Controlled release metformin formulations

Abstract

Sustained release pharmaceutical formulations comprising an antihyperglycemic drug or a pharmaceutically acceptable salt thereof are disclosed. The formulations provide therapeutic plasma levels of the antihyperglycemic drug to a human patient over a 24 hour period after administration.

We claim:  
     
         1 . A sustained release pharmaceutical formulation comprising an antihyperglycemic drug or a pharmaceutically acceptable salt thereof, wherein said formulation provides therapeutic plasma levels of said antihyperglycemic drug to a human patient over a 24 hour period after administration to said patient.  
     
     
         2 . The sustained release pharmaceutical formulation of    claim 1    wherein said administration is with or shortly after the evening meal.  
     
     
         3 . The sustained release pharmaceutical formulation of    claim 1    wherein the bioavailability of the antihyperglycemic drug is increased by the presence of food.  
     
     
         4 . The sustained release pharmaceutical formulation of    claim 1    wherein said formulation provides a T max  of the antihyperglycemic drug which occurs at a time from about 8 hours to about 12 hours after administration to said human patient.  
     
     
         5 . The sustained release pharmaceutical formulation of    claim 1    wherein said antihyperglycemic drug is metformin.  
     
     
         6 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof suitable for once daily dosing, said formulation providing a T max  of the metformin which occurs at a time from about 8 hours to about 12 hours after administration to a human patient.  
     
     
         7 . The sustained release pharmaceutical formulation of    claim 6    wherein said administration is with or shortly after the evening meal.  
     
     
         8 . A sustained release pharmaceutical formulation comprising metformin or a pharmaceutically acceptable salt thereof, said formulation suitable for once daily dosing and providing a peak of a mean plasma concentration/time curve of metformin at a time from about 4 hours to about 10 hours after administration.  
     
     
         9 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof suitable for once daily dosing, said formulation when administered with or after a meal to a human patient, providing a C max  of metformin from about 52.8% to about 75.1% of the C max  provided by an equivalent dose of metformin in an immediate release reference formulation.  
     
     
         10 . The sustained release pharmaceutical formulation of    claim 9    wherein said formulation provides a T max  of the metformin which occurs at a time from about 8 hours to about 12 hours after administration to said human patient.  
     
     
         11 . The sustained release pharmaceutical formulation of    claim 9    wherein the bioavailability of the drug is increased by the presence of food.  
     
     
         12 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof suitable for once daily dosing, said formulation when administered with or after a meal to a human patient, providing a T max  of metformin from about 182% to about 200% of the T max  provided by an equivalent dose of metformin in an immediate release reference formulation.  
     
     
         13 . The sustained release pharmaceutical formulation of    claim 12    wherein said formulation provides a T max  of the metformin which occurs at a time from about 8 hours to about 12 hours after administration to said human patient.  
     
     
         14 . The sustained release pharmaceutical formulation of    claim 12    wherein the bioavailability of the metformin is increased by the presence of food.  
     
     
         15 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof suitable for once daily dosing, said formulation when administered in the fasted state to a human patient, providing a T max  of metformin from about 173% to about 215% of the T max  provided by an equivalent dose of metformin in an immediate release reference formulation.  
     
     
         16 . The sustained release pharmaceutical formulation of    claim 15    wherein said formulation provides a T max  of the metformin which occurs at a time from about 8 hours to about 12 hours after administration to a human patient.  
     
     
         17 . The sustained release pharmaceutical formulation of    claim 15    wherein the bioavailability of the metformin is increased by the presence of food.  
     
     
         18 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof suitable for once daily dosing, said formulation upon administration to a human patient, providing a width at 50% of the height of a mean plasma concentration/time curve from about 6 hours to about 12 hours.  
     
     
         19 . The sustained release pharmaceutical formulation of    claim 18    wherein said formulation provides a T max  of the metformin which occurs at a time from about 8 hours to about 12 hours after administration.  
     
     
         20 . The sustained release pharmaceutical formulation of    claim 18    wherein the bioavailability of the metformin is increased by the presence of food.  
     
     
         21 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof suitable for once daily dosing, wherein a single administration of said formulation provides a lower mean fluctuation index in the plasma than a single administration of a substantially equal dose of an immediate release composition of metformin.  
     
     
         22 . The sustained release pharmaceutical formulation of    claim 21    wherein said formulation provides a T max  of the metformin which occurs at a time from about 8 hours to about 12 hours after administration to a human patient.  
     
     
         23 . The sustained release pharmaceutical formulation of    claim 21    wherein the bioavailability of the metformin is increased by the presence of food.  
     
     
         24 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: 
 after 2 hours 0-25% of the metformin or salt thereof is released;  
 after 4 hours 10-45% of the metformin or salt thereof is released;  
 after 8 hours 30-90% of the metformin or salt thereof is released;  
 after 12 hours not less than 50% of the metformin or salt thereof is released;  
 after 16 hours not less than 60% of the metformin or salt thereof is released;  
 and after 20 hours not less than 70% of the metformin or salt thereof is released.  
 
     
     
         25 . The sustained release pharmaceutical formulation of    claim 24    wherein after administration to a human patient, said formulation provides a bioavailability of metformin which is increased by the presence of food.  
     
     
         26 . The sustained release pharmaceutical formulation of    claim 24    wherein after administration to a human patient, said formulation provides a T max  of metformin which occurs at a time from about 8 hours to about 12 hours after said administration.  
     
     
         27 . A sustained release pharmaceutical formulation comprising a dose of metformin or a pharmaceutically acceptable salt thereof that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: 
 after 2 hours 0-15% of the metformin or salt thereof is released;  
 after 4 hours 20-40% of the metformin or salt thereof is released;  
 after 8 hours 45-90% of the metformin or salt thereof is released;  
 after 12 hours not less than 60% of the metformin or salt thereof is released;  
 after 16 hours not less than 70% of the metformin or salt thereof is released;  
 and after 20 hours not less than 80% of the metformin or salt thereof is released.  
 
     
     
         28 . The sustained release pharmaceutical formulation of    claim 27    wherein after administration to a human patient, said formulation provides a bioavailability of metformin which is increased by the presence of food.  
     
     
         29 . The sustained release pharmaceutical formulation of    claim 27    wherein after administration to a human patient, said formulation provides a T max  of metformin which occurs at a time from about 8 hours to about 12 hours after said administration.