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6/9/2008 Financial Disclosure y Consultant - Alcon Ophthalmic Preservatives: Past,, Present,, and Future - Allergan - Becton-Dickinson Becton Dickinson - ForSight Labs Terry Kim, MD Associate Professor of Ophthalmology Duke University School of Medicine Associate Director Cornea and Refractive Surgery Services Duke University Eye Center Drug Components y Active Drug yPreservative y Drug Delivery System y Viscosity-Increasing Agents - Hyperbranch Medical Technology - ISTA - SIO Healthcare Advisors Goal of Preservatives? yPrevention of antimicrobial activity y Prior studies: bacterial contamination can occur within one or two weeks of use (1) y Buffers and Stabilizers yProlongation of shelf life y Carrier Vehicle yPrevent biodegradation Regulation Preservative Effectiveness Test y United States Pharmacopeia (USP) Preservative Effectiveness Test (PET) y Inoculation with 1x10 6 colony forming units (cfu)/mL at Day 0 with each organism y Inoculation with the following: y Each organism is tested separately y Bacteria: y 1. Staphylococcus aureus y 2. Pseudomonas aeruginosa y 3. Escherichia coli y Fungi: y 1. Aspergillus niger y 2. Candida albicans y Test for survivors at Day 7, 14, and 28 y Requirements: y 1.0–log reduction by day 7 y 3.0-log reduction by day 14 y No increase in survivors at Day 14 y No increase in survivors from Days 14-28 y No increase in survivors for the fungi from Day 0 to Day 28 1 6/9/2008 Multiple Challenge Test Ocular Preservative chemical classifications 1. Quaternary Ammoniums: BAK 2. Mercurials: thimerosal 3 3. Alcohols: chlorobutanol chlorobutanol, benzyl alcohol 4. Carboxylic Acid: sorbic acid 5. Phenols: methyl / propyl paraben 6. Amidines: chlorhexadine 7. Miscellaneous: EDTA Rosenthal RA et al. Evaluation of the Preserving Efficacy of Lubricant Eye Drops with a Novel Preservation System. J Ocular Pharmacology and Therapeutics. 22:6, 2006. Cytotoxicity of Preservatives mechanism of action y Detergent Preservative: act upon microorganisms by altering cell membrane permeability and lysing cytoplasmic contents Detergent vs. Oxidative Preservatives Detergent Oxidative Benzalkonium Chloride (BAK) Stabilized oxychloro complex (SOC) Polyquauternium-1 (Polyquad) Sodium perborate Thimerosal y Oxidative Preservative: small molecules that penetrate cell membranes and interfere with cell function Noecker R. Effects of Common Ophthalmic Preservatives on Ocular Health. Advances in Therapy. 18:5, 9, 2001. Cytotoxicity of Preservatives mechanism of action y Quaternary Ammoniums: break cell membranes and precipitate cytoplasmic enzymes (detergent) y Mercurial Preservatives: poison microbial enzymes and directly kill microorganisms (oxidative) p disorganize g the bacterial membrane to increase y Alcoholic Compounds: membrane permeability (d) y Sorbic Acid: inhibits bacterial enzyme for oxidation (o) y Phenolic Chemicals: cell lysis by disrupting cell walls or membranes (d) y Chlorhexadine: inhibits potassium transmemb. transport (o) Thimerosal y Originally patented in 1927 y Eli Lilly began to use Thimerosal as a preservative after finding it 40-50x as effective as phenol against S. aureus y Placed in antiseptic ointments, creams, jellies, and sprays y Placed in DPT vaccine as a preservative y 1970’s Æ first reports of potential neurotoxicity related to large volumes of topical antiseptic use Adsorbotear Liquifilm Forte Neosporin Ophthalmic 2 6/9/2008 Thimerosal Thimerosal y 1976 Æ FDA review concluded that use of Thimerosal in DPT vaccine was not dangerous y Higher incidence of allergic conjunctivitis y However, in 1990’s concerns about methylmercury based poisoning p g led to a reduction in the reference doses for methylmercury y 2-6% of adults have demonstrated positive skin patch test reaction to thimerosal y Has been largely g y removed from ophthalmics p y Coincided with time period of large increase in autism diagnosis y 2001 the FDA recommended removal of Thimerosal from childhood vaccines based on methylmercury as no standard for ethylmercury existed Benzalkonium chloride (BAK) Benzalkonium chloride (BAK) y Most Common Ophthalmic Preservative (72%) y 0.1% and 0.05% Æ Cell lysis immediately Alphagan y Quaternary ammonium compound y 0.01% Æ Cell death within 24 hours y Typically concentration of 0.01%0 005% 0.005% y Dose dependent response of corneal epithelial cell toxicity y Cell membrane permeability Æ Lysis y Accumulates in ocular tissue y Enhances drug penetration through cornea (9 – 99x fold) by increasing spacing between epithelial cells y Clinically: y Problematic if doses > QID y Dry-Eye Syndrome patients Abelson MB, Fink K. How to handle BAK Talk. Review of Ophthalmology. 9: 12, Dec 2002. Bernal DL, Ubels JL. Quantitative evaluation of the corneal epithelial barrier: effect of Artificial tears and preservatives. Current Eye Research. 10:7, 1991. Benzalkonium chloride (BAK) Azopt Betagan Betoptic p Cosopt Rescula Timoptic Trusopt Xalatan Hypotears Naphcon-A Vasocon-A Visine BAK Effect on Cornea 2007 Report of the International Dry Eye Workshop (DEWS). The Ocular Surface 5:75-200, 2007. BAK on Corneal Epithelial Surface Tear Film Instability E ith li l D Epithelial Damage Epithelial Cell Apoptosis Decrease MUC5A (gel forming mucin secreted by the goblet cells of the ocular surface) Increase ICAM De Saint Jean, M et al. Toxicity of preserved and unpreserved antiglaucoma topical drugs in an in vitro model of conjunctival cells. Current Eye Research. 20:2, 2, 2000. Abelson MB et al. The Downside of Tear Preservatives. Review of Ophthalmology. 5, 2002. (intracellular adhesion molecule for cell to cell adhesion: a marker for inflammation) 3 6/9/2008 Stabilized Oxychloro Complex (SOC) (Purite) Polyquaternium-1 (Polyquad) y Quaternary ammonium y Introduced to ophthalmic products in 1996; Sodium Chlorite has been used since 1944 for water purification. y Used in contact lens care solutions y Less corneal damage and breakdown of intraepithelial cell junctions compared with standard BAK y 99.5% Chlorite (ClO2), 0.5% Chlorate (ClO3), Chl i Di Chlorine Dioxide id (t (trace)) y Corneal uptake of carboxyfluorescein: y BAK: 9-99 fold increase y Polyquad: 0-4 fold increase y Oxidative action of chlorite y Formation of chlorine dioxide in the presence of microbial acidic environments leads to disruption of protein synthesis Alphagan-P y Components dissipate into components already Refresh Tears found in human tears (Na+, Cl-, O2, and H20) y Oxidative y Corneal epithelial cell metaplasia y Converted to hydrogen peroxide when combined with H20 y Subepithelial fibrosis y Tear film physiology changes y Rapidly decomposed to water and oxygen by catalases and tear film enzymes y Cytotoxicity y Preferential destruction of mucin cells GenTeal y frequency of instillation Bernal DL, Ubels JL. Quantitative evaluation of the corneal epithelial barrier: effect of Artificial tears and preservatives. Current Eye Research. 10:7, 1991. y Increased immune reaction against tear components y Have been cited as cause of early glaucoma surgery failure y Historically a bleaching agent y concentration of preservative y Confocal microscopy and histologic studies confirmed less corneal toxicity with PQ-1 vs. BAK Preservatives Dilemma Sodium Perborate Factors Affecting the Ocular Tolerance of Preservatives Systane Tears Naturale II Dry Eye: A Practical Guide to Ocular Surface Disorders and Stem Cell Surgery. Ed. Agarwal A. 2006. Preservative Effect on Cornea y Directly: modifying anatomical and physiological the epithelium which affects optical properties and epithelial barrier function y duration of treatment y physiological state of cornea y Indirectly: modifying tear film leading to ocular non-wetting tear disorders y wearing of contact lenses y product polymer interaction 4 6/9/2008 Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br. J. Ophthalmol. 86:418-423, 2002. Ocular Symptoms y In an unmasked study of 4107 glaucoma patients, the h ffrequency off ocular l surface f changes was twice as high in those receiving preserved drops, and the frequency of signs and symptoms were dose related. Preservative-Induced Toxic Conjunctivitis y Conjunctival hyperemia y Hyperemic lid margins y Follicular conjunctivitis y Preferentially to inferior conjunctiva y Chemosis y Absence of preauricular lymphadenopathy y Superficial punctate keratopathy To Preserve or Not Preserve? Future Directions y Decreased number of daily doses y Improved viscosity-increasing agents y Preservative-free formulations y Newer formulations in which preservative breaks down on contact with tear film to the component ions already present in tear film y New techniques of ocular drug delivery An Alternative Preservative Unique Ionic Buffer System TM 5 6/9/2008 References Abelson MB, Fink K. How to handle BAK Talk. Review of Ophthalmology. 9: 12, Dec 2002. Abelson MB et al. The Downside of Tear Preservatives. Review of Ophthalmology. 5, 2002. Bernal DL, Ubels JL. Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives. Current Eye Research. 10:7, 1991. De Saint Jean, M et al. Toxicity of preserved and unpreserved antiglaucoma topical drugs in an in vitro model of conjunctival cells cells. Current Eye Research Research. 20:2 20:2, 2 2, 2000 2000. Noecker R. Effects of Common Ophthalmic Preservatives on Ocular Health. Advances in Therapy. 18:5, 9, 2001. Dry Eye: A Practical Guide to Ocular Surface Disorders and Stem Cell Surgery. Ed. Agarwal A. 2006. Rosenthal RA et al. Evaluation of the Preserving Efficacy of Lubricant Eye Drops with a Novel Preservation System. J Ocular Pharmacology and Therapeutics. 22:6, 2006. Labbe, A et al. Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. J Ocular Pharm and Therapeutics 22:4, 2006 6