用于肺部给药的磷酸奥司他韦微粉的制备及肺组织分布初步考察

Preparation and Preliminary Investigation on Lung Distribution of Oseltamivir Phosphate Powders for Pulmonary Administration

磷酸奥司他韦(1)是一种神经氨酸酶抑制剂类抗流感病毒药物。采用喷雾干燥方法制备了可用于肺部吸入给药的1微粉。通过正交设计得到的最优处方为:1 20%、亮氨酸20%、甘露醇60%,溶于去离子水中配成2%的溶液,喷雾干燥制得体积平均径为(2.907±0.105)μm、休止角为(29.2±2.0)°的微粉,产率为(58.1±3.2)%。使用Aerolizer~?吸入装置对装入胶囊的微粉进行雾化分散,测得其微细粒子分数为(36.2±2.8)%。大鼠肺部刺激性试验表明该微粉无明显肺部刺激性。肺组织分布试验表明1微粉肺部给药后大鼠肺部活性代谢产物奥司他韦羧酸含量高于口服同剂量1微粉溶液组。提示本研究制得的1微粉吸入后对呼吸道病毒感染可能会比口服发挥更好的治疗作用。

Oseltamivir phosphate （1）, one of neuraminidase inhibitors, is usually used for the treatment and prophylaxis of infections with influenza A and B virus subtypes. In this study, 1 powders were prepared by spray drying method for pulmonary inhalation administration. The formulation was optimized by orthogonal design. The optimal formulation was as follows： 1 （20%）, leucine （20%） and mannitol （60%） were dissolved in deionized water to make a 2 % solution, followed by spray drying to obtain 1 powders with the volume averaged diameter of （2.907±0.105）μm, the repose angle of （29.2±2.0）°, and the yield of （58.1±3.2） %. The drug was shown to be stable in the spray drying process. The powders were filled into capsules and dispersed using Aerolier, and the fine particle fraction （FPF） was （36.2a： 2.8） %. Lung stimulation tests showed the powders had no obvious toxicity to lung tissues of rats. Lung distribution studies was performed with rats as the animal model, and oseltamivir carboxylate, the bioactive metabolite of 1, in lungs was determined by HPLC. The results showed that higher concentration of oseltamivir carboxylate in lung tissues could be obtained following pulmonary administration compared with oral administration of the same dosage; AUC of the pulmonary group was （22.15±5.18）μg·h·g^-1, which was higher than that of the oral group [ （6.84±2.41）μg·h·g^-1]. These results indicated that 1 powders prepared in this study might be used to treat the influenza virus infection with higher efficiency than the oral preparations.