Stratum corneum intercellular penetration

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. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

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. 

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. 

A number of works investigated the interaction between niosomes and human skin. With niosomes prepared from Ci2 alcohol polyoxyethylene ether and cholesterol, vesicular structures of about 100 nm size have been observed between the first and second layers of human corneocytes 48 h after incubation as well as in the deeper strata of the skin [37], The authors concluded that the structures visualized in the deeper regions could be vesicles reorganized from individual molecules that penetrated the skin. In another study, electron micrographs illustrated that niosomes containing surfactants and cholesterol affected only the most superficial corneocytes. Moreover, two-photon fluorescence microscopy confirmed that fluorescent probe encapsulated in niosomes was confined to the intercellular spaces within the apical stratum corneum layers [56]. 

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. 

Figure 7 The possible mechanisms involved in the effect of penetration enhancers on the lipid organization of the intercellular domains in the stratum corneum. (A) Intercalation of the enhancer in the lipid lamellae. (B) Phase separation between enhancer and skin lipids in the lamellae. (C) Phase separation between lipid lamellae and an enhancer-rich phase. (D) Intercalation of the enhancer in the lipid lamellae and simultaneous phase separation between lipid lamellae and enhancer. (E) Phase separation within the lamellae and separation between an enahncer-rich phase and the lamellar phase. (F) Disappearance of the lamellar phases.

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. 

In addition to movement through shunts, polar substances may diffuse through the outer surface of the protein filaments of the hydrated stratum corneum, while nonpolar molecules dissolve in and diffuse through the nonaqueous lipid matrix between the protein filaments. The rate of percutaneous absorption through this intercellular lipid pathway is correlated to the partition coefficient of the penetrant, as presented above in Fick s law. 

Another popular physical enhancement method that has routes in physical therapy and sports rehabilitation clinics is sonophoresis. Sonophoresis involves the use of ultrasound as a source of disrupting intercellular lipid structures in the stratum corneum [39,40].The sound waves produced by the device induce cavitation of the lipids found within the stratum corneum, which then opens channels and allows the chemical compound to easily penetrate the skin. This is a safe and reversible process that has received much attention in the literature and by pharmaceutical companies. 

The particles of cyclodextrin-grafted silicone are also the vehicles for the transport of the active substance to the site of its therapeutic action. In the case of anti-fnngal dosage form for topical administration action, penetration and slow release in the skin is searched for [21-23]. The stratum corneum top layer is made of cor-neocytes separated by a lipidic intercellular medium. Internal layers, epidermis and dermis are essentially aqueous media. The top layer is hydrophobic whereas the internal layers are hydrophilic. The penetration into the skin is controlled by the hydrophobic character of the particles. Hydrophobic materials easily penetrate and possibly accumulate in the stratum corneum. A slow release of the drug into the deep hydrophilic layers is possible from this medium. Silicone emulsions are often selected for cosmetic formulations because of the favorable spreading of silicone oils at the skin surface together with their low-irritancy properties. 

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/ ... 

The precise mode of interaction between lipid vesicles and skin remains unclear. There is considerable doubt about the ability of whole vesicles to permeate intact stratum corneum. The majority of evidence suggests that vesicles can penetrate the outer cell layers of the stratum corneum where desmosomal linkages have become disrupted and presumably, the keratinocytes are less tightly bound and surrounded by a mixture of intercellular lipid and sebum. However, continuing diffusion of vesicles through the approximately 60 nm intercellular space of the deeper layers of the stratum corneum seems unlikely. Current thinking suggests... 

Chemical absorption pathways can hypothetically involve both intercellular and intracellular passive diffusion across the epidermis and dermis and/or transappendageal routes, via hair follicles and sweat pores. Most available research has concentrated on the stratum corneum as the primary barrier to absorption, although the viable epidermis and dermis can also contribute resistance to the percutaneous penetration of specific chemical classes, for... 

Consequently, eliminating aU or part of the stratum corneum drastically enhances the absorption of physical and chemical agents that could not have penetrated an intact protective stratum corneum. The ability of a product to penetrate the skin also depends on how it interacts with the corneocytes and the intercellular matrix. At the same molecular weight, a proteolytic product will penetrate the skin more readily than a product that is not proteolytic. The more liposoluble a molecule is, the greater its partition between the vehicle and the skin barrier and as a result its ability to penetrate is improved. Another factor to be taken into account is how solvents interact ethanol diffuses better in the stratum corneum when it is mixed with oil rather than water. How well hydrated the stratum corneum is also plays an essential role in the skin s absorption capacity. When the stratum corneum is hydrated, products can be absorbed up to 10 times more efficiently. Hydration swells... 

Terminally differentiated keratinocytes of the stratum corneum are known as comeocytes and are largely devoid of normal cellular functions, being predominantly composed of protein (keratin). The ultrastructure of the stratum corneum is described by the brick and mortar model (Elias, 1983 Figure 3). The functional implication of this architecture is that some skin penetrants must diffuse via a long and tortuous route between adjacent comeocytes, thus reducing their rate of absorption. This is known as the intercellular route. In contrast, some chemicals may diffuse equally through both comeocytes and the lipid mortar, resulting in a transcellular route. 

Figure 3. Schematic representation of the stratum corneum ( Brick and Mortar model ) and corresponding routes of transcellular and intercellular penetration...

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