# US 2014/0193498 A1 · Compositions and Methods for Treating Metabolic Disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0193498 A1 - Document ID: US20140193498A1 - Status: Published application - Kind: A1 - Application number: 14/147,449 - Filed: 2014-01-03 - Published: 2014-07-10 - Earliest claimed: 2013-01-05 - Applicants: Elcelyx Therapeutics, Inc. - Inventors: Alain D. BARON; Mark S. FINEMAN; Terri KIM; Stephen Kwaku DORDUNOO - Web page: https://patentgrep.com/patent/US20140193498A1 ## CPC - A61K 9/2846: {Poly(meth)acrylates} - A61K 9/2886: {having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer (of the type active core-drug layer-inactive layer A61K9/209)} - A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 1/12: Antidiarrhoeals - A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61P 3/04: Anorexiants; Antiobesity agents - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Compositions and methods for improving the pharmacokinetics and reducing the risk of adverse events resulting from biguanide compound administration are provided, comprising administering delayed release formulations of such compounds having a lag phase release. ## Claims ### Claim 1 A delayed-release pharmaceutical composition for biguanide compound delivery, comprising an oral dosage form having a core comprising a therapeutically effective amount of a biguanide compound and an enteric coating surrounding said core that delays release of said biguanide compound after ingestion until reaching the distal small intestine, and further minimizes the release of said biguanide compound from said oral dosage form for a lag phase of at least about ten minutes after contacting a pH of at least about 6.0. ### Claim 2 (depends on 1) The pharmaceutical composition according to claim 1, wherein said lag phase is at least about ten minutes after contacting a pH of at least about 6.5. ### Claim 3 (depends on 1, 2) The pharmaceutical composition according to claim 1 or claim 2, wherein said enteric coating has a coating weight of at least about 4.5 mg/cm2, more preferably at least about 5.0 mg/cm2 ### Claim 4 (depends on 1, 2) The pharmaceutical composition according to claim 1 or claim 2, wherein said enteric coating is applied to said oral dosage form to at least about a 3.0% to at least about a 6.0% (wt/wt) weight gain. ### Claim 5 The pharmaceutical composition according to any one of the preceding claims, wherein said oral dosage form releases less than about 10% or 5% of the therapeutically effective amount of said biguanide compound after contacting an aqueous medium at a pH of less than about 2 for two hours, followed by contacting an aqueous medium at a pH equal to or less than about 5.5 for 30 to 45 minutes. ### Claim 6 The pharmaceutical composition according to any one of the preceding claims, wherein said oral dosage form releases less than about 15%, 10%, or 5% of the therapeutically effective amount of said biguanide compound during said lag phase. ### Claim 7 The pharmaceutical composition according to any one of the preceding claims, wherein said oral dosage form releases between about 75% to about 100% of the therapeutically effective amount of said biguanide compound within about 90 minutes after contacting a pH of about 6.8. ### Claim 8 The pharmaceutical composition according to any one of the preceding claims, wherein said enteric coating comprises a polymer that is insoluble in acidic media, but dissolves above pH 7.0. ### Claim 9 (depends on 8) The pharmaceutical composition according to claim 8, wherein said polymer is Eudragit FS. ### Claim 10 The pharmaceutical composition according to any one of the preceding claims, wherein said enteric coating further comprises a polymer that is insoluble at pH 5.5 and below, but dissolves above pH 5.5. ### Claim 11 (depends on 10) The pharmaceutical composition according to claim 10, wherein said polymer is Eudragit L. ### Claim 12 (depends on 11) The pharmaceutical composition according to claim 11, wherein said Eudragit FS and said Eudragit L are present in about a 7:5 to about a 5:7 ratio. ### Claim 13 (depends on 12) The pharmaceutical composition according to claim 12, wherein said Eudragit FS and said Eudragit L are present in about a 6:4 to about a 4:6 ratio. ### Claim 14 (depends on 12) The pharmaceutical composition according to claim 12, wherein said enteric coating comprises about 60% Eudragit FS and about 40% Eudragit L. ### Claim 15 The pharmaceutical composition according to any one of the preceding claims, further comprising a seal coating between the core and the enteric coating, providing a total coating thickness of at least about 4% to 7% (wt./wt.) weight gain, more preferably at least about a 4.5% to 6% (wt./wt.) weight gain. ### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) The pharmaceutical composition according to any one of claims 1-14, further comprising a seal coating between the core and the enteric coating, providing a total coating thickness of at least about 21 mg/cm2 to 41 mg/cm2, more preferably at least about 23 mg/cm2 to at least about 35 mg/cm2. ### Claim 17 (depends on 16, 17) The pharmaceutical composition according to claim 16 or 17, wherein the seal coating comprises hypromellose, titanium dioxide, polyethylene glycol 400, polysorbate 80, triacetin, talc, and combinations thereof. ### Claim 18 The pharmaceutical composition according to any one of the preceding claims, wherein said biguanide compound is selected from the group consisting of metformin, phenformin, buformin and imeglimin. ### Claim 19 (depends on 18) The pharmaceutical composition according to claim 18 wherein said biguanide compound comprises metformin or a salt thereof. ### Claim 20 (depends on 19) The pharmaceutical composition according to claim 19, wherein said biguanide comprises metformin hydrochloride. ### Claim 21 The pharmaceutical composition according to any of the preceding claims, where said oral dosage form comprises an enterically-coated tablet, capsule or microsphere. ### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) A method of reducing the risk of adverse events resulting from biguanide compound administration, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of claims 1-21. ### Claim 23 (depends on 22) The method according to claim 22, wherein the adverse event is lactic acidosis. ### Claim 24 (depends on 22) The method according to claim 22, wherein said adverse event is a gastrointestinal complication selected from the group consisting of nausea, diarrhea, dyspepsia, and vomiting. ### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) A method of treating metabolic disorders in a patient in need thereof, comprising administering to said patient a pharmaceutical composition according to any one of claims 1-21. ### Claim 26 (depends on 25) The method according to claim 25, wherein said patient has a contraindication for the biguanide compound. ### Claim 27 (depends on 26) The method according to claim 26, 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. ### Claim 28 (depends on 27) The method according to claim 27, wherein the patient has moderate renal impairment, severe renal impairment, or end stage renal disease which results in impaired clearance of the biguanide compound. ### Claim 29 (depends on 25, 26, 27, 28) The method according to any one of claims 25-28, wherein the patient in need thereof has hyperglycemia. ### Claim 30 (depends on 29) The method according to claim 29, wherein the hyperglycemia is chronic. ### Claim 31 (depends on 29, 30) The method according to claim 29 or 30, wherein the hyperglycemia is caused by type II diabetes. ### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) A method of reducing the onset of diabetes in a subject with pre-diabetes, comprising administering to the subject a pharmaceutical composition according to any one of claims 1-21. ### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) A method of inducing weight loss in a subject, comprising administering to the subject a pharmaceutical composition according to any one of claims 1-21.