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Pharmaceutical Services

Part 4: Buffers & Preservatives

Excipients for Ophthalmic Drug Delivery:

Existing & Emerging Technologies to Tackle the Unique Challenges of Drug Delivery to the Eye

Part 4 of 4: Buffers & Preservatives

The surface of the eye is a warm, moist, and exposed surface with limited immune defenses when compared to other parts of the body. Microorganisms can adhere, form biofilms, and thrive when given the opportunity. In 2023, EzriCare® Artificial Tears and Delsam® Pharma Artificial Tears, both OTC, preservative-free, carboxymethylcellulose-based eyedrops, were contaminated with a carbapenem-resistant Pseudomonas aeruginosa strain. The products were recalled but not before four deaths due to sepsis, 14 cases of vision loss, and more than 80 infections. To prevent these tragedies, a combination of drug formulation excipients, packaging, and good manufacturing practices must work together to prevent the contamination of microorganisms.

Callan Pharma Services specializes in maximizing an excipient’s impact on the safety and efficacy of an API. In this 4-part series we’ll review those excipients already used in approved ophthalmic pharmaceuticals, and discuss emerging technologies being developed to tackle unsolved challenges. In final Part 4, we’ll discuss Buffers and Preservatives.

Part 4: Buffers & Preservatives

Buffers and preservatives are often a last thought when designing a drug formulation. However, these excipients are vital to a stable, safe, and effective pharmaceutical. Preservatives prevent the growth of opportunistic microorganisms which can contaminate a formulation, especially necessary in multi-use eyedroppers. The most common mode of antimicrobial action is disruption of the cell membranes by one of more mechanisms. Buffers are weak acids and their conjugate bases (or vice versa) which resist changes in pH when acids or bases are introduced by external factors or degradation of the drug formulation itself.

Described below are the categories of buffers and preservatives employed in ophthalmic drug formulations:   

  1. Preservatives – The choice to use a preservative in an ophthalmic drug formulation or use a preservative free approach is often dictated by the indication. Preservatives can prevent microbial contamination, but these agents are also ocular irritants and are a particular problem for patients who require frequent, or long-term dosing (e.g., glaucoma or dry eye). The following are the main categories of preservatives used in ophthalmic pharmaceuticals:
    1. Quaternary Ammonium Compounds (QACs) – These cationic surfactants interact with the negatively charged phospholipids in the membrane of microbes, while their hydrocarbon tail inserts into the lipid bilayer. However, this mechanism is not limited to microbes and can also damage health tissue. The most commonly used preservative in ophthalmic drugs is a member of this class: benzalkonium chloride (BAK), typically included in concentrations ranging from 0.004 to 0.02%. Other QACs include benzododecinium bromide (BDD) and polyquaternium-1 (Polyquad®). The latter was developed by Alcon as a safer QAC—its larger molecular weight reduces permeation and thus damage of corneal cells.
    2. Oxidative Preservatives – these compounds act by generating reactive oxygen species (ROS) upon application to the eye, including singlet oxygen (¹O₂). The ROS disrupt microbial metabolism, damaging cellular functions needed for survival and propagation. Purite® was developed by Allergan as an alternative to the QACs. It comprises a mixture of chlorite (ClO₂⁻), chlorate (ClO₃⁻), and chlorine dioxide (ClO₂) in equilibrium. Upon administration to the environment of the eye (heat, light, and tear film), the components ultimately convert to inert sodium, chloride ions and water. Another member of this class is sodium perborate which breaks down to release hydrogen peroxide (H2O2), which damages microbes itself, and also forms ROS in situ.
    3. Ionic-Buffered Preservatives – developed as an alternative to the traditional preservatives, Alcon introduced SofZia® as the anti-microbial agent in its travoprost formulation (branded as TRAVATAN Z®). SofZia® is a mixture of borate, propylene glycol, sorbitol, and zinc. This creates a stabilized ionic buffer environment with the zinc contributing the most to the antimicrobial action by destabilizing cell membranes, and displacing metal cofactors in microbial enzymes.
  2. Buffers – Eyes are sensitive to acidic and alkaline solutions; pH <6.5 and >8.5 can cause discomfort and irritation when applied topically to the eye. Buffers are added to help maintain a pH between these outliers, allowing for a comfortable application of a drug. The lacrimal fluid is a complex mixture of proteins and salts, including bicarbonate and phosphate buffering systems. It is no surprise these buffering systems are used in ophthalmic drug formulations along with other categories:
    1. Neutral Buffers – when the desired pH is close to 7, phosphate (H₂PO₄⁻/HPO₄²⁻), borate ([B(OH)₄]⁻), and bicarbonate (HCO3⁻) buffer systems are employed. Phosphate is the most common, used in the 0.1 to 0.3% w/v range for topical eye pharmaceuticals.
    2. Slightly Acidic Buffers – for target pH values near 6, organic buffer systems using acetate and citrate are utilized. Citrate has weak antimicrobial action as well; by chelating to microbial metal cofactors (e.g., Fe3+ and Cu2+) it can disrupt their cellular activity.

Emerging Technologies: Preservative-Free  

Instead of developing new preservatives, the industry is trending towards preservative-free approaches. Single-dose ophthalmic products eliminate the need for a preservative (e.g., ketorolac tromethamine ophthalmic solution; ACUVAIL®). However, this approach is cost inefficient and often overly burdensome to the patient. More and more, drug formulators are turning to cutting edge multi-use, preservative-free delivery systems; generally categorized as either (1) unidirectional valve and filter based, or (2) airless pump dispensers. One example of an airless design is the COMOD® (COntinuous MOno Dose) system developed by URSAPHARM (Saarbrücken, Germany). This is a purely mechanical device which delivers a single drop with each actuation. The manufacturer claims the device can deliver at least 300 discrete drops (10 mL size), all while the contents remain sterile for 6 months. Checkout their video on how it operates: https://ursapharm.de/en/systems-and-production/comod-system/.