Microenvironment pH modified solid dispersion of Toltrazuril as a new strategy to improve the treatment of...

The phylum Apicomplexa contains some of the most serious human and veterinary parasites, including Eimeria magna, Toxoplasma gondii, and many others. Toltrazuril (TOL) has activity against multiple stages of Apicomplexan parasites, but its clinical use is limited by low bioavailability. In present study, we prepared one new formulation named the microenvironment pH modified solid dispersion (pH_M-SD), which was composed of three components including Ca(OH)₂, TOL, and PVPk30 with the weight ratio of 1:8:8. In vivo evaluation for bioavailability and efficacy of the pH_M-SD was conducted following oral administration and hypodermic injection. The performance of the pH_M-SD was also contrast to corresponding results of raw material drug and commercial Baycox® to evaluate the advantages for clinical application. The results showed that the bioavailability of prototype TOL and its active metabolites toltrazuril sulfoxide (TOLSO), toltrazuril sulfone (TOLSO₂) in rabbits were improved remarkably after oral administration of the pH_M-SD. The safety of the pH_M-SD via oral administration was adequately verified via the histopathological examination. We subsequently evaluated effects of the pH_M-SD on Eimeria magna oocysts and Toxoplasma gondii tachyzoites. In vivo anti-coccidia efficacy further confirmed that the pH_M-SD could be used as a strategy to minimize the oocyst exposure. In vitro cytotoxicity and anti-Toxoplasma tests showed that the pH_M-SD had little damage to host cells within the concentration of 100 μg/ mL, and the anti-Toxoplasma efficacy was significantly improved compared with TOL. Combined with the above-mentioned experimental results, we conclude that the pH_M-SD maybe a promising candidate for providing better clinical outcomes.