利用热熔挤出技术制备和表征白藜芦醇缓释固体分散体

doi:10.5246/jcps.2023.03.014

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (3): 165-179.DOI: 10.5246/jcps.2023.03.014

• 【研究论文】 • 下一篇

利用热熔挤出技术制备和表征白藜芦醇缓释固体分散体

高美琪¹, 吴佳丽¹, 朱文静¹, 张晓彤¹, 樊文玲¹^,²^,^*()

1. 南京中医药大学药学院, 江苏南京 210023
2. 江苏省中医药健康养生技术工程研究中心, 江苏南京 210023

收稿日期:2022-10-09 修回日期:2022-11-16 接受日期:2022-12-10 出版日期:2023-03-31 发布日期:2023-03-30
通讯作者: 樊文玲
作者简介:
+ Tel.: +86-18013870107, E-mail: fanwenling123456@163.com
基金资助:
The Jiangsu Postgraduate Research Practice Innovation Program (Grant No. BK20161403) and the 55^th Postdoctoral Project (Grant No. 021062001001).

The preparation and characterization of sustained-release solid dispersion of resveratrol by hot-melt extrusion technology

Meiqi Gao¹, Jiali Wu¹, Wenjing Zhu¹, Xiaotong Zhang¹, Wenling Fan¹^,²^,^*()

1 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
2 Jiangsu Provincial Technology Engineering Research Center of TCM Health Preservation, Nanjing 210023, China

Received:2022-10-09 Revised:2022-11-16 Accepted:2022-12-10 Online:2023-03-31 Published:2023-03-30
Contact: Wenling Fan

摘要/Abstract

摘要：

本文旨在制备、表征和评价固体分散体对低溶解度和高熔点的白藜芦醇(RES)的能力。采用热熔挤出法(HME)制备缓释固体分散体(SRSD), 使用疏水-亲水聚合物混合物(Eudragit RS和Poloxamer 188)控制RES的释放。使用单因素试验系统研究了配方和工艺参数对制备工艺的影响。接着, 采用Box-Behnken设计(三因素、三水平)对SRSD的制备工艺进行优化。使用差示扫描量热法和 X-射线衍射来确定固体分散体的物理状态, 使用扫描电子显微镜观察其表面特性, 使用傅里叶红外光谱探寻辅料之间的化学相互作用。通过溶出度试验考察其动力学和释药时间。体外研究表明, 制备出的白藜芦醇固体分散体的释放遵循Weibull模型。最终使用热熔挤出技术成功制备了白藜芦醇缓释固体分散物(RESRS P188-SRSD), 其中药物与载体的质量比为1:3, 释放调节剂为P188, 剂量为10%。该制剂稳定性好, 溶出度提高了10倍。

关键词: 缓释固体分散体, 白藜芦醇, 热熔挤出, 响应面设计

Abstract:

In the present study, we aimed to prepare, characterize, and evaluate the capability of solid dispersion (SD) for resveratrol (RES) with low solubility and high melting points. A sustained-release solid dispersion (SRSD) was prepared by hot melt extrusion (HME). The release of RES was controlled using a hydrophobic-hydrophilic polymer mixture (Eudragit RS and Poloxamer 188). The effects of formula and process parameters were systematically studied by univariate analysis. Then the Box-Behnken design (three factors, three levels) was used to optimize the preparation process of SRSD. Differential scanning calorimetry and X-ray diffraction were adopted to determine the physical state of SD. Scanning electron microscopy was used to observe its surface properties, and Fourier transform infrared spectroscopy was used to explore chemical interactions between excipients. Dissolution studies were carried out to investigate the kinetics and drug release time. In vitro studies showed that RES release followed the Weibull model kinetic. RES SRSD (RESRS P188-SRSD) was successfully prepared using HME, in which the mass ratio of the drug to the carrier was 1:3, the release regulator was P188, and the dosage was 10%. The stability of the preparation was good, and the dissolution was increased by 10 times.

Key words: Sustained-release solid dispersion, Resveratrol, Hot-melt extrusion, Box-Behnken design

Supporting:

高美琪, 吴佳丽, 朱文静, 张晓彤, 樊文玲. 利用热熔挤出技术制备和表征白藜芦醇缓释固体分散体[J]. 中国药学(英文版), 2023, 32(3): 165-179.

Meiqi Gao, Jiali Wu, Wenjing Zhu, Xiaotong Zhang, Wenling Fan. The preparation and characterization of sustained-release solid dispersion of resveratrol by hot-melt extrusion technology[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(3): 165-179.

图/表 30

Table 1. Single-factor experiment programs.

Table 2. The factors and responses of the BBD.

Table 3. Release model equations.

Figure 1. TGA spectrum of RES, sustained-release carriers, and release modifiers.

Figure 2. TGA spectrum of RES, sustained-release carriers, and release modifiers.

Table 4. The solubility parameter values for drugs and carriers.

Figure 3. DSC diagram of SD prepared by different drug loading rations.

Figure 4. Dissolution curves of SD prepared by different drug loading ratios.

Figure 5. DSC diagram of SD prepared by different release modifiers.

Figure 6. Dissolution curves of SD prepared by different release modifiers.

Figure 7. DSC diagram of SD prepared by different amounts of release modifier.

Figure 8. Dissolution curves of SD prepared by different amounts of release modifier.

Figure 9. DSC diagram of solid dispersion prepared at different barrel temperatures.

Figure 10. Dissolution curves of SD prepared at different barrel temperatures.

Figure 11. DSC diagram of SD prepared at different screw speeds.

Figure 12. Dissolution curves of SD prepared at different screw speeds.

Table 5. Results of BBD.

Table 6. Variance analysis of regression model.

Table 7. Equilibrium solubility of RES and RES-SD.

Figure 13. Dissolution curves of RES, physical mixture and sustained-release solid dispersion.

Figure 14. Dissolution curves of three batches of SRSD.

Figure 15. IR spectrum of RES, carries, PM, and RES/RS/P188-SRSD.

Figure 16. XRD spectrum of RES, carries, PM, and RES/RS/P188-SRSD.

Figure 17. SEM microscopy of RES (A), RS (B), PEG6000 (C), PM (D), and RES/RS/PEG6000-SRSD (E).

Figure 18. DSC curves of RES, carries, PM, and RES/RS/P188-SRSD.

Table 8. The release pattern of RES/RS/P188-SRSD.

Figure 19. XRD spectrum of long-term retention test.

Table 9. The result of the long-term retention test.

Table 10. Pharmacokinetic parameters of raw RES and SRSD in rats after oral administration.

Figure 20. Plasma concentration-time curves in rats after oral administration of RES and SRSD.

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利用热熔挤出技术制备和表征白藜芦醇缓释固体分散体

The preparation and characterization of sustained-release solid dispersion of resveratrol by hot-melt extrusion technology

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