Metformin glycinate salt for blood glucose control

• US 8,703,183 B2
• Filed: 12/24/2010
• Issued: 04/22/2014
• Est. Priority Date: 06/26/2008
• Status: Expired

• Current Assignee: Laboratorios Silanes S.A. de C.V. (The Silanes Group, Mexico)
• Original Assignee: Laboratorios Silanes S.A. de C.V. (The Silanes Group, Mexico)
• Inventors: Lara, Jose Manuel FranciscoOchoa
• Primary Examiner(s): Oswecki, Jane C
• Application Number:
  US12/928,985
• Publication Number:
  US 20110171142A1
• Time in Patent Office: 1,215 Days
• Field of Search: 424/451, 424/452, 424/455, 424/456, 424/464, 424/465, 424/466, 514/479, 514/483, 562/400, 562/512, 562/553, 562/560, 562/561, 562/624, 562/875
• US Class Current: 424/451
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07C 229/08 the nitrogen atom of the amino group being further bound to hydrogen atoms
• CPC Class Codes: C07C 279/26 X and Y being nitrogen atoms, i.e. biguanides

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.

Claims

1. A salt which comprises metformin and glycinate, forming a 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<sup>−

1</sup>, 1,618.78 cm<sup>−

1</sup>, and 1,573.96 cm<sup>−

1</sup>.

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 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 metformin glycinate salt together with pharmaceutically acceptable diluent or carrier.

8. A tablet formulation comprising an effective amount of metformin glycinate salt as claimed in claim 1, or pharmaceutical composition thereof in admixture with excipients.

9. A tablet formulation as claimed in claim 8 wherein the excipients comprise a compression an additive to provide sheen to tablet, a disintegrant and a lubricant.

10. A tablet formulation as claimed in 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 metformin glycinate salt as claimed in claim 1, or pharmaceutical composition thereof in admixture with excipients.

14. A method of treating hyperglycemia in warm-blooded animals, comprising administering a therapeutically effective amount of metformin glycinate salt as claimed in claim 1, or pharmaceutical compositions thereof.

15. The method of claim 14 comprising administering various doses of 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.

20. The pharmaceutical composition of claim 6 wherein the metformin glycinate salt is in combination with one or more additional active agents.

12. A method of producing the metformin glycinate salt, comprising the following steps:

a) preparing the solution of metformin hydrochloride;

b) separating the hydrochloride counterion by passing a 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 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 in order to create insolubility in the medium and favor crystallization of a saturated medium, and precipitate the excess glycine.

19. The metformin glycinate salt prepared from the method of claim 12.