Benzalkonium chloride effects

Although this chapter is directed toward ophthalmic products, it is largely applicable to parenteral and even nonsterile products (solutions, emulsions, and suspensions). The choice of preservative is limited to only a few chemicals that have been found, over the years, to be safe and effective for this purpose. These are benzalkonium chloride, thimerosal, methyl- and propylparaben, phenylethanol, chlorhexidine,... 

The most widely used preservative remains benzalkonium chloride, which often is supplemented with disodium edetate. The benzalkonium chloride defined in the USP monograph is the quaternary ammonium compound alkylbenzyldimethylammonium chloride, in which the alkyl portion is composed of a mixture of chain lengths ranging from C8 to C16. This compound s popularity is based, despite its compatibility limitations, on its being the most effective and rapid-acting preservative with excellent chemical stability. It is stable over a wide pH range and does not... 

The conventional concentration of benzalkonium chloride in eyedrops is 0.01%, with a range of 0.004-0.02% [111]. While uptake of benzalkonium chloride itself into ocular tissues is limited [113], even lower concentrations of benzalkonium chloride have been reported to enhance corneal penetration of other compounds including therapeutic agents [93,112,114]. The differential effect of this preservative on the cornea compared to the conjunctiva can be exploited to target a drug for corneal absorption and delivery to the posterior segment of the eye [115]. Its use has been proposed as a means of delivering systemic doses by an ocular route of administration [116]. 

Other quaternary ammonium germicides, ben-zethonium chloride and benzalkonium bromide, have been used in several ophthalmic solutions. While these have the advantage of not being a chemical mixture, they do not possess the bactericidal effectiveness of benzalkonium chloride and are subject to the same incompatibility limitations. In addition, the maximum concentration for benzethonium chloride is 0.01%. Several new products that form gels in the eye, like Timolol Gel Forming Solution and Timoptic-XE, employ another quaternary preservative, BDAB, in the formulation. 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

Using regression analysis on a data set of about 50 different molecules, it was found that a. = —4.4,8 = —0.5, Df = 12 cm2/s, and =2.5x 10 5 cm2/s [192], A graphic representation of the effect of relative molecular mass (Mr) and distribution coefficient on corneal permeability is shown in Fig. 13. One observes a rapid reduction in permeability coefficient with decreasing P and increasing Mr. The addition of pores to the model, a mathematical construct, is necessary to account for permeability of polar molecules, such as mannitol and cromolyn. These would also be required for correlating effects of compounds, such as benzalkonium chloride, which may compromise the... 

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

Fig. 17.13. Electropherograms obtained for the analysis of a nasal formulation for the determinations of benzalkonium chloride (BC) in the presence of active pharmaceutical ingredient (R91274) and other placebo ingredients. Conditions 75 mM sodium phosphate buffer, pH = 2.3, 35 cm fused silica capillary (effective length 28.5 cm) x 75 pm I.D., injection 10 s at 35mbar, 20°C, 15 kV (positive polarity) resulting in a current of approximately 95 pA, detection UV 215 nm.

Potassium iodate is a fairly strong oxidizing agent that may be used in the assay of a number of pharmaceutical substances, for instance benzalkonium chloride, cetrimide, hydralazine hydrochloride, potassium iodide, phenylhydrazine hydrochloride, semicarbazide hydrochloride and the like. Under appropriate experimental parameters the iodate reacts quantitatively with both iodides and iodine. It is, however, interesting to observe here that the iodate titrations may be carried out effectively in the presence of saturated organic acids, alcohol and a host of other organic substances. 

Topical spermicides such as nonoxynol-9 (N9) and benzalkonium chloride act on sperm membranes through a detergent effect, namely, hydrophobe-hydrophobe interaction between the active and substrate (spermatozoa). The idea was to optimize the cationic/hydrophobic polymer in the drug delivery system so epithelial cells were protected without sacrificing the drug s spermicidal activity. One of the questions that needed to be answered in designing an optimum cationic/hydrophobe modified polymer was the effect of the hydrophobe on the drug activity (N9 initially, and other actives subsequently). 

Cho J-H, Kwun Y-S, Jang H-S, et al. Long-term use of preservatives on rat nasal respiratory mucosa effects of benzalkonium chloride and potassium sorbate. Laryngoscope 2000 110(2 Part 1) 312. 

Calcitonin is a peptide hormone produced in the thyroid gland that serves to lower serum calcium and phosphate levels by inhibiting bone resorption. Calcitonin has been used in the treatment of a variety of diseases, such as primary hyperparathyroidism, Paget s disease, and postmenopausal osteoporosis [99,100]. Salmon calcitonin has a longer half-life than human calcitonin. Salmon calcitonin, 3.6 kDa, is available as a nasal formulation that contains only benzalkonium chloride as a preservative, without an absorption enhancer, and as a parenteral product for injection. The direct effect of benzalkonium chloride on the nasal mucosa is under... 

Marttin, E., et al. 1996. Acute histopathological effects of benzalkonium chloride and absorption enhancers on rat nasal epithelium in vivo. Int J Pharm 141 151. 

Green, K., and A.M. Tonjum. 1975. The effect of benzalkonium chloride on the electropotential of the rabbit cornea. Acta Ophthalmol 53 348. 

As analytical capabilities improve, multiple procedures are linked together in series to effect analyses. Procedures combined in this manner are called hyphenated techniques. Ferrer and Furlong [124] combined multiple techniques—accelerated solvent extraction (ASE) followed by online SPE coupled to ion trap HPLC/MS/MS—to determine benzalkonium chlorides in sediment samples. Online SPE, especially coupled to HPLC, is being used more routinely. This approach allowed online cleanup of the ASE extract prior to introduction to the analytical column. 

The quaternary surfactants benzalkonium chloride (BAG) and benzethonium chloride are preferred by many manu-fecturers because of their stabihty, excellent antimicrobial properties in acid formulation, and long shelf life. They exhibit toxic effects on both the tear film and the corneal epithelium and have long been known to increase drug penetration. The toxicity of these compounds may be increased by the degree of acidity of the formulation. 

Desaint JM, Brignole F, Bringuier A, et al. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci 1999 40 619-630. 

Luhtala, S. Kahela, P. Kristofferson, E. Effect of benzalkonium chloride on crystal growth and aqueous solubility of carbamazepine. Acta Pharm. Fenn. 1990,... 

Benzalkonium chloride is composed of a mixture of alkyldimethylbenzylammonium chlorides. The hydro-phobic alkyl residues are paraffinic chains with 8-18 carbon atoms. Benzalkonium chloride is used as a preservative in suspensions and solutions for nasal sprays and in eye-drops. Depending on the concentration of the solution, local irritant effects can occur. In nasal sprays it can exacerbate rhinitis (1) and in eye-drops it can cause irritation or keratitis (2). 

HaUen H, Graf P. Benzalkonium chloride in nasal decon-gestive sprays has a long-lasting adverse effect on the nasal mucosa of healthy volunteers. Clin Exp Allergy 1995 25(5) 401-5. 

Additives to drug for inhalation, such as disodium edetate or benzalkonium chloride, can cause bronchoconstriction (14). This can lead to reduced therapeutic effectiveness of bronchodilators, for example salbutamol or ipratropium. Some products do and others do not contain these additives and an unexpected reduction in response to a bronchodilator may be the result of a casual change of product... 

Benzalkonium chloride at concentrations greater than 0.005 mg/ml causes histamine release from mast cells in vitro. At a concentration of 0.03 mg/ml an excess of 90% of the histamine content is released (5). This is in the range of the minimum concentration of benzalkonium chloride recommended as a disinfectant (0.025 mg/ml). Inhalation of benzalkonium chloride nebulizer solution causes concentration-related falls in FEVi in patients with asthma (6). Benzalkonium chloride 0.3 mg also causes a temporary increase in airway reactivity to histamine. This amount of benzalkonium chloride is similar to that in a 2.5 mg dose from a multidose vial of salbutamol (7). Ipratropium containing benzalkonium chloride 0.25 mg/ml causes bronchoconstriction in a proportion of patients with asthma. BronchodUatation is seen when 2 ml (0.5 mg) of preservative-free ipratropium bromide solution is inhaled (8). Benzalkonium chloride 0.1 mg/ml does not alter the bronchodUator effect of salbutamol. The difference between salbutamol and ipratropium may be the lower concentration of benzalkonium chloride in the salbutamol solution (0.1 versus 0.25 mg/ml) and the greater potency and more rapid onset of the bronchodilator response to salbutamol (9). Individual case reports suggest that... 

Zhang YG, Wright WJ, Tam WK, Nguyen-Dang TH, Salome CM, Woolcock AJ. Effect of inhaled preservatives on asthmatic subjects. II. Benzalkonium chloride. Am Rev Respir Dis 1990 141(6) 1405-8. 

Kwong T, Flatt A, Crane J, Beasley R. The effect of benzalkonium chloride on the bronchodUator response to salbutamol nebuhser solution. NZ Med J 1990 103(898) 457. 

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