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Perspectives of Positively Charged Nanocrystals of Tedizolid Phosphate as a Topical Ocular Application in Rabbits

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 t1/2 (h) and Cmax (ngmL−1) while there were 1.96-, 1.91-, 2.69- and 1.41-times increases in AUC0–24h,AUC0–∞,AUMC0–∞ and MRT0–∞, 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 (t1/2; 4.45 h) of TDZ and the prolonged ocular retention (MRT0–∞; 7.13 h) of NC1 was found, while a shorter half-life (t1/2; 2.66 h) of TDZ and MRT0–∞(t1/2; 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.

SUBMITTER: Alshememry A

PROVIDER: S-EPMC9325164 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Topical ophthalmic antibiotics show low efficacy due to the well-known physiological defense mechanisms of the eye, which prevents the penetration of exogenous substances. Here, we aimed to incorporate besifloxacin into liposomes containing amines as positively charged additives and to evaluate the influence of this charge on drug delivery in two situations: (i) iontophoretic and (ii) passive treatments. Hypothesis are (i) charge might enhance the electromigration component upon current application improving penetration efficiency for a burst drug delivery, and (ii) positive charge might prolong formulation residence time, hence drug penetration. Liposomes elaborated with phosphatidylcholine (LP PC) or phosphatidylcholine and spermine (LP PC: SPM) were stable under storage at 6 ºC for 30 days, showed mucoadhesive characteristics, and were non-irritant, according to HET-CAM tests. Electron paramagnetic resonance spectroscopy measurements showed that neither the drug nor spermine incorporations produced evident alterations in the fluidity of the liposome's membranes, which retained their structural stability even under iontophoretic conditions. Mean diameter and zeta potential were 177.2 ± 2.7 nm and - 5.7 ± 0.3 mV, respectively, for LP PC; and 175.4 ± 1.9 nm and + 19.5 ± 1.0 mV, respectively, for LP PC:SPM. The minimal inhibitory concentration (MIC) and the minimal bactericide concentration (MBC) of the liposomes for P. aeruginosa showed values lower than the commercial formulation (Besivance). Nevertheless, both formulations presented a similar increase in permeability upon the electric current application. Hence, liposome charge incorporation did not prove to be additionally advantageous for iontophoretic therapy. Passive drug penetration was evaluated through a novel in vitro ocular model that simulates the lacrimal flow and challenges the formulation resistance in the passive delivery situation. As expected, LP PC: SPM showed higher permeation than the control (Besivance). In conclusion, besifloxacin incorporation into positively charged liposomes improved passive topical delivery and can be a good strategy to improve topical ophthalmic treatments.

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Perspectives of Positively Charged Nanocrystals of Tedizolid Phosphate as a Topical Ocular Application in Rabbits

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