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 biguanide administration, comprising orally administering a therapeutically effective amount of a biguanide compound selected form the group consisting of metformin, phenformin, buformin and imeglimin in a delayed-release formulation adapted to minimize the systemic bioavailability of the biguanide compound to a patient having a metabolic disorder selected from the group consisting of obesity, dislipidemia, hyperglycemia, type II diabetes, prediabetes, gestational diabetes, and polycystic ovary syndrome, wherein said delayed-release formulation has reduced relative bioavailability of at least 20% compared to an immediate-release composition having the same amount of the biguanide compound, and the patient has a contraindication for the biguanide compound.
2. The method according to claim 1 , wherein the patient in need thereof has hyperglycemia.
3. The method according to claim 2 , wherein the hyperglycemia is chronic.
4. The method according to claim 3 , wherein the hyperglycemia is caused by type II diabetes.
5. The method according to claim 1 , wherein the biguanide compound has a reduced relative bioavailability of about 40, 50 or 60% in said delayed-release formulation in comparison with an immediate-release formulation having the same amount of said biguanide compound.
6. The method according to claim 1 , wherein the administration produces a mean plasma AUC 0-36 less than about 14,000, 13,000 or 12,000 ng*h/mL when said formulation is administered at 500 mg twice daily.
7. The method according to claim 1 , wherein the administration produces a mean C max less than about 800, 700 or 600 ng/mL when said formulation is administered at 500 mg twice daily.
8. The method according to claim 1 , wherein the biguanide compound is targeted for delivery to the small intestine, and the formulation comprises an oral dosage form enterically coated at a pH at or above 5.5.
9. The method according to claim 8 , wherein the biguanide compound is targeted for delivery to the distal small intestine, and the formulation comprises an oral dosage form enterically coated at a pH at or above 6.0 or 6.5.
10. The method according to claim 9 , wherein said oral dosage form further comprises a modified release component for at least a portion of said biguanide compound.
11. The method according to claim 9 , wherein the oral dosage form comprises less than 500 mg of the biguanide compound.
12. A method according to claim 1 , further comprising administration of a DPP-IV inhibitor.
13. A method according to claim 1 , further comprising administration of an anti-obesity or anti-diabetes agent.
14. The method according to claim 1 , wherein the patient has a contraindication selected from the group consisting of a hypoxic condition, impaired lactate clearance, and impaired clearance of the biguanide compound.
15. The method according to claim 14 , wherein the patient has a hypoxic condition.
16. The method according to claim 14 , wherein the patient has impaired lactate clearance.
17. The method according to claim 14 , wherein the patient has impaired clearance of the biguanide compound.
18. The method according to claim 1 , wherein the patient has moderate renal impairment, severe renal impairment, or endstage renal disease which results in impaired clearance of the biguanide compound.
19. The method according to claim 1 , wherein the resulting circulating plasma concentration of the biguanide compound is below about 1 μg/mL.
20. The method according to any one of claim 1 , 2 - 4 5 - 11 or 12 - 19 , wherein said biguanide compound is metformin or a salt thereof.
21. The method according to claim 20 , wherein said metformin or a salt thereof is metformin hydrochloride.
22. The method according to claim 1 , wherein the resulting circulating plasma concentration of the biguanide compound is below about 0.5 μg/mL.
23. The method according to claim 1 , wherein the resulting circulating plasma concentration of the biguanide compound is below about 0.25 μg/mL.
24. The method according to claim 1 , wherein said effective amount of a biguanide compound in a delayed-release formulation is administered to said patient once a day in the morning.
25. The method according to claim 24 , wherein said effective amount of a biguanide compound in a delayed-release formulation is administered with the morning meal.
26. The method according to claim 24 , wherein said effective amount of a biguanide compound is from about 1 mg to about 2000 mg.
27. The method according to claim 26 , wherein said effective amount of a biguanide compound is about 2000 mg.
28. The method according to claim 26 , wherein said effective amount of a biguanide compound is about 1500 mg.
29. The method according to claim 13 , wherein said anti-diabetic agent is selected from the group consisting of thiazolidinediones, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, DPP-IV inhibitors, incretin mimetics, and SGLT inhibitors.
30. The method according to claim 13 , wherein said anti-obesity agent is lorcaserin.
31. The method according to claim 13 , wherein said anti-obesity agent is phentermine.
32. The method according to claim 13 , wherein said anti-obesity agent is a combination of lorcaserin and phentermine.
33. The method according to claim 13 , wherein said anti-obesity agent is a combination of topiramate and phentermine.
34. The method according to claim 13 , wherein said anti-obesity agent is a combination of bupropion and naltrexone.
35. The method according to claim 13 , wherein said anti-obesity agent or said anti-diabetes agent is co-formulated with said biguanide compound and administered simultaneously in a combined formulation.
36. The method according to claim 35 , 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.
37. The method according to claim 1 , wherein said delayed-release formulation releases a therapeutically effective amount of biguanide compound distal of the duodenum, to one or more regions of the intestine.
38. The method according to claim 1 , wherein said delayed-release formulation releases a therapeutically effective amount of said biguanide compound distal of the jejunum, to one or more regions of the intestine.
39. The method according to claim 1 , wherein said metabolic disorder is type II diabetes.