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The compared consequences of preservatives

IV. Comparative Studies

These are crucial to understand the consequences of preservatives and sometimes the differences in the mechanism of action of each preservative. However, one should exercise caution when studying the comparative studies made on the behalf of some laboratories considering that these are usually slightly biased. As a rule, they usually present their preservative as being safe because it is safer than the one used by the competition. Nevertheless, such a conclusion is inaccurate: a preservative may be safer than another, may still be unsafe regardless of the comparison. In that configuration, benzalkonium is usually presented as the main culprit and probably the worst for the eye's surface (rightfully we may add). However, do not conclude that the other preserved substance has no impact whatsoever or even negligible consequences. Some studies have made the effort to compare the different substances to a similar non-preserved solution, or even to non-treated eyes (this last option is somewhat incoherent!). To sum up and simplify, a honest study will likely include the comparison of the preserved solution to the same product without the preservative and a control or neutral solution (sometimes a physiological saline solution).

Comparative study by Allergan - epithelial consequencesOn the left, a comparative study made on the behalf of Allergan on dry eye treatments. Some of Allergan's products using Purite® were compared to some other dry eye drops from the competition using detergent preservatives (such as Polyquad® et le Benzalkonium) and to the absence of treatment (it would have been more logical to compare it to the non-preserved version of the same.

The study was made over a period of 7 days with a four-times daily dose, when dry eyes require longer treatments (usually life-time or very long-term treatments of several years). Click on the image to display a set of photographs showing epithelial cells presenting a rather normal appearance when no treatment was applied, slightly modified cells when using Purite®, altered cells when using Polyquad® and very severely altered (some voided from their content) when using benzalkonium. This study in a brochure on dry eye treatments for New Zealand dry eye sufferers.



These studies enabled us to reach the following conclusions:

1. The absence of preservative is always preferable and non-preserved options are always less damaging.

2. Detergent preservatives such as quaternary ammoniums (such as BAK) are always more damaging than oxidative preservatives. Benzalkonium is usually presented as the worst solution to preserved drops despite being one of the most commonly used.

3. Oxidative preservatives have less negative consequences and a closer to control or non-preserved solutions. But let's not forget that minimal short-term consequences on healthy eyes do not imply long-term safety for fragile corneas (especially considering that many pathologies require long-term or life treatments and certainly frequent dosing).

Comparative Charts


Preservative free solution/Control Study
Benzalkonium Polyquaternium Thiomersal
caused a 9.24 to 99.28 fold increase in CF uptake (more corneal staining) caused a 0 to 4 fold increase in CF uptake (less corneal staining than BAK) caused  0 to 4 fold increase in CF uptake (less corneal staining than BAK) No increase in CF uptake (Corneal Staining similar to control) 1
compared to control: dramatically altered the corneoconjunctival surface; decreased tear production. significantly decreased goblet cell density compared. Some abnormalities were observed with in vivo confocal microscopy. No decreased tear production compared to control.


No significant changes (compared to preserved) 2

** = No data

Benzalkonium Control Study
[glaucoma drug with BAK] induced significantly higher inflammatory levels in the conjunctival epithelium ; significant decrease in MUC5AC-positive cells;impairment of goblet cell density and mucin production [glaucoma drug preservative-free] no significant expression of the inflammatory marker compared with normal untreated eyes 3
[glaucoma drug with BAK]  symptoms were more prevalent with preserved than with PF drops: discomfort upon instillation (43% versus 17%), & symptoms between instillations such as burning-stinging (40% vs 22%), foreign body sensation (31% vs 14%), dry eye sensation (23% vs 14%), tearing (21% vs 14%), and eyelid itching (18% vs 10%). [glaucoma drug preservative-free]A reduction in the symptoms and signs was observed when patients changed from P to PF eye drops 4


Benzalkonium Polyquaternium Purite oxychloro complex Sodium Perborate Cetrimide phenylmercury borate Study
BAK (0.01%): 5% +/- 1% retention of neutral red and 58% +/- 2% for a European drop + disruption of the epithelial membrane; BAK (0.01%): 5% +/- 1% retention of neutral red minimal membrane disruption no membrane disruption 58% +/- 2% neutral red retention 34% +/- 1% retention 27% +/- 2% retention 5
BAK showed the highest cytotoxicity, with a 95%, 69%, and 56% neutral red release at 100, 100, and 50 ppm, respectively 13% neutral red release


 20% neutral red relase 66% neutral red release 73%  neutral red release
extensive superficial erosion of the epithelium and a lack of protruding microvilli  extensive superficial erosion of the epithelium and a lack of protruding microvilli (less extent than BAK) no defect or superficial erosion no defect or superficial erosion    
cytotoxic effects, either in vivo or in vitro cytotoxic effects, either in vivo or in vitro no adverse effect on epithelial cells in vitro or on in vivo; less disruptive to cellular integrity than other preservatives currently used cytotoxic effects, either in vivo or in vitro cytotoxic effects, either in vivo or in vitro cytotoxic effects, either in vivo or in vitro
In general, the cytotoxicity observed for each preservative, from least to most, is as follows: the oxychloro complex; polyquaternium-1; sodium perborate; BAK 0.005%; cetrimide, phenylmercury borate; and BAK 0.01%.


Studies (some studies' abstracts may be available at Pubmed) used for this article

1. 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]

2.. Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives, Lopez Bernal D, Ubels JL. Department of Ophthalmology, Medical College of Wisconsin, Milwaukee 53226, Curr Eye Res. 1991 Jul;10(7):645-56. PMID: 1914501 [PubMed - indexed for MEDLINE]

3. Pisella PJ, Debbasch C, Hamard P, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci 2004; 45:1360-1368.

4. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 2002; 86:418-423.

5. Purite May be Gentler Preservative for Lubrication Solutions, Robert J. Noecker, MD, Ophthalmology Times,  November 1, 2001.



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