Powell M F, Sanders L M, Rogerson A, Si V
Institute of Pharmaceutical Sciences, Syntex Research, Palo Alto, California.
Pharm Res. 1991 Oct;8(10):1258-63. doi: 10.1023/a:1015847628047.
The degradation of native LHRH in aqueous buffers of pH approximately 1-10 obeyed the rate equation, kobs = kH + alpha H+ + ko + kHO-(alpha HO-)x, where x at 60-100 degrees C was approximately 0.64 and temperature independent. Extrapolation to 25 degrees C using the Arrhenius equation and secondary rate constants showed that native LHRH is reasonably stable at pH 5.4, giving a shelf life (t90) of approximately 5 years. Regarding physical properties, hydrophobic LHRH analogues nafarelin and detirelix were found to be surface active as demonstrated by a decrease in apparent surface tension with increased peptide concentration. The CMC for detirelix at pH 7.4 was determined to be 5.3 x 10(-4) M (0.88 mg/ml), and that for nafarelin, greater than 2 mg/ml. At higher concentrations (approximately 4-8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence, less than 0.001). The thermodynamic stability of these peptide liquid crystals was probed by determining their melting points (Tcm) in the presence of propylene glycol, a solvent which proved to be efficacious at suppressing gelation and at destabilizing liquid crystals as measured by a reduction in Tcm.
在pH约为1 - 10的水性缓冲液中，天然促黄体激素释放激素（LHRH）的降解遵循速率方程：kobs = kH + αH⁺ + ko + kHO⁻(αHO⁻)ˣ，其中在60 - 100℃时x约为0.64且与温度无关。使用阿伦尼乌斯方程和二级速率常数外推至25℃表明，天然LHRH在pH 5.4时相当稳定，保质期（t90）约为5年。关于物理性质，疏水性LHRH类似物那法瑞林和地来瑞林被发现具有表面活性，表现为随着肽浓度增加表观表面张力降低。地来瑞林在pH 7.4时的临界胶束浓度（CMC）测定为5.3×10⁻⁴ M（0.88 mg/ml），那法瑞林的CMC大于2 mg/ml。在较高浓度（约4 - 8 mg/ml）下，那法瑞林和地来瑞林形成了消光呈波纹状的向列型液晶（双折射，小于0.001）。通过在丙二醇存在下测定它们的熔点（Tcm）来探究这些肽液晶的热力学稳定性，丙二醇被证明在抑制凝胶化和使液晶不稳定方面有效，这可通过Tcm降低来衡量。
