A Highly Concentrated and Taste-Improved Aqueous Formulation of Efavirenz for a More Appropriate Pediatric Management of the Anti-HIV Therapy

Diego A.      Chiappetta; Christian      Hocht; Alejandro      Sosnik

Abstract

Pediatric HIV is scarce in developed countries; 90% of pediatric HIV patients are in developing countries. In contrast, children represent 15% of the new infections in poor countries. Approximately 90% of the HIV-positive children do not have access to antiretrovirals (ARVs). Without treatment, 50% of the patients die before the 2 years of age. Efavirenz (EFV, aqueous solubility ~4 μg/mL, 40-45% bioavailability), a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a first-choice pediatric AμV. To assure therapeutic plasma concentrations, the low oral bioavailability demands the administration of relatively high EFV doses. Aqueous EFV irritates the oral mucosa, causing a Burning Mouth Syndrome (BMS). A triglyceride-based liquid formulation of EFV (30 mg/mL) is not commercially available worldwide, making the appropiate dose adjustment and the swallowing difficult. More importantly, clinical trials indicated that the oral bioavailability of this oily solution is lower than that of the solid one. Moreover, a relatively high inter-subject variability has been found. The present work reports the development and full characterization of a concentrated (20 mg/mL, 2%) and taste-masked aqueous formulation of EFV for a more appropriate management of the pediatric anti-HIV therapy. Formulations displayed high physicochemical stability over time under regular storage conditions. Release assays in vitro showed a burst effect (2 h) and zero-order kinetics later on (between 2 and 24 h), compatible with the oral administration route and release. Finally, taste tests performed by adult healthy volunteers indicated that the unique combination of flavors and sweeteners employed (i) reduced the intensity of the BMS and (ii) shortened its duration significantly. Overall results indicate that the cost-effective and scalable nanotechnological strategy proposed could enable the more covenient and compliant administration of lower EFV doses. Due to a better pharmacokinetic profile, this would result in similar plasma levels than higher doses administered in solid or triglyceridesoluble form. In this context, some reduction of the treatment cost can be envisioned. This could improve the access of less affluent pediatric patients to medication in poor countries.

Keywords: Efavirenz liquid formulation, Pediatric HIV, Taste masking test, Physicochemical stability, in vitro drug delivery

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