Enteric and hydrophilic polymers enhance dissolution and absorption of poorly soluble acidic drugs based on micro-environmental pH-modifying solid dispersion

Abstract

The oral bioavailability of poorly water-soluble active pharmaceutical ingredient (API) is often inadequate for the desired therapeutic effect. Micro-environmental pH-modifying solid dispersion (micro pHm SD) is an effective method for enhancing the dissolution of pH-dependent soluble APIs. However, erratic bioavailability of these drugs was often found when the micro pHm SD of the drugs was orally administrated and passed through the gastrointestinal tract. Because the added alkalizer in micro pHm SD could be neutralized by the acid in the stomach, as a result not enough alkalizer is left to form alkaline micro-environment around the drug in the intestine, leading to poor dissolution and bioavailability of API. Enteric polymers are applicable materials for site-specific drug delivery that are insoluble in gastric tract but soluble in the intestine targeted for drug release. In this study, a poorly water-soluble model drug, toltrazuril (TOL), was prepared as enteric micro pHm SD with enteric, hydrophilic polymers and alkalizer. The surface of enteric micro pHm SD tablets staining and alkalizer protection test in the acid dissolution medium qualitatively and quantitatively confirmed the protective effects of the enteric polymer on the alkalizer. Dissolution studies revealed that the drug release from the enteric micro pHm SDs was improved significantly compared with micro pHm SD with no enteric polymer. The pH-dependent solubility of enteric polymer had effects on the dissolution of APIs from the SDs in neutral medium. Enteric micro pHm SDs with higher proportion of enteric polymer showed higher Cmax and dissolution rate of TOL. The physicochemical characterization and the molecular interaction between drug and matrix were analyzed by electron microscopy (SEM), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR), finding that the formation of hydrogen bonds between TOL and matrix was helpful to promote dissolution of TOL. Ca(OH)2-TOL-PVPk30-HPMCAS 8: 8: 18: 6 was determined as the most optimal enteric micro pHm SD, which significantly improved the bioavailability of TOL and its active metabolism (TOLSO, TOLSO2) in pharmacokinetic study and could effectively reduce the irritation of the gastrointestinal mucosa caused by the alkalizer Ca(OH)2 when the SD was orally administrated to rabbits. The present study demonstrates that formulating APIs with poor water solubility as enteric micro pHm SD is an effective method for protecting the alkalizer in SD and improving the dissolution of APIs and the bioavailability following oral administration.