静电喷雾法制备透明质酸钠介孔微球

doi:10.5246/jcps.2024.11.071

中国药学(英文版) ›› 2024, Vol. 33 ›› Issue (11): 985-1000.DOI: 10.5246/jcps.2024.11.071

• 【研究论文】 • 下一篇

静电喷雾法制备透明质酸钠介孔微球

黄维¹, 朱洁¹, 冯颖淑³, 杨丹⁴, Caleb Kesse Firempong¹, 屈阳¹, 何海冰⁵^,^*(), 刘宏飞¹^,²^,⁵^,^*()

^1. 江苏大学药学院, 江苏镇江 212013
^2. 江苏苏南药业工业有限公司, 江苏镇江 212400
^3. 镇江医学院医学化学研究所, 镇江市功能化学重点实验室, 江苏镇江 212028
^4. 扬子江药业集团南京海陵药业有限公司, 江苏南京 210046
^5. 江苏海之宏生物医药有限公司, 江苏南通 226001

收稿日期:2024-02-16 修回日期:2024-03-26 接受日期:2024-05-18 出版日期:2024-12-10 发布日期:2024-12-10
通讯作者: 何海冰, 刘宏飞

Synthesis of mesoporous sodium hyaluronate microspheres via electrostatic spray method

Wei Huang¹, Jie Zhu¹, Yingshu Feng³, Dan Yang⁴, Caleb Kesse Firempong¹, Yang Qu¹, Haibing He⁵^,^*(), Hongfei Liu¹^,²^,⁵^,^*()

¹ College of Pharmacy, Jiangsu University, Zhenjiang 212013, Jiangsu, China
² Jiangsu Sunan Pharmaceutical Industrial Co., LTD, Zhenjiang 212400, Jiangsu, China
³ Zhenjiang Key Laboratory of Functional Chemistry, Institute of Medicine & Chemical Engineering, Zhenjiang College, Zhenjiang 212028, Jiangsu, China
⁴ Yangtze River Pharmaceutical Group Nanjing Hailing Pharmaceutical Company, Nanjing 210046, Jiangsu, China
⁵ Jiangsu Haizhihong Biomedical Co., Ltd, Nantong 226001, Jiangsu, China

Received:2024-02-16 Revised:2024-03-26 Accepted:2024-05-18 Online:2024-12-10 Published:2024-12-10
Contact: Haibing He, Hongfei Liu
Supported by:
The 2023 Nantong Social Livelihood Science and Technology Plan, the 2023 Nantong Jianghai Talents Project, and the 2022 New Drugs and Platform Enhancement Project of the Yangtze Delta Drug Advanced Research Institute. Zhenjiang Science and Technology Project (Grant No. SH2020048), China Postdoctoral Science Foundation (Grant No. 2020M681532), Jiangsu Planned Projects for Postdoctoral Research Funds (Grant No. 2020Z209), and Natural Science Research Projects of Universities in Jiangsu Province (Grant No. 20KJD350001).

摘要/Abstract

摘要：

本研究采用静电喷雾技术制备透明质酸钠介孔微球(SHMM), 解决了配方开发过程中透明质酸钠(SH)双螺旋结构的锁水能力问题。本文采用单因素试验对溶剂类型、SH和聚环氧乙烷浓度、流速、电喷雾电压和针头直径等因素进行了考察, 获得了透明质酸钠微球的最佳处方工艺, 制备出了形貌和粒径均较好的微球。同时采用单因素试验对致孔剂浓度和干燥温度进行了评价, 制备出了具有明显孔结构的介孔微球。3批介孔微球的孔隙率为2.30% ± 1.51%, 在水中均表现出负电位, 证明其具有良好的结合带正电蛋白药物的能力。本文成功制备了包封率高、载药量高的重组人干扰素α-2b交联介孔微球(rhIFN α-2b-SHCMM), 研究结果为后期离子交换载药提供了可行性。

关键词: 静电喷雾, 离子交换技术, 透明质酸钠介孔微球

Abstract:

In the present study, we employed electrostatic spray technology to fabricate mesoporous microspheres containing sodium hyaluronate (SHMM). This approach aimed to overcome a significant challenge in the formulation development process, specifically addressing the limited water-locking ability inherent to the double-helix structure of sodium hyaluronate (SH). Various parameters were systematically investigated, including the solvent employed, concentrations of SH and poly (ethylene oxide), electrospray flow rate, voltage settings, and needle diameter. Through systematic single-factor testing, we identified the optimal formulation process for generating SH microspheres characterized by favorable morphology and particle size. Additionally, a similar single-factor examination focused on the concentration of the pore-forming agent and the drying temperature, leading to the successful production of mesoporous microspheres with discernible pores. The porosity of the three distinct batches of mesoporous microspheres was consistently measured at 20.30% ± 1.51%. Moreover, all these microspheres displayed a negative surface potential when suspended in water, affirming their strong capacity to bind with positively charged protein drugs. These findings underscored the feasibility of drug loading through ion exchange in subsequent stages. Notably, the successful preparation of recombinant human interferon α-2b crosslinked mesoporous microspheres (rhIFN α-2b-SHCMM) was achieved, demonstrating both high entrapment efficiency and an enhanced drug loading capacity.

Key words: Electrostatic spray, Ion exchange technology, Sodium hyaluronate mesoporous microspheres

Supporting:

黄维, 朱洁, 冯颖淑, 杨丹, Caleb Kesse Firempong, 屈阳, 何海冰, 刘宏飞. 静电喷雾法制备透明质酸钠介孔微球[J]. 中国药学(英文版), 2024, 33(11): 985-1000.

Wei Huang, Jie Zhu, Yingshu Feng, Dan Yang, Caleb Kesse Firempong, Yang Qu, Haibing He, Hongfei Liu. Synthesis of mesoporous sodium hyaluronate microspheres via electrostatic spray method[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(11): 985-1000.

图/表 22

Figure 1. Mechanism of DL and release of HA by IE.

Figure 2. Equipment and principles of electro-spraying technology.

Table 1. Single-factor level for the prescription process of SHM.

Table 2. Single-factor level table for the prescription process of SHMM.

Figure 3. Effect of CSH on the morphology of SHM (A: 2%; B: 5%; C: 8%).

Figure 4. Effect of CPEO on the particle size of SHM (A: 0.2%; B: 0.4%; C: 0.7%).

Figure 5. Effect of solvent on the morphology of SHM (A: Water; B: Water: ethanol: DMF = 2:1:1, v/v/v; C: Water: ethanol = 1:1, v/v).

Figure 6. Effect of voltage on the morphology of SHM (A: 10 kV; B: 15 kV; C: 20 kV).

Figure 7. Effect of flow rate on morphology of SHM. (A: 0.02 mm/min; B: 0.05 mm/min; C: 0.08 mm/min).

Figure 8. Effect of the inner diameter of the needle on morphology and particle size of SHM (A: 0.4 mm; B: 0.6 mm; C: 0.86 mm).

Figure 9. Scanning electron micrograph of SHM.

Figure 10. Grain diameter distribution map of SHM.

Table 3. Effect of CNH4HCO3 on porosity.

Table 4. Effect of drying temperature on porosity.

Figure 11. Scanning electron micrograph of SHMM.

Figure 12. Grain diameter distribution map of SHMM.

Table 5. Zeta potential of porous SHMM (n = 3).

Table 6. The porosity of different batches of SHMM.

Table 7. DL and EN of rhIFN α-2b-SHCMM (n = 3).

Table 8. In vitro degradation of SHCMM.

Figure 13. Accumulative release of rhIFN α-2b-SHCMM (n = 3).

Figure 14. Cytotoxicity evaluation of SH and SHCMM (n = 3).

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静电喷雾法制备透明质酸钠介孔微球

Synthesis of mesoporous sodium hyaluronate microspheres via electrostatic spray method

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