Simultaneous Delivery of Econazole, Terbinafine and Amorolfine with Improved Cutaneous Bioavailability: A Novel Micelle-Based Antifungal “Tri-Therapy”

Si Gou,Yogeshvar N. Kalia,Michel Monod,Denis Salomon

doi:10.3390/pharmaceutics14020271

Abstract

Lack of accurate diagnosis and the use of formulations designed to address the poor aqueous solubility of antifungal agents, but not optimized for delivery, contribute to unsatisfactory outcomes for topical treatment of cutaneous mycoses. The objective of this study was to develop a micelle-based antifungal formulation containing econazole (ECZ), terbinafine (TBF) and amorolfine (AMF) using D-α-tocopheryl polyethylene glycol succinate (TPGS) for simultaneous cutaneous delivery of three agents with complementary mechanisms of action. The antifungal “tri-therapy” micelle-based formulation containing 0.1% ECZ, 0.1% TBF and 0.025% AMF had a drug loading 10-fold lower than the “reference” marketed formulations (Pevaryl®, 1% ECZ; Lamisil®, 1% TBF; Loceryl®, 0.25% AMF). Finite dose application of the micelle-based formulation for 6 h resulted in a statistically equivalent deposition of ECZ (p > 0.05) and TBF (p > 0.05) from the 2 systems, and a 2-fold higher accumulation of AMF (p = 0.017). Antifungal concentrations above MIC80 against Trichophyton rubrum were achieved in each skin layer with the “tri-therapy”, which also exhibited a preferential deposition of each antifungal agent in pilosebaceous unit (PSU)-containing biopsies as compared with PSU-free biopsies (p < 0.05). A planned clinical study will test whether these promising results translate to improved therapeutic outcomes in vivo.

Highlights

Accepted: 21 January 2022Dermatomycosis is a widespread condition characterized by both superficial and subcutaneous infections of keratinous tissues [1,2]
Standard treatments using azole compounds and terbinafine are effective in many cases of cutaneous dermatophytosis, oral medication for an extensive period of time may lead to significant side effects [7,8] and the treatment efficiency of antifungal drugs depends on their ability to achieve an effective concentration in the target skin layers
It is well recognized that topical administration of antifungal agents is desirable for the management of localized cutaneous mycoses due to the targeted delivery to the site of infection, which decreases the risk of side effects and drug interactions associated with systemic therapies [9]

Summary

Introduction

Accepted: 21 January 2022Dermatomycosis is a widespread condition characterized by both superficial and subcutaneous infections of keratinous tissues [1,2]. Standard treatments using azole compounds and terbinafine are effective in many cases of cutaneous dermatophytosis, oral medication for an extensive period of time may lead to significant side effects [7,8] and the treatment efficiency of antifungal drugs depends on their ability to achieve an effective concentration in the target skin layers. It is well recognized that topical administration of antifungal agents is desirable for the management of localized cutaneous mycoses due to the targeted delivery to the site of infection, which decreases the risk of side effects and drug interactions associated with systemic therapies [9]. The poor aqueous solubility of many antifungal agents makes their formulation difficult and results in limited cutaneous bioavailability.

Objectives

Methods

Results