US2436673A - Therapeutic peroxide composition - Google Patents

Description

ML OXYGEN PER 5 @RAME .GF PERO`MDE F. S. ELTGN THERAPEUTC FEROXIDE COMOSITION Filed May ll, 1944 TIME IN HOURS INVENTOR @055er 6. S//fU-o/v'.

Patented Feb. 24,` 1948 UNITEDVYSVTATES PATENT OFFICE 2,436,673 THRAPEU'IIC PEROXIDE COMPOSITION Robert S. Shelton, Mariemont, Ohio, assignor to The Wm. S. Merrell Company, Cincinnati, Ohio,

Va corporation of Delaware Application May 11, 1944, Serial No. 535,209

Claims. (Cl. 167-72) This invention relates to compositions of matter and more particularly to peroxide compositions.

For various therapeutic, prophylactic and other purposes, solid peroxides have been found advantageous as a source of active oxygen, since these compounds decompose when brought into contact with water, especially in the presence of various other substances, to give off free oxygen.

In such uses it is commonly required that free oxygen be supplied continuously over a relatively long period of time, e. g. over 24 hours or even several days, but it is desirable that within the time of the desired treatment substantially all of the available oxygen be released and it is likewise highly desirable that the material, during manufacture, storage and shipment, should remain stable and should not lose any material part of its available oxygen until that is required during its use.

'I'hus in recent years peroxides have been found useful in the treatment of certain persistent and deep-,seated infections. Experience has shown zinc peroxide to be most advantageous for this purpose. It has been found necessary, however,

before using zinc peroxide for this purpose, to activate it by a special heat treatment, for example, by heating for four hours in a carefully regulated dry oven. The material after this treatment, is unstable and cannot be stored for any considerable length of time or handled under ordinary shipping conditions without loss of activity. 'I'his has meant that the material has had to be specially treated immediately before each use; and this type of therapy has, therefore, had to be limited to the larger hospitals and clinics where special equipment for this heat treatment could be made available; moreover, the preparation of the peroxide has substantially increased the cost of such treatment.

It is accordingly an object of my present invention to provide improved peroxide compositions which are stable under practicable conditionspf storage and shipment, either dry or when made up in water-free ointment, e. g. of the type set forth and claimed in my co-pending application, Serial No. 462,962, led October 22, `1942, of which the present application is a continuation-in-part. Another object of the invention is to provide peroxide compositions which give a greater total oxygen yield per unit of peroxide used. Another object of the invention is to provide peroxide compositions which give a greater sustained oxygen yield.

, with these ends in view, 1 have found that diierent peroxides in combination, as hereinafter more particularly described, mutually activate each other so that both the rate of oxygen evolution and the period of sustained oxygen evolution are greatly increased; and it follows that the total oxygen evolution is even more strongly increased.

As one'example of my invention, I have found specifically that -zinc peroxide of pharmaceutical grade, in the stable form in which it is supplied in commerce and without activation by the heat treatment as referred to above, when mixed with calcium peroxide gives off unexpectedly large amounts of oxygen in the presence of water or aqueous liquids.

This I have shown graphically in the accompanying drawing, wherein the oxygen evolution is plotted with the `ordinate representing milliliters of oxygen per 5 grams of peroxide and the abscissae representing time in hours. The figures plotted are actual figures for the peroxide in contact with human plasmav at 37 C. It will be observed that the unactivated zinc peroxide gives 01T during the first 24 hours, something less than five milliliters per iive grams of peroxide. Calcium peroxide alone is more active, giving off approximately double the amount of oxygen during the rst 24'hours, but the oxygen evolution is very quickly over and not sustained, even to a small extent, as in the case of the zinc peroxide. The addition of calcium` peroxide in the proportion of ve parts of calcium peroxide to parts of zinc peroxide produces an increase in total oxygen much greater than the proportionate increase which might be expected from the greater activity of calcium peroxide. Moreover this small addition of calcium peroxide brings about a sudden initial release of almost the entire oxygen evolution during the rst three hours. When the amount of calcium peroxide added to the zinc peroxide is doubled, using one part of calcium peroxide to ten parts ofzinc peroxide, the effect is even more startling and much more benecial. In this case the total oxygen evolution in 24 hours is multiplied more than Sevenfold and, what is even more important, this increase in total oxygen evolution is accompaniedlby an increase in the sustained oxygen evolution. Whereas, after the first four hours oxygen is evolved from the zinc peroxide alone at a rate less than 119 of the 24 hour total in each hour with the ten to one mixture of zinc peroxide and calcium peroxide, the evolution after the rst four hours is at the rate of approximately 4% per hour and when stated in terms of milliliters of oxygen per gram of peroxide the rate is approximately .01

of a milliliter per gram per hour for the unactivated zinc peroxide alone and approximately .08 for the ten to one zinc peroxide-calcium peroxide mixture. l

For purposes of comparison I have also included in this graph a similarplot of `zinc peroxide activated by the ordinary oven treatment. It will be observed that, althoughY the ordinary activation treatment greatly improves the peroxide from its unactivated state, a mixture with calcium peroxide in accordance with the present invention produces almost as much improvement again, beyond the ordinary activated zinc peroxide. Moreover, whereas the ordinary activated zinc peroxide becomes unstable when thusv activated, a mixture of calciumperoxide and zinc peroxide remains suciently stable for handlingA With reasonable precautions in manufacture, packaging, storage and= shipping, and the activity such as isV illustratedin the accompanying graph occurs. onlyl when the material. is exposed to the aqueousliquid". Y

When the amount of calcium peroxide is increased beyond the ratio,'the advantage is decreased'ior the purposes herein set forth. The reason for this striking advantage in this particular range of proportions is not at present understood", but. is well established by experience.

I have iound, in 'fact,that it is entirely feasible `to combine such a mixture in pharmaceutical preparations, providingI only that the entire composition is water-free and remains so during stor- 'ageA and shipment, to this end advantageously being non-hygroscopic, and that the zinc peroxide and activating peroxide are in such intimate admixture that the zinc peroxide is chemically aff'ected by the activatingperoxide Whenever it is exposed to moisture sufcientto produce substantial oxygen evolution. For this purpose, I have foundparticuliarly desirable a vehicle composed of the waxy polycondensation products of ethylene glycol, more properly described as the polyoxyethylene diols. These may be used in various mixtures and in mixture with the lower liquid polyoxyethylene diols or other glycol solvents, to give any desired consistency. Thus I` have used for' surgical dressings a soft plastic ointment made up with a waxy polyoxyethylene diol melting in the range 34C. to 41 C., available commercially under the 'trade name Carbowax 1590, mixed with about half its' weight of hexa ethylene glycoll or nona ethylene glycol.

I have also found that the composition of the present invention can advantageously be used in connection with the invention described and claimed in my co-pending application, Serial No. 462,962, using in the composition one of the quaternary ammonium salt wetting agents and especially one of the germicidal pyridinium salt wetting agents, which serves both to bring the peroxides more quickly and'ntimately into contact with the aqueous body fluid and likewise to bring the evolved oxygen more readily and completely into the tissues on which the composition is used; and at the same time, as set forth in my said prior co-pending application, the peroxide and the Quaternary ammonium germicide each seems to prepare the pathogenic organisms in some way for a more effective action by the other or to support the anti-bacterial' action of the' other. At least it is found that the combination of the two is more effective in its germicidal ac tion than could be expected from the known activities of each under other conditions.

As one particular example of my invention a surgical ointment for use as described above, can be made up with the following composition:

Per cent Zinc peroxide l0 Calcium peroxide 1 Cetylpyridiniuml chloridee- 0.2 .Carbowax 1500 59.8 Hexa ethylene glycol 29 All ingredients are substantially water-free when mixed and4 all are sufficiently non-hygroscopic so that the material, when handled with ordinary precaution and packaged in moisture-tight packages, can be stored, shipped and used Without extraordinary precautions.

Instead of hexa ethylene glycol, one may use nona ethylene glycol or other liquid glycol and instead oi the Carbowax 1500 a higher polyoxyethylene diol can be used. with suitable adjustment of the proportion of lower polyoxyethylene diol to produce the desired consistency. VInstead of the cetylpyridinium chloride other quaternaryfammonium wetting'agents can'be used, and: particularly the germicidal wetting -agents of this type, e. g. asset forth in my patents Nos. 2,295,564 and 2,295,505 and my co-peridingv applications, Serial No; 450,616, iiled' Julyll, 1942, now Patent No. 2,357,479, and Serial No. 500,340, iiled August 28, 1943. I have found especially advantageous for this purpose the N-propyl tridecyl pyridinium chloride.

Asy another exampleV of the invention, suppositories, e. g. for treatment of' chronic ulcers' of the vagina. or rectum, may be made of the following composition:

Per cent Zinc peroxide l0 Calcium peroxide 1 N-propyl tridecyl pyridinium chloride 0.2 Boric acid 1 CarbovvaxA 1500.. 72.2

Spermaceti I5 Aromatics and incidental ingredients 0.6

In this composition4 also we may make substitutions as indicated with Example 1. Other water-free, water-soluble vehicles as may be, or as may become, available may be substituted for the polyoxyethylene diols. Numerous other types of pharmaceutical com` positions will be suggested to those skilled in the art from what has been saidV above and for some purposes it may even be desirable to use the dry mixture ofperoxides withoutv other ingredients, merely mixing these with water or other aqueous liquid when they are used.

Although I have found thisactivation eiect to be most advantageous with the combination of zinc peroxide and' calcium peroxide andv to. reach a maximum at about the ten to oneratio specified above, it shouldbe understood that my. invention is notflimitedl to thisparticular ratio- As indicated above, there is an unexpected increase in. the oxygenv evolutioneven with lower, percentages. of 'calcium peroxide and' likewise. withhigher per-I centages the increased activity persists. For surgicall compositions made up-,irrappro-4 priate vehicles, I have found best resultswith percentages of the zinc peroxide or Vother prin-- cipal peroxide up to 40%, oi .the total,j.and Ythe activating peroxide. in. a lesser amount. up to, 6% of the total. I claim: V y 1. A therapeutic and prophylactic composition for use in contact with delicate living tissues and adapted, when in contact with an aqueous medium, to evolve free oxygen, said composition comprising 100 parts of zinc peroxide intimately mixed with between 5 and 15 parts of calcium peroxide, said composition being free from Water and from insoluble diluents which would substantially obstruct interaction of said peroxides in the presence of Water.

2. A therapeutic and prophylactic composition for use in contact with delicate living tissues and adapted, when in contact with an aqueous medium, to evolve free oxygen, said composition comprising 'zinc peroxide intimately mixed with approximately one-tenth its Weight of calcium peroxide, said composition being free from water and from insoluble diluents which would substantially obstruct interaction of said peroxides in the presence of water.

3. A therapeutic and prophylactic composition which comprises a mixture of ten parts of calcium peroxide to one hundred parts of zinc peroxide and two parts of a cetyl pyridinium chloride-in a soft plastic base comprising 290 parts of hexa ethylene glycol and 598 parts of a higher polyoxyethylene diol of melting range about 34 C. to 40 C.

4. A therapeutic and prophylactic composition i which comprises a mixture of ten parts of calcium peroxide to one hundred parts of zinc peroxide REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 916,692 Von Foregger Mar. 30, 1909 2,290,710 Rice et al July 2l, 1942 OTHER REFERENCES Article by Reid et al., Annals of Surgery, Oct` The Lancet (London), Jan. 3, 1942, pp. 7 to 9. Amer. J. Surgery, May 1942, pp. 353-74. J. Exptl. Med. 'I3 (1941) pages 252 to 256.

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