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

THE PRESERVATION OF OPHTHALMIC PREPARATIONS 373 unsatisfactory (23). A practical ideal at present would appear to be the aseptic preparation of ophthalmic ointments, using sterile ingredients. Preservation of solutions The possibility of contamination from pathogenic organisms subsequent to sterilization makes it necessary for multidose containers to be preserved using a suitable antibacterial agent. The capacity of small inocula of Ps.aeruginosa to cause infection, together with the neutralizing properties of the cornea towards anti- bacterial agents, make it preferable that these agents be capable of maintaining sterility. Much of the earlier work assessing preservatives is of reduced value because of inadequate experimental procedures. Riegelman et al (11) quoted numerous papers which did not state the precautions taken to ensure the absence of bacteriostatic concentrations of preservative in sub- cultures testing for recovery. They discussed the inadequacy of dilution techniques designed to inactivate preservatives and introduced in vivo procedures as well as in vitro tests involving chemical antagonists. They consistently found that organisms would produce infections, and could be recovered from the cornea while in vitro cultures were apparently negative. Subsequent improvement of the antagonist/recovery broth reduced the discrepancy. Kohn et al (24,25) further developed this important principle of comparing in vivo with in vitro procedures and obtained exact correlation. Several chemical agents have been proposed as suitable ophthalmic preservatives and it seemed appropriate to consider each separately. Esters of p-hydroxybenzoic acid A combination of methyl and propyl phydroxybenzoates has been used in the form of "Solution for Eye Drops" until this preparation was replaced by chlorocresol in the British Pharmaceutical Codex 1963. Subsequently this Codex was amended (26), and Solution for Eye Drops reintroduced. Brown et al (4) have commented on these changes. Klein et al (27) tested two combinations of the esters at three concentrations up to 0.16% against 108/ml Ps.aeruginosa present in three eye-drop preparations--Sodium fluorescein 2%, atropine sulphate 0.5%, eserine salicylate 0.25%. Contact times were up to 24 hr after which subcultures were made testing for sterility. They found that both combinations 1 (Nipasept) and 2 (Nipa 82727) were ineffective at all concentrations in fluorescein drops, and growth occurred after subculture at each contact time up to 24 hr. 0.16%