91 Å) ( Labrador et al., 2012). Diffraction intensities were corrected for air (empty cell) scattering and primary-beam intensity changes to enable comparison between different measurements. The corrected diffraction intensities are plotted as a function of BTK inhibitor solubility dmso the scattering vector Q defined as Q = (4π sin θ)/λ, where θ and λ are the diffraction angle and the wavelength, respectively. One measurement per SC sample was performed at 32 °C. To investigate if glycerol and urea affect the SC molecular organization differently than water at elevated temperatures, as previously shown ( Bouwstra et al., 1995), we performed

additional measurements on all samples at elevated temperatures. One measurement was performed per sample at following temperatures: 50 °C, 70 °C, 80 °C (WAXD) 90 °C (SAXD), and finally again at 32 °C after allowing the samples to cool down

for approx. 1 h. In these experiments the SC samples were heated for approx. 30 min at each temperature. The results from the measurements at elevated temperatures are presented in Fig. S2 in the Supplementary material. We study the steady state flux (Jss) of the model drug Mz across skin membranes, focusing on the effect of a varying water BMS354825 gradient in the presence of glycerol and urea. Thus, the skin membrane is placed in several gradients; a gradient in water activity, a gradient in glycerol or urea activity, and a gradient in Mz activity.

The water activity in the receptor solution (PBS solution) is held constant at physiological conditions, and the water activity in the donor formulation is regulated by the addition of glycerol or urea, or a combination of one of these molecules and the water-soluble polymer PEG (MWPEG ∼ 1500 Da, see Section 2.4.). Any addition of solute molecules to an aqueous solution leads to a reduction of the water activity, and it is therefore clear that all donor formulations investigated have water activities lower than one ( Evans and Wennerström, 1999). The experiments presented here can be divided into two types; in the first type the concentration of glycerol or urea is adjusted, and whatever in the second type the concentration of glycerol or urea is fixed at 20 wt% and the concentration of PEG is regulated. Glycerol and urea are small molecules that are likely to partition into the skin membrane, similar to what is expected for water. On the other hand, it is established that the relatively large size of the polymer used in this work assures that it does not penetrate into the skin membrane due to size exclusion ( Albèr et al., unpublished results, Tsai et al., 2001 and Tsai et al., 2003). Table 1 summarizes experimental data on steady state fluxes of Mz across skin and silicone membranes for all formulations investigated.