| Objective:Brinzolamide (BLZ) is the second carbonic anhydrase inhibitor (CAIs) which was used to treat glaucoma; however, its use is restricted due to some unwanted adverse events. The goal of this study was to develop BLZ loaded liquid crystalline nanoparticles (BLZ LCNPs) and to figure out the possibility of LCNPs as a new therapeutic system for glaucoma. The goal of this study was to design an innovative carrier built on LCNPs as an ocular delivery system of BLZ that would decrease ocular irritancy and promote bioavailability. BLZ LCNPs were prepared, and their internal configuration was further analyzed by TEM and SAXS. In vitro and in vivo profiles were studied finally taking AZOPT(?) as positive control.Methods:1The in vitro quantitative determination of BLZ was performed by HPLC; preformulation study included solubility, partition coefficients, which provided a theoretical basis for the formulation design;2LCNPs preparation methods and determination of entrapment efficiency (EE%) were investigated. Optimized formulation was obtained by single factor, orthogonal design method;3The physicochemical properties of LCNPs were investigated. Infrared spectroscopy, transmission electron microscopy (TEM) and small angle X-ray scattering (SAXS) measurement were employed for the analysis of the LCNPs. Then the in vitro release, Ex vivo corneal penetration study and LCNPs stability were studied;4Rabbits were used as animal model. BLZ concentrations in aqueous humor were determined by HPLC. In vivo evaluations of different preparations were studied by the same body of self-control method, including pharmacodynamics (determining the percentage decrease in intraocular pressure), pharmacokinetics and long time ocular irritation;Results:1BLZ detection wavelength was set254nm and the detective method validation was reasonable. The solubility of BLZ was about41.61μg/mL and1538.05μg/mL in water and STF, respectively. An increase of solubility was observed when the pH value increased, and there was linear correlation between solubility and partition coefficients.2Modified emulsification method was employed to prepare LCNPs. EE%was determined by ultrafiltration method. The preparation process was good reproducibility;3Transmission electron micrograph of LCNPs showed that the particles had nearly spherical shape, the mean particle size was about190nm. The mean particle size measured was185nm with a narrow particle distribution of polydispersity index,0.118. LCNPs exhibited slight negative zeta potential value at-1.7mV. pH value and osmotic pressure were in compliance with requirements of ocular drug formulations. The average drug entrapment efficiency and loading were94.64%and1.86%, respectively. FI-IR, TEM and SAXS measurements suggested that the majority of the LCNPs were less ordered arrangement of crystals, and this was favorable for increasing the drug loading capacity. BLZ-LCNPs in vitro release curve was fitted Weibull equation. The studies of drug release showed that there was a burst release at pattern initial stage, and then showed a sustained release behavior. The ex vivo apparent permeability coefficient of BLZ LCNP systems demonstrated a3.47-fold increase compared with that of AZOPT(?);4HPLC was used to determine the BLZ concentrations in rabbit aqueous humor, and the detective method was reasonable. Therapeutic efficacy after administration of SLNs could continue over8h, and drug concentrations in aqueous humor were significantly higher than solution at every time point. There were no sign of irritation effects to ocular tissues in rabbit eyes after long time administration;Conclusion:In this study, LCNPs were investigated as an ocular drug delivery system. BLZ LCNPs provided appropriate particle size with better tolerability, good IOP-lowering strength as AZOPT(?) in lower doses and longer duration of action. Consequently, the ophthalmic bioavailability of BLZ has been greatly improved. It proposed that LCNPs are favorable therapeutic system for local administration in the treatment of glaucoma. |
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