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Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity (DTH) reaction induced by repeated contact with sensitizers. The ability of a chemical to act as a sensitizer has most frequently been tested in animals. As the use of animals for these purposes is gradually and globally being phased out, there is a need for reliable in vitro surrogate assays. Currently proposed in vitro assays are designed to test four key events of the adverse outcome pathway (AOP) involving covalent modification of self-proteins by sensitizers (haptenation) and presentation of new antigens (hapten/carrier complexes) to the immune system. There appears to be imperfect alignment of in vitro assays with clinical and/or animal data, suggesting possibly additional mechanisms of ACD development. Indeed, studies on allergies to small drugs, small chemical-induced HLA-peptide exchange for vaccination purposes and cosmetic ingredient-induced exposure of autoantigens suggest a possibility of DTH response promotion by hapten/carrier-independent mechanisms. Therefore, there is a need for additional appropriate in vitro assays, in order to achieve maximal concordance between clinical and/or animal data and in vitro assays. In this paper, we will review evidence supporting the idea of diverse mechanisms of ACD development. We will also discuss the impact of these multiple mechanisms, on the AOP and on the in vitro assays that should be used for allergen detection. We will propose alloreactivity-like reactions, aided by computer modeling and biochemical tests of compound-HLA binding, as additional tools for better prediction of DTH reactions, resulting from exposure to ingredients in cosmetic products. The combination of the proposed tests, along with the existing assays, should further enhance animal-free assessment of sensitizing potential of individual chemicals. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is a major contributor to high attrition rates among candidate and market drugs and a key regulatory, industry, and global health concern. While acute and dose-dependent DILI, namely, intrinsic DILI, is predictable and often reproducible in preclinical models, the nature of idiosyncratic DILI (iDILI) limits its mechanistic understanding due to the complex disease pathogenesis, and recapitulation using in vitro and in vivo models is extremely challenging. However, hepatic inflammation is a key feature of iDILI primarily orchestrated by the innate and adaptive immune system. This review summarizes the in vitro co-culture models that exploit the role of the immune system to investigate iDILI. Particularly, this review focuses on advancements in human-based 3D multicellular models attempting to supplement in vivo models that often lack predictability and display interspecies variations. Exploiting the immune-mediated mechanisms of iDILI, the inclusion of non-parenchymal cells in these hepatoxicity models, namely, Kupffer cells, stellate cells, dendritic cells, and liver sinusoidal endothelial cells, introduces heterotypic cell–cell interactions and mimics the hepatic microenvironment. Additionally, drugs recalled from the market in the US between 1996–2010 that were studies in these various models highlight the necessity for further harmonization and comparison of model characteristics. Challenges regarding disease-related endpoints, mimicking 3D architecture with different cell–cell contact, cell source, and the underlying multi-cellular and multi-stage mechanisms are described. It is our belief that progressing our understanding of the underlying pathogenesis of iDILI will provide mechanistic clues and a method for drug safety screening to better predict liver injury in clinical trials and post-marketing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

United States regulatory and research agencies may rely upon skin sensitization test data to assess the sensitization hazards associated with dermal exposure to chemicals and products. These data are evaluated to ensure that such substances will not cause unreasonable adverse effects to human health when used appropriately. The US Consumer Product Safety Commission, the US Environmental Protection Agency, the US Food and Drug Administration, the Occupational Safety and Health Administration, the National Institute for Occupational Safety and Health, and the US Department of Defense are member agencies of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). ICCVAM seeks to identify opportunities for the use of non-animal replacements to satisfy these testing needs and requirements. This review identifies the standards, test guidelines, or guidance documents that are applicable to satisfy each of these agency's needs; the current use of animal testing and flexibility for using alternative methodologies; information needed from alternative tests to fulfill the needs for skin sensitization data; and whether data from non-animal alternative approaches are accepted by these US federal agencies. [ABSTRACT FROM AUTHOR]

The "gluten-free" final rule, published by the U.S. Food and Drug Administration (FDA) in 2013, is intended to provide safe food choices for people suffering from celiac disease. This final rule is not applicable for cosmetic products. As a result, analytical methods for gluten estimation in cosmetics are warranted to aid in the determination of the presence of gluten in these products. A survey of 36 cosmetic products was conducted to measure gluten content by three different ELISAs. None of the nine gluten-free-labeled cosmetics included detectable gluten. The gluten content in six cosmetics was 15.2-1453.5 ppm by one competitive ELISA, whereas three cosmetics contained 11.7-572.3 ppm gluten when quantitated with two sandwich ELISAs. Gluten or hydrolyzed wheat protein was found as an ingredient in five cosmetics with detectable gluten levels. A poor recovery of gluten was observed for most of the cosmetics in the foundation/blush/powder category by ELISA kits. This finding warrants a need for improved analytical methods for gluten estimation in cosmetics. [ABSTRACT FROM AUTHOR]

The objectives of the present study were to formulate and optimize different sized liquid and solid nanocrystalline formulations and evaluate their in vitro and in vivo performance to determine the effect of particle size on the oral bioavailability of solid nanocrystalline formulations. Nanotechnology is a promising approach to solve the problem of poor oral bioavailability of Biopharmaceutical Classification System class II/IV compounds. However, the highly exposed surface area of nanocrystals and hence their high Gibb's free energy poses a great challenge to nanocrystalline suspension stabilization. In this study, stabilization was achieved by preparing spray-dried nanocrystalline powders. A design of experiment approach was utilized to optimize the nanocrystalline suspensions/powders. On the basis of drug solubility studies, polyvinylpyrrolidone 40 KDa and sodium lauryl sulfate were selected for wet milling processing. Mannitol was chosen as the auxiliary excipient for spray-drying processing. In vitro dissolution utilizing a United States Pharmacopeia (USP) apparatus II showed superior release profiles for both liquid and nanocrystalline powder formulations compared with coarse-sized and unmilled formulations. Significantly, the oral bioavailability of nanocrystalline formulations with particle size of 280 nm was more than 20 times that of the unmilled formulation, whereas the nanocrystalline formulation with particle size of 750 nm showed only a 2.8 times increase in bioavailability compared with the unmilled formulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3018-3028, 2015 [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the in vitro dissolution performance of the different sized spray-dried nano-crystalline powders of naproxen. A DoE approach was used to formulate and optimize nano-crystalline suspensions. The critical wet milling operation parameters were i . e ., drug concentration, drug-to-stabilizer ratio, stabilizer type (HPMC E15 or Tween 80) and milling intensity. The nano-crystalline suspensions were optimized for size and physical stability and then spray-dried to obtain nano-crystalline powders. Trehalose and lactose were investigated as spray-drying auxiliary excipients to achieve non-aggregating powders. Particle size, DSC and PXRD were utilized for characterization of powder formulations. A modified USP apparatus II was utilized to determine the in vitro release/dissolution of powder formulations. The size of the nano-crystalline suspensions was dependent on drug concentration and milling intensity. HPMC E15 containing formulations were better in terms of the spray-dried powder yield compared to Tween 80 containing formulations. Trehalose was selected to formulate non-aggregating nano-crystalline powders. No polymorphic changes were observed following the wet milling and spray-drying processes. Size dependent in vitro dissolution profiles, utilizing a dialysis sac method were obtained for the crystalline powders. [ABSTRACT FROM AUTHOR]

Purpose: This study focuses on the formulation optimization, in vitro and in vivo performance of differently sized nano-crystalline liquid suspensions and spray-dried powders of a poorly soluble BCS class II compound i.e. Danazol. Methods: A DoE approach was utilized to optimize stabilizer concentration and formulate danazol (BCS class II) nano-crystalline suspensions and dry powders via wet milling followed by spray drying. Solubility studies were performed to select best stabilizers. Particle size, PXRD, contact angle measurement and in vitro dissolution were utilized in characterization of the liquid and spray-dried powder formulations. Results: The liquid nano-crystalline suspensions followed particle size-dependent dissolution rates i.e. faster dissolution for smaller crystals. The spray-dried nano-crystal powders did not show fast dissolution profiles compared to the liquid nano-crystalline suspension. The poor dissolution of the spray-dried powder correlated to its high LogP value ( i.e. LogP 4.53) and poor wetting (or polar surface-area). In vivo bioavailability studies showed superior performance of the liquid nano-crystalline suspensions compared to other milled and un-milled formulations. Conclusion: Wet-milling and spray-drying optimization for danazol nano-crystalline suspension was performed. This study indicates that drug candidates with high LogP values and low polar surface area may not be suitable for formulation as dry nano-crystals. [ABSTRACT FROM AUTHOR]