Bos J D, Meinardi M M
Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands.
Exp Dermatol. 2000 Jun;9(3):165-9. doi: 10.1034/j.1600-0625.2000.009003165.x.
Human skin has unique properties of which functioning as a physicochemical barrier is one of the most apparent. The human integument is able to resist the penetration of many molecules. However, especially smaller molecules can surpass transcutaneously. They are able to go by the corneal layer, which is thought to form the main deterrent. We argue that the molecular weight (MW) of a compound must be under 500 Dalton to allow skin absorption. Larger molecules cannot pass the corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually all common contact allergens are under 500 Dalton, larger molecules are not known as contact sensitizers. They cannot penetrate and thus cannot act as allergens in man; 2) the most commonly used pharmacological agents applied in topical dermatotherapy are all under 500 Dalton; 3) all known topical drugs used in transdermal drug-delivery systems are under 500 Dalton. In addition, clinical experience with topical agents such as cyclosporine, tacrolimus and ascomycins gives further arguments for the reality of the 500 Dalton rule. For pharmaceutical development purposes, it seems logical to restrict the development of new innovative compounds to a MW of under 500 Dalton, when topical dermatological therapy or percutaneous systemic therapy or vaccination is the objective.
人类皮肤具有独特的特性，其中作为物理化学屏障发挥作用是最明显的特性之一。人体的皮肤能够抵抗许多分子的渗透。然而，尤其是较小的分子能够经皮穿透。它们能够穿过被认为是主要屏障的角质层。我们认为，化合物的分子量（MW）必须低于500道尔顿才能实现皮肤吸收。较大的分子无法穿过角质层。支持这一“500道尔顿规则”的论据如下：1）几乎所有常见的接触性过敏原分子量都低于500道尔顿，较大的分子不是已知的接触性致敏剂。它们无法穿透，因此在人体中不能作为过敏原起作用；2）局部皮肤治疗中最常用的药剂分子量都低于500道尔顿；3）经皮给药系统中所有已知的局部用药分子量都低于500道尔顿。此外，环孢素、他克莫司和子囊霉素等局部用药的临床经验为500道尔顿规则的实际应用提供了更多论据。出于药物研发目的，当目标是局部皮肤治疗、经皮全身治疗或疫苗接种时，将新型创新化合物的研发限制在分子量低于500道尔顿似乎是合理的。
