共研磨法制备吸入用丹酚酸—丹参酮复合微粉及其表征(1)
[摘要]建立了一种将丹参中的脂溶性和水溶性有效成分共微粉化的方法，制备得到了适用于肺部吸入给药的丹酚酸-丹参酮复合微粉。以湿法球磨粉碎为制备方法，复合微粉1～5 μm体积分数为评价指标，采用中心组合实验设计(central composite design，CCD)-效应面法进行工艺优化。通过扫描电镜、激光粒度分布仪、X-射线衍射分析仪等对复合微粉进行质量评价，并测定其流动性和引湿性。结果显示最优制备工艺条件下得到的丹酚酸-丹参酮复合微粉粒径分布均一，D50为2.33 μm，1～5 μm体积分数为80.82%，休止角为(50.60±1.13)°，临界相对湿度约为77%。共微粉化使药物微粒的粒径显著减小，药物的无定形物稍有增加，对粉体的流动性、吸湿性无显著影响。该研究表明湿法球磨可用于性质差异大的多种成分的共微粉化，制备得到适于吸入的丹酚酸-丹参酮复合微粉，为进一步吸入粉雾剂的制备提供基础。
[关键词]丹参总酚酸；总丹参酮；湿法球磨粉碎；中心组合实验设计；吸入粉雾剂
[Abstract]Salvianolic acids and tanshinones are main hydrophilic and lipophilic extracts from Salvia Miltiorrhiza with significant anti-pulmonary fibrosis effects. The aim of this study was to prepare a co-micronized salvianolic acids-tanshinones composite powder for inhalation using a planetary ball mill. The micronization process parameters were optimized by central composite design (CCD) and response surface methodology (RSM). Treatment time， rotation speed and the ball/sample weight ratio were selected as the independent variables， and the volume fraction of particle size in 1-5 μm was taken as the dependent variable. The powder properties were evaluated by scanning electron microscopy (SEM)， laser diffraction and X-ray powder diffraction (XRPD). The powder flow and hygroscopicity were determined with repose angle， compressibility index and critical relative humidity(CRH). According to the results， the salvianolic acids-tanshinones composite powder produced in optimal conditions had a narrow and unimodal particle size distribution and a smaller D50 of 2.33 μm. The volume fraction of particle size in 1-5 μm was 80.82%. The repose angle was (50.60±1.13)o， and the critical relative humidity is about 77%. After being micronized， the particle size significantly reduced， and the number of amorphous substances slightly increased， with no significant changes in powder flow and hygroscopicity. These findings indicate that the grinding method with a planetary ball mill can be used to co-micronize various components with different properties and prepare composite drug powders for dry powder inhalation.
[Key words]salvianolic acids； tanshinones； ball mill； central composite design； inhalation
丹参是中医治疗心血管系统疾病的常用药物，其主要有效成分包括水溶性酚酸类化合物和脂溶性丹参酮类化合物。大量研究显示2类成分对特发性肺纤维化均具有良好的疗效[1-2]，丹酚酸以抗氧化[3]和抑制成纤维细胞增殖[4-5]作用为主，而丹参酮则主要通过减轻炎症反应[6]、抑制成纤维细胞增殖和活化[7-8]、促进细胞外基质水解[9]等途径。2类成分的作用机制有重合，也相互补充，可从多途径发挥联合治疗特发性肺纤维化的作用。
行星式球磨机常用于多种药效成分或与其他辅料的混合及共微粉化，可实现亚微米级甚至纳米级[10]的超微粉碎[11]，通过减小粒径和粉体间的相互修饰显著提高有效成分的溶出[12-13]，增加药物的黏膜渗透[14]和体内吸收[15]。由于其药物用量少，成本低、产率高、操作简便、适应性强，故在实验室制剂处方研究中应用广泛。本研究采用行星式球磨机将丹参抗肺纤维化有效部位——水溶性酚酸类成分和脂溶性丹参酮类成分共微粉化，以CCD进行工艺优化，制备得到适用于肺部吸入的丹酚酸-丹参酮复合微粉(STW)，并对其粉体学性质进行评价，为进一步吸入粉雾剂的制备提供基础。 (翟文文 戴俊东 刘乐环 黄瑞雪 黎翊君 茅玉炜 蒋俏丽)
[关键词]丹参总酚酸；总丹参酮；湿法球磨粉碎；中心组合实验设计；吸入粉雾剂
[Abstract]Salvianolic acids and tanshinones are main hydrophilic and lipophilic extracts from Salvia Miltiorrhiza with significant anti-pulmonary fibrosis effects. The aim of this study was to prepare a co-micronized salvianolic acids-tanshinones composite powder for inhalation using a planetary ball mill. The micronization process parameters were optimized by central composite design (CCD) and response surface methodology (RSM). Treatment time， rotation speed and the ball/sample weight ratio were selected as the independent variables， and the volume fraction of particle size in 1-5 μm was taken as the dependent variable. The powder properties were evaluated by scanning electron microscopy (SEM)， laser diffraction and X-ray powder diffraction (XRPD). The powder flow and hygroscopicity were determined with repose angle， compressibility index and critical relative humidity(CRH). According to the results， the salvianolic acids-tanshinones composite powder produced in optimal conditions had a narrow and unimodal particle size distribution and a smaller D50 of 2.33 μm. The volume fraction of particle size in 1-5 μm was 80.82%. The repose angle was (50.60±1.13)o， and the critical relative humidity is about 77%. After being micronized， the particle size significantly reduced， and the number of amorphous substances slightly increased， with no significant changes in powder flow and hygroscopicity. These findings indicate that the grinding method with a planetary ball mill can be used to co-micronize various components with different properties and prepare composite drug powders for dry powder inhalation.
[Key words]salvianolic acids； tanshinones； ball mill； central composite design； inhalation
丹参是中医治疗心血管系统疾病的常用药物，其主要有效成分包括水溶性酚酸类化合物和脂溶性丹参酮类化合物。大量研究显示2类成分对特发性肺纤维化均具有良好的疗效[1-2]，丹酚酸以抗氧化[3]和抑制成纤维细胞增殖[4-5]作用为主，而丹参酮则主要通过减轻炎症反应[6]、抑制成纤维细胞增殖和活化[7-8]、促进细胞外基质水解[9]等途径。2类成分的作用机制有重合，也相互补充，可从多途径发挥联合治疗特发性肺纤维化的作用。
行星式球磨机常用于多种药效成分或与其他辅料的混合及共微粉化，可实现亚微米级甚至纳米级[10]的超微粉碎[11]，通过减小粒径和粉体间的相互修饰显著提高有效成分的溶出[12-13]，增加药物的黏膜渗透[14]和体内吸收[15]。由于其药物用量少，成本低、产率高、操作简便、适应性强，故在实验室制剂处方研究中应用广泛。本研究采用行星式球磨机将丹参抗肺纤维化有效部位——水溶性酚酸类成分和脂溶性丹参酮类成分共微粉化，以CCD进行工艺优化，制备得到适用于肺部吸入的丹酚酸-丹参酮复合微粉(STW)，并对其粉体学性质进行评价，为进一步吸入粉雾剂的制备提供基础。 (翟文文 戴俊东 刘乐环 黄瑞雪 黎翊君 茅玉炜 蒋俏丽)