Informative title: Topical formulations of miltefosine for cutaneous leishmaniasis in a BALB/c mouse

11 Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania and 12 affects approximately 10 million people worldwide. Currently available drugs are not ideal due to high 13 cost, toxicity, parenteral administration and suboptimal efficacy. Miltefosine is the only oral 14 treatment (Impavido®) available to treat CL, given over a period of 28 days with common side effects 15 such as vomiting and diarrhoea. 16 Objective. To explore the local application of miltefosine as a topical formulation to enhance activity 17 and reduce the drug’s adverse effects. 18 Methods. The anti-leishmanial activity of miltefosine was confirmed in vitro against several Leishmania 19 species. The permeation of miltefosine, in different solvents and solvent combinations, through 20 BALB/c mouse skin was evaluated in vitro using Franz diffusion cells. The topical formulations which 21 enabled the highest drug permeation or skin disposition were tested in vivo in BALB/c mice infected 22 with L. major. 23 Results. The overall permeation of miltefosine through skin was low regardless of the solvents used. 24 This was reflected in limited anti-leishmanial activity of the drug formulations when applied topically 25 in vivo. All topical formulations caused skin irritation. 26 Conclusions. We conclude that miltefosine is not an appropriate candidate for the topical treatment 27 of CL. 28