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Claims for Patent: 5,439,689

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Claims for Patent: 5,439,689

Title: Diltiazem formulation
Abstract:The present invention is directed to a diltiazem formulation suitable for one a day administration. The formulation contains a blend of diltiazem beads having two differing dissolution profiles.
Inventor(s): Hendrickson; Dennis L. (Overland Park, KS), Dimmitt; Dan C. (Belton, MO), Williams; Mark S. (Kansas City, MO), Skultety; Paul F. (Leawood, KS), Baltezor; Michael J. (Lees Summit, MO)
Assignee: Carderm Capital L.P. (CH)
Application Number:08/164,062
Patent Claims: 1. A method of treating cardiovascular disorders with a diltiazem formulation suitable for a once-a-day oral administration comprising:

administering an effective amount of a diltiazem formulation having A) a rapid release component and B) a delayed release component;

A) wherein said rapid release component comprises:

1) a diltiazem 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 first suitable polymeric coating material which substantially envelops said diltiazem core so that said diltiazem exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37.degree. C. in 0.1N HCl 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) wherein said delayed release component comprises:

1) a diltiazem 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 polymeric coating material which substantially envelops said diltiazem core so that said diltiazem exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII, at 37.degree. C. in 0.1N HCl at 100 rpm:

a) from 0-45% of total diltiazem is released after 12 hours of measurement in said apparatus;

b) from 0-75% of total diltiazem is released after 18 hours of measurement in said apparatus, and

c) not less than 40% of total diltiazem is released after 24 hours of measurement in said apparatus,

wherein said diltiazem formulation 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 measurement in said apparatus;

c) from 35-70% of total diltiazem is released after 18 hours 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.

2. The method according to claim 1 wherein said second polymeric coating of said delayed release component contains from 10-75 w/w % of polymerized acrylate based upon the total weight of the delayed release component.

3. The method according to claim 2 wherein said second polymeric coating comprises from 15-50 w/w % of the delayed release component.

4. The method according to claim 3 wherein 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.

5. The method according to claim 4 wherein said second polymeric coating contains a plasticizer in the range of 5-15 w/w % based upon the total weight of the polymeric coating.

6. The method according to claim 5 wherein said plasticizer is tributyl citrate and acetyl tributyl citrate.

7. The method according to claim 6 wherein said second polymeric coating comprises about 25 w/w % of the total weight of the delayed release component.

8. The method according to claim 7 wherein 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 neutral monomers wherein the ratio of copolymer a) to copolymer b) is 95:5.

9. The method according to claim 8 wherein said delayed release component 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.

10. The method according to claim 1 wherein said rapid release component 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.

11. The method according to claim 10 wherein said first polymeric coating of said rapid release component 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.

12. The method according to claim 11 wherein said first polymeric coating comprises from 10-15 w/w % of the total weight of the rapid release component.

13. The method according to claim 1 wherein said diltiazem formulation 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.

14. A delayed release diltiazem formulation suitable for oral administration comprising:

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 polymeric coating material which substantially envelops said diltiazem core so that said diltiazem exhibits the following in-vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII, at 37.degree. C. in 0.1N HCl at 100 rpm:

a) from 0-5% of total diltiazem is released after 12 hours of measurement in said apparatus;

b) from 0-20% of total diltiazem is released after 18 hours of measurement in said apparatus;

c) from 50-90% of total diltiazem is released after 24 hours of measurement in said apparatus, and,

d) from 80-100% of total diltiazem is released after 30 hours of measurement in said apparatus.

15. A diltiazem formulation according to claim 14 wherein said polymeric coating contains from 10-75 w/w % of polymerized acrylate based upon the total weight of the formulation.

16. A diltiazem formulation according to claim 15 wherein said polymeric coating comprises from 15-50 w/w % of the total weight of the formulation.

17. A diltiazem formulation according to claim 16 wherein 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.

18. A diltiazem formulation according to claim 17 wherein said polymeric coating contains a plasticizer in the range of 5-15 w/w % based upon the total weight of the polymeric coating.

19. A diltiazem formulation according to claim 18 wherein said plasticizer is tributyl citrate and-acetyl tributyl citrate.

20. A diltiazem formulation according to claim 19 wherein said polymeric coating comprises about 25 w/w % of the total weight of the formulation.

21. A diltiazem formulation according to claim 20 wherein said 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 neutral monomers wherein the ratio of copolymer a) to copolymer b) is 95:5.

22. The method according to claim 1 wherein said delayed release component exhibits the following in-vitro dissolution profile in 0.1N HCl:

a) from 0-15% of total diltiazem is released after 12 hours of measurement 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.
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