Film-Forming Systems for the Delivery of DNDI-0690 to Treat Cutaneous Leishmaniasis.

Katrien Van Bocxlaer,Kerri-Nicola Mcarthur,Mo Alavijeh,Andy Harris,Stéphanie Braillard,Simon L Croft,Charles E Mowbray

doi:10.3390/pharmaceutics13040516

Abstract

In cutaneous leishmaniasis (CL), parasites reside in the dermis, creating an opportunity for local drug administration potentially reducing adverse effects and improving treatment adherence compared to current therapies. Polymeric film-forming systems (FFSs) are directly applied to the skin and form a thin film as the solvent evaporates. In contrast to conventional topical dosage forms, FFSs strongly adhere to the skin, favouring sustained drug delivery to the affected site, reducing the need for frequent applications, and enhancing patient compliance. This study reports the first investigation of the use of film-forming systems for the delivery of DNDI-0690, a nitroimidazole compound with potent activity against CL-causing Leishmania species. A total of seven polymers with or without plasticiser were evaluated for drying time, stickiness, film-flexibility, and cosmetic attributes; three FFSs yielded a positive evaluation for all test parameters. The impact of each of these FFSs on the permeation of the model skin permeant hydrocortisone (hydrocortisone, 1% (w/v) across the Strat-M membrane was evaluated, and the formulations resulting in the highest and lowest permeation flux (Klucel LF with triethyl citrate and Eudragit RS with dibutyl sebacate, respectively) were selected as the FFS vehicle for DNDI-0690. The release and skin distribution of the drug upon application to Leishmania-infected and uninfected BALB/c mouse skin were examined using Franz diffusion cells followed by an evaluation of the efficacy of both DNDI-0690 FFSs (1% (w/v)) in an experimental CL model. Whereas the Eudragit film resulted in a higher permeation of DNDI-0690, the Klucel film was able to deposit four times more drug into the skin, where the parasite resides. Of the FFSs formulations, only the Eudragit system resulted in a reduced parasite load, but not reduced lesion size, when compared to the vehicle only control. Whereas drug delivery into the skin was successfully modulated using different FFS systems, the FFS systems selected were not effective for the topical application of DNDI-0690. The convenience and aesthetic of FFS systems alongside their ability to modulate drug delivery to and into the skin merit further investigation using other promising antileishmanial drugs.

Highlights

The leishmaniases are a group of neglected tropical diseases that typically affect populations in low- and middle-income countries
The most prevalent form of this disease is cutaneous leishmaniasis (CL) which is characterised by skin lesions ranging from closed nodules to plaques and ulcers—symptoms typically situated on exposed body parts [1,2]
We explored the use of film-forming systems (FFSs) as a skin delivery system for the poorly water-soluble DNDI-0690 to treat single and closed CL

Summary

Introduction

The leishmaniases are a group of neglected tropical diseases that typically affect populations in low- and middle-income countries. The most prevalent form of this disease is cutaneous leishmaniasis (CL) which is characterised by skin lesions ranging from closed nodules to plaques and ulcers—symptoms typically situated on exposed body parts [1,2]. Current treatments are unsatisfactory and limited due to adverse effects, variable efficacy, Pharmaceutics 2021, 13, 516. Pharmaceutics 2021, 13, 516 cost, logistical challenges [3], and lengthy treatment durations, which sometimes involve invasive drug administration [4]. In localised CL, the Leishmania parasites are primarily located in the dermis, favouring local drug administration in order to achieve high skin concentrations with minimal systemic exposure and associated potential adverse effects. High local drug concentrations can be challenging to achieve due to the efficient barrier properties of the stratum corneum. It is especially difficult for conventional topical dosage forms such as creams and gels as they are not designed for sustained drug delivery and often fail to ensure persistent contact with the skin [9]

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