Mizoe Takuto, Ozeki Tetsuya, Okada Hiroaki
Laboratory of Pharmaceutics and Drug Delivery, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
AAPS PharmSciTech. 2008;9(3):755-61. doi: 10.1208/s12249-008-9109-x. Epub 2008 Jun 18.
The purpose of this study was to use a four-fluid nozzle spray drier as a new one-step method for preparing rifampicin (RFP)-containing mannitol microparticles. A RFP-acetone/methanol (2:1) solution and aqueous solutions of mannitol (MAN) were simultaneously supplied through different liquid passages of a four-fluid nozzle spray drier and then dried to obtain MAN microparticles containing RFP. Using a cascade impactor, the in vitro aerosol performance of RFP powder and RFP-MAN microparticles with 1:5, 1:10, and 1:20 ratios was compared. The in vivo retention of RFP in the lungs of rats after intratracheal administration of 1:20 RFP-MAN microparticles was also compared. The RFP-MAN microparticles had better aerosol performance than RFP powder and delivery to the lung stages improved as the fraction of MAN was increased. For the 1:20 RFP-MAN microparticles, deposition in stages 2-7 was approximately 43%, which is sufficient for treatment. Approximately 8% of the RFP-MAN microparticles were deposited in stages 6-7, which corresponds to alveoli containing alveolar macrophages. The initial retention of RFP in the lung following pulmonary delivery of 1:20 RFP-MAN microparticles was higher than following oral or intravenous administration of RFP, but the elimination was rapid, resulting in the disappearance of RFP from the lung within 4 h. The plasma concentration-time profile of RFP after intratracheal administration of 1:20 RFP-MAN microparticles was consistent with the profile for RFP retention in the lung. Addition of cholesterol or phosphatidylcholine to RFP had little effect on its retention in the lung. The RFP-MAN microparticles were effective for delivery of RFP to the lung, but the RFP rapidly removed from the lung into the blood circulation. This study demonstrated that RFP-containing MAN microparticles prepared in one step using the four-fluid nozzle spray drier efficiently deliver RFP to the lung, although methods must be developed to prolong its retention and improve targeting to alveolar macrophages.
本研究的目的是使用四流体喷嘴喷雾干燥器作为一种新的一步法来制备含利福平（RFP）的甘露醇微粒。将RFP - 丙酮/甲醇（2:1）溶液和甘露醇（MAN）水溶液通过四流体喷嘴喷雾干燥器的不同液体通道同时供应，然后干燥以获得含RFP的MAN微粒。使用级联撞击器，比较了RFP粉末以及比例为1:5、1:10和1:20的RFP - MAN微粒的体外气溶胶性能。还比较了气管内给予1:20 RFP - MAN微粒后RFP在大鼠肺部的体内滞留情况。RFP - MAN微粒的气溶胶性能优于RFP粉末，并且随着MAN比例的增加，肺部递送阶段有所改善。对于1:20 RFP - MAN微粒，第2 - 7阶段的沉积约为43%，这足以用于治疗。约8%的RFP - MAN微粒沉积在第6 - 7阶段，这对应于含有肺泡巨噬细胞的肺泡。肺部递送1:20 RFP - MAN微粒后RFP在肺部的初始滞留高于口服或静脉注射RFP后的情况，但消除迅速，导致RFP在4小时内从肺部消失。气管内给予1:20 RFP - MAN微粒后RFP的血浆浓度 - 时间曲线与RFP在肺部的滞留曲线一致。向RFP中添加胆固醇或磷脂酰胆碱对其在肺部的滞留影响很小。RFP - MAN微粒对将RFP递送至肺部有效，但RFP迅速从肺部进入血液循环。本研究表明，使用四流体喷嘴喷雾干燥器一步制备的含RFP的MAN微粒可有效地将RFP递送至肺部，尽管必须开发方法来延长其滞留时间并改善对肺泡巨噬细胞的靶向性。
