赤芍总苷纳米混悬剂的制备、表征及药动学评价

doi:10.5246/jcps.2018.02.011

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (2): 99-108.DOI: 10.5246/jcps.2018.02.011

赤芍总苷纳米混悬剂的制备、表征及药动学评价

张金凤¹, 吴凡¹, 韩嘉艺¹, 荣景宏¹, 李艺¹, 刘宇¹, 梁啸¹, 王欣¹, 潘昊¹, 刘宏生³, 陈立江^1,2*

1. 辽宁大学药学院, 辽宁沈阳 110036
2. 辽宁省新药研发重点实验室, 辽宁沈阳 110036
3. 辽宁大学生命科学院, 辽宁沈阳 110036

出版日期:2018-03-03 发布日期:2018-03-01
通讯作者: Tel.: +86-024-62202303, E-mail: chlj16@163.com
基金资助:
Innovation Team Project (Grant No. LT2015011) from the Education Department of Liaoning Province, Important Scientific and Technical Achievements Transformation Project (Grant No. Z17-5-078) and Applied Basic Research Project (Grant No. F16205144) of Science and Technology Bureau of Shenyang, and the Liaoning Provincial Education Department Project of China (Grant No. L2015192).

Preparation, characterization and pharmacokinetic studies of total paeony glycoside nanocrystals

Jinfeng Zhang¹, Fan Wu¹, Jiayi Han¹, Jinghong Rong¹, Yi Li¹, Yu Liu¹, Xiao Liang¹, Xin Wang¹, Hao Pan¹, Hongsheng Liu³, Lijiang Chen^1,2*

1. School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China
2. Liaoning Key Laboratory of New Drug Research & Development, Shenyang 110036, China
3. School of Life Sciences, Liaoning University, Shenyang 110036, China

Online:2018-03-03 Published:2018-03-01
Contact: Tel.: +86-024-62202303, E-mail: chlj16@163.com
Supported by:
Innovation Team Project (Grant No. LT2015011) from the Education Department of Liaoning Province, Important Scientific and Technical Achievements Transformation Project (Grant No. Z17-5-078) and Applied Basic Research Project (Grant No. F16205144) of Science and Technology Bureau of Shenyang, and the Liaoning Provincial Education Department Project of China (Grant No. L2015192).

摘要/Abstract

摘要：

赤芍总苷是从赤芍中得到的有效部位, 它具有许多的生物学活性。然而, 由于其溶解性差, 生物利用度也非常低, 使其应用受到限制。本研究将赤芍总苷制备成纳米混悬剂以增加溶解度, 提高其口服生物利用度。采用沉淀-高压均质法制备赤芍总苷纳米混悬剂。用动态光散射法(DLS)测定其粒径、Zeta电位分别为(210.2±2.5) nm, (–22.4±1.2) mV。差示扫描量热图(DSC)结果显示, TPG在混悬剂中呈晶体状态, 晶型并未改变。透射电镜(TEM)结果表明赤芍总苷纳米混悬剂呈球状晶体。采用液相色谱串联质谱法(LC-MS/MS)测定赤芍总苷纳米混悬剂在大鼠体内药物动力学参数, 与赤芍总苷混悬液组药物动力学数据相比, AUC_0–∞明显增大(约1.85倍), 表明赤芍总苷纳米混悬剂可以提高赤芍总苷的生物利用度, 是一种很有前景的给药体系。

关键词: 赤芍总苷, 纳米晶体, 高压均质法, 药物动力学, 生物利用度

Abstract:

Total paeony glycoside (TPG) is obtained from Radix Paeoniae Rubra with a variety of bioactivities. However, the low solubility and bioavailability limit its application. The present study aimed to develop TPG nanocrystals to increase the dissolution and then improve the oral bioavailability. TPG nanocrystals were prepared via precipitation and high-pressure homogenization method. The physical-chemical properties of the optimal TPG nanocrystals in terms of particle size, zeta potential, morphology and crystallinity were evaluated. The results showed that TPG nanocrystals had a mean particle size of (210.2±2.5) nm, a polydispersity index of 0.191±0.033 and a zeta potential of (–22.4±1.2) mV. The result of differential scanning calorimetry showed that the nanocrystals were still in crystalline state after the preparation procedure. Transmission electron microscopy (TEM) results showed that the nanosuspension was in spherical shape. The pharmacokinetics of TPG nanocrystals for rats was investigated by liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Compared with the TPG coarse suspension, TPG nanocrystals exhibited significant increase in AUC_0–∞ (approximately 1.85-fold). Taken together, TPG nanocrystals could be used as a promising drug delivery system due to the enhanced oral bioavailability of TPG.

Key words: Total paeony glycoside, Nanocrystals, High-pressure homogenization, Pharmacokinetics, Bioavailability

中图分类号:

R969.1

Supporting:

张金凤, 吴凡, 韩嘉艺, 荣景宏, 李艺, 刘宇, 梁啸, 王欣, 潘昊, 刘宏生, 陈立江. 赤芍总苷纳米混悬剂的制备、表征及药动学评价[J]. 中国药学(英文版), 2018, 27(2): 99-108.

Jinfeng Zhang, Fan Wu, Jiayi Han, Jinghong Rong, Yi Li, Yu Liu, Xiao Liang, Xin Wang, Hao Pan, Hongsheng Liu, Lijiang Chen. Preparation, characterization and pharmacokinetic studies of total paeony glycoside nanocrystals[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(2): 99-108.

参考文献

[1] Zhang, W.; Dai S.M. Mechanisms Involved in the Therapeutic Effects of Paeonia Lactiflora Pallas in Rheumatoid Arthritis. Int. Immunopharmacol. 2012, 14, 27-31.

[2] Lan, R.J.; Xiang, Z.Z.; Zhong, Z.Q. Recent Advances in Study of Components and Pharmacological Roles of Radix Paeoniae Rubra. Chin. Pharmacol. Bull. 2003, 9, 965-970.

[3] Xu, H.Y.; Chen, Z.W.; Wu, Y.M. Antitumor Activity of Total Paeony Glycoside against Human Chronic Myelocytic Leukemia K562 Cell Lines In Vitro and In Vivo. Med. Oncol. 2012, 29, 1137-1147.

[4] Wang, Y.; Chen, M.; Xu, S. Analgesic Effect of Total Glucosides of Paeonia Lactiflora. Chin. J. Pharmacol. Toxicol. 1988, 2, 6-10.

[5] Xu, W.; Zhong, W.; Liu, J.; Liu, H.; Zhu, B. Study on Anti-Tumor Effect of Total Glycosices from Radix Paeoniae Rubra in S180 Tumor-Bearing Mice. Afr. J. Tradit. Complement Altern. Med. 2013, 10, 580-585.

[6] Long, J.; Gao, M.; Kong, Y.; Shen, X.; Du, X.; Son, Y.O.; Shi, X.; Liu, J.; Mo, X. Cardioprotective Effect of Total Paeony Glycosides against Isoprenaline-Induced Myocardial Ischemia in Rats. Phytomedicine. 2012, 19, 672-676.

[7] Luo, C.; Wang, H.; Chen, X.; Cui, Y.; Long, J.; Mo, X.; Liu, J. Protection of H9c2 Rat Cardiomyoblasts against Oxidative Insults by Total Paeony Glucosies from Radix Paeoniae Rubrae. Phytomedicine. 2013, 21, 20-24.

[8] Ou-Yang, Y. Research of Alcohol Extract of Paeonia Lactiflora Pall in Anti-Inflammatory and Analgesic Effect. J. Math. Med. 2008, 21, 600-602.

[9] Xu, X.X.; Qi, X.M.; Zhang, W.; Zhang, C.Q.; Wu, X.X.; Wu, Y.G.; Wang, K.; Shen, J.J. Effects of Total Glucosides of Paeony on Immune Regulatory Toll-Like Receptors TLR2 and 4 in the Kidney from Diabetic Rats. Phytomedicine. 2014, 21, 815-823.

[10] Li, R.; Guo, W.; Fu, Z.; Ding, G.; Zou, Y.; Wang, Z. Hepatoprotective Action of Radix Paeoniae Rubra Aqueous Extract against CCl4-Induced Hepatic Damage. Molecules. 2011, 16, 8684-8694.

[11] Dou, Z.H., Luo, L.; Lu, D. Purification of Total Paeony Glycoside by Macroporous Resin with Double Indices of Albiflorin and Paeoniflorin. J. Chin. Med. Mater. 2009, 8, 1282-1284.

[12] Müller, R.H.; Jacobs, C.; Kayser, O. Nanosuspensions As Particulate Drug Formulations in Therapy: Rationale for Development and What We Can Expect for the Future. Adv. Drug Deliv.Rev. 2001, 47, 3-19.

[13] Scholz, P.; Keck, C.M. Nanocrystals: From Raw Material to the Final Formulated Oral Dosage Form-A Review. Curr. Pharm. Des. 2015, 21, 4217-4228.

[14] Keck, C.M.; Müller, R.H. Drug Nanocrystals of Poorly Soluble Drugs Produced by High Pressure Homogenization. Eur. J. Pharm. Biopharm. 2006, 62, 3-16.

[15] Böhm, B.H.; Müller, R.H. Lab-Scale Production Unit Design for Nanosuspensions of Sparingly Soluble Cytotoxic Drugs. Pharm. Sci. Technolo. Today. 1999, 2, 336-339.

[16] Kesisoglou, F.; Panmai, S.; Wu, Y. Nanosizing—Oral Formulation Development and Biopharmaceutical Evaluation. Adv. Drug Deliv. Rev. 2007, 59, 631-644.

[17] Müller, R.H.; Gohla, S.; Keck, C.M. State of the Art of Nanocrystals-Special Features, Production, Nanotoxicology Aspects and Intracellular Delivery. Eur. J. Pharm. Biopharm. 2011, 78, 1-9.

[18] Zhang, Y.; Zhan, Y.; Pang, N.; Liu, Y.; Cheng, S.; Li, J.; Du, Y.; Qi, X. Preparation, Characterization and Pharma-cokinetics of 10-Hydroxycamptothecin Nanosuspension. J. Chin. Pharm. Sci. 2017, 26, 574-581.

[19] Liu, C.Z.; Chang, J.H.; Zhang, L.; Xue, H.F.; Liu, X.G.; Liu, P.; Fu, Q. Preparation and Evaluation of Diosgenin Nanocrystals to Improve Oral Bioavailability. AAPS PharmSciTech. 2016, 1-10.

[20] Liu, Y.; Xie, P.; Zhang, D.; Zhang, Q.A. Mini Review of Nanosuspensions Development. J. Drug Target. 2012, 20, 209-223.

[21] Wang, Y.; Liu, Z.; Zhang, D.; Gao, X.; Zhang, X.; Duan, C.; Jia, L.; Feng, F.; Huang, Y.; Shen, Y.; Zhang, Q. Development and In Vitro Evaluation of Deacety Mycoepoxydiene Nanosuspension. Colloids Surf. B. 2011, 83, 189-197.

[22] Li, L.; Liu, Y.; Wang, J.; Chen, L.; Zhang, W.; Yan, X. Preparation, In Vitro and In Vivo Evaluation of Bexarotene Nanocrystals with Surface Modification by Folate-Chitosan Conjugates. Drug Deliv. 2014, 1-9.

[23] Fu, Q.; Ma, M.; Li, M.; Wang, G.; Guo, M.; Li, J.; Hou, Y.; Fang, M. Improvement of Oral Bioavailability for Nisoldipine Using Nanocrystals. Powder Technol. 2017, 305, 757-763.

[24] Gao, L.; Liu, G.; Ma, J.; Wang, X.; Zhou, L.; Li, X. Drug Nanocrystals: In Vivo Performances. J. Controlled Release. 2012, 160, 418-430.

赤芍总苷纳米混悬剂的制备、表征及药动学评价

Preparation, characterization and pharmacokinetic studies of total paeony glycoside nanocrystals

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