Development of a highly-concentrated nelfinavir mesylate aqueous micellar formulation for pediatric anti-HIV therapy.

MORETTON M.A.; TAIRA C.; FLOR S.; BERNABEU E.; LUCANGIOLI S.; HOCHT C.; CHIAPPETTA D.A.

Cordoba

Congreso; RICIFA 2014; 2014

Worldwide an estimated of 3.4 million children are living with Human Immunodeficiency Virus (HIV). Prolonged High Activity Antiretroviral Therapy regimes could present low-patient compliance, especially in children, affecting therapeutic success. Nelfinavir mesylate (NFV) is a non-peptidic HIV-1 protease inhibitor recommended for children over 2 years-old. It exhibits pH-dependant aqueous solubility which results highly restricted at physiological pH value. This represents a clinical limitation due to the reduction on drug absorption and unpredictable drug bioavailability. Moreover a liquid formulation of NFV is not commercially available worldwide. In this framework, the present work reports the development and characterization of a highly concentrated aqueous micellar formulation of NFV employing D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as micelle-former biomaterial. TPGS critical micellar concentration in distilled water (0.02 %w/v) and phosphate buffer pH 7.4 (0.013 %w/v) was determined by the hydrophobic probe solubilization method at 25 °C. A sharp increase on NFV aqueous solubility in both, distilled water (19.7-fold) and buffer pH 7.4 (17,698-fold) was observed where drug aqueous solubility was increased up to 80.3 mg/mL (TPGS 10 %w/v). Micellar size and size distribution of NFV-loaded TPGS micelles (10 %w/v) was 5.6 nm (PDI: 0.29) as determined by dynamic light scattering. Micelles presented a spherical morphology as it was characterized by transmission electronic microscopy. An almost linear in vitro NFV release profile was observed over 6 h for TPGS micellar dispersions (10 %w/v) where total drug cumulative release was 56%. Finally, in vivo data showed a significant (p