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PubMed1999

Adsorption of benzalkonium chloride by filter membranes: mechanisms and effect of formulation and processing parameters.

The purpose of this study was to elucidate the mechanism(s) of adsorption of benzalkonium chloride (BAK) by filter membranes and to determine the effect of formulation and processing parameters on the adsorption of BAK. Six different sterilizing grade filter membranes were used in this study. Adsorption was monitored by passing an aqueous solution of BAK at pH 6 through a 47-mm (14.2 cm2 effective filter area) disk filter membrane and measuring the UV absorption of the filtrate with a UV micro flow cell. Hydrophobic and/or electrostatic forces were chiefly responsible for adsorption. The adsorption properties of each filter membrane could be related to its composition. Membranes that were hydrophilic and nonionic or hydrophilic and cationic adsorbed little BAK. However, membranes that were hydrophobic or anionic exhibited significant BAK adsorption. Adsorption followed the Langmuir equation and adsorptive capacities ranged from 116 to 429 micrograms/47 mm membrane (8.17-30.23 micrograms/cm2). Formulation factors studied included the concentration of BAK, the presence of a tonicity-modifying agent (sodium chloride, mannitol, glycerin), and the presence of a chelating agent (edetate disodium). The greatest increase in adsorption of BAK occurred when sodium chloride or edetate disodium was used with membranes that contained cationic sites. The effects of flow rate, temperature, autoclaving, interrupting the flow, and presaturating the filter membrane were the processing parameters studied. The rate of adsorption was inversely related to flow rate and the extent of adsorption was inversely related to temperature. Presaturation of the filter membrane with BAK was an effective method to reduce the adsorption of BAK during filtration.

Adsorption↗
PubMed2002

Sorption of benzoic acid, sorbic acid, benzyl alcohol, and benzalkonium chloride by flexible tubing.

Earlier studies using methylparaben, propylparaben, and several types of flexible tubing showed that the parabens are sorbed by a number of commonly used tubing. The sorption increased with increase in time of contact and the tubing surface area. The temperature and pH ranges tested did not affect sorption. Current studies evaluated other commonly used antimicrobial preservatives used in oral, parenteral, opthalmic, nasal, and other pharmaceutical products. These preservatives include benzoic acid, sorbic acid, benzyl alcohol, and benzalkonium chloride. Results show that all preservatives, except benzalkonium chloride, are sorbed by several types of flexible tubing. After 24 hr, some types of tubing sorbed over 40% of benzoic acid, benzyl alcohol, and about 30% of sorbic acid. Significant losses were observed within a few hours. No sorption of benzalkonium chloride occurred in the tubing tested. Three different types of fluoropolymer resin tubing, Teflon (flourinated ethylene propylene (FEP), Teflon perfluoroalkoxy) (PFA) and Teflon polytetrafluoroethylene (PTFE, NXT), fluoropolymer FEP laminated Tygon tubing, and Zelite do not sorb any of the preservatives. Silicone tubing shows the highest sorption of preservatives. After 120 hr, as much as 64% of the preservative is sorbed by some tubing. Detailed studies using silicone tubing show that the sorption increases with increase in surface area at 25 degrees C, and increasing the temperature to 40 degrees C shows little change in sorption. At the concentration range generally used in formulations, the concentration of the preservative has no significant effect on sorption. Refilling the tubing with fresh preservative solution after contact with preservative solution for 168 hr still causes extensive sorption of the preservative. Desorption studies indicate that the sorbed preservatives are desorbed in water to a limited extent over 120 hr. Results are important in situations where short or extended interruptions occur in the processing and filling of products. This can lead to decreased and variable results due to residence of the solution in the tubing.

Adsorption↗
PubMed1994

G-protein ligands inhibit in vitro reactions of vacuole inheritance.

During budding in Saccharomyces cerevisiae, maternal vacuole material is delivered into the growing daughter cell via tubular or vesicular structures. One of the late steps in vacuole inheritance is the fusion in the bud of vesicles derived from the maternal vacuole. This process has been reconstituted in vitro and requires isolated vacuoles, a physiological temperature, cytosolic factors, and ATP (Conradt, B., J. Shaw, T. Vida, S. Emr, and W. Wickner. 1992. J. Cell Biol. 119:1469-1479). We now report a simple and reliable assay to quantify vacuole-to-vacuole fusion in vitro. This assay is based on the maturation and activation of vacuole membrane-bound pro-alkaline phosphatase by vacuolar proteinase A after vacuole-to-vacuole fusion. In vitro fusion allowed maturation of 30 to 60% of pro-alkaline phosphatase. Vacuoles prepared from a mutant defective in vacuole inheritance in vivo (vac2-1) were inactive in this assay. Vacuole fusion in vitro required a vacuole membrane potential. Inhibition by nonhydrolyzable guanosine derivatives, mastoparans, and benzalkonium chloride suggest that GTP-hydrolyzing G proteins may play a key role in the in vitro fusion events.

Amino Acid Sequence↗
PubMed2003

Forty years of disinfectant failure: outbreak of postinjection Mycobacterium abscessus infection caused by contamination of benzalkonium chloride.

Benzalkonium chloride (BC) continues to be used as an antiseptic and contributes to serious outbreaks of disease. In July 1999, 6 postinjection joint infections caused by Mycobacterium abscessus were reported to the Texas Department of Health (Austin). We investigated this outbreak and identified 12 case patients who had been seen by the same physician and who had received an intra-articular or periarticular steroid injection during the period of 1 April through 31 July 1999. M. abscessus was cultured from either joint fluid or periarticular soft-tissue specimens obtained from 10 patients. We cultured environmental samples, and we compared isolates recovered from case patients with environmental isolates by pulsed-field gel electrophoresis and randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Four environmental samples containing diluted BC yielded M. abscessus. Clinical and environmental strains of M. abscessus were indistinguishable by RAPD-PCR. The case patients' strain was resistant to BC. The use of BC as an antiseptic should be discontinued.

Adult↗
PubMed1994

Contaminated disinfectants in health clinics in Ilorin, Nigeria.

Five of 18 samples of working dilutions of disinfectants used in the University of Ilorin Teaching Hospital, the University Clinic, and three other urban medical centers were found to be contaminated with bacteria. The results confirmed that disinfectants in storage support the growth of infectious agents, underlining the need to use fresh preparations of disinfectants.

Bacteria↗
PubMed2002

Formulation effects on ocular absorption of brimonidine in rabbit eyes.

Purite (stabilized oxychloro complex) and benzalkonium chloride (BAK) are preservatives. We investigated formulation effects on ocular absorption of brimonidine in rabbit eyes. The formulations compared were: Alphagan (0.2% brimonidine tartrate/0.005% BAK, pH 6.4), Brimonidine-Purite (0.2% brimonidine tartrate/0.005% Purite, pH 7.2), and Brimonidine-PF (0.2% brimonidine tartrate, preservative-free (PF), pH 6.4) solutions. The study was conducted in a cross-over fashion; albino rabbits (n = 18) were given a single 35 microl drop of each test formulation in each eye. Aqueous humor samples were collected at selected times post-dose from subgroups of 2 rabbits per timepoint and analyzed for brimonidine concentrations by LC-MS/MS. The AUC and Cmax were calculated. The results showed rapid ocular absorption of brimonidine, with peak concentrations at 0.33-1 hr. The AUC(0-5hr) values were 3.78 +/- 0.38, 2.77 +/- 0.22, and 2.49 +/- 0.22 microg-hr/ml (mean +/- SEM) for Brimonidine-Purite, Alphagan and Brimonidine-PF, respectively. The corresponding Cmax values were 2.69 +/- 0.72, 1.74 +/- 0.13, and 1.24 +/- 0.22 microg/ml (mean +/- SEM). Brimonidine-Purite provided significantly higher AUC(0-5hr) than Alphagan (p < 0.05). No statistical significant difference in AUC(0-5hr) was found between Alphagan and Brimonidine-PF. In conclusion, 0.2% Brimonidine-Purite was 1.4 and 1.5 times more ocularly bioavailable in rabbits than 0.2% Alphagan and 0.2% Brimonidine-PF, respectively.

Absorption↗
PubMed2002

Comparative permeability of human and rabbit corneas to cyclosporin and tritiated water.

Diffusion of cyclosporin A (CsA) and water through fresh and frozen (liquid nitrogen, -85 degrees C) human and rabbit corneas was compared to establish the appropriateness of using the latter tissue as a model for its human counterpart for in vitro permeability studies. Permeation of CsA in the presence of three penetration enhancers, 0.01% benzalkonium chloride (BZCl), 20% dimethylsulfoxide (DMSO), 10% and 20% Cremophor-EL was also studied. Permeability was determined using a flow-through diffusion apparatus (20 degrees C, 24 hours). ANOVA, Duncan's multiple range test, and an unpaired t-test were used to determine steady state kinetics and flux differences over time intervals. No statistically significant differences in flux values of CsA and water could be detected between fresh and frozen/thawed human and rabbit corneas. The diffusion of water was significantly lower across frozen/thawed rabbit cornea than across the same human tissue. CsA flux rates across frozen/thawed rabbit cornea in the presence of all three enhancers increased significantly when compared to the same tissues without enhancer, except in the presence of 20% Cremophor-EL after 18 hours. The rabbit cornea appears to be an appropriate in vitro model for studying human transcorneal penetration of drugs. Smaller M(w) substances, however, may have higher diffusion rates across frozen/thawed human corneal tissue.

Animals↗
PubMed2003

A collaborative evaluation of the cytotoxicity of two surfactants by using the human corneal epithelial cell line and the WST-1 test.

This study was undertaken to investigate the use of the in vitro test WST-1, an assay of cell proliferation and viability, for a preliminary safety evaluation of topical ophthalmic preparations. The cytotoxicity of two surfactants, benzalkonium chloride (BAC) and polyoxyethylene-20-stearyl ether (Brij78, PSE) was independently investigated in four laboratories in the EU by using an immortalized human corneal epithelial (HCE) cell line. The HCE cells were exposed to BAC and PSE for 5 min, 15 min, and 1 hour, and the results of the HCE-WST-1 tests were collected and compared. After one-hour exposure, the EC(50) values in BAC-treated cells in the presence of serum ranged between 0.0650 +/- 0.0284 (mean +/- SD) mM, and those in the absence of serum 0.0296 +/- 0.0081 mM. The corresponding values for PSE were 0.0581 +/-.0300 mM and 0.0228 +/-.0063 mM. There were variations in the results between different laboratories, with coefficients of variation ranging from 31 to 121%, mean 58%. The use of one-hour exposure time is to be preferred, and the elimination of serum in the culture medium is recommended to avoid both underestimation of toxic effects and variability of the test results.

Benzalkonium Compounds↗
PubMed2004

Effects of the preservative purite on the bioavailability of brimonidine in the aqueous humor of rabbits.

PURPOSE: To determine aqueous humor concentrations of brimonidine given the following ophthalmic formulations in female New Zealand White Rabbits: (1) BAK-preserved brimonidine tartrate 0.20% at a pH of 6.4; (2) BAK-preserved brimonidine tartrate 0.15% at a pH of 6.4, and (3) Purite((R))-preserved brimonidine tartrate 0.15% at a pH of 7.3. METHODS: Eighteen (18) animals were given a 35-microL drop of formulation into each eye. Aqueous humor samples were collected at 9 time points over 8 hours. Brimonidine concentrations were quantified using LC-MS/MS. RESULTS: The C(max) was achieved between 0.33-0.67 hours postdosing for all 3 formulations. Mean C(max) after Purite-preserved brimonidine tartrate 0.15% was 88% higher than that after BAK-preserved brimonidine tartrate 0.15% (p = 0.040), and 44% higher than that after BAK-preserved brimonidine tartrate 0.20% (p = 0.0784). AUC(0-3 hr) values were comparable for all 3 formulations. CONCLUSIONS: Purite-preserved brimonidine tartrate 0.15% produced higher peak concentrations than BAK-preserved brimonidine tartrate 0.15%. It also had a concentration that was comparable to BAK-preserved brimonidine tartrate 0.20%. The differences in safety may result from the change in preservative.

Animals↗
PubMed1986

Corneal permeability of aldose reductase inhibitor, M79175. I. In vitro study using corneal permeability apparatus.

Transcorneal permeability of M79175, aldose reductase inhibitor (Eisai), and various factors influencing it were examined using excised rabbit cornea mounted on the methacrylate apparatus. High permeability was exhibited and this was independent of the concentration of M79175. Cornea hydrated by exposure to the eye drop solution of high concentration of benzalkonium chloride, which had an enhancing effect on the permeability of M79175. Corneal hydration was also caused by the solution of low pH. These findings will show the basic conditions for this eye drop solution to be an artificial tear fluid.

Aldehyde Reductase↗
PubMed1988

The effects of topical and general anesthesia on ocular drug levels and intraocular pressure lowering activity of topically applied carbonic anhydrase inhibitors.

Treatment with topical anesthetics was reported to increase corneal permeability and improve ocular drug bioavailability. These changes were attributed to the loss of reflex blinking, reduction of tear secretion and appearance of superficial corneal epithelial lesions. A recent report showed that pretreatment with Ophthetic (0.5% proparacaine HCl) (OPH) in pentobarbital-anesthetized rabbits significantly increased the permeability of the lipophobic carbonic anhydrase inhibitor (CAI) benzolamide (B) and transformed it to a highly active ocular hypotensive drug. This did not affect the permeability and activity of other, more lipophilic, CAI like methazolamide and ethoxzolamide (E). Similar experiments in awake rabbits using other CAI failed to reproduce the finding reported for B. We compared the ocular drug levels and the intraocular pressure lowering (delta IOP) with and without application of Ophthetic prior to 1 drop of 2% suspensions, in groups of anesthetized and conscious albino rabbits. In unanesthetized rabbits pretreatment with Ophthetic, lidocaine or benzalkonium had minimal and insignificant effects on ocular drug levels and delta IOP of B as well as E. On the other hand, Ophthetic or lidocaine pretreatment in anesthetized rabbits led to a highly significant increase in both ocular drug levels and hypotensive activity of B. We conclude that the error introduced by pretreatment with OPH occurs only in the presence of pentobarbital anesthesia and has little relevance to the normal, unanesthetized condition.

Administration, Topical↗
PubMed2000

Change of calcium and cAMP concentration by adrenoceptor agents in cultured porcine corneal endothelial cells.

It has been reported that beta-adrenergic receptors are localized in the corneal endothelial cells. In this study, the change of cellular signal transduction, such as intracellular calcium and cAMP, was determined with pure adrenergic agonists and commercial antiglaucoma adrenergic agents. The intracellular calcium of cultured porcine corneal endothelial cells was inhibited by 10 microM isoproterenol and norepinephrine, but enhanced by propranolol and 50 mM KCl. In the case of phenylephrine, calcium mobility did not alter significantly. Verapamil, at 10 microM, decreased intracellular calcium concentration. In the presence of isoproterenol, cellular cAMP concentration increased from 28.8 pmole/mg protein (1 microM) to 42.2 pmole/mg protein (100 microM) compared with control of 6.07 pmole/mg protein. Incubation with commercial adrenergic eye drops, such as betaxolol, caused the cAMP concentration to increase from 21.6 pmole/mg protein (0.0005%) to 39.1 pmole/mg protein (0.05%). Adding commercial levobunolol and timolol into cells caused cellular cAMP to increase from 14.3 pmole/mg protein (0.0005%) to 840.5 pmole/mg protein (0.05%) and from 115.2 pmole/mg protein (0.00025%) to 931.0 pmole/mg protein (0.025%), respectively. However, the preservative, benzalkonium chloride, increased cellular cAMP from 15.4 pmole/mg protein (0.00001 mg/ml) to 1087.4 pmole/mg protein (0.01 mg/ml). It is concluded that the intracellular calcium of corneal endothelium decreases when the cellular adrenergic receptor is activated by agonists. Benzalkonium chloride, due to its preservative in commercial antiglaucoma agents which increases cellular cAMP, may alter corneal endothelial physiology through long-term use.

Adrenergic Agonists↗
PubMed2004

Development of cultured rabbit corneal epithelium for drug permeation studies: a comparison with excised rabbit cornea.

The aim of this study was to prepare and test an artificial corneal epithelium (reconstituted rabbit corneal epithelium, RRCE) exhibiting barrier characteristics and paracellular permeability similar to those of native rabbit cornea. The RRCE was obtained from a rabbit corneal epithelium (RCE) cell line grown for 8 days in submerged culture, then for 7 days in air-interface conditions on Snapwell polyester membranes. Permeation studies on the RRCE were carried out in comparison with rabbit excised corneas in vitro, using timolol maleate (TM) as the test drug, alone and in association with the following ocular permeation enhancers: benzalkonium chloride, ethylene-diaminetetraacetic acid sodium salt, polyethoxylated castor oil, polyoxyethylene stearyl ether, sodium deoxycholate, and escin. The integrity of the RRCE was assessed by measuring the transepithelial electrical resistance (TEER) during culture time and after every permeation experiment. When TM was tested alone, the permeation parameters (apparent permeability coefficient, lag time) obtained with the RRCE were similar to those of excised rabbit corneas. The artificial epithelium, however, was less sensitive than native cornea to the effect of permeation enhancers.

Adjuvants, Pharmaceutic↗
PubMed2006

Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study.

PURPOSE: The aim of this study was to compare, in vivo on a rat model, two different preservatives- benzalkonium chloride (BAC) and polyquaternium-1 (PQ-1)-using new experimental approaches. METHODS: Thirty (30) eyes of 15 male Lewis rats were used in this study. Rats were randomly divided into five groups instilled twice a day for 11 days with eye drops containing different concentrations of preservatives, 0.1% BAC, 0.5% BAC, 0.1% PQ-1, 0.5% PQ-1, and balanced salt solution (BSS) as a control. The ocular surface toxicity of these two preservatives was investigated using new in vivo experimental approaches. Slit-lamp examination, the fluorescein test, the red phenol test, impression cytology, and in vivo corneal confocal microscopy were used to evaluate the rat ocular surface after preservative instillation. Histology sections and immunohistochemistry were also examined to confirm these results. RESULTS: Compared to PQ-1, BAC consistently and dramatically altered the corneoconjunctival surface as evaluated by slit-lamp examination, the fluorescein test, impression cytology, in vivo confocal microscopy, and histology. The 0.5% BAC solution also significantly decreased tear production compared to the control. Although 0.5% PQ-1 significantly decreased goblet cell density in comparison to the control, and some abnormalities were observed with in vivo confocal microscopy, no statistically significant differences were observed between these two groups using the tear production test, slit-lamp and fluorescein evaluation, or histology. CONCLUSION: Using an acute rat model of ocular toxicity by comparing preservatives at high concentrations, we demonstrated in vivo that high doses of PQ-1 were much less toxic than BAC. In vivo confocal microscopy and impression cytology are new promising experimental approaches to studying the rat corneoconjunctival surface, particularly in the field of ocular surface toxicity.

Animals↗
PubMed2006

Efficacy of spray disinfection with a 2-propanol and benzalkonium chloride containing solution before epidural catheter insertion--a prospective, randomized, clinical trial.

BACKGROUND: Skin disinfection before neuroaxial blockade procedures is usually obtained with sterile swabs impregnated in disinfectant. Spray disinfection is also an option which is frequently used in minor invasive procedures. The purpose of our study was to compare the efficacy of conventional swab disinfection with spray disinfection prior to epidural catheterization. METHODS: Seventy patients who requested epidural analgesia were randomly selected. The first group (n=35) received disinfection with swabs (SW) containing 2-propanol and benzalkonium chloride. The other 35 patients received spray (SP) disinfection with the same solution. Three microbiological cultures were obtained: one culture prior to skin disinfection, a second immediately after disinfection and a third from the tip of the epidural catheter upon removal. RESULTS: One patient in the SW group had a positive skin culture immediately after the disinfection with a very low number of colony forming units. The other skin culture specimens were all sterile in both groups. The colonization rate of catheters was not statistically different between the groups at removal. CONCLUSION: In this study, spray disinfection was equally efficacious compared with the conventional skin disinfectant technique. Our results support the routine use of this simple and cheap alternative method of skin disinfection before epidural anaesthesia.

2-Propanol↗