Abstract
Chemical enhancers (CEs) decreased the barrier of the stratum corneum (SC) to enhance drug permeation. This was a “dynamic” behavior, which involved three processes including passing in, acting on, and passing out of the SC. However, compared with mature “static” researches about acting on the SC, the other two processes were poorly understood. This work aimed to probe the dynamic behavior of CEs and modulate it for satisfactory effectiveness. The investigating method of CEs’ dynamic behavior was established to obtain the rate of CEs passing in and out of the SC. An analysis attribution was conducted to obtain the possible reasons for the quite different dynamic behavior of CEs based on log P, solubility parameter, and minimum binging energy. It demonstrated the rate of CEs passing in and out of the SC was dependent on CE affinity with the SC and the interaction between CEs and the SC, respectively. The relevance between CEs’ dynamic behavior and the extent of decreasing SC barrier was confirmed by transepidermal water loss (TEWL). The higher rate of CE passing in the SC and a lower rate of passing out of the SC may contribute to an increased concentration of CEs in the SC, leading to a stronger ability to decrease the SC barrier. More importantly, two biodegradable CEs (Leu-Dod and Ser-Dod) of dodecanol were synthesized and achieved a modulation of its dynamic behavior to obtain more satisfactory effectiveness of enhancing drug permeation. This work was meaningful for the guidance of rationally promoting CEs’ effectiveness from a dynamic perspective, which was an unprecedented attempt in this field.
This is a preview of subscription content, log in via an institution to check access.
References
Zeng L, Song W, He W, Zhang J, Wang Y, Bian J, et al. Unconventional passive enhancement of transdermal drug delivery: toward a mechanistic understanding of penetration enhancers releasing from acrylic pressure-sensitive adhesive of patches. Pharm Res. 2020;37(9). https://doi.org/10.1007/s11095-020-02901-0.
Lane ME. Skin penetration enhancers. Int J Pharm. 2013;447(1-2):12–21. https://doi.org/10.1016/j.ijpharm.2013.02.040.
Nina Dragicevic-Curic HIM. Percutaneous penetration enhancers chemical methods in penetration enhancement. Berlin: Springer; 2015.
Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37. https://doi.org/10.1016/j.addr.2012.09.032.
Lundborg M, Wennberg CL, Narangifard A, Lindahl E, Norlen L. Predicting drug permeability through skin using molecular dynamics simulation. J Control Release. 2018;283:269–79. https://doi.org/10.1016/j.jconrel.2018.05.026.
Li SK, Chantasart D. Skin permeation enhancement in aqueous solution: correlation with equilibrium enhancer concentration and octanol/water partition coefficient. J Pharm Sci. 2019;108(1):350–7. https://doi.org/10.1016/j.xphs.2018.08.014.
Agrawala P, Ritschel WA. Influence of 1-dodecylhexahydro-2H-azepin-2-one (Azone) on the in vitro permeation of verapamil hydrochloride across rat, hairless mouse, and human cadaver skin. J Pharm Sci. 1988;77(9):776–8.
Zhang S, Song W, Wu H, Wang J, Lv H. Lecithins-zein nanoparticles for antifungal treatment: enhancement and prolongation of drug retention in skin with reduced toxicity. Int J Pharm. 2020;590:119894. https://doi.org/10.1016/j.ijpharm.2020.119894.
Liang S-YLR-C. The effect of ultraviolet B irradiation on the isolated porcine stratum corneum: colorimetric and ATR/FT-IR spectroscopic investigations. Biomed Res. 1994.
Chantasart D, Pongjanyakul T, Higuchi WI, Li SK. Effects of oxygen-containing terpenes as skin permeation enhancers on the lipoidal pathways of human epidermal membrane. J Pharm Sci. 2009;98(10):3617–32. https://doi.org/10.1002/jps.21666.
Vavrova K, Zbytovska J, Hrabalek A. Amphiphilic transdermal permeation enhancers: Structure-activity relationships. Curr Med Chem. 2005;12(19):2273–91. https://doi.org/10.2174/0929867054864822.
Zhao H, Liu C, Yang D, Wan X, Shang R, Quan P, et al. Molecular mechanism of ion-pair releasing from acrylic pressure sensitive adhesive containing carboxyl group: roles of doubly ionic hydrogen bond in the controlled release process of bisoprolol ion-pair. J Control Release. 2018;289:146–57. https://doi.org/10.1016/j.jconrel.2018.09.024.
Liu X, Quan P, Li S, Liu C, Zhao Y, Zhao Y, et al. Time dependence of the enhancement effect of chemical enhancers: molecular mechanisms of enhancing kinetics. J Control Release. 2017;248:33–44. https://doi.org/10.1016/j.jconrel.2017.01.017.
Janusova B, Skolova B, Tuekoerova K, Wojnarova L, Simunek T, Mladenka P, et al. Amino acid derivatives as transdermal permeation enhancers. J Control Release. 2013;165(2):91–100. https://doi.org/10.1016/j.jconrel.2012.11.003.
Laugel CYN, Baillet A. ATR-FTIR spectroscopy: a chemometric approach for studying the lipid organisation of the stratum corneum. Chem Phys Lipids. 2005;135(1):55–68. https://doi.org/10.1016/j.chemphyslip.2005.02.001.
Abe A, Saito M, Kadhum WR, Todo H, Sugibayashi K. Establishment of an evaluation method to detect drug distribution in hair follicles. Int J Pharm. 2018;542(1–2):27–35.
Karande P, Jain A, Ergun K, Kispersky V, Mitragotri S. Design principles of chemical penetration enhancers for transdermal drug delivery. Proc Natl Acad Sci U S A. 2005;102(13):4688–93. https://doi.org/10.1073/pnas.0501176102.
Ibrahim SA, Li SK. Chemical enhancer solubility in human stratum corneum lipids and enhancer mechanism of action on stratum corneum lipid domain. Int J Pharm. 2010;383(1-2):89–98. https://doi.org/10.1016/j.ijpharm.2009.09.014.
Chantasart D, Li SK. Structure enhancement relationship of chemical penetration enhancers in drug transport across the stratum corneum. Pharmaceutics. 2012;4(1):71–92. https://doi.org/10.3390/pharmaceutics4010071.
Hadgraft J. Modulation of the barrier function of the skin. Skin Pharmacol Physiol. 2001;14(Suppl. 1):72–81.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (No. 81703452) and Double First-Class Innovative Team (CPU2018GY28).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
ESM 1
(DOCX 19 kb)
Rights and permissions
About this article
Cite this article
Zeng, L., Yang, G., Liu, J. et al. Probing Dynamic Behavior of Chemical Enhancers Passing In and Out of the Stratum Corneum and Modulation by Biodegradable Enhancer. AAPS PharmSciTech 22, 139 (2021). https://doi.org/10.1208/s12249-021-02009-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/s12249-021-02009-7