Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages over the conventional dosage forms such as tablets, capsules and injections. Currently there are about eight drugs marketed as transdermal patches. Examples of such products include nitroglycerin (angina pectoris), clonidine (hypertension), scopolamine (motion sickness), nicotine (smoking cessation), fentanil (pain) and estradiol (estrogen deficiency). Since skin is an excellent barrier for drug transport, only potent drugs with appropriate physicochemical properties (low molecular weight, adequate solubility in aqueous and non-aqueous solvents, etc) are suitable candidates for transdermal delivery. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for transdermal administration. The permeation of drugs through skin can be enhanced by physical methods such as iontophoresis (application of low level electric current) and phonophoresis (use of ultra sound energy) and by chemical penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance the permeation of drugs across the skin. The CPE increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum, the outer most layer of skin, to reduce its diffusional resistance. These compounds increase skin permeability also by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle. This review compiles the various CPE used for the enhancement of TDD, the mechanism of action of different chemical enhancers and the structure-activity relationship of selected and extensively studied enhancers such as fatty acids, fatty alcohols and terpenes. Based on the chemical structure of penetration enhancers (such as chain length, polarity, level of unsaturation and presence of some special groups such as ketones), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhancement. Our review also discusses the various factors to be considered in the selection of an appropriate penetration enhancer for the development of transdermal delivery systems.

Transdermal iontophoresis is the administration of ionic therapeutic agents through the skin by the application of a low-level electric current. This article presents an overview of transdermal iontophoretic delivery of drugs, including peptides and oligonucleotides. Recent advances in the area of iontophoretic delivery, including devices, hydrogel formulations, safety, clinical relevance and future prospects, are discussed. Electroporation, another method of electrically assisted drug delivery, is also briefly reviewed. Transdermal iontophoresis appears to be a promising technique for the delivery of a variety of compounds in a controlled and preprogrammed manner. Transdermal iontophoresis would be particularly useful in the delivery of hydrophilic drugs produced by biotechnology (peptides and oligonucleotides). However, because of the complex physicochemical properties of peptides, many factors must be carefully considered for the proper design of an iontophoretic drug delivery system for peptides. Iontophoresis has been successfully used in the delivery of small peptides, such as leuprolide and calcitonin analogues, in humans. However, it appears that transdermal iontophoresis may not be a suitable method for the systemic delivery of larger peptides (>7,000D). The combined use of iontophoresis and electroporation may be more effective in the delivery of peptides, proteins, genes and oligonucleotides. The long-term safety of iontophoresis, patient compliance with the technique and the commercial success of this technology are yet to be demonstrated. Iontophoretic delivery of drugs would be beneficial in the treatment of certain skin disorders such as skin cancer, psoriasis, dermatitis, venous ulcers, keloid and hypertrophic scars. Investigations on reverse iontophoresis may yield interesting results that would be useful in the noninvasive measurement of clinically important molecules in the body.

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Transdermal delivery of melatonin would be advantageous in the treatment of sleep disorders considering the short biological half-life of melatonin and its variable bioavailability via the oral route. This study looked at suitable penetration enhancers for the transdermal permeation of melatonin. The permeation of melatonin was enhanced by all saturated and unsaturated fatty acids across both rat and porcine skin. There was a parabolic relationship between the carbon chain length of saturated fatty acids and the enhancement of melatonin permeation across rat and porcine skin. For rat skin, the maximum flux was observed with undecanoic acid (45.33 microg cm(-2) h(-1)) which enhanced the flux of melatonin 8.6 times compared with the control, whereas lauric acid produced the maximum flux of melatonin (24.98 microg cm(-2) h(-1); 4-7 times) across porcine skin. An increase in the number of double bonds in cis-9-octadecanoic acid increased the flux of melatonin across rat skin. In contrast, with porcine skin, the flux of melatonin decreased as the number of double bonds increased, although the flux values were not statistically significant. Treatment of rats with undecanoic acid, oleic acid and linolenic acid for 3 h using Hill top chamber enhanced the transepidermal water loss significantly. The maximum transepidermal water loss was observed with undecanoic acid and linolenic acid among saturated and unsaturated fatty acids, respectively. Nonanoic acid and myristic acid did not cause a significant change in the transepidermal water loss. The enhancement effect of saturated fatty acids on the permeation of melatonin was dependent on the chain-length of the fatty acid in both rat and porcine skin. While an increase in the number of double bonds in the fatty acid increased the flux of melatonin in rat skin, no significant difference in the flux was observed with porcine skin. The permeation enhancement of melatonin by saturated and unsaturated fatty acids across rat skin was significantly higher than that of porcine skin. A positive correlation was observed between the permeation enhancement effect of the fatty acids across rat skin in-vitro and the transepidermal water loss in rats in-vivo, suggesting that there is a similarity in the mechanism by which fatty acids enhance the permeation of melatonin and in the enhancement of transepidermal water loss. We conclude that saturated fatty acids such as undecanoic acid or lauric acid which showed maximum permeation across rat and porcine skin, respectively, may be used as potential penetration enhancers in the development of a transdermal delivery system for melatonin.

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