Metformin glycinate for blood glucose control

Abstract

The present invention relates to metformin glycinate salt and pharmaceutical compositions thereof for the treatment of diabetes mellitus. The method includes administration of the metformin glycinate salt by various routes selected from oral, intravenous injectable, intramuscular injectable, nasal, intraperitoneal, or sublingual, in order to achieve a reduction in blood glucose levels. The invention further relates to the synthesis of a new 1,1-dimethylbiguanide glycinate salt, called Metformin Glycinate. The resulting salt exhibits advantages over other metformin salts. These advantages are due, in the first place, to the fact that the glycine counterion exhibits hypoglycemic effects by itself. Moreover, the salt exhibits more rapid absorption, reaching higher plasma concentrations than those produced with metformin hydrochloride.

The invention claimed is: 
     
       1. A salt which comprises metformin and glycinate, forming a metformin Metformin glycinate salt, (N,N-dimethylimidodicarbonimidic diamide glycinate) having the formula as follows: 
       
         
           
           
               
               
           
         
       
     
     
       2. The metformin glycinate salt of  claim 1 , having a nuclear magnetic resonance (NMR) proton spectrum displacement at 2,814 ppm, 2,916 ppm, and 4,677 ppm. 
     
     
       3. The metformin glycinate salt of  claim 1 , having carbon-13 spectrum displacements at 37,754 ppm, 44,824 ppm, 158,761 ppm, 160,308 ppm, and 180,049 ppm. 
     
     
       4. The metformin glycinate salt of  claim 1 , having infrared (IR) spectrum characteristic absorption signals at 3,367.34 cm −1 , 3,175,88 cm −1 , 1,618.78 cm −1 , and 1,573.96 cm −1 . 
     
     
       5. The metformin glycinate salt of  claim 1 , wherein the monocrystal X-ray diffraction obtained corresponds to a triclinic crystal of spatial group P-1, with the following cell dimensions,
 a=5.993 A° 
 b=8.673 A° 
 c=10.51 A° 
 α=90.94° 
 β=95.10° 
 γ=107.58°. 
 
     
     
       6. A pharmaceutical composition comprising an effective amount of said metformin glycinate salt of  claim 1 , as an active ingredient, said composition in the form of a tablet, caplet, gel, paste, powder, prolonged-release granules, capsule, prolonged-release tablet, liquid with buffer agent, effervescent tablets, suspension, syrup, aerosol or other pharmaceutical formulations. 
     
     
       7. The pharmaceutical composition of  claim 6  comprising an effective amount of said metformin glycinate salt together with pharmaceutically acceptable diluent or carrier. 
     
     
       8. A tablet formulation comprising an effective amount of said metformin glycinate salt as claimed in of  claim 1 , or pharmaceutical composition thereof in admixture with excipients. 
     
     
       9. A The tablet formulation as claimed in of  claim 8  wherein the excipients comprise a compression an additive to provide sheen to tablet, a disintegrant and a lubricant. 
     
     
       10. A The tablet formulation as claimed in of  claim 8  wherein the excipients comprise microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycollate and magnesium stearate. 
     
     
       11. A capsule formulation comprising an effective amount of said metformin glycinate salt as claimed in of  claim 1 , or pharmaceutical composition thereof in admixture with excipients. 
     
     
       12. A method of producing the metformin glycinate salt, comprising the following steps:
 a) preparing the a solution of metformin hydrochloride; 
 b) separating the hydrochloride counterion by passing a the solution of metformin hydrochloride salt through ion-exchange column in order to produce free metformin; 
 c) dissolving the free metformin in an aqueous medium; 
 d) adding glycine to the aqueous medium at ambient temperature under constant stirring to obtain the a resulting mixture of glycine and metformin; 
 e) concentrating the resulting mixture; 
 f) adding a solvent wherein glycine is insoluble is added until the excess thereof precipitates; 
 g) filtering the mixture in order to eliminate the excess glycine; 
 h) evaporating the resulting filtrate until a second precipitate is produced; and 
 i) washing and purifying the second precipitate to obtain metformin glycinate salt. 
 
     
     
       13. The method of  claim 12 , further comprising adding an organic solvent in (f) which does not react with the components present and wherein glycine is insoluble its order to create insolubility in the medium and favor crystallization of a saturated medium, and precipitate the excess glycine. 
     
     
       14. A method of treating hyperglycemia in warm-blooded animals, comprising administering a therapeutically effective amount of said metformin glycinate salt as claimed in of  claim 1 , or pharmaceutical compositions thereof. 
     
     
       15. The method of  claim 14  comprising administering various doses of said metformin glycinate in an amount sufficient to achieve a reduction in blood glucose levels by various routes selected from oral, intravenous injectable, intramuscular injectable, nasal, intraperitoneal, or sublingual. 
     
     
       16. The method of  claim 14  wherein said metformin glycinate salt exhibits about 40 fold reduction in glucose level as compared to metformin hydrochloride. 
     
     
       17. The method of  claim 14  wherein said metformin glycinate salt or pharmaceutical compositions thereof modulates diabetes or treats diabetes and its related symptoms, complications and disorders. 
     
     
       18. The method of  claim 14  wherein said metformin glycinate salt or pharmaceutical compositions thereof are administered at a dosage range of about 100 mg to about 3.5 g. 
     
     
       19. The metformin glycinate salt prepared from the method of  claim 12 . 
     
     
       20. The pharmaceutical composition of  claim 6  wherein the metformin glycinate salt is in combination with one or more additional active agents. 
     
     
       21. The metformin glycinate of claim 1, wherein said metformin glycinate melts at 166-172° C. 
     
     
       22. The metformin glycinate of claim 21, wherein said metformin glycinate has characteristic IR peaks of about 3,367 cm −1 , 3,175 cm −1 , 1,618 cm −1 , 1,573 cm −1 , and 1494 cm −1 . 
     
     
       23. A pharmaceutical composition comprising said metformin glycinate of claim 21 and one or more pharmaceutically acceptable excipients. 
     
     
       24. The pharmaceutical composition of claim 23, wherein said composition is a tablet or a capsule. 
     
     
       25. The pharmaceutical composition of claim 23, wherein said composition comprises about 1050 mg of said metformin glycinate. 
     
     
       26. The pharmaceutical composition of claim 23, wherein said one or more pharmaceutically acceptable excipients comprise dibasic calcium phosphate, povidone, starch sodium glycolate, colloidal silicon dioxide, talc, and magnesium stearate. 
     
     
       27. The pharmaceutical composition of claim 26, wherein said composition further comprises a coating. 
     
     
       28. The pharmaceutical composition of claim 27, wherein said composition comprises about 1050 mg metformin glycinate. 
     
     
       29. The pharmaceutical composition of claim 27, wherein said coating is an enteric coating. 
     
     
       30. The pharmaceutical composition of claim 29, wherein said metformin glycinate has characteristic IR peaks of about 3367 cm −1 , 1573 cm −1 , and 1494 cm −1 . 
     
     
       31. The pharmaceutical composition of claim 27, wherein the composition is a tablet. 
     
     
       32. The pharmaceutical composition of claim 20, wherein said one or more additional active agents comprise an antihyperlipidemic agent, a plasma HDL-raising agent, an antihypercholesterolemic agent, or a combination thereof. 
     
     
       33. The pharmaceutical composition of claim 20, wherein said one or more additional active agents are an HMG-CoA reductase inhibitor and aspirin. 
     
     
       34. The pharmaceutical composition of claim 20, wherein said one or more additional active agents are an HMG-CoA reductase inhibitor and a beta blocker. 
     
     
       35. A method of treating type 2 diabetes in a warm-blood animal comprising administering to said warm-blooded animal in need thereof a therapeutically effective amount of said metformin glycinate of claim 21. 
     
     
       36. The method of claim 14, wherein said metformin glycinate is administered at a dose of about 1050 mg or said pharmaceutical composition comprises about 1050 mg metformin glycinate. 
     
     
       37. The method of claim 36, wherein said warm-blood animal is a human. 
     
     
       38. The method of claim 37, wherein said administration provides a C max  of about 591 ng/ml, a T max  of about 2.5 hours, and an AUC (10-24)  of about 26 ng•ml/h. 
     
     
       39. The method of claim 37, wherein said human has type 2 diabetes. 
     
     
       40. The method of claim 37, wherein said administration is once a day or twice a day. 
     
     
       41. The method of claim 40, wherein said administration is once a day. 
     
     
       42. The method of claim 14, wherein said method further comprises administering one or more additional active agents to said warm-blooded animal. 
     
     
       43. The method of claim 42, wherein said one or more additional active agents comprise an antihyperlipidemic agent, a plasma HDL-raising agent, an antihypercholesterolemic agent, or a combination thereof. 
     
     
       44. The method of claim 43, wherein said one or more additional active agents are an HMG-CoA reductase inhibitor and aspirin. 
     
     
       45. The method of claim 43, wherein said one or more additional active agents are an HMG-CoA reductase inhibitor and a beta blocker. 
     
     
       46. A method of producing metformin glycinate comprising the following steps:
 a) releasing free metformin from metformin hydrochloride by ion-exchange;   b) adding glycine to an aqueous liquid comprising the free metformin;   c) adding a solvent wherein glycine is insoluble to the aqueous liquid until excess glycine precipitates; and   d) removing the precipitated glycine to obtain a liquid comprising said metformin glycinate.   
     
     
       47. The method of claim 46, wherein the method further comprises the following steps:
 concentrating the liquid of b) before c), and   e) concentrating the liquid of d) to obtain said metformin glycinate.   
     
     
       48. The metformin glycinate prepared by the method of claim 46. 
     
     
       49. The metformin glycinate prepared by the method of claim 47.