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Biopharmaceutical classification systems (BCS) class III drugs belongs to a group of drugs with high solubility in gastrointestinal (GI) fluids and low membrane permeability result in significantly low bioavailability. Self-emulsifying drug delivery systems (SEDDS) considered a suitable candidate to enhance the bioavailability of poorly soluble drugs by improving their membrane permeability, however, incorporating hydrophilic drugs in to these carriers remained a great challenge. The aim of this study was to develop hydrophobic ion pairs (HIPs) of a model BCS class-III drug tobramycin (TOB) in order to incorporate into SEDDS and improve its bioavailability. HIPs of TOB were formulated using anionic surfactants sodium docusate (DOC) and sodium dodecanoate (DOD). The efficiency of HIPs was estimated by measuring the concentration of formed complexes in water, zeta potential determination and log P value evaluation. Solubility studies of HIPs of TOB with DOC were accomplished to screen the suitable excipients for SEDDS development. Consequently, HIPs of TOB with DOC were loaded into SEDDS and assessed the log DSEDDS/release medium and dissociation of these complexes at different intestinal pH over time. Moreover, cytotoxic potential of HIPs of TOB and HIPs loaded SEDDS formulations was evaluated. HIPs of TOB with DOC exhibited the maximum precipitation efficiency at a stoichiometric ratio of 1:5. Log P of HIPs of TOB improved up to 1500-fold compared to free TOB. Zeta potential of TOB was shifted from positive to negative during hydrophobic ion pairing (HIP). HIPs of TOB with DOC was loaded at a concentration of 1% (w/v) into SEDDS formulations. Log DSEDDS/release medium of loaded complexes in to oily droplets was above 2 and dissociated up to 20% at various pH within 4 h. Finding of this study suggested that improvement of the lipophilic character of BCS class-III drugs followed by incorporation into oily droplets can be deliberated as a promising tool to enhance the permeation across biological membranes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Asad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The present work aimed to form hydrophobic ion pairs (HIPs) of a small molecule remaining inside the oily droplets of SEDDS to a high extent. HIPs of ethacridine and various surfactants classified by functional groups of phosphates, sulfates, and sulfonates were formed and precipitation efficiency, log D n -octanol/water , and solubility in different excipients were investigated. Most lipophilic HIPs were incorporated into SEDDS and evaluated regarding drug release. Docusate HIPs showed the highest increase in lipophilicity with a precipitation efficiency of 100%, a log D n -octanol/water of 2.66 and a solubility of 132 mg/mL in n -octanol, 123 mg/mL in oleyl alcohol, and 40 mg/mL in medium chain triglycerides. Docusate HIPs were incorporated into three SEDDS of increasing lipophilicity (F1 < F2 < F3) based on medium chain triglycerides, oleyl alcohol, Kolliphor EL, and Tween 80 (F1: 1 + 5 + 2 + 2; F2: 3 + 3 + 2 + 2; F3: 5 + 1 + 4 + 0). Highest achievable payloads ranged from 74.49 mg/mL (F3) to 97.13 mg/mL (F1) and log D SEDDS/RM increased by at least 7.5 units (4.99, F1). Drug release studies via the diffusion membrane method confirmed minor release of docusate HIPs from all SEDDS (<2.7% within 4 h). In conclusion, highly lipophilic HIPs remain inside the oily phase of SEDDS and likely reach the absorption membrane in intact form.

In many jurisdictions, dispersants are included in contingency plans as a viable countermeasure that can help reduce the overall environmental impact of marine oil spills. When used, it is imperative to monitor the progression of dispersant and oil to assess their environmental fate and behaviour. Amphiphilic salt dioctyl sodium sulfosuccinate (DOSS) is the major effective component of the most commonly available dispersants, such as Corexit® EC9500A. Without proper sample preparation, dispersed oil in water samples could interfere with the accurate analysis of DOSS and easily contaminate the LC-MS system. In this work, solid phase extraction (SPE) weak anion exchange (WAX) cartridges were used to separate oil and DOSS in aqueous samples. DOSS was accurately determined by liquid chromatography coupled with a high resolution Orbitrap mass spectrometer (LC-HRMS). Oil fingerprinting analysis was conducted and total petroleum hydrocarbons (TPHs), polycyclic aromatic hydrocarbons (PAHs), and petroleum biomarkers were determined by gas chromatography-flame ionization detection (GC-FID) and mass spectrometry (GC-MS). This SPE-LC/GC-MS method was used for the analysis of oil-dispersant water samples containing a mixture of Corexit® EC9500A and a selection of crude oils and refined petroleum products. Nearly a 100% DOSS recovery was obtained for various oil-surfactant conditions. Parallel quantitation of oils with dispersants was achieved using this method. A portion of the TPH loss was possibly attributed to oil retained by the SPE column. Chemical fingerprints and diagnostic ratios of target compounds in recovered dispersed oil overall remain unchanged compared with those of all studied oils., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Dioctyl Sodium Sulfosuccinate (DOSS, CAS 577-11-7) is a chemical emulsifying surfactant that is widely used in the food and the cosmetic industry, and it is also the major component of the crude oil chemical dispersant Corexit™. Despite of its wide use, the studies related to its negative effect have been evaluated mainly in marine environments showing that DOSS is highly bioactive, extremely low volatile, and potential to persist in the environment longer than other dispersant components. Up to date, there is no available information of DOSS concentration in freshwater environments, little is known about its downstream fate after excretion and its effect on freshwater organisms. The objective of this study was to evaluate the effect of DOSS at different concentrations in embryos and adults of zebrafish Danio rerio in an acute-static bioassays of 96 h. The median lethal concentration in embryos was 33.3 mg/L. Malformations started to be observed at 10 mg/L. In adults, the gene expression analysis in gill tissues showed a deregulation in genes associated with the antioxidant system and the nucleotide excision repair mechanism. Additionally, Micronuclei (DNA damage) in erythrocytes, and fat degeneration in liver, hypertrophy and hyperplasia in gills, and hyaline drops in kidney tissues were also observed. In conclusion, the concentrations of DOSS evaluated here would be of health relevance to fish based on morphological alterations in embryos and changes in the gene expression profile, DNA damage and tissue impairment in adults., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hydrophobic ion pairing is a promising strategy to raise the lipophilic character of therapeutic peptides and proteins. In past studies, docusate, an all-purpose surfactant with a dialkyl sulfosuccinate structure, showed highest potential as hydrophobic counterion. Being originally not purposed for hydrophobic ion pairing, it is likely still far away from the perfect counterion. Thus, within this study, docusate analogues with various linear and branched alkyl residues were synthesized to derive systematic insights into which hydrophobic tail is most advantageous for hydrophobic ion pairing, as well as to identify lead counterions that form complexes with superior hydrophobicity. The successful synthesis of the target compounds was confirmed by FT-IR, 1 H-NMR, and 13 C-NMR. In a screening with the model protein hemoglobin, monostearyl sulfosuccinate, dioleyl sulfosuccinate, and bis(isotridecyl) sulfosuccinate were identified as lead counterions. Their potential was further evaluated with the peptides and proteins vancomycin, insulin, and horseradish peroxidase. Dioleyl sulfosuccinate and bis(isotridecyl) sulfosuccinate significantly increased the hydrophobicity of the tested peptides and proteins determined as logP or lipophilicity determined as solubility in 1-octanol, respectively, in comparison to the gold standard docusate. Dioleyl sulfosuccinate provided an up to 8.3-fold higher partition coefficient and up to 26.5-fold higher solubility in 1-octanol than docusate, whereas bis(isotridecyl) sulfosuccinate resulted in an up to 6.7-fold improvement in the partition coefficient and up to 44.0-fold higher solubility in 1-octanol. The conjugation of highly lipophilic alkyl tails to the polar sulfosuccinate head group allows the design of promising counterions for hydrophobic ion pairing. STATEMENT OF SIGNIFICANCE: Hydrophobic ion pairing enables efficient incorporation of hydrophilic molecules into lipid-based formulations by forming complexes with hydrophobic counterions. Docusate, a sulfosuccinate with two branched alkyl tails, has shown highest potential as anionic hydrophobic counterion. As it was originally not purposed for hydrophobic ion pairing, its structure is likely still far away from the perfect counterion. To improve its properties, analogues of docusate with various alkyl tails were synthesized in the present study. The investigation of different alkyl residues allowed to derive systematic insights into which tail structures are most favorable for hydrophobic ion pairing. Moreover, the lead counterions dioleyl sulfosuccinate and bis(isotridecyl) sulfosuccinate bearing highly lipophilic alkyl tails provided a significant improvement in the hydrophobicity of the resulting complexes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Reverse micelle (RM) aggregates have a wide range of applications in various areas of science and technology. A continuous demand exists to replace interfacial surfactant molecules with various nonconventional amphiphiles. Ionic liquid (IL)-like surfactants (IL-surf's) constitute a class of such molecules that are being researched extensively. Here, we have formulated several water/IL-surf/oil microemulsions by optimizing the core droplet size with varying oil phases. The best composition of water/[BMIM][AOT]/IPM ([BMIM][AOT]: 1-butyl-3-methylimidazolium dioctyl sulfosuccinate; IPM: isopropyl myristate) was then analyzed in detail through experimental and computer simulations. Our results from DLS measurements suggest a structural transition from spherical aggregates in the parent water/[Na][AOT]/IPM solution to cylindrical droplets in the IL-surf-based system. The Raman and ATR-FTIR spectral analysis suggest a variation in the microstructure of the water/oil interface due to the differential interaction of the counterions with AOT headgroups and water. Molecular dynamics simulation results provided the direct image of the interface showing a structured versus uneven water/oil interface in [Na][AOT] versus [BMIM][AOT] RMs, where the larger [BMIM] cations weakly bind with the AOT headgroups due to their low charge density. Finally, an application of this IL-surf-based formulation was tested by carrying out a Heck cross-coupling reaction that showed significantly higher yield under milder reaction conditions.

Aerosol-OT reverse micelles represent a chemical construct where surfactant molecules self-assemble to stabilize water nanodroplets 1-10 nm in diameter. Although commonly assumed to adopt a spherical shape, all-atom molecular dynamics simulations and some experimental studies predict a nonspherical shape. If these aggregates are not spherical, then what shape do they take? Because the tools needed to evaluate the shape of something that lacks regular structure, order, or symmetry are not well developed, we present a set of three intuitive metrics─coordinate-pair eccentricity, convexity, and the curvature distribution─that estimate the shape of an amorphous object, and we demonstrate their use on a simulated aerosol-OT reverse micelle. These metrics are all well-established methods and principles in mathematics, and each provides unique information about the shape. Together, these metrics provide intuitive descriptions of amorphous shapes, facilitate ways to quantify those shapes, and follow their changes over time.

Considering the remarkable applicability of ionic liquids (ILs) in bio-catalysis involving enzymes, herein, we report new IL based aqueous microemulsions as a catalytic reactor for cytochrome c (Cyt-c). Microemulsions (μEs), comprising water as the polar component, imidazolium (cation) and dioctylsulfosuccinate (AOT) (anion) based biamphiphilic ionic liquid (BAIL) as the surfactant and a hydrophobic ionic liquid (HIL) as the non-polar component have been prepared and characterized. The use of BAIL has promoted the formation of μEs without any co-surfactant, owing to its higher surface activity. The effect of ester- or amide-functionalization of the alkyl chain of the imidazolium cation of BAILs on the phase behavior of μEs has been investigated. The prepared μEs have been characterized via conductivity, dynamic light scattering (DLS), UV-vis absorption and steady-state fluorescence (using external polarity probes) techniques. The prepared μEs have been employed as nano-reactors for exploring the catalytic activity of Cyt-c. The formed BAIL-water nano-interfaces in reverse μEs have exerted a positive effect on the catalytic activity of Cyt-c stored in a water pool of reverse μEs. A five-fold higher rate constant in μEs as compared to buffer establishes μEs as a better catalytic medium. Furthermore, the differing nature of nano-interfaces created by BAILs and water in reverse μEs, depending on the functionalization of the alkyl chain of the cationic part of BAIL, has exerted varying influence on the catalytic activity of Cyt-c. It is expected that the present work will result in providing a versatile platform for the creation of new IL and water based μEs for bio-catalytic applications.

The structure and conductivity of AOT (sodium bis(2-ethylhexyl) sulfosuccinate) solutions (2.5 × 10 -4 -2.5 × 10 -1 M) in n-hexadecane-chloroform mixture at the chloroform concentration from 50 to 100 vol% were studied. The diffusion ordered spectroscopy NMR study revealed that in the indicated range, the observed hydrodynamic diameter of micelles depends only on the AOT concentration and does not depend on the chloroform content. Molar fractions of free AOT molecules and those aggregated into micelles were calculated using the Lindman's law: at concentrations above 2.5 × 10 -1 М, the solutions contain mostly the micelles, whereas at concentrations below 2.5 × 10 -4 M, the solutions contain AOT molecules. The transition region contains both the AOT molecules and the micelles. Conductivity measurements were used to determine free charge carriers in the bulk of solutions and their contributions to conductivity., (© 2020 Wiley-VCH GmbH.)

Peptides are therapeutic molecules with high potential to treat a wide variety of diseases. They are large hydrophilic compounds for which absorption is limited by the intestinal epithelial border covered by mucus. This study aimed to evaluate the potential of Hydrophobic Ion Pairing combined with Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) to improve peptide transport across the intestinal border using Caco-2 cell monolayers (enterocyte-like model) and Caco-2/HT29-MTX co-cultured monolayers (mucin-secreting model). A Hydrophobic Ion Pair (HIP) was formed between Leuprolide (LEU), a model peptide, and sodium docusate. The marked increase in peptide lipophilicity enabled high encapsulation efficiencies in both NLC (84%) and SLN (85%). After co-incubation with the nanoparticles, confocal microscopy images of the cell monolayers demonstrated particles internalization and ability to cross mucus. Flow cytometry measurements confirmed that 82% of incubated SLN and 99% of NLC were internalized by Caco-2 cells. However, LEU transport across cell monolayers was not improved by the nanocarriers. Indeed, combination of particles platelet-shape and HIP low stability in the transport medium led to LEU burst release in this environment. Improvement of peptide lipidization should maintain encapsulation and enable benefit from nanocarriers enhanced intestinal transport., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The lipophilic character of peptides can be tremendously improved by hydrophobic ion pairing (HIP) with counterions to be efficiently incorporated into lipid-based nanocarriers (NCs). Herein, HIPs of exenatide with the cationic surfactant tetraheptylammonium bromide (THA) and the anionic surfactant sodium docusate (DOC) were formed to increase its lipophilicity. These HIPs were incorporated into lipid based NCs comprising 41% Capmul MCM, 15% Captex 355, 40% Cremophor RH and 4% propylene glycol. Exenatide-THA NCs showed a log D lipophilic phase (LPh)/release medium (RM) of 2.29 and 1.92, whereas the log D LPh/RM of exenatide-DOC was 1.2 and -0.9 in simulated intestinal fluid and Hanks' balanced salts buffer (HBSS), respectively. No significant hemolytic activity was induced at a concentration of 0.25% (m/v) of both blank and loaded NCs. Exenatide-THA NCs and exenatide-DOC NCs showed a 10-fold and 3-fold enhancement in intestinal apparent membrane permeability compared to free exenatide, respectively. Furthermore, orally administered exenatide-THA and exenatide-DOC NCs in healthy rats resulted in a relative bioavailability of 27.96 ± 5.24% and 16.29 ± 6.63%, respectively, confirming the comparatively higher potential of the cationic surfactant over the anionic surfactant. Findings of this work highlight the potential of the type of counterion used for HIP as key to successful design of lipid-based NCs for oral exenatide delivery., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: The study was aimed to investigate the impact of superassociation of hydrophobic ion pairs (HIPs) on membrane permeability., Methods: Toluidine blue O (TBO) as a cationic model compound was complexed with anionic counter ions having different physiochemical properties namely dodecanoate (DD), oleate (OL), deoxycholate (DC), docusate (DO) and dodecyl sulfate (DS). TBO HIPs were characterized regarding log P, zeta potential and stability over 8 h at pH 7.4. Association and dissociation constants (K a and K d ) were calculated by applying quasi-equilibrium equation to the double reciprocal plots of log P versus counter ion concentrations. Permeation studies of free TBO, superassociated TBO HIPs and HIPs applied as entirely dissociated form were carried out across human colorectal adenocarcinoma-derived cell line (Caco-2) and freshly excised rat intestinal mucosa., Results: TBO HIPs of increasing lipophilicity ranging from log P 0.59 to 2.35 were obtained as a result of ion pairing with anionic counter ions. Zeta potential of TBO shifted from positive to negative due to ion pairing. HIPs with DO and DS showed highest stability at pH 7.4. Association constant (K a ) values for TBO HIPs were found in the following rank order; DS > DO > OL > DC > DD. Due to superassociation of HIPs, permeation of TBO was efficiently improved up to 3.1-fold across Caco-2 cells and up to 2.5-fold across rat intestinal mucosa., Conclusion: Superassociated HIPs showed generally a significantly higher membrane permeability than free TBO and entirely dissociated HIPs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Encapsulation of crocin (CN), having large nonlinear optical (NLO) properties, can be utilized in studies of photodynamic therapy (PDT). For this purpose, photo-physical and NLO properties of CN encapsulation with and without cell culture medium (CCM) were investigated. As well, nonlinear absorption (NLA) coefficient and nonlinear refractive (NLR) indices were found to be 10 -7 (cm W -1 ) and 10 -12 (cm 2  W -1 ); respectively. The results revealed that NLO properties of CN had changed through its dipole moment. Reflecting on the theory of Bilot and Kawski, it was evidenced that the dipole moment of CN could change with a nano-droplet size. Furthermore, it was demonstrated that RPMI-1640 as a growth medium had failed to change NLO properties of CN encapsulated in nano-droplet. Accordingly, the encapsulated CN in nano-droplet in the form of a photosensitizer (PS) was suggested as a good candidate to examine PDT under in-vitro conditions.

Poor wetting and/or particle aggregation are the shortcomings of the dried nanocrystalline suspensions, which subsequently might hinder the superior dissolution performance of the nano-crystalline suspensions. The objective of this study was to evaluate the effect of wetting agents and disintegrants on the dissolution performance of dried nanocrystals of an active pharmaceutical ingredient (API) with poor wetting property. Danazol, a BCS Class II compound with high LogP and low polar surface area, was chosen as a model compound for this study. Danazol nanocrystalline suspension was prepared by wet-media milling and converted into powder via spray granulation either with mannitol or microcrystalline cellulose as carriers at a drug: carrier ratio of 1:9 w/w. Danazol nanocrystalline suspension showed a superior dissolution performance compared to an un-milled danazol suspension. Dried danazol nanocrystals suffered from poor wetting leading to hindered dissolution performance i.e. ~ 40% and ~ 15% drug dissolution within 15 min for the mannitol and microcrystalline cellulose-based granules, respectively. Addition of a lipophilic surfactant (i.e. docusate sodium) at a surfactant: drug ratio of 0.015: 1 w/w during granulation helped in retaining the superior drug dissolution rates i.e. more than 80% drug dissolution within 15 min for mannitol-based granules by enhancing the wettability of dried danazol nanocrystals when compared to a hydrophilic surfactant (i.e. poloxamer 188) or disintegrant (i.e. sodium starch glycolate or croscarmellose sodium). The fast-dissolving mannitol-based granules containing danazol nanocrystals and docusate sodium were compressed into a tablet dosage form. The tablets containing danazol nanocrystals with docusate sodium showed a superior dissolution performance compared to a tablet containing un-milled danazol with docusate sodium., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Silver nanoparticles (AgNPs) represent one of the most abundant biocidal nanomaterials contained in more than 30% of nano-enabled consumer products and 75% of nanomedical products. The cumulative exposure of the general population may therefore reach critical and potentially hazardous levels. Due to data gaps on AgNP effects in humans, it is urgent to further evaluate their possible toxicity, particularly in vulnerable systems like the nervous one. As AgNPs may cross the blood brain and placental barriers, this study evaluated the in vitro effect of different AgNPs on neuronal precursor cells. For this purpose, 10 nm-sized AgNPs were stabilized with five different coating agents rendering a neutral, positive and negative surface charge. Murine neural stem cells (mNSCs) were used as cellular model to test AgNP neurotoxicity by evaluating the range of toxicity endpoints including cellular viability, apoptosis induction, oxidative stress response, cellular and mitochondrial membrane damages, DNA damage, inflammation response, and neural stem cell regulation. Our results clearly showed that the neurotoxic potential of AgNPs was not dependent on their surface charge or coating agents used for their surface stabilization. All AgNP types exhibited significant toxicity in neuronal precursor cells at an in vitro dose of 5 mg Ag/L or lower., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Reverse micelles (RMs) composed of water and sodium bis(2-ethylhexyl)sulfosuccinate (AOT) in isooctane have a remarkably narrow size distribution around a mean value determined by the water loading ratio of the system. It has been proposed that RMs establish this equilibrium size distribution either by the diffusion of individual components through the isooctane phase or by cycles of fusion and fission. To examine these mechanisms, a 24 μs all-atom molecular dynamics simulation of a system containing one small RM and one large RM was performed. Results show that the net movement of water from the small RM to the large RM occurred in a direction that made the small RM smaller and the large RM larger-according to water loading ratios that would have been appropriate for their size. Changes in AOT number that would bring the water loading ratio of each RM closer to that of the overall system only occurred via cycles of RM fusion and fission. These behaviors are most likely driven by the electrostatics of sodium AOT and the dielectric effects of water.

Objective: The aim of this study was to develop self-emulsifying drug delivery systems (SEDDS) for oral delivery of therapeutic proteins through hydrophobic ion pairing. Method: Horseradish peroxidase (HRP), a model protein, was ion paired with sodium docusate to increase its hydrophobicity. The formed enzyme - surfactant complex was incorporated into SEDDS, followed by permeation studies across Caco-2 cell monolayer and freshly excised rat intestine. Results: Hydrophobic ion pairs (HIP) were formed between HRP and sodium docusate with the efficiency of 87.49 ± 1.35%. The formed complex maintained 60.97 ± 1.48% of the original enzyme activity. The ion pair was subsequently loaded into SEDDS with a payload of 0.1% (mass per cent, m/m). The obtained emulsion formed by SEDDS had a droplet size in the range from 20 to 200 nm with negative zeta potential. Permeation mechanism of the enzyme was energy-dependent and the encapsulation of the HIP complex in SEDDS enhanced the permeation of the enzyme through the Caco-2 cell monolayer and freshly excised rat intestine by 4 times and 2.5 times compared to the free enzyme, respectively. Conclusion: According to these findings, hydrophobic ion pairing followed by incorporation to SEDDS might be considered as a potential strategy for oral delivery of therapeutic proteins.

A high resolution mass spectrometry method was developed for the environmental impact monitoring of oil spill dispersants. Previously reported instability of dioctyl sulfosuccinate (DOSS) dispersant tracer was addressed by the new procedure. The method monitors both DOSS and its degradation product, monooctyl sulfosuccinate (MOSS), by liquid chromatography time-of-flight mass spectrometry. The related isomer, 4-(2-ethylhexyl) 2-sulfobutanedioate, was chromatographically resolved from MOSS but was not a product of DOSS degradation. Using this direct injection method (10 μL), the practical lower limit of quantitation was 0.5 nM for each analyte, a concentration equivalent to 0.22 ng mL -1 , or 0.30 ng mL -1 including initial dilution factor with acetonitrile. The method was shown applicable to analysis of the dispersants Corexit® EC9500 A, Finasol OSR 52, Slickgone NS, and Slickgone EW for which DOSS is an active ingredient. A marine microcosm study of Corexit EC9500A, together with diluted bitumen (dilbit), at 15 ± 1 °C, provided evidence of the stoichiometric conversion of DOSS to MOSS under conditions reflecting a western Canadian marine environment. The advantage of the developed method is in its ability to extend environmental seawater sample collection time from 4 days for DOSS alone, to 14 days when both DOSS and MOSS are simultaneously analysed and results combined. The collection time is likely extended beyond the 14 day period with cooler temperatures. Preservation of collected seawater samples using sodium hydroxide, converting DOSS into MOSS in situ, was rejected due to stability issues. Addition of disodium ethylenediaminetetraacetic acid did not improve hold times, thus eliminating the theory of cation induced micelle effects causing DOSS loss., (Copyright © 2019. Published by Elsevier B.V.)

Peptides are rarely orally administrated due to rapid degradation in the gastrointestinal tract and low absorption at the epithelial border. The objective of this study was to encapsulate a model water-soluble peptide in biodegradable and biocompatible solid lipid-based nanoparticles, i.e. Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) in order to protect it from metabolic degradation. Leuprolide (LEU) and a LEU-docusate Hydrophobic Ion Pair (HIP) were encapsulated in SLN and NLC by High Pressure Homogenization. The particles were characterized regarding their Encapsulation Efficiency (EE), size, morphology, peptide release in FaSSIF-V2, and protective effect towards proteases. Nanoparticles of 120 nm with platelet structures were obtained. Formation of HIP led to a significant increase in LEU EE. Particle size was moderately affected by the presence of simulated fluids. Nonetheless, an important burst release was observed upon dispersion in FaSSIF-V2. NLC were able to improve LEU-HIP resistance to enzymatic degradation induced by trypsin but presented no advantages in presence of α-chymotrypsin. SLN provided no protection regarding both proteases. Despite an increased amount of encapsulated peptide in solid lipid-based nanoparticles following HIP formation, the important specific surface area linked to their platelet structures resulted in an important peptide release upon dispersion in FaSSIF-V2 and limited protection towards enzymatic degradation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The toxic action of surfactant used as a stabilizer of metal nanoparticles have been studied with the aim to determine separate contributions of surfactant monomers and micelles to cell viability decrease. Basing on (1) the well-known ability of surfactant molecules to form micelles in solution at a critical micelle concentration (CMC) and (2) the results reported in literature, showing that toxicity of various surfactants increases when their concentration exceeds CMC, we supposed that surfactant molecules and micelles may differ in their toxic effect on cells. This supposition was verified on the anionic surfactant aerosol-OT (AOT) used as a stabilizer of silver nanoparticles (AgNPs) in studies of their cytotoxicity on Jurkat cells by means of the MTT test. Two samples of AgNPs stabilized with AOT in concentrations higher (3 mM) and lower (1 mM) than its CMC in water were introduced to the cell medium as water solutions diluted to obtain nanoparticle concentrations in the range 1-7 μg/mL. Cell viability changes were registered after 24 h incubation. It was found that AgNPs of similar average size (about 16 nm), synthesized by the same procedure, introduced to the same concentrations in cell medium, produced a different effect on cell viability. Namely, decrease in cell viability was observed for AgNPs with 3 mM AOT, while no noticeable changes were registered for AgNPs with 1 mM AOT. A similar difference was detected for the corresponding dilutions of 3 mM and 1 mM AOT water solutions. We assumed that the toxicity dependence on AOT concentration originated from the difference in toxic action of the two different AOT forms - molecules (monomers) and micelles - present in the AgNPs and AOT solution. The approach was suggested for estimation of the separate contributions of monomers and micelles to the total AOT toxicity; changes of these contributions with AgNPs or AOT concentration were also determined. The results obtained may prove to be useful in studies of the biological activity of surfactants applied both as nanoparticle stabilizers and as agents working in medicine as suppressors of various infections., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Therapeutic peptides are facing an increasing interest as drugs for the treatment of many diseases. The challenge in the administration of such drugs, due to inherent properties of these peptides, is to make them bioavailable. Self-emulsifying drug delivery systems (SEDDS) are considered a suitable and promising strategy to deliver the peptides and increase their bioavailability. However, to enter into the SEDDS nanodroplets, the peptides must be made hydrophobic by complexation with surfactants (formation of hydrophobic ion pair, HIP). The aim of this work is to assess the possibility to quantify the amount of released peptides and of the remaining docusate/peptide HIP in the nanodroplets by Taylor Dispersion Analysis (TDA) on two therapeutic peptides (leuprorelin and desmopressin). It also clearly demonstrates that the logP value of the peptide has a strong influence on the extent of HIP inside of the SEDDS nanodroplets. For instance leuprorelin-docusate complex (logP = 3) was 100% inside of the nanodroplets at low ionic strength, while for desmopressin-docusate complex (logP = 0.5) only 30% were able to enter the nanodroplets. It was also shown that an increase in the ionic strength of the release media allowed to increase the amount of released peptide up to 80% for leuprorelin and 100% for desmopressin, at physiological ionic strength. TDA experiments allowed to determine the partitioning coefficient, logD value, of the peptide between the SEDDS and continuous aqueous phases. In conclusion, this work demonstrates that TDA is a rapid, straightforward and useful technique for developing SEDDS formulations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pyridine-based small-molecule drugs, vitamins, and cofactors are vital for many cellular processes, but little is known about their interactions with membrane interfaces. These specific membrane interactions of these small molecules or ions can assist in diffusion across membranes or reach a membrane-bound target. This study explores how minor differences in small molecules (isoniazid, benzhydrazide, isonicotinamide, nicotinamide, picolinamide, and benzamide) can affect their interactions with model membranes. Langmuir monolayer studies of dipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylethanolamine (DPPE), in the presence of the molecules listed, show that isoniazid and isonicotinamide affect the DPPE monolayer at lower concentrations than the DPPC monolayer, demonstrating a preference for one phospholipid over the other. The Langmuir monolayer studies also suggest that nitrogen content and stereochemistry of the small molecule can affect the phospholipid monolayers differently. To determine the molecular interactions of the simple N-containing aromatic pyridines with a membrane-like interface, 1 H one-dimensional NMR and 1 H- 1 H two-dimensional NMR techniques were utilized to obtain information about the position and orientation of the molecules of interest within aerosol-OT (AOT) reverse micelles. These studies show that all six of the molecules reside near the AOT sulfonate headgroups and ester linkages in similar positions, but nicotinamide and picolinamide tilt at the water-AOT interface to varying degrees. Combined, these studies demonstrate that small structural changes of small N-containing molecules can affect their specific interactions with membrane-like interfaces and specificity toward different membrane components.

The present study investigated oil dispersant toxicity to fish species typical of the cooler regions of Canada, together with less well-documented issues pertaining to oil dispersant monitoring. The oil dispersant toxicity of Corexit EC9500A was assessed for the freshwater fish species rainbow trout and the seawater species coho, chinook, and chum, with a final median lethal concentration (LC50) acute lethality range between 35.3 and 59.8 mg/L. The LC50 range was calculated using confirmed 0-h dispersant concentrations that were justified by fish mortality within the first 24 h of exposure and by variability of the dispersant indicator dioctyl sulfosuccinate (DOSS) used to monitor concentrations at later time points. To investigate DOSS as an oil dispersant indicator in the environment, microcosm systems were prepared containing Corexit EC9500A, Finasol OSR52, Slickgone NS, and Slickgone EW dispersants together with diluted bitumen. The DOSS indicator recovery was found to be stable for up to 13 d at 5 °C, 8 d at 10 °C, but significantly less than 8 d at ≥15 °C. After 3 d at temperatures ≥15 °C, the DOSS indicator recovery became less accurate and was dependent on multiple environmental factors including temperature, microbial activity, and aeration, with potential for loss of solvents and stabilizers. A final assessment determined DOSS to be a discrepant indicator for long-term monitoring of oil dispersant in seawater. Environ Toxicol Chem 2018;37:1309-1319. © 2018 SETAC., (© 2018 SETAC.)

The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log D SEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses. Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152nm, 112nm and 191nm and a zeta potential of -3.7, -4.6 and -5.7mV, respectively. They were completely stable towards degradation by lipase and showed a log D SEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17×10 -9 cm 2 /s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs., Control: According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Effective and efficient spreading of drug formulations on the pulmonary mucosal layer is key to successful delivery of therapeutics through the lungs. The pulmonary mucus layer, which covers the airway surface, acts as a barrier against therapeutic agents, especially in the case of chronic lung diseases due to increased thickness and viscosity of the mucus. Therefore, spreading of the drug formulations on the airways gets harder. Although spreading experiments have been conducted with different types of formulations on mucus-mimicking subphases, a highly effective formulation is yet to be discovered. Adding surfactant to such formulations decreases the surface tension and triggers the Marangoni forces to enhance the spreading behavior. In this study, catanionic (cationic + anionic) surfactant mixtures composed of dodecyltrimethylammonium bromide (DTAB) and dioctyl sulfosuccinate sodium salt (AOT) mixed at various mole ratios are prepared and their spreading behavior on both mucin and cystic fibrosis (CF) mucus models is investigated for the first time in the literature. Synergistic interaction is obtained between the components of the DTAB/AOT mixtures, and this interaction has enhanced the spreading of the formulation drop on both the mucin and CF mucus models when compared with the spreading performances of selected conventional surfactants. It is proposed that the catanionic surfactant mixtures, especially when mixed at the molar ratios of 8/2 and 7/3 (DTAB/AOT), improve the spreading even on the cystic fibrosis sputum model. As it is vital to transport a sufficient amount of drug to the targeted region for the treatment of diseases, this study presents an important application of the fundamentals of colloidal science to pharmaceutical nanotechnology.

Reverse micelles (RMs) made with sodium bis(2-ethylhexyl)sulfosuccinate suspended in isooctane are commonly used experimental models of aqueous microenvironments. However, there are important unanswered questions about the very characteristic that makes them of interest, namely their size. To explore the factors that determine the size of RMs, all-atom molecular dynamics simulations of RMs with different sizes but the same water-loading ratio were performed. An Anton 2 machine was used so that systems of the necessary size could be extended into the microsecond timescale, and mass exchange processes could be observed. Contrary to hypothesis, there were no net gains or losses of water by diffusion between RMs of different size. However, gains and losses did occur following fusion events. RM fusion followed RM contact only when waters were present among the hydrophobic surfactant chains at the point of contact. The presence of an encapsulated 40-residue amyloid beta peptide did not directly promote RM fusion, but it quickly and efficiently terminated each fusion event. Before fusion terminated, however, the size of the peptide-containing RM increased without a corresponding change in its water-loading ratio. We conclude that the mass transfer between RMs is most likely accomplished through transient fusion events, rather than through the diffusion of component molecules through the organic phase. The behavior of the amyloid beta peptide in this system underscores its propensity to embed in, and fold in response to, multiple interactions with the surfactant layer.

Coumarin derivatives are well known fluorescence reporters for investigating biological systems due to their strong micro-environment sensitivity. Despite having wide range of environment sensitive fluorescence probes, the potential of 6,7-dimethoxy-coumarin has not been studied extensively so far. With a perspective of its use in protein studies, namely using the unnatural amino acid technology or as a substrate for hydrolase enzymes, we study acetyloxymethyl-6,7-dimethoxycoumarin (Ac-DMC). We investigate the photophysics and hydration dynamics of this dye in aerosol-OT (AOT) reverse micelles at various water contents using the time dependent fluorescence shift (TDFS) method. The TDFS response in AOT reverse micelles from water/surfactant ratio of 0 to 20 confirms its sensitivity towards the hydration and mobility of its microenvironment. Moreover, we show that the fluorophore can be efficiently quenched by halide ions. Hence, we conclude that the 6,7-dimethoxy-methylcoumarin fluorophore is useful for studying hydration parameters in biologically relevant systems.

The development of biophysical systems that enable an understanding of the structure and ligand-binding properties of G-quadruplex (GQ)-forming nucleic acid sequences in cells or models that mimic the cellular environment would be highly beneficial in advancing GQ-directed therapeutic strategies. Herein, the establishment of a biophysical platform to investigate the structure and recognition properties of human telomeric (H-Telo) DNA and RNA repeats in a cell-like confined environment by using conformation-sensitive fluorescent nucleoside probes and a widely used cellular model, bis(2-ethylhexyl) sodium sulfosuccinate reverse micelles (RMs), is described. The 2'-deoxy and ribonucleoside probes, composed of a 5-benzofuran uracil base analogue, faithfully report the aqueous micellar core through changes in their fluorescence properties. The nucleoside probes incorporated into different loops of H-Telo DNA and RNA oligonucleotide repeats are minimally perturbing and photophysically signal the formation of respective GQ structures in both aqueous buffer and RMs. Furthermore, these sensors enable a direct comparison of the binding affinity of a ligand to H-Telo DNA and RNA GQ structures in the bulk and confined environment of RMs. These results demonstrate that this combination of a GQ nucleoside probe and easy-to-handle RMs could provide new opportunities to study and devise screening-compatible assays in a cell-like environment to discover GQ binders of clinical potential., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Conventional atomistic computer simulations, involving perhaps up to 10 6 atoms, can achieve length-scales on the order of a few 10s of nm. Yet many heterogeneous systems, such as colloids, nano-structured materials, or biological systems, can involve correlations over distances up 100s of nm, perhaps even 1μm in some instances. For such systems it is necessary to invoke coarse-graining, where single atoms are replaced by agglomerations of atoms, usually represented as spheres, in order for the simulation to be performed within a practical computer memory and time scale. Small angle scattering and reflectivity measurements, both X-ray and neutron, are routinely used to investigate structure in these systems, and traditionally the data have been interpreted in terms of discrete objects, such as spheres, sheets, and cylinders, and combinations thereof. Here we combine the coarse-grained computer simulation approach with neutron small angle scattering to refine the structure of a heterogeneous system, in the present case a reverse aqueous micelle of sodium-dioctyl sulfosuccinate (AOT) and iso-octane. The method closely follows empirical potential structure refinement and involves deriving an empirical interaction potential from the scattering data. As in traditional coarse-grained methods, individual atoms are replaced by spherical density profiles, which, unlike real atoms, can inter-penetrate to a significant extent. The method works over an arbitrary range of length-scales, but is limited to around 2 orders of magnitude in distance above a specified dimension. The smallest value for this dimension is of order 1nm, but the largest dimension is arbitrary. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editor: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to evaluate the protective effect of self-emulsifying drug delivery systems (SEDDS) for therapeutic peptides towards intestinal proteases and reduced glutathione (GSH)., Methods: Sodium docusate was applied as anionic surfactant for hydrophobic ion pairing with leuprorelin (LEU), insulin (INS) and desmopressin (DES). The complexes were loaded into SEDDS that were characterized regarding droplet size distribution and zeta potential. The release profile of the peptides was examined by dialysis membrane method. Enzymatic digestion studies were performed by applying α-chymotrypsin, trypsin and elastase. Furthermore, the protective effect of SEDDS towards degradation through thiol-disulfide exchange reactions was examined by addition of GSH., Results: SEDDS showed a mean droplet size of 0.27-3.9μm and a zeta potential of -25 to -33mV. All formulations provided a sustained release of the peptides over 6h. Degradation of the model peptides by intestinal proteases and GSH could only be observed in the release medium. In the oily phase of SEDDS neither any of the proteases nor GSH was soluble (≤0.1%). Furthermore, no degradation of the model peptides by proteases and GSH took place in the oily phase of SEDDS., Conclusion: SEDDS can provide a 100% protective effect towards protease degradation and deactivation by GSH. According to this, SEDDS might be promising tools for oral delivery of peptide drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Carboxymethyl chitosan (CMCh), as a non-toxic, biocompatible and biodegradable semi-synthetic biopolymer with mucoadhesive properties, is widely investigated for targeting drug or gene delivery applications. Here, fabrication of CMCh nanoparticles will be reported using a reverse (w/o) micellar system to provide particles with tuneable mean sizes. Reverse microemulsions were prepared by dispersing aqueous solution of CMCh in n-hexane using sodium-bis(ethylhexyl)-sulfosuccinate (AOT) and glutaraldehyde (GA) as an emulsifier and a crosslinking agent, respectively. The obtained particles were perfectly spherical in the nanometric size range (40-140 nm) with a narrow size distribution according to the FE-SEM images. To determine the effective parameters on the mean nanosphere size, CMCh, AOT and GA concentrations were varied according to a full-factorial, three-level design-of-experiments. After evaluating the results, it was found that AOT and CMCh concentrations had a significant effect on the mean nanosphere size while GA concentration surprisingly showed non-significant, minor effects on the same response.

Aim: The aim of this study was the formation and characterization of various ion pairs of therapeutic peptides with different surfactants in order to reach a high payload in self-emulsifying drug delivering systems (SEDDS)., Methods: Hydrophobic ion pairs (HIP) were formed between the anionic surfactants sodium docusate, dodecylsulfate and oleate and the peptides leuprorelin (LEU), insulin (INS) and desmopressin (DES). The efficiency of HIP formation was evaluated by quantifying the amount of formed complexes, log P value determination in n-octanol/water via HPLC and zeta potential measurements. Solvents and surfactants were screened regarding their complex solubilizing properties. Subsequently, peptide complexes were incorporated into SEDDS followed by payload and stability determination., Results: Independent from the type of peptide, docusate showed the most efficient HIP properties followed by dodecylsulfate and oleate. Ratios of 2:1 for LEU, 6:1 for INS and 1.5:1 for DES led to the highest quantity of formed complexes with docusate and log P increased at least by 3 units. The more docusate was added to each peptide, the more negative became the zeta potential of the resulting complex. Incorporating these optimized complexes into novel SEDDS containing Capryol 90, Labrafil M 2125 CS, Labrasol ALF, Peceol, propylene glycol, tetraglycol, Transcutol HP and Tween 20 allowed payloads of the LEU, DES and INS complexes above 10%. Moreover, SEDDS exhibited high stability and constant negative zeta potential over a 4h incubation time., Conclusion: Following the procedure described herein payloads >10% can be achieved for peptide drugs in SEDDS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v. injection of the particles. Two polyethylene oxide containing stabilizers; (distearoyl phosphatidylethanol amine (DSPE)) -PEG2000 and the triblock copolymer Pluronic F127, were investigated, with and without polyvinylpyrrolidone K30/Aerosol OT (PVP/AOT) present. The solubility in water was around 10nM for the compound, measured from nanocrystals, but 1000 times higher in 4% human serum albumin. The particles were physically stable during the time investigated. The zeta potential was around -30 and -10mV for DSPE-PEG2000 and Pluronic F127 stabilized particles, respectively, at the conditions selected. The dissolution rate was similar for all four formulations and similar to the theoretically predicted rate. Critical micelle concentrations were determined as 56nM and 1.4μM for DSPE-PEG2000 and Pluronic F127, respectively. The adsorption isotherms for the PEG lipid showed a maximum adsorbed amount of about 1.3mg/m 2 , with and without PVP/AOT. Pluronic F127 showed a higher maximum amount adsorbed, at around 3.1mg/m 2 , and marginally lower with PVP/AOT present. Calculated data showed that the layer of Pluronic F127 was thicker than the corresponding DSPE-PEG2000 layer. The total amount of particles distributed mainly to the liver, and the hepatocellular distribution in vitro (Liver sinusoidal endothelial cells and Kupffer cells), differed depending on the stabilizing mixture on the particles. Overall, DSPE-PEG2000 stabilized nanocrystals (with PVP/AOT) accumulated to a larger degree in the liver compared to particles with Pluronic F127 on the surface. A theoretical model was developed to interpret in vivo pharmacokinetic profiles, explaining the balance between dissolution and liver uptake. With the present, fundamental data of the nanocrystal formulations, the platform for forthcoming in vivo studies was settled., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, surfactant dioctyl sodium sulphosuccinate (DOSS)-mediated immobilized bacterial pretreatment of waste activated sludge (WAS) was experimentally proved to be an efficient and economically feasible process for enhancing the biodegradability of WAS. The maximal floc disruption with negligible cell cleavage was achieved at surfactant dosage of 0.009 g/g SS. Results of the outcome of bacterial pretreatment of sludge biomass revealed that chemical oxygen demand (COD) solubilization for deflocculated (EPS removed-bacterially pretreated) sludge was 20 %, which was higher than that of flocculated (14 %) or control (5 %). The pretreatment was swift in deflocculated sludge with a rate constant of about 0.064 h -1 . Biochemical methane potential (BMP) assay resulted in significant methane yield at 0.24 gCOD/gCOD for deflocculated sludge. Economic assessment of the proposed method showed a net profit of about 57.39 USD/ton of sludge.

Reverse micelles (RMs) made from water and sodium bis(2-ethylhexyl) sulfosuccinate (AOT) are commonly studied experimentally as models of aqueous microenvironments. They are small enough for individual RMs to also be studied by molecular dynamics (MD) simulation, which yields detailed insight into their structure and properties. Although RM size is determined by the water loading ratio (i.e., the molar ratio of water to AOT), experimental measurements of RM size are imprecise and inconsistent, which is problematic when seeking to understand the relationship between water loading ratio and RM size, and when designing models for study by MD simulation. Therefore, a systematic study of RM size was performed by MD simulation with the aims of determining the size of an RM for a given water loading ratio, and of reconciling the results with experimental measurements. Results for a water loading ratio of 7.5 indicate that the interaction energy between AOT anions and other system components is at a minimum when there are 62 AOT anions in each RM. The minimum is due to a combination of attractive and repulsive electrostatic interactions that vary with RM size and the dielectric effect of available water. Overall, the results agree with a detailed analysis of previously published experimental data over a wide range of water loading ratios, and help reconcile seemingly discrepant experimental results. In addition, water loss and gain from an RM is observed and the mechanism of water exchange is outlined. This kind of RM model, which faithfully reproduces experimental results, is essential for reliable insights into the properties of RM-encapsulated materials.

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 8 dialkyl sulfosuccinate salts for use in cosmetics, finding that these ingredients are safe in cosmetics in the present practices of use and concentration when formulated to be nonirritating. The dialkyl sulfosuccinate salts primarily function as surfactants in cosmetics. The Panel reviewed the new and existing available animal and clinical data in making its determination of safety. The Panel found it appropriate to extrapolate the data on diethylhexyl sodium sulfosuccinate to assess the safety of the entire group because all of the diesters are of a similar alkyl chain length, all are symmetrically substituted, and all have similar functions in cosmetic formulations., (© The Author(s) 2016.)

Targeted drug delivery systems are of special importance in cancer therapies, since serious side effects resulting from unspecific accumulation of highly toxic chemotherapeutics in healthy tissues can restrict effectiveness of the therapy. In this work we present the method of preparing biocompatible, polyelectrolyte nanoparticles containing the anticancer drug that may serve as a vehicle for passive tumor targeting. The nanoparticles were prepared via direct encapsulation of emulsion droplets in a polyelectrolyte multilayer shell. The oil cores that contained paclitaxel were stabilized by docusate sodium salt/poly-l-lysine surface complex (AOT/PLL) and were encapsulated in shells formed by the LbL adsorption of biocompatible polyelectrolytes, poly-L-glutamic acid (PGA) and PLL up to 5 or 6 layers. The surface of the nanoparticles was pegylated through the adsorption of the pegylated polyelectrolyte (PGA-g-PEG) as the outer layer to prolong the persistence of the nanocarriers in the circulation. The synthesized nanoparticles were stable in cell culture medium containing serum and their average size was 100nm, which makes them promising candidates for passive targeted drug delivery. This notion was further confirmed by the results of studying the biological effects of nanoformulations on two tumor cell lines: mouse colon carcinoma cell line CT26-CEA and the mouse mammary carcinoma cell line 4T1. The empty polyelectrolyte nanoparticles did not affect the viability of the tested cells, whereas encapsulated paclitaxel retained its strong cytotoxic/cytostatic activity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The present work reports the effect of confinement, and temperature therein, on the conformational fluctuation dynamics of domain-I of human serum albumin (HSA) by fluorescence correlation spectroscopy (FCS). The water-pool of a sodium bis(2-ethylhexyl)sulfosuccinate (AOT) reverse micelle has been used as the confined environment. It was observed that the conformational fluctuation time is about 6 times smaller compared to bulk medium when confined in a water-pool of 3.5 nm radius. On increasing the size of the water-pool the conformational fluctuation time was found to increase monotonically and approaches the bulk value. The effect of confinement is on par with the general belief about the restricted motion of a macromolecule upon confinement. However, the effect of temperature was found to be surprising. An increase in the temperature from 298 K to 313 K induces a larger change in the conformational fluctuation time in HSA, when confined. In the bulk medium, apparently there is no change in the conformational fluctuation time in the aforementioned temperature range, whereas, when HSA is present in an AOT water-pool of radius 3.5 nm, about an 88% increase in the fluctuation time was observed. The observed prominent thermal effect on the conformational dynamics of domain-I of HSA in the water-pool of an AOT reverse micelle as compared to in the bulk medium was concluded to arise from the confined solvent effect.

The present studies were aimed at formulating AZD2811-loaded polylactic acid-polyethylene glycol (PLA-PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading-up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer. Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not. A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved preclinical efficacy and tolerability data were generated for the pamoic acid lead formulation, which has been selected for evaluation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT 02579226). This work clearly demonstrates the importance of assessing a wide range of drug release rates during formulation screening as a critical step for new drug product development, and how utilizing hydrophobic ion pairing enabled this promising nanoparticle formulation to proceed into clinical development., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Keeping in view the role of neurotransmitters (NTs) in central nervous system diseases and in controlling various physiological processes, present study is aimed to study the binding of neurotransmitters (NTs) such as norepinephrine hydrochloride (NE) and serotonin hydrochloride (5-HT) with twin tailed surfactant sodium bis(2-ethylhexyl)sulfosuccinate (AOT). Spectroscopic and electrochemical measurements combined with microcalorimetric measurements were used to characterize the interactions between AOT and NTs. Meteoric modifications to emission profile and absorption spectra of NTs upon addition of AOT are indicative of the binding of NTs with AOT. Distinct interactional states such as formation of ion-pairs, induced and regular micelles with adsorbed NTs molecules have been observed in different concentration regimes of AOT. The formation of ion-pairs from oppositely charged NTs and AOT is confirmed by the reduced absorbance, quenched fluorescence intensity and decrease in peak current (ipa) as well as shifts in peak potential (Epa) values. The stoichiometry and formation of the NTs-AOT complexes has been judged and the extent of interactions is quantitatively discussed in terms of binding constant (K) and free energy of binding (ΔG°). The enthalpy (ΔH°mic) and free energy of micellization (ΔG°mic) for AOT in presence and absence of NTs are determined from the enthalpy curves., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hypothesis: Sodium dioctylsulfosuccinate (Aerosol OT or NaAOT) is a well-studied charging agent for model poly(methyl methacrylate) (PMMA) latexes dispersed in nonpolar alkane solvents. Despite this, few controlled variations have been made to the molecular structure. A series of counterion-exchanged analogs of NaAOT with other alkali metals (lithium, potassium, rubidium, and cesium) were prepared, and it was expected that this should influence the stabilization of charge on PMMA latexes and the properties of the inverse micelles., Experiments: The electrophoretic mobilities of PMMA latexes were measured for all the counterion-exchanged AOT analogs, and these values were used to calculate the electrokinetic or ζ potentials. This enabled a comparison of the efficacy of the different surfactants as charging agents. Small-angle scattering measurements (using neutrons and X-rays) were performed to determine the structure of the inverse micelles, and electrical conductivity measurements were performed to determine the ionized fractions and Debye lengths., Findings: Sodium AOT is a much more effective charging agent than any of the other alkali metal AOTs. Despite this, the inverse micelle size and electrical conductivity of NaAOT are unremarkable. This shows a significant non-periodicity in the charging efficiency of these surfactants, and it emphasizes that charging particles in nonpolar solvents is a complex phenomenon., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

In this computational study we present molecular dynamics (MD) simulations of reverse micelles, i.e. nano-scale water pools encapsulated by sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and dissolved in isooctane. Although consisting of highly polar components, such micro-emulsions exhibit surprisingly low dielectric permittivity, both static and frequency-dependent. This finding is well supported by experimental dielectric measurements. Furthermore, the computational dielectric spectra of reverse micelles with and without the polar protein ubiquitin are almost identical. A detailed component analysis of our simulated systems reveals the underlying mechanism of the observed dielectric depolarisation. While each component by itself would make a remarkable contribution to the static dielectric permittivity, mutual compensation leads to the observed marginal net result. This compensatory behavior is maintained for all but the highest frequencies. Dielectric model theory adapted to the peculiarities of reverse micelles provides an explanation: embedding a system in a cavity engulfed by a low dielectric medium automatically leads to depolarization. In this sense experiment, simulation and theory are in accordance.

A series of eight sodium sulfonic acid surfactants with differently branched tails (four double-chain sulfosuccinates and four triple-chain sulfocarballylates) were studied as charging agents for sterically stabilized poly(methyl methacrylate) (PMMA) latexes in dodecane. Tail branching was found to have no significant effect on the electrophoretic mobility of the latexes, but the number of tails was found to influence the electrophoretic mobility. Triple-chain, sulfocarballylate surfactants were found to be more effective. Several possible origins of this observation were explored by comparing sodium dioctylsulfosuccinate (AOT1) and sodium trioctylsulfocarballylate (TC1) using identical approaches: the inverse micelle size, the propensity for ion dissociation, the electrical conductivity, the electrokinetic or ζ potential, and contrast-variation small-angle neutron scattering. The most likely origin of the increased ability of TC1 to charge PMMA latexes is a larger number of inverse micelles. These experiments demonstrate a small molecular variation that can be made to influence the ability of surfactants to charge particles in nonpolar solvents, and modifying molecular structure is a promising approach to developing more effective charging agents.

Quantification of stabilizer content in microparticles and other products is of great importance for formulation development, drug product quality control as well as for reproducible manufacturing. A fast and sensitive HPLC method with evaporative light scattering detection (ELSD) capable of detecting docusate sodium (DOSS), poly (lactic-co-glycolic acid) (PLGA; Resomer RG 503 H) and R-1,2-dioleoyloxy-3-trimethylammonium-propane (DOTAP) in a single run was successfully developed. In contrast to previously described methods, hydrolysis of PLGA as pretreatment is not necessary, thereby enabling accurate quantification of stabilizer next to the intact matrix polymer. This method was used to investigate the impact of washing procedures of polymeric microparticles manufactured either with anionic stabilizer DOSS or with cationic stabilizer DOTAP. High amounts of DOSS were detected in the washing water. This finding was consistent with the result that no DOSS could be detected in the washed and dried microparticles (

The propensity of peptides to form α-helices has been intensely studied using theory, computation, and experiment. Important model peptides for the study of the coil-to-helix transition have been alanine-lysine (AKA) peptides in which the lysine residues are placed on opposite sides of the helix avoiding charge repulsion while enhancing solubility. In this study, the effects of capped versus zwitterionic peptide termini on the secondary structure of alanine-rich peptides in reverse micelles are explored. The reverse micelles are found to undergo substantial shape fluctuations, a property observed in previous studies of AOT reverse micelles in the absence of solvated peptide. The peptides are observed to interact with water, as well as the AOT surfactant, including interactions between the nonpolar residues and the aliphatic surfactant tails. Computation of IR spectra for the amide I band of the peptide allows for direct comparison with experimental spectra. The results demonstrate that capped AKA2 peptides form more stable α helices than zwitterionic AKA2 peptides in reverse micelles. The rotational anisotropy decay of water is found to be distinctly different in the presence or absence of peptide within the reverse micelle, suggesting that the introduction of peptide significantly alters the number of free waters within the reverse micelle nanopool. However, neither the nature of the peptide termini (capped or charged) nor the degree of peptide helicity is found to significantly alter the balance of interactions between the peptides and the environment. Observed changes in the degree of helicity in AKA2 peptides in bulk solution and in reverse micelle environments result from changes in peptide confinement and hydration as well as direct nonpolar and polar interactions with the water-surfactant interface.

The use of polymeric nanoparticles (NPs) in pharmacology provides many benefits because this approach can increase the efficacy and selectivity of active compounds. However, development of new nanocarriers requires better understanding of the interactions between NPs and the immune system, allowing for the optimization of NP properties for effective drug delivery. Therefore, in the present study, we focused on the investigation of the interactions between biocompatible polymeric NPs and a murine macrophage cell line (RAW 264.7) and a human monocytic leukemia cell line (THP-1). NPs based on a liquid core with polyelectrolyte shells were prepared by sequential adsorption of polyelectrolytes (LbL) using AOT (docusate sodium salt) as the emulsifier and the biocompatible polyelectrolytes polyanion PGA (poly-l-glutamic acid sodium salt) and polycation PLL (poly l-lysine). The average size of the obtained NPs was 80 nm. Pegylated external layers were prepared using PGA-g-PEG (PGA grafted by PEG poly(ethylene glycol)). The influence of the physicochemical properties of the NPs (charge, size, surface modification) on viability, phagocytosis potential, and endocytosis was studied. Internalization of NPs was determined by flow cytometry and confocal microscopy. Moreover, we evaluated whether addition of PEG chains downregulates particle uptake by phagocytic cells. The presented results confirm that the obtained PEG-grafted NPs are promising candidates for drug delivery.

Ionic liquid active pharmaceutical ingredients (IL APIs) are novel materials in which the ions themselves are APIs, but the pure salt is a liquid under ambient conditions. It has been found that IL APIs can have superior performance relative to their conventional salt analogues, but the mechanism for this is unclear. We have used molecular simulations to estimate the aqueous phase association constants of the IL API lidocainium docusate and their sodium and chloride counterparts. Lidocainium is the cationic form of lidocaine, a local anesthetic, while the docusate anion is an emollient. From strongest to weakest, the calculated association constants are 10.1 M(-1) (lidocainium docusate); 0.77 M(-1) (sodium chloride); 0.086 M(-1) (sodium docusate); and 0.065 M(-1) (lidocainium chloride). These results suggest that the experimentally observed enhanced efficacy of lidocainium docusate relative to the traditional drug formulation as a lidocaine hydrochloride salt could result from association of the ions in aqueous solution and at the cell membrane, leading to a synergistic activity effect.

Proton-transfer kinetics in both ionic and neutral reverse micelles were studied by time-correlated single-photon counting investigations of the fluorescent photoacid 8-hydroxypyrene-1,3,6-trisulfonate (HPTS). Orientational dynamics of dissolved probe molecules in the water pools of the reverse micelles were also investigated by time-dependent fluorescence anisotropy measurements of MPTS, the methoxy derivative of HPTS. These experiments were compared to the same experiments in bulk water. It was found that in ionic reverse micelles (surfactant Aerosol OT, AOT), orientational motion (fluorescence anisotropy decay) of MPTS was relatively unhindered, consistent with MPTS being located in the water core of the reverse micelle away from the water-surfactant interface. In nonionic reverse micelles (surfactant Igepal CO-520, Igepal), however, orientational anisotropy displayed a slow multiexponential decay consistent with wobbling-in-a-cone behavior, indicating MPTS is located at the water-surfactant interface. HPTS proton transfer in ionic reverse micelles followed kinetics qualitatively like those in bulk water, albeit slower, with the long-time power law time dependence associated with recombination of the proton with the dissociated photoacid, suggesting a modified diffusion-controlled process. However, the power law exponents in the ionic reverse micelles are smaller (∼ -0.55) than that in bulk water (-1.1). In neutral reverse micelles, proton-transfer kinetics did not show discernible power law behavior and were best represented by a two-component model with one relatively waterlike population and a population with a faster fluorescence lifetime and negligible proton transfer. We explain the Igepal results on the basis of close association between the probe and the neutral water-surfactant interface, with the probe experiencing a distribution of more and less waterlike environments. In addition, the observation in bulk water of a power law t(-1.1) for diffusion-controlled recombination is in contrast to the theoretical prediction of t(-1.5) and previously reported observations. The difference from prior experimental results is discussed.

Presented paper is a continuation of our studies on morin interaction with AOT (sodium bis(2-ethylhexyl) sulfosuccinate) reversed micelles solutions in two solvents: ethanol and n-decanol. Now we focused on morin influence on size and diffusion phenomena in the system morin/solvent/AOT/water. In this paper precise measurements of dynamic light scattering (DLS) of the effects of temperature, solvents (alcohols), water on the size and diffusion of AOT reversed micelles in the morin/AOT/alcohol/water system are reported. The concentrations of AOT were varied from 0.51 to 0.78mol/L. Morin concentration in during auto-correlation function registration was not the same in each solvent because of its different solubility depending on the solvent. Water concentration in the studied systems was defined by R parameter according to relation: R=(H2O)/(AOT) and was equal 0 and 30 in ethanol, and 0 in n-decanol. DLS measurements were done at 298.15 and 308.15K. DLS experiment involved on detection two relaxation modes (fast and slow) in the systems containing AOT reversed micelles, water, morin and solvents (ethanol and n-decanol). The DLS data clearly show the solvent influence as well as morin presence on AOT reversed micelles size and consequently their diffusion coefficients. Contrary to n-decanol strong competition between morin and ethanol molecules in AOT reversed micelles palisade layer has been found. It suggests that morin molecules replaced ethanol in AOT reversed micelles and locate in their palisade layer strongly increasing AOT reversed micelles size. Furthermore, it was found a sharp increase in correlation radii of slow modes of AOT reversed micelles containing morin molecules and their diffusion coefficients diminishing., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Infection is a common problem in trauma and orthopaedic surgery. Antibiotic-loaded biomaterials are used locally to clear infections as an adjunct to systemic antibiotics. Gentamicin-sulphate (GEN-SULPH) is commonly used in antibiotic-loaded biomaterials, although it displays high water solubility resulting in quick diffusion from the carrier., Objective: Preparation of a lipophilic derivative of gentamicin to reduce solubility and obtain a slower release. Subsequently, entrapment of this lipophilic gentamicin within poly(trimethylene carbonate) (PTMC) matrices., Methods: Hydrophobic ion-pairing was used to prepare lipophilic gentamicin (GEN-AOT). The susceptibility of Staphylococcus aureus NCTC 12973 and Staphylococcus epidermidis 103.1 for GEN-AOT was tested and the viability of fibroblasts upon exposure to GEN-AOT was assessed. GEN-AOT was then loaded into PTMC films., Results: GEN-AOT was successfully prepared as confirmed by FTIR-spectroscopy. GEN-AOT was bactericidal for S. epidermidis and S. aureus at 0.5 μM and 8.5 μM, respectively. At 1.1 μM GEN-AOT no reduction in fibroblast viability was observed. At 11 μM the reduction was ∼50% . PTMC discs loaded with GEN-AOT were prepared by compression molding., Conclusions: Lipophilic GEN-AOT was at least as potent as GEN-SULPH. For S. epidermidis it was even more potent than GEN-SULPH. More than 50% fibroblast cell viability was maintained at bactericidal concentration for both bacterial strains.