Katakam M, Bell L N, Banga A K
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, AL 36849-5503, USA.
J Pharm Sci. 1995 Jun;84(6):713-6. doi: 10.1002/jps.2600840609.
The physical stability of a human growth hormone (hGH) formulation upon exposure to air/water interfaces (with vortex mixing) and to nonisothermal stress [determined by differential scanning calorimetry (DSC)] was investigated. The effect of these stresses on the formation of soluble and insoluble aggregates was studied. The aggregates were characterized and quantified by size exclusion-HPLC and UV spectrophotometry. Vortex mixing of hGH solutions (0.5 mg/mL) in phosphate buffer, pH 7.4, for just 1 min caused 67% of the drug to precipitate as insoluble aggregates. These aggregates were noncovalent in nature. Non-ionic surfactants prevented the interfacially induced aggregation at their critical micelle concentration (cmc) for Pluronic F-68 (polyoxyethylene polyoxypropylene block polymer) and Brij 35 (polyoxyethylene alkyl ether) and above the cmc for Tween 80 (polyoxyethylene sorbitan monooleate). However, the same surfactants failed to stabilize hGH against thermal stress in DSC studies. Higher concentrations of surfactants actually destabilized hGH as evidenced by the decrease in the onset temperature for the denaturation endotherm.
研究了人生长激素（hGH）制剂在暴露于空气/水界面（通过涡旋混合）和非等温应力[通过差示扫描量热法（DSC）测定]时的物理稳定性。研究了这些应力对可溶性和不溶性聚集体形成的影响。通过尺寸排阻高效液相色谱法和紫外分光光度法对聚集体进行表征和定量。在pH 7.4的磷酸盐缓冲液中，将hGH溶液（0.5 mg/mL）涡旋混合仅1分钟，就导致67%的药物以不溶性聚集体形式沉淀。这些聚集体本质上是非共价的。非离子表面活性剂在其临界胶束浓度（cmc）时可防止界面诱导的聚集，对于普朗尼克F-68（聚氧乙烯聚氧丙烯嵌段聚合物）和Brij 35（聚氧乙烯烷基醚）而言，在其cmc时可防止，对于吐温80（聚氧乙烯山梨醇单油酸酯）而言，在高于其cmc时可防止。然而，在DSC研究中，相同的表面活性剂未能使hGH抵抗热应力。更高浓度的表面活性剂实际上使hGH不稳定，变性吸热峰起始温度的降低就证明了这一点。
