药学学报

Category	Key factor	Impact mechanism/characteristy	Ref.
Skin physiology	SC thickness	Eyelid/post-auricular < forehead < forearm < palm/sole; thickness increases inversely correlating with permeation efficiency	[17]
Skin integrity	Compromised barrier function in wounded / diseased skin substantially increases permeation	[17]
Hydration level	Increased hydration expands corneocytes and disorders intercellular lipids, enhancing permeation	[17]
Skin temperature	Elevated temperature increases cutaneous blood flow, lipid fluidity, and molecular diffusion coefficients, collectively improving permeation	[17]
Disease state	Altered skin structure and permeability (e.g., hyperkeratosis in psoriasis; barrier defect in eczema)	[17]
Drug factors	Age	Infantile skin (thinner barrier) shows higher permeation; aged skin (atrophic, reduced perfusion) exhibits decreased absorption	[17,18]
Molecular weight	Less than 500 Da	[17,18]
Lipophilicity (log P)	LogP 1-3 optimal for stratum corneum penetration; high logP causes stratum corneum retention; low logP limits lipid partitioning	[17,18]
Dissociation state	Non-ionized molecules penetrate better; ionized drugs require iontophoresis	[17,18]
Melting point	Less than 200 ℃	[17,18]
Patches/cataplasms	High drug-loading capacity and strong adhesion; occlusive effect promotes skin hydration	[17,18]
Dosage form	Ointments/creams	Oleaginous bases facilitate lipophilic drug delivery; oil-in-water emulsions enhance hydrophilic drug release	[17,19]
Gels	Hydrophilic matrix enables easy application and favors hydrophilic drug release	[17,19]
Liniments	Ethanol content disrupts stratum corneum lipids; enables rapid drug onset	[17,19]

Category	Key factor	Impact mechanism/characteristy	Ref.
Skin physiology	SC thickness	Eyelid/post-auricular < forehead < forearm < palm/sole; thickness increases inversely correlating with permeation efficiency	[17]
Skin integrity	Compromised barrier function in wounded / diseased skin substantially increases permeation	[17]
Hydration level	Increased hydration expands corneocytes and disorders intercellular lipids, enhancing permeation	[17]
Skin temperature	Elevated temperature increases cutaneous blood flow, lipid fluidity, and molecular diffusion coefficients, collectively improving permeation	[17]
Disease state	Altered skin structure and permeability (e.g., hyperkeratosis in psoriasis; barrier defect in eczema)	[17]
Drug factors	Age	Infantile skin (thinner barrier) shows higher permeation; aged skin (atrophic, reduced perfusion) exhibits decreased absorption	[17,18]
Molecular weight	Less than 500 Da	[17,18]
Lipophilicity (log P)	LogP 1-3 optimal for stratum corneum penetration; high logP causes stratum corneum retention; low logP limits lipid partitioning	[17,18]
Dissociation state	Non-ionized molecules penetrate better; ionized drugs require iontophoresis	[17,18]
Melting point	Less than 200 ℃	[17,18]
Patches/cataplasms	High drug-loading capacity and strong adhesion; occlusive effect promotes skin hydration	[17,18]
Dosage form	Ointments/creams	Oleaginous bases facilitate lipophilic drug delivery; oil-in-water emulsions enhance hydrophilic drug release	[17,19]
Gels	Hydrophilic matrix enables easy application and favors hydrophilic drug release	[17,19]
Liniments	Ethanol content disrupts stratum corneum lipids; enables rapid drug onset	[17,19]

Category

Key factor

Impact mechanism/characteristy

Ref.

Skin physiology

SC thickness

Eyelid/post-auricular < forehead < forearm < palm/sole; thickness increases inversely correlating with permeation efficiency

[17]

Skin integrity

Compromised barrier function in wounded / diseased skin substantially increases permeation

[17]

Hydration level

Increased hydration expands corneocytes and disorders intercellular lipids, enhancing permeation

[17]

Skin temperature

Elevated temperature increases cutaneous blood flow, lipid fluidity, and molecular diffusion coefficients, collectively improving permeation

[17]

Disease state

Altered skin structure and permeability (e.g., hyperkeratosis in psoriasis; barrier defect in eczema)

[17]

Drug factors

Age

Infantile skin (thinner barrier) shows higher permeation; aged skin (atrophic, reduced perfusion) exhibits decreased absorption

[17,18]

Molecular weight

Less than 500 Da

[17,18]

Lipophilicity (log P)

LogP 1-3 optimal for stratum corneum penetration; high logP causes stratum corneum retention; low logP limits lipid partitioning

[17,18]

Dissociation state

Non-ionized molecules penetrate better; ionized drugs require iontophoresis

[17,18]

Melting point

Less than 200 ℃

[17,18]

Patches/cataplasms

High drug-loading capacity and strong adhesion; occlusive effect promotes skin hydration

[17,18]

Dosage form

Ointments/creams

Oleaginous bases facilitate lipophilic drug delivery; oil-in-water emulsions enhance hydrophilic drug release

[17,19]

Gels

Hydrophilic matrix enables easy application and favors hydrophilic drug release

[17,19]

Liniments

Ethanol content disrupts stratum corneum lipids; enables rapid drug onset

[17,19]

跨越皮肤屏障: 中药高效经皮递送的研究与应用探讨

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曾莉娟 , 吴雨歌 , 李亚梅 , 王著显 , 刘强 ^*

药学学报 | 综述 2026,61(4): 1107-1119

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药学学报 |综述 2026 , 61 (4) : 1107 -1119

跨越皮肤屏障: 中药高效经皮递送的研究与应用探讨

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曾莉娟, 吴雨歌, 李亚梅, 王著显, 刘强^*

作者信息

南方医科大学中医药学院, 广东广州 510515

通讯作者:

刘强, Tel: 13189091968, E-mail: liuqiang@smu.edu.cn

作者简介:

作者贡献:

曾莉娟负责综述撰写工作; 吴雨歌、李亚梅、王著显负责提供修改意见; 刘强负责指导论文撰写、修改论文并定稿。

Overcoming the skin barrier: Advances in efficient transdermal delivery of traditional Chinese medicine

Li-juan ZENG, Yu-ge WU, Ya-mei LI, Zhu-xian WANG, Qiang LIU^*

Affiliations

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China

出版时间: 2026-04-12 doi: 10.16438/j.0513-4870.2025-0775

文章导航

摘要

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中药经皮递送系统凭借其避免肝脏首过效应、维持稳定血药浓度、提高患者依从性及长效缓释等优势, 已成为替代传统给药方式的重要选择, 尤其适用于慢性疾病治疗。然而, 皮肤角质层的“砖墙结构”屏障与中药有效成分的复杂性严重制约了中药经皮递送效率, 并增加了质量控制与机制研究的难度。为突破上述瓶颈, 近年来微针、纳米载体(脂质体、纳米乳、聚合物纳米粒、纳米晶体及自组装纳米胶束)、促渗剂、离子导入、超声等技术为中药高效经皮递送提供了新策略, 促渗技术联用突破单一技术局限。这些技术在皮肤病治疗、疼痛管理和伤口愈合等领域展现出显著的临床价值。

关键词

中药 / 经皮递送 / 角质层 / 促渗 / 新技术

Abstract

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The transdermal delivery system of traditional Chinese medicine (TCM) has emerged as a vital alternative to conventional administration routes, particularly for chronic disease management, owing to its advantages in avoiding hepatic first-pass effects, maintaining stable blood drug concentrations, improving patient compliance, and enabling sustained release. However, the efficiency of TCM transdermal delivery is significantly constrained by the "brick-and-mortar structure" barrier of the stratum corneum and the inherent complexity of TCM components, which also complicates quality control and mechanistic studies. To address these challenges, innovative strategies have been developed in recent years, including microneedles, nanocarriers (liposomes, nanoemulsions, polymeric nanoparticles, nanocrystals and self-assembled nanomicelles), permeation enhancers, iontophoresis, and sonophoresis. Synergistic permeation-enhancing strategies further overcome limitations of single-technique approaches. These technologies demonstrate substantial clinical value in dermatological therapy, pain management, wound healing, and related fields.

Key words

traditional Chinese medicine / transdermal drug delivery / stratum corneum / penetration enhancer / new technology

引用本文

曾莉娟, 吴雨歌, 李亚梅, 王著显, 刘强. 跨越皮肤屏障: 中药高效经皮递送的研究与应用探讨. 药学学报, 2026 , 61 (4) : 1107 -1119 . DOI: 10.16438/j.0513-4870.2025-0775

Li-juan ZENG, Yu-ge WU, Ya-mei LI, Zhu-xian WANG, Qiang LIU. Overcoming the skin barrier: Advances in efficient transdermal delivery of traditional Chinese medicine[J]. Acta Pharmaceutica Sinica, 2026 , 61 (4) : 1107 -1119 . DOI: 10.16438/j.0513-4870.2025-0775

正文

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中药经皮给药制剂是指采用特定的方法和基质将中药单体、中药有效成分、单味药及中药复方制备成专供外用的剂型, 通过作用于皮肤局部或经皮肤吸收进入体循环而发挥药效, 从而达到疾病治疗或预防的目的^[1-4]。其核心优势在于规避肝脏首过效应、维持稳定血药浓度、长效缓释及提高患者依从性等^[2]。相较于注射和口服途径, 经皮给药的无创特性与便捷操作使其成为理想的替代给药策略^[3]。中药经皮给药制剂涵盖贴膏剂、软膏剂、乳膏剂、凝胶剂、搽剂、酊剂等多种《中华人民共和国药典》收载剂型^[5]。然而, 皮肤作为机体首要物理屏障, 其角质层独特的“砖墙结构”^[6](由高度有序排列的神经酰胺、胆固醇、脂肪酸等脂质构成致密屏障) 对中药大分子及高极性成分形成显著渗透阻力, 成为中药经皮高效递送面临的核心挑战。

相较于化学药物, 中药经皮给药制剂更具复杂性: 有效成分不明, 制剂成型原理不清, 药物成分复杂多样, 成分理化性质差异显著。这使得中药经皮制剂的设计及高效跨越皮肤屏障的难度倍增^[7]。本文系统综述了中药经皮递送的关键特性与现存挑战, 归纳总结了近年来高效经皮递送技术的创新进展(如微针、纳米载体及促透剂协同增效等), 并分析其在皮肤病治疗、疼痛管理及伤口愈合等领域的临床应用与典型案例。为克服皮肤屏障限制, 提升中药的经皮渗透效率提供参考, 对中药高效经皮给药制剂的开发及应用具有指导意义。

1　中药经皮递送的特点与挑战

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1.1　成分复杂性带来的多靶点协同效应

中药制剂多由复方组成, 中药复方成分复杂, 包含了一系列具有多种药理活性的小分子化合物, 具有多样的结构框架^[8]。部分小分子化合物成分具有较好的脂溶性和分子质量适中等特点, 为经皮递送提供了物质基础。中药成分的复杂性赋予中药复方多靶点协同作用的潜力, 从多个途径对机体进行整体调节, 从综合的角度治疗多种疾病^[9]。Dai等^[10]将单味中药地榆、当归、地骨皮、大黄、地黄、甘草、白芷制备成复方地榆凝胶贴膏(中药复方), 复方地榆凝胶贴膏多成分协同增效, 使其在急慢性创面的治疗中取得良好疗效。延胡索、川乌和三七的配伍是活血化瘀的经典组合。研究发现, 三者主要中药单体成分(延胡索乙素、乌头碱、人参皂苷Rg1) 在体外透皮实验中表现出显著协同效应。苯甲酰基乌头原碱(乌头碱的低毒衍生物) 与延胡索乙素联用, 可延长镇痛作用时间并减少皮肤刺激, 体现了中药复方在增效与减毒中的双重优势^[11]。Jiang等^[12]将中药单体甘草酸与青藤碱配伍, 制备青藤碱-甘草酸自组装纳米水凝胶。该体系中, 青藤碱通过抑制NF-κB通路减少TNF-α、IL-6等促炎因子分泌, 而甘草酸可阻断MAPK信号通路, 进一步降低IL-1β和COX-2表达, 形成双重抗炎效应, 显著抑制炎症反应并提高关节靶向性。该研究验证了中药成分“1+1 > 2”的多靶点协同效应, 为中药复方制剂的现代化设计提供了新思路。

1.2　作用机制与质量控制的复杂性

中药复方制剂成分复杂, 活性成分不明确或难以明确, 不同批次的药材及不同生产工艺使得中药在有效成分含量、杂质等方面可能存在差异, 这增加了质量控制的难度^[13]。缺乏完善的质量评价标准是制约中药产业发展的重要因素^[14], 同时也限制了中药经皮给药的发展。目前, 对于中药经皮递送系统的质量评价方法和指标体系尚不统一, 难以全面、客观地评估其疗效和安全性。

尽管多成分的协同作用赋予了中药显著的优势和独特的治疗特性, 但复杂的成分也在阐明生物机制、质量控制和标准化方面带来了挑战^[8], 这也给中药经皮给药制剂的研究带来了非常大的困难^[15]。中药及复方的多组分、成分间的相互作用及有效成分的不确定使经皮递送的研究更为复杂^[11]。在中药经皮递送系统中, 有效成分与透皮载体的相互作用、有效成分与制剂辅料间的相互作用及有效成分的稳定性等也需要严格控制, 难以明确的有效成分及不清楚的作用机制使中药经皮给药的产业发展具有极大的挑战性。

1.3　治疗效果的温和性

中药治疗的核心优势在于其多靶点网络调控与系统性稳态调节作用, 表现为温和、累积的药效特征。这一特性赋予其显著的安全性优势、长期恢复生理稳态的能力及不易诱发耐药性的特点。然而, 温和性亦导致其起效相对缓慢, 在应对急重症时疗效不及现代药物精准快速, 且生物利用度局限进一步制约临床应用^[8]。

1.4　中药经皮递送的局限性

皮肤角质层是药物经皮吸收的主要屏障, 其“砖墙结构”使得大多数药物难以透过, 从而限制了中药经皮递送的效率^[16]。表1^[17-19]概括了影响中药经皮吸收的主要因素, 如皮肤生理因素、药物因素及剂型因素。中药复方成分的复杂性增加了经皮递送的难度; 70%的天然草药产物具有疏水特性, 导致溶解度低, 生物利用度受限^[20]; 许多中药有效成分分子质量较大、极性较高, 导致其透皮能力相对较弱。中药复方中不同成分之间的极性差异导致溶解度波动, 使其经皮递送面临巨大的挑战。例如, 黄芩苷是一种从中药黄芩中提取的黄酮类化合物, 具有优异的抗氧化性能, 使其成为化妆品领域的“潜力股”。然而黄芩苷分子质量较大, 使其难以渗透皮肤屏障, 可能导致局部浓度过高, 引发皮肤刺激, 从而限制其在皮肤领域的应用^[21]。三七总皂苷是中药三七的有效成分, 其主要单体成分为人参皂苷Rb1、人参皂苷Rg1、人参皂苷Re、三七皂苷R1等, 具有活血祛瘀, 通脉活络等功效, 但由于其分子质量大且极性较强, 不利于透过皮肤屏障被吸收^[16]。葛根素(分子质量416.38, logP = -0.35) 和京尼平苷(分子质量388.37, logP = -1.01) 由于更大的分子质量和极性, 其透皮效率显著低于蛇床子素(分子质量244.29, logP = 3.85)、川芎嗪(分子质量136.19, logP = 2.34)、阿魏酸(分子质量194.18, logP = 1.26)^[22]。部分中药有效成分具有特殊的化学性质, 容易在皮肤表面发生降解或失活, 进一步降低了其经皮吸收的效果。中药挥发油类成分(如高良姜油、干姜油) 含有大量萜类物质, 兼有促进渗透与治疗疾病的双重特点, 但其化学性质极不稳定, 易氧化失活, 导致制剂稳定性下降^[23]。中药复方成分复杂, 多种有效成分之间在经皮递送过程中存在相互之间的影响。复方成分的相互作用也可能加剧不稳定问题, 如延胡索乙素与乌头碱共存时虽可协同增效, 但复方中极性差异可能引发溶解度波动, 进一步限制透皮速率^[11]。皮肤活性表皮内含有多种药物代谢酶, 可使药物分解^[11]。

1.5　大剂量需求与载药/递送效率的瓶颈

除皮肤屏障外, 中药经皮制剂还普遍面临“高剂量-低载药”矛盾, 而剂量偏大的根本原因是外用经皮递送效率太低。复方每日生药量常达数克, 远超化学透皮贴片的毫克级负荷。致密的角质层对分子质量 > 500 Da、极性高的药物渗透效率低下。即使制剂载药量高, 药物透皮速率慢也可能导致皮肤表面浓度饱和(漏槽效应不足), 限制持续渗透。因此, 如何兼顾载药容量、经皮递送效率与皮肤耐受性是解决中药大剂量经皮给药的关键。

2　提高中药经皮递送效率的策略与热点技术

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2.1　微针技术

微针(microneedles, MNs) 是一种基于物理促渗机制的新型透皮递送技术, 其结构由微米级针尖(通常100~3 000 μm) 以高密度阵列形式集成于基底材料表面构成^[24]。针体几何参数(如长度、直径、锥角) 可根据药物理化性质及治疗靶点需求进行精准调控, 例如针对角质层穿透深度优化或局部病灶的缓释设计。微针通过机械穿刺在角质层形成瞬时微孔道, 既克服了皮肤屏障对药物渗透的限制, 又避免了传统注射针触及真皮层神经与毛细血管引发的疼痛或出血风险^[2,25]。根据微针在皮肤内释放药物原理的不同, 可分为固体微针、空心微针、涂层微针、可溶微针和水凝胶微针5种(图1)^[26]。中药微针既具备了中药的天然益处又兼具微针在经皮递送的独特优势, 使中药有效成分更易渗透进入皮肤深层而增加药物吸收, 发挥治疗效果^[27]。值得注意的是, 微针穿刺形成的微孔道可为后续高载药量或高浓度制剂的渗透提供低阻力通道。通过改变微针的结构设计(如增加微针长度、宽度等) 及改变微针的材料选择, 可提高微针的载药容量及载药效率, 使其成为解决大剂量中药经皮递送瓶颈的关键技术^[25]。

近年来, 微针技术作为突破皮肤屏障的关键策略, 在中药经皮递送领域展现出显著优势。从材料设计与功能整合角度, 可溶性微针因其生物相容性高、递送精准的特点成为研究热点。例如, 透明质酸基可溶性微针负载侧柏叶提取物, 通过光交联技术构建具有双网络结构的水凝胶微针, 其机械强度达3.5 MPa, 可穿透角质层直达真皮层, 并通过释放PO-ex激活Wnt/β-catenin通路, 通过“机械刺激-药物协同”双重作用机制显著促进毛囊再生(毛发密度提升228%)^[28]。槲皮素是从水果和蔬菜中提取的类黄酮, 具有出色的抗氧化和抗衰老特性; 葛根素是从葛根中分离出来的异黄酮, 是一种常用的血管扩张剂, 可增加微血管血流量并促进血管生成。然而, 槲皮素和葛根素都表现出较差的水溶性, 限制了它们的实际应用。研究者们开发了铁螯合槲皮素/葛根素纳米粒子的气动微针贴剂, 显著增强了药物输送效率, 促进毛发再生^[29]。即使在较低的给药频率下, 活性微针也表现出比外用米诺地尔更好的毛发再生诱导作用, 有望成为一种有效的“抗毛囊衰老”脱发治疗新策略。Zhang等^[30]提出了一种光热响应性多孔空心微针, 用于中药的可控递送以促进伤口愈合。载有大黄素的微针能通过近红外光照加热促进药物释放, 体内外实验中表现出良好的抗菌性能和按需药物释放能力, 有效促进糖尿病伤口愈合。Luan等^[31]开发的核壳微针实现pH/光热双响应释放: 聚多巴胺-MXene核层负载雷公藤内酯(光热控释), 聚乙烯醇壳层载白芍总苷(pH响应释药)。体内实验显示, 多功能响应型核壳微针能有效减少皮肤纤维化关键因子, 改善皮肤纤维化和毛细血管病变, 具有重要的临床应用潜力。

2.2　纳米载体

2.2.1　脂质体

脂质体是以两亲性磷脂分子为核心构建的仿生型药物递送系统, 其通过分子自组装形成具有类脂双分子层结构的封闭囊泡。脂质体凭借其仿生双分子层结构与皮肤角质层脂质的高度亲和性^[32], 成为中药经皮递送的有效载体。其独特的亲水内核-疏水夹层结构特性允许同步负载亲水性和疏水性药物成分^[33,34], 因此, 对于极性差异显著的中药单体成分, 可通过脂质体实现复方多组分的共输送(图2)。脂质体通过角质层脂质融合扩大细胞间隙、重组脂质排列削弱屏障功能、以及毛囊靶向递送显著克服皮肤“砖墙”屏障^[35-37], 实现中药成分的高效经皮递送。激光共聚焦显微观察显示, 中药单体成分(如鬼臼毒素) 脂质体在毛囊皮脂腺部位的荧光强度显著高于非毛囊区域(48 h曲线下面积高1.63倍), 表明毛囊皮脂腺是脂质体递送的高效通道^[38]。此外, 对脂质体进行表面修饰, 可达到细胞或受体靶向的目的, 且修饰后的脂质体可以增加药物的皮内滞留量, 提升经皮递送效率^[39]。

马钱子碱是中药马钱子(马钱子科) 的苦味生物碱之一, 是一种有效的镇痛和抗炎药, 可缓解关节炎和创伤性疼痛, 但由于其不良反应发生率较高而限制了临床应用^[40]。研究发现, 将马钱子碱制备成脂质体水凝胶可显著促进马钱子碱的皮肤渗透, 且对完整皮肤和破损皮肤均无刺激性, 为马钱子碱的新剂型研发和临床应用提供了理论依据^[41]。Liu等^[42]将中药活性单体成分豆蔻明与脂质体技术结合, 显著提高了难溶性中药单体豆蔻明的经皮渗透能力和毛囊靶向能力。动物试验研究表明, 豆蔻明负载脂质体制剂可促进毛发生长, 加速毛囊向生长期转化, 其效果优于对照组和已上市的米诺地尔制剂, 且对皮肤无明显刺激性, 为抗雄激素性脱发提供了优越的递送系统。Altamimi等^[43]研究了木犀草素弹性脂质体(使用Span 80为表面活性剂) 的优化制备及其用于经皮递送控制乳腺癌的效果。结果显示, 与药物混悬液相比, 优化的脂质体配方显著促进了木犀草素的经皮渗透。优化的脂质体配方24 h经皮累积渗透量是药物混悬液的6.2倍, 且皮肤中药物滞留量是药物混悬液的4.5倍, 证明弹性脂质体是提升疏水性中药单体成分(如木犀草素) 经皮递送效率的有效策略。

2.2.2　纳米乳

纳米乳是由油相、水相、表面活性剂及辅助表面活性剂按特定比例自发形成的热力学稳定胶体分散体系, 其粒径范围通常为10~100 nm, 具有透明或半透明、低黏度及各向同性的特征(图3) ^[39,44]。该体系通过表面活性剂分子在油水界面的定向排列实现稳定, 其核心优势包括低毒性、无刺激性、长期稳定性及增强靶向作用, 适用于多种给药途径, 尤其在经皮递送领域备受关注^[45]。纳米乳作为中药经皮递送的高效载体, 其促渗机制通过多维度协同作用实现: 首先, 纳米乳体系通过两亲性结构与皮肤角质层脂质双层高度相容, 显著提升脂质流动性并改变其排列密度, 诱导脂质双分子层发生扭曲或松散化, 从而削弱角质层屏障功能^[39,44]; 其次, 表面活性剂作为核心促渗成分, 通过增加药物浓度梯度、降低皮肤界面张力, 促进中药有效成分在皮肤褶皱及微观间隙中的沉积与渗透, 缩短递送时滞^[45]。此外, 纳米乳的超低界面张力特性使其与皮肤紧密贴合^[44], 形成药物储库效应, 增强难溶性中药有效成分(如黄酮类、萜类) 的溶解度和跨膜扩散效率。研究发现, 纳米乳可掩盖油性药物的不良气味, 增强患者依从性, 并对中药易水解或氧化成分提供稳定性保护, 从而提高生物利用度与治疗效果^[46]。

木香作为传统草药在临床中应用广泛, 但其核心活性单体成分(如木香酯、去氢木香酯) 因低水溶性和化学不稳定性, 严重制约了制剂的开发, 使其显著的镇痛、抗炎等药理活性尚未得到充分挖掘。Zhang等^[47]将木香提取物的制备成纳米乳, 体外渗透测试表明, 木香提取物纳米乳中木香酯和去氢木香酯的渗透比分别约为木香提取物水溶液的6.33和8.20倍。药代动力学研究显示, 与水溶液相比, 木香提取物纳米乳经皮给药后, 木香酯和去氢木香酯的血浆浓度更高, 释放时间更长, 体内生物利用度更高。此外, 皮肤刺激性测试表明木香提取物纳米乳对完整皮肤和破损皮肤均安全, 具有良好的经皮递送潜力。Chen等^[48]设计了一种复方丹参-艾纳香纳米乳凝胶, 其在体外展现了优异的稳定性和皮肤渗透性。与物理混合物相比, 纳米乳凝胶在体内显著增强了抑制瘢痕形成的能力, 且治疗后瘢痕更趋平坦、粉色且柔软, 胶原蛋白Ⅰ/Ⅲ比值和TGF-β1及Smad2蛋白水平降低, 同时促进了微血管的生长和重塑, 表明复方丹参-艾纳香纳米乳凝胶有望有效解决皮肤屏障特性问题, 为肥厚瘢痕的预防和治疗提供新策略。He^[49]研究表明, 草乌甲素纳米乳可显著增强药物的透皮吸收效率与制剂稳定性, 进一步将其制备为凝胶贴膏剂型后, 不仅优化了经皮渗透性能, 还可实现缓释效应, 为类风湿性关节炎的治疗提供了新型递送策略。雷公藤甲素是雷公藤的有效成分之一, 研究发现, 雷公藤甲素纳米乳凝胶12 h经皮累积渗透率显著高于其普通软膏剂^[50]。大鼠体内结果显示, 雷公藤甲素纳米乳凝胶在皮肤中的浓度显著高于血液, 且高于其普通软膏剂, 表明雷公藤甲素纳米乳凝胶具有良好的经皮递送效果, 为中药经皮递送系统研究提供了新技术和方法。

2.2.3　聚合物纳米粒

聚合物纳米粒是由生物可降解的合成聚合物(如聚乳酸、聚乳酸-羟基乙酸共聚物) 或天然聚合物(如壳聚糖、明胶) 构建的纳米级递送系统, 其粒径范围通常为10~1 000 nm^[51]。根据结构差异可分为两类: 纳米囊(含液体/半固体载药核心与聚合物外壳) 和纳米球(完全由聚合物基质构成的固体颗粒) (图4) ^[44]。聚合物纳米粒凭借其生物黏附性、低刺激性及对光、pH等环境因素的稳定性^[52], 可有效保护易降解的中药有效成分(如酚类化合物绿原酸), 并通过分子亲和性增强药物的负载与递送效率, 为中药复方复杂成分的经皮递送提供了兼具保护性与靶向性的创新解决方案。研究表明, 完整聚合物纳米粒因粒径限制难以通过被动扩散穿透致密角质层^[53], 但可通过以下机制增强中药有效成分透皮效率^[54]: ①毛囊靶向与储库效应: 纳米粒优先聚集于毛囊及皮肤褶皱处, 作为药物缓释载体持续释放活性成分, 局部高浓度梯度驱动药物向深层组织扩散; ②表面理化特性调控: 聚合物纳米粒与皮肤相互作用影响其在皮肤中的分布与渗透, 进而影响经皮渗透效率。纳米粒表面电荷(如阳离子修饰) 可增强与皮肤负电荷区域的相互作用, 提升药物释放量^[55]。

研究表明, 聚合物纳米粒可有效调控药物在皮肤中的分布与滞留, 增强局部贮留并实现缓释效果^[56-58]。Caon等^[56]研究了基于脂质和聚合物的纳米结构对姜黄素经皮递送的影响, 发现聚乳酸-羟基乙酸共聚物纳米粒能显著增强姜黄素在表皮的保留, 分别比姜黄素固体脂质纳米粒和纳米乳高出2.49和3.32倍, 表明共聚物纳米粒可调控姜黄素在皮肤中的分布和保留。Wang等^[58]制备了补骨脂素聚乳酸-羟基乙酸共聚物纳米粒并研究其对人体皮肤的渗透特性, 发现该纳米粒具有良好的释放性能, 在人体皮肤中具有明显的缓控释特征, 能增加药物在皮肤中的贮存量, 有望成为降低补骨脂素光化学疗法毒副作用的新型经皮给药制剂。

2.2.4　纳米晶体

纳米晶体技术通过将药物分子与稳定剂(如非离子聚合物或离子表面活性剂) 直接构成为100~1 000 nm的纳米级分散体系, 开创了“无载体”递送新模式^[59,60]。该技术为中药难溶性成分的经皮递送提供有效解决方案, 其核心优势包括: ①高载药量, 因不含额外载体, 药物负载量高(接近100%), 可在治疗部位实现高局部浓度^[61]; ②增溶效应, 纳米级尺寸赋予极大比表面积^[62], 显著提升难溶性中药成分的饱和溶解度和溶出速率^[61]; ③低辅料需求, 减少辅料用量, 规避传统纳米载体(如脂质体、纳米乳) 因大量辅料引发的毒副作用风险。在中药经皮递送中, 纳米晶体克服皮肤屏障, 提升难溶性成分的生物利用度的机制包括^[62,63]: ①浓度梯度驱动, 高比表面积增加药物饱和溶解度, 扩大表皮与制剂间的浓度梯度, 强化被动扩散效率; ②毛囊靶向渗透, 纳米级尺寸使其易富集于毛囊通道, 通过附属器途径将药物递送至深层皮肤, 并延长滞留时间。

中药靛玉红的纳米晶体凝胶通过电静吸附作用与透明质酸结合, 形成针对银屑病治疗的CD44靶向复合物^[64]。实验结果显示, 纳米晶体凝胶能显著提高靛玉红的皮肤渗透性且皮肤中靛玉红积累增加。此外, 在银屑病小鼠模型中, 靛玉红纳米晶体凝胶能够显著改善银屑病症状, 增强抗银屑病效果, 作为一种有效的针对银屑病的局部药物递送系统, 为治疗银屑病提供了新的方法。Li等^[65]开发了芦丁纳米晶体凝胶以改善黄酮类化合物芦丁极低水溶性导致经皮渗透性差的问题。研究发现, 芦丁纳米晶体凝胶显著增强了芦丁的经皮递送效率, 其在小鼠模型上的透皮量是粗药凝胶的3倍以上, 并在药效学研究中显示出有效的预防皮肤光老化和组织损伤的作用。Liu等^[66]采用反溶剂沉淀技术制备了野黄芩素纳米晶体, 明显改善了野黄芩素的溶出度与体外释放度。Tang等^[67]通过湿法研磨技术制备了中药丹参提取物的纳米晶体, 研究发现丹参纳米晶体能有效改善丹参提取物的经皮递送, 并可提高药物在皮肤中的累积量从而在痤疮皮损处持续释放药物。丹参纳米晶体最小抑菌浓度和最小杀菌浓度显著低于丹参粗提悬浮液, 为丹参提取物在痤疮治疗中的应用提供了新的途径。Quan等^[68]通过高压均质法制备了甘草提取物中的18β-甘草次酸纳米晶体, 并与两性壳聚糖形成复合物。结果表明, 甘草次酸纳米晶体与两性壳聚糖通过静电吸附形成的复合物能显著提高甘草次酸的经皮渗透性, 其累积渗透性从56.5%增加到75.3%。在紫外线照射诱导的小鼠皮肤光老化模型中, 复合物能有效改善光老化特征, 保护皮肤结构完整性, 抑制MMP-1和MMP-3的异常表达, 减少紫外线对胶原纤维结构的损伤, 从而有效改善小鼠皮肤光老化, 为中药经皮递送提供了新策略。

2.2.5　自组装纳米胶束

自组装纳米胶束是由两亲性分子(含亲水基团与疏水基团) 在溶液中达到临界浓度后, 通过非共价键自发形成的热力学稳定纳米聚集体^[69] (粒径通常为10~100 nm)。中药单体成分来源广泛, 其结构的特异性使其极易通过非共价相互作用而自组装形成聚集体或自组装颗粒^[70]。中药单体甘草酸、丹参酮IIA、黄芩苷等可通过氢键、静电力、范德华力、π-π相互作用、疏水相互作用等作用力自组装成胶束^[8], 无需外源性表面活性剂。自组装纳米胶束在中药经皮递送中具有独特的优势^[8]: 增溶与促渗双重功能; 降低刺激性与生物相容性高; 双亲性中药单体成分可同时包载多种活性分子, 实现“一载体多药物”的协同递送。

甘草酸是从中药甘草中提取的有效单体, 具有良好的生物相容性和安全性。甘草酸具有两亲结构, 其分子结构包含亲水性和疏水性区域, 这种独特的性质使其能够在特定条件下自组装成纳米胶束, 使其成为药物递送系统中的有效载体^[71-73]。据报道, 甘草酸可以包封水溶性差且不稳定的药物, 促进其皮肤渗透, 增强生物相容性, 并可实现毛囊靶向^[69,74-76]。Liang等^[69]研究了基于隐丹参酮和甘草酸的自组装胶束在痤疮治疗中的应用, 通过薄膜分散水化法制备了甘草酸-隐丹参酮胶束, 并对其进行了体外和体内实验。结果表明, 甘草酸-隐丹参酮胶束在48 h内的累积药物渗透量明显高于隐丹参酮溶液, 与隐丹参酮溶液相比, 甘草酸-隐丹参酮胶束在皮肤真皮层中的隐丹参酮保留率高出6.61倍, 表明甘草酸是隐丹参酮皮肤递送的有效载体, 甘草酸-隐丹参酮胶束显著提高了隐丹参酮的水溶性和皮肤渗透性, 且具有良好的生物相容性和安全性。Wang等^[77]研究了甘草酸和氧化苦参碱组成的离子液体, 通过自组装形成胶束以增强抗光老化信号肽(PAL-4) 的经皮递送。研究发现, 甘草酸-氧化苦参碱自组装胶束能显著提高PAL-4的水溶性和皮肤渗透性。10%的甘草酸-氧化苦参碱自组装胶束显著促进了PAL-4的皮肤渗透和皮下滞留, 使PAL-4的体外经皮渗透量提高了5.64倍, 并在体内动物模型中表现出优异的抗光老化效果。

2.3　促渗剂

为克服皮肤屏障, 研究者们开发了系列促渗技术, 但目前最常用、最经济、使用最方便的促渗手段仍然是透皮促渗剂^[78]。中药经皮给药制剂中使用的促渗剂包括化学促渗剂和天然促渗剂两大类, 其中化学合成促渗剂包括表面活性剂、吡咯烷酮、氮酮、丙二醇等, 通过扰乱角质层脂质的有序排列, 使角质层蛋白质变性, 改变角质层的溶解性能显著减弱角质层屏障^[79-81]。天然促渗剂包括冰片、薄荷脑、中药挥发油等^[4], 由于成分复杂, 其促渗机制不尽相同。研究表明, 冰片可能改变角质层脂质的排列和增加角质层流动性而发挥促透作用^[82]; 薄荷脑通过改变表皮细胞间质结构, 促使角质层细胞间隙发生可逆性扩张, 从而有效降低皮肤组织对异源性药物的屏障阻隔效应^[83]。中药挥发油作为天然促渗剂是近年来研究的热点, 其应用越来越得到重视^[4,84]。Zhou等^[85]的研究表明, 高良姜挥发油对蛇床子素的促透效果优于相同剂量的氮酮和油酸; Wu等^[86]发现乳木果油对利多卡因的促透作用优于氮酮; Zhao等^[87]研究结果表明, 桉叶油、艾叶油、当归油、连翘油对黄藤素透皮给药均产生一定程度的影响, 其中艾叶油的促透效果最为显著。虽然化学和天然促渗剂本身不直接解决制剂载药量问题, 但它们能显著提升药物的经皮渗透速率和累积渗透量。对于大剂量中药经皮给药, 选用高效促渗剂是实现足量药物在有效时间内透皮吸收的关键辅助手段。

苷类成分作为中药外用制剂的核心活性组分, 虽具有显著的药理活性特征, 但其较高极性特性导致透皮渗透效率受限。Huang等^[88]考察了5种中药挥发油(高良姜油、薄荷油、干姜油、胡椒油、吴茱萸油) 对3种苷类单体成分(栀子苷、龙胆苦苷、芍药苷) 的体外经促透效果, 结果表明, 高良姜油、薄荷油、干姜油、胡椒油对3种苷类成分的经皮透过具有促进作用, 且显著降低大鼠的皮肤屏障功能。Tuntiyasawasdikul等^[89]制备了小山柰甲氧基黄酮贴片, 研究发现油酸使总甲氧基黄酮的渗透通量比对照组增加了1.25倍, 而薄荷醇缩短了滞后时间。当油酸和薄荷醇结合时, 观察到甲氧基黄酮的最大通量和最短的滞后时间, 表明薄荷醇与油酸具有协同作用。Quan等^[90]研究发现, 在众多促透剂中, 油酸显示出对豨莶草提取物最大的促透效果, 其促透增强比为3.32; 以10%油酸作为促渗剂开发出具有良好抗炎镇痛作用的豨莶草提取物透皮贴剂。Sabir等^[91]开发了姜黄素负载的固体脂质纳米粒贴片, 体外透皮试验结果显示, 与不含促渗剂的贴片相比, 含促渗剂的姜黄素贴片的增强比高达6.5倍, 促渗剂在中药经皮递送中发挥着重要的作用。

2.4　离子导入

离子导入技术是一种在外部施加低强度直流电场(通常电流密度约0.1~1.0 mA) 的非侵入性给药方法, 通过电场力驱动离子型药物或中性药物穿过皮肤屏障^[92]。其双机制协同增效^[93]: 电迁移定向驱动带电药物阳离子中药成分(如生物碱) 在阳极作用下经皮渗透, 阴离子成分则通过阴极实现跨膜转运; 电渗流促进中性分子经皮递送。离子导入的核心优势在于可通过实时调节电流强度精准控制药物释放速率, 实现透皮通量精准调控^[94]。通过优化电场参数(电压、电流)、药液性质(电荷状态、离子强度) 等可提升药物分子经皮递送效能(图5)^[95,96]。离子导入促渗技术适用于慢性疾病(如癌症、糖尿病) 的治疗, 同时在常规疗法应答有限的皮肤疾病(如皮肤癌、银屑病) 中显现显著治疗潜力。

中药离子导入技术能最大限度的增加药物浓度, 提高中药经皮递送效率^[97]。Chen等^[98]针对单膝骨性关节炎患者的对照研究显示: 治疗组采用牛膝醇提物离子导入疗法, 对照组实施直流电常规治疗。两组治疗后疼痛视觉模拟评分及骨关节炎指数均较治疗前显著降低(P < 0.05), 但治疗组在疼痛缓解与关节功能改善方面疗效显著优于对照组。Jiang等^[99]研究发现, 离子导入技术可实现快速可控的盐酸青藤碱经皮递送, 且盐酸青藤碱稳态流量与电流密度的相关性良好(r = 0.999 3), 而与其浓度无相关性。临床研究证实, 自拟痛风方配合中药离子导入治疗痛风高尿酸血症效果显著, 能够有效提升尿酸排泄, 改善患者肾功能, 缓解炎症反应, 并降低疾病复发率^[100]。Jin等^[101]通过穴位离子导入法考察蒲公英多糖对急性乳腺炎大鼠炎性因子的改善作用, 研究证实蒲公英多糖经穴位离子导入能够有效抑制急性乳腺炎大鼠促炎细胞因子的产生及表达, 发挥显著的抗炎效果, 突显了离子导入技术在提升药物疗效方面的优势。

2.5　超声技术

超声促渗技术是利用超声波能量(通常分为高频与低频, 其中低频超声更优) 促进药物经皮渗透的物理方法, 其核心机制基于三大效应^[92,102]: ①空化效应(主导机制): 超声波诱导皮肤组织内气核振动形成气泡, 破裂时产生瞬时孔道并扰乱角质层脂质双分子层有序结构, 显著提升皮肤通透性; ②热效应: 声能转化为热能, 扩张皮肤血管及腺体口径, 加速血流并增加药物扩散系数; ③声微流效应: 引发药物在介质中的对流转运, 协同增强渗透效率。该技术通过程序化控制可实现精准给药, 可用于提升难溶性中药有效成分的经皮递送效率。Pan等^[103]采用自制中药方(含白芍、当归、丹参等15味中药材) 超声经皮局部给药用于治疗类风湿性关节炎肾虚血瘀证的关节疼痛, 临床研究表明可快速缓解患者关节疼痛症状并取得较好疗效。Tian等^[104]的研究发现, 低频超声能显著促进由乐必子、辛纳皮、桂枝、茯苓、枸杞和赤芍组成的中药复方经皮递送, 该中药复方经低频超声可有效减轻恶性胸腔积液, 改善癌症患者的生活质量。Zhang等^[105]运用超声促渗技术提高中药马钱子的局部药物浓度, 发现最佳的超声波穿透可以使穿透深度超过110 μm, 马钱子碱的浓度增加到2~3倍。

2.6　促渗技术联用

为突破单一促渗技术的效率瓶颈, 研究者提出促渗技术联用策略: 通过协同整合不同作用机制的促渗方法, 在降低单一技术强度或促渗剂用量的同时, 显著提升药物透皮效率与用药安全性, 为中药复方复杂成分的高效递送提供优化路径, 也对克服大剂量中药经皮递送瓶颈具有重要的应用前景。Guo等^[106]研究证实, 微针与纳米结构脂质载体的物理-化学双促渗策略可协同解决高乌头生物碱的经皮递送瓶颈: 微针联合高乌头生物碱纳米结构脂质载体组的血药浓度-时间曲线下面积较单一高乌头生物碱纳米结构脂质载体组提升6.68倍(高乌甲素) 与6.66倍(冉乌头碱), 较微针联合物理混合物组提升2.72倍(高乌甲素) 与3.16倍(冉乌头碱), 凸显技术联用对难溶性中药成分的高效递送价值。白脉软膏促渗技术研究表明^[107], 3%丙二醇显著提高各成分透皮效率, 甘草酸铵、甘松新酮、姜黄素的促渗倍数分别为空白组的1.74、1.60、3.73倍, 综合效果呈脂溶性成分优势(姜黄素 > 甘草酸铵 > 甘松新酮); 而超声对水溶性甘草酸铵的促透效果优于丙二醇。因此, 针对复方中水/脂溶性成分的渗透差异性, 丙二醇与超声联用可实现互补增效——丙二醇主导脂溶性成分(甘松新酮、姜黄素) 渗透, 超声优化水溶性成分(甘草酸铵) 递送, 为多成分中药经皮制剂提供协同解决方案。Xie^[108]研究表明, 超声波可协同活化化学促渗剂, 显著提升延胡索乳膏中延胡索乙素的体外经皮累积透过量, 证实促渗剂-超声联用策略对生物碱类中药成分的递送增效作用。Sansanaphongpricha等^[109]将金纳米粒子装载于脂质体中, 结合阴极离子电渗疗法, 显著提升了生姜提取物的细胞吸收和皮肤渗透, 有望用于治疗皮肤炎症及相关癌症。

3　展望与挑战

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中药经皮递送系统凭借其避免肝脏首过效应、维持稳定血药浓度、提高患者依从性及实现长效缓释等优势, 已成为替代传统给药方式的理想选择, 尤其在慢性疾病管理中展现出巨大潜力。然而, 皮肤角质层的“砖墙结构”屏障及中药复方的复杂性构成了主要挑战, 导致透皮效率低及质量控制难。近年来, 药剂学与材料科学的交叉融合推动了高效递送技术的突破: 微针技术通过机械穿刺形成瞬时微孔道, 实现精准递送; 纳米载体技术利用仿生亲和、增溶效应及毛囊靶向显著提升药物渗透; 促渗剂通过扰乱脂质排列等增强透皮递送效率; 物理技术如离子导入和超声提供非侵入性解决方案; 而促渗技术联用则通过多机制协同突破大剂量中药经皮递送瓶颈。

中药经皮给药制剂在局部与全身治疗中均展现出独特优势, 其应用场景适配需结合疾病特征与中药有效成分特性进行优化选择。在局部治疗方面, 对于皮肤病、创面愈合、瘢痕修复等以病灶局部为靶点的适应症, 脂质体、纳米乳、聚合物纳米粒、纳米晶体、自组装纳米胶束等制剂可通过毛囊靶向与表皮储库效应实现深层皮肤滞留, 是首选策略。在全身治疗领域, 用于类风湿关节炎、疼痛、痛风等需系统暴露的慢性病, 可借助微针、离子导入或超声-促渗剂联用等技术以提升通量。

然而, 仍存在一些问题需要解决。首先, 中药复方多组分理化性质的差异制约多成分的同步渗透, 极性差异引发的溶解度波动进一步加剧递送难度。部分中药单体成分兼具药效与载体功能, 例如, 甘草酸在展现显著抗炎、抗氧化和免疫调节作用的同时, 具有自组装的内在特性, 未来的研究可挖掘更多具自组装特性的中药单体成分, 利用其自组装潜能构建智能递药库。同时, 针对中药复方成分的复杂性, 开发新型智能载体系统, 如基于脂质体、纳米乳和聚合物纳米粒的多室结构载体, 实现中药多成分的同步递送, 增强药物的生物利用度。其次, 大多数的研究只针对有效性, 而中药有效成分-皮肤-载体三元系统的分子作用机制尚未明晰。未来的研究需结合药学、化学、材料科学、生物学、计算机等学科的综合研究, 使用先进的技术方法如多组学技术和分子成像, 探索中药有效成分、皮肤、载体之间的相互作用, 为中药高效经皮递送系统的设计提供理论支持。

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2026年第61卷第4期

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doi: 10.16438/j.0513-4870.2025-0775

接收时间：2025-07-06
首发时间：2026-09-21
出版时间：2026-04-12

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收稿日期：2025-07-06
修回日期：2025-09-18

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南方医科大学中医药学院, 广东广州 510515

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刘强, Tel: 13189091968, E-mail: liuqiang@smu.edu.cn

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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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