**5. Methods of modulation of cutaneous permeability**

When a substance is applied on the skin with a simple vehicle the therapeutic result can be unsatisfactory because of the insufficient concentration obtained in the application area [**25**]. In the last few years strategies have been developed in order to increase the efficacy of the vehicle [**26**]. They may be of chemical, biochemical or physical order.

#### **5.1 Chemical enhancers**

In order to increase the penetration the vehicle may be integrated with enhancers that by interacting with intercellular lipids improve the diffusion coefficient of the substance in the stratum corneum. Chemical enhancers may: a) increase the diffusibility of the substance inside the barrier, b) increase the solubility in the vehicle or both, or c) improve the partition coefficient.

These substances may frequently have a not specific action. Enhancers of this type, that are not widely used, are Azone, Dermac SR-38, and oleic acid [**27**]. In some cases, however, these have an irritating effect and must be carefully evaluated in the various preparations [**28**].

Excipients like ethanol, propylene-glycol, and dimethylsulfoxide (DMSO) may increase the diffusion by altering the organization of lipids of the horny layer [**29**]. The interference with the biosynthesis of some lipids may alter the structure of the barrier and increase the penetration. Methods have also been studied that interfere with secretion and organization of lipids (e.g., brefeldine, monetine, and cloroquine). In addition, enhancers that alter the supramolecolar organization of the bistratified lamellae (synthetic analogs of fats, inducing abnormalities of the organization of the membranes; complex precursors that can not be metabolized, etc.) have been studied. These methods produce an alteration of the critical molar ratio among ceramides, cholesterol, and fatty acids; if there is decrease or excess of one of these 3 key lipids, the lamellar organization cannot be maintained. There may be separation of the phases with more permeable interestitial spaces and formation of a new way of penetration [**30**].

The efficacy of the enhancers may be increased by inhibition of the metabolic reaction of repair once the alteration of the barrier has been obtained. This would involve inhibiting metabolic sequences that can rebuild and maintain the barrier function. Inhibitors of enzymes with relevant functions (e.g., lovastatin) or specific inhibitors of enzymes synthesizing ceramides or fatty acids induces alteration of the molar ratio of the three critical lipids and leads to discontinuity in the lamellar layer system [**31**]. Other enhancements may be obtained by modifying the polarity [**32**].

The number of drugs for which transdermic methods for systemic use has been possible is very small and restricted to lipophilic and low molecular weight substances (e.g. nicotinic acid, nitroglycerin, clonidine, steroid hormones, and scopolamine) [**33**].

#### **5.2 Carrier vesicular systems**

64 Contact Dermatitis

amount of water linked to polar groups by hydration does not alter the organization of lipids and does not reduce of permeability [**17**]. The effect of the hydration however has a discontinuous effect; the increase in permeability may be by ten times for some substances and very limited for others [**18**]. Occlusion partially hinders the loss of humidity of the skin, increasing the content of water of the horny layer. However the NMF level in the horny layer is almost zero. It seems therefore that there is a homeostatic mechanism that prevents hyperhydration of the skin [**9**]. Occlusion may increase the absorption by several times, especially for hydrophilic compounds. However, in some conditions it may promote the formation of a reservoir effect. The acidity of the cutaneous surface, controlling homeostasis and enzymatic activities, influences permeability [**19**]; the metabolic activity of the skin (enzymatic oxidoreductive processes) may modify the substances applied, influencing

Absorption is also influenced by other skin properties that vary at different cutaneous anatomical sites. For instance, the absorption diminishes greatly as one moves from the

Age influences skin absorption. Various biological activities are lower in the skin of the aged individual. Great variation is also noted for the premature infant and neonate, who have greater cutaneous permeability [**21**]. There are no experimental data confirming the validity of friction on transcutaneous absorption [**6**]. Alterations of the barrier induce modifications of TEWL [**9**]. In addition, the horny layer may be defined as a biosensor; alterations of external humidity regulate proteolysis of filaggrin, synthesis of lipids, DNA, and proteins

The cutaneous bioavailability of most commercial dermatological formulations IS about

The active substances of topical formulations are generally absorbed in small quantities; only a reduced fraction passes from the vehicle into the stratum corneum. The greater part remains on the surface of the skin, subject to loss in several ways such as by sweating, chemical degradation, and removal. Future standards would therefore aim to make formulations not merely high in concentration, but pharmaceutically optimized to have an elevated (50-100%) bioavailability. On the other hand, one must consider the marked variations of the different cutaneous areas and skin conditions that make uncertain the therapeutic equivalence when compared with other ways of administration in clinical

When a substance is applied on the skin with a simple vehicle the therapeutic result can be unsatisfactory because of the insufficient concentration obtained in the application area [**25**]. In the last few years strategies have been developed in order to increase the efficacy of the

In order to increase the penetration the vehicle may be integrated with enhancers that by interacting with intercellular lipids improve the diffusion coefficient of the substance in the

within keratinocytes, which can lead also to inflammatory phenomena [**22**].

**5. Methods of modulation of cutaneous permeability** 

vehicle [**26**]. They may be of chemical, biochemical or physical order.

permeability and effects.

1-5% of applied dose [**23**].

conditions [**24**].

**5.1 Chemical enhancers** 

palpebral skin to the plantar surfaces [**20**].

Liposome formulations can be very effective. However, they probably increase penetration only through the transappendigeal avenue [**34**]. Niosomes and transferosomes, formed by modified liposomes (phosphatidilcoline, sodium cholate, ethanol), are systems based on the ability of vesicles to cross the unaltered horny layer because of the osmotic gradient between external and internal layers of the barrier. These are "flexible" vesicles able to transport their contents through the intercellular tortuous route of the corneous layer.

#### **5.3 Scratch-patch test**

Although closed patch tests are the mainstay for the evaluation of allergic contact dermatitis, occasionally, even when appropriate concentrations of allergens are used and contact allergy is strongly suspected, positive reactions are not always obtained. As in the cases that will be described patch test with high molecular weight substances as heparin,

Topical Delivery of Haptens: Methods of Modulation of the

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Pharmacokinetics 1987. p 1-9.

York: Marcel Dekker, Inc; 2002. p 401-498.

corneum. Skin Pharmacol 1997;10:235-46.

xerotic skin. Br J Dermatol Res 1989;121:588-64.

modulator. J Invest Dermatol 1991;96:845-51.

Marcel Dekker, Inc; 2002. p 61-88.

2nd Ed; 2006.

1983;24:120-30.

2002. p 89-195.

1969-78

1998;9:65-9.

1968;80:437-50.

**6. References** 

Cutaneous Permeability to Increase the Diagnosis of Allergic Contact Dermatitis 67

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[2] Smith EW, Maibach HI. Penetration percutaneous enhancers. UK: Taylor and Francis,

[3] Lampe MA, Burlingame AL, Whitney J, Williams ML, Brown BE, Roitman E. Human

[4] Elias PM, Menon GK. Structural and lipid biochemical correlates of the epidermal

[5] Elias PM, Tsai JC, Menon GK, editor. Skin barrier, percutaneous drug delivery and

[6] Elias PM, Feingold KR, Menon JK. The stratum corneum, two compartments model and

[7] Surber C, Davis AF. Bioavailability and Bioequivalence of Dermatological Formulations

[8] Roberts MS, Cross SE, Pellett MA. Skin transport. In: Kenneth AW, editor.

[9] Menon GK, Elias PM. Morphologic basis for a pore-pathway in mammalian stratum

[10] Watkinson AC, Brain KR. Basic mathematical principles in skin permeation.: In:

[12] Franz TJ. Pharmacokinetics and skin in: Skin barrier, percutaneous drug delivery and

[13] Orecchia G, Sangalli ME, Gazzaniga A, et al. Topical photochemotherapy of vitiligo

[14] Roberts M, Cross SE, Pellett MA. Skin transport In: Kenneth AW, editor. Dermatological and Transdermal Formulations. New York: Marcel Dekker, Inc; 2002. [15] Middleton JD. The mechanism of water binding in stratum corneum. Br J Dermatol

[16] Horii I, Nakajama Y, Obate Ml. Stratum corneum hydration and aminoacids contant in

[17] Imokawa G, Kuno H, Kawai M. Stratum corneum lipids serve as bound-water

[11] Franz TJ. Kinetics of cutaneous drug penetration. Int J Dermatol 1983;22:499-505.

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pharmacokinetics. Mosby: Dermatology; 2003. p 1235-52.

Bronaugh RL, Maibach HI. Percutaneous Absorption: Drugs - Cosmetics - Mechanisms - Methodology (Drugs and the Pharmaceutical Sciences). Informa

stratum corneum lipids: characterization and regional differences. J Lipid Res

its functional implication. In: Basel, Karger Shroot B, Shaefer H, editors. Skin

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Dermatological and Transdermal FormulationsNew York: Marcel Dekker, Inc;

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with a new khellin formulation: preliminary clinical results. J Dermatol Treat

or low molecular weight as acyclovir may give doubtful results in sensitized patients, possibly due to poor penetration of this substances through the epidermis. Scratch–patch testing, by compromising epidermal barrier function, enables enhanced penetration of substances into the skin [**35-37**]. The method is performed by causing mechanical injury to the epidermis with a sterile skin prick lancet in order to compromise the stratum corneum, which represents the most important barrier limiting hapten penetration. The test reactions are usually read after D2 and D3, when possible, also after D4 and D7. The method of grading a positive scratch–patch test is identical to that used for conventional patch testing with no differences. It can be used for many drugs: low molecular wheight molecules (e.g. *β*-blockers, antiviral drugs etc.) and also high molecular wheight molecules (e.g. heparin etc.):
