Ethyl salicylate

Expanded Poly(tetrafluoroethylene) Blood Vessel Grafts with Embedded Reactive Oxygen Species (ROS)-Responsive Antithrombogenic Drug for Elimination of Thrombosis.[Pubmed:32496045]

ACS Appl Mater Interfaces. 2020 Jul 1;12(26):29844-29853.

Treatment of cardiovascular diseases suffers from the lack of transplantable small-diameter blood vessel (SDBV) grafts that can prohibit/eliminate thrombosis. Although expanded poly(tetrafluoroethylene) (ePTFE) has the potential to be used for SDBV grafts, recurrence of thrombus remains the biggest challenge. In this study, a reactive oxygen species (ROS)-responsive antithrombogenic drug synthesis and a bulk coating process were employed to fabricate functional ePTFE grafts capable of prohibiting/eliminating blood clots. The synthesized drug that would release antiplatelet Ethyl salicylate (ESA), in responding to ROS, was dissolved in a polycaprolactone (PCL) solution, followed by a bulk coating of the as-fabricated ePTFE grafts with the PCL/drug solution. Nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM) were employed to investigate and confirm the synthesis and presence of the ROS-responsive drug in the ePTFE grafts. The ESA release functions were demonstrated via the drug-release profile and dynamic anticoagulation tests. The biocompatibility of the ROS-responsive ePTFE grafts was demonstrated via lactate dehydrogenase (LDH) cytotoxicity assays, live and dead cell assays, cell morphology, and cell-graft interactions. The ROS-responsive, antithrombogenic ePTFE grafts provide a feasible way for maintaining long-term patency, potentially solving a critical challenge in SDBV applications.

Diffusion modelling of percutaneous absorption kinetics. Predicting urinary excretion from in vitro skin permeation tests (IVPT) for an infinite dose.[Pubmed:32018051]

Eur J Pharm Biopharm. 2020 Apr;149:30-44.

In this work, we developed a number of generalised skin diffusion based pharmacokinetic models to relate published in vivo urinary excretion data to matching experimentally generated in vitro human skin permeation test (IVPT) data for a series of topically applied salicylate esters. A simplified linear in vivo model was found to inadequately describe the time course of urinary excretion over the entire sampling period. We represented the skin barrier as both a one layer (stratum corneum) and a two-layer (stratum corneum with viable epidermis) diffusion model and convoluted their Laplace solutions with that for a single exponential disposition phase to describe the urinary excretion profiles in the Laplace domain. We also derived asymptotic approximations for the model and estimated the conditions under which they could be used. We then sought to develop in vitro - in vivo relationships (IVIVR) for topically applied methyl, ethyl and glycol salicylates using our experimental IVPT data and the literature urinary excretion data. Good linear IVIVRs for ethyl and glycol salicylates were obtained, but the IVIVR for mEthyl salicylate was poor, perhaps because of topical stimulation of local skin blood flow by mEthyl salicylate. The ratio of the hydrated to dehydrated skin permeation for all salicylate esters was the same in both the IVPT and in vivo studies. A diffusion based one compartment pharmacokinetic model was also developed to describe the urinary excretion of solutes after removal of topical products and to compare the mEthyl salicylate skin permeation for five different body sites. The work presented here is consistent with the development of skin IVIVRs, but suggests that different skin conditions, application sites and local skin effects may affect model predictions.

Simultaneous analysis of volatile and semi-volatile components in a topical formulation by gas chromatography using a programmed temperature vaporization inlet and flame ionization detection.[Pubmed:30974410]

J Pharm Biomed Anal. 2019 Jul 15;171:65-72.

Topical formulations are medications applied locally on the skin to treat ailment. They are made up of complex mixtures of active ingredients and excipients. Till date, no analytical method has been found in literature that is able to simultaneously analyze volatile and semi-volatile actives present in topical formulations. In this work, an analytical procedure by gas chromatography equipped with a programmed temperature vaporizing (PTV) inlet and a flame ionization detector was developed and validated for the simultaneous quantitative determination of volatile and semi-volatile actives such as camphor, L-menthol, mEthyl salicylate, Ethyl salicylate, salicylic acid, glycol monosalicylate and capsaicin in a topical formulation. Liquid-liquid extraction was used to isolate the components of interest prior to injection into the gas chromatographic system. All target analytes were completely separated from each other and a linear calibration curve was achieved for all analytes with a determination coefficient > 0.995. 2-phenoxyethanol was used as internal standard for quantitation. Good repeatability and recovery values were achieved and reported. This method reports for the first time, the simultaneous quantitative analysis of volatile and semi-volatile active pharmaceutical ingredients in a single measurement. The developed method was successfully applied to the analysis of real pharmaceutical samples and the described analytical protocols can be recommended for routine analysis of both volatile and semi-volatile actives in the topical formulation.

Enhancing the stability of a carboxylesterase by entrapment in chitosan coated alginate beads.[Pubmed:30814894]

Turk J Biol. 2018 Aug 9;42(4):307-318.

A carboxylesterase isolated from Aeromonas caviae MTCC 7725 was immobilized by entrapping it in chitosan coated calcium alginate beads. This was characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and Fourier transform infrared spectroscopy (FTIR). The activity of the native and immobilized enzyme was measured at various temperatures, pH levels, and organic solvents. The optimum temperature for activity of the native enzyme was found to be 40 degrees C and this increased to 50 degrees C on immobilization. The immobilized enzyme showed enhanced stability and high residual activity in various organic solvents as compared to the free enzyme. An environmentally benign approach was used for the synthesis of Ethyl salicylate using the immobilized enzyme. The product obtained was confirmed by GC-MS. The kinetic parameters, such as K m and Vmax, were also determined for the native and immobilized enzyme. The immobilized enzyme retained 50% of its activity after vfie cycles. The immobilized enzyme retained 80% and 40% of its activity at 4 degrees C and at 37 degrees C, respectively, at the end of 40 days. The results obtained from our study show that the immobilized enzyme can serve as a robust catalyst for industrial applications.

Salicylamide derivatives for iron and aluminium sequestration. From synthesis to complexation studies.[Pubmed:29685783]

J Trace Elem Med Biol. 2018 Dec;50:580-588.

This paper presents an easy, fast and economic synthesis of chelating agents for medical, environmental and analytical applications, and the evaluation of the stability of their complexes with Fe(3+) and Al(3+). Complex formation equilibria with Cu(2+) and Zn(2+) metal ions were also studied to evaluate if the chelating agents can perturb the homeostatic equilibria of these essential metal ions. Effective chelating agents for metal ions, in addition to their well-known medical uses, find an increasing number of applications in environmental remediation, agricultural applications (supplying essential elements in an easily available form), and in analytical chemistry as colorimetric reagents. Besides the stability of the complexes, the lack of toxicity and the low cost are the basic requisites of metal chelating agents. With these aims in mind, we utilized Ethyl salicylate, a cheap molecule without toxic effects, and adopted a simple synthetic strategy to join two salicylate units through linear diamines of variable length. Actually, the mutual position of the metal binding oxygen groups, as well as the linker length, affected protonation and complex formation equilibria. A thorough study of the ligands is presented. In particular, the complex formation equilibria of the three ligands toward Fe(3+), Al(3+), Zn(2+) and Cu(2+) ions were investigated by combined potentiometric and spectrophotometric techniques. The results are encouraging: all the three ligands form stable complexes with all the investigated metal ions, involving the oxygen donor atoms from the 2-hydroxybenzamido unit, and nitrogen atoms in copper and zinc coordination.

An improvement of LLNA:DA to assess the skin sensitization potential of chemicals.[Pubmed:28321039]

J Toxicol Sci. 2017;42(2):129-136.

We developed a modified local lymph node assay based on ATP (LLNA:DA), termed the Two-Stage LLNA:DA, to further reduce the animal numbers in the identification of sensitizers. In the Two-Stage LLNA:DA procedure, 13 chemicals ranging from non-sensitizers to extreme sensitizers were selected. The first stage used reduced LLNA:DA (rLLNA:DA) to screen out sensitive chemicals. The second stage used LLNA:DA based on OECD 442 (A) to classify those potential sensitizers screened out in the first stage. In the first stage, the SIs of the methyl methacrylate, salicylic acid, mEthyl salicylate, Ethyl salicylate, isopropanol and propanediol were below 1.8 and need not to be tested in the second step. Others continued to be tested by LLNA:DA. In the second stage, sodium lauryl sulphate and xylene were classified as weak sensitizers. a-hexyl cinnamic aldehyde and eugenol were moderate sensitizers. Benzalkonium chloride and glyoxal were strong sensitizers, and phthalic anhydride was an extreme sensitizer. The 9/9, 11/12, 10/11, and 8/13 (positive or negative only) categories of the Two-Stage LLNA:DA were consistent with those from the other methods (LLNA, LLNA:DA, GPMT/BT and HMT/HPTA), suggesting that Two-Stage LLNA:DA have a high coincidence rate with reported data. In conclusion, The Two-Stage LLNA:DA is in line with the "3R" rules, and can be a modification of LLNA:DA but needs more study.

Mechanistic Evaluation of Hydration Effects on the Human Epidermal Permeation of Salicylate Esters.[Pubmed:27634383]

AAPS J. 2017 Jan;19(1):180-190.

We sought to understand when and how hydration enhances the percutaneous absorption of salicylate esters. Human epidermal membrane fluxes and stratum corneum solubilities of neat and diluted solutions of three esters were determined under hydrated and dehydrated conditions. Hydration doubled the human epidermal flux seen for methyl and Ethyl salicylate under dehydrated conditions and increased the flux of neat glycol salicylate 10-fold. Mechanistic analyses showed that this hydration-induced enhancement arises mainly from an increase in the stratum corneum diffusivity of the three esters. Further, we showed that unlike methyl and Ethyl salicylate, glycol salicylate is hygroscopic and the approximately 10-fold hydration-induced flux enhancement seen with neat glycol salicylate may be due to its ability to hydrate the stratum corneum to a greater extent. The hydration-induced enhancements in in vitro epidermal flux seen here for glycol and Ethyl salicylate were similar to those reported for their percutaneous absorption rates in a comparable in vivo study, whilst somewhat higher enhancement was seen for mEthyl salicylate in vivo. This may be explained by a physiologically induced self enhancement of neat mEthyl salicylate absorption in vivo which is not applicable in vitro.

Estimating Maximal In Vitro Skin Permeation Flux from Studies Using Non-sink Receptor Phase Conditions.[Pubmed:27312087]

Pharm Res. 2016 Sep;33(9):2180-94.

PURPOSE: This study explored the impact of non-sink receptor conditions on the in vitro skin permeation test (IVPT) and sought to estimate equivalent sink condition IVPT data. METHODS: Simulated diffusion model and experimental IVPT data were generated for Ethyl salicylate across human epidermal membranes in Franz diffusion cells using six different receptor phases, with a 10 fold variation in Ethyl salicylate solubility. RESULTS: Both simulated and experimental IVPT - time profiles were markedly affected by receptor phase solubility and receptor sampling rates. Similar sink condition equivalent estimated maximum fluxes were obtained by nonlinear regression and adjustment of linear regression estimates of steady state flux for relative saturation of the receptor phase over time for the four receptor phases in which the Ethyl salicylate was relatively soluble. The markedly lower steady - state fluxes found for the other two phases in which Ethyl salicylate was less soluble was attributed to an aqueous solution boundary layer effect. CONCLUSIONS: Non-sink receptor phase IVPT data can be used to derive equivalent sink receptor phase IVPT data provided the receptor phase solubility and hydrodynamics are sufficient to minimise the impact of aqueous diffusion layers on IVPT data.

Evaluation of the full evaporation technique for quantitative analysis of high boiling compounds with high affinity for apolar matrices.[Pubmed:24831424]

J Chromatogr A. 2014 Jun 27;1348:63-70.

In order to reduce inaccuracies due to possible matrix effects in conventional static headspace-gas chromatography (sHS-GC), it is standard practice to match the composition of calibration standards towards the composition of the sample to be analysed by adding blank matrix. However, the latter is not always available and in that case the full evaporation technique (FET) could be a solution. With FET a small sample volume is introduced in a HS vial and compounds of interest are completely evaporated. Hence no equilibrium between the condensed phase and vapour phase exists. Without the existence of an equilibrium, matrix effects are less likely to occur. Another issue often encountered with sHS-sampling is that low vapour pressure compounds with a high affinity for the dilution medium show a limited sensitivity. FET has proven to be an appropriate solution to address this problem too. In this work, the applicability of FET for the quantitative analysis of high boiling compounds in different complex apolar matrices is examined. Data show that FET is an excellent tool to overcome matrix effects often encountered with conventional sHS analysis. The tested method shows excellent accuracy with recovery values around 100% as well as repeatability with RSD values around 1% for the quantification of high boiling compounds (bp>200 degrees C) such as camphor, menthol, mEthyl salicylate and Ethyl salicylate in various matrices. LOQ values were found to be around 0.3mug per vial. Following validation of the technique, several topical pharmaceutical formulations like ThermoCream((R)), Reflexspray((R)), Vicks Vaporub((R)) and Radosalil((R)) were examined. For the latter, a comparison has been made with a sHS-method described in literature.

Quantitation of Ten Flavor Compounds in Unburned Tobacco Products.[Pubmed:26388954]

Anal Methods. 2014;6(13):4698-4704.

Most research on unburned tobacco has focused on the harmful chemicals associated with the tobacco itself. However, certain flavor additives in tobacco products can pose additional health risks. Flavors like camphor, coumarin, pulegone, eugenol, mEthyl salicylate, menthol and diphenyl ether have exhibited biological activity and/or toxicity in both lab animals and humans. This publication presents a new GC/MS method for the quantitation of ten flavor compounds (eucalyptol, camphor, menthol, pulegone, Ethyl salicylate, mEthyl salicylate, cinnamaldehyde, eugenol, diphenyl ether and coumarin) in a variety of tobacco products, including smokeless products and cigar filler. Excellent linearity (>0.997), accuracy (93.9% - 106.6%) and precision (C.V., 0.5% - 3.0%) were achieved for all flavor analytes measured. A summary of the concentrations of these flavors in selected international smokeless tobacco (SLT) products including zarda, quiwam, gutkha, and khaini varieties from Southeast Asia and snuff, clove cigarette filler and flavored cigar filler from the United States is reported. High concentrations of eugenol (2110 mug/g), coumarin (439 mug/g), camphor (1060 mug/g) and diphenyl ether (4840 mug/g) were found in selected products. Accurate identification and quantitation of potentially hazardous flavor compounds is important because they can exist in relatively high levels in some tobacco products, including international SLT products. We outline a versatile method which can be used to quantitate flavor compounds in multiple types of tobacco products.

Plasticized branched aliphatic oligoesters as potential mucoadhesive drug carriers.[Pubmed:24183958]

Int J Pharm. 2013 Dec 31;458(2):282-6.

Three oligoesters with different molar mass and degree of branching, intended as drug carriers, were synthesized and their thermal, rheological, adhesive, and drug release properties were studied. Triethyl citrate, ethyl pyruvate, Ethyl salicylate, mEthyl salicylate, triacetin and tributyrin at a concentration of 20% were tested as plasticizers to improve drug incorporation, and application of the polymeric system. All of the tested plasticizers significantly depressed the Tg by at least 25.5 degrees C. Plasticized oligoesters possessed remarkable adhesive properties on mucin in vitro, the adhesion is at least twofold bigger than it is for gels of cellulose derivatives. It was demonstrated that adhesivity increased with decreasing viscosity of oligoester matrices. In vitro dissolution tests of the flat matrices showed the prolongation of fluconazole release up to over 3 days for the oligoester carrier with the highest molar weight and degree of branching. Depending on the matrix hydrophilization, plasticizing led to an acceleration of the fluconazole release, the 3-h burst effect increased three times.

Preparation of Aryl-Susbstituted 2-Oxyindoles by Superelectrophilic Chemistry.[Pubmed:24058216]

Tetrahedron Lett. 2013 Jun 19;54(25):3245-3247.

A series of pyridyl-substituted 3-hydroxy-2-oxyindoles have been prepared and reacted with arenes in superacid promoted Friedel-Crafts reactions. The product aryl-substituted 2-oxyindoles are formed in generally good yields. With substituted arenes such as toluene, bromobenzene, or Ethyl salicylate, the Friedel-Crafts reactions occur with excellent regioselectivity. A mechanism is proposed involving dicationic, superelectrophilic species leading to the electrophilic aromatic substitution chemistry.

The estrogenic potential of salicylate esters and their possible risks in foods and cosmetics.[Pubmed:22197706]

Toxicol Lett. 2012 Mar 7;209(2):146-53.

Salicylate esters (SEs), a class of chemicals extensively used as flavor and fragrance additives in foods, beverages and a wide variety of consumer products, are suspected to have estrogenic activity based on chemical analysis of in silica molecular docking. We evaluated the estrogenic potentials of phenyl salicylate (PhS), benzyl salicylate (BzS), phenEthyl salicylate (PES), Ethyl salicylate (ES) and mEthyl salicylate (MS) using an in vitro human estrogen receptor alpha (hERalpha)-coactivator recruiting assay and in vivo immature rodent uterotrophic bioassays. We found that PhS, BzS and PES showed obvious in vitro hERalpha agonistic activities; BzS in particular exhibited a higher estrogenic activity compared to bisphenol A (BPA). The uterine weights were significantly increased in mice treated with 11.1, 33.3, 100 and 300 mg/kg/day BzS and 33.3mg/kg/day PES and rats treated with 3.7, 11.1, 33.3 and 100mg/kg/day BzS for 3 days (P<0.05). Finally, we transformed the daily intakes and the dermal exposures of SEs in the real world into estradiol equivalent concentrations (EEQs). We found that the EEQ of BzS daily intake in consumers in the U.S. and the EEQs of dermal BzS and PES exposure among high-volume users worldwide were higher than the maximum secure daily estradiol intake recommended by the U.S. Food and Drug Administration (FDA). In particular, the EEQ for dermal BzS exposure was up to 162 ng EEQ/kg, which is 3.3 times higher than the maximal acceptable daily E(2) intake recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

Optimization and validation of liquid chromatography and headspace-gas chromatography based methods for the quantitative determination of capsaicinoids, salicylic acid, glycol monosalicylate, methyl salicylate, ethyl salicylate, camphor and l-menthol in a topical formulation.[Pubmed:22094014]

J Pharm Biomed Anal. 2012 Feb 23;60:51-8.

Capsaicinoids, salicylic acid, methyl and Ethyl salicylate, glycol monosalicylate, camphor and l-menthol are widely used in topical formulations to relieve local pain. For each separate compound or simple mixtures, quantitative analysis methods are reported. However, for a mixture containing all above mentioned active compounds, no assay methods were found. Due to the differing physicochemical characteristics, two methods were developed and optimized simultaneously. The non-volatile capsaicinoids, salicylic acid and glycol monosalicylate were analyzed with liquid chromatography following liquid-liquid extraction, whereas the volatile compounds were analyzed with static headspace-gas chromatography. For the latter method, liquid paraffin was selected as compatible dilution solvent. The optimized methods were validated in terms of specificity, linearity, accuracy and precision in a range of 80% to 120% of the expected concentrations. For both methods, peaks were well separated without interference of other compounds. Linear relationships were demonstrated with R(2) values higher than 0.996 for all compounds. Accuracy was assessed by performing replicate recovery experiments with spiked blank samples. Mean recovery values were all between 98% and 102%. Precision was checked at three levels: system repeatability, method precision and intermediate precision. Both methods were found to be acceptably precise at all three levels. Finally, the method was successfully applied to the analysis of some real samples (cutaneous sticks).