Development of Dermal Lidocaine Nanosuspension Formulation by the Wet Milling Method Using Experimental Design: In Vitro/In Vivo Evaluation.

Lidocaine (LID), frequently used in dermal applications, is a nonpolar local anesthetic agent that is practically insoluble in water. The main aim of this study is to develop the nanosuspension formulation of LID using the design of experiments (DoE). The improved solubility and dissolution rate provided by nanosizing are expected to result in enhanced dermal bioavailability. Nanosuspension formulations were developed by a wet media milling method using different stabilizer types [poloxamer (POL) and poly(vinyl alcohol) (PVA)]. Characterization studies of the nanosuspensions were carried out using DSC, FTIR, XRD, and SEM in vitro release from the dialysis membrane and ex vivo permeation studies using rat skin were performed. Analgesic/anesthetic effects were evaluated using the tail-flick test in in vivo studies. Particle size (PS), polydispersity index (PDI), and zeta potential (ZP) values were found as 171.7 ± 3.52 nm, 0.251 ± 0.036, and -32.2 ± 0.907 mV for POL/LID nanosuspensions and 262.1 ± 29.42 nm, 0.453 ± 0.071, and -20.2 ± 3.50 mV for PVA/LID nanosuspensions, respectively. Compared to the coarse suspension of LID, it was determined that it accumulated in the skin approximately 1.81 times more in the POL/LID nanosuspension formulation and 1.79 times more in the PVA/LID nanosuspension formulation. According to analgesic effect and related AUC data, nanosuspension formulation was found to be statistically more effective than coarse suspension. It is concluded that DoE is a useful tool in determining process parameters when developing nanosuspensions by the wet media milling method, and POL is a suitable nonionic polymer to stabilize nanosuspensions.