Compositions and dosage forms for enhanced absorption of metformin

• US 20050158374A1
• Filed: 10/29/2004
• Published: 07/21/2005
• Est. Priority Date: 10/31/2003
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Wong, Patrick S.L., Yan, Dong, Guittard, George V.
• Application Number:
  US10/978,141
• Publication Number:
  US 20050158374A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/295 Iron group metal compounds
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 33/26 Iron; Compounds thereof
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics

Abstract

A complex comprised of metformin and a transport moiety, such as a fatty acid, is described. The complex has an enhanced absorption in the gastrointestinal tract, particularly the lower gastrointestinal tract. The complex, and compositions and dosage forms prepared using the complex, provide for absorption by the body of the drug through a period of ten to twenty-four hours, thus enabling a once-daily dosage form for metformin.

Claims

1. A substance comprised of metformin and a transport moiety, said metformin and said transport moiety forming a complex.

2. The substance of claim 1, wherein said transport moiety, prior to complex formation, is a fatty acid of the form CH₃(C_nH_2n)COOH, where n is from 4-16.

3. The substance of claim 2, wherein said fatty acid is capric acid or lauric acid.

8. A dosage form comprising the substance of claim 1.

9. The dosage form of claim 8, wherein the dosage form is an osmotic dosage form.

10. The dosage form of claim 9, comprised of (i) a push layer;

(ii) drug layer comprising a metformin-transport moiety complex;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

11. The dosage form of claim 9, comprised of (i) a semipermeable wall provided around an osmotic formulation comprising a metformin-transport moiety complex, an osmagent, and an osmopolymer;

and (ii) an exit.

12. The dosage form of claim 9, wherein the dosage form provides a total daily dose of between 500-2550 mg.

4. A composition, comprising,

a complex comprised of metformin and a transport moiety, and

a pharmaceutically acceptable vehicle,

wherein said composition has an absorption in the lower gastrointestinal tract at least four-fold higher than metformin hydrochloride.

5. The composition of claim 4, wherein said transport moiety is a fatty acid, prior to complex formation, of the form CH₃(C_nH_2n)COOH, where n is from 4-16.

6. The composition of claim 5, wherein said fatty acid is capric acid or lauric acid.

7. A dosage form comprising the composition of claim 4.

16. A method for treating hyperglycemia in a subject, comprising:

administering the composition of claim 4.

17. The method of claim 16, wherein said administering is via oral administration.

13. An improvement in a dosage form comprising metformin or a salt of metformin, the improvement comprising a dosage form comprised of a complex of metformin and a transport moiety.

14. The improved dosage form of claim 13, wherein said transport moiety, prior to complex formation, is a fatty acid of the form CH₃(C_nH_2n)COOH, where n is from 4-16.

15. The improved dosage form of claim 14, wherein said fatty acid is capric acid or lauric acid.

18. A method of preparing a metformin-transport moiety complex, comprising

providing metformin base;

providing a transport moiety;

combining the metformin base and the transport moiety in the presence of a solvent having a dielectric constant less than that of water;

whereby said combining forms a complex comprised of the metformin base and the transport moiety.

19. The method of claim 18, wherein said combining comprises contacting in a solvent having a dielectric constant at least two fold lower than the dielectric constant of water.

20. The method of claim 19, wherein said solvent is selected from the group consisting of methanol, ethanol, acetone, benzene, methylene chloride, and carbon tetrachloride.

21. A method of improving G.I. absorption of metformin, comprising

providing a complex comprised of metformin and a transport moiety, said complex characterized by a tight-ion pair bond;

and

administering the complex to a patient.

22. The method of claim 21, wherein the improved absorption comprises improved lower gastrointestinal absorption.

23. The method of claim 21, wherein the improved absorption comprises improved absorption in the upper gastrointestinal tract.

24. A method of treating a subject having Type II diabetes, comprising

administering a complex comprised of metformin and a transport moiety;

administering a second therapeutic agent.

25. The method of claim 24, wherein said administering a second therapeutic agent comprises administering a second therapeutic agent that is an anti-diabetic agent.

26. The method of claim 25, wherein said administering a second therapeutic agent comprises administering a dipeptidyl peptidase IV inhibitor.

27. The method of claim 24, wherein said administering includes administering a complex of metformin and a fatty acid transport moiety, said fatty acid prior to complex formation having the form CH₃(C_nH_2n)COOH, where n is from 4-16.

28. The method of claim 27, wherein said fatty acid is capric acid or lauric acid.

29. The method of claim 24, wherein said administering of the complex includes orally administering the complex.

30. The method of claim 27, wherein said oral administration is achieved by orally administering the complex in an osmotic dosage form.

31. The method of claim 30, comprised of (i) a push layer;

(ii) drug layer comprising a metformin-fatty acid complex;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

32. The method of claim 30, comprised of (i) a semipermeable wall provided around an osmotic formulation comprising a metformin-fatty acid complex, an osmagent, and an osmopolymer;

and (ii) an exit.

33. The method of claim 29, wherein the dosage form provides a total daily dose of between 500-2550 mg.

34. The method of claim 24, wherein said administering of the DPP IV inhibitor is via oral administration.

35. A compound comprising metformin and a transport moiety, said compound prepared by a process of (i) providing metformin base;

(ii) providing a transport moiety;

(iii) combining the metformin base and the transport moiety in the presence of a solvent having a dielectric constant less than that of water, where said combining forms a complex between the metformin base and the transport moiety associated by a tight-ion pair bond.

36. The compound according to claim 35, wherein said transport moiety is a fatty acid of the form CH₃(C_nH_2n)COOH, where n is from 4-16.

37. The compound of claim 36, wherein said fatty acid is capric acid or lauric acid.