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These diffusivities are estimates obtained by in vitro experiment (stratum corneum) or by comparison with small tissues in which diffusivities have been measured (all others). They do not account for regional variations across the body surface, so on both counts must be considered highly approximate. bHighly approximate and variable, depending on blood flow patterns.

°This is sufficiently small to discount transeccrine diffusion contributions in the general treatment.

dAll depend on the physicochemical nature of the drug and vehicle as well as the physicochemical mature of respective tissues.

These diffusivities are estimates obtained by in vitro experiment (stratum corneum) or by comparison with small tissues in which diffusivities have been measured (all others). They do not account for regional variations across the body surface, so on both counts must be considered highly approximate. bHighly approximate and variable, depending on blood flow patterns.

°This is sufficiently small to discount transeccrine diffusion contributions in the general treatment.

dAll depend on the physicochemical nature of the drug and vehicle as well as the physicochemical mature of respective tissues.

It is thought that both the stratum corneum and the sebum are, to first good approximations, lipoidal routes. Consequently, drug substances of diminishing polarity should partition out of water into the key transport regimes within these routes to increasing extents. Homologues formed by extending the length of an alkyl chain provide a means for testing this hypothesis because of the fact that oil/water (o/w) partition coefficients of alkyl homologues grow exponentially. One can therefore probe the fundamental physical behaviors of lipid membranes as long as (in the permeability domain where) permeability coefficients are directly related to o/w partitioning. The slope of log (partition coefficient)

against alkyl chain length plot indicates the sensitivity of partitioning between the phases in question to the addition of a methylene group (a -CH2- group). The value of ¿[log (Ko/w)]/ dn, the slope, is referred to as the 7t-value for the partitioning system in question. The revalue for the partitioning of homologues between octanol and water is very close to 0.5. Thus, regardless of the homologous series in question, octanol/water partition coefficient increases by a factor of about 10 for every two methylene units added to an alkyl chain. With a 7t-value of greater than 0.6, hexane/water partitioning evidences an even greater lipoidal sensitivity. On the basis of permeation of n-alkanols through human skin (and the permeability partitioning relationship), human stratum corneum appears have a 7t-value slightly less than 0.3 (3). The low partitioning sensitivity to the addition of a methylene group suggests that the stratum corneum's lipoidal phase is considerably more polar than the reference organic solvents. This still means that, all else equal, partition coefficients increase rapidly by this route. The follicular route in seemingly more nonpolar than the route through the stratum corneum. This suggests that the region of direct partitioning dependency of permeability by this route would be narrower than found for the transdermal pathway (44,45). Recent studies have demonstrated that the correlation between partition coefficients of octanol/water, artificial sebum/water, and stratum corneum/water is somewhat complicated (41,42). A good linear relationship exists between the partition coefficient of sebum/water and the carbon chain length in the 4-hydroxybenzoate series compounds, but not for compounds with more diverse structures. The partition coefficient between stratum corneum/water is relatively higher for methyl-4-hydroxybenzoate, lower for ethyl-4-hydroxybenzoate, and then exponentially increases with the increase in alkyl chain length, reflecting the polar and nonpolar matrix property of stratum corneum. The permeability of the lipophilic compounds is much higher across sebum than across the stratum corneum, indicating that the transfollicular permeation could play a measurable role in the initial phase of percutaneous absorption, even though the relative permeation area is much smaller than for transepidermal permeation. However, the water-rich dermis functions as a primary barrier for lipophilic permeates. Excellent linear relationships between sebum permeability and log P for the 4-hydroxybenzoates homologues and hydrocortisone esters were observed, though the slopes were different (41,42). Within the tested compounds, the sebum permeability of an ionizable compound, lidocaine HC1, is six orders of magnitude lower than that of hydrocortisone 21-caprylate, demonstrating an extremely wide range of permeability of molecules across sebum plugs. Clearly, sebum serves an almost impermeable barrier to highly polar compounds but a friendly pathway to lipophilic compounds. This mechanism is critical when sebaceous glands and follicles are targeting sites and the lipophilic therapeutic agents are applied on sebaceous follicle-rich area, such as facial and scalp skin. It is well documented that molecules at log P of 2 to 3 are desirable for transdermal delivery because skin flux decreases at higher log Ps. However, the decrease in sebum flux with increased lipophilicity occurred in a more lipophilic range compared to that of skin flux. In case of the 4-hydroxybenzoic acid ester compounds, the decline in sebum flux was shown at clog P > 4 or the alkyl side chain > C6. Figure 4 demonstrates a window between hexyl 4-hydroxybenzoate and nonyl 4-hydroxybenzoate (C6-C9) in which the skin flux of these compounds is extremely low but the sebum flux and sebum partition remain high. Molecules falling into this window would be ideal candidates for sebum or follicular-targeted delivery because of lower systemic exposure and higher localization in the pilosebaceous unit.

So far only steady-state conditions for permeation have been considered. But in all phenomena involving the mass transport of substances across membranes, one also has to consider the time it takes for gradients to be set up across the membranes by molecules moving randomly within the substance of the membranes. This early period of permeation

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