THE PRESERVATION OF OPHTHALMIC PREPARATIONS 391 that they should react. I am not sure that anybody has shown whether in fact it does happen at this concentration. DR. O. D. PmDDLE : Can you make any comments on the physical stability of comparatively low molecular weight preservatives such as chlorobutanol or phenyl- ethanol in solutions contained in polyethylene or other plastic bottles ? DR. BROWN: It seems very likely that there is absorption of some sort between plastics and phenols and as far as we know, not that we know very much, very little is published on this. I think it is very important and we, at Bristol, are certainly coming to the conclusion that we should be progressing towards mass produced, small volume eye drop preparations, rather than extemporaneous preparations as the norm. Information about the effect of these low molecular weight preservatives in the presence of plastics would be useful. MR. M. J. GRovEs: We were interested to note that you refer to Bronopol under the heading of agents not widely used as preservatives, the inference being that it could possibly be considered as a preservative for eye drops. We are also interested in this but we would like to sound a note of warning since Bronopol is not stable at an alkaline pH. We have examined the eye drops officially formulated in the British Pharmaceutical Codex. A number of these are alkaloidal solutions and hence acidic in reaction. But of the g0 eye drops in the Codex, 10 would appear to be either directly incompatible with Bronopol or contraindicated because of the pH. The use of Bronopol as a preservative is therefore somewhat limited and in addition it would be necessary to establish beyond reasonable doubt, that this new antibacterial, and I emphasize the word new or untried, is completely safe to use in the eye. Some work in our own laboratories which has been undertaken on the effect of Bronopol in rabbit eyes had given encouraging results so far, but there is limited information at present on the effects on human eye. We can only reiterate Dr. Harold Davis' comment at the recent British Pharmaceutical Conference, to the effect that reliable information about safety must be obtained under the conditions in which the materials can be used. DR. BRowN: I agree and I would like to point out that Bronopol is mentioned under the heading of agents not widely used as preservatives. In the summary and conclusions we have not made any reference to it at all. We have ignored it, because more work will clearly have to be done on it, as you have suggested. M•ss B. CROSHAW: There is a further word of caution'I would like to add regarding Bronopol. Although we have shown that it is bacteriostatic against both gram- negative and gram-positive bacteria at similar concentrations, the bactericidal activity is much greater against gram-negative organisms than against gram-positive. For this reason we would not recommend the use of Bronopol alone as a satisfactory pre- servative for ophthalmic solutions. Although you do not like combinations, we would only consider it in combination with benzalkonium chloride or something similar. I do not think we should be arguing whether A chromobacter is or is not pathogenic to eyes. I think any organism in an eye drop must be regarded as a potential pathogen, and a preservative that does not deal with it can not really be considered as satisfactory. Concerning the use of chlorhexidine and its breakdown on heating: Are the breakdown products bacteriologically active?

392 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS DR. BROWN: I agree completely with the first part of your remarks. I would just like to comment on your remark that we do not like combinations, as I do not think this is correct. We have stated that they should not be used indis- criminately. A great deal of work has been done on synergism, antagonism, and additive action. It was originally thought that if you had one antibiotic that killed cells in the body and another one that did the same, then obviously the two together would be twice as good. This, of course, was not true and we were merely referring to the fact that they should not be combined indiscriminately. I agree that any organism which is happily surviving in the presence of the preservative, should be regarded as potentially dangerous. I only made the remark because I thought that Mr. Jeffries was perhaps referring to Aerobacta, and not A chrornobacter. We were rather timid about our reference to breakdown of chlorhexidine because the literature contains too many personal communications and statements of opinion. Nevertheless we have it on good authority that heating chlorhexidine in solution and autoclaving it, did in fact produce compounds which could well be toxic and that this would have to be examined before using this method. This would not preclude the use of chlorhexidine in a filtered solution, or sterilizing in some other way. I do not know whether these degradation products are harmful to the bacteria. MR. A. G. HOPKINS : At the present time quaternary ammonium compounds are becoming suspect as causing indurated ulcers, especially in damaged tissue. Does this not rule out substances like benzalkonium chloride, cetrimide, etc. ? DR. BROWN: We have heard about many defects of the quaternary ammonium compounds, particularly benzalkonium chloride. It has been stated, for example, that it dissolves the intercellular cement of the cornea. I have never heard of this particular problem but I think perhaps the problem is eliminated if, when using the damaged eye, no preservative at all is used unless it is absolutely necessary. Certainly during an operation when you are irrigating, say, the anterior chamber, you should use sterile saline or sterile water, or whatever it is that is required, without any preservative. What real evidence there is about this type of ulcer I do not know. Is it more than a report ? MR. A. G. HOPKINS: It is quite factual and there have been some reports in the last two or three weeks on this. In fact the use of Dequadin, Dequalinium chloride and even cetrimide is being curtailed because of these reports. I do not know whether anyone else has heard anything about this. DR. BROWN .' In America benzalkonium chloride has been used for a good number of years as a preservative of choice, and has been the official preservative. There are a good number of hospitals in America and I should have thought that benzal- konium chloride had been exposed to sufficient possibilities causing problems, to have really stood the test. We have only been able to find about two cases where there was proof that a resistant strain to benzalkonium chloride had arisen. I think it is easy, if you abuse the techniques, to produce resistant strains to benzolkonium chloride. MR. J. A. MYERs: Are you now in a position to suggest a suitable preservative for any of the eye drops in the British Pharmaceutical Codex ? DR. BROWN: We would like to suggest, and I am not sure, that the B.P.C.