Intercellular lipids

It is a lipophilic compound which removes intercellular lipids that are covalently linked to the cornified envelope surrounding epithelial cells [3]. It also enhances penetration of other agents. Resorcinol (m-dihydroxy benzene) is structurally and chemically similar to phenol. It disrupts the weak hydrogen bonds of keratin [4]. Lactic acid is an alpha hydroxy acid which causes corneocyte detachment and subsequent desquamation of the stratum corneum [5]. 

Salicylic acid (ortho hydroxybenzoic add) is a beta hydroxy acid agent. It is a lipophilic compound which produces desquamation of the stratum corneum via removal of intercellular lipids [3] (see salicylic acid section). Given its keratolytic effects, it has become an increasingly popular superficial peeling agent. Salicylic acid peels induce injury via thinning or removal of the stratum corneum. In addition, salicylic acid potentially enhances the penetration of TCA. 

The intercellular route is considered to be the predominantly used pathway in most cases, especially when steady-state conditions in the stratum corneum are reached. In case of intercellular absorption, substance transport occurs in the bilayer-structured, continuous, intercellular lipid domain within the stratum corneum. Although this pathway is very tortuous and therefore much longer in distance than the overall thickness of the stratum corneum, the intercellular route is considered to yield much faster absorption due to the high diffusion coefficient of most drugs within the lipid bilayer. Resulting from the bilayer structure, the intercellular pathway provides hydrophilic and lipophilic regions, allowing more hydrophilic substances to use the hydrophilic and more lipophilic substances to use the lipophilic route. In addition, it is possible to influence this pathway by certain excipients in the formulation. 

In addition to the intercellular lipids of the buccal mucosa, there appear to be other barriers which may reduce the ability of an exogenous compound to permeate the buccal mucosa. These include the salivary film and mucus layer, the basement membrane, and a metabolic barrier. 

As the final outer stratum comeum is formed the phospholipid bilayer deteriorates and intercellular lipid layers are formed.k l These contain principally ceramides, cholesterol, and free fatty acids. Some sphingolipids are covalently attached to proteins.3... 

Penetration enhancers have different mechanisms of action depending on their physicochemical properties. Some examples of penetration enhancers and their mechanisms are bile salts (micellization and solubilization of epithelial lipids), fatty acids such as oleic acid (perturbation of intracellular lipids) [25,26], azone (l-dodecylazacycloheptan-2-one) (increasing fluidity of intercellular lipids), and surfactants such as sodium lauryl sulfate (expansion of intracellular spaces). The complete list of enhancers and their mechanism of actions are discussed in detail in Chapter 10. 

Compounds that penetrate the stratum corneum via the transepidermal route may follow a transcellular (or intracellular) or intercellular pathway (see Figure 11.1). Because of the highly impermeable character of the cornified envelope (see previous section), the tortuous intercellular pathway has been suggested to be the route of preference for most drug molecules [32], This is confirmed by several microscopic transport studies, in which compounds have been visualized in the intercellular space of the stratum corneum [33-35]. Moreover, it has been demonstrated that drug permeation across stratum corneum increases many folds after lipid extraction [36], Hence, knowledge of the structure and physical properties of the intercellular lipids is crucial to broaden our insight into the skin barrier function. 

The composition of the free fatty acids is also unique. In both human and pig stratum cornea, the free fatty acid fraction consists mainly of long and saturated hydrocarbon chains [44,45], Oleic and linoleic acid are the only unsaturated free fatty acids detected in the stratum corneum. There are various sterols present in human stratum corneum, of which cholesterol predominates. Cholesterol is the only major lipid class that is present in both plasma membranes and the intercellular lipid lamellae. Cholesterol is synthesized in the epidermis and this synthesis is independent of the hepatic one. A minor fraction is sulfated to... 

Cholesterol sulfate is another intercellular lipid. Addition of low levels of cholesterol sulfate, as observed in normal healthy stratum corneum, to lipid mixtures has little effect on the phase behavior at room temperature. However, addition of high levels of cholesterol sulfate, at levels similar to that observed in the skin disease recessive X-linked ichthyosis, promotes the formation of the long periodicity phase, induces the formation of a fluid phase, and increases the solubility of cholesterol in the lamellar phases [72,80],... 

Madison, K.C., et al. Presence of intact intercellular lipid lamellae in the upper layers of the stratum corneum. J Invest Dermatol 88 714. 

McIntosh, T.J., M.E. Stewart, and D.T. Downing. 1996. X-ray diffraction analysis of isolated skin lipids Reconstitution of intercellular lipid domains. Biochemistry 35 3649. 

FIGURE 12.1 Penetration enhancer activity, (a) Action at intercellular lipids. Some of the ways by which penetration enhancers attack and modify the well-organized intercellular lipid domain of the stratum comeum. (b) Action at desmosomes and protein structures. Such dramatic disruption by enhancers (particularly potent solvents) as they split the stratum corneum into additional squames and individual cells would be clinically unacceptable, (c) Action within comeocytes. Swelling, further keratin denaturation and vacuolation within individual horny layer cells would not be so drastic but would usually be cosmetically challenging (see Menon and Lee [69] for further details). (Reproduced from Barry, B.W., Nat. Biotechnol. 22, 165, 2004. With permission.)... 

FIGURE 12.5 The fatty acid, oleic acid, illustrating the bent cis structure that would disrupt intercellular lipid packing much more than the trans form. 

Dermal and transdermal delivery requires efficient penetration of compounds through the skin barrier, the bilayer domains of intercellular lipid matrices, and keratin bundles in the stratum corneum (SC). Lipid vesicular systems are a recognized mode of enhanced delivery of drugs into and through the skin. However, it is noteworthy that not every lipid vesicular system has the adequate characteristics to enhance skin membrane permeation. Specially designed lipid vesicles in contrast to classic liposomal compositions could achieve this goal. This chapter describes the structure, main physicochemical characteristics, and mechanism of action of prominent vesicular carriers in this field and reviews reported data on their enhanced delivery performance. 

In addition to the electrorepulsive effect, iontophoresis may also enhance drug delivery by electroosmosis. Small ions like Na+, if included, for example, as part of a buffer system in a formulation, may be iontophoresed into the skin and carry with them solvating water molecules. These molecules may in turn carry other penetrants with them into the membrane, and in this way iontophoresis may also enhance the delivery of uncharged drug species. Iontophoresis, as well as electroosmosis, may also generally disorganize the intercellular lipids and produce a membrane more permeable to penetrants. 

Formulation additives used in topical drug or pesticide formulations can alter the stratum comeum barrier. Surfactants are least likely to be absorbed, but they can alter the lipid pathway by fluidization and delipidization of lipids, and proteins within the keratinocytes can become denatured. This is mostly likely associated with formulations containing anionic surfactants than non-ionic surfactants. Similar effects can be observed with solvents. Solvents can partition into the intercellular lipids, thereby changing membrane lipophilicity and barrier properties in the following order ether/acetone > DMSO > ethanol > water. Higher alcohols and oils do not damage the skin, but they can act as a depot for lipophilic drugs on the skin surface. The presence of water in several of these formulations can hydrate the skin. Skin occlusion with fabric or transdermal patches, creams, and ointments can increase epidermal hydration, which can increase permeability. 

Figure 4 Nat 106 liposomes have a strong effect on the microstructure of the stratum corneum. The corneocytes (C) were swollen considerably, and the smooth ultrastructure of the intercellular lipid lamellae showed flattened spherical structures (see arrows). The linear arranged keratin filaments along the cell boundary of the corneocytes are absent. The scale bar indicates 0.1 pm. 

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