Background: Artemisinin-based combination therapy is currently recommended worldwide for the treatment of\r\nuncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on\r\nthe initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co-formulation\r\ntablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of\r\nboth industrialized and low income countries.\r\nMethods: Pharmaceutical development was performed by a research laboratory at the University Bordeaux\r\nSegalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further\r\ntransferred to a company specialized in pharmaceutical development, and then provided to another company for\r\nclinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal)\r\nwithin a larger Public Private partnership (the FACT project), set up by WHO/TDR, M�©decins Sans Fronti�¨res and the\r\nDrugs for Neglected Disease initiative (DNDi).\r\nResults: The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles\r\nwhile preventing artesunate degradation under tropical conditions. Several options were attempted and failed to\r\nprovide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH\r\nregulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in\r\ncontrolled conditions. However, long-term stability could be achieved, in experimental batches under GMP\r\nconditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu\r\nblisters. Conduction of the workplan was monitored by DNDi.\r\nConclusions: Collaborations between research and industrial groups greatly accelerated the process of\r\ndevelopment of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the\r\ndevelopment process, and no intellectual property right was claimed. This approach resulted in a rapid technology\r\ntransfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO prequalification\r\nof the fixed-dose co-formulation together with DNDi. The bi-layered tablet is made available under\r\nthe names of Coarsucam�® and Artesunate amodiaquine Winthrop�®, Sanofi-Aventis. The issue related to the\r\ndifficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of\r\napplied research is discussed.
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