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喷雾干燥制备吉非替尼固体分散体及其改善的黏膜黏附性和药物溶出度。

Solid Dispersions of Gefitinib Prepared by Spray Drying with Improved Mucoadhesive and Drug Dissolution Properties.

机构信息

Drug Discovery, Delivery and Patient Care Theme, Department of Pharmacy, Kingston University London, Kingston upon Thames, KT1 2EE, UK.

Department of Pharmacy, Al-Mustafa University College, Baghdad, Iraq.

出版信息

AAPS PharmSciTech. 2022 Jan 4;23(1):48. doi: 10.1208/s12249-021-02187-4.

Abstract

Gefitinib is a tyrosine kinase inhibitor that is intended for oral administration yet suffers poor bioavailability along with undesirable side effects. To enhance its solubility and allow colon targeting, gefitinib (ZD) and blends of different ratios of polymers (ternary dispersion) were prepared in organic solution, and solid dispersions were generated employing the spray drying (SD) technique. The methylmethacrylate polymer Eudragit S 100 was incorporated for colon targeting; polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) were utilised to improve the solubility of ZD. SEM, DSC, XRPD, FT-IR, dissolution and cytotoxicity studies were undertaken to characterise and evaluate the developed formulations. SEM images revealed that the rod-shaped crystals of ZD were transformed into collapsed spheres with smaller particle size in the spray-dried particles. DSC, FTIR and XRPD studies showed that ZD loaded in the spray-dried dispersions was amorphous. ZD dissolution and release studies revealed that while a significant (P < 0.05) increase in the ZD dissolution and release was observed from HPMC-based solid dispersion at pH 7.2 (up to 95% in 15 h), practically no drug was released at pH 1.2 and pH 6.5. Furthermore, the HPMC-based solid dispersions displayed enhanced mucoadhesive properties compared with PVP-based ones. Interestingly, cell viability studies using the neutral red assay showed that PVP and HPMC-based solid dispersions had no additional inhibitory effect on Caco-2 cell line compared to the pure drug.

摘要

吉非替尼是一种酪氨酸激酶抑制剂,用于口服,但生物利用度差,且有不良副作用。为了提高其溶解度并实现结肠靶向,我们在有机溶剂中制备了吉非替尼(ZD)和不同比例聚合物的混合物(三元分散体),并采用喷雾干燥(SD)技术生成固体分散体。将甲基丙烯酸甲酯聚合物 Eudragit S 100 用于结肠靶向;使用聚乙烯吡咯烷酮(PVP)和羟丙基甲基纤维素(HPMC)来提高 ZD 的溶解度。通过 SEM、DSC、XRPD、FT-IR、溶解和细胞毒性研究对所开发的制剂进行了表征和评价。SEM 图像显示,喷雾干燥颗粒中 ZD 的棒状晶体转化为更小粒径的塌陷球体。DSC、FTIR 和 XRPD 研究表明,喷雾干燥分散体中负载的 ZD 为无定形。ZD 的溶解和释放研究表明,在 pH 7.2 时,基于 HPMC 的固体分散体显著(P < 0.05)增加了 ZD 的溶解和释放(在 15 小时内达到 95%),而在 pH 1.2 和 pH 6.5 时几乎没有药物释放。此外,与基于 PVP 的固体分散体相比,基于 HPMC 的固体分散体显示出增强的粘膜粘附特性。有趣的是,使用中性红测定法的细胞活力研究表明,与纯药物相比,基于 PVP 和 HPMC 的固体分散体对 Caco-2 细胞系没有额外的抑制作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5449/8816420/ca415fdc5c24/12249_2021_2187_Fig1_HTML.jpg

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