Compartmental modeling of skin absorption and desorption kinetics: Donor solvent evaporation, variable diffusion/partition coefficients, and slow equilibration process within stratum corneum.

This work expands the recently developed compartmental model for skin transport to model variable diffusion and/or partition coefficients, and the presence of slow equilibration/slow binding kinetics within stratum corneum. The model was validated by comparing it with the diffusion model which was solved numerically using the finite element method. It was found that the new compartmental model predictions agreed well with that of the diffusion model, providing a sufficient number of compartments was used. The compartmental model was applied to two previously published experimental data sets: water penetration and desorption data and the finite dose dermal penetration of testosterone. Significant improvement of the fitting quality for all these data sets was achieved using the compartmental model.

3D-Printed Franz cells - update on optimization of manufacture and evaluation.

OBJECTIVES: Laboratory in vitro permeation processes require the use of modified Franz type diffusion cells which are conventionally fabricated from glass. Fragility and high cost are frequently associated with this type of laboratory apparatus. The purpose of our present research was to develop a simple, economical and versatile approach to manufacture Franz type cells using additive manufacturing (AM). METHODS: Graphical Franz diffusion cell designs were reproduced with a stereolithography (SLA) 3D printer and assessed over a minimum period of 24 h. The surface morphology of AM printouts was analysed before and after compatibility studies using scanning electron microscopy (SEM). Comparative permeation studies in both glass and AM Franz type diffusion cells were conducted using a caffeine solution (1.5 mg mL-1 ), applied to a model silicone membrane. RESULTS: Testing of the 3D printed scaffolds confirmed similar recovery of the permeant when compared to glass cells: 1.49 ± 0.01 and 1.50 ± 0.01 mg mL-1 , respectively, after 72 h. No significant differences were visible from the SEM micrographs demonstrating consistent, smooth and non-porous surfaces of the AM Franz cells' core structure. Permeation studies using transparent 3D printed constructs resulted in 12.85 ± 0.53 µg cm-2 caffeine recovery in the receptor solution after 180 min with comparable permeant recovery, 11.49 ± 1.04 µg cm-2 , for the glass homologues. CONCLUSION: AM constructs can be considered as viable alternatives to the use of conventional glass apparatus offering a simple, reproducible and cost-effective method of replicating specialised laboratory glassware. A wider range of permeants will be investigated in future studies with these novel 3D printed Franz diffusion cells.

OBJECTIF: les processus de perméation in vitro en laboratoire nécessitent l'utilisation de cellules de diffusion de type Franz modifiées, fabriquées traditionnellement en verre. La fragilité et un coût élevé sont fréquemment associés à ce type d'appareil de laboratoire. L'objectif de nos travaux de recherche actuels était de développer une approche simple, économique et polyvalente pour fabriquer des cellules de type Franz à l'aide de la fabrication additive (FA). MÉTHODES: les conceptions des cellules de diffusion Franz graphiques ont été reproduites avec une imprimante 3D stéréolithographie (SLA) et évaluées sur une période minimum de 24 h. La morphologie de surface des impressions FA a été analysée avant et après des études de compatibilité à l'aide de la microscopie électronique à balayage (MEB). Des études comparatives de perméation des cellules de diffusion de type Franz en verre et FA ont été réalisées à l'aide d'une solution de caféine (1,5 mg ml-1 ) appliquée à un modèle de membrane en silicone. RÉSULTATS: les tests des supports imprimés 3D ont confirmé une récupération similaire du perméant par rapport aux cellules de verre : 1,49 ± 0,01 et 1,50 ± 0,01 mg ml-1 , respectivement, après 72 h. Aucune différence significative n'a été observée sur les micrographiques MEB, montrant des surfaces cohérentes, lisses et non poreuses de la structure centrale des cellules Franz FA. Les études de perméation utilisant des constructions transparentes imprimées en 3D ont conduit à une récupération de la caféine de 12,85 ± 0,53 µg cm-2 dans la solution de récepteur après 180 min avec une récupération de perméant comparable, 11,49 ± 1,04 µg cm-2 , pour les homologues de verre. CONCLUSION: les constructions FA peuvent être considérées comme des alternatives viables à l'utilisation d'appareils de verre conventionnels offrant une méthode simple, reproductible et rentable de réplication de la verrerie de laboratoire spécialisée. Une gamme plus large de perméants sera étudiée dans de futures études avec ces nouvelles cellules de diffusion Franz imprimées en 3D.

Characterization and topical delivery of phenylethyl resorcinol.

OBJECTIVE: Phenylethyl resorcinol (PR) has been used widely in the personal care industry as a novel skin lightening ingredient. Surprisingly, there is only limited information describing the physicochemical properties of this active. Therefore, the primary objective of this study was to perform a comprehensive characterization of PR. A secondary objective was to investigate the delivery of this molecule to mammalian skin. METHODS: Phenylethyl resorcinol was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and nuclear magnetic resonance (NMR). A new high-performance liquid chromatographic (HPLC) method for analysis of PR was developed and validated. The log P (octanol water partition coefficient), value, solubility and short-term stability of PR in a series of vehicles were also determined using HPLC. The evaporation of the selected vehicles was examined using dynamic vapour sorption (DVS). The permeation profiles of PR were investigated under finite dose conditions in porcine and human skin. RESULTS: The melting point of PR was determined to be 79.13 °C and the measured log P (octanol water partition coefficient) at 21 °C was 3.35 ± 0.03. The linearity of the HPLC analytical method was confirmed with an r2 value of 0.99. Accuracy of the method was evaluated by average recovery rates at three tested concentrations, and the values ranged from 99 to 106%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.19 and 0.57 µg mL-1 , respectively. The solubility of PR in PG, DMI, glycerol was within the range of 367 to 877 mg mL-1 . The stability of PR in tested solvents was also confirmed by the 72 h stability studies. From the DVS studies, 70-125% of applied formulations were recovered at 24 h. The permeation through porcine skin at 24 h ranged from 4 to 13 µg cm-2 , while the corresponding amounts of PR delivered through human skin were 2 to 10 µg cm-2 . CONCLUSION: The physicochemical properties of PR confirm it is suitable for dermal delivery. In this study, propylene glycol was the most promising vehicle for PR delivery to human skin. Future work will expand the range of vehicles studied and explore the percutaneous absorption from more complex formulations.

OBJECTIF: Le phényléthyl résorcinol (PR) est largement utilisé dans le secteur des soins personnels comme ingrédient éclaircissant pour la peau. Pour autant, on ne dispose que d'informations limitées concernant les propriétés physicochimiques de ce principe actif. C'est pourquoi cette étude avait pour objectif principal de réaliser une caractérisation exhaustive du PR. Son objectif secondaire était d'étudier l'administration de cette molécule à la peau de mammifères. MÉTHODES: Le phényléthyl résorcinol a été caractérisé par calorimétrie différentielle à balayage (CDB), analyse thermogravimétrique (ATG) et par résonance magnétique nucléaire (RMN). Pour analyser le PR, une nouvelle méthode de chromatographie liquide à haute performance (CLHP) a été développée et validée. On s'est servi de la CLHP pour déterminer les propriétés suivantes du PR : log P (coefficient de partage octanol/eau), valeur, solubilité et stabilité à court terme du PR dans plusieurs véhicules. L'évaporation des véhicules sélectionnés a été examinée par sorption de vapeur dynamique (DVS). Les profils de perméabilité du PR ont été étudiés dans des conditions de dose finie dans des peaux porcine et humaine. RÉSULTATS: On a pu déterminer que le point de fusion du PR était de 79,13 °C et le log P (coefficient de partage octanol/eau) à 21 °C était de 3,35 ± 0.03. La linéarité de la méthode analytique de la CLHP a été confirmée avec une valeur r2 de 0,99. L'exactitude de la méthode a été évaluée par les taux moyens de récupération à trois concentrations testées, avec des valeurs résultantes comprises entre 99 et 106 %. La limite de détection (LD) et la limite de quantification (LQ) ont été déterminées à 0,19 et 0,57 µg/ml_ 1, respectivement. La solubilité du PR dans le PG, le DMI et le glycérol reste dans une plage comprise entre 367 et 877 mg/ml _ 1. La stabilité du PR dans les solvants testés a également pu être confirmée par les études de stabilité à 72 h. Parmi les formulations appliquées lors des études de DVS, 70 à 125 % de celles-ci ont été récupérées à 24 h. La pénétration par la peau porcine à 24 h était comprise entre 4 et 13 µg/cm_ 2, tandis que les quantités de PR correspondantes délivrées à travers la peau humaine étaient de 2 à 10 µg/cm_ 2. CONCLUSION: Les propriétés physicochimiques du PR confirment qu'il est adapté à l'administration dermique. Dans le cadre de cette étude, le propylène glycol est apparu comme le véhicule le plus prometteur pour l'administration de PR dans la peau humaine. De futurs travaux étudieront davantage de véhicules et examineront l'absorption percutanée lors de l'emploi de formulations plus complexes.

3D-printed Franz type diffusion cells.

OBJECTIVE: Franz cells are routinely used to measure in vitro skin permeation of actives and must be inert to the permeant under study. The aim of the present work was to develop and manufacture transparent Franz-type diffusion cells using 3D printing. Printouts were then tested using a range of model active compounds. The study also aims to identify the critical 3D-printing parameters necessary for the process, including object design, choice of printing resin, printout curing and post-curing settings and introduction of model coatings. METHODS: Transparent Franz cells were constructed using an online computer aided design program and reproduced with different stereolithography 3D printers. The two acrylate-based resins used for the fabrication process were a commercially available product and a polymer synthesised in-house. Comparative studies between glass and 3D-printed Franz cells were conducted with selected model actives: terbinafine hydrochloride (TBF), niacinamide (NIA), diclofenac free acid (DFA) and n-methyl paraben (MPB). In preliminary studies, MPB showed the lowest recovery when exposed to the receptor compartment of 3D printed cells. Consequently, in vitro permeation studies were carried out using only MPB with polydimethylsiloxane (PDMS) membrane. RESULTS: A decrease in the amounts of selected compounds was observed for transparent 3D-printed Franz cells compared to glass cells. MPB showed the lowest recovery (53.8 ± 13.1%) when compared with NIA (74.9 ± 4.0%), TBF (81.5 ± 12.0%) and DFA (90.2 ± 12.9%) after 72 h. Permeation studies conducted using 3D-printed transparent cells with PDMS membrane also showed a decrease in MPB recovery of 51.4 ± 3.7% for the commercial resin and 94.4 ± 3.5% for the polymer synthesised in-house, when compared to glass cells. Although hydrophobic coatings were subsequently applied to the 3D-printed cells, the same reduction in MPB concentration was observed in the receptor solution. CONCLUSION: Transparent Franz cells were successfully prepared using 3D printing and were observed to be robust and leak-proof. There are few resins currently available for preparation of transparent materials and incompatibilities between the actives investigated and the 3D-printed cells were evident. Hydrophobic coatings applied as barriers to the printed materials did not prevent these interactions.

Compartmental modeling of skin transport.

The primary objective of this study is to introduce a simple and flexible mathematical approach which models transport processes in skin using compartments. The main feature of the presented approach is that the rate constants for exchange between compartments are derived from physiologically relevant diffusional transport parameters. This allows for better physical interpretation of the rate constants, and limits the number of parameters for the compartmental model. The resulting compartmental solution is in good agreement with previously published solutions for the diffusion model of skin when ten or more compartments are used. It was found that the new compartmental model with three compartments provided a better fit of the previously publish water penetration data than the diffusion model. Two special cases for which it is difficult to implement the diffusion model were considered using our compartmental approach. In both cases the compartmental model predictions agreed well with the diffusion model.

Hexamidine salts - applications in skin health and personal care products.

Hexamidine (HEX) has been used as a preservative in topical preparations since the 1950s. A number of studies also indicate that the molecule plays a beneficial role in skin homoeostasis. In this review, we describe the physicochemical properties of hexamidine diisethionate (HEX D) and the corresponding hydrochloride salt (HEX H). The biocidal and protease inhibition properties of HEX are outlined as well as the effects of HEX on lipid processing enzymes, corneocyte maturity, stratum corneum thickness and transepidermal water loss (TEWL). Skin permeation properties of HEX D and HEX H are summarized, and formulation approaches for effective dermal targeting of HEX are discussed.

In vitro-in vivo correlation in skin permeation.

PURPOSE: In vitro skin permeation studies have been used extensively in the development and optimisation of delivery of actives in vivo. However, there are few reported correlations of such in vitro studies with in vivo data. The aim of this study was to investigate the skin permeation of a model active, niacinamide, both in vitro and in vivo. METHODS: Conventional diffusion cell studies were conducted in human skin to determine niacinamide permeation from a range of vehicles which included dimethyl isosorbide (DMI), propylene glycol (PG), propylene glycol monolaurate (PGML), N-methyl 2-pyrrolidone (NMP), Miglyol 812N® (MG), and mineral oil (MO). Single, binary or ternary systems were examined. The same vehicles were subsequently examined to investigate niacinamide delivery in vivo. For this proof-of-concept study one donor was used for the in vitro studies and one volunteer for the in vivo investigations to minimise biovariability. Analysis of in vitro samples was conducted using HPLC and in vivo uptake of niacinamide was evaluated using Confocal Raman spectroscopy (CRS). RESULTS: The amount of niacinamide permeated through skin in vitro was linearly proportional to the intensity of the niacinamide signal determined in the stratum corneum in vivo. A good correlation was observed between the signal intensities of selected vehicles and niacinamide signal intensity. CONCLUSIONS: The findings provide further support for the use of CRS to monitor drug delivery into and across the skin. In addition, the results highlight the critical role of the vehicle and its disposition in skin for effective dermal delivery.

The effects of esterified solvents on the diffusion of a model compound across human skin: an ATR-FTIR spectroscopic study.

Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy has been used to investigate the effects of three fatty acid esters on skin permeation. Propylene glycol diperlargonate (DPPG), isopropyl myristate (IPM) and isostearyl isostearate (ISIS) were selected as pharmaceutically relevant solvents with a range of lipophilicities and cyanophenol (CNP) was used as a model drug. The resultant data were compared with that obtained when water was used as the solvent. The diffusion of CNP, DPPG and IPM across epidermis was successfully described by a Fickian model. When ISIS was used as a solvent Fickian behaviour was only obtained across isolated stratum corneum suggesting that the hydrophilic layers of the epidermis interfere with the permeation of the hydrophobic ISIS. The diffusion coefficients of CNP across epidermis in the different solvents were not significantly different. Using chemometric data analysis diffusion profiles for the solvents were deconvoluted from that of the skin and modelled. Each of these solvents was found to diffuse at a faster rate across the skin than CNP. DPPG considerably increased the concentration of CNP in the stratum corneum in comparison with the other solvents indicating strong penetration enhancer potential. In contrast IPM produced a similar CNP concentration in the stratum corneum to water with ISIS resulting in a lower CNP concentration suggesting negligible enhancement and penetration retardation effects for these two solvents respectively.

A new paradigm in dermatopharmacokinetics - Confocal Raman spectroscopy.

Confocal Raman spectroscopy (CRS) is a novel approach which has been used to determine stratum corneum thickness and to profile endogenous skin components. However, the utility of this technique for probing drug disposition in vivo has not been explored to date. In this paper we report the use of CRS to investigate the fate of ibuprofen after application from simple formulations which were previously investigated using the tape-stripping approach. Ibuprofen was prepared in propylene glycol (PG) and propylene glycol/water (PG/H2O) solutions. The formulations were then applied to the volar aspect of the forearm of human volunteers. The results confirmed that ibuprofen distribution profiles in the stratum corneum were comparable to previously published data from tape stripping experiments. We propose CRS as a non-invasive method for dermatopharmacokinetic evaluation of topical pharmaceutical formulations.

Influence of niacinamide containing formulations on the molecular and biophysical properties of the stratum corneum.

Niacinamide-containing moisturisers are known be efficacious in alleviating dry skin conditions and improving stratum corneum (SC) barrier function. However, the mechanisms of action of niacinamide at the molecular level in the SC are still not well understood. Previously, we have reported the development of novel methods to probe SC barrier properties in vivo. The aim of the present study was to characterise changes in Trans Epidermal Water Loss (TEWL), corneocyte surface area and maturity, selected protease activities and SC thickness after repeated application of a simple vehicle containing niacinamide. A commercial formulation was also included as a reference. The left and right mid-volar forearms of 20 healthy volunteers were used as study sites, to which topical formulations were applied twice daily for 28 days. After successive tape-stripping, corneocyte maturity and surface area were assessed. In addition, activity of the desquamatory kallikrein (KLK) protease enzymes KLK5 and KLK7, and tryptase and plasmin (implicated in inflammatory process) were measured using a fluorogenic probe assay. The amount of protein removed and TEWL were also recorded. SC thickness before and after treatment was determined using Confocal Raman Spectroscopy (CRS). Overall (i) corneocyte maturity and surface area decreased with increasing number of tape strips, (ii) activity of both the desquamatory and inflammatory enzymes was highest in the outer layers of the SC and decreased with depth (iii) TEWL increased as more SC layers were removed. Furthermore, areas treated with formulations containing niacinamide were significantly different to pre-treatment baseline and untreated/vehicle-control treated sites, with larger and more mature corneocytes, decreased inflammatory activity, decreased TEWL and increased SC thickness. These data (a) confirm the utility of measures and metrics developed previously for the non-invasive assay of SC barrier function, (b) present an holistic picture of a SC compartment managing barrier function through dynamic optimisation of pathlength and quality of building materials used, and (c) shed new light on niacinamide as a topical formulation adjunct with unique SC barrier-augmentation properties.

Influence of penetration enhancer on drug permeation from volatile formulations.

Previously we have reported the influence of supersaturation on the permeation of fentanyl across model membranes and skin. The findings indicated that the vehicle and, specifically its residence time in skin, influence the ability of the formulation to enhance membrane drug permeation. The aim of the present study was to probe the role of vehicle components on (trans)dermal drug delivery in more detail. To this end, three commonly used chemical penetration enhancers were selected for investigation namely, propylene glycol (PG), octyl salicylate (OSAL) and isopropyl myristate (IPM). A further objective was to clarify the mechanism of action of OSAL. Model spray formulations were prepared consisting of 10% (v/v) of individual enhancers in ethanol. Saturated and supersaturated systems were evaluated for their ability to promote fentanyl transport across human skin in vitro. Mass balance studies and determination of the extent of uptake of enhancers by skin were also conducted. The results indicated that increasing the degree of drug saturation (DS) does not promote drug permeation for formulations in PG but increasing drug DS did promote drug permeation for IPM and some OSAL systems. This probably reflects faster depletion of PG compared with IPM and OSAL. Non-linear modelling of the permeation data indicated that PG and IPM act to promote drug solubility in the membrane whereas OSAL appears to act as a skin penetration enhancer by increasing drug diffusivity in the skin.

Rational formulation design.

To be efficacious and to satisfy the requirements for claim substantiation, a cosmetic formulation must achieve effective targeting of an active in the skin. Although the basic principles governing the skin permeation and disposition of molecules have been known for many years, attention has been far less focused on the role of the vehicle, particularly at cosmetically relevant doses. In this article, we discuss the necessity to understand the fate of the formulation components as well as the active once applied onto skin. Recent data confirm that the residence time of the formulation constituents can have a profound impact on the fate of the active. Approaches to identify the ideal vehicle for skin delivery are considered critically, specifically the recent work on 'formulating for efficacy' (FFE) by the late Johann Wiechers. Essentially, FFE aims to match the active with the optimal vehicle for skin delivery based on matching polarity/solubility values of the trinity of skin, active and vehicle. The emerging importance of techniques that provide insight to how the vehicle distributes in and on skin is highlighted.

The role of vehicle interactions on permeation of an active through model membranes and human skin.

Previous work from this group has focused on the molecular mechanism of alcohol interaction with model membranes, by conducting thermodynamic and kinetic analyses of alcohol uptake, membrane partitioning and transport studies of a model compound (i.e. methyl paraben) in silicone membranes. In this article, similar membrane transport and partitioning studies were conducted in silicone membranes to further extend the proposed model of alcohol interactions with silicone membranes to include other vehicles more commonly used in dermal formulations, that is, isopropyl myristate (IPM), dimethyl isosorbide (DMI), polyethylene glycol (PEG) 200, PEG 400 and Transcutol P® (TC). More importantly, membrane partitioning studies were conducted using human SC to evaluate the application of the proposed model of solvent-enhanced permeation in simple model membranes for the more complex biological tissue. The findings support a model of vehicle interactions with model membranes and skin where high solvent uptake promotes drug partitioning (i.e. K) by enabling the solute to exist within the solvent fraction/solvent-rich areas inside the membrane or skin in a concentration equivalent to that in the bulk solvent/vehicle. High solvent sorption may also ultimately impact on the membrane diffusional characteristics, and thus the diffusion coefficient of the solute across the membrane. The implications for skin transport are that increased partitioning of a drug into the SC may be achieved by (i) selecting vehicles that are highly taken up by the skin and also (ii) by having a relatively high concentration (i.e. molar fraction) of the drug in the vehicle. It follows that, in cases where significant co-transport of the solvent into and across the skin may occur, its depletion from the formulation and ultimately from the skin may lead to drug crystallization, thus affecting dermal absorption.

Comparison of gravimetric and spectroscopic approaches to quantify stratum corneum removed by tape-stripping.

Skin surface tape-stripping is an extensively used technique to examine the distribution profile, penetration and safety of various active compounds. It is also a widely accepted method to probe skin barrier properties and more specifically, those of the stratum corneum (SC). The amount of SC removed by tape-stripping is generally determined either gravimetrically or by extraction and measurement of SC proteins. A novel infra-red densitometry (IRD) technique has recently been introduced to measure SC protein content. In the present study, IRD was investigated as an alternative method to measure the mass of SC removed by tape-stripping. Tape-stripping experiments were conducted on human volunteers. The weight of the stratum corneum removed was assessed by the gravimetric approach and by IRD. Transepidermal water loss (TEWL) was also measured before and after each tape-strip. A linear correlation coefficient was obtained for the data from the gravimetric and IRD measurements (r(2)=0.65; n=240). IRD is therefore proposed as a rapid, non-destructive alternative to the gravimetric approach to estimate the amount of SC removed by tape-stripping in vivo.

Formulation issues associated with transdermal fentanyl delivery.

Supersaturation has previously been studied as a mechanism to enhance membrane transport of fentanyl from propylene glycol:water formulations (PG:H(2)O) across silicone. In this study these supersaturated fentanyl formulations were evaluated in human skin. A number of polymers were also screened for their ability to stabilise the supersaturated formulations and permeation was evaluated for both infinite and finite doses. For infinite dose studies, permeation in skin increased linearly with increasing degree of drug saturation (DS) for formulations containing 0.5, 1, 2 DS of fentanyl and a 3 DS formulation stabilised with 1% (w/v) hydroxypropylcellulose (HPC). An excellent correlation was obtained for flux values in silicone compared with flux values in skin, for infinite dose studies for formulations containing 0.5, 1, 2 DS of fentanyl and the 3 DS formulation stabilised HPC. The concentration of the fentanyl in the stratum corneum also increased in proportion to the DS. However the same trend was not observed for finite dose studies. This is because the depletion of the solvent carrier promotes drug crystallisation with consequent implications for membrane transport. Tape-stripping experiments indicated that supersaturation of the drug is maintained in the outer layers of the stratum corneum. The ideal vehicle must, therefore, maintain the drug in solution on and in the skin in a sustained manner for effective transdermal delivery.

Influence of Aqueous Cream BP on corneocyte size, maturity, skin protease activity, protein content and transepidermal water loss.

BACKGROUND: Aqueous Cream BP is frequently prescribed for patients with eczema and is known to induce sensitivity in certain patients and also to decrease the thickness of the stratum corneum (SC). We have previously reported methodology to quantify corneocyte maturity and size, protease activity and protein content within different levels of the SC. OBJECTIVES: The aim of the present study was to investigate changes in corneocyte size, corneocyte maturity, selected protease activities, protein content and transepidermal water loss (TEWL) in normal skin after a 28-day application of Aqueous Cream BP. METHODS: The left and right mid volar forearms of six healthy female volunteers were selected as the study sites. Aqueous Cream BP was applied twice daily to treated sites for 28 days. At the end of this period, the site was tape-stripped and corneocyte maturity, corneocyte size and protease activity of the desquamatory kallikrein proteases, KLK5 and KLK7, and the inflammatory proteases tryptase and plasmin were measured. Protein content and TEWL measurements were also recorded. RESULTS: Corneocyte maturity and size decreased with increasing number of tape strips, and were significantly lower in treated sites compared with untreated sites. Protease activity and TEWL values were higher (P < 0·05) for the treated sites compared with untreated sites. The amount of protein removed from deeper layers of treated sites was significantly lower than from untreated sites. CONCLUSIONS: We report rapid minimally invasive measures of the effects of Aqueous Cream BP at the cellular and molecular level of the skin. Treatment with this formulation is associated with increased desquamatory and inflammatory protease activity. Changes in corneocyte maturity and size are also indicative of accelerated skin turnover induced by chronic application of this emollient. These findings question firmly the routine prescription of this preparation as a moisturizer in patients with atopic dermatitis.

Enhanced permeation of fentanyl from supersaturated solutions in a model membrane.

The aim of the present study was to investigate the permeation of fentanyl from supersaturated formulations when applied to silicone membrane. Silicone was chosen in order to separate the effects of supersaturation from other possible influences of volatile formulation components on biological membranes. Supersaturated formulations containing either propylene glycol/water (PG/H(2)O) or propylene glycol/ethanol (PG/Et) were prepared containing varying degrees of saturation (DS) of fentanyl. Permeation of finite and infinite doses of the PG/H(2)O formulations, and finite doses of the PG/Et formulations was investigated using Franz-type diffusion cells. For the PG/H(2)O formulations a good correlation between the flux and the DS of the formulation up to 5 DS for infinite dose studies (r(2)=0.99), and up to 7 DS for finite dose studies (r(2)=0.98), was evident. Similarly, for the PG/Et formulations there is a good correlation between the mean flux and the theoretical DS of the formulation (r(2)=0.95). Except for the 2 DS formulations, no significant differences were seen in the mean flux between PG/H(2)O and PG/Et finite dose studies. The larger fluxes observed for infinite doses of the PG/H(2)O formulations versus finite doses reflect changes in the effective area of diffusion over the time of the experiment for the latter set of experiments. The permeation enhancement observed for PG/Et formulations confirms that enhanced drug thermodynamic activity was induced by ethanol evaporation.

Opto-Thermal Transient Emission Radiometry (OTTER) to image diffusion in nails in vivo.

This work describes the first application of Opto-Thermal Transient Emission Radiometry (OTTER), an infrared remote sensing technique, to probe the extent to which solvents permeate the human nail in vivo. Decanol, glycerol and butyl acetate were selected as model solvents. After application of the solvents, individually, to human volunteers, OTTER was used to depth profile the solvents. The permeation rate of the solvents was ranked as glycerol>decanol>butyl acetate. It is possible that some of the butyl acetate may have evaporated during the experiment. The ability of decanol to extract lipids from biological tissue is also considered. These preliminary results demonstrate the potential of OTTER as a tool to identify optimal excipients with which to target drugs to the nail.

Depth profiling of stratum corneum biophysical and molecular properties.

BACKGROUND: The barrier function of the skin may be characterized by a number of biophysical and molecular methods. Variation in the barrier properties as a function of depth has not been explored in detail. OBJECTIVES: To characterize changes in corneocyte surface area, corneocyte maturity, selected protease activities and transepidermal water loss (TEWL) in the ventral forearm with increasing depth. METHODS: The left mid-ventral forearm of 22 healthy volunteers was selected as the study site. After tape stripping, corneocyte maturity and surface area were assessed. The protease activity of the desquamatory kallikrein proteases, KLK5 and KLK7, and inflammatory tryptase was measured using a fluorogenic probe assay. Protein content and TEWL were also recorded. RESULTS: Corneocyte maturity and surface area decreased with increasing number of tape strippings, i.e. depth into the skin. More mature corneocytes were typically larger than less mature corneocytes. The protease activities of both the desquamatory and inflammatory enzymes together with the protein content were highest in the outer layers of the stratum corneum and decreased with depth. As expected, TEWL increased as more stratum corneum layers were removed. There were no statistical differences between men and women or caucasian and black subjects for all of the parameters studied. CONCLUSIONS: The techniques used in this study provide rapid noninvasive measures of the spatial distribution of corneocyte maturity and surface area as well as protease activity and protein content within different levels of the stratum corneum layers. The methods used will allow mechanistic insight into the effects of formulation excipients and active ingredients on epidermal turnover and skin barrier function.

Optimisation of cosolvent concentration for topical drug delivery III--influence of lipophilic vehicles on ibuprofen permeation.

Previously, we have reported the effects of water, ethanol, propylene glycol and various binary and ternary mixtures of these solvents on the permeation of ibuprofen in model membranes and in skin. The present study investigates the influence of lipophilic vehicles on the transport of ibuprofen in silicone membrane and in human skin. The permeation of ibuprofen was measured from mineral oil (MO), Miglyol® 812 (MG) and binary mixtures of MO and MG. The solubility of ibuprofen was 5-fold higher in MG than in MO, however, the permeation of ibuprofen from the pure vehicles and combinations of both was comparable in silicone membrane. Additionally, there were no significant differences in skin permeation for MO and MG vehicles. When the permeation of various hydrophilic and lipophilic vehicles is considered, a trend between flux values for the model membrane and skin is evident (r(2) = 0.71). The findings suggest that silicone membrane may provide information on qualitative trends in skin permeation for vehicles of diverse solubility and partition characteristics.