(W1130-06-36) Investigation on Role of Penetration Enhancers to Improve Topical Permeability of Clotrimazole

Purpose: Clotrimazole, a synthetic imidazole derivative, is a broad-spectrum antifungal agent extensively utilized in the treatment of various dermatophyte infections and candidiasis. Despite its therapeutic efficacy, its clinical application is significantly hindered by its poor aqueous solubility and limited dermal penetration, leading to suboptimal skin retention and reduced therapeutic effectiveness when applied topically. The hydrophobic nature of clotrimazole further exacerbates this issue. To overcome these challenges, the incorporation of chemical penetration enhancers (CPEs) has been explored as a strategy to augment topical delivery of clotrimazole. The objective of this research work is to study the effect of different CPEs such as Capmul® GMO-50, Capmul® MCM, Capmul® PG-12, Capmul® PG-8, Kollicream® IPM, and Kollicream® OA, on the in vitro drug release of clotrimazole.

Methods: Various 1% w/w clotrimazole cream formulations were prepared by incorporating 1.5% w/w of different CPEs. These formulations were evaluated for physicochemical parameters, including viscosity, texture analysis, pH, drug content, and in vitro drug release characteristics. Centrifugation testing was performed to assess the robustness and stability of the semisolid formulations by subjecting them to mechanical stress and observing any phase separation. Based on the results of these trials and on comparison with marketed product, further batches were taken with higher concentration (5%) of selected CPEs. The steady state flux (Jss) and permeability coefficient (Kp) of the developed batches were calculated and compared with that of the marketed cream. The enhancement ratio in Jss and Kp was calculated for understanding the effect of various CPEs. Stability studies of the optimized cream formulation was carried out at 25 °C ± 2 °C/60 ± 5% RH and 40 °C ± 2 °C/75 ± 5% RH—in laminated tubes for stability assessment.

Results: The optimized formulation F5C (5% Kollicream® IPM) exhibited a viscosity of 28,960 ± 1.23cP, hardness of 203.5 ± 0.37g, and an adhesive force of 96 ± 0.27g. It achieved a cumulative drug release of 40.27 ± 1.23 % at 8 hours, significantly higher than the 13.55 ± 0.57 % observed for the marketed formulation. Furthermore, formulation F5C exhibited the highest enhancement ratios of 3.962 for Jss and 3.66 for Kp, indicating significantly improved clotrimazole penetration compared to the marketed formulation. The optimized formulation, F5C, was found to exhibit good stability upon stability testing, with no significant changes observed in its physical appearance, pH, viscosity, or drug content over the testing period.

Conclusion: The study underscores the critical role of penetration enhancers in optimizing drug permeation through artificial membranes. Among the tested enhancers, Kollicream® IPM proved to be the most effective, followed by Capmul® GMO 50 and Kollicream® OA. The optimized formulation of clotrimazole cream demonstrated superior penetration characteristics compared to the marketed formulation, which suggests promising potential for the topical delivery of clotrimazole.

References: 1) Hmingthansanga V, Singh N, Banerjee S, Manickam S, Velayutham R, Natesan S. Improved topical drug delivery: Role of permeation enhancers and advanced approaches. Pharmaceutics. 2022 Dec 15;14(12):2818.
2) Virani A, Dholaria N, Mohd H, Albayati N, Michniak-Kohn B. Effect of chemical penetration enhancers on the transdermal delivery of olanzapine in human skin in vitro. AAPS Open. 2024 May 1;10(1):4.


Figure 1: Comparative IVRT of batches with 5% CPE and marketed formulation


Figure 2: Comparison of Steady state flux (Jss) and Permeability coefficient (Kp)