Preservatives in ophthalmic formulations
a narrative review on myths, truths and news
DOI:
https://doi.org/10.70313/2718.7446.v17.n01.283Keywords:
ophthalmic preservatives, preservative-free, preservative-soft, ocular surface, glaucoma, quality of life, myopia, presbyopiaAbstract
As people age and life expectancy increases, they are more likely to develop chronic conditions such as glaucoma, dry eye and reactive hypersensitivity. These conditions also require long-term topical ophthalmic treatments, which may contain preservatives. The main function of preservatives in ophthalmic formulations is to preserve the drug product and prevent contamination, so that they can be used safely until their expiration date. The use of preservatives for short periods can be beneficial, for example by facilitating pharmacokinetic aspects of antibiotics, thanks to their potential epithelial toxicity. But in prolonged treatments, preservatives have been shown to cause toxicity on the ocular surface, which is dependent on their concentration, frequency of instillation and total time of use. This has been observed mainly in glaucoma and dry eye disease, affecting the patient's quality of life, therapeutic compliance and expected results. In turn, it is also beginning to be relevant in view of the growing boom in the pharmacological management of presbyopia and myopia (in the pediatric population); which in most cases tends to be prolonged.
Therefore, new preservative options that are gentler and friendlier to the ocular surface are being developed, as well as innovative strategies to avoid the use of preservatives altogether. This paper has reviewed and updated the subject, highlighting the importance of considering and identifying the presence and/or variety of preservatives in prolonged treatments.
References
Goldstein MH, Silva FQ, Blender N et al. Ocular benzalkonium chloride exposure: problems and solutions. Eye (Lond) 2022; 36: 361-368.
Furrer P, Mayer JM, Gurny R. Ocular tolerance of preservatives and alternatives. Eur J Pharm Biopharm 2002; 53: 263-280.
Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther 2001; 18: 205-215.
Baudouin C, Labbé A, Liang H et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010; 29: 312-334.
Steven DW, Alaghband P, Lim KS. Preservatives in glaucoma medication. Br J Ophthalmol 2018; 102: 1497-1503.
Kallings LO, Ringertz O, Silverstolpe L. Microbiological contamination of medical preparations. Acta Pharm Suec 1966; 3: 219-228.
Thyssen JP, Linneberg A, Menné T, Johansen JD. The epidemiology of contact allergy in the general population--prevalence and main findings. Contact Dermatitis 2007; 57: 287-299.
Tosti A, Tosti G. Thimerosal: a hidden allergen in ophthalmology. Contact Dermatitis 1988; 18: 268-273.
Geier DA, Sykes LK, Geier MR. A review of thimerosal (Merthiolate) and its ethylmercury breakdown product: specific historical considerations regarding safety and effectiveness. J Toxicol Environ Health B Crit Rev 2007; 10: 575-596.
Kim DW, Shin J, Lee CK et al. Comparison of ocular surface assessment and adherence between preserved and preservative-free latanoprost in glaucoma: a parallel-grouped randomized trial. Sci Rep 2021; 11: 14971.
Freeman PD, Kahook MY. Preservatives in topical ophthalmic medications: historical and clinical perspectives. Expert Rev Ophthalmol 2009; 4: 59-64.
Tu EY. Balancing antimicrobial efficacy and toxicity of currently available topical ophthalmic preservatives. Saudi J Ophthalmol 2014; 28: 182-187.
Herrero Vanrell R. Generalidades de los conservantes en las formulaciones oftálmicas. Arch Soc Esp Oftalmol 2007; 82: 531-532.
Rogov AG, Goleva TN, Sukhanova EI et al. Mitochondrial dysfunctions may be one of the major causative factors underlying detrimental effects of benzalkonium chloride. Oxid Med Cell Longev 2020, 2020: 8956504.
Walsh K, Jones L. The use of preservatives in dry eye drops. Clin Ophthalmol 2019; 13: 1409-1425.
Kowalski RP, Kowalski BR, Romanowski EG et al. The in vitro impact of moxifloxacin and gatifloxacin concentration (0.5% vs 0.3%) and the addition of benzalkonium chloride on antibacterial efficacy. Am J Ophthalmol 2006; 142: 730-735.
Hedengran A, Kolko M. The molecular aspect of anti-glaucomatous eye drops: are we harming our patients? Mol Aspects Med 2023; 93: 101195.
Hedengran A, Freiberg J, May Hansen P et al. Comparing the effect of benzalkonium chloride-preserved, polyquad-preserved, and preservative-free prostaglandin analogue eye drops on cultured human conjunctival goblet cells. J Optom 2024; 17: 100481.
Epstein SP, Chen D, Asbell PA. Evaluation of biomarkers of inflammation in response to benzalkonium chloride on corneal and conjunctival epithelial cells. J Ocul Pharmacol Ther 2009; 25: 415-424.
Brignole-Baudouin F, Desbenoit N, Hamm G et al. A new safety concern for glaucoma treatment demonstrated by mass spectrometry imaging of benzalkonium chloride distribution in the eye, an experimental study in rabbits. PLoS One 2012; 7: e50180.
Sarkar J, Chaudhary S, Namavari A et al. Corneal neurotoxicity due to topical benzalkonium chloride. Invest Ophthalmol Vis Sci 2012; 53: 1792-1802.
Hedengran A, Steensberg AT, Virgili G et al. Efficacy and safety evaluation of benzalkonium chloride preserved eye-drops compared with alternatively preserved and preservative-free eye-drops in the treatment of glaucoma: a systematic review and meta-analysis. Br J Ophthalmol 2020; 104: 1512-1518.
Nagstrup AH. The use of benzalkonium chloride in topical glaucoma treatment: an investigation of the efficacy and safety of benzalkonium chloride-preserved intraocular pressure-lowering eye drops and their effect on conjunctival goblet cells. Acta Ophthalmol 2023; 101, Suppl 278: 3-21.
Ammar DA, Noecker RJ, Kahook MY. Effects of benzalkonium chloride-preserved, polyquad-preserved, and sofZia-preserved topical glaucoma medications on human ocular epithelial cells. Adv Ther 2010; 27: 837-845.
Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol 2008; 86: 716-726.
Rossi GCM, Scudeller L, Rolle T et al. From benzalkonium chloride-preserved latanoprost to polyquad-preserved travoprost: a 6-month study on ocular surface safety and tolerability. Expert Opin Drug Saf 2015; 14: 619-623.
Codling CE, Hann AC, Maillard JY, Russell AD. An investigation into the antimicrobial mechanisms of action of two contact lens biocides using electron microscopy. Contact Lens Anterior Eye 2005; 28: 163-168.
Codling CE, Maillard JY, Russell AD. Aspects of the antimicrobial mechanisms of action of a polyquaternium and an amidoamine. J Antimicrob Chemother 2003; 51: 1153-1158.
Paimela T, Ryhänen T, Kauppinen A et al. The preservative polyquaternium-1 increases cytoxicity and NF-kappaB linked inflammation in human corneal epithelial cells. Mol Vis 2012; 18: 1189-1196.
Katz LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma 2002; 11: 119-126.
Charnock C. Are multidose over-the-counter artificial tears adequately preserved? Cornea 2006; 25: 432-437.
Kaur IP, Lal S, Rana C et al. Ocular preservatives: associated risks and newer options. Cutan Ocul Toxicol 2009; 28: 93-103.
Magnet A, Gomes TS, Pardinas C et al. Can artificial tears prevent Acanthamoeba keratitis?: an in vitro approach. Parasit Vectors 2018; 11: 50.
Xu M, Sivak JG, McCanna DJ. Comparison of the effects of ophthalmic solutions on human corneal epithelial cells using fluorescent dyes. J Ocul Pharmacol Ther 2013; 29: 794-802.
Zhang H, Wu H, Yang J, Ye J. Sodium perbarate and benzalkonium chloride induce DNA damage in Chang conjunctival epithelial cells. Cutan Ocul Toxicol 2017; 36: 336-342.
Kahook MY, Noecker RJ. Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears. Cornea 2008; 27: 339-343.
Tau J, Passerini MS, Del Papa M et al. A novel ophthalmic latanoprost 0.005% nanoemulsion: a cytotoxicity study. Graefes Arch Clin Exp Ophthalmol 2022; 260: 1941-1946.
Stewart WC, Oehler JC, Choplin NT et al. A comfort survey of timolol hemihydrate 0.5% solution once or twice daily vs timolol maleate in sorbate. J Curr Glaucoma Pract 2013; 7: 11-16.
Jansook P, Loftsson T. Aqueous prostaglandin eye drop formulations. Pharmaceutics 2022; 14: 2142.
Casiraghi JF, Grigera D, Peyret JA et al. efficacy and tolerability of a new latanoprost 0.005% BAK-free nanoemulsion: a nonrandomized open-label trial. Re:GEN Open 2021; 1: 110-116. Disponible en: https://www.liebertpub.com/doi/10.1089/regen.2021.0018
Na KH, Yoo C, Park JH, Kim YY. Eye drop dispenser type and medication possession ratio in patients with glaucoma: single-use containers versus multiple-use bottles. Am J Ophthalmol 2018; 188: 9-18.
Vasdev N, Chaudhari N, Polaka S et al. Current progress in preservative-free topical ophthalmic formulations. J Drug Deliver Sci Tech 2023; 79: 103996.
Sellier F. Using intelligent design to deliver safe preservative-free multi-dose eye drops. On Drug Delivery 2016. Disponible en:
LaboratoriesThea. The ABAK® system. Clermont-Ferrand: Laboratoires Théa, [2015] Disponible en: https://www.laboratoires-thea.com/fr/node/1232 y Bayer. hydraSense® delivery system. Mississauga: Bayer Inc., [2017]. Disponible en: https://www.hydrasense.ca/en/eye-care/long-lasting--relief-for-dry-eyes/
Davidson Z. Developing an efficient ophthalmic device combination product. On Drug Delivery 2020; 104: 16-19. Disponible en: https://www.ondrugdelivery.com/developing-an-efficient-ophthalmic-device-combination-product/
Zimmerman TJ, Hahn SR, Gelb L et al. The impact of ocular adverse effects in patients treated with topical prostaglandin analogs: changes in prescription patterns and patient persistence. J Ocul Pharmacol Ther 2009; 25: 145-152.
Baudouin C. Mechanisms of failure in glaucoma filtering surgery: a consequence of antiglaucomatous drugs? Int J Clin Pharmacol Res 1996; 16: 29-41.
Wolfram C, Stahlberg E, Pfeiffer N. Patient-reported nonadherence with glaucoma therapy. J Ocul Pharmacol Ther 2019; 35: 223-228.
Uusitalo H, Chen E, Pfeiffer N et al. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmol 2010; 88: 329-336.
Misiuk-Hojlo M, Pomorska M, Mulak M et al. The RELIEF study: tolerability and efficacy of preservative-free latanoprost in the treatment of glaucoma or ocular hypertension. Eur J Ophthalmol 2019; 29: 210-215.
Seong HJ, Lee K, Lee SJ et al. Efficacy and safety of preservative-free latanoprost eyedrops compared with preserved prostaglandin analogues in patients with open-angle glaucoma. Korean J Ophthalmol 2021; 35: 235-241.
Jandroković S, Vidas Pauk S, Lešin Gaćina D et al. Tolerability in glaucoma patients switched from preserved to preservative-free prostaglandin-timolol combination: a prospective real-life study. Clin Ophthalmol 2022; 16: 3181-3192.
Baudouin C, Denoyer A, Desbenoit N et al. In vitro and in vivo experimental studies on trabecular meshwork degeneration induced by benzalkonium chloride (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2012; 110: 40-63.
Kumar S, Singh T, Ichhpujani P, Vohra S. ocular surface disease with BAK preserved travoprost and polyquaternium 1 (polyquad) preserved travoprost. Rom J Ophthalmol 2019; 63: 249-256.
Hedengran A, Freiberg JC, Hansen PM et al. Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: effect on cultured human conjunctival goblet cells and their physicochemical properties. Acta Ophthalmol 2022; 100: 819-827.
Zhou X, Zhang X, Zhou D et al. A narrative review of ocular surface disease related to anti-glaucomatous medications. Ophthalmol Ther 2022; 11: 1681-1704.
Aihara M, Oshima H, Araie M, EXTraKT study group. Effects of SofZia-preserved travoprost and benzalkonium chloride-preserved latanoprost on the ocular Surface: a multicentre randomized single-masked study. Acta Ophthalmol 2013; 91: e7-e14.
Kanamoto T, Kiuchi Y, Ocular Surface Disease and Glaucoma Study Group et al. Comparison of the toxicity profile of benzalkonium chloride-preserved tafluprost and SofZia-preserved travoprost applied to the ocular surface. J Ocul Pharmacol Ther 2015; 31: 156-164.
Mundorf T, Wilcox KA, Ousler GW 3rd. et al. Evaluation of the comfort of Alphagan P compared with Alphagan in irritated eyes. Adv Ther 2003; 20: 329-336.
Harasymowycz P, Hutnik C, Rouland JF et al. Preserved versus preservative-free latanoprost for the treatment of glaucoma and ocular hypertension: a post hoc pooled analysis. Adv Ther 2021; 38: 3019-3031.
Baudouin C. Ocular surface and external filtration surgery: mutual relationships. Dev Ophthalmol 2017; 59: 67-79.
Chamard C, Larrieu S, Baudouin C et al. Preservative-free versus preserved glaucoma eye drops and occurrence of glaucoma surgery: a retrospective study based on the French national health insurance information system, 2008-2016. Acta Ophthalmol 2020; 98: e876-e881.
Costagliola C, Prete AD, Incorvaia C et al. Ocular surface changes induced by topical application of latanoprost and timolol: a short-term study in glaucomatous patients with and without allergic conjunctivitis. Graefes Arch Clin Exp Ophthalmol 2001; 239: 809-814.
Thein AS, Hedengran A, Azuara-Blanco A et al. adverse effects and safety in glaucoma patients: Agreement on Clinical Trial Outcomes for Reports on Eye Drops (ASGARD): a Delphi Consensus Statement. Am J Ophthalmol 2022; 241: 190-197.
Stapleton F, Alves M, Bunya VY et al. TFOS DEWS II epidemiology report. Ocul Surf 2017; 15: 334-365.
Gomes JAP, Azar DT, Baudouin C et al. TFOS lifestyle: Impact of elective medications and procedures on the ocular surface. Ocul Surf 2023; 29: 331-385.
Fraunfelder FT, Sciubba JJ, Mathers WD. The role of medications in causing dry eye. J Ophthalmol 2012; 2012: 285851.
Ha JY, Sung MS, Park SW. Effects of preservative on the Meibomian gland in glaucoma patients treated with prostaglandin analogues. Chonnam Med J 2019; 55: 156-162.
Nijm LM, Schweitzer J, Gould Blackmore J. Glaucoma and dry eye disease: opportunity to assess and treat. Clin Ophthalmol 2023; 17: 3063-3076.
Kolko M, Gazzard G, Baudouin C et al. Impact of glaucoma medications on the ocular surface and how ocular surface disease can influence glaucoma treatment. Ocul Surf 2023; 29: 456-468.
Zaleska-Żmijewska A, Strzemecka E, Wawrzyniak ZM, Szaflik JP. Extracellular MMP-9-based assessment of ocular surface inflammation in patients with primary open-angle glaucoma. J Ophthalmol 2019; 2019: 1240537.
Martone G, Frezzotti P, Tosi GM et al. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009; 147: 725-735.
Vitoux MA, Kessal K, Melik Parsadaniantz S et al. Benzalkonium chloride-induced direct and indirect toxicity on corneal epithelial and trigeminal neuronal cells: proinflammatory and apoptotic responses in vitro. Toxicol Lett 2020; 319: 74-84.
Ribeiro MVMR, Barbosa FT, Ribeiro LEF et al. Effectiveness of using preservative-free artificial tears versus preserved lubricants for the treatment of dry eyes: a systematic review. Arq Bras Oftalmol 2019; 82: 436-445.
Yıldırım N, Bozkurt B, Yüksel N et al. Prevalence of ocular surface disease and associated risk factors in glaucoma patients: a survey study of ophthalmologists. Turk J Ophthalmol 2022; 52: 302-308.
Hong J, Bielory L. Allergy to ophthalmic preservatives. Curr Opin Allergy Clin Immunol 2009; 9: 447-453.
Marini MC, Berra ML, Girado F et al. Efficacy and toxicity evaluation of bepotastine besilate 1.5% preservative-free eye drops vs olopatadine hydrochloride 0.2% BAK-preserved eye drops in patients with allergic conjunctivitis. Clin Ophthalmol 2023; 17: 3477-3489.
Li G, Akpek EK, Ahmad S. Glaucoma and ocular surface disease: more than meets the eye. Clin Ophthalmol 2022; 16: 3641-3649.
Schwab IR, Linberg JV, Gioia VM et al. Foreshortening of the inferior conjunctival fornix associated with chronic glaucoma medications. Ophthalmology 1992; 99: 197-202.
Thorne JE, Anhalt GJ, Jabs DA. Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology 2004; 111: 45-52.
Janderová M, Filouš A, Hložánek M et al. The effect of therapy on the ocular surface in patients with unilateral pediatric glaucoma purpose: the aim of the study was to evaluate ocular surface and. Cesk Slov Oftalmol 2021; 77: 28-34.
Donthineni PR, Das AV, Basu S. Dry eye disease in children and adolescents in India. Ocul Surf 2020; 18: 777-782.
Alves M, Dias AC, Rocha EM. Dry eye in childhood: epidemiological and clinical aspects. Ocul Surf 2008; 6: 44-51.
Ha A, Kim SJ, Shim SR et al. Efficacy and safety of 8 atropine concentrations for myopia control in children: a network meta-analysis. Ophthalmology 2022; 129: 322-333.
Berton B, Chennell P, Yessaad M et al. Stability of ophthalmic atropine solutions for child myopia control. Pharmaceutics 2020; 12: 781.
Thygesen J. Glaucoma therapy: preservative-free for all? Clin Ophthalmol 2018; 12: 707-717.
Villacorta Gassmann P. Cuestionarios: herramientas de estudio en oftalmología. Oftalmol Clín Exp 2023; 16: e6-e14.
Rossi GCM, Pasinetti GM, Scudeller L, Bianchi PE. Ocular surface disease and glaucoma: how to evaluate impact on quality of life. J Ocul Pharmacol Ther 2013; 29: 390-394.
Lemij HG, Hoevenaars JG, van der Windt C, Baudouin C. Patient satisfaction with glaucoma therapy: reality or myth? Clin Ophthalmol 2015; 9: 785-793.
Kumar S, Singh T, Ichhpujani P et al. Correlation of ocular surface disease and quality of life in Indian glaucoma patients: BAC-preserved versus BAC-free travoprost. Turk J Ophthalmol 2020; 50: 75-81.
Benozzi J, Benozzi G, Orman B. Presbyopia: a new potential pharmacological treatment. Med Hypothesis Discov Innov Ophthalmol 2012; 1: 3-5.
Benozzi G, Pérez C, Leiro J et al. Presbyopia treatment with eye drops: an eight year retrospective study. Transl Vis Sci Technol 2020; 9: 25.
Facal S, Leiro J, Gualtieri A et al. Ocular surface evaluation in patients treated with pharmacological treatment for presbyopia. Int J Ophthalmic Pathol 2018; 7. Disponible en: https://www.scitechnol.com/peer-review/ocular-surface-evaluation-in-patients-treated-with-pharmacological-treatment-for-presbyopia-3XD1.php?article_id=7971
Benozzi G, Cortina ME, Gimeno E et al. A multicentric study of pharmacological treatment for presbyopia. Graefes Arch Clin Exp Ophthalmol 2021; 259: 2441-2450.
Haghpanah N, Alany R. Pharmacological treatment of presbyopia: a systematic review. Eur J Transl Myol 2022; 32: 10781.
Vejarano F, Alió J, Iribarren R, Lança C. Non-miotic improvement in binocular near vision with a topical compound formula for presbyopia correction. Ophthalmol Ther 2023; 12: 1013-1024.
Kannarr S, El-Harazi SM, Moshirfar M et al. Safety and efficacy of twice-daily pilocarpine hcl in presbyopia: the Virgo phase 3, randomized, double-masked, controlled study. Am J Ophthalmol 2023; 253: 189-200.
Harrison L. FDA approves eye drops for presbyopia. Medscape, Nov 1st, 2021. Disponible en: https://www.medscape.com/viewarticle/961999?form=fpf
Holland E, Karpecki P, Fingeret M et al. Efficacy and safety of CSF-1 (0.4% pilocarpine hydrochloride) in presbyopia: pooled results of the NEAR phase 3 randomized, clinical trials. Clin Ther 2024; 46: 104-113.
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Consejo Argentino de Oftalmología
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Con esta licencia no se permite un uso comercial de la obra original, ni la generación de obras derivadas. Las licencias Creative Commons permiten a los autores compartir y liberar sus obras en forma legal y segura.
