Cutaneous drug delivery

While the model helps us understand the chemical structure dependencies of skin permeability, it isn t all that useful for calculating permeability coefficients because of the many iffy assumptions it contains. A different tack has to be taken to gain a sense of the limits, especially the upper limit, of cutaneous drug delivery. There is no lower limit. Even proteins penetrate intact skin to some extent. Some idea of the upper... 

M. Kreilgaard. Assessment of cutaneous drug delivery using microdialysis. Adv. Drug Deliv. Rev. 54 S99-S I2 I (2002). 

Kreilgaard M. Influence of microemulsions on cutaneous drug delivery. Adv Drug Delivery Rev 2002 54 S77-S98. 

Fresta, M., and G. Puglisi. 1996. Application of liposomes as potential cutaneous drug delivery systems. In vitro and in vivo investigation with radioactively labelled vesicles. J Drug Target 4 95. 

Whereas microneedles are designed to pierce through the outer layers of skin, the controlled destruction or adhesive removal of the stratum corneum represent alternative methods for overcoming the penetrative barrier to cutaneous drug delivery. 

P. Wotton, B. Mollgaard, J. Hadgraft, and A. Hoelgaard, Vehicle effect on topical drug delivery. III. Effect of azon on the cutaneous permeation of metronidazole and propylene glycol, Int. J. Pharm. 24 19-26 (1985). 

Noonan, P.K. and R.C. Wester (1989). Cutaneous metabolism of xenobiotics, in Percutaneous Absorption Mechanisms, Methodology, Drug Delivery, 2nd Edn, R.L. Bronaugh and H.I. Maibach (Eds), Marcel Dekker, New York, pp. 53-75. 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

Noonan, P. K., and R. C. Wester. 1989. Cutaneous metabolism of xenobiotics. In Percutaneous absorption Mechanisms, methodology, drug delivery, 2nd ed. Edited by R. L. Bronaugh, and H. I. Maibach. New York Marcel Dekker, pp. 53-75. 

Schmidt, R. J. 1989. Cutaneous side effects in transdermal drug delivery Avoidance strategies. In Transdermal drug delivery, edited by J. Hadgraft and R. H. Guy. New York Marcel Dekker, pp. 83-97. 

Guy RH, Hadgraft J, Bucks DA (1987) Transdetmal drug delivery and cutaneous metabolism. Xenobiotica 17 325-343... 

Cutaneous biotransformation is mostly associated with the stratum basale layer where there can be phase I and phase II metabolism. However, the skin is not very efficient, compared to the liver. The epidermal layer accounts for the major portion of biochemical transformations in skin, although the total skin activity is low (2-6% that of the liver). Where activity is based on epidermis alone, that layer is as active as the liver or, in the case of certain toxicants, several times more active. For some chemicals, metabolism can influence absorption, and transdermal delivery systems of drugs utilize this activity. For example prodrug such as lipid esters are applied topically, and cutaneous esterases liberate the free drug. These basal cells and extracellular esterases have been shown to be involved in detoxification of several pesticides and bioactivation of carcinogens such as benzo(a)pyrene. For rapidly penetrating substances, metabolism by the skin is not presently considered to be of major significance, but skin may have an important first-pass metabolic function, especially for compounds that are absorbed slowly. 

The different steps involved in drug transfer from a delivery system to the cutaneous circulation are shown in Figure 2 [7-10]. Drugs diffusing through the skin may be subject to various loss processes which are difficult to quantify but will be discussed. The first step in the total transfer process is diffusion from the device. In its simplest form, the device could be an ointment base which will... 

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