Topical therapies are an appropriate alternative to systemic therapies for treatment of cutaneous leishmaniasis since they are associated with lower costs, fewer side effects, and the possibility of self- administration. It is hypothesized tht a combination of novel fabrication technologies (e.g., multiple foci two photon polymerization of a zirconium oxide hybrid material, polydimethylsiloxane micromolding, and piezoelectric inkjet printing) and conventional drug delivery materials (e.g., a biodegradable acid anhydride copolymer containing alternating maleic anhydride and methyl vinyl ether groups and the pharmacologic agent amphotericin B) can be used to prepare amphotericin B-loaded biodegradable polymer microneedles for topical therapy of cutaneous leishmaniasis at lower amphotericin B doses than conventional methods. Methodology: Objective I will involve chemical, physical, mechanical, and in vitro biological characterization of amphotericin B-loaded biodegradable polymer materials, microneedles, and microneedle arrays. Objective II will involve characterization of amphotericin B-loaded microneedles and microneedle arrays with porcine skin. Objective III will involve an in initial toxicology study to determine an appropriate dose level for microneedle- based amphotericin B delivery. Efficacy experiments against an Old World cutaneous leishmaniasis species (L. major) and a New World cutaneous leishmaniasis species (L. mexicana) will be undertaken; comparisons to conventional agents (e.g., intravenously-delivered amphotericin B liposomes, topical paromomycin, and oral miltefosine) will be made. Alterations in kidney function in animal subjects that receive amphotericin B-loaded microneedles will be assessed from serum blood urea nitrogen, creatinine, albumin, and total protein values. Innovation: The stratum corneum layer of the skin obstructs transport of many types of pharmacologic agents, including charged, large, and/or polar pharmacologic agents. It is hypothesized that microneedle-based topical treatment of amphotericin B may be achieved at lower amphotericin B doses than conventional amphotericin B delivery methods since microneedles physically disrupt the stratum corneum layer. Processing amphotericin B- loaded microneedles is also complicated by the fact that amphotericin B exhibits poor solubility in aqueous solutions. Although incorporation of amphotericin B within microneedles may be difficult via conventional methods (e.g., mixing or dip coating), piezoelectric inkjet printing may be used to deposit an amphotericin B coating onto the surfaces of microneedles. The input and processing costs for amphotericin B-loaded microneedles ($ 0.10/device) are quite low and are significantly lower than those for liposomal formulations. Significance: The data from the proposed program will facilitate studies comprehensive in vivo studies and eventually clinical studies that will examine the effectiveness of amphotericin B-loaded microneedles.
Around 350 million individuals worldwide are at risk of contracting leishmaniasis, which is considered by the World Health Organization to be one of the most significant tropical diseases . Increased travel to tropical environments has led to an escalation in the incidence of leishmaniasis. In addition, the movement of individuals from endemic regions to nonendemic regions (e.g., the United States) has been associated with an increase in the incidence of leishmaniasis. Furthermore, changes in sandfly habitat due to human encroachment in endemic regions (e.g., clearing of land for agricultural purposes) have been associated with an increase in the incidence of leishmaniasis. High blood pressure and kidney toxicity are some of the shortcomings associated with systemic delivery of the most potent antileishmanial drug in clinical use, amphotericin B. In this proposal, piezoelectric inkje printing will be used to prepare coatings of amphotericin B on Gantrez(r) biodegradable acid anhydride copolymer microneedles; these amphotericin B-coated Gantrez(r) microneedles will be used for topical treatment of cutaneous leishmaniasis. The in vivo studies from this program will form the basis for clinical studies that will evaluate the safety and efficacy of amphotericinB-loaded Gantrez(r) microneedles.  Neghina R, Neghina AM. Leishmaniasis, a global concern for travel medicine. Scandinavian Journal of Infectious Diseases. 2010; 42(8):563-70.