李楠 李旭 程鹏 孔令钰 冯仁蕊 谭淞文

摘 要 目的：制備一种新型的纳米多孔花形乳糖（FL）装载姜黄素（Cur）干粉吸入剂（DPI），为难溶性药物治疗慢性阻塞性肺疾病提供一种安全、高效的肺内递药方式。方法：采用溶液吸附法制备FL微粒装载Cur（Cur-FL）复合粉末。以载药量和吸附率为指标，通过单因素试验优选Cur投药浓度、Cur与FL的投药比例（m/m）和吸附时间，以确定Cur-FL复合粉末的最佳制备工艺。采用傅里叶变换红外光谱、扫描电子显微镜、差示扫描量热法等技术对以最优工艺制备的Cur-FL复合粉末的理化性质进行表征;测定其含水量并考察其空气动力学性质;通过体外模拟人工肺液环境，探讨其体外释药行为。结果：Cur-FL复合粉末的最佳制备工艺为Cur投药浓度5 mg/mL、Cur与FL的投药比例1 ∶ 4、吸附时间1 h。所得复合粉末的载药量为（23.37±0.43）%、包封率为（91.64±0.44）%、吸附率为（30.50±0.72）%。Cur-FL微粒呈花形外观;Cur被物理吸附在FL微粒孔隙内，未发生化学变化。Cur-FL复合粉末的松密度为（0.21±0.02） g/cm3、振实密度为（0.33±0.01） g/cm3、休止角为（24.07±0.31） °、平均粒径为（3.96±0.80） μm、空气动力学粒径为（3.33±0.99） μm、含水量为（5.63±0.24）%、排空率为（92.53±0.87）%、体外有效部位沉积率为（45.93±1.77）%;其在人工肺液中的24 h溶解度[（358.93±1.67） μg/mL]为Cur的3.28倍、48 h累积体外释放率（90.21%）为Cur的1.63倍，而Cur+FL物理混合物不能提高Cur在人工肺液中的溶解度和释放度。结论：所制Cur-FL复合粉末的体外释药性能较好，且其粉体学性质、溶解性、水分、流动性及空气动力学性能等均符合《中国药典》对DPI的要求。

关键词 姜黄素;花形乳糖;干粉吸入剂;制备;体外释药

中图分类号 R943 文献标志码 A 文章编号 1001-0408（2021）07-0794-08

ABSTRACT   OBJECTIVE： To preparea novel Curcumin （Cur） dry powder inhalation （DPI） loaded by nanoporous flower-shaped lactose （FL）， and to provide a safe and effective intrapulmonary drug delivery method for the therapy of chronic obstructive pulmonary disease with insoluble drugs. METHODS： FL-loaded Cur （Cur-FL） compound powder was prepared by solution adsorption method. Using drug-loading amount and adsorption rate as indicators， single-factor experiment was used to optimize Cur concentration，Cur-FL ratio （m/m） and adsorption time so as to determine the optimal preparation technology for Cur-FL compound powder. Fourier transform infrared spectroscopy， scanning electron microscope and differential scanning calorimetry were used to characterize the physical and chemical properties of Cur-FL compound powder prepared with optimal technology. The water content and aerodynamic properties were determined; in vitro drug release behavior was investigated by simulating the environment of artificial lung fluid. RESULTS： The optimal preparation technology of Cur-FL compound powder was Cur concentration of 5      mg/mL， Cur-FL ratio of 1 ∶ 4， adsorption time of 1 h. The drug-loading amount of compound powder was （23.37±0.43）%， the encapsulation rate was （91.64±0.44）%， and the adsorption rate was （30.50±0.72）%. Cur-FL particles were flower shaped;Cur was physically adsorbed in the pores of FL without chemical changes. The bulk density of Cur-FL compound was （0.21±0.02）     g/cm3， tap density was （0.33±0.01） g/cm3， angle of repose was （24.07±0.31） °， average particle size was （3.96±0.80）  μm， aerodynamic particle size was （3.33±0.99） μm， water content was （5.63 ±0.24）%， emptying rate was （92.53±0.87）%， and deposition rate of effective parts in vitro was （45.93±1.77）%. Its 24 h solubility in artificial lung fluid [（358.93±1.67） μg/mL] were 3.28 times of Cur， 48 h cumulative release ratesin in vitro （90.21%） were 1.63 times of Cur， but Cur+FL physical mixture could not improve the solubility and release of Cur in artificial lung fluid. CONCLUSIONS： Cur-FL compound powder has good in vitro release property， and its powder properties， solubility， water content， fluidity and aerodynamic properties meet the requirements of DPI in Chinese Pharmacopoeia.

KEYWORDS   Curcumin; Flower-shaped lactose; Dry powder inhaler; Preparation; in vitro drug release

慢性阻塞性肺疾病（Chronic obstructive pulmonary disease，COPD）是一种以持续呼吸道症状和气流受限为特征的炎性疾病[1]。……