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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.

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.

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.

Preparation des acyloxyalkyl α-ethers, du phenol, pyrocatechol, benzenethiol et oestra-17β diol, par reaction de ces phenols avec des chlorures ou iodures d'α-acyloxyalkyle dans l'acetone en presence de K 2 CO 3

Hydrocortisone-21-lysinate was synthesized as an amino acid prodrug of hydrocortisone to serve as a substrate for brush border aminopeptidases. This strategy was developed to demonstrate that an improvement in oral absorption could be obtained through reconversion in vivo. The aqueous stability of hydrocortisone-21-lysinate was studied over the pH range 3-8 at 25 degrees C. Reversible acyl migration of the lysine group between the 21- and 17-position hydroxyl groups was observed as well as hydrolysis. The observed half-life for direct hydrolysis of hydrocortisone-21-lysinate is 40 d at pH 3 and 30 min at pH 7. The relative instability at pH 7 is probably due to electrostatic stabilization of the negatively charged tetrahedral intermediate by the protonated amino groups.

Synthese par reaction de fluorure de Ag (I) avec le bromo-2 stearate de methyle dans une solution aqueuse d'acetonitrile

Synthese par reaction de fluorure de Ag (I) avec le bromo-2 stearate de methyle dans une solution aqueuse d'acetonitrile

Lithio ethyl acetate is a superior reagent for the transformation of 1H-2-benzopyran-1-ones to naphthoates.