Key Laboratory of Applied Technology of Green-Eco-Healthy Animal Husbandry of Zhejiang Province, College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, 311300, China.
Jixian Honors College, Zhejiang A&F University, Hangzhou, 311300, China.
AAPS PharmSciTech. 2022 Jan 31;23(1):65. doi: 10.1208/s12249-022-02208-w.
Furosemide (FMD), as a potent circulating diuretic, is commonly used for the treatment of hypertension and edema arising from cardiac, renal, and hepatic failure. However, the low solubility of furosemide restricts its dissolution and bioavailability. In this study, Polyvinylpyrrolidone K30 (PVP-K30), mesoporous (Syloid 244FP, Syloid XDP 3050), and non-mesoporous (Aeroperl 300, Aerosil 200) silica were chosen as combined carrier to develop novel amorphous solid dispersions of furosemide, and then its dissolution and bioavailability were evaluated. Characterization study included XRD, DSC, TGA, SEM, FT-IR, and molecular docking. We found that FMD:PVP-K30:244FP achieved its best performance in terms of dissolution at the ratio of 1:1:1 when PVP-K30 and mesoporous silica Syloid 244FP (244FP) were chosen as combined carrier. SEM, DSC, and XRD studies indicated that furosemide existed in an amorphous form in the solid dispersion. FT-IR and molecular docking analysis showed that there might be an intermolecular interaction between FMD and the carrier. Moreover, the in vivo pharmacokinetics study revealed that the bioavailability of solid dispersion in rats had significant improvement. In particular, Cmax and AUClast were greatly increased by 2.69- and 2.08-fold in the solid dispersion (FMD-PVP-K30-244FP) group, respectively, and the relative bioavailability was 208.00%. In conclusion, the solid dispersion (FMD-PVP-K30-244FP) can significantly improve the solubility and oral bioavailability of furosemide. Mesoporous silica can be used as an excellent carrier material for furosemide, which can provide new ideas and methods for improving the stability of solid dispersion and further improving the dissolution of insoluble drugs. Graphical Abstract.
速尿（FMD）作为一种强效的循环利尿剂，常用于治疗心力衰竭、肾衰竭和肝衰竭引起的高血压和水肿。然而，速尿的低溶解度限制了其溶解和生物利用度。在本研究中，选用聚乙烯吡咯烷酮 K30（PVP-K30）、介孔（Syloid 244FP、Syloid XDP 3050）和非介孔（Aeroperl 300、Aerosil 200）硅作为联合载体，开发速尿的新型无定形固体分散体，并对其溶解和生物利用度进行了评价。表征研究包括 XRD、DSC、TGA、SEM、FT-IR 和分子对接。我们发现，当选择 PVP-K30 和介孔硅 Syloid 244FP（244FP）作为联合载体时，FMD：PVP-K30：244FP 在 1：1：1 的比例下在溶解方面表现最佳。SEM、DSC 和 XRD 研究表明，速尿在固体分散体中以无定形形式存在。FT-IR 和分子对接分析表明，FMD 和载体之间可能存在分子间相互作用。此外，体内药代动力学研究表明，固体分散体在大鼠体内的生物利用度有显著提高。特别是，在固体分散体（FMD-PVP-K30-244FP）组中，Cmax 和 AUClast 分别增加了 2.69 倍和 2.08 倍，相对生物利用度为 208.00%。总之，固体分散体（FMD-PVP-K30-244FP）可显著提高速尿的溶解度和口服生物利用度。介孔硅可用作速尿的优良载体材料，可为提高固体分散体的稳定性和进一步提高难溶性药物的溶解度提供新的思路和方法。
