STABLE FORMULATIONS OF ACE INHIBITORS, AND METHODS FOR PREPARATION THEREOF
The present invention provides stable formulations of ACE inhibitors, especially enalapril maleate, that can be manufactured in a time efficient, cost effective manner. Such formulations can be prepared simply and on a large industrial scale. The present invention also provides methods for the preparation of stable formulations of ACE inhibitors, especially enalapril maleate.
1 . A method of preparing a stable formulation of quinapril hydrochloride which comprises the steps of:
dispersing or dissolving a metal compound in an alcohol to form a metallic alcoholic dispersion;
mixing quinapril hydrochloride into said metallic alcoholic dispersion; and mixing until a clear solution is attained, the stable formulation being substantially free of hydrolytic breakdown products after incubation at 60° C. with 75% relative humidity for 10 days.
2 . The method of claim 61 wherein said alcohol comprises ethanol and water.
3 . The method of claim 61 wherein said metal compound is selected from the group consisting of sodium bicarbonate, sodium hydroxide, and sodium hydrogen carbonate.
4 . The method of claim 61 wherein said metal is an alkali metal.
5 . The method of claim 61 wherein said metal is an alkali earth metal.
6 . The method of claim 61 further comprising adding at least one excipient to said metallic alcoholic dispersion to prior to the mixing of said quinapril hydrochloride into said metallic alcoholic dispersion.
7 . The method of claim 66 further comprising adding an antioxidant to said clear solution.
8 . The method of claim 67 wherein said antioxidant is selected from the group consisting of butyl hydroxyl anisol, butyl hydroxyl toluene, maleic acid, and ascorbic acid.
9 . The method of claim 66 wherein said excipient comprises microcrystalline cellulose.
10 . The method of claim 66 further comprising blending the excipient and the clear solution to form a granulate.
11 . The method of claim 70 further comprising drying the granulate.
12 . The method of claim 71 further comprising adding a lubricant to the dried granulate.
13 . The method of claim 72 wherein the lubricant is a sterate.
14 . The method of claim 73 wherein the stearate is magnesium stearate or glycerol monostearate.
15 . The stabilized formulation of claim 14 which contains less than 5% breakdown products by weight of the quinapril hydrochloride formulation after incubation at 60° C. with 75% relative humidity for 10 days.
16 . The stabilized formulation of claim 16 which contains less than 2.5% breakdown products by weight of the quinapril hydrochloride formulation after incubation at 60° C. with 75% relative humidity for 10 days.
17 . The stabilized formulation of claim 17 which contains less than 1% breakdown products by weight of the quinapril hydrochloride formulation after incubation at 60° C. with 75% relative humidity for 10 days.
18 . A stabilized formulation of quinapril hydrochloride prepared in accordance with claim 13 .
19 . The stabilized formulation of claim 19 which contains less than 5% quinaprilat and quinapril-DKP by weight of the quinapril hydrochloride formulation after incubation at 60° C. with 75% relative humidity for 10 days.
20 . The stabilized formulation of claim 20 which contains less than 2.5% quinaprilat and quinapril-DKP by weight of the quinapril hydrochloride formulation after incubation at 60° C. with 75% relative humidity for 10 days.
21 . The stabilized formulation of claim 21 which contains less than 1% quinaprilat and quinapril-DKP by weight of the quinapril maleate formulation after incubation at 60° C. with 75% relative humidity for 10 days.