Molecular Size as the Main Determinant of Solute Maximum Flux Across the Skin

Abstract

One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J(max), mol per cm(2) per h) from a given vehicle. In this work, J(max) values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k(p)) are optimally correlated to solute octanol-water partition coefficient (K(ow)) and molecular weight (MW) was found to be the dominant determinant of J(max) for this literature data set: log J(max)=-3.90-0.0190MW (n=87, r(2)=0.847, p<0.001). Estimated solubility in octanol (S(oc)) was also a determinant, but improvement in the regression by the addition of log S(oc) was small (r(2) increased to 0.856). Addition of other physicochemical parameters to MW by forward stepwise regression only marginally improved the regression with a melting point (Mpt) term (r(2)=0.879) and then hydrogen bonding acceptor capability (H(a)) (r(2)=0.917) is significant. Validation of the equation above was carried with a number of other data sets: an aqueous vehicle with full- and split-thickness skin (r(2)=0.784, n=56), some pure solutes (r(2)=0.537, n=34), an aqueous vehicle with ionizable solutes (r(2)=0.282, n=54) and solutes from a propylene glycol vehicle (r(2)=0.484, n=36). An analysis of the entire database gave the equation log J(max)=-4.52-0.0141MW (n=278, r(2)=0.688, p<0.001), with inclusion of Mpt and H(a) increasing r(2) to 0.760 (n=269). Separate analysis of full- and split-thickness skin data confirmed that the dermal resistance term had only a marginal effect on overall J(max). Application of the latter model to an in vivo situation where the dermal capillary bed is slightly below the epidermal-dermal junction revealed that the dermal resistance term was unnecessary for in vivo predictions for most solutes.

Regulating the Skin Permeation Rate of Escitalopram by Ion-pair Formation with Organic Acids

“…According to the flux value of ion-pair complexes and their physicochemical properties listed in Table III, the skin permeability of ESP altered due to the altered physicochemical properties of ESP by forming ion-pair complexes with organic acids. Many previous studies about skin permeation reported that the physicochemical properties of drugs including log K o/w and MW could affect the skin permeability of drugs (20,21). Ma et al and Tan et al also found that the flux of drug was influenced by the pK a of counter-ions (22,23).…”

Data Quality in the Human and Environmental Health Sciences: Using Statistical Confidence Scoring to Improve QSAR/QSPR Modeling

“…[6][7][8][9][10][11] The most recognised and applied QSPR to predict the skin permeability coefficient (k p ) is that developed by Potts and Guy in 1992 (Eq. 2).…”

From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment

“…the route of entry into the viable skin is via passive diffusion through the stratum corneum. Depending on lipophilicity and molecular weight, the rate and route of transport across stratum corneum varies, predominating through either the lipid bilayers, corneocytes or via appendages such as sweat ducts and hair follicles (Potts and Guy, 1992;Mitragotri, 2003;Magnusson et al, 2004). Once present in the viable skin, the ingredient will distribute between extra-and intra-cellular space, where there is the potential for both phase I (activation of pro-haptens) and phase II (predominantly clearing) metabolism (Gibbs et al, 2007;Hagvall et al, 2008;van Eijl et al, 2012).…”