Gregory A. McClelland

The Solubility-Modulated Osmotic Pump: In Vitro/in Vivo Release of Diltiazem Hydrochloride

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem · HC1 as a model drug. Diltiazem · HC1 has an aqueous solubility >590 mg/ml (37°C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ ml; 37°C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of >80% of an initial diltiazem · HC1 load. Devices were prepared with cores that contained diltiazem · HC1 and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of ∼75% of the initial diltiazem HC1 load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.

Controlled porosity solubility- and resin-modulated osmotic drug delivery systems for release of diltiazem hydrochloride

Abstract The drug release kinetics from controlled porosity osmotic pumps have been effectively manipulated through application of either solubility- or resin-modulation methods. The solubility of diltiazem hydrochloride was modulated (reduced) for an extended period of 12–14 h through incorporation of controlled release sodium chloride elements into the core tablet formulations. Other diltiazem hydrochloride core tablets were prepared which contained the positively charged anion-exchange resin (poly(4-vinylpyridine). In both instances, in vitro diltiazem hydrochloride release profiles that were zero-order and pH-independent were obtained without chemical modification of the drug. Release from devices that contained neither solubility- nor resin-modulation components was substantially first-order and highly pH-dependent. Solubility-modulated devices administered to dogs released diltiazem hydrochloride with similar in vivo/in vitro kinetics. These approaches may be applied in general to extend osmotic pump technology to drugs with intrinsic water solubilities that are too high or low for conventional osmotic pump formulations.

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.

Evaluation of Sustained/Controlled-Release Dosage Forms of 3-Hydroxy-3-methylglutaryl–Coenzyme A (HMG-CoA) Reductase Inhibitors in Dogs and Humans

Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.