Abstract
The aim of this study was the successful utilization of the positively charged nanocrystals (NCs) of Tedizolid Phosphate (TZP) (0.1% w/v) for topical ocular applications. TZP belongs to the 1, 3-oxazolidine-2-one class of antibiotics and has therapeutic potential for the treatment of many drug-resistant bacterial infections, including eye infections caused by MRSA, penicillin-resistant Streptococcus pneumonia and vancomycin-resistant Enterococcus faecium. However, its therapeutic usage is restricted due to its poor aqueous solubility and limited ocular availability. It is a prodrug and gets converted to Tedizolid (TDZ) by phosphatases in vivo. The sterilized NC1 was subjected to antimicrobial testing on Gram-positive bacteria. Ocular irritation and pharmacokinetics were performed in rabbits. Around a 1.29 to 1.53-fold increase in antibacterial activity was noted for NC1 against the B. subtilis, S. pneumonia, S. aureus and MRSA (SA-6538) as compared to the TZP-pure. The NC1-AqS was "practically non-irritating" to rabbit eyes. There was around a 1.67- and 1.43 fold increase in t(1/2) (h) and C-max (ngmL(-1)) while there were 1.96-, 1.91-, 2.69- and 1.41-times increases in AUC(0-24h),AUC(0-infinity),AUMC(0-infinity) and MRT0-infinity, respectively, which were found by NC1 as compared to TZP-AqS in the ocular pharmacokinetic study. The clearance of TDZ was faster (11.43 mLh(-1)) from TZP-AqS as compared to NC1 (5.88 mLh(-1)). Relatively, an extended half-life (t(1/2); 4.45 h) of TDZ and the prolonged ocular retention (MRT0-infinity; 7.13 h) of NC1 was found, while a shorter half-life (t(1/2); 2.66 h) of TDZ and MRT0-infinity(t(1/2); 5.05 h)was noted for TZP-AqS, respectively. Cationic TZP-NC1 could offer increased transcorneal permeation, which could mimic the improved ocular bioavailability of the drug in vivo. Conclusively, NC1 of TZP was identified as a promising substitute for the ocular delivery of TZP, with better performance as compared to its conventional AqS.