Ophthalmic Preparations

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Chapter: Pharmaceutical Microbiology : Sterile Pharmaceutical Products

Medication intended for instillation on to the surface of the eye is formulated in aqueous solution as eye drops or lotion or in an oily base as an ointment. Because of the possibility of eye infection occurring, particularly after abrasion or damage to the corneal surface, all ophthalmic preparations must be sterile.



A)   Design Philosophy


Medication intended for instillation on to the surface of the eye is formulated in aqueous solution as eye drops or lotion or in an oily base as an ointment. Because of the possibility of eye infection occurring, particularly after abrasion or damage to the corneal surface, all ophthalmic preparations must be sterile. As there is a very poor blood supply to the anterior chamber, defence against microbial invasion is minimal; furthermore, it appears to provide a particularly good environment for growth of bacteria. As well as being sterile, eye products should also be relatively free from particles that might cause damage to the cornea. However, unlike aqueous injections the recommended vehicle is purified water because the presence of pyrogens is not clinically significant.


Another type of sterile ophthalmic product is the contact lens solution. However, unlike the other types this is not used for medication purposes but merely as wetting, cleaning and soaking conditions for contact lenses.


B)   Eye Drops


Some typical excipients for eye drops are given in Table 22.1. Eye drops are presented for use in (1) sterile single-dose plastic sachets (often termed Minims) containing 0.3–0.5 ml of liquid, (2) multiple-dose amber fluted eye dropper bottles including the rubber teat as part of the closed container or supplied separately, or (3) plastic bottles with integral dropper. A breakable seal indicates that the dropper or cap has not been removed prior to initial use. Although a standard design of bottle is used in hospitals, many proprietary products are manufactured in plastic bottles designed to improve safety and care of use. The maximum volume in each container is limited to 10 ml. Because of the likelihood of microbial contamination of eye dropper bottles during use (arising from repeated opening or contact of the dropper with infected eye tissue or the hands of the patient), it is essential to protect the product with a preservative (Matthews & Skinner, 2006). Eye drops for surgical theatre use should be supplied in single-dose containers.


Examples of preservatives are phenylmercuric nitrate or acetate (0.002% w/v), chlorhexidine acetate (0.01% w/v), thiomersal (0.01% w/v) and benzalkonium chloride (0.01% w/v). Chlorocresol is too toxic to the corneal epithelium, but 8-hydroxyquinoline and thiomersal may be used in specific instances. The principal consideration in relation to antimicrobial properties is the activity of the bactericide against Pseudomonas aeruginosa, a major source of serious nosocomial eye infections. There is some concern over the toxicity of mercurials, and their use is becoming less common. Although benzalkonium chloride is probably the most active of the recommended preservatives, it cannot always be used because of its incompatibility with many compounds commonly used to treat eye diseases, nor should it be used to preserve eye drops containing anaesthetics. As benzalkonium chloride reacts with natural rubbers, silicone or butyl rubber teats should be substituted and products should not be stored for more than 3 months after manufacture because silicone rubber is permeable to water vapour. As with all rubber components, the rubber teat should be pre-equilibrated with the preservative before use. Thermostable eye drops and lotions are sterilized at 121°C for 15 minutes. For thermolabile drugs, filtration sterilization followed by aseptic filling into sterile containers is necessary. Eye drops in plastic bottles are prepared aseptically.


In order to lessen the risk of eye drops becoming heavily contaminated, either by repeated inoculation or by the growth of resistant organisms in the solution, use is restricted to 1 month after the container is first opened. This is usually reduced to 7 days for hospital ward use on one eye of a single patient. The period is shorter in the hospital environment because of the greater danger of contamination by potential pathogens, particularly pseudomonads.


B)  Eye Lotions


Eye lotions are isotonic solutions used for washing or bathing the eyes. They are sterilized by autoclaving in relatively large-volume containers (100 ml or greater) of coloured fluted glass with a rubber closure and screw-cap, or packed in plastic containers with a screw-cap or tear-off seal. They may contain a preservative if intended for intermittent domiciliary use for up to 7 days. If intended for first aid or similar purposes, however, no bactericide is included and any remaining solution is discarded after 24 hours.


C)   Eye Ointments


Eye ointments are prepared in a semisolid base—e.g. Simple Eye Ointment BP, which consists of yellow soft paraffin (8 parts), liquid paraffin (1 part) and wool fat (1 part). The base is filtered when molten to remove particles and sterilized at 160°C for 2 hours. The drug is incorporated prior to sterilization if heat-stable, or added aseptically to the sterile base. Finally the product is aseptically packed in clear sterile aluminium or plastic tubes. As the product contains virtually no water, the danger of bacteria proliferating in the ointment is negligible.


D)  Contact Lens Solutions


Most contact lenses are worn for optical reasons as an alternative to spectacles. Contact lenses are of two types: hard lenses, which are hydrophobic, and soft lenses, which may be either hydrophilic or hydrophobic. The surfaces of lenses must be wetted before use and wetting solutions are used for this purpose. Hard, and more especially, soft lenses become heavily contaminated with protein material during use and therefore must be cleaned before disinfection. Contact lenses are potential sources of eye infection and, consequently, microorganisms should be removed before the lens is again inserted into the eye. Lenses must also be clean and easily wettable by lachrymal secretions. Contact lens solutions are thus sterile solutions of the various types described below. Apart from achieving their stated functions, either singly or in combination, all solutions must be non-irritating or must protect against microbial contamination during use and storage.


                i)  Wetting solutions


These are used to hydrate the surfaces of hard lenses after disinfection. As they must also cope with chance contamination, they must contain a preservative as well as a wetting agent. They may be isotonic with lachrymal secretions and be formulated to a pH of about 7.2 for compatibility with normal tears.


                ii)  Cleaning solutions


These are responsible for the removal of ocular debris and protein deposits, and contain a cleaning agent that consists of a surfactant and/or an enzyme product. As they must also cope with chance contamination, they contain a preservative, are isotonic and have a pH of about 7.2.


           iii)                 Soaking solutions


These are solutions for disinfection of lenses but also maintain the lenses in a hydrated state. The antimicrobial agents used for disinfecting hard lenses are those used in eye drops (benzalkonium, chlorhexidine, phenylmercuric acetate or nitrate, thiomersal and chlorbutol). Ethylenediamine tetraacetic acid (EDTA) is usually present as a synergist. Benzalkonium chloride and chlorbutol are strongly bound to hydrophilic soft contact lenses and therefore cannot be used in storage solutions for these; chlorhexidine and thiomersal are usually employed. It must be added that the concentrations of all preservatives used in contact lens solutions are lower than those employed in eye drops, to minimize irritancy. Hydrogen peroxide is becoming commonly used but must be inactivated before the lenses are inserted onto the eyes. Finally, heat may be utilized as an alternative method to disinfect soft contact lenses, especially the hydrophilic types. Lenses are boiled in isotonic saline.


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