title: Bioavailability enhancement of atovaquone using hot melt extrusion technology.
abstract: Emerging parasite resistance and poor oral bioavailability of anti-malarials are the two cardinal issues which hinder the clinical success of malaria chemotherapy. Atovaquone-Proguanil is a WHO approved fixed dose combination used to tackle the problem of emerging resistance. However, Atovaquone is a highly lipophilic drug having poor aqueous solubility (less than 0.2 μg/ml) thus reducing its oral bioavailability. The aim of the present investigation was to explore hot melt extrusion (HME) as a solvent-free technique to enhance solubility and oral bioavailability of Atovaquone and to develop an oral dosage form for Atovaquone-Proguanil combination. Solid dispersion of Atovaquone was successfully developed using HME. The solid dispersion was characterized for DSC, FTIR, XRD, SEM, and flow properties. It was filled in size 2 hard gelatin capsules. The formulation showed better release as compared to Malarone® tablets, and 3.2-fold and 4.6-fold higher bioavailability as compared to Malarone® tablets and Atovaquone respectively. The enhanced bioavailability also resulted in 100% anti-malarial activity in murine infection model at 1/8(th) therapeutic dose. Thus the developed methodology shows promising potential to solve the problems associated with Atovaquone therapy, namely its high cost and poor oral bioavailability, resulting in increased therapeutic efficacy of Atovaquone.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, India.
authors.forename: Laxman
authors.initials: L
authors.lastname: Kate
authors.affiliation: Department of Physics, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Gokarna
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Borhade
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Prabhu
authors.affiliation: Department of Physics, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, India.
authors.forename: Vinita
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400005, India.
authors.forename: Sulabha
authors.initials: S
authors.lastname: Pathak
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400005, India.
authors.forename: Shobhona
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, India. Electronic address: vb.patravale@ictmumbai.edu.in.
authors.forename: Vandana
authors.initials: V
authors.lastname: Patravale
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053626:Atovaquone / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D004338:Drug Combinations; D065546:Drug Liberation; D006358:Hot Temperature; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects; D002727:Proguanil / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013678:Technology, Pharmaceutical
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C109496:atovaquone, proguanil drug combination; D002727:Proguanil; D053626:Atovaquone
keywords: Atovaquone; Bioavailability; Hot melt extrusion; Malaria; Proguanil; Solid dispersion