药学学报, 2022, 57(4): 1180-1186
闫鑫, 曹玉珍, 姜小梅, 汪曣, 石玉杰. 离子液体对环孢素A口服吸收的影响[J]. 药学学报, 2022, 57(4): 1180-1186.
YAN Xin#, CAO Yu-zhen, JIANG Xiao-mei, WANG Yan, SHI Yu-jie. The effect of ionic liquid on the oral absorption of cyclosporine A[J]. Acta Pharmaceutica Sinica, 2022, 57(4): 1180-1186.

闫鑫1#, 曹玉珍1#, 姜小梅1, 汪曣1, 石玉杰2*
1. 天津大学精仪学院, 天津 300072;
2. 北京大学药学院, 北京 100191
研究基于胆碱和香茅酸的离子液体([Cho][CA],COCA)对难溶性药物环孢素A (CsA)口服吸收的影响。由胆碱和香茅酸采用一步中和法制备COCA,对其进行质谱、核磁共振氢谱1H-NMR和红外光谱表征后,采用超声辅助法制备CsA-离子液体(CsA-COCA),并将其灌装于肠溶胶囊,液相色谱-串联质谱法(LC-MS/MS)检测大鼠分别口服CsA-COCA胶囊剂及CsA混悬剂后全血中CsA的浓度,并采用DAS 2.0软件计算药代动力学参数。动物福利和实验过程均遵循北京大学医学部动物伦理委员会的规定。研究结果表明,与口服10 mg·kg-1 CsA混悬液相比,口服相同剂量的离子液体制剂所获得的CsA的药时曲线下面积(area under the curve,AUC)提高了2.81倍,半衰期(half-life time,T1/2)延长了4.41倍,平均驻留时间(mean residence time,MRT)提高了1.77倍。本研究制备的COCA可显著促进CsA在大鼠体内的口服吸收,且能延长其半衰期。本研究可为CsA等难溶性药物的口服制剂研究提供借鉴。
关键词:    离子液体      环孢素A      口服吸收      难溶性药物      液相色谱-串联质谱     
The effect of ionic liquid on the oral absorption of cyclosporine A
YAN Xin#1#, CAO Yu-zhen1#, JIANG Xiao-mei1, WANG Yan1, SHI Yu-jie2*
1. School of Precision Instrument and Opto-Electronics Engineering, Tianjin University, Tianjin 300072, China;
2. School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
To investigate the effect of ionic liquid based on choline and citronellic acid ([Cho] [CA], COCA) on the oral absorption of poorly soluble drug cyclosporin A (CsA), COCA was synthesized using choline and citronellic acid by one-step neutralization method, and then characterized by mass spectrometry, 1H-NMR, and infrared spectrophotometry. Next, CsA-ionic liquid (CsA-COCA) was prepared by ultrasonic-assisted method and filled into enteric-coated capsules. After oral administration of CsA-COCA capsules or CsA suspension preparation in rats, CsA concentration in whole blood was assayed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and the pharmacokinetic parameters were calculated by DAS 2.0 software. All animal care and experiments followed the approval of Institutional Animal Care and Use Committee at Peking University Health Science Center. The results indicated that compared with oral administration of 10 mg·kg-1CsA suspension, the area under the curve (AUC), half-life time (T1/2), and mean residence time (MRT) of CsA obtained by oral administration the same dose of CsA-COCA increased by 2.81, 4.41, and 1.77 times, respectively. The COCA prepared in this study can significantly promote the oral absorption of CsA in rats, and prolong the half-life. This study can provide reference for the study of oral formulation of insoluble drugs such as CsA.
Key words:    ionic liquid    cyclosporine A    oral absorption    poorly soluble drug    LC-MS/MS   
收稿日期: 2021-11-22
DOI: 10.16438/j.0513-4870.2021-1668
基金项目: 国家自然科学基金资助项目(81603041).
通讯作者: 石玉杰,Tel:86-10-82801590,E-mail:yujiestone@bjmu.edu.cn
Email: yujiestone@bjmu.edu.cn
PDF(1223KB) Free
闫鑫  在本刊中的所有文章
曹玉珍  在本刊中的所有文章
姜小梅  在本刊中的所有文章
汪曣  在本刊中的所有文章
石玉杰  在本刊中的所有文章

[1] Lei Z, Chen B, Koo YM, et al. Introduction:ionic liquids[J]. Chem Rev, 2017, 117:6633-6635.
[2] Deetlefs M, Fanselow M, Seddon KR. Ionic liquids:the view from mount improbable[J]. RSC Adv, 2016, 6:4280-4288.
[3] Egorova KS, Gordeev EG, Ananikov VP. Biological activity of ionic liquids and their application in pharmaceutics and medicine[J]. Chem Rev, 2017, 117:7132-7189.
[4] Shi Y, Zhao Z, Gao Y, et al. Oral delivery of sorafenib through spontaneous formation of ionic liquid nanocomplexes[J]. J Control Release, 2020, 322:602-609.
[5] Banerjee A, Ibsen K, Brown T, et al. Ionic liquids for oral insulin delivery[J]. Proc Natl Acad Sci U S A, 2018, 115:7296-7301.
[6] Angsantikul P, Peng K, Curreri AM, et al. Ionic liquids and deep eutectic solvents for enhanced delivery of antibodies in the gastrointestinal tract[J]. Adv Funct Mater, 2020, 31:2002912.
[7] Guada M, Beloqui A, Kumar M, et al. Reformulating cyclosporine A (CsA):more than just a life cycle management strategy[J]. J Control Release, 2016, 225:269-282.
[8] Rohan G, Neha D. BCS class IV drugs:highly notorious candidates for formulation development[J]. J Control Release, 2017, 248:71-95.
[9] Wang K, Qi JP, Weng EF, et al. Enhancement of oral bioavailability of cyclosporine A:comparison of various nanoscale drug-delivery sustems[J]. Int J Nanomedicine, 2014, 9:4991-4999.
[10] Guan P, Lu Y, Qi J, et al. Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt[J]. Int J Nanomedicine, 2011, 6:965-974.
[11] Keohane K, Rosa M, Coulter IS, et al. Enhanced colonic delivery of ciclosporin A self-emulsifying drug delivery system encapsulated in coated minispheres[J]. Drug Dev Ind Pharm, 2016, 42:245-253.
[12] Guada M, Lana H, Gil AG, et al. Cyclosporine A lipid nanoparticles for oral administration:pharmacodynamics and safety evaluation[J]. Eur J Pharm Biopharm, 2016, 101:112-118.
[13] Tsipotis E, Gupta NR, Raman G, et al. Bioavailability, efficacy and safety of generic immunosuppressive drugs for kidney transplantation:a systematic review and meta-analysis[J]. Am J Nephrol, 2016, 44:206-218.
[14] Beig A, Miller JM, Lindley D, et al. Head-to-head comparison of different solubility-enabling formulations of etoposide and their consequent solubility-permeability interplay[J]. J Pharm Sci, 2015, 104:2941-2947.
[15] Yan R, Xu L, Wang Q, et al. Cyclosporine A nanosuspensions for ophthalmic delivery:a comparative study between cationic nanoparticles and drug-core mucus penetrating nanoparticles[J]. Mol Pharm, 2021, 18:4290-4298.
[16] Zhao P, Zhang XQ, Jiang XH, et al. LC-MS/MS determination of cyclosporine A in Beagle blood and bioequivalence study of cyclosporine A microemulsion[J]. Chin J Pharm Anal (药物分析杂志), 2015, 35:1965-1970.
[17] Wu ZH. A New Method for Liquid Chromatography Coupled with Tandem Mass Spectrometry Method by Detection of Four Immunosuppressants in Whole Blood and Dried Blood Spots (LC-MS/MS法定量检测全血和干血斑中4种免疫抑制剂的研究)[D]. Tianjin:Tianjin University, 2020.
[18] Zhai XH, Liu XX, Lu JQ, et al. Establishment of LC-MS/MS assay for the determination of blood immunosuppressive agents level simultaneously[J]. Chin Hosp Pharm (中国医院药学杂志), 2019, 39:774-780.
[19] Guo W, Chen WX, Shang H, et al. Recommendations for clinical application of liquid chromatography-mass spectrometry[J]. Chin J Lab Med (中华检验医学杂志), 2017, 40:770-779.
[20] Sobolesky PM, Smith BE, Hubbard JA, et al. Validation of a liquid chromatography-tandem mass spectrometry method for analyzing cannabinoids in oral fluid[J]. Clin Chim Acta, 2019, 491:30-38.
[21] Song S, Yu HZ, Zhu CL, et al. Cyclosporin A osmotic pump tablets which can form supersaturated micelles[J]. Acta Pharm Sin (药学学报), 2019, 54:22-28.
[22] Han YH, Ouyang P, Zhang YF, et al. Comprehensive analysis of chloroaluminate and composite ionic liquids using direct analysis in real time mass spectrometry[J]. Sci China Chem (中国科学:化学), 2020, 50:720-728.
[23] Cecchini MM, Steinkoenig J, Reale S, et al. Universal mass spectrometric analysis of poly(ionic liquid)s[J]. Chem Sci, 2016, 10:1039.
[24] Steinkoenig J, Cecchini MM, Goldmann AS, et al. Just add salt:a mass spectrometric analysis method for imaging anion-exchanged poly(ionic liquid)s[J]. Macromol Rapid commun, 2016, 37:1662-1666.
[25] Liu WH. Synthesis and Study on Extraction of Benzimidazolium Ionic Liquids (苯并咪唑类离子液体的合成及其萃取性能研究)[D]. Jinan:Shandong University, 2019.
[26] Peng Y, Huang H, Nie B, et al. Research progress of individualized dosage regimens of cyclosporin A based on its population pharmacokinetics[J]. Prog Pharm Sci (药学进展), 2020, 44:426-432.
[27] Shamshina JL, Kelley SP, Gurau G, et al. Chemistry:develop ionic liquid drugs[J]. Nature, 2015, 528:188-189.
[28] Nurunnabi M, Ibsen KN, Tanner EEL, et al. Oral ionic liquid for the treatment of diet-induced obesity[J]. Proc Natl Acad Sci U S A, 2019, 116:25042-25047.