EP0320097A1 — Controlled absorption diltiazem formulations

Claim 1

Independent Claim 236 words

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.

Claim 2

Dependent Claim 236 words

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.

Claim 3

Dependent Claim 161 words

A controlled absorption diltiazem pellet formulation according to Claim 1, wherein the release of diltiazem from said pellet is at a rate following 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.

Claim 4

Dependent Claim 161 words

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.

Claim 5

Dependent Claim 123 words

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 th-c 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.

Claim 6

Dependent Claim 123 words

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.

Claim 7

Dependent Claim 120 words

A controlled absorption diltiazem pellet formulation according to any one of Claims 1 to 5, wherein the core comprises: a) a powder mixture containing diltiazem or a pharmaceutically acceptable salt thereof, an organic acid selected from 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.

Claim 8

Dependent Claim 50 words

A controlled absorption diltiazem pellet formulation according to any one of Claims 1 to 6, wherein the water soluble polymer in the core or membrane is the same or different and is selected from polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose or polyethylene glycol or a mixture thereof.

Claim 9

Dependent Claim 49 words

A controlled absorption diltiazem pellet formulation according to any one of Claims 1 to 6, 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.

Claim 10

Dependent Claim 97 words

A controlled absorption diltiazem pellet formulation according to any one of Claims 1 to 8, wherein the water insoluble polymer in the core or membrane is selected from 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 terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) or polyurethane or a mixture thereof.

Claim 11

Dependent Claim 49 words

A controlled absorption diltiazem pellet formulation according to any one of Claims 1 to 8, wherein the water insoluble polymer in the core or membrane is replaced by a polymeric material which is slightly permeable to diltiazer and water and comprises a copolymer of acrylic and methacrylic acid esters.

Claim 12

Dependent Claim 85 words

A process for the production of a controlled absorption diltiazem pellet formulation according to any one of Claims 1 to 10, 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 any one of Claims 1 to 5.

Claim 13

Dependent Claim 182 words

A controlled absorption diltiazem formulation for oral administration comprising pellets according to any one of Claims 1 to 3 or any one of Claims 6 to 10 when dependent on any one of Claims 1 to 3, 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 dissoluticn 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.

Claim 14

Dependent Claim 59 words

A controlled absorption formulation for oral administration comprising pellets according to any one of Claims 1 to 10 and 12, further comprising an ACE-inhibitor or a pharmaceutically acceptable salt thereof, said ACE-inhibitor preferably being selected from 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.

Claim 15

Dependent Claim 39 words

Use of diltiazem or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the control of hypertension and the symptoms of angina over a twenty-four hour period following administration of a single therapeutically effective dose thereof.

Claim 16

Dependent Claim 39 words

Use of diltiazem or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the control of hypertension and the symptoms of angina over a twenty-four hour period following administration of a single therapeutically effective dose thereof.

Claim 17

Dependent Claim 30 words

Use according to Claim 14, wherein there is administered once-daily in combination or concomitantly with the diltiazem or pharmaceutically acceptable salt thereof a single therapeutically effective dose of an ACE-inhibitor.

Controlled absorption diltiazem formulations

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