Development of patches containing the association of Artemether - Lumefantrine for the treatment of malaria caused by Plasmodium falciparum

Author(s)

Fabiana Volpe Zanutto

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2019-02-28

Examining board members

Mary Ann Foglio; Marcos Luciano Bruschi; Marco Vinícius Chaud; Daniel Youseff Bargieri; João Ernesto de Carvalho

• Advisor: Mary Ann Foglio

Abstract

Herein we report the development of transdermal drug delivery systems containing an association of artemether (Art) and lumefantrine (Lum)-loaded, with the focus on expanding the options to malaria treatment in communities isolated from the cities, without access to hospitals. Art-Lum are considered standard golden for malaria treatment (WHO, 2018). Art has fast onset action, reducing the parasitemia in a few hours after administration. Lum acts more slowly, eliminating the residual parasites. The transdermal delivery route is a favorable alternative pathway with advantages over oral or parenteral routes that include avoiding first passage metabolism, preventing gastrointestinal degradation and, additionally, increase the children¿s adhesion, which are the main victims from malaria around the world. Among the developed systems, there are liquid crystalline systems (LCs), electrospinning membranes (EM) and microneedles (MNs) nanosuspensions (NNs) loaded arteméter (Art) ¿ lumefantrine (Lum). The formulations of Art and Lum were developed separately and in the association. The permeation profiles of the drugs were studied and quantified by UPLC/MS. The best results for Lum were achieved with MNs (217 µg/cm2/24 hrs). For Art films, the best permeation profile was (~6000 µg/cm2/24 hrs). To select the suit drug delivery system, in vitro studies with Plasmodium falciparum 3D7 were performed. In these studies, it was verified that the cell culture did not evolve in the presence of LCs, ME and bioadhesives. Only formulations of MNs were possible to be tested in vitro, and thus, the bioavailability and evaluation studies of the antimalarial activity in vivo in a murine model of Plasmodium yoleii infection with the MNs developed were carried out. For the in vivo experiments, C57BL / 6J mice were used. The bioavailability studies were performed in healthy animals (without infection), in which two treatment regimens were evaluated: a) single dose, in which 1 MN Art-Lum was applied on the 1st day of treatment and removed after 72 hrs and b) 1x /day /3 days, which included the daily exchange of MNs during the 3 days of treatment. In these studies, the Cmax of Lum was observed at 4?g / mL of plasma, during the period of 72 hrs, when the application scheme of the MNs 1x / day / 3 days was used. Art Cmax was 375 ?g / mL and the Cmax of dihydroartemisinin, Art's active metabolite, was 3125 ?g / mL, both at 6 hrs, indicating that the MNs are able to prolong the time the drug stays in the blood. In the antimalarial activity studies, the mice were infected with 106 Plasmodium yoelii 17XNL erythrocytes and treated with Art-Lum MNs from day 0 of the infection in the MNs application scheme 1x/day/3 days, which demonstrated a 99.5% reduction in parasitemia by day 12 post-infection. The present results suggest that the treatment using Art-Lum MNs keeps the treated animals below 0.5% of parasitemia, that is, they are able to abolish the infection (AU)

• FAPESP's process: 14/16008-3 - Development of patches containing the association of artemether - lumefantrine for the treatment of malaria caused by Plasmodium falciparum
• Grantee: Fabiana Volpe Zanutto
• Support Opportunities: Scholarships in Brazil - Doctorate