Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor efficacy through administration of a controlled-porosity osmotic pump dosage form.
An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the beta-hydroxyacid form of simvastatin, a potent HMG-CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and Cmax that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia.
McClelland
G A
GA
INTERx Research Corporation, Merck Sharp & Dohme Research Laboratories, Lawrence, Kansas 66047.
Stubbs
R J
RJ
Fix
J A
JA
Pogany
S A
SA
Zentner
G M
GM
D000818:Animals; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004285:Dogs; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009997:Osmotic Pressure; D019821:Simvastatin; D012995:Solubility; D013607:Tablets
D003692:Delayed-Action Preparations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013607:Tablets; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin