Evaluation of in vitro SARS-CoV-2 inactivation by a new quaternary ammonium compound: Bromiphen bromide.

The pneumonia (COVID-19) outbreak caused by the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which unpredictably exploded in late December of 2019 has stressed the importance of being able to control potential pathogens with the aim of limiting their spread. Although vaccines are well known as a powerful tool for ensuring public health and controlling the pandemic, disinfection and hygiene habits remain crucial to prevent infection from spreading and maintain the barrier, especially when the microorganism can persist and survive on textiles, surfaces, and medical devices. During the coronavirus disease pandemic, around half of the disinfectants authorized by the US Environmental Protection Agency contained quaternary ammonium compounds (QACs); their effectiveness had not been proven. Herein, the in vitro SARS-CoV-2 inactivation by p-bromodomiphen bromide, namely bromiphen (BRO), a new, potent, and fast-acting QAC is reported. This study demonstrates that BRO, with a dose as low as 0.02%, can completely inhibit SARS-CoV-2 replication in just 30 s. Its virucidal activity was 10- and 100-fold more robust compared to other commercially available QACs, namely domiphen bromide and benzalkonium chloride. The critical micellar concentration and the molecular lipophilicity potential surface area support the relevance of the lipophilic nature of these molecules for their activity.

Traditional Chinese medicine: saponins, critical micellar concentrations and partition coefficients.

INTRODUCTION: Traditional Chinese medicine (TCM) revolves around complex mixtures bound to specific roles within the formulation, among which saponin-containing plants with alleged properties of harmonising or detoxifying other compounds present in the preparations. OBJECTIVE: This article deals with the study of these interactions with, as a model, the interaction between saponins and selected active principles. METHODS: The measurement of the partition coefficient between water and octanol (logP) was used as an indicator and determined by nuclear magnetic resonance (NMR) for these active principles in the presence of saponins. For each compound, a graph was constructed showing the evolution of logP with increasing concentrations of saponins. RESULTS: Four distinct patterns of interactions were distinguished. Pattern A showed a constant decrease of logP, pattern B showed a decrease followed by a plateau, in pattern C the logP did not vary until the critical micellar concentration (CMC) and decreased afterwards, and pattern D exhibited an increase of logP. These properties were linked to the ability of saponins to form micelles in water once the CMC is reached. The interaction of aconitine and saponins followed pattern D, thus explaining the detoxification of herbal preparations using Aconitum with licorice. The licorice facilitated the extraction of the notoriously water-insoluble artemisinin from Artemisia annua. CONCLUSION: This investigation confirms that the physical properties of micelle forming saponins are intimately linked to a modification of behaviour of the other molecules in solution, as seen with the alteration of logP and the four types of interactions presented.

Self-Association of the Anion of 7-Oxodeoxycholic Acid (Bile Salt): How Secondary Micelles Are Formed.

Bile acid anions are steroidal biosurfactants that form primary micelles due to the hydrophobic effect. At higher concentrations of some bile acid anions, secondary micelles are formed; hydrogen bonds connect primary micelles. Monoketo derivatives of cholic acid, which have reduced membrane toxicity, are important for biopharmaceutical examinations. The main goal is to explain why the processes of formation of primary and secondary micelles are separated from each other, i.e., why secondary micelles do not form parallel to primary micelles. The association of the anion of 7-oxodeoxycholic acid (a monoketo derivative of cholic acid) is observed through the dependence of the spin-lattice relaxation time on total surfactant concentration T1 = f(CT). On the function T1 = f(CT), two sharp jumps of the spin-lattice relaxation time are obtained, i.e., two critical micellar concentrations (CMC). The aggregation number of the micelle at 50 mM total concentration of 7-oxodeoxycholic acid anions in the aqueous solution is 4.2 ± 0.3, while at the total concentration of 100 mM the aggregation number is 9.0 ± 0.9. The aggregation number of the micelle changes abruptly in the concentration interval of 80-90 mM (the aggregation number determined using fluorescence measurements). By applying Le Chatelier's principle, the new mechanism of formation of secondary micelles is given, and the decoupling of the process of formation of primary and secondary micelles at lower concentrations of monomers (around the first critical micellar concentration) and the coupling of the same processes at higher equilibrium concentrations of monomers (around the second critical micellar concentration) is explained. Stereochemically and thermodynamically, a direct mutual association of primary micelles is less likely, but monomeric units are more likely to be attached to primary micelles, i.e., 7-oxodeoxycholic acid anions.

Effect of 1,2-propanediol on the Critical Micelle Concentration of Decyltrimethylammonium Bromide at Temperatures from 293.15 K to 308.15 K.

It is well known that polar organic compounds, such as alcohols and polyols, exert an appreciable influence on water structure and thus have important effects on surfactant micellization. These substances are often used to modify the properties of surfactants in aqueous solutions, increasing the practical applications they have in diverse industries. In this work, the critical micelle concentration (CMC) of decyltrimethylammonium bromide (C10TAB) in water and in 1,2-propanediol aqueous solutions was determined from both sound velocity and surface tension measurements as a function of surfactant concentration in the temperature range of (293.15 to 308.15) K. The critical micelle concentration of the surfactant increases as the concentration of 1,2-propanediol becomes higher, while the effect on temperature does not show important changes within the range considered. At the selected temperatures, the standard thermodynamic parameters of micellization suggests that the addition of 1,2-propanediol makes the micellization process less favorable. Thermodynamic analysis suggests that the micelle formation of C10TAB is an entropy-driven process at the temperatures considered in this study.

Wide-Antimicrobial Spectrum of Picolinium Salts.

Nosocomial infections, which greatly increase morbidity among hospitalized patients, together with growing antibiotic resistance still encourage many researchers to search for novel antimicrobial compounds. Picolinium salts with different lengths of alkyl chains (C12, C14, C16) were prepared by Menshutkin-like reaction and evaluated with respect to their biological activity, i.e., lipophilicity and critical micellar concentration. Picolinium salts with C14 and C16 side chains achieved similar or even better results when in terms of antimicrobial efficacy than benzalkoniums; notably, their fungicidal efficiency was substantially more potent. The position of the methyl substituent on the aromatic ring does not seem to affect antimicrobial activity, in contrast to the effect of length of the N-alkyl chain. Concurrently, picolinium salts exhibited satisfactory low cytotoxicity against mammalian cells, i.e., lower than that of benzalkonium compounds, which are considered as safe.

Effect of self-assembly on antimicrobial activity of double-chain short cationic lipopeptides.

Short cationic antimicrobial lipopeptides with surfactant-like structure are promising antibiotic candidates that preferentially target microbial membranes. Therefore, we focused our study on double-chain lipopeptides, (C10-16)2Dab-KKK-NH2 and (C10-16)2Dap-KKK-NH2, where Dab and Dap are 2,4-diaminobutyric and 2,3-diaminopropionic acids, respectively. We tried to answer a question how the self-assembly behaviour affects biological activities of the tested compounds. The subject compounds were synthesized by solid-phase method and screened for their antimicrobial and haemolytic activities. Cytotoxicity tests on human keratinocytes were carried out for the most promising lipopeptides. Self-assembly properties were evaluated by both experimental and theoretical methods. Interactions with membrane models were examined using the ITC and FTIR techniques. All the lipopeptides studied showed the tendency to self-assembly in solution, and this behaviour was affected by the length of the hydrocarbon chains. Acyl chain elongation supported the formation of the bilayer structure and deprived the lipopeptides of antimicrobial activity. A multi-step mechanism of interaction with a negatively charged membrane was observed for the short-chain lipopeptides, indicating other processes accompanying the binding process. Short-chain lipopeptides were able to penetrate into the liposome's interior and/or cause the rupture of the liposome, this being compatible with their high antimicrobial activity.

Effect of Molecular Composition of Head Group and Temperature on Micellar Properties of Ionic Surfactants with C12 Alkyl Chain.

The paper analyses influences of the temperature and hydrophilic groups on micellar properties of ionic surfactants with 12-carbonic hydrophobic chains. The aim is to assess the impact of hydrophilic groups and temperature on thermodynamic parameters and micellization. This knowledge is indispensable for the formulation of new dosage forms. The method uses conductometric measurements. The following hydrophilic groups are analyzed: trimethylammonium bromide, trimethylammonium chloride, ethyldimethylammonium bromide, didodecyldimethylammonium bromide, pyridinium chloride, benzyldimethyl-ammonium chloride, methylephedrinium bromide, cis and trans-[(2-benzyloxy)-cyclohexyl-methyl]-N, N-dimethylammonium bromide, sodium sulphate and lithium sulphate. Except for a few cases, there is a good agreement between values of critical micellar concentrations (CMC) and critical vesicle concentration (CVC) obtained here and those which were obtained by other authors and/or by other physicochemical methods. Values of the CMC are compared with respect to the molar masses of hydrophilic groups. It was found that CMC values increased non-linearly with increasing system temperature. The degrees of counterion binding and thermodynamic parameters, like the standard molar Gibbs energy, enthalpy and entropy of micellization are determined and discussed in detail. The results obtained will be incorporated into in silico processes of modeling and design of optimal dosage forms, a current interdisciplinary research focus of the team.

Micellar Aggregation Behavior of Alkylaryl Sulfonate Surfactants for Enhanced Oil Recovery.

Alkylaryl sulfonate is a typical family of surfactants used for chemically enhanced oil recovery (EOR). While it has been widely used in surfactant-polymer flooding at Karamay Oilfield (40 °C, salinity 14,000 mg/L), its aggregation behavior in aqueous solutions and the contribution of aggregation to EOR have not been investigated so far. In this study, raw naphthenic arylsulfonate (NAS) and its purified derivatives, alkylaryl monosulfonate (AMS) and alkylaryl disulfonate (ADS), were examined under simulated temperature and salinity environment of Karamay reservoirs for their micellar aggregation behavior through measuring surface tension, micellar size, and micellar aggregation number. It was found that all three alkylaryl sulfonate surfactants could significantly lower the surface tension of their aqueous solutions. Also, it has been noted that an elevation both in temperature and salinity reduced the surface tension and critical micellar concentration. The results promote understanding of the performance of NAS and screening surfactants in EOR.

Surfactant properties of humic acids extracted from volcanic soils and their applicability in mineral flotation processes.

Surface Tension (ST) of water solutions of humic acids extracted from volcanic ash derived soils (soil humic acids, S-HA), were measured under controlled conditions of pH (13.0), temperature (25 °C) and ionic strength (NaOH 0.1M) to establish the Critical Micellar Concentration (CMC). All S-HA were characterized by elemental analysis, acid-base titration, Transmission Electronic Microscopy (TEM) micrographs, isoelectric point (IEP) and solid state 13C-NMR. After that, these humic acids were evaluated as potential biomaterials to be used in mineral flotation processes, where a series of experiments were conducted at different S-HA and molybdenite ratio (from 0.2 to 50 g ton-1) establishing the IEP of all resultant materials. The use of solid state 13C-NMR enabled the following sequence of intensity distribution areas of S-HA to be established: O/N Alkyl>Alkyl C>Aromatic C>Carboxyl. The experimental values of ST and the calculated CMC (ranging from 0.8 to 3.3 g L-1) revealed that for S-HA no relationship between the abundance groups and their behavior as surfactant materials was observed. In relation with IEP determined for all materials, the highest surface charge, which can be useful for flotation processes, was obtained with 0.2 g of S-HA per ton of molybdenite. Additionally, TEM studies confirm the formation of pseudoaggregates for all the S-HA considered. Finally, the S-HA could be considered as an alternative to chemical products and commercial humic acids materials in mineral flotation processes.

Determination of Critical Micellar Concentration of Homologous 2-Alkoxyphenylcarbamoyloxyethyl-Morpholinium Chlorides.

The critical micellar concentrations of selected alkyloxy homologues of local anesthetic 4-(2-{[(2-alkoxyphenyl)carbamoyl]oxy}ethyl)morpholin-4-ium chloride with nc = 2, 4, 5, 6, 7, 8, and 9 carbons in alkyloxy tail were determined by absorption spectroscopy in the UV⁻vis spectral region with the use of a pyrene probe. Within the homologous series of the studied amphiphilic compounds, the ln(cmc) was observed to be dependent linearly on the number of carbon atoms nc in the hydrophobic tail: ln(cmc) = 0.705⁻0.966 nc. The Gibbs free energy, necessary for the transfer of the methylene group of the alkoxy chain from the water phase into the inner part of the micelle at the temperature of 25 °C and pH ≈ 4.5⁻5.0, was found to be −2.39 kJ/mol. The experimentally determined cmc values showed good correlations with the predicted values of the bulkiness of the alkoxy tail expressed as the molar volume of substituent R, as well as with the surface tension of the compounds.

Clear, Aqueous Topical Drop of Triamcinolone Acetonide.

The objective of this study was to develop a clear aqueous mixed nanomicellar formulation (NMF) of triamcinolone acetonide (TA) with a combination of nonionic surfactant hydrogenated castor oil 60 (HCO-60) and octoxynol-40 (Oc-40). In order to delineate the effects of drug-polymer interactions on entrapment efficiency (EE), loading efficiency (LE), and critical micellar concentration (CMC), a design of experiment (DOE) was performed to optimize the formulation. In this study, full-factorial design has been used with HCO-60 and OC-40 as independent variables. All formulations were prepared following solvent evaporation and film rehydration method, characterized with size, polydispersity, shape, morphology, EE, LE, and CMC. A specific blend of HCO-60 and Oc-40 at a particular wt% ratio (5:1.5) produced highest drug EE, LE, and smallest CMC (0.0216 wt%). Solubility of TA in NMF improved 20 times relative to normal aqueous solubility. Qualitative 1H NMR studies confirmed the absence of free drug in the outer aqueous NMF medium. Moreover, TA-loaded NMF appeared to be highly stable and well tolerated on human corneal epithelial cells (HCEC) and human retinal pigment epithelial cells (D407 cells). Overall, these studies suggest that TA in NMF is safe and suitable for human topical ocular drop application.

Hydrophobic tail length plays a pivotal role in amyloid beta (25-35) fibril-surfactant interactions.

The amyloid ß-peptide fragment comprising residues 25-35 (Aß25-35 ) is known to be the most toxic fragment of the full length Aß peptide which undergoes fibrillation very rapidly. In the present work, we have investigated the effects of the micellar environment (cationic, anionic, and nonionic) on preformed Aß25-35 fibrils. The amyloid fibrils have been prepared and characterized by several biophysical and microscopic techniques. Effects of cationic dodecyl trimethyl ammonium bromide (DTAB), cetyl trimethylammonium bromide (CTAB), anionic sodium dodecyl sulfate (SDS), and nonionic polyoxyethyleneoctyl phenyl ether (Triton X-100 or TX) on fibrils have been studied by Thioflavin T fluorescence, UV-vis spectroscopy based turbidity assay and microscopic analyses. Interestingly, DTAB and SDS micelles were observed to disintegrate prepared fibrils to some extent irrespective of their charges. CTAB micelles were found to break down the fibrillar assembly to a greater extent. On the other hand, the nonionic surfactant TX was found to trigger the fibrillation process. The presence of a longer hydrophobic tail in case of CTAB is assumed to be a reason for its higher fibril disaggregating efficacy, the premise of their formation being largely attributed to hydrophobic interactions. Proteins 2016; 84:1213-1223. © 2016 Wiley Periodicals, Inc.

Importance of critical micellar concentration for the prediction of solubility enhancement in biorelevant media.

This study evaluated if the intrinsic surface properties of compounds are related to the solubility enhancement (SE) typically observed in biorelevant media like fasted state simulated intestinal fluids (FaSSIF). The solubility of 51 chemically diverse compounds was measured in FaSSIF and in phosphate buffer and the surface activity parameters were determined. This study showed that the compound critical micellar concentration parameter (CMC) correlates strongly with the solubility enhancement (SE) observed in FaSSIF compared to phosphate buffer. Thus, the intrinsic capacity of molecules to form micelles is also a determinant for each compound's affinity to the micelles of biorelevant surfactants. CMC correlated better with SE than lipophilicity (logD), especially over the logD range typically covered by drugs (2 < logD < 4). CMC can become useful to guide drug discovery scientists to better diagnose, improve, and predict solubility in biorelevant media, thereby enhancing oral bioavailability of drug candidates.

Envisioning the Future: Nanomicelles Revolutionizing Ocular Drug Delivery.

Due to the complexities of the eye's anatomy and physiology, achieving targeted drug delivery with minimal harm to healthy eye tissues has proven to be difficult. The focus of the review is on the potential of lipid and polymer micelle-based drug delivery systems, specifically nanomicelles, to overcome these challenges and improve the absorption of insoluble drugs. Nanomicelles offer several advantages, such as enhanced drug release kinetics, increased drug incorporation, and improved formulation of hydrophobic medicines. The review provides insights into various excipients, preparation methods, and evaluation techniques used in nanomicellar-based drug delivery systems. Furthermore, the review highlights current research and patents related to nanomicelles in ocular drug delivery, suggesting growing interest and potential for future developments in this field. Nanomicelles present a promising approach that may revolutionize ocular drug delivery and open new possibilities for treating various ocular diseases while minimizing adverse effects on healthy eye tissues.

Small-angle X-ray scattering unveils the internal structure of lipid nanoparticles.

Lipid nanoparticles own a remarkable potential in nanomedicine, only partially disclosed. While the clinical use of liposomes and cationic lipid-nucleic acid complexes is well-established, liquid lipid nanoparticles (nanoemulsions), solid lipid nanoparticles, and nanostructured lipid carriers have even greater possibilities. However, they face obstacles in being used in clinics due to a lack of understanding about the molecular mechanisms controlling their drug loading and release, interactions with the biological environment (such as the protein corona), and shelf-life stability. To create effective drug delivery carriers and successfully translate bench research to clinical settings, it is crucial to have a thorough understanding of the internal structure of lipid nanoparticles. Through synchrotron small-angle X-ray scattering experiments, we determined the spatial distribution and internal structure of the nanoparticles' lipid, surfactant, and the bound water in them. The nanoparticles themselves have a barrel-like shape that consists of coplanar lipid platelets (specifically cetyl palmitate) that are covered by loosely spaced polysorbate 80 surfactant molecules, whose polar heads retain a large amount of bound water. To reduce the interface cost of bound water with unbound water without stacking, the platelets collapse onto each other. This internal structure challenges the classical core-shell model typically used to describe solid lipid nanoparticles and could play a significant role in drug loading and release, biological fluid interaction, and nanoparticle stability, making our findings valuable for the rational design of lipid-based nanoparticles.

Factors affecting the viscosity of sodium hypochlorite and their effect on irrigant flow.

AIM: To assess the influence of concentration, temperature and surfactant addition to a sodium hypochlorite solution on its dynamic viscosity and to calculate the corresponding Reynolds number to determine the corresponding flow regimen. METHODOLOGY: The dynamic viscosity of the irrigant was assessed using a rotational viscometer. Sodium hypochlorite with concentrations ranging from 0.6% to 9.6% was tested at 37 and 22 °C. A wide range of concentrations of three different surfactants was mixed in 2.4% sodium hypochlorite for viscosity measurements. The Reynolds number was calculated under each condition. Data were analysed using two-way anova. RESULTS: There was a significant influence of sodium hypochlorite concentration (P < 0.001) and temperature (P < 0.001) on dynamic viscosity: the latter significantly increased with sodium hypochlorite concentration and decreased with temperature. A significant influence of surfactant concentration on dynamic viscosity (P < 0.001) occurred, especially for high surfactant concentrations: 6.25% for benzalkonium chloride, 15% for Tween 80 and 6.25% for Triton X-100. Reynolds number values calculated for a given flow rate (0.14 mL s(-1)), and root canal diameter (sizes 45 and 70) clearly qualified the irrigant flow regimen as laminar. CONCLUSIONS: Dynamic viscosity increased with sodium hypochlorite and surfactant concentration but decreased with temperature. Under clinical conditions, all viscosities measured led to laminar flow. The transition between laminar and turbulent flow may be reached by modifying different parameters at the same time: increasing flow rate and temperature whilst decreasing irrigant viscosity by adding surfactants with a high value of critical micellar concentration.

Basic principles for biosurfactant-assisted (bio)remediation of soils contaminated by heavy metals and petroleum hydrocarbons - A critical evaluation of the performance of rhamnolipids.

Despite the fact that rhamnolipids are among the most studied biosurfactants, there are still several gaps which must be filled. The aim of this review is to emphasize and to indicate which issues should be taken into account in order to achieve efficient rhamnolipids-assisted biodegradation or phytoextraction of soils contaminated by heavy metals and petroleum hydrocarbons without harmful side effects. Four main topics have been elucidated in the review: effective concentration of rhamnolipids in soil, their potential phytotoxicity, susceptibility to biodegradation and interaction with soil microorganisms. The discussed elements are often closely associated and often overlap, thus making the interpretation of research results all the more challenging. Each dedicated section of this review includes a description of potential issues and questions, an explanation of the background and rationale for each problem, analysis of relevant literature reports and a short summary with possible application guidelines. The main conclusion is that there is a necessity to establish regulations regarding effective concentrations for rhamnolipids-assisted remediation of soil. The use of an improper concentration is the direct cause of all the other discussed phenomena.

Determining suitable surfactant concentration ranges to avoid protein unfolding in pharmaceutical formulations using UV analysis.

Protein stability is fundamental to maintain pharmaceutical efficacy in the nascent field of biologics. One particular property that is essential for therapeutic effect is retention of the folded 3-dimensional conformation, i.e. once unfolding has occurred the biologic is often rendered inactive. In this work we propose a modified form of a recently published UV spectroscopic method that identifies protein unfolding. In this study we determine concentration limits to avoid protein unfolding of two model surfactants, namely polysorbate 20 and polysorbate 80, by correlating surfactant concentration with percentage 'unfolded' for three model proteins. For each scenario two distinct regions were observed, firstly surfactant concentrations at which no unfolding had occurred, followed by a second region whereby unfolding steadily increased with surfactant concentration. In general for the combinations analysed in this study, this second region began to appear around ten times below the critical micellar concentration of each surfactant, regardless of the protein or polysorbate chosen. It is therefore proposed that this adapted method could be used by researchers in the early stages of formulation development as a convenient and simple screening tool to confirm the 'onset of unfolding' concentration for protein-surfactant formulations, thus helping to optimise surfactant concentration selection in pharmaceutical formulations to maintain the benefits of surfactants yet avoid inadvertent unfolding.

Effect of antidiabetic drug metformin hydrochloride on micellization behavior of cetylpyridinium bromide in aqueous solution.

Herein, the interaction of an antidiabetic drug, metformin hydrochloride (MHCl), and a cationic surfactant, cetylpyridinium bromide (CPB) is investigated in an aqueous medium. The critical micellar concentration (CMC) of CPB is estimated through conductivity experiments and found to be reduced on adding MHCl and further decreased in the presence of NaCl. The reduced CMC is attributed to the solubilization of MHCl by CPB through micellization and the micellization is found to be thermodynamically spontaneous that experiences an augmentation in the presence of NaCl. This is identified from the negative value of standard free energy (ΔG0m). The higher negative value of ΔG0m (-55.41 kJ mol-1) for CPB + MHCl + NaCl than CPB (-37.89 kJ mol-1) and CPB + MHCl (-34.08 kJ mol-1) is suggestive of the above phenomenon. The positive values of ΔS0m in all three cases confirm that the micellization is entropy driven. The binding of MHCl on CPB is quantified by estimating binding constant using the Benesi-Hildebrand (B-H) plot through UV-visible spectral methods. The binding constant values were calculated to be 2.70 M-1 for CPB + MHCl + NaCl compared to 1.258 M-1 for CPB + MHCl predicting a favoring of micellization in the presence of NaCl which is higher than that in the presence of co-solvents. The molecular interaction of MHCl and CPB is justified using FT-IR and NMR techniques. The surface properties of drug surfactant interactions are assessed using SEM techniques. The point of interaction between the drug and surfactant is visualized through the molecular docking approach. The results suggest that CPB would be an effective solubilizer for developing MHCl drug formulations.Communicated by Ramaswamy H. Sarma.

Binary Polymeric Surfactant Mixtures for the Development of Novel Loteprednol Etabonate Nanomicellar Eyedrops.

The treatment of several ocular inflammatory conditions affecting different areas of the ocular globe involves the administration of topical ophthalmic formulations containing corticosteroids. This research was aimed at evaluating the solubilising efficacy of 5.0% w/w of different binary mixtures of commercial amphiphilic polymeric surfactants with the purpose of obtaining nanomicellar solutions containing a high amount of loteprednol etabonate (LE). The selected LE-TPGS/HS nanomicelles, containing 0.253 mg/mL of the drug, had a small size (=13.57 nm) and uniform distribution (Polydispersity Index = 0.271), appeared completely transparent and perfectly filterable through 0.2 µm membrane filter, and remained stable up to 30 days at 4 °C. The critical micellar concentration (CMCTPGS/HS) was 0.0983 mM and the negative value of the interaction parameter between the polymeric-surfactant-building unit (ßTPGS/HS = -0.1322) confirmed the ability of the polymeric surfactants to interact, favouring the dissolution of LE into nanomicelles. The disappearance of the endothermic peak of LE in the DSC analysis confirmed the interactions of LE with the polymeric surfactants. LE-TPGS/HS produced in vitro LE which sustained diffusion for 44 h (more than 40% of encapsulated LE). Furthermore, the lack of a significant cytotoxic effect on a sensitive corneal epithelial cell line makes it a candidate for further biological studies.