Exploring the Benefits of Preservative-Free Ophthalmic Solutions in the Management of Glaucoma: A Comprehensive Review
DOI:
https://doi.org/10.37285/ijpsn.2024.17.3.11Abstract
Glaucoma is a worldwide major cause of vision loss; it is mainly caused due to the degeneration of retinal cells. Its symptoms usually appear at a later stage and thus chances of vision loss are high. Ophthalmic formulations have vast applications in the treatment of several ocular disorders such as glaucoma, dry eye syndrome, and many more. Conventional dosage forms such as eye drops have been used for the treatment of glaucoma for several years but they need to be sterile, especially multi-dose formulations. Ophthalmic dosage forms generally include preservatives such as Benzalkonium chloride (BAK) to maintain the sterility of the formulations which in some cases, were reported with severe ocular irritation and toxicity including corneal damage, ocular inflammation, and conjunctival injury even though used in minute concentration. Thus, there is a dire need to review the preservative-free ophthalmic formulations (PFOF) for the treatment and management of glaucoma to overcome the side effects associated with preserved formulations and to eliminate the irritation and toxicity caused by the preservatives. This article details the current research progress and development of PFOFs for the treatment of glaucoma. Moreover, a brief on preservative-free options of ophthalmic solutions and their applications in glaucoma, with a special focus on factors limiting their development has also been presented. In addition, this review also provides up-to-date information regarding the use of preservative-free antiglaucoma treatment.
Downloads
Metrics
Keywords:
Ophthamic, Glaucoma, Safety, Sterility, Preservative-free, Dosage formPublished
How to Cite
Issue
Section
References
Rahić O, Tucak A, Omerović N, Sirbubalo M, Hindija L, Hadžiabdić J, Vranić E. Novel drug delivery systems fighting glaucoma: Formulation obstacles and solutions. Pharmaceutics. 2020 Dec 26;13(1):28.
Schuster AK, Erb C, Hoffmann EM, Dietlein T, Pfeiffer N. The diagnosis and treatment of glaucoma. DeutschesÄrzteblatt International. 2020 Mar;117(13):225.
Kingman S. Glaucoma is second leading cause of blindness globally. Bulletin of the World Health Organization. 2004;82:887-8
Wu Y, Szymanska M, Hu Y, Fazal MI, Jiang N, Yetisen AK, Cordeiro MF. Measures of disease activity in glaucoma. Biosensors and Bioelectronics. 2022 Jan 15;196:113700.
Dietze J, Blair K, Havens SJ. Glaucoma. StatPearls [Internet]. 2022 Jan.
Stein JD, Khawaja AP, Weizer JS. Glaucoma in adults—Screening, diagnosis, and management: A review. Jama. 2021 Jan 12;325(2):164-74.
Coroi MC, Bungau S, Tit M. Preservatives from the eye drops and the ocular surface. Rom J Ophthalmol. 2015;59:2–5.
YADGAROV A, Garg R. Preservative-Free Alternatives. Glaucoma Today. 2021.
Fea AM, Novarese C, Caselgrandi P, Boscia G. Glaucoma Treatment and Hydrogel: Current Insights and State of the Art. Gels. 2022 Aug 17;8(8):510.
Weinreb R. Weinreb RN, Aung T, Medeiros FA. The Pathophysiology and. Treatment of Glaucoma A Review. Jama-J Am Med Assoc. 2014 May 14;311(18):1901-11. Doi: 10.1001/jama.2014.3192
Agarwal R, Gupta SK, Agarwal P, Saxena R, Agrawal SS. Current concepts in the pathophysiology of glaucoma. Indian journal of ophthalmology. 2009 Jul 1;57(4):257-66.
Lee SH, Kim TW, Lee EJ, Kil H. Association between Optic Nerve Sheath Diameter and Lamina Cribrosa Morphology in Normal-Tension Glaucoma. Journal of Clinical Medicine. 2023 Jan;12(1):360.
Burgoyne CF, Downs JC, Bellezza AJ, Suh JK, Hart RT. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Progress in retinal and eye research. 2005 Jan 1;24(1):39-73.
Leske MC, Connell AM, Wu SY, Hyman LG, Schachat AP. Risk factors for open-angle glaucoma: the Barbados Eye Study. Archives of ophthalmology. 1995 Jul 1;113(7):918-24.
Saha BC, Kumari R. Lifestyle modifications–A new dimension in glaucoma management. Kerala Journal of Ophthalmology. 2022 Sep 1;34(3):199.
Tatton WG, Chalmers-Redman RME, Tatton NA. Apoptosis and anti-apoptosis signalling in glaucomatous retinopathy. Eur J Ophthalmol 2001;(11 Suppl 2):S12-22.
Gupta N, Yücel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol 2007;18:110-4.
Pascale A, Drago F, Govoni S. Protecting the retinal neurons from glaucoma: Lowering ocular pressure is not enough. Pharmacol Res 2012;66:19-32.
Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S. Ocular benzalkonium chloride exposure: problems and solutions. Eye. 2022 Feb;36(2):361-8.
Freeman PD, Kahook MY. Preservatives in topical ophthalmic medications: historical and clinical perspectives. Expert Rev Ophthalmol. 2009;4:59–64.
Sarkar R. Effects of preservatives used in ocular medications on the eye: A comparative review. Ophthalmology Journal. 2021;6:44-52. Doi: 10.5603/OJ.2021.0009
Cha SH, Lee JS, Oum BS, Kim CD. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clinical & experimental ophthalmology. 2004 Apr;32(2):180-4. De Saint Jean M, Brignole F, Bringuier AF, Bauchet A, Feldmann G, Baudouin C. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Investigative ophthalmology & visual science. 1999 Mar 1;40(3):619-30.
Rasmussen CA, Kaufman PL, Kiland JA. Benzalkonium chloride and glaucoma. J Ocul Pharm Ther. 2014;30:163–9.
Konstas AG, Labbé A, Katsanos A, Meier-Gibbons F, Irkec M, Boboridis KG, Holló G, García-Feijoo J, Dutton GN, Baudouin C. The treatment of glaucoma using topical preservative-free agents: an evaluation of safety and tolerability. Expert Opinion on Drug Safety. 2021 Apr 3;20(4):453-66.
Baudouin C, de Lunardo C. Short term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. British journal of ophthalmology. 1998 Jan 1;82(1):39-42.
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 ophthalmologica. 2013 Feb;91(1):e7-14.
Ruangvaravate N, Choojun K, Srikulsasitorn B, Chokboonpiem J, Asanatong D, Trakanwitthayarak S. Ocular surface changes after switching from other prostaglandins to tafluprost and preservative-free tafluprost in glaucoma patients. Clinical Ophthalmology. 2020 Oct 7:3109-19.
Kim EJ, Kim YH, Kang SH, Lee KW, Park YJ. In vitro effects of preservative-free and preserved prostaglandin analogs on primary cultured human conjunctival fibroblast cells. Korean journal of ophthalmology. 2013 Dec 1;27(6):446-53.
Aguayo Bonniard A, Yeung JY, Chan CC, Birt CM. Ocular surface toxicity from glaucoma topical medications and associated preservatives such as benzalkonium chloride (BAK). Expert opinion on drug metabolism & toxicology. 2016 Nov 1;12(11):1279-89.
Meda R, Wang Q, Paoloni D, Harasymowycz P, Brunette I. The impact of chronic use of prostaglandin analogues on the biomechanical properties of the cornea in patients with primary open-angle glaucoma. British Journal of Ophthalmology. 2017 Feb 1;101(2):120-5.
Kahook MY, Ammar DA. In vitro toxicity of topical ocular prostaglandin analogs and preservatives on corneal epithelial cells. Journal of ocular pharmacology and therapeutics. 2010 Jun 1;26(3):259-63.
Erichev VP, Volzhanin AV. Non-preservative glaucoma treatment. National Journal glaucoma. 2020 Apr 20;19(1):69-78.
Pinto LA, Vandewalle E, Gerlier L, Stalmans I, CosoptUD Switch Study Group. Improvement in glaucoma patient quality of life by therapy switch to preservative-free timolol/dorzolamide fixed combination. Ophthalmologica. 2014;231(3):166-71.
Thygesen J. Glaucoma therapy: preservative-free for all?. Clinical Ophthalmology. 2018 Apr 13:707-17.
Boimer C, Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: the PESO study. Journal of Glaucoma. 2013 Dec 1;22(9):730-5.
Kestelyn PA, Kestelyn PG, De Bacquer D, Stevens AM. Switch from BAK-preserved to preservative-free latanoprost decreases anterior chamber flare in POAG patients. International Ophthalmology. 2019 Jan 15;39:105-9.
Misiuk-Hojlo M, Pomorska M, Mulak M, Rekas M, Wierzbowska J, Prost M, Wasyluk J, Lubinski W, Podboraczynska-Jodko K, Romaniuk W, Kinasz R. The RELIEF study: Tolerability and efficacy of preservative-free latanoprost in the treatment of glaucoma or ocular hypertension. European journal of ophthalmology. 2019 Mar;29(2):210-5.
Iester M, Telani S, Frezzotti P, Motolese I, Figus M, Fogagnolo P, Perdicchi A, Beta-Blocker Study Group. Ocular surface changes in glaucomatous patients treated with and without preservatives beta-blockers. Journal of ocular pharmacology and therapeutics. 2014 Aug 1;30(6):476-81.
Van Went C, Brasnu E, Hamard P, Baudouin C, Labbé A. The influence of ocular surface diseases in the management of glaucoma. Journal francaisd'ophtalmologie. 2011 Apr 1;34(4):230-7.
Thieme H, van der Velden KK. Preservatives from the perspective of glaucoma surgery. Der Ophthalmologe. 2012 Nov;109:1073-6.
Baudouin C, Pisella PJ, Fillacier K, Goldschild M, Becquet F, De Saint Jean M, Béchetoille A. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999 Mar 1;106(3):556-63.
Baudouin C. Mechanisms of failure in glaucoma filtering surgery: a consequence of antiglaucomatous drugs?. International journal of clinical pharmacology research. 1996 Jan 1;16(1):29-41.
Baudouin C. Side effects of antiglaucomatous drugs on the ocular surface. Current opinion in ophthalmology. 1996 Apr 1;7(2):80-6.
Kaur IP, Lal S, Rana C, Kakkar S, Singh H. Ocular preservatives: associated risks and newer options. CutanOculToxicol. 2009;28:93–103.
Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther. 2001;18:205–15.
Figus M, Agnifili L, Lanzini M, Brescia L, Sartini F, Mastropasqua L, Posarelli C. Topical preservative-free ophthalmic treatments: An unmet clinical need. Expert Opinion on Drug Delivery. 2021 Jun 3;18(6):655-72.
Ishibashi T, Yokoi N, Kinoshita S. Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride. Journal of glaucoma. 2003 Dec 1;12(6):486-90.
Baudouin C. Allergic reaction to topical eyedrops. Current opinion in allergy and clinical immunology. 2005 Oct 1;5(5):459-63.
Asbell PA. Increasing importance of dry eye syndrome and the ideal artificial tear: consensus views from a roundtable discussion. Current medical research and opinion. 2006 Nov 1;22(11):2149-57.
Baudouin C, de Lunardo C. Short term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. British journal of ophthalmology. 1998 Jan 1;82(1):39-42.
Malishevskaya TN, Petrov SY, Kosakyan SM, Vlasova SA. When is preservative-free therapy of glaucoma needed and advisable?. Russian Ophthalmological Journal. 2021 Sep 11;14(3):25-31.
Ruangvaravate N, Choojun K, Srikulsasitorn B, Chokboonpiem J, Asanatong D, Trakanwitthayarak S. Ocular surface changes after switching from other prostaglandins to tafluprost and preservative-free tafluprost in glaucoma patients. Clinical Ophthalmology. 2020 Oct 7:3109-19.
Furrer P, Mayer JM, Gurny R. Ocular tolerance of preservatives and alternatives. Eur J Pharm Biopharm. 2002;53(3):263–280.
Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Progress in retinal and eye research. 2010 Jul 1;29(4):312-34.
Hedengran A, Steensberg AT, Virgili G, Azuara-Blanco A, Kolko M. 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. British Journal of Ophthalmology. 2020 Nov 1;104(11):1512-8.
Sanford M. Preservative-free latanoprost eye drops in patients with primary open-angle glaucoma/ocular hypertension. Clinical drug investigation. 2014 Jul;34:521-8.
Cucherat M, Stalmans I, Rouland JF. Relative efficacy and safety of preservative-free latanoprost (T2345) for the treatment of open-angle glaucoma and ocular hypertension: an adjusted indirect comparison meta-analysis of randomized clinical trials. Journal of Glaucoma. 2014 Jan 1;23(1):e69-75. Doi: 10.1097/IJG.0b013e3182a075e6
Henry JC, Peace JH, Stewart JA, Stewart WC. Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared with prior prostaglandin therapy. Clinical Ophthalmology. 2008 Sep 1;2(3):613-21.
Khalaf T, Joseph D, Abdulrehman B. Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution. InБюллетень медицинских интернет-конференций 2016 (Vol. 6, No. 5, pp. 775-775). Общество с ограниченной ответственностью «Наука и инновации».
Renieri G, Führer K, Scheithe K, Lorenz K, Pfeiffer N, Thieme H. Efficacy and tolerability of preservative-free eye drops containing a fixed combination of dorzolamide and timolol in glaucoma patients. Journal of ocular pharmacology and therapeutics. 2010 Dec 1;26(6):597-603.
Hamacher T, Airaksinen J, Saarela V, Liinamaa MJ, Richter U, Ropo A. Efficacy and safety levels of preserved and preservative‐free tafluprost are equivalent in patients with glaucoma or ocular hypertension: results from a pharmacodynamics analysis. Acta Ophthalmologica. 2008 Sep;86:14-9.
Chabi A, Varma R, Tsai JC, Lupinacci R, Pigeon J, Baranak C, Noble L, Lines C, Ho TW. Randomized clinical trial of the efficacy and safety of preservative-free tafluprost and timolol in patients with open-angle glaucoma or ocular hypertension. American journal of ophthalmology. 2012 Jun 1;153(6):1187-96.
Stalmans I, Oddone F, Cordeiro MF, Hommer A, Montesano G, Ribeiro L, Sunaric-Mégevand G, Rossetti L. Comparison of preservative-free latanoprost and preservative-free bimatoprost in a multicenter, randomized, investigator-masked cross-over clinical trial, the SPORT trial. Graefe's Archive for Clinical and Experimental Ophthalmology. 2016 Jun;254(6):1151-8.
Brignole-Baudouin F, Riancho L, Liang H, Nakib Z, Baudouin C. In vitro comparative toxicology of polyquad-preserved and benzalkonium chloride-preserved travoprost/timolol fixed combination and latanoprost/timolol fixed combination. Journal of ocular pharmacology and therapeutics. 2011 Jun 1;27(3):273-80.
Aptel F, Pfeiffer N, Schmickler S, Clarke J, Lavín-Dapena C, Moreno-Montañés J, Żarnowski T, Csutak A, Jugaste T, Volksone L, Astakhov YS. Noninferiority of preservative-free versus BAK-preserved Latanoprost-timolol fixed combination eye drops in patients with open-angle glaucoma or ocular hypertension. Journal of Glaucoma. 2019 Jun 1;28(6):498-506.
Liang H, Brignole-Baudouin F, Pauly A, Riancho L, Baudouin C. Polyquad-preserved travoprost/timolol, benzalkonium chloride (BAK)-preserved travoprost/timolol, and latanoprost/timolol in fixed combinations: a rabbit ocular surface study. Advances in therapy. 2011 Apr;28(4):311-25.
Park SW, Lee J, Kook MS. Efficacy, Safety and Patient-Reported Outcomes with Preservative-Free (PF) Tafluprost or PF-Dorzolamide/Timolol Compared with Preserved Latanoprost: A Prospective Multicenter Study in Korean Glaucoma Patients with Ocular Surface Disease. Pharmaceuticals. 2022 Feb 7;15(2):201.
Lemmens S, Rossetti L, Oddone F, Sunaric-Mégevand G, Hommer A, Vandewalle E, Francesca Cordeiro M, McNaught A, Montesano G, Stalmans I. Comparison of preserved bimatoprost 0.01% with preservative-free tafluprost: A randomised, investigator-masked, 3-month crossover, multicentre trial, SPORT II. European Journal of Ophthalmology. 2022 Mar;32(2):968-75.
Skov AG, Rives AS, Freiberg J, Virgili G, Azuara-Blanco A, Kolko M. Comparative efficacy and safety of preserved versus preservative-free beta-blockers in patients with glaucoma or ocular hypertension: a systematic review. Acta ophthalmologica. 2022 May;100(3):253-61. Harasymowycz P, Hutnik C, Rouland JF, Negrete FJ, Economou MA, Denis P, Baudouin C. Preserved versus preservative-free latanoprost for the treatment of glaucoma and ocular hypertension: a post hoc pooled analysis. Advances in Therapy. 2021 Jun;38(6):3019-31.
Uusitalo H, Chen E, Pfeiffer N, BrignoleBaudouin F, Kaarniranta K, Leino M, Puska P, Palmgren E, Hamacher T, Hofmann G, Petzold G. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta ophthalmologica. 2010 May;88(3):329-36.
Janulevičienė I, Derkač I, Grybauskiene L, Paulauskaitė R, Gromnickaite R, Kuzmienė L. Effects of preservative-free tafluprost on tear film osmolarity, tolerability, and intraocular pressure in previously treated patients with open-angle glaucoma. Clinical Ophthalmology (Auckland, NZ). 2012;6:103.
Kuppens EV, de Jong CA, Stolwijk TR, De Keizer RJ, Van Best JA. Effect of timolol with and without preservative on the basal tear turnover in glaucoma. British journal of ophthalmology. 1995 Apr 1;79(4):339-42.
Duru Z, Ozsaygili C. Preservative-free versus preserved brimonidine% 0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy, safety, and potential advantages. Cutaneous and ocular toxicology. 2020 Jan 2;39(1):21-4.
Zhou T, Miao Y, Li Z, Lu P, Liang Z, Yang J, He J, Xia H, Zhang Z, Zhang J. A comparative ocular pharmacokinetics study of preservative-free latanoprost unit-dose eye drops and a benzalkonium chloride-preserved branded product following topical application to rabbits. Journal of Ocular Pharmacology and Therapeutics. 2020 Sep 1;36(7):522-8.
Daull P, Buggage R, Lambert G, Faure MO, Serle J, Wang RF, Garrigue JS. A comparative study of a preservative-free latanoprost cationic emulsion (Catioprost) and a BAK-preserved latanoprost solution in animal models. Journal of ocular pharmacology and therapeutics. 2012 Oct 1;28(5):515-23.
Tokuda N, Kitaoka Y, Matsuzawa A, Tsukamoto A, Sase K, Sakae S, Takagi H. Changes in ocular surface characteristics after switching from benzalkonium chloride-preserved latanoprost to preservative-free tafluprost or benzalkonium chloride-preserved tafluprost. Journal of ophthalmology. 2017 Aug 2;2017.
Hommer A, Kimmich F. Switching patients from preserved prostaglandin-analog monotherapy to preservative-free tafluprost. Clinical Ophthalmology (Auckland, NZ). 2011;5:623.
Kim DW, Shin J, Lee CK, Kim M, Lee S, Rho S. Comparison of ocular surface assessment and adherence between preserved and preservative-free latanoprost in glaucoma: a parallel-grouped randomized trial. Scientific Reports. 2021 Jul 22;11(1):1-9.
Rouland JF, Traverso CE, Stalmans I, El Fekih L, Delval L, Renault D, Baudouin C. Efficacy and safety of preservative-free latanoprost eyedrops, compared with BAK-preserved latanoprost in patients with ocular hypertension or glaucoma. British journal of ophthalmology. 2013 Feb 1;97(2):196-200.
Inoue D, Mohamed YH, Uematsu M, Kitaoka T. Corneal damage and its recovery after instillation of preservative-free versus preserved latanoprost eye drops. Cutaneous and Ocular Toxicology. 2020 Apr 2;39(2):158-64.
Economou MA, Laukeland HK, Grabska-Liberek I, Rouland JF. Better tolerance of preservative-free latanoprost compared to preserved glaucoma eye drops: the 12-month real-life FREE study. Clinical ophthalmology (Auckland, NZ). 2018;12:2399.
Jandroković S, Vidas Pauk S, Lešin Gaćina D, Skegro I, Tomić M, Masnec S, Kuzman T, Kalauz M. Tolerability in Glaucoma Patients Switched from Preserved to Preservative-Free Prostaglandin-Timolol Combination: A Prospective Real-Life Study. Clinical Ophthalmology. 2022 Jan 1:3181-92.
Kim JM, Kim TW, Kim CY, Kim HK, Park KH. Comparison of the intraocular pressure-lowering effect and safety of brimonidine/timolol fixed combination and 0.5% timolol in normal-tension glaucoma patients. Japanese journal of ophthalmology. 2016 Jan;60(1):20-6.
Aptel F, Choudhry R, Stalmans I. Preservative-free versus preserved latanoprost eye drops in patients with open-angle glaucoma or ocular hypertension. Current Medical Research and Opinion. 2016 Aug 2;32(8):1457-63.
Kim JM, Park SW, Seong M, Ha SJ, Lee JW, Rho S, Lee CE, Kim KN, Kim TW, Sung KR, Kim CY. Comparison of the safety and efficacy between preserved and preservative-free latanoprost and preservative-free tafluprost. Pharmaceuticals. 2021 May 24;14(6):501.
Kim DW, Shin J, Lee CK, Kim M, Lee S, Rho S. Comparison of ocular surface assessment and adherence between preserved and preservative-free latanoprost in glaucoma: a parallel-grouped randomized trial. Scientific Reports. 2021 Jul 22;11(1):1-9.
Müllertz O, Hedengran A, Mouhammad ZA, Freiberg J, Nagymihály R, Jacobsen J, Larsen SW, Bair J, Utheim TP, Dartt DA, Heegaard S. Impact of benzalkonium chloride-preserved and preservative-free latanoprost eye drops on cultured human conjunctival goblet cells upon acute exposure and differences in physicochemical properties of the eye drops. BMJ Open Ophthalmology. 2021 Dec 1;6(1):e000892.
Kim JM, Sung KR, Lee JW, Kyung H, Rho S, Kim CY. Efficacy and safety of newly developed preservative-free latanoprost 0.005% eye drops versus preserved latanoprost 0.005% in open angle glaucoma and ocular hypertension: 12-week results of a randomized, multicenter, controlled phase III trial. International Journal of Ophthalmology. 2021;14(10):1539.
Harasymowycz P, Hutnik C, Rouland JF, Negrete FJ, Economou MA, Denis P, Baudouin C. Preserved versus preservative-free latanoprost for the treatment of glaucoma and ocular hypertension: a post hoc pooled analysis. Advances in Therapy. 2021 Jun;38(6):3019-31. Ilechie A, Abokyi S, Boateng G, Koffuor GA. Effect of preserved and preservative-free timolol eye drops on tear film stability in healthy Africans. Nigerian Medical Journal: Journal of the Nigeria Medical Association. 2016 Mar;57(2):104.
Lopes NL, Gracitelli CP, Chalita MR, de FARIA NV. Ocular surface evaluation after the substitution of benzalkonium chloride preserved prostaglandin eye drops by a preservative-free prostaglandin analogue. Medical Hypothesis, Discovery and Innovation in Ophthalmology. 2019;8(1):52.
Jaenen N, Baudouin C, Pouliquen P, Manni G, Figueiredo A, Zeyen T. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. European journal of ophthalmology. 2007 May;17(3):341-9.
Kestelyn PA, Kestelyn PG, De Bacquer D, Stevens AM. Switch from BAK-preserved to preservative-free latanoprost decreases anterior chamber flare in POAG patients. International Ophthalmology. 2019 Jan;39(1):105-9.
Wu JH, Wang TH, Huang JY, Su CC. Ocular Surface Disease in Glaucoma Patients Randomized to Benzalkonium Chloride-Containing Latanoprost and Preservative-Free Bimatoprost. Journal of Ocular Pharmacology and Therapeutics. 2021 Dec 1;37(10):556-64.
Ali AF, Salama RM, Soliman MA. Effect of preservative-free and preserved prostaglandin analogues on the histology of cornea of adult male Guinea pigs following repeated exposure. Folia Morphologica. 2020 Dec 23. Doi: 10.5603/FM.a2020.0146
Pellinen P, Lokkila J. Corneal penetration into rabbit aqueous humor is comparable between preserved and preservative-free tafluprost. Ophthalmic research. 2009;41(2):118-22.
Mohammed I, Kulkarni B, Faraj LA, Abbas A, Dua HS, King AJ. Profiling ocular surface responses to preserved and non‐preserved topical glaucoma medications: a 2‐year randomized evaluation study. Clinical & Experimental Ophthalmology. 2020 Sep;48(7):973 82.
Ishibashi T, Yokoi N, Kinoshita S. Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride. Journal of glaucoma. 2003 Dec 1;12(6):486-90.
Muñoz Negrete FJ, Lemij HG, Erb C. Switching to preservative-free latanoprost: impact on tolerability and patient satisfaction. Clinical Ophthalmology. 2017 Mar 21:557-66.
Martinez-de-la-Casa JM, Perez-Bartolome F, Urcelay E, Santiago JL, Moreno-Montañes J, Arriola-Villalobos P, Benitez-del-Castillo JM, Garcia-Feijoo J. Tear cytokine profile of glaucoma patients treated with preservative-free or preserved latanoprost. The ocular surface. 2017 Oct 1;15(4):723-9.
Kwon J, Heo JH, Kim HM, Song JS. Comparison of cytotoxic effects on rabbit corneal endothelium between preservative-free and preservative-containing dorzolamide/timolol. Korean Journal of Ophthalmology. 2015 Oct 1;29(5):344-50.
Birkhoff M, Ritter A. AN EYE ON THE FUTURE OF PRESERVATIVE-FREE DROPS.
Wilson LA. To preserve or not to preserve, is that the question?. The British Journal
of Ophthalmology. 1996 Jul;80(7):583.
Rosin LM, Bell NP. Preservative toxicity in glaucoma medication: clinical evaluation
of benzalkonium chloride-free 0.5% timolol eye drops. Clinical Ophthalmology (Auckland, NZ).2013;7:2131. doi: 10.2147/OPTH.S41358
Coroi MC, Bungau S, Tit M. Preservatives from the eye drops and the ocular surface.
Rom J Ophthalmol. 2015;59:2–5.
Saisyo A, Shimono R, Oie S, Kimura K, Furukawa H. The risk of microbial contamination in multiple-dose preservative-free ophthalmic preparations. Biol Pharm Bull. 2017;40:182–6.
Figus M, Agnifili L, Lanzini M, Brescia L, Sartini F, Mastropasqua L, Posarelli C. Topical preservative-free ophthalmic treatments: An unmet clinical need. Expert Opinion on Drug Delivery. 2021 Jun 3;18(6):655-72.
Yoon S, Regn M. Packaging Development: Multi-Dose Container Closure for Preservative-free Products, Extractable/Leachables from Packaging, New Technologies. InOphthalmic Product Development: From Bench to Bedside 2022 Feb 7 (pp. 229-245). Cham: Springer International Publishing.
D.D. Delivery, Ophthalmic Squeeze Dispenser – Eliminating the Need for Additives in Multidose Preservative-free Eyecare Formulations, 2017 [cited 2023 21 Jan]; Available from: https://drug-dev.com/ophthalmic-squeeze-dispense r-eliminating-the-need-for-additives-in-multidose-preservative-free-eyecare-formulations/.
Teping C, Wiedemann B. The COMOD system. A preservative-free multidose container for eyedrops. Klinische Monatsblatter fur Augenheilkunde. 1994 Oct 1;205(4):210-7. Doi: 10.1055/s-2008-1045518
Aeropump, The 3K® System with Triple Protection, 2021 cited 21-01- 2023], https://www.aeropump.de/en/products/ophthalmological.
Birkhoff M. Delivering on the growing need for topical preservative-free ophthalmic treatments. ONdrugDelivery Magazine. 2020 Jan(104):8-12.
Zoe Davidson Developing an efficient ophthalmic device combination product. ON drug delivery magazine. 2020 Jan 24, 16-19 [cited 2023, 24 Jan] available from: https://www.nemera.net/wp-content/uploads/2021/05/ODD-Ophthalmic-Drug-Delivery_Nemera_2020-01.pdf
ABAK pure technology in a bottle- Laboratories Thea [cited 2023, 24 Jan] Available from: https://www.laboratoires-thea.com/medias/abak_brochure_eng.pdf
Rahman MQ, Tejwani D, Wilson JA, Butcher I, Ramaesh K. Microbial contamination of preservative-free eye drops in multiple application containers. British journal of ophthalmology. 2006 Feb 1;90(2):139-41.
Perry HD, Donnenfeld ED. Issues in the use of preservative-free topicals. Managed care (Langhorne, Pa.). 2003 Dec 1;12(12 Suppl):39-41.
Lee JH, Kang MJ, Sim HE, Hwang JH. Microbial Contamination of Preservative-Free Artificial Tears Based on Instillation Techniques. Pathogens. 2022 May 18;11(5):592.
Tatham AJ, Sarodia U, Gatrad F, Awan A. Eye drop instillation technique in patients with glaucoma. Eye. 2013 Nov;27(11):1293-8.
Tsegaw A, Tsegaw A, Abula T, Assefa Y. Bacterial contamination of multi-dose eye drops at ophthalmology department, University of Gondar, Northwest Ethiopia. Middle East African Journal of Ophthalmology. 2017 Apr;24(2):81.
Kim MS, Kim HK, Kim JM, Choi CY. Comparison of contamination rates between preserved and preservative-free fluoroquinolone eyedrops. Graefe's Archive for Clinical and Experimental Ophthalmology. 2013 Mar;251(3):817-24.
da Costa AX, Yu MC, de Freitas D, Cristovam PC, LaMonica LC, Dos Santos VR, Gomes JA. Microbial cross-contamination in multidose eyedrops: the impact of instillation angle and bottle geometry. Translational vision science & technology. 2020 Jun 3;9(7):7-.
Furrer P, Mayer JM, Gurny R. Ocular tolerance of preservatives and alternatives. European journal of pharmaceutics and biopharmaceutics. 2002 May 1;53(3):263-80.
Costagliola C, Parmeggiani F, Sebastiani A. Assessing the cost-effectiveness of switching from a β-blocker to latanoprost in the treatment of ocular hypertension. Expert Opinion on Pharmacotherapy. 2003 Oct 1;4(10):1775-88.
Winfield AJ, Jessiman D, Williams A, Esakowitz L. A study of the causes of non-compliance by patients prescribed eyedrops. British Journal of Ophthalmology. 1990 Aug 1;74(8):477-80.
Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surgery, Lasers and Imaging Retina. 1995 May 1;26(3):233-6.
Robin AL, Muir KW. Medication adherence in patients with ocular hypertension or glaucoma. Expert Review of Ophthalmology. 2019 Sep 3;14(4-5):199-210.
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. American Journal of Ophthalmology. 2018 Apr 1;188:9-18.
Robin AL, Muir KW. Medication adherence in patients with ocular hypertension or glaucoma. Expert Review of Ophthalmology. 2019 Sep 3;14(4-5):199-210.
CE. Antiglaucoma drugs: The role of preservative-free formulations. Saudi Journal of Ophthalmology. 2011 Oct 1;25(4):389-94.
E. Karavas, et al., Preservative-free Pharmaceutical Ophthalmic Compositions, 2019. Google Patents.
S. Likitlersuang, et al., Preservative-free Brimonidine and Timolol Solutions, 2019. Google Patents.
E. Karavas, Preservative-free Pharmaceutical Composition for Ophthalmic Administration Containing Bimatoprost and Timolol, 2019. Google Patents.
M.V. Shah, D. Bahri, M.K. Singh, Preservative-free Ophthalmic Pharmaceutical Formulation, 2017. Google Patents.
F. Pilotaz, F. Mercier, H. Chibret, Preservative-free Prostaglandin-Based Ophthalmic Solution, 2014. Google Patents.
T. Reunamaki, et al., Method and Composition for Treating Ocular Hypertension and Glaucoma, 2018. Google Patents.
S. Likitlersuang, et al., Preservative-free Bimatoprost and Timolol Solutions, 2015. Google Patents.