Study on the compatibility between pharmaceutical excipient polyethylene glycol 6000 and antiepileptic active pharmaceutical ingredients levetiracetam

Published on Feb. 08, 2024Total Views: 917 times Total Downloads: 517 times Download Mobile

Author: JIANG Yun ^1, ²  ZHOU Ying ^1, ² ZHAO Yong ^1, ² ZHENG Jinfeng ^1, ² LIU Yanming ^1, ²

Affiliation: 1. Hunan Institute for Drug Control, Changsha 410001, China 2. NMPA Key Laboratory for Pharmaceutical Excipients Engineering Technology Research, Changsha 410001, China

Keywords: Levetiracetam Polyethylene glycol 6000 Compatibility

DOI: 10.12173/j.issn.1008-049X.202311107

Reference: JIANG Yun, ZHOU Ying, ZHAO Yong, ZHENG Jinfeng, LIU Yanming.Study on the compatibility between pharmaceutical excipient polyethylene glycol 6000 and antiepileptic active pharmaceutical ingredients levetiracetam[J].Zhongguo Yaoshi Zazhi,2023,26(12): 57-65.DOI:10.12173/j.issn.1008-049X.202311107.[Article in Chinese]  Copied

Abstract
Full-text
References

Abstract

Objective To investigate the compatibility between antiepileptic active pharmaceutical ingredient (API) levetiracetam and binder polyethylene glycol 6000, and provide a basis for evaluating and ensuring the safety of drugs.

Methods Levetiracetam and polyethylene glycol 6000 from different producers were mixed in a certain proportion, and placed under different conditions according to the test method of stability influencing factors. The compatibility of levetiracetam and polyethylene glycol 6000 was analyzed by differential scanning calorimetry and HPLC, respectively, and the thermal variations, changes of levetiracetam appearance and related substances were investigated.

Results After being placed under high humidity (relative humidity of 90%) and light (4 500 Lx) for 10 days, the compatibility between API and pharmaceutical excipients was proved good, while under the conditions of high temperature of 50℃ and 60℃, polyethylene glycol 6000 interacted with levetiracetam, resulting in the growth of levetiracetam related substances including impurity A and total amount of impurities, along with the production of two unknown impurities. Polyethylene glycol 6000 from different producers and different batches had different effects on the related substances of levetiracetam.

Conclusion There is a risk of compatibility between levetiracetam and polyethylene glycol 6000 under elevated temperatures, and it is recommended that preparation producers optimize product prescriptions and improve the quality and safety of drugs.

Full-text

Please download the PDF version to read the full text: download

References

1.郑明慧, 白建强. 基于LKB1/AMPK信号通路探究金雀异黄酮对癫痫大鼠海马神经元凋亡和自噬的影响 [J].中国药师, 2022, 25(11): 1904-1910. [Zheng MH, Bai JQ. Impacts of genistein on the apoptosis and autophagy of hippocampal neurons in epileptic rats based on LKB1/AMPK signaling pathway[J]. China Pharmacist, 2022, 25(11): 1904-1910.] DOI: 10.19962/j.cnki.issn1008-049X.2022.11.006.

2.杨泽萍, 马雪, 李红健, 等. GA-BP神经网络、多元线性回归预测新疆癫痫患儿拉莫三嗪血药浓度[J]. 中国药师, 2022, 25(9): 1598-1602. [Yang ZP, Ma X, Li HJ et al. Prediction of the blood concentration of lamotrigine in Xinjiang epileptic children by GA-BP neural network and multiple linear regression[J]. China Pharmacist,2022,25(9):1598-1602.] DOI: 10.19962/j.cnki.issn1008-049X.2022.09.019.

3.Keppra and Keppra XR (levetiracetam) Briefing Materials[EB/OL]. [2023/11/07]. https://www.fda.gov/media/107293/.

4.赵婷, 李红健, 孙岩, 等. 新疆不同民族癫痫患儿HLA-B*1502基因多态性与芳香族ASMs诱导的皮肤不良反应相关性研究[J]. 药物流行病学杂志, 2023, 32(2): 151-157. [Zhao T, Li HJ, Sun Y, et al. Relationship between HLA-B*1502 gene polymorphism and skin adverse reactions caused by aromatic ASMs in children with epilepsy of different nationalities in Xinjiang[J]. Chinese Journal of Pharmacoepidemiology, 2023, 32(2): 151-157.] DOI: 10.19960/j.issn.1005-0698.202302004.

5.马雪, 李红健, 赵婷, 等. MDR1 G2677T/A基因多态性与癫痫患儿左乙拉西坦血药浓度的相关性研究[J]. 中国药师, 2022, 25(2): 273-277. [Ma X, Li HJ, Zhao T, et al. Study on the relationship between MDR1 G2677T/A gene polymorphism and serum concentration of levetiracetam in children with epilepsy [J]. China Pharmacist, 2022, 25(2): 273-277.] DOI: 10.19962/j.cnki.issn1008-049X.2022.02.013.

6.UCB医药有限公司. 包括左乙拉西坦的药物组合物及其制备方法: 中国专利, CN200680001279. 9[P]. 2007-11-07.

7.Han S, Kim C, Kwon D. Thermal/oxidative degradation and stabilization of polyethylene glycol[J]. Polymer, 1997, 38(2): 317-323. DOI: 10.1016/S0032-3861(97)88175-X.

8.ICH Q8 (R2) Pharmaceutical development[EB/OL]. (2009-08) [2023/11/07] https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf.

9.化学药物制剂研究基本技术指导原则[S]. 2005.

10.梁荣财, 范本杰, 孙考祥, 等. 阿替洛尔与片剂辅料相容性的热分析考察[J]. 中国药业, 2009, 18(10): 19-20. [Liang RC, Fan BJ, Sun KX, et al. Study on compatability between atenolol and tablet excipients by DSC[J]. China Pharmaceuticals, 2009, 18(10): 19-20.] DOI: 10.3969/j.issn.1006-4931.2009.10.013.

11.吴向军, 颜携国, 邓英光. 恩替卡韦片的原辅料相容性[J]. 中国药物经济学, 2021, 16(4): 115-120. [Wu XJ, Yan XG, Deng YG. Study on the drug-excipient compatibility of entecavir tablets[J].China Journal of Pharmaceutical Economics, 2021, 16(4): 115-120.] DOI: 10.12010/j.issn.1673-5846.2021.04.02.

12.Sivaneswari S, Karthikeyan E, Chandana PJ, et al. Novel expandable gastro retentive system by unfolding mechanism of levetiracetam using simple lattice design-formulation optimization and in vitro evaluation[J]. Bulletin of Faculty of Pharmacy Cairo University, 2017, 55(1): 63-72. DOI: 10.1016/j.bfopcu.2017.02.003.

13.李军, 文屏, 高咏莉, 等. 阿替洛尔片原料与辅料相容性问题的探讨[J]. 中国药师, 2014, 17(8): 1428-1429. [Li J, Wen P, Gao YL, et al. Discussion on compatibility between atenolol and different excipients[J]. China Pharmacist, 2014, 17(8): 1428-1429.] DOI: 10.3969/j.issn.1008-049X.2014.08.063.

14.中国药典2020年版. 四部[S]. 2020: 457-460.

15.EP11.0版[S]. 2022: 3219-3220.

16.USP现行版[S]. 2023: 1-3.

17.Scientific discussion on Keppra from EMA[EB/OL]. [2023/12/05]. https://www.ema.europa.eu/en/documents/scientific-discussion/keppra-epar-scientific-discussion_en.pdf.

18.谢富春, 朱长春, 张玉清. 聚乙二醇合成工艺[J]. 化学推进剂与高分子材料, 2005, 3(4): 6-9. [Xie FC, Zhu CC, Zhang YQ. Synthesis technology of polyethylene glycol[J], Chemical Propellants & Polymeric Materials, 2005, 3(4):6-9.] DOI: 10.3969/j.issn.1672-2191.2005.04.002.

19.绪国梅,郭振,李晓光.聚乙二醇6000的精制方法研究[J].化工时刊, 2019, 33(2): 18-19. [Xu GM, Guo Z, Li XG. Study on the purification of polyethylene glycol 6000[J].Chemical Industry Times,2019, 33(2): 18-19.] DOI: 10.16597/j.cnki.issn.1002-154x.2019.02.006.

20.郑金凤, 赵勇, 谢莹莹, 等. 药用辅料聚乙二醇6000质量评价及质量研究[J]. 中南药学, 2023, 21(8): 2185-2190. [Zheng JF, Zhao Y, Xie YY, et al. Quality evaluation and quality research of polyethylene glycol 6000[J]. Central South Pharmacy, 2023, 21(8): 2185-2190.] DOI: 10.7539/j.issn.1672-2981.2023.08.037.

21.蔡如琳, 胡伟, 胡冬芳, 等. 不同相对分子质量聚乙二醇的热氧降解行为[J]. 高分子材料科学与工程, 2017, 33(3): 107-110, 115. [Cai RL, Hu W, Hu DF, et al. Thermo-oxidative degradation of different molecular weight polyethylene glycol[J]. Polymer Material Science and Engineering, 2017, 33(3): 107-110, 115.] DOI: 10.16865/j.cnki.1000-7555.2017.03.019.

22.张少桦, 王锦刚, 蒋海松. HPLC法检查左乙拉西坦缓释片的有关物质[J].中国药房, 2014, 25(13): 1212-1215. [Zhang SH, Wang JG, Jiang HS. Determination of related substances in levetiracetam sustained-release tablets by HPLC[J]. China Pharmacy, 2014, 25(13): 1212-1215.] DOI: CNKI:SUN:ZGYA.0.2014-13-024.

23.陈慧, 元延芳, 张瑞, 等. 关于编制"十四五"药品安全规划的思考[J]. 中国药师, 2021, 24(10): 1873-1876. [Chen H, Yuan YF, Zhang R, et al. Thinking about the formulation of the Fourteenth Five-year plan for drug safety work[J]. China Pharmacist, 2021, 24(10): 1873-1876.] DOI: 10.19962/j.cnki.issn1008-049X.2021.10.020.