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Claims for Patent: 4,894,240

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Claims for Patent: 4,894,240

Title: Controlled absorption diltiazem 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 (Athlone, IE), Panoz; Donald E. (Tuckerstown, BM)
Assignee: Elan Corporation plc (Athlone, IE)
Application Number:07/121,225
Patent Claims: 1. A diltiazem pellet formulation for oral administration, said pellet comprising a core to 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 20:1 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 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 being effective to permit release of said diltiazem from said pellet at a rate allowing controlled absorption thereof over a twenty four 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 0.05M KCl at pH 7.0 and at 100 r.p.m. 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 a total of 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.

2. A pellet formulation according to claim 1, wherein the organic acid is selected from the group consisting of one or more of the following acids: adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid.

3. A 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.

4. A pellet formulation according to claim 1, wherein the diltiazem or pharmaceutically acceptable salt thereof and organic acid are present in a ratio of 5:1 to 3:1.

5. A pellet formulation according to claim 1, wherein the core includes a lubricant selected from the group consisting of one or more of the following: sodium stearate, magnesium stearate, stearic acid and talc.

6. A pellet formulation according to claim 5, wherein the diltiazem and lubricant are present in a ratio of from 5:1 to 100:1.

7. A 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 pellet formulation according to claim 7, wherein the water soluble polymer 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 pellet formulation according to claim 7, wherein the water soluble polymer 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 pellet formulation according to claim 7, wherein the water insoluble polymer 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(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.

11. A pellet formulation according to claim 7, wherein the water insoluble polymer 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 pellet formulation according to claim 7, wherein the diltiazem, organic acid and polymeric material are built up on an inert core.

13. A pellet formulation according to claim 12, wherein the inert core is a non-pareil bead or seed of sugar/starch having an average diameter in the range 0.4-0.8 mm.

14. A pellet formulation according to claim 1, wherein the core includes one or more additional components selected from the group consisting of a dispersing agent, aglidant and a surfactant.

15. A pellet formulation according to claim 1, wherein the water insoluble polymer of the 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(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.

16. A pellet formulation according to claim 1, wherein the water soluble polymer of the membrane is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethylene glycol or a mixture thereof.

17. A pellet formulation according claim 1, wherein the water insoluble polymer of the membrane is replaced by a major proportion of a polymer which is slightly permeable to diltiazem and water and the water soluble polymer of the membrane is replaced by a minor proportion of a polymer which is freely permeable to diltiazem and water.

18. A pellet formulation according to claim 17, wherein each of the slightly permeable and freely permeable polymers comprises a copolymer of acrylic and methacrylic acid esters having the desired permeability characteristics.

19. A pellet formulation according to claim 1, which includes a plasticizing agent selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and an acetylated monoglyceride.

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

21. A controlled absorption diltiazem formulation for oral administration comprising pellets as claimed in claim 1, 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 0.05M KCl at pH 7.0 and at 100 r.p.m. substantially corresponds to the following:

(a) from 5 to 35% of the total diltiazem is released after 2 hours of measurement in saio 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 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.

22. A controlled absorption diltiazem formulation according to claim 21, wherein up to 25% by weight of the formulation is the rapid release form of diltiazem.

23. A controlled absorption diltiazem formulation according to claim 22, wherein the rapid release form of diltiazem comprises 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 20:1 to 1:1.

24. A capsule or tablet comprising a formulation of pellets according to claim 1.

25. A capsule or tablet comprising a formulation of pellets according to claim 21.

26. A 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 20:1 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 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 being effective to permit release of said diltiazem from said pellet at a rate allowing controlled absorption thereof over a twenty four hour period following oral administration, said rate being measured in vivo and having a Tmax between 10 and 14 hours.

27. A pellet formulation according to claim 26 wherein Tmax is between 12 and 14 hours.

28. A 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 20:1 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 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 being effective to permit release of said diltiazem from said pellet at a rate allowing controlled absorption thereof over a twenty four 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 0.05M KCl at pH 7.0 and at 100 r.p.m. substantially corresponds to a dissolution pattern wherein after a total of 8 hours of measurement in said apparatus from 30 to 75% of the total diltiazem is released from said pellet and wherein after a total of 24 hours of measurement in said apparatus not less than 85% of the total diltiazem is released from said pellet.
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