Optimisation of cosolvent concentration for topical drug delivery III--influence of lipophilic vehicles on ibuprofen permeation.

Previously, we have reported the effects of water, ethanol, propylene glycol and various binary and ternary mixtures of these solvents on the permeation of ibuprofen in model membranes and in skin. The present study investigates the influence of lipophilic vehicles on the transport of ibuprofen in silicone membrane and in human skin. The permeation of ibuprofen was measured from mineral oil (MO), Miglyol® 812 (MG) and binary mixtures of MO and MG. The solubility of ibuprofen was 5-fold higher in MG than in MO, however, the permeation of ibuprofen from the pure vehicles and combinations of both was comparable in silicone membrane. Additionally, there were no significant differences in skin permeation for MO and MG vehicles. When the permeation of various hydrophilic and lipophilic vehicles is considered, a trend between flux values for the model membrane and skin is evident (r(2) = 0.71). The findings suggest that silicone membrane may provide information on qualitative trends in skin permeation for vehicles of diverse solubility and partition characteristics.

Optimisation of cosolvent concentration for topical drug delivery - II: influence of propylene glycol on ibuprofen permeation.

The influence of formulation components on drug thermodynamic activity and on membrane properties has not been extensively studied to date. Propylene glycol (PG) has a long history of use as a component of topical pharmaceutical and cosmetic preparations. In the present study we investigated the influence of PG on the solubility and membrane permeability characteristics of ibuprofen in silicone and skin using binary (PG:water) and ternary (ethanol:PG:water) solvent systems. Fluxes were maximum for 70:30 PG:water systems in silicone membrane; however, for experiments conducted with skin, the flux of ibuprofen systematically increased with increasing amounts of PG. For silicone membrane, the flux values of ibuprofen from ternary ethanol:PG:water (25:25:50 and 50:25:25) systems were 1.2- and 1.5-fold higher than the highest values observed from the PG:water systems. A comparison of the data from occluded versus non-occluded studies suggested that the ethanol content was the critical determinant of flux enhancement in these systems. For human skin, a PG:water (50:50) mixture enhanced ibuprofen flux to the same extent as the corresponding ethanol:PG:water (25:25:50) system. However, the ternary system, ethanol:PG:water (50:25:25), demonstrated the greatest enhancement. An analysis of the partition and diffusion parameters for experiments conducted with skin confirmed that the influence of PG in the PG:water systems is primarily on the solubility and partitioning behaviour of ibuprofen. The ternary systems also appear to influence skin partition behaviour rather than diffusivity when compared with the permeation parameters of ibuprofen from saturated aqueous solutions.

Influence of ethanol on the solubility, ionization and permeation characteristics of ibuprofen in silicone and human skin.

In the context of topical and transdermal delivery, cosolvents may be expected to enhance solubility, modify drug partitioning behaviour and alter skin barrier properties. In the present study, we have investigated systematically the influence of increasing amounts of the cosolvent ethanol on the solubility, ionization, and permeability characteristics of ibuprofen in silicone and in skin. The possibility of ibuprofen self-association was also examined. As the amount of ethanol was raised from 0 to 100%, ibuprofen solubility was enhanced 5,500-fold relative to its aqueous solubility. Up to 50%, the pK(a) of ibuprofen shifted from 4.44 to 5.68. Infrared spectroscopy confirmed the presence of ibuprofen in both monomer and dimer forms in vehicles containing 75 and 100% ethanol. In silicone membranes, the flux of ibuprofen increased 8-fold over the range of ethanol concentrations studied (0-100%) relative to aqueous solutions, with the highest flux observed for 100% ethanol. However, in skin, the flux of ibuprofen was optimal for 50:50 and 75:25 ethanol-water vehicles (>10-fold flux enhancement). The lower ibuprofen flux from pure ethanol may reflect the alcohol's ability to dehydrate human skin. In general, the flux data confirm that increasing ethanol content enhances the solubility of ibuprofen in silicone and human skin as well as in the vehicle itself.