Bozdaganyan Marine E, Orekhov Philipp S
School of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia.
N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia.
Membranes (Basel). 2021 May 29;11(6):410. doi: 10.3390/membranes11060410.
The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs-linoleic acid (LA) and ethanol-through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid. In our simulations, we probed the effects of individual CPEs as well as their combination on various properties of the SC membrane and the lidocaine penetration across it. We demonstrated that the addition of both CPEs decreases the membrane thickness and the order parameters of the DPCE hydrocarbon chains. Moreover, LA also enhances diffusion of the SC membrane components, especially cholesterol. The estimated potential of mean force (PMF) profiles for the lidocaine translocation across SC in the presence/absence of two individual CPEs and their combination demonstrated that while ethanol lowers the free energy barrier for lidocaine to enter SC, LA decreases the depth of the free energy minima for lidocaine inside SC. These two effects supposedly result in synergistic penetration enhancement of drugs. Altogether, the present simulations provide a detailed molecular picture of CPEs' action and their synergistic effect on the penetration of small molecular weight therapeutics that can be beneficial for the design of novel drug and cosmetics formulations.
寻找新的透皮给药（TDD）制剂是医学和美容领域的一个重要研究方向。具有特定物理化学性质、能够增加活性成分透过角质层（SC）的分子被称为化学渗透促进剂（CPE），并且研究表明一些CPE可以协同发挥作用。在本研究中，我们通过含胆固醇、N - 硬脂酰鞘氨醇（DCPE）和山嵛酸的SC模型膜，对由两种CPE（亚油酸（LA）和乙醇）促进的利多卡因递送进行了粗粒度（CG）分子动力学（MD）模拟。在我们的模拟中，我们探究了单一CPE及其组合对SC膜的各种性质以及利多卡因透过该膜的影响。我们证明，两种CPE的添加均降低了膜厚度以及DPCE烃链的序参数。此外，LA还增强了SC膜成分的扩散，尤其是胆固醇。在存在/不存在两种单一CPE及其组合的情况下，利多卡因跨SC转运的平均力势（PMF）分布估计表明，虽然乙醇降低了利多卡因进入SC的自由能垒，但LA降低了SC内利多卡因自由能最小值的深度。这两种效应可能共同导致药物的协同渗透增强。总之，本模拟为CPE的作用及其对小分子治疗药物渗透的协同效应提供了详细的分子层面图景，这可能有助于新型药物和化妆品制剂的设计。
