一线抗乙肝病毒药物恩替卡韦处方前研究

蒋瑞; 王腾腾; 汤胜男; 张艺雯; 张鹏; 张春燕

doi:10.3760/cma.j.issn.1007-1245.2020.15.004

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国际医药卫生导报

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ENGLISH ABSTRACT

一线抗乙肝病毒药物恩替卡韦处方前研究

作者及单位信息

出版日期： 2020 -08 -01 ·

DOI： 10.3760/cma.j.issn.1007-1245.2020.15.004

Preformulation study on first-line anti-HBV drug entecavir

Authors Info & Affiliations

Jiang Rui

School of Pharmacy, Jining Medical University, Rizhao 276826, China

Wang Tengteng

School of Pharmacy, Yantai University, Yantai 264005, China; The State Key Laboratory of Long-acting and Targeting Drug Delivery System, Luye Pharma Group, Yantai 264005, China

Tang Shengnan

School of Pharmacy, Yantai University, Yantai 264005, China; The State Key Laboratory of Long-acting and Targeting Drug Delivery System, Luye Pharma Group, Yantai 264005, China

Zhang Yiwen

School of Pharmacy, Jining Medical University, Rizhao 276826, China

Zhang Peng

School of Pharmacy, Jining Medical University, Rizhao 276826, China

Zhang Chunyan

School of Pharmacy, Jining Medical University, Rizhao 276826, China

Published： 2020 -08 -01 ·

DOI： 10.3760/cma.j.issn.1007-1245.2020.15.004

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摘要

目的对耐药率低、抗病毒作用强的一线抗乙肝病毒药物恩替卡韦进行处方前研究，为开发其新型制剂提供参考和依据。

方法对恩替卡韦外观、晶型和溶解性等进行考察，建立高效液相等度洗脱法进行含量测定，测定恩替卡韦在不同有机溶剂和不同磷酸盐缓冲液中的溶解性，以及其在不同pH条件下的表观油水分配系数。

结果恩替卡韦为类白色结晶性粉末，无臭无味，易溶于二甲基亚砜，可溶于甲醇，难溶于乙腈、丙酮、二氯甲烷和乙酸乙酯。HPLC法在5～100 µg•ml ^-1浓度范围内线性关系良好（R＝0.999 9）。油水分配系数随pH值的升高而增大。

结论本研究建立的定量测定恩替卡韦的HPLC法准确可靠，处方前研究表明，恩替卡韦微溶于水，难溶于多种有机溶剂，需采用适宜的方法进行恩替卡韦新制剂的开发。

关键词：恩替卡韦;微球;处方前研究;溶解度

ABSTRACT

ObjectiveTo perform a preformulation study for entecavir, a first-line anti-HBV drug with low drug resistance and strong antiviral effect, so as to provide theoretical basis for the development of entecavir sustained-release microspheres.

MethodsThe appearance, crystal form, and solubility of entecavir were investigated. A high performance liquid chromatography (HPLC) method for the quantitative determination of entecavir was established. The solubility of entecavir in different organic solvents and different phosphate buffers were determined, and the apparent oil-water partition coefficients at different pH conditions were measured.

ResultsEntecavir was a white crystalline powder, odorless and tasteless. It is highly soluble in dimethyl sulfoxide, soluble in methanol, and difficult to soluble in some organic solvents such as acetonitrile, acetone, dichloromethane, and ethyl acetate. The quantitative HPLC method for the entecavir determination showed a good linearity in the range of 5-100 μg/ml (R=0.999 9). The oil-water partition coefficient increased with the increase of pH value.

ConclusionsThe determination method of entecavir by HPLC established in this study is accurate and reliable. The present results indicate that entecavir is slightly soluble in water and insoluble in some organic solvents. The new entecavir preparations should be developed by suitable methods.

KEYWORDS： Entecavir;Microspheres;Preformulation research;Solubility

Corresponding author: Zhang Chunyan, Email: mocdef.6ab21302naynuhcgnahz

FUNDING:

Innovation Training Program Items of Undergraduates of Jining Medical University（cx2019024）

Innovation Training Program Items of Undergraduates of Shandong Province（S201910443007）

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No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission.

All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified.

引用本文

蒋瑞,王腾腾,汤胜男,等. 一线抗乙肝病毒药物恩替卡韦处方前研究[J]. 国际医药卫生导报,2020,26(15)：2172-2178.

DOI:10.3760/cma.j.issn.1007-1245.2020.15.004

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乙型病毒性肝炎（简称乙肝）是由乙肝病毒（hepatitis B virus，HBV）引起的、以肝脏炎性病变为主，并可引起多器官损害的一种疾病 ^{[
1
]}。乙肝广泛流行于世界各国，尽管随着乙肝疫苗的广泛应用、血液制品的筛选以及抗病毒治疗，乙肝的感染率已呈下降趋势，但是，HBV感染仍是全球性的公共卫生问题，乙肝仍是发展中国家的主要疾病，在亚洲和非洲的部分地区仍然存在疫情 ^{[
2
]}。目前正在使用的抗乙肝治疗方法可以控制HBV病毒载量在较低水平，但由于潜入人体细胞核内的共价闭合环状DNA（cccDNA）具有高度的稳定性，在细胞核内可以维持数月至数年，很难完全从体内清除 ^{[
3
]}，因此，乙肝是一种需要长期治疗的疾病。

恩替卡韦是一种耐药率低、抗病毒作用强的一线抗HBV药物。但其用药过程中存在以下两点亟待解决的问题：一是用药周期长，包括恩替卡韦在内的抗HBV药物必须定期服用至少2～3年，直到满足终止治疗的要求。在治疗过程中擅自停药可导致病毒反跳，出现黄疸和肝功能代谢失常以及乙型肝炎严重急性发作 ^{[
4
,

5
,

6
,

7
]}；二是食物摄入对恩替卡韦的吸收有明显影响：恩替卡韦与食物同服会导致药物吸收略有延迟（从0.75 h到1～1.5 h），Cmax降低4.4%，AUC降低18%～20% ^{[
8
]}。为提高恩替卡韦的疗效，应每天空腹服用，但空腹服药会加重恶心、呕吐、腹痛、腹泻、腹部不适和消化不良等不良反应，导致患者依从性差，治疗效果差。鉴于以上两点，有必要开发恩替卡韦的新型制剂 ^{[
9
,

10
]}，避免患者自行断药引起的病毒反跳以及空腹服药引起的副作用，延长给药间隔，提高患者用药安全性和顺应性。

本实验中，利用扫描电镜表征了恩替卡韦在电镜下的外观形貌，采用粒度测试仪测定了恩替卡韦原料药的粒度分布，通过差示扫描量热仪和粉末X射线衍射检测，确认了恩替卡韦的熔点和晶体结构。建立了准确、可靠的恩替卡韦体外分析高效液相色谱测定方法。对恩替卡韦在不同有机溶剂、不同pH值的磷酸盐缓冲液、含有适量吐温-80、甲醇、乙腈的磷酸盐缓冲液中的溶解性进行了测定，为恩替卡韦新制剂的处方设计、制备工艺、体外药物释放介质的选择提供参考和依据。

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摘要
参考文献

参考文献

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Grimm D , Thimme R , Blum HE . HBV life cycle and novel drug targets[J]. Hepatol Int, 2011,5(2):644-653. DOI: 10.1007/s12072-011-9261-3 .