Ophthalmic products
The formulation, preparation and uses of ophthalmic preparations
The packaging and labelling requirements for ophthalmic preparations
Advising patients on the use of eye medication and on any adverse effects
The anatomy and physiology of the eye in relation to the administration of medication and the wearing of contact lenses
The properties of contact lenses in relation to their physicochemical composition
The wearing of and caring for contact lenses and the various products available to facilitate comfort, effectiveness, convenience and safety
The role of antimicrobial preservatives in ophthalmic products
Advising patients on the possible adverse effects of concurrent medication and the sensible use of cosmetics when wearing contact lenses
Introduction
The human eye is a remarkable organ and the ability to see is one of our most treasured possessions. Thus, the highest standards are necessary in the compounding of ophthalmic preparations and the greatest care is required in their use. It is necessary that all ophthalmic preparations are sterile and essentially free from foreign particles.
These preparations may be categorized as follows:
Eye drops including solutions, emulsions and suspensions of active medicaments for instillation into the conjunctival sac
Eye lotions for irrigating and cleansing the eye surface, or for impregnating eye dressings
Eye ointments, creams and gels containing active ingredient(s) for application to the lid margins and/or conjunctival sac
Contact lens solutions to facilitate the wearing and care of contact lenses
Parenteral products for intracorneal, intravitreous or retrobulbar injection
Ophthalmic inserts placed in the conjunctival sac and designed to release active ingredient over a prolonged period
Medicaments contained in ophthalmic products include:
Anaesthetics used topically in surgical procedures
Anti-infectives such as antibacterials, antifungals and antivirals
Anti-inflammatories such as corticosteroids and antihistamines
Antiglaucoma agents to reduce intraocular pressure, such as beta-blockers
Astringents such as zinc sulphate
Diagnostic agents such as fluorescein which highlight damage to the epithelial tissue
Miotics such as pilocarpine which constrict the pupil and contract the ciliary muscle, increasing drainage from the anterior chamber
Mydriatics and cycloplegics such as atropine, which dilate the pupil and paralyse the ciliary muscle and thus facilitate the examination of the interior of the eye.
Anatomy and physiology of the eye
Figure 42.1 gives an indication of the relevance of the external structures of the eye and the structure of the eyelids to the application of medication and the wearing of contact lenses (see p.406 also).
Formulation of eye drops
The components of an eye drop formulation are given below:
Active ingredient(s) to produce desired therapeutic effect
Vehicle, usually aqueous but occasionally may be oil
Antimicrobial preservative to eliminate any microbial contamination during use and thus maintain sterility; it should not interact adversely with the active ingredient(s)
Adjuvants to adjust tonicity, viscosity or pH in order to increase the ‘comfort’ in use and to increase the stability of the active ingredient(s); they should not interact adversely with other components of the formulation
Suitable container for administration of eye drops which maintains the preparation in a stable form and protects from contamination during preparation, storage and use.
The single most important requirement of eye drops is that they are sterile. Historically, instances of microbially contaminated eye drops have been reported; the contaminating organism, Pseudomonas aeruginosa, is difficult to treat successfully and can cause loss of the eye.
Antimicrobial preservatives
Multiple-dose eye drops contain an effective antimicrobial preservative system, which is capable of withstanding the test for efficacy of antimicrobial preservatives of the British Pharmacopoeia (BP 2007). This ensures that the eye drops are maintained sterile during use and will not introduce contamination into the eyes being treated. Normal healthy eyes are quite efficient at preventing penetration by microorganisms. Eyes that have damaged epithelia are compromised and may be colonized by microorganisms. This has to be guarded against. The lack of vascularity of the cornea and certain internal structures of the eye make it very susceptible and difficult to treat once infection has been established.
No single substance is entirely satisfactory for use as a preservative for ophthalmic solutions. The systems that have been used, based on work of the author and others in the 1960s, have formed the basis of effective preservation over the subsequent years.
Eye drops specifically formulated for use during intraocular surgery should not contain a preservative because of the risk of damage to the internal surfaces of the eye. Diagnostic dyes should preferably be supplied as single-dose preparations. Preservatives which are suitable for a selection of eye drops are given in Box 42.1.
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.
Viscosity enhancers
There is a general assumption that increasing the viscosity of an eye drop increases the residence time of the drop in the eye and results in increased penetration and therapeutic action of the drug. Most commercial preparations have their viscosities adjusted to be within the range 15–25 millipascal seconds (mPas). However, gently pressing downwards on the inside corner of the closed eye restricts the drainage channel into the nasal cavity and prolongs contact time. This has been recommended to increase the therapeutic index of antiglaucoma medications. Under normal conditions, a large proportion of a typical 50 μL drop will have drained from the conjunctival sac (capacity 25 μL) within 30 s. There will be no trace of the drop after 20 min.
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.
pH adjustment
The best compromise is required after considering the following factors:
The pH offering best stability during preparation and storage
The pH offering the best therapeutic activity
Most active ingredients are salts of weak bases and are most stable at an acid pH but most active at a slightly alkaline pH.
The lachrymal fluid has a pH of 7.2–7.4 and also possesses considerable buffering capacity. Thus a 50 μL eye drop which is weakly buffered will be rapidly neutralized by lachrymal fluid. Where it is possible, very acidic solutions, such as adrenaline acid tartrate or pilocarpine hydrochloride, are buffered to reduce a stinging effect on instillation. Suitable buffers are shown in Box 42.2.
Antioxidants
Reducing agents are preferentially oxidized and are added to eye drops in order to protect the active ingredient from oxidation. Active ingredients requiring protection include adrenaline (epinephrine), proxymetacaine, sulfacetamide, tetracaine, phenylephrine and physostigmine.
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.
Chelating agents
Traces of heavy metals can catalyse breakdown of the active ingredient by oxidation and other mechanisms. Therefore, chelating agents such as disodium edetate may be included to chelate the metal ions and thus enhance stability. Disodium edetate is a very useful adjuvant to ophthalmic preparations at concentrations of up to 0.1% w/v to enhance antibacterial activity and chemical stability. It has also been used at higher concentrations as an eye drop for the treatment of lime burns in cattle.
Bioavailability
The effect of pH on the therapeutic activity of weak bases such as atropine sulphate has already been indicated under the section on pH adjustment. At acid pH, these bases exist in the ionized hydrophilic form. In order to penetrate the cornea, the bases need to be at alkaline pH so that they are in the unionized lipophilic form. Thus at tear pH (7.4) they are able to penetrate the outer lipid layer of the lipid–water–lipid sandwich, which constitutes the physicochemical structure of the cornea. Once inside the epithelium the undissociated free base will partially dissociate. The water-soluble dissociated moiety will then traverse the middle aqueous stromal layer of the cornea. When the dissociated drug reaches the junction of the stroma and the endothelium it will again partially associate, forming the lipid-soluble moiety and thus cross the endothelium. Finally, the drug will dissociate into its water-soluble form and enter the aqueous humour. From here it can diffuse to the iris and the ciliary body which are the sites of its pharmacological action (see Fig. 42.1). Thus, the most effective penetration of the lipophilic–hydrophilic–lipophilic corneal membrane is by active ingredients having both hydrophilic and lipophilic forms. For example, highly water-soluble steroid phosphate esters have poor corneal penetration but the less water-soluble, more lipophilic steroid acetate has much better corneal penetration.
Storage conditions
To minimize degradation of eye drop ingredients, storage temperature and conditions must be considered at the time of formulation. The stability of several drugs used in eye drops is improved by refrigerated storage (2–8°C), e.g. chloramphenicol.
Containers for eye drops
Containers should protect the eye drops from microbial contamination, moisture and air. Container materials should not be shed or leached into solution, neither should any of the eye drop formulation be adsorbed or absorbed by the container. If the product is to be sterilized in the final container, all parts of the container must withstand the sterilization process.
Containers may be made of glass or plastic and may be single- or multiple-dose containers. The latter should not contain more than 10 mL. Both single-dose and multiple-dose packs must have tamper-evident closures and packaging.
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.
Figure 42.2 Plastic eye drop bottle. (A) Rigid plastic cap. (B) Polythene friction plug containing baffle that produces uniform drops. (C) Polythene bottle.
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