Claims for Patent: 4,863,742

Summary for Patent: 4,863,742

Title:	Controlled absorption pharmaceutical composition
Abstract:	A controlled absorption verapamil containing pellet formulation for oral adminstration comprises a core of a powder mixture containing verapamil or a pharmaceutically acceptable salt thereof and an organic acid and a polymeric material, 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 and a multi-layer membrane surrounding said core, the number of layers in said membrane and the ratio of the various polymers comprising the membrane being effective to permit release of the verapamil from the pellet at a rate allowing controlled absorption thereof over a 24 hour period following oral administration, said rate being measured in vivo and having a Tmax between 6 and 16 hours.
Inventor(s):	Panoz; Donald E. (Tuckerstown, BM), Geoghegan; Edward J. (Westmeath, IE)
Assignee:	Elan Corporation PLC (Athlone, IE)
Application Number:	07/064,765
Patent Claims:	1. A controlled absorption verapamil containing pellet formulation for oral administration, said pellet comprising: (i) a core of (a) a powder mixture containing verapamil 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 or a mixture thereof, and (b) a polymeric material containing a major proportion of a pharmaceutically acceptable water soluble polymer and a minor proportion of a pharmaceutically acceptable water insoluble 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; and (ii) a multi-layer membrane surrounding said core and containing a major proportion of a pharmacuetically acceptable film-forming, water-insoluble polymer and a minor proportion of a pharmaceutically acceptable film-forming, water-soluble polymer; the ratio of said verapamil to said organic acid in the core, the number of layers in said membrane and the ratio of said water-soluble polymers to said water-insoluble polymers being effective to permit release of said verapamil from said pellet at a rate allowing controlled absorption thereof over a 24 hour period following oral administration, said rate being measured in vivo and having a Tmax between 6 and 16 hours. 2. A pellet formulation according to claim 1, which has a Tmax in vivo between 7 and 10 hours. 3. A controlled absorption verapamil containing pellet formulation for oral administration, said pellet comprising: (1) a core of (a) a powder mixture containing verapamil 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 or a mixture thereof, and (b) a polymeric material containing a major proportion of a pharamaceutically acceptable water soluble polymer and a minor proportion of a pharamaceutically acceptable water insoluble 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; and (ii) a multi-layer membrane surrounding said core and containing a major proportion of a pharamaceutically acceptable film-forming, water-insoluble polymer and a minor proportion of a pharmaceutically acceptable film-forming, water-soluble polymer; the ratio of said verapamil to said organic acid in the core, the number of layers in said membrane and the ratio of said water-soluble polymers to said water-insoluble polymers being effective to permit release of said verapamil from said pellet at a rate which is substantially pH independent and which allows controlled absorption thereof over a 24 hour period following oral administration, said rate being measured in vitro as a dissolution rate of said pellet in a potassium chloride medium which, when measured in a basket in a basket assembly according to U.S. Pharmacopoeia XXI at 37.degree. C., substantially corresponds to the following: (a) from 0 to 25% of the total verapamil is released after one hour of measurement in said assembly; (b) from 0 to 35% of the total verapamil is released after four hours of measurement in said assembly; (c) from 30 to 60% of the total verapamil is released after a total of eight hours of measurement in said assembly; (d) from 50 to 75% of the total verapamil is released after eleven hours of measurement in said assembly; and (e) not less than 80% of the total verapamil is released after twenty-four hours of measurement in said assembly. 4. A pellet formulation according to claim 1, wherein the verapamil or pharmaceutically acceptable salt thereof and organic acid are present in a ratio of from 1:1 to 10:1. 5. A pellet formulation according to claim 3, wherein the verapamil or pharmaceutically acceptable salt thereof and organic acid are present in a ratio of from 1:1 to 10:1. 6. A pellet formulation according to claim 1, wherein the polymeric material of the core includes a major proportion of a polymer which is freely permeable to verapamil and water. 7. A pellet formulation according to claim 3, wherein the polymeric material of the core includes a major proportion of a polymer which is freely permeable to verapamil and water. 8. A pellet formulation according to claim 6, wherein the polymeric material of the core includes a minor proportion of a polymer which is slightly permeable to verapamil and water. 9. A pellet formulation according to claim 7, wherein the polymeric material of the core includes a minor proportion of a polymer which is slightly permeable to verapamil and water. 10. A pellet formulation according to claim 1, wherein the water soluble polymer is selected from the group consisting of hydroxypropylmethylcellulose and polyvinylpyrrolidone. 11. A pellet formulation according to claim 6, wherein the polymeric material which is freely permeable to verapamil and water comprises a copolymer of acrylic and methacrylic acid esters. 12. A pellet formulation according to claim 7, wherein the polymeric material which is freely permeable to verapamil and water comprises a copolymer of acrylic and methacrylic acid esters. 13. A pellet formulation according to claim 1, wherein the water insoluble polymer is selected from the group consisting of methylcellulose, ethylcellulose, propylcellulose and shellac. 14. A pellet formulation according to claim 8, wherein the polymer which is slightly permeable to verapamil and water comprises a copolymer of acrylic and methacrylic acid esters. 15. A pellet formulation according to claim 9, wherein the polymer which is slightly permeable to verapamil and water comprises a copolymer of acrylic and methacrylic acid esters. 16. A pellet formulation according to claim 1, wherein the verapamil, organic acid and polymeric material are built up on an inert core. 17. A pellet formulation according to claim 3, wherein the verapamil, organic acid and polymeric material are built up on an inert core. 18. A pellet formulation according to claim 16, wherein the inert core is a non-pareil seed having an average diameter of from 0.3 to 0.7 mm. 19. A pellet formulation according to claim 17, wherein the inert core is a non-pareil seed having an average diameter of from 0.3 to 0.7 mm. 20. A pellet formulation according to claim 1, wherein the core includes one or more additional components selected from the group consisting of a lubricant, a dispersing agent and a surfactant. 21. A pellet formulation according to claim 3, wherein the core includes one or more additional components selected from the group consisting of a lubricant, a dispersing agent and a surfactant. 22. A pellet formulation according to claim 1, wherein the water insoluble polymer of the membrane is selected from the group consisting of shellac, cellulose acetate and ethylcellulose. 23. A pellet formulation according to claim 3, wherein the water insoluble polymer of the membrane is selected from the group consisting of shellac, cellulose acetate and ethylcellulose. 24. A pellet formulation according to claim 22, wherein the water soluble polymer of the membrane is selected from the group consisting of polyvinylpyrrolidone, polyvinylalcohol and hydroxypropylmethylcellulose. 25. A pellet formulation according to claim 23, wherein the water soluble polymer of the membrane is selected from the group consisting of polyvinylpyrrolidone, polyvinylalcohol and hydroxypropylmethylcellulose. 26. A pellet formulation according to claim 1, wherein multi-layer membrane is composed of a major proportion of a polymer which is slightly permeable to verapamil and water and a minor proportion of a polymer which is freely permeable to verapamil and water. 27. A pellet formulation according to claim 26, wherein each of the slightly permeable and freely permeable polymers comprises a copolymer of acrylic and methacrylic acid esters having the desired permeability characteristics. 28. A pellet formulation according to claim 1, wherein the multi-layer membrane is composed of a major proportion of a non-porous polymer and a minor proportion of a porous polymer. 29. A pellet formulation according to claim 1, which contains verapamil hydrochloride as the active ingredient. 30. A process for the production of a pellet formulation according to claim 1, which comprises forming a core of verapamil or a pharmaceutically acceptable salt thereof and an organic acid and enclosing the core in a membrane of a film-forming polymer or mixture thereof which permits release of the verapamil or a pharmaceutically acceptable salt thereof in the manner set out in claim 1. 31. A controlled absorption verapamil formulation for oral administration comprising a blend of pellets as defined in claim 1 in admixture with pellets of a rapid release form of verapamil to ensure a rapid attainment of effective therapeutic blood levels of verapamil within one hour following administration, said rapid release pellets comprising pellets as defined in claim 1 without said multi-layer membrane. 32. A controlled absorption verapamil formulation for oral administration comprising a blend of pellets as defined in claim 3 in admixture with pellets of a rapid release form of verapamil to ensure a rapid attainment of effective therapeutic levels of verapamil within one hour following administration, said rapid release pellets comprising pellets as defined in claim 3 without said multi-layer membrane the formulation having a dissolution rate which is substantially pH independent and which when measured in a basket assembly according to U.S. Pharmacopoeia XXI at 37.degree. C. has the following characteristics: (a) from 10 to 25% of the total verapamil is released after one hour of measurement in said assembly; (b) from 20 to 35% of the total verapamil is released after four hours of measurement in said assembly; (c) from 35 to 60% of the total verapamil is released after eight hours of measurement in said assembly; (d) from 50 to 75% of the total verapamil is released after eleven hours of measurement in said assembly; and (e) not less than 80% of the total verapamil is released after twenty-four hours of measurement in said assembly. 33. A pellet formulation according to claim 31, which contains up to 12.5% by weight of said rapid release form of verapamil. 34. A pellet formulation according to claim 32, which contains up to 12.5% by weight of said rapid release form of verapamil. 35. A capsule or tablet comprising a formulation of pellets according to claim 31. 36. A capsule or tablet comprising a formulation of pellets according to claim 32. 37. A method of treating or controlling blood pressure in a subject suffering from mild to moderate hypertension, comprising administering to said subject on a once per day basis a dose effective to lower the blood pressure of said subject, of a verapamil-containing controlled absorption formulation comprising effective amounts of a first component formulated to provide an effective blood pressure lowering amount of verapamil within one hour following administration and a second component formulated to provide a maximum blood pressure lowering effect within 6 to 16 hours following administration, wherein said formulation contains up to 12.5% by weight of said first component. 38. A method of controlling or preventing angina attacks or reducing the incidence of angina attacks in a subject suffering from angina pectoris, comprising administering to said subject on a once per day basis a dose effective to improve the blood supply and hence increase the oxygen supply in the myocardium of said subject, of a verapamil-containing controlled absorption formulation comprising effective amounts of a first component formulated to provide an amount of verapamil effective to increase the oxygen supply to the myocardium within one hour following administration and a second component formulated to provide a maximum supply of oxygen to the myocardium within 6 to 16 hours following administration, wherein said formulation contains up to 12.5% by weight of said first component.