Compositions and methods for treating metabolic disorders
Methods for improving the gastrointestinal tolerability of biguanide compounds and for treating metabolic disorders and/or inducing weight loss in patients in need thereof, particularly in individuals having a contraindication for treatment with biguanide compounds, are provided comprising administering delayed release formulations of such biguanide compounds, including metformin, targeted to the small intestine.
1. A method of improving the gastrointestinal tolerability of and/or reducing gastrointestinal complications resulting from metformin administration in a renally impaired subject having diabetes, comprising administering to said subject a therapeutically effective amount of metformin or a salt thereof in a delayed-release formulation, wherein the delayed-release formulation releases a therapeutically effective amount of said metformin or a salt thereof distal of the duodenum, to one or more regions of the intestine, and wherein the resulting circulating plasma concentration of the metformin is below about 1 μg/mL.
2. The method according to claim 1 , wherein the metformin has a reduced relative average bioavailability in said delayed-release formulation in comparison with an immediate-release formulation having the same amount of said metformin or salt thereof.
3. The method according to claim 1 , wherein the administration produces a mean plasma AUC 0-36 less than about 14,000 ng*h/mL when said formulation is administered at 1000 mg total daily dose.
4. The method according to claim 1 , wherein the mean plasma C max , of said metformin is less than about 1100 ng/ml when administered at 1000 mg total daily dose.
5. The method according to claim 1 , wherein the delayed-release formulation comprises about 1 mg to about 2000 mg of metformin or a salt thereof.
6. A method according to claim 1 , further comprising administration of a DPP-IV inhibitor.
7. A method according to claim 1 , further comprising administration of an antiobesity or anti-diabetes agent.
8. The method according to claim 1 , wherein said metformin or a salt thereof is metformin hydrochloride.
9. The method according to claim 1 , wherein the circulating plasma concentration of the metformin is below about 0.5 μg/mL.
10. The method according to claim 1 , wherein the circulating plasma concentration of the metformin is below about 0.25 μg/mL.
11. The method according to claim 7 , wherein said antidiabetic agent is selected from thiazolidinediones, sulfonylureas, meglitinides, alphaglucosidase inhibitors, DPP-IV inhibitors, incretin mimetics, and SGLT inhibitors.
12. The method according to claim 7 , wherein said anti-obesity agent is lorcaserin.
13. The method according to claim 7 , wherein said anti-obesity agent is phentermine.
14. The method according to claim 7 , wherein said anti-obesity agent is a combination of lorcaserin and phentermine.
15. The method according to claim 7 , wherein said anti-obesity agent is a combination of topiramate and phentermine.
16. The method according to claim 7 , wherein said anti-obesity agent is a combination of bupropion and naltrexone.
17. The method according to claim 7 , wherein said anti-obesity agent or said antidiabetes is co-formulated with said metformin or a salt thereof and administered simultaneously in a combined formulation.
18. The method according to claim 17 , wherein said combined formulation is provided in the form of a delayed release component coupled with an immediate release component in a unitary dosage form.
19. The method according to claim 1 , wherein the delayed-release formulation comprises an enteric coating.
20. The method according to claim 19 , wherein the enteric coating has an onset of release of said metformin or a salt thereof at or above about pH 6.5.
21. The method according to claim 1 , wherein the delayed-release formulation has an onset of release of said metformin or a salt thereof at or above about pH 6.5.
22. The method according to claim 1 , wherein the delayed-release formulation has an onset of release of said metformin or a salt thereof at or above about pH 7.0.
23. The method according to claim 1 , wherein the delayed-release formulation releases a therapeutically effective amount of said metformin or a salt thereof distal of the jejunum, to one or more regions of the intestine.
24. The method according to any one of claims 1 - 3 , wherein said renally impaired patient has moderate or severe renal impairment.
25. The method according to claim 1 , wherein the metformin has a reduced relative average bioavailability of about 60% in said delayed-release formulation in comparison with an immediate-release formulation having the same amount of said metformin or salt thereof.
26. The method according to claim 1 , wherein the metformin has a reduced relative average bioavailability of about 50% in said delayed-release formulation in comparison with an immediate-release formulation having the same amount of said metformin or salt thereof.
27. The method according to claim 1 , wherein the metformin has a reduced relative average bioavailability of about 40% in said delayed-release formulation in comparison with an immediate-release formulation having the same amount of said metformin or salt thereof.
28. The method according to claim 1 , wherein the administration produces a mean plasma AUC 0-36 less than about 13,000 ng*h/mL when said formulation is administered at 1000 mg total daily dose.
29. The method according to claim 1 , wherein the administration produces a mean plasma AUC 0-36 less than about 12,000 ng*h/mL when said formulation is administered at 1000 mg total daily dose.
30. The method according to claim 19 , wherein the enteric coating has an onset of release of said metformin or a salt thereof at or above about pH 7.0.