Abstract

This study investigates the effects of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of micro-environment pH modifying solid dispersions(pH_M-SD) for the poorly water-soluble model drug Toltrazuril (TOL). Various pH_M-SDs were prepared using Ca(OH)₂ as a pH-modifier in hydrophilic polymers, including polyethylene glycol 6000 (PEG6000), polyvinylpyrrolidonek30 (PVPk30) and hydroxypropyl methylcellulose (HPMC). Based on the results of physicochemical characterizations and in-vitro dissolution testing, the representative ternary (Ca(OH)₂:TOL:PEG6000/HPMC/PVPk30 = 1:8:24, w/w/w) and binary (TOL:PVPk30 = 1:3, w/w) solid dispersionswere selected and optimized to perform in-vivo pharmacokinetic study. The micro-environment pH modification improved the in-vitro water-solubility and in-vivo bioavailability of parent drug TOL.Furthermore, the addition of alkalizers not only enhanced the release and absorption of prototype drug, but also promoted the generation of active metabolites, including toltrazuril sulfoxide (TOLSO)and toltrazuril sulfone (TOLSO₂). The in-vitro dissolution profiles and in-vivo absorption, distributionand metabolism behaviors of the pH_M-SDs varied with polymer type. Moreover, in-vivo bioavailability ofthree active pharmaceutical ingredients increased with an increase in in-vitro dissolution rates of the drug from the pH_M-SDs prepared with various polymers. Therefore, a non-sink in-vitro dissolution method can be used to predict thein-vivo performance of pH_M-SDs formulated with various polymers with trend consistency. In-vitro andin-vivo screening procedures revealed that the pH_M-SD composed of Ca(OH)₂, TOL and PVPk30 at a weight ratio of 1:8:24, of which the safety was adequately proved via histopathologicalexamination, may be a promising candidate for providing better clinical outcomes.

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