Preservatives benzalkonium chloride

The method was separately validated 19] to simultaneously measure the content of a basic drug and the preservative benzalkonium chloride in a liquid formation. 

Morimoto, K. Uehara, Y. Iwanaga, K. Kakemi, M. Ohashi, Y. Tanaka, A. Nakai, Y. Influence of absorption enhancers (bile salts) and the preservative (benzalkonium chloride) on mucociliary function and permeation barrier function in rabbit tracheas. Eur. J. Pharm. Sci. 1998, 6 (3), 225-230. 

In this case the allergic reaction was caused by dorzolamide hydrochloride and not the preservative, benzalkonium chloride, since therapy was uneventfully continued with timolol maleate, which also contains benzalkonium chloride as a preservative. This is the first report of this phenomenon with a carbonic anhydrase inhibitor. 

Cases of allergic conjnnctivitis and blepharitis have been reported with the preservatives benzalkonium chloride and mercnrial salts, althongh benzalkonium at the commonly nsed concentration of 0.01% produces no evident damage. These adverse reactions can be prevented by rinsing hard lenses in clean water before insertion in the eye and by boihng soft lenses in normal saline after cleaning. 

At pH 7, tragacanth has been reported to considerably reduce the efficacy of the antimicrobial preservatives benzalkonium chloride, chlorobutanol, and methylparaben, and to a lesser extent that of phenol and phenylmercuric acetate. However, at pH < 5 tragacanth was reported to have no adverse effects on the preservative efficacy of benzoic acid, chlorobutanol, or methylparaben. ... 

Thimersol preservative, benzalkonium chloride, alcohol Benzalkonium chloride, EDTA... 

All eye drops for allergic conjunctivitis contain the preservative benzalkonium chloride, which is absorbed into soft contact lenses and released onto the cornea during wear, causing inflammation and irritation. Soft lenses should not be worn while using these products gas-permeable lenses may be inserted 30 minutes after using the eye drops. 

Some excipients, such as the preservative benzalkonium chloride (BAC), can also act as penetration enhancers. Madhu et al. studied the influence of BAC/EDTA (disodium edetate) on ocular bioavailability of ketorolac tromethamine following topical ocular instillation onto normal and de-epithelialized rabbit corneas in vitro and in vivo (28), demonstrating its ability to disrupt epithelial cell tight junctions, and so enhance penetration. 

The combination of benzalkonium chloride and betaphenylethanol in final concentrations of 0.05 g/L and 4 g/L, respectively, is sometimes used to preserve eye drops (but with care and restrictions as betaphenylethanol often causes irritation). In that case, for the preparation of 10 mL of 0.5 % Atropine sulfate eye drops, 0.5 mg of benzalkonium chloride and 40 mg of betaphenylethanol are required. The preservatives can be added to the prepared solution by droplets as follows the amount of 40 mg of betaphenylethanol corresponds to two drops of this liquid preservative benzalkonium chloride is used as a 0.5 % stock solution five drops (100 mg of the stock solution) are needed. 

Fig. 10.8 A where the R substituents are alkyl or heterocyclic radicals to give compounds such as cetyltrimethylammonium bromide (cetrimide), cetylpyridinium chloride and benzalkonium chloride. Inspection of the stmctures of these compounds (Fig. 10.8B) indicates the requirement for good antimicrobial activily of having a chain length in the range Cg to Cig in at least one of the R substituents. In the pyridinium compounds (Fig. 10.8C) three of the four covalent links may be satisfied by the nitrogen in a pyridine ring. Polymeric quaternary ammonium salts such as polyquatemium 1 are finding increasing use as preservatives.

Examples of preservatives are phenylmercuric nitrate or acetate (0.002% w/v), chlorhexidine acetate (0.01 % w/v), thiomersal (0.01 % w/v) and benzalkorrium chloride (0.01 % w/v). Chlorocresol is too toxic to the comeal epithehum, but 8-hydroxyquinoline and thiomersal may be used in specific instances. The principal considerahon in relation to antimicrobial properties is the activity of the bactericide against Pseudomonas aeruginosa, a major source of serious nosocomial eye infections. Although benzal-konium chloride is probably the most active of the recommended preservatives, it cannot always be used because of its incompatibility with many compounds commonly used to treat eye diseases, nor should it be used to preserve eye-drops containing anaesthetics. Since benzalkonium chloride reacts with natural mbber, silicone or butyl rabber teats should be substituted. Since silicone mbber is permeable to water vapour, products should not be stored for more than 3 months after manufacture. As with all mbber components, the mbber teat should be pre-equilibrated with the preservative prior to... 

Substances that have been used as preservatives for disperse systems include chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, parabens, and others [76,77]. The use of cationic antimicrobial agents such as quaternary ammonium compounds (e.g., benzalkonium chloride) is contraindicated in many cases because they may be inactivated by other formulation components and/or they may alter the charge of the dispersed phase. Clay suspensions and gels should be adequately preserved with nonionic antimicrobial preservatives. The use of preservatives is generally limited to products that are not intended for parenteral use. Intravenous injectable... 

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]. 

Numerous studies comparing benzalkonium chloride with other preservatives have been described in the literature. Many of the articles give conflicting results, not surprising considering the many different test methods, formulas, and criteria used to arrive at these diverse conclusions. However, adequate information is available in the literature to permit the manufacturer to select... 

Some strains of P. aeruginosa are resistant to benzalkonium chloride and, in fact, can be grown in solutions concentrated in this agent. This has caused great concern because of the virulent nature of this organism in ocular infections, as discussed previously. Thus, it was an important finding in 1958 that the acquired resistance could be eliminated by the presence of ethylenediaminetetracetic acid (sodium edetate) in the formulation. This action of EDTA has been correlated with its ability to chelate divalent cations, and it is commonly used as a preservative aid [125]. The use of disodium EDTA, where compatible, is recommended in concentrations up to 0.1%. 

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],... 

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... 

Soft contact lenses The preservative in brimonidine, benzalkonium chloride, may be absorbed by soft contact lenses. Instruct patients wearing soft contact lenses to wait at least 15 minutes after instilling brimonidine to insert soft contact lenses. Renal/Hepatic function impairment Use caution when treating patients with hepatic or renal impairment. 

Bacterial keratitis Bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products has been reported. Serious damage to the eye and subsequent loss of vision may result from using contaminated preparations. Benzalkonium chloride Benzalkonium chloride is a preservative used in some of these products that may be absorbed by soft contact lenses. Patients wearing soft... 

Benzalkonium chloride ( ) is used as an antimicrobial preservative in Nasonex. It is quantifiable using a HPLC method with a column that has a cyano group chemically bonded to porous silica particles. The HPLC was equipped with a UV-Vis detector, a 150 mm x 4.6 mm, 3- jm Spherisorb S3 CN column. The mobile phase consisted of 45% acetonitrile in 0.05 M phosphate buffer (pH 6.0). The flow rate was set at 1 mL/min. The following procedure was used for sample and standard preparations. About 2.5 g of Nasonex was transferred into a 25-mL volumetric flask. This was diluted to volume with acetonitrile and... 

Each milliliter of NASALCROM nasal spray contains 40 mg of cromolyn sodium in purified water with 0.01% benzalkonium chloride to preserve and 0.01% EDTA (ede-... 

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. 

Benzalkonium chloride Preservative Magnesium stearate Tablet lubricant... 

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... 

Nebulizer solutions are often presented as concentrated solutions from which aliquots are withdrawn for dilution before administration. Such solutions require the addition of preservatives, e.g. benzalkonium chloride, and antioxidants (e.g. sulphites). Both excipient types have been implicated with paradoxical bronchospasm and hence the current tendency to use small unit-dose solutions that are isotonic and free from preservatives and antioxidants. 

Presoaked lenses are considered a more efficient and reliable delivery system. However, the soaking of lenses in ophthalmic formulations to incorporate the drag into the lens may cause toxicity to corneal epithelium because preservatives, such as benzalkonium chloride, have a great affinity for the hydrophilic contact lens material and are concentrated in the contact lens. Contact lens for sensitive wearers may also cause foreign-body sensation, blurring and decreased oxygen tension on the corneal surface resulting from occlusion by contact lens. 

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