Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Drug Deliv Transl Res. 2018 Feb;8(1):54-63. doi: 10.1007/s13346-017-0433-0.
Transdermal drug delivery is advantageous over other conventional drug administration routes. However, it can be inefficient because of the natural barrier of the stratum corneum which is the uppermost layer of the skin. A previous study verified that the treatment of magainin pore-forming peptide with N-lauroylsarcosine (NLS) on human skin can increase skin permeability by 47-fold. However, NLS is well known as a potential skin irritant. The irritation potential of NLS is known to decrease when mixed with sorbitan monolaurate (S20). Encouraged by these results, we combined S20 with magainin-NLS to enhance transdermal drug transport with less skin irritation. In this study, nine groups with magainin and NLS:S20 mixtures at different concentrations and weight fractions were screened to maximize their synergistic effect. To quantify the efficacy to toxicity ratio of each formulation, we defined the ratio as the "enhancement ratio/irritation potential (ER/IP)." The ER was observed by Franz cell diffusion of the target drug fluorescein, and the IP was measured by the cytotoxicity of the NIH/3T3 mouse fibroblast cell line. As a result, the magainin with the NLS:S20 mixture increased the permeability of porcine skin as well as decreased the toxicity. Among the various combinations, a formulation of 2% (w/v) NLS:S20 with a weight fraction of 0.6:0.4 had the largest ER/IP. ATR-FTIR spectroscopy of the formulations and skin was done to analyze the interactions in the formulations themselves and between the formulations and the skin. Both the intercellular lipidic route and transcellular route through the stratum corneum protein were involved in the delivery of fluorescein. This study turned pore-forming peptides into an efficient and safe penetration enhancer by combining them with other chemical penetration enhancers. Moreover, this discovery could be a possible method for enabling the transdermal delivery of macromolecules.
经皮给药优于其他传统的药物给药途径。然而，由于皮肤的最外层角质层的天然屏障，它可能效率低下。先前的研究证实，用 N-月桂酰肌氨酸（NLS）处理阳离子抗菌肽（magainin）可以使皮肤的通透性增加 47 倍。然而，NLS 是众所周知的潜在皮肤刺激性物质。当与山梨醇单月桂酸酯（S20）混合时，NLS 的刺激性潜力会降低。受这些结果的鼓舞，我们将 S20 与 magainin-NLS 结合使用，以在减少皮肤刺激的同时增强药物的经皮传递。在这项研究中，我们筛选了 9 组不同浓度和重量分数的 magainin 和 NLS:S20 混合物，以最大限度地发挥它们的协同作用。为了量化每种配方的功效与毒性比，我们将该比值定义为“增强比/刺激性潜力（ER/IP）”。通过荧光素的Franz 细胞扩散来观察 ER，通过 NIH/3T3 小鼠成纤维细胞系的细胞毒性来测量 IP。结果表明，magainin 与 NLS:S20 混合物增加了猪皮的通透性，同时降低了毒性。在各种组合中，NLS:S20 重量比为 0.6:0.4 的 2%（w/v）配方具有最大的 ER/IP。对配方和皮肤进行衰减全反射傅里叶变换红外光谱（ATR-FTIR）分析，以分析配方本身和配方与皮肤之间的相互作用。细胞间脂质途径和穿过角质层蛋白的细胞内途径都参与了荧光素的传递。通过将这些成孔肽与其他化学渗透增强剂结合使用，本研究将成孔肽转化为一种高效、安全的渗透增强剂。此外，这一发现可能为实现大分子的经皮传递提供一种可能的方法。
