Pharmaceutical formulations

Abstract

The pharmacokinetic profile of the SGLT2 inhibitor bexagliflozin can be improved by formulating it as an extended release tablet. Compared with standard immediate-release dosage forms these tablets can permit a lower peak plasma concentration, C max , while maintaining plasma concentrations at therapeutic levels for a desired period. This can be used, for instance, to administer lower doses while still providing the same pharmacological effect.

1 . An extended-release tablet comprising bexagliflozin. 
     
     
         2 . The extended-release tablet of  claim 1 , further comprising a mucoadhesive. 
     
     
         3 . The extended-release tablet of  claim 1 , wherein an in vitro dissolution test in simulated gastric fluid, releases ≤17% of its bexagliflozin after 1 hour and releases ≥80% after 8 hours. 
     
     
         4 .- 5 . (canceled) 
     
     
         6 . The extended-release tablet of  claim 3 , wherein the in vitro dissolution test is performed with a United States Pharmacopoeia (USP) Apparatus 1 at 50 rpm with 900 mL of 0.1 N HCl at 37±0.5° C. 
     
     
         7 . (canceled) 
     
     
         8 . The extended-release tablet of  claim 1 , wherein said tablet provides a plasma bexagliflozin C max  of ≤8 ng/mL per mg of bexagliflozin in the tablet in a fasted subject having a body mass greater than 60 kg. 
     
     
         9 .- 18 . (canceled) 
     
     
         19 . The extended-release tablet of  claim 1 , comprising 20 mg bexagliflozin, wherein and an in vitro dissolution test performed with a United States Pharmacopoeia (USP) Apparatus 1 at 50 rpm with 900 mL of 0.1 N HCl at 37±0.5° C., releases ≤17% of its bexagliflozin after 1 hour, releases between 20-45% of its bexagliflozin after 3 hours, releases between 45-75% of its bexagliflozin after 5 hours, and releases ≥80% of its bexagliflozin after 8 hours. 
     
     
         20 .- 24 . (canceled) 
     
     
         25 . The extended-release tablet of  claim 1 , wherein bexagliflozin is in the form of a crystalline solid. 
     
     
         26 . The extended-release tablet of  claim 1 , comprising a monolithic matrix in which bexagliflozin is dispersed within solid excipient(s) which comprise a water-insoluble substance. 
     
     
         27 . The extended-release tablet of  claim 26 , wherein the water-insoluble substance is glyceryl dibehenate. 
     
     
         28 . The extended-release tablet of  claim 27 , including 30-35% by weight glyceryl dibehenate. 
     
     
         29 . The extended-release tablet of  claim 1 , wherein the tablet has a density below 1.04 g/cm 3  and can float in simulated gastric fluid. 
     
     
         30 . The extended-release tablet of  claim 1 , wherein the tablet further comprises a solubilizer. 
     
     
         31 . The extended-release tablet of  claim 30 , wherein the solubilizer comprises a poloxamer, such as poloxamer 188. 
     
     
         32 . The extended-release tablet of  claim 31 , including 10-12% by weight poloxamer 188. 
     
     
         33 . The extended-release tablet of  claim 1 , wherein the tablet further comprises a filler. 
     
     
         34 . The extended-release tablet of  claim 33 , wherein the tablet further comprises lactose and/or microcrystalline cellulose. 
     
     
         35 . The extended-release tablet of  claim 34 , including 11-13% by weight lactose and/or 18-20% by weight microcrystalline cellulose. 
     
     
         36 . The extended-release tablet of  claim 1 , wherein the tablet further comprises a glidant and/or a lubricant. 
     
     
         37 . The extended-release tablet of  claim 36 , wherein the tablet further comprises magnesium stearate and/or colloidal silicon dioxide. 
     
     
         38 . The extended-release tablet of  claim 37 , including 1.5-2.5% by weight magnesium stearate and/or 1.0-1.5% by weight colloidal silicon dioxide. 
     
     
         39 . The extended-release tablet of  claim 1 , wherein the tablet further comprises a mucoadhesive. 
     
     
         40 . The extended-release tablet of  claim 39 , wherein the mucoadhesive is a polyethylene oxide. 
     
     
         41 . The extended-release tablet of  claim 40 , including 16-20% by weight polyethylene oxide having an average molecular weight of approximately 900,000 or greater. 
     
     
         42 . The extended-release tablet of  claim 1 , wherein the tablet has a coating surrounding a core. 
     
     
         43 . The extended-release tablet of  claim 42 , wherein the coating (i) comprises polyvinyl alcohol and (ii) is present at between 2.5-3.5% of the core's weight. 
     
     
         44 . The extended-release tablet of  claim 1 , wherein the tablet has a hardness between 20-100 N and/or a friability of ≤1% by weight. 
     
     
         45 . A extended-release tablet of  claim 1 , further comprising glyceryl dibehenate; polyethylene oxide; lactose; poloxamer 188; microcrystalline cellulose; colloidal silicon dioxide; and magnesium stearate; and optionally having a coating comprising polyvinyl alcohol. 
     
     
         46 . The extended-release tablet of  claim 45 , having the following composition per tablet: bexagliflozin, between 5-50 mg; glyceryl dibehenate, between 100-140 mg; polyethylene oxide, between 50-75 mg; lactose, between 40-50 mg; poloxamer 188, between 40-45 mg; microcrystalline cellulose, between 60-80 mg; colloidal silicon dioxide, between 4-5 mg; and magnesium stearate, between 6-9 mg; optionally also having 10-12 mg of the coating. 
     
     
         47 . A batch of tablets which include an amount of bexagliflozin between 5-50 mg wherein, when tablets are assessed in an in vitro dissolution assay conducted in USP Apparatus 1 charged with 900 mL of 0.1 N HCl and stirred at a rate of 50 rpm with the temperature maintained at 37±0.5° C., from which 10 mL is extracted at 1, 3, 5 and 8 hours after being added to the HCl, at least one of the following criteria is satisfied: (i) six tablets of the batch are analyzed and all six tablets release ≤17% of their bexagliflozin after 1 hour, release between 20-45% of their bexagliflozin after 3 hours, release between 45-75% of their bexagliflozin after 5 hours, and release ≤80% of their bexagliflozin after 8 hours; (ii) six tablets did not satisfy criteria (i), but the average bexagliflozin release for those six tablets and six further tablets is ≤17% after 1 hour, between 20-45% after 3 hours, between 45-75% after 5 hours, and ≥80% after 8 hours, and the bexagliflozin release seen by all twelve tablets falls no more than 2 mg outside these release criteria; or (iii) twelve tablets did not satisfy criteria (ii), but the average bexagliflozin release for those twelve tablets and twelve further tablets is ≤17% after 1 hour, between 20-45% after 3 hours, between 45-75% after 5 hours, and ≥80% after 8 hours; not more than 2 of the 24 tablets are more than 10% outside each of the ranges of ≤17% after 1 hour, between 20-45% after 3 hours, between 45-75% after 5 hours, and ≥80% after 8 hours; and none of the tablets is more than 20% outside each of the ranges of ≤17% after 1 hour, between 20-45% after 3 hours, between 45-75% after 5 hours, and ≥80% after 8 hours. 
     
     
         48 . The batch of  claim 47 , wherein the tablets release (a) between 45-72% of its bexagliflozin after 5 hours (b) between 50-70% of its bexagliflozin after 5 hours (c) between 49-69% of its bexagliflozin after 5 hours or (d) between 48-68% of its bexagliflozin after 5 hours. 
     
     
         49 . A batch of extended release bexagliflozin tablets which include an amount of bexagliflozin between 5-50 mg wherein:
 (a) upon administration to an appropriately constituted cohort of healthy fasted subjects, a first representative sample set of tablets from the batch provides on one occasion a first mean logarithm of the C max  and a first mean logarithm of the AUC 0-t , and a second representative sample of tablets from the batch produces on a different occasion a second mean logarithm of the C max  and a second mean logarithm of the AUC 0-t , and wherein the differences between the first and second mean logarithms of the C max  and between the first and second mean logarithms of the AUC 0-t  both exhibit 90% confidence intervals, the endpoints of which lie between −0.22314 and +0.22314.   (b) upon administration to an appropriately constituted cohort of healthy subjects each provided on one occasion a single tablet from a first representative tablet sample set in the fasted state, and on a different occasion a single tablet from a second representative tablet sample set in the fed state, the mean differences in ln(C max ) and ln(AUC 0-t ) both exhibit a 90% confidence interval, the endpoints of which lie between −0.22314 and +0.58779;   (c) upon administration to an appropriately constituted cohort of fasted healthy subjects each provided on one occasion a single tablet from a first representative tablet sample set without any prior dosage of a parenteral GLP-1 receptor agonist, and on a different occasion, a single tablet from a second representative tablet sample set 30 minutes following an approved dosage of a parenteral GLP-1 receptor agonist, the mean differences in ln(C max ) and ln(AUC 0-t ) both exhibit a 90% confidence interval wherein the upper bound of the interval is less than 0.69315; and/or (d) upon administration to an appropriately constituted cohort of healthy subjects each provided on one occasion a single tablet from a first representative tablet sample set in the fasted state, and on a different occasion, a single tablet from a second representative tablet sample set in the fed state, the differences created by subtracting the values for the T max  for the fasted state from the values for the T max  for the fed state exhibit a median that is less than or equal to 3.5 hours.   
     
     
         50 .- 55 . (canceled) 
     
     
         56 . A method for treating a subject suffering from diabetes or its symptoms, comprising a step of administering to the subject the tablet of  claim 1 .