The Study On The Ophthalmic Drug Delivery System Of Levofloxacin Hydrochloride

The complexity of the eye and its special pharmacokinetic environment, which present great challenges in designing ophthalmic dosage forms, promote more effective drug delivery systems with better compliance to be developed. In this dissertation, levofloxacin hydrochloride (LVFX) was selected as the model drug, then an ophthalmic solution of LVFX and an in situ thermosensitive gelling ophthalmic drug delivery system for LVFX were developed, as well as the tear elimination kinetics and aqueous humor pharmacokinetics in rabbits were mainly studied. Main sections were included in this paper:The solubility and oil/water partition coefficient of LVFX were correlated with the pH value of aqueous media.LVFX is freely soluble in water at various pH conditions. The maximum oil/water partition coefficient is at pH 6.5. In vitro analytical methods of determining the content of LVFX and the related substances have been established and tested.In accordance with quality control of CP2005, LVFX ophthalmic solution was prepared. The formulation screening for in situ thermosensitive gel was performed using modulated gelation temperature (GT) and kinetics of gel dissolution and drug release. The optimal formulation of in situ gel was obtained with 20%poloxamer 407, 8%poloxamer 188 and 0.2%sodium hyaluronate.The main pharmaceutical properties of ophthalmic drug delivery system for LVFX such as osmotic pressure, viscosity, stability and irritancy were studied. The stability and irritancy of the ophthalmic solution of LVFX and in situ thermosensitive gel of LVFX complied with the requirement for ophthalmic application, and no irritation was observed.The tears were obtained by filter paper method. RP-HPLC method for determination of LVFX in rabbit tears was developed. The results of the tear elimination kinetics study showed that the AUC0-t and MRT for LVFX in situ thermosensitive gel were 2.73 and 3.12 folds than the control, respectively. Microdialysis sampling combined with HPLC-MS was used for the study of pharmacokinetics in aqueous humor. The factors affecting the recovery of the microdialysis probe were studied, and the probes were perfused at a flow rate of 2μl/min. The recovery and delivery for LVFX were coincident 62.62%, in vitro assessed using concentration difference method. The in vivo recovery of the three probes planted in three rabbit eyes were 45.85%,48.50%,41.92%, respectively, determined by retrodialysis method. The results of the aqueous humor pharmacokinetic study showed that the AUC0-t and MRT for LVFX in situ thermosensitive gel were 2.3 and 1.4 folds, respectively, in contrast with that of the control group, with higher Cmax and postponed Tmax. The in situ thermosensitive gel had substaintially increased the bioavailability of levofloxacin and showed great potential in ophthalmic application.