Development of long-acting rivastigmine drug-in-adhesive patch utilizing ion-pair strategy and characterization of controlled release mechanism

Abstract

The purpose of present study was to develop a long-acting drug-in-adhesive patch of rivastigmine (RVS) to achieve controlled release under high drug loading. Formulation factors including ion-pair, pressure sensitive adhesive (PSA), drug-loading and permeation enhancers were investigated through in vitro skin permeation experiments. Optimized patch was evaluated by pharmacokinetic study. The mechanism of controlled release was studied by FTIR, Raman, DSC, rheology study and molecular modeling. The optimized patch composed of RVS-SA (equal to 30% RVS), 15% POCC as permeation enhancer and AAOH as PSA matrix. The RVS in optimized patch was basically permeated at a uniform rate, and the ratio of the skin permeation amount (2803.38 ± 153.85 μg/cm2) in 72 hours to that of the control group (1000.89 ± 62.45 μg/cm2) was 2.8. The plasma concentration of RVS was stable for 72 hours in vivo (AUCoptimized = 5721.30 ± 1994.87 h ng/mL, MRT0-t = 29.55 ± 2.49 h), and Cmax was significantly controlled. The results of the study on the controlled release mechanism showed that the addition of counter ion formed hydrogen bonds with RVS and PSA respectively, which reduced the fluidity and molecular mobility of PSA, and enhanced the interaction between RVS and PSA, thus achieving the purpose of long-acting effect. In conclusion, long-acting drug-in-adhesive patch of RVS was developed, and provided a new idea for the long term drug delivery of Alzheimer's disease.