Potential of imaging analysis in establishing skin concentration-distance profiles for topically applied FITC-dextran 4 kDa

Quantitatively determining the skin concentration-distance profiles of topically applied drugs is important for evaluating their safety and efficacy. The aim of the present study was to quantitatively visualize the distribution of hydrophilic drugs through the skin using confocal laser scanning microscopy (CLSM) in order to obtain skin concentration-distance profiles. FITC-dextran with a molecular weight of approximately 4 kDa (FD-4) was selected as the model fluorescent drug in the present study, and excised pig ear skin was used. The skin concentration of FD-4 at each depth of a skin section was assessed by imaging analysis of the intensity of fluorescence. The FD-4 skin concentration-distance profile obtained was analyzed using Fick’s second law of diffusion, and was markedly similar to that using skin permeation parameters in the skin permeation study. These results suggest that the present CLSM method may be a promising tool for quantitatively visualizing the concentration-distance profiles of drugs through the skin

Development and optimization of orally and topically applied liquid crystal-drug formulations

学位授与機関：城西大学 学位記番号：博乙第79号，学位の種別：博士（薬科学）， 学位授与年月日： 平成29年(2017年)9月20日 (94p.)博士（薬科学）城西大

Mathematical Model to Predict Skin Concentration after Topical Application of Drugs

Skin permeation experiments have been broadly done since 1970s to 1980s as an evaluation method for transdermal drug delivery systems. In topically applied drug and cosmetic formulations, skin concentration of chemical compounds is more important than their skin permeations, because primary target site of the chemical compounds is skin surface or skin tissues. Furthermore, the direct pharmacological reaction of a metabolically stable drug that binds with specific receptors of known expression levels in an organ can be determined by Hill’s equation. Nevertheless, little investigation was carried out on the test method of skin concentration after topically application of chemical compounds. Recently we investigated an estimating method of skin concentration of the chemical compounds from their skin permeation profiles. In the study, we took care of “3Rs” issues for animal experiments. We have proposed an equation which was capable to estimate animal skin concentration from permeation profile through the artificial membrane (silicone membrane) and animal skin. This new approach may allow the skin concentration of a drug to be predicted using Fick’s second law of diffusion. The silicone membrane was found to be useful as an alternative membrane to animal skin for predicting skin concentration of chemical compounds, because an extremely excellent extrapolation to animal skin concentration was attained by calculation using the silicone membrane permeation data. In this chapter, we aimed to establish an accurate and convenient method for predicting the concentration profiles of drugs in the skin based on the skin permeation parameters of topically active drugs derived from steady-state skin permeation experiments

Mathematical Model to Predict Skin Concentration after Topical Application of Drugs

Skin permeation experiments have been broadly done since 1970s to 1980s as an evaluation method for transdermal drug delivery systems. In topically applied drug and cosmetic formulations, skin concentration of chemical compounds is more important than their skin permeations, because primary target site of the chemical compounds is skin surface or skin tissues. Furthermore, the direct pharmacological reaction of a metabolically stable drug that binds with specific receptors of known expression levels in an organ can be determined by Hill’s equation. Nevertheless, little investigation was carried out on the test method of skin concentration after topically application of chemical compounds. Recently we investigated an estimating method of skin concentration of the chemical compounds from their skin permeation profiles. In the study, we took care of “3Rs” issues for animal experiments. We have proposed an equation which was capable to estimate animal skin concentration from permeation profile through the artificial membrane (silicone membrane) and animal skin. This new approach may allow the skin concentration of a drug to be predicted using Fick’s second law of diffusion. The silicone membrane was found to be useful as an alternative membrane to animal skin for predicting skin concentration of chemical compounds, because an extremely excellent extrapolation to animal skin concentration was attained by calculation using the silicone membrane permeation data. In this chapter, we aimed to establish an accurate and convenient method for predicting the concentration profiles of drugs in the skin based on the skin permeation parameters of topically active drugs derived from steady-state skin permeation experiments.Open Access Journa

In Vitro and In Silico Approaches to Evaluate Usefulness and Safety of Chemical Compounds Applied or Exposed on Skin

Recently, animal experiments become very difficult to be done in the research and development of cosmetics and cosmeceuticals due to animal welfare and 3Rs (replacement, reduction, refinement) concept. However, usefulness and safety of these preparations must be strictly guaranteed before human use. We thus proposed three sets of extrapolation methods to estimate in vivo profiles from in vitro and in silico approaches, to evaluate permeation profiles through real human skin from those through animal skin and cultured human skin model, and to estimate responses such as usefulness and safety of cosmetics and cosmeceuticals from their skin permeation and concentration profiles. Although we need more data and discussion, the present extrapolation methods must be very useful for estimation of cosmetics and cosmeceuticals without using animal experiments.本総説は、日本薬学会第133年会シンポジウムS29-103で発表した内容を中心に記述したものである

Usefulness of liquid–crystal oral formulations to enhance the bioavailability and skin tissue targeting of p-amino benzoic acid as a model compound

Topical formulations are not always suitable to deliver active ingredients to large areas of skin. Thus, in this study, we aimed to develop an oral formulation for skin tissue targeting with a high bioavailability using liquid crystal (LC) dispersions comprising cubosomes of a mal-absorptive model compound, p-amino benzoic acid (PABA), which is an active element in cosmeceuticals, dietary supplements and skin disorder medicines. The bioavailability and skin concentration of PABA were investigated after oral administration in rats. The effect of the remaining amount of the LC formulation in the stomach on the pharmacokinetic profiles of orally administered PABA was evaluated. The skin permeation and concentration of PABA were also investigated using an in vitro permeation experiment. As a result, the bioavailability of PABA was significantly improved by administration of PABA-LC formulations compared with PABA solution alone, although the effect was greatly influenced by the type of LC-forming lipids. The in vitro skin permeation study showed that the PABA concentration in the skin when applied from the dermis side was higher than when applied from the epidermis side. These findings suggested that oral administration advantageously supports skin targeting, and oral LC formulations could be a promising material in cosmeceutical, dietary and clinical fields

In Silico Estimation of Skin Concentration of Dermally Metabolized Chemicals

Background: A great deal of in silico estimation methods were proposed for skin concentration and permeation of drugs by many researchers including us. The aim of the present study was to expand our in silico estimation method of skin concentration to dermally metabolized chemicals.&nbsp;Materials and Methods: A three-layered diffusion model consisting of stratum corneum, viable epidermis and dermis was constructed based on Fick’s second law of diffusion incorporated with Michaelis–Menten equation and plasma clearance in the viable epidermis and dermis, respectively. Ethyl nicotinate was used as a model chemical, and the in vivo skin concentration of the ester and its metabolite, nicotinic acid were measured after topical application to hairless rats. Permeation parameters were determined from the in vitro permeation data through full-thickness skin and stripped skin after application of the ester or acid with and without esterase inhibitor treatment. Metabolic parameters were obtained from the metabolic profile of the ester using skin homogenate.&nbsp;Results and Conclusion: The skin concentrations calculated from our improved model using the permeation and metabolic parameters obtained beforehand were similar to the observed values. Influence of cutaneous enzyme distribution and plasma clearance on the skin concentrations were also estimated using appropriately modified models, resulting in higher influence on the acid than the ester. This estimation method will become an effective tool to assess the efficacy and safety of dermally metabolized chemicals.</p

Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-MTM

Purpose: The usefulness of the synthetic membrane, Strat-M? as an alternative to human and animal skins was evaluated by estimating the skin permeabilities of chemical compounds. Method: Thirteen chemical compounds with molecular weights (M.W.) of 152?289 and lipophilicities (log Ko/w) of ?0.9 to 3.5 were selected. Strat-M?, excised human skin, or hairless rat skin was set in a Franz-type diffusion cell and a saturated solution of each chemical compound was applied to determine membrane permeation profiles. The obtained permeability coefficients (log P) were compared among these membranes. Results and discussion: Elevations were observed in log P for Strat-M? with an increase in the log Ko/w of the applied compounds, and similar results were observed with the human and hairless rat skins. A correlation was obtained in log P values between Strat-M? and human or hairless rat skin. Furthermore, the diffusion and partition parameters of chemicals in Strat-M? were similar to those in the excised human and rat skins. These results suggest that Strat-M? could be used as an alternative to animal or human skin in permeation studies

In Vitro Permeation and Skin Retention of α-Mangostin Proniosome

The current investigation evaluated the potential of proniosome as a carrier to enhance skin permeation and skin retention of a highly lipophilic compound, α-mangostin. α-Mangostin proniosomes were prepared using the coacervation phase seperation method. Upon hydration, α-mangostin loaded niosomes were characterized for size, polydispersity index (PDI), entrapment efficiency (EE) and ζ-potential. The in vitro permeation experiments with dermis-split Yucatan Micropig (YMP) skin revealed that proniosomes composed of Spans, soya lecithin and cholesterol were able to enhance the skin permeation of α-mangostin with a factor range from 1.8- to 8.0-fold as compared to the control suspension. Furthermore, incorporation of soya lecithin in the proniosomal formulation significantly enhanced the viable epidermis/dermis (VED) concentration of α-mangostin. All the proniosomal formulations (except for S20L) had significantly (p<0.05) enhanced deposition of α-mangostin in the VED layer with a factor range from 2.5- to 2.9-fold as compared to the control suspension. Since addition of Spans and soya lecithin in water improved the solubility of α-mangostin, this would be related to the enhancement of skin permeation and skin concentration of α-mangostin. The choice of non-ionic surfactant in proniosomes is an important factor governing the skin permeation and skin retention of α-mangostin. These results suggested that proniosomes can be utilized as a carrier for highly lipophilic compound like α-mangostin for topical application.Regular Articl