1-脱氧野尻霉素控释微丸的制备工艺优化及其药动学研究

doi:10.3969/j.issn.1673-5854.2020.03.007

生物质化学工程 ›› 2020, Vol. 54 ›› Issue (3): 45-53.doi: 10.3969/j.issn.1673-5854.2020.03.007

1-脱氧野尻霉素控释微丸的制备工艺优化及其药动学研究

孙照英¹,赵华南²,刘志明^1,*()

1. 东北林业大学材料科学与工程学院, 黑龙江哈尔滨 150040
2. 哈药集团技术中心, 黑龙江哈尔滨 150020

收稿日期:2019-07-01 出版日期:2020-05-30 发布日期:2020-06-13
通讯作者: 刘志明 E-mail:554610961@qq.com
作者简介:孙照英(1980-),女,黑龙江哈尔滨人,博士生,主要从事纤维素衍生物药物缓控释研究
基金资助:
黑龙江省自然科学基金资助项目(C2015055);林业公益性行业科研专项(201504602)

Optimization of 1-Deoxynojirimycin Controlled-release PelletsPreparation and Its Pharmacokinetics Study

Zhaoying SUN¹,Huanan ZHAO²,Zhiming LIU^1,*()

1. College of Material Science and Engineering, Northeast Forestry University, Harbin 150040, China
2. Harbin Pharmaceutical Group R&D Center, Harbin 150020, China

Received:2019-07-01 Online:2020-05-30 Published:2020-06-13
Contact: Zhiming LIU E-mail:554610961@qq.com

摘要/Abstract

摘要：

1-脱氧野尻霉素控释微丸采用挤出滚圆和流化床方法进行制备。首先使用羟丙基甲基纤维素和微晶纤维素等辅料制备分散体、丸芯，再使用羟丙基甲基纳米纤维素邻苯二甲酸酯作为主要包衣材料进行包衣，并装入胶囊。采用SEM观察微丸的微观形态，以及测定其产率、脆碎度、密度、水分含量和粒径分布等物理性质，研究结果显示微丸性质符合中国药典标准规定。在体外释药试验中，溶出介质和放置方式对药物释放无显著影响，释放过程符合Baker-Lonsdale模型。对比研究1-脱氧野尻霉素原料药、分散体微丸和控释微丸在比格犬体内的控释特性，结果表明：与1-脱氧野尻霉素原料药相比，分散体微丸和控释微丸分别使1-脱氧野尻霉素的生物利用度提高了183.37%和243.87%。此外，1-脱氧野尻霉素控释微丸的体内-体外研究的相关性分析可知体外溶出和体内吸收之间呈现良好的线性关系。

关键词: 1-脱氧野尻霉素, 控释微丸, 溶出度, 生物利用度

Abstract:

1-Deoxynojirimycin controlled release pellets were prepared by extrusion-spheronization and fluidized bed. At first, a solid dispersed 1-deoxynojirimycin were made with hydroxypropyl methyl cellulose and microcrystalline cellulose and then it was subsequently coated by hydroxypropyl methylcellulose phthalate to obtain controlled release pellets. The morphology of pellets was observed by scanning electron microscopy and the yield, friability, tapped density, bulk, moisture content, and particle size distribution were also evaluated. The results showed that the properties of pellets conformed to the Chinese pharmacopoeia. In the in vitro drug release test, the dissolution medium(pH value 1.2, 4.0, 5.5, 6.8) and placement method(no placement, 6 months of accelerated placement and 12 months of long-term placement) had no significant effect on drug release, and the release process was consistent with the Baker-Lonsdale model. The controlled release properties of free 1-deoxynojirimycin, dispersible pellets and controlled-release pellets in beagle dogs was compared. The results showed that the dispersible pellets and the controlled release pellets of 1-deoxynojirimycin enhanced bioavailability of 1-deoxynojirimycin by 186.30% and 235.47%, respectively, compared to free 1-deoxynojirimycin. Furthermore, the correlation analysis in vitro-in vivo studies for controlled release matrix pellets of 1-deoxynojirimycin demonstrated good linear relationships between dissolution in vitro and absorption in vivo.

Key words: 1-deoxynojirimycin, controlled-release pellets, dissolution, bioavailability

中图分类号:

TQ35

孙照英,赵华南,刘志明. 1-脱氧野尻霉素控释微丸的制备工艺优化及其药动学研究[J]. 生物质化学工程, 2020, 54(3): 45-53.

Zhaoying SUN,Huanan ZHAO,Zhiming LIU. Optimization of 1-Deoxynojirimycin Controlled-release PelletsPreparation and Its Pharmacokinetics Study[J]. Biomass Chemical Engineering, 2020, 54(3): 45-53.

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参考文献 21

1	李有贵, 钟石, 朱俭勋, 等. 桑叶1-脱氧野尻霉素(DNJ)对高脂血症小鼠糖脂代谢的影响[J]. 蚕业科学, 2017, 43 (4): 662- 670.
2	郭时印, 李林, 周虹, 等. 1-脱氧野尻霉素对α-葡萄糖苷酶的抑制作用机制[J]. 食品科学, 2019, 40 (5): 45- 50.
3	HU X Q , THAKUR K , CHEN G H , et al. Metabolic effect of 1-deoxynojirimycin from mulberry leaves on db/db diabetic mice using liquid chromatography-mass spectrometry based metabolomics[J]. Journal of Agricultural & Food Chemistry, 2017, 65 (23): 4658- 4667.
4	ZHANG Y L , GAO H L , LIU R I J , et al. Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase[J]. Bioorganic & Medicinal Chemistry Letters, 2017, 27 (18): 4309- 4313.
5	CHEN W K , LIANG T T , ZOU W , et al. Neuroprotective effect of 1-deoxynojirimycin on cognitive impairment, β-amyloid deposition, and neuroinflammation in the SAMP8 mice[J]. Biomedicine & Pharmacotherapy, 2018, 106 (2): 92- 97.
6	SHUANG E , YAMAMOTO K , SAKAMOTO Y , et al. Intake of mulberry 1-deoxynojirimycin prevents colorectal cancer in mice[J]. Journal of Clinical Biochemistry & Nutrition, 2017, 61 (1): 47- 52.
7	刘毓婷, 苏峰, 刘为中, 等. 缓控释微丸制剂的研究进展[J]. 广州化工, 2017, 45 (24): 34- 36. doi: 10.3969/j.issn.1001-9677.2017.24.013
8	刘云飞. 基于专利数据分析的国内外缓控释微丸技术现状研究[J]. 创新科技, 2018, 18 (10): 55- 60.
9	LI S , XIAO L , DENG H B , et al. Remote controlled drug release from multi-functional Fe₃O₄/GO/Chitosan microspheres fabricated by an electrospray method[J]. Colloids and Surfaces B:Biointerfaces, 2017, 151 (9): 354- 362.
10	LOU Z C , HAN H , MAO D , et al. Qualitative and quantitative detection of PrP^Sc based on the controlled release property of magnetic microspheres using surface plasmon resonance(SPR)[J]. Nanomaterials, 2018, 8 (2): 107.
11	KANTH V R , KAJJARI P B , MADALAGERI P M , et al. Blend hydrogel microspheres of carboxymethyl chitosan and gelatin for the controlled release of 5-fluorouracil[J]. Pharmaceutics, 2017, 9 (2): 1- 13.
12	曹韩韩, 杜若飞, 杨嘉宁, 等. 中药粉体的物理性质与屈服压力的相关性分析[J]. 中国实验方剂学杂志, 2014, 20 (5): 14- 17.
13	易林.麦秸粉末温压成形工艺及力学行为研究[D].长沙:中南林业科技大学, 2012.
14	李英华, 贺兵. 库伦卡尔费休仪测甲醇中微量水分含量测量结果不确定度的评估[J]. 环球市场信息导报, 2018, (25): 125. doi: 10.3969/j.issn.1005-4901.2018.25.098
15	胡大为, 胡小芳, 林丽莹. 粉体粒度分布分形维数与流动性及硬脂酸镁改进流动性关系[J]. 中国粉体技术, 2007, 13 (4): 18- 22.
16	马锐, 牛剑钊, 张启明, 等. 药品检验中篮法和桨法溶出仪机械校验探讨[J]. 药物分析杂志, 2016, 36 (5): 873- 877.
17	张作法, 金洁, 时连根. 反相高效液相色谱法测定桑枝中1-脱氧野尻霉素的含量[J]. 中国药学杂志, 2007, 42 (7): 535- 538. doi: 10.3321/j.issn:1001-2494.2007.07.016
18	孙宜华, 熊惟皓, 李晨辉. ZnO-Al₂O₃混合粉体水基悬浮液性能的研究[J]. 无机材料学报, 2009, (2): 207- 210.
19	黄莹莹. 奥卡西平片的人体相对生物利用度研究[J]. 北方药学, 2018, 15 (6): 152- 153. doi: 10.3969/j.issn.1672-8351.2018.06.125
20	VUKOSAVJEVIC B , KINDER L D , SIEPMANN J , et al. Novel insights into controlled drug release from coated pellets by confocal Raman microscopy[J]. Journal of Raman Spectroscopy, 2016, 47 (7): 757- 762. doi: 10.1002/jrs.4896
21	MIAO Y F , CHEN G G , REN L L , et al. Preparation and evaluation of ziprasidone-phospholipid complex from sustained-release pellet formulation with enhanced bioavailability and no food effect[J]. Journal of Pharmacy & Pharmacology, 2016, 68 (2): 185- 194.

模型 kinetic model	方程 equation	pH值 pH value	R
零级模型 Zero-order model	Q_t = 0.0376t + 0.1475	1.2	0.9355
	Q_t = 0.0375t + 0.1378	4.0	0.9245
	Q_t = 0.0295t + 0.1833	5.5	0.9421
	Q_t = 0.0317t + 0.1941	6.8	0.9535
一级模型 First-order model	ln(1 - Q_t) = - 0.0854t - 0.2541	1.2	0.9362
	ln(1 - Q_t) = - 0.0453t - 0.3548	4.0	0.9658
	ln(1 - Q_t) = - 0.0659t - 0.1823	5.5	0.9764
	ln(1 - Q_t) = - 0.0677t - 0.4328	6.8	0.9704
Ritger-Peppas模型 Ritger-Peppas model	Q_t = 0.1754t^{1 / 2} - 0.0533	1.2	0.9633
	Q_t = 0.1976t^{1 / 2} - 0.0653	4.0	0.9751
	Q_t = 0.2076t^{1 / 2} - 0.0965	5.5	0.9693
	Q_t = 0.1654t^{1 / 2} - 0.0951	6.8	0.9768
Higuchi扩散模型 Higuchi diffusion model	lnQ_t = 0.6744lnt - 2.9816	1.2	0.9754
	lnQ_t = 0.7639lnt - 2.3541	4.0	0.9714
	lnQ_t = 0.8744lnt - 1.9869	5.5	0.9716
	lnQ_t = 0.7644lnt - 2.0971	6.8	0.9804
Weibull模型 Weibull model	(1 - Q_t)1 / 3 = - 0.0243t + 0.9795	1.2	0.9734
	(1 - Q_t)1 / 3 = - 0.0334t + 0.8748	4.0	0.9804
	(1 - Q_t)1 / 3 = - 0.0459t + 0.7628	5.5	0.9775
	(1 - Q_t)1 / 3 = - 0.0271t + 0.9091	6.8	0.9746
Baker-Lonsdale模型 Baker-Lonsdale model	3 / 2[1-(1-Q_t)2 / 3] - Q_t = 0.0095t - 0.0067	1.2	0.9977
	3 / 2[1-(1-Q_t)2 / 3] - Q_t = 0.0087t - 0.0084	4.0	0.9922
	3 / 2[1-(1-Q_t)2 / 3] - Q_t = 0.0138t - 0.0107	5.5	0.9901
	3 / 2[1-(1-Q_t)2 / 3] - Q_t = 0.0153t - 0.0158	6.8	0.9973

样品sample	C_max / (μg· L ^{- 1})	t_{1 / 2} / h	T_max / h	AUC_{0-36 h} / (μg· h· L ^{- 1})
1-脱氧野尻霉素原料药 free 1-deoxynojirimycin	384.79 ± 33.64	3.75 ± 0.31	2.34	964.82 ± 79.36
1-脱氧野尻霉素分散体微丸 1-deoxynojirimycin dispersible pellets	677.63 ± 76.98	4.43 ± 0.62	4.14	1797.49 ± 126.79
1-脱氧野尻霉素控释微丸 1-deoxynojirimycin controlled release pellets	487.94 ± 36.83	7.82 ± 0.74	6.65	2254.83 ± 253.54

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[2]	孙照英, 袁淑杰, 赵华南, 丁辉, 刘志明. 1-脱氧野尻霉素控释微丸的制备及其性能研究[J]. 生物质化学工程, 2018, 52(5): 25-30.

1-脱氧野尻霉素控释微丸的制备工艺优化及其药动学研究

Optimization of 1-Deoxynojirimycin Controlled-release PelletsPreparation and Its Pharmacokinetics Study

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