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Details for Patent: 5,616,345

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Details for Patent: 5,616,345

Title: Controlled absorption diltiazen formulation for once-daily administration
Abstract:A diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of the diltiazem from the pellet at a rate allowing controlled absorption thereof over a twenty four hour period following oral administration.
Inventor(s): Geoghegan; Edward J. (Athlone, IE), Mulligan; Seamus (Gainesville, GA), Panoz; Donald E. (Tuckerstown, BM)
Assignee: Elan Corporation PLC (Athlone, IE)
Filing Date:Nov 04, 1994
Application Number:08/334,864
Claims:1. A process for the production of a diltiazem pellet formulation for oral administration comprising:

a) forming a core of diltiazem or a pharmaceutically acceptable salt thereof and an organic acid having a diltiazem to organic ratio of from 20:1 to 1:1;

b) enclosing the core in a membrane containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer, having a release of said diltiazem from said pellet formulation at a rate allowing controlled absorption thereof over a 24-hour period following oral administration, said rate being measured in vitro in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05M KCl at a pH 7.0 and at 100 r.p.m. and substantially corresponding to the following dissolution pattern:

1) from 0 to 35% of the total diltiazem is released after 2 hours of measurement in said apparatus;

2) from 5 to 45% of the total diltiazem is released after 4 hours of measurement in said apparatus;

3) from 30 to 75% of the total diltiazem is released after a total of 8 hours of measurement in said apparatus;

4) from 60 to 95% of the total diltiazem is released after 13 hours of measurement in said apparatus; and

5) not less than 85% of the total diltiazem is released after 24 hours of measurement in said apparatus.

2. The process of claim 1 further comprising the organic acid being selected from the group consisting of adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid.

3. The process according to claim 1 further comprising the step of forming a core comprising:

a) a powder mixture containing diltiazem or a pharmaceutically acceptable salt thereof and an organic acid selected from the group consisting of adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid; and

b) a polymeric material containing a major proportion of a pharmaceutically acceptable water soluble synthetic polymer and a minor proportion of a pharmaceutically acceptable water insoluble synthetic polymer.

4. The process according to claim 1 further comprising the water soluble polymer being selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyhnethyl cellulose and polyethylene glycol or a mixture thereof.

5. The process according to claim 1 further comprising replacing the water soluble polymer with a polymeric material which is freely permeable to diltiazem and water and comprising a copolymer of acrylic and methacrylic acid esters.

6. The process according to claim 1 further comprising selecting the water insoluble polymer from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate ), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and polyurethane or a mixture thereof.

7. The process according to claim 1 further comprising the step of replacing the water insoluble polymer by a polymeric material which is not freely permeable to diltiazem and water and comprises a copolymer of acrylic and methaerylic acid esters.

8. The process according to claim 3 further comprising the step of coating the diltiazem, organic acid and polymeric material on an inert core.

9. The process according to claim 1 further comprising the step of including a quantity of a rapid release form of diltiazem.

10. The process according to claim 9 further comprising the diltiazem formulation having a dissolution rate which when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05M Kcl at pH 7.0 and at 100 r.p.m. and substantially corresponding to the following:

a) from 5 to 35% of the total diltiazem is released after 2 hours of measurement in said apparatus;

b) from 10 to 45% of the total diltiazem is released after 4 hours of measurement in said apparatus;

c) from 30 to 75% of the total diltiazem is released after a total of 8 hours of measurement in said apparatus;

d) from 60 to 95% of the total diitiazem is released after 13 hours of measurement in said apparatus; and

e) not less than 85% of the total diitiazem is released after 24 hours of measurement in said apparatus.

11. The process according to claim 1 further comprising formulating the pellets in a capsule or tablet.

12. The process according to claim 9 further comprising formulating the pellets as a capsule or tablet.
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