The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership

Abstract

Background: Artemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co-formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries.

Methods: Pharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal) within a larger Public Private partnership (the FACT project), set up by WHO/TDR, Médecins Sans Frontières and the Drugs for Neglected Disease initiative (DNDi).

Results: The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long-term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DNDi.

Conclusions: Collaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the development process, and no intellectual property right was claimed. This approach resulted in a rapid technology transfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO pre-qualification of the fixed-dose co-formulation together with DNDi. The bi-layered tablet is made available under the names of Coarsucam® and Artesunate amodiaquine Winthrop®, Sanofi-Aventis. The issue related to the difficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of applied research is discussed.

Figure 1

FACT Partnerships. Key: Uni = University; pharma dev = pharmaceutical development; PK = pharmacokinetics, PD = pharmacodynamics.

Figure 2

Bilayer tablets manufacturing process.

Figure 3

Buffer effect of ASAQ tablets containing pH regulator (CaCO₃) while adding HCl 0,1N.

Figure 4

Tablet AS and DHA content of ASAQ monolayer tablets, after 3 months at 40°C/75%RH blistered. Key: AS = artesunate; DHA = dihydroartesunate; black dotted lines: specifications of AS content (100 ± 5 mg/tablet). Mean of 10. AS content in black, on the left Y axis; DHA content in grey, on the right Y axis Tablet formulations are summarized in the table under histogrammes.

Figure 5

Long-term stability study of ASAQ bilayer Aluminium blistered tablets in ambient conditions. AS & AQ content (Y axis) and DHA content (cited above histogrammes) of batch n° 30154C04. Key: AS = artesunate; DHA = dihydroartesunate; AQ = amodiaquine; black dotted lines: specifications of AS&AQ content (100 ± 5%). Mean of 20.

Figure 6

Dissolution profiles of AS and AQ bilayer ASAQ tablets compared to commercially available reference tablets. Key: Panel A: dissolution profiles of AS in high (30154C03) and low (30154C04) dosage bilayer ASAQ tablets compared to commercialized AS tablets Arsumax^® Panel B: dissolution profiles of AQ of high (30154C03) and low (30154C04) dosage bilayer ASAQ tablets compared to commercialized AQ tablets Flavoquine^®.

Figure 7

Bordeaux team partner interaction. Key: Uni = University