药学学报

Component	Function	Material
Backing layer	Provide support to the patches, avoid drug loss and external contamination	Chemical stable, high flexible, good compatible materials such as polyurethane, polyethylene, polyvinyl chloride, nonwoven fabric
Pressure-sensitive adhesive	Make patches adhere to the skin closely, regulate rate and extent of drug release, etc.	Non-toxic, non-irritant materials such as polyacrylic, polyisobutylene or silicone pressure-sensitive adhesive
Rate controlling membrane	Provide a constant rate of drug release from the reservoir to the skin	EVA, porous polyethylene film, etc.
Matrix and reservoir materials	Primary components acting as a backbone or reservoir of patches	PVP, EVA, polyvinyl alcohol, HPMC, pressure-sensitive adhesive, gelatin, carbomer, etc.
Release liners	Act as packaging materials, protect the adhesive layer from contamination	PVC, polyethylene, polyester, etc.

Component

Function

Material

Backing layer

Provide support to the patches, avoid drug loss and external contamination

Chemical stable, high flexible, good compatible materials such as polyurethane, polyethylene, polyvinyl chloride, nonwoven fabric

Pressure-sensitive adhesive

Make patches adhere to the skin closely, regulate rate and extent of drug release, etc.

Non-toxic, non-irritant materials such as polyacrylic, polyisobutylene or silicone pressure-sensitive adhesive

Rate controlling membrane

Provide a constant rate of drug release from the reservoir to the skin

EVA, porous polyethylene film, etc.

Matrix and reservoir materials

Primary components acting as a backbone or reservoir of patches

PVP, EVA, polyvinyl alcohol, HPMC, pressure-sensitive adhesive, gelatin, carbomer, etc.

Release liners

Act as packaging materials, protect the adhesive layer from contamination

PVC, polyethylene, polyester, etc.

Component	Function	Material
Backing layer	Provide support to the patches, avoid drug loss and external contamination	Chemical stable, high flexible, good compatible materials such as polyurethane, polyethylene, polyvinyl chloride, nonwoven fabric
Pressure-sensitive adhesive	Make patches adhere to the skin closely, regulate rate and extent of drug release, etc.	Non-toxic, non-irritant materials such as polyacrylic, polyisobutylene or silicone pressure-sensitive adhesive
Rate controlling membrane	Provide a constant rate of drug release from the reservoir to the skin	EVA, porous polyethylene film, etc.
Matrix and reservoir materials	Primary components acting as a backbone or reservoir of patches	PVP, EVA, polyvinyl alcohol, HPMC, pressure-sensitive adhesive, gelatin, carbomer, etc.
Release liners	Act as packaging materials, protect the adhesive layer from contamination	PVC, polyethylene, polyester, etc.

Component

Function

Material

Backing layer

Provide support to the patches, avoid drug loss and external contamination

Chemical stable, high flexible, good compatible materials such as polyurethane, polyethylene, polyvinyl chloride, nonwoven fabric

Pressure-sensitive adhesive

Make patches adhere to the skin closely, regulate rate and extent of drug release, etc.

Non-toxic, non-irritant materials such as polyacrylic, polyisobutylene or silicone pressure-sensitive adhesive

Rate controlling membrane

Provide a constant rate of drug release from the reservoir to the skin

EVA, porous polyethylene film, etc.

Matrix and reservoir materials

Primary components acting as a backbone or reservoir of patches

PVP, EVA, polyvinyl alcohol, HPMC, pressure-sensitive adhesive, gelatin, carbomer, etc.

Release liners

Act as packaging materials, protect the adhesive layer from contamination

PVC, polyethylene, polyester, etc.

分子间相互作用调控经皮给药系统中药物释放与渗透的研究进展

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涂希 , 洪卫漫 , 邓昌坚 , 方海红 , 彭亮 , 陈振华 ^* , 李阳彪 ^*

药学学报 | 综述 2025,60(12): 3720-3729

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药学学报 |综述 2025 , 60 (12) : 3720 -3729

分子间相互作用调控经皮给药系统中药物释放与渗透的研究进展

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涂希, 洪卫漫, 邓昌坚, 方海红, 彭亮, 陈振华^*, 李阳彪^*

作者信息

江西科技师范大学药学院, 江西南昌 330013

通讯作者:

陈振华, E-mail: zhenhuachen@jxstnu.edu.cn

李阳彪, E-mail: liyangbiao1985@163.com

作者简介:

作者贡献:

涂希负责文章撰写与修改; 洪卫漫协助配图制作; 邓昌坚协助文献收集与校样; 方海红、彭亮参与文章修改; 李阳彪、陈振华负责文章的框架设计、审阅及修改。

Research advances in intermolecular interactions regulating drug release and permeation in transdermal drug delivery systems

Xi TU, Wei-man HONG, Chang-jian DENG, Hai-hong FANG, Liang PENG, Zhen-hua CHEN^*, Yang-biao LI^*

Affiliations

School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, China

出版时间: 2025-12-12 doi: 10.16438/j.0513-4870.2025-0613

文章导航

摘要

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近年来, 以透皮贴剂、凝胶贴膏为代表的经皮给药系统的研究方兴未艾。药物、压敏胶、透皮吸收促进剂与皮肤成分间的相互作用, 包括氢键、离子相互作用、偶极-偶极相互作用等, 在调控透皮贴剂中药物的释放与渗透过程中发挥关键作用, 从而影响药物的经皮吸收效率。红外光谱、分子模拟或分子对接、差示扫描量热法、拉曼光谱、核磁共振等方法被用于表征透皮贴剂中的多种分子间相互作用。本综述旨在总结透皮贴剂中药物释放与经皮渗透过程的分子机制, 为新型经皮给药系统的设计与研究提供有益的理论指导。

关键词

贴剂 / 经皮给药系统 / 药物释放 / 经皮渗透 / 分子间相互作用

Abstract

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In recent years, the research of transdermal drug delivery systems (TDDS) represented by patches and gel plasters is in the ascendant. The interactions between drugs, pressure-sensitive adhesives, permeation enhancers and skin components, including hydrogen bonds, ionic interactions, dipole-dipole interactions, etc., play a key role in regulating the release and penetration of drugs in transdermal patches, thus affecting the efficiency of transdermal absorption of drugs. Infrared spectroscopy, molecular simulations or molecular docking, differential scanning calorimetry, Raman spectroscopy, nuclear magnetic resonance and other methods have been widely used to characterize multiple intermolecular interactions in patches. The aim of this review is to summary the molecular mechanisms of drug release from patches and transdermal permeation processes, provide useful theoretical guidance for the design and research of novel transdermal drug delivery systems.

Key words

patches / transdermal drug delivery system / drug release / transdermal permeation / intermolecular interaction

引用本文

涂希, 洪卫漫, 邓昌坚, 方海红, 彭亮, 陈振华, 李阳彪. 分子间相互作用调控经皮给药系统中药物释放与渗透的研究进展. 药学学报, 2025 , 60 (12) : 3720 -3729 . DOI: 10.16438/j.0513-4870.2025-0613

Xi TU, Wei-man HONG, Chang-jian DENG, Hai-hong FANG, Liang PENG, Zhen-hua CHEN, Yang-biao LI. Research advances in intermolecular interactions regulating drug release and permeation in transdermal drug delivery systems[J]. Acta Pharmaceutica Sinica, 2025 , 60 (12) : 3720 -3729 . DOI: 10.16438/j.0513-4870.2025-0613

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经皮给药系统(transdermal drug delivery systems, TDDS) 是指药物以一定的速率透过皮肤经毛细血管吸收进入人体血液循环并达到有效血药浓度, 实现疾病预防或治疗的一种新型给药途径, 也称为透皮贴剂^{[1, 2]}。TDDS可以克服口服给药存在的一些问题, 如首过效应、药物对胃肠道的刺激性、由于酶水解或化学降解导致的药物不稳定等^[3]。与注射给药相比, 使用更方便, 患者依从性好, 尤其适用于儿童等群体, 发现不良反应时可随时中断给药, 能长时间维持恒定的血药浓度, 减少峰谷现象^{[4, 5]}, 使TDDS成为一种有发展潜力的、被广泛接受的、日益流行的新型给药方式, 是继口服、注射给药后的第3大给药系统^[6]。

皮肤是人体最大的器官, 作为第一道防线用于屏蔽微生物等外来物质的侵入, 同时也限制了大部分药物的透皮吸收^[7]。皮肤由表皮、真皮和皮下组织三部分组成(图1), 还包括汗腺、皮脂腺、毛囊等附属器。表皮可分为角质层和活性表皮层(细分为透明层、颗粒层、棘层和基底层), 厚度约为50~100 μm。角质层厚约10~20 μm, 包含死亡的角质细胞, 其中充满角蛋白丝, 嵌入连续的多层细胞间脂质中。皮肤脂质组成与大多数生物膜有很大的不同, 主要成分是神经酰胺、脂肪酸和胆固醇等^{[8, 9]}。表皮下面是真皮层, 含有丰富的毛细血管。

药物的透皮吸收过程主要包括: ①释放过程, 即药物从透皮贴剂中释放, 进入皮肤表面; ②渗透, 药物以扩散的形式透过各皮肤层^[10]。研究发现多种类型的分子间相互作用对药物从贴剂中释放、从皮肤中渗透有重要的作用, 不仅调控经皮渗透速率, 还能影响药物在压敏胶中的饱和载药量、实现长效恒速的治疗作用^[11]。氢键、离子相互作用、偶极-偶极相互作用等能够调控药物从贴剂中的释放^{[12, 13]}, 例如有研究显示含有羧基的压敏胶可以与碱性药物形成离子键, 压敏胶中含有羧基的量越多, 碱性药物从贴剂中的释放越少。对于药物在皮肤中的渗透过程, 药物、透皮吸收促进剂、角质层中的细胞间脂质、角蛋白等的分子间相互作用, 能够改变皮肤的屏障性, 从而促进或减小药物的经皮渗透速率^[14], 合理调控这些作用力, 可以优化药物的经皮吸收效率。透皮贴剂的药物释放和经皮渗透过程中, 分子间相互作用发挥着关键作用, 因此, 本文将从药物、压敏胶、透皮吸收促进剂、皮肤中的成分的角度来阐述分子间相互作用与药物释放、渗透之间的关系。

1　经皮给药系统概述

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1.1　经皮给药系统的发展历程

目前, 经皮给药系统可分为4代: 第1代基于药物分子的被动扩散透过皮肤, 不借助任何的促渗透技术; 第2代为使用透皮吸收促进剂等方法增强皮肤的渗透性, 主要递送小分子药物^[15]; 第3代为借助电致孔、超声导入、或微针等破坏角质层屏障递送小分子药物、生物大分子等^[16-19]; 第4代TDDS是结合生物电子技术的智能可穿戴设备^{[20, 21]}, 能够通过实时监控体内生理信号水平调节药物经皮递送。

1.2　透皮贴剂的类型与辅助材料

现代经皮给药系统一般指透皮贴剂, 根据药物的释放机制和透皮贴剂的组成结构的不同(表1), 可分成储库型、黏胶分散型、聚合物骨架型等^[22]: ①储库型: 储库型贴剂主要由背衬层、药物储库、控释膜、黏合层、防黏层组成。药物储库被包裹固定在控释膜和背衬层之间, 药物的释放速率由控释膜的材料和性质决定, 可以实现恒速释放药物; ②黏胶分散型: 黏胶分散型透皮贴剂制备简单, 药物溶解或分散在压敏胶中, 随着剂量的减少, 药物的释放速率减慢; ③聚合物骨架型: 在聚合物骨架型透皮贴剂中, 药物均匀分散在骨架材料中, 再将压敏胶黏附在含药层周围或直接黏附在含药层上, 利用压敏胶、骨架材料的特性控制药物的释放。

2　分子间相互作用的类型及其表征手段

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2.1　分子间相互作用的类型

2.1.1　氢键

氢键通常发生在富电子的杂原子和缺电子的氢之间^[23], 与化学键相比, 氢键的键能要小得多, 而比一般的范德华力键能大。氢键的本质是缺电子氢原子与高电子云密度原子间的定向吸引作用, 兼具共价作用与非共价作用的特征^{[24, 25]}。氢键在经皮给药系统中发挥着重要作用, 例如药物与角质层中的脂质可以形成氢键, 干扰脂质的有序排列、影响药物在角质层中的混溶性与分配能力, 从而影响药物的经皮吸收^[26]。

除了普通的氢键以外, 还存在离子型氢键和双离子型氢键。离子型氢键是中性分子和带电荷的离子之间形成的氢键, 双离子型氢键是两个带电物质之间形成的氢键^[27]。

2.1.2　离子相互作用

离子相互作用是指带有正电荷(阳离子) 和带有负电荷(阴离子) 之间的相互作用, 经皮给药系统中使用的离子液体、离子对也属于该范畴。经皮给药系统中常用的载体如凝胶、聚合物或微粒, 通常具有离子性质或者能与药物通过离子相互作用结合^[28]。药物与载体之间的离子相互作用能够稳定药物分子, 防止降解, 影响药物的释放, 或者改变药物的极性和亲水性, 影响其在皮肤中的渗透性能。

离子液体是由阳离子和阴离子组成的盐, 通常在100 ℃以下保持液态^[29]。研究表明, 形成离子液体的机制包括离子相互作用、强电荷辅助氢键和范德华力等^[30], 药物形成离子液体后, 对其释放、经皮渗透特性会有影响^[31]。

离子对是指带相反电荷的离子由于库仑力的作用而短暂松弛结合的缔合体, 将药物与其反离子以非共价结合, 改变药物的理化性质, 进而达到调节药物经皮吸收的作用^[32-35]。离子对策略对药物释放的影响较复杂^[36，37], 一方面, 离子对策略可以增强药物与压敏胶之间的相互作用, 抑制药物的释放; 另一方面, 离子对策略可以提高压敏胶分子的运动性, 有利于药物从贴剂中的释放。

2.1.3　偶极-偶极相互作用

偶极-偶极相互作用(dipole-dipole interactions) 是一种分子间的相互作用, 主要存在于具有永久偶极矩的分子之间。偶极矩是分子内正负电荷分布不对称所导致的电荷分离, 形成电偶极^[38]。偶极-偶极相互作用强度取决于分子间的距离及偶极矩的大小, 通常弱于共价键和离子键。

2.1.4　 π-π堆积

π-π堆积一般为两个不饱和的体系之间产生的非共价相互作用, 主要发生在芳香环体系(如苯环、吡咯环等) 之间, 通过其离域π电子云的相互作用形成。

2.2　分子间相互作用的表征方法

2.2.1　红外光谱

红外光谱是分子选择性吸收某些波长的红外线, 引起分子中振动能级和转动能级的跃迁, 检测红外线被吸收的情况可得到物质的红外光谱。Li等^[39]发现含有羟基的压敏胶分别在3 464和3 525 cm^-1处出现C=O泛频峰和O-H伸缩振动峰, 当加入非那雄胺后, C=O泛频峰和O-H伸缩振动峰均向低波数移动, 表明药物和压敏胶之间存在强的偶极-偶极和氢键相互作用。

2.2.2　分子模拟或对接

分子模拟或对接从理论计算上鉴别药物与压敏胶之间^[40]、透皮吸收促进剂与角质层脂质之间^[41]的分子相互作用所涉及的功能基团, 例如使用AutoDock计算药物-压敏胶复合物, 从最优群中选择最低能量构象用于后续分析, 如果氢键供体和氢键受体间的距离小于临界距离则认为形成氢键。

2.2.3　差示扫描量热法

差示扫描量热法(differential scanning calorimetry, DSC) 通过测量样品和参比物质之间的温差, 分析其在加热或冷却过程中发生的热效应, 如熔化、玻璃化转变、结晶、相变等^[42]。通过测定DSC, 可以从热行为的变化中揭示聚合物的分子运动性、与药物分子间的相互作用等^[43]。

2.2.4　拉曼光谱

拉曼光谱(Raman spectroscopy) 是一种常用的分析技术, 拉曼散射是光与物质相互作用后, 散射光频率发生偏移的现象, 这个频率偏移(即拉曼位移) 与分子振动、旋转等有关。分子间的相互作用通常会改变分子的振动频率, 例如形成氢键通常会导致分子中某些振动的频率降低, 发生红移^[44]。

2.2.5　核磁共振

核磁共振可提供原子水平的结构和分子间相互作用的表征, 包括¹H NMR、¹³C NMR、二维核磁等。Liu等^[45]测定普萘洛尔和含有羧基(COOH) 的压敏胶的¹³C固态NMR, 压敏胶中的COOH的化学位移为183, 而在压敏胶和药物混合物中, 在该化学位移处峰消失, 表明在普萘洛尔和压敏胶之间形成了离子相互作用。

3　分子间相互作用对贴剂中药物释放过程的影响

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透皮贴剂中药物的释放是指药物克服聚合物基质的分子间相互作用, 从压敏胶中释放后到达皮肤表面的过程。释放过程受很多因素的影响, 包括压敏胶的种类、药物的理化性质、载药量、释放介质或皮肤表面的水合情况等, 而药物-压敏胶、药物-压敏胶-透皮吸收促进剂之间的相互作用对调控释放过程起到关键作用。目前, 采用桨碟法、扩散池法等测定透皮贴剂的释放度。

3.1　药物-压敏胶的分子间相互作用对药物释放过程的影响

压敏胶是指只需施加轻度压力, 即可与被黏物牢固黏合的胶黏剂, 它的主要功能是帮助贴剂与皮肤黏附, 用作药物和其他辅料的基质。因此, 除了贴剂的黏附性外, 压敏胶还影响TDDS的其他关键质量属性, 如药物释放速率、经皮药物透过量和制剂成品的物理和化学稳定性^[46]。贴剂中常用的压敏胶包括聚丙烯酸酯压敏胶、聚异丁烯压敏胶、热熔压敏胶、硅酮压敏胶。压敏胶分子结构中包含不同的官能团, 例如Duro-Tak 87-4098聚丙烯酸酯压敏胶不含有游离的官能团, Duro-Tak 87-2287压敏胶含有羟基, Duro-Tak 87-2051压敏胶含有羧基, 压敏胶与药物的分子间相互作用在饱和载药量和释放动力学方面起着重要作用。然而, 载药量和释放速率之间的微妙平衡是一项艰巨的挑战, 因为压敏胶与药物的分子间相互作用大、亲和力高往往意味着饱和载药量高, 但过大的分子间相互作用力可能会导致释放受阻, 实现这种平衡对于设计有效的经皮给药系统至关重要^[47]。

为了实现在压敏胶中的高载药量和控制药物释放, Zhang等^[48]合成了一种具有羟苯基的压敏胶(HP-PSA), 选择8种R₃N型、R₂NH型和无N型结构的模型药物, 研究结果表明HP-PSA与R₃N型或R₂NH型药物之间形成了双离子型氢键, 强度大于普通氢键, 导致载药量变高、药物从压敏胶中释放速率减慢, 但不影响总的释放性能, 从而达到长效缓控释的目的(图2)。Luo等^[49]通过自由基引发的溶液聚合法合成了含有酰胺基团的聚丙烯酸酯压敏胶, 选择依托度酸、酮洛芬、吉非罗齐、佐米曲坦、普萘洛尔和利多卡因为模型药物, 结果表明6种药物的释放速率均随压敏胶中酰胺基团浓度的增加而降低, 然而只有佐米曲坦和普萘洛尔的经皮渗透率降低。进一步的机制研究揭示药物分子会与压敏胶中的酰胺基团发生相互作用, 当药物分子从透皮贴剂中释放出来时, 主要受药物与酰胺基团之间的氢键相互作用的调控, 同时还受压敏胶的自由体积的影响。酰胺基团不仅与药物直接相互作用, 还降低了压敏胶分子链的热运动和自由体积, 同样导致药物释放变慢。Nan等^[50]从压敏胶的分子运动性、压敏胶与药物的分子间相互作用两方面系统地阐明了金属配位的聚丙烯酸酯压敏胶中药物释放的分子机制, 以酮洛芬和多奈哌齐为模型药物, 研究发现在酮洛芬的控释过程中起主导作用的是压敏胶与药物之间的氢键相互作用, 而不是压敏胶的分子运动性, 而铁离子与酮洛芬之间的配位键相互作用进一步减缓了酮洛芬的释放。

药物与压敏胶之间形成的范德华力和偶极-偶极相互作用也会影响药物的释放, Ding等^[51]研究发现这些相互作用减小了聚异丁烯压敏胶的分子运动性和自由体积, 从而阻碍了药物在压敏胶中的释放。Liu等^[52]合成了具有羟基的压敏胶, 以6种理化性质不同但分子体积相近的药物为模型, 采用回归分析方法对其理化性质与释放行为之间的关系进行了研究, 结果表明载药量为2.0%的贴剂中药物的释放行为与药物分子的极化率和logP (分别指代偶极-偶极相互作用和亲脂性) 相关。接着, 通过傅里叶变换红外光谱结果, 推断偶极-偶极相互作用和logP是药物释放行为的主要调控因素。

Yang等^[53]制备了5种含有不同羧基官能团数量的聚丙烯酸酯压敏胶, 体外释放实验表明普萘洛尔的释放行为随着压敏胶中羧基官能团数量的增加而减少, 随着药物-压敏胶离子相互作用强度的增加而线性下降。在另一项研究中, 使用一种药物-离子液体策略来增加药物在压敏胶中的载药量, 经强离子型氢键与普通氢键的协同作用使得压敏胶的载药量提高了5.0倍, 同时表现出优越的药物释放性能^[54]。同样使用离子液体策略, 在研究包含氟比洛芬-利多卡因离子液体的透皮贴剂的释放机制时, 发现具有低介电常数的压敏胶主要通过偶极-偶极相互作用、氢键与药物相互作用, 具有高介电常数的压敏胶主要通过离子键、离子型氢键与药物相互作用^[55]。

3.2　药物-压敏胶-透皮吸收促进剂的分子间相互作用对药物释放过程的影响

透皮吸收促进剂是指一种能暂时性的调节皮肤通透性的物质, 能可逆地改变角质层的屏障功能, 增强药物经皮透过性的一类物质。目前使用的透皮吸收促进剂包括: 水、二甲基亚砜、吡咯酮类、脂肪酸及其酯、Azone及其衍生物、表面活性剂、尿素及其衍生物、醇类、萜类等^[56]。

药物、压敏胶和透皮吸收促进剂之间的分子相互作用也会对药物的释放产生影响。Zhang等^[57]合成了一种含有羟苯基的新型压敏胶, 以多奈哌齐为模型药物, 贴剂中分别加入不同的透皮吸收促进剂, 多奈哌齐与压敏胶形成了双离子型氢键, 导致在压敏胶中药物的溶解性增加, 处方中加入含有酯基的透皮吸收促进剂可与多奈哌齐形成弱的氢键, 促进药物的释放, 处方中加入含有羧基的油酸可与多奈哌齐形成强的离子型氢键, 导致药物的释放变慢, 处方中加入含有羟基的透皮吸收促进剂可与多奈哌齐形成强的氢键, 基本不影响药物的释放速率。Song等^[58]研究透皮吸收促进剂在酒石酸比索洛尔(BSP-T) 贴剂释放中的作用, 实验结果表明, 一方面, Span等吸收促进剂具有较强的形成氢键的能力, 可能会干扰BSP-T与压敏胶之间的氢键作用, 从而降低二者的相互作用, 有利于BSP-T从压敏胶中释放出来; 另一方面, 透皮吸收促进剂还促进了压敏胶自由体积的形成, 加快BSP-T从压敏胶中的释放过程。

4　分子间相互作用对贴剂中药物经皮渗透过程的影响

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4.1　药物经皮吸收的途径

药物经皮吸收进入体循环的途径包括经表皮途径和经附属器途径, 由于皮肤附属器占角质层面积的比例很小, 因此, 经表皮途径是大部分药物经皮吸收的主要途径, 但是对于一些离子型药物或者纳米载体, 经皮肤附属器途径是其透过皮肤的重要途径^{[59, 60]}。经表皮途径又可分为跨细胞途径和细胞间途径, 前者药物穿过角质细胞到达活性表皮, 后者药物通过角质层中的细胞间脂质双分子层到达活性表皮。由于角质细胞渗透性低, 且药物通过跨细胞途径时需经多次亲水/亲脂环境的分配过程, 所以跨细胞途径在经表皮途径中只占极小部分^[61]。

角质层位于表皮的最外层, 是大多数物质经皮吸收的最主要屏障, 具有致密的“砖-泥浆”结构, 细胞间脂质被认为是“泥浆”, 具有高度不溶性角质化包膜和角蛋白的角质细胞被认为是“砖”, 通过桥粒和紧密连接相连^[62-64]。首先, 桥粒和紧密连接形成的致密结构导致角质层中的细胞间隙较小, 限制了蛋白质等大分子药物的渗透; 其次, 角质细胞的角质化包膜和细胞间脂质层都是脂溶性的, 从而限制了水溶性药物对皮肤的渗透, 而脂溶性药物可以绕过角质细胞, 通过细胞间脂质层进行扩散, 当然, 这并不意味着只要药物是脂溶性的, 它就可以通过角质层, 因为角质层不是一个完全脂溶性的环境。角质层中的角蛋白含有天然保湿因子, 可为角质层提供约20%的水合作用^[65]。水性的活性表皮层和真皮层很多时候不是经皮吸收的主要限速步骤, 与完整皮肤相比, 去角质层皮肤(包含活性表皮层和真皮层) 用于体外经皮渗透实验时, 很多药物的渗透速率会增加, 时滞常会减小, 但部分脂溶性过大的药物倾向于留在角质层而非分配进入皮肤深层和体循环, 从而表现为经皮渗透性能减小^{[66, 67]}。因此, TDDS对药物的理化性质有很高的要求, 包括适当的logP值、溶解性、分子质量等^[68]。

4.2　药物-皮肤成分间相互作用对药物渗透过程的影响

角质层中的细胞间脂质主要由神经酰胺(约占40%~50%)、胆固醇(约占20%~30%) 及游离脂肪酸(约占7%~13%) 组成^[69], 神经酰胺属于鞘脂家族, 由极性头部和不饱和的疏水性脂肪链组成, 形成很强的分子间氢键, 维持细胞间脂质层状结构和角质层屏障的稳定性。此外, 位于角质细胞内的角蛋白呈现极性和非极性的两亲性特征, 因此, 神经酰胺为主的细胞间脂质和角蛋白都会影响药物的经皮渗透^[70], 含有氢键受体或供体的药物可与角质层中的脂质结合, 形成强、中、弱的分子间相互作用, 促进或者抑制药物经皮渗透过程。适当强度的药物-皮肤成分间相互作用有利于干扰细胞间脂质的有序排列, 从而促进药物的经皮吸收。

药物的分子结构跟经皮渗透性密切相关, 在角质层中, 具有4′-OH结构的黄酮类化合物能够借助4′-OH与神经酰胺中的C=O相互作用, 从而提高其与神经酰胺的混溶性, 扰乱脂质的有序排列, 从而增加黄酮类化合物的经皮渗透性(图3)^[71]。Zhang等^[72]研究氟比洛芬对映异构体的经皮渗透差异性, 发现手性氟比洛芬的经皮渗透性差异不是由药物的理化性质引起的, 而取决于药物和皮肤成分之间的相互作用, (S)-氟比洛芬由于其立体构型, 容易与皮肤脂质的-CONH基团形成更强的氢键, 更容易扰乱脂质排列, 另外, (S)-构型氟比洛芬比(R)-构型更容易与角蛋白相互作用, 将角蛋白的α-螺旋结构转化为β-折叠结构, 使角质细胞更具渗透性, 实验结果表明, (S)-氟比洛芬的经皮渗透和滞留量是(R)-构型的1.5倍。

近年来, 离子液体应用于经皮给药系统的研究日益增多, 药物的性质(溶解度、渗透性等) 可以通过带相反电荷的反离子进行有利调节。Ren等^[73]采用离子液体和控释聚合物策略制备了阿塞那平72 h长效透皮贴剂, 经ATR-FTIR、拉曼光谱和分子动力学模拟等确证阿塞那平和3-甲氧基丙酸组成的离子液体能够影响角质层脂质的流动性、改变角蛋白的构象, 从而增加经皮渗透速率。类似的, 低共熔溶剂是由两种或多种物质按一定比例混合而成的低熔点混合溶剂, 其熔点显著低于每一个单组分的熔点。有研究者制备了3种基于米氮平和中链脂肪酸(C₁₀~C₁₂) 的低共熔溶剂用于米氮平的经皮给药, ATR-FTIR结果证明低共熔溶剂策略促进药物经皮渗透的机制是干扰角质层中脂质的有序排列, 脂质结构紊乱程度越大, 能更好地促进药物通过角质层^[74]。

由静电相互作用结合的两个带相反电荷的离子形成的离子对是实现药物经皮递送的有效策略。一方面, 对于渗透性较差的药物, 离子对的形成可以促进透皮吸收; 另一方面, 对于高渗透性的药物, 可以降低其渗透速率, 达到长效治疗的效果。有研究表明, 胍法辛和辛酸组成离子对后, 具有改变皮肤脂质结构的作用, 增强胍法辛的经皮渗透效果^[75]。Li等^[76]通过离子对策略研制一种含有反离子(肉桂酸等) 的高乌甲素透皮贴剂, 研究发现反离子增加高乌甲素经皮渗透的原因是反离子与高乌甲素结合形成离子对后, 反离子与皮肤中的角蛋白形成氢键等相互作用, 使角蛋白从α-螺旋向β-折叠转变, 削弱了角质层的屏障功能, 从而增加药物的经皮吸收。为了实现长效缓释, 有研究将比索洛尔与不同的有机酸制成离子对, 体外经皮渗透速率显著减少, 动物药代动力学实验表明, MRT_0-t延长, 血药浓度更加平稳, 离子对和皮肤角质层之间的相互作用是不同离子对渗透速率差异的主要原因^{[77, 78]}。

4.3　药物-透皮吸收促进剂-皮肤成分间相互作用对药物渗透过程的影响

应用透皮吸收促进剂是改善药物经皮渗透的重要方法^{[79, 80]}, 透皮吸收促进剂在处方中的用量会影响促透效果, 添加量太少, 促透作用不明显, 用量过大则可能引起皮肤的刺激性和过敏性。透皮吸收促进剂通过多种机制增强药物的经皮吸收: ①与角质层的脂质相互作用, 破坏脂质的有序排列或增加脂质的流动性; ②作用于角质细胞内的角蛋白, 促进水合作用^[81]; ③溶解角质层中的脂质, 降低角质层的屏障功能; ④增加药物在脂质层中的溶解度, 从而促进药物分配进入角质层^[82]。

Wang等^[83]研究了7种透皮吸收促进剂对10种甘草黄酮类化合物的促渗透作用, 发现辣椒素、聚甘油-3二油酸酯(polyglyceryl-3 dioleate, POCC) 对角质层脂质的流动性、角质层水损失、皮肤表面结构的变化影响最大, 因而促渗透作用最强。辣椒素和POCC的这种促渗透作用跟甘草黄酮类的logP相关, 对低渗透性药物有更高的促渗透作用, 机制研究表明, 辣椒素能完全占据药物-皮肤成分相互作用位点, POCC只能占据大部分的药物-皮肤成分相互作用位点, 因此, 调节角质层脂质的流动性、药物-透皮吸收促进剂-皮肤成分之间的相互作用可以控制药物的经皮渗透性。

冰片是一种中药来源的透皮吸收促进剂, 研究表明其对低脂水分配系数、高分子质量的药物的促渗透作用更明显, 通过改变角质层的致密形态, 扰乱神经酰胺和游离脂肪酸分子在脂质层中的有序排列, 进一步提高药物在脂质层中的扩散速率, 促进药物的透皮吸收^[84]。Xu等^[85]以POCC为吸收促进剂, 研究其对10种不同理化性质的药物的促渗透作用, 结果表明其对各种药物的促渗比在2.23~7.45之间, 药物-POCC-皮肤成分间不同强度的相互作用是导致不同促渗比的主要原因, POCC对具有低极性表面积和极化率(代表偶极-偶极相互作用的强度) 的药物的促渗作用更强是因为这些药物与皮肤中的脂质相互作用(氢键、偶极-偶极相互作用等) 的可能性更小, 导致POCC更易与皮肤中的脂质相互作用, 扰乱脂质的有序排列, 从而增加药物透过角质层。

5　展望

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经皮给药系统作为一种非侵入式给药, 具有独特的优点, 尤其适用于儿童与老人等, 因此, 在临床上的应用日益增多, 受到了制药工业领域的广泛关注。然而, 由于皮肤强大的屏障作用, 即使是有效剂量较低的一些药物, 经皮渗透速率可能也难以满足治疗需要, 成为TDDS研发的最大障碍。近年来, 微针、离子导入、电穿孔等主动促渗透方法被大量用于经皮给药系统的研究, 然而由于这些技术制备工艺复杂或者成本较高, 目前基本没有相关产品上市。以透皮贴剂为代表的经皮给药系统仍然主要应用透皮吸收促进剂、离子对和改变压敏胶种类等策略优化处方, 提高药物的经皮吸收。

分子间相互作用在经皮给药系统中扮演了多重角色, 直接影响药物从贴剂中的释放和渗透过皮肤。分子间相互作用调控经皮给药系统中药物释放和渗透的研究取得了一定的进展, 未来可以应用一些更加先进的表征技术, 例如人工智能与大数据、质谱成像结合光谱成像、Flory-Huggins模型等, 深入研究药物、压敏胶、透皮吸收促进剂、皮肤成分之间的相互作用的动态变化规律, 加深对贴剂中药物经皮吸收分子机制的理解, 为新型经皮给药系统的处方设计与优化提供理论指导。

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2025年第60卷第12期

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doi: 10.16438/j.0513-4870.2025-0613

接收时间：2025-05-29
首发时间：2026-09-20
出版时间：2025-12-12

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收稿日期：2025-05-29
修回日期：2025-06-27

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江西科技师范大学药学院, 江西南昌 330013

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陈振华, E-mail: zhenhuachen@jxstnu.edu.cn

李阳彪, E-mail: liyangbiao1985@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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