Combination of ion-pair strategy and chemical enhancers for design of dexmedetomidine long-acting patches: Dual action mechanism induced longer controlled release and better delivery efficiency

The purpose of this study was to prepare a dexmedetomidine (Dex) 72 h long-acting patch by the combined use of ion-pair strategy and chemical enhancers (CEs), and to investigate molecular mechanisms of drug-loading enhancement and controlled release. The formulation of patch was optimized by single-factor investigation and Box-Behnken design. The pharmacokinetics, analgesic pharmacodynamics and irritation of the formulation were evaluated, respectively. Moreover, the effects of ion-pairs and CEs on the patch were characterized by DSC, rheology study, FTIR, and molecular docking, and the effects on the skin were evaluated by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR), Raman study, and molecular dynamics, respectively. The optimized formulation was 17.00 % (w/w) Dex-NA (Naphthoic acid), 7.20 % Polyglyceryl-3 dioleate (POCC), 25-AAOH as pressure sensitive adhesives (PSA) and 66.50 μm in thickness. Compared with the control group (Cmax = 62.02 ± 16.55 ng/mL, MRT0-t = 26.74 ± 1.27 h), the pharmacokinetics behavior of the optimization group was more stable and durable (Cmax = 31.22 ± 13.26 ng/mL, MRT0-t = 33.62 ± 1.62 h). Besides, it also showed good analgesic effect and no obvious irritation. The results indicated that Dex-NA both increased the drug-PSA interactions and inhibited the penetration of the drug into the skin. POCC increased the molecular mobility of the PSA and disrupted skin lipids thereby improving the drug penetration rate. In summary, the Dex long-acting patch was developed, which provided a reference for the combined application of ion-pair strategy and CEs in other long-acting transdermal delivery.