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).

372 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The United States Pharmacopoeia, the United States National Formul- ary and the International Pharmacopoeia all specify sterility for ophthalmic solutions. The British Pharmaceutical Codex 1963 stipulates sterility for eye drops only. Autoclaving in the final container is the method of choice because of the danger from pathogenic spore formers. This is still so with chemically preserved solutions because of the possibility of germination on the cornea, which can apparently eliminate the carry-over activity of a wide range of antibacterial agents (11). It is, however, unlikely that pathogenic spores would germinate in the ophthalmic container in the presence of an antibacterial agent, and at room temperature. Gamma radiation has proved a useful sterilizing agent for some heat labile ophthalmic prepara- tions and may prove to be of wide application (19). Eye drop containers Norton (20), and Richards et at (21) have shown that eye drop con- tainers available then in Britain for extemporaneous preparations were not satisfactory, and that closure units must be modified to provide satisfactory sealing during autoclaving. British Standards Institution Committee P. 188 is now engaged in producing a specification for a suitable multidose eye drop container. It seems possible, and desirable, that in the field of ophthalmic pre- parations, as with other classes of medicaments, there will be progressive movement away from extemporaneously prepared products. The time is opportune for bulk-manufactured sterile products of standard formulae, packed in simple plastic single and multidose containers. Several manu- facturers do this using methods which would normally be uneconomic for the individual pharmacist in a small business (22). Nevertheless, there is now available relatively inexpensive equipment for small scale extem- poraneous sterile filtration employing a modified syringe with membrane filter (15). Preservation of oils, creams and ointments There is little published work on the preservation of oils, creams and ointments. Ridley (16) has isolated Ps•.aeruginosa from eye ointments on several occasions. He proposed to eliminate the use of oils by replacing them with ointments dispensed in sterile tubes. The activity of bactericides in o/w dispersions has been shown to be influenced by many interacting factors and the ad hoc addition of preservatives shown to be