FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
PHARMACEUTICAL COMPOSITION COMPRISING REMOGLIFLOZIN FOR TREATMENT OF DIABETES MELLITUS
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
2
Technical Field of the Invention
The invention relates to 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 1400ng/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.
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
3
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. 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.
4
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.
Although several approaches have been reported in the art with respect to formulations comprising remogliflozin, there remains a substantial need in the art for new and improved pharmaceutical formulations of remogliflozin which exhibit advantageous effect on the treatment of type 2 diabetes mellitus. The present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
Summary of the Invention
In one embodiment, there is provided an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.
In another embodiment, there is provided 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
5
acceptable salt or ester thereof between about 300ng/ml to about 1400ng/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.
In another embodiment, there is provided 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 1400ng/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.
In another embodiment, 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.
In still another embodiment, the remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate. In still another embodiment, the remogliflozin etabonate is present in an amount of about 10mg to about 1000mg, preferably in an amount of about 50mg, or about 100mg, or about 250mg.
In still another embodiment, 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. Alternatively, 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.
6
In yet another embodiment, there is provided 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 1400ng/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.
In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about 100mg, 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 1100ng.hr/ml to about 6000ng.h/ml.
In yet another embodiment, there is provided 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 1400ng/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
7
disintegrant is present in weight ratio of about 1:0.01 to about 1:10 in either intra-granular portion or extra-granular portion.
In yet another embodiment, there is provided a kit comprising 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 1400ng/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.
In yet another embodiment, there is provided a method of treating a diabetes by administering to a subject in a need thereof 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 1400ng/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,
In yet another embodiment, 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.
In yet another embodiment, there is provided a process of preparing an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically
8
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 1400ng/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.
Detail Description of the Invention
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.
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
9
dose ranging trials with BID (Bis a day) and QD (Once a day) dosing regimens of 12-weeks duration and it has shown significant reduction in HbA1c levels as well as fasting plasma glucose concentrations at the end of 12 weeks compared to placebo. Among these, 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%). There was no incidence of diabetic keto-acidosis across clinical studies. Efforts were made to modify the formulation (i.e. biphasic formulation with immediate and delayed release components) to achieve adequate efficacy and safety with once daily dosing regimen; however results for dose ranging 12-week study conducted with this formulation did not show comparable glycemic efficacy and dose response as compared to BID regimen with IR formulation. There was a statistically significant reduction of HbA1c with all the doses tested. The present inventors have found a novel and stable immediate release compositions of remogliflozin or pharmaceutical acceptable salt or ester thereof, where in the composition is efficacious and pose no toxicity in clinical studies. The present compositions are also proved non-inferior to dapagliflozin marketed composition for the treatment of type 2 diabetes.
There is provided an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.
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
10
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.
As used herein, the terms "comprising", "including", "such as", and "for example" (or "e.g.") are used in their open, non-limiting sense.
"Subject" refers to an animal (especially mammal) or human being treated.
The term "treating" and its grammatical variants (e.g. "to treat," "treating," and "treatment") refer to administration of remogliflozin etabonate to a patient with the purpose of ameliorating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. Such symptoms may be chronic or acute; and such amelioration may be partial or complete.
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.
"Bioavailability" as used herein, refers to the amount of unchanged drug that reaches systemic circulation.
HbA1c: Glycated haemoglobin
“Cmax”: peak concentration during a dosing interval.
“Cmin”: minimum of trough concentration during a dosing interval
“Tmax”: time of peak drug concentration during a dosing interval.
“AUC”: area under the concentration-time curve
“AUC0-tau”: area under the concentration-time profile over a dosing interval
“AUC0-tauSS”: area under the concentration-time profile over a dosing interval at steady state.
QD: once daily
11
BID: twice in a day
There is provided 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 1400ng/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.
Particularly, there are provided 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 1400ng/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 10mg to about 1000mg. Alternatively, 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 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.
12
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. Alternatively, 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. In an embodiment, the intra-granular portion comprises diluent in about 5-30% w/w by weight of diluent or about 6% w/w by weight. In another embodiment, 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
13
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. In an embodiment, the intra-granular portion comprises disintegrant in about 1.5% w/w by weight of composition. In an embodiment, 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. 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 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.
14
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 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 1:0.01 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 1:0.05, or about 1:0.06. In most preferred embodiment, the disintegrant is crosscarmellose sodium. In certain embodiments, the disintegrant is present only in intra-granular portion. In certain embodiments, the disintegrant is present only in extra-granular portion. In certain embodiments, the disintegrant is present in both intra-granular portion as well as extra-granular portion.
15
In certain embodiments, the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about 1400ng/ml under fed or fasted condition. In an embodiment, the dose of 100mg of remogliflozin etabonate provides the plasma concentration (Cmax) between about 350ng/ml to about 1000ng/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.
In an embodiment, the dose of 250mg of remogliflozin etabonate provides the plasma concentration (Cmax) between about 400ng/ml to about 1300ng/ml, or about 600ng/ml to about 1350ng/ml, or about 1000ng/ml to about 1200ng/ml, or preferably about 1156ng/ml under fasted or fed condition.
Alternatively, 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 1000ng/ml, or about 1100ng/ml, or about 1200ng/ml, or about 1300ng/ml.
In certain embodiments, the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.
In an embodiment, the dose of 100mg 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 1000ng.hr/ml to about 3000ng.h/ml, or about 1100ng.hr/ml to about 2000ng.h/ml, or about 1200ng.hr/ml to about 1500ng.h/ml or preferably about 1407 ng.hr/ml under fasted or fed condition.
In an embodiment, the dose of 250mg of remogliflozin etabonate provides an AUC of in between about 1000ng.hr/ml to about 5000ng.h/ml, or about 2000ng.hr/ml to about
16
4500ng.h/ml, or about 3500ng.hr/ml to about 4000ng.h/ml, or preferably about 3737ng.hr/ml under fasted or fed condition.
Alternatively, the AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof is about 800ng.hr/ml or, about 900ng.hr/ml or, about 1000ng.hr/ml or, about 1100ng.hr/ml or, about 1200ng.hr/ml or, about 1300ng.hr/ml or, about 1400ng.hr/ml or, about 1500ng.hr/ml or, about 1600ng.hr/ml or, about 1700ng.hr/ml or, about 1800ng.hr/ml or, about 1900ng.hr/ml or, about 2000ng.hr/ml or, about 2100ng.hr/ml or, about 2200ng.hr/ml or, about 2300ng.hr/ml or, about 2400ng.hr/ml or, about 2500ng.hr/ml or, about 2600ng.hr/ml or, about 2700ng.hr/ml or, about 2800ng.hr/ml or, about 2900ng.hr/ml or, about 3000ng.hr/ml or, about 4000ng.hr/ml or, about 5000ng.hr/ml.
In certain embodiments, there are provided 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 1400ng/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.
In one embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about 100mg, 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
17
provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 1100ng.hr/ml to about 6000ng.h/ml.
In another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about 100mg, or about 250mg of remogliflozin etabonate, (b) about 5-30% w/w by weight of microcrystalline cellulose, (c) about 1-30% w/w by weight of crosscarmellose sodium, and (d) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion having (a) about 1-30% w/w by weight of crosscarmellose sodium, (b) about 5-60 % w/w by weight of microcrystalline cellulose and (c) about 0.1-5% w/w by weight of 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 1100ng.hr/ml to about 6000ng.h/ml.
In still another embodiment, there is provided 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 1400ng/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 1:0.01 to about 1:10 in either 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) about 50mg, or
18
about 100mg, 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 1100ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and crosscarmellose sodium is present in weight ratio of about 1:0.01 to about 1:10 in either intra-granular portion or extra-granular portion.
In further embodiments, there are provided a kits comprising 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 1400ng/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.
In certain embodiments, there is provided 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 1400ng/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
19
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.
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. Particularly in an embodiment, therapeutically effective amount of remogliflozin etabonate is administered in patients who have inadequate glycemic control with stable dose of metformin as monotherapy
In certain embodiments, there is provided a method of treating a diabetes by administering orally to a subject in a need thereof 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 1400ng/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 1:0.01 to about 1:10 in either intra-granular portion or extra-granular portion.
In an embodiment, subjects have HbA1c ≥ 7% but ≤ 10%. Preferably the subjects are in age group of ≥18 and ≤ 65 years of age, diagnosed with type 2 diabetes.
In another embodiment, 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 HbA1c levels of >7% to ≤10%.
20
In another embodiment, remogliflozin etabonate immediate release tablet is administered once or twice in a day with or without food. Particularly, the composition is administered twice daily with food preferably at the same time.
In another embodiment, the 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 HbA1c levels of >7% to ≤10%; comprising administering to a subject twice daily immediate release tablet comprising remogliflozin etabonate in an about 50mg, or about 100mg, or about 250mg.
In certain embodiments, 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 (Tmax) were achieved rapidly for all three analytes with median Tmax ranging from 0.5 to 1.5 hours. In one embodiment, under fed state, there is a slight delay in Tmax with the medians ranging from 1.5 to 3 hours. In another embodiment, Cmax 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. In another embodiment, the 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. In another embodiment, the metabolite’s and prodrug’s AUCs are slightly higher under fed state. In another embodiment, an elimination half-lives (t1/2) for the active moieties (Remogliflozin and GSK279782) ranges from 1.55hrs to 2.8hrs in the fasting and fed state for 100mg and from 1.8hr to 3.7 hr respectively for 250mg. In another embodiment, across dose levels and diet conditions, the active moiety (Remogliflozin)
21
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).
In certain embodiments, invention composition comprising about 100mg or 250mg of remogliflozin or pharmaceutically acceptable salt or ester thereof when administered to diabetic subjects reduces HbA1c levels and hyperglycemia and are comparable with dapagliflozin 10 mg. In another embodiment, 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. In certain embodiments, remogliflozin or pharmaceutically acceptable salt or ester thereof at 100mg and 250 mg doses is non inferior to dapagliflozin 10 mg.
The embodiments of the invention have been described with help of below examples and but are not limited to specific examples.
Examples
Example 1: Immediate release formulation of remogliflozin etabonate.
Table 1
Ingredient
Quantity (mg/tab)
Intra-granular Portion
Remogliflozin Etabonate
250.000
Crosscarmellose (Ac – di – sol)
12.000
Microcrystalline Cellulose (Avicel PH 101)
51.670
Povidone Plasdone K 29/32
16.663
Purified Water
q.s
22
Extra-granular Portion
Crosscarmellose Sodium
16.800
Microcrystalline Cellulose (Avicel PH 102)
445.667
Magnesium Stearate
7.200
Total wt
800.000
1. Remogliflozin etabonate, crosscarmellose sodium and microcrystalline cellulose were sifted.
2. Povidone was dissolved in water to make clear binder solution.
3. Co-sifted material was granulated using binder solution.
4. Wet mass of step 3 was passed through mesh no # 12 and granules were dried.
5. Granules were lubricated with magnesium stearate along with crosscarmellose sodium and microcrystalline cellulose.
6. Lubricated granules were compressed to form tablets.
7. Final tablets were either coated or non-coated.
EXAMPLE 2: Single dose pharmacokinetic (PK) study results of remogliflozin etabonate immediate release formulation.
Inventors previously conducted a single dose PK study- 0355-17 with 250 mg immediate release tablet formulation in 30 healthy adult male subjects. In this study, remogliflozin was found to be safe and well tolerated with no serious or significant adverse events. In this study, as a precautionary measure to avoid any hypoglycemic event, 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.
23
Therefore, in order to perform a like-to-like comparison and to understand the PK characteristics, inventors conducted a study - 0637-17 in 65 healthy male volunteers (Study Protocol 0637-17) following single dose of remogliflozin etabonate, administered with water under fasted state (N=30) as well as under fed state (N=30). Both 100 and 250 mg dose levels were tested in this study. In order to confirm the impact of glucose solution on the PK profile of remogliflozin etabonate, a small subset of subjects (N=5) were administered with 250 mg of remogliflozin etabonate tablet along with 20% glucose solution.
Plasma concentration profiles:
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. Following oral administration of remogliflozin etabonate under fasted state, 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 Tmax with the medians ranging from 1.5 to 3 hours. When remogliflozin etabonate was administered with plain water an early Tmax 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 Tmax (5.5 to 6 hours).
24
This confirmed that the glucose solution administered along and/or during the study could be impacting the absorption, probably by interfering with the solubility of the prodrug (remogliflozin etabonate). Therefore for a like-to-like comparison of PK of remogliflozin etabonate with the historical data, the data from the current study is more appropriate.
Pharmacokinetic Parameters:
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.
The summary PK parameters of all the three analytes at 100 and 250 mg, under fasted and fed state are provided in table 2.
Table 2: Study 0637-17; summary PK Parameters of Remogliflozin etabonate (GSK 189075), Remogliflozin (GSK 189074) and metabolite (GSK 279782)
25
PK Parameters
Fasted State (100 mg); N=15
Fed State (100 mg); N=15
Unit
GSK 189075
GSK 189074
GSK 279782
GSK 189075
GSK 189074
GSK 279782
aTmax (h)
0.50
(0.25-1.50)
0.75
(0.50-2.00)
1.00
(0.75-2.00)
1.50
(0.25-3.00)
2.50
(0.50-3.00)
3.00
(1.50-4.00)
Cmax (ng/mL)
20.9 (82.0)
536.2 (29.3)
96.6 (50.2)
20.9 (60.6)
413.7 (32.7)
138.6 (31.1)
AUC0-t (ng.h/mL)
15.5 (66.5)
1259.5 (25.8)
316.3 (49.5)
38.5 (46.9)
1536.8 (19.2)
642.5 (35.8)
AUC0-inf (ng.h/mL)
17.4 (68.9)
1266.6 (25.7)
323.6 (48.5)
42.2 (41.8)
1546.6 (19.1)
651.1 (35.3)
t1/2 (h)
0.44 (84.7)
1.55 (13.1)
2.34 (13.1)
0.69 (41.0)
1.53 (15.8)
2.80 (12.4)
PK Parameters
Fasted State (250 mg); N=15
Fed State (250 mg); N=15
Unit
GSK 189075
GSK 189074
GSK 279782
GSK 189075
GSK 189074
GSK 279782
aTmax (h)
0.50
(0.25-2.00)
0.75
(0.25-4.00)
1.50
(0.50-4.50)
1.52
(0.25-3.00)
2.50
(1.50-4.00)
3.00
(2.50-4.52)
Cmax (ng/mL)
49.6 (89.5)
1275.3 (51.1)
286.3 (49.0)
39.0 (53.1)
1037.1 (16.1)
319.6 (41.4)
AUC0-t (ng.h/mL)
43.5 (76.0)
3168.8 (34.5)
1028.4 (41.3)
87.4 (46.6)
4286.9 (22.5)
1606.7 (36.2)
AUC0-inf (ng.h/mL)
49.7 (72.4)
3178.1 (34.4)
1037.1 (14.0)
89.0 (45.7)
4294.8 (22.5)
1617.3 (36.0)
t1/2 (h)
0.46 (44.6)
1.8 (15.4)
3.3 (15.6)
0.55 (30.5)
1.90 (28.1)
3.77 (14.9)
a: Median (Min-Max)
EXAMPLE 3: Comparison of PK data from study 0637-17 with Historical PK data
Historically, the PK of remogliflozin etabonate was evaluated in healthy volunteers in a number of clinical studies, following single oral dose of immediate release tablets
26
with plain water. The PK data after a single dose of 100 and 250 mg from the following historical studies was available for comparison (Table 3).
Table 3: Details of historical studies used for comparison of remogliflozin etabonate PK data.
Study Number
Study title
Dose; Treatment
Diet condition
KG2105259 (N=8)
A Randomized 4-way crossover study to evaluate the regional gastrointestinal absorption of GSK 189075, the active entity GSK 189074 and the active metabolite GSK 279782 in healthy volunteers.
100 mg; Treatment A (IR tablet)
Fasted
KG2105217 (N=12)
An Open label, randomized, single dose, cross-over study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of bioenhanced formulations of GSK 189075 in healthy subjects.
100 mg; Treatment C (IR tablet)
Fasted
KG2105217 (N=11)
An Open label, randomized, single dose, cross-over study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of bioenhanced formulations of GSK 189075 in healthy subjects.
100 mg; Treatment E (IR tablet)
Fed
KGT1101 (N=6)
A phase 1 Single Dose study of KGT-1681 (GSK 189075) in healthy subjects.
100 mg
(IR tablet)
Fasted
KG2108197 (N=20)
An Open label study in healthy volunteers to investigate the effect of ketoconazole on the pharmacokinetics of GSK 189075.
250 mg; Treatment A (IR tablet)
Fasted
KG2105253 (N=8)
An evaluation of the pharmacokinetics of a single oral dose of GSK 189075 in patients with varying degrees of renal insufficiency.
250 mg;
Control for mild renal impairment (IR tablet)
Fasted
27
KG2105253 (N=7)
An evaluation of the pharmacokinetics of a single oral dose of GSK 189075 in patients with varying degrees of renal insufficiency.
250 mg;
Control for moderate renal impairment (IR tablet)
Fasted
KGT1102
(N=6)
Phase 1 repeat dose study of KGT-1681 (GSK 189075) in healthy subjects.
*200 mg
(IR tablet)
Fasted
KGW111057 (N=27)
An open-label, randomized, single dose, crossover study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of modified release formulations of GSK189075 in
healthy volunteers.
250 mg
(IR tablet)
Fed
*: Extrapolated to 250 mg assuming proportionality for comparison
The comparison of PK data between the current study (0637-17) vs historical studies were performed descriptively as well as graphically using the exposure parameters (Cmax and AUC). The geometric mean Cmax and AUC estimates in the historical clinical studies has shown considerable between study variability. Therefore instead of a descriptive comparison of Cmax and AUC of the current study with individual historical studies, a grand mean of Cmax and AUC for each analyte was calculated across the historical studies and was compared with grand mean (fasted and fed) of the current study. The comparison of the PK data are presented below for each analyte separately.
GSK 189074 (Remogliflozin)
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. In the historical studies at 250 mg, the geometric mean Cmax of GSK 189074 ranged from 805 ng/mL to 1563 ng/mL indicating considerable between study
28
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. Similarly, in the historical studies at 250 mg, the geometric mean AUC0-inf 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 AUC0-inf from historical studies was estimated to be 2250 ng.h/mL. The average AUC0-inf (fasted and fed) of the current study was estimated to be 3737 ng.h/mL. The ratio of the grand mean AUC0-inf of the current study to that of the historical studies is around 1.66, indicating at 250 mg the GSK 189074 AUC0-inf 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. In the historical studies at 100 mg, the geometric mean Cmax 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 Cmax from historical studies was estimated to be 389 ng/mL. The average Cmax (fasted and fed) of the current study was estimated to be 475 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical studies is around 1.22, indicating at 100 mg the GSK 189074 Cmax in the current study is comparable with that of the historical studies. Similarly, in the historical studies at 100 mg, the geometric mean AUC0-inf 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 AUC0-inf from historical studies was estimated to be 706 ng.h/mL. The average AUC0-inf (fasted and fed) of the current study was estimated to be 1407 ng.h/mL. The ratio of the grand mean AUC0-inf of the current study to that of the historical studies is around 1.99, indicating the GSK 189074 AUC0-inf estimated in the current study is within 2-fold to that of the historical studies. A 2-fold difference in exposure at 100 mg dose level is not anticipated to be of clinical significance. This is shown in Table 4 as below.
29
Table 4: Summary of exposure parameters (Cmax and AUC) of GSK 189074 from individual studies and comparison with study 0637-17.
GSK189074
Geometric mean Cmax
Mean
SD
Min
Max
Ratio
Dose: 100 mg
ng/mL
ng/mL
ng/mL
ng/mL
ng/mL
0637-17 (N=15); Fasted
536
555.0
142.0
281.0
580.0
0637-17 (N=15); Fed
414
436.0
158.0
271.0
796.0
Grand Mean
475
#86
KG2105259 (N=8); Fasted
317
335.0
131.0
195.0
632.0
1.7
KG2105217 (N=12); Fasted
255
310.0
187.0
75.0
605.0
2.1
KG2105217 (N=11); Fed
230
265.0
131.0
53.0
507.0
1.8
KGT1101 (N=6); Fasted
753
782.0
248.0
594.0
1212.0
0.7
Grand Mean
389
#246
1.22
GSK189074
Geometric Mean AUC0-inf
Mean
SD
Min
Max
Ratio
Dose: 100 mg
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
0637-17 (N=15); Fasted
1267
1304
318
791
1869
0637-17 (N=15); Fed
1547
1574
315
1209
2351
Grand Mean
1407
#198
KG2105259 (N=8); Fasted
471
504
230
295
1046
2.69
KG2105217 (N=12); Fasted
504
566
287
210
1165
2.51
KG2105217 (N=11); Fed
606
676
315
183
1354
2.55
KGT1101 (N=6); Fasted
1242
1259
222
916
1598
1.02
Grand Mean
706
#362
1.99
GSK189074
Geometric mean Cmax
Mean
SD
Min
Max
Ratio
Dose: 250 mg
ng/mL
ng/mL
ng/mL
ng/mL
ng/mL
0637-17 (N=15); Fasted
1275
1419
679
543
2702
0637-17 (N=15); Fed
1037
1049
167
775
1338
30
Grand Mean
1156
#168
KG2108197 (N=20); Fasted
805
882
411
374
2036
1.58
aKG2105253 (N=8) ; Fasted
807
1014
722
292
2500
1.58
bKG2105253 (N=7) ; Fasted
1000
1043
344
748
1537
1.28
*KGT1102 (N=6); Fasted
1563
1789
944
653
3231
0.82
KGW111057 (N=27); Fed
892
927
276
572
1656
1.16
Grand Mean
1013
#317
1.14
GSK189074
Geometric Mean AUC0-inf
Mean
SD
Min
Max
Ratio
Dose: 250 mg
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
0637-17 (N=15); Fasted
3178
3341
1049
1760
4976
0637-17 (N=15); Fed
4295
4392
943
2555
6328
Grand Mean
3737
#790
KG2108197 (N=20); Fasted
1743
1859
698
994
3364
1.82
aKG2105253 (N=8) ; Fasted
1973
2096
815
1224
3596
1.61
bKG2105253 (N=7) ; Fasted
2262
2392
844
1398
3596
1.40
*KGT1102 (N=6); Fasted
3243
3379
1005
2109
4666
0.98
KGW111057 (N=27); Fed
2028
2120
656
1243
3502
2.12
Grand Mean
2250
#585
1.66
*: Extrapolated to 250 mg from the data at 200 mg, assuming linearity; a and b: Data from control subjects with normal renal function in the renal impairment study; #: standard deviation of the individual study geometric mean Cmax and AUCs
GSK 279782 (metabolite)
As observed in historical studies, 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. In the historical studies at 250 mg, the geometric mean Cmax of GSK 279782 ranged from 129
31
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. Similarly, in the historical studies at 250 mg, the geometric mean AUC0-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 AUC0-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, AUC0-inf under fasted state from the current study was used. The geometric mean AUC0-inf of the current study was estimated to be 1037 ng.h/mL. The ratio of the geometric mean AUC0-inf of the current study to that of the historical studies is around 1.58, indicating the GSK 279782 AUC0-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. In the historical studies at 100 mg, 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. Similarly, in the historical studies at 100 mg, the geometric mean AUC0-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 AUC0-inf from historical studies was estimated to be 257 ng.h/mL. The average AUC0-inf (fasted and fed) of the current study was estimated to be 488 ng.h/mL. The ratio of the grand mean AUC0-inf of the current study
32
to that of the historical studies is around 1.89, indicating the GSK 279782 AUC0-inf, estimated in the current study is within 2-fold to that of the historical studies. However, 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.
Table 5: Summary of exposure parameters (Cmax and AUC) of GSK 279782 from individual studies and comparison with study 0637-17
GSK279782
Geometric mean Cmax
Mean
SD
Min
Max
Ratio
Dose: 100 mg
ng/mL
ng/mL
ng/mL
ng/mL
ng/mL
0637-17 (N=15); Fasted
97
108
59
48
262
0637-17 (N=15); Fed
139
145
42
79
206
Grand Mean
118
#30
KG2105259 (N=8); Fasted
74
83
40
33
138
1.31
KG2105217 (N=12); Fasted
79
95
55
21
190
1.23
KG2105217 (N=11); Fed
70
80
40
18
152
1.99
KGT1101 (N=6); Fasted
150
162
74
85
301
0.65
Grand Mean
93
#38
1.27
GSK279782
Geometric Mean AUC0-inf
Mean
SD
Min
Max
Ratio
Dose: 100 mg
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
0637-17 (N=15); Fasted
324
359
180
172
801
0637-17 (N=15); Fed
651
687
231
368
1062
Grand Mean
488
#231
KG2105259 (N=8); Fasted
177
192
73
70
294
1.83
KG2105217 (N=12); Fasted
218
246
123
85
483
1.49
KG2105217 (N=11); Fed
240
266
115
78
467
2.71
KGT1101 (N=6); Fasted
393
408
125
267
642
0.82
Grand Mean
257
#94
1.90
33
GSK279782
Geometric mean Cmax
Mean
SD
Min
Max
Ratio
Dose: 250 mg
ng/mL
ng/mL
ng/mL
ng/mL
ng/mL
0637-17 (N=15); Fasted
286
318
165
128
820
0637-17 (N=15); Fed
320
342
123
130
592
Grand Mean
286
#24
KG2108197 (N=20); Fasted
203
222
86
71
344
1.41
aKG2105253 (N=8) ; Fasted
129
151
84
46
267
2.22
bKG2105253 (N=7) ; Fasted
238
259
113
136
443
1.20
*KGT1102 (N=6); Fasted
240
253
93
155
425
1.19
KGW111057 (N=27); Fed
-
-
-
-
-
-
Grand Mean
203
#52
1.41
GSK279782
Geometric Mean AUC0-inf
Mean
SD
Min
Max
Ratio
Dose: 250 mg
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
0637-17 (N=15); Fasted
1037
1120
485
554
2180
0637-17 (N=15); Fed
1617
1705
538
773
2594
Grand Mean
1327
#410
KG2108197 (N=20); Fasted
617
677
298
285
1365
1.68
aKG2105253 (N=8) ; Fasted
468
500
188
277
794
2.22
bKG2105253 (N=7) ; Fasted
744
789
315
470
1429
1.39
*KGT1102 (N=6); Fasted
801
823
218
639
1206
1.29
KGW111057 (N=27); Fed
-
-
-
-
-
Grand Mean
658
#148
1.58
*: Extrapolated to 250 mg from the data at 200 mg, assuming linearity; a& b: Data from control subjects with normal renal function in the renal impairment study; #: standard deviation of the individual study geometric mean Cmax and AUCs
GSK 189075 (Prodrug)
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
34
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. In the historical studies, at 250 mg dose 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. Similarly in the historical studies, at 250 mg dose the GSK 189075 geometric mean AUC0-inf ranged from 27 ng.h/mL to 61 ng.h/mL, indicating considerable between study variability (2.3-fold difference). The grand mean AUC0-inf of the historical studies were about 43 ng.h/mL and the average AUC0-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 AUC0-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. In the historical studies, at 100 mg dose 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. In the historical studies, at 100 mg dose the GSK 189075 geometric mean AUC0-inf ranged from 11 ng.h/mL to 16 ng.h/mL (1.5-fold difference). The grand mean AUC0-inf of the historical studies were about 13 ng.h/mL and the average AUC0-inf (fasted and
35
fed) from the current study is 30 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical study is 2.2, indicating GSK 189075 AUC0-inf is higher to that of the historical studies. However, considering the minimal exposure and no contribution to efficacy, this difference is not anticipated to be clinically significant. This is shown in Table 6 as below.
Table 6: Summary of exposure parameters (Cmax and AUC) of GSK 189075 from individual studies and comparison with study 0637-17.
GSK 189075
Geometric mean Cmax
Mean
SD
Min
Max
Ratio
Dose: 100 mg
ng/mL
ng/mL
ng/mL
ng/mL
ng/mL
0637-17 (N=15); Fasted
21
26
19
7
70
0637-17 (N=15); Fed
21
24
15
8
66
Grand Mean
21
#0
KG2105259 (N=8); Fasted
13
15
9
7
36
1.62
KG2105217 (N=12); Fasted
10
13
11
3
39
2.10
KG2105217 (N=11); Fed
7
10
7
2
25
3.00
KGT1101 (N=6); Fasted
30
32
9
18
44
0.70
Grand Mean
15
#10
1.40
GSK 189075
Geometric Mean AUC0-inf
Mean
SD
Min
Max
Ratio
Dose: 100 mg
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
0637-17 (N=15); Fasted
17
20
11
6
38
0637-17 (N=15); Fed
42
46
19
24
82
Grand Mean
30
#18
KG2105259 (N=8); Fasted
13
13
13
13
1.31
KG2105217 (N=12); Fasted
11
11
5
6
19
1.55
KG2105217 (N=11); Fed
13
14
7
6
24
3.23
KGT1101 (N=6); Fasted
16
16
4
12
20
1.06
Grand Mean
13
#2
2.23
36
GSK 189075
Geometric mean Cmax
Mean
SD
Min
Max
Ratio
Dose: 250 mg
ng/mL
ng/mL
ng/mL
ng/mL
ng/mL
0637-17 (N=15); Fasted
50
64
46
17
174
0637-17 (N=15); Fed
39
43
18
13
77
Grand Mean
45
#8
KG2108197 (N=20); Fasted
31
43
33
6.3
116
1.61
aKG2105253 (N=8) ; Fasted
42
59
45
11
135
1.19
bKG2105253 (N=7) ; Fasted
53
66
42
13
135
0.94
*KGT1102 (N=6); Fasted
46
54
30
18
100
1.08
KGW111057 (N=27); Fed
57
67
39
22
184
0.68
Grand Mean
46
#10
0.97
GSK 189075
Geometric Mean AUC0-inf
Mean
SD
Min
Max
Ratio
Dose: 250 mg
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
ng.hr/mL
0637-17 (N=15); Fasted
50
61
48
21
196
0637-17 (N=15); Fed
89
97
40
47
169
Grand Mean
70
#28
KG2108197 (N=20); Fasted
27
31
16
12
64
1.85
aKG2105253 (N=8) ; Fasted
44
49
25
23
91
1.14
bKG2105253 (N=7) ; Fasted
42
53
32
10
91
1.19
*KGT1102 (N=6); Fasted
41
48
25
20
76
1.21
KGW111057 (N=27); Fed
61
68
36
27
188
1.46
Grand Mean
43
#12
1.61
*: Extrapolated to 250 mg from the data at 200 mg, assuming linearity; a & b: Data from control subjects with normal renal function in the renal impairment study; #: standard deviation of the individual study geometric mean Cmax and AUCs
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.
37
Species
Dose (mg/kg)
Gender
Analyte
Safety Margins
Mouse
2000
M
GSK 189075
20.7
13 week
NOAEL
GSK 189074
21.5
GSK 279782
23.5
F
GSK 189075
36.9
GSK 189074
29.4
GSK 279782
21.3
Rat
1200
M
GSK 189075
74.4
26 week
NOAEL
GSK 189074
17.2
GSK 279782
21.5
F
GSK 189075
44.9
GSK 189074
19.3
GSK 279782
32.9
Dog
650
M
GSK 189075
450.0
52 week
NOAEL
GSK 189074
16.9
GSK 279782
2.9
F
GSK 189075
523.1
GSK 189074
21.4
GSK 279782
4.0
*Human
250 mg, BID
M
GSK 189075
140
GSK 189074
7474
GSK 279782
2654
*: Steady state human AUC with 250 mg BID is calculated by doubling the single dose AUC0-inf (average of fasted and fed state)
Below is the summary of the above PK studies:
 When remogliflozin etabonate was administered with plain water under fasted state, an early Tmax was observed (Median: 0.5 hour to 1.5 hour) for all three
38
analytes. Under fed state, there was a slight delay in Tmax in comparison to fasted state with the medians ranging from 1.5 to 3 hours, similar to that in the historical studies.
 Similar to the historical studies, in study 0637-17 the active moiety (GSK 189074) showed the highest Cmax and AUC, followed by metabolite GSK 279782. The metabolite exposure was 24 to 43% of active moiety, similar to that observed in the historical studies indicating comparable extent of metabolite formation.
 The inactive prodrug (GSK 189075) had the lowest Cmax and AUC (around 1 to 3% of that of active moiety), similar to that observed in the historical studies. The elimination half-lives of all 3 analytes were also comparable with that of the historical data.
 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 AUC0-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).
 Based on the systemic exposures and the in-vitro SGLT-2 inhibition rate constant (KI), 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.
 In addition, there are adequate safety margins for all the 3 analytes in comparison to the plasma exposures in long term toxicology studies conducted in mouse, rat, and dogs. The anticipated safety margins with a 250 mg BID
39
regimen for GSK 189075: 21 to 523-fold, for GSK 189074: 17 to 29-fold, and for GSK 279782: 3 to 33-fold.
Overall, in comparison to historical studies, there were no clinically relevant differences in the pharmacokinetics after a single dose of Remogliflozin etabonate formulation at 100 and 250 mg in Indian subjects. Further, there were no safety concerns and no hypoglycemic events are reported in the study. The plasma exposure in clinic at 250 mg BID are anticipated to be many fold lower than the plasma exposure at NOAEL doses in long term toxicology studies indicating adequate safety margins even at 250 mg dose.
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.
Objective: 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. HbA1c 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
40
(>1000 mg per day in subjects not tolerating) and have inadequate glycemic control (i.e. HbA1c ≥ 7% but ≤ 10% at screening).
Design: This was a 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multi-center study to evaluate the efficacy and safety of remogliflozin etabonate in comparison to dapagliflozin in subjects with type 2 diabetes who have inadequate glycemic control with stable dose of metformin as monotherapy. Subjects with HbA1c ≥ 7% but ≤ 10% at Screening (Visit 1) were considered eligible for randomization, on fulfilling other study inclusion criteria. For each subject, the study began when signed informal consent form (ICF) was provided. Eligible subjects were randomized to receive one of the following treatments in a double blind, double dummy design. Matching placebo(s) were used to blind the three treatment arms and every subject received a total of 3 tablets twice daily including one of the following active study drugs along with matching placebo(s) for the other two study drugs.
Arm 1: Remogliflozin etabonate 100 mg, administered as 1 tablet BID for 24 weeks
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.
In addition, subjects were continued to receive metformin at stable doses of > 1500 mg per day (> 1000 mg per day in subjects not tolerating), throughout the study period in an open label manner. Balanced randomization was ensured in the Arm 1 and Arm 2 (i.e. remogliflozin etabonate 100 mg and remogliflozin etabonate 250 mg Tablets) and randomization was stratified for baseline HbA1c level (HbA1c 7-7.9%, 8-8.9% and 9-10%) at randomization visit. The end of the study was the date of the last study visit for the last subject in the study. An overview of the study design is shown figure 1.
41
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. However key assessments (eg. HbA1c, FPG, total body weight) were repeated at the Randomization visit (Visit 2) before study drug administration for obtaining most accurate baseline values to be used for efficacy analysis. 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 (PK) 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.
The results from this study are summarized below in table 1, 2 and 3.
Table 8: Analysis of Mean Change in Glycosylated Haemoglobin (HbA1c%) Levels (PP Population): MMRM
42
Visit Statistics Dapagliflozin 10 mg (N=101) Remogliflozin etabonate 100mg (N=163) Remogliflozin etabonate 250mg (N=166) Mean Change From Baseline – Week 1 (Day 8) LSM (SE) -0.13 (0.051) -0.12 (0.043) -0.12 (0.043) Difference: LSM (SE) 0.01 (0.056) 0.01 (0.057) 90% CI [-0.09, 0.10] [-0.08, 0.10] P value1 <0.001 <0.001 95% CI [-0.10, 0.12] [-0.10, 0.12] P value2 0.899 0.870 Mean Change From Baseline - Week 12 (Day 85) LSM (SE) -0.40 (0.105) -0.49 (0.084) -0.63 (0.083) Difference: LSM (SE) -0.09 (0.129) -0.23 (0.129) 90% CI [-0.30, 0.12] [-0.44, -0.02] P value1 <0.001 <0.001 95% CI [-0.35, 0.16] [-0.48, 0.02] P value2 0.479 0.076 Mean Change From Baseline - Week 24 (Day 169) LSM (SE) -0.58 (0.116) -0.72 (0.093) -0.77 (0.090) Difference: LSM (SE) -0.14 (0.144) -0.19 (0.143) 90% CI [-0.38, 0.10] [-0.42, 0.05] P value1 <0.001 <0.001 95% CI [-0.42, 0.14] [-0.47, 0.09] P value2 0.332 0.190
CI = confidence interval; HbA1c = glycosylated haemoglobin; LSM = least squares mean; PP = per protocol; MMRM = mixed model repeated measures; SE = standard error
Difference: LSM (SE) between arms is calculated for remogliflozin etabonate 100 mg or remogliflozin etabonate 250 mg vs dapagliflozin 10 mg (remogliflozin etabonate - dapagliflozin).
The 90% CI and 95% CI for the LSM difference in HbA1c% levels between arms are calculated for remogiflozin etabonate 100 mg or remogliflozin etabonate 250 mg minus dapagliflozin 10 mg.
43
P value1 is calculated for the 1-sided non-inferior test with non-inferiority margin 0.35, P value2 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 HbA1c% value, centre, visit and treatment as covariates.
Exclude rescue medication subjects at each visit.
Table 9: Analysis of Mean Change in Fasting Plasma Glucose (FPG) Concentrations, mg/dL (PP Population): MMRM Visit Statistics Dapagliflozin 10 mg (N=101) Remogliflozin etabonate 100 mg (N=163) Remogliflozin etabonate 250 mg (N=166) Mean Change From Baseline –Week 1 (Day 8) LSM (SE) 1.81 (3.722) -4.03 (3.039) -4.13 (3.010) Difference: LSM (SE) -5.84 (4.425) -5.94 (4.432) 95% CI [-14.54, 2.86] [-14.66, 2.77] P value1 0.188 0.181 Mean Change From Baseline - Week 12 (Day 85) LSM (SE) -10.38 (3.677) -9.01 (2.994) -14.53 (2.972) Difference: LSM (SE) 1.37 (4.356) -4.15 (4.371) 95% CI [-7.19, 9.94] [-12.74, 4.45] P value1 0.753 0.343 Mean Change From Baseline - Week 24 (Day 169) LSM (SE) -20.23 (3.595) -17.86 (2.953) -20.94 (2.931) Difference: LSM (SE) 2.37 (4.258) -0.71 (4.268) 95% CI [-6.00, 10.74] [-9.10, 7.68] P value1 0.578 0.867
CI = confidence interval; LSM = least squares mean; MMRM = mixed model repeated measures; PP = per protocol; SE = standard error
Difference: LSM (SE) between treatment arms is calculated for remogliflozin etabonate 100 mg or remogliflozin etabonate 250 mg vs dapagliflozin 10 mg (remogliflozin etabonate - dapagliflozin).
The 95% CI for the LSM difference in FPG, mg/dL between treatment arms is calculated for remogliflozin etabonate 100 mg or remogliflozin etabonate 250 mg vs dapagliflozin 10 mg.
44
P value1 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.
Conclusions
 Both 100 mg and 250 mg doses of remogliflozin etabonate reduced HbA1c levels at 24 weeks and met the target when compared with dapagliflozin 10 mg. Remogliflozin etabonate 100mg and 250 mg doses were found to be non inferior to dapagliflozin 10 mg (means: 0.14%, 0.19%; 90% CIs: [0.38%, 0.10%], [0.42%, 0.05%], respectively) with high statistical significance (P values for both comparisons: <0.001; PP population), in subjects with T2DM. The primary efficacy endpoint was achieved with both 100 mg and 250 mg doses of remogliflozin etabonate.
 Results were confirmed by secondary analysis in the Modified Intention To Treat (mITT) population and all sensitivity analyses in both PP and mITT populations by the methods of MMRM, and ANCOVA with OC, ANCOVA with LOCF, and ANCOVA with IR on the primary efficacy endpoint
 Overall, all the secondary endpoints showed no significant differences between 100 mg or 250 mg dose of remogliflozin etabonate and dapagliflozin 10 mg (P>0.05).
 No effect of HbA1c level strata at baseline was observed on the difference between 100 mg and 250 mg doses of remogliflozin etabonate in HbA1c level reduction.
45
We claim:
1. 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 1400ng/ml 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.
2. The pharmaceutical composition of claim 1, wherein 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.
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 3, wherein the remogliflozin etabonate is present in an amount of about 10mg to about 1000mg.
5. The pharmaceutical composition of claim 3, wherein the remogliflozin etabonate is present in an amount of about 50mg, or about 100mg, or about 250mg.
6. The pharmaceutical composition of claim 2, wherein the diluent is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, sorbitol, sucrose and combinations thereof.
46
7. The pharmaceutical composition of claim 6, wherein the diluent is present in a concentration of about 5-60% w/w by weight of composition.
8. 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.
9. The pharmaceutical composition of claim 8, wherein the disintegrant is present in a concentration of about 1-30% w/w by weight of composition.
10. 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.
11. The pharmaceutical composition of claim 10, wherein the glidant is present in a concentration of about 0.1-5% w/w by weight of composition.
12. 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.
13. The pharmaceutical composition of claim 12, wherein the binder is present in a concentration of about 0.1-10% w/w by weight of composition.
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.
47
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 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 6, wherein the diluent is microcrystalline cellulose.
20. The pharmaceutical composition of claim 8, wherein the disintegrant is crosscarmellose sodium.
21. The pharmaceutical composition of claim 10, wherein the glidant is magnesium stearate.
22. The pharmaceutical composition of claim 12, wherein the binder is polyvinylpyrrolidone.
23. The pharmaceutical composition of claim 8, wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in a weight ratio of about 1:0.01 to about 1:10.
24. The pharmaceutical composition of claim 8, wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in a weight ratio of about 1:0.05 or about 1:0.06.
48
25. 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, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about 1400ng/ml 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.
26. 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 1400ng/ml 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.
27. An immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about 100mg, or about 250mg of remogliflozin etabonate, (b) about 5-30% w/w by weight of microcrystalline cellulose, (c) about 1-30% w/w by weight of crosscarmellose sodium, and (d) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion having (a) about 1-30% w/w by weight of crosscarmellose sodium, (b) about 5-60 % w/w by weight of microcrystalline cellulose and (c) about 0.1-5% w/w by weight of 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 or the composition provides an AUC of remogliflozin or pharmaceutically
49
acceptable salt or ester thereof between about 1100ng.hr/ml to about 6000ng.h/ml.