Sterility Preservatives

Sterility of and Preservatives in Ocular Drugs

Lecture Overview

• Key Topics: Manufacture and Sterility, Preservatives, D Value, Classes, Examples, Effects on Ocular Surface, Other Issues

• Learning Outcomes:

  • Understanding the sterile conditions required to manufacture eye drops and the potential impact of contamination.

  • Comprehension of preservatives used in ophthalmic products and associated risks.

Manufacture of Ophthalmic Drugs

• Sterile Manufacturing Procedures:

  • HVAC System: Maintains temperature, controls airborne particles using HEPA filters, manages room pressure, and limits humidity.

  • Sterilised Containers: Used in aseptic environments, applying aseptic filling and capping methods.

Sterility of Ophthalmic Solutions

• Importance of Sterility: Prevents the introduction of pathogens to the eye.

• Production Methods:

  • Autoclaving: Uses pressure at 121°C for 15 minutes to destroy microorganisms but may decompose some drugs.

  • Filtration: Aseptically filters using porous membranes (~0.22µm) to prevent bacteria (~ 0.5 um) passage but does not filter viruses.

Tests of Sterility

• Conduct under aseptic conditions to prevent contamination.

• Culture Media Preparation:

  • Fluid thioglycollate for anaerobic bacteria; detects aerobic bacteria.

  • Soya-bean casein digest medium for fungi and aerobic bacteria.

• Testing Procedure:

  • Transfer contents to be tested, filter, and transfer to culture medium followed by 14 days of incubation.

  • Check for microbial growth; lack of growth indicates compliance.

Importance of Drug Sterility

• Case Study: Framingham pharmacy linked to 377 fungal infections and 28 deaths due to poorly prepared steroid injections.

• Recalls and Issues:

  • Ameridose LLC recalls products due to sterility testing failures, contamination risks, and shipping issues before sterility results are available.

Recalls of Ophthalmic Drugs

• Notable Recalls:

  • Zovirax Ointment: Recalled Oct 2014 due to metal particles, risk of eye damage, causing product shortage.

  • Diamox Tablets: Recalled Feb 2016 for potential fungal contamination.

Requirement of Preservatives in Multi-Use Preparations

• Essential to maintain sterility post-opening.

• Risks of Preservatives:

  • Can cause corneal toxicity and allergic reactions, disrupting the tear film.

  • Issues more common in patients with pre-existing tear film anomalies or prolonged use.

  • Problems typically resolve after stopping treatment or switching to preservative-free products.

Ideal Criteria of Preservatives

• Non-irritating yet effective.

• Non-sensitising

• possess anti-bacterial and anti-fungal properties.

• render sterility over a reasonable period of time

• chemical stability.

• Should not interfere with primary ingredient activity.

Categories of Preservatives

• Bacteriostatic: Inhibits bacterial growth.

• Bactericidal: Destroys bacteria.

• Fungistatic: Inhibits fungal growth.

• Fungicidal: Destroys fungi.

• Typically, preservatives used in ocular tissues show bacteriostatic properties.

Rate of Destruction of Bacteria

• Factors influencing effectiveness include:

  • Nature of preservative, organism type, dispersion degree, organic matter amount, temperature, pH, viscosity agents, and solution age.

D-value

• Ability of a preservative to kill organisms

• Defines the time to decrease microorganism counts by 90% (1 log unit).

• A lower D-value indicates a stronger antimicrobial effect, with bacteria being killed more rapidly than fungi.

Types of Preservatives in Ocular Drugs

1. Surfactants:

   • Detergents and ionically charged molecules that alter interface relationships.

   • Disrupt plasma membranes and improve drug penetration.

   • Usually have bactericidal properties.

   • They have a "toxicity" effect, disturbing tears and corneal health.

   • Can be inactivated by organic matter but are stable.

   • Examples: CX, BAK.

2. Chemical Toxins:

   • Block normal metabolic processes of cells.

   • Act non-selectively on all cells and may cause allergic reactions.

   • Do not affect tear production.

   • Examples: Thimerosal (TH), iodine, alcohols.

3. Oxidative Preservatives:

   • Penetrate cell membranes/walls and interfere with essential cellular functions.

   • Example: Hydrogen peroxide.

Common Preservatives

• Benzalkonium Chloride: Effective but can disrupt tear film.

• Chlorhexidine: Effective against various bacteria; less corneal toxicity compared to BAK.

• Thimerosal: Banned in many contexts due to mercury concerns; can cause hypersensitivity.

• Sodium Perborate: Converts to hydrogen peroxide in the eye; utilized in lubricant eye drops.

• SofZia: Reduces epithelial cell damage in glaucoma medications.

• EDTA: Chelating agent that enhances preservative action; low toxicity.

Benzalkonium Chloride (BKC/BAK/BAC)

• Type: Cationic detergent that acts on membrane permeability, extremely effective.

• Combination: Often combined with EDTA.

• Functionality: Antibacterial and antifungal properties.

• Applications: Used for preservation of eye drops, instrument sterilization, cleaning of skin, and improving corneal penetration of drugs.

• Stability: Stable with a long shelf life.

• Concentration: Typical concentration is 0.01%, with a range of 0.004% to 0.02% found in glaucoma medications.

• Side Effects: Disrupts tear film and can cause corneal toxicity.

• Usage Restriction: Not for intraocular use.

Chlorhexidine

• Type: Disinfectant used in skin/hand cleaners (e.g., Hibitane 5%) and eye drops (0.02%) - may have a role in treating acanthamoeba keratitis.

• Surfactant Properties: The positively charged chlorhexidine molecule binds to the negatively charged bacterial cell wall, rupturing the cell membranes.

• Effectiveness: Effective against bacteria (both gram-positive and gram-negative) and yeasts (broad spectrum).

• Compatibility: Not used in conjunction with sulfates of atropine or neomycin (precipitates).

• Corneal Effects: Less corneal epithelial effect than BAK.

• Sensitivity: Some individuals may develop sensitivity to chlorhexidine.

• Oral Use Caution: In some mouthwash formulations; if used too often, may damage the mouth’s healthy bacteria.

Cetrimide

• Type: Antiseptic.

• Combination: Chlorhexidine increases effectiveness (e.g., SAVLON contains both cetrimide and chlorhexidine).

• Usage: Popular in the UK, with concentrations ranging from 0.005% to 0.02% for eye drops.

• Side Effects: After prolonged application, may induce toxic epitheliopathy.

  

Polyquaternium-1 (Polyquad)

• Type: Detergent-type preservative derived from BAK.

• Composition: Polymeric quaternary ammonium antimicrobial preservative.

• Mechanism: Bacterial cells attract Polyquad, yet human corneal epithelial cells tend to repel the compound, leading to less toxicity.

• Effect on Goblet Cells: Can decrease numbers of conjunctival goblet cells and affect mucous production in tears.

• Contact Lenses: Does not concentrate in contact lenses.

  

Chlorobutanol

• Type: Alcohol-based chemical toxin formed by simple nucleophilic addition of chloroform and acetone.

• Action: Acts via cell lysis, disrupting microbial cell membrane lipid configuration.

• Effectiveness: Bacteriostatic (effective against gram-positive and gram-negative bacteria) and fungistatic.

• Concentration: Typically used in concentrations ranging from 0.03% to 0.5%.

• Combination: Enhances actions when combined with BAK and also used with EDTA.

• Irritation: Relatively non-irritating compared to BAK.

• Usage Restriction: Not for use with soft contact lenses.

• Stability: A volatile compound that can diffuse through plastic bottles during prolonged storage and is unstable at room temperature.

Thimerosal (Thiomersal)

• Type: Organomercury compound (chemical toxin); was in many multidose vaccines but recently banned to fulfill the aim of reducing mercury exposure (replaced by single dose vials in developed countries).

• Popularity: Once very popular; 0.005% concentration in all contact lens solutions.

• Allergic Reactions: Can cause red, irritated eyes with epithelial changes, photophobia, and lacrimation.

• Hypersensitivity: 25 to 50% of people develop a delayed hypersensitivity follicular reaction – increases IgG tear antibodies.

• Effectiveness: Not as effective as many other preservatives, such as chlorhexidine and chlorobutanol.

Stabilised Oxychloro Complex (Purite)

• Type: Oxidative preservative (chloride/oxygen compound).

• Decomposition: Converts to water & NaCl, neutralized by human cells, doesn’t accumulate.

• Effectiveness: Effective against microorganisms – even at low concentrations (0.005%).

• Toxicity: Reduced toxicity, improved tolerability profile; well tolerated when administered frequently.

• Applications: Found in Alphagan P (brimonidine tartrate for glaucoma).

Sodium Perborate

• Type: Oxidative preservative (0.005% - 0.01%).

• Conversion: Converts to hydrogen peroxide when combined with water.

• Decomposition: Decomposed to water and oxygen in the eye.

• Effectiveness: Broad spectrum activity against bacteria and Aspergillus (fungus).

• Applications: Found in Genteal lubricant eye drops.

SofZia

• Type: Unique ionic buffer containing borate, sorbitol, propylene glycol, and zinc.

• Mechanism: Inactivated by cations in the tear film; results in less ocular surface cytotoxicity.

• Applications: Used in travoprost (Travatan Z, Alcon, glaucoma medication; earlier formulation contained BAK).

• Benefits: Switching from a glaucoma medication with BAK to one with SofZia results in reduced SPK (less corneal epithelial cell damage).

• The rapid and complete reduction of all microbial challenges demonstrates that antimicrobial activity of latanoprost with 0.02% BAK exceeds that of travoprost with SofZia preservative system

Sorbate (Sorbic Acid)

• Limited Anti-Microbial Activity: Exhibits weak antimicrobial properties.

• Mechanism of Action: Inhibits growth of cells primarily through acidification.

• Chemical Reactions: Can react with other compounds to form derivatives that possess enhanced preservative effects.

• Energy Utilization: Causes waste of cellular energy stores.

• Safety Profile: Often promoted as safe for sensitive eyes and contact lens wearers due to its low toxicity.

• Additional Uses: Also utilized as a food preservative.

EDTA (Edetate Disodium)

• Chelating Agent: Binds metals which aids preservative action and can treat calcium deposits in the eye.

• Preservative Enhancement: Assists the action of preservatives such as thimerosal and BAK.

• Toxicity: Low-toxicity but also aids in detoxification.

• Common Applications: Found in many glaucoma medications like Acular and Betagan.

• Additional Uses: Also present in conditioners, cleansers, moisturizers, aftershaves, deodorants, and mouthwashes.

• Water Softening: Softens water.

• Side Effects: Can cause contact dermatitis.