中国药学杂志

Formulation	Model	Ethanol percentage/%	Kinetic release equation	r
A	Zero-order	0	M_t/M_∞=0.135t	0.990 1
		5	M_t/M_∞=0.139t	0.993 1
		20	M_t/M_∞=0.115t	0.995 5
		40	M_t/M_∞=0.125t	0.998 2
	First-order	0	M_t/M_∞=1-e^-0.002^t	0.995 0
		5	M_t/M_∞=1-e^-0.002^t	0.993 6
		20	M_t/M_∞=1-e^-0.002^t	0.996 8
		40	M_t/M_∞=1-e^-0.002^t	0.991 3
	Higuchi	0	M_t/M_∞=2.842t^0.5	0.974 1
		5	M_t/M_∞=2.931t^0.5	0.974 5
		20	M_t/M_∞=2.435t^0.5	0.974 0
		40	M_t/M_∞=2.621t^0.5	0.968 8
	Korsmeryer-Peppas	0	M_t/M_∞=0.319t^0.863	0.994 4
		5	M_t/M_∞=0.315t^0.870	0.996 5
		20	M_t/M_∞=0.256t^0.874	0.998 1
		40	M_t/M_∞=0.210t^0.918	0.999 0
B	Zero-order	0	M_t/M_∞=0.148t	0.994 2
		5	M_t/M_∞=0.150t	0.992 1
		20	M_t/M_∞=0.139t	0.998 0
		40	M_t/M_∞=0.135t	0.998 9
	First-order	0	M_t/M_∞=1-e^-0.003^t	0.989 7
		5	M_t/M_∞=1-e^-0.003^t	0.990 5
		20	M_t/M_∞=1-e^-0.002^t	0.987 7
		40	M_t/M_∞=1-e^-0.002^t	0.987 7
	Higuchi	0	M_t/M_∞=3.133t^0.5	0.975 7
		5	M_t/M_∞=3.195t^0.5	0.977 0
		20	M_t/M_∞=2.927t^0.5	0.970 7
		40	M_t/M_∞=2.844t^0.5	0.970 9
	Korsmeryer-Peppas	0	M_t/M_∞=0.392t^0.845	0.997 6
		5	M_t/M_∞=0.449t^0.826	0.996 7
		20	M_t/M_∞=0.271t^0.894	0.999 1
		40	M_t/M_∞=0.271t^0.890	0.999 7
C	Zero-order	0	M_t/M_∞=0.118t	0.999 0
		5	M_t/M_∞=0.119t	0.999 2
		20	M_t/M_∞=0.103t	0.999 5
		40	M_t/M_∞=0.101t	0.998 4
	First-order	0	M_t/M_∞=1-e^-0.002^t	0.992 8
		5	M_t/M_∞=1-e^-0.002^t	0.991 8
		20	M_t/M_∞=1-e^-0.002^t	0.994 3
		40	M_t/M_∞=1-e^-0.001^t	0.996 1
	Higuchi	0	M_t/M_∞=2.477t^0.5	0.969 3
		5	M_t/M_∞=2.499t^0.5	0.968 1
		20	M_t/M_∞=2.163t^0.5	0.969 1
		40	M_t/M_∞=2.147t^0.5	0.974 6
	Korsmeryer-Peppas	0	M_t/M_∞=0.191t^0.924	0.999 7
		5	M_t/M_∞=0.183t^0.933	0.999 8
		20	M_t/M_∞=0.184t^0.908	0.999 9
		40	M_t/M_∞=0.268t^0.845	0.999 7

Formulation

Model

Ethanol
percentage/%

Kinetic release
equation

Zero-order

M_t/M_∞=0.135t

0.990 1

M_t/M_∞=0.139t

0.993 1

M_t/M_∞=0.115t

0.995 5

M_t/M_∞=0.125t

0.998 2

First-order

M_t/M_∞=1-e^-0.002^t

0.995 0

M_t/M_∞=1-e^-0.002^t

0.993 6

M_t/M_∞=1-e^-0.002^t

0.996 8

M_t/M_∞=1-e^-0.002^t

0.991 3

Higuchi

M_t/M_∞=2.842t^0.5

0.974 1

M_t/M_∞=2.931t^0.5

0.974 5

M_t/M_∞=2.435t^0.5

0.974 0

M_t/M_∞=2.621t^0.5

0.968 8

Korsmeryer-Peppas

M_t/M_∞=0.319t^0.863

0.994 4

M_t/M_∞=0.315t^0.870

0.996 5

M_t/M_∞=0.256t^0.874

0.998 1

M_t/M_∞=0.210t^0.918

0.999 0

Zero-order

M_t/M_∞=0.148t

0.994 2

M_t/M_∞=0.150t

0.992 1

M_t/M_∞=0.139t

0.998 0

M_t/M_∞=0.135t

0.998 9

First-order

M_t/M_∞=1-e^-0.003^t

0.989 7

M_t/M_∞=1-e^-0.003^t

0.990 5

M_t/M_∞=1-e^-0.002^t

0.987 7

M_t/M_∞=1-e^-0.002^t

0.987 7

Higuchi

M_t/M_∞=3.133t^0.5

0.975 7

M_t/M_∞=3.195t^0.5

0.977 0

M_t/M_∞=2.927t^0.5

0.970 7

M_t/M_∞=2.844t^0.5

0.970 9

Korsmeryer-Peppas

M_t/M_∞=0.392t^0.845

0.997 6

M_t/M_∞=0.449t^0.826

0.996 7

M_t/M_∞=0.271t^0.894

0.999 1

M_t/M_∞=0.271t^0.890

0.999 7

Zero-order

M_t/M_∞=0.118t

0.999 0

M_t/M_∞=0.119t

0.999 2

M_t/M_∞=0.103t

0.999 5

M_t/M_∞=0.101t

0.998 4

First-order

M_t/M_∞=1-e^-0.002^t

0.992 8

M_t/M_∞=1-e^-0.002^t

0.991 8

M_t/M_∞=1-e^-0.002^t

0.994 3

M_t/M_∞=1-e^-0.001^t

0.996 1

Higuchi

M_t/M_∞=2.477t^0.5

0.969 3

M_t/M_∞=2.499t^0.5

0.968 1

M_t/M_∞=2.163t^0.5

0.969 1

M_t/M_∞=2.147t^0.5

0.974 6

Korsmeryer-Peppas

M_t/M_∞=0.191t^0.924

0.999 7

M_t/M_∞=0.183t^0.933

0.999 8

M_t/M_∞=0.184t^0.908

0.999 9

M_t/M_∞=0.268t^0.845

0.999 7

Formulation	Model	Ethanol percentage/%	Kinetic release equation	r
A	Zero-order	0	M_t/M_∞=0.135t	0.990 1
		5	M_t/M_∞=0.139t	0.993 1
		20	M_t/M_∞=0.115t	0.995 5
		40	M_t/M_∞=0.125t	0.998 2
	First-order	0	M_t/M_∞=1-e^-0.002^t	0.995 0
		5	M_t/M_∞=1-e^-0.002^t	0.993 6
		20	M_t/M_∞=1-e^-0.002^t	0.996 8
		40	M_t/M_∞=1-e^-0.002^t	0.991 3
	Higuchi	0	M_t/M_∞=2.842t^0.5	0.974 1
		5	M_t/M_∞=2.931t^0.5	0.974 5
		20	M_t/M_∞=2.435t^0.5	0.974 0
		40	M_t/M_∞=2.621t^0.5	0.968 8
	Korsmeryer-Peppas	0	M_t/M_∞=0.319t^0.863	0.994 4
		5	M_t/M_∞=0.315t^0.870	0.996 5
		20	M_t/M_∞=0.256t^0.874	0.998 1
		40	M_t/M_∞=0.210t^0.918	0.999 0
B	Zero-order	0	M_t/M_∞=0.148t	0.994 2
		5	M_t/M_∞=0.150t	0.992 1
		20	M_t/M_∞=0.139t	0.998 0
		40	M_t/M_∞=0.135t	0.998 9
	First-order	0	M_t/M_∞=1-e^-0.003^t	0.989 7
		5	M_t/M_∞=1-e^-0.003^t	0.990 5
		20	M_t/M_∞=1-e^-0.002^t	0.987 7
		40	M_t/M_∞=1-e^-0.002^t	0.987 7
	Higuchi	0	M_t/M_∞=3.133t^0.5	0.975 7
		5	M_t/M_∞=3.195t^0.5	0.977 0
		20	M_t/M_∞=2.927t^0.5	0.970 7
		40	M_t/M_∞=2.844t^0.5	0.970 9
	Korsmeryer-Peppas	0	M_t/M_∞=0.392t^0.845	0.997 6
		5	M_t/M_∞=0.449t^0.826	0.996 7
		20	M_t/M_∞=0.271t^0.894	0.999 1
		40	M_t/M_∞=0.271t^0.890	0.999 7
C	Zero-order	0	M_t/M_∞=0.118t	0.999 0
		5	M_t/M_∞=0.119t	0.999 2
		20	M_t/M_∞=0.103t	0.999 5
		40	M_t/M_∞=0.101t	0.998 4
	First-order	0	M_t/M_∞=1-e^-0.002^t	0.992 8
		5	M_t/M_∞=1-e^-0.002^t	0.991 8
		20	M_t/M_∞=1-e^-0.002^t	0.994 3
		40	M_t/M_∞=1-e^-0.001^t	0.996 1
	Higuchi	0	M_t/M_∞=2.477t^0.5	0.969 3
		5	M_t/M_∞=2.499t^0.5	0.968 1
		20	M_t/M_∞=2.163t^0.5	0.969 1
		40	M_t/M_∞=2.147t^0.5	0.974 6
	Korsmeryer-Peppas	0	M_t/M_∞=0.191t^0.924	0.999 7
		5	M_t/M_∞=0.183t^0.933	0.999 8
		20	M_t/M_∞=0.184t^0.908	0.999 9
		40	M_t/M_∞=0.268t^0.845	0.999 7

Formulation

Model

Ethanol
percentage/%

Kinetic release
equation

Zero-order

M_t/M_∞=0.135t

0.990 1

M_t/M_∞=0.139t

0.993 1

M_t/M_∞=0.115t

0.995 5

M_t/M_∞=0.125t

0.998 2

First-order

M_t/M_∞=1-e^-0.002^t

0.995 0

M_t/M_∞=1-e^-0.002^t

0.993 6

M_t/M_∞=1-e^-0.002^t

0.996 8

M_t/M_∞=1-e^-0.002^t

0.991 3

Higuchi

M_t/M_∞=2.842t^0.5

0.974 1

M_t/M_∞=2.931t^0.5

0.974 5

M_t/M_∞=2.435t^0.5

0.974 0

M_t/M_∞=2.621t^0.5

0.968 8

Korsmeryer-Peppas

M_t/M_∞=0.319t^0.863

0.994 4

M_t/M_∞=0.315t^0.870

0.996 5

M_t/M_∞=0.256t^0.874

0.998 1

M_t/M_∞=0.210t^0.918

0.999 0

Zero-order

M_t/M_∞=0.148t

0.994 2

M_t/M_∞=0.150t

0.992 1

M_t/M_∞=0.139t

0.998 0

M_t/M_∞=0.135t

0.998 9

First-order

M_t/M_∞=1-e^-0.003^t

0.989 7

M_t/M_∞=1-e^-0.003^t

0.990 5

M_t/M_∞=1-e^-0.002^t

0.987 7

M_t/M_∞=1-e^-0.002^t

0.987 7

Higuchi

M_t/M_∞=3.133t^0.5

0.975 7

M_t/M_∞=3.195t^0.5

0.977 0

M_t/M_∞=2.927t^0.5

0.970 7

M_t/M_∞=2.844t^0.5

0.970 9

Korsmeryer-Peppas

M_t/M_∞=0.392t^0.845

0.997 6

M_t/M_∞=0.449t^0.826

0.996 7

M_t/M_∞=0.271t^0.894

0.999 1

M_t/M_∞=0.271t^0.890

0.999 7

Zero-order

M_t/M_∞=0.118t

0.999 0

M_t/M_∞=0.119t

0.999 2

M_t/M_∞=0.103t

0.999 5

M_t/M_∞=0.101t

0.998 4

First-order

M_t/M_∞=1-e^-0.002^t

0.992 8

M_t/M_∞=1-e^-0.002^t

0.991 8

M_t/M_∞=1-e^-0.002^t

0.994 3

M_t/M_∞=1-e^-0.001^t

0.996 1

Higuchi

M_t/M_∞=2.477t^0.5

0.969 3

M_t/M_∞=2.499t^0.5

0.968 1

M_t/M_∞=2.163t^0.5

0.969 1

M_t/M_∞=2.147t^0.5

0.974 6

Korsmeryer-Peppas

M_t/M_∞=0.191t^0.924

0.999 7

M_t/M_∞=0.183t^0.933

0.999 8

M_t/M_∞=0.184t^0.908

0.999 9

M_t/M_∞=0.268t^0.845

0.999 7

格列齐特缓释片的剂量倾泻研究

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吴兆伟 , 李婷立 , 张逢时 , 王铁松 , 王琳 , 吴斌 , 胡琴 ^* , 张喆 ^*

中国药学杂志 | 论著 2024,59(4): 324-329

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中国药学杂志 | 论著 2024, 59(4): 324-329

格列齐特缓释片的剂量倾泻研究

全屏

吴兆伟, 李婷立, 张逢时, 王铁松, 王琳, 吴斌, 胡琴^*, 张喆^*

作者信息

北京市药品检验研究院, 国家药品监督管理局仿制药研究与评价重点实验室, 中药成分分析与生物评价北京市重点实验室, 北京 102206

吴兆伟,男,硕士,副主任药师研究方向:化学药品质量控制研究

通讯作者:

*胡琴,女,主任药师研究方向:化学药品质量控制研究 Tel:(010)52779622;

张喆,男,副主任药师研究方向:化学药品质量控制研究 Tel:(010)52779623

Dose Dumping Study for Gliclazide Sustained-Release Tablets

WU Zhaowei, Li Tingli, ZHANG Fengshi, WANG Tiesong, WANG Lin, WU Bin, HU Qin^*, ZHANG Zhe^*

Affiliations

NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine, Beijing Institute for Drug Control, Beijing 102206, China

出版时间: 2024-02-22 doi: 10.11669/cpj.2024.04.005

文章导航

摘要

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目的研究影响格列齐特缓释片在含乙醇溶液中释放的因素,并对其发生剂量倾泻的风险进行评估。方法采用高效液相色谱法(HPLC)测定不同乙醇浓度介质下的3种市售制剂的释放曲线,研究其释放机制并通过相似因子(f₂)评价剂量倾泻的风险。结果在含体积分数5%,20%,40%乙醇的pH 7.4磷酸盐缓冲液介质中,100 r·min^-1条件下,各制剂的释放曲线相似,各制剂的骨架溶蚀速度是影响释放的关键因素。结论各市售制剂均有足够的乙醇耐受性,乙醇诱导的剂量倾泻风险较小。

关键词

剂量倾泻 / 格列齐特缓释片 / 乙醇诱导 / 释放曲线 / 高效液相色谱法

Abstract

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OBJECTIVE To evaluate the effects of drug release for gliclazide sustained-release tablets in ethanolic media and conduct the risk assessment for the dose dumping. METHODS Release profiles of gliclazide sustained-release tablets from 3 manufactures in different ethanolic media were determined by HPLC.Release mechanisms were analyzed and the risk of dose dumping was evaluated by the similar factors (f₂) of the release data. RESULTS Release profiles of formulations in the presence of 5%, 20% and 40% ethanol of pH 7.4 phosphate buffer media at 100 r·min^-1 were similar.The erosion rate was the key factor that affected the release profiles of gliclazide sustained-release tablets. CONCLUSION The commercial formulations are considered to be robust against alcohol effects and the risk of alcohol-induced dose dumping is relatively little.

Key words

dose dumping / gliclazide sustained-release tablet / alcohol-inducement / release profile / HPLC

引用本文

吴兆伟, 李婷立, 张逢时, 王铁松, 王琳, 吴斌, 胡琴, 张喆. 格列齐特缓释片的剂量倾泻研究. 中国药学杂志, 2024 , 59 (4) : 324 -329 . DOI: 10.11669/cpj.2024.04.005

WU Zhaowei, Li Tingli, ZHANG Fengshi, WANG Tiesong, WANG Lin, WU Bin, HU Qin, ZHANG Zhe. Dose Dumping Study for Gliclazide Sustained-Release Tablets[J]. Chinese Pharmaceutical Journal, 2024 , 59 (4) : 324 -329 . DOI: 10.11669/cpj.2024.04.005

正文

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剂量倾泻被广泛地定义为缓控释制剂的全部或绝大部分药物在短时间内的快速释放^[1]。药物与含乙醇饮料共同服用引起的剂量倾泻被称为乙醇诱导的剂量倾泻。缓控释制剂可以帮助保持更一致的血药浓度,改善患者的依从性,减少副作用,其在正常情况下是缓慢释放的,但在特殊情况下,比如饮酒,药物释放速度可能发生改变,药物性质也可能从难溶性转变为易溶性,导致血药浓度的突然改变,引发药品安全性风险。此外,缓控释制剂通常单次给药量较大,其产品设计要求缓慢释放,但控制释放的高分子辅料和膜控材料在上述情况下可能被溶解或变性,导致药物释放方式、速率和程度发生变化,引发药品安全性风险^[2]。2005年,经过氢吗啡酮缓释胶囊退市事件后,美国食品药品监督管理局(FDA)和欧洲药品管理局(EMA)先后建议对缓控释制剂进行乙醇诱导的剂量倾泻考察^[3-5]。

格列齐特为第二代磺脲类降糖药,是用于治疗饮食疗法、运动治疗和减轻体重不足以控制血糖的成人2型糖尿病的首选药物。与其他磺脲类药物相同,在进餐间隔时间不规则或少食用1餐或数餐时使用格列齐特缓释片可能会发生低血糖。另外,用药后患者可能发生出汗、焦虑、心动过速、心绞痛及心律失常等肾上腺素能反调节症状,以及腹痛、恶心、消化不良及便秘等胃肠道功能障碍^[6]。目前我国尚无明确相关技术指南指导剂量倾泻方面相应研究^[7],本研究考察不同浓度乙醇对格列齐特缓释片释放行为的影响,评估乙醇诱导发生剂量倾泻的风险,为仿制药研发、体内外评价及建立我国相关技术指南提供参考依据。

1 仪器与试药

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1.1 仪器

LC-20A高效液相色谱仪(日本岛津公司);708-DS溶出仪(美国Agilent公司);XS-205分析天平,PB602-N pH计(德国梅特勒-托利多仪器有限公司);SB-25-12DT超声仪(宁波新芝生物科技股份有限公司);HZQ-F160振荡培养箱(哈尔滨东联电子技术开发有限公司)。

1.2 试药

格列齐特对照品(批号:100267-202107,99.9%,中国食品药品检定研究院);无水乙醇、氨水均为优级纯,乙酸铵为分析纯,乙腈为色谱纯,水为纯化水;格列齐特缓释片(市售,企业A、B、C,以企业A样品作为参比制剂);辅料(企业C)。

2 方法

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2.1 剂量倾泻释放条件

参照FDA、EMA相关要求^[8-9]及格列齐特缓释片已有国家标准释放度检查方法建立剂量倾泻释放条件。即取本品,按溶出度与释放度测定法(《中国药典》2020年版四部通则0931第二法)^[10],分别以pH 7.4磷酸盐缓冲液(取磷酸二氢钾1.36 g,加0.1 mol·L^-1氢氧化钠溶液79 mL,用水稀释至200 mL,即得)、pH 7.4磷酸盐缓冲液-乙醇(95∶5、80∶20、60∶40)为释放介质(以下简称为4种释放介质或用不含乙醇介质、含体积分数5%乙醇介质、含体积分数20%乙醇介质、含体积分数40%乙醇介质代称),介质体积为900 mL,温度为(37.0±0.5)℃,转速为100 r·min^-1,在15,30,60,90,120,240,480和720 min分别取溶液10 mL,滤过,并即时在溶出杯中补充相同体积、相同温度的释放介质,取续滤液作为供试品溶液。

2.2 对照品溶液配制

精密称取格列齐特对照品约16.6 mg,置100 mL量瓶中,加乙腈2 mL溶解,用相应释放介质稀释至刻度,摇匀,精密量取5 mL,置25 mL量瓶中,用相应释放介质稀释至刻度,摇匀,即得每1 mL约含0.033 2 mg的对照品溶液。

2.3 色谱条件

色谱柱为Waters XBridge C₁₈色谱柱(4.6 mm×250 mm,5 μm);以0.01 mol·L^-1乙酸铵溶液(用氨水调节pH至8.4)-乙腈(80∶20)为流动相;检测波长为226 nm;流速为1.3 mL·min^-1;柱温为40 ℃;进样量为50 μL。

2.4 专属性

取4种释放介质中的空白溶液、空白辅料溶液、对照品溶液和供试品溶液按“2.3”项下色谱条件进样分析,记录色谱图(图1)。结果表明,空白溶剂、空白辅料均对样品测定无干扰。

2.5 线性

精密称取格列齐特对照品约10.6 mg置200 mL量瓶中,加乙腈2 mL溶解,分别加4种释放介质稀释至刻度,摇匀,作为各自介质的线性储备溶液1(约0.053 mg·mL^-1)。精密称取格列齐特对照品约8.3 mg置250 mL量瓶中,加乙腈2 mL溶解,分别加4种释放介质稀释至刻度,摇匀,作为各自介质的线性储备溶液2(约0.033 2 mg·mL^-1)。取2种线性储备溶液分别逐级稀释得到格列齐特约0.026 5、0.016 6、0.006 64、0.003 32、0.001 66、0.000 664、0.000 332 mg·mL^-1的系列线性溶液,连同线性储备溶液1、2按“2.3”项下色谱条件进样分析,记录色谱图。以格列齐特浓度(ρ)对峰面积(Y)进行线性回归,线性方程按介质中乙醇含量从低至高(含乙醇体积分数0%,5%,20%和40%)为Y=78 142 702ρ+30(r²=1.000 0)、Y=78 342 231ρ+486(r²=1.000 0)、Y=78 253 204ρ+2 882(r²=1.000 0)、Y=79 463 742ρ-392(r²=1.000 0)。结果表明格列齐特在0.000 332~0.053 mg·mL^-1内不同释放介质中均呈现良好的线性关系,符合实验要求。

2.6 回收率

精密称取格列齐特对照品,按处方比例加入辅料适量,加乙腈2 mL溶解后分别用4种释放介质稀释成高、中、低3个浓度(即100%,50%,20%水平)各3份的回收率溶液,取上述溶液,按“2.3”项下色谱条件下进行测定,记录色谱图。取上述溶液,按“2.3”项下色谱条件下进行测定,记录色谱图。按介质乙醇含量从低至高(含乙醇体积分数0%,5%,20%和40%),格列齐特的回收率分别为 100.1%、101.2%、100.0%和 100.4%,相对标准偏差(RSD)分别为 0.3%、0.5%、0.7%和 0.4%(n=9),结果表明,回收率良好。

2.7 进样精密度

取4种释放介质中的对照品溶液,分别按“2.3”项下色谱条件连续进样6次。按介质乙醇含量从低至高(含乙醇体积分数0%,5%,20%和40%)峰面积RSD分别为0.03%、0.4%、0.2%、0.6%,结果表明,精密度良好。

2.8 稳定性

取4种释放介质中的供试品溶液,分别于室温下放置0、2、4、6、8、12 h按“2.3”项下色谱条件进样测定峰面积,按介质乙醇含量从低至高(含乙醇体积分数0%,5%,20%和40%)峰面积RSD分别为0.1%、0.1%、0.2%、0.2%,结果表明,稳定性良好。

3 结果

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3.1 剂量倾泻实验结果

按“2.1”项下释放条件和“2.3”项下色谱条件测定3家企业格列齐特缓释片市售制剂A、B、C的累积释放度,以药物累积释放度为纵坐标,取样时间点为横坐标绘制累积释放曲线图,结果见图2~4。在不同乙醇浓度下,市售制剂A的720 min累计释放度大小排序依次为含体积分数5%乙醇介质>不含乙醇介质>含体积分数40%乙醇介质>含体积分数20%乙醇介质而市售制剂B、C的720 min累计释放度大小排序依次为含体积分数5%乙醇介质>不含乙醇介质>含体积分数20%乙醇介质>含体积分数40%乙醇介质。结果显示,乙醇对3种制剂释放的影响更为复杂可能含有多重影响因素而并非单向增加或减小的关系。格列齐特在体积分数0%乙醇与体积分数5%乙醇中的释放速率快于在体积分数20%乙醇与体积分数40%乙醇中的释放速率。

3.2 平衡溶解度试验

为研究乙醇对制剂释放的影响因素,配制格列齐特在水及4种释放介质中的过饱和溶液(n=3),置37 ℃振荡培养箱中以200 r·min^-1振摇24 h,滤过,稀释成与对照品溶液相近的浓度按“2.3”项下色谱条件测定。格列齐特在水、不含乙醇介质、含体积分数5%乙醇介质、含体积分数20%乙醇介质、含体积分数40%乙醇介质中的平衡溶解度依次为0.05、1.46、1.87、3.42和5.92 mg·mL^-1。结果显示随着乙醇浓度升高,格列齐特平衡溶解度升高,其趋势与累计释放度曲线不尽相同,说明影响累计释放度曲线的主要因素并非主成分的溶解度。

3.3 释放机制

为考察制剂在含乙醇介质中的释放机制,采用4种常用的数学模型方程分别对市售制剂A、B、C在4种释放介质中的释药数据进行拟合,结果见表1。4种模型中基于扩散理论的Higuchi方程的相关系数最低,基于扩散溶蚀结合理论的Korsmeryer-Peppas方程相关系数最高,表明Korsmeryer-Peppas方程模拟更适合于该制剂。市售制剂A、B为圆柱形,市售制剂C为薄片型。对于圆柱形样品当n<0.45(薄片型为0.5)时,药物释放符合fick扩散机制,当0.45<n<0.89(薄片型为1.0),药物释放符合扩散机制和溶蚀机制的协同作用,当n>0.89(薄片型为1.0)时释放机制主要为骨架溶蚀机制。结果显示,市售制剂A在含体积分数0%,5%和20%乙醇介质中,药物释放为扩散机制和溶蚀机制的协同作用,且以骨架溶蚀为主导,在含体积分数40%的乙醇介质中药物释放为骨架溶蚀机制。市售制剂B在含体积分数0%,5%乙醇介质中,药物释放为扩散机制和溶蚀机制的协同作用,以骨架溶蚀为主导,在含体积分数20%和40%的乙醇介质中药物释放为骨架溶蚀机制。市售制剂C在4种释放介质中药物释放均为扩散机制和溶蚀机制的协同作用,且均以骨架溶蚀为主导。结果表明,fick扩散机制对药物释放影响较少,骨架溶蚀速度是影响释放的关键因素。

3.4 溶蚀失重试验

为验证溶蚀速度对药物释放的影响,取称重后的市售制剂A、B、C(n=3)在4种释放介质中按“2.1”项下释放条件进行试验,分别于2、8、12 h取出样品,干燥至恒重,分别计算样品的失重百分数。见公式1。

公式(1)$ \text { 失重 }(\%)=\frac{(\text { 初始质量-干爆后质量 })}{\text { 初始质量 }} \times 100 \%$

结果见图5~7。结果显示,各市售制剂累计释放度曲线均与其失重曲线趋势基本一致,验证了样品在不同乙醇浓度介质下的溶蚀速度差异是累计释放度曲线差异的主要原因之一。

3.5 相似因子评价

相似因子法(f₂)是常用来比较受试制剂与参比制剂的溶出曲线是否相似的一种非模型依赖法。见公式2。

公式(2)$ f_{2}=50 \times \log _{10}\left\{\left[1+\frac{1}{n} \sum_{t=1}^{n}\left(R_{t}-T_{t}\right) 2\right]^{-0.5} \times 100\right\}$

式中,n为取样时间点个数,R_t为参比制剂在t时刻的平均溶出度,T_t为受试制剂在t时刻的平均溶出度。如受试制剂与参比制剂的相似因子(f₂)≥50,则认为两条溶出曲线相似。以市售制剂A在各释放介质中的累计释放度曲线作为参比,计算市售制剂B、C在与之相同的释放介质中累计释放度曲线的相似因子,结果市售制剂B在含体积分数0%、5%、20%和40%乙醇介质中的相似因子分别为67.40、70.06、56.80和73.72。市售制剂C在含体积分数0%、5%、20%和40%乙醇介质中的相似因子分别为61.03、58.91、67.85和56.21。各相似因子均大于50,市售制剂B、C与市售制剂A在各释放介质中释放度曲线相似。另以各市售制剂在不含乙醇介质中的累计释放度曲线作为参比,计算各市售制剂在其他含乙醇介质中累计释放度曲线的相似因子,结果市售制剂A在含体积分数5%,20%和40%乙醇介质中的相似因子分别为87.54、60.22、68.63。市售制剂B在含体积分数5%,20%和40%乙醇介质中的相似因子分别为91.90、73.75、66.58。市售制剂C在含体积分数5%,20%和40%乙醇介质中的相似因子分别为98.34、65.73、62.92。结果显示各受试曲线相似因子均大于50,累计释放度曲线相似,且未发生药物的突释,显示各制剂均有足够的酒精耐受性,其乙醇诱导的剂量倾泻风险较小。

4 讨论

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释放介质的选择:FDA推荐使用0.1 mol·L^-1盐酸溶液及其不同浓度的乙醇溶液作为释放介质,EMA推荐使用常规检验用的释放介质与其不同浓度的乙醇溶液作为释放介质^[8-9]。首先尝试使用0.1 mol·L^-1盐酸溶液及其一定比例的乙醇溶液作为释放介质按“2.3”项下色谱条件测定,结果显示在4 h内格列齐特缓释片已经降解了16.3%,溶液不稳定。此外,经测定用加乙醇的0.1 mol·L^-1盐酸溶液溶解供试品溶液,主成分峰型易发生改变,因此采用0.1 mol·L^-1盐酸溶液做释放介质无法稳定地测定溶出液中格列齐特的量。最终参照EMA推荐选择采用格列齐特缓释片已有国家标准释放度检查方法中的释放介质磷酸盐缓冲液(pH 7.4)作为剂量倾泻试验的基础释放介质。

通过溶解度、释药动力学模型及溶蚀失重速率等的考察,该品种制剂在乙醇介质中的累计释放度受制剂释药扩散速度、骨架溶蚀速度及原料药溶解度等因素的共同作用,其中骨架溶蚀速度是影响释放的关键因素。通过相似因子(f₂)考察,各市售制剂在含乙醇介质中的累计释放度曲线与非乙醇介质中相似,显示各制剂均有足够的乙醇耐受性,乙醇诱导的剂量倾泻风险可控,安全性较高。本研究对格列齐特缓释片市售制剂的剂量倾泻风险进行了摸底,为类似仿制药的处方开发设计和建立我国相关技术指南提供实例参考。

参考文献

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2024年第59卷第4期

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doi: 10.11669/cpj.2024.04.005

接收时间：2022-10-17
首发时间：2025-11-13
出版时间：2024-02-22

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收稿日期：2022-10-17

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北京市药品检验研究院, 国家药品监督管理局仿制药研究与评价重点实验室, 中药成分分析与生物评价北京市重点实验室, 北京 102206

通讯作者:

*胡琴,女,主任药师研究方向:化学药品质量控制研究 Tel:(010)52779622;

张喆,男,副主任药师研究方向:化学药品质量控制研究 Tel:(010)52779623

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Formulation	Model	Ethanol percentage/%	Kinetic release equation	r
A	Zero-order	0	M_t/M_∞=0.135t	0.990 1
		5	M_t/M_∞=0.139t	0.993 1
		20	M_t/M_∞=0.115t	0.995 5
		40	M_t/M_∞=0.125t	0.998 2
	First-order	0	M_t/M_∞=1-e^-0.002^t	0.995 0
		5	M_t/M_∞=1-e^-0.002^t	0.993 6
		20	M_t/M_∞=1-e^-0.002^t	0.996 8
		40	M_t/M_∞=1-e^-0.002^t	0.991 3
	Higuchi	0	M_t/M_∞=2.842t^0.5	0.974 1
		5	M_t/M_∞=2.931t^0.5	0.974 5
		20	M_t/M_∞=2.435t^0.5	0.974 0
		40	M_t/M_∞=2.621t^0.5	0.968 8
	Korsmeryer-Peppas	0	M_t/M_∞=0.319t^0.863	0.994 4
		5	M_t/M_∞=0.315t^0.870	0.996 5
		20	M_t/M_∞=0.256t^0.874	0.998 1
		40	M_t/M_∞=0.210t^0.918	0.999 0
B	Zero-order	0	M_t/M_∞=0.148t	0.994 2
		5	M_t/M_∞=0.150t	0.992 1
		20	M_t/M_∞=0.139t	0.998 0
		40	M_t/M_∞=0.135t	0.998 9
	First-order	0	M_t/M_∞=1-e^-0.003^t	0.989 7
		5	M_t/M_∞=1-e^-0.003^t	0.990 5
		20	M_t/M_∞=1-e^-0.002^t	0.987 7
		40	M_t/M_∞=1-e^-0.002^t	0.987 7
	Higuchi	0	M_t/M_∞=3.133t^0.5	0.975 7
		5	M_t/M_∞=3.195t^0.5	0.977 0
		20	M_t/M_∞=2.927t^0.5	0.970 7
		40	M_t/M_∞=2.844t^0.5	0.970 9
	Korsmeryer-Peppas	0	M_t/M_∞=0.392t^0.845	0.997 6
		5	M_t/M_∞=0.449t^0.826	0.996 7
		20	M_t/M_∞=0.271t^0.894	0.999 1
		40	M_t/M_∞=0.271t^0.890	0.999 7
C	Zero-order	0	M_t/M_∞=0.118t	0.999 0
		5	M_t/M_∞=0.119t	0.999 2
		20	M_t/M_∞=0.103t	0.999 5
		40	M_t/M_∞=0.101t	0.998 4
	First-order	0	M_t/M_∞=1-e^-0.002^t	0.992 8
		5	M_t/M_∞=1-e^-0.002^t	0.991 8
		20	M_t/M_∞=1-e^-0.002^t	0.994 3
		40	M_t/M_∞=1-e^-0.001^t	0.996 1
	Higuchi	0	M_t/M_∞=2.477t^0.5	0.969 3
		5	M_t/M_∞=2.499t^0.5	0.968 1
		20	M_t/M_∞=2.163t^0.5	0.969 1
		40	M_t/M_∞=2.147t^0.5	0.974 6
	Korsmeryer-Peppas	0	M_t/M_∞=0.191t^0.924	0.999 7
		5	M_t/M_∞=0.183t^0.933	0.999 8
		20	M_t/M_∞=0.184t^0.908	0.999 9
		40	M_t/M_∞=0.268t^0.845	0.999 7

Formulation

Model

Ethanol
percentage/%

Kinetic release
equation

Zero-order

M_t/M_∞=0.135t

0.990 1

M_t/M_∞=0.139t

0.993 1

M_t/M_∞=0.115t

0.995 5

M_t/M_∞=0.125t

0.998 2

First-order

M_t/M_∞=1-e^-0.002^t

0.995 0

M_t/M_∞=1-e^-0.002^t

0.993 6

M_t/M_∞=1-e^-0.002^t

0.996 8

M_t/M_∞=1-e^-0.002^t

0.991 3

Higuchi

M_t/M_∞=2.842t^0.5

0.974 1

M_t/M_∞=2.931t^0.5

0.974 5

M_t/M_∞=2.435t^0.5

0.974 0

M_t/M_∞=2.621t^0.5

0.968 8

Korsmeryer-Peppas

M_t/M_∞=0.319t^0.863

0.994 4

M_t/M_∞=0.315t^0.870

0.996 5

M_t/M_∞=0.256t^0.874

0.998 1

M_t/M_∞=0.210t^0.918

0.999 0

Zero-order

M_t/M_∞=0.148t

0.994 2

M_t/M_∞=0.150t

0.992 1

M_t/M_∞=0.139t

0.998 0

M_t/M_∞=0.135t

0.998 9

First-order

M_t/M_∞=1-e^-0.003^t

0.989 7

M_t/M_∞=1-e^-0.003^t

0.990 5

M_t/M_∞=1-e^-0.002^t

0.987 7

M_t/M_∞=1-e^-0.002^t

0.987 7

Higuchi

M_t/M_∞=3.133t^0.5

0.975 7

M_t/M_∞=3.195t^0.5

0.977 0

M_t/M_∞=2.927t^0.5

0.970 7

M_t/M_∞=2.844t^0.5

0.970 9

Korsmeryer-Peppas

M_t/M_∞=0.392t^0.845

0.997 6

M_t/M_∞=0.449t^0.826

0.996 7

M_t/M_∞=0.271t^0.894

0.999 1

M_t/M_∞=0.271t^0.890

0.999 7

Zero-order

M_t/M_∞=0.118t

0.999 0

M_t/M_∞=0.119t

0.999 2

M_t/M_∞=0.103t

0.999 5

M_t/M_∞=0.101t

0.998 4

First-order

M_t/M_∞=1-e^-0.002^t

0.992 8

M_t/M_∞=1-e^-0.002^t

0.991 8

M_t/M_∞=1-e^-0.002^t

0.994 3

M_t/M_∞=1-e^-0.001^t

0.996 1

Higuchi

M_t/M_∞=2.477t^0.5

0.969 3

M_t/M_∞=2.499t^0.5

0.968 1

M_t/M_∞=2.163t^0.5

0.969 1

M_t/M_∞=2.147t^0.5

0.974 6

Korsmeryer-Peppas

M_t/M_∞=0.191t^0.924

0.999 7

M_t/M_∞=0.183t^0.933

0.999 8

M_t/M_∞=0.184t^0.908

0.999 9

M_t/M_∞=0.268t^0.845

0.999 7