Development of a lyophilization formulation that preserves the biological activity of the platelet-inducing cytokine interleukin-11 at low concentrations
Development of a lyophilization formulation that preserves the biological activity of the platelet-inducing cytokine interleukin-11 at low concentrations
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DOI：
10.1211/0022357001773643
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发表时间：
2000-01-01
影响因子：
3.3
通讯作者：
Mire-Sluis, A
中科院分区：
文献类型：
--
作者：
Page, C;Dawson, P;Mire-Sluis, A
重组人白介素11(rhIL-11)是一种在至少一个国家获得许可的生物治疗产品，用于在化疗期间对抗血小板减少症，以及在一系列其他疾病的临床试验中使用。在尝试在低浓度下冷冻干燥IL-11之后，很明显发生了可恢复的生物活性的显著损失。对各种因素的研究，包括冷冻干燥的容器类型，发现表面对玻璃的吸附是导致溶液中rhIL-11活性丧失的主要因素(在室温下3h后下降40%)，以及冷冻干燥后的活性损失。为了解决这一问题，研究了包含人血清白蛋白(HSA)、海藻糖和吐温-20组合的不同配方。两种配方成功地通过冷冻干燥和随后的重建(配方相对于原始材料的效价大于或等于0.97)完全保留了rhIL-11的生物活性。在六个月的加速降解研究中，证明了使用这些制剂的冻干重组人白细胞介素11的稳定性(预计在-20摄氏度储存后效价每年下降小于或等于1.4%)。总之，我们开发了一种辅料组合(0.5%人血清白蛋白、0.1%海藻糖和0.02%吐温-20在磷酸二氢钾缓冲液(pH 7.4)中)，以在玻璃容器中形成稳定的重组人白细胞介素11冻干产品，没有任何效力。这些发现应该有助于低剂量重组人白细胞介素11产品的开发，并对那些使用这种材料和其他具有类似物理性质的材料的人发出警告，而不采取适当的预防措施以避免因吸附而造成的损失。
Recombinant human interleukin-11 (rhIL-11) is a licensed biological therapeutic product in at least one country and is used to combat thrombocytopenia during chemotherapeutic regimens, as well as undergoing clinical trials for a range of other disorders. Following attempts to lyophilize IL-11 at low concentrations, it was clear that a significant loss of recoverable biological activity occurred.Investigation of a variety of factors, including the type of container in which the rhIL-11 was lyophilized, revealed that surface adsorption to glass was a major factor resulting in loss of activity of rhIL-11 in solution (>40% reduction after 3 h at room temperature), in addition to losses of activity post-lyophilization. To overcome this problem, different formulations containing combinations of human serum albumin (HSA), trehalose and Tween-20 have been investigated.Two formulations were successful ire entirely preserving the biological activity of rhIL-11 through lyophilization and subsequent reconstitution (potency estimates of formulated relative to original material being greater than or equal to 0.97). Accelerated degradation studies, performed at intervals over a six-month period, demonstrated the stability of freeze-dried rhIL-11 using these formulations (predicted annual reduction in potency after storage at -20 degrees C less than or equal to 1.4%).In conclusion, we have developed a working combination of excipients (0.5% HSA, 0.1% trehalose and 0.02% Tween-20 in potassium phosphate buffer (pH 7.4)) to formulate a stable rhIL-11 freeze-dried product in glass containers, with no lass in potency. These findings should facilitate development of low dose rhIL-11 products and be an indicator of caution to those using this and other material with similar physical properties, without taking appropriate precautions to avoid losses through adsorption.