Preparation and Characterization of Lidocaine-Loaded, Microemulsion-Based Topical Gels

Abstract

Microemulsion-based gels (MBGs) were prepared for transdermal delivery of lidocaine and evaluated for their potential for local anesthesia. Lidocaine solubility was measured in various oils, and phase diagrams were constructed to map the concentration range of oil, surfactant, cosurfactant, and water for oil-in-water (o/w) microemulsion (ME) domains, employing the water titration method at different surfactant/cosurfactant weight ratios. Refractive index, electrical conductivity, droplet size, zeta potential, pH, viscosity, and stability of fluid o/w MEs were evaluated. Carbomer^® 940 was incorporated into the fluid drug-loaded MEs as a gelling agent. Microemulsion-based gels were characterized for spreadability, pH, viscosity, and in-vitro drug release measurements, and based on the results obtained, the best MBGs were selected and subsequently subjected to ex-vivo rat skin permeation anesthetic effect and irritation studies. Data indicated the formation of nano-sized droplets of MEs ranging from 20 - 52 nm with a polydispersity of less than 0.5. In-vitro release and ex-vivo permeation studies on MBGs showed significantly higher drug release and permeation in comparison to the marketed topical gel. Developed MBG formulations demonstrated greater potential for transdermal delivery of lidocaine and advantage over the commercially available gel product, and therefore, they may be considered as potential vehicles for the topical delivery of lidocaine.

Keywords: Lidocaine; Local Anesthesia; Microemulsion; Microemulsion-Based Gel; Phase Diagrams; Skin Permeation.

Figure 1.. Structure of lidocaine

Figure 2.. Solubility study of lidocaine in various oils. Data expressed in mean ± SEM (n = 3).

Figure 3.. Phase diagrams of systems consisting of triacetin as the oil phase (right apex), distilled water (left apex); A, Transcutol^® P; B, PG; and C, PEG 400 as co-surfactant and various surfactants (top apex) namely Tween 80 (green), Labrasol^® (red), Cremophor^® EL (yellow), and Cremophor^® RH40 (purple) at various R_sm of a, 1: 1; b, 1: 2, and c, 2: 1. The colored area in the oil-poor part of the phase diagram represents the o/w ME domain.

Figure 4.. Rheogram of ME₅ formulation

Figure 5.. Rheogram of MG₆ formulation

Figure 6.. Stability of MEs after 15 months of storage at room temperature. As seen, all formulations except ME₁₃ were clear without any turbidity or sedimentation.

Figure 7.. Stability of MBGs after 9 months of storage at room temperature. No textural change or breakdown was observed in the formulations investigated.

Figure 8.. In-vitro drug release profiles of formulation MG₃, MG₄ and MG₅ through an artificial membrane. Data are shown as means ± SEM (n = 3). One-way ANOVA followed by Tukey’s post-test multiple comparisons were conducted (*P < 0.05: significant; **P < 0.01: very significant; and ***P < 0.001: extremely significant, in comparison with the marketed product).

Figure 9.. Drug permeation from MG₃, MG₄, and MG₅ systems through abdominal rat skin. Data are shown as means ± SEM (n = 3). The difference between the release percentage of the formulations was statistically analyzed by one-way ANOVA followed by Tukey's post-test (*P < 0.05: significant; **P < 0.01: very significant; and ***P < 0.001: extremely significant, in comparison with the marketed product).

Figure 10.. Paw withdrawal threshold of the selected formulations (MG₃, MG₄, & MG₅) to mechanical stimulation (von Frey filaments). Data are shown as means ± SEM, n = 8 rats per group (n = 8). Two-way ANOVA followed by Bonferroni post-test.

Figure 11.. The area under the curve (AUC10-210 min) of withdrawal threshold time-course of the selected formulations (MG₃, MG₄, & MG₅) to mechanical stimulation (von Frey filaments). Data are shown as means ± SEM, n = 8 rats per group (n = 8). One-way ANOVA followed by Tukey's post-test multiple comparisons were conducted.