Claims for Patent: 6,660,300

Summary for Patent: 6,660,300

Title:	Method of use of a biphasic controlled release delivery system for high solubility pharmaceuticals and method
Abstract:	A biphasic controlled release delivery system for pharmaceuticals which have high water solubility, such as the antidiabetic metformin HCl salt, is provided which provides a dosage form that has prolonged gastric residence so that a dosing regimen of at least one gram metformin, once daily, may be achieved while providing effective control of plasma glucose. The delivery system includes (1) an inner solid particulate phase formed of substantially uniform granules containing a pharmaceutical having a high water solubility, and one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, and (2) an outer solid continuous phase in which the above granules of inner solid particulate phase are embedded and dispersed throughout, the outer solid continuous phase including one or more hydrophobic polymers, one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, which may be compressed into tablets or filled into capsules. Methods for forming the so-described biphasic controlled release delivery system and using such biphasic controlled release delivery system for treating diabetes are also provided.
Inventor(s):	Timmins; Peter (Irby, GB), Dennis; Andrew B. (Barnston, GB), Vyas; Kiren A. (Canterbury, GB)
Assignee:	Bristol-Myers Squibb Co. (Princeton, NJ)
Application Number:	10/224,945
Patent Claims:	1. A method for treating diabetes comprising administering once daily to a mammalian patient in need of treatment a therapeutically effective amount of a pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of said inner solid particulate phase are dispersed and embedded, the particles of said inner solid particulate phase comprising (a) a pharmaceutical having a high water solubility selected from metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and said outer solid continuous phase comprising an extended release material, wherein the total extended release material content in both said inner solid particulate phase and said outer continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation. 2. The method for treating diabetes as defined in claim 1 wherein said pharmaceutical formulation is a biphasic heterogeneous controlled release formulation which is designed to release pharmaceutical from the particles forming said inner solid particulate phase through said outer solid continuous phase into the upper gastrointestinal tract. 3. The method for treating diabetes as defined in claim 1 wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 30 to about 65% by weight of the pharmaceutical formulation. 4. The method for treating diabetes as defined in claim 1 wherein said pharmaceutical is metformin hydrochloride. 5. The method for treating diabetes as defined in claim 1 wherein said extended release material present in said inner solid particulate phase is different from the extended release material present in said outer solid continuous phase. 6. The method for treating diabetes as defined in claim 1 wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 35 to about 60% by weight of the pharmaceutical formulation. 7. The method for treating diabetes as defined in claim 3 wherein said inner solid particulate phase contains from about 5 to about 95% extended release material based on the weight of said inner solid particulate phase, and the outer solid continuous phase contains from about 40 to about 100% extended release material based on the weight of said outer solid continuous phase. 8. The method for treating diabetes as defined in claim 1 wherein said formulation when ingested by a human reduces maximum attained plasma-metformin concentration (Cmax) by at least about 15% (relative to marketed rapid-release metformin formulations), and increases time to reach maximum metformin-plasma concentration (Tmax) by at least about 30% (relative to marketed rapid-release metformin formulations), while having an insignificant effect on area under the plasma-metformin concentration time curve (AUC) and % urinary recovery (UR) of the dose of metformin (relative to marketed rapid-release metformin formulations). 9. The method for treating diabetes as defined in claim 1 wherein said formulation contains metformin in a therapeutically effective amount which allows a patient a dosing regimen of at least one gram metformin, or a pharmaceutically acceptable salt thereof, once daily, while providing effective control of plasma glucose. 10. The method for treating diabetes as defined in claim 9 wherein said formulation provides for a dosing regimen of from about 1 to about 3 grams once daily. 11. The method for treating diabetes as defined in claim 9 wherein said inner solid particulate phase is in the form of discrete individual particles or granules and said outer solid continuous phase is a substantially continuous matrix having individual particles forming said inner solid particulate phase embedded therein and dispersed throughout. 12. The method for treating diabetes as defined in claim 9 wherein said formulation when ingested by a human reduces maximum attained plasma-metformin concentration (Cmax) by at least about 15% (relative to marketed rapid-release metformin formulations), and increases time to reach maximum metformin-plasma concentration (Tmax) by at least about 30% (relative to marketed rapid-release metformin formulations), while having an insignificant effect on area under the plasma-metformin concentration time curve (AUC) and % urinary recovery (UR) of the dose of metformin (relative to marketed rapid-release metformin formulations). 13. The method for treating diabetes as defined in claim 1 wherein said metformin is metformin (2:1) fumarate. 14. The method of treating diabetes as defined in claim 1 wherein said inner solid particulate phase of said formulation is present in a weight ratio to said outer solid continuous phase within the range from about 0.5:1 to about 4:1. 15. The method of treating diabetes as defined in claim 1 wherein said pharmaceutical is present in said inner solid particulate phase of said formulation in an amount within the range from about 10 to about 98% weight of said inner solid particulate phase. 16. The method for treating diabetes as defined in claim 1 wherein said extended release material present in said inner solid particulate phase of said formulation comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials; and said extended release material in said outer solid continuous phase of said formulation comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials. 17. The method for treating diabetes as defined in claim 16 wherein said extended release material present in said inner solid particulate phase comprises one or more ionic polymers and said extended release material present in said outer solid continuous phase comprises one or more non-ionic polymers. 18. The method for treating diabetes as defined in claim 17 wherein said ionic polymer comprises sodium alginate, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose, and said non-ionic polymer comprises hydroxypropylmethylcellulose 2208 USP, viscosity grade ranging from about 4000 to about 100,000 cps and/or hydroxypropylmethyl cellulose 2910 USP viscosity grade ranging from about 3 to about 150 cps. 19. The method for treating diabetes as defined in claim 1 wherein said inner solid particulate phase of said pharmaceutical formulation has a mean particle size within the range from about 30 .mu.m to about 0.8 mm. 20. The method for treating diabetes as defined in claim 1 wherein said inner solid particulate phase of said pharmaceutical formulation comprises metformin, metformin hydrochloride, metformin succinate (2:1) salt or metformin fumarate (2:1) salt, and ethyl cellulose and/or sodium carboxymethyl cellulose and/or glycerylmonostearate and said outer solid continuous phase comprises hydroxypropylmethylcellulose 2208 USP (100,000 cps), and/or hydroxypropylmethylcellulose 2910 USP (5 cps) and/or microcrystalline cellulose. 21. The method for treating diabetes as defined in claim 1 wherein said pharmaceutical formulation further comprises another antihyperglycemic agent and/or hypolipidemic agent. 22. The method for treating diabetes as defined in claim 21 wherein said other antihyperglycemic agent is a sulfonyl urea, a glucosidase inhibitor, a thiazolidenedione, insulin, or glucogon-like peptide-1. 23. The method for treating diabetes as defined in claim 21 wherein said other antihyperglycemic agent is glyburide, glipizide, pioglitazone or rosiglitazone. 24. The method for treating diabetes as defined in claim 21 wherein said hypolipidemic agent is an MTP inhibitor, a squalene synthetase inhibitor, and HMG CoA reductase inhibitor, a fibric acid derivative, an ACAT inhibitor, a cholesterol absorption inhibitor, an ileal Na.sup.+/ bile cotransporter inhibitor, a bile acid sequestrant and/or nicotinic acid or a derivative thereof. 25. The method for treating diabetes as defined in claim 21 wherein said hypolipidelmic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin. 26. The method for treating diabetes as defined in claim 21 wherein said metformin is present in a weight ratio to said other antihyperglycemic agent or hypolipidemic agent within the range from about 0.01:1 to about 300:1. 27. A method for treating diabetes comprising administering a pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of said inner solid particulate phase are dispersed and embedded, the particles of said inner solid particulate phase comprising (a) metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and said outer solid continuous phase comprising an extended release material, wherein said extended release material present in said inner solid particulate phase is different from the extended release material present in said outer solid continuous phase and wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation. 28. The method for treating diabetes as defined in claim 27 comprising administering said pharmaceutical formulation which is a biphasic heterogeneous controlled release formulation which is designed to release metformin from the particles forming said inner solid particulate phase through said outer solid continuous phase into the upper gastrointestinal tract. 29. The method for treating diabetes as defined in claim 27 wherein the metformin is metformin hydrochloride. 30. The method for treating diabetes as defined in claim 27 wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 30 to about 65% by weight of the pharmaceutical formulation. 31. The method for treating diabetes as defined in claim 27 wherein said inner solid particulate phase contains from about 5 to about 95% extended release material based on the weight of said inner solid particulate phase. 32. The method for treating diabetes as defined in claim 27 wherein said outer solid continuous phase contains from about 40 to about 100% extended release material based on the weight of said outer solid continuous phase. 33. The method for treating diabetes as defined in claim 27 wherein said inner solid particulate phase is in the form of discrete individual particles or granules and said outer solid continuous phase is a substantially continuous matrix having individual particles forming said inner solid particulate phase embedded therein and dispersed throughout. 34. The method for treating diabetes as defined in claim 27 wherein said metformin is metformin (2:1) fumarate. 35. The method of treating diabetes as defined in claim 27 wherein said inner solid particulate phase is present in a weight ratio to said outer solid continuous phase within the range from about 0.5:1, to about 4:1. 36. The method of treating diabetes as defined in claim 27 wherein said metformin is present in said inner solid particulate phase in an amount within the range from about 10 to about 98% by weight of the inner solid particulate phase. 37. The method of treating diabetes as defined in claim 27 wherein the extended release material present in said inner solid particulate phase comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials; and the extended release material in said outer solid continuous phase comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials. 38. The method of treating diabetes as defined in claim 37 wherein the extended release material present in the inner solid particulate phase comprises one or more ionic polymers and the extended release material present in said outer solid continuous phase comprises one or more non-ionic polymers. 39. The method of treating diabetes as defined in claim 38 wherein said ionic polymer comprises sodium alginate, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose, and said non-ionic polymer comprises hydroxypropylmethylcellulose 2208 USP, viscosity grade ranging from about 4000 to about 100,000 cps and/or hydroxypropylmethyl cellulose 2910 USP viscosity grade ranging from about 3 to about 150 cps. 40. The method of treating diabetes as defined in claim 27 wherein said inner solid particulate phase has a mean particle size within the range from about 30 mm to about 0.8 mm. 41. The method of treating diabetes as defined in claim 27 wherein said inner solid particulate phase comprises metformin, metformin hydrochloride metformin succinate (2:1) salt or metformin fumarate (2:1) salt, and ethyl cellulose and/or sodium carboxymethyl cellulose and/or glycerylmonostearate and said outer solid continuous phase comprises hydroxypropylmethylcellulose 2208 USP (100,000 cps), and/or hydroxypropylmethylcellulose 2910 USP (5 cps) and/or microcrystalline cellulose. 42. The method of treating diabetes as defined in claim 27 wherein said pharmaceutical formulation further comprises another antihyperglycemic agent and/or a hypolipidemic agent. 43. The method of treating diabetes as defined in claim 42 wherein said other antihyperglycemic agent is a sulfonyl urea, a glucosidase inhibitor, a thiazolidenedione, insulin, or glucogon-like peptide-1. 44. The method of treating diabetes as defined in claim 42 wherein the other antihyperglycemic agent is glyburide, glipizide, pioglitazone or rosiglitazone. 45. The method of treating diabetes as defined in claim 42 wherein said hypolipidemic agent is an MTP inhibitor, a squalene synthetase inhibitor, an HMG CoA reductase inhibitor, a fibric acid derivative, an ACAT inhibitor, a cholesterol absorption inhibitor, an ileal Na.sup.+/ bile cotransporter inhibitor, a bile acid sequestrant and/or nicotinic acid or a derivative thereof. 46. The method of treating diabetes as defined in claim 42 wherein said hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin. 47. The method of treating diabetes as defined in claim 27 wherein said formulation when ingested by a human reduces maximum attained plasma-metformin concentration (Cmax) by at least about 15% (relative to marketed rapid-release metformin formulations), and increases time to reach maximum metformin-plasma concentration (Tmax) by at least about 30% (relative to marketed rapid-release metformin formulations), while having an insignificant effect on area under the plasma-metformin concentration time curve (AUC) and % urinary recovery (UR) of the dose of metformin (relative to marketed rapid-release metformin formulations). 48. A method of lowering insulin resistance which comprises administering once daily to a mammalian patient in need of such treatment a therapeutically effective amount of a pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of said inner solid particulate phase are dispersed and embedded, the particles of said inner solid particulate phase comprising (a) a pharmaceutical having a high water solubility selected from metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and said outer solid continuous phase comprising an extended release material, wherein the total extended release material content in both said inner solid particulate phase and said outer continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation. 49. The method of lowering insulin resistance as defined in claim 48 wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 30 to about 65% by weight of the pharmaceutical formulation. 50. The method of lowering insulin resistance as defined in claim 48 wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 35 to about 60% by weight of the pharmaceutical formulation. 51. The method of lowering insulin resistance as defined in claim 48 wherein said formulation when ingested by a human reduces maximum attained plasma-metformin concentration (Cmax) by at least about 15% (relative to marketed rapid-release metformin formulations), and increases time to reach maximum metformin-plasma concentration (Tmax) by at least about 30% (relative to marketed rapid-release metformin formulations), while having an insignificant effect on area under the plasma-metformin concentration time curve (AUC) and % urinary recovery (UR) of the dose of metformin (relative to marketed rapid-release metformin formulations). 52. The method of lowering insulin resistance as defined in claim 48 wherein said extended release material present in said inner solid particulate phase comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials; and the extended release material in said outer solid continuous phase comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials. 53. The method of lowering insulin resistance as defined in claim 48 wherein said inner solid particulate phase of said pharmaceutical formulation comprises metformin, metformin hydrochloride, metformin succinate (2:1) salt or metformin fumarate (2:1) salt, and ethyl cellulose and/or sodium carboxymethyl cellulose and/or glycerylmonostearate and said outer solid continuous phase comprises hydroxypropylmethylcellulose 2208 USP (100,000 cps), and/or hydroxypropylmethylcellulose 2910 USP (5 cps) and/or microcrystalline cellulose. 54. The method of lowering insulin resistance as defined in claim 48 wherein said pharmaceutical formulation further comprises another antihyperglycemic agent and/or hypolipidemic agent. 55. A method of lowering insulin resistance which comprises administering to a mammalian patient in need of such treatment a therapeutically effective amount of a pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of said inner solid particulate phase are dispersed and embedded, the particles of the inner solid particulate phase comprising (a) metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and said outer solid continuous phase comprising an extended release material, wherein the extended release material present in said inner solid particulate phase is different from the extended release material present in said outer solid continuous phase and wherein the total extended release material content in both said inner solid particulate phase and said outer solid continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation. 56. The method of lowering insulin resistance as defined in claim 55 wherein the total extended release material content in both said inner solid particulate phase and said out solid continuous phase is within the range from about 30 to about 65% by weight of the pharmaceutical formulation. 57. The method of lowering insulin resistance as defined in claim 55 wherein the extended release material present in said inner solid particulate phase comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials; and the extended release material in said outer solid continuous phase comprises one or more hydrophilic polymers, and/or one or more hydrophobic polymers and/or one or more other hydrophobic materials. 58. The method of lowering insulin resistance as defined in claim 55 wherein said inner solid particulate phase comprises metformin, metformin hydrochloride, metformin succinate (2:1) salt or metformin fumarate (2:1) salt, and ethyl cellulose and/or sodium carboxymethyl cellulose and/or glycerylmonostearate and said outer solid continuous phase comprises hydroxypropylmethylcellulose 2208 USP (100,000 cps), and/or hydroxypropylmethylcellulose 2910 USP (5 cps) and/or microcrystalline cellulose. 59. The method of lowering insulin resistance as defined in claim 55 wherein said pharmaceutical formulation further comprises another antihyperglycemic agent and/or hypolipidemic agent. 60. The method of lowering insulin resistance as defined in claim 55 wherein said formulation when ingested by a human reduces maximum attained plasma-metformin concentration (Cmax) by at least about 15% (relative to marketed rapid-release metformin formulations), and increases time to reach maximum metformin-plasma concentration (Tmax) by at least about 30% (relative to marketed rapid-release metformin formulations), while having an insignificant effect on area under the plasma-metformin concentration time curve (AUC) and % urinary recovery (UR) of the dose of metformin (relative to marketed rapid-release metformin formulations).