Chen B L, Arakawa T
Amgen Inc., Thousand Oaks, CA 91320, USA.
J Pharm Sci. 1996 Apr;85(4):419-26. doi: 10.1021/js9504393.
Keratinocyte growth factor (KGF) has limited stability in aqueous media, as it undergoes denaturation followed by aggregation at 37 degrees C. Heparin and anionic polymers have been shown to increase the denaturation temperatures and extend the half-life of the monomeric, native form of KGF during storage. These polymers, however, bind more than one protein molecule with high affinity, and such tight complex formation may cause problems for clinical use. In this study, we have tested low molecular weight additives, such as osmolytes and salts, for their effects on the stability of KGF against thermal denaturation and high-temperature storage. Salts such as NaCl, sodium phosphate, ammonium sulfate, and sodium citrate were highly effective in increasing both the denaturation temperature and storage stability. The fact that the same additives stabilize KGF against both stresses is consistent with the idea that the storage stability is determined by denaturation followed by aggregation. Among the osmolytes tested, N,N'-dimethylglycine, trehalose, and sucrose were also effective stabilizers. However, quantitative comparison of the osmolytes tested indicated that their effectiveness on the thermal denaturation and the storage stability is not exactly parallel, suggesting that other factors also contribute to the storage stability.
角质形成细胞生长因子（KGF）在水性介质中的稳定性有限，因为它在37℃下会发生变性并随后聚集。肝素和阴离子聚合物已被证明可提高变性温度并延长KGF单体天然形式在储存期间的半衰期。然而，这些聚合物会以高亲和力结合多个蛋白质分子，而这种紧密复合物的形成可能会给临床应用带来问题。在本研究中，我们测试了低分子量添加剂，如渗透剂和盐，它们对KGF抗热变性和高温储存稳定性的影响。诸如氯化钠、磷酸钠、硫酸铵和柠檬酸钠等盐在提高变性温度和储存稳定性方面非常有效。相同的添加剂能使KGF抵抗两种应力的事实与储存稳定性由变性后聚集决定的观点一致。在所测试的渗透剂中，N，N'-二甲基甘氨酸、海藻糖和蔗糖也是有效的稳定剂。然而，对所测试渗透剂的定量比较表明，它们对热变性和储存稳定性的有效性并不完全平行，这表明其他因素也对储存稳定性有贡献。
