Vlugt-Wensink K D F, Meijer Y J, van Steenbergen M J, Verrijk R, Jiskoot W, Crommelin D J A, Hennink W E
Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands.
Eur J Pharm Biopharm. 2007 Nov;67(3):589-96. doi: 10.1016/j.ejpb.2007.04.011. Epub 2007 May 4.
The possibility was investigated to modulate the encapsulation efficiency and release of human growth hormone (hGH) from hydroxyl ethyl methacrylated dextran (dex-HEMA) hydrogel microspheres by using excipients. Microspheres were prepared by polymerization of dex-HEMA in an aqueous two-phase system of this polymer and PEG with or without excipients (Tween 80, pluronic F68, sucrose, NaCl, urea or methionine). High hGH encapsulation efficiencies (50-70%) were obtained for microspheres prepared without excipients and with Tween 80, NaCl or methionine. Substantially lower encapsulation efficiencies (27% and 19%, respectively) were obtained for microspheres prepared in the presence of sucrose and urea, which was attributed to the more favoured partitioning of hGH over the PEG-phase due to higher hydrophobicity of the (partly) denatured hGH. Likely, differences in precipitate size of the encapsulated hGH resulted in different release profiles between microspheres prepared without excipients (biphasic release: 2 days delay time followed by 6 days release) and the release profile for microspheres prepared with Tween 80, pluronic F68, sucrose, NaCl and urea (release over a period of 6-8 days (without a delay time)). Microspheres prepared with methionine showed a concentration-dependent delay time varying from 0 to 2 days followed by almost zero-order release over 6 days, attributed to the effect of methionine on the polymerization of dex-HEMA. Especially, Tween 80 and methionine are attractive excipients since hGH was encapsulated in high yield (60-70%) and the protein was released from the microspheres mainly in its monomeric form without a delay time and with an almost zero-order release over 6-8 days.
研究了使用辅料调节人生长激素（hGH）从甲基丙烯酸羟乙酯化葡聚糖（dex-HEMA）水凝胶微球中的包封效率和释放的可能性。通过在该聚合物与聚乙二醇（PEG）的水两相体系中，在有或没有辅料（吐温80、泊洛沙姆F68、蔗糖、氯化钠、尿素或蛋氨酸）的情况下聚合dex-HEMA来制备微球。对于在没有辅料以及有吐温80、氯化钠或蛋氨酸的情况下制备的微球，获得了较高的hGH包封效率（50 - 70%）。在蔗糖和尿素存在的情况下制备的微球，其包封效率显著较低（分别为27%和19%），这归因于（部分）变性的hGH具有更高的疏水性，使得hGH在PEG相中的分配更有利。可能是，包封的hGH沉淀大小的差异导致了在没有辅料制备的微球（双相释放：延迟2天，随后释放6天）与用吐温80、泊洛沙姆F68、蔗糖、氯化钠和尿素制备的微球的释放曲线（在6 - 8天内释放（无延迟时间））之间存在差异。用蛋氨酸制备的微球显示出浓度依赖性的延迟时间，从0到2天不等，随后在6天内几乎呈零级释放，这归因于蛋氨酸对dex-HEMA聚合的影响。特别是，吐温80和蛋氨酸是有吸引力的辅料，因为hGH以高产率（60 - 70%）被包封，并且蛋白质从微球中释放时主要以单体形式，没有延迟时间，并且在6 - 8天内几乎呈零级释放。
