New Candidate Preservative in Ophthalmic Solution Instead of Benzalkonium Chloride: 1,3-Didecyl-2-methyl Imidazolium Chloride.

Benzalkonium chloride (BAC) is a useful preservative for ophthalmic solutions but has some disadvantageous effects on corneal epithelium, especially keratinocytes. Therefore, patients requiring the chronic administration of ophthalmic solutions may suffer from damage due to BAC, and ophthalmic solutions with a new preservative instead of BAC are desired. To resolve the above situation, we focused on 1,3-didecyl-2-methyl imidazolium chloride (DiMI). As a preservative for ophthalmic solutions, we evaluated the physical and chemical properties (absorption to a sterile filter, solubility, heat stress stability, and light/UV stress stability), and also the anti-microbial activity. The results indicated that DiMI was soluble enough to prepare ophthalmic solutions, and was stable under severe heat and light/UV conditions. In addition, the anti-microbial effect of DiMI as a preservative was considered to be stronger than BAC. Moreover, our in vitro toxicity tests suggested that DiMI is safer to humans than BAC. Considering the test results, DiMI may be an excellent candidate for a new preservative to replace BAC. If we can overcome manufacturing process issues (soluble time and flushing volume) and the insufficiency of toxicological information, DiMI may be widely adopted as a safe preservative, and immediately contribute to the increased well-being of all patients.

Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: Effect on cultured human conjunctival goblet cells and their physicochemical properties.

PURPOSE: To investigate the effect of polyquaternium-1 (PQ)-preserved and benzalkonium chloride (BAK)-preserved travoprost eye drops on viability of primary human conjunctival goblet cell (GC) cultures and on secretion of mucin and cytokines. Furthermore, to evaluate the physicochemical properties of the branded travoprost eye drop Travatan® and available generics. METHODS: The effect of travoprost eye drops was evaluated on GC cultures. Cell viability was assessed through lactate dehydrogenase (LDH) and tetrazolium dye (MTT) colorimetric assays. Mucin secretion was evaluated by immunohistochemical staining. Secretion of interleukin (IL)-6 and IL-8 was measured using BD Cytometric Bead Arrays. pH, viscosity, droplet mass, osmolality and surface tension were measured for all included eye drops. RESULTS: In the LDH assay, BAK travoprost caused significant GC loss after 2 hrs of incubation compared to the control. PQ travoprost caused no GC loss at any time point. Both PQ- and BAK travoprost caused secretion of mucin to the cytoplasma. No difference in IL-6 and IL-8 secretion was identified compared to controls. The pH values for the generics were lower (pH 6.0) than the pH value for Travatan (pH 6.7; p < 0.0001). The viscosity was lowest for Travatan, while the mean droplet mass was higher for Travatan (35 mg) than the generics (28-30 mg; p ≤ 0.0318). The osmolality and surface tension did not differ between the eye drops investigated. CONCLUSION: BAK travoprost caused GC loss, indicating that PQ preservation may be preferable in treatment of glaucoma. Furthermore, physicochemical properties of branded and generic travoprost eye drops can not be assumed to be identical.

Soft Surface Nanostructure with Semi-Free Polyionic Components for Sustainable Antimicrobial Plastic.

Surface antimicrobial materials are of interest as they can combat the critical threat of microbial contamination without contributing to issues of environmental contamination and the development drug resistance. Most nanostructured surfaces are prepared by post fabrication modifications and actively release antimicrobial agents. These properties limit the potential applications of nanostructured materials on flexible surfaces. Here, we report on an easily synthesized plastic material with inherent antimicrobial activity, demonstrating excellent microbicidal properties against common bacteria and fungus. The plastic material did not release antimicrobial components as they were anchored to the polymer chains via strong covalent bonds. Time-kill kinetics studies have shown that bactericidal effects take place when bacteria come into contact with a material for a prolonged period, resulting in the deformation and rupture of bacteria cells. A scanning probe microscopy analysis revealed soft nanostructures on the submicron scale, for which the formation is thought to occur via surface phase separation. These soft nanostructures allow for polyionic antimicrobial components to be present on the surface, where they freely interact with and kill microbes. Overall, the new green and sustainable plastic is easily synthesized and demonstrates inherent and long-lasting activity without toxic chemical leaching.

Antimicrobial Face Shield: Next Generation of Facial Protective Equipment against SARS-CoV-2 and Multidrug-Resistant Bacteria.

Transparent materials used for facial protection equipment provide protection against microbial infections caused by viruses and bacteria, including multidrug-resistant strains. However, transparent materials used for this type of application are made of materials that do not possess antimicrobial activity. They just avoid direct contact between the person and the biological agent. Therefore, healthy people can become infected through contact of the contaminated material surfaces and this equipment constitute an increasing source of infectious biological waste. Furthermore, infected people can transmit microbial infections easily because the protective equipment do not inactivate the microbial load generated while breathing, sneezing or coughing. In this regard, the goal of this work consisted of fabricating a transparent face shield with intrinsic antimicrobial activity that could provide extra-protection against infectious agents and reduce the generation of infectious waste. Thus, a single-use transparent antimicrobial face shield composed of polyethylene terephthalate and an antimicrobial coating of benzalkonium chloride has been developed for the next generation of facial protective equipment. The antimicrobial coating was analyzed by atomic force microscopy and field emission scanning electron microscopy with elemental analysis. This is the first facial transparent protective material capable of inactivating enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in less than one minute of contact, and the methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. Bacterial infections contribute to severe pneumonia associated with the SARS-CoV-2 infection, and their resistance to antibiotics is increasing. Our extra protective broad-spectrum antimicrobial composite material could also be applied for the fabrication of other facial protective tools such as such as goggles, helmets, plastic masks and space separation screens used for counters or vehicles. This low-cost technology would be very useful to combat the current pandemic and protect health care workers from multidrug-resistant infections in developed and underdeveloped countries.

Biological Synergy and Antimicrobial Mechanism of Hydroxypropyltrimethyl Ammonium Chloride Chitosan with Benzalkonium Chloride.

Preservatives in eye drops have always been the focus of people's attention. Benzalkonium chloride (BAC) is one of the most frequently used bacteriostatic agents in eye drops, which has broad-spectrum and efficient bactericidal ability. However, the inappropriate dosage of BAC may lead to high cytotoxicity. Therefore, adding low-toxic hydroxypropyltrimethyl ammonium chloride chitosan (HACC) can not only achieve antimicrobial effect, but also have the advantages of moisturizing and biocompatibility. In this paper, the minimum inhibitory concentrations (MICs) of HACC and BAC were evaluated against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Diphtheroid bacillus and Candida albicans. Based on the MIC of each antimicrobial agent, an antimicrobial assay was performed to investigate the antimicrobial ability of disinfectant solution. Besides, cytotoxicity had also been assessed. When the HACC/BAC solution at weight ratio of 150/1 showed a highest antimicrobial efficiency and the cell proliferation rates were the highest in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Furthermore, the cell leakage was examined by UV absorption, indicating the great synergistic antimicrobial effect between HACC and BAC. What is more, the results of micromorphology research suggested that as the result of repulsive force between the two molecules, the average particle size of HACC would decrease. Finally, the impedance experiment showed that with the addition of BAC, current density would increase significantly, suggesting that more positive charge group was exposed to aqueous solution, leading the the increase of antimicrobial ability. Based on these results, HACC-BAC combination solution might be a promising novel antimicrobial group for biomedical applications.

Separation and purification of pyrroloquinoline quinone from Gluconobacter oxydans fermentation broth using supramolecular solvent complex extraction.

In this paper, new supramolecular extractants, which contained surfactant, alkane and alkanol, were designed and used to separate PQQ. After a series of tests, the optimal extractant composition was determined as benzalkalonium (C8-C16) chloride (BC): n-hexane:n-pentanol, and the highest extraction rate could reach 98%. The extraction equilibrium could be reached in five minutes. The mechanism of the extraction selectivity was inferred as an ion-pair and π-π complexation interaction between PQQ and BC, which was indicated by UV and fluorescence quenching experiments. To recycle the organic extractant, the extract was back-extracted with sodium chloride solution. After extraction, back extraction and crystallization, an isolated product with a purity of 97.5% was obtained from G. oxydans fermentation broth. The product was identified as PQQ by HPLC analysis and MS. Above all, the present research developed a simple and efficient method for the separation of PQQ from fermentation broth.

Influence of type, concentration, exposure time, temperature, and presence of organic load on the antifungal efficacy of industrial sanitizers against Aspergillus brasiliensis (ATCC 16404).

Parameters such as type and concentration of the active compound, exposure time, application temperature, and organic load presence influence the antimicrobial action of sanitizers, although there is little data in the literature. Thus, this study aimed to evaluate the antifungal efficacy of different chemical sanitizers under different conditions according to the European Committee for Standardization (CEN). Aspergillus brasiliensis (ATCC 16404) was exposed to four compounds (benzalkonium chloride, iodine, peracetic acid, and sodium hypochlorite) at two different concentrations (minimum and maximum described on the product label), different exposure times (5, 10, and 15 min), temperatures (10, 20, 30, and 40 °C), and the presence or absence of an organic load. All parameters, including the type of sanitizer, influenced the antifungal efficacy of the tested compounds. Peracetic acid and benzalkonium chloride were the best antifungal sanitizers. The efficacy of peracetic acid increased as temperatures rose, although the opposite effect was observed for benzalkonium chloride. Sodium hypochlorite was ineffective under all tested conditions. In general, 5 min of sanitizer exposure is not enough and >10 min are necessary for effective fungal inactivation. The presence of organic load reduced sanitizer efficacy in most of the tested situations, and when comparing the efficacy of each compound in the presence and absence of an organic load, a difference of up to 1.5 log CFU was observed. The lowest concentration recommended on the sanitizer label is ineffective for 99.9% fungal inactivation, even at the highest exposure time (15 min) or under the best conditions of temperature and organic load absence. Knowledge of the influence exerted by these parameters contributes to successful hygiene since the person responsible for the sanitization process in the food facility can select and apply a certain compound in the most favorable conditions for maximum antifungal efficacy.

Benzalkonium Chloride Disinfectants Induce Apoptosis, Inhibit Proliferation, and Activate the Integrated Stress Response in a 3-D in Vitro Model of Neurodevelopment.

We previously found that the widely used disinfectants, benzalkonium chlorides (BACs), alter cholesterol and lipid homeostasis in neuronal cell lines and in neonatal mouse brains. Here, we investigate the effects of BACs on neurospheres, an in vitro three-dimensional model of neurodevelopment. Neurospheres cultured from mouse embryonic neural progenitor cells (NPCs) were exposed to increasing concentrations (from 1 to 100 nM) of a short-chain BAC (BAC C12), a long-chain BAC (BAC C16), and AY9944 (a known DHCR7 inhibitor). We found that the sizes of neurospheres were decreased by both BACs but not by AY9944. Furthermore, we observed potent inhibition of cholesterol biosynthesis at the step of DHCR7 by BAC C12 but not by BAC C16, suggesting that cholesterol biosynthesis inhibition is not responsible for the observed reduction in neurosphere growth. By using immunostaining and cell cycle analysis, we found that both BACs induced apoptosis and decreased proliferation of NPCs. To explore the mechanisms underlying their effect on neurosphere growth, we carried out RNA sequencing on neurospheres exposed to each BAC at 50 nM for 24 h, which revealed the activation of the integrated stress response by both BACs. Overall, these results suggest that BACs affect neurodevelopment by inducing the integrated stress response in a manner independent of their effects on cholesterol biosynthesis.

Synthesis and Properties of Cleavable Quaternary Ammonium Compounds.

Quaternary ammonium compounds are widely used as antiseptic and disinfectant. It is been a concern that their widespread use will lead to an increase of environmental problems, therefore the development of biodegradable surfactants is necessary. The present research is aimed at the design of novel amphiphilic molecules with similar properties to those already known but more biodegradable. Based on benzalkonium chloride (BAC), novel carbonate cleavable surfactants (CBAC) were synthesized. The breakable carbonate sites make CBAC compounds more degradable and potentially more biodegradable than their non-cleavable BAC analogues. Natural products such as fatty alcohols (C8-C16) and N,N-dimethyl-2-aminoethanol were used as reagents for the synthesis of CBAC8-16. These amphiphilic compounds were characterized in terms of surface properties and antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and moulds. The novel surfactants showed similar surface activities in aqueous solutions when compared to BAC. Also, the surface activity/structure relationship revealed that carbonate cleavable surfactants with n-decyl group (CBAC10) showed the same behaviour as non-cleavable BAC. Furthermore, compounds containing n-octyl (CBAC8), n-decyl (CBAC10) and n-dodecyl (CBAC12) group showed strong antimicrobial activities.

Alcohol-free hand sanitizer and other quaternary ammonium disinfectants quickly and effectively inactivate SARS-CoV-2.

BACKGROUND: SARS-CoV-2 is the virus responsible for the current global pandemic, COVID-19. Because this virus is novel, little is known about its sensitivity to disinfection. METHODS: We performed suspension tests against SARS-CoV-2 using three commercially available quaternary ammonium compound (Quat) disinfectants and one laboratory-made 0.2% benzalkonium chloride solution. FINDINGS: Three of the four formulations completely inactivated the virus within 15 s of contact, even in the presence of a soil load or when diluted in hard water. CONCLUSION: Quats rapidly inactivate SARS-CoV-2, making them potentially useful for controlling SARS-CoV-2 spread in hospitals and the community.

Kinetics and distribution of benzalkonium compounds with different alkyl chain length following intravenous administration in rats.

Benzalkonium chloride is widely used in disinfectants. Several toxicological and fatal cases have been reported; however, little is known about its kinetics and distribution. We investigated the kinetic characteristics and distribution of benzalkonium cation (BZK) based on the length of the alkyl chains C12, C14, and C16. Rats were treated intravenously with BZK solution (dose, 13.9 mg/kg) containing equal amounts of the three homologues. Kinetic parameters in the blood were assessed, and BZK distribution in the blood and tissues was examined both in rapid intravenous (IV) and drip intravenous (DIV) administrations. BZK concentrations were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). BZK with longer alkyl chains showed lower elimination tendencies and remained in the blood for a longer duration. Concentrations of BZK were higher in the heart, lung, spleen, and kidney than those in the blood, and lower in the brain and fat. In both the IV and DIV groups, the lung, liver, spleen, and fat samples showed higher concentrations of the longer alkyl chains (BZK-C12 < -C14 < -C16), and the opposite trend was observed in the kidney (BZK-C16 < -C14 < -C12). Only the heart and muscle samples displayed the homologues in ratios comparable to the original administered solutions. Differences between IV and DIV groups could be identified by comparing concentrations of BZK homologues in the heart, lung, spleen, and kidney samples. We found that the kinetics and distribution of BZK were influenced by the alkyl chain length, and analysing each BZK homologues in blood and tissue samples may provide useful information.

Lipophilic Arginine Esters: The Gateway to Preservatives without Side Effects.

This study hypothesized that long carbon chain cationic arginine (Arg) esters can be considered as toxicologically harmless preservatives. Arg-esters with C18 and C24 carbon chains, namely, arginine-oleate (Arg-OL) and arginine-decyltetradecanoate (Arg-DT), were synthesized. Structures were confirmed by FT-IR, 1H NMR, and mass spectroscopy. Both Arg-esters were tested regarding hydrophobicity in terms of log Poctanol/water, critical micelle concentration (CMC), biodegradability, cytotoxicity, hemolysis, and antimicrobial activity against Escherichiacoli (E. coli), Staphylococcusaureus (S. aureus), Bacillussubtilis (B. subtilis), and Enterococcusfaecalis (E. faecalis). Log Poctanol/water of arginine was raised from -1.9 to 0.3 and 0.6 due to the attachment of C18 and C24 carbon chains, respectively. The critical micelle concentration of Arg-OL and Arg-DT was 0.52 and 0.013 mM, respectively. Both Arg-esters were biodegradable by porcine pancreatic lipase. In comparison to the well-established antimicrobials, benzalkonium chloride (BAC) and cetrimide, Arg-esters showed significantly less cytotoxic and hemolytic activity. Both esters exhibited pronounced antimicrobial properties against Gram-positive and Gram-negative bacteria comparable to that of BAC and cetrimide. The minimum inhibitory concentration (MIC) of Arg-esters was <50 µg mL-1 against all tested microbes. Overall, results showed a high potential of Arg-esters with long carbon chains as toxicologically harmless novel preservatives.

Effects of Benzalkonium Chloride and Preservative-Free Composition on the Corneal Epithelium Cells.

Purpose: Benzalkonium Chloride (BAK) is reported to have the potential to damage the cornea. We developed a composition with broad-spectrum antimicrobial activity without preservatives by combining trometamol, boric acid, and ethylenediaminetetraacetic acid (TBE). This study aimed at evaluating the corneal damage caused by TBE and comparing it with that caused by BAK. Methods: SV40-immortalized human corneal epithelial cell line (HCE-T) was treated with BAK or TBE, and the cell viability was measured. The exposure time that caused 50% cell death (CDT50) was calculated. Transepithelial electrical resistance (TEER) was measured before and after treatment with BAK or TBE. Occludin was detected with immunostaining and Western blotting after treatment with BAK or TBE. The effect of BAK or TBE on membrane-associated mucins was evaluated with rose bengal (RB) staining. Results: In the BAK group, cell viability decreased in a dose-dependent manner. The viability of the TBE group was significantly greater than that of the BAK group. The CDT50 of the TBE group is greater than that of the BAK groups. In the BAK groups, the recovery of TEER was delayed in a dose-dependent manner, whereas in the TBE group, the recovery occurred earlier. Localization of occludin was disrupted, and the amount of occludin was significantly reduced among the cells exposed to BAK. The area stained with RB in the BAK groups increased, whereas that in the TBE group did not increase. Conclusion: These results suggest that the application of TBE would be useful for developing preservative-free ophthalmic preparations that offer both sufficient safety and antimicrobial activity.

A Comparative Ocular Pharmacokinetics Study of Preservative-Free Latanoprost Unit-Dose Eye Drops and a Benzalkonium Chloride-Preserved Branded Product Following Topical Application to Rabbits.

Purpose: To evaluate the aqueous humor pharmacokinetics of a preservative-free 0.005% latanoprost unit-dose eye drop (test drug) compared with that of a benzalkonium chloride (BAK)-preserved 0.005% latanoprost branded product (control drug) following topical application to rabbits. Methods: A total of 120 healthy New Zealand albino rabbits were administrated test eye drops (T group) or control eye drops (C group) for a comparative pharmacokinetics study. The aqueous humor was collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after a single dose or multiple doses. Ultraperformance liquid chromatography-tandem quadrupole mass spectrometry was employed to detect latanoprost free acid (LTA, the active metabolite of latanoprost) in the aqueous humor. Results: For the single-dose study, there was no significant difference (t-test, P > 0.05) in the peak concentration (Cmax) of LTA in aqueous humor between the T group (69.0 ± 23.4 ng/mL) and C group (73.8 ± 28.7 ng/mL). The area under the curve values over 12 h (AUC0-12h) of LTA for the 2 groups were 254.4 (ng/mL) × h and 219.5 (ng/mL) × h, respectively. For the multidose study, there was also no significant difference (t-test, P > 0.05) in the Cmax of LTA in the aqueous humor between the T group (86.8 ± 21.2 ng/mL) and C group (70.5 ± 25.9 ng/mL). The AUC0-12h values of LTA for the 2 groups were 274.5 (ng/mL) × h and 256.3 (ng/mL) × h, respectively. Conclusions: The preservative-free 0.005% latanoprost unit-dose eye drops demonstrated similar pharmacokinetic properties to the BAK-preserved branded product following topical application to rabbits.

Benzalkonium chloride and cetylpyridinium chloride induce apoptosis in human lung epithelial cells and alter surface activity of pulmonary surfactant monolayers.

Quaternary ammonium compounds (e.g., benzalkonium chloride (BAC) and cetylpyridinium chloride (CPC)) constitute a group of cationic surfactants are widely used for personal hygiene and medical care despite the potential pulmonary toxicity. To examine whether BAC and CPC aerosols deposited in the alveolar region alter pulmonary function, we studied the effects on pulmonary surfactant using two-step in vitro models; cytotoxicity using A549 alveolar epithelial cell and changes in surface activity of the pulmonary surfactant monolayer using both Surfacten® and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Cell viability was decreased with BAC and CPC dose-dependently. A comparison of cytotoxicity among BAC homologues with different length of alkyl chain showed that C16-BAC, which has the longest alkyl chain, was more cytotoxic than C12- or C14-BAC. Caspase-3/7 activity and cleaved form of caspase-3 and PARP were increased in BAC- and CPC-exposed cells. The elevated caspase-3/7 activity and their cleaved active forms were abolished by caspase-3-inhibitor. Furthermore, we examined the features of the surface pressure/trough area (π-A) isotherm by the Langmuir-Wilhelmy method and atomic force microscopy (AFM) images of lipid monolayers on a subphase containing BAC, CPC, or pyridinium chloride (PC, as a control). The π-A isotherms showed that addition of BAC or CPC yielded dose-dependent increases in surface pressure without compression, indicating that BAC and CPC expand the isotherm to larger areas at lower pressure. The collapse pressure diminished with increasing concentration of CPC. Topographic images indicated that BAC and CPC resulted in smaller condensed lipid domains compared to the control. Conversely, PC without hydrocarbon tail group, showed no cytotoxicity and did not change the isotherms and AFM images. These results indicate that BAC and CPC cause cell death via caspase-3-dependent apoptotic pathway in A549 cells and alter the alveolar surfactant activity. These effects can be attributed to the long alkyl chain of BAC and CPC.

Benzalkonium ion sorption to peat and clays: Relative contributions of ion exchange and van der Waals interactions.

Due to their use in various domestic and industrial formulations, benzalkonium compounds have been isolated in many environmental matrices. Sorption to soil components has been shown to play a key role in their environmental fate. Whereas sorption of benzalkonium compounds to soils is attributed to cation exchange and van der Waals forces, the relative contributions of these two mechanisms at environmental levels have not been clearly defined. In this study a previously reported algal toxicity assay-based method was employed to determine the distribution coefficients (Kd) of benzalkonium compounds between water and soil components, at environmental concentrations. Cation exchange capacity corrected Kd values for organic matter and clays were all within one order of magnitude. This implies that ion exchange is the dominant mechanism of sorption for benzalkonium compounds. When the sorption data were used to compute sorption energies for four homologues of benzalkonium ions, the magnitude of the free energy change of sorption increased with size of the molecule. The increase in sorption energy could be partly explained by increased energy of hydration with addition of methylene groups to the alkyl chain. A model that predicts sorption coefficients of benzalkonium compounds to soils using organic carbon content and cation exchange capacity was also defined. When tested using an artificial soil, the model estimates were all within one order of magnitude of the experimental values.

Antimicrobial properties of benzalkonium chloride derived polymerizable deep eutectic solvent.

Benzalkonium chloride (BC) is a quaternary ammonium antimicrobial agent used in a variety of applications. In this work, BC was prepared into deep eutectic solvent (DES) with acrylic acid (AA) or methacrylic acid (MA). Within the newly prepared DES, BC is responsible for antimicrobial properties, while AA and MA are responsible for polymerization. Three types of microorganisms, E. coli (gram-negative bacilli), S. aureus (gram-positive cocci) and C. albicans (fungi), were assessed for antimicrobial properties through agar diffusion test. DES viscosity measurements and polymerizations were also conducted to assist the antimicrobial performance analysis. From this study, stronger antimicrobial effectiveness of BC-AA DES towards S. aureus and C. albicans was observed, while smaller inhibition zone widths were obtained for BC-AA DES polymer compared to BC-AA DES monomer which may due to the limited active component transportation after polymerization. When changing AA to MA, increased structural complexity and decreased linearity may limit the molecule movement thus reduce the inhibition zone width, which could be proved by the calculated activation energy results. Accurately determined eutectic ratio of DES is recommended to get optimized drug release control. This work offers a new sight for preparation of antimicrobial materials with stronger effectiveness and limited release.

Drug-templated mesoporous silica nanocontainers with extra high payload and controlled release rate.

The possibility of one-step creating of pH-sensitive mesostructured silica-based nanocontainers with exceptionally high payload using associates of two antiseptics (including hydrolyzable one) as templates is demonstrated. The effects of the template nature and the conditions of the sol-gel process on the porous structure of silica nanocontainers are studied and discussed. The kinetics of the templating drug release from such containers is studied and some features of this process are analyzed. It is shown that the drug release rate can be tuned by varying the medium pH. The bactericidal activity of two encapsulated antiseptics against the Staphylococcus aureus is evaluated in vitro by agar diffusion method with replacement of agar with agarose. The diameters of the inhibition zones for silica-based containers loaded with antiseptics increased with the pre-diffusion time at 4 °C. At the same time, empty containers (after elimination of antiseptics by etching) did not reveal any bactericidal properties.

Identification of novel disinfection byproducts in pool water: Chlorination of the algaecide benzalkonium chloride.

The maintenance of public swimming pools requires numerous technological steps. One of the most important issues involves microbiological safety. Benzalkonium chloride (BAC) encompasses homologous alkylbenzyldimethylammonium chlorides with various alkyl chains, in particular C12 and C14, and is known as a popular algaecide for keeping water clean. In addition to BAC, NaOCl and UV-irradiation are also used to treat pool water as additional technological steps. Therefore, BAC itself can become a precursor of disinfection byproducts (DBPs). High-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS), with accurate mass measurements, has allowed the discovery of several groups of DBPs that are related to BAC in public pool water in Arkhangelsk (Russia). These DBPs include numerous isomeric monochlorinated derivatives ([C21H37ClN]+ and [C23H41ClN]+), hydroxyl derivatives ([C21H38NO]+ and [C23H42NO]), carbonyl ([C21H36NO]+ and [C23H40NO]+), and dicarbonyl derivatives ([C21H34NO2]+ and [C23H38NO2]+). In addition, chlorinated alcohols, ketones and ketoalcohols of BAC were also detected, including [C21H35ClNO]+, [C21H37ClNO]+ and [C21H35ClNO2]+ for BAC-12; and [C23H39ClNO]+, [C23H41ClNO]+ and [C23H39ClNO2]+ for BAC-14. MS/MS allowed reliable elucidation of the structures of novel DBPs, proving that chlorination starts via radical substitution in the long aliphatic chains of BAC. UV-irradiation dramatically accelerates the reaction completely destroying the original compounds in less than an hour, while the array of the intermediate products remains the same as in the dark. The formation of other DBPs proceeds due to further reactions of these primary products. The concentrations of novel DBPs in pool water reach µg L-1 levels. These conclusions were proved by conducting model reactions of BAC with NaOCl.

Optimization of the Interaction between Diclofenac and Ibuprofen with Benzalkonium Chloride to Prepare Ocular Nanosuspension.

BACKGROUND: Non-steroidal anti-inflammatory drugs are most commonly used in the management of ocular inflammations. These drugs have poorly aqueous solubility and weakly acidic nature. They interact with cationic quaternary ammonium compound benzalkonium chloride, used as a preservative in ophthalmic formulations, to form insoluble complexes. To overcome this incompatibility solubilizers like polysorbate 80, lysine salts, tocopheryl polyethylene glycol succinate etc. are used which are quite irritating and affect the corneal integrity. OBJECTIVE: The objective of the present study is to formulate nonirritating, compatible, microbiologically stable ophthalmic formulation with good corneal permeation characteristics. The interaction between diclofenac sodium or ibuprofen with benzalkonium chloride was optimized using a central composite experimental design to prepare nanosuspensions by nanoprecipitation. METHODS: The optimized batches of nanosuspensions were evaluated for ex vivo corneal permeation study, preservative challenge test and physical stability. The optimal concentrations of benzalkonium chloride for diclofenac sodium (0.1%, w/v) and ibuprofen (0.1% w/v) nanosuspensions were determined to be 0.002%(w/v), which had a respective average particle size of 440 nm and 331 nm, respectively. The nanosuspensions of diclofenac sodium and ibuprofen provided 1.6 and 2.1- fold higher ex vivo corneal permeation than their respective conventional aqueous solution dosage forms. Further, the concentration of benzalkonium chloride used in the formulations showed adequate preservative efficacy. RESULTS: The optimized nanosuspension formulations of diclofenac and ibuprofen were found to be physically stable and microbiologically safe with greater corneal penetration than the conventional solution dosage forms.