雾化对不同性质活性成分皮肤递送行为的影响及机制

Effects and mechanisms of atomization on the transdermal delivery behavior of active ingredients with diverse properties

摘要

系统考察以雾化作为经皮促渗方式对不同理化性质活性成分皮肤递送行为的影响及其作用机制。以猪耳背皮为体外模型，采用 Franz 扩散池进行皮肤渗透实验，于不同时段收集透皮接收液，并分离制备角质层与活性表皮和真皮层样本。通过高效液相色谱、荧光衍生化及共聚焦激光扫描显微镜建立定量或可视化检测方法，比较有无雾化条件下腺苷（AD）、传明酸（TXA）、钙黄绿素（CAL）和生育酚乙酸酯（TA）的皮肤滞留量及经皮透过量。同时，采用经皮水分散失（TEWL）测定和全反射傅里叶变换红外光谱（ATR-FTIR）对雾化促渗机制进行分析。实验结果显示，雾化在不同程度上提高了 4 种活性成分的角质层与活性表皮和真皮层滞留量和经皮透过量，其中对相对分子质量较小且油水分配性质适中的 TXA 促渗效果最为显著，对高度亲水的 AD 和高度亲脂的 TA 促渗效果相对有限，但雾化显著增加了 TA 在皮肤中的滞留量。TEWL 测定结果显示，雾化处理后 4 h 内皮肤通透性升高，8 h 内基本恢复；ATR-FTIR 分析提示，雾化可能通过扰动角质层脂质有序性与角蛋白构象，促进活性成分透过皮肤屏障。本研究为雾化经皮给药技术的发展及相关雾化产品的设计与开发提供了理论依据和实验参考。

Abstract

This study systematically examined the effects of atomization as a transdermal permeation enhancer on the transdermal delivery of active ingredients with different physicochemical properties and investigated the underlying mechanisms. Porcine ear skin served as an in vitro model, and skin permeation experiments were conducted using Franz diffusion cells. Receptor fluids were collected at specific time points, and samples of the stratum corneum and viable epidermis–dermis were separated and prepared. Quantitative and visualization methods, including high-performance liquid chromatography, fluorescence derivatization, and confocal laser scanning microscopy, were used to compare skin retention and transdermal permeation of adenosine (AD), tranexamic acid (TXA), calcein (CAL), and tocopheryl acetate (TA) under atomized and non-atomized conditions. Additionally, transepidermal water loss (TEWL) measurements and attenuated total reflectance–Fourier transform infrared spectroscopy (ATR-FTIR) were employed to analyze the mechanism behind the penetration enhancement caused by atomization. The findings showed that atomization increased skin retention within the stratum corneum and viable epidermis–dermis, as well as the transdermal permeation of all four active ingredients to varying degrees. The most significant enhancement was observed for TXA, which has a relatively low molecular weight and moderate lipophilicity, while the enhancement effects for highly hydrophilic AD and highly lipophilic TA were comparatively limited; however, atomization significantly increased the skin retention of TA. TEWL results indicated that skin permeability increased within 4 hours after atomization and largely recovered within 8 hours. ATR-FTIR analysis suggested that atomization may facilitate transdermal delivery by disrupting the lipid order and keratin conformation in the stratum corneum.This study provides theoretical support and experimental references for the advancement of atomization transdermal delivery technology，as well as the design and development of related atomization products.

关键词

雾化给药 / 经皮促渗 / 腺苷 / 传明酸 / 钙黄绿素 / 生育酚乙酸酯 / 经皮水分散失 / 傅里叶变换红外光谱

Key words

atomization transdermal delivery / transdermal penetration enhancement / adenosine / tranexamic acid / calcein / tocopherol acetate / transepidermal water loss / Fourier transform infrared spectroscopy

参考文献

[1] Li XZ, Liu SW, He Y. Innovative nanomedicine approaches for psoriasis: advancements, challenges, and future directions[J]. Nano Biomed Eng, 2025, 17(3): 333-345.

[2] Rane B, Gadekar P, Patil V, et al. Fabrication and optimization of febuxostat—loaded liposomal gel using the Box—Behnken design for gout treatment[J]. Nano Biomed Eng, 2024, 16(3): 484-497.

[3] Huang YH, Hu CS, Ke YJ, et al. Evaluating the effectiveness of a novel atomized liquid needle—free transdermal delivery system[J]. Drug Deliv Transl Res, 2017, 7(5): 609-616.

[4] Hsieh TJ, Chen PY, Wang HY, et al. Study on anti—inflammatory effects of and muscle recovery associated with transdermal delivery of Chaenomeles speciosa extracts using supersonic atomizer on rat model[J]. Antioxidants, 2024, 13(6): 702.

[5] Han RF, Wang SY, Li JT, et al. The efficacy study of trinity permeation synergism on anti—aging[J]. J Dermatol Sci Cosmet Technol, 2024, 1(3): 100043.

[6] Li JT, Wang SY, Han RF, et al. A cutting—edge atomization—based methodology for enhancing formulation ability to resist photoaging[J]. J Dermatol Sci Cosmet Technol, 2024, 1(4): 100045.

[7] Chuang FJ, Wang YW, Chang LR, et al. Enhanced skin neocollagenesis through the transdermal delivery of poly—L—lactic acid microparticles by using a needle—free supersonic atomizer[J]. Biomater Adv, 2023, 154: 213619.

[8] Iannitti T, Palmieri B, Aspiro A, et al. A preliminary study of painless and effective transdermal botulinum toxin A delivery by jet nebulization for treatment of primary hyperhidrosis[J]. Drug Des Devel Ther, 2014, 8: 931-935.

[9] Li HL. Study on the effect of aerosol spray technology on the transdermal absorption of cosmetic ingredients[J]. Chem Eng Des Commun (化工设计通讯), 2023, 49(3): 92—94.

[10] Kang G, Tu TNT, Kim S, et al. Adenosine—loaded dissolving microneedle patches to improve skin wrinkles, dermal density, elasticity and hydration[J]. Int J Cosmet Sci, 2018, 40(2): 199-206.

[11] Lee J, Noh M, Jang J, et al. Skin penetration enhancer—incorporated lipid nanovesicles (SPE—LNV) for skin brightening and wrinkle treatment[J]. ACS Appl Mater Interfaces, 2022, 14(32): 36331-36340.

[12] Gaćina K, Krstanović Ćosić A. The use of tranexamic acid in dermatology[J]. Acta Clin Croat, 2023, 62(2): 368-372.

[13] Chen TY, Xue J, Wang Q. Tranexamic acid for the treatment of hyperpigmentation and telangiectatic disorders other than melasma: an update[J]. Clin Cosmet Investig Dermatol, 2024, 17: 2151-2163.

[14] Tokudome Y, Tsukiji H. Mannosylerythritol lipid B enhances the skin permeability of the water—soluble compound calcein via OH stretching vibration changes[J]. Colloids Interfaces, 2020, 4(1): 10.

[15] Moddaresi M, Brown MB, Tamburic S, et al. Tocopheryl acetate disposition in porcine and human skin when administered using lipid nanocarriers[J]. J Pharm Pharmacol, 2010, 62(6): 762-769.

[16] Trevithick JR, Xiong H, Lee S, et al. Topical tocopherol acetate reduces post—UVB, sunburn—associated erythema, edema, and skin sensitivity in hairless mice[J]. Arch Biochem Biophys, 1992, 296(2): 575-582.

[17] Lee JD, Kim JY, Jang HJ, et al. Percutaneous permeability of 1—phenoxy—2—propanol, a preservative in cosmetics[J]. Regul Toxicol Pharmacol, 2019, 103: 56-62.

[18] Herman A, Herman AP. Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: a review[J]. J Pharm Pharmacol, 2015, 67(4): 473-485.

[19] Abe A, Saito M, Kadhum WR, et al. Establishment of an evaluation method to detect drug distribution in hair follicles[J]. Int J Pharm, 2018, 542(1/2): 27-35.

[20] Hoppel M, Baurecht D, Holper E, et al. Validation of the combined ATR—FTIR/tape stripping technique for monitoring the distribution of surfactants in the stratum corneum[J]. Int J Pharm, 2014, 472(1/2): 88-93.

[21] Yeo S, Jung S, Cho HK, et al. Design and characterization of elastic artificial skin containing adenosine—loaded solid lipid nanoparticles for treating wrinkles[J]. Pharmaceutics, 2020, 13(1): 33.

[22] Omar MA, Anwer EF, Nour El—Deen DAM. Derivatization of tranexamic acid for its rapid spectrofluorimetric determination in pure form and pharmaceutical formulations: application in human plasma[J]. Spectrochim Acta A Mol Biomol Spectrosc, 2021, 247: 119111.

[23] Chen Y, Cun DM, Quan P, et al. Saturated long—chain esters of isopulegol as novel permeation enhancers for transdermal drug delivery[J]. Pharm Res, 2014, 31(8): 1907-1918.

[24] Makhlouf A, Elnawawy T. Hair regrowth boosting via minoxidil cubosomes: Formulation development, in vivo hair regrowth evaluation, histopathological examination and confocal laser microscopy imaging[J]. Int J Pharm, 2023, 634: 122665.

[25] Lee WR, Shen SC, Aljuffali IA, et al. Erbium—yttrium—aluminum—garnet laser irradiation ameliorates skin permeation and follicular delivery of antialopecia drugs[J]. J Pharm Sci, 2014, 103(11): 3542-3552.

[26] Nada A, Krishnaiah YSR, Zaghloul AA, et al. In vitro and in vivo permeation of vitamin E and vitamin E acetate from cosmetic formulations[J]. Med Princ Pract, 2011, 20(6): 509-513.

[27] Zeng LJ, Yang GQ, Liu JP, et al. Probing dynamic behavior of chemical enhancers passing in and out of the stratum corneum and modulation by biodegradable enhancer[J]. AAPS PharmSciTech, 2021, 22(4): 139.

[28] Sato ET, Machado N, Araújo DR, et al. Fourier transform infrared absorption (FTIR) on dry stratum corneum, corneocyte—lipid interfaces: experimental and vibrational spectroscopy calculations[J]. Spectrochim Acta A Mol Biomol Spectrosc, 2021, 249: 119218.

[29] Obata Y, Utsumi S, Watanabe H, et al. Infrared spectroscopic study of lipid interaction in stratum corneum treated with transdermal absorption enhancers[J]. Int J Pharm, 2010, 389(1/2): 18-23.

[30] Gunnarsson M, Mojumdar EH, Topgaard D, et al. Extraction of natural moisturizing factor from the stratum corneum and its implication on skin molecular mobility[J]. J Colloid Interface Sci, 2021, 604: 480-491.

[31] Williams SF, Wan H, Chittock J, et al. Characterization of skin barrier defects using infrared spectroscopy in patients with atopic dermatitis[J]. Clin Exp Dermatol, 2024, 49(5): 466-477.

基金资助

国家自然科学基金项目(82374049)