Slow-release preparation of diltiazem, and a medicine provided thereby

Abstract

The slow release preparation obtained by the method of the invention reduces the number of times the medicine needs to be taken per day, and also provides lower peaks of concentration in the blood after the medicine has been taken while simultaneously ensuring that the lowest concentration in the blood remains higher over a period of time.

We claim: . .1. A slow release acid-free Galenical preparation of pharmaceutically acceptable Diltiazem comprising microgranules of the type constituted by a central core coated with layers containing the active substance, with each microgranule having an outer membrane, the preparation being wherein its outer membrane is adapted to release the Diltiazem applied to the neutral core into an aqueous medium at the following rate measured using the method of the United States Pharmacopea No. 21: 
     
        insufficiency..!.. .    A medicine according to claim 1, comprising the microgranules contained in a unit preparation of the capsule type at a dose of between 100 mg and 500 mg of Diltiazem per unit and intended to be taken once a day for treating angina poctoris, hypertension, or peripheral or cerebral circulatory insufficiency..!.. .8. A medicine according to claim 7, including microgranules contained in a unit presentation of the capsule, sachet, or pill type, at a dose of 300 mg of Diltiazem per unit and intended to be taken once a day for treating hypertension..!.. .9. A medicine according to claim 6 or 7, wherein the equilibrium concentrations of Diltiazem obtained in the blood flow over a day lies substantially in the range 40 to 300 nanograms per milliliter of blood 
     
     
        sampled..!..Iadd.     A slow release acid-free Galenical preparation of pharmaceutically acceptable Diltiazem comprising microgranules of the type constituted by a central core coated with layers containing the active substance, with each microgranule having an outer membrane, the preparation being wherein its outer membrane is adapted to release the Diltiazem applied to the neutral core into an aqueous medium at the following rates measured using the method of the United States Pharmacopeia No. 21: (a) between 5% and 35% after one hour;   (b) between 15% and 40% after two hours;   (c) between 20% and 50% after three hours;   (d) between 30% and 75% after four hours;   (e) between 40% and 80% after six hours;   (f) between 55% and 95% after eight hours whereas said preparation comprises, relative to the total weight of microgranules, 8% to 15% by weight of neutral core, layers of Diltiazem comprising 60% to 85% by weight mixed with polyvinylpyrrolidone comprising 4% to 6% by weight, and 1% to 20% by weight outer membrane wherein the outer membrane includes, expressed in terms of total microgranule weight, 2% to 5% shellac and 1% to 3% ethylcellulose and 0% to 10% talc. .Iaddend..Iadd.11. A Galenical preparation according to claim 10 wherein the outer membrane is constituted by means of an organic solution of acetone or ethyl alcohol type containing shellac and ethylcellulose with 70 parts shellac to 30 parts ethylcellulose, said parts being parts by dry weight. .Iaddend..Iadd.12. A Galenical preparation according to claim 10 wherein the outer membrane of each microgranule includes not more than 10% talc, the percentage being relative to the total weight of microgranules. .Iaddend..Iadd.13. A Galenical preparation according to claim 11 wherein the Diltiazem is released into an aqueous medium as measured using the method of USP No. 21 at rates lying substantially between:   (a) 10% to 20% after one hour;   (b) 30% to 45% after four hours;   (c) 60% to 75% after eight hours. .Iaddend..Iadd.14. A medicine according to claim 10, comprising the microgranules contained in the unit preparation of the capsule type at a dose between 50 mg and 200 mg of Diltiazem per unit and intended to be taken twice a day for treating angina pectoris, hypertension, or peripheral or cerebral circulatory insufficiency. .Iaddend..Iadd.15. A medicine according to claim 10 comprising the microgranules contained in a unit preparation of the capsule type at a dose between 100 mg and 500 mg of Diltiazem per unit and intended to be taken once a day for treating angina pectoris, hypertension, or peripheral or cerebral circulatory insufficiency. .Iaddend..Iadd.16. A medicine according to claim 15 including microgranules contained in the unit presentation of the capsule, sachett, or pill type, at a dose of 300 mg of Diltiazem per unit and intended to be taken once a day for treating hypertension. .Iaddend..Iadd.17. A medicine according to claim 16 wherein the equilibrium concentrations of Diltiazem obtained in the blood flow over a day lies substantially in the range 40 to 300 nanograms per millimeter of blood sampled. .Iaddend..Iadd.18. A slow release acid-free Galenical preparation of pharmaceutically acceptable Diltiazem comprising microgranules of the type constituted by a central core coated with layers containing the active substance, with each microgranule having an outer membrane, the preparation being wherein its outer membrane is adapted to release the Diltiazem applied to the neutral core into an aqueous medium at the following rates measured using the method of the United States Pharmacopeia No. 21:   (a) between 5% and 35% after one hour;   (b) between 15% and 40% after two hours;   (c) between 20% and 50% after three hours;   (d) between 30% and 75% after four hours;   (e) between 40% and 80% after six hours;   (f) between 55% and 95% after eight hours whereas said preparation comprises, relative to the total weight of microgranules, 8% to 15% by weight of neutral core, layers of Diltiazem comprising 60% to 85% by weight mixed with polyvinylpyrrolidone comprising 4% to 6% by weight, and 1% to 20% by weight outer membrane, wherein the outer membrane includes, expressed in terms of total microgranule weight, 1% to 15% by weight ethylcellulose and 0.4% to 4% by weight plasticizer. .Iaddend..Iadd.19. A Galenical preparation according to claim 18 wherein the outer membrane is constituted by a plasticizer of the dibutylsebacate type inserted in an aqueous suspension having 30% percent ethylcellulose with 100 parts by weight ethylcellulose and 15 to 25 parts by weight plasticizer with the weights being expressed in terms of dry weight. .Iaddend..Iadd.20. A Galenical preparation according to claim 19 wherein the Diltiazem is released into an aqueous medium as measured using the method of USP No. 21 at a rate lying substantially between:   (a) 15% to 35% after one hour;   (b) 55% to 75% after four hours;   (c) 75% to 95% after eight hours. .Iaddend.a