Purpose: Skin fungal infections continue to increase year by year on a global level. The main obstacle in the management of topical fungal infections is the formidable barrier function of the skin, restricting effective penetration of most molecules. Various topical formulations of terbinafine containing the base and the hydrochloride salt are currently available but have limited efficacy. As there are limited data in the literature relating to the physicochemical properties of the base, the initial goal of this work was to conduct a comprehensive characterisation of the molecule. A secondary aim of this project was to develop novel formulations with improved skin delivery compared with the commercial terbinafine base preparation.
Methods: Terbinafine base was synthesised in house followed by nuclear magnetic resonance (NMR) analysis. Both the base and salt form were characterised using Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). A new High Performance Liquid Chromatography (HPLC) method was developed and validated for analysis of the base form. In order to develop novel topical formulations for terbinafine base, a number of solvents were selected and stability studies were conducted. Subsequently single, binary and ternary formulations (1% w/w) were prepared and evaluated with Franz type diffusion cells and mass balance studies in porcine skin.
Results: NMR spectroscopy confirmed the complete conversion of the hydrochloride salt to terbinafine base. Thermal Analysis showed one endothermic event for both base and salt forms, indicating that the melting points of terbinafine base and salt are 41.3°C and 213.5°C. The molecule exhibited excellent stability in various solvents over 5 days. From the permeation and mass balance results for neat solvents Transcutol® (TC), propylene glycol (PG), ethanol (EtOH) and isopropyl alcohol (IPA) were identified as the most efficacious solvents, delivering significantly higher amounts of terbinafine to the skin compared with the commercial formulation. Binary formulations of lipophilic (IPM, PGML) and hydrophilic solvents (TC, PG, EtOH) were prepared in different ratios but did not deliver significantly higher amounts of active into the skin compared with the commercial formulation (one-way ANOVA, *p ≤ 0.05). However, binary formulations comprising of PG-TC and PG-EtOH delivered more than 15% of the applied dose of drug into the skin (Figure 1). The results for the ternary formulations indicated that the PG-EtOH-IPM and TC-PG-IPM formulations delivered significantly higher amounts of drug (9.01% - 11.44%) into the skin compared with the commercial preparation (Figure 2).
Conclusion: The results reported here clearly show that various prototype formulations that have been developed are more effective than the commercial formulation in targeting terbinafine to the skin. The next stages of the work will focus on further optimisation of these formulations with evaluation of their performance using in vitro human skin and in vivo human volunteer studies.
Bruno Santos– Lecturer, London Metropolitan University
Rebecca Lever– Senior Lecturer, UCL School of Pharmacy, England
Jonathan Hadgraft– Professor Emeritus, UCL School of Pharmacy, London, England
Majella Lane– Senior Lecturer, UCL School of Pharmacy, England