Patent EA-003101-B1 (EA)
Title: Biphasic controlled release delivery system for high solubility pharmaceuticals and method
Inventor: TIMMINS PETER
IPC: A61K9/52
Filed: 1999-03-10
Abstract: 1. A pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of the inner solid particulate phase are dispersed and embedded, the particles of the inner solid particulate phase comprising (a) a pharmaceutical having a high water solubility; and (b) an extended release material, and the outer solid continuous phase comprising an extended release material, wherein a total amount of the extended release material in the inner solid particulate phase and simultaneously in the outer solid continuous phase is from about 25 to about 75% of the weight of said pharmaceutical formulation. 2. The pharmaceutical formulation as defined in Claim 1 which is a biphasic heterogeneous controlled release formulation which is designed to release a pharmaceutical from the particles forming the inner solid particulate phase through the outer solid continuous phase into the upper gastrointestinal tract. 3. The pharmaceutical formulation as defined in Claim 1 wherein the pharmaceutical is metformin hydrochloride. 4. The pharmaceutical as defined in Claim 1 wherein the inner solid particulate phase is in the form of discrete individual particles or granules and the outer solid continuous phase is a substantially continuous matrix having individual particles forming the inner solid particulate phase embedded therein and dispersed throughout. 5. The pharmaceutical formulation as defined in Claim 1 wherein the inner solid particulate phase is present in a weight ratio to the outer solid continuous phase within the range from about 0.5: 1, to about 4: 1. 6. The pharmaceutical formulation as defined in Claim 1 wherein the pharmaceutical is present in the inner solid particulate phase in an amount within the range from about 10 to about 98% by weight of the inner solid particulate phase. 7. The pharmaceutical formulation as defined in Claim 1 wherein the extended release material present in the inner solid particulate phase comprises one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more other type hydrophobic materials; and the extended release material in the outer solid continuous phase comprises one or more hydrophilic polymers, one or more hydrophobic polymers and/or one or more other type hydrophobic materials. 8. The pharmaceutical formulation as defined in Claim 1 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 the outer solid continuous phase comprises one or more nonionic polymers. 9. The pharmaceutical formulation as defined in Claim 1 wherein the ionic polymer comprises sodium alginate, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose, and the non-ionic polymer comprises hydroxypropylmethylcellulose 2910 USP, viscosity grade ranging from about 4000 to about 100,000 cps (from about 4 to about 100 Pa s) and hydroxypropylmethyl cellulose 2208 USP viscosity grade ranging from about 3 to about 150 cps (from about 3 mPa.s to about 0.15 Pa s) and/or microcrystalline collulose. 10. The pharmaceutical formulation as defined in Claim 1 wherein the inner solid particulate phase has a mean particle size within the range from about 30 Rm to about 0.8 mm. 11. The pharmaceutical formulation as defined in Claim 1 wherein the 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 the outer solid continuous phase comprises hydroxypropylmethylcellulose 2208 USP (100,000 cps=100 Pa s)), and/or hydroxypropylmethylcellulose 2910 USP (5 cps=5 mPa s)) and/or microcrystalline cellulose. 12. The pharmaceutical formulation as defined in Claim 1 wherein the pharmaceutical is a combination of metformin or a pharmaceutically acceptable salt thereof and another antihyperglycemic agent. 13. A method for preparing a biphasic controlled release delivery system, which comprises forming an inner solid particulate phase comprising individual particles comprising a pharmaceutical having a high water solubility and an extended release material and mixing the individual particles forming the inner solid particulate phase with an outer solid continuous phase comprising an extended release material to thereby disperse and embed the individual particles forming the inner solid particulate phase in the outer solid continuous phase. 14. A biphasic controlled release delivery system formed by the method as defined in Claim 13. 15. A method for treating diabetes which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of the formulation as defined in Claim 1.