In yet another aspect of the invention, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and wherein the said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, metformin or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipients to obtain a granules, (ii) mixing said granule of step (i) with the pharmaceutically acceptable excipients and compressing to obtain a tablet dosage form, and (iii) coating the said a tablet dosage form.
In one embodiment, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipiens, and wherein said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, metformin or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipients to obtain a granule, (ii) mixing said granules of step (i) with the pharmaceutically acceptable excipients and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.
In another embodiment, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) an extra-granular portion comprising a disintegrant and a lubricant, and wherein said process comprises steps of: (i) sifting and mixing the remogliflozin etabonate, metformin hydrochloride, the diluent, the disintegrant and the binder to obtain a granule, (ii) mixing said granules of step (i) with the extra-granular
24
portion comprising the disintegrant and the lubricant and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.
In yet another embodiment, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) an extra-granular portion comprising a crosscarmellose sodium and magnesium stearate, and wherein said process comprises steps of: (i) sifting and mixing the remogliflozin etabonate, metformin hydrochloride, microcrystalline cellulose, crosscarmellose sodium, polyvinylpyrrolidone to obtain a granule, (ii) mixing said granules of step (i) with the extra-granular portion comprising crosscarmellose sodium and magnesium stearate and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.
In yet another embodiment, there is provided a process of preparing an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) microcrystalline cellulose, (d) crosscarmellose sodium, and (e) polyvinylpyrrolidone, and (B) an extra-granular portion comprising a crosscarmellose sodium and magnesium stearate, and wherein said process comprises steps of: (i) sifting and mixing the remogliflozin etabonate, metformin hydrochloride, microcrystalline cellulose, crosscarmellose sodium, polyvinylpyrrolidone to obtain a granule, (ii) mixing said granules of step (i) with the extra-granular portion comprising crosscarmellose sodium and magnesium stearate and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form, and wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15, and wherein the remogliflozin etabonate and the crosscarmellose sodium is present in weight ratio of about 1:0.1 to about 1:10 in the intra-granular portion or extra-granular portion.
25
In one embodiment, there is provided a method of treating diabetes using an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) an extra-granular portion comprising a disintegrant and a lubricant.
The embodiments of the invention have been described with help of below examples and but are not limited to specific examples.
Examples
Example 1: Pharmaceutical compositions
Compositions
1A
1B
1C
1D
100 mg + 500 mg
250 mg + 500 mg
100 mg + 1000 mg
250 mg + 1000 mg
Sr.No.
Ingredients
% w/w
mg/tablet
% w/w
mg/tablet
% w/w
mg/tablet
% w/w
mg/tablet
Intra-granular Portion
1
Remogliflozin Etabonate
11.11
100.000
27.78
250.00
6.80
100.000
16.63
250.00
2
Metformin HCl
55.56
500.000
55.56
500.00
68.03
1000.000
66.53
1000.00
3
Crosscarmellose Sodium
2.25
20.240
2.25
20.24
2.16
31.810
2.25
33.81
4
Avicel PH 101
23.71
213.400
7.07
63.65
17.74
260.727
7.26
109.13
5
Ferric Oxide Yellow
0.03
0.250
0.00
0.00
0.03
0.400
0.00
0.00
6
Povidone K 29/32
1.51
13.550
1.51
13.55
1.54
22.638
1.51
22.64
7
Purified Water
q.s
q.s
q.s
q.s
Extra-Granular Portion
8
Crosscarmellose Sodium
2.69
24.200
2.69
24.20
2.75
40.425
2.75
40.425
9
Magnesium Stearate
0.93
8.360
0.93
8.360
0.95
14.000
0.95
14.000
880.000
880.00
1470.000
1470.00
Coating
10
Opadry*
2.22
20
2.22
20
2.20
33.00
2.20
33.00
Total Weight
900.00
900.00
1503.00
1503.00
26
Manufacturing Process:
1. Remogliflozin Etabonate, Metformin HCl, Crosscarmellose Sodium, Microcrystalline cellulose (Avicel PH 101) and Ferric Oxide Yellow were sifted and mixed well.
2. Povidone was dissolved in water to get clear solution.
3. Step 1 dry mix was granulated with step 2 solution to get wet mass.
4. Above wet mass was dried and passed through comill to get granules of #18 sieve (1000micron).
5. Above granules were blended with Crosscarmellose Sodium and lubricated with Magnesium Stearate.
6. Granules were compressed using suitable punch to get the tablet.
7. Coating solution was prepared by dispersing Opadry in water, this dispersion was used to coat the above tablets.
Example 2: Pharmaceutical Tablet compositions
Ingredients
2A
2B
2C
2D
2E
Quantity in % w/w
Intra-Granular Portion
Remogliflozin Etabonate
27.71
27.71
27.71
27.71
27.71
Metformin HCl
55.43
55.43
55.43
55.43
55.43
Crosscarmellose Sodium
2.21
-
-
-
-
Sodium starch glycollate
-
2.21
2.21
-
-
L-Substituted Hydroxy Propyl Cellulose
-
-
-
-
2.21
27
Starch
-
-
-
2.21
-
Microcrystalline cellulose(Avicel PH 101)
7.29
-
-
-
-
Dicalcium phosphate
-
-
7.29
-
-
Lactose
-
7.29
-
7.29
-
Mannitol
-
-
-
-
7.29
Povidone K 29/32
1.33
1.33
-
-
-
Hydroxypropyl Cellulose
-
-
-
1.33
-
Ethyl Cellulose
-
-
1.33
-
-
Polyvinyl Alcohol
-
-
-
-
1.33
Purified Water
Qs
Qs
Qs
Qs
Qs
Extra-Granular Portion
Crosscarmellose Sodium
2.60
-
-
-
-
Magnesium Stearate
0.96
0.96
-
-
-
Glyceryl Dibehanate
-
-
0.96
0.96
-
Sod. Stearyl Fumarate
-
-
-
-
0.96
Opadry
2.43
2.43
2.43
2.43
2.43
Manufacturing Process: Tablets are manufactured as described by process in example 1
Example 3: One month stability data of the formulations prepared as per example 1.
Storage condition
250C ± 20C & 60% RH ± 5 % RH
300C ± 20C & 75 % RH ± 5 % RH
400C ± 20C & 75 % RH ± 5 % RH
28
Test
Specification
Initial
1M
1M
1M
RS Remogliflozin
i) Imp A
NMT 1.5%
0.05
0.05
0.06
0.05
ii) Single Max.
NMT 0.5%
0.15
0.16
0.16
0.16
iii)Total Imp
NMT 3.0%
0.27
0.38
0.37
0.36
RS for Metformin
i) Dicyandiamide
NMT 0.1%
0.002
0.003
0.003
0.003
ii) Single Max
NMT 0.1%
0.006
0.004
0.003
0.010
iii) Total impurities
NMT 0.6%
0.016
0.007
0.009
0.016
Assay
a) Remogliflozin
90.0 % to 110.0 % L.A
99.6
100.0
102.3
100.5
b) Metformin HCl
90.0 % to 110.0 % L.A
99.4
97.4
96.6
97.5
Water Content
2.18
1.67
1.53
1.55
EXAMPLE 4: In-vivo Studies
The effect of the fixed dose combination of remogliflozin etabonate and metformin hydrochloride on glycemic control during Oral Glucose Tolerance Test (OGTT) in adult healthy-Sprague Dawley (SD) rats, healthy-C57Bl/6J mice, adult Zucker Diabetic Fatty (ZDF) rats and adult db/db mice was compared with the respective monotherapies.
Animals were fasted for 16-18 hours before the experiment. On the day of experiment the animals were randomized based on their whole blood glucose (WBG) by tail-snip method using a hand-held glucometer and were assigned to respective treatments for the Oral Glucose Tolerance test.
29
The animals were given a single oral administration of either Vehicle (10ml/kg) or remogliflozin alone or metformin alone or a combination of remogliflozin and metformin (See figures).
Animals were given respective treatments before an oral glucose load of 2 g/kg. Blood glucose concentration was measured at 30, 60, 90 and 120 min post glucose load using hand-held glucometer. Area under the curve of blood glucose levels from 0 to 120 min (AUCg 0-120) was calculated for all the treatment groups and improvement in glycemic control was determined by percent reduction of AUC 0-120 of combination versus monotherapy. Statistical comparisons are made by One-way ANOVA followed by Dunnett’s using GraphPad Prism (version 5.02) software with p<0.05 being statistically significant.
As shown in Figure 1A, Remogliflozin etabonate 1mg/kg decreased blood glucose AUC by 15%, Metformin hydrochloride 30mg/kg decreased blood glucose AUC by 2% and the combination of remogliflozin etabonate and metformin hydrochloride decreased blood glucose AUC by 23%. Further, as shown in figure 1B, Remogliflozin etabonate 1mg/kg decreased blood glucose AUC by 15%, Metformin hydrochloride 100mg/kg decreased blood glucose AUC by 53%, and the combination of remogliflozin etabonate and metformin hydrochloride decreased blood glucose AUC by 67%.
30
We claim:
1. An immediate release pharmaceutical composition comprising: (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipients, and wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof present in a weight ratio of about 1:1 to about 1:15.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients are one or more of a diluent, a disintegrant, a binder, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof.
3. The pharmaceutical composition of claim 1, wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate.
4. The pharmaceutical composition of claim 1, wherein the metformin or pharmaceutically acceptable salt thereof is metformin hydrochloride.
5. The pharmaceutical composition of claim 3, wherein the remogliflozin etabonate is present in an amount of about 10mg to about 1000mg.
6. The pharmaceutical composition of claim 4, wherein the metformin hydrochloride is present in an amount of about 10mg to 1500mg.
31
7. The pharmaceutical composition of claim 3, wherein the remogliflozin etabonate is present in an amount of about 100mg or 250mg.
8. The pharmaceutical composition of claim 4, wherein the metformin hydrochloride is present in an amount of about 500mg, or 800mg, or 1000mg.
9. The pharmaceutical composition of claim 1, wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof, and metformin or pharmaceutically acceptable salt thereof present in a weight ratio of about 1:2, or about 1:4, or about 1:5, or about 1:10.
10. The pharmaceutical composition of claim 2, wherein the diluent is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, micro 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, sucrose and combinations thereof.
11. The pharmaceutical composition of claim 2, wherein the disintegrant is selected from the group consisting of crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combination thereof.
12. The pharmaceutical composition of claim 2, wherein the glidant is selected from the group consisting of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate and combination thereof.
32
13. The pharmaceutical composition of claim 2, wherein the binder is selected from the group consisting of starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols and combination thereof.
14. The pharmaceutical composition of claim 2, wherein the preservative is selected from the group consisting 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.
15. The pharmaceutical composition of claim 2, wherein the buffering agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof.
16. The pharmaceutical composition of claim 2, wherein the chelating agent is selected from the group consisting of ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives.
17. The pharmaceutical composition of claim 2, wherein the polymer is selected from the group consisting of gum arabic, sodium based lignosulfonate, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate and combination thereof.
18. The pharmaceutical composition of claim 2, wherein the solvent is selected from the group consisting of water; tetrahydrofuran; alcohols, such as methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes such as
33
pentane, hexane and heptane; ketones, such as acetone and methyl ethyl ketone; chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, such as ethyl acetate and combination thereof.
19. The pharmaceutical composition of claim 11, wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.1 to about 1:10.
20. The pharmaceutical composition of claim 19, wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.08 or about 1:0.2 or about 1:0.3.
21. An immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin or pharmaceutically acceptable salt or ester thereof, (b) metformin or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient.
22. An immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15.
34
23. The pharmaceutical composition of claim 21, wherein the pharmaceutically acceptable excipients selected from the group consisting of a diluent, a disintegrant, a glidant, a binder, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, and combinations thereof.
24. A bilayer tablet dosage form comprising: (A) a first layer comprising (a) remogliflozin etabonate, (b) metformin hydrochloride, and (c) a pharmaceutically acceptable excipient, and (B) a second layer comprising a pharmaceutically acceptable excipient, and wherein the remogliflozin etabonate, and metformin hydrochloride present in a weight ratio of about 1:1 to about 1:15.
25. A bilayer tablet dosage form comprising: (A) a first layer comprising: (a) remogliflozin etabonate, (b) metformin hydrochloride, (c) a diluent, (d) a disintegrant, and (e) a binder, and (B) a second layer comprising a disintegrant and a lubricant.
26. A bilayer tablet dosage form comprising: (A) a first layer comprising: (a) about 10mg to about 1000mg of remogliflozin etabonate, (b) about 10mg to 1500mg of metformin hydrochloride, (c) about 5-30% w/w by weight of microcrystalline cellulose, (d) about 1-30% w/w by weight of crosscarmellose sodium, and (e) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B)
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a second layer comprising about 1-30% w/w by weight of crosscarmellose sodium and about 0.1-5% w/w by weight of magnesium stearate.