Appendages route

The skin permeation capacity of a drug is a function of the physicochemical properties of the permeating agent. Broadly, three possible routes of skin transport, namely, intercellular, transcellular, and appendageal routes, are advocated [Roberts et al., 2002] [Fig. 16.3]. 

This synthetic route, reported in 1969 by Tichy and Sicher [13], differs from the Whitlock approach discussed earlier, because it involves a key synthetic intermediate of type C (Scheme 13.1.1). That is to say, the bicyclo[2.2.2]octane precursor bears two appendages in contrast to the intermediate of type B involved in Whitlock s synthesis. 

The transcellular pathway has been discredited as a major pathway, although some polar substances can penetrate the outer surface of the protein filaments of hydrated stratum comeum. The transfollicularpathway is really an invagination of the epidermis into the dermis, and the chemical still has to penetrate the epidermis to be absorbed into the blood stream. This is also a regarded as minor route. Sweat pores are not lined with the stratum comeum layer, but the holes are small, and this route is still considered a minor route for chemical absorption. In general, the epidermal surface is 100 to 1000 times the surface area of skin appendages, and it is likely that only very small and/or polar molecules penetrate the skin via these appendages. 

The major barrier of the skin is the outermost dead layer, the stratum corneum. A number of routes of penetration of a drug, across this region can be identified. First, the appendages, the pilosebaceous and eccrine glands, form a potential shunt route across the stratum corneum. The relative surface area of these is very small (<0.1%) and there has been little conclusive evidence to suggest that this is a major route. Second, the penetrant could diffuse across the entire stratum corneum through the dead cells, the corneocytes. A large surface area is available but the... 

Taken together with the other work described above, the SECM results emphasize the importance of appendageal pathways in iontophoresis. However, it is clear that both the SECM and the VPE show that nonappendageal routes exist as well, and that neither technique can visualize or quantify the pathways of ion flow within the skin. Further mechanistic work addressing these gaps in our knowledge is therefore warranted. 

The xanthate transfer process provides a simple and uniquely powerful route to a-tetralones, another family of important aromatic derivatives [69-71]. a-Tetralones are starting materials for the synthesis of a host of medicinally important compoimds. They are precursors to naphthalenes, naphthols, naphthylamines, and ring expansion through the Beckmann rearrangement provides access to benzazepine derivatives. The two examples in Scheme 34 illustrate, on one hand, the possibility of preparing a tetralone with a carbohydrate-derived appendage [69] and, on the other, the synthesis of a substituted naphthol 59 by aromatisation of tetralone 58 through acid... 

SAFETY PROFILE Poison by ingestion, intraperitoneal, parenteral, intravenous, and intramuscular routes. Human systemic effects by ingestion (skin and appendages) hair effects. Human mutation data reported. An experimental teratogen. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of NOx. 

Fig. 1 Routes of passive penneation across the stratum comeum (SC) (a) intercellular lipid pathway (b) appendageal transport and (c) transcellular path.

Recently, ionic liquids with amino acids as anions were synthesized by neutralization between [C2mim][OH] and amino acids [88], Tetrabutylphosphonium amino acids [P(C4)4][AA] were synthesized by the reaction of tetrabutylphosphonium hydroxide [P(C4)4][OH] with amino acids, including glycine, L-alanine, l-/1-alanine, L-serine and L-lysine [89], The esters or amide derivatives of bromoacetic acid were either commercially available or formed in one step via the reaction of bromoacetyl bromide with the appropriate alcohol or amine [90-92], An advantage of this route is that a wide range of ester and amide side chains can be prepared easily. For ionic liquids with anions other than bromide, a metathesis reaction was employed to introduce the counter ion of choice. Additionally, functionalized ionic liquids with electrophilic alkene-type appendages were synthesized. 

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