ABSTRACT
OBJECTIVE: Posaconazole (PCZ) is an antifungal drug, which acts by inhibiting the lanosterol-14α-demethylase enzyme. It is a biopharmaceutical classification system class II drug with its bioavailability being limited by poor aqueous solubility. The aim of this study was to improve the oral bioavailability of PCZ by preparing nanocrystalline solid dispersion (NCS). METHODS: PCZ-NCS was prepared by a combination of precipitation and high-pressure homogenization followed by freeze-drying. Several different surfactants and polymers were screened to produce NCS with smaller particle size and higher stability. RESULTS: The optimized NCS formulation containing 0.2% Eudragit S100 and 0.2% SLS was found to provide the average particle size of 73.31 ± 4.7 nm with a polydispersity index of 0.23 ± 0.03. Scanning electron microscopy revealed the preparation of homogeneous and rounded particles. Differential scanning calorimetry and X-ray diffraction confirmed crystalline nature of NCS. Nanonization increased the saturation solubility of PCZ by about 18-fold in comparison with the neat drug. Intrinsic dissolution study showed 93% dissolution of PCZ within the first 10 min. In vivo pharmacokinetic study in Wistar rats showed that Cmax and AUCtotal of PCZ-NCS increased by 2.58- and 2.64-fold compared to the marketed formulation. CONCLUSION: PCZ-NCS formulation presents a viable approach for enhancing the oral bioavailability of PCZ.
Subject(s)
Antifungal Agents , Biological Availability , Nanoparticles , Particle Size , Rats, Wistar , Solubility , Triazoles , Animals , Nanoparticles/chemistry , Triazoles/pharmacokinetics , Triazoles/administration & dosage , Triazoles/chemistry , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacokinetics , Rats , Male , Administration, Oral , Drug Compounding/methods , Drug Liberation , X-Ray Diffraction/methods , Freeze Drying , Chemistry, Pharmaceutical/methods , Surface-Active Agents/chemistry , Calorimetry, Differential Scanning/methodsABSTRACT
A high-performance liquid chromatography/electrospray ionization tandem mass spectrometry method was developed and validated for the quantification of zidovudine in rat plasma. Following solid-phase extraction, the analytes were separated using an isocratic mobile phase on a reverse phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 268/127 for zidovudine and m/z 230/112 for the internal standard. The method exhibited a linear dynamic range of 5-500 ng/mL for zidovudine in rat plasma. The lower limit of quantification was 5 ng/mL with a relative standard deviation of less than 8%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 1.5 min for each sample made it possible to analyze more than 400 plasma samples per day. The validated method was applied for pharmacokinetic studies of the novel drug delivery systems of zidovudine in rats.
Subject(s)
Chromatography, High Pressure Liquid/methods , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Zidovudine/blood , Animals , Injections, Intravenous , Lamivudine/blood , Methanol/chemistry , Rats , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Solid Phase Extraction/methods , Water , Zidovudine/administration & dosage , Zidovudine/pharmacokineticsABSTRACT
A rapid, reliable HPLC method with UV detection (240 nm) was developed and validated for quantitation of saquinavir in mice brain and testis. Saquinavir and the internal standard were isolated from homogenized tissue matrices using liquid-liquid extraction procedure and were then analyzed using an isocratic mobile phase by reversed-phase liquid chromatography. The lower limit of quantification was 50 ng/g for both brain and testis. A linear dynamic range of 50-5000 ng/g for both brain and testis was established. This HPLC method was validated with between-batch precision of 0.5-4.4 and 1.5-5.5% for brain and testis, respectively. The between-batch accuracy was 94.7-105.9% and 97.5-105.0% for brain and testis, respectively. The present method was applied for tissue distribution studies of the novel drug delivery systems of saquinavir in mice.
