AIM: 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. MATERIALS & 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. CONCLUSION: 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.
AIM: 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. MATERIALS & 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. CONCLUSION: 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.
Authors: Mónica M Calderón; Scott R Penzak; Alice K Pau; Parag Kumar; Maryellen McManus; Raul M Alfaro; Joseph A Kovacs Journal: Clin Infect Dis Date: 2016-01-20 Impact factor: 9.079