反溶剂重结晶法制备布地奈德超细颗粒及其肺部给药体外评价

Preparation of Budesonide Ultra-fine Particles by Antisolvent Recrystallization and their in vitro Evaluation for Pulmonary Delivery

利用反溶剂重结晶法对平喘药布地奈德进行了超细颗粒的制备研究。当以甲醇为溶剂,水为反溶剂时,分别考察了甲醇-水的体积比、混合强度和干燥方式对产品平均粒径和收率的影响。结果表明,当布地奈德甲醇溶液与水的体积比为1:7,搅拌转速高于5000r·min-1时,浆料中可得到平均长径3μm、短径2μm、厚度200nm的椭圆形片状颗粒,并且一次收率为96.02%。将此布地奈德浆料通过真空干燥和喷雾干燥后,产品均可保持浆料中颗粒的大小与形貌,而经喷雾冷冻干燥后则变为10～20μm左右的球形颗粒。FT-IR和XRD分析显示,与原料药和气流粉碎商品相比,反溶剂重结晶制得的布地奈德的化学结构与晶型均无改变。此外,经肺部给药体外评价,椭圆形片状颗粒具有最优的沉积分布,FPF值高达60%以上,分别比原料药和气流粉碎商品提高了9倍和1.5倍。

The budesonide ultra-fine particles were delivery. Methanol was used to form the budesonide prepared by antisolvent recrystallization for pulmonary solution, and the water was chosen as the antisolvent to induce precipitation. The main factors affecting the particle size of the precipitates were investigated; they are the volume ratio of methanol to water, the stirring speed and the drying methods. The results indicate that the elliptic flaky particles with average 3 μm in length, 2μm in width and 200 nm in thickness were obtained from the slurry when the ratio of methanol to water is 1：7 and the stirring speed is over 5000 r·min^-1; and the recovery of the recrystallization process can be up to 96.02%. The size and morphology of the particles in the slurry do not change after vacuum drying or spray drying. However, the spray-freeze dried particles have spherical shape with 10-20μm in diameter. As assessed by FT-IR and XRD, all the as-prepared budesonide dry powders have the same chemical structure and crystal form as the raw material and jet-milled budesonide. In vitro evaluations with an Aerolizer inhaler and a multi-stage liquid impinger show that the flaky particles have better aerosol performance because their FPF value （fine particle fraction） could be over 60%, which is 9 times and 1.5 times higher than that of raw material and jet-milled budesonide, respectively.