Lauric acid solution thermodynamics and effects on stratum corneum permeability

The transdermal route of administering therapeutic agents is currently limited to only a few drugs due, in part, to a nescience of how permeability enhancers alter the barrier of the stratum corneum. Rational design of delivery systems is precluded by obscure flux-vehicle composition relationships that results from using customary experimental protocols. Methodologies are needed to more carefully study permeability-enhancement mechanism(s) without confounding organic-solvent vehicle effects or non-equilibrium conditions within the membrane. A novel experimental method was developed, characterized, and applied to study the effects of a model penetration enhancer, lauric acid, on the permeability of hydrocortisone and 4-hydroxybenzyle alcohol through human stratum corneum. Dilute aqueous solutions of enhancer were used in both the donor and receiver chambers thus allowing an equilibrium between the vehicle phase and the membrane to be established. Due to the enhancement data, the solubility of lauric acid was characterized as a function of pH, ionic strength, and temperature. Permeability coefficients were measured as a function of vehicle pH and enhancer concentration at 32°C. At temperatures between 28°C-32°C, a lauric acid mesophase formed in suspensions of lauric acid or potassium hydrogen dilaurate over a small pH region that depended on ionic strength. The solubility of lauric acid as measured in ultra-filtered samples from turbid suspension containing mesophase and in filtered samples from optically clear suspension could be rationalized by assuming only monomer exists in equilibrium with the solid phase, with no evidence for the existence of small molecular-weight aggregates of lauric acid. Mannitol trapping experiments demonstrated the presence of vesicles in the mesophase region. A mass-action law for lauric acid mesophase formation was derived from the monomer-mesophase concentration relationships. This model accounts for the observed cooperativity, composition, pH-dependence, and temperature-dependence of mesophase formation. The mass-action law supports the hypothesis that a domain of the intact vesicle is the unit in equilibrium with lauric acid monomer is solution. The concept of unit domains may have general application to lipid bilayer self-assembly. Steady-state enhancement factors for hydrocortisone and 4-hydroxybenzyl alcohol were largely reversible suggesting the establishment of equilibrium with respect to enhancer uptake. Molar enhancement factor-pH profiles were sigmoidal suggesting that both free acid and anion participate as enhancers. Lauric acid uptake by stratum corneum depended linearly on enhancer concentration, while enhancement factors were non-linearly related to enhancer concentration.