Mechanistic study into the enhanced transdermal permeation of a model beta-blocker, propranolol, by fatty acids: a melting point depression effect.

Transdermal permeation of propranolol through human skin in the presence of fatty acid (lauric, capric) penetration enhancers has been investigated. Thermal analysis showed that binary mixtures of propranolol with either fatty acid were not simple mechanical mixtures of the two components. Propranolol formed 1:1 molar addition compounds with both lauric and capric acids; the addition compound produced from propranolol and lauric acid (m.p. 79 degrees C) also developed eutectic systems with both propranolol (m.p. 54 degrees C) and lauric acid (m.p. 16 degrees C). Similarly, the addition compound made from propranolol and capric acid (m.p. 97 degrees C) formed eutectic systems with propranolol (m.p. 83 degrees C) and capric acid (m.p. 15 degrees C). Infrared analyses indicated that the addition compounds were fatty acid salts of the beta-blocker. The nature of the species permeating through human epidermal membranes from binary mixtures of propranolol with the fatty acids was investigated using a novel attenuated total reflectance Fourier transform infrared method. There was no clear difference in permeation rates of the fatty acids compared with the beta-blocker, suggesting that the permeating species was the intact addition compound. The influence of melting point depression of the beta-blocker fatty acid systems on transdermal permeation was predicted from a mathematical model; predicted and experimentally determined data correlated well thus providing an alternative explanation as to the mode of action of these permeation enhancers.

Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen.

The formation of eutectic systems between ibuprofen (ibu) and seven terpene skin penetration enhancers was studied and, by using the eutectic systems as donors, the effects of melting point depression of the delivery system on transdermal delivery were investigated. A range of ibu:terpene binary mixtures were melted together, cooled, and recrystallised. Composition/melting point phase diagrams were determined by DSC and FT-IR analysis was used to investigated the nature of the interaction. Permeation of ibu across human epidermal membrane from the eutectic system was measured and compared to the flux from a saturated aqueous solution across skin and skin pretreated with the terpenes. The eutectic, i.e. minimum, melting points of these systems ranged from 32 degrees C for ibu:thymol 40:60 (% w/w) to -13 degrees C for ibu:1,8-cineole 40:60 (% w/w) compared to 76 degrees C for ibu alone. FT-IR studies indicated that only the terpenes which formed hydrogen bonds with ibu produced eutectic systems. Each set of ibu:terpene eutectic systems produced a significant (t-test, p = 0.05) increase in flux compared to a saturated aqueous solution applied to untreated and to terpene pretreated skin. For example, ibu:thymol 40:60 (% w/w) produced a flux of 150 micrograms/cm2/h, 5.9 times the flux from a saturated aqueous solution with thymol pretreated skin and 12.7 times the flux from a saturated aqueous solution across non-pretreated skin. In conclusion, a hydrogen bonding interaction is the primary mechanism by which some terpenes form binary eutectic mixtures with ibu. The resultant melting point depression of the delivery system is correlated with a significant increase in transdermal permeation.