Kim Min-Soo, Jin Shun-Ji, Kim Jeong-Soo, Park Hee Jun, Song Ha-Seung, Neubert Reinhard H H, Hwang Sung-Joo
Chungnam National University, Daejeon, Republic of Korea.
Eur J Pharm Biopharm. 2008 Jun;69(2):454-65. doi: 10.1016/j.ejpb.2008.01.007. Epub 2008 Jan 18.
In this work, amorphous atorvastatin calcium nanoparticles were successfully prepared using the supercritical antisolvent (SAS) process. The effect of process variables on particle size and distribution of atorvastatin calcium during particle formation was investigated. Solid state characterization, solubility, intrinsic dissolution, powder dissolution studies and pharmacokinetic study in rats were performed. Spherical particles with mean particle size ranging between 152 and 863 nm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration and feed rate ratio of CO2/drug solution. XRD, TGA, FT-IR, FT-Raman, NMR and HPLC analysis indicated that atorvastatin calcium existed as anhydrous amorphous form and no degradation occurred after SAS process. When compared with crystalline form (unprocessed drug), amorphous atorvastatin calcium nanoparticles were of better performance in solubility and intrinsic dissolution rate, resulting in higher solubility and faster dissolution rate. In addition, intrinsic dissolution rate showed a good correlation with the solubility. The dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with unprocessed drug by the enhancement of intrinsic dissolution rate and the reduction of particle size resulting in an increased specific surface area. The absorption of atorvastatin calcium after oral administration of amorphous atorvastatin calcium nanoparticles to rats was markedly increased.
在本研究中,采用超临界抗溶剂(SAS)法成功制备了无定形阿托伐他汀钙纳米颗粒。研究了制备过程中工艺变量对阿托伐他汀钙粒径和粒度分布的影响。进行了固态表征、溶解度、固有溶出度、粉末溶出度研究以及大鼠体内药代动力学研究。通过改变沉淀容器压力和温度、药物溶液浓度以及CO2/药物溶液的进料速率比等工艺参数,获得了平均粒径在152至863 nm之间的球形颗粒。XRD、TGA、FT-IR、FT-拉曼、NMR和HPLC分析表明,阿托伐他汀钙以无水无定形形式存在,且在SAS处理后未发生降解。与结晶形式(未处理药物)相比,无定形阿托伐他汀钙纳米颗粒在溶解度和固有溶出速率方面表现更佳,从而具有更高的溶解度和更快的溶出速率。此外,固有溶出速率与溶解度呈现良好的相关性。无定形阿托伐他汀钙纳米颗粒的溶出速率相较于未处理药物显著提高,这是由于固有溶出速率的增强以及粒径的减小导致比表面积增加所致。大鼠口服无定形阿托伐他汀钙纳米颗粒后,阿托伐他汀钙的吸收显著增加。