title: Cyclodextrin/poly(anhydride) nanoparticles as drug carriers for the oral delivery of atovaquone.
abstract: The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl-β-cyclodextrin (HPCD), 2,6-di-O-methyl-β-cyclodextrin (DCMD), randomly methylated-β-cyclodextrin (RMCD) and sulfobuthyl ether-β-cyclodextrin (SBECD). Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes. For the pharmacokinetic studies, ATO formulations were administered orally in rats. Overall, ATO displayed a higher affinity for methylated cyclodextrins than for the other derivatives. However, for in vivo studies, both ATO-DMCD-NP and ATO-HPCD-NP were chosen. These nanoparticle formulations showed more adequate physicochemical properties in terms of size (<260 nm), drug loading (17.8 and 16.9 μg/mg, respectively) and yield (>75%). In vivo, nanoparticle formulations induced higher and more prolonged plasmatic levels of atovaquone than control suspensions of the drug in methylcellulose. Relative bioavailability of ATO when loaded in nanoparticles ranged from 52% (for ATO-HPCD NP) to 71% (for ATO-DMCD NP), whereas for the suspension control formulation the bioavailability was only about 30%. The encapsulation of atovaquone in cyclodextrins-poly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.
authors.affiliation: Diseases of the Developing World-DDW, Tres Cantos Medicines Development Campus, GlaxoSmithKline R&D, 28760 Tres Cantos, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Calvo
authors.forename: José Luis
authors.initials: JL
authors.lastname: Lavandera
authors.forename: Maite
authors.initials: M
authors.lastname: Agüeros
authors.forename: Juan M
authors.initials: JM
authors.lastname: Irache
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D053626:Atovaquone / Q000494:pharmacology*; D001682:Biological Availability; D055598:Chemical Phenomena; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D015195:Drug Design; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D049388:Polyanhydrides / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D004337:Drug Carriers; D049388:Polyanhydrides; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D053626:Atovaquone