| Azithromycin(AZI), known as a synthetic macrocyclic lactone antibiotic, is effective in bacterial conjunctivitis caused by a wide range of pathogenic bacterium such as staphylococcus, streptocossus, rod, mycoplasma and chlamydia. It has been included in the focus of drugs to combat eye infections such as trachoma conjunctivitis by the World Health Organization. In order to paly advantages of AZI in the treatment of eye infections and to overcome the problems of traditional dosages such as low bioavailability, the purpose of this study was to prepare and evaluate a new AZI ocular administration with stable physical and chemical properties—AZIE.An HPLC method in use of ion-pair reagents(sodium heptanesulfonate) was established for determination of AZI, the method validations were carried out and approved. The solubility, stability and oil phase-water phase partition of AZI were closely related with the pH of mediums. By increasing the pH of mediums, the solubility decreased and the oil phase-water phase partition turned higher. AZI was relatively stable with pH 6.0-6.5.The solubility of AZI in long-chain oils such as LCT, safflower oil and castor oil were all below 5mg·g-1 while it was 21.805 mg·g-1 in MCT. Therefore, MCT could be selected as an oil solvent for preparing AZIE.High pressure homogenization method was used to prepare AZIE. The final formulation and preparing process of AZIE were as follows:Tween80 0.4%, F68 0.4%, EL-40 0.3%, glycerol 2.2%, EDTA-2Na 0.05% and benzalkonium bromide 0.003% were dissolved in water for injection stirring at 70℃to obtain a water phase. Then, VE 0.05% was dissolved in MCT 8.5% stirring at 75℃to obtain a oil phase. Meanwhile, AZI 1.0%, soybean lecithin 1.8% and stearylamine 0.3% were co-dissolved in ethanol with stirring at 75℃in a water bath, then were mixed with the oil phase. The ethanol was removed by evaporation under a stream of nitrogen, and a clear oil phase was obtained. The oil phase was added to the water phase and mixed using a high-shear mixer at 10,000 rpm about 5 minutes to prepare the primary emulsion. After adjusting the pH to about 7.0 with 0.1 mol·L-1 HCl or 0.1 mol·L-1 NaOH solution, the primary emulsion was passed through a high pressure homogenizer(70 Mpa,8 cycles). Finally, the product was sealed in 10 ml bottles.The characterisics including PSD,ζ-potential, drug content and entrapment efficiency of three batches of AZIE were 188.6±67.517nm,24.40mV,101.8% and 90.1%,respectively. Freeze-thaw and shaking stability tests showed that AZIE had good shaking and coalescence stability. It was applicable to industrial production and transportation. The contrast tests were studied between AZIE and AZIS. Compared with AZIS, the results showed that AZIE had a more prominent advantage in viscosity, surface tension, as well as physical and chemical properties such as chemical stability. The physiochemical characters of three batches of AZIE were evaluated in detail. The AZIE could maintain stable for 6 months no weather at 6±2℃or at 25±2℃.UPLC/MS/MS method was established to determine AZI in rabbits tear. The results of pharmacokinetics showed that AZIE and AZIS had similar pharmacokinetic characteristics. AUCo-t and T1/2 of AZIE and AZIS were (2461.583±885.257) and(1532.389±441.595)μg·mL-1·h, and (3.898±1.325) and (2.388±0.815)h, respectively. The results showed that compared with AZIS, AZIE could stay in the conjunctival sac with a long time and had a certain role in improving bioavailability. |
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