In Vitro Evaluation of the Release of Albuterol Sulfate from Polymer Gels: Effect of Fatty Acids on Drug Transport Across Biological Membranes

Abstract

ABSTRACTIn this investigation, the diffusion of the beta2 agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37°C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel® (hydroxypropylcellulose) and Methocel® (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel®. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of ˜0.09 mg/hr cm2 was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6–14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.