Modelling dermal drug distribution after topical application in human.

PURPOSE: To model and interpret drug distribution in the dermis and underlying tissues after topical application which is relevant to the treatment of local conditions. METHODS: We created a new physiological pharmacokinetic model to describe the effect of blood flow, blood protein binding and dermal binding on the rate and depth of penetration of topical drugs into the underlying skin. We used this model to interpret literature in vivo human biopsy data on dermal drug concentration at various depths in the dermis after topical application of six substances. This interpretation was facilitated by our in vitro human dermal penetration studies in which dermal diffusion coefficient and binding were estimated. RESULTS: The model shows that dermal diffusion alone cannot explain the in vivo data, and blood and/or lymphatic transport to deep tissues must be present for almost all of the drugs tested. CONCLUSION: Topical drug delivery systems for deeper tissue delivery should recognise that blood/lymphatic transport may dominate over dermal diffusion for certain compounds.

Viscoelastic and Deformation Characteristics of Structurally Different Commercial Topical Systems.

Rheological characteristics and shear response have potential implication in defining the pharmaceutical equivalence, therapeutic equivalence, and perceptive equivalence of commercial topical products. Three creams (C1 and C3 as oil-in-water and C2 as water-in-oil emulsions), and two gels (G1 and G2 carbomer-based) were characterized using the dynamic range of controlled shear in steady-state flow and oscillatory modes. All products, other than C3, met the Critical Quality Attribute criteria for high zero-shear viscosity (η0) of 2.6 × 104 to 1.5 × 105 Pa∙s and yield stress (τ0) of 55 to 277 Pa. C3 exhibited a smaller linear viscoelastic region and lower η0 (2547 Pa∙s) and τ0 (2 Pa), consistent with lotion-like behavior. All dose forms showed viscoelastic solid behavior having a storage modulus (G') higher than the loss modulus (G″) in the linear viscoelastic region. However, the transition of G' > G″ to G″ > G' during the continual strain increment was more rapid for the creams, elucidating a relatively brittle deformation, whereas these transitions in gels were more prolonged, consistent with a gradual disentanglement of the polymer network. In conclusion, these analyses not only ensure quality and stability, but also enable the microstructure to be characterized as being flexible (gels) or inelastic (creams).

Measurement of Hansen Solubility Parameters of Human Stratum Corneum.

Hansen Solubility Parameters (HSP) of human stratum corneum (SC) represent its polarity and are very important for design and optimization of dermatological formulations. However, there is no directly measured data available in the literature for such a crucial property, which is the subject of the present investigation. HSP of the SC was measured by solvent uptake here. 18 solvents/mixtures with different HSP values were selected and their uptake by the SC was measured at 32 °C. The solvents were then divided into good and bad solvents according to their uptake into the SC. The HSP discrete parts of "atomic dispersion forces (δD)", "dipolar intermolecular forces (δP)", and "hydrogen bonding (δH)" were then calculated using uptake data and HSPiP software. Results showed that δD, δP, and δH values of the SC at 32 °C are 16.5, 12, 7.7 respectively. The obtained HSP values, which were measured for the first time here, were then used to interpret enhancement effects of permeation enhancers and the uptake of vehicles by the SC using Relative Energy Difference (RED), with good correlations. SC HSP values can be further used in transdermal drug delivery, cosmetic formulations, safety issues, etc.

Alternative Methods to Animal Studies for the Evaluation of Topical/ Transdermal Drug Delivery Systems.

It is critical to develop an effective understanding of the interaction between the drug, delivery system and skin in order to predict and assess skin penetration and permeation. Experimental models for the assessment of topical and transdermal delivery systems must permit evaluation of these complex interactions. Whilst in the past, animal models were commonly used, recent regulatory guidelines, based on 3R principles (refinement, reduction, replacement), encourage the rational use of animals. Alternative methods have been proposed for use in the development of topical and transdermal delivery systems which are often used in combination. We will review the current state of the art in alternative methods for topical and transdermal delivery systems development, including technologies that can assist in the characterization of skin penetration/permeation studies.