**1. Introduction**

396 Pharmacology

Tejedor, A.; Torres, A.M.; Castilla, M.; Lazaro, J.A.; de Lucas, C. & Caramelo, C. (2007).

Xiao, Z.; Li, C.; Shan, J.; Luo, L.; Feng, L.; Lu, J.; Li, S.; Long, D. & Li, Y. (2011). Mechanisms

ISSN 0300-7995

0250-8095

Cilastatin protection against cyclosporin A-induced nephrotoxicity: clinical evidence. *Current Medical Research Opinion*, Vol.19, No.10, (March 2007), pp. 505-13,

of renal cell apoptosis induced by cyclosporine A: a systematic review of in vitro studies. *American Journal of Nephrology*, Vol.33, No.69, (May 2011), pp. 558-66, ISSN

> The application of preparations to the skin for medical purposes is as old as the history of medicine itself, with references to the use of ointments and salves found in the records of Babylonian and Egyptian medicine.(López-Castellano & Merino, 2010) The historical development of permeation research is well described by Hadgraft & Lane, 2005. Over time, the skin has become an important route for drug delivery in which topical, regional or systemic effects are desired (Domínguez-Delgado, et al., 2010). Nevertheless, skin constitutes an excellent barrier and presents difficulties for the transdermal delivery of therapeutic agents, since few drugs possess the characteristics required to permeate across the stratum corneum in sufficient quantities to reach a therapeutic concentration in the blood. In order to enhance drug transdermal absorption different methodologies have been investigated developed and patented (Rizwan et al., 2009). To date many chemical and physical approaches have been applied to increase the efficacy of the material transfer across the intact skin. These are termed 'Novel' due to recent development with satisfactory results in the field of drug delivery (Patel et al., 2010). Improvement in physical permeationenhancement technologies has led to renewed interest in transdermal drug delivery. Some of these novel advanced transdermal permeation enhancement technologies include: iontophoresis, electroporation, ultrasound, microneedles to open up the skin and the use of transdermal nanocarriers (Díaz-Torres, 2010; Escobar-Chávez & Merino, 2010a).

<sup>\*</sup> Corresponding Author

Chemical and Physical Enhancers for Transdermal Drug Delivery 399

area of 0.1%. In this way, diffusion through the skin is controlled by the particular characteristics of the stratum corneum. In order to obtain a sufficient drug flux and, in turn, the therapeutical objectives in question, an alternative is to use chemical percutaneous enhancers. These substances alter some of the properties of the stratum corneum. (López-

**2.2 Direct effects on the skin due to the use of transdermal penetration enhancers** 

The lipid–protein-partititioning theory sets out the mechanisms by which enhancers alter skin lipids, proteins and/or partitioning behaviour (Barry, 1991): i) They act on the stratum corneum intracellular keratin by denaturing it or modifying its conformation, causing subsequent swelling and increased hydration; ii) They affect the desmosomes that maintain cohesion among corneocytes; iii) They modify the intercellular lipid domains to reduce the barrier-like resistance of the bilayer lipids. Disruption to the lipid bilayers can be homogeneous when the enhancer is distributed evenly within the complex bilayer lipids, but the accelerant is more likely to be heterogeneously concentrated within the domains of the bilayer lipids and iv) They alter the solvent nature of the stratum corneum, thus aiding the partitioning of the drug or a co-solvent into the tissue.(López-Castellano & Merino, 2010)

**2.3 Indirect effects on the skin due to the use of transdermal penetration enhancers**  Chemical enhancers can produce: *a)* Modification of the thermodynamic activity of the vehicle. The permeation of a good solvent from the formulation, such as ethanol, can increase the thermodynamic activity of a drug; *b)* It has been suggested that, by permeating through the membrane, a solvent can 'drag' the permeant with it, though this concept is somewhat controversial and requires confirmation; *c)* Solubilising the permeant within the donor, especially when solubility is very low, as in the case of aqueous donor solutions, can reduce depletion effects and prolong drug permeation.(López-Castellano & Merino, 2010)

The classification of percutaneous enhancers is frequently based on the chemical class to which

**Pyrrolidones and derivatives** N-methyl-2-pyrrolidone, 2-pyrrolidone **Azone and derivatives** Azone® (1-dodecylazacycloheptan-2-one)

> **Terpenes** Menthol, Limonene **Fatty acids** Oleic acid, Undecanoic acid

**Alcohols** Ethanol, Caprylic alcohol, Propylene glycol

Sodium lauryl sulfate, Cetyltrimethyl amonium bromide, Sorbitan monolaurate, Polisorbate 80, Dodecyl dimethyl ammoniopropane sulfate

the compounds belong. Table 1 shows the principal classes of percutaneous enhancers.

**Dioxolane derivatives** SEPA®

**CHEMICAL CLASS COMPOUNDS Water** Water **Sulfoxides and similar chemicals** Dimethyl sulfoxide, Dodecyl methyl sulfoxide **Ureas** Urea

**2.4 Classification of percutaneous chemical enhancers** 

**Surfactants (Anionic, Cationic, Nonionic, Zwitterionic)** 

Table 1. Principal classes of percutaneous enhancers.

Castellano & Merino, 2010)
