PVA-g-mPEG接枝聚合物的制备及其防药物滥用性能

doi:10.16085/j.issn.1000-6613.2021-0474

摘要/Abstract

摘要：

阿片类药物的滥用问题日益严重，目前防滥用制剂局限在以往已有的技术，在开发新材料方向却少有报道，为此本文通过分子设计提出以接枝改性的方法制备一种具有防滥用性能的新型PVA-g-mPEG接枝聚合物。以聚乙烯醇（PVA）、单甲氧基聚乙二醇（mPEG）和环氧氯丙烷（ECH）为原料，采用两步反应合成法制备聚乙烯醇/单甲氧基聚乙二醇的接枝聚合物（PVA-g-mPEG），研究了反应温度对接枝率的影响。通过傅里叶红外光谱、核磁共振氢谱、差示扫描量热法以及X射线衍射法对产物进行表征。另外，以盐酸二甲双胍为模型药物，制备了接枝聚合物骨架片，考察了材料的防滥用性能。结果表明：随着接枝率的升高（43.44%，81.23%，120.48%），在水中20min时分别有28.3%、20.8%和12.9%的药物被提取，表明接枝聚合物具有一定的防滥用效果，对开发新的防滥用药的药用辅料具有较好的指导作用。

关键词: 聚合物, 化学反应, 制备, 接枝, 防滥用

Abstract:

The abuse of opioids is becoming more and more serious. The abuse deterrent formulations are limited to the existing technologies, but there are few reports on the development of new materials at present. Therefore, a novel PVA-g-mPEG graft polymer with anti-abuse performance was prepared by grafting modification through molecular design. Polyvinyl alcohol/mono-methoxypolyethylene glycol graft polymer (PVA-g-mPEG) was prepared with polyvinyl alcohol (PVA), mono-methoxypolyethylene glycol (mPEG) and epichlorohydrin (ECH) by a two-step reaction method. The effect of reaction temperature on the grafting rate was studied. The graft polymer was characterized by FTIR, ¹H NMR, DSC and XRD. In addition, using metformin hydrochloride as model drug, the graft polymer matrix tablets were prepared, and the anti-abuse performance of the materials was investigated. The results showed that with the increase of grafting ratio (43.44%, 81.23%, 120.48%), 28.3%, 20.8% and 12.9% of drugs were extracted from water in 20min, respectively, which indicates that the graft polymer had a certain anti-abuse effect and good guiding effect on the development of new anti-abuse pharmaceutic adjuvant materials.

Key words: polymers, chemical reaction, preparation, graft, anti-abuse

中图分类号:

O633.1

杨璐, 李效文, 李凤和, 姚日生. PVA-g-mPEG接枝聚合物的制备及其防药物滥用性能[J]. 化工进展, 2022, 41(2): 930-937.

YANG Lu, LI Xiaowen, LI Fenghe, YAO Risheng. Preparation and anti-drug abuse performance of PVA-g-mPEG graft polymer[J]. Chemical Industry and Engineering Progress, 2022, 41(2): 930-937.

图/表 12

图1 PVA-g-mPEG接枝聚合物的合成原理

表1 盐酸二甲双胍片剂处方

处方组成	质量分数/%
载药聚合物	33
微晶纤维素	33
聚乙烯吡咯烷酮	33
硬脂酸镁	0.5
二氧化硅	0.5

图2 不同ECH物质的量投料比对mPEG-Cl合成的影响

图3 不同反应温度对PVA-g-mPEG接枝聚合物接枝率的影响

图4 原料及合成产物的FTIR谱图

图5 PVA-g-mPEG的1H NMR谱图

图6 原料、物理混合物及合成产物的DSC谱图

图7 原PVA及合成产物的XRD谱图

图8 PVA-g-mPEG接枝聚合物在水中的溶胀曲线

表2 不同基质载药材料的药物包封率及载药量

样品	包封率/%	载药量/%
PVA	88.1	39.1
PVA-g-mPEG-1	90.4	46.4
PVA-g-mPEG-2	91.5	52.7
PVA-g-mPEG-3	92.2	51.9

图9 不同载药基质的盐酸二甲双胍片在水中的药物提取率

1—mPEG；2—PVA；3—PVA-g-mPEG-1；4—PVA-g-mPEG-2；5—PVA-g-mPEG-3

图10 不同载药基质的盐酸二甲双胍片分别在pH 1.2及pH 6.8溶液中的药物释放

1—mPEG；2—PVA；3—PVA-g-mPEG-1；4—PVA-g-mPEG-2；5—PVA-g-mPEG-3

参考文献 23

1	WEBSTER L R, MARKMAN J, CONE E J, et al. Current and future development of extended-release, abuse-deterrent opioid formulations in the United States[J]. Postgraduate Medicine, 2017, 129(1): 102-110.
2	MCNAUGHTON E C, COPLAN P M, BLACK R A, et al. Monitoring of Internet forums to evaluate reactions to the introduction of reformulated OxyContin to deter abuse[J]. Journal of Medical Internet Research, 2014, 16(5): e119.
3	KATZ N, DART R C, BAILEY E, et al. Tampering with prescription opioids: nature and extent of the problem, health consequences, and solutions[J]. The American Journal of Drug and Alcohol Abuse, 2011, 37(4): 205-217.
4	MAINCENT J, ZHANG F. Recent advances in abuse-deterrent technologies for the delivery of opioids[J]. International Journal of Pharmaceutics, 2016, 510(1): 57-72.
5	ORMAN J S, KEATING G M. Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence[J]. Drugs, 2009, 69(5): 577-607.
6	HERRY C, MONTI A, VAUZELLE-KERVROEDAN F, et al. Reducing abuse of orally administered prescription opioids using formulation technologies[J]. Journal of Drug Delivery Science and Technology, 2013, 23(2): 103-110.
7	MASTROPIETRO D J, OMIDIAN H. Abuse-deterrent formulations. Part 2: Commercial products and proprietary technologies[J]. Expert Opinion on Pharmacotherapy, 2015, 16(3): 305-323.
8	BARTHOLOMAEUS J H, ARKENAU-MARIĆ E, GALIA E. Opioid extended-release tablets with improved tamper-resistant properties[J]. Expert Opinion on Drug Delivery, 2012, 9(8): 879-891.
9	MA L, DENG L, CHEN J. Applications of poly(ethylene oxide) in controlled release tablet systems: a review[J]. Drug Development and Industrial Pharmacy, 2014, 40(7): 845-851.
10	PALMER D, LEVINA M, FARRELL T P, et al. The influence of hydro-alcoholic media on drug release[J]. Pharmaceutical Technology, 2011, 35(7): 55-58.
11	CROWLEY M M, ZHANG F, KOLENG J J, et al. Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion[J]. Biomaterials, 2002, 23(21): 4241-4248.
12	NIJENHUIS A J, COLSTEE E, GRIJPMA D W, et al. High molecular weight poly(L-lactide) and poly(ethylene oxide) blends: thermal characterization and physical properties[J]. Polymer, 1996, 37(26): 5849-5857.
13	RAHMAN Z, YANG Y, KORANG-YEBOAH M, et al. Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations[J]. International Journal of Pharmaceutics, 2016, 502(1/2): 138-150.
14	杨琦. 聚环氧乙烷的合成及催化剂体系[J]. 石化技术, 2007, 14(3): 44-48.
	YANG Qi. Synthesis of poly(ethylene oxide) and its catalysts[J]. Petrochemical Industry Technology, 2007, 14(3): 44-48.
15	ZHENG Y S, YING L Q, SHEN Z Q. Polymerization of propylene oxide by a new neodymium complex of calixarene derivative[J]. Polymer, 2000, 41(4): 1641-1643.
16	王万丽, 罗勇, 陆平晔, 等. 有机氨钙催化聚合聚氧化乙烯[J]. 精细与专用化学品, 2008, 16(15): 23-25, 2.
	WANG W L, LUO Y, LU P Y, et al. Preparation of poly(ethylene oxide) catalyzed by calcium-ammoniate[J]. Fine and Specialty Chemicals, 2008, 16(15): 23-25, 2.
17	张治国, 尹红. 环氧乙烷和环氧丙烷开环聚合[J]. 化学进展, 2007, 19(1): 145-152.
	ZHANG Zhiguo, YIN Hong. Ring-opening polymerization of ethylene oxide and propylene oxide[J]. Progress in Chemistry, 2007, 19(1): 145-152.
18	李菊梅. 聚氧化乙烯合成工艺研究[J]. 石化技术与应用, 2008, 26(2): 128-130.
	LI Jumei. Study on synthetic technology of poly(ethylene oxide)[J]. Petrochemical Technology & Application, 2008, 26(2): 128-130.
19	MORTENSEN A, AGUILAR F, CREBELLI R, et al. Safety of the proposed amendment of the specifications for the food additive polyvinyl alcohol-polyethylene glycol-graft-co-polymer (E 1209)[J]. EFSA Journal, 2017, 15(6): e04865.
20	张丽娟, 程原. 醚化改性聚乙烯醇的合成研究[J]. 中国胶粘剂, 2008, 17(2): 36-39.
	ZHANG Lijuan, CHENG Yuan. Synthesize on modification for polyvinyl alcohol by etherifying agent[J]. China Adhesives, 2008, 17(2): 36-39.
21	ZHANG M, XU T Y, CUI Y, et al. Study on preparation and sensitive properties of polyethylene glycol(PEG)/polyvinyl alcohol(PVA) thermo-sensitive hydrogel[J]. Advanced Materials Research, 2011, 306/307: 41-45.
22	LIN X L, ZHOU M S, WANG S Y, et al. Synthesis, structure, and dispersion property of a novel lignin-based polyoxyethylene ether from kraft lignin and poly(ethylene glycol)[J]. ACS Sustainable Chemistry & Engineering, 2014, 2(7): 1902-1909.
23	MADDINENI S, BATTU S K, MOROTT J, et al. Formulation optimization of hot-melt extruded abuse deterrent pellet dosage form utilizing design of experiments[J]. The Journal of Pharmacy and Pharmacology, 2014, 66(2): 309-322.

[1]	徐晨阳, 都健, 张磊. 基于图神经网络的化学反应优劣评价[J]. 化工进展, 2023, 42(S1): 205-212.
[2]	高彦静. 单原子催化技术国际研究态势分析[J]. 化工进展, 2023, 42(9): 4667-4676.
[3]	林晓鹏, 肖友华, 管奕琛, 鲁晓东, 宗文杰, 傅深渊. 离子聚合物-金属复合材料（IPMC）柔性电极的研究进展[J]. 化工进展, 2023, 42(9): 4770-4782.
[4]	朱传强, 茹晋波, 孙亭亭, 谢兴旺, 李长明, 高士秋. 固体高分子脱硝剂选择性非催化还原NO _x 特性[J]. 化工进展, 2023, 42(9): 4939-4946.
[5]	吴海波, 王希仑, 方岩雄, 纪红兵. 3D打印催化材料开发与应用进展[J]. 化工进展, 2023, 42(8): 3956-3964.
[6]	李伯耿, 罗英武, 刘平伟. 聚合物产品工程研究内容与方法的思考[J]. 化工进展, 2023, 42(8): 3905-3909.
[7]	王报英, 王皝莹, 闫军营, 汪耀明, 徐铜文. 聚合物包覆膜在金属分离回收中的研究进展[J]. 化工进展, 2023, 42(8): 3990-4004.
[8]	吕程远, 张函, 杨明旺, 杜健军, 樊江莉. 生物成像用二氧杂环丁烷余辉发光体系的研究进展[J]. 化工进展, 2023, 42(8): 4108-4122.
[9]	李润蕾, 王子彦, 王志苗, 李芳, 薛伟, 赵新强, 王延吉. CuO-CeO₂/TiO ₂ 高效催化CO低温氧化反应性能[J]. 化工进展, 2023, 42(8): 4264-4274.
[10]	储甜甜, 刘润竹, 杜高华, 马嘉浩, 张孝阿, 王成忠, 张军营. 有机胍催化脱氢型RTV硅橡胶的制备和可降解性能[J]. 化工进展, 2023, 42(7): 3664-3673.
[11]	于静文, 宋璐娜, 刘砚超, 吕瑞东, 武蒙蒙, 冯宇, 李忠, 米杰. 一种吲哚基超交联聚合物In-HCP对水中碘的吸附作用[J]. 化工进展, 2023, 42(7): 3674-3683.
[12]	吴展华, 盛敏. 绝热加速量热仪在反应安全风险评估应用中的常见问题[J]. 化工进展, 2023, 42(7): 3374-3382.
[13]	俞俊楠, 俞建峰, 程洋, 齐一搏, 化春键, 蒋毅. 基于深度学习的变宽度浓度梯度芯片性能预测[J]. 化工进展, 2023, 42(7): 3383-3393.
[14]	余希希, 张金帅, 雷文, 刘承果. 基于动态共价键自修复的光固化高分子材料研究进展[J]. 化工进展, 2023, 42(7): 3589-3599.
[15]	于丁一, 李圆圆, 王晨钰, 纪永升. pH响应性木质素水凝胶的制备及药物控释[J]. 化工进展, 2023, 42(6): 3138-3146.