Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery

Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages ove r the conventional dosage forms such as tablets, capsules and injections. C urrently there are about eight drugs marketed as transdermal patches. Examp les of such products include nitroglycerin (angina pectoris), clonidine (hy pertension), scopolamine (motion sickness), nicotine (smoking cessation), f entanil (pain) and estradiol (estrogen deficiency). Since skin is an excell ent barrier for drug transport, only potent drugs with appropriate physi-co chemical cochemical properties (low molecular weight, adequate solubility i n aqueous and non-aqueous solvents, etc) are suitable candidates for transd ermal delivery. Penetration enhancement technology is a challenging develop ment that would increase significantly the number of drugs available for tr ansdermal administration. The permeation of drugs through skin can be enhan ced by physical methods such as iontophoresis (application of low level ele ctric current) and phonophoresis (use of ultra sound energy) and by chemica l penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance th e permeation of drugs across the skin. The CPE increase skin permeability b y reversibly altering the physicochemical nature of the stratum corneum, th e outer most layer of skin, to reduce its diffusional resistance. These com pounds increase skin permeability also by increasing the partition coeffici ent 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 t he enhancement of TDD, the mechanism of action of different chemical enhanc ers and the structure-activity relationship of selected and extensively stu died enhancers such as fatty acids, fatty alcohols and terpenes. Based on t he chemical structure of penetration enhancers (such as chain length, polar ity, level of unsaturation and presence of some special groups such as keto nes), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhan cement. Our review also discusses the various factors to be considered in t he selection of an appropriate penetration enhancer for the development of transdermal delivery systems.