Less efficient skin penetration of the metal allergen Pd2+ compared to Ni2+ and Co2+ from patch test preparations.

BACKGROUND: Contrary to Ni2+- and Co2+-induced allergic contact dermatitis (ACD), reactions against Pd2+ are rare. However, Pd2+ activates a larger T cell fraction in vitro, suggesting an inefficient skin penetration. OBJECTIVES: This study compares Ni2+, Co2+ and Pd2+ skin penetration from commonly used diagnostic patch test preparations (PTPs) and aqueous metal salt solutions. METHODS: Using Franz diffusion cell assays, we applied the metals in PTPs (5% NiSO4, 1% CoCl2, 2% PdCl2 and 3% Na2PdCl4) and in solution to pigskin for 48 h, thereby mirroring the time frame of a patch test. The different compartments were analysed individually by inductively coupled plasma mass spectrometry. RESULTS: Metal ions were mainly retained in the upper stratum corneum layers. After application of PTPs, concentrations in the viable skin were lower for Pd2+ (1 and 7 µM) compared to Ni2+ and Co2+ (54 and 17 µM). CONCLUSIONS: Ni2+ and Co2+ penetrated the skin more efficiently than Pd2+ and thus may sensitize and elicit ACD more easily. This was observed for ions applied in petrolatum and aqueous solutions. We hypothesize that the differently charged metal complexes are responsible for the varying skin penetration behaviours.

Other Schistosomatoidea and Diplostomoidea.

Trematodes of the order Diplostomida are well known as serious pathogens of man, and both farm and wild animals; members of the genus Schistosoma (Schistosomatidae) are responsible for human schistosomosis (schistosomiasis) affecting more than 200 million people in tropical and subtropical countries, and infections of mammals and birds by animal schistosomes are of great veterinary importance. The order Diplostomida is also rich in species parasitizing other major taxa of vertebrates. The "Aporocotylidae" sensu lato are pathogenic in fish, "Spirorchiidae" sensu lato in reptiles. All these flukes have two-host life cycles, with asexually reproducing larvae usually in mollusks and occasionally in annelids, and adults usually live in the blood vessels of their vertebrate hosts. Pathology is frequently associated with inflammatory reactions to eggs trapped in various tissues/organs. On the other hand, the representatives of Diplostomidae and Strigeidae have three- or four-host life cycles in which vertebrates often serve not only as definitive but also as intermediate or paratenic hosts. Pathology is usually associated with migration of metacercariae and mesocercariae within the host tissues. The impact of these trematode infections on both farm and wild animals may be significant.

Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium.

Skin penetration of an active pharmaceutical ingredient is key to developing topical drugs. This penetration can be adjusted for greater efficacy and/or safety through the selection of dosage form. Two emerging dosage forms, cream-gel and gel-in-oil emulsion, were tested for their ability to deliver diclofenac into the skin, with the target of maximising skin retention while limiting systemic exposure. Prototypes with varying amounts of solvents and emollients were formulated and evaluated by in vitro penetration testing on human skin. Cream-gel formulas showed better skin penetration than the emulgel benchmark drug even without added solvent, while gel-in-oil emulsions resulted in reduced diffusion of the active into the receptor fluid. Adding propylene glycol and diethylene glycol monoethyl ether as penetration enhancers resulted in different diclofenac penetration profiles depending on the dosage form and whether they were added to the disperse or continuous phase. Rheological characterisation of the prototypes revealed similar profiles of cream-gel and emulgel benchmark, whereas gel-in-oil emulsion demonstrated flow characteristics suitable for massaging product into the skin. This study underlined the potential of cream-gel and gel-in-oil emulsions for adjusting active penetration into the skin, broadening the range of choices available to topical formulation scientists.

Evaluation of Emulgel and Nanostructured Lipid Carrier-Based Gel Formulations for Transdermal Administration of Ibuprofen: Characterization, Mechanical Properties, and Ex-Vivo Skin Permeation.

In transdermal applications of nonsteroidal anti-inflammatory drugs, the rheological and mechanical properties of the dosage form affect the performance of the drug. The aim of this study to develop emulgel and nanostructured lipid carrier NLC-based gel formulations containing ibuprofen, evaluate their mechanical properties, bioadhesive value and ex-vivo rabbit skin permeability. All formulations showed non-Newtonian pseudoplastic behavior and their viscosity values are suitable for topical application. The particle size of the nanostructured lipid carrier system was found to be 468 ± 21 nm, and the encapsulation efficiency was 95.58 ± 0.41%. According to the index of viscosity, consistency, firmness, and cohesiveness values obtained as a result of the back extrusion study, E2 formulation was found to be more suitable for transdermal application. The firmness and work of shear values of the E2 formulation, which has the highest viscosity value, were also found to be the highest and it was chosen as the most suitable formulation in terms of the spreadability test. The work of bioadhesion values of NLC-based gel and IBU-loaded NLC-based gel were found as 0.226 ± 0.028 and 0.181 ± 0.006 mJ/cm2 respectively. The percentages of IBU that penetrated through rabbit skin from the Ibuactive-Cream and the E2 were 87.4 ± 2.11% and 93.4 ± 2.72% after 24 h, respectively. When the penetration of ibuprofen through the skin was evaluated, it was found that the E2 formulation increased penetration due to its lipid and nanoparticle structure. As a result of these findings, it can be said that the NLC-based gel formulation will increase the therapeutic efficacy and will be a good alternative transdermal formulation.

Preparing a novel baicalin-loaded microemulsion-based gel for transdermal delivery and testing its anti-gout effect.

We previously demonstrated that baicalin had efficacy against gouty arthritis (GA) by oral administration. In this paper, a novel baicalin-loaded microemulsion-based gel (B-MEG) was prepared and assessed for the transdermal delivery of baicalin against GA. The preparation method and transdermal capability of B-MEG was screened and optimized using the central composite design, Franz diffusion cell experiments, and the split-split plot design. Skin irritation tests were performed in guinea pigs. The anti-gout effects were evaluated using mice. The optimized B-MEG comprised of 50 % pH 7.4 phosphate buffered saline, 4.48 % ethyl oleate, 31.64 % tween 80, 13.88 % glycerin, 2 % borneol, 0.5 % clove oil and 0.5 % xanthan gum, with a baicalin content of (10.42 ± 0.08) mg/g and particle size of (15.71 ± 0.41) nm. After 12 h, the cumulative amount of baicalin permeated from B-MEG was (672.14 ± 44.11) µg·cm-2. No significant skin irritation was observed following B-MEG application. Compared to the model group, B-MEG groups significantly decreased the rate of auricular swelling (P < 0.01) and number of twists observed in mice (P < 0.01); and also reduced the rate of paw swelling (P < 0.01) and inflammatory cell infiltration in a mouse model of GA. In conclusion, B-MEG represents a promising transdermal carrier for baicalin delivery and can be used as a potential therapy for GA.

Topical application of a novel anti-interleukin-17A antibody fragment penetrates psoriatic skin: Results of a randomised, double-blind, placebo-controlled Phase Ib study.

Interleukin (IL)-17A underlies the pathogenesis of chronic plaque psoriasis (CPP). Well-tolerated, effective IL-17A inhibitors for mild-to-moderate CPP are needed. ZL-1102 is a novel antibody fragment targeting IL-17A. To assess the safety, tolerability, preliminary efficacy and skin penetration of a topical 1% ZL-1102 hydrogel in patients with mild-to-moderate CPP, a two-part, Phase Ib study was conducted. Open-label Part A: six patients received a single topical application of ZL-1102 onto a psoriatic plaque; double-blind Part B: 53 patients were randomised 1:1 to twice-daily ZL-1102 or vehicle for 4 weeks. Key primary endpoints included treatment-emergent adverse events (TEAEs), tolerability and changes in local psoriasis area and severity index (PASI). TEAEs occurred in two (33.3%) patients in Part A and in 16 (59.3%) and 13 (50.0%) patients in the ZL-1102 and vehicle arms, respectively, in Part B. No grade ≥3 TEAEs were seen with ZL-1102. ZL-1102 led to numerically greater changes in local PASI versus vehicle (-28.8% vs. -17.2%), with good local tolerability. The trend towards local PASI improvement was accompanied by biomarker changes based on RNA sequencing, indicative of ZL-1102 penetration into psoriatic plaques. Topical ZL-1102 showed good safety, local tolerability and a trend towards improved local PASI; skin penetration was observed without measurable systemic exposure. ACTRN12620000700932.

Micelles-in-Liposome Systems Obtained by Proliposomal Approach for Cannabidiol Delivery: Structural Features and Skin Penetration.

Deformable liposomes represent valuable drug carriers for cutaneous administration. Nevertheless, the fluid lipid membrane can favor the drug leakage during storage. Proliposomes may represent a suitable strategy to solve this issue. As an alternative, a novel carrier, which encloses hydrophobic drugs in the inner core of vesicles, namely, a drug-in-micelles-in-liposome system (DiMiL), has been proposed. In this work, we investigated the possible advantages of combining these two approaches to obtain a formulation able to enhance the skin penetration of cannabidiol (CBD). Proliposomes were prepared by spray-drying or slurry method testing lactose, sucrose, and trehalose as carriers at different sugar/lipid weight ratios. The ratio between soy-phosphatidylcholine (main lipid) and Tween 80 was instead fixed at 85:15 w/w. DiMiL systems were extemporaneously obtained by the hydration of proliposomes with a Kolliphor HS 15 micellar dispersion (containing CBD, when appropriate). Based on the technological properties, sucrose and trehalose at 2:1 sugar/lipid ratio resulted in the best carriers for spray-dried and "slurried" proliposomes, respectively. Cryo-EM images clearly showed the presence of micelles in the aqueous core of lipid vesicles and the presence of sugars did not alter the structural organization of DiMiL systems, as demonstrated by SAXS analyses. All formulations were highly deformable and able to control CBD release regardless of the presence of sugar. The permeation through human epidermis of CBD carried by DiMiL systems was significantly improved compared to that obtained loading the drug in conventional deformable liposomes with the same lipid composition or in an oil solution. Furthermore, the presence of trehalose led to a further slight increase of the flux. Altogether, these results demonstrated that proliposomes may be a valuable intermediate for the preparation of deformable liposome-based cutaneous dosage forms, improving the stability without compromising the overall performances.

Confocal Raman Spectroscopic Characterization of Dermatopharmacokinetics Ex Vivo.

Confocal Raman spectroscopy is being assessed as a tool with which to quantify the rate and extent of drug uptake to and its clearance from target sites of action within the viable epidermis below the skin's stratum corneum (SC) barrier. The objective of this research was to confirm that Raman can interrogate drug disposition within the living layers of the skin (where many topical drugs elicit their pharmacological effects) and to identify procedures by which Raman signal attenuation with increasing skin depth may be corrected and normalized so that metrics descriptive of topical bioavailability may be identified. It was first shown in experiments on skin cross-sections parallel to the skin surface that the amide I signal, originating primarily from keratin, was quite constant with depth into the skin and could be used to correct for signal attenuation when confocal Raman data were acquired in a "top-down" fashion. Then, using 4-cyanophenol (CP) as a model skin penetrant with a strong Raman-active C≡N functionality, a series of uptake and clearance experiments, performed as a function of time, demonstrated clearly that normalized spectroscopic data were able to detect the penetrant to at least 40-80 µm into the skin and to distinguish the disposition of CP from different vehicles. Metrics related to local bioavailability (and potentially bioequivalence) included areas under the normalized C≡N signal versus depth profiles and elimination rate constants deduced post-removal of the formulations. Finally, Raman measurements were made with an approved dermatological drug, crisaborole, for which delivery from a fully saturated formulation into the skin layers just below the SC was detectable.

Quantification of Chemical Uptake into the Skin by Vibrational Spectroscopies and Stratum Corneum Sampling.

Evaluation of the bioavailability of drugs intended to act within the skin following the application of complex topical products requires the application of multiple experimental tools, which must be quantitative, validated, and, ideally and ultimately, sufficiently minimally invasive to permit use in vivo. The objective here is to show that both infrared (IR) and Raman spectroscopies can assess the uptake of a chemical into the stratum corneum (SC) that correlates directly with its quantification by the adhesive tape-stripping method. Experiments were performed ex vivo using excised porcine skin and measured chemical disposition in the SC as functions of application time and formulation composition. The quantity of chemicals in the SC removed on each tape-strip was determined from the individually measured IR and Raman signal intensities of a specific molecular vibration at a frequency where the skin is spectroscopically silent and by a subsequent conventional extraction and chromatographic analysis. Correlations between the spectroscopic results and the chemical quantification on the tape-strips were good, and the effects of longer application times and the use of different vehicles were clearly delineated by the different measurement techniques. Based on this initial investigation, it is now possible to explore the extent to which the spectroscopic approach (and Raman in particular) may be used to interrogate chemical disposition deeper in the skin and beyond the SC.

Neurog1-Derived Peptides RMNE1 and DualPep-Shine Penetrate the Skin and Inhibit Melanin Synthesis by Regulating MITF Transcription.

Anti-pigmentation peptides have been developed as alternative skin-lightening agents to replace conventional chemicals that have adverse effects on the skin. However, the maximum size of these peptides is often limited by their low skin and cell penetration. To address this issue, we used our intra-dermal delivery technology (IDDT) platform to identify peptides with hypo-pigmenting and high cell-penetrating activity. Using our cell-penetrating peptides (CPPs) from the IDDT platform, we identified RMNE1 and its derivative RMNE3, "DualPep-Shine", which showed levels of α-Melanocyte stimulating hormone (α-MSH)-induced melanin inhibition comparable to the conventional tyrosinase inhibitor, Kojic acid. In addition, DualPep-Shine was delivered into the nucleus and regulated the gene expression levels of melanogenic enzymes by inhibiting the promoter activity of microphthalmia-associated transcription factor-M (MITF-M). Using a 3D human skin model, we found that DualPep-Shine penetrated the lower region of the epidermis and reduced the melanin content in a dose-dependent manner. Furthermore, DualPep-Shine showed high safety with little immunogenicity, indicating its potential as a novel cosmeceutical ingredient and anti-pigmentation therapeutic agent.

Assessment of penetration and permeation of caffeine by confocal Raman spectroscopy in vivo and ex vivo by tape stripping.

OBJECTIVE: Tape stripping is an often-used non-invasive destructive method to investigate the skin penetration of a substance. In recent years, however, the suitability of confocal Raman spectroscopy (CRS) as a non-invasive method of non-destructive examination of the skin has become increasingly apparent. In this study, we compared invasion and depletion penetration and permeation kinetics of a 2% caffeine solution with and without 1,2-pentanediol as a penetration enhancer measured with CRS and tape stripping. METHODS: Porcine skin was used for tape stripping and human skin for CRS. 2% caffeine solution was applied to the skin for different incubation times. Human skin was then examined by CRS while caffeine was extracted from porcine skin and quantified via reverse-phase HPLC. Fluxes were also measured and calculated by sum of the total amounts of caffeine penetrated into the skin. RESULTS: Without penetration enhancers, there is hardly any difference between the penetration profiles of the two measurement methods for invasion, but the curves for depletion are different. Furthermore, the calculated flux values for the invasion are almost identical, but for the depletion the tape stripping values are about twice as high as the CRS values. CONCLUSION: The relevance of conducting invasion and depletion studies became clear and was able to show the still existing problems in the comparability of CRS and tape stripping.

OBJECTIF: Le décapage au ruban adhésif est une méthode destructive non invasive fréquemment utilisée pour examiner la pénétration cutanée d'une substance. Cependant, ces dernières années, la pertinence de la spectroscopie raman confocale, une méthode non invasive pour examiner la peau de manière non destructive, a été de plus en plus mise en évidence. Dans cette étude, nous avons comparé les cinétiques d'invasion et de déplétion de la pénétration et de la perméation d'une solution de caféine à 2 % avec et sans 1,2-pentanediol en tant qu'amplificateur de pénétration, mesurées par spectroscopie raman confocale et par décapage au ruban adhésif. MÉTHODES: La peau de porc a été utilisée pour le décapage au ruban adhésif et la peau humaine pour la spectroscopie raman confocale. Une solution de caféine à 2 % a été appliquée sur la peau pendant différents temps d'incubation. La peau humaine a ensuite été examinée par spectroscopie raman confocale tandis que la caféine a été extraite de la peau porcine et quantifiée par HPLC en phase inverse. Les flux ont également été mesurés et calculés par la somme des quantités totales de caféine ayant pénétré dans la peau. RÉSULTATS: Sans amplificateurs de pénétration, il n'y a presque aucune différence entre les profils de pénétration des deux méthodes de mesure pour l'invasion, mais les profils pour la déplétion sont différents. De plus, les valeurs de flux calculées pour l'invasion sont presque identiques, mais pour la déplétion, les valeurs de ruban adhésif sont environ deux fois plus élevées que les valeurs CRS. CONCLUSION: La pertinence de conduire des études d'invasion et de déplétion est devenue claire et a pu montrer les problèmes toujours existants dans la comparabilité du CRS et du décapage au ruban adhésif.

Itraconazole-loaded microemulsions: formulation, characterization, and dermal delivery using shed snakeskin as the model membrane.

Microemulsions (MEs) were developed for dermal delivery of 1% w/w itraconazole (ITZ). Solubility of ITZ in various oils was investigated and clove oil was selected as oil phase. Pseudoternary phase diagrams were constructed by titration method. The system containing clove oil as oil phase, Tween®80 as surfactant, and 1:1 mixture of water and polyethylene glycol 400 as aqueous phase provided the largest ME region. It was selected for the formulation development of ITZ-loaded MEs. Physicochemical stability was evaluated at 4 °C, room temperature (25 °C), and 45 °C for three months. In vitro permeation and retention studies were assessed using shed snakeskin as a model membrane. Antifungal activity was investigated by agar diffusion method. Results indicated that incorporation of ITZ in the selected MEs did not affect physical properties. Physicochemical data after storage periods revealed that the most suitable storage temperature was 4 °C. Skin permeation and retention data indicated that water-in-oil (w/o) ITZ-loaded MEs had superior dermal delivery of ITZ than oil-in-water (o/w) ITZ-loaded ME and ITZ-oily solution. Moreover, w/o ITZ-loaded MEs showed larger inhibition zones against C. albicans and T. rubrum than a commercial gel. Therefore, w/o ITZ-loaded MEs possibly provided effective dermal delivery and antifungal activity to treat superficial fungal infections.

Preparation of Conotoxin-Encapsulated Chitosan Nanoparticles and Evaluation of Their Skin Permeability.

µ-Conotoxin CnIIIC (conotoxin, CTX)-loaded chitosan nanoparticles (CTX-NPs) were prepared using the ionic cross-linking method. The CTX-NPs were spherical and well with a polydispersity index of 0.292 ± 0.039, drug loading efficiency of 25.9 ± 1.2%, and encapsulation efficiency of 95.6 ± 1.3%. In vitro release studies showed that the release behavior of CTX-NPs in a pH 5.0 acetate buffer followed zero-order kinetics. In vitro transdermal experiments using Franz diffusion cells mounted with mouse abdominal skin demonstrated that the cumulative intradermal deposition amount of CTX per unit area in 8 h (D8) and permeability coefficient (Pf) of CTX loaded on CTX-NPs were 2.30- and 7.71-times that of the CTX solution. In vivo transdermal experiments in mice showed that the amount of CTX deposited in the skin after 8 h of CTX saline administration was significantly lower than that of CTX deposited in the skin after administration of CTX-NPs. In vitro fluorescence labeling transdermal studies through Franz diffusion cells mounted with mouse abdominal skin indicated that CTX-NPs aggregated at hair follicles. Skin irritation tests in mice indicated that the irritation due to CTX-NPs was negligible. The cytotoxicity experiment showed that the viability of Balb/c 3T3 cells with CTX-NPs containing 230 µg/mL (0.08 µM) CTX was greater than 75%. CTX-NPs increase intradermal deposition of CTX by accumulating in hair follicles, which has positive implications for transdermal penetration of CTX.

ex vivo-in vivo comparison of drug penetration analysis by confocal Raman microspectroscopy and tape stripping.

When it comes to skin penetration analysis of a topically applied formulation, the number of suitable methods is limited, and they often lack in spatial resolution. In vivo studies are pivotal, especially in the approval of a new product, but high costs and ethical difficulties are limiting factors. For that reason, good ex vivo models for testing skin penetration are crucial. In this study, caffeine was used as a hydrophilic model drug, applied as a 2% (w/w) hydrogel, to compare different techniques for skin penetration analysis. Confocal Raman microspectroscopy (CRM) and tape stripping with subsequent HPLC analysis were used to quantify caffeine. Experiments were performed ex vivo and in vivo. Furthermore, the effect of 5% (w/w) 1,2-pentanediol on caffeine skin penetration was tested, to compare those methods regarding their effectiveness in detecting differences between both formulations.

Transdermal Delivery of a Hydrogen Sulphide Donor, ADT-OH Using Aqueous Gel Formulations for the Treatment of Impaired Vascular Function: an Ex Vivo Study.

PURPOSE: Hydrogen sulphide (H2S) is an important signalling molecule involved in the regulation of several physiological and pathophysiological processes. The objective of this study was to investigate the feasibility of transdermal delivery of ADT-OH, a H2S donor, by investigating the transdermal flux of aqueous gels loaded with penetration enhancers or liposomes. Furthermore, we explored the ability of permeated ADT-OH to promote angiogenesis and mitochondrial bioenergetics in HUVEC cells. METHODS: Aqueous hypromellose gels (5% w/v) were prepared with up to 10% v/v propylene glycol (PG) or deformable liposomes with 0.025% w/w ADT-OH. ADT-OH permeation from formulations across excised murine skin into PBS was quantified over 24 h using HPLC-UV detection. Media was collected and applied to HUVEC cells to evidence ADT-OH functionality following permeation. Tube formation assays were performed as indicative of angiogenesis and mitochondrial oxygen consumption was evaluated using a Seahorse XF24. RESULTS: Increasing the loading of PG caused an increase in ADT-OH permeation rate across skin and a decrease in dermal drug retention whereas liposomal gels produced a slow-release profile. Treatment of HUVEC's using conditioned media collected from the ADT-OH loaded permeation studies enhanced tube formation and the basal oxygen consumption rates after 30 min of treatment. CONCLUSIONS: These findings demonstrate that transdermal delivery of ADT-OH may provide a promising approach in the treatment of impaired vascular function. Gels prepared with 10% v/v PG have the potential for use in conditions requiring rapid H2S release whereas liposomal loaded gels for treatment requiring sustained H2S release.

The wash-in effect and its significance for mass casualty decontamination.

Decontamination of skin by washing may increase dermal absorption, a phenomenon known as the wash-in effect. The wash-in effect is frequently discussed in studies investigating casualty decontamination where potentially life-saving interventions may enhance the dermal penetration of toxic chemicals, leading to an increase in incidence of morbidity and rates of mortality. However, the wash-in effect is seldom investigated within the context of mass casualty decontamination and real-life consequences are therefore poorly understood. This paper reviews the existing literature on the wash-in effect to highlight the proposed mechanisms for enhanced absorption and evaluate the wash-in effect within the context of mass casualty chemical decontamination.

Time-course quantitative mapping of caffeine within the epidermis, using high-contrast pump-probe stimulated Raman scattering microscopy.

BACKGROUND: An assessment of the drug penetration and distribution profiles within the skin is essential in dermatology and cosmetology. Recent advances in label-free imaging technologies have facilitated the direct detection of unlabeled compounds in tissues, with high resolution. However, it remains challenging to provide quantitative time-course distribution maps of drugs within the complex skin tissue. The present study aims at acquiring the real-time quantitative skin penetration profiles of topically applied caffeine, by means of a combination of pump-probe phase-modulated stimulated Raman scattering (PM-SRS) and confocal reflection microscopy. The recently developed PM-SRS microscopy is a unique imaging tool that can minimize strong background signals through a pulse-shaping technique, while providing high-contrast images of small molecules in tissues. MATERIALS AND METHODS: Reconstructed human skin epidermis models were used in order to analyze caffeine penetration in tissues. The penetration profiles of caffeine in an aqueous solution, an oil-in-water gel, and a water-in-oil gel were examined by combining PM-SRS and confocal reflection microscopy. RESULTS: The characteristic Raman signal of caffeine was directly detected in the skin model using PM-SRS. Integrating PM-SRS and confocal reflection microscopy allowed real-time concentration maps of caffeine to be obtained from formulation samples, within the skin model. Compared with the conventional Raman detection method, PM-SRS lowered the background tissue-oriented signals and supplied high-contrast images of caffeine. CONCLUSION: We successfully established real-time skin penetration profiles of caffeine from different formulations. PM-SRS microscopy proved to be a powerful, non-invasive, and real-time depth-profile imaging technique for use in quantitative studies of topically applied drugs.

Lateral Dermal Penetration Is Dependent on the Lipophilicity of Active Ingredients.

INTRODUCTION: With its large surface area, skin facilitates a topical administration of active ingredients, and thus percutaneous delivery to a specific target site. Due to its high barrier function and different diffusion characteristics, skin governs the efficacy of these active ingredients and a bioavailability in the epidermal and dermal tissue. OBJECTIVE: In order to characterize the vertical and lateral movement of molecules into and inside the skin, the diffusivity of active ingredients with different physicochemical properties and their penetration ability in different dermal skin layers was investigated. METHODS: A novel lateral dermal microdialysis (MD) penetration setup was used to compare the diffusion characteristics of active ingredients into superficial and deep-implanted MD membranes in porcine skin. The corresponding membrane depth was determined via ultrasound and the active ingredients concentration via high-pressure liquid chromatography measurement. RESULTS: The depth depended penetration of superficial and deep-implanted MD membranes and the quantitative diffusivity of two active ingredients was compared. An experimental lateral MD setup was used to determine the influence of percutaneous skin penetration characteristics of an active ingredient with different lipophilic and hydrophilic characteristics. Therefore, hydrophilic caffeine and lipophilic LIP1, which have an identical molecular weight but different lipophilic characteristics, were tested for their penetration ability inside a propylene glycol and oleic acid formulation. CONCLUSION: The vertical and lateral penetration movement of caffeine was found to exceed that of LIP1 through the hydrophilic dermal environment. The findings of this study show that the lipophilicity of active ingredients influences the penetration movement and that skin enables a conical increasing lateral diffusivity and transdermal delivery.

N,N-Diethyl-3-toluamide Formulation Based on Ethanol Containing 0.1% 2-Hydroxypropyl-ß-cyclodextrin Attenuates the Drug's Skin Penetration and Prolongs the Repellent Effect without Stickiness.

N,N-diethyl-3-toluamide (DEET) is one of the most widely used insect repellents in the world. It was reported that a solution containing 6-30% cyclodextrin (CD) as a solvent instead of ethanol (EtOH) provided an enhancement of the repellent action time duration of the DEET formulation, although the high-dose CD caused stickiness. In order to overcome this shortcoming, we attempted to prepare a 10% DEET formulation using EtOH containing low-dose CDs (ß-CD, 2-hydroxypropyl-ß-CD (HPßCD), methyl-ß-CD, and sulfobutylether-ß-CD) as solvents (DEET/EtOH/CD formulations). We determined the CD concentration to be 0.1% in the DEET/EtOH/CD formulations, since the stickiness of 0.1% CDs was not felt (approximately 8 × 10-3 N). The DEET residue on the skin superficial layers was prolonged, and the drug penetration into the skin tissue was decreased by the addition of 0.1% CD. In particular, the retention time and attenuated penetration of DEET on the rat skin treated with the DEET/EtOH/HPßCD formulation was significantly higher in comparison with that of the DEET/EtOH formulation without CD. Moreover, the repellent effect of DEET was more sustained by the addition of 0.1% HPßCD in the study using Aedes albopictus. In conclusion, we found that the DEET/EtOH/HPßCD formulations reduced the skin penetration of DEET and prolonged the repellent action without stickiness.

Improved stability and skin penetration through glycethosomes loaded with glycyrrhetinic acid.

OBJECTIVE: In recent years, glycyrrhetinic acid (GA) has been popularly used in cosmetics because of its anti-inflammatory and anti-oxidant effects. However, due to the poor water solubility of GA and the barrier effect of human skin, the penetration of GA through the skin may be hindered. Liposomes are a common delivery system for functional compounds in cosmetics. Nonetheless, the stability and transdermal effect of traditional liposomes are limited. The aim of this work was to prepare a new liposome system that contained glycerol and ethanol to enhance the stability of the vesicles and promote the penetration of GA into the skin. METHODS: The glycethosomes were prepared by ethanol injection and sonication method. The effects of different concentrations of glycerol and ethanol on the particle size, polydispersity (PDI), entrapment efficiency (EE), stability and rheological properties of vesicles were evaluated. Lipophilic and hydrophilic fluorescent probes were used to investigate the microviscosity of vesicles. In vitro permeation tests were performed with pig skin in Franz cells and the concentration of GA in different skin layers was determined by high-performance liquid chromatography (HPLC). The ability of different vesicles to induce lipid extraction and fluidization was analysed by using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). RESULTS: When glycerol was 50% and ethanol was 25%, the obtained glycethosomes had the smallest particle size and the best stability with a mean particle size of 94.5 nm, PDI 0.216 and 99.8% EE. Fluorescence probe studies indicated that the microviscosity of glycethosomes was the largest when the concentration of glycerol and ethanol was 50% and 25%, which was consistent with the storage stability of glycethosomes. It was found that the glycethosomes had the best transdermal effect and the total skin permeation percentage of GA was 20.67%, while those of ethosomes, glycerosomes, liposomes and dispersion were 10.56%, 9.38%, 7.78% and 5.02%, respectively. And glycethosomes had effectively lipid extraction and fluidization effect on the skin stratum corneum. CONCLUSION: Compared with other traditional liposomes, glycethosomes can significantly improve the stability of vesicles and the transdermal effect of GA. Glycethosomes is promising vesicles for the delivery of GA.

OBJECTIF: Ces dernières années, l'acide glycyrrhétinique (AG) a souvent été utilisé dans le domaine des cosmétiques en raison de ses effets anti-inflammatoires et anti-oxydants. Cependant, la faible solubilité de l'AG dans l'eau et l'effet barrière de la peau humaine peuvent entraver la pénétration de l'AG à travers la peau. Les liposomes sont fréquemment utilisés comme système d'administration pour les composés fonctionnels dans les cosmétiques, mais la stabilité et l'effet transdermique des liposomes traditionnels demeurent limités. Ce travail a eu pour but de préparer un nouveau système liposomal à base de glycérol et d'éthanol pour améliorer la stabilité des vésicules et favoriser la pénétration de l'AG à travers la peau. MÉTHODES: Les glycéthosomes ont été préparés par injection d'éthanol et suivant une méthode de sonication. Les effets des différentes concentrations de glycérol et d'éthanol sur la taille des particules, la polydispersité (PDI), l'efficacité de capture (entrapment efficiency, EE), la stabilité et les propriétés rhéologiques des vésicules ont été évalués. Des sondes fluorescentes lipophiles et hydrophiles ont été utilisées pour étudier la microviscosité des vésicules. Des tests de perméation in vitro ont été réalisés avec de la peau de porc dans des cellules de Franz, et la concentration d'AG dans différentes couches cutanées a été déterminée par chromatographie en phase liquide à haute performance (CLHP). La capacité des différentes vésicules à induire une extraction lipidique et une fluidisation a été analysée à l'aide d'une spectroscopie infrarouge à réflectance totale atténuée et transformée de Fourier (TR-FTIR). RÉSULTATS: Avec des proportions de 50 % de glycérol et de 25 % d'éthanol, les glycéthosomes obtenus avaient la plus petite taille de particules et la meilleure stabilité avec une taille moyenne de particules de 94,5 nm, une PDI de 0,216 et une efficacité de capture de 99,8 %. Les études par sonde de fluorescence ont indiqué que la microviscosité des glycéthosomes était à son pic lorsque les concentrations de glycérol et d'éthanol s'élevaient respectivement à 50 % et 25 %, soit des proportions cohérentes avec la stabilité de conservation des glycéthosomes. Les glycéthosomes ont présenté le meilleur effet transdermique, et le pourcentage total de perméation cutanée de l'AG était de 20,67 %, tandis que ce pourcentage s'élevait, pour les éthosomes, les glycérosomes, les liposomes et la dispersion, à respectivement 10,56 %, 9,38 %, 7,78 % et 5,02 %. Les glycéthosomes ont aussi eu un effet efficace sur la couche cornée de la peau en ce qui concerne l'extraction des lipides et la fluidisation. CONCLUSION: Comparés aux liposomes traditionnels, les glycéthosomes peuvent améliorer de façon significative la stabilité des vésicules et l'effet transdermique de l'AG. Les glycéthosomes semblent ainsi constituer des vésicules prometteuses pour l'administration d'AG.