Enabling Oral Amphotericin B Delivery by Merging the Benefits of Prodrug Approach and Nanocarrier-Mediated Drug Delivery

Amphotericin B (AmB) is gold standard therapy for leishmaniasis and fungal infections. Considering the global disease burden, nearly 90% of cases occur in economically vulnerable countries, making the cost of AmB therapy a critical healthcare challenge in controlling disease burden. All currently marketed AmB products are administered through an intravenous (i.v.) route and involve high treatment costs. Designing an orally effective AmB formulation can substantially reduce the cost of therapy and improve patient compliance.

However, it is a challenging task because of the distinctive physicochemical properties of AmB. Previously, we developed a lipid-based prodrug of AmB, AmB-oleyl conjugate (AmB-OA), which showcased remarkable stability in the gastrointestinal (GI) environment and improved intestinal permeation. Hereby, we have developed self-nanoemulsifiying drug delivery system (SNEDDS) of AmB-OA to further enhance the oral bioavailability of AmB and potentiate its therapeutic benefits. SNEDDS was developed by screening a wide range of oils, surfactants, and cosurfactants, and formulation composition was optimized using extreme vertices design. AmB-OA SNEDDS possessed the ability of quick self-nanoemulsification on dilution (droplet size ∼56 nm) along with remarkable stability in the GI environment. Accelerated stability (40 °C/75% relative humidity) studies and freeze–thaw cycling studies proved that the formulation was stable at tropical conditions as well as temperature cycling stress.

Drug transport analysis in Caco-2 cells revealed a remarkable increase in drug transport for AmB-OA SNEDDS compared to AmB along with minimal cellular toxicities. AmB-OA SNEDDS showcased ∼8.9-fold higher AUCTot than AmB in in vivo pharmacokinetic study, proving the effectiveness of formulation to enhance oral bioavailability. In vivo toxicity analysis highlighted the ameliorated toxicity risk associated with SNEDDS formulation. Therefore, the AmB-OA SNEDDS formulation may provide a cost-friendly and effective strategy to resolve the oral AmB drug delivery challenge.

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Article information: Kaushik Thanki, Tushar Date, and Sanyog Jain. ACS Biomaterials Science & Engineering Article ASAP. DOI:10.1021/acsbiomaterials.0c01505

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