Development of controlled release intramuscular Artemether-Loaded Poly (lactic co-glycolic acid) (PLGA) Microspheres for treatment of severe malaria in children

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APRIL, 2016
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Malaria is a febrile disease caused by the plasmodium parasite and has plagued subSaharan Africa for many years. Severe or complicated malaria is a medical emergency, which has very high mortality rates especially among children under five years. Many preventive and control measures have been used over the years to combat this menace. Chemotherapy through parenteral administration is the principal means of combating severe malaria. Artemether is a derivative of artemisinin antimalarial available as intramuscular injection for the treatment of severe malaria in children. The purpose of this study was to develop controlled release intramuscular PLGA microspheres of artemether to replace the multiple injection regimen of artemether drug currently available for children under five years. The improvement of current available treatment regimen for children will be a significant contribution to the management of malaria in children under five years. These children are the most affected by the disease. Two resomers (RG503H and RG502H) of a biodegradable and biocompatible polymer, PLGA were used to formulate microspheres by the single emulsion solvent evaporation method. Microspheres of the clinically relevant size range of 45-90 μm were characterized by light microscopy, scanning electron microscopy and particle size analysis. The degradation of the microspheres was studied by determining their mass loss, water uptake and molecular weight profiles by gel permeation chromatography. The in vitro release of artemether from the formulated microspheres in phosphate buffered saline with 0.02 % tween 80 (PBST) was studied. Experimental male Sprague-Dawley rats were injected with formulated microspheres and the in vivo iii release of artemether was studied. A Liquid chromatography/tandem mass spectrometric method (LC-MS/MS) was used to analyze plasma samples taken from the rats and to quantify artemether present in the plasma samples. Well-formed, spherical microspheres with smooth surfaces were formulated at high drug loading (20-25 %) and loading efficiencies (59-74 %). The polydispersed microsphere sizes were normally distributed with mean size of 70 and 69 μm for RG502H and RG503H polymers, respectively. The microspheres exhibited controlled release of artemether over 21 days in vitro with ~ 66-73 % release in 7 days. The declining molecular weight profiles, mass loss and water uptake profiles of the drug-loaded microspheres demonstrated that artemether release from the microspheres was due to polymer erosion and diffusion through the polymer. Mathematical modeling of the release of artemether showed that the RG502H and RG503H formulations fitted the Higuchi (fickian diffusion) and Korsemeyer-Peppas (non-fickian diffusion) models, respectively . Preliminary in vivo tests conducted showed that the artemether is released in vivo and can be successfully quantified with LC-MS/MS
A thesis submitted to the Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences in partial fulfilment of the requirements for the degree of Doctor of Philosophy.