【作者】 降立川；

【导师】 陈建峰；

【作者基本信息】 北京化工大学 ， 化学工程， 2007， 硕士

【摘要】 布地奈德(Budesonide, BUD)是第一个高度选择性的吸入型糖皮质激素药物,目前市场占有率为国际上抗哮喘药物的前三位,主要用于吸入剂型。对于吸入剂型,其颗粒是能否到达靶向目标起到疗效,粒子的大小是最关键的因素之一。本课题主要利用反溶剂重结晶法制备超细BUD颗粒,系统地研究了：(1)在烧杯中溶剂-反溶剂种类及比例、混合方式及强度、结晶温度与结晶时间等实验参数对BUD颗粒大小的影响规律；(2)表面活性剂对结晶过程的控制作用；(3)在微通道反应器和超重力旋转床中BUD的结晶过程。并将上述自制的超细BUD粉体制成了干粉吸入剂,利用多层液体撞击器(Multi-Stage Liquid Impinger, MSLI)研究了BUD颗粒的体外模拟沉降分布情况。结果表明,在溶剂-1/水(或溶剂-2/水)体系中,当BUD溶剂-1(或溶剂-2)溶液浓度为2.5～3.0%(g·mL-1)、溶液/水的体积比为1：(7～10)、结晶温度为5℃,搅拌转速大于5000r·min-1,搅拌时间5min及普通干燥温度为60℃时,可以得到长径为1-5μm、厚度小于300nm、且粒度分布均匀的纺锤形(或方形)片状BUD粉体颗粒,所得两种粉体尺寸上无显著差异,后者的分散性能略优于前者。在表面活性剂-1(浓度为0.16%,g·mL-1)存在的情况下,制备得到了长轴在1·5μm之间单分散状的椭球形颗粒。通过考察微反应器和超重力旋转床中的制备过程,发现BUD颗粒的生长过程中存在无定型和结晶型两个状态,通过控制外部搅拌条件或添加表面活性剂的方法可得到稳定的结晶型颗粒。采用红外光谱仪、X射线衍射仪等进行分析测试,所有自制结晶型产品的化学组成和晶体结构均与原料药完全吻合。此外经MSLI测试,体外模拟肺部沉积量最高可达68.57%,比原料药结果(7.33%)提高了近10倍。结果表明其性能优于原料药,充分显现了超细化药物的优势所在。更多还原

【Abstract】 Budesonide (BUD) is the first high-selectivity inhaled glucocorticosteroid (IGCS) drug, and its market sales are ranking first in the pharmaceuticals for the treatment of asthma. For IGCS, the particle size and corresponding size distribution are the key factors, which determine if drug particles can reach the site of action. Drug particles with smaller diameter are easier to enter the respiratory tract and reach the alveoli. Therefore, the particle size reduction is a very effective method to improve the efficiency of pulmonary drug delivery.In this study, ultra-fine BUD particles were successfully prepared by anti-solvent recrystallization method. The following parts were systematically investigated:(1) the effects of experimental parameters on particle size and morphology, such as the solvent and anti-solvent, the volume ratio of solution to anti-solvent, temperature, concentration of BUD solution and stirring speed, etc.,(2) the effects of surfactants in the crystallization process,(3) the crystallization process of BUD particles in micro-reactor and inside circulation rotating packed bed (RPB). Furthermore, the properties of as-prepared BUD powders were assessed by multi-stage liquid impinger (MSLI), in a new formulation, dry powder inhaler (DPI).When solvent-1and/or solvent-2used as the solvent, ultra-fine BUD particles with flake-like could be prepared and their particle size could be well-controlled under the following conditions:the volume ratio of solution to anti-solvent1/(7～10), crystallization temperature5℃, BUD solution concentration0.025～0.03g/ml, stirring speed at5000rpm, stirring time5min and oven drying at60℃. The mean major axis size and thickness of the particles were1～5μm and lower than300nm respectively, with narrow particle size distribution. There was not apparently difference in particle size between the powders prepared in solvent-1and solvent-2. In the presence of surfactant-1(0.16%, g·mL-1), mono-dispersed particles with ellipsoidal shape could be prepared by anti-solvent recrystallization method. The mean diameter of the particles in major axis was1～5μm. Additionally, by studying the preparation process in micro-reactor and RPB, it was proved that there existed a transformation from amorphism to crystallinity in the particle growth. Stable crystalline particles could be obtained by controlling the stirring conditions and/or adding some surfactants.The Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) analysis indicated that no chemical decomposition took place during the process, and no crystal structure of the drug occurred. In deposition experiment, the fine partial fraction (FPFemitted) of BUD drug powder was68.57%, almost ten times than that of raw material. The as-prepared powders could be used for inhalation directly and be good for improving drugs bioavailability.更多还原