Fixed artesunate-amodiaquine combined pre-formulation study for the treatment of malaria.
Artemisinin-based combination therapies, including artesunate (AS) + amodiaquine (AQ), are the currently recommended first-line treatment of uncomplicated falciparum malaria. Fixed-dose co-formulations offer logistic and adherence advantages. This paper reports the initial research phase of the pre-development process of an AS-AQ formulation, further developed by the Drug for Neglected Diseases Initiative (DNDi). Results demonstrate that AS and AQ are not compatible, and AS degradation is related to three main parameters: water content (>1%), elevated temperature (80 degrees C in dry condition) and possibly the 4-aminoquinoline moiety. Furthermore, AS and AQ incompatibility led to AS degradation and pharmaco-technical changes in classical wet granulation tablets. Both active principles are stable as dry powders. These investigations led to further development of various co-formulations, including the bilayer tablet currently on the market.
Kauss
Tina
T
Laboratory of Galenic Pharmacy and Biopharmacy, Bordeaux 2 University, France. tina.kauss@u-bordeaux2.fr
Fawaz
Fawaz
F
Guyot
Michel
M
Lagueny
Anne-Marie
AM
Dos Santos
Isabelle
I
Bonini
François
F
Olliaro
Piero
P
Caminiti
Antonella
A
Millet
Pascal
P
D000655:Amodiaquine / Q000737:chemistry* / Q000627:therapeutic use; D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use; D037621:Artemisinins / Q000737:chemistry* / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical; D004338:Drug Combinations; D004339:Drug Compounding; D004355:Drug Stability; D000431:Ethanol / Q000737:chemistry; D005240:Feasibility Studies; D006358:Hot Temperature; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D016778:Malaria, Falciparum / Q000188:drug therapy*; D011208:Powders; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013607:Tablets; D014867:Water / Q000737:chemistry
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011208:Powders; D012997:Solvents; D013607:Tablets; C515299:amodiaquine, artesunate drug combination; D014867:Water; D000655:Amodiaquine; D000431:Ethanol