Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors and HMG-CoA reductase
View Patent ↗A solid amorphous dispersion comprises a cholesteryl ester transfer protein (CETP) inhibitor, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase inhibitor), and a concentration enhancing polymer. At least a major portion of the CETP inhibitor in the dispersion is amorphous. The solid amorphous dispersion provides concentration-enhancement of the CETP inhibitor when administered to an aqueous use environment.
1. A composition consisting of a solid amorphous dispersion, said dispersion consisting of
(1) a cholesteryl ester transfer protein (CETP) inhibitor,
(2) an acid sensitive HMG-CoA reductase inhibitor, and
(3) a concentration-enhancing polymer selected from the group consisting of neutral polymers, neutralized acidic polymers, and mixtures thereof;
wherein at least 60 wt % of each of said CETP inhibitor and said HMG-CoA reductase inhibitor in said dispersion is amorphous, and said dispersion has a relative degree of improvement in chemical stability of said HMG-CoA reductase inhibitor of at least about 1.1 relative to a control composition consisting essentially of a solid amorphous dispersion of said CETP inhibitor, said HMG-CoA reductase inhibitor, and the acidic polymer hydroxypropyl methyl cellulose acetate succinate, wherein at least a major portion of both said CETP inhibitor and said HMG-CoA reductase inhibitor in said control composition is amorphous.
2. The composition of claim 1 wherein at least 90 wt % of said HMG-CoA reductase inhibitor is amorphous.
3. The composition of claim 1 wherein at least 90 wt % of said CETP inhibitor is amorphous.
4. The composition of claim 1 wherein said CETP inhibitor in said dispersion is substantially homogeneous.
5. The composition of claim 1 wherein said dispersion has at least one glass-transition temperature intermediate that of a glass-transition temperature of said CETP Inhibitor and a glass-transition temperature of said concentration-enhancing polymer.
6. The composition of claim 1 further comprising a base.
7. The composition of claim 1 wherein said concentration-enhancing polymer is a neutral polymer selected from the group consisting of polyvinyl pyrrolidone, poloxamers, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose acetate, and blends thereof.
8. The composition of claim 1 wherein said concentration-enhancing polymer is a neutralized form of an acidic polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, and blends thereof.
9. The composition of claim 1 wherein said CETP inhibitor is selected from the group consisting of [2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester (torcetrapib), [2R,4S]-4[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, and (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol, (2R,4R,4aS)-4-[amino-(3,5-bis-(trifluoromethyl-phenyl)-methyl]-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1-carboxylic acid isopropyl ester, S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate, trans-4-[[[2-[[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2H-tetrazol-5-yl)amino]methyl]-4-(trifluoromethyl)phenyl]ethylamino]methyl]-cyclohexaneacetic acid, and trans-4-[[[2-[[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2H-tetrazol-5-yl)amino]methyl]-5-methyl-4-(trifluoromethyl)phenyl]ethylamino]methyl]-cyclohexaneacetic acid.