Enhanced release of lidocaine from supersaturated solutions of lidocaine in a pressure sensitive adhesive.

摘要

Transdermal drug delivery systems consisting of a pressure sensitive adhesive (PSA) supersaturated with drug have been studied with the objective of enhancing drug release. Lidocaine (LC) and Duro-TakRTM87-2287 (PSA) were the model components. In vitro release of drug through a composite membrane consisting of multiple layers of cellulose membrane and a silicone membrane was significantly higher from supersaturated LC/PSA systems compared to systems in which drug had crystallized. Drug loading was an important factor influencing the release of lidocaine from the prototype transdermal delivery systems. The DT2287 PSA hydrated when in contact with water, and the presence of LC accelerated this process. Slow crystallization was also observed during the drug release experiments and was highly dependent on the hydration state of the drug/PSA systems. This suggests that hydration of drug/PSA systems may be an important factor in drug release when water is present. e.g., from the stratum corneum when a transdermal system occludes the skin, and may account for the non-Fickian release of LC from these systems.; The physical stability of the systems was evaluated kinetically and thermodynamically using thermal analysis and then applying theories of nucleation, e.g., the Fisher-Turnbull equation; and phase transformation, e.g., the Avrami equation. From this analysis nucleation rather than the crystal growth process appears to govern the crystallization of LC from the supersaturated LC/PSA systems. Nucleation is a diffusion-controlled process, which is therefore closely dependent on the viscoelastic properties of the PSA medium. Nonetheless some of the thermodynamic features of the crystallization of LC in drug/PSA systems, i.e., Tcrit, were retained from crystalline LC. Crystallization of LC in the PSA systems also had a two-phase temperature dependence with the values of key kinetic parameters, such as the Avrami exponent and the Avrami constant, remaining constant over a low temperature range. Over a higher temperature range, however, the crystallization behavior of LC cannot be explained by the conventional Avrami theory, and a new hypothesis has been proposed suggesting that the nucleation rate increased exponentially with time. To reconcile the apparent differences between the classical theory of nucleation and the proposed hypothesis, a two-step nucleation process is suggested. (Abstract shortened by UMI.)