Effects of soap–water wash on human epidermal penetration

Skin decontamination is a primary interventional method used to decrease dermal absorption of hazardous contaminants, including chemical warfare agents, pesticides and industrial pollutants. Soap and water wash, the most common and readily available decontamination system, may enhance percutaneous absorption through the “wash‐in effect.” To understand better the effect of soap–water wash on percutaneous penetration, and provide insight to improving skin decontamination methods, in vitro human epidermal penetration rates of four C¹⁴‐labeled model chemicals (hydroquinone, clonidine, benzoic acid and paraoxon) were assayed using flow‐through diffusion cells. Stratum corneum (SC) absorption rates of these chemicals at various hydration levels (0–295% of the dry SC weights) were determined and compared with the results of the epidermal penetration study to clarify the effect of SC hydration on skin permeability. Results showed accelerated penetration curves of benzoic acid and paraoxon after surface wash at 30 min postdosing. Thirty minutes after washing (60 min postdosing), penetration rates of hydroquinone and benzoic acid decreased due to reduced amounts of chemical on the skin surface and in the SC. At the end of the experiment (90 min postdosing), a soap–water wash resulted in lower hydroquinone penetration, greater paraoxon penetration and similar levels of benzoic acid and clonidine penetration compared to penetration levels in the non‐wash groups. The observed wash‐in effect agrees with the enhancement effect of SC hydration on the SC chemical absorption rate. These results suggest SC hydration derived from surface wash to be one cause of the wash‐in effect. Further, the occurrence of a wash‐in effect is dependent on chemical identity and elapsed time between exposure and onset of decontamination. By reducing chemical residue quantity on skin surface and in the SC reservoir, the soap–water wash may decrease the total quantity of chemical absorbed in the long term; however, the more immediate accelerated absorption of chemical toxins, particularly chemical warfare agents, may be lethal. Copyright © 2015 John Wiley & Sons, Ltd.     

Drug Distribution in Human Skin Using Two Different In Vitro Test Systems: Comparison with In Vivo Data

Purpose. Two in vitro test systems used to study drug penetration into human skin—the Franz diffusion cell (FD-C) and the Saarbruecken penetration model (SB-M)—were evaluated, and the results were compared with data gained under analogous in vivo conditions. Methods. Excised human skin was used in all in vitro experiments. Flufenamic acid dissolved in wool alcohols ointment, was chosen as a model drug, and the preparation was applied using infinite dose conditions. To acquire quantitative information about the drug penetration, the skin was segmented into surface parallel sections at the end of each experiment, first by tape stripping the stratum corneum (SC), and second by cutting the deeper skin layers with a cryomicrotome. The flufenamic acid was extracted from each sample and assayed by high performance liquid chromatography (HPLC). For in vivo experiments, only the tape stripping technique was used. Results. a) Drug penetration into the SC: In both in vitro test systems the total drug amounts detected in the SC were found to increase over the different incubation times. Similar conditions were obtained in vivo, but on a lower level. Using Michaelis-Menten kinetics, the m_max value was calculated for the skin of two donors. The relations of the m_max values for the FD-C and the SB-M closely correspond (1.26 [donor 1] and 1.29 [donor 2]). A direct linear correlation of the drug amount in the SC and the time data were found for in vivo with both in vitro test systems.%b) Drug penetration into the deeper skin layers: The detected drug amounts in the deeper skin layers continuously increased with the incubation time in the SB-M, while in the FD-C, only very small drug amounts were observed after incubation times of 30 and 60 minutes. It was also noticed, that the drug amounts rose steeply at time points 3 and 6 hours. Additional studies showed a remarkable penetration of water into the skin from the basolateral acceptor compartment in the FD-C. This could explain the different drug transport into the deeper skin layers between the two in vitro test systems. Conclusions. Both in vitro models showed comparable results for the drug penetration into the SC and a robust correlation with in vitro data. Different results were obtained for the deeper skin layers. Whether a correlation between in vitro and in vivo data is also possible here has to be investigated by further experiments.     

Chemomorphic Analysis of Malathion in Skin Layers of the Rat: Implications for the Use of Dermatopharmacokinetic Tape Stripping in Exposure Assessment to Pesticides

The dermatopharmacokinetic (DPK) method of dermal tape stripping may prove to be a valuable addition to risk assessment protocols for toxic substances as it has been for the assessment of bioequivalence and bioavailability of topical dermatologic drugs. The measurement of drug penetration into stratum corneum (SC) with respect to time is thought to be comparable with drug distribution in underlying tissues. To examine this possibility, the dermal penetration and absorption characteristics of [(14)C]malathion in the Sprague-Dawley rat was examined by three analytical techniques. [(14)C]Malathion was applied in different vehicles for 30-min and 1-h periods of exposure. Penetration into the SC was assessed by tape stripping followed by instant electronic autoradiography (IEA). Also, the (14)C activity retained in three successive 16 microm sections of the skin application site was determined by IEA and malathion was identified by Fourier transform infrared microscopy (FTIR microscopy). Absorbed [(14)C]malathion was measured in selected tissues, organs, and the residual carcass by liquid scintillation counting (LSC). Penetration into the SC followed a linear trend. The capacity of the SC reservoir for malathion amounted to approximately 1% of the dermal dose, while approximately 6% of the dose was absorbed. Results from this study support the view that LSC remains the method of choice to efficiently and reliably quantify absorption of a radiolabeled test substance. IEA offers the ability of the user to visualize the extent and profile of dermal absorption. When IEA is combined with FTIR microscopy, an effectual tool for studying the penetration of chemicals into layers of the skin emerges. The combined use of the three analytical techniques can be used to test the validity of the DPK method in hazard evaluation and exposure assessment of the organophosphorus insecticides.     

Assessment of the percutaneous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway

It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound.     

Topical Penetration of Piroxicam Is Dependent on the Distribution of the Local Cutaneous Vasculature

The mechanism of the topical delivery of piroxicam, a nonsteroidal antiinflammatory drug, has been controversial as to whether systemic absorption is required for topical efficacy. This study, using in vivo pigs treated with topical ³H-piroxicam gel, was designed to assess the role of systemic absorption on its delivery to deep tissues. Further, the role of the structure of the cutaneous vasculature (e.g., direct cutaneous or musculocutaneous) was studied. Finally, piroxicam delivery was measured using in vitro diffusion cells with pig skin obtained from the same sites to determine inherent permeability independent of vascular anatomy. These studies showed that penetration of the radiolabel occurred in subcutaneous and muscle tissue only under the dosed sites and not at the remote sites, ruling out systemic absorption as a prerequisite for local delivery. Tissue penetration in vivo was enhanced at the musculocutaneous compared to the direct cutaneous sites. In contrast, in vitro flux was identical in skin harvested from the two vascular sites, suggesting that the vasculature plays a pivotal role in deep tissue penetration of piroxicam. In conclusion, local delivery of topical drugs occurs independent of systemic absorption and the nature of the cutaneous vasculature at different sites must be taken into consideration for optimal delivery.     

Assessment of the Lateral Diffusion and Penetration of Topically Applied Drugs in Humans Using a Novel Concentric Tape Stripping Design

Purpose

To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique.

Method

Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin.

Results

CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3?mins ranged between 83.0 and 92.9?% and decreased to between 64.5 and 66.9?% at 3?h. IBU recovery further decreased to 47.7?±?5.6?% at 6?h, correlating with greater in vitro penetration relative to CAF and HC.

Conclusion

Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.     

Isolated human/animal stratum corneum as a partial model for 15 steps in percutaneous absorption: emphasizing decontamination,Part I

Since the advent of World War II, governments and laboratories have made a concerted effort to improve prophylactic and therapeutic interventions counteracting cutaneously directed chemical warfare agents (CWA), and by inference, common industrial and consumer dermatotoxicants. In vitro percutaneous penetration assays, first utilized by Tregear in the 1940s and presently in various modifications, have been fundamental to this effort. Percutaneous penetration, often considered a simple one‐step diffusion process, consists of at least 15 steps. The first part of this review covers the initial steps related to absorption and excretion kinetics, vehicle characteristics, and tissue disposition. Importantly, the partitioning behavior and stratum corneum (SC) diffusion by a wide physicochemical array of compounds shows that many compounds have similar diffusion coefficients determining their percutaneous absorption in vivo. After accounting for anatomical SC variation, the penetration flux value of a substance depends mainly on its SC/vehicle partition coefficient. Additionally, the SC acts as a ‘reservoir’ for topically applied molecules and application of tape stripping has been found to quantify the chemical remaining in the SC which can predict total molecular penetration in vivo. Decontamination is of particular concern and even expediting standard washing procedures after dermal chemical exposure often fails to remove chemicals. This overview summarizes knowledge of percutaneous penetration extending insights into the complexities of penetration, decontamination and potential newer assays that may be of practical importance. Copyright © 2012 John Wiley & Sons, Ltd.     

Topical bioavailability of triamcinolone acetonide: effect of occlusion

BACKGROUND/AIMS: Occlusion by covering the skin with an impermeable wrap enhances skin hydration, affects drug absorption and can induce the formation of a drug reservoir within the stratum corneum. This is desired in local therapy with topical corticosteroids. The aim of the study was to investigate the effect of occlusion before (experiment 1) and after (experiment 2) application on the penetration of triamcinolone acetonide (TACA) into the stratum corneum. METHODS: The experiments were conducted on the forearms of 10 healthy volunteers. In experiment 1, 100 microg/cm(2) TACA in acetone were applied on 3 sites per arm, one arm having been pre-occluded for 16 h. In experiment 2, the same dose was applied on 2 sites per arm, and one arm was occluded after application until skin sampling. Stratum corneum samples were removed by tape stripping at 0.5, 4 and 24 h (experiment 1) and 4 and 24 h (experiment 2) after application. Corneocytes and TACA were quantified by ultraviolet-visible spectroscopy and HPLC, respectively. The total TACA amount penetrated into the stratum corneum was evaluated by multifactor ANOVA. RESULTS: TACA penetration into the stratum corneum with and without pre-occlusion (experiment 1) showed no significant difference and decreased with time. Occlusion after application (experiment 2) produced a marked TACA accumulation within the stratum corneum, which persisted for 24 h. CONCLUSION: Pre-occlusion showed no effect on the topical bioavailability of TACA in the stratum corneum. In contrast, post-occlusion enhanced the TACA penetration by a factor of 2, favouring the development of a drug reservoir.     

Dermal Penetration of Fentanyl: Inter‐ and Intraindividual Variations

Abstract: Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra‐ and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21–105 ng/cm²/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter‐individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate‐determining factor for the other individuals included in this study.     

Lasers as an approach for promoting drug delivery via skin

Introduction: Using lasers can be an effective drug permeation-enhancement approach for facilitating drug delivery into or across the skin. The controlled disruption and ablation of the stratum corneum (SC), the predominant barrier for drug delivery, is achieved by the use of lasers. The possible mechanisms of laser-assisted drug permeation are the direct ablation of the skin barrier, optical breakdown by a photomechanical wave and a photothermal effect. It has been demonstrated that ablative approaches for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, quick recovery of SC integrity and the fact that skin surface contact is not needed. In recent years, the concept of using laser techniques to treat the skin has attracted increasing attention.

Areas covered: This review describes recent developments in using nonablative and ablative lasers for drug absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of lasers, highlighting the potential of this technique for greatly increasing drug absorption via the skin. Lasers with different wavelengths and types are employed to increase drug permeation. These include the ruby laser, the erbium:yttrium-gallium-garnet laser, the neodymium-doped yttrium-aluminum-garnet laser and the CO₂ laser. Fractional modality is a novel concept for promoting topical/transdermal drug delivery. The laser is useful in enhancing the permeation of a wide variety of permeants, such as small-molecule drugs, macromolecules and nanoparticles.

Expert opinion: This potential use of the laser affords a new treatment for topical/transdermal application with significant efficacy. Further studies using a large group of humans or patients are needed to confirm and clarify the findings in animal studies. Although the laser fluence or output energy used for enhancing drug absorption is much lower than for treatment of skin disorders and rejuvenation, the safety of using lasers is still an issue. Caution should be used in optimizing the feasible conditions of the lasers in balancing the effectiveness of permeation enhancement and skin damage.     

Oleic Acid as Optimizer of the Skin Delivery of 5-Aminolevulinic Acid in Photodynamic Therapy

Purpose In photodynamic therapy (PDT), topically applied aminolevulinic acid (5-ALA) is converted to protoporphyrin IX (PpIX), which upon light excitation induces tumor destruction. To optimize 5-ALA-PDT via improving the highly hydrophilic 5-ALA limited penetration into the skin, we propose the use of the known skin penetration enhancer, oleic acid (OA). Methods In vitro skin penetration and retention of 5-ALA (1% w/w) were measured in the presence or absence of OA (2.5, 5.0, and 10.0% w/w) in propylene glycol (PG) using porcine ear skin as the membrane. In vivo accumulation of PpIX, 4 h after application, was determined fluorometrically in healthy mice skin by chemical extracton of skin samples. In vivo PpIX fluorescence kinetics was also investigated by noninvasive techniques using an optical fiber probe, for 30 min up to 24 h after topical application of 1.0% 5-ALA + 10.0% OA in PG on hairless mice skins. Results The flux and in vitro retention of 5-ALA in viable epidermis increased in the presence of 10.0% (w/w) OA. The amounts of PpIX, evaluated both by chemical tissue extractions and in vivo measurements by an optical fiber probe, increased after applying 5-ALA formulations containing 5.0 or 10.0% OA. Moreover, in vivo kinetic studies showed an increase in skin PpIX accumulation when formulations containing 10% OA were used; PpIX accumulation was also maintained longer compared to controls. Conclusions Both in vitro and in vivo results show the OA potential as an optimizer of 5-ALA skin delivery.     

Hair follicles contribute significantly to penetration through human skin only at times soon after application as a solvent deposited solid in man

AIMS

The aim of this study was to define the underlying relative penetration of caffeine through hair follicles and through intact stratum corneum with time in vivo through pharmacokinetic modelling.

METHODS

Caffeine plasma concentration–time profiles after topical application into skin with or without hair follicle blocking were modelled using the Wagner–Nelson method or a compartmental model with first order absorption and elimination. Pharmacokinetic parameters describing absorption rate and extent of absorption through hair follicles or the stratum corneum were determined separately and compared with each other.

RESULTS

The obtained pharmacokinetic parameters from the two methods were similar. The absorption rate constant of caffeine for hair follicles was nearly 10 times higher than that for the stratum corneum and the percentage of absorption from hair follicles was more than half of that of the stratum corneum. In addition, the absorption from the stratum corneum showed an approximately 10 min delay while there was no delay for absorption from hair follicles. All caffeine absorbed by hair follicles occurs within 30 min of application and accounts for 10.5 to 33.8% of the total amount absorbed across the skin for all subjects, whereas absorption of caffeine through the stratum corneum can occur over several hours.

CONCLUSION

Hair follicles contribute significantly to percutaneous absorption of caffeine after topical application in man in vivo only at times soon after application.     

Effect of menthone and related compounds on skin permeation of drugs with different lipophilicity and molecular organization of stratum corneum lipids

The objective of this article was to investigate the enhancing effect of menthone, menthol and pulegone on the transdermal absorption of drugs with different lipophilicity and probe their mechanisms of action at molecular level. Five model drugs, namely osthole, tetramethylpyrazine, ferulic acid, puerarin and geniposide, which were selected based on their lipophilicity denoted by logK_o/w, were tested using in vitro permeation studies in which Franz diffusion cells and rat skin were employed. Infrared spectroscopy and molecular dynamic simulation were used to investigate the effect of these enhancers on the stratum corneum (SC) lipids, respectively. Three compounds could effectively promote the transdermal absorption of drugs with different lipophilicity, and the overall promoting capacities were in the following increasing order: pulegone?<?menthol?<?menthone. The penetration enhancement ratio was roughly in parabolic curve relationships with the drug lipophilicity after treatment with menthol or menthone, while the penetration enhancement effect of pulegone hardly changed with the alteration of the drug lipophilicity. The molecular mechanism studies suggested that menthone and menthol enhanced the skin permeability by disordering the ordered organization of SC lipids and extracted part of SC lipids, while pulegone appeared to promote drug transport across the skin only by extracting part of SC lipids.     

Liposomes in topical photodynamic therapy

Introduction: Topical photodynamic therapy (PDT) refers to topical application of a photosensitizer onto the site of skin disease which is followed by illumination and results in death of selected cells. The main problem in topical PDT is insufficient penetration of the photosensitizer into the skin, which limits its use to superficial skin lesions. In order to overcome this problem, recent studies tested liposomes as delivery systems for photosensitizers.

Areas covered: This paper reviews the use of different types of liposomes for encapsulating photosensitizers for topical PDT. Liposomes should enhance the photosensitizers' penetration into the skin, while decreasing its absorption into systemic circulation. Only few photosensitizers have currently been encapsulated in liposomes for topical PDT: 5-aminolevulinic acid (5-ALA), temoporfin (mTHPC) and methylene blue.

Expert opinion: Investigated liposomes enhanced the skin penetration of 5-ALA and mTHPC, reduced their systemic absorption and reduced their cytotoxicity compared with free drugs. Their high tissue penetration should enable the treatment of deep and hyperkeratotic skin lesions, which is the main goal of using liposomes. However, liposomes still do not attract enough attention as drug carriers in topical PDT. In vivo studies of their therapeutic effectiveness are needed in order to obtain enough evidence for their potential clinical use as carriers for photosensitizers in topical PDT.     

Pig Ear Skin ex Vivo as a Model for in Vivo Dermatopharmacokinetic Studies in Man

Objective The objective was to investigate pig ear skin as a surrogate for human skin in the assessment of topical drug bioavailability by sequential tape-stripping of the stratum corneum (SC). The potential benefits of ex vivo investigations are manifold: ethical approval is not required, multiple replicate experiments are more easily performed, and toxic compounds can be evaluated.Materials and Methods Ex vivo experiments on isolated pig ears were compared with in vivo studies in human volunteers. Four formulations, comprising the model drug, ibuprofen, in different propylene glycol (PG)-water mixtures (25:75, 50:50, 75:25 and 100:0), were compared.Results Derived dermatopharmacokinetic parameters characterizing the diffusion and partitioning of the drug in the SC ex vivo were consistent with those in vivo following a 30-minute application period. Further, the non-steady-state ex vivo results could be used to predict the in vivo concentration profile of the drug across the SC when a formulation was administered for 3 h (i.e., close to steady-state).Conclusions Taken together, the results obtained suggest that pig ear skin ex vivo has promise as a tool for topical formulation evaluation and optimization.     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

Dermatopharmacokinetics: Factors Influencing Drug Clearance from the Stratum Corneum

Purpose  The dermatopharmacokinetic methodology, in which tape stripping of the stratum corneum (SC) is used to access the amount of drug accumulated in the skin barrier, has been proposed for the quantification of topical drug bioavailability. This investigation examined the clearance phase of a model drug from the SC after a short application of an infinite dose. Methods  A saturated solution of ibuprofen in propylene glycol/water was applied to the forearm of human volunteers for 30 min. The formulation was then removed and the drug profile across the SC was assessed immediately, and over the next 4 h. Results  The clearance phase depends only on drug diffusivity in the SC. However, the expected, progressive “flattening” of the concentration profiles with increasing time post-formulation removal was not observed. It was subsequently deduced, using infrared spectroscopy, that the rapid percutaneous diffusion of propylene glycol, relative to ibuprofen, resulted in the transient maintenance of a saturated drug concentration at the SC surface even after removal of the original formulation. Conclusions  The important role of formulation excipients in topical delivery is demonstrated, and the local disposition of cosolvents within the SC may impact significantly on drug dermatopharmacokinetics and local bioavailability.     

Topical delivery of silymarin constituents via the skin route

Aim:

Silibinin (SB), silydianin (SD), and silychristin (SC) are components of silymarin. These compounds can be used to protect the skin from oxidative stress induced by ultraviolet (UV) irradiation and treat it. To this end, the absorption of silymarin constituents via the skin was examined in the present report.

Methods:

Transport of SB, SD, and SC under the same thermodynamic activity through and into the skin and the effects of pH were studied in vitro using a Franz diffusion assembly.

Results:

The lipophilicity increased in the order of SCin vivo topical application for 4 and 8 h, the skin deposition of SB was higher than those of SD and SC by 3.5∼4.0- and 30∼40-fold, respectively. The skin disruption and erythema test demonstrated that the topical application of these compounds for up to 24 h caused no apparent skin irritation.

Conclusion:

The basic profiles of silymarin permeation via skin route were established.     

Bioequivalence Methodologies for Topical Drug Products: <Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">Ex Vivo</Emphasis> Studies with a Corticosteroid and an Anti-Fungal Drug

Objective

To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application.

Materials and Methods

In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed.

Results

For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment.

Conclusions

In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A “one-size-fits-all” approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.

     

In vitro penetration properties of solid lipid nanoparticles in intact and barrier-impaired skin

Treatment of skin diseases implies application of a drug to skin with an impaired epidermal barrier, which is likely to affect the penetration profile of the drug substance as well as the carrier into the skin. To elucidate this, the effect of skin barrier damage on the penetration profile of a corticosteroid applied in solid lipid nanoparticles (SLN) composed of different lipids, varying in polarity, was studied. The studies were carried out in vitro using impaired and intact porcine ear skin, and the SLN were compared with a conventional ointment. It was shown that a significantly higher amount of corticosteroid remained in the skin, intact as well as barrier impaired, when SLN was used as a vehicle. In general, the penetration profile of the drug substance into the skin was affected by the type of lipid used in the formulation and related to lipid polarity and drug substance solubility. When formulated in SLN and applied to intact skin, the permeation of the drug substance across the skin was significantly reduced, as compared to the ointment. Altogether, in both barrier-impaired and intact skin, a higher amount of drug substance remained in the skin during application of SLN for 6, 16, and 24 h, as compared to the ointment. These results emphasize the applicability of SLN to create a drug reservoir in skin, with the drug localized distinctively in the stratum corneum.