Stratum corneum disrupting

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]. 

Exfoliants such as glycolic acid or lactic acid result in decreased corneocyte adhesion and stimulate epidermal growth by disrupting the stratum corneum... 

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 18.4 Methylene blue staining of dry-etch (a) and wet-etch (b) microneedle-treated human skin. Disruptions within the stratum corneum indicate microneedle penetration efficiency. 

Cosmetic creams and lotions may be formulated with ingredient designed to penetrate the outer layer of the skin (the stratum corneum), or explicitly not to enter this layer. Liposomes can be a useful means of delivering selected chemical species since they form lamellar liquid crystalline structures on the surface of skin, do not disrupt the outermost layer of skin and therefore do not cause skin irritation [236]. See also Section 14.2 on vesicles and drug delivery. 

Feingold and his coworkers demonstrated an important role of nuclear hormone receptor on epidermal differentiation and stratum corneum barrier formation. Activation ofPPARa Peroxisome proliferator-activated receptor a by farnesol also stimulated the differentiation of epidermal keratinocytes.42 Cornified envelope formation, involcrin, and transglutaminase protein, and mRNA levels were also increased by the activation of PPARo . Interestingly, the inflammatory response was also inhibited by the treatment.43 They also showed that topical application of PPARo activators accelerated the barrier recovery after tape stripping or acetone treatment and prevented the epidermal hyperplasia induced by repeated barrier disruption.42 Regulation of the nuclear hormone receptor would open a new possibility for improvement of the cutaneous barrier. 

Fluhr, J.W. et al., Impact of anatomical location on barrier recovery, surface pH and stratum corneum hydration after acute barrier disruption, Br. J. Dermatol., 146, 770, 2002. 

To improve topical therapy, it is advantageous to use formulation additives (penetration enhancers) that will reversibly and safely modulate the barrier properties of the skin. Fick s first law of diffusion shows that two potential mechanisms are possible. The two constants that could be altered significantly are the diffusion coefficient in the stratum corneum and the concentration in the outer regions of the stratum corneum. Thus, one of mechanisms of action of an enhancer is for it to insert itself into the bilayer structures and disrupt the packing of the adjacent lipids, thereby, reducing the microviscosity. The diffusion coefficient of the permeant will increase This effect has been observed using ESR and fluorescence spectroscopy [16,17]. 

Due to the brick-and-mortar structure of the stratum corneum, the skin is a difficult layer to permeate across for most active pharmaceutical ingredients. Because of this diffusional barrier, new strategies have been developed to allow compounds to better penetrate the stratum corneum [28], These strategies can be defined as either chemical or physical approaches to disrupting the barrier function of the skin. 

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. 

Stratum corneum, the nonliving layer of skin, is refractory as a substrate for chemical reactions, hut it has a strong physical affinity for water. The chemical stability of stratum corneum is evident in its mechanical barriers which include insoluble cell membranes, matrix-embedded fibers, specialized junctions between cells, and intercellular cement. The hygroscopic properties of stratum corneum appear to reside in an 80 A-thick mixture of surface-active proteins and lipids that forms concentric hydrophilic interfaces about each fiber. This combination of structural features and surface-active properties can explain how stratum corneum retains body fluids and prevents disruption of living cells by environmental water or chemicals. 

Mono- and sesquiterpenes are known to increase percutaneous resorption by increasing the diffusion in the stratum corneum and/or disruption of the intercellular lipid barrierJ It has been shown that there is a major difference between different types of terpenes e.g., it was shown that d-limonene did not disrupt the intercellular bilayers, whereas 1-8-cineole seemed lipid disruptive at physiological temperatures/ ... 

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 cornified cell envelope is the outermost layer of a corneocyte, and mainly consists of tightly bundled keratin filaments aligned parallel to the main face of the corneocyte. The envelope consists of both protein and lipid components in that the lipid is attached covalently to the protein envelope. The envelope lies adjacent to the interior surface of the plasma membrane. " The corneocyte protein envelope appears to play an important role in the structural assembly of the intercellular lipid lamellae of the stratum corneum. The corneocyte possesses a chemically bound lipid envelope comprised of A-co-hydroxyceramides, which are ester linked to the numerous glutamate side chains provided possibly by both the ot-helical conformation and p-sheet conformation of involucrin in the envelope protein matrix. In the absence of A-oo-hydro-xyceramides, the stratum corneum intercellular lipid lamellae were abnormal and permeability barrier function was disrupted. 

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... 

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