Gerald S. Rork

The controlled porosity osmotic pump

Abstract The zero-order release of water soluble, osmotically active agents from tablets coated with controlled porosity walls has been investigated. The walls were sponge-like in appearance and substantially permeable to both water and dissolved solutes. The rate of release was a function of the wall thickness, level of leachable additives incorporated and permeability of the polymer component of the walls, the total solubility of the core tablet, the drug load, and the osmotic pressure difference across the wall. Release was insensitive to the pH and degree of agitation in the receptor media. Release was primarily due to an osmotic pump mechanism. Steady-state release rates were calculated from basic water and solute permeabilities of the walls and correlated with actual device performance. The concept of osmotically actuated drug delivery on an equivalent mass per unit surface area basis was demonstrated and extended, as well, to multiparticulate dosage forms.

Osmotic flow through controlled porosity films: An approach to delivery of water soluble compounds☆

Abstract The zero-order release of water soluble, osmotically active agents from tablets coated with controlled porosity walls has been investigated. The walls were sponge-like in appearance and substantially permeable to both water and dissolved solutes. Mechanical strengths of the walls were measured. The rate of release was a function of the wall thickness, level of leachable additives incorporated and permeability of the polymer component of the walls, the total solubility of the core tablet, the drug load, and the osmotic pressure difference across the wall. Release was insensitive to the pH and degree of agitation in the receptor media. Release was primarily due to an osmotic pump mechanism. Steady-state release rates were calculated from basic water and solute permeabilities of the walls and correlated with actual device performance. The concept of osmotically actuated drug delivery on an equivalent mass per unit surface area basis was demonstrated and extended, as well, to multiparticulate dosage forms.

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.

Systemic delivery of timolol after dermal application: Transdermal flux and skin irritation potential in the rat and dog.

Timolol, a beta-adrenergic antagonist, was evaluated for transdermal flux with rat skin in vitro and with the dog in vivo. Skin irritation after dermal application of timolol was assessed in the rat in vivo. Drug flux across rat skin in vitro ranged between 2 and 110 µg cm−2 hr−1, dependent on the formulation. The transdermal flux of timolol in the dog was greater than 10 µg cm−2 hr−1. This estimate was based on the degree of antagonism of isoproterenol challenge following transdermal administration of timolol relative to that obtained following intravenous administration of timolol. Irritation was observed in the rat after occluded dermal application of timolol free base but was not observed when the concentration of the drug in the formulation was decreased.

Surface wetting effects in the lipid osmotic pump

Abstract An osmotically driven system for the controlled release of lipoidal drugs is described. The system consists of a solid, low melting core surrounded by a semipermeable membrane that controls the rate of drug release. The core contains the drug, a lipid carrier, and an osmotic agent. In operation, water passes through the semipermeable membrane, interacts with the osmotic agent, and increases the pressure within the system, which forces the lipid carrier and drug through orifices in the coating. For this system to pump the lipid carrier rather than the osmotic agent solution, the semipermeable membrane must be preferentially wetted by the lipid phase rather than the aqueous phase containing the osmotic agent. A technique is described for measuring contact angles as an indication of the surface wetting properties of cellulose acetate films in order to predict which membranes might selectively pump the lipid phase in a coated tablet. The results from the contact angle measurements show good correlation with actual tablet performance.

An in vitro drug release rate method for lipoidal materials

Abstract A multiparticulate preparation of an osmotically mediated, controlled release system for lipoidal materials is described. Spherical beads containing a lipid carrier, an osmotic agent and a lipid soluble model drug were made and a microporous, polymeric coating applied. When placed in an aqueous medium, the coated beads controllably released first the lipid carrier (containing the model drug), then the osmotic agent. A technique is described for measuring the in vitro release rate profile of the lipoidal components of the beads using microporous polypropylene films. Sorption of the lipoidal components by the film occurred following release from the beads in an aqueous medium. Films were removed at specific times for analysis. The lipoidal components were extracted from the film with ethanol and the model drug content determined by spectrophotometry. This technique may be useful for other systems requiring release rate/dissolution testing of lipoidal agents in an aqueous medium.