生物等效性和生物利用度杂志

抽象的

Oral Liquid Formulation of Etravirine for Enhanced Bioavailability

Jyothy John and Dong Liang

Aim: Etravirine is the first drug in the second generation of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Despite its use in clinical management of HIV infected patients, the drug has very limited bioavailability due to low water solubility and low gastrointestinal permeability. The majority of currently available anti-AIDS drugs in the U.S. market are in solid dosage forms. There is a need of introducing an oral liquid dosage formulation, especially for those AIDS patients who are often unable to swallow a pill. Methods: Co-solvent formulations of etravirine were prepared using 1-methyl-2-pyrrolidinone, Labrasol, and water after evaluating the etravirine solubility in various solvents. A long term stability study was carried out to examine the physical stability of an optimal oral formulation of etravirine. Pharmacokinetic studiesof etravirine were conducted in rats to evaluate bioavailability of the drug. Four groups of jugular vein-cannulated male Sprague- Dawley rats were orally administered etravirine dosage forms such asetravirine solution in DMSO (2.5 mg/kg), commercial etravirine tablets (200 mg/kg), and an optimized liquid formulation (25 mg/kg and 50 mg/kg), respectively. Serial blood samples were collected at predetermined time points. Plasma samples were analyzed for etravirine concentration using a validated LC-MS/MS assay. Pharmacokinetic and statistical data analysis was performed using WinNonlin and Systat. Results: A co-solvent dosage formulation of etravirine was developed containing 5 mg/mL of etravirine dissolved in 3.5% 1-methyle 2-pyrrolidinone, 46.5% Labrasol, and 50% water. The formulation was found to be stable after 21 months storage at room temperature. The drug formulation was successfully administered to rats without any signs of acute toxicity. Pharmacokinetic study showed over 40-times superior oral bioavailability of the formulation as compared with the marketed Intelence® Tablet formulation. Conclusion: A stable co-solvent liquid solution formulation of etravirine was developed with significantly improved oral bioavailability for potential clinical application.