US5286497A — Diltiazem formulation

Claim 1

Independent Claim 380 words

A diltiazem formulation suitable for once-a-day oral administration comprising a blend of: A) a sufficient quantity of rapid release diltiazem beads which further comprise 1) a diltiazem core containing an effective amount of diltiazem of a pharmaceutically acceptable salt thereof, optionally in association with pharmaceutically acceptable excipients and; 2) a sufficient quantity of a first suitable polymeric coating material which substantially envelops said diltiazem core so that said diltiazem bead exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37° C. at 100 rpm: a) from 0-40% of total diltiazem is released after 3 hours of measurement in said apparatus, and; b) from 30-100% of total diltiazem is released after 6 hours of measurement in said apparatus, and; B) a sufficient quantity of delayed release diltiazem beads which further comprise: 1) a central core containing an effective amount of diltiazem or a pharmaceutically acceptable salt thereof, optionally in association with pharmaceutically acceptable excipients, and; 2) a sufficient quantity of a second suitable polymeric coating material which substantially envelops said diltiazem core so that said diltiazem bead exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII, at 37° C. in 0.1N HCl at 100 rpm: a) from 0-15% of total diltiazem is released after 12 hours in said apparatus; b) from 0-45% of total diltiazem is released after 18 hours of measurement in said apparatus, and; c) not less than 45% of total diltiazem is released after 24 hours of measurement in said apparatus, wherein said blend exhibits the following in-vitro dissolution pattern when measured in a type 2 dissolution apparatus (paddle), according to U.S. Pharmacopeia XXII, in 0.1N HCl at 100 rpm: a) from 20-45% of total diltiazem is released after 6 hours of measurement in said apparatus; b) from 25-50% of total diltiazem is released after 12 hours of measurement in said apparatus; c) from 35-70% of total diltiazem is released after 18 hours of measurement in said apparatus; d) not less than 70% of total diltiazem is released after 24 hours of measurement in said apparatus; and e) not less than 85% of total diltiazem is released after 30 hours of measurement in said apparatus.

Claim 2

Dependent Claim 380 words

A diltiazem formulation suitable for once-a-day oral administration comprising a blend of: A) a sufficient quantity of rapid release diltiazem beads which further comprise 1) a diltiazem core containing an effective amount of diltiazem of a pharmaceutically acceptable salt thereof, optionally in association with pharmaceutically acceptable excipients and; 2) a sufficient quantity of a first suitable polymeric coating material which substantially envelops said diltiazem core so that said diltiazem bead exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37° C. at 100 rpm: a) from 0-40% of total diltiazem is released after 3 hours of measurement in said apparatus, and; b) from 30-100% of total diltiazem is released after 6 hours of measurement in said apparatus, and; B) a sufficient quantity of delayed release diltiazem beads which further comprise: 1) a central core containing an effective amount of diltiazem or a pharmaceutically acceptable salt thereof, optionally in association with pharmaceutically acceptable excipients, and; 2) a sufficient quantity of a second suitable polymeric coating material which substantially envelops said diltiazem core so that said diltiazem bead exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII, at 37° C. in 0.1N HCl at 100 rpm: a) from 0-15% of total diltiazem is released after 12 hours in said apparatus; b) from 0-45% of total diltiazem is released after 18 hours of measurement in said apparatus, and; c) not less than 45% of total diltiazem is released after 24 hours of measurement in said apparatus, wherein said blend exhibits the following in-vitro dissolution pattern when measured in a type 2 dissolution apparatus (paddle), according to U.S. Pharmacopeia XXII, in 0.1N HCl at 100 rpm: a) from 20-45% of total diltiazem is released after 6 hours of measurement in said apparatus; b) from 25-50% of total diltiazem is released after 12 hours of measurement in said apparatus; c) from 35-70% of total diltiazem is released after 18 hours of measurement in said apparatus; d) not less than 70% of total diltiazem is released after 24 hours of measurement in said apparatus; and e) not less than 85% of total diltiazem is released after 30 hours of measurement in said apparatus.

Claim 3

Dependent Claim 43 words

A diltiazem formulation according to claim 1 in which said second polymeric coating of said delayed release diltiazem bead contains from 10-75 w/w % of polymerized acrylate based upon the total weight of the polymeric coating of a dried delayed release diltiazem bead.

Claim 4

Dependent Claim 29 words

A diltiazem formulation according to claim 2 in which said second polymeric coating comprises from 15-50 w/w % of the total weight of a dried delayed release diltiazem bead.

Claim 5

Dependent Claim 36 words

A diltiazem formulation according to claim 3 in which said polymerized acrylate is a copolymer of ethyl acrylate and methyl methacrylate which contains trimethylammoniumethyl methacrylate in a range of about 1:40 relative to the neutral monomers.

Claim 6

Dependent Claim 39 words

A diltiazem formulation according to claim 4 in which said second polymeric coating contains a plasticizer in the range of 5-15 w/w % based upon the total weight of the polymeric coating of a dried delayed release diltiazem bead.

Claim 7

Dependent Claim 18 words

A diltiazem formulation according to claim 5 in which said plasticizer is tributyl citrate and acetyl tributyl citrate.

Claim 8

Dependent Claim 29 words

A diltiazem formulation according to claim 6 in which said second polymeric coating comprises about 25 w/w % of the total weight of a dried delayed released diltiazem bead.

Claim 9

Dependent Claim 74 words

A diltiazem formulation according to claim 7 in which said second polymeric coating contains a) a copolymer of ethyl acrylate and methyl methacrylate which contains trimethylammoniumethyl methacrylate in a range of about 1:40 relative to the neutral monomers and b) a copolymer of ethyl acrylate and methyl methacrylate which contains trimethylammoniumethyl methacrylate in a range of about 1:20 relative to the neutral monomers wherein the ratio of copolymer a) to copolymer b) is 95:5.

Claim 10

Dependent Claim 87 words

A diltiazem formulation according to claim 8 wherein said delayed release diltiazem bead exhibits the following in-vitro dissolution profile in 0.1N HCl: a) from 0-5% of total diltiazem is released after 6 hours of measurement in said apparatus, b) from 0-10% of total diltiazem is released after 12 hours of measurement in said apparatus, c) from 0-35% of total diltiazem is released after 18 hours of measurement in said apparatus, and, d) from 50-90% of total diltiazem is released after 24 hours of measurement in said apparatus.

Claim 11

Dependent Claim 55 words

A diltiazem formulation according to claim 1 in which said rapid release diltiazem bead exhibits the following dissolution rate: a) from 0-20% of total diltiazem is released after 3 hours of measurement in said apparatus, and; b) from not less than 50% of total diltiazem is released after 6 hours of measurement in said apparatus.

Claim 12

Dependent Claim 80 words

A diltiazem formulation according to claim 10 in which said first polymeric coating of said rapid release diltiazem bead contains a) a copolymer of ethyl acrylate and methyl methacrylate which contains trimethylammoniumethyl methacrylate in a range of about 1:40 relative to the neutral monomers and b) a copolymer of ethyl acrylate and methyl methacrylate which contains trimethylammoniumethyl methacrylate in a range of about 1:20 relative to the neutral monomers wherein the ratio of copolymer a) to copolymer b) is 95:5.

Claim 13

Dependent Claim 28 words

A diltiazem formulation according to claim 11 wherein said first polymeric coating comprises from 10-15 w/w % of the total weight of a dried rapid release diltiazem bead.

Claim 14

Dependent Claim 83 words

A diltiazem formulation according to claim 1 wherein said blend exhibits the following in-vitro dissolution profile: a) from 25-40% of total diltiazem is released after 6 hours of measurement in said apparatus; b) from 30-45% of total diltiazem is released after 12 hours of measurement in said apparatus; c) from 40-65% of total diltiazem is released after 18 hours of measurement in said apparatus; and d) not less than 75% of total diltiazem is released after 24 hours of measurement in said apparatus.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1997-02-14	1997-08-16	1998-02-15	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2001-02-14	2001-08-16	2002-02-15	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2005-02-14	2005-08-16	2006-02-15	$7700.00	Window Closed / Lapsed

Diltiazem formulation

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