Evaluation of the safety and efficacy of skin penetration enhancer Putocrin®.

BACKGROUND: Substances that can efficiently enhance skin penetration while exerting no adverse effect are useful for drug and cosmetics formulation. OBJECTIVE: To investigate the safety and enhance skin penetration efficacy of Putocrin®, a combination containing 2% isosorbide dimethyl ether, 1% pentanediol, and 0.5% inositol. METHODS: An in vitro keratinocyte cell assay using 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide (MTT), and an in vitro EpiKutis® skin study adopted hematoxylin and eosin staining, immunostaining, and liquid chromatography-mass spectrometry (LC-MS) analysis were carried out to investigate the safety of Putocrin®. A pigskin-Franz cell system experiment applied high-performance liquid chromatography (HPLC) to compare the skin penetration efficiency of fluorescein isothiocyanate (Fitc)-labeled tranexamic acid with or without the assistance of Putocrin®. The safety and efficacy of Putocrin® was further evaluated on zebrafish embryos. RESULTS: The MTT assay showed that Putocrin® at concentration ≤2.5% did not significantly affect cell viability. The in vitro EpiKutis® skin study revealed that 2.5% Putocrin® did not affect skin morphology, filaggrin content, ceramide/protein, or fatty acid/protein ratios, but significantly increased loricrin content by 86.00% (p < 0.001). The pigskin-Franz cell penetration experiment demonstrated that Fitc-labeled tranexamic acid could barely penetrate the skin (with penetration rate of 1.121%), while Putocrin® significantly enhanced the penetration rate up to 83.983%, which was close to unlabeled tranexamic acid (90.013%). The zebrafish embryo study showed that 2.5% Putocrin® did not exert observable toxicity and obviously assisted the skin penetration of Fitc-labeled tranexamic acid into fish embryos. These results indicate the strong enhancing skin penetration potency of Putocrin®. CONCLUSION: This study demonstrated the safety as well as the strong enhancing skin penetration potency of Putocrin® for cosmetics formulation use.

Development and Optimization of Dipyridamole- and Roflumilast-Loaded Nanoemulsion and Nanoemulgel for Enhanced Skin Permeation: Formulation, Characterization, and In Vitro Assessment.

This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies were conducted to select the oil, surfactant, and co-surfactant. Phase diagrams were constructed using the aqueous phase titration method. All the formulations were in nanoscale, and Formula (F2) (which contains oleic acid oil as the oil phase, a mixture of Surfactant Tween 80 and co-surfactant (ethanol) at a ratio of 1:2 in addition to distilled water as an aqueous phase in a ratio of 1:5:4, respectively) was the selected formula depending on the particle size, PDI, and zeta potential. Formula (F2) has the best ratio because it gives the smallest nanoemulsion globule size (particle size average of 167.1 nm), the best homogenicity (lowest PDI of 0.195), and the highest stability (higher zeta potential of -32.22). The selected formula was converted into a nanoemulgel by the addition of 0.5% (w/w) xanthan gum (average particle size of 172.7 nm) and the best homogenicity (lowest PDI of 0.121%) and highest stability (higher zeta potential of -28.31). In conclusion, the selected formula has accepted physical and chemical properties, which enhanced skin penetration.

MALDI Mass Spectrometry Imaging and Semi-Quantification of Topically Delivered Lactic Acid.

BACKGROUND: Lactic acid is a common active ingredient in many topical skincare products; however, measuring its delivery into the skin is challenging due to the presence of a large level of endogenous lactic acid. In this study, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to quantitatively and qualitatively measure the delivery of lactic acid into the skin from a range of topical skincare products. MATERIALS AND METHODS: Porcine skin samples were treated with various skincare products containing lactic acid. After 24 h, skin samples were sectioned and treated via H&E staining or prepared for MALDI-MSI using chemical derivatization. Samples were then analyzed by MALDI-MSI imaging to obtain lactic acid distribution in the entire skin section. RESULTS: Due to the high level of endogenous lactic acid in the skin, a "triple isotope" of lactic acid (L-Lactic acid-13 C3 ), was needed to provide full resolution from the skin's background signal with MALDI-MSI. With this approach, the topically delivered lactic acid could be quantitatively and qualitatively analyzed from a variety of skincare products. CONCLUSIONS: The combination of L-Lactic acid-13 C3 and MALDI-MSI was successfully used to quantitatively and qualitatively measure the topical delivery of lactic acid from a variety of skincare products. This approach could be used in future work to better understand the mode of action of lactic acid as an active ingredient in skincare products.

Application of a Customised Franz-Type Cell Coupled with HPTLC to Monitor the Timed Release of Bioactive Components in Complex Honey Matrices.

The aim of this study was to assess the release profile of components in five different honeys (a New Zealand Manuka and two Western Australian honeys, a Jarrah honey and a Coastal Peppermint honey) and their corresponding honey-loaded gel formulations using a custom-designed Franz-type diffusion cell in combination with High-Performance Thin-Layer Chromatography (HPTLC). To validate the suitability of the customised setup, release data using this new approach were compared with data obtained using a commercial Franz cell apparatus, which is an established analytical tool to monitor the release of active ingredients from topical semisolid products. The release profiles of active compounds from pure honey and honey-loaded formulations were found to be comparable in both types of Franz cells. For example, when released either from pure honey or its corresponding pre-gel formulation, the percentage release of two Jarrah honey constituents, represented by distinct bands at RF 0.21 and 0.53 and as analysed by HPTLC, was not significantly different (p = 0.9986) at 12 h with over 99% of these honey constituents being released in both apparatus. Compared to the commercial Franz diffusion cell, the customised Franz cell offers several advantages, including easy and convenient sample application, the requirement of only small sample quantities, a large diffusion surface area, an ability to analyse 20 samples in a single experiment, and lower cost compared to purchasing a commercial Franz cell. Thus, the newly developed approach coupled with HPTLC is conducive to monitor the release profile of minor honey constituents from pure honeys and honey-loaded semisolid formulations and might also be applicable to other complex natural-product-based products.

Oleuropein-Rich Gellan Gum/Alginate Films as Innovative Treatments against Photo-Induced Skin Aging.

Olea europaea L. leaf extracts (OLEs) represent highly value-added agro-industrial byproducts, being promising sources of significant antioxidant compounds, such as their main component, oleuropein. In this work, hydrogel films based on low-acyl gellan gum (GG) blended with sodium alginate (NaALG) were loaded with OLE and crosslinked with tartaric acid (TA). The films' ability to act as an antioxidant and photoprotectant against UVA-induced photoaging, thanks to their capability to convey oleuropein to the skin, were examined with the aim of a potential application as facial masks. Biological in vitro performances of the proposed materials were tested on normal human dermal fibroblasts (NhDFs), both under normal conditions and after aging-induced UVA treatment. Overall, our results clearly show the intriguing properties of the proposed hydrogels as effective and fully naturally formulated anti-photoaging smart materials for potential use as facial masks.

Parallel evaluation of alternative skin barrier models and excised human skin for dermal absorption studies in vitro.

Skin permeation is a primary consideration in the safety assessment of cosmetic ingredients, topical drugs, and human users handling veterinary medicinal products. While excised human skin (EHS) remains the 'gold standard' for in vitro permeation testing (IVPT) studies, unreliable supply and high cost motivate the search for alternative skin barrier models. In this study, a standardized dermal absorption testing protocol was developed to evaluate the suitability of alternative skin barrier models to predict skin absorption in humans. Under this protocol, side-by-side assessments of a commercially available reconstructed human epidermis (RhE) model (EpiDerm-200-X, MatTek), a synthetic barrier membrane (Strat-M, Sigma-Aldrich), and EHS were performed. The skin barrier models were mounted on Franz diffusion cells and the permeation of caffeine, salicylic acid, and testosterone was quantified. Transepidermal water loss (TEWL) and histology of the biological models were also compared. EpiDerm-200-X exhibited native human epidermis-like morphology, including a characteristic stratum corneum, but had an elevated TEWL as compared to EHS. The mean 6 h cumulative permeation of a finite dose (6 nmol/cm2) of caffeine and testosterone was highest in EpiDerm-200-X, followed by EHS and Strat-M. Salicylic acid permeated most in EHS, followed by EpiDerm-200-X and Strat-M. Overall, evaluating novel alternative skin barrier models in the manner outlined herein has the potential to reduce the time from basic science discovery to regulatory impact.

Innovative Rocuronium Bromide Topical Formulation for Targeted Skin Drug Delivery: Design, Comprehensive Characterization, In Vitro 2D/3D Human Cell Culture and Permeation.

Cutaneous squamous cell carcinoma (cSCC) is the second-most common type of non-melanoma skin cancer and is linked to long-term exposure to ultraviolet (UV) radiation from the sun. Rocuronium bromide (RocBr) is an FDA-approved drug that targets p53-related protein kinase (PRPK) that inhibits the development of UV-induced cSCC. This study aimed to investigate the physicochemical properties and in vitro behavior of RocBr. Techniques such as thermal analysis, electron microscopy, spectroscopy and in vitro assays were used to characterize RocBr. A topical oil/water emulsion lotion formulation of RocBr was successfully developed and evaluated. The in vitro permeation behavior of RocBr from its lotion formulation was quantified with Strat-M® synthetic biomimetic membrane and EpiDerm™ 3D human skin tissue. Significant membrane retention of RocBr drug was evident and more retention was obtained with the lotion formulation compared with the solution. This is the first systematic and comprehensive study to report these findings.

Optimising nasal powder drug delivery - Characterisation of the effect of excipients on drug absorption.

The nasal physiology offers great potential for drug delivery but also poses specific challenges, among which the short residence time of applied drugs is one of the most striking. Formulating the drug as powder and using functional excipients are strategies to improve drug absorption. As nasal powders are still the minority on the market, there is a lack of data regarding their characterisation. This work aims at the characterisation of selected fillers (mannitol, microcrystalline cellulose) and mucoadhesives (pectin, chitosan glutamate, hydroxypropyl cellulose) with a set of methods that allows distinguishing their influences on dissolution and permeation of drugs, and on the viscoelasticity of the nasal fluid and thus the nasal residence time. Rheological studies revealed a potential of undissolved particles to prolong the residence time by increasing the elasticity of the nasal fluid. The assessment of drug dissolution showed a decreased dissolution rate in presence of insoluble or gelling excipients, which can be beneficial for drugs with low permeability, since embedded drugs are cleared slower than plain solutions. Drug permeation as important factor for the selection of excipients was evaluated with an RPMI 2650 cell model. Distinguishing the effects of excipients enables an effective selection of the most promising substances.

Análise do perfil de liberação do princípio ativo peróxido de hidrogênio por diferentes géis clareadores dentais / Analysis of the release profile of the active ingredient hydrogen peroxide by different tooth whitening gels

O objetivo desse estudo foi analisar o perfil de liberação do princípio ativo peróxido de hidrogênio por diferentes géis clareadores no decorrer do período de aplicação. Para tal diferentes géis clareadores à base de peróxido de hidrogênio para uso na técnica em consultório foram levados à câmara doadora de uma célula de difusão vertical (célula Franz). Foi empregado como meio de difusão uma membrana de éster de celulose com porosidade de 100-500 Daltons. A câmara receptora foi preenchida com água ultrapura. Os seguintes géis foram testados: Whiteness HP (FGM), Whiteness HP Blue (FGM), Whiteness HP Automix (FGM), Potenza Bianco (PHS do Brasil), Opalescence Boost (Ultradent), e Pola Office Plus (SDI); solução de peróxido 35% controle. O peróxido de hidrogênio liberado pelo gel se difundiu através da membrana e se misturou com a água na câmara receptora. Uma amostra de 40µl foi coletada da câmara receptora a cada 5 min, durante 45 minutos e foi reposto o mesmo volume de 40 µl em água ultrapura. A concentração de peróxido na amostra (mg/ml) foi determinada em triplicata a cada momento, utilizando um espectrofotômetro leitor de microplacas e reagente enzimático. A normalidade e homoscedasticidade dos dados foram avaliadas pelos testes de Shapiro-Wilk e Levene. Os dados de quantidade acumulada de peróxido foram submetidos ao teste de análise de variância ANOVA a 2 fatores (tipo de gel x tempo) e teste de Tukey. Para todas as análises foi adotado um nível de significância de 5%. Diferenças significativas foram observadas para os fatores agente clareador (p=0,0001) e tempo (p=0,0001), assim como para a interação entre eles (p=0,0001). Os resultados do teste de Tukey para o fator agente clareador quanto à quantidade cumulativa de peróxido foram: WHPB-14,04(6,60)a, WHP19,51(8,61)b, WHPA-23,20(10,48)c, POP-26,53(11,13)d, PB-28,29(10,99)de, OPB31,03(11,81)e, Controle 79,12(32,27)f. Para o fator tempo, em minutos, os resultados foram: 5 9,64(6,70)a, 10-17,42(11,60)b, 15-24,03(16,86)c, 20-29,50(20,44)d, 25-33,93(23,00)e, 30-38,41(25,83)f, 35-41,52(27,32)fg, 40-44,11(28,47)gh, 45- 46,50(29,72)h. Os resultados do teste ANOVA de medidas repetidas mostraram diferenças significativas (p=0,00) em relação a concentração inicial e final de peróxido para os fatores agente clareador, momento de leitura e para a interação entre eles. Agentes clareadores com maior concentração inicial de peróxido de hidrogênio apresentaram maior liberação cumulativa do ingrediente ativo; a liberação de peróxido de hidrogênio de diferentes géis clareadores ocorre de maneira gradual em relação ao tempo de aplicação, porém essa liberação não ocorre de maneira constante.(AU)

The aim of this study was to analyze the release profile of the active ingredient hydrogen peroxide by different bleaching gels over the course of the application period. For this purpose, different bleaching gels based on hydrogen peroxide for use in the in-office technique were taken to the donor chamber of a vertical diffusion cell (Franz cell). A cellulose ester membrane with a porosity of 100-500 Daltons was used as diffusion medium. The receiving chamber was filled with ultrapure water. The following gels were tested: Whiteness HP (FGM), Whiteness HP Blue (FGM), Whiteness HP Automix (FGM), Potenza Bianco (PHS do Brasil), Opalescence Boost (Ultradent), and Pola Office Plus (SDI); 35% peroxide control solution. The hydrogen peroxide released by the gel diffused through the membrane and mixed with the water in the receiving chamber. A 40µl sample was collected from the receiving chamber every 5 min for 45 minutes and the same volume of 40 µl was replaced in ultrapure water. The peroxide concentration in the sample (mg/ml) was determined in triplicate at each time point, using a microplate reader spectrophotometer and enzymatic reagent. Data normality and homoscedasticity were evaluated using the Shapiro-Wilk and Levene tests. Accumulated amount of peroxide data was submitted to 2-way ANOVA test of variance (type of gel x time) and Tukey's test. For all analyses, a significance level of 5% was adopted. Significant differences were observed for the factors bleaching agent (p=0.0001) and time (p=0.0001), as well as for the interaction between them (p=0.0001). The results of the Tukey test for the bleaching agent factor regarding the cumulative amount of peroxide were: WHPB-14.04(6.60)a, WHP-19.51(8.61)b, WHPA-23.20(10 ,48)c, POP-26.53(11.13)d, PB 28.29(10.99)de, OPB-31.03(11.81)e, Control-79.12(32.27) )f. For the time factor, in minutes, the results were: 5-9.64(6.70)a, 10-17.42(11.60)b, 15-24.03(16.86)c, 20- 29.50(20.44)d, 25-33.93(23.00)e, 30- 38.41(25.83)f, 35-41.52(27.32)fg, 40-44, 11(28.47)gh, 45-46.50(29.72)h. The results of the repeated measures ANOVA test showed significant differences (p=0.00) in relation to the initial and final peroxide concentration for the factors bleaching agent, reading time and the interaction between them. Bleaching agents with a higher initial concentration of hydrogen peroxide showed a greater cumulative release of the active ingredient; The release of hydrogen peroxide from different whitening gels occurs gradually in relation to the application time, but this release does not occur constantly. (AU)

Evaluations of Skin Permeability of Cannabidiol and Its Topical Formulations by Skin Membrane-Based Parallel Artificial Membrane Permeability Assay and Franz Cell Diffusion Assay.

Introduction: Cannabinoids including cannabidiol (CBD) have attracted enormous interest as bioactive ingredients for various dermatological and/or cosmeceutical uses. However, topical applications of cannabinoids might be limited without a fundamental understanding of their skin permeability. Herein, we aimed to evaluate the skin permeability of CBD and its topical formulations using artificial skin membrane assays. The solubility and stability of CBD in various surfactants that are commonly used in topical applications were also evaluated. Methods: CBD and two CBD-incorporated topical formulations (cream and gel) were prepared for this study. Computational predictions (SwissADME and DERMWIN™) and the parallel artificial membrane permeability assay (PAMPA) were used to evaluate the skin permeability of CBD isolate. The Franz cell diffusion (in vitro release testing) assay was used to evaluate the skin permeability of CBD formulations. The solubility and stability of CBD in surfactants were assessed by high-performance liquid chromatography and mass spectrometry analysis. Results: CBD isolate showed favorable skin permeability in the SwissADME and DERMWIN™ predictions (-Log Kp of 3.6 and 5.7 cm/s, respectively) and PAMPA (-LogPe value of 5.0 at pH of 6.5 and 7.4). In addition, CBD had higher solubility (378.4 µg/mL) in surfactant Tween 20 as compared to its solubility in polyisobutene. In an acidic environment (pH 5 and 6), Tween 20 maintained the CBD content at 81% and 70% over 30 days, respectively. CBD in the formulations of cream and gel also had moderate skin permeability in the Franz cell diffusion assay. Conclusion: Data from artificial membrane-based assays support that CBD is a skin permeable cannabinoid and the permeability and stability of its formulations may be influenced by several factors such as surfactant and pH environment. Findings from our study suggest that CBD may have suitable skin permeability for the development of dermatological and/or cosmeceutical applications but further studies using in vivo models are warranted to confirm this.

Validation and testing of a new artificial biomimetic barrier for estimation of transdermal drug absorption.

Human skin remains the most reliable model for studying the transdermal permeation of active compounds. Due to the limited source, porcine skin has been used extensively for performing penetration tests. Performing penetration studies by using human and animal skin, however, would also involve a series of ethical issues and restrictions. For these reasons, new biomimetic artificial barriers are being developed as possible alternatives for transdermal testing. If appropriately optimized, such products can be cost-effective, easily standardized across laboratories, precisely controlled in specific experimental conditions, or even present additional properties compared to the human and animal skin models such as negligible variability between replicates. In this current work we use the skin mimicking barrier (SMB) for drug permeability tests. The aim was to evaluate the suitability of the new barrier for studying the percutaneous absorption of the lipophilic extract of the plant Zingiber officinale Roscoe in vitro and compare its permeability ability with the artificial membrane Permeapad® and porcine skin. Our results showed that the permeability values obtained through the SMB are comparable are comparable to those obtained by using the porcine skin, suggesting that the new barrier may be an acceptable in vitro model for conducting percutaneous penetration experiments.

Cyclodipeptides: From Their Green Synthesis to Anti-Age Activity.

Cyclodipeptides (CDPs) or diketopiperazines (DKPs) are often found in nature and in foodstuff and beverages and have attracted great interest for their bioactivities, biocompatibility, and biodegradability. In the laboratory, they can be prepared by green procedures, such as microwave-assisted cyclization of linear dipeptides in water, as performed in this study. In particular, five CDPs were prepared and characterized by a variety of methods, including NMR and ESI-MS spectroscopies and single-crystal X-ray diffraction (XRD), and their cytocompatibility and anti-aging activity was tested in vitro, as well as their ability to penetrate the different layers of the skin. Although their mechanism of action remains to be elucidated, this proof-of-concept study lays the basis for their future use in anti-age cosmetic applications.

Occupational exposure assessment with solid substances: choosing a vehicle for in vitro percutaneous absorption experiments.

Percutaneous occupational exposure to industrial toxicants can be assessed in vitro on excised human or animal skins. Numerous factors can significantly influence skin permeation of chemicals and the flux determination. Among them, the vehicle used to solubilize the solid substances is a tricky key step. A "realistic surrogate" that closely matches the exposure scenario is recommended in first intention. When direct transposition of occupational exposure conditions to in vitro experiments is impossible, it is recommended that the vehicle used does not affect the skin barrier (in particular in terms of structural integrity, composition, or enzymatic activity). Indeed, any such effect could alter the percutaneous absorption of substances in a number of ways, as we will see. Potential effects are described for five monophasic vehicles, including the three most frequently used: water, ethanol, acetone; and two that are more rarely used, but are realistic: artificial sebum and artificial sweat. Finally, we discuss a number of criteria to be verified and the associated tests that should be performed when choosing the most appropriate vehicle, keeping in mind that, in the context of occupational exposure, the scientific quality of the percutaneous absorption data provided, and how they are interpreted, may have long-range consequences. From the narrative review presented, we also identify and discuss important factors to consider in future updates of the OECD guidelines for in vitro skin absorption experiments.

Parabens Permeation through Biological Membranes: A Comparative Study Using Franz Cell Diffusion System and Biomimetic Liquid Chromatography.

Parabens (PBs) are used as preservatives to extend the shelf life of various foodstuffs, and pharmaceutical and cosmetic preparations. In this work, the membrane barrier passage potential of a subset of seven parabens, i.e., methyl-, ethyl-, propyl- isopropyl, butyl, isobutyl, and benzyl paraben, along with their parent compound, p-hydroxy benzoic acid, were studied. Thus, the Franz cell diffusion (FDC) method, biomimetic liquid chromatography (BLC), and in silico prediction were performed to evaluate the soundness of both describing their permeation through the skin. While BLC allowed the achievement of a full scale of affinity for membrane phospholipids of the PBs under research, the permeation of parabens through Franz diffusion cells having a carbon chain > ethyl could not be measured in a fully aqueous medium, i.e., permeation enhancer-free conditions. Our results support that BLC and in silico prediction alone can occasionally be misleading in the permeability potential assessment of these preservatives, emphasizing the need for a multi-technique and integrated experimental approach.

Natural Formulations Based on Olea europaea L. Fruit Extract for the Topical Treatment of HSV-1 Infections.

In the present study, a hydroxytyrosol-rich Olea europaea L. fruit extract (OFE) was added to three thoroughly green formulations-hydrogel, oleogel, and cream-in order to evaluate their antiviral activity against HSV-1. The extract was characterized by different analytical techniques, i.e., FT-IR, XPS, and TGA. HPLC analyses were carried out to monitor the content and release of hydroxytyrosol in the prepared formulations. The total polyphenol content and antioxidant activity were investigated through Folin-Ciocâlteu's reagent, DPPH, and ABTS assays. The ability of the three formulations to convey active principles to the skin was evaluated using a Franz cell, showing that the number of permeated polyphenols in the hydrogel (272.1 ± 1.8 GAE/g) was significantly higher than those in the oleogel and cream (174 ± 10 and 179.6 ± 2 GAE/g, respectively), even if a negligible amount of hydroxytyrosol crossed the membrane for all the formulations. The cell viability assay indicated that the OFE and the three formulations were not toxic to cultured Vero cells. The antiviral activity tests highlighted that the OFE had a strong inhibitory effect against HSV-1 with a 50% inhibitory concentration (IC50) at 25 µg/mL, interfering directly with the viral particles. Among the three formulations, the hydrogel exhibited the highest antiviral activity also against the acyclovir-resistant strain.

Testing Topical Products Specifically to Reduce Inflammatory Pain from Gout: Transdermal NSAID Delivery and Monosodium Urate Solubility.

Purpose: Gout is caused by crystals of monosodium urate (MSU) in the joints. Topical nonsteroidal anti-inflammatory drug products (NSAIDs) are often the first-choice immediate treatment. This study examined the effect of commercially available and newly developed transdermal NSAID products on the solubility of MSU in a physiologically relevant system, alongside the efficacy of transdermal NSAID delivery. Materials and Methods: Drug permeability of 7 commercially available topical NSAID products, alongside 3 newly developed "Gout Buster" products, was evaluated in vitro using pig's ear skin in Franz diffusion cells. The standard Franz cell experimental protocol was adapted to include assessment of MSU solubility in phosphate buffered saline for each product. Some materials were also tested via direct solubility studies. Results: The amount of drug delivered transdermally varied significantly between different formulations, with the best ibuprofen delivery being ~5 times higher than the lowest, and best diclofenac delivery being ~3.5 times higher than the lowest. Changes in formulations and the drug concentration in the product both affected the amount of drug delivered. Overall ibuprofen permeation was higher than diclofenac. The commercially available products showed little or no effect on the MSU solubility (99-103% vs control). The Gout Buster products showed significant improvement in the MSU solubility after permeation through skin (120-126%). Increased sodium levels reduced the solubility of MSU in direct solubility studies. Conclusion: In these trials, the Gout Buster products showed significantly improved permeation of both ibuprofen and diclofenac over the commercial products at similar drug concentrations, and showed significant improvement for MSU solubility. Increased sodium levels reduced the solubility of MSU and could cause more crystallisation in vivo. Therefore, topical NSAID products with the Gout Buster formulation may have the best likelihood of both reducing inflammation and helping re-dissolve the MSU crystals that cause gout.

Convective Solvent Transport Pathways for Absorption of Drugs from Topical Formulation.

Physicochemical and formulation factors influencing penetration of drugs from topical products into the skin and mechanisms of drug permeation are well investigated and reported in the literature. However, mechanisms of drug absorption during short-term exposure have not been given sufficient importance. In this project, the extent of absorption of drug molecules into the skin from aqueous and ethanolic solutions following a 5-min application period was investigated. The experiments demonstrated measurable magnitude of absorption into the skin for all the molecules tested despite the duration of exposure being only few minutes. Among the two solvents used, absorption was greater from aqueous than ethanolic solution. The results suggest that an alternative penetration pathway, herein referred to as the convective transport pathway, is likely responsible for the rapid, significant uptake of drug molecules during initial few minutes of exposure. Additionally, absorption through the convective transport pathways is a function of the physicochemical nature of the formulation vehicle rather than the API.

Ethosomes and Transethosomes as Cutaneous Delivery Systems for Quercetin: A Preliminary Study on Melanoma Cells.

The present study is aimed to design ethosomes and transethosomes for topical administration of quercetin. To overcome quercetin low bioavailability, scarce solubility and poor permeability that hamper its pharmaceutical use, the drug was loaded in ethosomes and transethosomes based on different concentrations of phosphatidylcholine. Vesicle morphology was studied by cryogenic transmission electron microscopy, while size distribution and quercetin entrapment capacity were evaluated up to 3 months, respectively, by photon correlation spectroscopy and high-performance liquid chromatography. The antioxidant property was studied by photochemiluminescence test. Quercetin release and permeation was investigated in vitro, using Franz cells associated to different membranes. In vitro assays were conducted on human keratinocytes and melanoma cells to study the behavior of quercetin-loaded nano-vesicular forms with respect to cell migration and proliferation. The results evidenced that both phosphatidylcholine concentration and quercetin affected the vesicle size. Quercetin entrapment capacity, antioxidant activity and size stability were controlled using transethosomes produced by the highest amount of phosphatidylcholine. In vitro permeation studies revealed an enhancement of quercetin permeation in the case of transethosomes with respect to ethosomes. Notably, scratch wound and migration assays suggested the potential of quercetin loaded-transethosomes as adjuvant strategy for skin conditions.

Transdermal permeation of inorganic cerium salts in intact human skin.

The stratum corneum protects the body against external agents, such as metals, chemicals, and toxics. Although it is considered poorly permeable to them, comprising the major barrier to the permeation of such substances, it may become a relevant gate of entry for such molecules. Cerium (Ce) is a lanthanide that is widely used in catalytic, energy, biological and medicinal applications, owing to its intrinsic structural and unique redox properties. Cerium salts used to produce cerium oxide (CeO2) nanostructures can potentially come into contact with the skin and be absorbed following dermal exposure. The objective of this study was to investigate the percutaneous absorption of three inorganic Ce salts: cerium (III) chloride (CeCl3); cerium (III) nitrate (Ce(NO3)3) and ammonium cerium (IV) nitrate (Ce(NH4)2(NO3)6), which are commonly adopted for the synthesis of CeO2 using in vitro - ex vivo technique in Franz diffusion cells. The present work shows that Ce salts cannot permeate intact human skin, but they can penetrate significantly in the epidermis (up to 0.29 µg/cm2) and, to a lesser extent in dermis (up to 0.11 µg/cm2). Further studies are required to evaluate the potential effects of long-term exposure to Ce.

Novel modified vertical diffusion cell for testing of in vitro drug release (IVRT) of topical patches.

The vertical diffusion cell is an in vitro laboratory device for the study of drug release and permeation of semi-solid topical formulations and topical patches. Both static and dynamic versions of the diffusion cell are used in practice, the operation of which can be automated. The device is available at a reasonable cost for smaller, mainly transdermal patches, the amount of sampling fluid is replenished at the same time as the sample, in the same amount as the amount sampled without automation of the system, and simultaneous replenishment of acceptor fluid by hydrostatic pressure helps keeping the acceptor chamber bubble-free.