Controlled absorption pharmaceutical composition

Claim 2

A controlled absorption verapamil containing pellet formulation for oral administration, characterised in that the pellet comprises: (i) a core of (a) a powder mixture containing verapamit or a pharmaceutically acceptable salt thereof and an organic acid selected from 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 pharmaceutically acceptable film-forming, water-insoluble polymer and a minor proportion of a pharmaceutically acceptable film-forming, water-soluble polymer, 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, preferably between 7 and 10 hours.

Claim 3

A controlled absorption verapamil containing pellet formulation for oral administration, characterised in that the pellet comprises: (i) a core of (a) a powder mixture containing verapamil or a pharmaceutically acceptable salt thereof and an organic acid selected from 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 pharmaceutically acceptable film-forming, water-insoluble polymer and a minor proportion of a pharmacutically acceptable film-forming, water-soluble polymer, the number of layers in said membrane and the ratio of said water-soluble polymers to said water-insoluble polymer 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 vitro as a dissolution rate of said pellet in a potassium chloride medium which, when measured in a basket assembly according to U.S. Pharmacopoeia XXI at 37° C, substantially corresponds to the following: a) from 0 to 250/0 of the total verapamil is released after one hour of measurement in said assembly; b) from 0 to 350/o of the total verapamil is released after four hours of measurement in said assembly; c) from 30 to 600/ 0 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 800/0 of the total verapamil is released after twenty-four hours of measurement in said assembly.

Claim 4

A controlled absorption verapamil containing pellet formulation for oral administration, characterised in that the pellet comprises: (i) a core of (a) a powder mixture containing verapamil or a pharmaceutically acceptable salt thereof and an organic acid selected from 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 pharmaceutically acceptable film-forming, water-insoluble polymer and a minor proportion of a pharmacutically acceptable film-forming, water-soluble polymer, the number of layers in said membrane and the ratio of said water-soluble polymers to said water-insoluble polymer 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 vitro as a dissolution rate of said pellet in a potassium chloride medium which, when measured in a basket assembly according to U.S. Pharmacopoeia XXI at 37° C, substantially corresponds to the following: a) from 0 to 250/0 of the total verapamil is released after one hour of measurement in said assembly; b) from 0 to 350/o of the total verapamil is released after four hours of measurement in said assembly; c) from 30 to 600/ 0 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 800/0 of the total verapamil is released after twenty-four hours of measurement in said assembly.

Claim 5

A pellet formulation according to Claim I or 2, characterised in that the verapamil or pharmaceutically acceptable salt thereof and organic acid are present in a ratio of from 1:1 to 10:1.

Claim 6

A pellet formulation according to any one of Claims I to 3, characterised in that the polymeric material of the core includes a major proportion of a polymer which is freely permeable to verapamil and water.

Claim 7

A pellet formulation according to any preceding claim, charactrised in that the polymeric material of the core includes a minor proportion of a polymer which is slightly permeable to verapamil and water.

Claim 8

A pellet formulation according to any one of Claims 1 to 3, characterised in that the water soluble polymer is selected from hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Claim 9

A pellet formulation according to Claim 4, characterised in that the polymeric material which is freely permeable to verapamil and water comprises a copolymer of acrylic and methacrylic acid esters.

Claim 10

A pellet formulation according to any one of Claims I to 3, characterised in that the water insoluble polymer is selected from methylcellulose, ethylcellulose, propylcellulose and shellac.

Claim 11

A pellet formulation according to Claim 5, characterised in that the polymer which is slightly permeable to verapamil and water comprises a copolymer of acrylic and methacrylic acid esters.

Claim 12

A pellet formulation according to any preceding claim, characterised in that the verapamil, organic acid and polymeric material are built up on an inert core.

Claim 13

II. A pellet formulation according to any preceding claim, characterised in that the core includes one or more additional components selected from a lubricant, a dispersing agent and a surfactant.

Claim 14

A pellet formulation according to any preceding claim, characterised in that the water insoluble polymer of the membrane is selected from shellac, cellulose acetate and ethylcellulose.

Claim 15

A pellet formulation according to Claim 12, characterised in that the water soluble polymer of the membran is selected from polyvinylpyrrolidone, polyvinylalcohol and hydroxypropylmethylcellulose.

Claim 16

A pellet formulation according to any one of Claims I to 12, characterised in that the 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.

Claim 17

A pellet formulation according to Claim 14, characterised in that each of the slightly permeable and freely permeable polymers comprises a copolymer of acrylic and methacrylic acid esters having the desired permeability characteristics.

Claim 18

A pellet formulation according to any one of Claims I to 12, characterised in that the multi-layer membrane is composed of a major proportion of a non-porous polymer and a minor proportion of a porous polymer.

Claim 19

A process for the production of a pellet formulation according to any one of Claims I to 16, characterised in that a core of verapamil or a pharmaceutically acceptable salt thereof and an organic acid is formed and in that the core is enclosed 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 I or 2.

Claim 20

A controlled absorption verapamil formulation for oral administration, characterised in that it comprises a blend of pellets as defined in Claim I 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 I without said multi-layer membrane.

Claim 21

A controlled absorption verapamil formulation for oral administration, characterised in that it comprises a blend of pellets as defined in any one of Claims 2 to 16 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 any one of Claims I to 16 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° 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 350/0 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 800/0 of the total verapamil is released after twenty-four hours of measurement in said assembly.

Claim 22

A pellet formulation according to Claim 18 or 19, characterised in that it contains up to 12.5% by weight of said rapid release form of verapamil.

Claim 23

A capsule or tablet comprising a formulation of pellets according to any one of Claims 18 to 20.