聚乙二醇诱导沉淀干扰素α-2a,然后真空干燥:开发一种获得干燥稳定粉末的新工艺。

AAPS PharmSci Pub Date : 2004-01-26 DOI:10.1208/ps060104
Vikas K Sharma, Devendra S Kalonia
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引用次数: 0

摘要

对基于聚乙二醇(PEG)诱导蛋白质沉淀,然后在有糖存在的情况下进行真空干燥以获得干蛋白粉的新型工艺的开发进行了可行性研究。测定了干扰素α-2a(IFNalpha2a)在各种 PEG 存在下的表观溶解度,并研究了溶液 pH 值、离子强度和温度的影响。IFNalpha2a 沉淀在 25 摄氏度、100 毫托的保存温度下按原样或在甘露醇和/或曲哈糖存在下进行干燥。干燥后的 IFNalpha2a 制剂在 40 摄氏度(3 个月)下进行了加速稳定性研究,并将其稳定性与类似的冻干制剂进行了比较。结果表明,在 pH 值为 6.5、溶液离子强度为 71 mM 的条件下,使用 10% wt/vol PEG 1450 可以沉淀 90% 以上的蛋白质。对沉淀物进行真空干燥只会导致 IFNalpha2a 形成不溶性的聚集体;然而,加入甘露醇或曲海洛糖可防止这种情况的发生。添加过量的甘露醇可降低残余水分含量,使最终干燥产品的处理效果更好。在 40 摄氏度下贮存 3 个月后,在含有 IFNalpha2a:曲哈洛糖:甘露醇(重量比为 1:10:100)的干燥制剂中,加速贮存稳定性未显示任何聚集现象,氧化 IFNalpha2a 的形成率低于 5%。这种真空干燥制剂的稳定性与类似的冻干制剂相当。
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Polyethylene glycol-induced precipitation of interferon alpha-2a followed by vacuum drying: development of a novel process for obtaining a dry, stable powder.

Feasibility studies were performed on the development of a novel process based on polyethylene glycol (PEG)-induced precipitation of proteins followed by vacuum drying in the presence of sugars to obtain dry protein powders. Apparent solubility of interferon alpha-2a (IFNalpha2a) was determined in the presence of various PEGs and the effect of solution pH, ionic strength, and temperature was investigated. IFNalpha2a precipitate was dried at a shelf temperature of 25 degrees C at 100 mTorr either as it is or in the presence of mannitol and/or trehalose. The dried IFNalpha2a formulations were subjected to accelerated stability studies at 40 degrees C (3 months), and the stability was compared with that of a similar lyophilized formulation. The results indicated that more than 90% of the protein could be precipitated using 10% wt/vol PEG 1450 at pH 6.5 at a solution ionic strength of 71 mM. Vacuum drying of the precipitate only resulted in the formation of insoluble aggregates of IFNalpha2a; however, this was prevented by the addition of either mannitol or trehalose. The addition of excess mannitol resulted in low residual moisture content and better handling of the final dried product. Accelerated storage stability did not show any aggregation and showed less than 5% formation of oxidized IFNalpha2a in the dried formulation containing IFNalpha2a:trehalose:mannitol in a 1:10:100 wt/wt ratio upon storage at 40 degrees C for 3 months. The stability of this vacuum dried formulation was comparable with that of a similar lyophilized formulation.

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