Penetration Enhancers

Because transdermal absorption is relatively slow, there has been a large amount of work concerned with finding materials which will increase the penetration rate of drugs through the skin. Such materials are called penetration enhancers. Penetration enhancers are believed to operate by increasing the permeability of the stratum corneum, either in the lipid or the keratinised protein regions. It is unlikely that many materials penetrate as far as the epidermis in sufficient concentration to increase its ability to transport hydrophobic drugs. The largest class of penetration enhancers appear to fluidise the lipid channels. These include dimethyl sulphoxide (DMSO) at high concentrations, decylmethyl sulphoxide, and azone. These materials are known to influence lipid structure31 but are also polar and capable of swelling proteinaceous regions. Lipid fluidity appears to be the most important factor since at low concentrations substances such as DMSO swell keratin but do not appreciably improve absorption. However, it is only high surface concentrations (>60%) which affect skin lipid fluidity and cause an increase in drug penetration.

Certain penetration enhancers, such as propylene glycol, assist other enhancers to enter the skin. For example, azone is more soluble in propylene glycol than water, so propylene glycol assists its penetration. Additionally, propylene glycol may hydrate keratinised regions of the stratum corneum. Consequently, the azone/propylene glycol mixture is one of the most efficient of currently used penetration enhancers. Isopropyl palmitate combined with triethylene glycol monomethyl ether provides an excellent transdermal flux enhancer in vitro, but its effectiveness in vivo has not yet been reported32. A range of other enhancers of less importance, including fatty acids, esters, urea, and terpenes, have been reviewed by Walker and Smith33.

Biodegradable enhancers like dodecyl N, N-dimethylamino acetate (DDAA) and N-(2-hydroxyethyl)-2-pyrrolidone have been synthesized to decrease duration of action and toxicity. DDAA and azone caused approximately equal transdermal penetration enhancement of model drugs in vitro, but DDAA was less irritant and its irritant effects lasted for only 4 days34.

A further possibility for penetration enhancement is to influence the nature of the lipid channels by altering lipid biosynthesis in the skin. The intercellular lipid domains of the stratum corneum contain a mixture of cholesterol, free fatty acids, and ceramides. Each of these lipid classes is required for normal barrier function. Selective inhibition of either cholesterol, fatty acid, or ceramide synthesis in the epidermis delays barrier recovery rates after the barrier has been damaged. Possible enhancers using this approach are 5-(tetradecyloxy)-2-furancarboxylic acid which inhibits fatty acid synthesis, and fluvastatin which inhibits cholesterol synthesis. A study by Tsai35 in hairless mice demonstrated that these two agents in combination could increase the absorption rate of lidocaine by a factor of 8.

Surfactants appear to assist the penetration of polar materials, and it is believed that their mode of action is on the keratinised protein regions of the stratum corneum36. It is possible that a combination of hydration and protein conformational change is responsible for this effect. The most powerful surfactants, such as sodium dodecyl sulphate, denature and uncoil keratin proteins, leading to a more porous hydrated structure, through which drugs can diffuse more easily. Such materials also are known to have membrane-solubilizing actions so they probably also influence lipid structure. They are however too irritant for clinical application.

The use of colloidal systems such as liposomes to enhance drug penetration is not particularly successful to date. Conventional liposomes do not appear to pass through intact stratum corneum although there is some evidence that they are phagocytosed by keratinocytes, at least in vivo, and so may be taken up in damaged skin where the stratum corneum is broken37. A number of authors have examined the possibility that liposomes may be able to enhance the absorption of drugs by the appendageal route, but these studies are complicated by the difficulty of handling model systems38. "Transfersomes" have been used for percutanous delivery in animals and humans39. These are liposomes which are constructed from lipid mixtures which are extremely deformable, so that they can squeeze through the pores between the layers of stratum corneum lipid (typically 20-30 nm). The driving force for this penetration is the water activity gradient in the skin; if the skin is occluded so that the water concentration gradient in the stratum corneum is removed, transfersomes do not penetrate.

A number of workers have reported the use of cyclodextrins as penetration enhancers for extremely lipophilic drugs. It is difficult to assess such studies since the cyclodextrin influences the vehicle behaviour as well as that of the skin, and hydrophilic cyclodextrins would not be expected to show significant absorption through the stratum corneum. This area has been reviewed in detail by Matsuda and Arima40.

The skin will respond to drugs and/or skin permeation enhancers by inflammatory and immune reactions. A fundamental difficulty with the development of penetration enhancers is that an attempt is being made to alter the skin structure; this is almost certain to provoke an irritant reaction. Both sodium dodecyl sulphate and DMSO are irritant; azone is probably the least irritant, partly since it is active at low (1%) concentrations. This problem is made more severe since irritation is often found in transdermal therapy even before penetration enhancers are used.

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