Stratum bilayer

Although most of the ceramides in the stratum bilayer appear to play a role in establishing barrier function, one stmcturally unusual ceramide appears to function as a molecular rivet. Downing and co-workers [30-32] developed this concept to explain their inability to quantitatively recover ceramides by chloroform-methanol extraction techniques without prior alkaline hydrolysis [31]. Accordingly, this unusual ceramide may link adjacent bilayers and/or provide a covalent linkage between bilayers and comeocytes. 

Studies of the interactions between water and the Hpid constituents of the stratum corneum suggest that the supply of water per se is not responsible for skin quaHty and condition. Water vapor from lower layers provides a constant supply of moisture to the epidermis. Instead, the abiHty of the skin to retain the moisture is critical, and this abiHty depends on the HpidlameUar bilayers that occupy the spaces between the ceUs of the stratum corneum (44—46). 

The stratum corneum consists of separated, nonviable, cornified, almost nonpermeable corneocytes embedded into a continuous lipid bilayer made of various classes of lipids, for example, ceramides, cholesterol, cholesterol esters, free fatty acids, and triglycerides [6], Structurally, this epidermis layer is best described by the so-called brick-and-mortar model [7], The stratum corneum is crucial for the barrier function of the skin, controlling percutaneous absorption of dermally applied substances and regulating fluid homeostasis. The thickness of the stratum corneum is usually 10-25 /an, with exceptions at the soles of the feet and the palms, and swells several-fold when hydrated. All components of the stratum corneum originate from the basal layer of the epidermis, the stratum germinativum. 

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. 

Of particular interest are membranes prepared of an inert porous support carrying natural or artificial lipids. These coatings may comprise a single component, such as isopropylmyristate or dodecanol [99, 106], or mixtures of comparable composition as the stratum corneum intercellular bilayer [107, 108], Usually, synthetic lipids are used, due to an elaborate isolation procedure for stratum corneum lipids, with limited yield and the necessity of separation of triglycerides, originating from subcutaneous fatty tissue or skin care products [109],... 

Substituting hx = 3.6 cm and K ip/w = K - into Eq. 28 Johnson et al. calculated solute lateral diffusion coefficients in stratum corneum bilayers from macroscopic permeability coefficients. Measurements with highly ionized or very hydrophilic compounds were not performed because of the possible transport along a nonlipoidal pathway. Comparison of the computed Aat values with experimentally determined data for fluorescent probes in extracted stratum corneum lipids [47] showed a highly similar curve shape. The diffusion coefficient for the lateral transport showed a bifunctional size dependence with a weaker size dependence for larger, lipophilic compounds (> 350 Da), than... 

Johnson ME, Blankschtein D, Langer R (1997) Evaluation of solute permeation through the stratum corneum lateral bilayer diffusion as the primary transport mechanism. J Pharm Sci 86 1162-1172. 

Johnson ME, Berk DA, Blankschtein D, Golan DE, Jain RK, Langer RS (1996) Lateral diffusion of small compounds in human stratum corneum and model lipid bilayer systems. Biophys J 71 2656-2668. 

Using a similar approach, Notman et al. [81], determined the free energy for pore formation in bilayers composed of ceramide, as a model for the stratum corneum of the skin, both in the presence and in the absence of DMSO. Without DMSO, the bilayer was in the gel phase, and interestingly, a hydrophobic pore was observed with a high free-energy barrier ( 60 kj/mol). In the presence of DMSO, the bilayer was more fluid, and the more typical hydrophilic pore was observed, with a much smaller activation energy of 20kJ/mol. This work provided a thermodynamic and structural explanation for the enhanced permeability of skin by DMSO. 

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... 

In comparison to the skin, the buccal mucosa offers higher permeability and faster onset of drug delivery, whereas the key features which help it score over the other mucosal route, the nasal delivery system, include robustness, ease of use, and avoidance of drug metabolism and degradation. The buccal mucosa and the skin have similar structures with multiple cell layers at different degrees of maturation. The buccal mucosa, however, lacks the intercellular lamellar bilayer structure found in the stratum corneum, and hence is more permeable. An additional factor contributing to the enhanced permeability is the rich blood supply in the... 

To obtain an additional enhancement effect alongside the creation of pores in the stratum corneum bilayers... 

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. 

Tezel and Mitragotri [66] describe a theoretical analysis of the interaction of cavitation bubbles with the stratum corneum lipid bilayers. Three modes were evaluated—shock-wave emission, microjet penetration into the stratum corneum, and impact of microjet on the... 

Tezel, A., and S. Mitragotri. 2003. Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis. Biophys J 85 3502. 

Chemical PEs have recently been studied for increasing transdermal delivery of ASOs or other polar macromolecules [35]. Chemically induced transdermal penetration results from a transient reduction in the barrier properties of the stratum corneum. The reduction may be attributed to a variety of factors such as the opening of intercellular junctions due to hydration [36], solubilization of the stratum corneum [37, 38], or increased lipid bilayer fluidization [39, 40]. Combining various surfactants and co-solvents can be used to achieve skin penetration, purportedly resulting in therapeutically relevant concentrations of ASO in the viable epidermis and dermis [41]. In summary, it appears feasible to deliver ASO to the skin using a number of different delivery techniques and formulations. 

---