背景:坎地沙坦酯(CC)是一种选择性血管紧张素II受体拮抗剂,广泛用于治疗高血压。CC是P-糖蛋白(P-gp)的底物,导致它流出到肠腔.它实际上也不溶于水,并且具有低的口服生物利用度(14%)。因此,本研究旨在通过开发固体分散体系(SDSs)并使用模拟药代动力学研究证实体外结果来改善CC的体外溶出。
方法:使用聚乙烯吡咯烷酮(PVP)作为水溶性聚合物制备SDSs,EudragitE100(EE100)作为pH依赖性可溶性载体,和这两种聚合物的组合。进行了制备的系统在三种溶出介质中的饱和溶解度和溶出速率研究。选择优化的系统SE-EE5进行进一步研究,包括DSC,XRD,FTIR,FESEM,DLS,TSEM,IVIVC卷积研究,和稳定性研究。
结果:当使用EE100以1:5(w/w)的药物与聚合物(SE-EE5SD)的比例配制为固体分散体基质时,CC的溶解度显着增加了27,037.344倍,与纯药物的溶解度相比。发现通过优化的SDS提高CC的溶解度和溶解速率的机理是通过将结晶CC转化为无定形形式以及在低于5的pH下溶解时形成纳米颗粒。仪器分析测试表明CC和EE100之间具有良好的相容性,并且药物与聚合物之间没有化学相互作用。此外,稳定性测试证实优化的体系在25°C储存三个月后是稳定的。
结论:采用EE100聚合物作为基质的固体分散体技术在提高溶解度方面取得了显著成功,溶出度,随后,水不溶性药物如CC的生物利用度。
BACKGROUND: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study.
METHODS: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies.
RESULTS: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C.
CONCLUSIONS: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.