Stepensky David, Chorny Michael, Dabour Ziad, Schumacher Ilana
Research & Quality Control Laboratory, The Medical Corps, Mil. P.O. Box 02149, Israel Defense Forces, Israel Defense Forces, Israel.
J Pharm Sci. 2004 Apr;93(4):969-80. doi: 10.1002/jps.20010.
Injectable formulations of L-adrenaline are commonly used in emergency medicine. Despite numerous studies, the comparative contribution and kinetics of the L-adrenaline inactivation pathways during storage have not been conclusively evaluated. We examined the kinetics of L-adrenaline degradation in a prospective study and determined the extent of drug inactivation by different pathways during and beyond the stipulated product shelf-life in 42 batches of adrenaline ampules stored under controlled conditions. The content of L-adrenaline and degradation products was determined with a chiral high-performance liquid chromatography (HPLC) assay, and the degradation products were identified by mass spectrometric detection as D-adrenaline and L- and D-adrenaline sulfonate. The kinetics of the content change with storage was analyzed simultaneously for L-adrenaline and the degradation products using kinetic modeling. The lower acceptable level of adrenaline content in the formulation stated by US Pharmacopoeia (90% as a sum of L- and D-isomers) was attained after 2.0 years of storage, at which time the content of the therapeutically active L-isomer amounted to as low as 85%. The modeling revealed significant differences in the degradation kinetics in the formulations produced before and after 1997, whose cause remained unidentified in this study.
左旋肾上腺素的注射剂常用于急救医学。尽管进行了大量研究，但储存期间左旋肾上腺素失活途径的相对贡献和动力学尚未得到最终评估。我们在一项前瞻性研究中检查了左旋肾上腺素降解的动力学，并确定了在受控条件下储存的42批肾上腺素安瓿在规定产品保质期内及之后不同途径导致的药物失活程度。用手性高效液相色谱（HPLC）分析法测定左旋肾上腺素和降解产物的含量，并用质谱检测法鉴定降解产物为D - 肾上腺素以及L - 和D - 肾上腺素磺酸盐。使用动力学模型同时分析了左旋肾上腺素和降解产物含量随储存时间的变化动力学。美国药典规定的制剂中肾上腺素含量的较低可接受水平（L - 和D - 异构体总和的90%）在储存2.0年后达到，此时治疗活性L - 异构体的含量低至85%。模型显示1997年前后生产的制剂在降解动力学上存在显著差异，本研究中其原因尚不明。
