The challenges of formulating recombinant human growth hormone (rhGH) into sustained-release polymeric microspheres include two mutual causal factors, protein denaturing by the formulation process and severe initial burst release related with relative high dose. The stabilizers to protect the proteins must not evoke osmotic pressure inside the microspheres, and the contact of the protein with the interface between water and organic solution of the polymer must be minimized. To meet these criteria, rhGH was pre-formulated into polysaccharide particles via an aqueous–aqueous emulsion in the present study, followed by encapsulating the particles into microspheres through a self-regulated process to minimize the contact of the protein with the water–oil interface. Polysaccharides as the protein stabilizer did not evoke osmotic pressure as small sugar stabilizers, the cause of severe initial burst release. Reduced initial burst enabled reduced protein loading to 9% (from 22% of the once commercialized Nutropin depot), which in turn reduced the dosage form index from 80 to 8.7 and eased the initial burst. A series of physical chemical characterizations as well as biologic and pharmacokinetic assays confirmed that the present method is practically feasible for preparing microspheres of proteins.

中文翻译：

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使用自调控过程制备的保留自然状态hGH的PLGA微球。

将重组人类生长激素（rhGH）配制成缓释聚合物微球的挑战包括两个相互的因果关系：配制剂过程中的蛋白质变性和与较高剂量相关的严重的初始爆炸释放。保护蛋白质的稳定剂不得引起微球内部的渗透压，并且蛋白质与水和聚合物有机溶液之间的界面的接触必须最小化。为了满足这些标准，在本研究中，rhGH通过水-水性乳液预先配制为多糖颗粒，然后通过自调节过程将颗粒包封到微球中，以最大程度地减少蛋白质与水-油界面的接触。作为蛋白质稳定剂的多糖没有像小的糖稳定剂那样引起渗透压，而是引起严重的初始爆炸释放的原因。减少的初始爆发使蛋白质负载降低到9％（从曾经商业化的Nutropin贮库中的22％降低），从而将剂型指数从80降低到8.7，并减轻了初始爆发。一系列的物理化学表征以及生物学和药代动力学测定证实了本方法对于制备蛋白质微球是切实可行的。