Advertisement

Ocular Preservatives: Risks and Recent Trends in Its Application in Ocular Drug Delivery (ODD)

  • Sabyasachi MaitiEmail author
  • Sayantan Sadhukhan
  • Paromita Bakshi
Chapter

Abstract

Topical application of eye drops, ointments, gels, or emulsions to treat ocular anterior segment diseases is preferred due to the ease of administration and low cost. Preservatives are the most important ingredients in ocular formulations next to active ingredient. These are often included to prevent the chances of inadvertent contamination of the ocular formulations preserved in multidose containers, most frequently during opening and application to the infected eyes. Indeed preservatives that kill or damage growing microbial cells may also be toxic to growing cells of the ocular tissues. Clinical studies suggest that the long-term use of ophthalmic preparations for effective therapy may induce major and frequent ocular surface changes causing allergic or inflammatory reactions such as redness, stinging, burning, irritation, eye dryness, or less frequently conjunctivitis or corneal damage. With the aging of population, the need for treatments of ocular diseases has become more important than ever. Increasingly high incidences of ocular disorders demand better, more effective, and innovative treatments without appreciable toxic manifestations because the preservation of vision is critical for improving the quality of life. This chapter addresses various commonly used ocular preservatives along with their ocular toxicity, newer preservatives, or other options coming up in this arena.

Keywords

Ophthalmic preparations Ocular preservatives Organomercurials Stabilized oxychloro complex (SOC) Polyquaternium-1 Ionic-buffered preservative Mucoadhesive ophthalmics Ocular toxicity Corneal damages 

References

  1. 1.
    Freeman PD, Kahook MY (2009) Preservatives in topical ophthalmic medications: historical and clinical perspectives. Expert Rev Ophthalmol 4:59–64CrossRefGoogle Scholar
  2. 2.
    Colin C (2006) Are multidose over-the-counter artificial tears adequately preserved? Basic investigations. Cornea 25:432–437CrossRefGoogle Scholar
  3. 3.
    Schein OD, Hibberd PL, Starck T, Baker AS, Kenyon KR (1992) Microbial contamination of in-use ocular medications. Arch Ophthalmol 110:82–85CrossRefPubMedGoogle Scholar
  4. 4.
    Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F (2010) Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 29:312–334CrossRefPubMedGoogle Scholar
  5. 5.
    Burstein NL (1980) Preservative cytotoxic threshold for BKC and chlorhexidine digluconate in cat and rabbit corneas. Invest Ophthalmol Vis Sci 32:2259–2265Google Scholar
  6. 6.
    Kaur IP, Lal S, Rana C, Kakkar S, Singh H (2009) Ocular preservatives: associated risks and newer options. Cutan Ocul Toxicol 28:93–103CrossRefPubMedGoogle Scholar
  7. 7.
    Baudouin C, Pisella PJ, Fillacier K et al (1999) Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology 106:556–563CrossRefPubMedGoogle Scholar
  8. 8.
    Cooper JW, Gunn C (2000) Ophthalmic products. In: Carter SL (ed) Dispensing for pharmaceutical students, 12th edn. CBS Publisher and Distributors, New Delhi, pp 634–662Google Scholar
  9. 9.
    Shaw AJ, Balls M, Clothier RH, Bateman ND (1991) Predicting ocular irritancy and recovery from injury using Madin-Darby canine kidney cells. Toxicol In Vitro 5:169–174CrossRefGoogle Scholar
  10. 10.
    Takahashi N (1982) Cytotoxicity of mercurial preservatives in cell culture. Ophthalmic Res 14:63–69CrossRefPubMedGoogle Scholar
  11. 11.
    Martin SM, Tsao F-P (1998) Method of preserving ophthalmic solutions and compositions therefor. US patent 5725887Google Scholar
  12. 12.
    Block SS (2001) Disinfection, sterilization, and preservation, 5th edn. Lippincott Williams & Wilkins, Philadelphia, p 311Google Scholar
  13. 13.
    Becquet F, Goldschild M, Moldovan MS, Ettaiche M, Gastaud P, Baudouin C (1998) Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface. Curr Eye Res 17:419–425CrossRefPubMedGoogle Scholar
  14. 14.
    Xu Y, Zhao D, Gao C, Zhou L, Pang G, Sun S (2012) In vitro activity of phenylmercuric acetate against ocular pathogenic fungi. J Antimicrob Chemother 67:1941–1944CrossRefPubMedGoogle Scholar
  15. 15.
    Tomlinson A, Trees GR (1991) Effect of preservatives in artificial tear solutions on tear film evaporation. Ophthalmic Physiol Opt 11:48–52CrossRefPubMedGoogle Scholar
  16. 16.
    Fassihi AR, Naidoo NT (1989) Irritation associated with tear-replacement ophthalmic drops. A pharmaceutical and subjective investigation. S Afr Med J 75:233–235PubMedGoogle Scholar
  17. 17.
    Tripathi BJ, Tripathi RC (1989) Cytotoxic effects of BKC and chlorobutanol on human corneal epithelial cells in vitro. Lens Eye Toxic Res 6:395–403PubMedGoogle Scholar
  18. 18.
    Nordt SP (1996) Chlorobutanol toxicity. Ann Pharmacother 30:1179–1180PubMedGoogle Scholar
  19. 19.
    Doughty MJ (1994) Acute effects of chlorobutanol- or BKC-containing artificial tears on the surface features of rabbit corneal epithelial cells. Optom Vis Sci 71:562–572CrossRefPubMedGoogle Scholar
  20. 20.
    Kilp H, Brewitt H (1984) Cytotoxicity of preservatives: a scanning electron microscopic and biochemical investigation. Chibret Int J Ophthalmol 1:4–20Google Scholar
  21. 21.
    Li HF, Petroll WM, Mo¨ller-Perderson T, Maurer JK, Cavanagh HD, Jester JV (1997) Epithelial and corneal thickness measurements by in vivo confocal microscopy through focusing (CMTF). Curr Eye Res 16:214–221CrossRefPubMedGoogle Scholar
  22. 22.
    Berdy GJ, Abelson MB, Smith LM, George MA (1992) Preservative-free artificial tear preparations. Assessment of corneal epithelial toxic effects. Arch Ophthalmol 110:528–532CrossRefPubMedGoogle Scholar
  23. 23.
    de Saint JM, Brignole F, Bringuier A-F, Bauchet A, Feldman G, Baudouin C (1999) Effects of BKC on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci 40:619–630Google Scholar
  24. 24.
    Herreras JM, Pastor C, Calonge M, Asensio VM (1992) Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology 99:1082–1088CrossRefPubMedGoogle Scholar
  25. 25.
    Schwab IR, Linberg JV, Gioia VM, Benson WH, Chao GM (1992) Foreshortening of the inferior conjunctival fornix associated with chronic glaucoma medications. Ophthalmology 99:197–202CrossRefPubMedGoogle Scholar
  26. 26.
    Longstaff S, Wormald RP, Mazover A, Hitchings RA (1990) Glaucoma triple procedures: efficacy of intraocular pressure control and visual outcome. Ophthalmic Surg 21:786–793PubMedGoogle Scholar
  27. 27.
    Gangrade NK, Gaddipati NB, Ganesan MG, Reddy IK (1996) Topical ophthalmic formulations: basic considerations. In: Reddy IK (ed) Ocular therapeutics and drug delivery: a multi-disciplinary approach. Technomic, Basel, pp 377–403Google Scholar
  28. 28.
    Ashton P, Diepold R, Pla¨tzer A, Lee VHL (1990) Effect of chlorhexidine acetate on the corneal penetration of sorbitol from an arnolol formulation in the pigmented rabbit. J Ocul Pharmacol 6:37–42CrossRefPubMedGoogle Scholar
  29. 29.
    Durand-Cavagna G, Delort P, Duprat P, Bailly Y, Plazonnet B, Gordon LR (1989) Corneal toxicity studies in rabbits and dogs with hydroxyethylcellulose and BKC. Fundam Appl Toxicol 13:500–508CrossRefPubMedGoogle Scholar
  30. 30.
    Christiansen M, Cohen S, Rinehart J et al (2004) Clinical evaluation of an HPguar gellable lubricant eye drop for the relief of dryness of the eye. Curr Eye Res 28:55–62CrossRefGoogle Scholar
  31. 31.
    Nelson JD, Farris RL (1988) Sodium hyaluronate and polyvinyl alcohol artificial tear preparations a comparison in patients with keratoconjunctivitis sicca. Arch Ophthalmol 106:484–487CrossRefPubMedGoogle Scholar
  32. 32.
    Brignole-Baudouin F, Riancho L, Liang H, Baudouin C (2011) Comparative in vitro toxicology study of travoprost polyquad-preserved, travoprost BAK-preserved, and latanoprost BAK-preserved ophthalmic solutions on human conjunctival epithelial cells. Curr Eye Res 36:979–988CrossRefPubMedGoogle Scholar
  33. 33.
    Labbé A, Pauly A, Liang H, Brignole-Baudouin F, Martin C, Warnet JM, Baudouin C (2006) Comparison of toxicological profiles of BKC and polyquaternium-1: an experimental study. J Ocul Pharmacol Ther 22:267–278CrossRefPubMedGoogle Scholar
  34. 34.
    Ammar DA, Noecker RJ, Kahook MY (2010) Effects of BKC-preserved, polyquad-preserved, and sofZia-preserved topical glaucoma medications on human ocular epithelial cells. Adv Ther 27:837–845CrossRefPubMedGoogle Scholar
  35. 35.
    Paimela T, Ryhänen T, Kauppinen A, Marttila L, Salminen A, Kaarniranta K (2012) The preservative polyquaternium-1 increases cytoxicity and NF-kappaB linked inflammation in human corneal epithelial cells. Mol Vis 18:1189–1196PubMedPubMedCentralGoogle Scholar
  36. 36.
    Choy CK, Cho P, Boost MV (2012) Cytotoxicity and effects on metabolism of contact lens care solutions on human corneal epithelium cells. Clin Exp Optom 95:198–206CrossRefPubMedGoogle Scholar
  37. 37.
    Abelson MB, Udell IJ (2000) Conjunctiva, cornea, and sclera. In: Albert DM, Jakobiec FA (eds) Principles and practice of ophthalmology, 2nd edn. WB Saunders, Philadelphia, pp 1689–1692Google Scholar
  38. 38.
    Grant R, Ajello M, Vlass E (1996) Salt water or high tech? A look at two new rinsing solutions for contact lenses. Optician 212:38–41Google Scholar
  39. 39.
    Paugh JR, Brennan NA, Efron N (1988) Ocular response to hydrogen peroxide. Am J Optom Physiol Opt 65:91–98CrossRefPubMedGoogle Scholar
  40. 40.
    Vaughan JS, Porter DA (1993) A new in vitro method for assessing the potential toxicity of soft contact lens care solutions. CLAO J 19:54–57PubMedGoogle Scholar
  41. 41.
    Rozen S, Abelson M, Giovanoni A, Welch D (1998) Assessment of the comfort and tolerance of 0.5% carboxymethylcellulose preserved with Purite (Refresh Tears) in dry eye sufferers. Invest Ophthalmol Vis Sci 39:451Google Scholar
  42. 42.
    Noecker R (2001) Effects of common ophthalmic preservatives on ocular health. Adv Ther 18:205–215CrossRefPubMedGoogle Scholar
  43. 43.
    Karageszian VH, Karageozian HL, Climent A, Munoz S, Cuevas G, Gallegos VG (2003) Determine the in-vitro antimicrobial preservative effectiveness of a new broad spectrum antimicrobial preservative “Oxyd”. Invest Ophthalmol Vis Sci 44:1469Google Scholar
  44. 44.
    Kahook MY (2007) Travoprost Z. Ophthalmic solution with sofZia: clinical safety and efficacy. Expert Rev Ophthalmol 2:363–368CrossRefGoogle Scholar
  45. 45.
    Lewis RA, Katz G, Weiss MJ (2007) Travoprost 0.004% with and without BKC: a comparison of safety and efficacy. J Glaucoma 16:98–103CrossRefPubMedGoogle Scholar
  46. 46.
    Yee RW, Norcom EG, Zhao XC (2006) Comparison of the relative toxicity of travoprost 0.004% without BAK and latanoprost 0.005% in an immortalized human cornea epithelial cell culture system. Adv Ther 23:511–518CrossRefPubMedGoogle Scholar
  47. 47.
    Debbasch C, Brignole F, Pisella P-J, Warnet J-M, Rat P, Baudouin C (2001) Quaternary ammoniums and other preservatives’ contribution in oxidative stress and apoptosis on Chang conjunctival cells. Invest Ophthalmol Vis Sci 42:642–652PubMedGoogle Scholar
  48. 48.
    Baines MG, Cai F, Backman HA (1991) Ocular hypersensitivity to thiomersal in rabbits. Invest Ophthalmol Vis Sci 32:2259–2265PubMedGoogle Scholar
  49. 49.
    Yanochko GM, Khoh-Reiter S, Evans MG, Jessen BA (2010) Comparison of preservative-induced toxicity on monolayer and stratified Chang conjunctival cells. Toxicol In Vitro 24:1324–1331CrossRefPubMedGoogle Scholar
  50. 50.
    Brahma AK, Pande M (1994) Comparative conjunctival toxicity of subconjunctival preservative-free gentamicin and subconjunctival preservative-free cefuroxime. Eur J Implant Refract Surg 6:57–58CrossRefGoogle Scholar
  51. 51.
    Smith L, George M, Berdy G, Abelson M (1991) Comparative effects of preservative free tear substitutes on the rabbit cornea: a scanning electron microscopic evaluation (ARVO abstract). Invest Ophthalmol Vis Sci 32 (Suppl):733Google Scholar
  52. 52.
    Tsubota K (1998) Tear dynamics and dry eye. Prog Retin Eye Res 17:565–596CrossRefPubMedGoogle Scholar
  53. 53.
    Holy FJ (1978) Surface chemical evaluation of artificial tears and their ingredients II. Interaction with superficial lipid layer. Cont Intraoc LENS Med J 4:52–65Google Scholar
  54. 54.
    Arffa RC (1997) Toxic and allergic reactions to topical ophthalmic medications. In: Arffa RC (ed) Grayson’s diseases of the cornea. Mosby, St. Louis, pp 669–683Google Scholar
  55. 55.
    Cai F, Backman HA, Baines MG (1988) Thiomersal: an ophthalmic preservative which acts as a hapten to elicit specific antibodies and cell mediated immunity. Curr Eye Res 7:341–351CrossRefPubMedGoogle Scholar
  56. 56.
    Fuchs T, Meinert A, Aberer W et al (1993) BKC-a relevant contact allergen or irritant? Results of a multicentre study of the German contact allergy group. Houtzart 44:699–702Google Scholar
  57. 57.
    Pisella PJ, Pouliquen P, Baudouin C (2002) Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 86:418–423CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Green K (1992) The role of surfactants as bactericides in topical drug delivery. STP Pharm Sci 2:34–38Google Scholar
  59. 59.
    Grant RL, Acosta D (1996) Prolonged adverse effects of BKC and sodium dodecyl sulfate in a primary culture system of rabbit corneal epithelial cells. Fundam Appl Toxicol 33:71–82CrossRefPubMedGoogle Scholar
  60. 60.
    Lemp MA, Zimmerman LE (1988) Toxic endothelial degeneration in ocular surface disease treated with topical medications containing BKC. Am J Ophthalmol 105:670–673CrossRefPubMedGoogle Scholar
  61. 61.
    Weinreb RN, Wood I, Tomazzoli L, Alvarado J (1986) Subconjunctival injections. Preservatives-related changes in the corneal endothelium, Invest. Ophthalmol Vis Sci 27:525–531Google Scholar
  62. 62.
    Tripathi BJ, Tripathi RC, Kolli SP (1992) Cytotoxicity of ophthalmic preservatives on human corneal epithelium. Lens Eye Toxic Res 9:361–375PubMedGoogle Scholar
  63. 63.
    Kahook MY, Noecker RJ (2008) Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, Latanoprost with 0.02% BKC, and preservative-free artificial tears. Cornea 27:339–343CrossRefPubMedGoogle Scholar
  64. 64.
    Mondino BJ, Brawman-Mintzer O, Boothe WA (1987) Immunological complications of soft contact lenses. J Am Optom Assoc 58:832–835PubMedGoogle Scholar
  65. 65.
    Chapman JM, Cheeks L, Green K (1990) Interactions of BKC with soft and hard contact lenses. Arch Ophthalmol 108:244–246CrossRefPubMedGoogle Scholar
  66. 66.
    Way WA, Matsumoto S, Apel LJ, Wiese A, Tarlo K, Vehige J (2001) Purite as a non-disruptive preservative for lubricating eye drop solutions in comparison to alternative preservatives. Invest Ophthalmol Vis Sci 42:S39Google Scholar
  67. 67.
    Lopez B, Ubel J (1991) Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives. Curr Eye Res 10:7645–7656Google Scholar
  68. 68.
    Pham XT, Huff JW (1999) Cytotoxicity evaluation of multipurpose contact lens solutions using an in vitro test battery. CLAO J 25:28–35PubMedGoogle Scholar
  69. 69.
    Epstein EP, Ahdoot M, Marcus E, Asbell PA (2009) Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells. J Ocul Pharmacol Ther 25:113–119CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Gaddipati NB, Gangrade NK, Ganesan MG, Reddy IK (1996) Packaging aspects of ophthalmic products. In: Reddy IK (ed) Ocular therapeutics and drug delivery: a multi-disciplinary approach. Technomic, Basel, pp 529–541Google Scholar
  71. 71.
    Van Santvliet L, Sam T, Ludwig A (1996) Packaging of ophthalmic solutions – influence on stability, sterility, eye drops instillation and patient compliance. Eur J Pharm Biopharm 42:375–384Google Scholar
  72. 72.
    Oldham GB, Andrews V (1996) Control of microbial contamination in unpreserved eyedrops. Br J Ophthalmol 80:588–591CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Palmer RM, Kaufman HE (1995) Tear film, pharmacology of eye drops, and toxicity. Curr Opin Ophthalmol 6:11–16CrossRefPubMedGoogle Scholar
  74. 74.
    Kaufman HE, Steinemann TI, Lehman E, Thompson HW, Varnell ED, Jacob-labarre JT, Gebhardt BM (1994) Collagen-based drug delivery and artificial tears. J Ocul Pharmacol Ther 10:17–27CrossRefGoogle Scholar
  75. 75.
    Luo L, Li D, Corrales R, Pflugfelder S (2005) Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface. Eye Contact Lens 31:186–193CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Sabyasachi Maiti
    • 1
    Email author
  • Sayantan Sadhukhan
    • 1
  • Paromita Bakshi
    • 1
  1. 1.Gupta College of Technological Sciences (College of Pharmacy)AsansolIndia

Personalised recommendations