Benzalkonium chloride

This quaternary ammonium compound is the preservative of choice. It is in over 70% of commercially produced eye drops and over a third of these also contain disodium edetate, usually at 0.1% w/v.

Benzalkonium chloride is not a pure material, but is a mixture of alkylbenzyldimethyl ammonium compounds. This permits a mixture of alkyl chain lengths containing even numbers of carbon atoms between 8 and 18 and results in products of different activities. The longer the carbon chain length, the greater the antibacterial activity but the less the solubility. Therefore the manufacturer should seek to maximize the activity within the constraints of solubility. This means maximizing the proportions of C₁₂, C₁₄ and C₁₆. It should be noted that Benzalkonium Chloride BP contains 50% w/v benzalkonium chloride.

Benzalkonium chloride is well tolerated on the eye up to concentrations of 0.02% w/v but is usually used at 0.01% w/v. It is stable to sterilization by autoclaving. The compound has a rapid bactericidal action in clean conditions against a wide range of Gram-positive and Gram-negative organisms. It destroys the external structures of the cell (cell envelope). It is active in the controlled aqueous environment and pH values of ophthalmic solutions. Activity is reduced in the presence of multivalent cations (Mg²⁺, Ca²⁺). These compete with the antibacterial for negatively charged sites on the bacterial cell surface. It also has its activity reduced if heated with methylcellulose or formulated with anionic and certain concentrations of non-ionic surfactants. Benzalkonium chloride is incompatible with fluorescein (large anion) and nitrates and is sorbed from solutions through contact with rubber.

The antibacterial activity of benzalkonium is enhanced by aromatic alcohols (benzyl alcohol, 2-phenylethanol and 3-phenylpropanol) and its activity against Gram-negative organisms is greatly enhanced by chelating agents such as disodium edetate. These agents chelate the divalent cations, principally Mg²⁺, of Gram-negative cells. These ions form bridges and bind the polysaccharide chains which protrude from the outer membrane of these cells. Thus, the integrity of the membrane is compromised and the benzalkonium chloride activity enhanced. This is particularly valuable in preserving against contamination with Pseudomonas aeruginosa.

The surface activity of benzalkonium chloride may be used to enhance the transcorneal passage of non-lipid-soluble drugs such as carbachol. Care must be taken since the preservative can solubilize the outer oily protective layer of the precorneal film. This film has an internal mucin layer in contact with the corneal and scleral epithelia, a middle aqueous layer and an outer oily layer. The oil prevents excessive aqueous evaporation and protects the inner surface of the lids from constant contact with water. The blink reflex helps maintain the integrity of the precorneal film. For these reasons, it is important not to use benzalkonium chloride to preserve local anaesthetic eye drops which abolish the blink reflex. The combined effect of the two agents causes drying of the eye surface and irritation of the cornea.

Chlorhexidine acetate or gluconate

Chlorhexidine is a cationic biguanide bactericide with antibacterial properties in aqueous solution similar to benzalkonium chloride. Its activity is often reduced in the presence of other formulation ingredients. It is used at 0.01% w/v. Its antibacterial activity against Gram-negative bacteria is enhanced by aromatic alcohols and by disodium edetate. Activity is antagonized by multivalent cations. Stability is greatest at pH 5–6 but it is less stable to autoclaving than benzalkonium chloride. Chlorhexidine salts are generally well tolerated by the eye although allergic reactions may occur.

Chlorobutanol

This chlorinated alcohol is used at 0.5% w/v and is effective against bacteria and fungi. Chlorobutanol is compatible with most ophthalmic products. The main disadvantages are its volatility, absorption by plastic containers and lack of stability at autoclave temperatures.

Organic mercurials

Phenylmercuric acetate and nitrate and thiomersal are organic mercurials. They are slowly active, at concentrations of 0.001–0.004% w/v, over a wide pH range against bacteria and fungi. Absorption by rubber is marked.

The organic mercurials should not be used in eye drops which require prolonged usage because this can lead to intraocular deposition of mercury (mercurialentis). Allergy to thiomersal is also possible.

Tonicity

Where possible, eye drops are made isotonic with lachrymal fluid (approximately equivalent to 0.9% w/v sodium chloride solution). In practice, the eye will tolerate small volumes of eye drops having tonicities in the range equivalent to 0.7–1.5% w/v sodium chloride. Nevertheless it is good practice to adjust the tonicity of hypotonic eye drops by the addition of sodium chloride to bring the solution to the tonicity of the lachrymal fluid. (See Ch. 19 for methods for calculating the amount of sodium chloride required.) Some preparations are themselves hypertonic and so no adjustment should be made.

Hypromellose

The hydroxypropyl derivative of methylcellulose is the most popular cellulose derivative employed for enhancing viscosity. It has good solubility characteristics (soluble in cold but insoluble in hot water) and good optical clarity. Typical concentrations in eye drop formulations are 0.5–2.0% w/v.

Polyvinyl alcohol

This is used at 1.4% w/v as a viscosity enhancer. It has a good contact time on the eye surface and good optical qualities. It withstands autoclaving and it can be filtered through a 0.22 μm filter.

Polyvinylpyrrolidone, polyethylene glycol and dextrin have also been used as viscolizing agents.

 The pH offering best stability during preparation and storage

 The pH offering the best therapeutic activity

 The comfort of the patient.

Sodium metabisulphite and sodium sulphite

Both may be used as antioxidants at 0.1% w/v. The former is preferred at acid pH and the latter at alkaline pH. Both are stable in solution when protected from light. Sodium metabisulphite possesses marked antimicrobial properties at acid pH and enhances the activity of phenylmercuric nitrate at acid pH. It is incompatible with prednisolone phosphate, adrenaline (epinephrine), chloramphenicol and phenylephrine.

Single-dose containers

The ‘Minims’® range is the most widely used type of single-dose eye drop container in the UK. It consists of an injection-moulded polypropylene container which is sealed at its base and has a nozzle sealed with a screw cap. This container is sterilized by autoclaving in an outer heat-sealed pouch with peel-off paper backing.

Plastic bottles

Most commercially prepared eye drops are supplied in plastic dropper bottles similar to the illustration in Figure 42.2. Bottles are made of polyethylene or polypropylene and are sterilized by ionizing radiation prior to filling under aseptic conditions with the previously sterilized preparation.