Formulation and characterization of atovaquone nanosuspension for improved oral delivery in the treatment of malaria.
OBJECTIVE
The objective of the present study was to develop an atovaquone (ATQ) nanosuspension and evaluate its ability to improve the pharmacokinetic and therapeutic efficacy on oral administration.


METHODS
The ATQ nanosuspension was prepared by a combination of microprecipitation and high-pressure homogenization. It was freeze dried and characterized for various physiochemical properties. In vivo pharmacokinetics was performed in rats whereas antimalarial efficacy was assessed in mice using a 4-day suppressive test.


RESULTS
The ATQ nanosuspension stabilized with Solutol(®) HS 15 (BASF India Ltd, Mumbai, India) and Capryol™ 90 (Gattefosse, Mumbai, India) exhibited a z-average diameter of 371.50 nm and a polydispersity index of 0.19. X-ray diffraction and differential scanning calorimetry analysis indicated no substantial changes in the crystalline state of ATQ nanocrystals. The aqueous solubility and in vitro dissolution rate were significantly increased by reducing the particle size. An in vivo pharmacokinetics study of the nanosuspension compared with a drug suspension and Malarone(®) (GlaxoSmithKline, Brentford, UK) exhibited an approximately 4.6-3.2-fold improvement in area under plasma concentration. A significant increase in Cmax and decrease in time to reach peak plasma concentration after administration was also observed. ATQ in nanosized form, even at one-quarter lower doses, exhibited greater reduction in parasitemia and prolonged survival compared with its reference formulations.


CONCLUSIONS
Results of this pilot study highlight the potential of nanosuspension as an efficient and commercially viable strategy for improving delivery of ATQ for malaria treatment.
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, Maharashtra, India.
Vivek
V
Borhade
Sulabha
S
Pathak
Shobhona
S
Sharma
Vandana
V
Patravale
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D053626:Atovaquone / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D004058:Diffusion; D004339:Drug Compounding / Q000379:methods; D004655:Emulsions / Q000737:chemistry*; D008288:Malaria / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D000962:Antimalarials; D004655:Emulsions; D053769:Nanocapsules; D053626:Atovaquone
4-day suppressive test; atovaquone; crystalline state; malaria; nanosuspension; oral absorption; particle size; solubility and dissolution