药学学报

Product	API	Technology	Company
Zanocin OD	Ofloxacin	Effervescent floating system	Ranbaxy, India
Riomet OD	Metformin hydrochloride	Effervescent floating system	Ranbaxy, India
Cifran OD	Ciprofloxacin	Effervescent floating system	Ranbaxy, India
Inon Ace Tablets	Sime´thicone	Foam-based floating system	Sato Pharma, Japan
ProQuin XR	Ciprofloxacin	Polymer-based swelling technology: AcuForm^TM	Depomed, USA
Glumetza	Metformin hydrochloride	Polymer-based swelling technology: AcuForm^TM	Depomed, USA
Prazopress XL	Prazosin hydrochloride	Effervescent and swelling-based floating system	Sun Pharma, Japan
Metformin hydrochloride	Metformin hydrochloride	Minextab floating system	Galenix, France
Cafelor LP	Cefaclor	Minextab floating system	Galenix, France
Tramadol LP	Tramadol	Minextab floating system	Galenix, France
Cipro XR	Ciprofloxacin hydrochloride and betaine	Erodible matrix-based system	Bayer, USA
Baclofen GRS	Baclofen	Coated multi-layer floating and swelling system	Sun Pharma, India
Coreg CR	Carvedilol	Gastroretention with osmotic system	GlaxoSmithKline, UK
Madopar	Levodopa and benserazide	Floating, CR capsule	Roche, UK
Liquid gaviscon	Alginic acid and sodium bicarbonate	Effervescent floating liquid alginate preparation	Reckitt Benckiser Healthcare, UK
Valrelease	Diazepam	Floating, CR capsule	Roche, UK
Cytotec	Misoprostol (100/200 µg)	Bilayer floating capsule	Pharmacia Limited, UK
Topalkan	Aluminum magnesium antacid	Floating liquid alginate	Pierre Fabre Medicament, France
Conviron	Ferrous sulfate	Colloidal gel forming floating system	Ranbaxy, India

Product

API

Technology

Company

Zanocin OD

Ofloxacin

Effervescent floating system

Ranbaxy, India

Riomet OD

Metformin hydrochloride

Effervescent floating system

Ranbaxy, India

Cifran OD

Ciprofloxacin

Effervescent floating system

Ranbaxy, India

Inon Ace Tablets

Sime´thicone

Foam-based floating system

Sato Pharma, Japan

ProQuin XR

Ciprofloxacin

Polymer-based swelling technology: AcuForm^TM

Depomed, USA

Glumetza

Metformin hydrochloride

Polymer-based swelling technology: AcuForm^TM

Depomed, USA

Prazopress XL

Prazosin hydrochloride

Effervescent and swelling-based floating system

Sun Pharma, Japan

Metformin hydrochloride

Minextab floating system

Galenix, France

Cafelor LP

Cefaclor

Minextab floating system

Galenix, France

Tramadol LP

Tramadol

Minextab floating system

Galenix, France

Cipro XR

Ciprofloxacin hydrochloride
and betaine

Erodible matrix-based system

Bayer, USA

Baclofen GRS

Baclofen

Coated multi-layer floating and swelling system

Sun Pharma, India

Coreg CR

Carvedilol

Gastroretention with osmotic system

GlaxoSmithKline, UK

Madopar

Levodopa and benserazide

Floating, CR capsule

Roche, UK

Liquid gaviscon

Alginic acid and sodium
bicarbonate

Effervescent floating liquid alginate preparation

Reckitt Benckiser Healthcare, UK

Valrelease

Diazepam

Floating, CR capsule

Roche, UK

Cytotec

Misoprostol (100/200 µg)

Bilayer floating capsule

Pharmacia Limited, UK

Topalkan

Aluminum magnesium
antacid

Floating liquid alginate

Pierre Fabre Medicament, France

Conviron

Ferrous sulfate

Colloidal gel forming floating system

Ranbaxy, India

Product	API	Technology	Company
Zanocin OD	Ofloxacin	Effervescent floating system	Ranbaxy, India
Riomet OD	Metformin hydrochloride	Effervescent floating system	Ranbaxy, India
Cifran OD	Ciprofloxacin	Effervescent floating system	Ranbaxy, India
Inon Ace Tablets	Sime´thicone	Foam-based floating system	Sato Pharma, Japan
ProQuin XR	Ciprofloxacin	Polymer-based swelling technology: AcuForm^TM	Depomed, USA
Glumetza	Metformin hydrochloride	Polymer-based swelling technology: AcuForm^TM	Depomed, USA
Prazopress XL	Prazosin hydrochloride	Effervescent and swelling-based floating system	Sun Pharma, Japan
Metformin hydrochloride	Metformin hydrochloride	Minextab floating system	Galenix, France
Cafelor LP	Cefaclor	Minextab floating system	Galenix, France
Tramadol LP	Tramadol	Minextab floating system	Galenix, France
Cipro XR	Ciprofloxacin hydrochloride and betaine	Erodible matrix-based system	Bayer, USA
Baclofen GRS	Baclofen	Coated multi-layer floating and swelling system	Sun Pharma, India
Coreg CR	Carvedilol	Gastroretention with osmotic system	GlaxoSmithKline, UK
Madopar	Levodopa and benserazide	Floating, CR capsule	Roche, UK
Liquid gaviscon	Alginic acid and sodium bicarbonate	Effervescent floating liquid alginate preparation	Reckitt Benckiser Healthcare, UK
Valrelease	Diazepam	Floating, CR capsule	Roche, UK
Cytotec	Misoprostol (100/200 µg)	Bilayer floating capsule	Pharmacia Limited, UK
Topalkan	Aluminum magnesium antacid	Floating liquid alginate	Pierre Fabre Medicament, France
Conviron	Ferrous sulfate	Colloidal gel forming floating system	Ranbaxy, India

Product

API

Technology

Company

Zanocin OD

Ofloxacin

Effervescent floating system

Ranbaxy, India

Riomet OD

Metformin hydrochloride

Effervescent floating system

Ranbaxy, India

Cifran OD

Ciprofloxacin

Effervescent floating system

Ranbaxy, India

Inon Ace Tablets

Sime´thicone

Foam-based floating system

Sato Pharma, Japan

ProQuin XR

Ciprofloxacin

Polymer-based swelling technology: AcuForm^TM

Depomed, USA

Glumetza

Metformin hydrochloride

Polymer-based swelling technology: AcuForm^TM

Depomed, USA

Prazopress XL

Prazosin hydrochloride

Effervescent and swelling-based floating system

Sun Pharma, Japan

Metformin hydrochloride

Minextab floating system

Galenix, France

Cafelor LP

Cefaclor

Minextab floating system

Galenix, France

Tramadol LP

Tramadol

Minextab floating system

Galenix, France

Cipro XR

Ciprofloxacin hydrochloride
and betaine

Erodible matrix-based system

Bayer, USA

Baclofen GRS

Baclofen

Coated multi-layer floating and swelling system

Sun Pharma, India

Coreg CR

Carvedilol

Gastroretention with osmotic system

GlaxoSmithKline, UK

Madopar

Levodopa and benserazide

Floating, CR capsule

Roche, UK

Liquid gaviscon

Alginic acid and sodium
bicarbonate

Effervescent floating liquid alginate preparation

Reckitt Benckiser Healthcare, UK

Valrelease

Diazepam

Floating, CR capsule

Roche, UK

Cytotec

Misoprostol (100/200 µg)

Bilayer floating capsule

Pharmacia Limited, UK

Topalkan

Aluminum magnesium
antacid

Floating liquid alginate

Pierre Fabre Medicament, France

Conviron

Ferrous sulfate

Colloidal gel forming floating system

Ranbaxy, India

Drug	Disease	Drawback	Ref
Metformin	Treatment of type 2 diabetes	Narrow absorption window and the best absorption part is the upper digestive tract	[6]
Revaprazan	Treatment of peptic ulcers	Poor dissolution properties and short half-life	[7]
Trazodone hydrochloride	Treat a major depressive disorder	Poor dissolution properties and a short half-life	[8]
Raloxifene	Treat osteoporosis in postmenopausal women	Poor dissolution properties	[9]
Ranitidine hydrochloride	Treatment of peptic ulcers	Narrow absorption window and a short half-life	[10]
Acyclovir	Treat infections caused by herpes simplex virus (HSV) or herpes zoster virus (VZV)	Narrow absorption window and a short half-life	[11]
Ofloxacin	Treatment of bacterial urogenital tract and respiratory tract infections	With a low solubility at alkaline pH	[12]
Metoprolol succinate	Treatment of hypertension, congestive heart failure, angina pectoris, and arrhythmia	Narrow absorption window and a short half-life	[13]
Verapamil	Treatment of hypertension and tachycardia	With a low solubility at alkaline pH	[14]
Clarithromycin	Helicobacter pylori in the treatment for upper respiratory tract infections	Short half-life	[15]
Famotidine HCl	For the treatment of gastrointestinal and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding and other gastrointestinal diseases	Narrow absorption window and low solubility in intestinal pH	[16]
Domperidone	Treatment of upper gastrointestinal diseases	Poor oral bioavailability, short biological half-life, and pH-dependent solubility	[17]

Drug

Disease

Drawback

Ref

Metformin

Treatment of type 2 diabetes

Narrow absorption window and the best absorption part is the upper digestive tract

[6]

Revaprazan

Treatment of peptic ulcers

Poor dissolution properties and short half-life

[7]

Trazodone hydrochloride

Treat a major depressive disorder

Poor dissolution properties and a short half-life

[8]

Raloxifene

Treat osteoporosis in postmenopausal women

Poor dissolution properties

[9]

Ranitidine hydrochloride

Treatment of peptic ulcers

Narrow absorption window and a short half-life

[10]

Acyclovir

Treat infections caused by herpes simplex virus (HSV) or herpes zoster virus (VZV)

Narrow absorption window and a short half-life

[11]

Ofloxacin

Treatment of bacterial urogenital tract and respiratory tract infections

With a low solubility at alkaline pH

[12]

Metoprolol succinate

Treatment of hypertension, congestive heart failure, angina pectoris, and arrhythmia

Narrow absorption window and a short half-life

[13]

Verapamil

Treatment of hypertension and tachycardia

With a low solubility at alkaline pH

[14]

Clarithromycin

Helicobacter pylori in the treatment for upper respiratory tract infections

Short half-life

[15]

Famotidine HCl

For the treatment of gastrointestinal and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding and other gastrointestinal diseases

Narrow absorption window and low solubility in intestinal pH

[16]

Domperidone

Treatment of upper gastrointestinal diseases

Poor oral bioavailability, short biological half-life, and pH-dependent solubility

[17]

Drug	Disease	Drawback	Ref
Metformin	Treatment of type 2 diabetes	Narrow absorption window and the best absorption part is the upper digestive tract	[6]
Revaprazan	Treatment of peptic ulcers	Poor dissolution properties and short half-life	[7]
Trazodone hydrochloride	Treat a major depressive disorder	Poor dissolution properties and a short half-life	[8]
Raloxifene	Treat osteoporosis in postmenopausal women	Poor dissolution properties	[9]
Ranitidine hydrochloride	Treatment of peptic ulcers	Narrow absorption window and a short half-life	[10]
Acyclovir	Treat infections caused by herpes simplex virus (HSV) or herpes zoster virus (VZV)	Narrow absorption window and a short half-life	[11]
Ofloxacin	Treatment of bacterial urogenital tract and respiratory tract infections	With a low solubility at alkaline pH	[12]
Metoprolol succinate	Treatment of hypertension, congestive heart failure, angina pectoris, and arrhythmia	Narrow absorption window and a short half-life	[13]
Verapamil	Treatment of hypertension and tachycardia	With a low solubility at alkaline pH	[14]
Clarithromycin	Helicobacter pylori in the treatment for upper respiratory tract infections	Short half-life	[15]
Famotidine HCl	For the treatment of gastrointestinal and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding and other gastrointestinal diseases	Narrow absorption window and low solubility in intestinal pH	[16]
Domperidone	Treatment of upper gastrointestinal diseases	Poor oral bioavailability, short biological half-life, and pH-dependent solubility	[17]

Drug

Disease

Drawback

Ref

Metformin

Treatment of type 2 diabetes

Narrow absorption window and the best absorption part is the upper digestive tract

[6]

Revaprazan

Treatment of peptic ulcers

Poor dissolution properties and short half-life

[7]

Trazodone hydrochloride

Treat a major depressive disorder

Poor dissolution properties and a short half-life

[8]

Raloxifene

Treat osteoporosis in postmenopausal women

Poor dissolution properties

[9]

Ranitidine hydrochloride

Treatment of peptic ulcers

Narrow absorption window and a short half-life

[10]

Acyclovir

Treat infections caused by herpes simplex virus (HSV) or herpes zoster virus (VZV)

Narrow absorption window and a short half-life

[11]

Ofloxacin

Treatment of bacterial urogenital tract and respiratory tract infections

With a low solubility at alkaline pH

[12]

Metoprolol succinate

Treatment of hypertension, congestive heart failure, angina pectoris, and arrhythmia

Narrow absorption window and a short half-life

[13]

Verapamil

Treatment of hypertension and tachycardia

With a low solubility at alkaline pH

[14]

Clarithromycin

Helicobacter pylori in the treatment for upper respiratory tract infections

Short half-life

[15]

Famotidine HCl

For the treatment of gastrointestinal and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding and other gastrointestinal diseases

Narrow absorption window and low solubility in intestinal pH

[16]

Domperidone

Treatment of upper gastrointestinal diseases

Poor oral bioavailability, short biological half-life, and pH-dependent solubility

[17]

Type	Mechanism	Drawback
Floating type	Relies on drug concentration being lower than gastric fluid concentration to float	Gastric fluid levels, body position after drug administration, and food intake all affect floating status
High density type	Relies on the density of the drug being higher than the density of the gastric juice, allowing the drug to sink	High technical requirements, difficult to make high-density particles with high drug content, possible material safety and biocompatibility issues
Swelling and expanding type	After oral administration, the drug comes into contact with gastric juices, expands and unfolds in volume, making the drug larger than the pyloric size and difficult to expel	Uneven or excessive swelling of the drug causing stomach upset or blockage
Magnetic type	Incorporation of magnetic material into the drug, using external magnets to control the position of the drug	Requires external magnetic field cooperation, affecting patient comfort
Bio/mucoadhesive type	Adhesive materials are added to the drug to adhere to the gastric mucosa or epithelial cell surface through adhesion	Adhesion may be reduced by physiological factors and food intake
Raft forming type	The drug absorbs water and swells to form a viscous cohesive gel that floats like a raft on the surface of the gastric juice	Complex preparation process and high cost
Superporous hydrogels	Utilising a super porous aqueous gel structure to increase the carrying capacity of the drug and prolong the residence time of the drug in the stomach	Complex preparation process, difficult to control pore structure and size
Synergistic type	Combines multiple mechanisms, such as floating, adhesion, swelling, etc., which work synergistically to prolong the residence time of the drug in the stomach and improve the delivery effect	Complex to prepare and optimise as there is a need to overcome synergistic problems with the various mechanisms involved
Nanoparticulate-based GRDDS	Use of nanocarriers and other technologies to extend the residence time of drugs in the stomach and improve targeting and bioavailability	Possible problems with biosafety and metabolic pathways of nanocarriers; high preparation costs
3D printing-based GRDDS	Design and preparation of GRDDS according to the individual needs of patients using 3D printing technology to increase individual differentiation of therapeutic effects	Higher costs make it difficult to achieve mass production

Type

Mechanism

Drawback

Floating type

Relies on drug concentration being lower than gastric fluid concentration to float

Gastric fluid levels, body position after drug administration, and food intake all affect floating status

High density type

Relies on the density of the drug being higher than the density of the gastric juice, allowing the drug to sink

High technical requirements, difficult to make high-density particles with high drug content, possible material safety and biocompatibility issues

Swelling and expanding type

After oral administration, the drug comes into contact with gastric juices, expands and unfolds in volume, making the drug larger than the pyloric size and difficult to expel

Uneven or excessive swelling of the drug causing stomach upset or blockage

Magnetic type

Incorporation of magnetic material into the drug, using external magnets to control the position of the drug

Requires external magnetic field cooperation, affecting patient comfort

Bio/mucoadhesive type

Adhesive materials are added to the drug to adhere to the gastric mucosa or epithelial cell surface through adhesion

Adhesion may be reduced by physiological factors and food intake

Raft forming type

The drug absorbs water and swells to form a viscous cohesive gel that floats like a raft on the surface of the gastric juice

Complex preparation process and high cost

Superporous hydrogels

Utilising a super porous aqueous gel structure to increase the carrying capacity of the drug and prolong the residence time of the drug in the stomach

Complex preparation process, difficult to control pore structure and size

Synergistic type

Combines multiple mechanisms, such as floating, adhesion, swelling, etc., which work synergistically to prolong the residence time of the drug in the stomach and improve the delivery effect

Complex to prepare and optimise as there is a need to overcome synergistic problems with the various mechanisms involved

Nanoparticulate-based GRDDS

Use of nanocarriers and other technologies to extend the residence time of drugs in the stomach and improve targeting and bioavailability

Possible problems with biosafety and metabolic pathways of nanocarriers; high preparation costs

3D printing-based GRDDS

Design and preparation of GRDDS according to the individual needs of patients using 3D printing technology to increase individual differentiation of therapeutic effects

Higher costs make it difficult to achieve mass production

Type	Mechanism	Drawback
Floating type	Relies on drug concentration being lower than gastric fluid concentration to float	Gastric fluid levels, body position after drug administration, and food intake all affect floating status
High density type	Relies on the density of the drug being higher than the density of the gastric juice, allowing the drug to sink	High technical requirements, difficult to make high-density particles with high drug content, possible material safety and biocompatibility issues
Swelling and expanding type	After oral administration, the drug comes into contact with gastric juices, expands and unfolds in volume, making the drug larger than the pyloric size and difficult to expel	Uneven or excessive swelling of the drug causing stomach upset or blockage
Magnetic type	Incorporation of magnetic material into the drug, using external magnets to control the position of the drug	Requires external magnetic field cooperation, affecting patient comfort
Bio/mucoadhesive type	Adhesive materials are added to the drug to adhere to the gastric mucosa or epithelial cell surface through adhesion	Adhesion may be reduced by physiological factors and food intake
Raft forming type	The drug absorbs water and swells to form a viscous cohesive gel that floats like a raft on the surface of the gastric juice	Complex preparation process and high cost
Superporous hydrogels	Utilising a super porous aqueous gel structure to increase the carrying capacity of the drug and prolong the residence time of the drug in the stomach	Complex preparation process, difficult to control pore structure and size
Synergistic type	Combines multiple mechanisms, such as floating, adhesion, swelling, etc., which work synergistically to prolong the residence time of the drug in the stomach and improve the delivery effect	Complex to prepare and optimise as there is a need to overcome synergistic problems with the various mechanisms involved
Nanoparticulate-based GRDDS	Use of nanocarriers and other technologies to extend the residence time of drugs in the stomach and improve targeting and bioavailability	Possible problems with biosafety and metabolic pathways of nanocarriers; high preparation costs
3D printing-based GRDDS	Design and preparation of GRDDS according to the individual needs of patients using 3D printing technology to increase individual differentiation of therapeutic effects	Higher costs make it difficult to achieve mass production

Type

Mechanism

Drawback

Floating type

Relies on drug concentration being lower than gastric fluid concentration to float

Gastric fluid levels, body position after drug administration, and food intake all affect floating status

High density type

Relies on the density of the drug being higher than the density of the gastric juice, allowing the drug to sink

High technical requirements, difficult to make high-density particles with high drug content, possible material safety and biocompatibility issues

Swelling and expanding type

After oral administration, the drug comes into contact with gastric juices, expands and unfolds in volume, making the drug larger than the pyloric size and difficult to expel

Uneven or excessive swelling of the drug causing stomach upset or blockage

Magnetic type

Incorporation of magnetic material into the drug, using external magnets to control the position of the drug

Requires external magnetic field cooperation, affecting patient comfort

Bio/mucoadhesive type

Adhesive materials are added to the drug to adhere to the gastric mucosa or epithelial cell surface through adhesion

Adhesion may be reduced by physiological factors and food intake

Raft forming type

The drug absorbs water and swells to form a viscous cohesive gel that floats like a raft on the surface of the gastric juice

Complex preparation process and high cost

Superporous hydrogels

Utilising a super porous aqueous gel structure to increase the carrying capacity of the drug and prolong the residence time of the drug in the stomach

Complex preparation process, difficult to control pore structure and size

Synergistic type

Combines multiple mechanisms, such as floating, adhesion, swelling, etc., which work synergistically to prolong the residence time of the drug in the stomach and improve the delivery effect

Complex to prepare and optimise as there is a need to overcome synergistic problems with the various mechanisms involved

Nanoparticulate-based GRDDS

Use of nanocarriers and other technologies to extend the residence time of drugs in the stomach and improve targeting and bioavailability

Possible problems with biosafety and metabolic pathways of nanocarriers; high preparation costs

3D printing-based GRDDS

Design and preparation of GRDDS according to the individual needs of patients using 3D printing technology to increase individual differentiation of therapeutic effects

Higher costs make it difficult to achieve mass production

胃滞留给药系统的研究进展

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吴艳梅 , 刘凤雪 , 宫苹 , 陈宁 , 郑威 ^*

药学学报 | 综述 2024,59(9): 2499-2508

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药学学报 | 综述 2024, 59(9): 2499-2508

胃滞留给药系统的研究进展

全屏

吴艳梅, 刘凤雪, 宫苹, 陈宁, 郑威^*

作者信息

哈尔滨商业大学, 黑龙江哈尔滨 150076

通讯作者:

^*郑威，E-mail: wei2013zheng@163.com

Advances in gastric retention drug delivery system

Yan-mei WU, Feng-xue LIU, Ping GONG, Ning CHEN, Wei ZHENG^*

Affiliations

Harbin University of Commerce, Harbin 150076, China

出版时间: 2024-09-12 doi: 10.16438/j.0513-4870.2024-0475

文章导航

摘要

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传统的口服给药方式, 由于胃排空速度快和胃肠道转运时间短, 导致药物在完全释放之前被排出, 降低了药物的生物利用度。为了保持药物在体内的有效浓度并发挥其最佳疗效, 通常需要增加给药次数。相比较而言, 胃滞留给药系统(gastric retention drug delivery system, GRDDS) 作为一种创新的给药方法, 延长药物在胃中的滞留时间, 减少了对胃肠道的刺激性, 提高了药物的生物利用度, 减少了患者的服药次数, 增强了患者的治疗依从性。近几年来, 国内外在GRDDS方面进行了广泛的研究, 本文总结了GRDDS研究进展, 对其上市情况、类型及体内外评价方法等方面进行综述。

关键词

胃滞留给药系统 / 胃滞留时间 / 生物利用度 / 依从性 / 体内外评价

Abstract

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The conventional oral drug delivery frequently results in the drug elimination before its complete release due to rapid gastric emptying and short gastrointestinal transport time, thus reducing the bioavailability of drug. In order to maintain an effective concentration of drug in the body and maximize its optimal efficacy, the frequency of administrations often needs to be increased. By contrast, gastric retention drug delivery system (GRDDS), as an innovative method of drug delivery, prolongs the retention time of the drug in the stomach and reduces irritation to the gastrointestinal tract. Consequently, it enhances the bioavailability of drug, reduces dosing frequency for patients and improves treatment adherence. In recent years, domestic and foreign studies have been conducted on gastric retention drug delivery systems. Here, we provide a comprehensive overview of the relevant literature published in recent years, examining their current marketing status, various types, as well as in vivo and in vitro evaluation methods.

Key words

gastric retention drug delivery system / retention time / bioavailability / compliance / in vivo and in vitro evaluation

引用本文

吴艳梅, 刘凤雪, 宫苹, 陈宁, 郑威. 胃滞留给药系统的研究进展. 药学学报, 2024 , 59 (9) : 2499 -2508 . DOI: 10.16438/j.0513-4870.2024-0475

Yan-mei WU, Feng-xue LIU, Ping GONG, Ning CHEN, Wei ZHENG. Advances in gastric retention drug delivery system[J]. Acta Pharmaceutica Sinica, 2024 , 59 (9) : 2499 -2508 . DOI: 10.16438/j.0513-4870.2024-0475

正文

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传统的口服给药因服用方便、成本低、安全性高、操作简单、易接受等特点, 被广泛用于临床治疗, 是常用的给药方式之一。尽管口服药物存在诸多优点, 仍有一些不利于发挥药效的因素, 如口服制剂生物利用度低、半衰期短和代谢率高等; 此外, 首过效应也会影响药物的吸收, 使药物到达吸收部位时不能发挥最佳药效。这些不利因素导致患者需要频繁给药, 影响患者的用药依从性^[1]。

胃滞留给药系统(gastric retention drug delivery system, GRDDS) 作为一种改进口服药物的新型系统, 旨在解决胃排空速度快和胃肠道转运时间短等问题, 从而提高药物的生物利用度和疗效, 减少患者的服药次数^[2]。该系统的作用机制是通过对药物进行特定的设计, 从而延长药物在胃内的滞留时间, 减少药物被排出的可能性。该系统也可以实现特异性药物释放, 尤其是对吸收窗窄、在胃肠道内发挥局部作用的药物^[3]。同时, 还能够降低药物在体内的代谢速率, 减少药物在肝脏和其他器官的代谢损失。

GRDDS作为一种新型的给药方式, 具有显著的优势(如提高药物生物利用度、减少给药次数、改善患者依从性、提高药物疗效、实现靶向给药等^[4]), 能够克服口服给药的诸多挑战, 为患者提供更加安全、有效的治疗方案。

目前, 国内外已经有一部分关于GRDDS的产品上市, 如胃漂浮片、胃内膨胀胶囊等。这些产品在上市之前经过了大量的临床研究以确保其安全性和有效性。对上市的产品及临床数据分析发现, 漂浮型制剂在胃滞留应用较为广泛, 而磁导向型相对较少。这是因为漂浮型制剂可以根据胃内环境的变化自行调整位置, 以达到药物缓释的效果; 而磁导向型制剂则需要外部磁力的引导才能实现准确的定位和药物释放, 其生产过程也相对复杂, 成本较高, 因此在市场推广的难度较大。表 1^[5]列举了国内外部分的胃滞留制剂。

1 胃滞留的合适候选药物

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GRDDS的目的是延长药物的胃保留时间, 尤其是针对一些特定类型的药物, 如特定吸收部位、碱性pH溶解性差、具有局部作用及半衰期短的药物等, 通过延长药物的胃滞留时间来提高药物的生物利用度和治疗效果, 减少患者给药次数, 提高患者的用药便利性和依从性。表 2^[6-17]列举了一些可适用于胃滞留的药物。

通过GRDDS, 这些药物的吸收和利用率都大大提高, 也有效地提高了其生物利用度, 减少了患者的服药次数, 进而提高了患者的用药便利性和依从性, 药物的安全性、稳定性和有效性等方面都得到了明显的改善。

2 影响胃滞留时间的因素

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影响胃滞留时间的因素可分为生理因素、制剂因素等, 其中生理因素为主要的影响因素^[18]。

2.1 生理因素

对于胃滞留给药途径来说, 其生理因素主要是受到胃的影响。从解剖角度来看, 胃主要分为胃底、胃体和胃窦3个区域^[19](图 1), 其中胃底位于胃的上端, 与食管相连, 胃体作为食物储存区, 而胃窦位于胃的下端, 与十二指肠相连。胃是消化系统的重要组成部分, 对食物的消化和吸收起着关键性作用。在饥饿状态下, 胃蠕动明显并伴随着肠蠕动, 同时分泌大量胃酸^[20], 这些生理过程对药物的吸收和转运产生极大的影响, 尤其是对于某些特定药物(如胃黏膜保护剂、降血压药、降血糖药等), 这些药物在空腹时服用, 药效增强, 但其他药物在空腹时服用, 药效降低; 在进食状态下, 胃蠕动逐渐缓慢从而导致胃排空速率减慢, 此时服用药物可能会延长药物在胃内的滞留时间, 导致胃部不适或引发其他不良反应。

除了上述因素外, 胃液pH、胃肠道功能、胃酸分泌情况、胃排空时间、药物的吸收部位及胃内环境等因素也会影响胃滞留时间^[21]。胃液pH主要是影响药物的溶解性和稳定性, 从而影响药物的胃保留时间; 胃肠道蠕动过快, 会导致药物快速通过胃肠道, 减少了药物在胃内的滞留时间; 胃酸分泌情况影响胃液pH, 进而影响药物的胃滞留时间; 胃排空时间往往会导致药物在上消化道的滞留时间变短, 因此影响胃排空过程的因素也影响胃滞留时间; 不同的药物在不同的吸收部位也会影响药物在胃内的保留时间; 胃内环境包括胃液成分和胃肠道菌群等, 这些因素也会影响药物在胃内滞留时间。

2.2 制剂因素

制剂的密度和制剂的大小也是决定胃内滞留时间的关键性因素^[22]。当其密度低于胃液密度, 在胃内呈现出漂浮状态, 从而提高了药物在胃内滞留的可能性, 此类药物属于漂浮型GRDDS, 当药物密度为2.5 g·cm^-3时, 胃滞留效果更加显著^[23]; 在制剂中加入一些重质材料, 药物在胃内呈现下沉状态, 可延长药物在胃内的滞留时间, 此类药物属于沉降型GRDDS。制剂尺寸过大也可延长药物在胃内的滞留时间, 但会导致血药浓度过高, 从而引发不良反应甚至药物中毒等情况; 相反, 制剂尺寸过小可能会导致药物在胃内呈现漂浮状态, 但无法达到发挥最佳药效所需浓度, 因此要增加给药次数。除了制剂的密度和大小会影响胃滞留时间外, 药物的溶解度、脂溶性、分子大小及剂型都会影响药物的滞留时间。

2.3 其他

除了上述提及的两种因素外, 服药患者的药物吸收也会受到服药患者的年龄、性别、身高、体重和患病史等因素的影响^[24]。因此, 在明确剂量和用药方式时, 医生需要综合考虑患者的个体差异, 以确保药物发挥最佳的治疗效果。

3 GRDDS的类型

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GRDDS是通过改善药物的释放速率和分布时间来增强药物的吸收。其关键是通过多种原理来延长药物的胃滞留时间。根据其滞留原理和设计不同, 分为漂浮型、高密度型、膨胀型、磁导向型、生物黏附型、浮筏型、超多孔水性凝胶型、协同型、纳米技术结合的GRDDS和3D打印结合的GRDDS等(图 2)。

3.1 漂浮型GRDDS

漂浮型GRDDS, 也称为低密度型GRDDS, 指药物经口服进入胃中后, 由于药物密度低于胃液的密度(通常为1.004 g·cm^-3), 使其漂浮在胃液表面^[25]。该给药系统的概念于1968年由Davis提出^[26], 是延长胃滞留时间的常用方法之一。该系统制备工艺简单, 对药物的要求较低, 并且减少了药物对胃肠道的刺激。根据其漂浮机制的不同, 可将漂浮型GRDDS分为非泡腾漂浮型和泡腾漂浮型两种类型^[27]。

3.1.1 非泡腾漂浮型GRDDS

非泡腾漂浮型GRDDS是以亲水性聚合物(如海藻酸盐、羟丙基甲基纤维素等) 为基质, 在药物表面形成黏性水合层, 从而实现药物的滞留。这种设计使药物停留在胃的上部溶胶层, 延长药物与胃壁的接触时间, 以提高药物的生物利用度和治疗效果。Thitinan等^[28]成功研制了一种内部含有空气隔室的新型胃滞留脉冲给药平台, 该平台在实现释时靶向给药的同时, 延长药物的胃滞留时间, 使得药物更有效地被人体吸收。

3.1.2 泡腾漂浮型GRDDS

泡腾型胃漂浮给药系统通过添加起泡剂(通常是碳酸盐或碳酸氢盐) 产生气体, 将药物包裹在浮动的气泡中, 以实现漂浮效果。这种漂浮状态延长药物在胃内的停留时间, 促进了药物的溶解和吸收, 进而增强了药效。此外, 该系统有助于提高药物的稳定性, 减少药物与胃酸或其他消化液的接触, 减少不良反应的发生。

Patel等^[2]以碳酸钠作为起泡剂, 通过直接压片法制备米格列奈漂浮骨架片。实验结果表明, 该骨架片在胃液中可以漂浮12 h, 这种剂型减少了给药频率, 减轻对胃肠道的刺激。Alqahtani等^[29]采用基于熔融沉积建模技术的3D打印技术制备胃滞留漂浮装置, 将其设计为双室圆形片剂, 外部隔室密封作为充气室, 为该装置提供浮力, 内部隔室填装盐酸普萘洛尔速释片剂。与参考片剂相比, 在体外漂浮时间大于24 h, 持续释药时间长达10 h, 在胃内滞留时间大大延长。

3.2 高密度型GRDDS

高密度型GRDDS通过在药物中添加重质材料(如钨、铁、钡等) 来增加药物的密度, 使其在胃内呈现沉积状态而不会排出体外。Guan等^[30]采用药用铁粉作为造气剂和增密剂研制了一种新型法莫替丁胃内渗透泵片, γ射线照相测定了^99mTc标记系统在Beagle犬胃内的滞留时间为7 h, 其滞留时间相较于普通制剂显著延长。由于高密度型GRDDS在临床研究方面相对较少, 及其技术要求高且制备高含药量的高密度颗粒困难, 因此其在临床应用中并不广泛。

3.3 膨胀型GRDDS

膨胀型GRDDS是将药物折叠成普通制剂的大小, 当其进入胃后与胃液接触, 药物体积膨胀(或展开), 使其无法通过幽门进入十二指肠, 随着药物的释放, 体积会逐渐溶蚀变小最终被排出体外^[31]。膨胀型GRDDS根据膨胀方式分为展开型和溶胀型^[32]。

3.3.1 展开型GRDDS

展开型GRDDS是通过设计特殊的药物载体来延长药物的胃保留时间, 这种给药系统使药物载体在口服时与普通制剂大小相同, 但在进入胃后通过特殊技术展开, 从而延长药物在胃内的滞留时间。药物载体的形状也影响药物的释放速度和滞留时间, 目前常用的形态有: 四面体、环形或平面膜(4-瓣、盘或交叉型) 等^[33]。Verma等^[34]设计一种由乙基纤维素和羟丙基甲基纤维素(HPMC K15) 制备的载药聚合物膜, 将其折叠放入硬胶囊内, 口服进入胃后展开, 使药物在胃内充分发挥药效。实验结果表明, 该药物在12 h内可实现缓慢释放。

3.3.2 溶胀型GRDDS

溶胀型GRDDS, 又称为塞式系统, 是指药物在口服进入胃后与胃液充分接触体积溶胀至尺寸大于幽门尺寸(15 mm), 导致药物无法排出体外, 从而延长药物的胃滞留时间^[35]。El-Zahaby等^[36]制备了一种左氧氟沙星溶胀型GRDDS, 用于治疗幽门螺旋杆菌感染。该制剂的制备过程中, 使用了结冷胶、海藻酸钠、果胶和黄原胶等材料。实验结果表明, 随着时间的推移, 片剂体积逐渐增大, 从而起到塞式剂型的作用。该给药系统可实现对药物释放速率的持续性控制。

3.4 磁导向型GRDDS

磁导向型GRDDS是在制剂中加入磁性材料来增强周围的磁场强度, 并利用外部磁铁施加外部磁场控制药物的位置, 以此延长药物在胃内的停留时间, 提高药物的吸收效果。此外, 这种系统还可根据需求控制药物的释放和分布。

Hao等^[37]采用单轴电喷雾法制备了一种新型胃特异性磁沉微球用以运载阿司匹林。这些微球在体内外均表现出较强的磁性, 在磁场条件下20 s后可实现沉降, 实验结果表明, ¹³¹I标记的磁沉微球在胃中滞留时间超过8 h。由于磁沉微球的特殊设计, 使药物能够长时间滞留于胃部, 从而提高抗菌效果。

3.5 生物黏附型GRDDS

生物黏附型GRDDS作为一种有效的给药方式, 适用于有局部作用及需要长时间停留在特定部位的药物。通过将含有黏性的材料加入到制剂中, 使药物能够与胃黏膜或者上皮细胞表面形成黏附力, 从而延长了药物的滞留时间, 促进药物的吸收和利用。

Pandey等^[38]成功开发了一种由药物释放速率控制膜组成的胃滞留黏附贴剂盐酸乐卡地平。该膜采用分层法, 选用Eudragit RSPO和RLPO制备双层贴剂, 以增强其黏附力。体外实验表明, 该制剂在家兔体内的释放时间可达12 h, 大大延长了药物在体内的滞留时间。

3.6 浮筏型GRDDS

浮筏型GRDDS是一种利用药物起泡赋形剂和凝胶(如含有碳酸盐或碳酸氢盐的海藻酸钠溶液) 制成的药物递送系统。当药物与胃液接触后, 药物溶胀形成含有二氧化碳的黏性凝胶, 这种凝胶类似筏子一样漂浮在胃液表面, 因此被称为浮筏型GRDDS^[39]。Abouelatta等^[40]利用浮筏型GRDDS来改善加巴喷丁的半衰期短、吸收期短、顺应性差等问题, 通过2³全因子设计优化处方变量后, 与市售的加巴喷丁速释口服液相比, 其最大血药浓度(C_max)、血药浓度-时间曲线下面积AUC_0-t和AUC_0-∞显著增加, 相对生物利用度也提高了1.70倍, 表明该系统能够显著提高加巴喷丁的生物利用度和疗效。

3.7 超多孔水性凝胶给药系统

超多孔水性凝胶是由亲水性高分子和非有机试剂相互形成的一种三维结构的复合材料, 其内部有许多超大孔结构, 这种材料具有吸水性强、溶胀速度快等优点, 能够在短时间内吸水溶胀^[41], 这种优点能有效地降低胃酸对药物的影响, 减少药物在胃酸环境中的降解, 从而提高药物的稳定性。为了区别不同性质的超多孔水性凝胶, 将其分为三代: 第一代为传统的超多孔水性凝胶具有快速高效的膨胀特性, 但力学性能较差; 第二代为复合型超多孔水性凝胶, 在力学性能上得到显著的改善, 但溶胀速率明显降低; 第三代为混合型超多孔水性凝胶, 具有良好的弹性, 常用于胃滞留装置和其他制药及医药生物领域^[42]。

Desu等^[43]对载有氟伐他汀的超多孔水性凝胶进行优化, 优化后的载药复合材料在10 h内释放药物量可达80%, 与市售的氟伐他汀混悬液相比, 药物C_max提高了2.36倍; 同时, AUC_0-24和吸收速率常数(K_a) 也分别提高了1.33倍和1.37倍。这些结果表明, 优化后的超多孔水性凝胶复合材料能够明显改善氟伐他汀的性能, 提高其在治疗高血压方面的效果。

3.8 协同型GRDDS

协同型GRDDS是综合利用了其他滞留原理的优点, 或者是为了弥补其缺点而设计的。这种给药系统可以被分为两种类型: 胃漂浮黏附协同型GRDDS和胃漂浮膨胀协同型GRDDS。

3.8.1 漂浮黏附协同型GRDDS

漂浮黏附协同型GRDDS是通过利用黏合剂和漂浮剂的优点制备药物载体, 使其能够在胃内同时实现黏附和漂浮状态。这种系统具有良好的稳定性, 可以有效地控制药物的释放速度, 避免药物在胃内过快释放或失效的问题。该给药系统还可实现药物的局部和全身控释^[44], 是目前发展较为完善的给药方法之一。Chen等^[45]开发了一种纳米胶束胃滞留微球, 该微球是由壳聚糖包覆的大黄素纳米胶束组成, 通过实验表明, 在给药后8 h, 纳米胶束微球仍在胃内保留, 这有利于更好地发挥药效, 同时也降低药物的毒副作用。

3.8.2 漂浮膨胀协同型GRDDS

漂浮膨胀协同型GRDDS结合了漂浮剂和膨胀剂的优点, 促使药物在胃内滞留实现控释效果。这两种辅料结合大大提高药物的释放效率, 减少不良反应的发生。

Lin等^[46]为了减少尼洛替尼的不良反应, 提高口服药物的利用度, 将其制备成一种新型的漂浮膨胀协同型GRDDS。研究发现, 聚合物赋形剂(HPMC 90 SH 100 K、HEC 250 HHX或PEO 7000 K) 和Kollidon SR组成的溶胀和漂浮剂对制剂的影响较大, 经过多次实验, 最终确定PEO 7000 K/Kollidon SR (P/K) 在7∶3的比例有最佳溶胀和漂浮能力。在药代动力学实验中发现, 该药物与市售的尼洛替尼相比具有明显的优势, 口服生物利用度提高了2.65~8.39倍。

由于盐酸环丙沙星的溶解度差和吸收性差, 需要反复给药, 但长时间使用广谱抗生素会产生耐药性, 因此Liang等^[47]设计出一种具有漂浮和溶胀能力的基于羟丙基甲基纤维素衍生物的盐酸环丙沙星胃内滞留片, 与市售环丙沙星片剂相比, 血药浓度明显提高, 同时也缩短了药物的初始滞留时间。总的来说, 基于羟丙基甲基纤维素衍生物的环丙沙星胃内滞留片能够快速达到治疗细菌所需浓度, 并且在长时间内维持血浆内抗生素浓度, 是目前一个具有前景的抗生素。

3.9 纳米技术结合GRDDS

近几年来, 纳米技术在胃滞留给药途径中的应用研究被广泛关注, 纳米技术结合的GRDDS是将药物载体设计成纳米尺寸的颗粒以实现更精确的药物释放。此外, 纳米技术还可用于改善药物的溶解度、增强稳定性、实现靶向输送等, 为GRDDS的性能优化提供了技术支持。Ngwuluka等^[48]研发了一种采用聚合物共混物制备的左旋多巴胃滞留药物递送系统。与常规剂型相比, 纳米负载的左旋多巴胃滞留药物递送系统在长时间内可实现药物的恒定释放, 在未来有望成为治疗帕金森病的新型药物缓释系统。

3.10 3D打印技术结合的GRDDS

3D打印技术是一种基于计算机辅助设计的连续材料层沉积形成三维结构的实体制造方法。目前, 该技术能够制备出具有特定释放性质的复杂结构, 从而实现个性给药^[49]。多潘立酮片由于其溶解性差和渗透性高等缺点, 需要反复给药才能达到最佳血药浓度。为了改善这些缺点, Charoenying等^[50]利用熔融沉积成型技术生产了一种胶囊形漂浮装置。该装置由两部分组成: 亲水帽(由带有充气孔的PVA制成) 和疏水体(由PLA构建), 该漂浮装置通过内部孔径来释放药物, 体内漂浮实验表明, 当亲水帽厚度达1.3 mm时, 漂浮时间可达10 h, 释放动力学符合零级释放, 有利于维持体内血药浓度的稳定性。本文作者所在课题组Zhou等^[51]制备的形状记忆载药复合膜经过编程为临时形状, 在体温温度刺激下可形变恢复成尺寸大于幽门的工作形状, 实现胃滞留。该膜可在人体最适温度下形变, 60 s后形状恢复率可达70%, 与纯木犀草素对比, 负载木犀草素的形状记忆复合膜的平均保留时间和半衰期都显著延长, 对未来口服治疗胃癌具有较大的潜力。

3D打印结合的GRDDS相较于其他GRDDS而言, 可以制备出复杂的空间结构, 优化药物的释放速度; 通过3D打印可将多种药物整合到一个载体中, 实现多功能药物的递送; 此外, 该技术还可提高药物的稳定性, 实现个性化给药。

综上所述, GRDDS有不同的类型, 这些类型的多样性是根据不同设计原理和技术结合, 总结各类GRDDS的作用机制和缺点归纳于表 3。

4 体内外评价方法

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为了了解GRDDS的滞留情况, 体内外评价变得尤为重要。体内评价主要是借助一些辅助手段来观察药物的滞留及吸收情况; 体外评价是通过实验来研究药物在胃内的释放情况、药物的溶出状态和生物利用度。

4.1 体内评价方法

4.1.1 γ-闪烁扫描

γ-闪烁扫描是利用放射性物质并结合γ闪烁照相机来追踪观察药物在胃内情况。目前, 该法应用较为广泛, 但所需费用较高。Kam等^[52]使用γ-闪烁扫描测量盐酸硫胺素胃漂浮片在进食和禁食条件下的胃内滞留情况, 结果显示, 在进食状态下, 胃漂浮片的滞留时间长达10 h; 在禁食状态下, 滞留时间为1.8 h, 两种状态相比, 在进食条件下的生物利用度提高了2.80倍。与传统的速释片相比较, 胃漂浮片在进食状态下吸收度增加了1.40倍, 而空腹时的吸收度是速释片的70%, 由结果可知, 盐酸硫胺素胃漂浮片可显著延长药物在胃内的滞留时间。Razavi等^[53]应用γ-闪烁扫描并结合双探测器单光子发射计算机断层扫描-计算机断层扫描系统, 观察服用盐酸二甲双胍胃漂浮片与普通片剂后的新西兰兔胃内滞留情况。实验结果表明, 与普通片剂相比, 用氧化钐(¹⁵³Sm₂O₃) 标记的胃漂浮片在胃内漂浮时间可长达12 h。

4.1.2 X射线成像

X射线成像是一种用于观察药物在胃内的动态变化的常用技术。通过在药物制剂中加入X射线无法透过的材料, 如铁粉或硫酸钡等作为造影剂, 使药物在X射线下可见。与γ-闪烁扫描相比, X射线成像具有操作简单、价格适中的特点, 由于其安全性问题, 不宜用于人体试验^[54]。

4.1.3 荧光成像法

荧光成像法是利用荧光染料或标记物来实现药物在胃内的定量或定性分析。Zhou等^[51]为了观察LPC (luteolin) 和LPC-PLA/PEG (7∶3) 的胃内滞留情况, 在LPC和LPC-PLA/PEG (7∶3) 中加入荧光材料, 在小鼠口服LPC和LPC-PLA/PEG (7∶3) 的不同时间点观察, 结果显示, 给药后8 h, LPC在小鼠胃内残留量减少, 而在10 h后几乎完全消失; 而LPC-PLA/PEG (7∶3) 口服8 h后, 在胃内观察到均匀且明显的荧光, 而在10 h后胃内几乎看不到荧光, 但在肠道内仍可观察到荧光信号。这表明LPC-PLA/PEG (7∶3) 可实现胃滞留, 为未来口服治疗胃癌提供了新型的递药系统。

4.1.4 核磁共振成像法

核磁共振成像利用核磁共振原理来获取人体内部结构和组织的高分辨率图像。在药物研究领域, 可以用于评估药物在胃内的情况。最常见的方法是向药物制剂中添加铁粉或带有磁性的颗粒, 使得这些药物在核磁共振设备中可见。通过对胃部进行扫描, 可以观察到药物在胃内的分布、运动情况及与其他物质的相互作用。Steingoetter等^[55]将带有磁性的Fe₂O₃颗粒加入胃漂浮片中, 用核磁共振技术来检测药物在胃内的漂浮情况。通过该技术, 可以实时观察药物在胃内的位置和运动状态, 进而评估药物的释放和吸收情况。这种方法为研究药物在胃内的行为提供了一种非侵入性的手段, 可以更全面地了解药物的药效学特性。

4.1.5 胃镜检查法

胃镜检查法是一种用于临床的内窥检查方法, 它通过导光纤管直接进入胃部, 以观察胃内情况, 也可以用于评估药物在胃内的滞留情况和展开情况。由于胃镜检查需要反复进入人体, 可能会给志愿者带来不便和不适, 因此这种方法会限制测定药物在胃内滞留情况的应用^[56]。Klausner等^[57]利用胃镜检查方法对左旋多巴在胃内的滞留和展开情况进行了测定。研究结果显示, 该制剂在胃内完全展开需要5~10 min, 并且可以保持展开形状长达2 h。这表明该制剂在胃内具有较好的展开性能, 有助于药物的滞留吸收, 促进药物更好地发挥药效。

4.1.6 超声波检查法

超声波检查法是一种利用超声波在界面上的声阻反射来实现成像的方法^[58]。在药物研究领域中, 通常被用于评估特定药物给药系统, 例如超多孔水性凝胶GRDDS。然而, 并非所有制剂都能产生明显的声阻反射, 这导致超声波检查法在某些情况下不太适用。对于那些无法产生清晰声阻反射的制剂, 可以应用其他成像技术, 例如核磁共振成像、荧光成像或者其他非侵入性的成像方法, 以更好地评估药物在胃内的情况和效果。

4.2 体外评价方法

4.2.1 胃滞留性能评价

胃滞留性能评价是为了查看药物在体外的起漂时间和持续漂浮时间, 目前常用的方法为直接观察法和浮力测定法^[59]。

直接观察法是一种用于测定药物起漂时间和持续漂浮时间的常用方法。其步骤是将药物放入人工胃液中, 用计时器记录药物的起漂时间和持续漂浮时间, 该法简单、易于操作、成本较低等, 也是目前常用的方法之一。Naiel等^[60]应用直接观察法观察配制的聚合物珠粒的漂浮能力, 将干燥好的聚合物珠粒放入新配制的人工胃液中, 水浴振荡恒定转速为50 r·min^-1, 温度37 ℃, 在实验中观察记录聚合物珠粒的起漂时间和持续漂浮时间。

浮力测定法是通过自制的浮力测定仪来测定药物在体外的起漂时间和持续漂浮时间。这种方法与直接观察法类似, 也用于评估药物的漂浮性能。Wang等^[61]应用自制的浮力测定仪测定盐酸曲马多胃漂浮缓释胶囊的体外浮力, 最终结果显示, 该胶囊在体外的最大浮力可达255 mg, 48 h内浮力一直维持在27 mg, 说明自制的盐酸曲马多胃漂浮缓释胶囊的持续漂浮能力良好。

4.2.2 体外溶出试验

溶出度是评价药物在规定条件下的溶出速率和程度的重要指标。在2020版《中华人民共和国药典》中用于测定溶出度的方法有篮法、浆法、小杯法、转筒法、流池法等, 其中篮法和浆法是目前最常用的方法。

Shakya等^[62]应用篮法测定氧氟沙星胃漂浮片的体外药物释放情况, 将药物置于篮中浸入含有900 mL 0.1 mol·L^-1 HCl的溶出容器中, 温度设置在37 ± 0.5 ℃, 以100 r·min^-1的速度搅拌, 在预定的时间间隔内收集样品, 使用紫外可见分光光度计在294 nm下测定, 绘制释药曲线, 与市售氧氟沙星对比, 释药性能相似, 但氧氟沙星胃漂浮片在胃内的漂浮时间较长, 有利于药物更好地释放。

Real等^[63]采用浆法测定氯硝柳胺的释放度, 将含有氯硝柳胺和纳米晶体的胶囊放入含有和不含2% Tween 80的900 mL 0.1 mol·L^-1 HCl, 使用USP Ⅱ溶出装置, 将温度设置在37 ± 0.5 ℃的条件下进行搅拌, 搅拌桨配置为50 r·min^-1, 在预定时间进行样品收集, 过滤除杂质后, 使用分光光度计在330 nm下测定, 经过分析发现含有2% Tween 80的0.1 mol·L^-1 HCl介质中溶出曲线呈增长趋势。结果表明, 经熔融固化打印技术打印的氯硝柳胺-纳米晶体的片剂在狗胃内滞留时间长达3 h, 与传统的剂型相比, 溶解度和局部释药能力大大增加, 有望成为未来治疗幽门螺旋杆菌感染的首选药物。

5 总结与展望

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GRDDS作为一种新型的药物递送技术, 具有许多优势, 如改善药物的吸收、降低药物降解的可能性、减少药物的不良反应、降低药物成本和提高药物疗效等。尽管GRDDS具有诸多优势, 但也有一些潜在的挑战和缺陷。其中之一是需要更先进的技术来设计和制备GRDDS, 以确保药物的精确释放; 此外, 如何克服胃滞留制剂在胃内降解的可能性及如何确保药物在胃肠道内的安全性等问题, 也是未来研究和开发过程中需要重点考虑的内容。虽然GRDDS存在一些挑战和缺陷, 但作为新型给药途径的巨大潜力不可忽视, 随着科学技术的发展和给药系统的不断改进, 相信GRDDS将会在未来得到广泛应用。

作者贡献: 吴艳梅负责撰写及修改综述; 刘凤雪负责提供撰写思路; 宫苹负责提供选题思路; 陈宁负责提供修改意见; 郑威全程指导。

利益冲突: 本文所有作者声明不存在利益冲突关系。

基金

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哈尔滨商业大学“青年科研创新人才”项目(2023-KYYWF-1037)

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2024年第59卷第9期

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doi: 10.16438/j.0513-4870.2024-0475

接收时间：2024-05-20
首发时间：2025-11-24
出版时间：2024-09-12

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收稿日期：2024-05-20
修回日期：2024-07-16

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哈尔滨商业大学“青年科研创新人才”项目(2023-KYYWF-1037)

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哈尔滨商业大学, 黑龙江哈尔滨 150076

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^*郑威，E-mail: wei2013zheng@163.com

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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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TxT

Product	API	Technology	Company
Zanocin OD	Ofloxacin	Effervescent floating system	Ranbaxy, India
Riomet OD	Metformin hydrochloride	Effervescent floating system	Ranbaxy, India
Cifran OD	Ciprofloxacin	Effervescent floating system	Ranbaxy, India
Inon Ace Tablets	Sime´thicone	Foam-based floating system	Sato Pharma, Japan
ProQuin XR	Ciprofloxacin	Polymer-based swelling technology: AcuForm^TM	Depomed, USA
Glumetza	Metformin hydrochloride	Polymer-based swelling technology: AcuForm^TM	Depomed, USA
Prazopress XL	Prazosin hydrochloride	Effervescent and swelling-based floating system	Sun Pharma, Japan
Metformin hydrochloride	Metformin hydrochloride	Minextab floating system	Galenix, France
Cafelor LP	Cefaclor	Minextab floating system	Galenix, France
Tramadol LP	Tramadol	Minextab floating system	Galenix, France
Cipro XR	Ciprofloxacin hydrochloride and betaine	Erodible matrix-based system	Bayer, USA
Baclofen GRS	Baclofen	Coated multi-layer floating and swelling system	Sun Pharma, India
Coreg CR	Carvedilol	Gastroretention with osmotic system	GlaxoSmithKline, UK
Madopar	Levodopa and benserazide	Floating, CR capsule	Roche, UK
Liquid gaviscon	Alginic acid and sodium bicarbonate	Effervescent floating liquid alginate preparation	Reckitt Benckiser Healthcare, UK
Valrelease	Diazepam	Floating, CR capsule	Roche, UK
Cytotec	Misoprostol (100/200 µg)	Bilayer floating capsule	Pharmacia Limited, UK
Topalkan	Aluminum magnesium antacid	Floating liquid alginate	Pierre Fabre Medicament, France
Conviron	Ferrous sulfate	Colloidal gel forming floating system	Ranbaxy, India

Product

API

Technology

Company

Zanocin OD

Ofloxacin

Effervescent floating system

Ranbaxy, India

Riomet OD

Metformin hydrochloride

Effervescent floating system

Ranbaxy, India

Cifran OD

Ciprofloxacin

Effervescent floating system

Ranbaxy, India

Inon Ace Tablets

Sime´thicone

Foam-based floating system

Sato Pharma, Japan

ProQuin XR

Ciprofloxacin

Polymer-based swelling technology: AcuForm^TM

Depomed, USA

Glumetza

Metformin hydrochloride

Polymer-based swelling technology: AcuForm^TM

Depomed, USA

Prazopress XL

Prazosin hydrochloride

Effervescent and swelling-based floating system

Sun Pharma, Japan

Metformin hydrochloride

Minextab floating system

Galenix, France

Cafelor LP

Cefaclor

Minextab floating system

Galenix, France

Tramadol LP

Tramadol

Minextab floating system

Galenix, France

Cipro XR

Ciprofloxacin hydrochloride
and betaine

Erodible matrix-based system

Bayer, USA

Baclofen GRS

Baclofen

Coated multi-layer floating and swelling system

Sun Pharma, India

Coreg CR

Carvedilol

Gastroretention with osmotic system

GlaxoSmithKline, UK

Madopar

Levodopa and benserazide

Floating, CR capsule

Roche, UK

Liquid gaviscon

Alginic acid and sodium
bicarbonate

Effervescent floating liquid alginate preparation

Reckitt Benckiser Healthcare, UK

Valrelease

Diazepam

Floating, CR capsule

Roche, UK

Cytotec

Misoprostol (100/200 µg)

Bilayer floating capsule

Pharmacia Limited, UK

Topalkan

Aluminum magnesium
antacid

Floating liquid alginate

Pierre Fabre Medicament, France

Conviron

Ferrous sulfate

Colloidal gel forming floating system

Ranbaxy, India

Drug	Disease	Drawback	Ref
Metformin	Treatment of type 2 diabetes	Narrow absorption window and the best absorption part is the upper digestive tract	[6]
Revaprazan	Treatment of peptic ulcers	Poor dissolution properties and short half-life	[7]
Trazodone hydrochloride	Treat a major depressive disorder	Poor dissolution properties and a short half-life	[8]
Raloxifene	Treat osteoporosis in postmenopausal women	Poor dissolution properties	[9]
Ranitidine hydrochloride	Treatment of peptic ulcers	Narrow absorption window and a short half-life	[10]
Acyclovir	Treat infections caused by herpes simplex virus (HSV) or herpes zoster virus (VZV)	Narrow absorption window and a short half-life	[11]
Ofloxacin	Treatment of bacterial urogenital tract and respiratory tract infections	With a low solubility at alkaline pH	[12]
Metoprolol succinate	Treatment of hypertension, congestive heart failure, angina pectoris, and arrhythmia	Narrow absorption window and a short half-life	[13]
Verapamil	Treatment of hypertension and tachycardia	With a low solubility at alkaline pH	[14]
Clarithromycin	Helicobacter pylori in the treatment for upper respiratory tract infections	Short half-life	[15]
Famotidine HCl	For the treatment of gastrointestinal and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding and other gastrointestinal diseases	Narrow absorption window and low solubility in intestinal pH	[16]
Domperidone	Treatment of upper gastrointestinal diseases	Poor oral bioavailability, short biological half-life, and pH-dependent solubility	[17]

Drug

Disease

Drawback

Ref

Metformin

Treatment of type 2 diabetes

Narrow absorption window and the best absorption part is the upper digestive tract

[6]

Revaprazan

Treatment of peptic ulcers

Poor dissolution properties and short half-life

[7]

Trazodone hydrochloride

Treat a major depressive disorder

Poor dissolution properties and a short half-life

[8]

Raloxifene

Treat osteoporosis in postmenopausal women

Poor dissolution properties

[9]

Ranitidine hydrochloride

Treatment of peptic ulcers

Narrow absorption window and a short half-life

[10]

Acyclovir

Treat infections caused by herpes simplex virus (HSV) or herpes zoster virus (VZV)

Narrow absorption window and a short half-life

[11]

Ofloxacin

Treatment of bacterial urogenital tract and respiratory tract infections

With a low solubility at alkaline pH

[12]

Metoprolol succinate

Treatment of hypertension, congestive heart failure, angina pectoris, and arrhythmia

Narrow absorption window and a short half-life

[13]

Verapamil

Treatment of hypertension and tachycardia

With a low solubility at alkaline pH

[14]

Clarithromycin

Helicobacter pylori in the treatment for upper respiratory tract infections

Short half-life

[15]

Famotidine HCl

For the treatment of gastrointestinal and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding and other gastrointestinal diseases

Narrow absorption window and low solubility in intestinal pH

[16]

Domperidone

Treatment of upper gastrointestinal diseases

Poor oral bioavailability, short biological half-life, and pH-dependent solubility

[17]

Type	Mechanism	Drawback
Floating type	Relies on drug concentration being lower than gastric fluid concentration to float	Gastric fluid levels, body position after drug administration, and food intake all affect floating status
High density type	Relies on the density of the drug being higher than the density of the gastric juice, allowing the drug to sink	High technical requirements, difficult to make high-density particles with high drug content, possible material safety and biocompatibility issues
Swelling and expanding type	After oral administration, the drug comes into contact with gastric juices, expands and unfolds in volume, making the drug larger than the pyloric size and difficult to expel	Uneven or excessive swelling of the drug causing stomach upset or blockage
Magnetic type	Incorporation of magnetic material into the drug, using external magnets to control the position of the drug	Requires external magnetic field cooperation, affecting patient comfort
Bio/mucoadhesive type	Adhesive materials are added to the drug to adhere to the gastric mucosa or epithelial cell surface through adhesion	Adhesion may be reduced by physiological factors and food intake
Raft forming type	The drug absorbs water and swells to form a viscous cohesive gel that floats like a raft on the surface of the gastric juice	Complex preparation process and high cost
Superporous hydrogels	Utilising a super porous aqueous gel structure to increase the carrying capacity of the drug and prolong the residence time of the drug in the stomach	Complex preparation process, difficult to control pore structure and size
Synergistic type	Combines multiple mechanisms, such as floating, adhesion, swelling, etc., which work synergistically to prolong the residence time of the drug in the stomach and improve the delivery effect	Complex to prepare and optimise as there is a need to overcome synergistic problems with the various mechanisms involved
Nanoparticulate-based GRDDS	Use of nanocarriers and other technologies to extend the residence time of drugs in the stomach and improve targeting and bioavailability	Possible problems with biosafety and metabolic pathways of nanocarriers; high preparation costs
3D printing-based GRDDS	Design and preparation of GRDDS according to the individual needs of patients using 3D printing technology to increase individual differentiation of therapeutic effects	Higher costs make it difficult to achieve mass production

Type

Mechanism

Drawback

Floating type

Relies on drug concentration being lower than gastric fluid concentration to float

Gastric fluid levels, body position after drug administration, and food intake all affect floating status

High density type

Relies on the density of the drug being higher than the density of the gastric juice, allowing the drug to sink

High technical requirements, difficult to make high-density particles with high drug content, possible material safety and biocompatibility issues

Swelling and expanding type

After oral administration, the drug comes into contact with gastric juices, expands and unfolds in volume, making the drug larger than the pyloric size and difficult to expel

Uneven or excessive swelling of the drug causing stomach upset or blockage

Magnetic type

Incorporation of magnetic material into the drug, using external magnets to control the position of the drug

Requires external magnetic field cooperation, affecting patient comfort

Bio/mucoadhesive type

Adhesive materials are added to the drug to adhere to the gastric mucosa or epithelial cell surface through adhesion

Adhesion may be reduced by physiological factors and food intake

Raft forming type

The drug absorbs water and swells to form a viscous cohesive gel that floats like a raft on the surface of the gastric juice

Complex preparation process and high cost

Superporous hydrogels

Utilising a super porous aqueous gel structure to increase the carrying capacity of the drug and prolong the residence time of the drug in the stomach

Complex preparation process, difficult to control pore structure and size

Synergistic type

Combines multiple mechanisms, such as floating, adhesion, swelling, etc., which work synergistically to prolong the residence time of the drug in the stomach and improve the delivery effect

Complex to prepare and optimise as there is a need to overcome synergistic problems with the various mechanisms involved

Nanoparticulate-based GRDDS

Use of nanocarriers and other technologies to extend the residence time of drugs in the stomach and improve targeting and bioavailability

Possible problems with biosafety and metabolic pathways of nanocarriers; high preparation costs

3D printing-based GRDDS

Design and preparation of GRDDS according to the individual needs of patients using 3D printing technology to increase individual differentiation of therapeutic effects

Higher costs make it difficult to achieve mass production