Gupta Rakesh, Badhe Yogesh, Rai Beena, Mitragotri Samir
Physical Science Research Area, Tata Research Development and Design Centre, TCS Research, Tata Consultancy Services 54B, Hadapsar Industrial Estate Pune - 411013 India
School of Engineering and Applied Sciences, Wyss Institute, Harvard University USA.
RSC Adv. 2020 Mar 24;10(21):12234-12248. doi: 10.1039/d0ra01692f.
Ethanol is widely used in various pharmaceutical and cosmetic formulations in order to enhance skin penetration of active ingredients. While it is well known that ethanol partitions into the skin and enhances the permeation of both polar and nonpolar molecules, the exact mechanisms by which it enhances skin permeability are not fully understood. Several mechanisms have been proposed including lipid extraction from the stratum corneum (SC), fluidisation of SC lipid bilayer, alteration of SC protein conformation and enhancement of the drug solubility in the SC lipids. In this study, we performed molecular dynamics (MD) simulations of SC lipid bilayers comprised of an equimolar mixture of ceramides, cholesterol and free fatty acid in the presence of aqueous mixtures of ethanol. Various unrestrained MD simulations were performed in the presence of aqueous ethanol solution at molar ratios () ranging from = 0 to = 1. It was found that ethanol enhances bilayer permeability by dual actions (a) extraction of the skin lipids and (b) enhancing the mobility of lipid chains. Ethanol's permeation enhancing effect arises from its superior ability to form hydrogen bonds with headgroup atoms of skin lipids. Further, the free energy of extraction of ceramides (CER) and fatty acids (FFA) from the lipid bilayer was studied using umbrella sampling simulations. The free energy of extraction of CER was found to be much higher compared to FFA for all ethanol concentrations which shows that CER are difficult to extract as compared to FFA. Finally, the permeation of benzoic acid drug molecules through the skin lipid bilayer is shown in presence of ethanol molecules. It was found that ethanol selectively targets the FFA of the skin lipid bilayer and extracts it out of the lipid bilayer within few microseconds. Further, ethanol penetrates inside the lipid layer and creates the channels from which drug molecules can easily cross the lipid layer. Our observations (both in unrestrained and umbrella sampling simulations) are consistent with the experimental findings reported in the literature. The simulation methodology could be used for design and testing of permeation enhancers (acting on skin SC lipid lamella) for topical and transdermal drug delivery applications.
乙醇被广泛用于各种药物和化妆品配方中，以提高活性成分对皮肤的渗透能力。虽然众所周知乙醇会分配到皮肤中并增强极性和非极性分子的渗透，但乙醇增强皮肤通透性的确切机制尚未完全了解。已经提出了几种机制，包括从角质层（SC）中提取脂质、SC脂质双层的流化、SC蛋白质构象的改变以及药物在SC脂质中溶解度的提高。在本研究中，我们在存在乙醇水溶液的情况下，对由神经酰胺、胆固醇和游离脂肪酸等摩尔混合物组成的SC脂质双层进行了分子动力学（MD）模拟。在摩尔比（）范围从 = 0到 = 1的乙醇水溶液存在下进行了各种无约束MD模拟。结果发现，乙醇通过双重作用增强双层通透性：（a）提取皮肤脂质；（b）增强脂质链的流动性。乙醇的渗透增强作用源于其与皮肤脂质头部基团原子形成氢键的卓越能力。此外，使用伞形采样模拟研究了从脂质双层中提取神经酰胺（CER）和脂肪酸（FFA）的自由能。发现在所有乙醇浓度下，CER的提取自由能都比FFA高得多，这表明与FFA相比，CER难以提取。最后，展示了在乙醇分子存在下苯甲酸药物分子通过皮肤脂质双层的渗透情况。结果发现，乙醇选择性地靶向皮肤脂质双层的FFA，并在几微秒内将其从脂质双层中提取出来。此外，乙醇渗透到脂质层内部并形成通道，药物分子可以通过这些通道轻松穿过脂质层。我们的观察结果（在无约束和伞形采样模拟中）与文献报道的实验结果一致。该模拟方法可用于设计和测试用于局部和透皮给药应用的渗透促进剂（作用于皮肤SC脂质薄片）。
