Extended release liquid compositions of metformin

Abstract

The present invention relates to extended release liquid compositions of metformin. The extended release liquid compositions are in the form of suspensions or reconstituted powder for suspensions. Said extended release liquid compositions comprise cores of metformin coated with a release-controlling agent, wherein the coated cores are dispersed in a suspension base. Said extended release liquid compositions provide the desired uniform extended release profile throughout the shelf-life of the composition. Furthermore, said extended release liquid compositions are bioequivalent to a reference composition. It also relates to processes for the preparation of said extended release liquid compositions.

1 . A stable extended release liquid composition of metformin characterized by a T max  in a range from about 3 hours to about 12 hours after a single dose administration under fed conditions, wherein the composition comprises: cores of metformin coated with a release-controlling agent, wherein the coated cores are dispersed in a suspension base,
 wherein an in-vitro dissolution release profile of the composition remains substantially similar to the initial in-vitro dissolution release profile upon storage for at least seven days, and   wherein the release-controlling agent is a pH-independent release-controlling agent, and wherein the diameter of the coated cores ranges from about 150 μm to about 500 μm.   
     
     
         2 . (canceled) 
     
     
         3 . A stable extended release liquid composition of metformin characterized by a pharmacokinetic profile having one or more features of: a C max  from about 0.4 ng/mL/mg to about 2.5 ng/mL/mg; an area under the curve (AUC) 0→∞  from about 2.0 ng·h/mL/mg to about 22.0 ng·h/mL/mg; and an area under the curve (AUC) 0→t  from about 2.5 ng·h/mL/mg to about 22.0 ng·h/mL/mg after a single dose administration under fed conditions,
 wherein the composition comprises: cores of metformin coated with a release-controlling agent, and wherein the coated cores are dispersed in a suspension base, 
 wherein an in-vitro dissolution release profile of the composition remains substantially similar to the initial in-vitro dissolution release profile upon storage for at least seven days, and 
 wherein the release-controlling agent is a pH-independent release-controlling agent, and wherein the diameter of the coated cores ranges from about 150 μm to about 500 μm. 
 
     
     
         4 . A stable extended release liquid composition of metformin characterized in that the liquid composition is bioequivalent to a marketed extended release tablet of metformin, wherein the composition comprises: cores of metformin coated with a release-controlling agent, and wherein the coated cores are dispersed in a suspension base, wherein an in-vitro dissolution release profile of the composition remains substantially similar to the initial in-vitro dissolution release profile upon storage for at least seven days, and wherein the release-controlling agent is a pH-independent release-controlling agent and wherein the diameter of the coated cores ranges from about 150 μm to about 500 μm. 
     
     
         5 . A stable extended release liquid composition of metformin comprising metformin hydrochloride in a concentration from about 25 mg/mL to about 500 mg/mL of the composition, wherein the composition comprises: cores of metformin coated with a release-controlling agent, and wherein the coated cores are dispersed in a suspension base, wherein an in-vitro dissolution release profile of the composition remains substantially similar to the initial in-vitro dissolution release profile upon storage for at least seven days, and wherein the release-controlling agent is a pH-independent release-controlling agent and wherein the diameter of the coated cores ranges from about 1:50 μm to about 500 μm. 
     
     
         6 . (canceled) 
     
     
         7 . The stable extended release liquid composition of  claim 1 , wherein the in-vitro dissolution release profile as determined by USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with a pH 6.8 at 37° C. is as follows:
 less than 30% of metformin released after 0.5 hour; 
 less than 70% of metformin released after 2 hours; and 
 more than 85% of metformin released after 12 hours. 
 
     
     
         8 . (canceled) 
     
     
         9 . The stable extended release liquid composition of  claim 1 , wherein the composition is characterized by having an osmolality ratio of at least about 1. 
     
     
         10 . (canceled) 
     
     
         11 . The stable extended release liquid composition of  claim 1 , wherein the suspension base has a viscosity of about 500 cps to about 15,000 cps. 
     
     
         12 . The stable extended release liquid composition of  claim 1 , wherein the suspension base comprises an osmogent. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The stable extended release liquid composition of  claim 3 , wherein the in-vitro dissolution release profile as determined by USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with a pH 6.8 at 37° C. is as follows:
 less than 30% of metformin released after 0.5 hour; 
 less than 70% of metformin released after 2 hours; and 
 more than 85% of metformin released after 12 hours. 
 
     
     
         19 . (canceled) 
     
     
         20 . The stable extended release liquid composition of  claim 3 , wherein the composition is characterized by having an osmolality ratio of at least about 1. 
     
     
         21 . (canceled) 
     
     
         22 . The stable extended release liquid composition of  claim 3 , wherein the suspension base has a viscosity of about 500 cps to about 15,000 cps. 
     
     
         23 . The stable extended release liquid composition of  claim 3 , wherein the suspension base comprises an osmogent. 
     
     
         24 . The stable extended release liquid composition of  claim 4 , wherein the in-vitro dissolution release profile as determined by USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with a pH 6.8 at 37° C. is as follows:
 less than 30% of metformin released after 0.5 hour; 
 less than 70% of metformin released after 2 hours; and 
 more than 85% of metformin released after 12 hours. 
 
     
     
         25 . (canceled) 
     
     
         26 . The stable extended release liquid composition of  claim 4 , wherein the composition is characterized by having an osmolality ratio of at least about 1. 
     
     
         27 . (canceled) 
     
     
         28 . The stable extended release liquid composition of  claim 4 , wherein the suspension base has a viscosity of about 500 cps to about 15,000 cps. 
     
     
         29 . The stable extended release liquid composition of  claim 4 , wherein the suspension base comprises an osmogent. 
     
     
         30 . The stable extended release liquid composition of  claim 5 , wherein the in-vitro dissolution release profile as determined by USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with a pH 6.8 at 37° C. is as follows:
 less than 30% of metformin released after 0.5 hour; 
 less than 70% of metformin released after 2 hours; and 
 more than 85% of metformin released after 12 hours. 
 
     
     
         31 . (canceled) 
     
     
         32 . The stable extended release liquid composition of  claim 5 , wherein the composition is characterized by having an osmolality ratio of at least about 1. 
     
     
         33 . (canceled) 
     
     
         34 . The stable extended release liquid composition of  claim 5 , wherein the suspension base has a viscosity of about 500 cps to about 15,000 cps. 
     
     
         35 . The stable extended release liquid composition of  claim 5 , wherein the suspension base comprises an osmogent. 
     
     
         36 . The stable extended release liquid composition of  claim 1 , wherein the suspension base comprises suspending agents and one or more osmogents selected from the group consisting of carbohydrates, water-soluble salts of inorganic acids; water-soluble salts of organic acids; water-soluble amino acids; urea or its derivatives; propylene glycol; glycerin; and mixtures thereof. 
     
     
         37 . The stable extended release liquid composition of  claim 3 , wherein the suspension base comprises suspending agents and one or more osmogents selected from the group consisting of carbohydrates, water-soluble salts of inorganic acids; water-soluble salts of organic acids; water-soluble amino acids; urea or its derivatives; propylene glycol; glycerin; and mixtures thereof. 
     
     
         38 . The stable extended release liquid composition of  claim 4 , wherein the suspension base comprises suspending agents and one or more osmogents selected from the group consisting of carbohydrates, water-soluble salts of inorganic acids; water-soluble salts of organic acids; water-soluble amino acids; urea or its derivatives; propylene glycol; glycerin; and mixtures thereof. 
     
     
         39 . The stable extended release liquid composition of  claim 5 , wherein the suspension base comprises suspending agents and one or more osmogents selected from the group consisting of carbohydrates, water-soluble salts of inorganic acids; water-soluble salts of organic acids; water-soluble amino acids; urea or its derivatives; propylene glycol; glycerin; and mixtures thereof.