A Novel Sustained-Release Formulation of Recombinant Human Growth Hormone and Its Pharmacokinetic, Pharmacodynamic and Safety Profiles
A Novel Sustained-Release Formulation of Recombinant Human Growth Hormone and Its Pharmacokinetic, Pharmacodynamic and Safety Profiles
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一种新型重组人生长激素缓释制剂及其药代动力学、药效学和安全性特征
DOI：
10.1021/mp300126t
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发表时间：
2012-07-01
影响因子：
4.9
通讯作者：
Su, Zhiguo
中科院分区：
文献类型：
--
作者：
Wei, Yi;Wang, Yuxia;Su, Zhiguo
研制了一种使用聚（单甲氧基聚乙二醇-co-D，L-丙交酯）（mPEG-PLA，PELA）微球的有效且安全的缓释rhGH 2个月的制剂，以减少用药频率。采用复乳法结合预混膜乳化技术成功制备了粒径分布窄的rhGH PELA微球。微球的窄尺寸分布将保证可重复的生产率和释放行为。此外，两亲性PELA改善了蛋白质药物的生物活性保留，因为它防止蛋白质与油/水界面和疏水网络接触，并调节酸性降解产物从载体系统的扩散。将PELA微球与市售rhGH溶液、常规聚（D，L-乳酸）（PLA）和聚（D，L-乳酸-共-乙醇酸）（PLGA）微球进行体内比较。在Sprague-Dawley（SD）大鼠中，与rhGH溶液、PLA或PLGA微球相比，rhGH-PELA给药可延长rhGH释放的持续时间（长达56天），并增加曲线下面积（AUC）。此外，与其他rhGH制剂相比，rhGH-PELA微球诱导的总胰岛素样生长因子-1（IGF-1）和胰岛素样生长因子结合蛋白-3（IGFBP-3）反应更大。在切除垂体的SD大鼠模型中，基于体重增加和胫骨生长板宽度，rhGH-PELA微球的药理学疗效优于每日给予rhGH溶液6天。注射部位的组织学检查表明，与注射PLA和PLGA微球后观察到的炎症反应相比，炎症反应明显较轻。rhGH-PELA微球在SD大鼠体内未检测到抗rhGH抗体，也未检测到对心、肝、肾的毒性作用。这些结果表明，rhGH-PELA微球在每两个月仅给药一次时具有临床有效性和安全性的潜力，这是一种更好的患者接受度和依从性的剂量方案。
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.