记者近日从中科院过程工程研究所获悉，由该所研究员马光辉领导的团队开发出了一种粒径均一的重组人生长激素缓释微囊。相关成果发表在国际学术期刊《分子制药学》上。
据了解，重组人生长激素（rhGH）在临床上广泛应用于治疗矮小症、严重烧伤、艾滋病患者的脂肪代谢障碍等多种疾病。但rhGH的半衰期短，必须频繁注射才能达到有效的血药浓度，这造成患者顺应性差。
针对此问题，科学家们对rhGH缓释微囊进行了大量的研究，但仍普遍存在微囊粒径不均一、无法持续释放、药物稳定性差等问题。同时，传统的疏水材料微囊在降解过程中产生的酸性产物，会造成注射部位发生炎症，引起严重的副反应。因此，开发安全有效的rhGH缓释微囊具有重要的研究意义。
此次马光辉团队首先利用W/O/W复乳液法将rhGH装载于两亲性材料聚乳酸—聚乙二醇共聚物乳液中，并结合快速膜乳化技术实现了微球粒径的均一性。后续的体内大鼠模型实验表明，该制剂能够有效延长rhGH在体内的释放，并且很好地保持了rhGH的活性，大鼠骨骼增长明显，提高了治疗效果。另外，与传统的聚乳酸（PLA）、聚乳酸—羟基乙酸共聚物（PLGA）微囊相比，该制剂不产生炎症反应，对心、肝、肾等主要脏器功能无影响，是一种安全的缓释载体。
该研究工作得到“973”项目和国家自然科学基金的资助。
A Novel Sustained-Release Formulation of Recombinant Human Growth Hormone and Its Pharmacokinetic, Pharmacodynamic and Safety Profiles
Yi Wei , Yuxia Wang , Aijun Kang §, Wei Wang , Sa V. Ho , Junfeng Gao , Guanghui Ma , and Zhiguo Su
An effective and safe formulation of sustained-release rhGH for two months using poly(monomethoxypolyethylene glycol-co-d,l-lactide) (mPEG-PLA, PELA) microspheres was developed to reduce the frequency of medication. The rhGH-loaded PELA microspheres with a narrow size distribution were successfully prepared by a double emulsion method combined with a premix membrane emulsification technique without any exogenous stabilizing excipients. The narrow size distribution of the microspheres would guarantee repeatable productivity and release behavior. Moreover, the amphiphilic PELA improved the bioactivity retention of protein drugs since it prevented protein contact with the oil/water interface and the hydrophobic network, and modulated diffusion of acidic degradation products from the carrier system. These PELA microspheres were compared in vivo with commercial rhGH solution, conventional poly(d,l-lactic acid) (PLA) and poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres. Administration of rhGH-PELA could extend the duration of rhGH release (for up to 56 days) and increase area under the curve (AUC) compared to rhGH solution, PLA or PLGA microspheres in Sprague–Dawley (SD) rats. In addition, rhGH-PELA microspheres induced a greater response in total insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) than other rhGH formulations. With a hypophysectomized SD rat model, the pharmacological efficacy of rhGH-PELA microspheres was shown to be better than that from daily administration of rhGH solutions over 6 days based on body weight gain and width of the tibial growth plate. Histological examination of the injection sites indicated a significantly milder inflammatory response than that observed after injection of PLA and PLGA microspheres. Neither anti-rhGH antibodies nor the toxic effects on heart, liver and kidney were detectable after administration of rhGH-PELA microspheres in SD rats. These results suggest that rhGH-PELA microspheres have the potential to be clinically effective and safe when administered only once every two months, a dose regimen for better patient acceptance and compliance.
