Bouwstra Joke A, Honeywell-Nguyen P Loan, Gooris Gert S, Ponec Maria
Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Prog Lipid Res. 2003 Jan;42(1):1-36. doi: 10.1016/s0163-7827(02)00028-0.
The natural function of the skin is to protect the body from unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. Since the lipids regions in the stratum corneum form the only continuous structure, substances applied onto the skin always have to pass these regions. For this reason the organization in the lipid domains is considered to be very important for the skin barrier function. Due to the exceptional stratum corneum lipid composition, with long chain ceramides, free fatty acids and cholesterol as main lipid classes, the lipid phase behavior is different from that of other biological membranes. In stratum corneum crystalline phases are predominantly present, but most probably a subpopulation of lipids forms a liquid phase. Both the crystalline nature and the presence of a 13 nm lamellar phase are considered to be crucial for the skin barrier function. Since it is impossible to selectively extract individual lipid classes from the stratum corneum, the lipid organization has been studied in vitro using isolated lipid mixtures. These studies revealed that mixtures prepared with isolated stratum corneum lipids mimic to a high extent stratum corneum lipid phase behavior. This indicates that proteins do not play an important role in the stratum corneum lipid phase behavior. Furthermore, it was noticed that mixtures prepared only with ceramides and cholesterol already form the 13 nm lamellar phase. In the presence of free fatty acids the lattice density of the structure increases. In stratum corneum the ceramide fraction consists of various ceramide subclasses and the formation of the 13 nm lamellar phase is also affected by the ceramide composition. Particularly the presence of ceramide 1 is crucial. Based on these findings a molecular model has recently been proposed for the organization of the 13 nm lamellar phase, referred to as "the sandwich model", in which crystalline and liquid domains coexist. The major problem for topical drug delivery is the low diffusion rate of drugs across the stratum corneum. Therefore, several methods have been assessed to increase the permeation rate of drugs temporarily and locally. One of the approaches is the application of drugs in formulations containing vesicles. In order to unravel the mechanisms involved in increasing the drug transport across the skin, information on the effect of vesicles on drug permeation rate, the permeation pathway and perturbations of the skin ultrastructure is of importance. In the second part of this paper the possible interactions between vesicles and skin are described, focusing on differences between the effects of gel-state vesicles, liquid-state vesicles and elastic vesicles.
皮肤的自然功能是保护身体免受外界不良影响。皮肤的主要屏障位于皮肤的最外层，即角质层。由于角质层中的脂质区域构成了唯一的连续结构，涂抹在皮肤上的物质总是必须穿过这些区域。因此，脂质区域的组织被认为对皮肤屏障功能非常重要。由于角质层脂质组成特殊，以长链神经酰胺、游离脂肪酸和胆固醇作为主要脂质类别，其脂质相行为不同于其他生物膜。在角质层中主要存在结晶相，但很可能有一部分脂质形成液相。结晶性质和13nm层状相的存在都被认为对皮肤屏障功能至关重要。由于不可能从角质层中选择性地提取单个脂质类别，因此已使用分离的脂质混合物在体外研究脂质组织。这些研究表明，用分离的角质层脂质制备的混合物在很大程度上模拟了角质层脂质相行为。这表明蛋白质在角质层脂质相行为中不发挥重要作用。此外，人们注意到仅用神经酰胺和胆固醇制备的混合物已经形成了13nm层状相。在游离脂肪酸存在的情况下，结构的晶格密度增加。在角质层中，神经酰胺部分由各种神经酰胺亚类组成，13nm层状相的形成也受神经酰胺组成的影响。特别是神经酰胺1的存在至关重要。基于这些发现，最近提出了一种关于13nm层状相组织的分子模型，称为“三明治模型”，其中结晶域和液相域共存。局部给药的主要问题是药物穿过角质层的扩散速率低。因此，已经评估了几种方法来暂时和局部增加药物的渗透速率。其中一种方法是将药物应用于含有囊泡的制剂中。为了阐明增加药物经皮转运所涉及的机制，关于囊泡对药物渗透速率、渗透途径和皮肤超微结构扰动的影响的信息很重要。在本文的第二部分，描述了囊泡与皮肤之间可能的相互作用，重点是凝胶态囊泡、液态囊泡和弹性囊泡的作用差异。
