青蒿琥酯体外临时静脉注射制剂的降解动力学研究。
Degradation kinetics of artesunate for the development of an ex-tempore intravenous injection.
机构信息
Jimma University Laboratory of Drug Quality (JuLaDQ) and School of Pharmacy, Jimma University, PO Box 378, Jimma, Ethiopia.
Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Ghent, Belgium.
出版信息
Malar J. 2022 Sep 6;21(1):256. doi: 10.1186/s12936-022-04278-4.
BACKGROUND
Artesunate is recommended by the World Health Organization (WHO) for parenteral treatment of severe Plasmodium falciparum malaria. However, artesunate is inherently unstable in an aqueous solution and hydrolyses rapidly after its preparation for injection. Therefore, the aim of the study was to evaluate the stabilizing effects of phosphate buffer and mannitol against short-term (ex-tempore) artesunate hydrolysis.
METHODS
A HPLC-UV isocratic method was developed using a reversed-phase fused core column (HALO RP-C18) and a mobile phase consisting of a mixture of 45% ammonium formate 10 mM in water (pH 4.5) and 55% methanol. Artesunate was formulated as aqueous solutions using a design of experiment (DOE) to investigate the artesunate stabilizing effects of pH (8-10), phosphate buffer strength (0.3-0.5 M), and mannitol (0-0.22 mmol/mL). The solutions were incubated at predefined temperatures (5, 25, and 40 °C) with subsequent analysis. Arrhenius equation was applied to model and evaluate the stability results.
RESULTS
The developed HPLC-based method using fused-core stationary phase allowed to selectively quantify artesunate in the presence of its main hydrolysis degradants; namely β-dihydroartemisinin (β-DHA) and α-dihydroartemisinin (α-DHA) within 10 min. By applying the Arrhenius equation, the rate of hydrolysis of the drug increased approximately by 3.4 as the temperature raised by 10 °C. Buffer strength was found to be the main factor affecting the hydrolysis rate constants at 5 and 25 °C (p < 0.05), the activation energy (p = 0.009), and the frequency factor (p = 0.045). However, the effect of the buffer was predominant on the activation energy and hydrolysis rate constants, revealing its stabilizing effect on the drug at lower buffer strength (0.3 M). Within the investigated range (pH = 8-10), pH was found to influence the activation energy, with a positive stabilizing effect in the pH range of 8-9. The addition of mannitol as stabilizing agent into artesunate aqueous formulation did not show an improved response.
CONCLUSION
Phosphate buffer was the main stability determining factor of artesunate in the aqueous intravenous (i.v.) formulation and was found to be more effective in stabilizing artesunate at a buffer strength of 0.3 M in pH 8-9, while mannitol lacked stabilizing effect.
背景
青蒿琥酯由世界卫生组织（WHO）推荐用于治疗严重的恶性疟原虫疟疾的静脉内给药。然而，青蒿琥酯在水溶液中本质上不稳定，并且在制备注射用后迅速水解。因此，本研究的目的是评估磷酸盐缓冲液和甘露醇对短期（临时）青蒿琥酯水解的稳定作用。
方法
采用高效液相色谱-紫外（HPLC-UV）等度法，使用反相熔合核柱（HALO RP-C18）和由 45%甲酸铵 10 mM 在水中（pH 4.5）和 55%甲醇组成的流动相。通过实验设计（DOE）将青蒿琥酯配制成水溶液，以研究 pH（8-10）、磷酸盐缓冲液强度（0.3-0.5 M）和甘露醇（0-0.22 mmol/mL）对青蒿琥酯稳定作用的影响。将溶液在预定温度（5、25 和 40°C）下孵育，然后进行分析。应用 Arrhenius 方程对稳定性结果进行建模和评估。
结果
使用熔合核固定相开发的 HPLC 方法能够在存在其主要水解降解产物（即β-二氢青蒿素（β-DHA）和α-二氢青蒿素（α-DHA）的情况下，在 10 分钟内选择性地定量青蒿琥酯。通过应用 Arrhenius 方程，药物的水解速率约增加 3.4 倍，温度升高 10°C。在 5 和 25°C 时，缓冲液强度被发现是影响水解速率常数的主要因素（p<0.05），以及活化能（p=0.009）和频率因子（p=0.045）。然而，缓冲液的作用主要是对药物的活化能和水解速率常数产生影响，在较低的缓冲强度（0.3 M）下显示出对药物的稳定作用。在所研究的范围内（pH=8-10），pH 被发现影响活化能，在 pH 8-9 的范围内具有正稳定作用。将甘露醇作为稳定剂添加到青蒿琥酯水性制剂中并没有显示出改善的效果。
结论
磷酸盐缓冲液是青蒿琥酯在水性静脉内（i.v.）制剂中的主要稳定性决定因素，在 pH 8-9 时，在 0.3 M 的缓冲强度下发现其对青蒿琥酯更有效稳定，而甘露醇缺乏稳定作用。
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