Novel formulations for Cutaneous Leishmaniasis

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2015Leishmaniasis is a parasitic disease caused by the protozoa Leishmania. It is endemic in more than 90 countries and has 0.7 to 1.3 million new cases every year. Cutaneous leishmaniasis (CL) is the most common form and it causes skin sores that can result in ulcerative lesions. CL lesions are usually found on exposed parts of the body such as the face, arms and legs. The actual therapy for CL includes pentavalent antimonials, meglumine antimoniate, amphotericin B, miltefosine, pentamidine isethionate, antifungal agents, paromomycin, granulocyte macrophage colony-stimulating factor as well as heat therapy or cryotherapy. However, all of this treatments present some problems as toxicity, limited efficacy, long time treatment and adverse effects leading to a withdrawal of the treatment by the patient. The main purpose of this project was the development of a topical formulation based on deformable lipidic nanovesicles, ethosomes, incorporating either the antibiotic PRM, trifluralin analogues (TFL-A) or both of them in a co-entrapment manner, as an innovative strategy to treat CL. DMSO vesicles were also tested for the stabilization of one particular active TFL-A. Ethosomes were basically composed of soybean phosphatidylcoline, ethanol and water, and the selected drugs were incorporated in different steps of the preparation method, according to their physico-chemical characteristics. Ethosomal systems were characterized in terms of drug incorporation, vesicles size, zeta potential and penetration through artificial membranes. In vitro permeation studies were also performed both through synthetic and biological membranes as well as cell viability assays. Almost all the formulations tested presented a mean diameter and a zeta potential in the expected values. Most formulations presented high incorporation efficacy values. Penetration and permeation assays showed that the different systems tested are suitable for topical application. Cell viability assays showed that most of the free drugs and their ethosomes formulation are not toxic to human skin cells. It is also possible to conclude that the ethosomal system causes a reduction of the toxicity of the drugs. In conclusion, it was possible to encapsulate PRM, TFL-A or both in ethosomes. The results obtained may constitute an advance in the therapy of C