Ocular Preservatives: Associated Risks and Newer Options
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Cutaneous and Ocular Toxicology, 2009; 28(3): 93–103 CRITICAL REVIEW Ocular preservatives: associated risks and newer options Indu Pal Kaur, Shruti Lal, Cheena Rana, Shilpa Kakkar and Harinder Singh University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India Abstract Presence of a preservative in an ocular medication has often been considered a culprit in damaging the epithelium. However, the inclusion of a preservative is equally necessary, especially in multiple-dose con- tainers, in order to protect against dangerous organisms accidentally gaining access during instillation. Benzalkonium chloride (BAK), chlorobutanol, chlorhexidine acetate (CHA), and phenylmercuric nitrate or acetate are some commonly used preservatives in eye preparations. New preservatives with a wide range of activity and good safety profiles have been introduced in the market, such as stabilized oxychloro com- plex (SOC), sofZia, and sodium perborate. In the present review, we discuss various conventional and newly proposed and patented preservative molecules for ocular use. Reasons for discontinuing traditional pre- servatives and the need for less-toxic molecules are discussed at length, along with newer options coming up in this area. Keywords: Preservative; ocular; newer; toxicity For personal use only. Introduction and stabilizers, and a vehicle by which all the above ingredients are “carried.” Of these, the preservative In chronic eye diseases, for effective therapy, ophthalmic has most often been considered the culprit in damag- medication is to be given regularly for longer durations ing the corneal epithelium, leading to disruption of than usual dosing regimens. Typical examples of such the glycocalyx, when drops are used beyond the rec- chronic pathologies are dry eye, glaucoma, and certain ommended dosing. This sequence of repeated dosing eye infections, especially fungal infections. Preservative leaves the epithelium unable to keep the tear film in is an important constituent of multiple-dose containers place and can lead to ocular surface disease. This is that helps to minimize the risk associated with acci- especially true for patients who overuse their artificial dental microbial contamination, but its frequent use tear products, use multiple ocular medications, suffer has been associated with alteration in the precorneal from chronic eye diseases like dry eye or glaucoma, or film. In patients suffering from dry eye, preservatives require postsurgery dosing of medication. In a way, Cutaneous and Ocular Toxicology Downloaded from www.informahealthcare.com by HINARI on 08/21/09 tend to aggravate the already existing problem; and in it is not incorrect to say that the preservatives are a glaucoma patients, the prolonged use of eye drops with “ necessary evil.” preservatives has been associated with changes in ocu- Today, ophthalmologists have numerous antiglau- lar surface accompanied by inflammation. In fact, con- coma medications and artificial tears from which to junctival biopsies in patients suffering from glaucoma choose. Although topically administered medications have revealed an increased number of immune cells and are increasingly used with apparent safety and good fibroblasts (1,2). tolerance, there is growing evidence that long-term use Ocular medications are composed of unique of topical drugs can induce changes in the ocular sur- mixtures of the active drug, a preservative, the drug face and may often produce damage to conjunctival and delivery system, viscosity-increasing agents, buffers corneal epithelial cells. There have been several reports Address for Correspondence: Indu Pal Kaur, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. Tel.: 91 172 2534113 (0); Fax: 91 172 2541142; E-mail: [email protected] (Received 06 January 2009; revised 24 April 2009; accepted 25 April 2009) ISSN 1556-9527 print/ISSN 1556-9535 online © 2009 Informa UK Ltd DOI: 10.1080/15569520902995834 http://www.informahealthcare.com/cot 94 I. P. Kaur et al. of the toxic effects of prolonged topical treatments, cannot neutralize chemical preservatives, so the pre- partly due to the preservatives associated with the for- servative is incorporated into the cell and causes cellular mulation of such treatments (3,4). In the eye, preserva- damage (21). tive turnover is very slow, and quaternary ammonium Oxidants—Oxidative preservatives are usually small molecules can be retained in ocular tissues for up to 7 molecules that penetrate cell membranes and inter- days (5). The lipophilic nature of some preservatives fere with cellular function (22). They can destabilize causes them to bind to the ocular tissues immediately cell membranes, but to a lesser degree than detergent after topical application. Previous studies by Burstein preservatives. Stabilized oxychloro complex (SOC) (4,5) have shown that topically applied benzalkonium and sodium perborate are 2 examples of oxidative pre- chloride (BAK), the most commonly used preservative servatives. At low levels, oxidative preservatives have in ophthalmic solutions, can cause morphologic disrup- an advantage over detergent preservatives because tion of the corneal epithelium at high concentrations. In they can provide enough activity against microorgan- addition, there is evidence that clinical concentrations isms while having only negligible toxicity on eukaryo- of BAK may change the ionic resistance of the cornea by tic cells. This is because many microorganisms do not intercalating into cellular membranes, which results in have the ability to cope with oxidative stress, whereas increased permeability (7). mammalian cells are equipped with antioxidants, oxi- Three types of mechanisms have been described: dases, and catalases to neutralize the effect of a low- detergent effects causing loss of tear film stability, toxic level oxidant. effects to the corneal and conjunctival epithelia, and This article concentrates on some of the most com- immunoallergic reactions (5,6). Furthermore, repeated monly used detergent and oxidative preservatives, doses of preserved eye drops can have a cumulative namely, BAK, phenyl mercuric nitrate or acetate, chor- effect, because the preservatives are in prolonged con- hexidine acetate (CHA), sorbic acid, chlorobutanol, tact with the epithelium. Several studies have confirmed sodium perborate, SOC, and polyquaternium-1. Other the participation of preservatives in induction of ocular preservatives found in ophthalmic preparations include surface inflammation (7,8), allergy (8), fibrosis (9), and benzododecinium bromide (BDD), cetrimonium chlo- dry eye syndrome (10,11). Preservatives are also sus- ride, thiomersal, methyl parahydroxybenzoate, poly- pected of strongly increasing the risk of failure of trab- quaternium ammonium chloride, polyaminopropyl eculectomy in glaucoma (12,13). biguanide, and hydrogen peroxide. Tables 1 and 2 con- In vitro models have been developed to predict the tain a list of commonly used products and associated For personal use only. cytotoxic potential of preservatives. These models were preservatives. essentially based on corneal epithelial cells (14,15) or on other epithelial systems with characteristics similar Table 1. Preservative-containing common glaucoma medications. to those of the superficial layer of the corneal epithelium Trade name of (Madin–Darby canine kidney cells) (16). The human Sr. No. glaucoma formulations Manufacturer Preservative continuous conjunctival cell line has also been useful 1. Alphagana Allergan 0.005% BAK for ocular toxicologic studies (17,18). It has been shown 2. Alphagan Pa Allergan 0.005% SOC that BAK is a strong proapoptotic agent in Chang’s con- 3. Azopta Alcon Laboratories 0.01% BAK junctival cells (19). 4. Betagana Allergan 0.005% BAK In the present review, we discuss conventional, 5. Betoptic Sa Alcon Laboratories 0.01% BAK newly proposed, and patented preservative molecules 6. Cosopta Merck & Co. 0.0075% BAK for ocular use. Reasons for discontinuing traditional 7. Resculaa Novartis Ophthalmics 0.015% BAK Cutaneous and Ocular Toxicology Downloaded from www.informahealthcare.com by HINARI on 08/21/09 preservatives and the need for less-toxic molecules are 8. Timoptica Merck & Co. 0.01% BAK discussed at length, along with newer options coming 9. Timoptic-XEa Merck & Co. 0.012% BDD up in this area. 10. Trusopta Merck & Co. 0.0075% BAK 11. Xalatana Pfizer 0.02% BAK 12. Humorsolb Merck & Co. 1:5,000 BAK Mechanism of action of preservatives 13. Iopidine eye dropsb Alcon Laboratories 0.01% BAK 14. Lumiganb Allergan 0.005% BAK Preservatives can be classified into 2 main categories, on 15. Ocupressb Bausch & Lomb 0.005% BAK the basis of their mechanism of action: 16. Optipranololb Bausch & Lomb 0.004% BAK Detergents—Detergent preservatives, such as BAK, 17. Propineb Allergan 0.04% BAK a act upon microorganisms by altering cell membrane Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther 2001; 18:205-215. permeability and lysing cytoplasmic contents (20). bhttp://www.rxlist.com. Accessed September 2008. Ocular toxicity can occur because some detergent pre- BAK = benzalkonium chloride; BDD = benzododecinium bromide; servatives can affect eukaryotic cells. Mammalian cells SOC = stabilized oxychloro complex. Ocular preservatives: risks and new options 95 Table 2. Multidose, over-the-counter medications for dry eye with or without preservatives. Sr. No. Trade name Manufacturer Active ingredients(s) Preservative 1. GenTeal