370 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ophthalmic solution may safely range from the equivalent of 0.7% to 1.5% sodium chloride. Most ophthalmic drugs have high molecular weights, and may usually be added to an isotonic vehicle without altering the tonicity to painful levels. This applies particularly to eye drops used in small volumes large volumes of eye lotions should be approximately isotonic. Hydrogen ion concentration Normal tears have a pH of about 7.4. They have the capacity to bring the pH of an unbuffered solution at pH as low as 3.5, or as high as 10.5, to within tolerable limits instantaneously (1). Most ophthalmic drugs, e.g. alkaloidal salts, in distilled water or isotonic saline have a negligible buffer capacity although some drugs, notably salts of pilocarpine and epinephrine, may overtax the buffer capacity. The United States National Formulary XI recommends a 2% boric acid solution (about pH 4.7) as a general ophthalmic vehicle. This solution will tend to neutralize alkali leached from the glass container, it has a satisfactory tonicity, and is at a pH where most ophthalmic drugs are stable to auto- claving as well as being therapeutically active. The United States Pharmacopoeia XVI recommends an isotonic phosphate buffer as an ophthalmic vehicle in addition to boric acid solution. Stability The stability of ophthalmic preparations during prolonged storage, and the effects of heat sterilization processes, must be considered during formu- lation. The effects of temperature and pH are particularly important. Buffering certain drugs in the physiological pH range makes them unstable, particularly at high temperatures. Most of the common ophthalmic drugs, however, in 2% boric acid solution can be autoclaved without seriously affecting their therapeutic activity. The U.S.N.F. XI states that the oxidative discolouration of physostigmine, epinephrine and phenylephrine under these circumstances may be reduced by the addition of 0.2% sodium bisulphite to the vehicle. Alkaline drugs such as the sulphonamides and fluorescein sodium should be prepared in sterile distilled water. Viscosity Methylcellulose is sometimes added to ophthalmic solutions to increase contact time with the cornea. Calculated quantities of a concentrated, hydrated stock solution of methylcellulose may be added to normal

THE PRESERVATION OF OPHTHALMIC PREPARATIONS 371 ophthalmic vehicles which may then be autoclaved, cooled, and the coagulated methylcellulose re-dispersed by agitation. PRESERVATION AGAINST MICRO-ORGANISMS There has recently been much discussion about the difficulties of pre- serving ophthalmic solutions against micro-organisms. The main problem is the exceptionally high resistance of Pseudomonas aeruginosa to chemical antibacterial agents. This pathogen causes serious difficulties in the control of cross-infection in general (2,3) but especially in ophthalmology (4). Some species of A erobacter are eye pathogens (5), and the problem is further complicated by the existence of pathogenic strains of the spore formers Bacillus subtilis (6) and Clostridium welchii (7). Pseudomonads have been isolated from most naturally occurring waters (8), and Ps.aeruginosa in particular has exceptionally simple require- ments and will grow in many ophthalmic solutions. This organism has been shown to use the hydroxybenzoates as a sole source of carbon (9). In addition, the temperature requirements for growth are wide. It is a virulent pathogen causing severe ocular infections (10). Relatively small inocula of about 50-100 cells have been shown to produce infection in rabbits' eyes (11,12). Fisher and Allen (13) have shown that Ps.aeruginosa produced an enzyme which destroys the cornea by degradation of corneal collagen. Ps.aeruginosa has consequently been recommended as the main refer- ence organism when selecting chemical preservatives for ophthalmic solutions. An adequate preservative should also be effective against a wide range of gram-positive and gram-negative organisms. The case for sterility An injured eye has less resistance to infection than the bloodstream, so that at least the same precautions should be taken in preparing ophthalmic solutions as in preparing solutions for intravenous use (14). The United States National Formulary XI states that all solutions for surgical use should be sterile, and prepared without a preservative because of danger of chemical damage to the inner structure of the eye. It has frequently been shown that a significant proportion of used, and unused, ophthalmic solutions were contaminated with Ps.aeruginosa, and that eye ointments are also liable to contamination (15,16,17). There is now wide- spread agreement that ideally ophthalmic medicaments should be dispensed in a sterile condition (11,15,18,4).