Fit of fluxes of sunscreens and other compounds from propylene glycol:water (30:70) through human skin and silicone membrane to the Roberts-Sloan equation: the effect of polar vehicle (or water) solubility.

It would be useful to develop a surrogate for animal skin, which could be use to predict flux through human skin. The fluxes (and physicochemical properties) of sunscreens and other compounds from propylene glycol (PG):water (AQ), 30:70, through human skin have previously been reported. We measured the fluxes of several of those sunscreens and other compounds from PG:AQ, 30:70, through silicone membrane and fit both sets of data to the Roberts-Sloan (RS) equation to determine any similarities. For both sets of data, the fluxes were directly dependent on their solubilities in a lipid solvent [octanol (OCT), in this case] and in a polar solvent (PG:AQ, 30:70, or AQ in this case) and inversely on their molecular weights. The fit of the experimental (EXP) fluxes through human skin in vivo to RS was excellent: r² = 0.92 if the vehicle (VEH) PG:AQ, 30:70 was the polar solvent (RS¹) or r² = 0.97 if water was the polar solvent (RS²). The fit of the EXP fluxes through silicone membrane to RS was good: r² = 0.80 if the VEH PG:AQ, 30:70, was the polar solvent (RS¹) or r² = 0.81 if water was the polar solvent (RS²). The correlations between their EXP fluxes through human skin in vivo and their EXP fluxes through silicone membrane were good (r² = 0.85). In addition, the correlation between EXP fluxes from PG:AQ, 30:70, through human skin in vivo and their fluxes calculated from the coefficients of the fit of solubilities, molecular weights and fluxes from water through silicone membranes from a previous n = 22 database to RS was even better (r² = 0.94). These results suggest that flux through human skin can be calculated from flux through a silicone membrane.

The sclerostin-bone protein interactome.

The secreted glycoprotein, sclerostin alters bone formation. To gain insights into the mechanism of action of sclerostin, we examined the interactions of sclerostin with bone proteins using a sclerostin affinity capture technique. Proteins from decalcified rat bone were captured on a sclerostin-maltose binding protein (MBP) amylose column, or on a MBP amylose column. The columns were extensively washed with low ionic strength buffer, and bound proteins were eluted with buffer containing 1M sodium chloride. Eluted proteins were separated by denaturing sodium-dodecyl sulfate gel electrophoresis and were identified by mass spectrometry. Several previously unidentified full-length sclerostin-interacting proteins such as alkaline phosphatase, carbonic anhydrase, gremlin-1, fetuin A, midkine, annexin A1 and A2, and collagen α1, which have established roles in bone formation or resorption processes, were bound to the sclerostin-MBP amylose resin but not to the MBP amylose resin. Other full-length sclerostin-interacting proteins such as casein kinase II and secreted frizzled related protein 4 that modulate Wnt signaling were identified. Several peptides derived from proteins such as Phex, asporin and follistatin that regulate bone metabolism also bound sclerostin. Sclerostin interacts with multiple proteins that alter bone formation and resorption and is likely to function by altering several biologically relevant pathways in bone.

Dermal and transdermal delivery: prodrugs.

Attempts to deliver drugs into and through the skin (dermal and transdermal delivery) have not been very successful because the physicochemical properties of drugs are often not optimal. Prodrugs can be used to optimize those physicochemical properties of drugs and optimize their delivery by transiently masking their polar functional groups. For a drug to cross the rate-limiting barrier to delivery (the stratum corneum) it must dissolve in and cross multiple lipid and aqueous phases within the stratum corneum. Prodrugs can be designed to exhibit increased lipid and aqueous solubilities resulting in increased delivery. In order to identify the optimal prodrugs, they must be evaluated as saturated solutions where their thermodynamic activities are maximal in the solution and in the skin. If prodrugs are evaluated at concentrations less than at saturation, inaccurate conclusions about the optimal physicochemical properties may result. Prodrugs must be designed to optimize both their lipid and aqueous solubilities to optimize their delivery into and through the skin.