Penetration enhancer lipid organization

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 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.

In the case of fatty acids, optimal penetration enhancement has been achieved with a chain length of approximately 9-12. In all cases correlation between the effect and chain-length was parabolic [102-106], Most probably this is due to a balance between the ability of the fatty acid to partition into the SC, which requires a certain degree of lipophilicity, and the ability to change the lipid organization in such a way that increased permeation is achieved when the penetration enhancer itself is in a fluid phase at physiological temperature. For example, long-chain unsaturated fatty acids are not able to create a fluid phase in the SC lipid domains, unless a eutectic mixture is formed with the SC lipids or unless the fatty acid is still dissolved in the solvent, in which it has been applied to the skin surface. 

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