Dept. Chemical and Pharmaceutical Sciences, University of Trieste, V. Giorgieri 1, Trieste, Italy.
Eur J Pharm Biopharm. 2012 May;81(1):131-41. doi: 10.1016/j.ejpb.2012.01.002. Epub 2012 Jan 17.
The 'classical' loop diuretic drug Furosemide has been used as a model compound to investigate the possibility of enhancing the dissolution rate of poorly water-soluble drugs using supercritical anti-solvent techniques (SASs). In the present study we report upon the in vitro bioavailability improvement of Furosemide through particle size reduction as well as formation of solid dispersions (SDs) using the hydrophilic polymer Crospovidone. Supercritical carbon dioxide was used as the processing medium for these experiments. In order to successfully design a CO(2) antisolvent process, preliminary studies of Furosemide microparticles generation were conducted using Peng Robinson's Equation of State. These preliminary studies indicated using acetone as a solvent with pressures of 100 and 200bar and a temperature of 313K would yield optimum results. These operative conditions were then adopted for the SDs. Micronization by means of SAS at 200bar resulted in a significant reduction of crystallites, particle size, as well as improved dissolution rate in comparison with untreated drug. Furosemide recrystallized by SAS at 100bar and using traditional solvent evaporation. Moreover, changes in polymorphic form were observed in the 200bar samples. The physicochemical characterization of Furosemide:crospovidone SDs (1:1 and 1:2 w/w, respectively) generated by SAS revealed the presence of the drug amorphously dispersed in the 1:2 w/w sample at 100bar still remaining stable after 6months. This sample exhibits the best in vitro dissolution performance in the simulated gastric fluid (pH 1.2), in comparison with the same SD obtained by traditional method. No interactions between drug and polymer were observed. These results, together with the presence of the selected carrier, confirm that the use of Supercritical fluids antisolvent technology is a valid mean to increase the dissolution rate of poorly soluble drugs. Theoretical in vivo-in vitro relation was predicted by means of a pharmacokinetics mathematical model.
“经典”的袢利尿剂呋塞米已被用作模型化合物，以研究使用超临界抗溶剂技术（SASs）提高低水溶性药物的溶解速率的可能性。在本研究中，我们报告了通过粒径减小以及使用亲水性聚合物交联聚维酮（Crospovidone）形成固体分散体（SDs）来提高呋塞米的体外生物利用度。超临界二氧化碳被用作这些实验的加工介质。为了成功设计 CO2 反溶剂工艺，我们使用 Peng Robinson 的状态方程对呋塞米微粉生成进行了初步研究。这些初步研究表明，使用丙酮作为溶剂，压力为 100 和 200bar，温度为 313K，将产生最佳结果。然后采用这些操作条件进行 SDs 的实验。在 200bar 下通过 SAS 进行的微米化导致结晶度、粒径显著降低，与未处理药物相比，溶解速率也得到改善。在 100bar 下通过 SAS 重结晶的呋塞米和使用传统溶剂蒸发法。此外，在 200bar 样品中观察到多晶型形式的变化。通过 SAS 生成的呋塞米：交联聚维酮 SDs（分别为 1:1 和 1:2w/w）的物理化学特性表明，药物以无定形状态分散在 1:2w/w 样品中，在 100bar 下仍保持稳定，6 个月后仍保持稳定。与通过传统方法获得的相同 SD 相比，该样品在模拟胃液（pH 1.2）中表现出最佳的体外溶解性能。未观察到药物与聚合物之间的相互作用。这些结果，再加上所选载体的存在，证实了使用超临界流体反溶剂技术是提高低溶解度药物溶解速率的有效方法。通过药代动力学数学模型预测了理论体内-体外关系。
