Preservatives in Topical Ophthalmic Medications: Historical and Clinical Perspectives

P. David Freeman; Malik Y. Kahook

Disclosures

Expert Rev Ophthalmol. 2009;4(1):59-64. 

In This Article

Evolution of Preservatives Since Benzalkonium Chloride

Cetrimonium is a detergent-type preservative. Its ophthalmic uses have included preservation of artificial tear preparations such as Civigel (Ciba Vision Ophthalmics, GA, USA) Table 1 . Cetrimonium causes keratinization and inflammatory infiltrates at the limbus and within the conjunctival stroma and epithelium.[3] Its corneo–conjunctival cell toxicity has been deemed similar to BAK. Owing to its antiseptic and cationic surfactant qualities, cetrimonium is used mostly as a softening agent in hair treatments. It is also used as a fermentation aid, a dispersant and in preservation of antifungal creams.

Chlorobutanol

Chlorobutanol is a detergent preservative that was formerly used as an active ingredient in hypnotic and sedative agents.[9] Chlorobutanol has been used as a preservative agent in artificial tears, where it has been documented to cause significant keratitis and irritation to the ocular surface.[15] While it damages the ocular surface cells, the toxic effects take longer to manifest in human corneas than do the effects of BAK.[16] Human corneal epithelial cells exposed to chlorobutanol display a decreased amount of mitoses and deterioration of overall cell integrity.[16] Chlorobutanol does not, however, affect the stability of the lipid component of the tear film.[17]

Although the antimicrobial activity of chlorobutanol is extensive,[18] its use has been limited due to the fact that it becomes unstable when stored at room temperature for extended periods of time. Unlike BAK, chlorobutanol does not act like a surfactant.[17] The method of action of chlorobutanol is cell lysis by way of disruption of microbial cell membrane lipid configuration.[17]

Edetate Disodium

Edetate disodium (EDTA) is a chelating agent used in a variety of nonophthalmic products, including hair conditioner, facial cleansers, aftershaves and deodorants. In the recycling industry, it has been used to recover lead from used lead-acid batteries. In the medical field, uses include the treatment of acute mercury poisoning, lead poisoning and hypercalcemia. EDTA has gained use in ophthalmic solutions owing to its ability to bind metals. Therapeutically, EDTA has been used to remove calcified plaques that occur in the superficial cornea in band keratopathy.[19] EDTA has also been used in eye washes to aid in neutralization of calcium hydroxide or lime burns to the cornea.

Edetate disodium also has preservative effects based on its ability to chelate. When added to topical medicines in low concentrations, EDTA has been shown to inactivate trace amounts of heavy metals, which aids in the preservation of the solution.[18] Ophthalmic solutions that have employed EDTA include Acular® (ketorolac tromethamine ophthalmic solution) and Betagan® (levobunolol hydrochloride ophthalmic solution USP).

Polyquaternium-1 (Polyquad®)


Polyquad® is a detergent-type preservative derived from BAK. Polyquad was formulated in the mid 1980s by Alcon as a preservative for contact lens storage solutions. It was developed because other preservatives (e.g., BAK) were known to become concentrated in contact lenses that had been stored in conventional lens solutions. When placed in an aqueous ocular environment, the contaminated contact lens can act as a reservoir of preservative that can later be released. Polyquad does not become concentrated in contact lenses.

Although it is a detergent, Polyquad has unique properties distinguishing it from BAK. Bacterial cells attract Polyquad, yet human corneal epithelial cells tend to repel the compound.[20] Polyquad is the main ingredient in Tears Naturale II (Alcon) and Opti-Free Express MultiPurpose Disinfecting Solution (Alcon), as well as other storage solutions for contact lenses.

While Polyquad has been shown to be much less toxic to the corneo–conjunctival surface than BAK,[21] it has been shown to cause superficial epithelial damage to the cornea.[22] The main detriment associated with polyquaternium-1 is its tendency to reduce the density of conjunctival goblet cells, thereby decreasing aqueous tear film production.[21]

Polyhexamethylene Biguanide

Polyhexamethylene biguanide (PHMB) has been used in contact lens solutions such as ReNu® (Bausch & Lomb, NY, USA) and has historically been a component of pool cleaners, skin disinfectants and urinary catheter flush solutions. The benefits of PHMB against Acanthamoeba and bacteria are well known.[23] PHMB has been shown to be nonirritating to human corneal cells; however, its antifungal activity is limited.[18] PHMB employs its microbial activity by integrating into bacterial cell walls, thereby disrupting its membrane and has been shown to lethally alter the transcription of bacterial DNA.[24]

Stabilized Oxychloro Complex

Stabilized oxychloro complex (Purite, Bio-Cide International Inc., OK, USA) is an oxidative-type preservative and was introduced into ophthalmic medicines in the mid 1990s under the trade name Purite. One of its derivatives, sodium chlorite, has been used in water purification systems since the 1940s.[25] Purite has become a component of several different types of artificial tear and antiglaucoma preparations, including brimonidine tartrate ophthalmic solution (Alphagan-P®, Allergan, CA, USA) and Refresh Tears (Allergan).

Stabilized oxychloro complex has been shown to be well tolerated by the ocular surface.[25] Even at very low concentrations of SOC (0.005%), the antimicrobial activity is broad.[4] This was substantiated during a trial in which SOC was administered to patients up to eight-times daily.[25] SOC has been shown to lack cytotoxicity in vivo; however, more studies are needed to assess ocular side effects independent of active ingredients.[26] The antimicrobial effects are broad and include antibacterial, antifungal and antiviral effects. Chemically, SOC is a mixture of chlorine dioxide, chlorite and chlorate.[4] When exposed to light, SOC dissociates into water, oxygen, sodium and chlorine free radicals.[27] The chlorine free radicals are thought to inhibit microorganism protein synthesis within cells by way of glutathione oxidation, which causes microbe cell death.[101]

Sodium Perborate (GenAqua™)

GenAqua™ is a preservative composed of sodium perborate and is contained in Genteal lubricant eye drops (Novartis Ophthalmics, NJ, USA). Sodium perborate is an oxidative preservative that has been used in dental hygiene solutions since the 1950s. When it was introduced in ophthalmic solutions, it was one of the first of the oxidative-type preservatives used. Sodium perborate alters protein synthesis within bacterial cells by oxidizing cell membranes and altering membrane-bound enzymes, causing enzymatic inhibition. Upon exposure to an aqueous environment, it is catalyzed into hydrogen peroxide, water and oxygen. This is a property exclusive to this compound. The hydrogen peroxide formed by this reaction effectively kills microbes.[26] Furthermore, the efficacy of GenAqua has been demonstrated on Aspergillus niger.[26] There are few studies documenting the ocular tolerability and side-effect profile of GenAqua.

SofZia™

SofZia™ is the most recent advancement in the field of ophthalmic preservatives and is the preservative system contained in one preparation of travoprost (Travatan Z®, Alcon, Texas). When exposed to cations, such as those that are normally encountered in the tear film of the eye, sofZia is deemed inactive. This is thought to induce less cytotoxicity to the ocular surface compared with more conventional preservatives.

Travatan Z was introduced as the first prostaglandin analogue to be preserved with a substance other than BAK. The sofZia system effectively preserves the medicine while it is being stored; however, when the drug is introduced into the eye, it is modified into harmless elements that are gentle on the ocular surface.[6] It has been demonstrated that sofZia-preserved travoprost induces corneal and conjunctival changes similar to preservative-free artificial tears. Furthermore, travoprost with sofZia also induced reduced amounts of conjunctival inflammation and corneal changes when compared with travoprost treated with BAK.[28]

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