球晶制粒技术制备水飞蓟宾缓释微球

摘要/Abstract

摘要： 目的提高水飞蓟宾的生物利用度。方法采用固体分散载体和阻滞性高分子材料, 使用固体分散与球晶制粒相结合的技术制备水飞蓟宾缓释微球。运用差示热分析及X-射线粉末衍射检测水飞蓟宾在微球中分散状态, 采用扫描电子显微镜观察微球的形态、表面结构和内部结构, 并对微球的特性如平均粒径、粒径分布、松密度进行评价。结果研制微球的大小可由搅拌速度来控制, 水飞蓟宾从缓释微球中的释放速度随分散剂的量的增加而增加, 阻滞剂可延缓药物的释放。微球中药物的释放速度能够通过调节分散剂和阻滞剂的比例来控制。X射线衍射与差示热分析结果表明: 水飞蓟宾以无定型高度分散在微球中。在40 ºC, 相对湿度75%条件下, 加速三个月, 药物释放与含量不会改变。结论水飞蓟宾缓释微球可通过采用固体分散与球晶制粒相结合的技术一步制成。该制备过程简便、重现性好、成本低, 是水不溶性药物制备缓释微球的有效方法。

关键词: 水飞蓟宾, 水飞蓟宾, 水飞蓟宾, 缓释微球, 缓释微球, 缓释微球, 固体分散, 固体分散, 固体分散, 球晶制粒技术, 球晶制粒技术, 球晶制粒技术

Abstract: Aim To improve the dissolution rate and bioavailability of silybin. Methods Sustained-release silybin microspheres were prepared by the spherical crystallization technique with solid-dispersing and release-retarding polymers. A differential scanning calorimeter and an X-ray diffractometer were used to investigate the dispersion state of silybin in the microspheres. The shape, surface morphology, and internal structure of the microspheres were observed using a scanning electron microscope. Characterization of the microspheres, such as average diameter, size distribution and bulk density of the microspheres was investigated. Results The particle size of the microspheres was determined mainly by the agitation speed. The dissolution rate of silybin from microspheres was enhanced by increasing the amount of the dispersing agents, and sustained by the retarding agents. The release rate of microspheres was controlled by adjusting the combination ratio of the dispersing agents to the retarding agents. The results of X-ray diffraction and differential scanning calorimetry analysis indicated that silybin was highly dispersed in the microspheres in amorphous state. The release profiles and content did not change after a three-month accelerated stability test at 40 ºC and 75% relative humidity. Conclusion Sustained-release silybin microspheres with a solid dispersion structure were prepared successfully in one step by a spherical crystallization technique combined with solid dispersion technique. The preparation process is simple, reproducible and inexpensive. The method is efficient for designing sustained-release microspheres with water-insoluble drugs.

Key words: silybin, silybin, sustained-release microsphere, sustained-release microsphere, solid dispersion, solid dispersion, spherical crystallization technique, spherical crystallization technique

中图分类号:

R943.41

R945.1

Supporting: ^*Corresponding author. Tel.: 86-551-5169060; fax: 86-551-5169061

胡容峰^*, 朱家壁, 马凤余, 许向阳, 孙玉亮, 梅康康, 李师. 球晶制粒技术制备水飞蓟宾缓释微球[J]. .

HU Rong-feng^*, ZHU Jia-bi, MA Feng-yu, XU Xiang-yang, SUN Yu-liang, MEI Kang-kang, LI Shi. Preparation of Sustained-release Silybin Microspheres by Spherical Crystallization Technique[J]. .

参考文献

[1] Li FQ, Hu JH, Wang HZ, et al. Relationship s between lattice changes and the function of dissolution imp rovement of in soluble drug silymarin based upon PEG 6000 solid dispersion system [J]. Acta Pharm Sin, 2002, 37 (4) : 294-298.
[2] Jiang B, Yin CH. Study on the bioavailability of silymarin-phosphatidylcholine complex in rabbits [J]. Chin J Pharm, 2002, 33 (12) : 598-600.
[3] Xiao YY, Song YM, Chen ZP, et al. Preparation of silybin-phospholipid complex and its bioavailability in rats [J]. Acta Pharm Sin, 2005, 40 (7) : 611-617.
[4] Julide A, Preparation and evaluation of controlled release furosemide microspheres by spherical crystallization [J]. Int J Pharm , 1989, 53 (2) : 99-105.
[5] WilsonWW. Monitoring crystallization experiments using dynamic light scattering: assaying and monitoring protein crystallization in solution [J]. Methods, 1990, 1 (1) : 110-117.
[6] Julide A. Furosemide-loaded ethyl cellulose microspheres prepared by spherical crystallization technique: morphology and release characteristics [J]. Int J Pharm, 1991, 76 (3) : 193-198.
[7] Kenji M, Yoichi K, Yoshiaki K, et al. Micromeritic characteristics and agglomeration mechanisms in the spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methods [J]. Powder Technology, 1993, 76 (1) : 57-64.
[8] Yoshiaki K, Cui FD, Hirofumi T, et al. Parameters determining the agglomeration behaviour and the micromeritic properties of spherically agglomerated crystals prepared by the spherical crystallization technique with miscible solvent systems [J]. Int J Pharm , 1995, 119 (2) : 139-147.
[9] Kazuo S, William JM, David JL, et al. Blends of amorphous-crystalline block copolymers with amorphous homopolymers: morphological studies by electron microscopy and small angle scattering [J]. Polymer, Vol 1996, 37 (20) : 4443-4453.
[10] Ribardière A, Tchoreloff P, Couarraze G, et al. Modification of ketoprofen bead structure produced by the spherical crystallization technique with a two-solvent system [J] Int J Pharm , 1996, 144 (2) : 195-207.
[11] Kachrimanis K, Ktistis G, Malamataris S. Crystallisation conditions and physicomechanical properties of ibuprofen-Eudragit S100 spherical crystal agglomerates prepared by the solvent-change technique [J]. Int J Pharm, 1998, 173 (1-2) : 61-74.
[12] Szabó-Révész P, Hasznos-Nezdei M, Farkas B, et al. Crystal growth of drugmaterials by spherical crystallization [J]. J Crystal Growth, 2002, 237-239 (3) : 2240-2245.
[13] Kawashima Y, Cui F, Takeuchi H, et al. Improvements in flowability and compressibility of pharmaceutical crystals for direct tabletting by spherical crystallization with a two-solvent system [J]. Powder Technology, 1994, 78 (2) : 151-157.
[14] Morishima K, Kawashima Y, Takeuchi H, et al. Tabletting properties of bucillamine agglomerates prepared by the spherical crystallization technique [J]. Int J Pharm, 1994, 105 (1) : 11-18.
[15] Szabó-Révész P, Göczö H, Pintye-Hódi K, et al. Development of spherical crystal agglomerates of an aspartic acid salt for direct tabletmaking [J]. Powder Technology, 2001, 114 (1-3) : 118-124.
[16] Martino PD, Cristofaro RD, Barthélémy C, et al. Improved comp ression properties of propyphenazone spherical crystals [J]. Int J Pharm , 2000, 197 (1-2) : 95-106.
[17] Kawashima Y, Imai M, Takeuchi H, et al. Improved flowability and compactibility of spherically agglomerated crystals of ascorbic acid for direct tableting designed by spherical crystallization process [J]. Powder Technology, 2003, 130 (3) : 283-289.
[18] Kawashima Y, Niwa T, Kakeuchi H, et al. Preparation of multiple unit hollow microspheres (microballoons) with acrylic resin containing tranilast and their drug release characteristics (in vitro) and floating behavior (in vivo) [J]. J Controlled Release, 1991, 16 (3) : 279-290.
[19] Niwa T, Takeuchi H, Hino T, et al. Preparation of biodegradable nanospheres of water-soluble and insoluble drugs with DL-lactide/glycolide copolymer by a novel spontaneous emulsification solvent diffusion method and the drug release behavior [J]. J Controlled Release, 1993, 25 (1-2) 1: 89-98.
[20] Cui FD, Yang MS, Jiang YY, et al. Design of sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion solvent diffusion method [J]. J Controlled Release, 2003, 91 (3) : 375-384.