RESUMO
Methylenediphenyl diisocyanate (MDI) substances used polyurethane production can range from their simplest monomeric forms (e.g., 4,4'-MDI) to mixtures of the monomers with various homologues, homopolymer, and prepolymer derivatives. The relative dermal or inhalation absorption of 39 constituents of these substances in human were predicted using the GastroPlus® program. Predicted dermal uptake and absorption of the three MDI monomers from an acetone vehicle was 84-86% and 1.4-1.5%, respectively, with lower uptake and absorption predicted for the higher MW analogs. Lower absorption was predicted from exposures in a more lipophilic vehicle (1-octanol). Modeled inhalation exposures afforded the highest pulmonary absorption for the MDI monomers (38-54%), with 3-27% for the MW range of 381-751, and <0.1% for the remaining, higher MW derivatives. Predicted oral absorption, representing mucociliary transport, ranged from 5 to 10% for the MDI monomers, 10-25% for constituents of MW 381-751, and ≤3% for constituents with MW > 900. These in silico evaluations should be useful in category-based, worst-case, Read-Across assessments for MDI monomers and modified MDI substances for potential systemic effects. Predictions of appreciable mucociliary transport may also be useful to address data gaps in oral toxicity testing for this category of compounds.
Assuntos
Exposição por Inalação/análise , Isocianatos/química , Isocianatos/farmacocinética , Pulmão/metabolismo , Absorção Cutânea/fisiologia , Administração por Inalação , Excipientes/química , Modelos Biológicos , Peso MolecularRESUMO
Systemic toxicity assessments for oral or parenteral drugs often utilize the concentration of drug in plasma to enable safety margin calculations for human risk assessment. For topical drugs, there is no standard method for measuring drug concentrations in the stratum basale of the viable epidermis. This is particularly important since the superficial part of the epidermis, the stratum corneum (SC), is nonviable and where most of a topically applied drug remains, never penetrating deeper into the skin. We investigated the relative concentrations of a prototype kinase inhibitor using punch biopsy, laser capture microdissection, and imaging mass spectrometry methods in the SC, stratum basale, and dermis of minipig skin following topical application as a cream formulation. The results highlight the value of laser capture microdissection and mass spectrometry imaging in quantifying the large difference in drug concentration across the skin and even within the epidermis, and supports use of these methods for threshold-based toxicity risk assessments in specific anatomic locations of the skin, like of the stratum basale.
Assuntos
Preparações Farmacêuticas/metabolismo , Absorção Cutânea/fisiologia , Pele/metabolismo , Animais , Epiderme , Humanos , Espectrometria de Massas , Medição de Risco , Suínos , Porco Miniatura/fisiologiaRESUMO
This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol-water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.
Assuntos
Mineração de Dados/métodos , Propionatos/administração & dosagem , Propionatos/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia , Administração Cutânea , Animais , Fenômenos Químicos , Camundongos , Camundongos Pelados , Técnicas de Cultura de Órgãos/métodos , Propionatos/química , Pele/efeitos dos fármacos , Pele/metabolismo , SolubilidadeRESUMO
At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16-18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.
Assuntos
Congressos como Assunto/normas , Exposição Ambiental/normas , Fidelidade a Diretrizes/normas , Exposição Ocupacional/normas , Organização para a Cooperação e Desenvolvimento Econômico/normas , Absorção Cutânea/efeitos dos fármacos , Exposição Ambiental/prevenção & controle , Substâncias Perigosas/metabolismo , Substâncias Perigosas/toxicidade , Humanos , Irlanda , Exposição Ocupacional/prevenção & controle , Absorção Cutânea/fisiologiaRESUMO
The aim of the present work was to develop a promising drug delivery system of oxiconazole nitrate-loaded solid lipid nanoparticles (SLNs) topical gel to enhance the drug effectiveness for the treatment of Tinea infection. SLNs were prepared by emulsification-solvent evaporation method. Particle size and entrapment efficiency of the prepared SLNs were investigated. An appropriate formulation was selected and examined for morphology and physicochemical characterization adopting Scanning electron microscope and Differential scanning colorimetry. In-vitro drug release was also investigated. The selected SLNs were loaded into 1% Carbopol 934 gel that was investigated for homogeneity, pH, grittiness, spreadability, viscosity and in vitro drug release. Clinical study for the developed gel system compared to the corresponding marketed product was conducted on 28 patients. The results revealed that the prepared oxiconazole nitrate SLNs had drug entrapment efficiency ranging from 41.34% to 75.07% and zeta potential lying between -13 and -50. Physicochemical characterization revealed a decrease in the drug crystallinity in the prepared SLNs. The gel formulation showed appropriate physical characteristics and sustained in-vitro drug release. Clinical study for the prepared oxiconazole nitrate SLNs gel showed significantly less side effects, better patient satisfaction and superior clinical improvement compared with the corresponding marketed product.
Assuntos
Resinas Acrílicas/administração & dosagem , Antifúngicos/administração & dosagem , Imidazóis/administração & dosagem , Nanopartículas/administração & dosagem , Absorção Cutânea/efeitos dos fármacos , Tinha/tratamento farmacológico , Resinas Acrílicas/síntese química , Resinas Acrílicas/metabolismo , Adulto , Animais , Antifúngicos/síntese química , Antifúngicos/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Composição de Medicamentos/métodos , Feminino , Géis , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Lipídeos , Masculino , Pessoa de Meia-Idade , Nanopartículas/química , Nanopartículas/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Absorção Cutânea/fisiologia , Tinha/metabolismo , Tinha/patologia , Adulto JovemRESUMO
PURPOSE: The purpose of this study was (a) to suggest a novel dermatopharmacokinetic (DPK) approach from which pharmacokinetic parameters relevant to the bioequivalence (BE) assessment of a topical formulation can be deduced while circumventing the need for numerous measurements and assumptions, and (b) to investigate whether this approach enables the correct conclusion of BE and bioinequivalence (BIE). METHODS: Bioequivalent and bioinequivalent formulations of acyclovir were compared versus a reference product (Zovirax®). Tape Stripping was conducted at only one dose duration during the uptake phase to generate drug content in stratum corneum versus time profiles, each time point corresponding to one stripped layer. Nonlinear mixed effect modeling (ADAPT5®) (MLEM algorithm) was used to fit the DPK data and to estimate the rate (Kin) and extent (FS) of drug absorption/input into the skin. Results were evaluated using the average BE approach. RESULTS: Estimated exposure metrics were within the usual BE limits for the bioequivalent formulation (FS: 102.4 [90%CI: 97.5-107.7]; Kin: 94.2 [90%CI: 83.7-106.0]), but outside those limits for the bioinequivalent formulation (FS: 43.4 [90%CI: 27.9-67.6]; Kin: 54.5 [90%CI: 36.6-81.1]). CONCLUSIONS: The proposed novel DPK approach was shown to be successful, robust and applicable to assess BE and BIE correctly between topical formulations.
Assuntos
Pomadas/química , Administração Cutânea , Disponibilidade Biológica , Química Farmacêutica/métodos , Epiderme/efeitos dos fármacos , Feminino , Humanos , Masculino , Pomadas/farmacocinética , Pomadas/farmacologia , Pele/efeitos dos fármacos , Absorção Cutânea/fisiologia , Equivalência TerapêuticaRESUMO
The present work attempts to develop and optimize the formula of a lipidic nanoemulsion (NE) containing sodium hyaluronate (HNa) and indomethacin (Ind) as HNa-Ind for enhanced transdermal antiarthritic activity. NEs were prepared by the spontaneous emulsification method and characterized by Fourier-transform infrared (FTIR) spectroscopy. The composition of the optimal formulation was statistically optimized using Box-Behnken experimental design method with three independent factors and was characterized for particle size, polydispersity index, and percent transmittance. The selected formula was tested for its in vitro antioxidant activity and in vivo anti-inflammatory activity. The optimized HNa-Ind NE formula was characterized and displayed a particle size of 12.87 ± 0.032 nm, polydispersity index of 0.606 ± 0.082, and 99.4 ± 0.1 percentage of transmittance. FTIR showed no interaction between HNa and Ind as a physical mixture. In addition, the optimized HNa-Ind NE was able to preserve the antioxidant ability of the two drugs, as evidenced through a 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition assay used to assess free radical scavenging ability. The cell viability was increased while the free radical scavenging activity was decreased (94.28% inhibition at higher concentrations compared with vitamin C as a reference with an inhibition of 100%). Moreover, the pharmacological anti-inflammatory potential of the optimized HNa-Ind NE formulation was assessed using an in vivo model. Compared with reference drugs (ibuprofen gel 5%), the remarkable activity of the optimized formulation was established using xylene-induced ear edema in mice model, in which the inflamed region reduced by 92.5% upon treatment. The optimized HNa-Ind NE formulation showed considerably higher skin permeation and drug deposition capability compared with the HNa-Ind solution. HNa-Ind NE was demonstrated to be a successful carrier with enhanced antioxidant and anti-inflammatory potential while showing better skin penetration, thus being a promising vehicle for transdermal drug delivery.
Assuntos
Desenvolvimento de Medicamentos/métodos , Ácido Hialurônico/síntese química , Indometacina/síntese química , Nanopartículas/química , Administração Cutânea , Animais , Emulsões , Feminino , Indometacina/metabolismo , Lipídeos , Masculino , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologiaRESUMO
PURPOSE: The changes in physiological functions as children grow and organ systems mature result in pharmacokinetic alterations throughout childhood. These alterations in children result in absorption, distribution, metabolism, and excretion of drugs that are different from those seen in the typical adult diseased population. SUMMARY: Changes in gastrointestinal motility and gastric pH in neonates and infants affect the absorption rate and bioavailability of drugs. Skin absorption rate and extent can be altered by different skin structures and perfusion in young children. Intramuscular and rectal absorption become less predictable in children due to erratic absorption site perfusion and other factors. Children's body compositions also differ greatly from that in adults. Water-soluble drugs distribute more extensively in newborns due to larger water content than in older children and adults. Drug elimination and excretion are also affected in pediatric population due to differences in liver and renal function. Immature enzyme development and renal function result in reduced clearance of drugs in young children. There are limited pharmacokinetic data available for many drugs used in children. CONCLUSION: Considering the changes in pharmacokinetics in children can help pharmacists optimize the dosing and monitoring of drugs and do the best they can to help this vulnerable population.
Assuntos
Desenvolvimento do Adolescente/fisiologia , Desenvolvimento Infantil/fisiologia , Conduta do Tratamento Medicamentoso , Taxa de Depuração Metabólica/fisiologia , Farmacocinética , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Absorção Gastrointestinal/fisiologia , Motilidade Gastrointestinal/fisiologia , Humanos , Lactente , Recém-Nascido , Rim/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Farmacêuticos , Absorção Cutânea/fisiologiaRESUMO
OBJECTIVE: The aim of this study was to develop a drug-in-adhesive patch for transdermal delivery of daphnetin (DA), which is a coumarin derivative in Girald Daphne, and to investigate the role of Transcutol P (TP) in the release and percutaneous permeation processes of DA. METHODS: Backing films, permeation enhancers and enhancer content in the transdermal patch were investigated through in vitro experiments using rat skin. Anti-inflammatory and analgesic effects of the optimized formulation were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. In addition, the enhancement effect of TP was investigated using differential scanning calorimetry (DSC), FTIR, and molecular dynamic simulation. RESULTS: The optimal formulation, composed of DURO-TAK® 87-2852, CoTranTM 9680, 1% DA, and 10% TP showed anti-inflammatory and analgesic effects. It was found that TP only promoted the release process of DA from its transdermal patch. Furthermore, the decrease of interaction between drug and pressure sensitive adhesive (PSA) as well as the improvement of PSA mobility due to TP addition were the main factors that enhanced the release of DA from patch. CONCLUSIONS: This study successfully used TP to develop a DA patch with good anti-inflammatory and analgesic effects, proving that TP promotes the release of DA by reducing the interaction between DA and PSA and increasing the mobility of PSA.
Assuntos
Etilenoglicóis/síntese química , Etilenoglicóis/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Adesivo Transdérmico , Umbeliferonas/síntese química , Umbeliferonas/farmacocinética , Administração Cutânea , Animais , Etilenoglicóis/administração & dosagem , Masculino , Camundongos , Ratos , Ratos Wistar , Absorção Cutânea/fisiologia , Umbeliferonas/administração & dosagemRESUMO
This study indicates the application of tape stripping (TS) for bioequivalence (BE) assessment of a topical cream product containing 5% acyclovir. A TS method, previously used successfully to assess BE of topical clobetasol propionate and clotrimazole formulations, was used to assess BE of an acyclovir cream (5%) formulation as well as a diluted acyclovir formulation (1.5%) applied to the skin of healthy humans. An appropriate application time was established by conducting a dose duration study using the innovator product, Zovirax® cream. Transepidermal water loss was measured and used to normalize thicknesses between subjects. The area under the curve (AUC) from a plot of amount of acyclovir/strip vs cumulative fraction of stratum corneum (SC) removed was calculated for each application site. BE was assessed using Fieller's theorem in accordance with FDA's guidance for assessment of BE of topical corticosteroids. Adco-acyclovir cream (5%) was found to be BE to Zovirax® cream, where the mean test/reference (T/R) ratio of the AUC's was 0.96 and the bioequivalence interval using a 90% confidence interval was 0.91-1.01 with a statistical power > 95%, whereas the diluted test product fell outside the BE acceptance criteria with T/R ratio of AUC of 0.23 and a 90% CI of 0.20-0.26. This study indicates that the data resulting from the application of this TS procedure has reinforced the potential for its use to assess BE of topical drug products intended for local action, thereby obviating the necessity to undertake clinical trials in patients.
Assuntos
Aciclovir/administração & dosagem , Aciclovir/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Creme para a Pele/administração & dosagem , Creme para a Pele/farmacocinética , Administração Tópica , Adulto , Antivirais/administração & dosagem , Antivirais/metabolismo , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Feminino , Humanos , Masculino , Absorção Cutânea/fisiologia , Equivalência TerapêuticaRESUMO
The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 23 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.
Assuntos
Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Glicerol/análogos & derivados , Micelas , Absorção Cutânea/efeitos dos fármacos , Triazóis/administração & dosagem , Animais , Animais Recém-Nascidos , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Composição de Medicamentos , Estabilidade de Medicamentos , Glicerol/administração & dosagem , Glicerol/química , Glicerol/metabolismo , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Absorção Cutânea/fisiologia , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/metabolismo , Triazóis/química , Triazóis/metabolismoRESUMO
Partition coefficients between human stratum corneum lipids and water (Ksclip/w) are collected or deduced from a variety of sources in a manner that approximately doubles the available data compared to the current state-of-the-art model (Hansen et al., Adv Drug Deliv Rev. 2013;65(2):251-264). An additional datum for water itself in porcine SC that considerably extends the molecular size and lipophilicity range of the data set is considered. The data are analyzed in terms of an extended linear free energy relationship involving octanol/water partition coefficients, Abraham solvation parameters, and a secondary, power law molecular weight dependence. The optimum fit to log Ksclip/w for the full data set reduces the standard error of prediction from 0.50 for a Hansen-like model to 0.39; corresponding multiplicative errors in Ksclip/w are reduced from a factor of 3.1 to one of 2.5. The difference in performance is driven by the water datum, which requires a more complex dependence on molecular size than that afforded by Abraham parameters. In the absence of the water value, the Hansen-like model, which does not include a dependence on molecular size, is essentially optimum. A comparison is presented to fluid-phase phospholipid-water systems, which have a demonstrably different structure-property relationship.
Assuntos
Fosfolipídeos/metabolismo , Absorção Cutânea/fisiologia , Pele/metabolismo , Água/metabolismo , Humanos , Octanóis/metabolismo , Tamanho da PartículaRESUMO
The aim of this study was to compare the biopharmaceutical characteristics and irritation potentials of microemulsions (MEs) and conventional systems (CSs) containing oil from Syagrus cearensis for topical delivery of Amphotericin B (AmB). Pseudo-ternary phase diagrams were constructed using a water titration method to develop the MEs, and the CSs were prepared according to the classical technique of phase inversion. In the skin permeation and retention study, dermatomed pig skin without stratum corneum was used as an alternative disturbed skin model. The irritation potential was evaluated using three different methods, chorioallantoic membrane assays (HET-CAM and CAM-TBS), and bovine corneal opacity and permeability (BCOP) test. The optimized formulation (ME1) consisting of 0.1% (w/w) Amphotericin B, 9.1% (w/w) catolé oil, 81% (w/w) Smix (1:1, Tween 20 and Kolliphor EL) possessed droplet size of 31.02 ± 0.9 nm, zeta potential of -23.4 mV, and viscosity 0.63 ± 0.1 Pa.s. ME1 exhibited greater retention of AmB in to skin layers (84.79 ± 2.08 µg cm-2) than all the others formulations. In general, MEs showed higher drug release and retention than CSs and all of the formulations showed greater retentivity than permeability. Only MEs developed using Labrasol/Plurol Oleique (L/PO) as the surfactant and co-surfactant exhibited a moderate irritation potential; all other MEs and CSs were classified as non-irritants or slight irritants. The results indicate that formulations containing oil from S. cearensis are promising alternatives for the delivery of AmB targeting the treatment of cutaneous leishmaniasis.
Assuntos
Anfotericina B/administração & dosagem , Óleo de Coco/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Absorção Cutânea/efeitos dos fármacos , Administração Tópica , Anfotericina B/química , Anfotericina B/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/metabolismo , Bovinos , Galinhas , Óleo de Coco/química , Óleo de Coco/metabolismo , Emulsões/administração & dosagem , Emulsões/metabolismo , Absorção Cutânea/fisiologia , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/metabolismo , SuínosRESUMO
Previous studies have shown that hydroxytyrosol (HT) can be a potential alternative therapeutic agent for the treatment of rheumatoid arthritis (RA). However, HT is extensively metabolized following oral administration, which leads to formulating HT in a topical vehicle to prolong drug action as well as to provide a localized effect. Hidrox-6 is a freeze-dried powder derived from fresh olives and contains a high amount of HT (â¼3%) and other polyphenols. Alginate bilayer films containing 5% and 10% Hidrox-6 were formulated. The films were characterized with respect to their physical, morphology, rheological properties; drug content uniformity; and in vitro drug release. Acute dermal irritancy tests and a skin sensitization study were carried out in rats. An efficacy study of the bilayer films for RA was conducted using Freund's adjuvant-induced polyarthritis rats. Animal data showed that the bilayer film formulations did not cause skin irritancy. The efficacy in vivo results showed that the Hidrox-6 bilayer films lowered the arthritic scores, paw and ankle circumference, serum IL-6 level and cumulative histological scores compared with those measured for controls. The topical Hidrox-6 bilayer films improve synovitis and inflammatory symptoms in RA and can be a potential alternative to oral RA therapy.
Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Olea , Álcool Feniletílico/análogos & derivados , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Artrite Experimental/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Adjuvante de Freund , Masculino , Técnicas de Cultura de Órgãos , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/química , Álcool Feniletílico/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Ratos , Ratos Wistar , Absorção Cutânea/fisiologia , Resultado do TratamentoRESUMO
Topical dermatotherapy is intended to be used on diseased skin. Novel drug delivery systems even address differences between intact and diseased skin underlining the need for pre-clinical assessment of different states of barrier disruption. Herein, we studied how short-term incubation in culture media compared to incubation in humidified chambers affects human skin barrier function and viability. On both models we assessed different types and intensities of physical and chemical barrier disruption methods with regard to structural integrity, biophysical parameters and cytokine levels. Tissue degeneration and proliferative activity limited the use of tissue cultures to 48h. Viability is better preserved in cultured tissue. Tape-stripping (50×TS) and 4h sodium lauryl sulfate (SLS) pre-treatment were identified as highly reproducible and effective procedures for barrier disruption. Transepidermal water loss (TEWL) values reproducibly increased with the intensity of disruption while sebum content and skin surface pH were of limited value. Interleukin (IL)-6/8 and various chemokines and proteases were increased in tape-stripped skin which was more pronounced in SLS-treated skin tissue extracts. Thus, albeit limited to 48h, cultured full-thickness skin maintained several barrier characteristics and responded to different intensities of barrier disruption. Potentially, these models can be used to assess pre-clinically the efficacy and penetration of anti-inflammatory compounds.
Assuntos
Absorção Cutânea/fisiologia , Pele/metabolismo , Quimiocinas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Concentração de Íons de Hidrogênio , Peptídeo Hidrolases/metabolismo , Sebo/metabolismo , Dodecilsulfato de Sódio/metabolismo , Tensoativos/metabolismo , Fita Cirúrgica , Técnicas de Cultura de Tecidos/métodos , Perda Insensível de Água/fisiologiaRESUMO
Ethanol-based topical antiseptic hand rubs, commonly referred to as alcohol-based hand sanitizers (ABHS), are routinely used as the standard of care to reduce the presence of viable bacteria on the skin and are an important element of infection control procedures in the healthcare industry. There are no reported indications of safety concerns associated with the use of these products in the workplace. However, the prevalence of such alcohol-based products in healthcare facilities and safety questions raised by the U.S. FDA led us to assess the potential for developmental toxicity under relevant product-use scenarios. Estimates from a physiologically based pharmacokinetic modeling approach suggest that occupational use of alcohol-based topical antiseptics in the healthcare industry can generate low, detectable concentrations of ethanol in blood. This unintended systemic dose probably reflects contributions from both dermal absorption and inhalation of volatilized product. The resulting internal dose is low, even under hypothetical, worst case intensive use assumptions. A significant margin of exposure (MOE) exists compared to demonstrated effect levels for developmental toxicity under worst case use scenarios, and the MOE is even more significant for typical anticipated occupational use patterns. The estimated internal doses of ethanol from topical application of alcohol-based hand sanitizers are also in the range of those associated with consumption of non-alcoholic beverages (i.e., non-alcoholic beer, flavored water, and orange juice), which are considered safe for consumers. Additionally, the estimated internal doses associated with expected exposure scenarios are below or in the range of the expected internal doses associated with the current occupational exposure limit for ethanol set by the Occupational Safety and Health Administration. These results support the conclusion that there is no significant risk of developmental or reproductive toxicity from repeated occupational exposures and high frequency use of ABHSs or surgical scrubs. Overall, the data support the conclusion that alcohol-based hand sanitizer products are safe for their intended use in hand hygiene as a critical infection prevention strategy in healthcare settings.
Assuntos
Anti-Infecciosos Locais/efeitos adversos , Etanol/efeitos adversos , Exposição Ocupacional/efeitos adversos , Administração por Inalação , Administração Tópica , Animais , Haplorrinos , Pessoal de Saúde , Humanos , Ratos , Medição de Risco , Segurança , Absorção Cutânea/fisiologiaRESUMO
In the field of skin research, confocal Raman microscopy is an upcoming analytical technique. Substantial technical progress in design and performance of the individual setup components like detectors and lasers as well as the combination with confocal microscopy enables chemically selective and non-destructive sample analysis with high spatial resolution in three dimensions. Due to these advantages, the technique bears tremendous potential for diverse skin applications ranging from the analysis of physiological component distribution in skin tissue and the diagnosis of pathological states up to biopharmaceutical investigations such as drug penetration kinetics within the different tissue layers. This review provides a comprehensive introduction about the basic principles of Raman microscopy highlighting the advantages and considering the limitations of the technique for skin applications. Subsequently, an overview about skin research studies applying Raman spectroscopy is given comprising various in vitro as well as in vivo implementations. Furthermore, the future perspective and potential of Raman microscopy in the field of skin research are discussed.
Assuntos
Dermatopatias/diagnóstico , Pele/metabolismo , Análise Espectral Raman/métodos , Administração Cutânea , Animais , Sistemas de Liberação de Medicamentos , Humanos , Medição de Risco/métodos , Absorção Cutânea/fisiologia , Fenômenos Fisiológicos da PeleRESUMO
Dermal absorption is a key parameter in non-dietary human safety assessments for agrochemicals. Conservative default values and other criteria in the EFSA guidance have substantially increased generation of product-specific in vitro data and in some cases, in vivo data. Therefore, data from 190 GLP- and OECD guideline-compliant human in vitro dermal absorption studies were published, suggesting EFSA defaults and criteria should be revised (Aggarwal et al., 2014). This follow-up article presents data from an additional 171 studies and also the combined dataset. Collectively, the data provide consistent and compelling evidence for revision of EFSA's guidance. This assessment covers 152 agrochemicals, 19 formulation types and representative ranges of spray concentrations. The analysis used EFSA's worst-case dermal absorption definition (i.e., an entire skin residue, except for surface layers of stratum corneum, is absorbed). It confirmed previously proposed default values of 6% for liquid and 2% for solid concentrates, irrespective of active substance loading, and 30% for all spray dilutions, irrespective of formulation type. For concentrates, absorption from solvent-based formulations provided reliable read-across for other formulation types, as did water-based products for solid concentrates. The combined dataset confirmed that absorption does not increase linearly beyond a 5-fold increase in dilution. Finally, despite using EFSA's worst-case definition for absorption, a rationale for routinely excluding the entire stratum corneum residue, and ideally the entire epidermal residue in in vitro studies, is presented.
Assuntos
Praguicidas/química , Praguicidas/metabolismo , Absorção Cutânea/fisiologia , Pele/metabolismo , Humanos , Medição de Risco , Solventes/química , Solventes/metabolismo , Água/química , Água/metabolismoRESUMO
This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.
Assuntos
Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/farmacocinética , Educação/tendências , Tecnologia Farmacêutica/tendências , Administração Tópica , Animais , Disponibilidade Biológica , Humanos , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia , Equivalência TerapêuticaRESUMO
A common dermal exposure assessment strategy estimates the systemic uptake of chemical in contact with skin using the fixed fractional absorption approach: the dermal absorbed dose is estimated as the product of exposure and the fraction of applied chemical that is absorbed, assumed constant for a given chemical. Despite the prominence of this approach there is little guidance regarding the evaluation of experiments from which fractional absorption data are measured. An analysis of these experiments is presented herein, and limitations to the fixed fractional absorption approach are discussed. The analysis provides a set of simple algebraic expressions that may be used in the evaluation of finite dose dermal absorption experiments, affording a more data-driven approach to dermal exposure assessment. Case studies are presented that demonstrate the application of these tools to the assessment of dermal absorption data.