Solid oral dosage form comprising a combination of metformin and glibenclamide

Abstract

The present invention relates to a solid oral dosage form comprising a combination of metformin and glibenclamide in which the size of glibenclamide is such that the glibenclamide bioavailability is comparable to the glibenclamide bioavailability obtained with a separate administration of metformin and glibenclamide.

What is claimed is:  
     
       1. A solid oral dosage form comprising a combination of metformin and glibenclamide in which the size of the glibenclamide is such that at most 10% of the particles are less than 2 μm and at most 10% of the particles are greater than 60 μm, so that the glibenclamide bioavailability is comparable to the glibenclamide bioavailability obtained with a separate administration of metformin and glibenclamide. 
     
     
       2. A solid pharmaceutical composition comprising metformin and glibenclamide in particulate form, wherein the size of the glibenclamide particles is such that at most 10% of the particles are less than 2 μm and at most 10% of the particles are greater than 60 μm. 
     
     
       3. A solid oral dosage form as claimed in  claim 1  in which the size of the glibenclamide is such that at most 10% of the particles are less than 3 μm and at most 10% of the particles are greater than 60  40 μm. 
     
     
       4. A solid oral dosage form comprising a combination of metformin and glibenclamide in which the size of glibenclamide is such that at most 25% of the particles are less than 11 μm and at most 25% of the particles are greater than 46 μm. 
     
     
       5. A solid oral dosage form of  claim 4 in which 50% of particles are less than 23 μm. 
     
     
       6. A solid oral dosage form as claimed in  claim 1  in which metformin is present as metformin salt and the weight ratio of metformin salt to glibenclamide is 50/1 to 250/1. 
     
     
       7. A solid oral dosage form as claimed in  claim 1  which is a tablet. 
     
     
       8. A tablet as claimed in  claim 7  which is obtained by a process comprising: 
       a) forming granules by wet granulation of a mixture of metformin and glibenclamide;  
       b) blending the granules with a tabletting aid  
       c) tabletting the blend thus obtained into tablets.  
     
     
       9. A method for treating non-insulin dependent diabetes or hyperglycaemia, comprising administering to a subject in need thereof, the composition of  claim 1 . 
     
     
       10. A method for treating non-insulin dependent diabetes or hyperglycemia, comprising administering to a subject in need thereof, the composition of  claim 2 . 
     
     
       11. A pharmaceutical composition comprising a single solid oral dosage form containing an effective dose of metformin and an effective dose of glibenclamide wherein, after oral administration thereof to a human, the bioavailability of glibenclamide is comparable to the bioavailability of glibenclamide achieved by oral administration of separate solid oral dosage forms to a human, one containing glibenclamide and the other metformin, in the same respective effective doses as in said single oral dosage form. 
     
     
       12. A pharmaceutical composition comprising a single solid oral dosage form containing an effective dose of metformin and an effective dose of glibenclamide wherein, after oral administration thereof to a human, the C max    and AUC of glibenclamide are comparable to the C   max    and AUC of glibenclamide achieved by oral administration of separate solid oral dosage forms to a human, one containing glibenclamide and the other metformin, in the same respective effective doses as in said single oral dosage form.   
     
     
       13. A pharmaceutical composition comprising a single solid oral dosage form containing an effective dose of metformin and an effective dose of glibenclamide wherein, after oral administration thereof to a human, the C max    and AUC of glibenclamide are ± 25   %  of the C   max    and AUC, respectively, of the glibenclamide achieved by oral administration to a human of separate solid oral dosage forms, one containing glibenclamide and the other metformin, in the same respective effective doses as in said single oral dosage form.   
     
     
       14. A pharmaceutical composition comprising a single solid oral dosage form containing an effective dose of metformin and an effective dose of glibenclamide wherein, after oral administration thereof to a human, the mean C max    and mean AUC values of glibenclamide are, respectively, ± 25   %  of  113  ng/ml and ± 25   %  of  842  ng/ml/hr, for a  5  mg unit dose of glibenclamide, or proportionally higher or lower values for higher or lower unit doses of glibenclamide, respectively.   
     
     
       15. A pharmaceutical composition comprising a single solid oral dosage form containing an effective dose of metformin and an effective dose glibenclamide wherein, after oral administration thereof to a human, the adjusted geometric mean C max    and adjusted geometric mean AUC values of glibenclamide are, respectively, ± 25   %  of  101  ng/ml and ± 25   %  of  780  ng/ml/hr, for a  5  mg unit dose of glibenclamide, or proportionally higher or lower values for higher or lower unit doses of glibenclamide, respectively.   
     
     
       16. A composition of one of claims  11 - 15  wherein the weight ratio of metformin to glibenclamide is  50 / 1  to  250 / 1 . 
     
     
       17. A composition of one of claims  11 - 15  wherein the weight ratio of metformin to glibenclamide is about  100 / 1 . 
     
     
       18. A composition of one of claims  11 - 15  wherein the weight ratio of metformin to glibenclamide is about  200 . 
     
     
       19. A composition of one of claims  11 - 15  wherein the unit dose of metformin is about  500  mg or about  250  mg. 
     
     
       20. A composition of  claim 19  wherein the unit dose of glibenclamide is  5 ,  2 . 5  or  1 . 25  mg. 
     
     
       21. A composition of one of claims  11 - 15  in the form of a tablet or capsule. 
     
     
       22. A composition of  claim 13  wherein said C max    and AUC values of glibenclamide in said single solid oral dosage form are ± 20   %  of said C   max    and AUC values, respectively, of glibenclamide in said separate glibenclamide solid oral dosage form.   
     
     
       23. A composition of  claim 13  wherein said C max    and AUC values of glibenclamide in said single solid oral dosage form are ± 15   %  of said C   max    and AUC values, respectively, of glibenclamide in said separate glibenclamide solid oral dosage form.   
     
     
       24. A composition of  claim 13  wherein said C max    and AUC values of glibenclamide in said single solid oral dosage form are ± 10   %  of said C   max    and AUC values, respectively, of glibenclamide in said separate glibenclamide solid oral dosage form.   
     
     
       25. A composition of  claim 13  wherein said C max    and AUC values of glibenclamide in said single solid oral dosage form are ± 5   %  of said C   max    and AUC values, respectively, of glibenclamide in said separate glibenclamide solid oral dosage form.   
     
     
       26. A composition of one of claims  14  or  15  wherein said C max    and AUC values are ± 20   %  of said numerical ranges.   
     
     
       27. A composition of one of claims  14  or  15  wherein said C max    and AUC values are ± 15   %  of said numerical ranges.   
     
     
       28. A composition of one of claims  14  or  15  wherein said C max    and AUC values are ± 10   %  of said numerical ranges.   
     
     
       29. A composition of one of claims  14  or  15  wherein said C max    and AUC values are ± 5   %  of said numerical ranges.   
     
     
       30. A method of treating non- insulin dependent diabetes or hyperglycemia comprising administering to a patient in need thereof a composition of one of claims  11 - 15 .   
     
     
       31. A method of achieving a bioavailability of glibenclamide in a human upon administering orally a single solid oral dosage form containing an effective dose of metformin and an effective dose of glibenclamide, said bioavailability being comparable to the bioavailability of glibenclamide achieved by oral administration of separate solid oral dosage forms to a human, one containing glibenclamide and the other metformin, in the same respective effective doses as in said single oral dosage form, comprising formulating glibenclamide with metformin in said single solid oral dosage form so as to assure said comparable bioavailability. 
     
     
       32. A method of increasing bioavailability of glibenclamide in a human upon administering orally a single solid oral dosage form containing an effective dose of metformin and an effective dose of glibenclamide, such that said increased bioavailability is comparable to the bioavailability of glibenclamide achieved by oral administration of separate solid oral dosage forms to a human, one containing glibenclamide and the other metformin, in the same respective effective doses as in said single oral dosage form, comprising formulating glibenclamide with metformin in said single solid oral dosage form so as to assure said comparable bioavailability. 
     
     
       33. A composition of one of claims  11 - 15  wherein metformin is present as a metformin salt. 
     
     
       34. A method of one of claims  31 - 32  wherein metformin is present as a metformin salt. 
     
     
       35. A method of  claim 30  wherein metformin is present as a metformin salt.