Gurinder Singh1, Roopa S Pai. 1. Al-Ameen College of Pharmacy, Department of Pharmaceutics , Bangalore, Karnataka , India roopaspai@yahoo.com.
Abstract
BACKGROUND: Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution and rapid first-pass metabolism in liver by CYP3A5, which result in low and erratic bioavailability. OBJECTIVE: The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides of ATV in an attempt to circumvent such obstacles. METHODS: Equilibrium solubility studies indicated the choice of Maisine 35-1 as lipid, and of Transcutol P and Span 20 as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X1) and surfactant (X2) as the critical factor variables. The SNEDDS were optimized (OPT) using 3(2) central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in situ single-pass intestinal perfusion studies of OPT formulation were investigated in Wistar rats. RESULTS: OPT formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT formulation. Augmentation in the values of Ka (1.96-fold) and AUC (2.57-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions. CONCLUSION: The studies, therefore, indicate the successful formulation development of SNEDDS with distinctly improved bioavailability of ATV.
BACKGROUND:Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution and rapid first-pass metabolism in liver by CYP3A5, which result in low and erratic bioavailability. OBJECTIVE: The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides of ATV in an attempt to circumvent such obstacles. METHODS: Equilibrium solubility studies indicated the choice of Maisine 35-1 as lipid, and of Transcutol P and Span 20 as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X1) and surfactant (X2) as the critical factor variables. The SNEDDS were optimized (OPT) using 3(2) central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in situ single-pass intestinal perfusion studies of OPT formulation were investigated in Wistar rats. RESULTS: OPT formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT formulation. Augmentation in the values of Ka (1.96-fold) and AUC (2.57-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions. CONCLUSION: The studies, therefore, indicate the successful formulation development of SNEDDS with distinctly improved bioavailability of ATV.
Entities:
Keywords:
bioavailability; central composite design; in vitro/in vivo correlation; pharmacokinetic study; self-nanoemulsifying drug-delivery system