Preservation and Preservatives

In 1953, the FDA required that all ophthalmic solutions be sterile (135). Preservatives are included as a major component of all multiple-dose eye solutions for the primary purpose of maintaining sterility in the opened product through its shelf life. Packaging ophthalmic solutions in the popular plastic eyedrop container has reduced, but not completely eliminated, the chances of inadvertent contamination. There can be a "suckback" of an unreleased drop when pressure on the bottle is released. If the tip is allowed to touch a nonsterile surface, contamination may be introduced. Therefore, it is important that the pharmacist instruct the patient on the proper method of dispensing from a plastic eyedrop container to minimize the hazards of contamination. The hazard is magnified in the busy clinical practice of the eye care professional where a diagnostic solution—there are many, including cycloplegics, mydriatics, and dyes—may be used for many patients from the same container. The cross-contamination hazard can be eliminated by the use of packages containing small volumes designed for single application only (i.e., unit dose). Since preservatives are not included in solutions packaged in unit-dose containers, and because these single-use packages still contain (as a large-scale manufacturing necessity) an amount in excess of the several drops (0.05-0.20 mL) required, patient and physician alike should be cautioned to avoid exhausting their entire contents in a multiuse application that will increase the hazard of contamination and defeat the purpose of this special packaging.

Preservative effectiveness testing is defined in both United States and European Pharmacopoeias, and global regulatory agencies require an evaluation and control of the effectiveness of the preservative against various microbial strains from the four major classes of eye pathogens, namely gram-positive cocci {Staphylococcus aureus), gramnegative rods (P. aeruginosa), yeasts (Candida albicans), and fungi (Aspergillus niger) (136).

In the ophthalmic literature, because of reports of loss of eyes from corneal ulcerations caused by eye solutions contaminated with P. aeruginosa, considerable emphasis is placed on the effectiveness of preservatives against Pseudomonas species. This organism is not the most prevalent cause of bacterial eye infections, even though it is a common inhabitant of human skin, but it is the most opportunistic and virulent. S. aureus is responsible for most bacterial infections of the eye. The eye seems to be remarkably resistant to infection when the corneal epithelium is intact due to the barrier properties discussed previously as well as the antimicrobial activity of lysozyme and other enzymes present in tears. When there is a corneal epithelial abrasion, organisms can enter freely and P. aeruginosa can grow readily in the cornea, rapidly producing an ulceration and loss of vision. This microorganism has been found as a contaminant in a number of studies on sterility of ophthalmic solutions, particularly in sodium fluorescein solutions used to detect corneal epithelial damage. The chances for serious infections and cross-contamination are greatly enhanced by multiple use of this dye solution—a danger that has led to the practice by the ophthalmologist of using sterile disposable applicator strips of fluorescein.

Recently, preclinical and clinical studies have reported that the long-term use of preserved topical medications in chronic ophthalmic conditions, such as glaucoma, may adversely affect the ocular surface at the expense of corneal health (137). Consequently, preservatives are thought to be partially responsible for ocular side effects, for chronic ophthalmic diseases manufacturers are developing products with either reduced preservatives or preservative-free formulations (138). Alternative packaging for multidose nonpreserved preparations and drugs administered in dry form (139) may offer nonpreserved choices for the formulator, but efficacy and compatibility of each drug with these systems must be investigated. Because experimental results reported in the literature have shown a somewhat higher incidence of adverse effects with preserved solutions compared with unpreserved, there is some question of the necessity for preservatives in some applications (140,141). However, preservatives can enhance drug efficacy, chemically balance a preparation, and enable a dosing form that promotes patient compliance. While some ophthalmic drugs may be formulated in an unpreserved form, many drugs cannot, and it is the challenge of the formulator to provide an acceptable balance of safety and effectiveness.

Choice of Preservative

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, polyquaternium-1, and polyaminopropyl biguanide. The chelating agent, EDTA, is sometimes used to increase activity against certain Pseudomonas strains, particularly solutions preserved with BAC. Chlorhexidine— as the hydrochloride, acetate, or gluconate salts—is used widely in the United Kingdom and Australia, but was not introduced into the United States until 1976, and only then for solutions intended for disinfection of soft contact lenses. This limited choice of preservative agents is further narrowed by the requirements of chemical and physical stability and compatibility with drugs, packaging, and contact lens materials. Many times it is necessary to design the formula to fit the requirements of the chosen preservative system since the buffer system and excipients can alter preservative action significantly. While it is recognized that excipients themselves may produce toxicity, and their use need be controlled, the large variety and number of available excipients prohibits discussion here, and the reader is referred to a pharmaceutical text that provides an excellent review (142).

Several guidelines are available in the literature for the pharmacist who must extemporaneously prepare an ophthalmic solution. The USP contains a section on ophthalmic solutions, as do other compendia and several standard textbooks. Since the pharmacist does not have the facilities to test the product, he or she should dispense only small quantities, with an expiration date of no more than 30 days. Refrigeration of the product should also be required as a precautionary measure. To reduce the largest potential source of microbial contamination, only sterile purified water should be used in compounding ophthalmic solutions. Sterile water for injection (WFI), USP, from unopened IV bottles or vials is the highest-quality water available to the pharmacist. Prepackaged sterile water with bacteriostatic agents should not be used.

Benzalkonium chloride The most widely used preservative remains BAC, which often is supplemented with disodium edetate. The BAC 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 Ci6. 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 degrade even under excessively hot storage conditions. It has pronounced surface-active properties, and its activity can be reduced by adsorption. It is cationic, which unfortunately can lead to a number of incompatibilities with large negatively charged molecules with the potential for producing salts of lower solubility and possibly precipitation. For example, it cannot be used with nitrates, salicylate, anionic soaps, and large anionic drugs, such as sodium sulfacetamide and sodium fluorescein. When feasible, it is usually advisable to design the formula to avoid these incompatible anions, rather than to substitute a less effective preservative. There are a number of helpful lists of incompatibilities of BAC in the literature, but they should not be relied upon entirely. Compatibility is determined by the total environment in which the drug molecules exist (i.e., the total product formula). The pharmaceutical manufacturer can sometimes design around what appears to be an incompatibility, whereas the extemporaneous compounder may not have this option, or more importantly, the ability to test the final product for its stability, safety, and efficacy.

The conventional concentration of BAC in eyedrops is 0.01%, with a range of 0.004% to 0.02% (143). While uptake of BAC itself into ocular tissues is limited (144), even lower concentrations of BAC have been reported to enhance corneal penetration of other compounds, including therapeutic agents (125,145,146). The differential effect of this preservative on the cornea compared with the conjunctiva can be exploited to target a drug for corneal absorption and delivery to the posterior segment of the eye (147). Its use has been proposed as a means of delivering systemic doses by an ocular route of administration (148).

Richards (149), Mullen et al. (150), and the American College of Toxicology (151) have summarized the literature of BAC. The conclusion drawn was that BAC, up to 0.02%, has been well substantiated as being suitable for use in topical ophthalmic solutions when the conditions of its use are properly controlled.

Numerous studies comparing BAC 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 appropriate tests for nearly any product. Generally, the USP (or similarly validated) test can be employed to decide which preservative system is most compatible with a specific composition. While multiple reports show BAC to have a somewhat higher incidence of ocular effects (152-154), this preservative remains one of the most effective available and generally assures an adequate level of preservative efficacy.

Some strains of P. aeruginosa are resistant to BAC 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 ethylenediaminetetraacetic acid (sodium edetate; EDTA) in the formulation. This action of EDTA has been correlated with its ability to chelate divalent cations and is commonly used as a preservative aid (155). The use of EDTA, where it is compatible, is recommended in concentrations up to 0.1%.

Other quaternary ammonium germicides, benzethonium 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 BAC and are subject to the same incompatibility limitations. In addition, the maximum concentration for benzethonium chloride is 0.01%.

Organic mercurials When BAC cannot be used in a particular formulation of a therapeutic agent—for example, pilocarpine nitrate, serine salicylate, or fluorescein sodium (because of potential anion-cation association)—one of three organic mercurials, phenylmercuric nitrate, phenylmercuric acetate, and thimerosal, had, until recent years, been used. Because of environmental concerns, however, the use of organic mercurials has fallen into disfavor. Although organic mercurials have not been implicated in classical mercurial toxicity, several countries have banned their use entirely, and other countries require its rigorous defense based on the absence of any suitable alternative. In those situations for which the use of an organic mercurial is the only avenue available, the usual range in concentration for the phenylmercuric compounds is 0.002% to 0.004% and for thimerosal 0.02% to 0.1%. Although they can be used effectively in some products, the mercurials are relatively weak and slow in their antimicrobial activity. The organic mercurials are generally restricted to use in neutral to alkaline solutions; however, they have been used successfully in slightly acid formulations. The phenyl mercuric ion can react with halide ions to form salts of lower solubility, reducing their effectiveness. Thimerosal has a greater solubility and is relatively more stable than the phenylmercuric compounds and has not been shown to deposit in the lens of the eye. The latter phenomenon has been observed with phenylmercuric compounds.

Ocular sensitization to thimerosal has been well documented over the years (156-162). Although thimerosal had at one time been referred to as the preservative of choice for soft contact lens care products (163-165), its use has been supplanted almost completely by the polyquaternium-1 and polybiguanide preservatives.

Since the organic mercurials offer an alternative to quaternary ammonium preservatives and since preservative efficacy of ophthalmic solutions is essential, the choice among these alternatives should be based on a benefit-to-risk analysis so long as a ban is not imposed on the use of these organometallic preservatives.

Chlorobutanol This aromatic alcohol has been an effective preservative and is still used in several ophthalmic products. Over the years, it has proved to be a relatively safe preservative for ophthalmic products (166) and has produced minimal effects in various tests (131,167,168). In addition to its relatively slower rate of activity, it imposes a number of limitations on the formulation and packaging. It possesses adequate stability when stored at room temperature in an acidic solution, usually about pH 5 or below. If autoclaved for 20 to 30 minutes at a pH of 5, it will decompose to about 30%. The hydrolytic decomposition of chlorobutanol produces hydrochloric acid (HC1), resulting in a decreasing pH as a function of time. As a result, the hydrolysis rate also decreases. Chlorobutanol is generally used at a concentration of 0.5%. Its maximum water solubility is only about 0.7% at room temperature, which may be lowered by active or excipients, and is slow to dissolve. Heat can be used to increase dissolution rate, but will also cause some decomposition and loss from sublimation. Concentrations as low as 0.125% have shown antimicrobial activity under the proper conditions.

Methyl- and propylparaben These esters of /j-hydroxybenzoic acid have been used primarily to prevent growth of molds, but in higher concentrations possess some weak antibacterial activity. Their effective use is limited by low aqueous solubility and by reports of stinging and burning sensations related to their use in the eye. They bind to a number of nonionic surfactants and polymers, thereby reducing their bioactivity. They are used in combination with the methyl ester at 0.03% to 0.1% and the propyl ester at 0.01% to 0.02%. Parabens have also been shown to promote corneal absorption (133).

Phenylethyl alcohol This substituted alcohol has been used at 0.5% concentration, but in addition to its weak activity, it has several limitations. It is volatile and will lose activity by permeation through a plastic package. It has limited water solubility, can be "salted out" of solution, and can produce burning and stinging sensations in the eye. It has been recommended primarily for use in combination preservative systems.

Polyquaternium-1 (POLYQUAD®) This preservative is still comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be in its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001% to 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 BAC (120,169). Various in vitro tests and in vivo evaluations substantiate the safety of this compound (169,170,171). 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 practically a nonexistent potential for sensitization. Its adsorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components (172).

Chlorhexidine Chlorhexidine, a bisbiguanide, has been demonstrated to be somewhat less toxic than BAC and thimerosal at clinically relevant concentrations (120,122,127, 173,174). This work was confirmed in a series of in vitro and in vivo experiments (169,175-177).

Polyaminopropyl biguanide This preservative is also comparatively new to ophthalmic formulations and has been used as a disinfectant in contact lens solutions. Polyaminopropyl biguanide (polyhexamethyl biguanide) also is a polymeric compound that has a low toxicity potential at the concentrations generally used in these solutions (170,178,179).

Cetrimonium chloride This preservative has been used in a dry eye treatment and was shown in a clinical study to have the same biocompatibility as another marketed preparation (180). Cetrimonium chloride (0.01%) produced the same corneal and conjunctival changes after one-month ocular administration in rats as the effective levels of other major preservatives (141).

Purite This preservative is a stabilized oxychloro complex and is used in brimonidine purite 0.1% and 0.15% and purite-preserved artificial tears. Purite has demonstrated antimicrobial efficacy and is reported to induce less corneal epithelial damage than BAC in a rabbit model (181,182). Clinical trials have also reported purite-containing formulations to be well tolerated (183,184).

SofZia This preservative system has been formulated in both OTC pharmaceuticals and in TRAVATAN Z® solution, an IOP-lowering medication. SofZia contains boric acid, propylene glycol, sorbitol, and zinc chloride. It has been reported that SofZia is less irritating than BAC (185-187).

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