Stefano A. Pogany

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 β-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 hy-percholesterolemia.

Improving the intestinal mucosal cell uptake of water insoluble compounds

A significant increase in intestinal mucosal cell uptake rate can be achieved by making brush border enzyme-labile derivatives of water insoluble compounds. The test compounds chosen were decanol, hexadecanol, their corresponding lysinate esters, hydrocortisone and its phosphate and succinate esters. Intestinal perfusion and intestinal ring uptake experiments in the alcohol study demonstrated that prodrug uptake was comparable to uptake of the free alcohol below the solubility of the parent compound; i.e., there was little or no loss in intestinal permeability. Prodrug uptake continued to increase linearly above the solubility of the free alcohol in the ring system. Similar results were obtained for hydrocortisone and its prodrugs when uptake was examined in the intestinal ring system; furthermore, rapid post-incubation freezing of the tissue coupled with an HPLC assay capable of separating drug from prodrug permitted determination of the species absorbed. In all cases, only free alcohol was detected in the tissue. Histological studies verified the integrity of intestinal tissue under experimental conditions. The in vitro technique is advantageous for screening drug absorption. The very substantial potential of this prodrug approach is demonstrated in particular with hexadecanol and hexadecyl lysinate, where the uptake rate of the prodrug was four orders of magnitude greater than that of the free alcohol.

Gas chromatographic assay for 3,9-diethylidene-2,4,8,10 tetraoxaspiro[5.5]undecane

Abstract A gas chromatographic method was developed, based on a reference standard, for analysis of the reactive diketene acetal 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU). The method is based on the conversion of DETOSU to 3,9-diethyl-3,9-dimethoxy-2,4,8,10-tetraoxaspiro[5.5]undecane, a stable ortho ester.