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Claims for Patent: 5,002,776

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Claims for Patent: 5,002,776

Title: Controlled absorption diltiazem formulations
Abstract:A controlled absorption 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 optionally 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, when said water soluble polymer is present, being effective to permit release of diltiazem from the pellet at a rate allowing controlled absorption thereof over not less than a twelve hour period following oral administration. The pellet has a dissolution rate in vitro which when measured in a dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 results in not more than 35% of the total diltiazem being released after 2 hours of measurement. Not more than 60% of the total diltiazem is released after four hours of measurement and 100% of the diltiazem is released no earlier than after 8 hours of measurement in said apparatus.
Inventor(s): Geoghegan; Edward J. (Athlone, IE), Mulligan; Seamus (Athlone, IE), Panoz; Donald E. (Tuckers Town, BM)
Assignee: Elan Corporation, PLC (Athlone, IE)
Application Number:07/273,192
Patent Claims: 1. A controlled absorption diltiazem pellet formulation for oral administration, said pellet comprising a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, the diltiazem component and the organic acid being present in a ratio of from 50:1 to 1:1, and a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer, the number of layers in said membrane and the ratio of said water soluble to water insoluble polYmer, when said water soluble polymer is present, being effective to permit release of said diltiazem from said pellet at a rate allowing controlled absorption thereof over, on the average, not less than a twelve hour period following oral administration, said rate being measured in vitro as a dissolution rate of said pellet, which when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 substantially corresponds to the following dissolution pattern:

a) no more than 35% of the total diltiazem is released after 2 hours of measurement in said apparatus;

b) no more than 60% of the total diltiazem is released after 4 hours of measurement in said apparatus; and

c) 100% of the diltiazem is released no earlier than after 8 hours of measurement in said apparatus.

2. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the release of diltiazem from said pellet is at a rate allowing controlled absorption thereof over a twenty-four hour period following oral administration, said rate being measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 which substantially corresponds to the following dissolution pattern:

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

b) from 0 to 45% of the total diltiazem is released after 4 hours of measurement in said apparatus;

c) from 10 to 75% of the total diltiazem is released after 8 hours of measurement in said apparatus;

d) from 25 to 95% of the total diltiazem is released after 13 hours of measurement in said apparatus; and

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

3. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the release of diltiazem from said pellet is at a rate allowing controlled absorption thereof over a twenty-four hour period following oral administration, said rate being measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 which substantially corresponds to the following dissolution pattern:

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

b) from 5 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 8 hours of measurement in said apparatus;

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

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

4. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the release of diltiazem from said pellet is at a rate allowing controlled absorption thereof over a twelve hour period following oral administration, said rate being measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 which substantially corresponds to the following dissolution pattern:

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

b) from 35 to 85% of the total diltiazem is released after 6 hours of measurement in said apparatus; and

c) 100% of the total diltiazem is released no earlier than after 8 hours of measurement in said apparatus.

5. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the release of diltiazem from said pellet is at a rate allowing controlled absorption thereof over a twelve hour period following oral administration, said rate being measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 which substantially corresponds to the following dissolution pattern:

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

b) from 55 to 80% of the total diltiazem is released after 6 hours of measurement in said apparatus; and

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

6. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the diltiazem or pharmaceutically acceptable salt thereof and organic acid are present in a ratio of from 10:1 to 2:1.

7. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the core comprises:

a) a powder mixture containing diltiazem or a pharmaceutically acceptable salt thereof, 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, said core comprising layers of said powder mixture and said polymeric material superimposed one upon the other and said polymeric material being present in an amount effective to ensure that all of said powder mixture is coated into said core.

8. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the water soluble polymer in the core or membrane is the same or different and is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethylene glycol or a mixture thereof.

9. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the water soluble polymer in the core or membrane is replaced by a polymeric material which is freely permeable to diltiazem and water and comprises a copolymer of acrylic and methacrylic acid esters.

10. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the water insoluble polymer in the core or membrane is selected 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(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 terephtalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and polyurethane or a mixture thereof.

11. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the water insoluble polymer in the core or membrane is replaced by a polymeric material which is slightly permeable to diltiazem and water and comprises a copolymer of acrylic and methacrylic acid esters.

12. A controlled absorption diltiazem pellet formulation according to claim 1, wherein the diltiazem, organic acid and polymeric material are built up on an inert core comprising a non-pareil seed of sugar/starch having an average diameter in the range 0.4-0.8 mm.

13. A controlled absorption diltiazem pellet formulation according to claim 1, which contains diltiazem hydrochloride as the active ingredient.

14. A process for the production of a controlled absorption diltiazem pellet formulation according to claim 1, which comprises forming a core of diltiazem, or a pharmaceutically acceptable salt thereof, an organic acid and other optional components and enclosing the core in a membrane of a film-forming polymer or mixture thereof as defined in claim 1 which permits release of the diltiazem or the pharmaceutically acceptable salt thereof in the manner set out in claim 1.

15. A controlled absorption diltiazem formulation for oral administration comprising pellets according to claim 1 for once-daily administration, said formulation including a sufficient quantity of a rapid release form of diltiazem so as to have a dissolution rate which when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 substantially corresponds to the following dissolution pattern:

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

b) from 10 to 60% of the total diltiazem is released after 4 hours of measurement in said apparatus;

c) from 30 to 90% of the total diltiazem is released after 8 hours of measurement in said apparatus;

d) from 60 to 100% of the total diltiazem is released after 13 hours of measurement in said apparatus; and

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

16. A controlled absorption formulation for oral administration comprising pellets according to claim 1, further comprising an ACE-inhibitor or a pharmaceutically acceptable salt thereof.

17. A controlled absorption formulation for oral administration comprising pellets according to claim 1, further comprising an ACE-inhibitor selected from the group consisting of captopril, fosenopril, enalapril, ramipril, zofenopril, quinapril, cilazapril, spirapril, lisinopril, delapril, pivalopril, fentiapril, indolapril, alacepril, tiapamil (N-(3,4-dimethoxyphenethyl)-3-[2-(3,4-dimethoxyphenyl)-1 3-dithian-2-yl]-N-methylpropylamine 1,1,3,3-tetraoxide), pentopril, rentiapril and perindopril.

18. A controlled absorption formulation for oral administration comprising pellets according to claim 1, further comprising an ACE-inhibitor selected from the group consisting of captopril and enalapril.

19. A controlled absorption diltiazem formulation comprising pellets according to claim 1 for once-daily administration, said formulation including a sufficient quantity of a rapid release form of diltiazem so as to have a dissolution rate which when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 substantially corresponds to the following dissolution pattern:

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

b) from 10 to 60% of the total diltiazem is released after 4 hours of measurement in said apparatus;

c) from 30 to 90% of the total diltiazem is released after 8 hours of measurement in said apparatus;

d) from 60 to 100% of the total diltiazem is released after 13 hours of measurement in said apparatus; and

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

further comprising an ACE-inhibitor or a pharmaceutically acceptable salt thereof.

20. A capsule or tablet formulation comprising pellets according to claim 1.
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