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The consequences of preservatives in eye drops

Here's the preservative paradox:

I. Overview of the General Consequences of Preservatives: Allergies and Cytotoxicity.

The consequences of preservatives in eye drops have been reported since 1941, however, we must recognize that little has changed since then. Nevertheless, there is now growing and overwhelming evidence that preservatives have serious adverse or even very severe consequences in ocular therapies.

ToxicBenzalkonium for instance, is a quaternary ammonium used a detergent, antiseptic, disinfectant, fungicide, bactericide, and spermicidal. You can easily imagine that its use on the ocular surface must have some consequences! However, Benzalkonium is one of most frequently used preservatives in eyedrops as well. One of the first obvious consequences of Benzalkonium preserved eye-drops is the disruption of the lachrymal or the tear film. The reason why is quite simple since all surfactant detergent are able to dissolve lipids. Therefore even a healthy tear film containing an adequate lipid layer will be altered by the presence of such a detergent. This disruption of the tear film may lead to dryness by increasing evaporation and inflammation and ocular surface damage. But Benzalkonium has other consequences including allergic, cytotoxic and storage side-effects. Benzalkonium modifies the proteins of the eye and may provoke two types of immunitary reactions: allergy or cytotoxicity. Indeed, several studies indicate that Benzalkonium provokes cell death (apoptosis) of the corneal epithelial cells. In doing so, Benzalkonium delays corneal wound healing. There is also evidence that Benzalkonium penetrates the eye and is stored in several ocular tissues (notably the conjunctiva, cornea, iris, retina, the lens, the aqueous humor, choroids coat, etc) [1]. Some studies even suggest that Benzalkonium may cause cataracts or change the color of your eyes’ irises by adding brownish spots on the iris. "Therefore eye drops with benzalkoniumBiological harzard chloride in concentrations above 0.005% should be abandoned in clinical therapy" as some authors state [6]. Since most drops use BAK in higher concentrations and that sterility is unlikely to be achieved with such minimal concentrations, we may conclude that BAK containing drops should not be used altogether. Futhermore, one study concludes that after the withdrawal of BAK, "The improvement was found to be proportional to the duration of the preceding BAC-containing therapy"[8]. This substance is a hazard to human corneal biology!

Benzalkonium is only one the most commonly used preservatives, but most comments above are applicable to all quaternary ammoniums to some extend.

Quaternary ammoniums are certainly amongst the most cytotoxic preservatives currently in use, but most studies reveal that all preservatives to date exert some kind of toxicity. Some are obviously better than other... or it might be even more appropriate to say that some are worse than others. Some are not really used anymore because they have caused too many allergic reactions (that's the case of thiomersal or thimerosal which is now seldom used). Some newer preservatives claim to be less aggressive than old ones and particularly when compared to BAK (that's the case of Purite®, GenAqua® and several types of polyquarterniums including Polyquad®) [5]. Most studies indicate in fact that they are less abrasive or toxic than BAK, which isn't obviously the same as to say they are not toxic or aggressive at all for the human eye. According to the lastest studies the gentlier preservatives are in fact oxidative ones such as Purite® and GenAqua®. There is still little independent studies to support these claim. It would seem wise to compare all preservatives between them, and to compare all of these to a saline solution or the same active substance but without the preservative. It would also be important to consider that studies are usually done on healthy eyes whereas drugs are meant for unhealthy ones. Therefore a preservative that could be considered safe for normal eyes may not be safe for dry eyes or fragile corneas. "The elimination of preservatives may be desirable in efforts to protect the integrity of the corneal surface and its interaction with the tear film" as one study puts it [7].

IrritantSo, laboratories and governmental medical agencies all over the world, independent comparative studies to confirm or infirm these claims are really welcomed if you are listening! Some of this products are sold with the warning of being ocular irritants by their manufacturers from the chemical industry. It's curious to notice that laboratories assume these may be safe to use eyedrops for unhealthy eyes.

More generally, according to the AOA [2], “Ophthalmic preservatives used in artificial tear solutions and their potential adverse effects are:

  • Thimerosal--hypersensitive reaction in an estimated 10-25 percent of users

  • Benzalkonium chloride--Preocular tear film instability, lowered breakup time (BUT), and disrupted corneal epithelial cell functions when dosed at commercial concentrations

  • Chlorobutanol--evaporation, corneal epithelial cell changes

  • Ethylenediaminetetraacetic acid (EDTA)--contact allergy

  • Chlorhexidine digluconate--storage in the corneal and conjunctival epithelium

II. Less Effective Eyedrops & Decreased Tolerance/Compliance

Another interesting aspect, which has been addressed by a few studies to date, is that preservatives may reduce the effectiveness of treatments particularly when inflammatory processes are involved (3) or when the abrasive effect of preservative is a serious contraindication for the eye disease. For instance, antihistaminic eyedrops are likely to be less effective due to the inflammatory process maintained by the preservative.  Besides that, with less stinging and adverse reaction to the preservative the patient’s compliance with the treatment is usually improved (4). So it’s actually in the pharmaceutical industry interest to address this issue… sooner than later.

A French prospective study to evaluate the occurrence of ocular adverse effects observed after administration of anti-allergic eye drops with (usually benzalkonium) and without a preservative in patients with allergic conjunctivitis included a total of 3090 patients with allergic conjunctivitis and treated with anti-allergic eye drops by 507 general practitioners located throughout France. The proportion of patients experiencing at least one adverse drug reaction was 24% for eye drops with no preservative and 89% for eye drops with a preservative. The study concluded by saying " Compliance was significantly higher for anti-allergic eye drops without preservative than for those with a preservative"[9].

Read the consequences Per Preservative


Studies (some studies' abstracts may be available at Pubmed)

1: Les Conservateurs en Ophtalmologie, Docteur Patrice Vo Tan, Docteur Yves Lachkar, Librairie Médicale Théa, 64 pages.

2: American Optometric Association. Care of the patient with ocular surface disorders. St. Louis (MO): American Optometric Association.

3: Comparative study of topical anti-allergic eye drops on human conjunctiva-derived cells: responses to histamine and IFN gamma and toxicological profiles Pauly A, Brignole-Baudouin F, Guenoun JM, Riancho L, Rat P, Warnet JM, Baudouin C. U598, INSERM, Cordeliers Biomedical Institute, 15 rue de l'ecole de medecine, 75006, Paris, France.  CONCLUSIONS: The ability of topical ocular anti-H(1) drugs to significantly reduce the production of IL-6 and IL-8 argues that they may help treat the inflammatory processes occurring in allergic ocular surface disorders. Nevertheless, preserved ophthalmic formulations may enhance epithelial conjunctival expression of ICAM-1 in the presence of a low inflammatory stimulus, such as IFNgamma, and displayed toxic as well as pro-oxidative effects on these cells. Therefore, BAC used as preservative might in part interfere with the potential anti-inflammatory properties of the active compound by modulating the immuno-inflammatory response of epithelial conjunctival cells. To display study click here

4: A comparative study of the ocular tolerance after administration of anti-allergic eye drops with or without a preservative. [Article in French] ,
Beden C, Helleboid L, Marmouz F, Liard F. Societe Naxis, Lyon, France. CONCLUSION: The prescription of eye drops with no preservative allows a significant decrease in ocular adverse drug reactions and a greater acceptance by the patient regarding his/her anti-allergic treatment.

5:  Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. Labbe A, Pauly A, Liang H, Brignole-Baudouin F, Martin C, Warnet JM, Baudouin C. Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, and INSERM U598, Cordeliers Biomedical Institute, University of Paris 5, Paris, France. PMID: 16910868, J Ocul Pharmacol Ther. 2006 Aug;22(4):267-78 [PubMed - indexed for MEDLINE]

6: How the most common preservative affects the Meibomian lipid layer, Kaercher T.; Hönig D.; Barth W., Orbit, Volume 18, Number 2, June 1999, pp. 89-97(9), Taylor & Francis Ltd.

7. Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride. Ishibashi T, Yokoi N, Kinoshita S, Department of Ophthalmology, Kyoto Prefectural University of medicine, Kyoto, Japan, J Glaucoma, 2003 Dec;12(6):486-90. PMID: 14646684 [PubMed - indexed for MEDLINE]

8. Topical timolol with and without benzalkonium chloride: epithelial permeability and autofluorescence of the cornea in glaucoma. de Jong C, Stolwijk, Kuppens, de Keizer R, van Best J, Department of Ophthalmology, Leiden University Hospital, The Netherlands. PMID: 8034210 [PubMed - indexed for MEDLINE].

9. Etude comparative de la survenue d’effets indésirables suite à l’administration de collyres anti-allergiques sans ou avec conservateur: A Comparative Study of the Ocular Tolerance After Administration of Anti-Allergic Eye Drops With or Without a Preservative, Beden, Cecile; Helleboid, Laurent; Marmouz, Farid; Liard, Francois, Société Naxis, Lyon, Service d’Ophtalmologie, Hôpital Tenon, Paris,  Cabinet d’Immuno-Allergologie, Pontoise, France Cabinet de Médecine Générale, Saint-Epain, France, Therapie, Volume 59, Number 2, 2004 , pp. 259-264(6)


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