Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis

Abstract

As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Leishmaniasis chemotherapy—challenges and opportunities

“…In the latter category, the topical approach offers advantages for simple CL (minimal systemic exposure, lesion protected from super‐infections) but has limitations for complex CL (multiple lesions, lesions close to eye, potentially metastasizing forms); systemic treatments have disadvantages (high systemic exposure versus low skin concentrations). A recent example of the rational pharmaceutical approach is the performance of studies with the anti‐protozoal agent, buparvaquone, where topical formulations that can deliver drugs to the infected dermal layer in rodent models of infection have been designed [46,47].…”

Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development

“…It is also used to improve topical drug delivery. Formulations for topical delivery of buparvaquone and a prodrug (3-phosphono-oxymethyl-buparvaquone) have been developed and characterized in in vitro human and mouse skin models [87]. Efficacy of topical formulations and phosphate prodrugs of buparvaquone in in vivo models of VL and CL has been reported [88].…”

Topical formulations of miltefosine for cutaneous leishmaniasis in a BALB/c mouse model

“…We confirmed the in vitro activity of miltefosine against a panel of species that cause CL with similar activities to previously reported. [24,25] Only the EC 50 values for L. mexicana were higher, probably due to the different strain used. Overall miltefosine was slightly less active against L. mexicana and L. major, which was not unexpected as difference in intrinsic sensitivity to miltefosine across Leishmania species is known.…”