Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations

doi:10.1016/S0168-3659(98)00187-4

Journal of Controlled Release

Volume 59, Issue 2, 20 May 1999, Pages 149-161

https://doi.org/10.1016/S0168-3659(98)00187-4 Get rights and content

Abstract

The outermost layer of the skin, stratum corneum (SC), provides an outstanding barrier against the external environment and is also responsible for skin impermeability toward most solutes. The barrier function is related to the unique composition of the SC lipids and their complex structural arrangement. The lipoidal matrix of the SC, therefore, is a target of penetration enhancer action. The literature on the skin barrier structure and function and on the mechanisms of action of some well established permeation promoters, with a focus on their impact on SC structural alterations, is reviewed. Data obtained from infrared, thermal, and fluorescence spectroscopic examinations of the SC and its components imply enhancer improved permeation of solutes through the SC is associated with alterations involving the hydrocarbon chains of the SC lipid components. Data obtained from electron microscopy and X-ray diffraction reveals that the disordering of the lamellar packing is also an important mechanism for increased permeation of drugs induced by penetration enhancers.

Introduction

The major limitation to transdermal drug delivery (TDD) is the skin itself. Being the outermost layer of the human organism, separating the internal from the external environment, the skin acts as a two-way barrier, i.e., preventing the ingress of foreign molecules and the egress of endogenous substances. The major barrier to penetration of matter through the skin is provided by a superficial layer of the skin, the stratum corneum (SC) and its compact structure 1, 2, 3. In addition, the barrier function is assisted by the metabolic activity of the skin, although the biotransformation capacity is considerably lower in skin than in the gut or liver [4].

In an attempt to overcome the problems arising from skin impermeability and biological variability and to raise the number of drug candidates for TDD, various approaches to reversibly remove the barrier resistance have been investigated. Among these approaches is the use of penetration enhancers [5]. Penetration enhancers are chemical compounds which are themselves pharmacologically inactive, but can partition into and interact with the SC constituents when incorporated into a transdermal formulation, thereby reducing the resistance of skin to drug diffusion 6, 7, 8. A penetration enhancer may also increase the thermodynamic activity of a drug, thus resulting in augmented drug flux. Other approaches to increase drug delivery through skin are chemical modification of a poorly penetrating drug into a pharmacologically inactive prodrug, which readily penetrates the skin 9, 10; electrical means such as iontophoresis [11]and electroporation [12]; and the application of ultrasound [13].

The focus of the present article is to review recent literature on the mechanisms of chemical penetration enhancers, in context with their impact on SC structure.

Section snippets

The structure of the skin

Skin is essentially composed of two major layers: an outer, unvascularized epithelial layer (the epidermis), and an inner layer (the dermis), which contains a rich supply of capillaries, nerves, sweat glands, sebaceous glands, and hair follicles that are supported by connective tissue [14]. The epidermis can be further divided into several anatomical layers which represent different stages of differentiation of cells –once formed from the stem cells on the basal membrane at the interface of

The stratum corneum barrier function

The barrier function of the skin is firmly attributed to the SC [2]. The SC has a water permeability approximately 1000 times lower than most other biological membranes, which has been attributed to the unique lipid composition and content of the SC 17, 18and, especially, the exceptional structural arrangement of the intercellular lipid matrix and the lipid envelope surrounding the corneocytes [19].

The essential role of the SC lipids in barrier properties has been demonstrated by removal of

Drug permeation routes

The absorption of drugs across the skin is believed to be passive [2]. Transdermal permeation can involve passage of molecules across the intact epidermis or through a shunt pathway offered by the relatively universally distributed hair follicles and eccrine glands. These skin appendages, however, actually occupy only 0.1% of the total human skin surface, and, therefore, it is now widely believed that the transepidermal pathway of passive diffusion is the principal pathway associated with the

Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations

The key to promoting the permeation of drugs across the skin to a significant degree is to alter the properties of the principal pathways associated with drug penetration across the SC, i.e., the lipoidal intercellular pathway and the polar pathway. However, due to the structure of the SC - continuity of the lipid barrier - interaction with SC intercellular lipids is of crucial importance for the effectiveness of penetration enhancer action.

Concluding Remarks

Although during the last 10 years an enormous amount of knowledge became available on the structure of the stratum corneum and the effect of solvents and penetration enhancers on this structure, still our knowledge on this tissue and its lipid organization is very limited. It is an important challenge for the next years' research to gain more knowledge on the complicated structure and the function of the skin barrier which eventually may lead to rational design of penetration enhancers.

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