Lipids intercellular lipid domains

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. 

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 5 Murine stratum comeum normal full thickness. Powder diffraction patterns obtained from mouse SC at 25°C. The upper figure shows the small-angle lamellar pattern produced by the intercellular lipid domains, with a repeat period of 131 2 A. The lower figure shows the wide-angle pattern produced by the lipid alkyl chains and the comeocyte envelope. See text. (Data from White et al., 1988.)...

Figure 12 Models for electron density profiles ofhuman and mouse stratum corneum intercellular lipid domains. Fourier transformation of the profiles produce diffracted intensities corisistent with the observed ones. The unit cell spacings of the human and mouse SC are 134 A and 132 A, respectively.

The substantial contributions of calorimetry and infrared spectroscopy to our knowledge base of SC biophysics speaks for themselves. Most notably, the pivotal role of the intercellular lipid domains in SC barrier function has been elucidated and has elevated the understanding of this complex membrane to a new level. In turn, this has allowed mechanisms of permeation and mechanisms of penetration enhancement to be examined and identified. Furthermore, the opportunity to monitor the uptake and distribution of topically administered chemicals into and within the SC offers a level of detail and quantification of the permeation process, in vivo in humans, that was unimaginable a decade ago. The variety of potential applications of these findings is considerable and will form the basis of substantial further work. 

Menthol also has been described as a potential penetration enhancer due to its preferential distribution into the intercellular spaces of the stratum corneum and its possible reversible disruption of the intercellular lipid domain/ ... 

There are clear differences between the oral mucosal membrane and other epithelial membranes of the intestine, nasal cavity and rectum. The oral mucosal membranes are less keratinized than the skin membranes and show a more loosely packed intercellular lipid domain. In terms of function of the absorption enhancement through the oral mucosal membrane, it can be said that it occurs principally through the... 

The primary diffusion barrier of the SC is caused by the intercellular lipid domains located between the comeocytes. Investigation of the physical properties and molecular structure of these lipid domains is an important step in understanding the percutaneous absorption, which gives an insight into the effects of the penetration enhancers on SC lipids. X-ray and electron diffraction studies using small- and wide-angle are the most direct and powerful tools for acquiring this structural information for SC. 

Fig. 124.2 Action of chemical penetration enhancers within the intercellular lipid domain...

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.)... 

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. 

FITC-Bac) delivered in vivo from ethosomes, penetrated the rat skin through the intercor-neocyte pathways, which typically exist along the lipid domain of the stratum corneum [95] (Figure 13.7). In contrast, significantly lower fluorescence staining of the intercellular penetration pathway and no inter- or intracorneocyte fluorescence were observed with FITC-Bac hydroethanolic solution and liposomes, respectively. 

The remarkable resistance of the SC intercellular lipid network to the passive penetration of therapeutic agents has intensified the search for devices, chemical and physical, with the ability to perturb this lipid environment. Of the many physical techniques investigated, iontophoresis (or electrically enhanced transdermal transport) has become an important focal point [160-162]. Unparalleled in its ability to deliver (noninvasively) ionized drugs across the skin, its modus operandi appears to be largely dependent on transcutaneous ion-conducting pathways (which may be paracellular), rather than a function of direct interaction with the lipid infrastructure [163]. Nevertheless, the effect of the applied current on the lipid (and protein) domains is a matter of interest with respect to both safety considerations (i.e., does the applied current induce stmctural alterations ) and mechanistic insight. ATR-FTIR has been used in a number of studies to discern the effect of iontophoresis on SC lipid and protein structures, both in vivo and in vitro. In separate studies, human SC was examined in vivo following the delivery of current at 0.1-0.2 mA/cm for 30... 

Challenges for the use of biophysical techniques remain, however, not the least of which is whether they can be developed to unravel the structural heterogeneity of the SC. To what extent will it be possible to define the different lipid domains within the intercellular spaces and at the comeocyte... 

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