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WO2019162841A1 - Composition pharmaceutique comprenant de la rémogliflozine pour le traitement du diabète sucré - Google Patents

Composition pharmaceutique comprenant de la rémogliflozine pour le traitement du diabète sucré Download PDF

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Publication number
WO2019162841A1
WO2019162841A1 PCT/IB2019/051353 IB2019051353W WO2019162841A1 WO 2019162841 A1 WO2019162841 A1 WO 2019162841A1 IB 2019051353 W IB2019051353 W IB 2019051353W WO 2019162841 A1 WO2019162841 A1 WO 2019162841A1
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WO
WIPO (PCT)
Prior art keywords
remogliflozin
pharmaceutical composition
pharmaceutically acceptable
ester
acceptable salt
Prior art date
Application number
PCT/IB2019/051353
Other languages
English (en)
Inventor
Ulhas Rameshchandra Dhuppad
Nitin Deshmukh
Krishna SADAPHAL
Monika TANDON
Sumit SANT
Girish GUDI
Vinu C A MENON
Vikas Joshi
Nikhil SAWANT
Original Assignee
Glenmark Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Limited filed Critical Glenmark Pharmaceuticals Limited
Publication of WO2019162841A1 publication Critical patent/WO2019162841A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to an immediate release pharmaceutical composition
  • an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • Cmax plasma concentration
  • 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.
  • 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.
  • 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 glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type 2 diabetes.
  • Remogliflozin etabonate is the pro-drug of remogliflozin.
  • Remogliflozin etabonate also known as 5-methyl-4- [4-( 1 -methylethoxy)benzyl] - 1 -( 1 -methylethyl)- 1 H-pyrazol-3-yl-6-0- (ethoxycarbonyl)-P -D-glucopyranoside has the following formula
  • Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes mellitus.
  • Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes in human subjects suffering from diabetes.
  • Efforts have been made to develop oral formulations of remogliflozin for the treatment of type II diabetes.
  • PCT publication W02012/006398A2 relates to a biphasic composition comprising remogliflozin etabonate delayed release portions dispersed in remogliflozin immediate release portions.
  • PCT publication W02009/022010A1 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 WO2010/092125 A 1 relates to a composition comprising (a) an SGLT2 inhibitor, and (b) a DPPIV inhibitor, and (c) a third anti-diabetic agent.
  • PCT publication has 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.
  • an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.
  • an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • Cmax plasma concentration
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and (B) an extra- granular portion comprising a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • 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, or combinations thereof.
  • the remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate.
  • the remogliflozin etabonate is present in an amount of about lOmg to about lOOOmg, preferably in an amount of about 50mg, or about lOOmg, or about 250mg.
  • the pharmaceutical composition comprises the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant in a weight ratio of about 1:0.01 to about 1: 10.
  • the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disinetgrant is present in weight ratio of about 1:0.05 or about 1 :0.06.
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) microcrystalline cellulose, (c) crosscarmellose sodium, and (d) polyvinylpyrrolidone, and (B) an extra-granular portion having (a) crosscarmellose sodium, (b) microcrystalline cellulose and (c) magnesium stearate, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 1 l00ng.hr/ml to about 6000ng.h/ml.
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1 :0.0l to about 1 :
  • kits comprising an immediate release pharmaceutical composition
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • a method of treating a diabetes by administering to a subject in a need thereof an immediate release pharmaceutical composition
  • an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant
  • the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml,
  • the invention composition are provided as tablet, capsule, powder, mini-tablet, suspension, solution, pill and like. In yet another embodiment, the invention composition are administered as once a daily, or twice a daily, or thrice a daily administration by oral route.
  • a process of preparing an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable excipients to obtain granules, (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.
  • Cmax plasma concentration
  • Remogliflozin etabonate (also referred as GSK189075) is a prodrug of remogliflozin that selectively inhibits SGLT2 and is shown to have a significantly short plasma half-life (ranging from 1.4 to 2.9 hrs) compared to other approved members (Dapagliflozin, Canagliflozin, Empagliflozin) of this class (half-life ranging from 10.6 to 13.1 hrs). Remogliflozin is being developed for use in the treatment of type 2 diabetes as monotherapy and in combination with existing anti-diabetic therapies. So far, a total of 26 clinical studies (Phase I, phase II and phase III) have been conducted in which 2050 subjects have been enrolled.
  • a total of 434 healthy volunteers including healthy obese subjects, 1152 subjects with type 2 diabetes, 10 subjects with type 1 diabetes and 19 special population subjects with mild or moderate renal impairment have been exposed to GSK189075 for up to 12 weeks, and at daily oral doses up to 4000 mg.
  • Safety and efficacy of remogliflozin in patients with type 2 diabetes has been evaluated in separate dose ranging trials with BID (Bis a day) and QD (Once a day) dosing regimens of l2-weeks duration and it has shown significant reduction in HbAlc levels as well as fasting plasma glucose concentrations at the end of 12 weeks compared to placebo.
  • the BID regimen showed better and more consistent efficacy and a discernible dose response effect compared to QD regimen, probably owing to its short half-life.
  • Remogliflozin administered as BID regimen has also been well tolerated in the clinical studies at doses up to 1000 mg BID with low incidence of glycosuria related adverse events such as urinary tract infections (0-4%) and genital fungal infections (0-8.5%).
  • glycosuria related adverse events such as urinary tract infections (0-4%) and genital fungal infections (0-8.5%).
  • an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.
  • an excipient includes a single excipient as well as two or more different excipients, and the like.
  • the term "about” is used synonymously with the term “approximately.”
  • 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.
  • Subject refers to an animal (especially mammal) or human being treated.
  • treating and its grammatical variants (e.g. “to treat,” “treating,” and “treatment”) refer to administration of remogliflozin etabonate to a patient with the purpose of ameliorating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. Such symptoms may be chronic or acute; and such amelioration may be partial or complete.
  • Bioavailability refers to the amount of unchanged drug that reaches systemic circulation.
  • HbAlc Glycated haemoglobin
  • T m ax time of peak drug concentration during a dosing interval.
  • AUCo- t auss area under the concentration-time profile over a dosing interval at steady state.
  • an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • Cmax plasma concentration
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • the remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate.
  • the remogliflozin etabonate is present in an amount of about lOmg to about lOOOmg.
  • the remogliflozin etabonate is present in an amount of about 20mg, or about 30mg, or about 40mg, or about 50mg, or about 60mg, or about 70mg, or about 80mg, or about 90mg, or about lOOmg, about l50mg, 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.
  • the invention composition comprises about 50mg, or about lOOmg or about 250mg of remogliflozin etabonate.
  • 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 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 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, 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 5-60% w/w by weight of composition.
  • the diluent is present in a concentration of about 8-55% w/w, or about 12-30% w/w, or about 14- 18% w/w by weight of composition.
  • the intra-granular portion comprises diluent in about 5-30% w/w by weight of diluent or about 6% w/w by weight.
  • the extra-granular portion comprises diluent in about 5-60% w/w or about 55% w/w by weight.
  • 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.
  • 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 intra-granular portion comprises disintegrant in about 1.5% w/w by weight of composition.
  • the extra-granular portion comprises disintegrant in about 2% 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.
  • 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 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.
  • 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.
  • 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.
  • EDTA ethylene diamine tetraacetic acid
  • 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.
  • the diluent is microcrystalline cellulose.
  • the disintegrant is crosscarmellose sodium.
  • the glidant is magnesium stearate.
  • the binder is polyvinylpyrrolidone.
  • a composition wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.01 to about 1 : 10.
  • a composition wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.05, or about 1 :0.06.
  • the disintegrant is crosscarmellose sodium.
  • the disintegrant is present only in intra-granular portion.
  • the disintegrant is present only in extra-granular portion.
  • the disintegrant is present in both intra-granular portion as well as extra-granular portion.
  • the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition.
  • the dose of lOOmg of remogliflozin etabonate provides the plasma concentration (Cmax) between about 350ng/ml to about lOOOng/ml, or about 400ng/ml to about 700ng/ml, or about 450ng/ml to about 600ng/ml, or preferably about 475ng/ml under fasted or fed condition.
  • the dose of 250mg of remogliflozin etabonate provides the plasma concentration (Cmax) between about 400ng/ml to about l300ng/ml, or about 600ng/ml to about l350ng/ml, or about lOOOng/ml to about l200ng/ml, or preferably about 1 l56ng/ml under fasted or fed condition.
  • the plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof is about 350ng/ml, or about 400ng/ml, or about 450ng/ml, or about 500ng/ml, or about 550ng/ml, or about 600ng/ml, or about 650ng/ml, or about 700ng/ml, or about 750ng/ml, or about 800ng/ml, or about 850ng/ml, or about 900ng/ml, or about 950ng/ml, or about lOOOng/ml, or about 1 lOOng/ml, or about l200ng/ml, or about l300ng/ml.
  • the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • the dose of lOOmg of remogliflozin etabonate provides an AUC of in between about 800ng.hr/ml to about 5000ng.h/ml, or about 900ng.hr/ml to about 4000ng.h/ml, or about l000ng.hr/ml to about 3000ng.h/ml, or about H00ng.hr/ml to about 2000ng.h/ml, or about l200ng.hr/ml to about l500ng.h/ml or preferably about 1407 ng.hr/ml under fasted or fed condition.
  • the dose of 250mg of remogliflozin etabonate provides an AUC of in between about l000ng.hr/ml to about 5000ng.h/ml, or about 2000ng.hr/ml to about 4500ng.h/ml, or about 3500ng.hr/ml to about 4000ng.h/ml, or preferably about 3737ng.hr/ml under fasted or fed condition.
  • the AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof is about 800ng.hr/ml or, about 900ng.hr/ml or, about l000ng.hr/ml or, about H00ng.hr/ml or, about l200ng.hr/ml or, about l300ng.hr/ml or, about l400ng.hr/ml or, about l500ng.hr/ml or, about l600ng.hr/ml or, about l700ng.hr/ml or, about l800ng.hr/ml or, about l900ng.hr/ml or, about 2000ng.hr/ml or, about 2l00ng.hr/ml or, about 2200ng.hr/ml or, about 2300ng.hr/ml or, about
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) microcrystalline cellulose, (c) crosscarmellose sodium, and (d) polyvinylpyrrolidone, and (B) an extra-granular portion having (a) crosscarmellose sodium,
  • composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 1 l00ng.hr/ml to about 6000ng.h/ml.
  • Cmax plasma concentration
  • AUC AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 1 l00ng.hr/ml to about 6000ng.h/ml.
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) about 5-30% w/w by weight of microcrystalline cellulose,
  • composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about H00ng.hr/ml to about 6000ng.h/ml.
  • Cmax plasma concentration
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1 :0.0l to about 1 :
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) microcrystalline cellulose, (c) crosscarmellose sodium, and (d) polyvinylpyrrolidone, and (B) an extra-granular portion having (a) crosscarmellose sodium, (b) microcrystalline cellulose and (c) magnesium stearate, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about H00ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and crosscarmellose sodium is present
  • kits comprising an immediate release pharmaceutical composition
  • an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
  • a process of preparing an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable excipients to obtain granules, (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.
  • Cmax plasma concentration
  • the present invention also provides a method of treating diabetes mellitus in a subject in need thereof by administering to the subject an immediate release composition comprising remogliflozin etabonate.
  • an immediate release composition comprising remogliflozin etabonate.
  • therapeutically effective amount of remogliflozin etabonate is administered in patients who have inadequate glycemic control with stable dose of metformin as monotherapy
  • a method of treating a diabetes by administering orally to a subject in a need thereof an immediate release pharmaceutical composition
  • an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant
  • the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate
  • subjects have HbAlc > 7% but ⁇ 10%.
  • the subjects are in age group of >18 and ⁇ 65 years of age, diagnosed with type 2 diabetes.
  • subjects receive stable dose of metformin > 1500 mg/day (> 1000 mg/day for subjects not tolerating) as monotherapy for at least 8 weeks prior to screening and having inadequate glycemic control at screening defined as HbAlc levels of >7% to ⁇ 10%.
  • remogliflozin etabonate immediate release tablet is administered once or twice in a day with or without food.
  • the composition is administered twice daily with food preferably at the same time.
  • composition is administered twice daily for the period of 24 weeks.
  • Present invention relates to a method of treating type 2 diabetes mellitus in a subject in need thereof who is 18 to 65 years of age and received stable dose of metformin > 1500 mg/day (> 1000 mg/day for subjects not tolerating) as monotherapy for at least 8 weeks prior to screening and having inadequate glycemic control at screening defined as HbAlc levels of >7% to ⁇ 10%; comprising administering to a subject twice daily immediate release tablet comprising remogliflozin etabonate in an about 50mg, or about lOOmg, or about 250mg.
  • the invention composition when administered orally produces characteristic pharmacokinetic profile for remogliflozin etabonate (GSK 189075), remogliflozin (GSK 189074), and metabolite of remogliflozin (GSK 279782), which has a similar potency to remogliflozin, wherein the maximum plasma concentrations (T max ) were achieved rapidly for all three analytes with median T max ranging from 0.5 to 1.5 hours. In one embodiment, under fed state, there is a slight delay in T max with the medians ranging from 1.5 to 3 hours.
  • C max is comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 0.77 to 1.44 and 0.81 to 1.12, respectively.
  • AUC of the active moiety is comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 1.22 to 2.01 and 1.35 to 1.56, respectively.
  • the metabolite’s and prodrug’s AUCs are slightly higher under fed state.
  • an elimination half-lives (ti /2 ) for the active moieties ranges from l.55hrs to 2.8hrs in the fasting and fed state for lOOmg and from l.8hr to 3.7 hr respectively for 250mg.
  • the active moiety shows the highest exposures, followed by metabolite (GSK 279782), ( ⁇ 25 to 42% of active moiety), whereas the inactive prodrug (GSK 189075), shows the lowest exposure ( ⁇ 3% of active moiety).
  • invention composition comprising about lOOmg or 250mg of remogliflozin or pharmaceutically acceptable salt or ester thereof when administered to diabetic subjects reduces HbAlc levels and hyperglycemia and are comparable with dapagliflozin 10 mg.
  • the treatment is for 4 weeks, or for 8 weeks, or 12 weeks, or for 24 weeks, or 36 weeks or up to a period until the disease symptoms ceased to show.
  • remogliflozin or pharmaceutically acceptable salt or ester thereof at lOOmg and 250 mg doses is non inferior to dapagliflozin 10 mg.
  • Example 1 Immediate release formulation of remogliflozin etabonate.
  • Co-sifted material was granulated using binder solution.
  • step 3 Wet mass of step 3 was passed through mesh no # 12 and granules were dried.
  • Granules were lubricated with magnesium stearate along with crosscarmellose sodium and microcrystalline cellulose.
  • EXAMPLE 2 Single dose pharmacokinetic (PK) study results of remogliflozin etabonate immediate release formulation.
  • PK study- 0355-17 with 250 mg immediate release tablet formulation in 30 healthy adult male subjects.
  • remogliflozin was found to be safe and well tolerated with no serious or significant adverse events.
  • remogliflozin etabonate tablet was administered along with glucose solution; whereas in the historical studies, subjects received remogliflozin tablet along with only water. Influence of glucose solution on the PK of remogliflozin precluded a comparison with historical PK profiles.
  • Remogliflozin etabonate Following oral administration of remogliflozin etabonate, three analytes (GSK 189075, GSK 189074 and GSK 279782) were quantified in plasma samples collected over a period of 24 hours, using a validated LC/MS/MS method.
  • Remogliflozin etabonate (GSK 189075) is inactive and is a prodrug that rapidly gets converted to the active moiety remogliflozin (GSK 189074), which then further metabolize to GSK 279782.
  • the remogliflozin (GSK 189074) showed the highest plasma exposure and is most important from safety and efficacy perspective, followed by GSK 279782 which showed relatively lower plasma exposure and less important from safety and efficacy perspective.
  • the inactive prodrug (GSK 189074) has very low serum exposure and is not anticipated to contribute towards efficacy or safety.
  • maximum plasma concentrations were achieved rapidly for all three analytes with median Tmax ranging from 0.5 to 1.5 hours. Under fed state, there was a slight delay in T max with the medians ranging from 1.5 to 3 hours.
  • T max medians ranging from 1.5 to 3 hours.
  • remogliflozin etabonate was administered with plain water an early T max was observed, and the plasma concentration profiles did not show prominent multiple peaks as seen in the previous study which was a single dose PK study with 250 mg immediate release tablet formulation in 30 healthy adult male subjects. While when remogliflozin etabonate was administered with glucose solution, there was a prolonged absorption with multiple peaks leading to a considerable delay in T max (5.5 to 6 hours).
  • the PK parameters were estimated for all the 3 analytes at both dose levels (100 and 250 mg). Both the Cmax and AUC of all the 3 analytes were largely dose proportional between 100 mg to 250 mg. Across dose levels and diet conditions, the active moiety (GSK 189074) showed highest exposures, followed by metabolite (GSK 279782) ( ⁇ 25 to 42% of active moiety). The inactive prodrug (GSK 189075) had the lowest exposure ( ⁇ 3% of active moiety), across the treatments. The elimination half-lives remained consistent for each analyte between the doses and diet conditions, with shortest half-life for the prodrug ( ⁇ 0.5 hours) and the longest for the metabolite ( ⁇ 3.8 hours).
  • the Cmax were generally comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 0.77 to 1.44 and 0.80 to 1.12, respectively.
  • the AUC of the active moiety also were generally comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 1.22 to 1.35, respectively.
  • the metabolite and prodrug AUCs were slightly higher under fed state, with fed/fasted ratio ranging from 1.6 to 2.0 and 2.0 to 2.5, respectively.
  • EXAMPLE 3 Comparison of PK data from study 0637-17 with Historical PK data
  • Table 3 Details of historical studies used for comparison of remogliflozin etabonate PK data.
  • GSK 189074 is the active moiety, showed the highest exposure among the 3 analytes in this study as well as in historical studies. GSK 189074 is the major contributor to efficacy and is the most important analyte for comparison in terms of efficacy and safety.
  • the geometric mean Cmax of GSK 189074 ranged from 805 ng/mL to 1563 ng/mL indicating considerable between study variability (1.9-fold difference).
  • the grand mean of Cmax from historical studies was estimated to be 1013 ng/mL.
  • the average Cmax (fasted and fed) of the current study was estimated to be 1156 ng/mL.
  • the ratio of the grand mean Cmax of the current study to that of the historical studies is around 1.14, indicating at 250 mg the GSK 189074 Cmax in the current study is comparable with that of the historical studies.
  • the geometric mean AUCo-i nf of GSK 189074 ranged from 1743 ng.h/mL to 3243 ng.h/mL indicating considerable between study variability (1.9-fold difference).
  • the grand mean of AUCo-i nf from historical studies was estimated to be 2250 ng.h/mL.
  • the average AUCo-i nf (fasted and fed) of the current study was estimated to be 3737 ng.h/mL.
  • the ratio of the grand mean AUCo- i nf of the current study to that of the historical studies is around 1.66, indicating at 250 mg the GSK 189074 AUCo-i nf estimated in the current study is within 2-fold to that of the historical studies and this difference is not anticipated to be of clinical significance.
  • the geometric mean C max of GSK 189074 ranged from 230 ng/mL to 753 ng/mL indicating considerable between study variability (3.3-fold difference).
  • the grand mean of C max from historical studies was estimated to be 389 ng/mL.
  • the average C max (fasted and fed) of the current study was estimated to be 475 ng/mL.
  • the ratio of the grand mean C max of the current study to that of the historical studies is around 1.22, indicating at 100 mg the GSK 189074 C max in the current study is comparable with that of the historical studies.
  • the geometric mean AUCo-i nf of GSK 189074 ranged from 471 ng.h/mL to 1242 ng.h/mL indicating considerable between study variability (2.6-fold difference).
  • the grand mean of AUCo- i nf from historical studies was estimated to be 706 ng.h/mL.
  • the average AUCo-i nf (fasted and fed) of the current study was estimated to be 1407 ng.h/mL.
  • Table 4 Summary of exposure parameters (C max and AUC) of GSK 189074 from individual studies and comparison with study 0637-17.
  • GSK 279782 is an active metabolite formed from GSK 189074 and the plasma exposures were around 24 to 43% of the GSK 189074 exposure. Hence though GSK 279782 is active, the contribution of GSK 279782 towards the efficacy is expected to be lower than that of GSK 189074.
  • the GSK 279782 exposures in the current study (0637-17) was also lower, around 24 to 42% of GSK 189074 exposure indicating comparable extent of metabolite formation.
  • the geometric mean Cmax of GSK 279782 ranged from 129 ng/mL to 240 ng/mL indicating considerable between study variability (1.9 -fold difference).
  • the grand mean of Cmax from historical studies was estimated to be 203 ng/mL. There were no historical PK data of GSK 279782 under fed state at the 250 mg dose level. Hence for the comparison, Cmax under fasted state from the current study was used.
  • the geometric mean Cmax in the current study was 286 ng/mL.
  • the ratio of the geometric mean Cmax of the current study to that of the historical studies is around 1.42, indicating GSK 189074 Cmax in the current study is largely comparable with that of the historical studies.
  • the geometric mean AUCo-inf of GSK 279782 ranged from 468 ng.h/mL to 801 ng.h/mL indicating considerable between study variability (1.7-fold difference).
  • the grand mean of AUCo-inf from historical studies was estimated to be 658 ng.h/mL. There were no historical PK data of GSK 279782 under fed state at the 250 mg dose level. Hence for the comparison, AUCo-inf under fasted state from the current study was used.
  • the geometric mean AUCo-inf of the current study was estimated to be 1037 ng.h/mL.
  • the ratio of the geometric mean AUCo-inf of the current study to that of the historical studies is around 1.58, indicating the GSK 279782 AUCo-inf, estimated in the current study is within 2-fold to that of the historical studies, which is not anticipated to be of clinical significance.
  • the geometric mean Cmax of GSK 279782 ranged from 70 ng/mL to 150 ng/mL indicating considerable between study variability (2.1 -fold difference).
  • the grand mean of Cmax from historical studies was estimated to be 93 ng/mL.
  • the average Cmax (fasted and fed) from the current study was estimated to be 118 ng/mL.
  • the ratio of the grand mean Cmax of the current study to that of the historical studies is around 1.26, indicating GSK 279782 Cmax in the current study is comparable with that of the historical studies.
  • the geometric mean AUCo-inf of GSK 279782 ranged from 177 ng.h/mL to 393 ng.h/mL indicating considerable between study variability (2.2-fold difference).
  • the grand mean of AUCo-inf from historical studies was estimated to be 257 ng.h/mL.
  • the average AUCo-inf (fasted and fed) of the current study was estimated to be 488 ng.h/mL.
  • the ratio of the grand mean AUCo-inf of the current study to that of the historical studies is around 1.89, indicating the GSK 279782 AUCo-inf , estimated in the current study is within 2-fold to that of the historical studies.
  • a less than 2-fold difference in exposure of the metabolite at 100 mg dose is not anticipated to be of clinical significance. This is shown in Table 5 as below.
  • GSK 189075 (remogliflozin etabonate) is the prodrug of GSK 189074 and is inactive. As observed in historical studies, GSK 189074 had the lowest plasma exposure among the 3 analytes, only about 1 to 3 % of the plasma exposures of active moiety (GSK 189074). GSK 189075 is also rapidly cleared and has the shortest half-life (around 0.5 hours) among the 3 analytes. As observed in the historical studies, the prodrug showed a rapid conversion to the active moiety in the current study as well with similar extent of conversion. The plasma exposures of GSK 279782 was 1 to 3% of that of active moiety and showed shortest half-life of around 0.5 hours, similar to what was reported in the historical studies.
  • the GSK 189075 geometric mean Cmax ranged from 31 ng/mL to 57 ng/mL indicating considerable between study variability (1.8-fold difference).
  • the grand mean Cmax of the historical studies were about 46 ng/mL and the average Cmax (fasted and fed) from the current study is 45 ng/mL.
  • the ratio of the grand mean Cmax of the current study to that of the historical study is 0.97, indicating GSK 189075 Cmax is comparable to that of the historical studies.
  • the GSK 189075 geometric mean AUCo-inf ranged from 27 ng.h/mL to 61 ng.h/mL, indicating considerable between study variability (2.3-fold difference).
  • the grand mean AUCO-inf of the historical studies were about 43 ng.h/mL and the average AUCo-inf (fasted and fed) from the current study is 70 ng/mL.
  • the ratio of the grand mean Cmax of the current study to that of the historical study is 1.6, indicating GSK 189075 AUCO-inf is within 2-fold to that of the historical studies. Considering the minimal exposure and no contribution to efficacy, this difference is not anticipated to be clinically significant.
  • the GSK 189075 geometric mean Cmax ranged from 7 ng/mL to 30 ng/mL indicating considerable between study variability (4.3-fold difference).
  • the grand mean Cmax of the historical studies were about 15 ng/mL and the average Cmax (fasted and fed) from the current study is 21 ng/mL.
  • the ratio of the grand mean Cmax of the current study to that of the historical study is 1.4, indicating GSK 189075 Cmax is generally comparable to that of the historical studies.
  • the GSK 189075 geometric mean AUCO-inf ranged from 11 ng.h/mL to 16 ng.h/mL (l.5-fold difference).
  • the grand mean AUCO-inf of the historical studies were about 13 ng.h/mL and the average AUC0- inf (fasted and fed) from the current study is 30 ng/mL.
  • Table 6 Summary of exposure parameters (Cmax and AUC) of GSK 189075 from individual studies and comparison with study 0637-17.
  • EXAMPLE 4 Safety margins for all the 3 analytes in comparison to the plasma exposures in long term toxicology studies.
  • Table 7 shows anticipated safety margins in humans with 250 mg bid relative to plasma exposures at NOAEL doses in long term toxicology studies.
  • Steady state human AUC with 250 mg BID is calculated by doubling the single dose AUCo m f ( average of fasted and fed state)
  • the exposure parameters (Cmax and AUC) generated in current study (0637-17) were compared with that of historical studies both descriptively and graphically.
  • the Cmax of all the 3 analytes from study 0637-17 was found to be generally comparable with ratios ranging from (GSK 189074: 1.14 to 1.22; GSK 279782: 1.27 to 1.41; and GSK 189075: 0.97 to 1.40).
  • the AUCo-inf of all the analytes were generally within 2-fold (GSK 189074: 1.66 to 1.99; GSK 279782: 1.58 to 1.90); and within 2.3-fold for inactive GSK 189075 (1.61 to 2.23).
  • GSK 189074 is the major contributor of efficacy, followed by GSK 279782, whereas GSK 189075 does not contribute to efficacy. Hence the slight differences in the exposures are not anticipated to be clinically significant.
  • EXAMPLE 5 A 24-week randomised, double -blind, double-dummy, parallel-group, multi-centre, active controlled study to evaluate efficacy and safety of remogliflozin etabonate in subjects with Type 2 diabetes mellitus.
  • the proposed phase 3 clinical study evaluated the efficacy and safety of remogliflozin etabonate administered as 100 mg or 250 mg BID in comparison to dapagliflozin 10 mg QD in the subjects who have inadequately controlled type 2 diabetes with stable dose of metformin.
  • Dapagliflozin was selected as an active comparator as it is approved as both monotherapy and as adjunct to other anti-diabetic agents and has shown significant glycemic efficacy in clinical trials.
  • a dose of 10 mg of Dapagliflozin once a day was selected based on approval and clinical usage.
  • HbAlc is an accepted surrogate for assessment of short-term clinical consequences of hyperglycemia, as well as the long-term microvascular complications of diabetes mellitus and were be evaluated as the primary efficacy endpoint in this study.
  • Study population Subjects with T2DM receiving stable doses of metformin as monotherapy for at least 8 weeks prior to screening at a dose of > 1500 mg per day (>1000 mg per day in subjects not tolerating) and have inadequate glycemic control (i.e. HbAlc > 7% but ⁇ 10% at screening).
  • Arm 2 Remogliflozin etabonate 250 mg, administered as 1 tablet BID for 24 weeks.
  • Arm 3 Dapagliflozin 10 mg, administered as 1 tablet QD in morning + Placebo administered as 1 tablet QD in evening, for 24 weeks.
  • Each subject underwent screening assessments on Visit 1 (Screening).
  • the screening period was for a total of 3 weeks duration and included at least 2 weeks of open label, lead-in period in which standard consultation for dietary and exercise modification was provided to all subjects in accordance with the applicable national/international guidelines (eg. American Diabetes Association. Standards of medical care in diabetes - 2016, ICMR guidelines for management of type 2 diabetes - 2005).
  • Assessments performed at the screening visit was considered for determining eligibility of the subject.
  • key assessments eg. HbAlc, FPG, total body weight
  • Double-blind study treatment was administered daily in randomized subjects for 24 weeks.
  • Subjects were required to visit at weeks 1 and 4 after randomization, followed by visits every 4 weeks until Week-24. An additional visit for a safety follow up was required 2 weeks after successful completion of the double -blind study treatment. Subjects were provided with diary at the time of randomization along with glucometer to record details about study drug administration, adverse events and self- monitored fasting plasma glucose levels. Subject were required to bring completed diary at each visit. Additionally a periodic telephonic follow up (at least once every fortnight) by study team was advised to ensure compliance.
  • Pharmacokinetic sampling was performed at specified time points in a subset of study population. Subjects consenting for the PK study were admitted for 24 hours on Day 1 and Day 8 for serial PK sampling.
  • Table 8 Analysis of Mean Change in Glycosylated Haemoglobin (HbAlc%) Levels (PP Population): MMRM
  • HbAlc glycosylated haemoglobin
  • LSM least squares mean
  • PP per protocol
  • MMRM mixed model repeated measures
  • SE standard error
  • P value 1 is calculated for the 1-sided non-inferior test with non-inferiority margin 0.35, P value 2 for 2-sided superior test.
  • P values are calculated for the comparison of treatment arms with treatment as main effect and by considering the baseline HbAlc% value, centre, visit and treatment as covariates.
  • LSM (SE) between treatment arms is calculated for remogliflozin etabonate 100 mg or
  • P value 1 is calculated for the comparison of treatment arms using MMRM with treatment as main effect and by considering the baseline FPG, mg/dL value, centre, visit, and treatment as covariates.

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Abstract

L'invention concerne une composition pharmaceutique à libération immédiate comprenant de la rémogliflozine ou un sel ou ester pharmaceutiquement acceptable de celle-ci et un excipient pharmaceutiquement acceptable. En particulier, l'invention concerne une composition pharmaceutique à libération immédiate comprenant : (A) une partie intra-granulaire comprenant de la rémogliflozine ou un sel ou un ester pharmaceutiquement acceptable de celle-ci et un excipient pharmaceutiquement acceptable, et (B) une partie extra-granulaire comprenant un excipient pharmaceutiquement acceptable, la composition fournissant une concentration plasmatique (Cmax) de la rémogliflozine ou d'un sel ou d'un ester pharmaceutiquement acceptable de celle-ci entre environ 300 ng/ml à environ 1400 ng/ml ou la composition fournit une ASC de la rémogliflozine ou du sel ou ester pharmaceutiquement acceptable de celle-ci entre environ 700 ng.hr/ml à environ 6000 ng.h/ml.
PCT/IB2019/051353 2018-02-21 2019-02-20 Composition pharmaceutique comprenant de la rémogliflozine pour le traitement du diabète sucré WO2019162841A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008116179A1 (fr) * 2007-03-22 2008-09-25 Bristol-Myers Squibb Préparations pharmaceutiques contenant de l'hydrate de propylèneglycol de dapagliflozine
WO2012006398A2 (fr) * 2010-07-09 2012-01-12 Bhv Pharma, Inc. Système d'administration à libération immédiate/retardée en combinaison pour des médicaments à courte demi-vie comprenant de la rémogliflozine
WO2018198102A1 (fr) * 2017-06-08 2018-11-01 Glenmark Pharmaceuticals Limited Préparations pharmaceutiques orales de rémogliflozine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008116179A1 (fr) * 2007-03-22 2008-09-25 Bristol-Myers Squibb Préparations pharmaceutiques contenant de l'hydrate de propylèneglycol de dapagliflozine
WO2012006398A2 (fr) * 2010-07-09 2012-01-12 Bhv Pharma, Inc. Système d'administration à libération immédiate/retardée en combinaison pour des médicaments à courte demi-vie comprenant de la rémogliflozine
WO2018198102A1 (fr) * 2017-06-08 2018-11-01 Glenmark Pharmaceuticals Limited Préparations pharmaceutiques orales de rémogliflozine

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