Franssen O, Vandervennet L, Roders P, Hennink W E
Department of Pharmaceutics, Faculty of Pharmacy, Universiteit Utrecht, P.O. Box 80.082 3508 TB, Utrecht, The Netherlands.
J Control Release. 1999 Aug 5;60(2-3):211-21. doi: 10.1016/s0168-3659(99)00074-7.
The preparation of protein-loaded degradable hydroxyethyl methacrylated dextran (dex-HEMA) hydrogels, cylindrical macroscopic gels as well as microspheres, is described. The hydrogels were degradable under physiological conditions (pH 7.0 and 37 degrees C), due to the presence of hydrolytically sensitive carbonate esters in the crosslinks of the gels. The degradation of dex-HEMA hydrogels was studied by swelling measurements and the release of dextran from the matrices. The hydrogels showed a progressive swelling in time, followed by a dissolution phase. The total degradation time ranged from 25 to more than 80 days and depended on the initial water content of the gels and the degree of substitution (DS) of dex-HEMA. IgG-loaded dex-HEMA microspheres (volume mean diameter of about 10 microm) were prepared with a high encapsulation efficiency (83-100%). Furthermore, it was possible to entrap more than 90% of the protein in both dex-HEMA microspheres and macroscopic hydrogels. Therefore, it was possible to obtain a completely degradation-controlled protein release. For degrading macroscopic dex-HEMA hydrogels as well as microspheres, a biphasic release of IgG was observed. The release was always faster during the second phase than during the first phase. Microspheres with an initial water content of 60% (w/w) had a significant release of 25-40% of the encapsulated IgG during the first phase. For microspheres with a water content of 50% (w/w), the released amount of protein during the first phase was marginal (less than 15%), resulting in delayed release profiles. The delay time increased with increasing crosslink density (determined by the DS and the water content) of the gels (longer degradation time) and decreasing pH of the incubation buffer (decreasing degradation rate). In addition, the delay time was considerably shorter (5-15 days) for dex-HEMA microspheres than for macroscopic hydrogels (10-37 days), due to a higher surface-to-volume ratio for the microspheres. This paper shows that the release of IgG from dex-HEMA hydrogels can be modulated by the composition (water content and DS) and the geometry of the gel (microspheres versus macroscopic gels).
本文描述了载有蛋白质的可降解甲基丙烯酸羟乙酯葡聚糖（dex-HEMA）水凝胶、圆柱形宏观凝胶以及微球的制备方法。由于凝胶交联中存在对水解敏感的碳酸酯，这些水凝胶在生理条件（pH 7.0和37℃）下可降解。通过溶胀测量以及葡聚糖从基质中的释放来研究dex-HEMA水凝胶的降解。水凝胶随时间逐渐溶胀，随后进入溶解阶段。总降解时间为25至80多天，这取决于凝胶的初始含水量以及dex-HEMA的取代度（DS）。制备了载有IgG的dex-HEMA微球（体积平均直径约为10微米），其包封效率较高（83 - 100%）。此外，在dex-HEMA微球和宏观水凝胶中均能包封超过90%的蛋白质。因此，有可能实现完全受降解控制的蛋白质释放。对于降解的宏观dex-HEMA水凝胶以及微球，观察到IgG呈现双相释放。第二阶段的释放总是比第一阶段更快。初始含水量为60%（w/w）的微球在第一阶段有25 - 40%的包封IgG显著释放。对于含水量为50%（w/w）的微球，第一阶段蛋白质的释放量很少（小于15%），导致释放曲线延迟。延迟时间随着凝胶的交联密度（由DS和含水量决定，降解时间更长）增加以及孵育缓冲液pH值降低（降解速率降低）而增加。此外，由于微球的表面积与体积比更高，dex-HEMA微球的延迟时间（5 - 15天）比宏观水凝胶（10 - 37天）短得多。本文表明，IgG从dex-HEMA水凝胶中的释放可通过凝胶的组成（含水量和DS）以及几何形状（微球与宏观凝胶）进行调节。
