| 主权项 |
1. A controlled release oral pharmaceutical formulation comprising a tablet consisting of a mixture of (A) extended release diltiazem pellets, and (B) a gel-forming material,
wherein (A) consists of:45-75% of the total weight of the tablet and is a heterogeneous population of extended release diltiazem pellets wherein the extended release diltiazem pellets comprise:
i) a pellet core comprising diltiazem; and ii) an extended release coating applied to the pellet core wherein the extended release coating controls the release of the drug from the pellet core so that the heterogeneous population of pellets exhibits a dissolution profile when tested in a USP Type 2 apparatus at 75 rpms, and 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) at 37° C.:
0-30% of the diltiazem is released after 2 hours;10-50% of the diltiazem is released after 4 hours;30-85% of the diltiazem is released after 8 hours;45-90% of the diltiazem is released after 12 hours;not less than 60% of the diltiazem is released after 16 hours;and not less than 70% of the diltiazem released after 20 hours; and (B) consists of:
(i) a polymer that can retain a fraction of imbibed fluid and exhibit a 2 to 50 fold volume increase selected from the group consisting of polyhydroxyalkylcellulose having a molecular weight greater than 50,000, poly(hydroxyalkylmethacrylate) having a molecular weight of from 5,000 to 5,0000,000, an acrylic acid polymer, a polymer of acrylic acid cross-linked with a polyalkyl ether of sucrose, and polyethylene oxide having a molecular weight of 100,000 to 5,000,000; and(ii) conventional processing excipients selected from fillers, lubricants, glidants, pigments, polishing agents and combinations of the foregoing; wherein the mixture of (A) and (B) is compressed into a tablet and the combination of the extended release coating on the extended release pellets and the polymer of the gel-forming material controls the release of the diltiazem from the tablet so the time of maximum blood plasma diltiazem concentration occurs about 10 to about 15 hours after administration of the tablet; and wherein the tablet exhibits a dissolution profile when tested in a USP Type 1 apparatus at 100 rpms, and 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) at 37° C.:
0-30% of the diltiazem is released after 1 hour;0-40% of the diltiazem is released after 4 hours;not less than 30% of the diltiazem is released after 12 hours; andnot less than 60% of the diltiazem is released after 24 hours; and wherein the polymer of the gel-forming material is 5-25% of the total weight of the tablet and the gel-forming material is free of flux enhancers selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfate, lithium sulfate, potassium acid phosphate, calcium lactate, tartaric acid, lactose, fructose, sucrose, mannitol, sorbitol and mixtures thereof and the tablet may optionally be coated with a water soluble seal coat, aesthetic coat, color coat or polishing coat. |
