title: 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.
authors.affiliation: School of Pharmacy, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK. t.garnier@herts.ac.uk
authors.forename: Tracy
authors.initials: T
authors.lastname: Garnier
authors.forename: Antti
authors.initials: A
authors.lastname: Mäntylä
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: M Jayne
authors.initials: MJ
authors.lastname: Lawrence
authors.forename: Marc B
authors.initials: MB
authors.lastname: Brown
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D000431:Ethanol / Q000737:chemistry; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016773:Leishmaniasis, Cutaneous; D008543:Melanins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009226:Myristates / Q000737:chemistry; D009285:Naphthoquinones / Q000737:chemistry / Q000378:metabolism*; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D019946:Propylene Glycol / Q000737:chemistry; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption
chemical_list: C481786:3-phosphonooxymethylbuparvaquone; D000981:Antiprotozoal Agents; D008543:Melanins; D009226:Myristates; D009285:Naphthoquinones; D010755:Organophosphates; D011355:Prodrugs; C046326:buparvaquone; C008205:isopropyl myristate; D000431:Ethanol; D011092:Polyethylene Glycols; D019946:Propylene Glycol