L. Roussel

Measurement, analysis and prediction of topical UV filter bioavailability.

The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Ficks second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.

Antimicrobial nanocapsules: from new solvent-free process to in vitro efficiency

Skin and mucosal infections constitute recurrent pathologies resulting from either inappropriate antiseptic procedures or a lack of efficacy of antimicrobial products. In this field, nanomaterials offer interesting antimicrobial properties (eg, long-lasting activity; intracellular and tissular penetration) as compared to conventional products. The aim of this work was to produce, by a new solvent-free process, a stable and easily freeze-dryable chlorhexidine-loaded polymeric nanocapsule (CHX-NC) suspension, and then to assess the antimicrobial properties of nanomaterials. The relevance of the process and the physicochemical properties of the CHX-NCs were examined by the assessment of encapsulation efficiency, stability of the nanomaterial suspension after 1 month of storage, and by analysis of granulometry and surface electric charge of nanocapsules. In vitro antimicrobial activities of the CHX-NCs and chlorhexidine digluconate solution were compared by measuring the inhibition diameters of two bacterial strains (Escherichia coli and Staphylococcus aureus) and one fungal strain (Candida albicans) cultured onto appropriate media. Based on the findings of this study, we report a new solvent-free process for the production of nanomaterials exhibiting antimicrobial activity, suitable stability, and easily incorporable as a new ingredient in various pharmaceutical products.

Influence of Excipients on Two Elements of the Stratum Corneum Barrier: Intercellular Lipids and Epidermal Tight Junctions

The skin is one of the most important organs in the human body due to its crucial role as an interface between the internal and external environments. Homeostasis and permeability of the skin barrier are regulated by a combination of several factors, biochemical and structural, in response to the external influences. The permeability barrier function is essentially fulfilled by the final product of epidermal differentiation – stratum corneum (SC). Efficiency of the SC barrier depends on the composition and the correct arrangement of its principal elements: (1) corneocytes linked by corneodesmosomes and (2) intercellular lipids covalently bound to the cross-linked corneocyte envelopes and organized in a multilayered extracellular matrix. Epidermal tight junctions (TJ) present in the granular layer may constitute an additional permeability barrier and play a role during the SC barrier formation. Cross-linked TJ-like structures persisting in the SC participate in the regulation of desquamation and may also influence barrier function. Most of the excipients, e.g., solvents, emulsifiers/detergents, moisturizers, and penetration enhancers, interact with the skin barrier. The latter are designed to modify the intercellular SC domains in order to reduce resistance of barrier lipid bilayers. Several mechanisms of action are individualized (extraction, fluidization, or disorganization of the intercellular lipid matrix) and may intervene separately, depending on the nature of the excipient, although combined actions are most frequently encountered. Excipients can also interact with the extracellular loops or the membrane domain of TJ, causing internalization of the TJ strands and loss of the additional TJ barrier. In the longer term, this effect may also impact the SC formation and function.

Deleterious effects of skin freezing contribute to variable outcomes of the predictive drug permeation studies using hydrophilic molecules.

To the editor Ex vivo and in vitro skin permeation tests are extensively used to evaluate transcutaneous penetration of drugs. However, surprisingly little attention is paid to the tissue morphology during such studies. We want to strike a cautionary note, important for the interpretation of experiments predicting transcutaneous drug absorption in vivo. Transcutaneous diffusion devices, called Franz cells, are most frequently used. Excised skin is positioned between the ‘donor’ and ‘receiver’ compartments of the device. The studied molecule applied to the ‘donor’ chamber must cross the skin barrier to be subsequently quantified in the ‘receiver’ fluid. Because of its availability in large quantities and its similarity to human skin, pig skin is frequently used for the tests (1). In accordance with the international recommendations, skin samples are stored at 20°C and thawed before experiments (S1). However, contradictory reports exist in the literature concerning the validity of the procedure (2,3). Most of the studies focus on the permeation results alone (S2, S3). Ensuring that the skin permeability barrier maintains its integrity prior to the tests is essential for the successful interpretation of permeation experiments and accurate prediction of the studied molecule’s behaviour in vivo. We evaluated the impact of freezing on porcine skin morphology and permeability. A detailed approach is described in the Data S1. Fresh skin samples from pig ear (0.7 mm thick) were compared with one or four times frozen, and ether-/chloroform-delipidated skin from nine animals. Skin biopsies were taken for ultrastructural studies prior to the permeability tests with 1% aqueous caffeine solution, a molecule recognized as a reference permeation compound. Caffeine was quantified in the ‘receiver’ compartment of Franz cells, filled with PBS, with highperformance liquid chromatography at different time-points during the 24-h experiment. Two model parameters were calculated by fitting the data of measured caffeine amount per unit of skin surface (Qt) versus time (t) to the following equation: Qt 1⁄4 Cd ðKLÞ D L2 t 1 6 2 p2 X1

Glycerol as a Skin Barrier Influencing Humectant

Glycerol, obtained mainly by saponification of oils and fats, is an important ingredient in pharmaceutical and cosmetic preparations. It acts as a humectant due mostly to its high hygroscopic property.

Thermosensitive Hydrogels in Dermatology: A Multidisciplinary Overview

Formulation of dermatological medicines in hospitals is a multidisciplinary challenge addressing pharmaceutical issues such as (1) excipient availability and safety, (2) drug solubility and diffusivity, (3) drug-excipient compatibility, (4) formulation stability, and (5) convenience of use. Thermosensitive hydrogels are polymeric excipients that exhibit interesting properties, especially solubilizing properties and the ability to physically respond to thermal physiological stimuli. The inclusion of such polymers in dermatological formula enables to produce “intelligent medicines” that outgrow problems encountered with conventional formulations and to design novel delivery systems. This chapter will detail pharmaceutical considerations about excipient choice and thermosensitive polymers and illustrate the possibilities they offer by various formulation and clinical application examples.