Compositions and Methods of Treating Metabolic Disorders

• US 20130177604A1
• Filed: 01/05/2013
• Published: 07/11/2013
• Est. Priority Date: 01/06/2012
• Status: Active Grant

• Current Assignee: Anji Pharmaceuticals, Inc.
• Original Assignee: Elcelyx Therapeutics, Inc.
• Inventors: Baron, Alain D., Fineman, Mark S., Beeley, Nigel R. A.
• Granted Patent: US 9,211,263 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• 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 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2813 Inorganic compounds
• CPC Class Codes: A61K 9/282 Organic compounds, e.g. fats
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 249/14 Nitrogen atoms
• CPC Class Codes: C07D 251/10 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 251/18 with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 255/02 not condensed with other rings
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links

Abstract

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.

Claims

1. A method of improving the gastrointestinal tolerability of and/or reducing gastrointestinal complications resulting from biguanide administration, comprising administering a therapeutically effective amount of a biguanide compound in a delayed-release formulation to a patient in need thereof.

9. The method according to any one of the preceding claims, wherein the patient in need thereof has hyperglycemia.

10. The method according to claim 9, wherein the hyperglycemia is chronic.

11. The method according to claim 9 or claim 10, wherein the hyperglycemia is caused by type II diabetes.

16. The method according to any one of claims 1-15, 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.

17. The method according to any one of claims 1-15, 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.

18. The method according to any one of claims 1-15, 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.

19. The method according to any one of the preceding claims, 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 5.0 or 5.5.

20. The method according to claim 19, 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.

21. The method according to claim 19 or 20, wherein said oral dosage form further comprises a modified release component for at least a portion of said biguanide compound.

22. The method according to claim 19 or 20, wherein the oral dosage form comprises less than 500 mg of the biguanide compound.

23. The method according to any one of the preceding claims, wherein said biguanide compound is selected from the group consisting of metformin, phenformin, buformin and imeglimin.

24. A method according to any one of the previous claims, further comprising administration of a DPP-IV inhibitor.

25. A method according to any one of the previous claims, further comprising administration of an anti-obesity or anti-diabetes agent.

2. A method of treating metabolic disorders in a patient in need thereof, comprising administering a therapeutically effective amount of a biguanide compound to said patient in a delayed-release formulation, wherein said patient has a contraindication for the biguanide compound.

3. The method according to claim 2, 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.

4. The method according to claim 3, wherein the patient has a hypoxic condition.

5. The method according to claim 3, wherein the patient has impaired lactate clearance.

6. The method according to claim 3, wherein the patient has impaired clearance of the biguanide compound.

7. The method according to claim 3, wherein the patient has moderate renal impairment, severe renal impairment, or endstage renal disease which results in impaired clearance of the biguanide compound.

8. The method according to claim 3, wherein the patient has chronic kidney disease.

12. A method of treating a renally impaired subject having diabetes, comprising administering a therapeutically effective amount of a biguanide compound to said subject in a delayed-release formulation.

13. A method of treating a diabetic subject having congestive heart failure, a hypoxic state and/or advanced liver disease, comprising administering a therapeutically effective amount of a biguanide compound to said subject in a delayed-release formulation.

14. A method of reducing the onset of diabetes in a subject with pre-diabetes, comprising administering a therapeutically effective amount of a biguanide compound to said subject in a delayed-release formulation.

15. A method of inducing weight loss in a subject, comprising administering a therapeutically effetive amount of a biguanide compound to said subject in a delayed release formulation.