Delivery of theophylline into excised human skin from alkanoic acid solutions: A “push‐pull” mechanism

Human skin samples are permeable to theophylline delivered from 1.5% solutions in various alkanecarboxylic acids and their mixtures. The respective permeability coefficients of theophylline, calculated from steady‐state flux, correlate negatively with the permeability coefficients of the donor carboxylic acids and positively with the excess free energy of theophylline in the donor phase, or “push” effect. An exception is propionic acid which enhances the penetration of theophylline by promoting its solubility in the skin‐propionic acid medium through the “pull” effect. The two effects operate jointly in the delivery of theophylline from a mixture of propionic and a higher acid such as lauric, resulting in a much higher flux than expected from theory. The “push” effect can be estimated from the solubility parameters of theophylline and those of the holding phases even though regular solution behavior is not strictly obeyed. The increase in the permeability coefficient with partial molal volume of theophylline in the donor phase seems to reach an upper limit or decrease beyond 119 cm³·mol⁻¹.