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What's a Preservative

What are the Consequences

Who's at Risk

Are Labs Aware of This

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What Preservative Which Drop

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Preservatives in eye drops

 

There are several antimicrobial preservatives used in ocular preparations that may be classified as follows:

First they may be divided into two types: chemical and oxidative.

 

I. Main Chemical Preservatives:

Chemical preservatives alter cell membrane permeability and lyse (divide) cytoplasmic contents.

Quaternary ammoniums, surfactant and disinfectant agents, among which are benzalkonium chloride, cetremide or cetrimonium chloride or bromide, benzododecinium bromide, miramine, cetylpyridinium chloride, polidronium chloride or polyquarternium-1, polyquaternium-42 (also known as polexitonium), sepazonium, etc 

Mercurial derivatives such as the phenylmercury salts (acetate, borate or nitrate), mercuriothiolate sodium (otherwise called thiomersal or thimerosal) and mercurobutol 

Amidines such as chlorhexidine digluconate or polyhexamethylene biguanide (PHMB)

Alcohols  such as chlorobutanol or phenylethanol,  phenoxyethanol

Parabens or esters such as parahydroxybenzoic acid,  methylparaben, propylparaben,

II. Oxidative Preservatives

Oxidative preservatives are able to penetrate cell membranes and interfere with a cell’s functions.

Sodium perborate or GenAqua® which works by oxidizing cell's membranes and disrupting cellular function. When combined with water, sodium perborate is converted to hydrogen peroxide, thus destroying micro-organisms. In contact with the tear film, it converts itself into oxygen and water molecules.

Stabilized oxychloro complex (SOC) or Purite® is a compound usually used for water sanitation.

Stabilized oxyborate complex  or Dissipate™

III. Anti-Oxidant Preservative and other complexes having a preservative activity

Edetic acid (EDTA, (di)sodium edetate)

Sodium silver chloride complex and silver sulfate

Sorbate (sorbic acid)
 

IV. Beware that many preservatives have synonyms and several commercial/trademark names:

Synonyms for BAK: parasterol, alkyl benzyl dimethylammonium chloride, alkyl dimethyl benzylammonium chloride, benirol, cequartryl, drapolene, enuclene, germitol, gesminol, rodalon, ammonyx, zephiran chloride, [various further trade names… but best known as Benzalkonium chloride.]

Synonyms for EDTA: H₄EDTA, Versene, ethylenedinitrilotetraacetic or ethylenediaminetetraacetic acid, Diaminoethanetetraacetic acid, N, N ' - 1 , 2 - ethanediylbis (N-(carboxymethyl) (glycine) edetic acid, ethylenedinitrilotetracetatic acid, celon A, gluma cleanser, nervanaid B acid, nullapon B acid, sequestrene AA, tetrine acid, titriplex, trilon BS, versene acid, vinkeil 100, warkeelate acid, YD 30, edetate (di or tri) sodium,  and various further trade names… but best known as EDTA. It’s "Funny" to notice that EDTA is mentioned as an eye-irritant by several manufacturers of the product for many applications.

Synonym for Cetremide: cetrimonium bromide or chloride

Synonyms for sodium chlorite: Purite® or stabilized oxychloro complex (SOC)

Synonyms for sodium perborate: PBS or GenAqua®.

Synonyms for polidronium chloride: polyquarternium-1 or Polyquad® or [(E)-4-[dimethyl-[(E)-4-[tris(2-hydroxyethyl)ammonio] but-2-enyl]ammonio]but-2-enyl]-tris(2-hydroxyethyl) azanium trichloride.

Synomyms for polexitonium: polyquarternium 42 or Busan 1507

 

V. What are preservatives for? Do preservatives really play their safety role? Why are they used then?

Preservative are added to preserve eyedrops to ensure the sterility over the course of several weeks and sometimes months (usually less than a month). So they're not there to prevent infection in the eye but just to maintain sterility of the bottle against microbes (viruses, bacteria, and fungi or molds.. But are they really effective in doing so?

Some studies indicate that preservative do not protect agains all type of possible contamination of the bottle. Quartenary ammoniums have a limited efficacy against some gram positive and negative bacteria but particluarly against some mould spores such as mycobacteria and clostridium for instance[1,2].

One study found that 29% of solutions were contaminated by micro-organisms[4]. Another study done in ophthalmic consultations services and in a home for the elderly [though usually trained in hygienic measures], demonstrated that 16,3 % of all bottles were contaminated, including  5,4 % very severely contaminated [5].

Another study on a broad range of preservatives, concluded that only the combination of Benzalkonium and EDTA was able to meet the safety criteria for European Pharmacopoeia[4]. But this combination is also one of the worst for the eye's heatlh (see What are the consequences?) . So long term efficacy seems to be a chimera if not a dangerous illusion leading to increased accidents. Since preserved bottles suppose many instillations, the risk is increased and usually the tip if infected due to improper use or some kind of contact with any contaminating surface (eye or finger for instance). With single use vials such problem does not exist.

You may find a very broad spectrum of litterature on this subject, particularly on contact lenses-related solutions and the CLARE syndrome.

 

1. Benzalkonium chloride: failures as an antiseptic, Hussey, JAMA,1976 Nov 22;236(21):2433

2. Conservateurs et Surface Oculaire, Quelques bonnes raisons pour abandonner l'utilisation des collyres conservés. Dr. Magda de Saint-Jean,  Pr. Christophe Baudouin, Librairie Médical Théa.

3. Microbial contamination of in-use ocular medications, O. D. Schein, P. L. Hibberd, T. Starck, A. S. Baker and K. R. Kenyon, Dana Center for Preventive Ophthalmology, Wilmer Institute, Johns Hopkins University, Baltimore, Md 21205. PMID: 1731727 [PubMed - indexed for MEDLINE]

4. Are Multidose Over-the-Counter Artificial Tears Adequately Preserved? Charnock, Colin PhD, Basic Investigations, Cornea. 25(4):432-437, May 2006.

5. Etude de la contamination bactérienne de collyres en usage clinique (Bacterial contamination study of in-use eyedrops), Raynaud C., Rigal D., Bonicel P, Service d'Ophtalmologie, CHU G. Montpied, BP 69, 63000 Clermont-Ferrand, FRANCE & Laveran H, Service d'Hygiène Hospitalière, Université d'Auvergne Clermont-Ferrand I, BP 38, 63000 Clermont-Ferrant, FRANCE.

 

This is what we call the 'Preservative Paradox!

Preserve our Eyes, not our Drops!

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  copyright © Keratos 2007