Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin
Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin
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DOI：
10.1002/jbm.a.30997
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发表时间：
2007-03-15
影响因子：
4.9
通讯作者：
Shimobouji, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Hahn, Sei Kwang;Kim, Ji Seok;Shimobouji, Tsuyoshi
透明质酸（HA）微水凝胶是一种新型的蛋白质药物控释载体。通过巯基化HA（HA-SH）形成二硫键制备HA水凝胶。在HA-SH水凝胶制备过程中，使用连四硫酸钠的促进剂原位负载EPO。当添加连四硫酸钠用于HA-SH水凝胶制备时，凝胶化时间从1天大幅缩短至30分钟。EPO在PBS中在37 ° C的体外释放显示，EPO从HA-SH水凝胶中快速释放3天，具有初始突释，然后缓慢释放长达9天。以HA-SH前驱体溶液为原料，通过反应性喷雾干燥制备了HA-SH微水凝胶。平均粒度近似于2.3 μ m，喷雾干燥后的含水量近似于14%。Ellman试验表明，连四硫酸钠不仅有助于快速交联反应，而且有助于减少喷雾干燥后HA-SH微水凝胶中残留的游离硫醇含量。用透明质酸酶SD降解后，从HA-SH微水凝胶中回收的EPO高于95%。从用RP-HPLC的分析来看，释放的EPO似乎是完整的。根据在Sprague道利（SD）大鼠中从HA-SH微水凝胶的EPO的体内释放测试，高于0.1 ng/mL的升高的EPO血浆浓度（其是EPO功效的临界最小浓度）维持长达7天。在体内试验期间和之后没有不良反应。(c)2006 Wiley Periodicals，Inc.
An injectable hyaluronic acid (HA) microhydrogel was successfully developed as a novel drug carrier for controlled release formulation of protein drugs. HA hydrogels were prepared by the disulfide bond formation of thiolated HA (HA-SH). EPO was loaded in situ during HA-SH hydrogel preparation using an accelerating agent of sodium tetrathionate. The gelation time was drastically reduced from a day to 30 min when sodium tetrathionate was added for HA-SH hydrogel preparation. In vitro release of EPO in PBS at 37 degrees C showed that EPO was rapidly released for 3 days with an initial burst and then slowly up to 9 days from HA-SH hydrogels. HA-SH microhydrogels were prepared by the reactive spray drying of diluted HA-SH precursor solution. The mean particle size was similar to 2.3 mu m and the water content after spray drying was similar to 14%. Ellman's test showed that sodium tetrathionate contributed not only for rapid crosslinking reaction but also for the reduction of residual free thiol content in HA-SH microhydrogels after spray drying. EPO recovery from HA-SH microhydrogels after degradation with hyaluronidase SD was higher than 95%. The released EPO appeared to be intact from the analysis with RP-HPLC. According to in vivo release test of EPO from HA-SH microhydrogels in Sprague Dawley (SD) rats, elevated plasma concentration of EPO higher than 0.1 ng/mL, which is a critical minimal concentration for EPO efficacy, was maintained up to 7 days. There was no adverse effect during and after the in vivo tests. (c) 2006 Wiley Periodicals, Inc.