The aim of this study was to investigate the effect of various skin preservation protocols on in vitro drug permeation, epidermal-dermal drug distribution, and electrical impedance properties of skin membranes. Acyclovir (AC) and methyl salicylate (MS) were selected as model drugs due to their different physicochemical properties and skin metabolic profiles. In particular, AC is relatively hydrophilic (logP -1.8) and not expected to be affected by skin metabolism, while MS is relatively lipophilic (logP 2.5) and susceptible to metabolism, being a substrate for esterase residing in skin. Skin from pig ears was used and freshly excised into split-thickness membranes, which were divided and immediately stored at five different storage conditions: a) 4 °C overnight (fresh control), b) 4 °C for 4 days, c) and d) -20 °C for 6 weeks and one year, respectively, and e) -80 °C for 6 weeks. Based on the combined results, general trends are observed showing that fresh skin is associated with lower permeation of both model drugs and higher skin membrane electrical resistance, as compared to the other storage conditions. Interestingly, in the case of fresh skin, significantly lower amounts of MS are detected in the epidermis and dermis compartments, implying higher levels of ester hydrolysis of MS (i.e., higher esterase activity). In line with this, the concentration of salicylic acid (SA) extracted from the dermis is significantly higher for fresh skin, as compared to the other storage conditions. Nevertheless, for all storage conditions, substantial amounts of SA are detected in the receptor medium, as well as in the epidermis and dermis, implying that esterase activity is maintained to some extent in all cases. For AC, which is not expected to be affected by skin metabolism, freeze storage (protocols c-e) is observed to result in higher accumulation of AC in the epidermis, as compared to the case of fresh skin, while the AC concentration in dermis is unaffected. These observations can be rationalized primarily by the observed lower permeability of fresh skin towards this hydrophilic substance. Finally, a strong correlation between AC permeation and electrical skin resistance is shown for individual skin membranes irrespective of storage condition, while the corresponding correlation for MS is inferior. On the other hand, a strong correlation is shown for individual membranes between MS permeation and electrical skin capacitance, while a similar correlation for AC is lower. The observed correlations between drug permeability and electrical impedance open up for standardizing in vitro data for improved analysis and comparisons between permeability results obtained with skin stored at different conditions.

Semifluorinated alkanes (SFAs) are aprotic solvents, which may be used as drug solvents for topical ocular applications, for instance, in dry eye syndrome. Their physical properties suggest that they might be prone to interaction with plastic materials, such as, polyethylene (PE) and polypropylene (PP), which are commonly used as packaging materials for pharmaceutical products. In this study, we investigate interactions of PE and PP with a liquid SFA perfluorohexyloctane (PFHO) using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and cross-polarized light microscopy. Binary phase diagrams of PFHO-PE and PFHO-PP systems demonstrating interactions of PFHO with the polymeric materials were constructed based on DSC data. According to this data, PFHO tends to lower the melting temperatures of PE and PP. The equilibrium values of solubilities of the polymers in PFHO and PFHO in the polymers were obtained by extrapolation of melting enthalpy data. Absorption of PFHO by PE and PP materials at ambient conditions after four weeks of equilibration was also studied by TGA. From the presented results, it may be concluded that thorough studies of interactions of PE or PP with SFAs are required when these materials are used as packaging components in SFA-based formulations.

The binary system perfluorohexyloctane (F6H8)–tetradecane (C14) was investigated in order to increase understanding of interactions of semifluorinated alkanes (SFAs) with hydrophobic molecules. The thermal phase behavior for F6H8 and C14 and their mixtures was determined using DSC. The activity coefficients for both components in the mixtures were calculated and Gibbs energy of mixing was determined. Furthermore, enthalpies of mixing were determined with ITC and structural investigations of the solid and the liquid phases were performed with SAXS and SWAXD. It was found that F6H8 displays one solid-solid transition at −42.3 °C (ΔH = 1.1 kJ/mol) and one solid-liquid transition at −5.9 °C (ΔH = 16.6 kJ/mol). Due to the low enthalpy of the solid-liquid transition it is likely that F6H8 is not fully crystallized in the solid phase but partly amorphous. The F6H8–C14 system displays a eutectic phase behavior and the liquid mixtures display a positive deviation from ideal mixing. C14 crystalizes in a triclinic unit cell as shown before, whereas crystallization of F6H8 in a lamellar rippled phase is shown for the first time. This ripple phase comprises a bilayer of tilted alternating heavily interdigitated F6H8 molecules in an oblique subunit cell.

Mucus covers the epithelium found in all intestinal tracts, where it serves as an important protecting barrier, and pharmaceutical drugs administrated by the oral, rectal, vaginal, ocular, or nasal route need to penetrate the mucus in order to reach their targets. Furthermore, the diffusion in mucus as well as the viscosity of mucus in the eyes, nose and throat can change depending on the relative humidity of the surrounding air. In this study we have investigated how diffusion through gels of mucin, the main protein in mucus, is affected by changes in ambient relative humidity (i.e. water activity). Already a small decrease in water activity was found to give rise to a significant decrease in penetration rate through the mucin gel of the antibacterial drug metronidazole. We also show that a decrease in water activity leads to decreased diffusion rate in the mucin gel for the fluorophore fluorescein. This study shows that it is possible to alter transport rates of molecules through mucus by changing the water activity in the gel. It furthermore illustrates the importance of considering effects of the water activity in the mucosa during development of potential pharmaceuticals.

Mometasone furoate (MF) is a potent steroid for treatment of e.g., eczema and psoriasis. It exerts its function by binding to the glucocorticoid receptors in viable epidermis and dermis. The aim of the current project was to estimate if two clinically equivalent 0.1% MF creams, one w/o (A) and one o/w (B) cream, might impose different systemic load, which is related to adverse side effects. We approached this question by combining analysis of drug permeability in flow through cells and membrane perturbation detected by impedance spectroscopy using excised porcine skin as membranes. We also analyzed the amount of drug that accumulates in the membranes following topical application of the two creams. The results show that both creams generate about the same amount of MF in skin, while cream A generates an order of magnitude higher drug flux through skin. Cream A also caused a twofold increase in the skin dielectric constant (ε), which may be attributed to an increased fluidity of the extracellular lipid matrix in the stratum corneum corresponding to a higher skin permeability. No significant change in skin ε was seen with cream B. To conclude, cream B appears to be the safer alternative as it does not seem to perturb the skin and imposes less systemic burden without sacrificing clinical efficacy