WO1989003179A1

WO1989003179A1 - Chlorine dioxide germicidal composition

Info

Publication number: WO1989003179A1
Application number: PCT/US1988/003512
Authority: WO
Inventors: Lester M. Partlow; François JOOSTE
Original assignee: New Generation Products, Inc.
Priority date: 1987-10-13
Filing date: 1988-10-11
Publication date: 1989-04-20
Also published as: AU2623188A

Abstract

Chlorine dioxide is stabilized and stored in a water free organic solvent at concentrations preferably less than about 5 % by weight. The chlorine dioxide is stable in the water-free organic solvent, and does not degrade appreciably. Once compounded, the solution can be diluted with an aqueous solution and used as a germicidal composition or topical antihistaminic compositions. Methods of making and using the composition are also disclosed.

Description

CHLO INE DIOXIDE GERMICIDAL COMPOSITION

Field; This invention relates to germicidal compositions generally, and to a chlorine dioxide germicidal composition specifically. State of the Art; Chlorine dioxide (C10₂) is an oxychlorine compound thought to exist almost entirely as a free radical. Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, page 612. It has a melting point of -59° Centigrade (C) and a boiling point of 11°C. It exists as a yellow gas at 25°C, which is explosive, and may detonate at pressures greater than 40 kilo pascals (kPa) .

Chlorine dioxide is soluble in water, and decomposes slowly even in a neutral aqueous solution in the absence of heat or light. Thus, 1% per week decomposes even when a neutral aqueous solution of 3-5 millimolar C10₂ is kept in a sealed container at a pH 7 in the refrigerator (approximately 4°C) . Granstrom, et al. "Generation and Use of Chlorine Dioxide in Water Treatment," Journal of the American Waterworks

Association, Vol..50, 1453-1466 (1958) . Since the temperature coefficient of C10₂ decomposition is 1.81, breakdown in water in the dark at ambient temperature (22°C) would proceed at a rate of 2.9% per week. Taube, et al., "Application of Radioactive Chlorine to the Study of the Mechanisms of Reactions Involving Changes in the Oxidation State of Chlorine," Journal of the American Chemical Society. 3330-3332 (1949) . Both rates are too rapid to permit commercial utilization of neutral aqueous solutions of C10₂ having a millimolar or greater concentration.

Under these conditions, decomposition proceeds via the following equation:

2C10₂ + 20H~ ^ H₂0 + C10₂ ^~ + C10₃ ^" This reaction is referred to as the "base-catalyzed decomposition" of C10₂ because the rate of breakdown increases with the increased alkalinity of the solution. The equilibrium constant for this reaction is 0.028, indicating that all of the C10₂ would eventually decompose. Taube, supra. 5 Other chemicals often found as contaminants in

CI0₂ preparations (e.g., chlorine (Cl₂) or hypochlorous acid (HOCl_ζaqλ) are thought to cause C10₂ to oxidize according to the following reactions, which reactions go to completion:

10. (1) 2C10₂ + Cl₂ + 2H₂0 ^=* 2C10₃~ + 2C1^" + 4H⁺

(2) 2C10₂ + HOC1 + H₂0^=^ 2C10₃~ + Cl~ + 3H⁺ Finally, chlorine dioxide decomposition is markedly stimulated by light. For example, decomposition of a neutral aqueous solution of chlorine dioxide stored

15 at ambient temperature and in normal light proceeds at approximately 10% per day. Granstrom, supra.

Satisfactory methods of storing and/or transporting C10₂ have not been available. Attempted methods of storing high concentrations of C102 are

20 disclosed in Chlorine Dioxide; Chemistry and Environmental Impact of Oxychlorine Compounds by W.S. Masschelein, Ann Arbor Science Publishers, Inc., 1979, on pages 138-140, the contents of which are incorporated hereby. These methods include: 1) addition of ammonium salts or long-

25 chain organic acids to an aqueous solution of C10 ; (2) storing concentrated C10₂ in an acidic medium (e.g. pH of 2 to 3) ; (3) hydrate formation; (4) storage as a compressed gas; and (5) "stabilization" techniques wherein the chlorine dioxide is "stored" as chlorite (C10 ^~) and

30 later generated by subsequent acidification of the storage solution. None of these methods have proved completely satisfactory.

Because of the chemical instability, explosive character, and lack of a satisfactory storage method, it

35 has generally been necessary for C10₂ to be manufactured at its place of use. Various methods exist for manufacturing C10₂. These methods include: (1) Acidification of Chlorite:

5C10~₂ + 4H⁺ = 4C10₂ + 2H₂0 + Cl^" (2) Oxidation of Chlorite by Chlorine: 2 NaC10₂ + Cl₂ = 2NaCl + 2C10₂

(3) Oxidation of Chlorite by Persulfate:

2NaC10₂ + Na₂S₂0₈ = 2C10₂ + 2Na₂S0₄

(4) Action of Acetic Anhydride on Chlorite: 2NaC10₂ + (CH₃C0)₂0 + H₂0 = C10₂ + NaCl^' +

CH₃COONa + H⁺

(5) Reduction of Chlorites by Acidification in the Presence of Oxalic Acid:

2 HC10₃ + H₂C₂0₄ = 2 C10₂ + 2 C0₂ + 2 H₂0 (6) Reduction of Chlorites by Sulfurous Anhydride:

2 NaCl0₃ + H₂S0₄+ S0₂ = 2C10₂ + 2 NaHS0₄ These six methods are also discussed in Masschelein, supra, on pages 111-140.

Once manufactured, chlorine dioxide has many useful applications. Its disinfecting capabilities have been known since the beginning of the twentieth century, and it has been used to disinfect swimming pool and drinking water since the 1950's.

More recently, chlorine dioxide has been used as a sterilizer for medical and dental equipment, Tsuchikura, Mitsuru, "Stabilized chlorine dioxide as medical and dental equipment sterilizer," Chemical Abstracts, No. 147203n, Vol. 103, 1985; as a fungicide, Tsuchikura, Mitsuru, "Stabilized chlorine dioxide as fungicide and drinking water disinfectant," Chemical Abstracts, No.

100401V, Vol. 103, 1985; as a toothpaste additive used to prevent dental caries, Tsuchikura, Mitsura, "Stabilized chlorine dioxide for toothpastes," Chemical Abstracts, No. 146993t, Vol. 103, 1985; as a disinfectant and deodorizer for beds, Tsuchikura, Minoru, "Stabilized chlorine dioxide as a disinfectant and deodorizer for beds," Chemical Abstracts. No. 175337n, Vol. 103, 1985; and as a mouthwash additive, Davidson, et al. "Chlorine dioxide generating disinfectant," Chemical Abstracts, No. 193, 181g, Vol. 104, 1986. In one chlorine dioxide mouthwash composition, available from the Biocide division of IMM of Spokane, Washington under the trademark OxyFresliS), 1000 parts per million (ppm) of "stabilized chlorine dioxide" are claimed to be present in solution. However, no more than 0.15% of this "stabilized chlorine dioxide" is actually present in solution as C10₂. The rest is present as another chemical. If more chlorine dioxide is needed, it must be generated immediately prior to use by acidification of the "stabilized chlorine dioxide" solution (e.g. by the addition of citric acid) . Inherently, the amount of chlorine dioxide in any such activated solution is variable as it changes with time following acidification; in addition, the solution contains other potentially undesirable ingredients such as sodium chlorate, sodium chlorite, and chlorous acid, some of which are present in high concentration.

Summary of the Invention This invention comprises chlorine dioxide germicidal compositions, methods for using chlorine dioxide in general and the germicidal compositions in particular, and a method of storing chlorine dioxide.

One chlorine dioxide germicidal composition of the present invention comprises an aqueous-organic solution and chlorine dioxide dissolved in said aqueous- organic solution. The aqueous organic solution consists essentially of an organic solvent (e.g. absolute alcohol) , water and C10 . It may be derived by diluting a non- aqueous concentrate with water to a desired concentration. Another germicidal composition of the present invention consists essentially of a germicidally effective I

^■5-

concentration of chlorine dioxide dissolved in a water- free organic solution. Preferred water-free organic solvents include absolute alcohol, carbon tetrachloride, or isopropanol, which do not react C10₂ or catalyze the 5 decomposition of C10₂ and are germicidal in their own right.

In both cases, the concentration of chlorine dioxide in solution is held within an effective range, sufficiently high for significant germicidal activity

10 (i.e. a germicidally effective concentration) , but below the level likely to cause significant tissue damage. "Concentration of chlorine dioxide," as used herein, designates the amount of free (i.e. available) chlorine dioxide present in solution, as distinguished from the

15 amount of "stabilized chlorine dioxide" (e.g. C10₂ ^~) referred to in currently available preparations. The term "stabilized" implies a chemical modification which is purposely avoided by this invention. Free chlorine dioxide will be present in solution in amounts varying

20 from about 2 parts per million (ppm) to about 50,000 ppm.

A method of storing high concentrations of chlorine dioxide comprising dissolving chlorine dioxide into a water-free organic solvent to form a storage solution of C10₂. The chlorine dioxide for storage can be

25 generated by known means. If it is produced as a gas, it may be "bubbled" through the water-free organic solvent in order to dissolve it into the solvent. The chlorine dioxide gas may be passed through a desiccator (e.g. a column packed with a desiccant or desiccating agent)

30 before bubbling it through the water-free organic solvent.

Water-free solvents useful in the invention include absolute alcohol, propylene glycol, polyethylene glycol, mineral oil, tween-80, surfactants, and emulsifiers. These water-free solvents, and others within

35 contemplation of the invention, do not react with C10₂ or catalyze the decomposition of C10₂• In addition, the water-free organic solvent and resultant storage solution of C10₂ is preferably soluble in, miscible with, or emulsifiable in water. Such water- free solvents can then be more readily incorporated for use in the aforementioned water-containing germicidal composition. The resultant storage solution of C10₂ should be stored in containers made of materials compatible with the components of the storage solution. Preferably, the storage solution is stored in a light- and air-tight container to minimize decomposition of the C10₂. Also, preferably no gas is allowed to exist in the storage container (i.e. the storage container is "topped off" with the storage solution.) Lack of a nongaseous phase is also preferred even after use of a portion of the storage container's contents.

In the practice of this invention, chlorine dioxide is synthesized as either a liquid or a gas. If it is synthesized as a liquid, it may be converted into a gas in conventional fashion. In any event, chlorine dioxide gas is dissolved for storage in a water-free organic solvent. In most cases, adequate dissolution can be effected by simply permitting the gas to bubble through the solvent, although alternative techniques could be utilized. The solvent should contain no constituent (e.g. water) which disassociates into hydroxyl (OH~) or other basic groups. Furthermore, once the C10₂ has been incorporated into the solvent, the resulting solution should not be exposed to heat; ultraviolet or other light; compounds which might react with C10₂ such as amine containing molecules; or compounds which might catalyze the decomposition of C10₂. Excess movement or shaking of the solution should be avoided. Absolute alcohol is a preferred water-free organic solvent, although generally any organic solvent of C10₂ (i.e. any organic solvent in which C10₂ dissolves) might be used which is soluble in or miscible with water (e.g. propylene glycol) or can be suspended in water via action or a detergent or other emulsifier (e.g., mineral oil) and is nonreactive with C10₂. If necessary, a chlorine scrubber and a desiccator are placed between the chlorine dioxide generator and the water-free solvent to remove any water and Cl₂ present before dissolution into the organic solvent.

The procedures of this invention produce a concentrated solution of chlorine dioxide in a water-free organic solvent. Although higher concentrations are achievable, for most purposes currently within contemplation, concentrations of less than about 5% by weight chlorine dioxide are preferred. In the absence of heat, light, or oxygen, a solution in this form can be stored indefinitely. Shortly before use, the concentrated organic solution may be -diluted with water (H₂0) to attain a desired use concentration of chlorine dioxide in aqueous solution as described in the first C10₂ composition. Alternatively, the concentrated organic solutions can be diluted to the final working concentration in either the same organic liquid initially used to capture the C10₂ or in another organic liquid. So long as the organic compounds do not react with or encourage decomposition of C10₂, such a dilution could be done either at or near the time of application or in the manufacture of the composition at a factory and the resulting solution would be expected to retain its excellent shelf and storage life. In addition, some preparations will be mild enough for use on living tissues (e.g., skin, wounds, oral, anal and vaginal cavities, etc.) . The diluted aqueous or organic solutions prepared in accordance with this invention may be applied to a surface which is to be disinfected or sanitized. The diluted solution is left in contact with the surface for a period of time sufficient to permit disinfection to take place. Typical contact times range from about one second to about five minutes, depending upon the strength of the solution, the nature of the surface to be treated, and the resistance of the specific microorganisms on the surface.

Detailed Description of the Preferred Embodiments

The germicidal compositions of the present invention comprise chlorine dioxide dissolved in one or more solvents. Chlorine dioxide is present in said compositions at concentrations sufficient to destroy microorganisms (a "germicidally effective concentration") . When the compositions are used as "antiseptics," i.e., the compositions are applied to living tissue of a user for the purpose of preventing the growth of, or destroying, microorganisms, the total concentration of the chlorine dioxide should be sufficiently low so as not to damage the living tissue of the user significantly (e.g. less than 1000 ppm of C10 in an aqueous, mixed aqueo.us-organic or organic solution) . When the composition is used as a disinfectant, i.e. used to destroy microorganisms on an inanimate surface, no such concentration limitation need be adhered to.

A typical germicidal composition of the present invention comprises chlorine dioxide dissolved in either an aqueous (i.e. water-containing) or an organic solution such as absolute alcohol. Use of C10 in an organic solution such as ethanol might result in additivity or super-additivity of germicidal effects. For use as a surface disinfectant, the concentration of C10₂ can be as high as 20,000 ppm. The germicidal composition will typically be made by 1) generating chlorine dioxide gas; 2) passing the generated gas through a chlorine scrubber to remove any free chlorine (Cl₂) ; 3) passing the resulting gas through a desiccator to remove water; 4) bubbling the resulting gas through a water-free organic solvent; and 5a) at or near the time of use, diluting the resulting C10₂ water- free organic solvent with an aqueous solution, or 5b) diluting the C10₂ concentrate with the same or a different organic liquid, either at the time of manufacture or at or near the time of use. Many methods exist for manufacturing or synthesizing chlorine dioxide and then later converting it into a gas. These methods are well known in the art. Typical methods are described in Masschelein, supra, on pages 9-11 and 112-140, and Kirk Othmer, supra, Vol. 5, on pages 615-617. The descriptions of the techniques set forth in these references are incorporated herein by reference.

Once manufactured, chlorine dioxide is preferably passed, as a gas, through a chlorine (Cl ) scrubber. Chlorine scrubbers are well known in the art and include passing the generated gas through a column containing either arsenite or solid sodium chlorite or a concentrated sodium chlorite solution. The column or solution absorbs the Cl₂ while allowing the C10₂ to pass unaltered. Industrial methods for purifying chlorine dioxide are described in Masschelein, supra, on pages 135-138, the contents of which are hereby incorporated by reference. Removing chlorine (Cl₂) is desirable since Cl₂ tends to increase the rate of oxidation, and thus deactivation, of the chlorine dioxide.

After passing through the chlorine scrubber, the C10₂ gas is then preferably passed through a desiccator in order to remove any water vapor present. Desiccants which do not react with C10₂ are preferred. The C10₂ gas, after being passed through the scrubber and the desiccator, is then bubbled through a water-free, organic solvent. The organic solvent is water free because the presence of water in solution may deactivate the C10₂, making it unavailable for use as a germicide. Water disassociates into hydride (H⁺) and hydroxyl (0H~) groups, and hydroxyl ion can stimulate the decomposition of chlorine dioxide and thus inactivate its germicidal effects. Water-free organic solvents useful in the present invention 1) are soluble in, miscible, with or emulsifiable in water, 2) do not react with or encourage the inactivation of C10₂ (e.g. contain no basic groups, amines, alkenes, alkyne bonds or other reactive groups) , and 3) are generally non toxic when applied topically to an animal. Other considerations when selecting a water- free organic solvent ^'for use in the invention, especially in considering use as an antiseptic, include possible toxicity to sites other than the skin, mutagenicity, carcinogenicity, teratogenicity, and the presence or absence of undesirable odors. Typical solvents are water- free alcohols, containing from one to four carbon atoms, glycerol, polyethylene glycol, propylene glycol, biocompatible emulsifying agents or other surfactants, and non-toxic alkenes such as mineral oil.

An ideal water-free organic solvent is absolute alcohol. This substance is greater than 99% ethyl alcohol, contains little or no water, is readily available and is relatively non-toxic to humans. Concentrations of greater than 5% chlorine dioxide by weight dissolved in absolute alcohol should generally be avoided, however, as these mixtures are potentially explosive. If used, the bubbling step for introducing C10₂ gas into the chosen solvent should be accomplished in the presence of an inert gas such as nitrogen as a diluent to avoid explosions and may prevent undesired deactivation of the chlorine dioxide by the presence of oxygen or air. Once dissolved in the water-free organic solvent, the resulting solution can be stored and transported safely. The C10₂ does not degrade appreciably. Greater than 99% of the C10₂ is free and available for use in absolute alcohol. If the chlorine dioxide was produced by one of the "cleaner" techniques, e.g. the Oxidation of Chlorite -li¬

fe,g NaC10₂) by Persulfate (Na₂S 0₈) technique or Action of Acetic Anhydride ((CH₃CO)₂0) on Chlorite technique, and the chlorine dioxide gasified and passed through a chlorine scrubber, then the only oxychloride generally present in the resulting organic solvent solution is chlorine dioxide. The resulting solution can then be titrated using standardized techniques to determine the amount of chlorine dioxide present in the organic solvent. Techniques for determining the concentration of C102 are disclosed in Kirk Othmer, supra, on- pages 617-618, the contents of which are hereby incorporated by reference.

After determining the concentration of chlorine dioxide in the organic solution, the solution can be diluted with a predetermined quantity of an aqueous solution to form an "aqueous organic solution." The aqueous-organic solution can be compounded to attain any concentration of C10₂ desired for the particular germicidal composition. Techniques for determining the amount of aqueous solution needed for a particular concentration of chlorine dioxide in the aqueous-organic solution are straight forward concentration calculations known to anyone skilled in the art. For aqueous solutions, this step will take place at the time of usage or when the germicidal composition is incorporated into a dosage form. For organic solutions, dilution to the final working concentration may occur either during manufacture and prior to packaging, or at the site of application.

The aqueous solution used to dilute the C10₂- organic solvent mix will generally contain water with or without buffering agents. The buffering agents will generally be used to maintain the pH between 2.0 and 7.0, although most pH values will work. Amine compounds and compounds which disassociate into amines, many compounds possessing double (alkenes) or triple (alkynes) carbon- carbon bonds, phenol-like compounds, chlorine, oxychlorine compounds other than C10₂ and other similar components are to be avoided because these substances tend to either react with or increase the deactivation rate of chlorine dioxide. Methods for choosing buffering systems are disclosed in Chase, et al. Remington's Pharmaceutical Sciences. Mack Printing Co., Easton, Pennsylvania, 16th ed. 1980, pages 238-240, the contents of which are hereby incorporated by reference. Typical buffering agents include borates and phosphates.

Once the C10₂-organic solvent mixture has been diluted with an appropriate aqueous or organic solution, the resulting mixtures should be kept free from ultraviolet or other light, oxygen (0₂) and air. Preferably, the mixture is kept cool until use.

Once diluted, the germicidal composition can be incorporated into several pharmaceutical dosage forms. These pharmaceutical dosage forms include aerosol containers, various foams, douches, enemas, saline rinses or washes, creams, gels, soaps, lotions, etc. The solution itself can be used to disinfect or sterilize inanimate items which come into contact with blood, such as razors, medical and dental tools, blood bank equipment, etc. Another use is as a general purpose sanitizer for toilet seats and bathrooms. Water, oil-water, alcohol- water, or entirely organic aerosols can be all be used as carriers for C10₂ solutions.

In order to increase the shelf-life of the aqueous germicidal composition of chlorine dioxide, the C10₂-containing organic solvent may be kept separate from the aqueous solution until the composition is to be used. Such a separation can be accomplished by using a pharmaceutical dosage form which maintains the separateness of the two solutions, but which combine the solutions at the time of use. For example, the C10₂ containing organic solvent can be kept in a separate container from the aqueous solution with which it is to be diluted. When the composition is to be used, the two separate solutions can then be combined for use. If the diluted solution is to be stored after mixing, it should be kept away from heat and light.

The diluted solutions of this invention can also be incorporated into an aerosol container. Aerosols are well known to those skilled in the art. Typical aerosol dosage forms are described in Remington's, supra, chapter 92, pages 1614-1618, the contents of which are hereby incorporated by reference. The aerosol dosage form is ideal, as the chlorine dioxide composition is kept free from light and air, both of which may increase the rate of breakdown of the chlorine dioxide into germicidally inactive compounds.

In germicidal activity, chlorine dioxide destroys most pathogens including HTLV-III virus (the putative cause of AIDS) , Herpes simplex I and II, Newcastle disease virus, phage OX-174, Sendai virus, Vaccinia virus, Poliovirus A, B, and C, Rotavirus, Echovirus, Coxsackieviruses A9 and B5, bacteriophage f2, Yersinia enterocolitica, Klebsiella pneumoniae, Escherichia coli ATCC No. 1129, three species of Salmonella. Staphylococcus aureus, Legionella pneumophila, Pseudomonas species, Listeria monocytogenes, both the bacteria and spores of four Bacillus species, wild type Actinomyces. Niphargus larvae, Arsellus aquaticus larvae, various alga (Scenede us, volvox, synedra, and sphaerotilus) , Nisseria gonorrhoeae. Treponema pallidum, Candida albicans, Trichomonas vaginalis, Lvmphogranuloma venerum chlamydia, and Cytomegalovirus. As little as 1 ppm of chlorine dioxide in solution will destroy 99,999 of 100,000 E . coli upon contact for five minutes. However, for purposes of this disclosure, germicidally effective concentrations of C10₂ are typically greater than about 2 ppm. Once made, the composition is easily used. The surface to be sanitized (either an inanimate object or living tissue) is contacted with the composition. Although destruction of many pathogens occurs at strengths as low as 0.75 ppm, the contact time required at such a low concentration to kill some pathogens may be longer than desirable. Preferably, the concentration of free chlorine dioxide in the germicidal composition varies from about 2 ppm to about 20,000 ppm. Concentrations of less than 1,000 ppm are considered desirable for antiseptic applications. The composition is then allowed to remain in contact with the surface being treated for a sufficient amount of time to allow the chlorine dioxide to destroy any susceptible micro-organisms present. Contact times vary from about one second to about five minutes, depending on the organism to be destroyed, the concentration of chlorine dioxide in the solution, degree of dilution due to presence of fluids on th surface, degree of efficacy necessary, and the surface area of the surface to be treated. The composition can be washed away after the germicidal or other desired activity has taken place.

Surfaces on which the germicidal composition can be used range from inanimate objects, such as operating tables, to living tissues such as damaged or infected skin or body cavities or tissues, including the nose, mouth, vagina, rectum, eye and ear. Surface disinfection of patient's skin and/or doctor's hands could be accomplished with the same germicidal composition. A longer contact time or a higher concentration may be needed for treating a body cavity, such as the vagina, due to either rugae, or the presence of material which might react with or dilute the C10₂, such as semen or saliva, which would lower the available concentration of C10₂ and prolong the contact time needed for C10₂'s biocidal effect. One pharmaceutical use of an aqueous solution of chlorine dioxide in general, or of one of the specific compositions herein described, is for the treatment of gastrointestinal infections. Alternatively, a dry pharmaceutical dosage form which will generate C10₂ in the gastrointestinal tract might be used for destroying such pathogens. An appropriate dry dosage form might comprise 1) sodium chlorite powders or crystals; and 2) an inert material in admixture with the sodium chlorite. The admixture of sodium chlorite and inert material will generate C10₂ in an acidic aqueous solution. The aqueous solution can already be acidic, can be made acidic by the separate addition of an acidifying agent (e.g. stomach acid) , or can be made acidic by the incorporation of a dry water soluble acidifying agent into the pharmaceutical dosage form. Typical dosage forms would include tablets, capsules, and pills. Methods for making tablets, capsules, and pills, and their respective ingredients are disclosed in Remington' s, supra, chapter 89, pages 1553-1593, the contents of which are hereby incorporated by reference. Typical inert materials would be diluents, binders, lubricants, disintegrators, coloring agents, and flavoring agents, all of which are well known to those skilled in the art.

A typical pharmaceutical dosage form for use in destroying pathogens of the gastrointestinal tract includes:

7.199 mg of NaC10₂ 75.2 mg of Milk Sugar (powder) 21.9 mg of Starch 20 mg of Talc

0.701 mg of Stearic Acid (powder) and each tablet would have a weight of 125 milligrams (mg) . The dosage form would be a tablet which was "dry granulated," i.e. enough ingredients for 10,000 tablets would be mixed thoroughly, compressed into slugs, ground and screened into 14-16 mesh granules, and recompressed into tablets using a 1/4-inch concave punch. Typical acidifying agents which could be included into the dosage form would be powders which when dissolved into the aqueous solution would be sufficiently strong enough to react with the NaC10₂ to form C10₂ (e.g. powdered citric acid) .

The previously described tablets are taken orally by a user with a predetermined quantity of water (e.g. 500 ml. for the described tablet) to form a germicidally effective concentration of C10₂ to destroy pathogens in the gastrointestinal tract, such as the causative pathogens of cholera, gastric enteritis, and amoebic dysentery. The user's stomach acid would be sufficient to acidify the sodium chlorite solution to generate the C10₂. If a problem exists with the user' s stomach acid secretion (e.g., he is suffering from achlorhydria) , an acidifying agent may be incorporated into the dosage form.

In an alternative embodiment, a liquid solution of C10₂ in general, the specific compositions described herein, or a dry preparation might be used to stabilize blood clots, a problem of real significance on moist tissue such as is encountered in body cavities such as the (1) gastrointestinal tract (from mouth to rectum inclusively) , (2) the urogenital tissues, (3) in the nose, ears and eyes, (4) in surgically exposed body cavities or tissues, and (5) at other sites where blood clot stabilization would be advantageous. Thus, healing of wounds, surgical scars, ulcers, tears and fissures might all be speeded. In a separate alternative embodiment, compositions containing C10₂ such as those described hereinabove could be mixed with saline or other solutions used for lavage of body cavities, tissues, orifices, wounds, or surgical sites to disinfect, reduce tissue swelling, and/or stabilize blood clots.

In an alternative embodiment, liquids containing C10₂ in general, the specific compositions described herein, and/or dry preparations could be used as an antihistamine and/or anti autacoid preparation. Chlorine dioxide reacts with amines so that both the C10₂ and the amine are altered. Applying C10₂ incorporated into one or more of the aforementioned compositions to an area of skin irritated due to the presence of histamine (e.g. a rash) , causes the irritation to subside sooner than when no treatment is given, due to the deactivation of histamine and at least some autacoids. Autacoids likely to be inactivated by the C10₂ compositions include histamine, serotonin, prosta glandins, prostacyclin, thromboxane, angiotensins, plasma kinins (kallidin and bradykinin) and other autacoids yet to be discovered which have similar chemical reactivity. Goodman & Gil an' s The

Pharmacological Basis of Therapeutics. 6th edition, p. 608-681, by A. G. Gilman, L. S. Goodman, and A. Gilman, 1980, MacMillan. Concentrations of C10 used in formulating a topical antihistamine or anti-autacoid compositions might vary from about 15 to about 100 ppm, but could contain as much as several thousand ppm.

The ability of C10₂ to inactivate histamine, bradykinin, and prostaglandin-like compounds may be used advantageously in a topical analgesic composition. Histamine, bradykinin, and the prostaglandin-like compounds are thought to serve as pain-carrying chemical messengers in the human body. The C10₂ deactivates these pain-carrying compounds, thereby decreasing the user's sensation of pain. The aforementioned anti-autacoid compositions are useful for the topical analgesic composition. Also, like the anti-autacoid compositions, the solvents used in the composition preferably carry the C10₂ through the surface to which the composition is applied to the location of the autacoid molecules. However, even C10₂ dissolved in just water may be useful in this topical analgesic composition.

In another alternative embodiment, the composition can be used as a free radical scavenger. Chlorine dioxide, being a free radical, reacts with other free radicals to deactivate them. Chlorine dioxide dissolved in a water-free organic solvent can then be diluted with another solution, such as normal saline, and the resulting solution may be used as a free radical scavenger. Concentrations of C10₂ used in formulating such a free radical scavenging solution vary from about 15 to about 100 ppm.

Well-established principles of selection and formulation are fully applicable in the practice of this invention. Accordingly, those skilled in the art will experience no difficulty in selecting compatible components for a formulation of the invention.

Reference herein to specific details of certain embodiments is not intended to restrict the scope of the appended claims.

Claims

Claims What is claimed is:

1. A germicidal composition comprising: an organic solution of chlorine dioxide consisting essentially of a water-free organic solvent and a germicidally effective concentration of chlorine dioxide dissolved in said water-free organic solvent; and water in admixture with said organic solution of chlorine dioxide, said water being present in such quantities that the concentration of chlorine dioxide dissolved in said germicidal composition remains germicidal.

2. The germicidal composition of Claim 1 wherein the water-free organic solvent is miscible with water.

3. The germicidal composition of Claim 2 containing at least about 2 ppm free chlorine dioxide.

4. The germicidal composition of Claim 3 wherein the pH of said composition is greater than about 2.

5. A topical anti-autacoid composition comprising: an aqueous-organic solution comprising an organic solvent and water; and chlorine dioxide dissolved in said aqueous-organic solution in a substantially free condition, said chlorine dioxide being present at a sufficient concentration to deactivate autacoids without causing tissue damage.

6. The topical anti-autacoid composition of Claim 5 wherein said chlorine dioxide present in said aqueous-organic solution is present at a concentration of about 15 to about 100 parts per million.

7. The topical anti-autacoid composition of

Claim 6 wherein said organic solvent is absolute alcohol.

8. The topical anti-autacoid composition of Claim 6 wherein said topical anti-autacoid composition is incorporated into an aerosol dosage form.

9. A method of storing chlorine dioxide comprising dissolving chlorine dioxide into a water-free organic solvent so as to form a storage mixture of chlorine dioxide wherein said chlorine dioxide does not decompose into other substances.

10. The method of Claim 9 wherein said dissolved chlorine dioxide is stored in the absence of light.

11. The method of Claim 10 wherein said dissolved chlorine dioxide is stored in the absence of air or oxygen.

12. The method of Claim 11 wherein said chlorine dioxide is dissolved into said water-free organic solvent by bubbling chlorine dioxide gas through said water-free organic solvent.

13. The method of Claim 12 including passing the chlorine dioxide gas through a desiccator before bubbling it through said water-free organic solvent.

14. The method of Claim 13 wherein said water- free organic solvent is an alcohol containing from one to four carbon atoms.

15. The method of Claim 14 wherein said water- free organic solvent is absolute alcohol.

16. The method of Claim 13 including passing the chlorine dioxide gas through a chlorine scrubber after generation of the chlorine dioxide gas.

17. A storage solution of chlorine dioxide consisting essentially of: a water-free organic solvent, and chlorine dioxide dissolved in said water-free organic solvent.

18. The storage solution of chlorine dioxide of

Claim 17 wherein said water-free organic solvent is miscible with water.

19. The storage solution of chlorine dioxide of Claim 18 wherein said water-free organic solvent is an alcohol having from about one to about four carbon atoms.

20. The storage solution of Claim 19 wherein said water-free organic solvent is absolute alcohol.

21. The storage solution of Claim 20 wherein the concentration of chlorine dioxide in said absolute alcohol is less than 5% by weight.

22. A method of making a germicidal composition comprising: passing chlorine dioxide gas through a water-free organic solvent until chlorine dioxide dissolves in said water-free organic solvent; and diluting said chlorine dioxide-containing, water-free organic solvent with a predetermined quantity of an aqueous solution so as to attain a germicidally effective concentration of chlorine dioxide in said water and water-free organic - solvent solution.

23^ The method of Claim 22 wherein said chlorine- dioxide gas is passed through said water-free organic solvent until said chlorine dioxide is present in said water-free organic solvent at a concentration of less than about 5 percent by weight.

24. The method of Claim 23 wherein said water- free organic solvent is miscible with water.

25. The method of Claim 24 wherein said water- free organic solvent is absolute alcohol.

26. The method of Claim 25 wherein said germicidal concentration of chlorine dioxide in said water and absolute alcohol solution is from about 2 to about 1000 parts per million.

27. A method of disinfecting a surface comprising: contacting said surface with a germicidal composition consisting essentially of chlorine dioxide and a water-free organic solvent; and maintaining said germicidal composition in contact with said surface for a duration sufficient to destroy microorganisms present on said surface.

28. The method of Claim 27 wherein said surface is the surface of an animal body cavity.

29. The method of Claim 28 wherein said animal body cavity is a human body cavity.

30. The method of Claim 29 wherein said human body cavity is a rectum.

31. The method of Claim 29 wherein said human body cavity is a vagina.

32. The method of Claim 29 wherein said germicidal composition is stored in an aerosol dispenser before use.

33. The method of Claim 29 wherein said germicidal composition is a liquid foam-like substance.

34. A germicidal composition consisting essentially of a water-free organic solvent and a germicidally effective amount of chlorine dioxide dissolved in said water-free solvent.

35. The germicidal composition of Claim 34 wherein said germicidal composition in said chlorine dioxide is present in an amount of at least two parts per million.

36. A pharmaceutical dosage form for use in destroying pathogens in the gastrointestinal tract comprising: sodium chlorite; and an inert material in admixture with said sodium chlorite, said admixture of sodium chlorite and inert material capable of generating chlorine dioxide in an acidic aqueous solution when said admixture is placed in said acidic aqueous solution.

37. The pharmaceutical dosage form of Claim 36 wherein said admixture contains from about 5 to about 30 milligrams of sodium chlorite powder.

38. The pharmaceutical dosage form of Claim 37 wherein said admixture includes a water soluble acidifying agent.

39. The pharmaceutical dosage form of Claim 38 wherein said pharmaceutical dosage form is a tablet and said inert material comprises a diluent and a binder.

40. A method of using the topical anti-autacoid composition of Claim 5 to afford pain relief to an individual having an injured area of skin comprising: applying a sufficient amount of said topical anti-autacoid composition to said injured area of skin so that a quantity of histamine and bradykinin present at said injured area of skin is deactivated, thereby affording pain relief to said individual.