Long acting formulation

Claim 1

A method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker selected from amlodipine, darodipine, floridipine, iodipine, isrodipine, mesudipine, nilvadipine, oxodipine, riodipine, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-[3-(4-[2-(tetrahydropyran-2-yloxy)ethyl]phenoxy)propoxycarbonyl]1,4-dihydropyridine, methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-l,4-dihydropyridine-3-carboxylate, 1,4-dihydro-2-hydroxymethyl-4-(m-nitrophenyl)-6-methyl-3,5-pyridine dicarboxylic acid diethyl ester, methyl (E)-3-phenyl-2 - propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, (E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester monohydrochloride, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine, 3,5-pyridinedicarboxylic acid 2-(((aminocarbonyl)oxy)methyl)-4-(2,3-dichlorophenyl)-1,4-dihydro-6-methyl-5-methyl-3-(1-methylethyl)ester, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and pharmaceutically acceptable salts thereof, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids.

Claim 2

A method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker selected from amlodipine, darodipine, floridipine, iodipine, isrodipine, mesudipine, nilvadipine, oxodipine, riodipine, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-[3-(4-[2-(tetrahydropyran-2-yloxy)ethyl]phenoxy)propoxycarbonyl]1,4-dihydropyridine, methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-l,4-dihydropyridine-3-carboxylate, 1,4-dihydro-2-hydroxymethyl-4-(m-nitrophenyl)-6-methyl-3,5-pyridine dicarboxylic acid diethyl ester, methyl (E)-3-phenyl-2 - propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, (E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester monohydrochloride, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine, 3,5-pyridinedicarboxylic acid 2-(((aminocarbonyl)oxy)methyl)-4-(2,3-dichlorophenyl)-1,4-dihydro-6-methyl-5-methyl-3-(1-methylethyl)ester, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and pharmaceutically acceptable salts thereof, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids.

Claim 5

The method of any one of claims 1 to 3 in which the pH-dependent binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester.

Claim 20

A method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker selected from amlodipine, darodipine, floridipine, iodipine, isrodipine, mesudipine, nilvadipine, oxodipine, riodipine, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-[3-(4-[2-(tetrahydropyran-2-yloxy)ethyl]phenoxy)propoxycarbonyl]1,4-dihydropyridine, methyl 2.6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate, 1,4-dihydro-2-hydroxymethyl-4-(m-nitrophenyl)-6-methyl-3,5-pyridine dicarboxylic acid diethyl ester, methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, (E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester monohydrochloride, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine, 3,5-pyridiredicarboxylic acid 2-(((aminocarbonyi)oxy)methy))-4-(2.3-dichlorophenyl)-1,4-dihydro-6-methyl-5-methyl-3-(1-methylethyl)ester, 1-ben2yi-3-pyrroiidinyi methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and pharmaceutically acceptable salts thereof, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids.

Claim 21

A method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker selected from amlodipine, darodipine, floridipine, iodipine, isrodipine, mesudipine, nilvadipine, oxodipine, riodipine, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-[3-(4-[2-(tetrahydropyran-2-yloxy)ethyl]phenoxy)propoxycarbonyl]1,4-dihydropyridine, methyl 2.6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate, 1,4-dihydro-2-hydroxymethyl-4-(m-nitrophenyl)-6-methyl-3,5-pyridine dicarboxylic acid diethyl ester, methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, (E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester monohydrochloride, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine, 3,5-pyridiredicarboxylic acid 2-(((aminocarbonyi)oxy)methy))-4-(2.3-dichlorophenyl)-1,4-dihydro-6-methyl-5-methyl-3-(1-methylethyl)ester, 1-ben2yi-3-pyrroiidinyi methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and pharmaceutically acceptable salts thereof, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids.

Claim 24

The method of any one of claims 1 to 3 in which the pH-dependent binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester.

Claim 25

The method of any one of claims 1 to 4 in which essentially spherical, non-coated, non-rugose particles having diameters up to 1.2 millimeters, comprised of an effective amount of calcium channel blocker in intimate admixture with at least about 3 weight percent of a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH are prepared.

Claim 27

The method of claims 5 or 6 in which at least 70 weight percent of the spherical particles have diameters which are within upper and lower limits which differ by not more than a factor of the square root of two from each other.

Claim 28

The method of any one of claims 5 to 7 in which the binder is substantially insoluble at a pH of less than about 4.5 and is soluble at a pH of greater than about 5.5.

Claim 29

The method of any one of claims 5 to 9 in which the spherical particles comprise: from 1 to 50 weight percent calcium channel blocker; and from 5 to 95 weight percent binder.

Claim 30

The method of any one of claims 1 to 9 in which a dosage form consisting essentially of an inert pharmaceutical carrier is provided in which is contained: (a) a long acting pharmaceutical composition for prolonged administration of a dihydropyridine calcium channel blocker prepared as in any one of claims 1 to 9 in combination with (b) a fast release pharmaceutical composition for administration of a loading dose of the calcium channel blocker, wherein the relative proportions of long acting pharmaceutical composition and fast release pharmaceutical composition are in the range of 50:50 to 100:0.