固体分散体系统提高难溶性坎地沙坦西酯的溶出度：体外评价和模拟药代动力学研究。

Solid dispersion systems for enhanced dissolution of poorly water-soluble candesartan cilexetil: In vitro evaluation and simulated pharmacokinetics studies.

机构信息

Pharmaceutics Department, College of Pharmacy, University of Basrah, Basrah, Iraq.

Pharmaceutics Department, College of Pharmacy, Almaaqal University, Basrah, Iraq.

出版信息

PLoS One. 2024 Jun 6;19(6):e0303900. doi: 10.1371/journal.pone.0303900. eCollection 2024.

DOI:10.1371/journal.pone.0303900

PMID:38843120

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11156308/

Abstract

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.

CONCLUSION

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.

摘要

背景

坎地沙坦西酯（CC）是一种广泛用于治疗高血压的选择性血管紧张素 II 受体拮抗剂。CC 是 P-糖蛋白（P-gp）的底物，导致其向肠腔流出。它在水中的实际溶解度也很低，口服生物利用度（14%）较低。因此，本研究旨在通过开发固体分散体系统（SDS）来提高 CC 的体外溶解率，并通过模拟药代动力学研究来验证体外结果。

方法

SDS 采用聚乙烯吡咯烷酮（PVP）作为水溶性聚合物、Eudragit E100（EE100）作为 pH 依赖性可溶性载体以及这两种聚合物的组合来制备。对三种溶出介质中制备的系统的饱和溶解度和溶出速率进行了研究。选择优化系统 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

与纯药物相比，当以 EE100 为 1:5（w/w）药物与聚合物的比例（SE-EE5 SD）将 CC 制成固体分散基质时，CC 的溶解度显著提高了 27037.344 倍。通过优化 SDS 提高 CC 的溶解度和溶解速率的机制被发现是通过将结晶 CC 转化为无定形形式以及在 pH 值低于 5 时溶解时形成纳米颗粒。仪器分析测试表明 CC 与 EE100 之间具有良好的相容性，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，在 25°C 下储存三个月后，优化系统是稳定的。