Download Ophthalmic Preservatives: Past, Present, and Future

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
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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
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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)
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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
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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
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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
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