Diana Jebun Nessa, Tao Ying, Du Qiran, Wang Meng, Kumar Chinta Uday, Wu Fei, Jin Tuo
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Pharmaceutics. 2020 Jul 20;12(7):683. doi: 10.3390/pharmaceutics12070683.
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.
将重组人生长激素（rhGH）制成缓释聚合物微球面临的挑战包括两个相互因果的因素，即制剂过程导致的蛋白质变性以及与相对高剂量相关的严重初始突释。保护蛋白质的稳定剂不能在微球内部引起渗透压，并且必须尽量减少蛋白质与聚合物水相和有机溶液界面的接触。为满足这些标准，在本研究中，rhGH先通过水-水乳液预制成多糖颗粒，然后通过自调节过程将颗粒包封入微球，以尽量减少蛋白质与水-油界面的接触。作为蛋白质稳定剂的多糖不会像小糖稳定剂那样引起渗透压，而小糖稳定剂是严重初始突释的原因。初始突释的减少使得蛋白质载药量降至9%（从曾经商业化的Nutropin depot的22%降至），这反过来又使剂型指数从80降至8.7，并缓解了初始突释。一系列物理化学表征以及生物学和药代动力学分析证实，本方法在制备蛋白质微球方面切实可行。
