| ObjectiveMethazolamide (MTZ) is an antiglaucoma drug; however, there are many side effects for its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTZ-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as an ophthalmic drug delivery system.Methods1 In vitro, the quantitative determination of MTZ was performed by HPLC. Preformulation study included solubility, partition coefficients and aqueous stability, provided a theoretical basis for the formulation design.2 SLNs preparation methods and determination of entrapment efficiency (EE %) were investigated. Optimized formulation was obtained by single factor evaluation, orthogonal design and Box-Behnken method.3 The physicochemical properties of SLNs were investigated. Infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction were employed for the analysis of the matrix state, polymorphism and phase behavior of the nanoparticles; then the in vitro release and SLNs stability were studied.4 Rabbits were used as animal model. MTZ concentrations in aqueous humor were determined by HPLC. In vivo evaluations of different preparations were studied including pharmacodynamics (determining the percentage decrease in intraocular pressure), pharmacokinetics and single-dose ocular irritation.Results1 MTZ was detected with HPLC at 290 nm and the method validation was reasonable. MTZ was slightly soluble in water, about 1.65 mg/mL. An increase of solubility was observed when the pH value increased, and there was certain linear correlation between solubility and partition coefficients. MTZ degradation followed first-order rate kinetic, the most stable pH was 5. Temperature, buffer concentration, ionic strength and phosphate buffer catalyzed the degradation of MTZ.2 Modified emulsion-solvent evaporation method was employed to prepare SLNs. EE% was determined by ultrafiltration method. The preparation process was of good reproducibility.3 Transmission electron micrograph of SLNs showed that the particles had nearly spherical shape. The mean particle size measured was 197.8 nm with a narrow particle distribution of polydispersity index, 0.239. SLNs exhibited positive zeta potential value at 32.7 mV. Osmotic pressure and pH value were in compliance with the requirements of ocular drug formulations. The average drug entrapment ef?ciency and loading were 68.39% and 2.49%, respectively. FI-IR, DSC and X-ray diffraction measurements suggested that the majority of the SLNs were less ordered arrangement of crystals, and this was favorable for increasing the drug loading capacity. MTZ-SLNs in vitro release curve fitted with Weibull equation. The study of drug release showed that there was a burst release at pattern initial stage, and then sustained release. The physical stability experiment indicated that the SLNs were stable for 30 days under 4℃.4 HPLC was a reasonable method used to determine the MTZ concentrations in rabbit aqueous humor. Therapeutic efficacy could continue over 8 h after administration of SLNs, and drug concentrations in aqueous humor were significantly higher than solution at every time point. There was no sign of irritation effects to ocular tissues in rabbit eyes. ConclusionThe process of MTZ-SLNs prepared was simple, which displayed good stability, therapeutic efficacy and no-irritation. Administration of SLNs could improve drug permeation, prolong duration, bioavailability, and reduce side effects which had good prospects for clinical application. |
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