New! View global litigation for patent families

US20100196512A1 - Treatment of Non-Oral Biological Tissue with Chlorine Dioxide - Google Patents

Treatment of Non-Oral Biological Tissue with Chlorine Dioxide Download PDF

Info

Publication number
US20100196512A1
US20100196512A1 US12690851 US69085110A US2010196512A1 US 20100196512 A1 US20100196512 A1 US 20100196512A1 US 12690851 US12690851 US 12690851 US 69085110 A US69085110 A US 69085110A US 2010196512 A1 US2010196512 A1 US 2010196512A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
chlorine
dioxide
tissue
composition
non
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12690851
Inventor
Andrew Patrick Full
Marcos Gomez
Frank S. Castellana
Barry Keven Speronello
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Catalysts LLC
BASF Corp
Original Assignee
BASF Catalysts LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/20Elemental chlorine; Inorganic compounds releasing chlorine

Abstract

Methods, devices, compositions, and systems for the alleviation of non-oral biological tissue infections by administration of chlorine dioxide are provided.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • [0001]
    This application claims the benefit pursuant to 35 U.S.C. §119(e) of U.S. Provisional Application Nos. 61/149,784, filed Feb. 4, 2009; 61/150,685, filed Feb. 6, 2009; and 61/187,198, filed Jun. 15, 2009, each of which is hereby incorporated by reference in its entirety herein.
  • BACKGROUND
  • [0002]
    Infections and inflammations of non-oral biological tissue are a common problem in mammals, including humans. Non-oral biological tissue infections include infections of non-oral mucosal tissue, skin and non-oral hard tissue such as fingernails. Examples of skin or hard tissue infections include acne, warts, ringworm, athlete's foot, and fungal infections of nails. All of these are commonly treated with one or more topical medicaments.
  • [0003]
    Examples of non-oral mucosal tissue include conjunctiva mucosa, vaginal mucosa and sinus mucosa. Sinus mucosal infection, often called sinusitis, can range from an acute infection to a chronic one. Symptoms include headache, toothache, nasal congestion, facial pain, night-time coughing, increase in asthma symptoms, and yellow or green nasal discharge. Vaginitis refers to inflammation of vaginal mucosal tissue and can arise from bacterial infection, yeast infection and other pathogen infection of the vaginal mucosa. Symptoms can include itching, discomfort, discharge, malodor, and discomfort during urination. Both sinusitis and vaginitis, particularly in treatment recalcitrant forms, feature biofilms (Swidsinski et al., 2005, Obstet. Gynecol. 106: 1013-1023; Swidsinski et al., 2008, Am. J. Obstet. Gynecol. 198:e1-6; Chiu et al., 2007, J. Antimicrob. Chemother. 59:1130-1134; Cohen et al., 2009, Am J Rhinol Allergy 23:255-260). It is believed these biofilms contribute significantly to treatment recalcitrance and contribute to recurrence in both vaginitis and sinusitis.
  • [0004]
    Chlorine dioxide is known to be a disinfectant, as well as a strong oxidizing agent. The bactericidal, algaecidal, fungicidal, bleaching, and deodorizing properties of chlorine dioxide are also well known. Therapeutic and cosmetic applications for chlorine dioxide are known. For example, U.S. Pat. No. 6,280,716 describes the use of stabilized chlorine dioxide solutions for the treatment of vaginal itching. U.S. Pat. No. 7,029,705 describes the use of stabilized chlorine dioxide solutions for a method of nasal hygiene. The traditional method for preparing chlorine dioxide involves reacting sodium chlorite with gaseous chlorine (Cl2(g)), hypochlorous acid (HOCl), or hydrochloric acid (HCl). The reactions proceed at much greater rates in acidic medium, so substantially all traditional chlorine dioxide generation chemistry results in an acidic product solution having a pH below 3.5.
  • [0005]
    Chlorine dioxide may also be prepared from chlorate anion by either acidification or a combination of acidification and reduction. At ambient conditions, all reactions using chlorate anion require strongly acidic conditions; most commonly in the range of 7-9 N. Heating of the reagents to higher temperature and continuous removal of chlorine dioxide from the product solution can reduce the acidity needed to less than 1 N.
  • [0006]
    A method of preparing chlorine dioxide in situ uses a solution referred to as “stabilized chlorine dioxide.” Stabilized chlorine dioxide solutions contain little or no chlorine dioxide, but rather, consist substantially of sodium chlorite at neutral or slightly alkaline pH. Addition of an acid to the sodium chlorite solution activates the sodium chlorite, and chlorine dioxide is generated in situ in the solution. The resulting solution is acidic. Typically, the extent of sodium chlorite conversion to chlorine dioxide is low, and a substantial quantity of sodium chlorite remains in the solution.
  • [0007]
    The current literature summarized above describes the use of chlorine dioxide compositions and methods that are damaging to biological tissues, including soft mucosal tissues. Methods, compositions, devices and systems for using chlorine dioxide for treatment of non-oral tissue in which biological tissue is not damaged are needed.
  • SUMMARY
  • [0008]
    The following embodiments meet and address these needs. The following summary is not an extensive overview. It is intended to neither identify key or critical elements of the various embodiments nor delineate the scope of them.
  • [0009]
    A method for alleviating a non-oral biological tissue infection is provided. The method comprises administering a composition comprising a chlorine dioxide source that includes chlorine dioxide or chlorine dioxide-generating components to the non-oral biological tissue, thereby alleviating the infection of the contacted tissue, wherein the administering step comprises one or more of: i) contacting the tissue with a substantially non-cytotoxic composition comprising the chlorine dioxide source; ii) contacting the tissue with a device comprising the chlorine dioxide source and oxy-chlorine anions, wherein the device delivers a substantially oxy-chlorine anion free chlorine dioxide composition to the tissue; or iii) contacting the tissue with a composition comprising the chlorine dioxide source and oxy-chlorine anions; and a barrier substance that substantially prohibits passage therethrough of the oxy-chlorine anions and permits passage therethrough of a substantially oxy-chlorine anion free chlorine dioxide composition, thereby enabling delivery of the substantially oxy-chlorine anion free chlorine dioxide composition to the tissue.
  • [0010]
    In some embodiments, the tissue infection is a soft biological tissue infection. The soft biological tissue infection can be a non-oral mucosa infection or a dermal infection. The non-oral mucosa infection can be selected from the group consisting of vaginitis, sinusitis, urethritis, and conjunctivitis. In other embodiments, the tissue infection is a dermal infection selected from the group consisting of uveitis, acne, common warts, tinea corpis (ringworm), tinea pedis (athlete's foot), tinea cruris (jock itch). In another embodiment, the tissue infection is a hard tissue infection such as tinea unguium (nail fungal infection).
  • [0011]
    In an embodiment, the composition comprises about 1 to about 1000 ppm chlorine dioxide. In another embodiment, the composition comprises about 20 to about 400 ppm chlorine dioxide
  • [0012]
    In some embodiments, the chlorine dioxide source comprises a particulate precursor of chlorine dioxide as the chlorine dioxide-generating components.
  • [0013]
    In an embodiment, the method further comprises administering a second therapeutic agent. Second therapeutic agents can be an antimicrobial agent such as an antibiotic or an antifungal, a retinoid, a steroid, salicylic acid, liquid nitrogen and the like. In one aspect, the composition comprising the chlorine dioxide source further comprises the second therapeutic agent. In another aspect, the method comprises administering a second composition comprising the second therapeutic agent. In some embodiments for alleviating sinusitis, the second therapeutic agent is an antimicrobial selected from the group consisting of: gatifloxacin, clindamycin, gentiamicin, ceftazidime, an aminoglycoside such as tobramyin and streptomycin, amphotericin B, itraconazole, ketoconazole, miconazole and nystatin. In some embodiments for alleviating vaginitis, the second therapeutic agent is an antimicrobial selected from the group consisting of neomycin, ribaximin, clindamycin, metronidazole, polymixin B, proguanil, econazole, and fluconazole. In some embodiments for alleviating acne, the second theraepeutic agent is selected from the group consisting of an antimicrobial agent, a retinoid, and a combination thereof. In some embodiments for alleviating tinea corpis, tinea cruris, or tinea pedia, the second therapeutic agent is an antimicrobial selected from the group consisting of terbinafine, miconazole, clotrimazole, ketoconazole, clotrimazole and tolnaftate.
  • [0014]
    In one aspect, the administering step comprises contacting the tissue with a substantially non-cytotoxic composition comprising the chlorine dioxide source. In some embodiments, the administering step comprises at least two substantially contiguous iterations of contacting the tissue with a substantially non-cytotoxic composition comprising the chlorine dioxide source. In some embodiments, the substantially non-cytotoxic composition comprises less than about 0.2 milligrams oxy-chlorine anion per gram composition. In some embodiments, the substantially non-cytotoxic composition has a pH from about 4.5 to about 11.
  • [0015]
    In another aspect, the administering step comprises contacting the tissue with a device comprising a chlorine dioxide source and oxy-chlorine anions, wherein the device delivers a substantially oxy-chlorine anion free chlorine dioxide composition to the tissue. In some embodiments, the device is an irrigation device. In some embodiments, the device comprises: an optional backing layer; a layer comprising the chlorine dioxide source; and a barrier layer interposed between the chlorine dioxide source layer and the tissue, wherein the barrier layer substantially prohibits passage therethrough of the oxy-chlorine anions and permits passage therethrough of the substantially oxy-chlorine anion free chlorine dioxide composition. The barrier film can be a film selected from the group consisting of polyurethane, polypropylene, polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidene dichloride, combination of polydimethylsiloxane and polytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane, and combinations thereof.
  • [0016]
    In another embodiment, the device comprises: a backing layer and a matrix affixed to the backing layer, wherein the matrix comprises: a chlorine dioxide source and oxy-chlorine anions; and a barrier substance that substantially prohibits passage therethrough of the oxy-chlorine anions and permits passage therethrough of the substantially oxy-chlorine anion free chlorine dioxide composition. In some embodiments of the device, the barrier substance is selected from the group consisting of polyurethane, polypropylene, polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidene dichloride, combination of polydimethylsiloxane and polytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane, polyethylene oxide, polyacrylates, mineral oil, paraffin wax, polyisobutylene, polybutene and combinations thereof.
  • [0017]
    In another embodiment, the administering step comprises contacting the tissue with a composition comprising a chlorine dioxide source, oxy-chlorine anions, and a barrier substance. In some embodiments of the composition, the barrier substance is selected from the group consisting of polyurethane, polypropylene, polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidene dichloride, combination of polydimethylsiloxane and polytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane, polyethylene oxide, polyacrylates, mineral oil, paraffin wax, polyisobutylene, polybutene, and combinations thereof.
  • [0018]
    Further provided is a method for alleviating a non-oral biological tissue infection, wherein the method comprises administering a composition comprising a chlorine dioxide source to the non-oral biological tissue, wherein the administering step comprises contacting the tissue with a substantially non-irritating composition comprising the chlorine dioxide source, thereby alleviating the infection of the contacted tissue. In some embodiments, the tissue infection is a non-oral mucosa infection. The non-oral mucosa infection can be selected from the group consisting of vaginitis, sinusitis, conjunctivitis, and uveitis. In other embodiments, the tissue infection is selected from the group consisting of acne, common warts, tinea corpis, tinea pedis, tinea cruris, and tinea unguium.
  • [0019]
    In some embodiments, the substantially non-irritating composition comprises about 1 to about 1000 ppm chlorine dioxide. In other embodiments, the substantially non-irritating composition comprises about 20 to about 400 ppm chlorine dioxide.
  • [0020]
    In some embodiments, the chlorine dioxide source of the substantially non-irritating composition comprises a particulate precursor of chlorine dioxide as the chlorine dioxide-generating components. In some embodiments, the substantially non-irritating composition comprises less than about 0.2 milligrams oxy-chlorine anion per gram composition. The substantially non-irritating composition can have a pH from about 4.5 to about 11.
  • [0021]
    In an embodiment, the method comprising the step of contacting a non-oral biological tissue with a substantially non-irritating composition comprising the chlorine dioxide source, further comprises administering a second therapeutic agent. Second therapeutic agents can be an antimicrobial agent such as an antibiotic or an antifungal, a retinoid, a steroid, salicylic acid, liquid nitrogen and the like. In one aspect, the composition comprising the chlorine dioxide source further comprises the second therapeutic agent. In another aspect, the method comprises administering a second composition comprising the second therapeutic agent. In some embodiments for alleviating sinusitis, the second therapeutic agent is an antimicrobial selected from the group consisting of: gatifloxacin, elindamycin, gentiamicin, ceftazidime, an aminoglycoside such as tobramyin and streptomycin, amphotericin B, itraconazole, ketoconazole, miconazole and nystatin. In some embodiments for alleviating vaginitis, the second therapeutic agent is an antimicrobial selected from the group consisting of neomycin, ribaximin, clindamycin, metronidazole, polymixin B, proguanil, econazole, and fluconazole. In some embodiments for alleviating acne, the second theraepeutic agent is selected from the group consisting of an antimicrobial agent, a retinoid, and a combination thereof. In some embodiments for alleviating tinea corpis, tinea cruris, or tinea pedia, the second therapeutic agent is an antimicrobial selected from the group consisting of terbinafine, miconazole, clotrimazole, ketoconazole, clotrimazole, and tolnaftate.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0022]
    For the purpose of illustrating the various compositions and methods, there are depicted in the drawings certain embodiments of the materials and methods disclosed herein. However, the compositions and their methods of use are not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings.
  • [0023]
    FIG. 1 is a graph depicting the log kill of bacteria in a biofilm as a function of chlorine dioxide dose. MRSA=methicillin resistance Staphylococcus aureus. PA=Pseudomonas aeruginosa.
  • DETAILED DESCRIPTION
  • [0024]
    The following description sets forth in detail certain illustrative aspects and implementations of the embodiments. These are indicative, however, of but a few of the various ways in which the principles of the various compositions and devices may be employed. Other objects, advantages, and novel features of the methods will become apparent from the following detailed description.
  • [0025]
    Chlorine dioxide can be of great utility in a variety of applications in biological systems as a result of its disinfectant, bactericidal, algaecidal, fungicidal, bleaching, and deodorizing properties. However, chlorine dioxide compositions have been determined to be damaging to biological tissues. One aspect arises in part from the inventors' determination that the cytotoxic component in chlorine dioxide compositions is not chlorine dioxide itself. Instead, oxy-chlorine anions present in chlorine dioxide compositions have been determined to be the cytotoxic component (absent other cytotoxic components). The methods described herein generally pertain to the administration of a composition comprising chlorine dioxide to a non-oral biological tissue in a substantially non-cytotoxic and/or non-irritating manner to alleviate an infection of a non-oral biological tissue. The methods described herein are useful in the treatment of any infection of a non-oral biological tissue susceptible to topical exposure of a biocidal agent, in particular, chlorine dioxide. The methods can be practiced on the non-oral tissue of any animal. Non-limiting examples of animals are mammals, such as humans, non-human primates, cattle, horses, dogs, sheep, goats, mice, rats, and pigs. In an embodiment, the methods are practiced on human non-oral tissue.
  • DEFINITIONS
  • [0026]
    Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cytopathicity analysis, microbial analysis, organic and inorganic chemistry, and dental clinical research are those well known and commonly employed in the art.
  • [0027]
    As used herein, each of the following terms has the meaning associated with it.
  • [0028]
    The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
  • [0029]
    It is understood that any and all whole or partial integers between any ranges set forth herein are included herein.
  • [0030]
    The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. Generally, “about” encompasses a range of values that are approximately plus/minus 10% of a reference value. For instance, “about 25%” encompasses values from approximately 22.5% to approximately 27.5%.
  • [0031]
    As used herein, a “non-oral biological tissue” refers to any animal tissue that is not located in the oral cavity and includes both soft and hard tissue. Biological tissue are used herein encompasses both largely intact tissue as well as tissue having one or more incisions, lacerations or other tissue-penetrating opening.
  • [0032]
    As used herein, “hard biological tissue” refers to toe and finer nails, hard keratinized tissues and the like, found in animals, such as mammals.
  • [0033]
    As used herein, a “soft biological tissue” refers to non-oral mucosal tissue, epidermal tissue, dermal tissue, and subcutaneous tissue (also called hypodermis tissue).
  • [0034]
    As used herein, a “non-oral mucosal tissue” refers to any mucosal tissue that is not located in the oral cavity. Exemplary non-oral mucosal tissues include, but are not limited to, vaginal mucosa, nasal and sinus mucosa, conjunctiva mucosa, genital mucosa such as glans penis, glans clitoridis, the inside of the prepuce (foreskin) and the clitoral hood, urinary mucosa such as the urethra and anal mucosa.
  • [0035]
    As used herein, a “non-oral biological tissue infection” refers to a disease or disorder of a non-oral biological tissue caused by a pathogenic infection. The pathogen may be bacterial, viral, protozoal, or fungal.
  • [0036]
    As used herein, a “biofilm” refers to a biological aggregate that forms a layer on a surface, the aggregate comprising a community of microorganisms embedded in an extracellular matrix of polymers. Typically, a biofilm comprises a diverse community of microorganisms, including bacteria (aerobic and anaerobic), algae, protozoa and fungi. Monospecies biofilms also exist.
  • [0037]
    As used herein, a disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, are reduced.
  • [0038]
    A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
  • [0039]
    A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease, is at risk for developing a disease, or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • [0040]
    As used herein, “biocidal” refers to the property of inactivating or killing pathogens, such as bacteria, algae, protists, viruses, and fungi (e.g., anti-bacterial, anti-algal, antiprotozoal, antiviral and antifungal). Antimicrobial refers to a biocidal agent.
  • [0041]
    The term “chlorine dioxide-generating components” refers to at least an oxy-chlorine anion source and an activator of chlorine dioxide generation. In some embodiments, the activator is an acid source. In these embodiments, the components optionally further includes a free halogen source. The free halogen source may be a cationic halogen source, such as chlorine. In other embodiments, the activator is an energy-activatable catalyst. In yet other embodiments, the activator is a dry or anhydrous polar material. In other embodiments, the activator is an aqueous fluid such as water, saliva, mucus, and wound exudate, and/or water vapor.
  • [0042]
    The term “polar material” as used herein, refers to a material which has, as a result of its molecular structure, an electrical dipole moment on a molecular scale. Most commonly, polar materials are organic materials which comprise chemical elements with differing electronegativities. Elements that can induce polarity in organic materials include oxygen, nitrogen, sulfur, halogens, and metals. Polarity may be present in a material to different degrees. A material may be considered more polar if its molecular dipole moment is large, and less polar if its molecular dipole moment is small. For example, ethanol, which supports the electronegativity of the hydroxyl over a short, 2-carbon chain may be considered relatively more polar compared to hexanol (C6H13OH) which supports the same degree of electronegativity over a 6-carbon chain. The dielectric constant of a material is a convenient measure of polarity of a material. A suitable polar material has a dielectric constant, measured at about 18-25° C., of greater than 2.5. The term “polar material” excludes water and aqueous materials. A polar material may be a solid, a liquid, or a gas.
  • [0043]
    The term “dry,” as used herein, means a material which contains very little free water, adsorbed water, or water of crystallization.
  • [0044]
    The term “anhydrous,” as used herein, means a material that does not contain water, such as free water, adsorbed water, or water of crystallization. An anhydrous material is also dry, as defined above. However, a dry material is not necessarily anhydrous, as defined herein.
  • [0045]
    An “efficacious amount” of an agent is intended to mean any amount of the agent that will result in a desired biological effect. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For a non-oral biological tissue infection, reduction and/or alleviation in the: extent of infection, duration of infection and/or frequency of infection can be used to gauge an efficacious amount. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • [0046]
    By “cytotoxic” is meant the property of causing lethal or sublethal damage to mammalian cell structure or function. A composition is deemed “substantially non-cytotoxic” or “not substantially cytotoxic” if the composition meets the United States Pharmacopeia (USP) biological reactivity limits of the Agar Diffusion Test of USP <87>“Biological Reactivity, in vitro,” (approved protocol current in 2007) when the active pharmaceutical ingredient (API) is present in an efficacious amount.
  • [0047]
    As used herein, “irritating” refers to the property of causing a local inflammatory response, such as reddening, swelling, itching, burning, or blistering, by immediate, prolonged, or repeated contact. For example, inflammation of a non-oral mucosal or dermal tissue in a mammal is an indication of irritation to that tissue. A composition is deemed “substantially non-irritating” or “not substantially irritating,” if the composition is judged to be slightly or not irritating using any standard method for assessing dermal or mucosal irritation. Non-limiting examples of methods useful for assessing dermal irritation include the use of in vitro tests using tissue-engineered dermal tissue, such as EpiDerm™ (MatTek Corp., Ashland, Mass.), which is a human skin tissue model (see, for instance, Chatterjee et al., 2006, Toxicol Letters 167: 85-94) or ex vivo dermis samples. Non-limiting examples of methods useful for mucosal irritation include: HET-CAM (hen's egg test-chorioallantoic membrane); slug mucosal irritation test; and in vitro tests using tissue-engineered nasal or sinus mucosa or vaginal-ectocervical tissues. Other useful methods of irritation measurement include in vivo methods, such as dermal irritation of rat or rabbit skin (e.g., the Draize skin test (OECD, 2002, Test Guidelines 404, Acute Dermal Irritation/Corrosion) and EPA Health Effects Testing Guidelines; OPPTS 870.2500 Acute Dermal Irritation). The skilled artisan is familiar with art-recognized methods of assessing dermal and mucosal irritation.
  • [0048]
    By “oxy-chlorine anion” is meant chlorite (ClO2 ) and/or chlorate (ClO3 ) anions.
  • [0049]
    By “substantially oxy-chlorine anion free chlorine dioxide composition” is meant a composition that contains an efficacious amount of chlorine dioxide and a non-cytotoxic and/or non-irritating concentration of oxychlorine anion, all as defined hereinabove. The composition may contain other components or may consist essentially of oxy-chlorine anion free chlorine dioxide. The composition may be a gas or vapor comprising or consisting essentially of chlorine dioxide, but may be any type of fluid, including a solution or a thickened fluid. The composition may be an aqueous fluid or a non-aqueous fluid.
  • [0050]
    By “stable” is meant that the components used to form chlorine dioxide, i.e., the chlorine dioxide forming ingredients, are not immediately reactive with each other to form chlorine dioxide. It will be understood that the components may be combined in any fashion, such as sequentially and/or simultaneously, so long as the combination is stable until such time that ClO2 is to be generated.
  • [0051]
    By “non-reactive” is meant that a component or ingredient as used is not immediately reactive to an unacceptable degree with other components or ingredients present to form chlorine dioxide or mitigate the ability of any component or ingredient to perform its function in the formulation at the necessary time. As the skilled artisan will recognize, the acceptable timeframe for non-reactivity will depend upon a number of factors, including how the formulation is to be formulated and stored, how long it is to be stored, and how the formulation is to be used. Accordingly, “not immediately reactive” will range from one or more minutes, to one or more hours, to one or more weeks.
  • [0052]
    The phrase “thickened fluid composition” encompasses compositions which can flow under applied shear stress and which have an apparent viscosity when flowing that is greater than the viscosity of the corresponding aqueous chlorine dioxide solution of the same concentration. This encompasses the full spectrum of thickened fluid compositions, including: fluids that exhibit Newtonian flow (where the ratio of shear rate to shear stress is constant and independent of shear stress), thixotropic fluids (which require a minimum yield stress to be overcome prior to flow, and which also exhibit shear thinning with sustained shear), pseudoplastic and plastic fluids (which require a minimum yield stress to be overcome prior to flow), dilatant fluid compositions (which increase in apparent viscosity with increasing shear rate) and other materials which can flow under applied yield stress.
  • [0053]
    A “thickener component” refers to a component that has the property of thickening a solution or mixture to which it is added. A “thickener component” is used to make a “thickened fluid composition” as described herein and above.
  • [0054]
    By “apparent viscosity” is meant the ratio of shear stress to shear rate at any set of shear conditions which result in flow. Apparent viscosity is independent of shear stress for Newtonian fluids and varies with shear rate for non-Newtonian fluid compositions.
  • [0055]
    The term “hydrophobic” or “water-insoluble,” as used with respect to organic polymers refers to an organic polymer, which has a water solubility of less than about one gram per 100 grams of water at 25° C.
  • [0056]
    By “acid source” is meant a material, usually a particulate solid material, which is itself acidic or produces an acidic environment when in contact with liquid water or solid oxy-chlorine anion.
  • [0057]
    The term “particulate” is defined to mean all solid materials. By way of a non-limiting example, particulates may be interspersed with each other to contact one another in some way. These solid materials include particles comprising big particles, small particles or a combination of both big and small particles.
  • [0058]
    By “source of free halogen” and “free halogen source” is meant a compound or mixtures of compounds which release halogen upon reaction with water.
  • [0059]
    By “free halogen” is meant halogen as released by a free halogen source.
  • [0060]
    By “particulate precursor of chlorine dioxide” is meant a mixture of chlorine-dioxide-forming components that are particulate. Granules of ASEPTROL (BASF, Florham Park, N.J.) are an exemplary particulate precursor of chlorine dioxide.
  • [0061]
    By “solid body” is meant a solid shape, typically a porous solid shape, or a tablet comprising a mixture of granular particulate ingredients wherein the size of the particulate ingredients is substantially smaller than the size of the solid body; by “substantially smaller” is meant at least 50% of the particles have a particle size at least one order of magnitude, and preferably at least two orders of magnitude, smaller than the size of solid body.
  • [0062]
    By “oxidizing agent” is meant any material that attracts electrons, thereby oxidizing another atom or molecule and thereby undergoing reduction. Exemplary oxidizing agents include chlorine dioxide and peroxides, such as hydrogen peroxide.
  • [0063]
    A “matrix,” as used herein, is a material that functions as a protective carrier of chlorine dioxide-generating components. A matrix is typically a continuous solid or fluid phase in the materials that can participate in a reaction to form chlorine dioxide are suspended or otherwise contained. The matrix can provide physical shape for the material. If sufficiently hydrophobic, a matrix may protect the materials within from contact with moisture. If sufficiently rigid, a matrix may be formed into a structural member. If sufficiently fluid, a matrix may function as a vehicle to transport the material within the matrix. If sufficiently adhesive, the matrix can provide a means to adhere the material to an inclined or vertical, or horizontal downward surface. A fluid matrix may be a liquid such that it flows immediately upon application of a shear stress, or it may require that a yield stress threshold be exceeded to cause flow. In some embodiments, the matrix is either a fluid, or capable of becoming fluid (e.g., upon heating) such that other components may be combined with and into the matrix (e.g., to initiate reaction to form chlorine dioxide). In other embodiments, the matrix is a continuous solid; chlorine dioxide generation can be initiated by, for instance, penetration of water or water vapor, or by light activation of an energy-activatable catalyst.
  • [0064]
    By “film” is meant a layer of a material having two dimensions substantially larger than the third dimension. A film may be a liquid or a solid material. For some materials, a liquid film can be converted into a solid film by curing, for instance, by evaporation, heating, drying and/or cross-linking.
  • [0065]
    As used herein, a “chlorine dioxide source” refers to one of chlorine dioxide, chlorine dioxide-generating components, or a combination of thereof. Unless otherwise indicated or evident from context, preferences indicated above and herein apply to the entirety of the embodiments discussed herein.
  • DESCRIPTION
  • [0066]
    Chlorine dioxide has well-documented potent biocidal activity. Disadvantageously, chlorine dioxide-containing compositions of the prior art can be cytotoxic and irritating to soft tissue and damaging to hard tissues. The cytotoxicity of chlorine dioxide-containing compositions results predominantly from the presence of oxy-chlorine anions, and not from the presence of chlorine, which can be a product of chlorine dioxide decomposition. By substantially preventing or inhibiting oxy-chlorine anions present in a chlorine-dioxide containing composition from contacting cells and tissues such as non-oral biological tissues that are targeted for treatment, tissue damage can be measurably reduced or minimized.
  • [0067]
    I. Non-Oral Tissue Infections
  • [0068]
    A. Non-Oral Mucosal
  • [0069]
    Methods are provided herein for the alleviation of a non-oral mucosal tissue infection by administering a chlorine dioxide composition in a non-cytotoxic and/or non-irritating manner. The method described herein can be used for alleviating any infection of non-oral mucosal tissue. In particular, the method can be used for any non-oral mucosal tissue infection, wherein the tissue can be topically contacted with a composition. Non-oral mucosal tissues include, but are not limited to, vaginal mucosa, nasal and sinus mucosa, conjunctiva mucosa, genital mucosa such as glans penis, glans clitoridis, the inside of the prepuce (foreskin) and the clitoral hood, urinary mucosa such as the urethral mucosa, and anal mucosa. Infections of non-oral mucosal tissue include, but are not limited to, vaginitis, sinusitis, urinary tract infections and urethritis. Non-oral mucosal tissue targeted for treatment may be substantially intact or may have one or more incisions, lacerations or other tissue-penetrating openings.
  • [0070]
    The method can be practiced therapeutically or prophylactically. Thus, the method can be practiced on a subject who exhibits signs of a non-oral mucosal tissue pathology for the purpose of diminishing or eliminating those signs. The method can also be practiced on a subject who does not exhibit signs of a non-oral mucosal tissue infection, is at risk for developing a non-oral mucosal tissue infection, or exhibits only early signs of a non-oral mucosal tissue infection for the purpose of decreasing the risk of developing pathology associated with the non-oral mucosal tissue.
  • [0071]
    Vaginitis refers to inflammation of vaginal mucosal tissue and can arise from bacterial infection, yeast infection and other pathogen infection of the vaginal mucosa. Pathogens that can cause vaginitis include Candida albicans, Gardnerella, Streptococcus spp. and Trichomonas vaginalis. Other pathogens that can cause vaginitis include Herpes, Campylobacter, Gonorrhea, Chlamydia, and Mycoplasma. Prior art prophylactic and therapeutic treatments for vaginitis include: oral or topical antibiotics, oral or topical antifungals and topical steroids. Antimicrobial agents currently used in the treatment of vaginitis include, but are not limited to, neomycin, ribaximin, clindamycin, metronidazole, polymixin B, proguanil, econazole, and fluconazole. Other therapeutic agents for vaginitis include steroids, such as estrogen. Risk factors for vaginitis include sexual activity, diabetes, pregnancy, immunosuppression, contraceptive device use, recent course of antiobiotics, douching, pelvic inflammatory disease and hormone replacement therapy.
  • [0072]
    Sinusitis refers to a sinus mucosal infection, which ranges from acute infection to chronic infection. The common causative pathogens of acute sinusitis are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Fungal infections are seen as causes for acute sinusitis in patients with diabetes or immune deficiencies, such as AIDS patients and immunosuppressed patients. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are also involved in chronic sinusitis, which can further feature involvement of Staphylococcus aureus and anaerobes. Prior art prophylactic and therapeutic treatments for sinusitis include: analgesics, oral antibiotics, nasal irrigation, steam inhalation, mucolytics, oral leukotrienes, oral decongestants and antihistamines. In some extreme cases of chronic sinusitis, surgery can be required to provide relief from the symptoms. Antimicrobial agents currently used in the treatment of sinusitis include, but are not limited to, gatifloxacin, clindamycin, gentiamicin, ceftazidime, an aminoglycoside such as tobramyin and streptomycin, amphotericin B, itraconazole, ketoconazole, miconazole and nystatin. Risk factors for sinusitis include nasal passage abnormality, immune system disorder, hay fever, or allergic condition, asthma, regular exposure to pollutants, use of mechanical ventilator and oral or IV steroid treatment.
  • [0073]
    Urethritis is an infection-induced inflammation of the urethra. The causative pathogens for urethritis include Neisseria gonorrhoeae, Chlamydia, herpes simplex virus, cytomegalovirus, Trichomonas and Escherichia coli. Treatment for urethritis commonly includes oral antibiotics or antivirals. Risk factors for urethritis include urinary tract infection, multiple sexual partners, history of STDs, being female, use of catheters, and use of vaginal creams, foams, and jellies.
  • [0074]
    The causative pathogens for urinary tract infections include Escherichia coli, Klebsiella, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus, saprophyticus and Staphylococcus aureus. Urinary tract infections are commonly treated using oral antibiotics. Risk factors for a urinary tract infection include sexual activity, indwelling bladder catheters, duration of catheterization, and being female.
  • [0075]
    Pink eye (conjunctivitis) is an inflammation or infection of the transparent membrane (conjunctival mucosa) that lines the eyelid and part of the eyeball. Viral conjunctivitis is commonly caused by an adenovirus. Staphylococci and Streptococci are the common bacteria underlying bacterial conjunctivitis. Viral conjunctivitis and bacterial conjunctivitis may affect one or both eyes. Risk factors for bacterial or viral conjunctivitis include having a cold, exposure to someone infected with the viral or bacterial form of conjunctivitis, and wearing of extended-wear contact lenses. Current treatment for bacterial conjunctivitis is topical antibiotic in the form of eyedrops or an ointment. There is no treatment for viral conjunctivitis; it must simply run its course.
  • [0076]
    Vaginitis, sinusitis, urethritis, urinary tract and conjunctivitis infections can manifest as a biofilm. Biofilms can be particularly difficult to disrupt, and therefore are often found in treatment-resistant forms of these mucosal tissue infections. Advantageously, chlorine dioxide is highly efficacious at disrupting, penetrating and/or otherwise inactivating biofilms. Use of chlorine dioxide alone or in combination with an antimicrobial can be efficacious in alleviating vaginitis, sinusitis, urethritis, urinary tract infections or other non-oral mucosal tissue infections.
  • [0077]
    B. Non-Oral Dermal or Hard Tissue Treatment
  • [0078]
    Methods are also provided herein for the alleviation of a non-oral dermal or hard tissue infection by administering a chlorine dioxide composition in a non-cytotoxic and/or non-irritating manner. The method described herein can be used for alleviating any infection of non-oral dermal or hard tissue. Non-oral dermal tissues include uvea, epidermal tissue, dermal tissue, and subcutaneous tissue (also called hypodermis tissue). Infections of non-oral dermal tissue include, but are not limited to, acne, common warts, tinea pedia, tinea cruris and tinea corpis. Non-oral hard tissue includes toe nails, fingernails and hard keratinized tissues. An exemplary hard biological tissue infection of nails includes tinea unguium. Non-oral dermal or hard tissue targeted for treatment may be substantially intact or may have one or more incisions, lacerations or other tissue-penetrating openings.
  • [0079]
    Representative non-oral dermal or hard tissue infections are described below. The claimed method is not intended, however, to be limited to treating only these infections. In particular, the method can be used for any non-oral dermal or hard tissue infection, wherein the tissue can be topically contacted with a composition.
  • [0080]
    Uveitis is swelling and irritation of the uvea, the middle layer of the eye. The uvea consists of a pigmented, highly vascular loose fibrous tissue. Most cases are anterior uveitis, which involves inflammation in the front part of the eye. Common treatment includes topical steroid in the form of eyedrops or ointments, sometime with a cycloplegic-mydriatic drug. Infectious uveitis is commonly caused by herpes simplex virus, varicella-zoster virus, and Cytomegalovirus (CMV). Risk factors for uveitis include Cytomegalovirus retinitis and Herpes Gingivostomatitis.
  • [0081]
    Acne vulgaris (acne) develops as a result of blockages in hair follicles in the skin. Inflammation can be caused by the bacteria Propionibacterium acnes, leading to inflammatory lesions in the dermis. Common treatments for acne include topical bacteriocidals such as benzoyl peroxide, topical antibiotics such as erythromycin, clindamycin and tetracycline, topical retinoids such as tretinoin and adapalene, and oral antibiotics.
  • [0082]
    Common warts are skin growths caused by human papillomavirus (HPV). Warts are commonly treated with tropical salicylic acid, freezing them with, e.g., liquid nitrogen, or burning with an electric needle.
  • [0083]
    Ringworm (also called tinea corpis) refers to a superficial fungal infection of dermal tissue of the body or the face. Ringworm is a dermatophyte infection. Dermatophytes are a group of related fungi that infect and survive on dead keratin, the top layer of the epidermis. The three most common fungi associated with ringworm are Trichophyton rubrum, Microsporum canis, and Trichophyton mentagrophytes. Treatment of ringworm is usually topical antifungals such as terbinafine, miconazole, clotrimazole, and ketoconazole. Risk factors include contact with ringworm lesions, contact with animals, soil, and plants, prolonged presence of warm, moist environment, and lack of good hygiene. Dermatophytes are also causative agents for tinea pedis (athlete's foot). The most common fungi associated with tinea pedis are Trichophyton rubrum, and Trichophyton mentagrophytes. Treatment is commonly topical antifungals, such as clotrimazole and tolnaftate.
  • [0084]
    Tinea cruris or “jock itch” is a fungal infection of the skin in the groin. The fungus that most commonly causes tinea cruris is called Trichophyton rubrum. Tinea cruris is typically treated with topical antifungal creams or ointments since the fungus affects the top layer of skin. Useful antifungals include tolnaftate, clotrimazole, and miconazole. A topical steroid can be used if the rash is itchy.
  • [0085]
    Fungal infection of finger and/or toe nails is called onychomycosis or tinea unguium. The fungal organism responsible for most fungal nail infections is Trichophyton rubrum. Treatment usually is several months of oral antifungal medication. Risk factors for tinea unguium include tight footwear that keeps toes warm and moist, repeated minor injury to the hyponychium, communal showers, having diabetes, and being immunocompromised.
  • [0086]
    II. Non-Cytotoxic and/or Non-Irritating Compositions
  • [0087]
    In one aspect, the method comprises administering a substantially non-cytotoxic and/or non-irritating composition comprising chlorine dioxide. In an embodiment, the composition consists essentially of chlorine dioxide as the active pharmaceutical ingredient (API). In other embodiments, the composition comprises chlorine dioxide and at least one other API, such as an antibiotic or antifungal. The composition optionally comprises one or more other components. Such components include, but are not limited to, coloring agents and fragrances. Other optional components include: antimicrobial agents such as antibacterial agents and antifungal agents, enzymes, malodor controlling agents, and the like. Exemplary antimicrobial agents for vaginitis include, but are not limited to, neomycin, ribaximin, clindamycin, metronidazole, polymixin B, proguanil, econazole, and fluconazole. Other therapeutic agents for vaginitis include steroids, such as estrogen. Exemplary antimicrobial agents for sinusitis include, but are not limited to, gatifloxacin, elindamycin, gentiamicin, ceftazidime, an aminoglycoside such as tobramyin and streptomycin, amphotericin B, itraconazole, ketoconazole, miconazole and nystatin. Other therapeutic agents useful for treating acne include erythromycin, clindamycin and tetracyclin, tretinoin and adapalene. Uveitis treatment can further include topical steroid and optionally a cyclplegic-mydriatic drug. Treatment for common warts can further comprise topica salicylic acid, freezing or burning. Other therapeutic agents useful for tinea corpus include clotrimazole and tolnaftate. Tolnaftate, clotimazole and miconazole are exemplary therapeutic agents for tinea cruris.
  • [0088]
    In some embodiments, all optional components are relatively resistant to oxidation by chlorine dioxide, since oxidation of composition components by chlorine dioxide will reduce the available chlorine dioxide for oxidation for its intended function. “Relatively resistant” means that in the time scale of preparing and using the chlorine dioxide-containing composition in an application, the function of the optional component is not unacceptably diminished, and the composition retains an acceptable level of efficacy/potency with respect to the chlorine dioxide and remains substantially non-cytotoxic. In some embodiments, the composition can remain substantially non-irritating. Guidance regarding identifying resistant components is provided in commonly-assigned U.S. patent application entitled “Additives for Chlorine Dioxide-Containing Compositions,” serial number (tbd), filed (tbd).
  • [0089]
    For compositions comprising an oxidizing agent consisting of chlorine dioxide, cytotoxicity results predominantly from the presence of oxy-chlorine anions, absent other constituents that contribute to cytotoxicity. Accordingly, in exemplary embodiments, a composition comprising chlorine dioxide that comprises zero milligram (mg) oxy-chlorine anion per gram composition to no more than about 0.25 mg oxy-chlorine anion per gram composition, from zero to about 0.24, 0.23, 0.22, 0.21, or 0.20 mg oxy-chlorine anion per gram composition, from zero to about 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, or 0.10 mg oxy-chlorine anion per gram composition and from zero to 0.09, 0.08, 0.07, 0.06, 0.05 or 0.04 mg oxy-chlorine anion per gram composition, absent other constituents that contribute to cytotoxicity, is substantially non-cytotoxic.
  • [0090]
    Soft tissue irritation can result from highly reactive oxygen species and/or extremes of pH, both acidic and basic. To minimize soft tissue irritation by the chlorine dioxide containing composition, the substantially non-cytotoxic composition has a pH of at least 3.5. In exemplary embodiments, the composition has a pH of at least 5, or, greater than about 6. In certain embodiments, the pH ranges from about 4.5 to about 11, from about 5 to about 9, or from greater than about 6 and less than about 8. In one embodiment, the pH is about 6.5 to about 7.5. The concentration of oxy-chlorine anions is not believed to be a primary contributor to soft tissue irritation.
  • [0091]
    Methods of preparing non-cytotoxic and/or non-irritating compositions comprising chlorine dioxide are described in commonly-assigned U.S. application Ser. Nos. 12/502,761 and 12/502,781, filed Jul. 14, 2009, entitled “Tooth Whitening Compositions and Methods,” and U.S. application Ser. Nos. 12/502,326 and 12/502,356, filed Jul. 14, 2009, entitled “Non-Cytotoxic Chlorine Dioxide Fluids,” each of which is incorporated herein by reference in its entirety.
  • [0092]
    In an embodiment, a substantially non-cytotoxic composition comprising chlorine dioxide can be prepared using a substantially pure chlorine dioxide solution having a neutral pH. In some embodiments, the substantially pure chlorine dioxide solution has a pH from about 5 to about 9, or from about 6.5 to about 7.5.
  • [0093]
    Substantially pure chlorine dioxide may be prepared by preparing a chlorine dioxide solution using any known method, then bubbling a gas (e.g., air) through that solution (sparging) and into a second container of deionized water, to prepare the product solution of substantially pure chlorine dioxide. Only ClO2 and possibly some water vapor is transferred from the source solution to the product solution. All the salt ingredients and acid remain behind in the source solution. Thus, there are no oxy-chlorine anions in the substantially pure product solution. One method of preparing chlorine dioxide comprises combining an aqueous solution of sodium chlorite with a mineral acid to reduce the solution pH to below about 3.5 and allowing the solution to react for a sufficient time, e.g., about 30 minutes, to generate chlorine dioxide. The resulting solution is then sparged as described above to prepare the product solution of substantially pure chlorine dioxide.
  • [0094]
    While the substantially pure chlorine dioxide may undergo a degree of decomposition, the rate is relatively slow. By keeping the solution capped and protected from ultraviolet exposure, the decomposition rate can be slowed to a rate of about 5% to about 25% reduction in chlorine dioxide in 7 days. Substantially pure chlorine dioxide may also be prepared using a pervaporation technique, such as that disclosed in U.S. Pat. No. 4,683,039. In addition, a metal chlorite and an acid source can be reacted in solution to yield high conversion to chlorine dioxide and produce a greater than 2000 ppm chlorine dioxide solution. The concentrated solution can then be buffered to a neutral pH. Similarly, a chlorine dioxide solution can be prepared using the composition described in U.S. Pat. No. 5,399,288, which yields a high concentration chlorine dioxide solution at acidic pH. The concentrated solution can then be buffered to achieve a substantially neutral pH to prepare a substantially pure chlorine dioxide solution.
  • [0095]
    Another source of a substantially pure chlorine dioxide solution is chlorine dioxide is prepared using an ASEPTROL (BASF Corp., Florham Park, N.J.) material, which are described in commonly-assigned U.S. Pat. Nos. 6,432,322 and 6,699,404. These patents disclose substantially anhydrous solid bodies comprising particulate components for preparing highly-converted solutions of chlorine dioxide when added to water. The particulate components in the solid bodies comprise a metal chlorite such as sodium chlorite, an acid source such as sodium bisulfate and optionally a source of free halogen such as the sodium salt of dichloroisocyanuric acid or a hydrate thereof (collectively referred to herein as “NaDCCA”). Chlorine dioxide is generated when an ASEPTROL material is contacted with water or an aqueous medium. ASEPTROL material can be made to have an extremely high conversion rate in an aqueous solution, as described in U.S. Pat. Nos. 6,432,322 and 6,699,404, resulting in high concentrations of chlorine dioxide and low concentrations of oxy-chlorine anion. Thus, ASEPTROL materials provide a way to efficiently generate chlorine dioxide at substantially neutral pH, thus avoiding problems existing with earlier, acidic chlorine dioxide-based products.
  • [0096]
    In some embodiments, the composition further comprises a thickener component which renders the composition a thickened aqueous fluid. To prepare a thickened aqueous composition comprising chlorine dioxide that is substantially non-cytotoxic and, in some embodiments, non-irritating, the substantially pure chlorine dioxide solution can be combined with a thickener component and an aqueous medium.
  • [0097]
    The aqueous thickened fluid composition used in practicing the method may comprise any thickener component in an aqueous medium, wherein the thickened fluid composition is non-cytotoxic and, in some embodiments, non-irritating to soft tissues. In addition, in exemplary embodiments, the thickener is not adversely affected by the chlorine dioxide on the time scale of composition preparation and use in treatment. Many thickener agents are known in the art, including, but not limited to carbomers (e.g., CARBOPOL, thickeners, Lubrizol Corp., Wickliffe, Ohio), carboxymethylcellulose (CMC), ethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose (HPMC), natural smectite clays (e.g., VEEGEM, R.T. Vanderbilt Co., Norwalk, Conn.), synthetic clays (e.g., LAPONITE (Southern Clay Products, Gonzales, Tex.), methylcellulose, superabsorbent polymers such as polyacrylates (e.g., LUQUASORB 1010, BASF, Florham Park, N.J.), poloxamers (PLURONIC, BASF, Florham Park, N.J.), polyvinyl alcohol, sodium alginate, tragacanth, and xanthan gum. Such thickening agents may be categorized into four groups: natural hydrocolloids (also referred to as “gum”), semisynthetic hydrocolloids, synthetic hydrocolloids, and clay. Some examples of natural hydrocolloids include acacia, tragacanth, alginic acid, carrageenan, locust bean gum, guar gum, and gelatin. Non-limiting examples of semisynthetic hydrocolloids include methylcellulose and sodium carboxymethylcellulose. Some examples of synthetic hydrocolloids (also referred to as “polymers” including polymers, cross-linked polymers, and copolymers) include polyacrylates, superabsorbent polymers, high molecular weight polyethylene glycols and polypropylene glycols, polyethylene oxides and CARBOPOL. Non-limiting examples of clay (including swelling clay) include LAPONITE, attapulgite, bentonite, and VEEGUM. In some embodiments, the thickener component is a semisynthetic hydrocolloid. An exemplary thickener component is hydroxypropyl methylcellulose or a carboxymethylcellulose (CMC).
  • [0098]
    In preparing a non-cytotoxic composition, one or more components of a composition may be combined prior to the time of preparation of a composition. Alternatively, all components of a composition may be prepared at the time of use. For either non-cytotoxic solutions or non-cytotoxic thickened compositions, optional other components suitable for the intended use of the non-cytotoxic chlorine dioxide solution, as described elsewhere herein, may be included. Chlorine dioxide in solution will decompose over time. To avoid problems arising from such decomposition, including loss of efficacy and generation of chlorite anions, in some embodiments the substantially pure chlorine dioxide solution is prepared immediately before its dilution or its combination with a thickener component and an aqueous medium.
  • [0099]
    In addition, in some embodiments, a thickened composition comprising chlorine dioxide can be prepared immediately before its use in a method of alleviating a non-oral tissue infection. “Immediately before” as used herein refers to a period no greater than that which would result in diminished efficacy or evidence of cytotoxicity. Generally, “immediately before” is less than about 14 days, and preferably no greater than about 24 hours and more preferably no greater than about 2 hours. In exemplary embodiments, the substantially pure chlorine dioxide solution is prepared within about 8 hours of the preparation of the composition. Precautions are also taken to avoid exposing the chlorine dioxide solution or the prepared composition to strong ultraviolet light or elevated temperature (e.g., temperature greater than ambient temperature, about 25° C.).
  • [0100]
    A substantially non-cytotoxic thickened composition comprising chlorine dioxide may also be prepared using a particulate precursor of ClO2 and an aqueous thickened fluid composition. Chlorine-dioxide-forming components include metal chlorites, metal chlorates, an acid source, and an optional halogen source. The particulate precursor may comprise one of these or any combination of these. An exemplary particulate precursor is an ASEPTROL product. An exemplary ASEPTROL product is ASEPTROL S-Tab2. ASEPTROL S-Tab2 has the following chemical composition by weight (%): NaClO2 (7%); NaHSO4 (12%); NaDCC (1%); NaCl (40%); MgCl2(40%). Example 4 of U.S. Pat. No. 6,432,322 describes an exemplary manufacture process of S-Tab2. Granules can be produced, either by comminuting pressed S-Tab2 tablets, or by dry roller compaction of the non-pressed powder of the S-Tab2 components, followed by breakup of the resultant compacted ribbon or briquettes, and then screening to obtain the desired size granule. Upon exposure to water or an aqueous thickened fluid, chlorine dioxide is generated from the ASEPTROL granules. In one embodiment, a substantially non-cytotoxic composition comprising chlorine dioxide is prepared by combining -40 mesh granules with an aqueous thickened fluid. In one embodiment, the thickener component of the thickened fluid is carboxymethylcellulose or HPMC. The skilled artisan will recognize that chlorine dioxide production in the thickened fluid composition prepared using a particulate precursor of ClO2, while rapid, is not instantaneous. Thus, sufficient time for the generation of chlorine dioxide, and corresponding consumption of chlorite anion, is necessary to obtain a substantially non-cytotoxic thickened fluid composition. The skilled artisan can readily determine what length of time is sufficient, in view of the teachings in this disclosure and the knowledge of the art.
  • [0101]
    In some embodiments, the aqueous thickened fluid is prepared sufficiently in advance of combining with the ASEPTROL granules to enable the complete hydration of the thickener component. In one embodiment, the thickened fluid composition is formed by adding high viscosity NaCMC powder to distilled water. The NaCMC is allowed to hydrate for at least 8 hours, and then the mixture is stirred to homogenize it. A substantially non-cytotoxic composition is then prepared by mixing the sized ASEPTROL granules with the NaCMC thickened fluid. Contact with the aqueous medium in the hydrated NaCMC mixture activates the ASEPTROL granules and chlorine dioxide is generated.
  • [0102]
    In another embodiment, the substantially non-cytotoxic thickened fluid composition may also be formed at the site of intended use. For instance, a body fluid such as mucus of mucosal tissue, or humid vapor such as exhaled air, may serve as the aqueous medium to activate particulate precursors of chlorine dioxide, such as ASEPTROL granules. In one embodiment, the mixture may be particulates in the form of a powder and mixed in a layer of thickener component thereby forming a thickened matrix. The matrix may be applied directly to a non-oral mucosa tissue, wherein exposure to moisture present in the tissue activates production of chlorine dioxide to form a substantially non-cytotoxic composition. Alternatively, the matrix may be moistened immediately prior to use and then applied to any non-oral tissue.
  • [0103]
    III. Devices and Compositions for Non-Cytotoxic Administration
  • [0104]
    In another aspect, the method is practiced with a device or composition that delivers a substantially oxy-chlorine anion free chlorine dioxide composition to the non-oral tissue. Such devices, compositions, systems and methods for administration of a composition comprising chlorine dioxide and oxy-chlorine anions in a way that the chlorine dioxide reaches the target tissue in an efficacious amount, but the oxy-chlorine anions are substantially inhibited from irritating target tissue or peripheral tissue not targeted for treatment, are described in commonly-assigned U.S. application Ser. Nos. 12/502,845, 12/502,858 and 12/502,877, filed Jul. 14, 2009, entitled “Methods, Systems and Devices for Administration of Chlorine Dioxide.” Generally, the method comprises providing a chlorine dioxide source that includes either chlorine dioxide itself or chlorine dioxide-generating components, and further includes the oxy-chlorine anions that cause cytotoxicity to tissues; and further providing an oxy-chlorine anion barrier that substantially prohibits passage therethrough of the oxy-chlorine anions and permits passage therethrough of chlorine dioxide. In some embodiments, the oxy-chlorine anion barrier can also substantially inhibit the passage therethrough of protons. The chlorine dioxide source is applied to the tissue with the oxy-chlorine anion barrier interposed between the chlorine dioxide source and the tissue, thus preventing or substantially minimizing the oxy-chlorine anion from reaching the tissue, thereby enabling delivery of a substantially oxy-chlorine anion free chlorine dioxide composition to the tissue.
  • [0105]
    The chlorine dioxide source may comprise any chlorine dioxide-containing composition or ingredients capable of forming chlorine dioxide in situ. In exemplary embodiments, the ingredients present in the chlorine dioxide source are compatible with the oxy-chlorine anion barrier during the practice of the method, as well as any pre-use period during which the ingredients are in contact with the barrier. By “compatible” is meant the ingredients do not adversely affect to an unacceptable degree the concentration of chlorine dioxide in the chlorine dioxide source, the inhibition of passage of oxy-chlorine anions, or the permitted passage of chlorine dioxide by the barrier.
  • [0106]
    The barrier may be in the form of a layer between the chlorine dioxide source and the infected non-oral mucosa tissue. In one aspect, the oxy-chlorine barrier, without the chlorine dioxide source, is applied to the tissue first. The chlorine dioxide source is then applied to the barrier layer. In other embodiments, the chlorine dioxide source is applied to the barrier first, and the combination is then applied to the tissue, wherein the barrier layer contacts the tissue. In embodiments where the chlorine dioxide source comprises chlorine dioxide-generating components, the generation of chlorine dioxide may be activated before, during, and/or after application of the barrier (with or without the chlorine dioxide source) to the non-oral tissue.
  • [0107]
    In another embodiment, the infected tissue may be contacted with a chlorine dioxide source containing a substantially non-cytotoxic and substantially non-irritating amount of oxy-chlorine anions while a second chlorine dioxide source may be located on the side of a barrier opposite the non-oral tissue such that additional chlorine dioxide from the second source may pass through the barrier to contact the non-oral tissue but passage through the barrier of oxy-chlorine anions in the second source is inhibited.
  • [0108]
    In another embodiment, the chlorine dioxide source may be dispersed in a matrix comprising one or more barrier substances, such that the oxy-chlorine anions are sequestered away from the tissue, while the chlorine dioxide passes through the barrier substance, if necessary, and the matrix to contact the non-oral tissue. In this embodiment, the matrix is applied to the tissue directly or to an optional intervening tissue-contacting layer. In one aspect, the matrix itself is the barrier substance. Exemplary matrix materials that may also function as the barrier include waxes such as paraffin wax, polyethylene, petrolatum, polysiloxanes, polyvinyl alcohol, ethylene-vinyl acetate (EVA), polyurethanes, mixtures thereof and the like. In another aspect, the chlorine dioxide source is coated or encapsulated by the barrier substance. Exemplary barrier substances include polyurethane, polypropylene, polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidene dichloride, combination of polydimethylsiloxane and polytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane, polyethylene oxide, polyacrylates, mineral oil, paraffin wax, polyisobutylene, polybutene and combinations thereof. Exemplary barrier substances also comprise compounds that bind to oxy-chlorine anions with high affinity and that impede or stop anion migration or diffusion such that a substantially oxy-chlorine anion free chlorine dioxide composition is delivered to a tissue. The compound may form an insoluble precipitate with the oxy-chlorine anion, thereby impeding or stopping diffusion. Alternatively, the compound is immobilized on a substance or material, thereby impeding diffusion or migration. The compound may be cationic, such as ammonium, pyridinium, imidazolium, phosphonium and sulfonium and other positively charged compounds that may be part of the matrix. Optionally, the compound can be immobilized on an oxy-chlorine anion barrier material, to the matrix or on the optional backing layer.
  • [0109]
    Various materials and membranes can be used as an oxy-chlorine anion barrier. The barrier can be in any form, and is typically either a fluid or a solid.
  • [0110]
    In some embodiments, the oxy-chlorine anion barrier is a fluid, such a petrolatum. In this embodiment, the fluid can be applied to the tissue first, or to an intervening tissue-contacting layer, to form the barrier as a layer and then chlorine dioxide source subsequently applied to the fluid barrier layer. The chlorine dioxide source can be applied as a particulate or can be encompassed in a material to form a film.
  • [0111]
    In some embodiments, the oxy-chlorine anion barrier is a nonporous membrane. The membrane can be any thickness and can be a single layer or plural layers, provided the membrane remains permeable to chlorine dioxide and substantially non-permeable to oxy-chlorine anions. An exemplary nonporous material is a polyurethane membrane. In some embodiments, the polyurethane membrane is from about 30 to about 100 microns, such as from about 38 to about 76 microns thick. Exemplary polyurethane membranes commercially available include CoTran™ 9701 (3M™ Drug Delivery Systems, St. Paul, Minn.) and ELASTOLLAN (BASF Corp., Wyandotte, Mich.). ELASTOLLAN products are polyether-based thermoplastic polyurethane. A specific example of ELASTOLLAN is ELASTOLLAN 1185A10.
  • [0112]
    In some embodiments, the oxy-chlorine anion barrier is a microporous membrane permeable to chlorine dioxide and substantially non-permeable to oxy-chlorine anions. The microporous membrane can be any thickness and can be a single layer or plural layers, provided the membrane remains permeable to chlorine dioxide and substantially non-permeable to oxy-chlorine anions. In one example, the microporous membrane can comprise thermo-mechanically expanded polytetrafluoroethylene (e.g., Goretex®) or polyvinylidenedifluoride (PVDF). See, for instance, U.S. Pat. No. 4,683,039. The procedure for formation of an expanded polytetrafluoroethylene is described in U.S. Pat. No. 3,953,566. An exemplary polytetrafluoroethylene (PTFE) membrane, interpenetrating polymer network (IPN) of polydimethylsiloxane and PTFE, is described in U.S. Pat. Nos. 4,832,009, 4,945,125, and 5,980,923. A commercially-available product of this type, Silon-IPN (Bio Med Sciences Inc., Allentown, Pa.), is a single layer and is available in thicknesses between 10 to 750 microns. In one embodiment, the microporous membrane is an IPN of silicone and PTFE having a thickness of about 16 microns. In another example, the membrane is microporous polypropylene film. An exemplary microporous polypropylene film is the material commercially-available from CHEMPLEX Industries (Palm City, Fla.), which is a single layer membrane about 25 microns thick, having a porosity of 55% and a pore size of about 0.21 microns X 0.05 microns. The microporous membrane material can be provided as a composite with supporting materials to provide the structural strength required for use. In some embodiments, the membrane is hydrophobic, wherein the hydrophobic nature of the membrane prevents both an aqueous reaction medium and an aqueous recipient medium from passing through the membrane, while allowing molecular diffusion of chlorine dioxide. Features to consider for the materials used for such a barrier include: hydrophobicity of the microporous material, pore size, thickness, and chemical stability towards the attack of chlorine dioxide, chlorine, chlorite, chlorate, chloride, acid, and base.
  • [0113]
    Various other materials and membranes can be used to form the barrier. For example, the barrier can comprise a microperforated polyolefin membrane; a polystyrene film that is substantially permeable to chlorine dioxide and substantially impermeable to ionic components of the composition; a pervaporation membrane formed from a polymeric material having a relatively open polymeric structure; a cellulose acetate film composite; a polysiloxane or polyurethane material; or a wax. Of course, for contact with soft mucosal tissues, the microporous barrier should be substantially non-irritating and substantially non-cytotoxic, particularly in the time scale of typical use of the device and composition.
  • [0114]
    The pore sizes in the barrier may vary widely, depending on the desired flow rate of the chlorine dioxide through the barrier. The pores should not be so small as to prevent chlorine dioxide gas flow therethrough but also should not be so large that liquid flow is permitted. In one embodiment, the pore size is about 0.21 microns×0.05 microns. The quantity and size of the pores of the barrier can vary widely, depending upon the temperature of the application, the hydrophobicity of the barrier material, the thickness of the barrier material, and also depending upon the desired flow rate of chlorine dioxide through the barrier. Fewer and smaller pores are needed for a given chlorine dioxide flow rate at higher temperature relative to lower temperature, as the vapor pressure of chlorine dioxide from the chlorine dioxide source is higher at the higher temperature. More and larger pores can be used with a highly hydrophobic barrier material, such as PTFE, compared to a less hydrophobic material, such as polyurethane, since the tendency for an aqueous chlorine dioxide source to flow through pores of a highly hydrophobic barrier is lower than it is through the pores of a less hydrophobic barrier. Considerations of barrier strength also dictate the porosity chosen. Generally, the barrier porosity varies from about 1 to about 98%, from about 25 to about 98%, or from about 50% to about 98%.
  • [0115]
    Also provided are systems, compositions, and devices useful for practicing the method. In one aspect, a system is provided for delivering a substantially oxy-chlorine anion free chlorine dioxide to a tissue. A typical system comprises a chlorine dioxide source that includes chlorine dioxide or chlorine dioxide-generating components, and oxy-chlorine anions as a first system component; and an oxy-chlorine anion barrier as a second system component, the barrier to be interposed between the chlorine dioxide source and the tissue, wherein the barrier substantially prohibits passage of the oxy-chlorine anions and permits passage of the substantially oxy-chlorine anion free chlorine dioxide composition, thereby enabling delivery of the substantially oxy-chlorine anion free chlorine dioxide to the tissue.
  • [0116]
    Compositions and devices are also provided to implement the methods and systems described above. Thus, one aspect features a composition for delivering a substantially oxy-chlorine anion free chlorine dioxide composition to a tissue. The composition comprises a matrix that includes a chlorine dioxide source comprising chlorine dioxide or chlorine dioxide-generating components, as well as oxy-chlorine anions, and at least one barrier substance that substantially prohibits passage of the oxy-chlorine anions but permits passage of the chlorine dioxide, thereby enabling delivery of the substantially oxy-chlorine anion free chlorine dioxide to the tissue. In one embodiment, the matrix can be a aqueous matrix, or a hydrophobic or anhydrous matrix such as petrolatum. In some embodiments, the matrix itself is the barrier substance. For instance, the matrix can be nonpolar or weakly polar for inhibiting diffusion of oxy-chlorine anions while permitting diffusion of chlorine dioxide.
  • [0117]
    The bulk of the matrix can be the barrier substance, or the matrix can comprise a sufficient amount of the barrier substance to carry out the selective delivery of the chlorine dioxide to the non-oral tissue. For instance, the matrix can comprise a polymeric material in which reactants or precursors for the formation of chlorine dioxide are embedded or dispersed, wherein the polymeric material is permeable to chlorine dioxide but substantially impermeable to oxy-chlorine anions. See, e.g., U.S. Pat. No. 7,273,567, which describes a composition comprising reactants or precursors and an energy-activatable catalyst embedded in polyethylene, which are activated to produce chlorine dioxide by exposure to light waves, and more particularly, by exposure to ultraviolet radiation.
  • [0118]
    In some embodiments, the matrix can be an adhesive matrix, such as an adhesive polymer matrix. Polymers useful in such adhesive matrices are substantially permeable to chlorine dioxide and are in exemplary embodiments relatively resistant to oxidation by chlorine dioxide so as to limit possible degradation of the polymer and possible consequential change in adhesion. Adhesive polymers are known in the art. See, e.g., U.S. Pat. No. 7,384,650.
  • [0119]
    The composition can be applied to the tissue, e.g., by spreading it on or otherwise applying it to the tissue, or by incorporating it into a delivery device, such as described below.
  • [0120]
    Various devices are envisioned for delivering a composition comprising chlorine dioxide and oxy-chlorine anions to target non-oral tissue such that an efficacious amount of chlorine dioxide contacts the target tissue, while the oxy-chlorine anions are substantially inhibited or prevented from contacting the tissue. The substantial inhibition reduces, minimizes or precludes damage or irritation to, the target tissue and any surrounding or peripheral tissues.
  • [0121]
    The devices are typically directionally oriented to comprise a layer distal to the tissue to be contacted and a layer proximal to the non-oral tissue to be contacted. The distal layer is also referred to herein as a backing layer. The devices may further comprise a release liner affixed to the tissue-contacting layer, to be removed prior to applying the device to the tissue. In one embodiment, the device comprises a layer comprising the chlorine dioxide source and a barrier layer. In another embodiment, the device comprises (1) a backing layer, (2) a layer comprising the chlorine dioxide source, and (3) a barrier layer. The barrier layer can be adapted to contact the non-oral tissue, or another tissue-contacting layer may be present between the barrier layer and the tissue. The barrier layer or the additional tissue-contacting layer can be adhesive. The optional additional tissue-contacting layer is also substantially permeable to chlorine dioxide. In some embodiments, the barrier layer can be made from a thermo-mechanically expanded polytetrafluoroethylene film. In some embodiments, the chlorine dioxide source is a particulate precursor of chlorine dioxide, such as granules of ASEPTROL.
  • [0122]
    Generally, the backing layer can be made of any suitable material that is substantially impermeable to chlorine dioxide and other components of the chlorine dioxide source. The backing layer can serve as a protective cover for the matrix layer and can also provide a support function. Exemplary materials for the backing layer include films of high and low-density polyethylene, polyvinylidene dichloride (PVDC), polyvinylidene difluoride (PVDF), polypropylene, polyurethane, metal foils and the like.
  • [0123]
    The optional tissue-contacting layer can be any material that is substantially permeable to chlorine dioxide. The optional tissue-contacting layer can be an absorbent material. Non-limiting examples for this layer include cotton or other natural fiber or synthetic fiber fabrics or meshes, foams and mats.
  • [0124]
    In another embodiment, the device comprises a backing layer and a matrix as described above, in which is dispersed the chlorine dioxide source and which comprises at least one barrier substance. The matrix can be adapted for contacting the tissue, or an additional tissue-contacting layer may be present. Either the matrix or the additional tissue-contacting layer can be adhesive. Typically, the matrix is prepared and then coated onto the backing layer.
  • [0125]
    Also contemplated is a device for continuously and/or intermittently providing a chlorine dioxide solution containing oxy-chlorine anions to a specific tissue. The device is an irrigation device described in commonly-assigned U.S. Application No. 61/149,784. The irrigation device can be used with a substantially non-cytotoxic and/or non-irritating chlorine dioxide composition as described elsewhere herein. In another aspect, the irrigation device described in commonly-assigned U.S. Application No. 61/149,784 is modified by the addition of an oxy-chlorine anion barrier. The modification is the addition of an oxy-chlorine anion barrier. Specifically, the device contemplated herein comprises a chamber comprising an oxy-chlorine anion barrier, wherein the device has an inlet port for supplying a chlorine dioxide solution into the chamber and an outlet port for removing chlorine dioxide solution and an opening covered by the oxy-chlorine anion barrier. The chamber is designed to form a tight substantially leak-proof seal with the tissue surrounding an infected area, wherein the opening is proximal to the infected area. The oxy-chlorine anion barrier is interposed between the infected area and the chamber opening. The chlorine dioxide solution containing oxy-chlorine anions is introduced into the chamber, and chlorine dioxide passes through the oxy-chlorine anion barrier covering the opening and thereby contacting the infected area, while the passage of oxy-chlorine anions through the barrier is limited to substantially non-cytotoxic and/or substantially non-irritating levels. This device, like the others described herein, enables the use of highly concentrated chlorine dioxide solutions (e.g., much greater than about 700 ppm) while minimizing or eliminating the cytotoxicity of oxy-chlorine anion typically found in such solutions.
  • [0126]
    Any method in the art for preparing chlorine dioxide may be used as the chlorine dioxide source to make chlorine dioxide in the devices and compositions that deliver a substantially oxy-chlorine anion free chlorine dioxide composition. For instance, there are a number of methods of preparing chlorine dioxide by reacting chlorite ions in water to produce chlorine dioxide gas dissolved in water. The traditional method for preparing chlorine dioxide involves reacting sodium chlorite with gaseous chlorine (Cl2(g)), hypochlorous acid (HOCl), or hydrochloric acid (HCl). However, because the kinetics of chlorine dioxide formation are high order in chlorite anion concentration, chlorine dioxide generation is generally done at high concentration (>1000 ppm), the resulting chlorine dioxide containing solution typically must be diluted for the use concentration of a given application. Chlorine dioxide may also be prepared from chlorate anion by either acidification or a combination of acidification and reduction. Chlorine dioxide can also be produced by reacting chlorite ions with organic acid anhydrides.
  • [0127]
    Chlorine dioxide-generating compositions, which are comprised of materials that will generate chlorine dioxide gas upon contact with water vapor, are known in the art. See, e.g., commonly-assigned U.S. Pat. Nos. 6,077,495; 6,294,108; and 7,220,367. U.S. Pat. No. 6,046,243 discloses composites of chlorite salt dissolved in a hydrophilic material and an acid releasing agent in a hydrophobic material. The composite generates chlorine dioxide upon exposure to moisture. Commonly-assigned U.S. Pat. Publication No. 2006/0024369 discloses a chlorine dioxide-generating composite comprising a chlorine dioxide-generating material integrated into an organic matrix. Chlorine dioxide is generated when the composite is exposed to water vapor or electromagnetic energy. Chlorine dioxide generation from a dry or anhydrous chlorine dioxide-generating composition by activation with a dry polar material is disclosed in commonly-assigned co-pending Application No. 61/153,847. U.S. Pat. No. 7,273,567 describes a method of preparing chlorine dioxide from a composition comprising a source of chlorite anions and an energy-activatable catalyst. Exposure of the composition to the appropriate electromagnetic energy activates the catalyst which in turn catalyzes production of chlorine dioxide gas.
  • [0128]
    Chlorine dioxide solutions can also be produced from solid mixtures, including powders, granules, and solid compacts such as tablets and briquettes, which are comprised of components that will generate chlorine dioxide gas when contacted with liquid water. See, for instance, commonly-assigned U.S. Pat. Nos. 6,432,322; 6,699,404; and 7,182,883; and U.S. Pat. Publication Nos. 2006/0169949 and 2007/0172412. In some embodiments, chlorine dioxide is generated from a composition comprising a particulate precursor of chlorine dioxide. Thus, the chlorine dioxide source comprises or consists essentially of a particulate precursor of chlorine dioxide. The particulate precursor employed can be an ASEPTROL product, such as ASEPTROL S-Tab2 and ASEPTROL S-Tab10. ASEPTROL S-Tab2 has the following chemical composition by weight (%): NaClO2 (7%); NaHSO4 (12%); sodium dichloroisocyanurate dihydrate (NaDCC) (1%); NaCl (40%); MgCl2 (40%). Example 4 of U.S. Pat. No. 6,432,322 describes an exemplary manufacture process of S-Tab2 tablets. ASEPTROL S-Tab10 has the following chemical composition by weight (%): NaClO2 (26%); NaHSO4 (26%); NaDCC (7%); NaCl(20%); MgCl2 (21%). Example 5 of U.S. Pat. No. 6,432,322 describes an exemplary manufacture process of S-Tab 10 tablets.
  • [0129]
    As described elsewhere herein, activation of chlorine dioxide generation can be prior to administration by contact of the chlorine dioxide-generating components with the appropriate agent (e.g., aqueous medium, electromagnetic energy, etc). Alternatively, chlorine dioxide generation initiated in situ, by contact with an aqueous medium, such as mucus.
  • [0130]
    IV. Chlorine Dioxide-Generating Components
  • [0131]
    Chlorine dioxide-generating components refer to at least an oxy-chlorine anion source and an activator of chlorine dioxide generation. In some embodiments, the activator is an acid source. In these embodiments, the components optionally further includes a free halogen source. The free halogen source may be a cationic halogen source, such as chlorine. In other embodiments, the activator is an energy-activatable catalyst. In yet other embodiments, the activator is a dry or anhydrous polar material.
  • [0132]
    Oxy-chlorine anion sources generally include chlorites and chlorates. The oxy-chlorine anion source may be an alkali metal chlorite salt, an alkaline earth metal chlorite salt, an alkali metal chlorate salt, an alkaline earth metal chlorate salt and combinations of such salts. In exemplary embodiments, the oxy-chlorine anion source is a metal chlorite. In some embodiments, the metal chlorite is an alkali metal chlorite, such as sodium chlorite and potassium chlorite. Alkaline earth metal chlorites can also be employed. Examples of alkaline earth metal chlorites include barium chlorite, calcium chlorite, and magnesium chlorite. An exemplary metal chlorite is sodium chlorite.
  • [0133]
    For chlorine dioxide generation activated by an acid source, the acid source may include inorganic acid salts, salts comprising the anions of strong acids and cations of weak bases, acids that can liberate protons into solution when contacted with water, organic acids, inorganic acids, and mixtures thereof. In some aspects, the acid source is a particulate solid material which does not react substantially with the metal chlorite during dry storage, however, does react with the metal chlorite to form chlorine dioxide when in the presence of an aqueous medium. The acid source may be water soluble, substantially insoluble in water, or intermediate between the two. Exemplary acid sources are those which produce a pH of below about 7, or below about 5.
  • [0134]
    Exemplary substantially water-soluble, acid-source-forming components include, but are not limited to, water-soluble solid acids such as boric acid, citric acid, tartaric acid, water soluble organic acid anhydrides such as maleic anhydride, and water soluble acid salts such as calcium chloride, magnesium chloride, magnesium nitrate, lithium chloride, magnesium sulfate, aluminum sulfate, sodium acid sulfate (NaHSO4), sodium dihydrogen phosphate (NaH2PO4), potassium acid sulfate (KHSO4), potassium dihydrogen phosphate (KH2PO4), and mixtures thereof. Exemplary acid-source-forming component is sodium acid sulfate (sodium bisulfate). Additional water-soluble, acid-source-forming components will be known to those skilled in the art.
  • [0135]
    Chlorine dioxide-generating components optionally comprise a source of free halogen. In one embodiment, the free halogen source is a free chlorine source, and the free halogen is free chlorine. Suitable examples of free halogen source used in the anhydrous compositions include dichloroisocyanuric acid and salts thereof such as NaDCCA, trichlorocyanuric acid, salts of hypochlorous acid such as sodium, potassium and calcium hypochlorite, bromochlorodimethylhydantoin, dibromodimethylhydantoin and the like. An exemplary source of free halogen is NaDCCA.
  • [0136]
    For chlorine dioxide generation activated by an energy-activatable catalyst, the energy-activatable catalyst is selected from the group consisting of a metal oxide, a metal sulfide, and a metal phosphide. Exemplary energy-activatable catalysts include metal oxides selected from the group consisting of titanium dioxide (TiO2); zinc oxide (ZnO); tungsten trioxide (WO3); ruthenium dioxide (RuO2); iridium dioxide (IrO2); tin dioxide (SnO2); strontium titanate (SrTiO3); barium titanate (BaTiO3); tantalum oxide (Ta2O5); calcium titanate (CaTiO3); iron (III) oxide (Fe2O3); molybdenum trioxide (MoO3); niobium pentoxide (NbO5); indium trioxide (In2O3); cadmium oxide (CdO); hafnium oxide (HfO2); zirconium oxide (ZrO2); manganese dioxide (MnO2); copper oxide (Cu2O); vanadium pentoxide (V2O5); chromium trioxide (CrO3); yttrium trioxide (YO3); silver oxide (Ag2O), TixZrl-xO2 wherein x is between 0 and 1, and combinations thereof. The energy-activatable catalyst can be selected from the group consisting of titanium oxide, zinc oxide, calcium titanate, zirconium oxide, and combinations thereof.
  • [0137]
    Chlorine dioxide-generating components optionally may be present in a matrix. Such matrices may be organic matrices, such as those described in commonly-assigned U.S. Pat. Publication No. 2006/0024369. In these matrices, chlorine dioxide is generated when the composite is exposed to water vapor or electromagnetic energy. The matrix may be a hydrous gel or an anhydrous gel. Hydrophobic matrices may also be employed. Hydrophobic matrix materials include water-impervious solid components such as hydrophobic waxes, water-impervious fluids such as hydrophobic oils, and mixtures of hydrophobic solids and hydrophobic fluids. In embodiments using a hydrophobic matrix, activation of chlorine dioxide may be a dry or anhydrous polar material, as described in co-pending U.S. Application No. 61/153,847.
  • [0138]
    V. Treatment Regimens
  • [0139]
    The method can comprise a single administration of the composition comprising chlorine dioxide or chlorine dioxide-generating components. In other embodiments, the method comprises one or more iterations of the contacting step. In an exemplary embodiment, iterations of the contacting step are substantially contiguous. In yet other embodiments, the composition comprises a second therapeutic agent in addition to the chlorine dioxide. In an embodiment, the second therapeutic agent is an antimicrobial agent, such as an antibiotic or antifungal agent. Contact with an infected non-oral biological tissue can be achieved by any method known in the art, including but not limited to, lavage (irrigation) with a fluid composition including continuous irrigation and intermittant irrigation, application of a cream or ointment composition, plasters, inserts such as suppositories, transdermal patches, and films. In some embodiments, the method further comprises a step of sonicating the composition while it is contacting the biological tissue. The sonication step is contemplated to increase the tissue penetration of the chlorine dioxide.
  • [0140]
    The method can further comprise alternating treatment steps wherein one step comprises administration of a composition comprising a chlorine dioxide source and a second step comprises administration of a composition comprising a second, non-chlorine-dioxide therapeutic agent. These steps may take place in any order and in multiple iterations. Consecutive steps may comprise the same composition or different compositions.
  • [0141]
    In the iterative embodiments, while the composition comprising a chlorine dioxide source can be the same in the iterations, it is more common that the composition in each iteration is fresh. In other words, the composition in one iteration is replaced with a fresh specimen of the composition. In embodiments using devices or compositions to deliver a substantially oxy-chlorine anion free chlorine dioxide composition to a tissue, the device or composition in one iteration is replaced with a fresh device or specimen of composition. By “fresh device” is meant a delivery device whose tissue interface for delivering ClO2 has not been previously exposed to a biological tissue. Accordingly, a fresh device has undergone minimal-to-no chlorine dioxide decay. In some embodiments, a single batch of the composition comprising a chlorine dioxide source is prepared at the start of treatment in a volume sufficient to cover the entire series of contiguous iterations, and fresh specimens are taken from the single batch for each iteration. In other embodiments, the composition comprising a chlorine dioxide is prepared fresh before each iteration.
  • [0142]
    The method can comprise two or more sequential steps of treatment with the composition comprising a chlorine dioxide source, followed by at least one step of treatment with the other therapeutic agent. The number and/and duration of treatments with the composition comprising a chlorine dioxide source can be the same or different as the number and/or duration of treatments with the second therapeutic composition. The composition comprising a chlorine dioxide source can be identical in the plural steps or can be different, such as a different concentration of chlorine dioxide. Similarly, the second therapeutic agent composition can be identical in the plural steps or can be different. Likewise, the duration of treatment steps can be the same or different for the composition comprising a chlorine dioxide source and for the second therapeutic agent composition.
  • [0143]
    The dosage of the composition varies within wide limits and may be adjusted to the individual requirements in each particular case. The dosage depends on the condition treated, the general state of health of the recipient, the number and frequency of administrations and other variables known to those of skill in the art. Accordingly, the amount of chlorine dioxide to be delivered to a non-oral tissue (i.e., an efficacious amount) will relate to the result intended from the application of chlorine dioxide to the tissue. The skilled artisan can readily determine the appropriate amount or amount range of chlorine dioxide to be efficacious for a given use. Generally, useful amounts comprise, for example, from about 1 to about 2000 ppm chlorine dioxide, at least about 1 to about 1000 ppm or at least about 20 to about 400 ppm. In some embodiments, the chlorine dioxide is present in the composition in at least about 5 ppm, at least about 20 ppm, or at least about 30 ppm. Typically, the amount of chlorine dioxide can range to about 1000 ppm, up to about 700 ppm, up to about 500 ppm and up to about 200 ppm. In one embodiment, the composition comprises about 30 to about 100 ppm chlorine dioxide. In some embodiments, a useful dose range can be from about 2.5 mg chlorine dioxide per area of contact (in square meters) to about 500 mg/m2 chlorine dioxide. Doses of at least about 10 mg/m2, at least about 15 mg/m2 and at least about 20 mg/m2 can also be useful.
  • [0144]
    The duration of contact with the tissue to obtain efficacy can be readily determined by the skilled artisan in view of the teachings herein and the knowledge in the art. The duration of contact will be influenced, for instance, by the type of infection, the presence or absence of biofilm, the tissue type, whether treatment is therapeutic or prophylactic, and the formulation of the chlorine dioxide composition (e.g, liquid or gel or a slow-release formulation). Advantageously, even after prolonged contact, the composition does not substantially irritate non-oral tissue. Generally, duration of contact ranges from seconds to minutes to hours to days. In some embodiments, the duration of contact can be at least about 60 seconds, at least about 1, 2, 3, 4, or 5 minutes, at least about 6, 7, 8, 9, or 10 minutes, or at least about 11, 12, 13, 14, or 15 minutes. In some embodiments, contact duration can range up to 16, 17, 18, 19, or 20 minutes, further up to 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes, and further up to about 35, 40, 45, 50, 55, or 60 minutes or longer in some circumstances. In certain embodiments, duration of contact ranges between about 1 and about 60 minutes, from about 5 minutes to about 30 minutes, or from about 10 to about 20 minutes. In some embodiments, duration of contact for a treatment is about 15 minutes. In some embodiments, the duration of contact ranges from at least about one (1) hour to about 72 hours, from at least about 8 hours to about 48 hours, or from at least about 12 hours to about 36 hours. In certain embodiments, duration of contact ranges from about 1 hour to about 6 hours, or from about 1.5 hours to about 4 hours.
  • [0145]
    Dosage of chlorine dioxide can also be in terms of concentration of chlorine dioxide in the composition used for treatment (in parts-per-million) times the duration (in minutes) of tissue contact with the chlorine dioxide (concentration×duration of contact). In some embodiments, dosage in terms of ppm-minute can range from about 100 ppm-minutes to about 10,000 ppm-minutes, or from about 200 ppm-minutes to about 5000 ppm-minutes. In embodiments where the method is practiced on an infection comprising a biofilm, dosage of at least about 200 ppm-minutes is useful.
  • [0146]
    The composition may be administered to a subject as frequently as several times daily, or it may be administered less frequently, such as once, once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of contact will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated and the method of contacting the tissue, etc. Treatment may comprise one episode of tissue contact or more than one episode. Treatment episodes may be substantially contiguous, separated in time (e.g., a few hours to a few days, a few days to a few weeks, and also longer intervals including several months to a year or more) or both. In some embodiments, treatment comprises at least two substantially contiguous episodes of tissue contact. The contiguous episodes can be the same duration in time such as about 15 minutes or different durations of time such as 10 minutes and 20 minutes. In some embodiments, the composition for each episode is freshly made. As used herein, “freshly made” means that the addition of chlorine dioxide to the other components of the final composition occurs within about one hour, within about 30 minutes, or within about 15 minutes before contacting a tissue with the composition.
  • [0147]
    The chlorine dioxide that comes into contact with the tissue is substantially oxy-chlorine anion free. In one embodiment, the substantially oxy-chlorine anion free chlorine dioxide that contacts the tissue comprises zero milligram (mg) oxy-chlorine anion per gram to no more than about 0.25 mg oxy-chlorine anion per gram, or from zero to 0.24, 0.23, 0.22, 0.21, or 0.20 mg oxy-chlorine anion per gram composition, or from zero to 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, or 0.10 mg oxy-chlorine anion per gram composition, or from zero to 0.09, 0.08, 0.07, 0.06, 0.05 or 0.04 mg oxy-chlorine anion per gram composition, absent other constituents that contribute to cytotoxicity, and is therefore substantially non-cytotoxic. In some embodiments, the substantially oxy-chlorine anion free chlorine dioxide comprises less than about 400 milligrams per square meter of contact area, less than about 375 mg/m2, less than about 350 mg/m2, than about 325 mg/m2, or than about 300 mg/m2 oxy-chlorine anions. In some embodiments, the substantially oxy-chlorine anion free chlorine dioxide comprises from zero to less than about 200 mg/m2 oxy-chlorine anions. In other embodiments, the substantially oxy-chlorine anion free chlorine dioxide comprises from zero to less than about 100 mg/m2 oxy-chlorine anions.
  • [0148]
    Oxy-chlorine anions can be measured in chlorine dioxide solutions or compositions using any method known to those skilled in the art, including ion chromatography following the general procedures of EPA test method 300 (Pfaff, 1993, “Method 300.0 Determination of Inorganic Anions by Ion Chromatography,” Rev. 2.1, US Environmental Protection Agency) or a titration method based on an amperometric method (Amperometric Method II in Eaton et al, ed., “Standard Methods for the Examination of Water and Wastewater” 19th edition, American Public Health Association, Washington D.C., 1995). Alternatively, oxy-chlorine anions may be measured by a titration technique equivalent to the amperometric method, but which uses the oxidation of iodide to iodine and subsequent titration with sodium thiosulfate to a starch endpoint in place of the amperometric titration; this method is referred to herein as “pH 7 buffered titration.” A chlorite analytical standard can be prepared from technical grade solid sodium chlorite, which is generally assumed to comprise about 80% by weight of pure sodium chlorite.
  • Examples
  • [0149]
    The methods are further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the methods should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.
  • [0150]
    Chlorine dioxide treatment involves exposing micro-organisms to chlorine dioxide for a period of time. Treatment conditions, often called the “dose or dosage” of chlorine dioxide, can be determined by calculating the integral of the chlorine dioxide concentration as a function of time, C(t), over the treatment time of use:
  • [0000]
    Dose = 0 T C ( t ) t ( 1 )
  • [0000]
    In systems where the chlorine dioxide concentration is generally constant over the treatment time (e.g., varies by less than ±10% relative) or varies linearly over the treatment time, an average chlorine dioxide concentration may be calculated by averaging the starting and ending concentrations and then multiplying that average chlorine dioxide concentration during an exposure period by the time of exposure (Average Concentration X Time). Dose is commonly given in units of ppm-minutes.
  • [0151]
    A series of experiments were conducted to estimate the dose of chlorine dioxide needed to kill bacterial biofilms consisting of Pseudomonas aeruginosa (PA), methicillin resistant Staphylococcus aureus (MRSA), or a combination of both.
  • [0152]
    Bacterial biofilms were grown for between 7 and 10 days on non-porous ceramic disks in a spinning disk biofilm reactor. The reactors were inoculated with PA, MRSA, or a mixture of MRSA and PA bacteria to produce PA, MRSA, or mixed PA/MRSA biofilms respectively.
  • [0153]
    Chlorine dioxide solutions were produced at different nominal concentrations using ASEPTROL® S-Tab 10 tablets, and the exact concentrations were then measured using a Hach Model 2400 UV/Vis spectrophotometer in accordance with the manufacturer's instructions. Pairs of biofilm-containing disks were immersed for different times in solutions of different chlorine dioxide concentrations, neutralized with dilute sodium thiosulfate solution, and then plated to determine the number of surviving bacteria on each disk. Two untreated disks were also exposed to neutralizing solution and plated to determine the starting bacterial counts. In all tests, the baseline bacterial counts were in the range of 107 to 107.5 colony-forming units per disk (cfu/disk). A one log reduction refers to reducing the cfu/disk by one order of magnitude, e.g., a reduction from 107.1 cfu/disk to 106.1 cfu/disk. Accordingly, a substantially complete kill is achieved if the log reduction of bacteria is about 7 to 7.5.
  • [0154]
    The table summarizes the test conditions used in the different experiments, and presents the results in terms of log reduction of the different bacterial organisms. In the case of mixed PA/MRSA biofilms, results are given as total bacteria. The data are also shown in FIG. 1.
  • [0000]
    TABLE
    ClO2 Log
    Exposure Concen- Conc × Reduction
    Time tration Time in Organism
    Sample # Organism (minutes) (ppm) (ppm-min) Count
    1 MRSA 1.0 208 208 5.5
    2 MRSA 5.0 204 1020 7.1
    3 MRSA 10.0 45 450 5.5
    3 MRSA 30.0 40 1200 5.1
    4 MRSA 30.0 175 5250 7.1
    6 PA 0.5 200 100 5.9
    7 PA 5.0 43 215 5.7
    8 PA 5.0 187 935 7.5
    9 PA 10.0 37 370 7.5
    10 PA 50.0 35 1750 7.5
    11 PA 50.0 166 8300 7.5
    12 MRSA + PA 10.0 52 520 5.5
    13 MRSA + PA 30.0 52 1560 7.4
    14 MRSA + PA 1.0 181 181 5.1
    15 MRSA + PA 5.0 160 800 7.4
    16 MRSA + PA 30.0 160 4800 7.4
  • [0155]
    These data show that complete kill of either a PA biofilm, a MRSA biofilm, or a mixed PA/MRSA biofilm was achieved with a dose of between about 400 and 1000 ppm-minutes (see Samples 2, 9 and 15). A PA biofilm appeared be slightly easier to kill than a MRSA biofilm, but the difference is small. A kill of about 5 orders of magnitude (i.e., 5 log) can be achieved at a dose of greater than about 200 ppm-min (see Samples 1, 7 and 12). These data demonstrate that chlorine dioxide has great potency for disrupting and eradicating biofilms.
  • [0156]
    The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.
  • [0157]
    While methods, devices, compositions, and systems described have been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations may be devised by others skilled in the art without departing from the true spirit and scope of the methods, devices, compositions, and systems. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims (20)

  1. 1. A method for alleviating a non-oral biological tissue infection, the method comprising administering to the non-oral biological tissue a composition comprising a chlorine dioxide source to provide an efficacious amount of chlorine dioxide,
    wherein the administering step comprises one or more of:
    i) contacting the tissue with a substantially non-cytotoxic composition comprising the chlorine dioxide source;
    ii) contacting the tissue with a device comprising the chlorine dioxide source and oxy-chlorine anions, wherein the device delivers a substantially oxy-chlorine anion free chlorine dioxide composition to the tissue; or
    iii) contacting the tissue with a composition comprising
    the chlorine dioxide source and oxy-chlorine anions; and
    a barrier substance that substantially prohibits passage therethrough of the oxy-chlorine anions and permits passage therethrough of a substantially oxy-chlorine anion free chlorine dioxide composition, thereby enabling delivery of the substantially oxy-chlorine anion free chlorine dioxide composition to the tissue,
    thereby alleviating the infection of the contacted tissue.
  2. 2. The method of claim 1, wherein the composition comprises about 1 to about 1000 ppm chlorine dioxide.
  3. 3. The method of claim 1, wherein the chlorine dioxide source comprises a particulate precursor of chlorine dioxide as chlorine dioxide-generating components.
  4. 4. The method of claim 1, wherein the non-oral biological tissue infection is a soft biological tissue infection.
  5. 5. The method of claim 1, wherein the non-oral biological tissue infection is a hard biological tissue infection.
  6. 6. The method of claim 1, wherein the composition further comprises a second therapeutic agent.
  7. 7. The method of claim 1, further comprising administering a second composition comprising a second therapeutic agent to the non-oral biological tissue.
  8. 8. The method of claim 1, wherein the administering step comprises at least two substantially contiguous iterations of contacting the tissue with a substantially non-cytotoxic composition comprising the chlorine dioxide source.
  9. 9. The method of claim 8, wherein the composition comprises less than about 0.2 milligrams oxy-chlorine anion per gram composition.
  10. 10. The method of claim 9, wherein the composition has a pH from about 4.5 to about 11.
  11. 11. The method of claim 1, wherein the administering step comprises irrigating the tissue with a substantially non-cytotoxic composition using an irrigation device.
  12. 12. The method of claim 1, wherein the administering step comprises contacting the tissue with a device comprising a chlorine dioxide source and oxy-chlorine anions, wherein the device is an irrigation device that delivers a substantially oxy-chlorine anion free chlorine dioxide composition to the tissue.
  13. 13. The method of claim 1, wherein the administering step comprises contacting the tissue with a composition comprising a chlorine dioxide source, oxy-chlorine anions, and a barrier substance.
  14. 14. A method for alleviating an infection of a non-oral biological tissue, the method comprising administering to the non-oral biological tissue composition comprising a chlorine dioxide source to provide an efficacious amount of chlorine dioxide, wherein the administering step comprises contacting the tissue with a substantially non-irritating composition comprising the chlorine dioxide source, thereby alleviating the infection of the contacted tissue.
  15. 15. The method of claim 14, wherein the composition comprises about 1 to about 1000 ppm chlorine dioxide.
  16. 16. The method of claim 14, wherein the chlorine dioxide source comprises a particulate precursor of chlorine dioxide as chlorine dioxide-generating components.
  17. 17. The method of claim 14, wherein the composition comprises less than about 0.2 milligrams oxy-chlorine anion per gram composition.
  18. 18. The method of claim 14, wherein the composition has a pH from about 4.5 to about 11.
  19. 19. The method of claim 14, wherein the non-oral biological tissue infection is a soft biological tissue infection.
  20. 20. The method of claim 14, wherein the non-oral biological tissue infection is a hard biological tissue infection.
US12690851 2009-02-04 2010-01-20 Treatment of Non-Oral Biological Tissue with Chlorine Dioxide Abandoned US20100196512A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US14978409 true 2009-02-04 2009-02-04
US15068509 true 2009-02-06 2009-02-06
US18719809 true 2009-06-15 2009-06-15
US12690851 US20100196512A1 (en) 2009-02-04 2010-01-20 Treatment of Non-Oral Biological Tissue with Chlorine Dioxide

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US12690851 US20100196512A1 (en) 2009-02-04 2010-01-20 Treatment of Non-Oral Biological Tissue with Chlorine Dioxide
CA 2759115 CA2759115A1 (en) 2009-02-04 2010-02-03 Treatment of non-oral biological tissue with chlorine dioxide
KR20117020498A KR20110116202A (en) 2009-02-04 2010-02-03 Treatment of non-oral biological tissue with chlorine dioxide
PCT/US2010/023023 WO2010091068A2 (en) 2009-02-04 2010-02-03 Treatment of non-oral biological tissue with chlorine dioxide
JP2011549232A JP2012516893A (en) 2009-02-04 2010-02-03 The treatment of non-oral biological tissue by chlorine dioxide
EP20100739054 EP2393500A4 (en) 2009-02-04 2010-02-03 Treatment of non-oral biological tissue with chlorine dioxide

Publications (1)

Publication Number Publication Date
US20100196512A1 true true US20100196512A1 (en) 2010-08-05

Family

ID=42397930

Family Applications (3)

Application Number Title Priority Date Filing Date
US12690851 Abandoned US20100196512A1 (en) 2009-02-04 2010-01-20 Treatment of Non-Oral Biological Tissue with Chlorine Dioxide
US12690843 Expired - Fee Related US8311625B2 (en) 2009-02-04 2010-01-20 Chlorine dioxide treatment for biological tissue
US13601623 Active US8703106B2 (en) 2009-02-04 2012-08-31 Chlorine dioxide treatment for biological tissue

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12690843 Expired - Fee Related US8311625B2 (en) 2009-02-04 2010-01-20 Chlorine dioxide treatment for biological tissue
US13601623 Active US8703106B2 (en) 2009-02-04 2012-08-31 Chlorine dioxide treatment for biological tissue

Country Status (6)

Country Link
US (3) US20100196512A1 (en)
EP (2) EP2393499A4 (en)
JP (2) JP2012516893A (en)
KR (2) KR20110116202A (en)
CA (2) CA2759115A1 (en)
WO (2) WO2010091066A2 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100012894A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
KR20110039461A (en) * 2008-07-15 2011-04-18 바스프 코포레이션 Methods, systems and devices for administration of chlorine dioxide
US20100196512A1 (en) * 2009-02-04 2010-08-05 Basf Catalyst Llc Treatment of Non-Oral Biological Tissue with Chlorine Dioxide
WO2013056071A1 (en) 2011-10-14 2013-04-18 Beam Technologies, Llc Oral health care implement and system with oximetry sensor
CN103040860A (en) * 2012-11-29 2013-04-17 刘学武 Method for initiating mammalian stem cells and application of chlorine dioxide in preparation of medicament for initiating mammalian stem cells
US9358085B2 (en) 2013-04-19 2016-06-07 The Procter & Gamble Company Device and method for cleaning dental appliances

Citations (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2071091A (en) * 1936-07-13 1937-02-16 Mathieson Alkali Works Inc Chemical manufacture
US3953566A (en) * 1970-05-21 1976-04-27 W. L. Gore & Associates, Inc. Process for producing porous products
US4104190A (en) * 1976-03-23 1978-08-01 Minnesota Mining And Manufacturing Company Generation of chlorine dioxide for disinfection and sterilization
US4330531A (en) * 1976-03-26 1982-05-18 Howard Alliger Germ-killing materials
US4585482A (en) * 1984-05-25 1986-04-29 Southern Research Institute Long-acting biocidal compositions and method therefor
US4671972A (en) * 1984-03-16 1987-06-09 Warner-Lambert Company Controlled release encapsulated hypochlorite deactivator for use in denture cleansers
US4683039A (en) * 1985-12-24 1987-07-28 Tenneco Canada Inc. (Erco Division) Membrane pervaporation process
US4689215A (en) * 1984-07-30 1987-08-25 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4808389A (en) * 1986-12-29 1989-02-28 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4818519A (en) * 1986-12-29 1989-04-04 Ratcliff Perry A Method and composition for prevention of plaque formation and plaque dependent diseases
US4828857A (en) * 1984-10-05 1989-05-09 Warner-Lambert Company Novel sweetener delivery systems
US4832009A (en) * 1987-12-23 1989-05-23 Bio Med Sciences, Inc. Semi-interpenetrating network polymer backsheet bandage
US4837009A (en) * 1986-03-31 1989-06-06 Ratcliff Perry A Method and composition for prevention of plaque formation and plaque dependent diseases
US4851213A (en) * 1986-03-31 1989-07-25 Ratcliff Perry A Method and composition for prevention and treatment of oral disease due to S. Sanguis
US4855135A (en) * 1984-07-30 1989-08-08 Ratcliff Perry A Method for debriding
US4925656A (en) * 1986-03-31 1990-05-15 Ratcliff Perry A Method for retarding formation of dental plaque
US4945125A (en) * 1987-01-05 1990-07-31 Tetratec Corporation Process of producing a fibrillated semi-interpenetrating polymer network of polytetrafluoroethylene and silicone elastomer and shaped products thereof
US5104660A (en) * 1989-11-21 1992-04-14 Bruce A. Barber Method of preparing an antimicrobial wound dressing
US5133701A (en) * 1989-04-06 1992-07-28 Sang In Han Disposable pressure wound irrigation device
US5200171A (en) * 1990-11-20 1993-04-06 Micropure, Inc. Oral health preparation and method
US5227168A (en) * 1989-11-21 1993-07-13 Bruce Barber Method of treating a wound
US5281412A (en) * 1991-12-30 1994-01-25 The Procter & Gamble Company Oral compositions
US5384134A (en) * 1988-05-06 1995-01-24 Alcide Corporation Anti-inflammatory formulations for inflammatory diseases
US5399288A (en) * 1992-07-23 1995-03-21 Abic Limited Solid composition releasing chlorine dioxide
US5407656A (en) * 1992-03-04 1995-04-18 Arco Research Co., Inc. Method and compositions for the production of chlorine dioxide
US5489435A (en) * 1993-07-06 1996-02-06 Ratcliff; Perry A. Composition for treatment of abnormal conditions of the epithelium of bodily orifices
US5526841A (en) * 1993-08-20 1996-06-18 Detsch; Steven G. Water line decontamination system
US5597561A (en) * 1994-12-14 1997-01-28 Alcide Corporation Adherent disinfecting compositions and methods of use in skin disinfection
US5719100A (en) * 1992-03-20 1998-02-17 Zahradnik; Rudolf Water treatment compositions
US5736165A (en) * 1993-05-25 1998-04-07 Allergan In-the-eye use of chlorine dioxide-containing compositions
US5738840A (en) * 1994-04-07 1998-04-14 Profresh Properties, Inc. Oral rinse and method of treating halitosis
US5879691A (en) * 1997-06-06 1999-03-09 The Procter & Gamble Company Delivery system for a tooth whitener using a strip of material having low flexural stiffness
US5944528A (en) * 1996-07-29 1999-08-31 Idex Dental Sciences, Inc. Chlorine dioxide tooth whitening compositions
US6039934A (en) * 1998-08-04 2000-03-21 Alliger; Howard Use of xanthan gum for gelling CIO2 and related species
US6046243A (en) * 1993-02-12 2000-04-04 Bernard Technologies, Inc. Compositions for sustained release of a gas
US6077495A (en) * 1997-03-03 2000-06-20 Engelhard Corporation Method, composition and system for the controlled release of chlorine dioxide gas
US6077502A (en) * 1998-02-27 2000-06-20 The Procter & Gamble Company Oral care compositions comprising chlorite and methods
US6106284A (en) * 1999-01-15 2000-08-22 Cronin; Richard J. Dental cast tray assembly
US6238643B1 (en) * 1997-11-07 2001-05-29 Engelhard Corporation Method and device for the production of an aqueous solution containing chlorine dioxide
US6280716B1 (en) * 1993-07-06 2001-08-28 Vortech, Inc. Method for treating itching of the vagina
US6280775B1 (en) * 1999-06-09 2001-08-28 Joseph Alan Sasson Antimicrobial oral composition and method of use
US6379658B1 (en) * 1999-12-21 2002-04-30 International Flavors & Fragrances Inc. Human sweat malodor counteractant composition and process for using same
US6425759B1 (en) * 2000-11-15 2002-07-30 Richard J. Cronin Dental cast tray assembly
US6432387B1 (en) * 2000-03-23 2002-08-13 Create Co., Ltd. Ionic tooth polishing agent
US6432322B1 (en) * 2000-02-02 2002-08-13 Engelhard Corporation Massive bodies for producing highly converted solutions of chlorine dioxde
US6551579B2 (en) * 1997-06-06 2003-04-22 The Procter & Gamble Company Delivery systems for a tooth whitener
US6582682B2 (en) * 2000-10-30 2003-06-24 Noville, Inc. Oral care compositions comprising stabilized chlorine dioxide
US20030152528A1 (en) * 2001-05-01 2003-08-14 Parminder Singh Hydrogel compositions for tooth whitening
US20040009138A1 (en) * 2002-05-20 2004-01-15 Kling William O. Skin cleanser compositions and methods of use
US6682721B2 (en) * 2000-03-17 2004-01-27 Lg Household & Healthcare Ltd. Patches for teeth whitening
US6719995B2 (en) * 2001-03-19 2004-04-13 The Procter & Gamble Company Systems for delivering a cosmetic and/or therapeutic active to oral surfaces using an integral carrier
US6759030B2 (en) * 2002-03-21 2004-07-06 Carl M. Kosti Bleach stable toothpaste
US6848905B2 (en) * 2002-08-20 2005-02-01 Archtek, Inc. Method of making a dental tray using a patient's teeth as a template
US6881061B2 (en) * 2002-09-30 2005-04-19 Mcneil-Ppc, Inc. Ultrasonic method for cleaning teeth
US6896518B2 (en) * 2002-06-28 2005-05-24 Scott Jacobs Teeth treatment device
US20050137109A1 (en) * 2003-12-17 2005-06-23 The Procter & Gamble Company Emulsion composition for delivery of bleaching agents to teeth
US20060024369A1 (en) * 2003-08-04 2006-02-02 Speronello Barry K Chlorine dioxide releasing composite article
US7004756B2 (en) * 2003-01-24 2006-02-28 Ultradent Products, Inc. Pre-shaped dental trays and treatment devices and methods that utilize such dental trays
US20060045855A1 (en) * 2004-09-02 2006-03-02 Sasson J A Oral composition for reducing plaque and microbial infections and whitening teeth
US7029705B2 (en) * 2002-07-30 2006-04-18 Fuhr Allan H Nasal hygiene method and composition
US20060088498A1 (en) * 2004-10-27 2006-04-27 Truox, Inc. Anti-microbial composition using in-situ generation of an oxidizing agent
US7040897B2 (en) * 2003-05-23 2006-05-09 Ultradent Products, Inc. Thin, flexible membrane dental trays and systems and methods utilizing such trays
US20060099550A1 (en) * 2004-11-10 2006-05-11 Ranir/Dcp Corporation Device and method for delivering an oral care agent
US7044737B2 (en) * 2004-03-05 2006-05-16 Liang Fu Ultrasound oral hygiene and therapeutic device
US20060169949A1 (en) * 2000-02-02 2006-08-03 Speronello Barry K Massive bodies containing free halogen source for producing highly converted thickened solutions of chlorine dioxide
US7087190B2 (en) * 2003-03-20 2006-08-08 Ecolab Inc. Composition for the production of chlorine dioxide using non-iodo interhalides or polyhalides and methods of making and using the same
US7087208B2 (en) * 2001-08-02 2006-08-08 Sampson Allison H Methods for making chlorous acid and chlorine dioxide
US20060183080A1 (en) * 2003-11-21 2006-08-17 Vasiliy Nosov Dental treatment kits and methods for forming customized dental trays
US7229647B2 (en) * 2003-10-09 2007-06-12 Sunggyu Lee Chlorine dioxide gel and associated methods
US20070172412A1 (en) * 2006-01-26 2007-07-26 Linda Hratko Thickened fluid composition comprising chlorine dioxide
US20080020064A1 (en) * 2006-07-21 2008-01-24 Advanced Vision Research Methods and compositions for the treatment of infection or infectious colonization of the eyelid, ocular surface, skin or ear
US20080025925A1 (en) * 2006-07-26 2008-01-31 Ultradent Products, Inc. Dental bleaching compositions having long-term rheological stability and devices, kits and methods that utilize such compositions
US20080023668A1 (en) * 2004-07-08 2008-01-31 Joseph Callerame Clathrate of chlorine dioxide
US20080041400A1 (en) * 2006-08-17 2008-02-21 Darnell Daniel H System and Process for Custom Molding Dental Trays
US7384650B2 (en) * 1999-11-24 2008-06-10 Agile Therapeutics, Inc. Skin permeation enhancement composition for transdermal hormone delivery system
US20090016973A1 (en) * 2007-07-09 2009-01-15 Micropure, Inc. Composition and Method for the Prevention of Oral Disease
US7514019B2 (en) * 2005-03-01 2009-04-07 Truox, Inc. Solvent-activated reactor including a gel layer
US7534368B2 (en) * 2005-03-01 2009-05-19 Truox, Inc. Oxidizing composition including a gel layer
US20100009009A1 (en) * 2008-07-10 2010-01-14 Micropure, Inc. Method and composition for prevention and treatment of oral fungal infections
US20100012892A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100030132A1 (en) * 2006-09-28 2010-02-04 Jeffrey Niezgoda Apparatus and method for wound, cavity, and bone treatment
US20100040548A1 (en) * 2006-12-10 2010-02-18 Chongxi Yu High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US20100062042A1 (en) * 2008-07-15 2010-03-11 Basf Catalysts Llc Methods, Systems and Devices for Administration of Chlorine Dioxide
US20100074970A1 (en) * 2008-08-26 2010-03-25 Micropure, Inc. Method and composition for preventing and healing osteonecrosis of the jaw
US20100159031A1 (en) * 2008-12-22 2010-06-24 Swenholt Karen C Nail fungus treatment and composition
US7875460B2 (en) * 2007-07-09 2011-01-25 Micropure, Inc. Method for determining the effectiveness of stabilized chlorine dioxide in a mouth rinse
US8311625B2 (en) * 2009-02-04 2012-11-13 Basf Corporation Chlorine dioxide treatment for biological tissue

Family Cites Families (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3123521A (en) 1964-03-03
US2071094A (en) 1934-05-11 1937-02-16 Mathieson Alkali Works Inc Chemical manufacture
GB608068A (en) 1945-03-12 1948-09-09 Mathieson Alkali Works Improvements in the manufacture of chlorine dioxide
US2701781A (en) 1949-12-30 1955-02-08 Charles Van Buren Aqueous chlorine dioxide antiseptic compositions and production thereof
US4060600A (en) 1972-10-26 1977-11-29 National Patent Development Corporation Treating teeth
US3873685A (en) 1973-09-10 1975-03-25 Fmc Corp Contiguous shaped chlorine releasing structure
US4177199A (en) 1978-12-11 1979-12-04 Bristol-Myers Company Silver salts of phosphanilic acid
US4574084A (en) 1983-02-25 1986-03-04 Peter Berger Process for the preparation of a modified aqueous chlorite solution, the solution prepared by this process and the use thereof
US5185161A (en) 1984-03-21 1993-02-09 Alcide Corporation Disinfection method and composition therefor
US5100652A (en) 1984-03-21 1992-03-31 Alcide Corporation Disinfecting oral hygiene compositions and process for using the same
US4986990A (en) 1984-03-21 1991-01-22 Alcide Corporation Disinfection method and composition therefor
DE3586959T2 (en) 1984-03-21 1993-04-29 Alcide Corp Disinfection methods and composition for it.
US4975285A (en) 1984-07-30 1990-12-04 Ratcliff Perry A Method for cleaning dental prosthetic devices
US4793989A (en) 1984-07-30 1988-12-27 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4886657A (en) 1984-07-30 1989-12-12 Ratcliff Perry A Method for preventing periodontitis
US4696811A (en) * 1984-07-30 1987-09-29 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4889714A (en) 1984-07-30 1989-12-26 Ratcliff Perry A Method for retarding dental plaque by killing streptococcus sanguis
US4788053A (en) 1984-07-30 1988-11-29 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4846165A (en) 1986-11-26 1989-07-11 Dentsply Research & Development Corp. Wound dressing membrane
US4786492A (en) 1986-03-31 1988-11-22 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4792442A (en) 1986-03-31 1988-12-20 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US5348734A (en) * 1990-11-20 1994-09-20 Micropure Inc. Oral health preparation and method
US4865848A (en) * 1987-02-26 1989-09-12 Alza Corporation Skin permeation enhancer compositions using sucrose esters
US4829129A (en) 1987-05-29 1989-05-09 International Dioxcide, Inc. Reaction product of polymer with chlorine dioxide
US4853202A (en) 1987-09-08 1989-08-01 Engelhard Corporation Large-pored crystalline titanium molecular sieve zeolites
US5009875A (en) 1988-08-03 1991-04-23 International Dioxcide, Inc. Process of preparing clorine dioxide and apparatus therefor
CA2003198C (en) 1988-11-29 1995-03-21 Anthony J. Dziabo, Jr. Aqueous ophthalmic solutions and method for preserving same
US4964466A (en) 1989-08-07 1990-10-23 Exxon Chemicals Patents Inc Hydraulic fracturing with chlorine dioxide cleanup
US5324447A (en) 1989-10-02 1994-06-28 Allergan, Inc. Method and activator compositions to disinfect lenses
US5116620A (en) 1989-11-21 1992-05-26 Bruce A. Barber Antimicrobial wound dressing
US5656279A (en) 1994-02-23 1997-08-12 Bio Med Sciences, Inc. Semi-interpenetrating polymer network scar treatment sheeting, process of manufacture and useful articles thereof
GB2289841B (en) * 1994-05-23 1998-04-15 Janina International Oral care products
GB9506172D0 (en) * 1995-03-27 1995-05-17 Jeyes Group Plc Lavatory cleansing
US7320594B1 (en) * 1995-08-31 2008-01-22 Biolase Technology, Inc. Fluid and laser system
GB2304706B (en) 1995-09-01 1999-06-30 Feedwater Treatment Services L Preparation and use of novel biocidal solutions
WO1997011676A1 (en) 1995-09-25 1997-04-03 Robert Eric Montgomery Tooth bleaching compositions
CA2161863A1 (en) 1995-10-31 1997-05-01 Michael Vivian Sefton Angiogenic material and uses thereof
US5738640A (en) * 1996-08-20 1998-04-14 Carlson-Orsi; Diane Upper spine and neck support cushion
US5820822A (en) 1996-10-25 1998-10-13 Kross; Robert D. Antimicrobial composition and method of use
US6007735A (en) 1997-04-30 1999-12-28 Ecolab Inc. Coated bleach tablet and method
US6136297A (en) 1997-06-06 2000-10-24 The Procter & Gamble Company Delivery system for an oral care substance using a strip of material having low flexural stiffness
US6436444B1 (en) 1997-09-26 2002-08-20 Ecolab Inc. Acidic aqueous chlorite teat dip providing shelf life sanitizing capacity and tissue protection
US6365131B1 (en) 1997-10-31 2002-04-02 J. B. Chemicals & Pharmaceuticals Ltd. Pharmaceutical dental formulation for topical application of metronidazole benzoate, chlorhexidine gluconate and local anesthetic
US6136348A (en) 1997-12-05 2000-10-24 Ratcliff; Perry A. Compound and method for degrading amino acids
US6114398A (en) 1998-03-03 2000-09-05 Ratcliff; Perry A. Personal lubricant to prevent and stop itching
DE19854349A1 (en) 1998-11-25 2000-05-31 Up To Dent Ag Balzers Agent for mouth care based on chlorine dioxide and zinc salt or peroxide, useful for prevention of caries, gingivitis and parodontitis and for treatment and control of halitosis
CN1264539A (en) 1999-02-26 2000-08-30 崔永成 Weakly acidic disinfectant
US6231830B1 (en) 1999-03-04 2001-05-15 George Madray Method of making molecular chlorine dioxide
US6451253B1 (en) 1999-04-14 2002-09-17 Vulcan Chemical Technologies, Inc. High concentration chlorine dioxide gel composition
US6229062B1 (en) 1999-04-29 2001-05-08 Basf Aktiengesellschaft Corporation Superabsorbent polymer containing odor controlling compounds and methods of making the same
DE60002471T2 (en) 1999-07-02 2004-02-19 The Procter & Gamble Company, Cincinnati Compositions for the release of oral care active ingredients comprising organosiloxane resins by use of a carrier strip redetachable
US7273567B1 (en) * 1999-11-24 2007-09-25 Microactive Corp. Energy-activated compositions for controlled sustained release of a gas
US6685921B2 (en) 2000-10-25 2004-02-03 The Procter & Gamble Company Dental care compositions
EP1370226A2 (en) * 2001-01-24 2003-12-17 Oraceutical LLC Topical oral care compositions
US6500408B2 (en) 2001-01-27 2002-12-31 Jc Technologies, Inc. Enamel-safe tooth bleach and method for use
US6669931B2 (en) 2001-03-29 2003-12-30 Curozone Ireland Limited Formulation for the remineralization of teeth
US20030235549A1 (en) 2001-05-01 2003-12-25 Parminder Singh Hydrogel compositions demonstrating phase separation on contact with aqueous media
US6696047B2 (en) 2001-09-13 2004-02-24 The Procter & Gamble Company Stable oral care compositions comprising chlorite
US7252096B2 (en) 2003-04-08 2007-08-07 Nalco Company Methods of simultaneously cleaning and disinfecting industrial water systems
US20030228264A1 (en) 2002-06-06 2003-12-11 Perna Salvatore F. Dissolvable teeth whitening apparatus
US20040131558A1 (en) 2002-06-21 2004-07-08 Hauck Douglas J. Oral disease prevention and treatment
GB0222091D0 (en) 2002-09-24 2002-10-30 Boots Co Plc Dental compositions and methods
US20040137079A1 (en) 2003-01-08 2004-07-15 Cook James N. Contact lens and eye drop rewetter compositions and methods
US6964571B2 (en) 2003-01-24 2005-11-15 Ultradent Products, Inc. Pre-shaped dental trays and treatment devices and methods that utilize such dental trays
US20080274066A1 (en) 2003-07-28 2008-11-06 Britesmile Professional, Inc. Compositions, Methods, Devices, and Kits for Maintaining or Enhancing Tooth Whitening
US7059858B2 (en) 2004-02-19 2006-06-13 Ultradent Products, Inc. Universal tray design having anatomical features to enhance fit
US7383946B2 (en) * 2004-03-26 2008-06-10 Hughes Kenneth D Materials for storing and releasing reactive gases
US8753612B2 (en) 2005-04-11 2014-06-17 Sylphar Nv Foam strip for the delivery of oral care compositions
US20080209650A1 (en) * 2005-05-03 2008-09-04 Ultreo, Inc. Oral hygiene devices
US20060292090A1 (en) 2005-06-22 2006-12-28 Deepak Sharma Oral care compositions, devices, and methods of using the same
US20060292092A1 (en) 2005-06-22 2006-12-28 Deepak Sharma Oral care compositions, devices, and methods of using the same
US20060198795A1 (en) 2005-11-07 2006-09-07 Giniger Martin S Multi-component oral care compositions
EP1957401A4 (en) 2005-11-14 2013-09-04 Cdg Environmental Llc Storage-stable aqueous solutions of chlorine dioxide and methods for preparing and using them
US20080292669A1 (en) 2005-11-22 2008-11-27 Smithklne Beecham Corportion Foamed Substrate and Method for Making Same
WO2007085018A3 (en) 2006-01-20 2007-11-29 Oculus Innovative Sciences Inc Methods of treating or preventing inflammation and hypersensitivity with oxidative reductive potential water solution
US9028748B2 (en) 2006-02-24 2015-05-12 Nanovibronix Inc System and method for surface acoustic wave treatment of medical devices
US8673297B2 (en) * 2006-02-28 2014-03-18 Basf Corporation Chlorine dioxide based cleaner/sanitizer
US20070231277A1 (en) 2006-03-31 2007-10-04 Deepak Sharma Multicomponent whitening compositions and containers
GB0609485D0 (en) 2006-05-12 2006-06-21 Glaxo Group Ltd Chlorine dioxide tooth whitening composition
US20070292365A1 (en) 2006-05-15 2007-12-20 Tim Clarot Method of mitigating and disrupting tartar buildup
US20070292369A1 (en) 2006-05-15 2007-12-20 Tim Clarot Method for preventing and reducing tartar buildup
US20070292363A1 (en) 2006-05-15 2007-12-20 Tim Clarot Method for prevention and treatment of periodontal disease
US20070298380A1 (en) 2006-06-26 2007-12-27 Ultradent Products, Inc. Dental treatment devices adapted for improved lingual side adhesion
US20080208179A1 (en) * 2006-10-26 2008-08-28 Reliant Technologies, Inc. Methods of increasing skin permeability by treatment with electromagnetic radiation
EP2130542A4 (en) 2007-02-16 2010-06-02 Taiko Pharmaceutical Co Ltd Broad-spectrum antiviral composition having excellent storage stability
CA2680934C (en) 2007-03-15 2016-08-16 Taiko Pharmaceutical Co., Ltd. Pure chlorine dioxide solution, and gel-like composition and foaming composition each comprising the same
US20110052725A1 (en) 2007-03-27 2011-03-03 Takashi Shibata Therapeutic agent for infectious skin and mucosal disease
US8926951B2 (en) * 2007-07-09 2015-01-06 Micropure, Inc. Composition for preventing oral disease by penetrating polymicrobial oral biofilms and killing oral pathogens
US20090028965A1 (en) 2007-07-26 2009-01-29 Clinimax Limited Multi-part disinfectant
CN102056629B (en) 2008-04-04 2013-06-05 新加坡国立大学 A photosensitising composition and its uses
US20100015252A1 (en) 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Polishing Compositions and Methods of Tooth Polishing Without Mechanical Abrasion
US8741325B2 (en) 2008-12-18 2014-06-03 The Hong Kong University Of Science And Technology Material for forming a multi-level antimicrobial surface coating and its preparation
EP2370351B1 (en) 2008-12-22 2016-03-09 Micropure, INC. Composition and method for reducing demineralization of teeth
US20100233101A1 (en) * 2009-02-13 2010-09-16 Micropure, Inc. Composition and method for the oxidative consumption of salivary biomolecules
US20120207853A1 (en) 2009-05-11 2012-08-16 Oculus Innovative Sciences, Inc. Methods of treating or preventing influenza associated illness with oxidative reductive potential water solutions

Patent Citations (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2071091A (en) * 1936-07-13 1937-02-16 Mathieson Alkali Works Inc Chemical manufacture
US3953566A (en) * 1970-05-21 1976-04-27 W. L. Gore & Associates, Inc. Process for producing porous products
US4104190A (en) * 1976-03-23 1978-08-01 Minnesota Mining And Manufacturing Company Generation of chlorine dioxide for disinfection and sterilization
US4330531A (en) * 1976-03-26 1982-05-18 Howard Alliger Germ-killing materials
US4671972A (en) * 1984-03-16 1987-06-09 Warner-Lambert Company Controlled release encapsulated hypochlorite deactivator for use in denture cleansers
US4585482A (en) * 1984-05-25 1986-04-29 Southern Research Institute Long-acting biocidal compositions and method therefor
US4689215A (en) * 1984-07-30 1987-08-25 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4855135A (en) * 1984-07-30 1989-08-08 Ratcliff Perry A Method for debriding
US4828857A (en) * 1984-10-05 1989-05-09 Warner-Lambert Company Novel sweetener delivery systems
US4683039A (en) * 1985-12-24 1987-07-28 Tenneco Canada Inc. (Erco Division) Membrane pervaporation process
US4925656A (en) * 1986-03-31 1990-05-15 Ratcliff Perry A Method for retarding formation of dental plaque
US4851213A (en) * 1986-03-31 1989-07-25 Ratcliff Perry A Method and composition for prevention and treatment of oral disease due to S. Sanguis
US4837009A (en) * 1986-03-31 1989-06-06 Ratcliff Perry A Method and composition for prevention of plaque formation and plaque dependent diseases
US4818519A (en) * 1986-12-29 1989-04-04 Ratcliff Perry A Method and composition for prevention of plaque formation and plaque dependent diseases
US4808389A (en) * 1986-12-29 1989-02-28 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
US4945125A (en) * 1987-01-05 1990-07-31 Tetratec Corporation Process of producing a fibrillated semi-interpenetrating polymer network of polytetrafluoroethylene and silicone elastomer and shaped products thereof
US4832009A (en) * 1987-12-23 1989-05-23 Bio Med Sciences, Inc. Semi-interpenetrating network polymer backsheet bandage
US5384134A (en) * 1988-05-06 1995-01-24 Alcide Corporation Anti-inflammatory formulations for inflammatory diseases
US5133701A (en) * 1989-04-06 1992-07-28 Sang In Han Disposable pressure wound irrigation device
US5104660A (en) * 1989-11-21 1992-04-14 Bruce A. Barber Method of preparing an antimicrobial wound dressing
US5227168A (en) * 1989-11-21 1993-07-13 Bruce Barber Method of treating a wound
US5200171A (en) * 1990-11-20 1993-04-06 Micropure, Inc. Oral health preparation and method
US5281412A (en) * 1991-12-30 1994-01-25 The Procter & Gamble Company Oral compositions
US5407656A (en) * 1992-03-04 1995-04-18 Arco Research Co., Inc. Method and compositions for the production of chlorine dioxide
US5651996A (en) * 1992-03-04 1997-07-29 Arco Research Co., Inc. Method and compositions for the production of chlorine dioxide
US5719100A (en) * 1992-03-20 1998-02-17 Zahradnik; Rudolf Water treatment compositions
US5399288A (en) * 1992-07-23 1995-03-21 Abic Limited Solid composition releasing chlorine dioxide
US6046243A (en) * 1993-02-12 2000-04-04 Bernard Technologies, Inc. Compositions for sustained release of a gas
US5736165A (en) * 1993-05-25 1998-04-07 Allergan In-the-eye use of chlorine dioxide-containing compositions
US5489435A (en) * 1993-07-06 1996-02-06 Ratcliff; Perry A. Composition for treatment of abnormal conditions of the epithelium of bodily orifices
US5618550A (en) * 1993-07-06 1997-04-08 Rbr Holdings Method for treatment of abnormal conditions of the epithelium of bodily orifices
US6280716B1 (en) * 1993-07-06 2001-08-28 Vortech, Inc. Method for treating itching of the vagina
US5526841A (en) * 1993-08-20 1996-06-18 Detsch; Steven G. Water line decontamination system
US5738840A (en) * 1994-04-07 1998-04-14 Profresh Properties, Inc. Oral rinse and method of treating halitosis
US5597561A (en) * 1994-12-14 1997-01-28 Alcide Corporation Adherent disinfecting compositions and methods of use in skin disinfection
US5944528A (en) * 1996-07-29 1999-08-31 Idex Dental Sciences, Inc. Chlorine dioxide tooth whitening compositions
US6077495A (en) * 1997-03-03 2000-06-20 Engelhard Corporation Method, composition and system for the controlled release of chlorine dioxide gas
US7220367B2 (en) * 1997-03-03 2007-05-22 Basf Catalysts Llc Method and system for the controlled release of chlorine dioxide gas
US5879691A (en) * 1997-06-06 1999-03-09 The Procter & Gamble Company Delivery system for a tooth whitener using a strip of material having low flexural stiffness
US6551579B2 (en) * 1997-06-06 2003-04-22 The Procter & Gamble Company Delivery systems for a tooth whitener
US6238643B1 (en) * 1997-11-07 2001-05-29 Engelhard Corporation Method and device for the production of an aqueous solution containing chlorine dioxide
US6077502A (en) * 1998-02-27 2000-06-20 The Procter & Gamble Company Oral care compositions comprising chlorite and methods
US6039934A (en) * 1998-08-04 2000-03-21 Alliger; Howard Use of xanthan gum for gelling CIO2 and related species
US6106284A (en) * 1999-01-15 2000-08-22 Cronin; Richard J. Dental cast tray assembly
US6280775B1 (en) * 1999-06-09 2001-08-28 Joseph Alan Sasson Antimicrobial oral composition and method of use
US7384650B2 (en) * 1999-11-24 2008-06-10 Agile Therapeutics, Inc. Skin permeation enhancement composition for transdermal hormone delivery system
US6379658B1 (en) * 1999-12-21 2002-04-30 International Flavors & Fragrances Inc. Human sweat malodor counteractant composition and process for using same
US6699404B2 (en) * 2000-02-02 2004-03-02 Engelhard Corporation Massive bodies containing free halogen source for producing highly converted solutions of chlorine dioxide
US6432322B1 (en) * 2000-02-02 2002-08-13 Engelhard Corporation Massive bodies for producing highly converted solutions of chlorine dioxde
US7182883B2 (en) * 2000-02-02 2007-02-27 Engelhard Corporation Massive bodies containing free halogen source for producing highly converted solutions of chlorine dioxide
US20060169949A1 (en) * 2000-02-02 2006-08-03 Speronello Barry K Massive bodies containing free halogen source for producing highly converted thickened solutions of chlorine dioxide
US6682721B2 (en) * 2000-03-17 2004-01-27 Lg Household & Healthcare Ltd. Patches for teeth whitening
US6432387B1 (en) * 2000-03-23 2002-08-13 Create Co., Ltd. Ionic tooth polishing agent
US6582682B2 (en) * 2000-10-30 2003-06-24 Noville, Inc. Oral care compositions comprising stabilized chlorine dioxide
US6425759B1 (en) * 2000-11-15 2002-07-30 Richard J. Cronin Dental cast tray assembly
US6719995B2 (en) * 2001-03-19 2004-04-13 The Procter & Gamble Company Systems for delivering a cosmetic and/or therapeutic active to oral surfaces using an integral carrier
US20030152528A1 (en) * 2001-05-01 2003-08-14 Parminder Singh Hydrogel compositions for tooth whitening
US7087208B2 (en) * 2001-08-02 2006-08-08 Sampson Allison H Methods for making chlorous acid and chlorine dioxide
US6759030B2 (en) * 2002-03-21 2004-07-06 Carl M. Kosti Bleach stable toothpaste
US20040009138A1 (en) * 2002-05-20 2004-01-15 Kling William O. Skin cleanser compositions and methods of use
US6896518B2 (en) * 2002-06-28 2005-05-24 Scott Jacobs Teeth treatment device
US7029705B2 (en) * 2002-07-30 2006-04-18 Fuhr Allan H Nasal hygiene method and composition
US6848905B2 (en) * 2002-08-20 2005-02-01 Archtek, Inc. Method of making a dental tray using a patient's teeth as a template
US6881061B2 (en) * 2002-09-30 2005-04-19 Mcneil-Ppc, Inc. Ultrasonic method for cleaning teeth
US7004756B2 (en) * 2003-01-24 2006-02-28 Ultradent Products, Inc. Pre-shaped dental trays and treatment devices and methods that utilize such dental trays
US7087190B2 (en) * 2003-03-20 2006-08-08 Ecolab Inc. Composition for the production of chlorine dioxide using non-iodo interhalides or polyhalides and methods of making and using the same
US7040897B2 (en) * 2003-05-23 2006-05-09 Ultradent Products, Inc. Thin, flexible membrane dental trays and systems and methods utilizing such trays
US20060024369A1 (en) * 2003-08-04 2006-02-02 Speronello Barry K Chlorine dioxide releasing composite article
US7229647B2 (en) * 2003-10-09 2007-06-12 Sunggyu Lee Chlorine dioxide gel and associated methods
US20060183080A1 (en) * 2003-11-21 2006-08-17 Vasiliy Nosov Dental treatment kits and methods for forming customized dental trays
US20050137109A1 (en) * 2003-12-17 2005-06-23 The Procter & Gamble Company Emulsion composition for delivery of bleaching agents to teeth
US7044737B2 (en) * 2004-03-05 2006-05-16 Liang Fu Ultrasound oral hygiene and therapeutic device
US20080023668A1 (en) * 2004-07-08 2008-01-31 Joseph Callerame Clathrate of chlorine dioxide
US20060045855A1 (en) * 2004-09-02 2006-03-02 Sasson J A Oral composition for reducing plaque and microbial infections and whitening teeth
US20060088498A1 (en) * 2004-10-27 2006-04-27 Truox, Inc. Anti-microbial composition using in-situ generation of an oxidizing agent
US20060099550A1 (en) * 2004-11-10 2006-05-11 Ranir/Dcp Corporation Device and method for delivering an oral care agent
US7534368B2 (en) * 2005-03-01 2009-05-19 Truox, Inc. Oxidizing composition including a gel layer
US7514019B2 (en) * 2005-03-01 2009-04-07 Truox, Inc. Solvent-activated reactor including a gel layer
US20070172412A1 (en) * 2006-01-26 2007-07-26 Linda Hratko Thickened fluid composition comprising chlorine dioxide
US20080020064A1 (en) * 2006-07-21 2008-01-24 Advanced Vision Research Methods and compositions for the treatment of infection or infectious colonization of the eyelid, ocular surface, skin or ear
US20080025925A1 (en) * 2006-07-26 2008-01-31 Ultradent Products, Inc. Dental bleaching compositions having long-term rheological stability and devices, kits and methods that utilize such compositions
US20080041400A1 (en) * 2006-08-17 2008-02-21 Darnell Daniel H System and Process for Custom Molding Dental Trays
US20100030132A1 (en) * 2006-09-28 2010-02-04 Jeffrey Niezgoda Apparatus and method for wound, cavity, and bone treatment
US20100040548A1 (en) * 2006-12-10 2010-02-18 Chongxi Yu High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US7875460B2 (en) * 2007-07-09 2011-01-25 Micropure, Inc. Method for determining the effectiveness of stabilized chlorine dioxide in a mouth rinse
US20090016973A1 (en) * 2007-07-09 2009-01-15 Micropure, Inc. Composition and Method for the Prevention of Oral Disease
US20100009009A1 (en) * 2008-07-10 2010-01-14 Micropure, Inc. Method and composition for prevention and treatment of oral fungal infections
US20100015066A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Non-Cytotoxic Chlorine Dioxide Fluids
US20100012894A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100012893A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100012892A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100015067A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100062042A1 (en) * 2008-07-15 2010-03-11 Basf Catalysts Llc Methods, Systems and Devices for Administration of Chlorine Dioxide
US20100062076A1 (en) * 2008-07-15 2010-03-11 Basf Catalysts Llc Non-Cytotoxic Chlorine Dioxide Fluids
US20100062043A1 (en) * 2008-07-15 2010-03-11 Basf Catalysts Llc Methods, Systems and Devices for Administration of Chlorine Dioxide
US20100112059A1 (en) * 2008-07-15 2010-05-06 Basf Catalysts Llc Methods, Systems and Devices for Administration of Chlorine Dioxide
US20100012891A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100074970A1 (en) * 2008-08-26 2010-03-25 Micropure, Inc. Method and composition for preventing and healing osteonecrosis of the jaw
US20100159031A1 (en) * 2008-12-22 2010-06-24 Swenholt Karen C Nail fungus treatment and composition
US8311625B2 (en) * 2009-02-04 2012-11-13 Basf Corporation Chlorine dioxide treatment for biological tissue

Also Published As

Publication number Publication date Type
KR20110116202A (en) 2011-10-25 application
WO2010091066A2 (en) 2010-08-12 application
EP2393500A4 (en) 2013-07-31 application
US20100198136A1 (en) 2010-08-05 application
CA2759112A1 (en) 2010-08-12 application
US8311625B2 (en) 2012-11-13 grant
US8703106B2 (en) 2014-04-22 grant
EP2393499A2 (en) 2011-12-14 application
WO2010091068A2 (en) 2010-08-12 application
US20130034507A1 (en) 2013-02-07 application
JP2012516891A (en) 2012-07-26 application
CA2759115A1 (en) 2010-08-12 application
KR20110126652A (en) 2011-11-23 application
EP2393499A4 (en) 2013-01-23 application
JP2012516893A (en) 2012-07-26 application
EP2393500A2 (en) 2011-12-14 application

Similar Documents

Publication Publication Date Title
Vera Wound healing, oral & topical activity of Aloe vera
US6328991B1 (en) Composition and method for prevention of sexually transmitted diseases, including aids
Warriner et al. Infection and the chronic wound: a focus on silver
US6709681B2 (en) Acidified nitrite as an antimicrobial agent
US6488965B1 (en) Synergistic antimicrobial preparations containing chlorite and hydrogen peroxide
US20080071206A1 (en) Device and method for treatment of dermatomycosis, and in particular onychomycosis
US20030185889A1 (en) Colloidal nanosilver solution and method for making the same
US20030054046A1 (en) Treatment of inflammatory skin conditions
US6605751B1 (en) Silver-containing compositions, devices and methods for making
US20030185704A1 (en) Physiologically balanced, ionized, acidic solution and methodology for use in wound healing
US20040137078A1 (en) Physiologically balanced, ionized, acidic solution and methodology for use in wound healing
US7255881B2 (en) Metal-containing materials
Melaiye et al. Silver and its application as an antimicrobial agent
US20030170314A1 (en) Compositions of metal-containing compounds
US20050037093A1 (en) Treatment of nail infections with no
US6989157B2 (en) Dry powders of metal-containing compounds
WO2001024839A1 (en) Silver-containing compositions, devices and methods for making
Cooper Iodine revisited
White An historical overview of the use of silver in wound management
WO2001054704A1 (en) Physiologically balanced, ionized, acidic solution and methodology for use in wound healing
US20050266081A1 (en) Antimicrobial silver hydrogels
US20030194444A1 (en) Methods of treating skin and integument conditions
WO2000027390A1 (en) Ionic silver complex
US20040191329A1 (en) Compositions and methods of metal-containing materials
US20030203046A1 (en) Solutions and aerosols of metal-containing compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: BASF CORPORATION, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:FULL, ANDREW PATRICK;GOMEZ, MARCOS;CASTELLANA, FRANK S.;AND OTHERS;SIGNING DATES FROM 20120625 TO 20120629;REEL/FRAME:028482/0174