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--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 g/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 cyclodextrinspoly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.

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“…Recently, the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone was characterised. This drug has broad spectrum anti-protozoan activity via inhibition effect in the respiratory chain of parasites including some that cause giardiasis, trichomoniasis, leishmaniasis and toxoplasmosis, water/food-related disease states, as well as malaria (Calvo, Luis Lavandera, Agueeros, & Irache, 2011). Atovaquone is a highly lipophilic substance with a poor solubility including in gastrointestinal fluids (Dressman & Reppas, 2000).…”

“…Atovaquone is a highly lipophilic substance with a poor solubility including in gastrointestinal fluids (Dressman & Reppas, 2000). When administered via tablet or suspension, atovaquone is irregularly absorbed and it shows a very poor bioavailability (Calvo et al, 2011), however, bioavailability is doubled by the simultaneous intake of food (23% in the fasted state and 47% in the fed state) ("Glaxo Smith Kline," 2010). Comparing bioadhesive nanoparticle formulations, carriers prepared in the presence of cyclodextrin derivatives had calculated relative oral bioavailability of atovaquone that were 1.6-2.2-times higher than for a control suspension (Calvo et al, 2011).…”

“…When administered via tablet or suspension, atovaquone is irregularly absorbed and it shows a very poor bioavailability (Calvo et al, 2011), however, bioavailability is doubled by the simultaneous intake of food (23% in the fasted state and 47% in the fed state) ("Glaxo Smith Kline," 2010). Comparing bioadhesive nanoparticle formulations, carriers prepared in the presence of cyclodextrin derivatives had calculated relative oral bioavailability of atovaquone that were 1.6-2.2-times higher than for a control suspension (Calvo et al, 2011). The cyclodextrin derivative-containing nanoparticles were thought to slow drug release such that release was better timed relative to the absorption rates in the gut (Calvo et al, 2011).…”

“…Comparing bioadhesive nanoparticle formulations, carriers prepared in the presence of cyclodextrin derivatives had calculated relative oral bioavailability of atovaquone that were 1.6-2.2-times higher than for a control suspension (Calvo et al, 2011). The cyclodextrin derivative-containing nanoparticles were thought to slow drug release such that release was better timed relative to the absorption rates in the gut (Calvo et al, 2011).…”

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“…Thus, when complexes were formed with either β-CD or HPβCD the drug loading was about 4 and 17%, respectively, whereas in the absence of oligosaccharide the paclitaxel loading in poly(anhydride) nanoparticles was only 0.03% [109]. Another possibility to incorporate the drug into nanoparticles may be its incubation with the cyclodextrin and the polymer prior to formation of nanoparticles [110]. Nevertheless, this formation of drug-cyclodextrin complex "in situ" yields, in general, low drug loading values.…”