Oculus Patent | Method Of Using Oxidative Reductive Potential Water Solution In Dental Applications

Patent: Method Of Using Oxidative Reductive Potential Water Solution In Dental Applications

Publication Number: 20170071980

Publication Date: 20170316

Applicants: Oculus

Abstract

Methods of using oxidative reduction potential (ORP) water solution that is stable for at least twenty-four hours in dental applications are provided. The ORP water solution can be administered to patients for the routine disinfection of the oral cavity as part of an on-going program of oral hygiene. The ORP water solution can further be used to irrigate and/or disinfect oral tissues and surfaces during dental procedures, oral surgery, or maxillo-facial surgery. Also, the ORP water solution can be administered to treat patients with damage to the oral tissues caused by disease or surgery.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application is a continuation of U.S. patent application Ser. No. 11/416,091, filed on May 2, 2006, and claims the benefit of U.S. Provisional Patent Application No. 60/760,635 filed Jan. 20, 2006; 60/760,567 filed Jan. 20, 2006; 60/760,645 filed Jan. 20, 2006; 60/760,557 filed Jan. 20, 2006; 60/730,743 filed Oct. 27, 2005; and 60/676,883 filed May 2, 2005; each of which is hereby incorporated herein in their entirety by reference.

FIELD OF THE INVENTION

[0002] This invention pertains to a method of treating periodontal disease and other dental conditions by administration of oxidative reductive potential water solutions.

BACKGROUND OF THE INVENTION

[0003] Periodontal (gum) diseases, including gingivitis and periodontitis, are serious infections that, left untreated, can lead to tooth loss. Periodontal disease can affect one tooth or many teeth. Periodontal disease begins when the bacteria in “plaque,” a sticky, colorless film that constantly forms on teeth, causes the gums to become inflamed. In the mildest form of the disease, gingivitis, the gums redden, swell and bleed easily. Gingivitis is often caused by inadequate oral hygiene. Gingivitis is reversible with professional treatment and good oral home care.

[0004] Untreated gingivitis can advance to periodontitis. With time, plaque can spread and grow below the gum line. Toxins produced by the bacteria in plaque irritate the gums. Gums can then separate from the teeth, forming spaces between the teeth and gums that become infected. As the disease progresses, gum tissue and bone are destroyed. Eventually, teeth can become loose and may have to be removed by periodontal surgery.

[0005] The main cause of periodontal disease is bacterial plaque. However, factors such as genetics, pregnancy, puberty, poor nutrition, stress, smoking, diabetes and other systemic diseases, and medications can contribute to periodontal disease. Antibiotics are often used in combination with mechanical plaque removal (scaling) in the treatment of more advanced periodontal disease. Nevertheless periodontal disease remains the cause of significant morbidity and expense to society. Accordingly, there is a need for additional novel effective treatments for periodontal disease.

[0006] In particular, root canal infection, an infectious disease of bacterial etiology, is an important cause of tooth loss in the world. Current therapeutic modalities include scaling and root plaining of the surfaces of the teeth to eliminate bacterial plaque and calculus, and the use of antiseptic solutions to combat the infectious process caused by a wide spectrum of oral micro-organisms. These antiseptics, however, have high toxicity and consequently cannot be used for prolonged periods. In addition, some of the commonly used antiseptics have adverse side effects such as distortion of taste and staining of teeth.

[0007] Oxidative reductive potential (ORP) water, also known as super-oxidized water, can be used as a non-toxic disinfectant to eradicate microorganisms, including bacteria, viruses and spores, in variety of settings. For example, ORP water may be applied in the healthcare and medical device fields to disinfect surfaces and medical equipment. Advantageously, ORP water is environmentally safe and, thus, avoids the need for costly disposal procedures. ORP water also has application in wound care, medical device sterilization, food sterilization, hospitals, consumer households and anti-bioterrorism.

[0008] Although ORP water is an effective disinfectant, it has an extremely limited shelf-life, usually only a few hours. As a result of this short lifespan, the production of ORP water must take place in close proximity to where ORP water is to be used as a disinfectant. This means that a healthcare facility, such as a hospital, must purchase, house and maintain the equipment necessary to produce ORP water. Additionally, prior manufacturing techniques have not been able to produce sufficient commercial-scale quantities of ORP water to permit its widespread use as a disinfectant at healthcare facilities.

[0009] Accordingly, a need exists for an ORP water that is stable over an extended period of time and methods of using such an ORP water. A need also exists for cost-effective methods of preparing commercial-scale quantities of ORP water. The present invention provides such an ORP water and methods of preparing and using such an ORP water.

[0010] ORP water has also been used as a tissue cell growth promoter in patients as described in U.S. Patent Application Publication 2002/0160053 A1. However, the application of water that quickly loses contact with tissue does not maximize the effectiveness of the treatment. Accordingly, a need exists for compositions containing ORP water that remain in contact with the tissue being treated and that are stable over an extended period of time. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

[0011] The present invention provides a method of treating periodontal disease in a patient by administering an oxidative reductive potential (ORP) water solution, wherein the solution is stable for at least twenty-four hours. The invention also is directed to a method of treating periodontal disease in a patient by administering an oxidative reductive potential water solution, wherein the solution comprises anode water and cathode water. In one embodiment, the ORP water solution used in the method of the invention comprises hydrogen peroxide and one or more chlorine species.

[0012] The present invention additionally provides a method of treating damaged oral tissue, which method comprises contacting the impaired or damaged tissue with a therapeutically effective amount of an ORP water solution, wherein the solution is stable for at least twenty-four hours. The method includes treating tissue, which has been impaired or damaged by oral surgery or which has been impaired or damaged by causes that are not necessarily related to surgery, e.g., burns, cuts, abrasions, scrapes, rashes, ulcers, puncture wounds, infections, and the like.

[0013] The present invention also relates to a method of using an ORP water solution as an irrigant in an oral or maxillo-facial dental procedure by administering an ORP water solution to a patient in an amount sufficient to irrigate the site.

[0014] The present invention further provides a method of disinfecting a surface, which method comprises contacting the surface with an anti-infective amount of an ORP water solution, wherein the solution is stable for at least twenty-four hours. The surface can be biological, inanimate, or a combination of such surfaces can be disinfected in accordance with the present invention. Biological surfaces include, e.g., muscle tissue, bone tissue, organ tissue, mucosal tissue, and combinations thereof, can be disinfected in accordance with the present invention. Inanimate surfaces include, e.g., surgically implantable devices, prosthetic devices, and medical devices.

[0015] Another aspect of the present invention includes a formulation for topical administration comprising an oxidative reductive potential water solution and a thickening agent, wherein the formulation is stable for at least twenty-four hours.

[0016] The invention also pertains to a pharmaceutical dosage form comprising (1) a formulation for topical administration comprising an oxidative reductive potential water solution and a thickening agent and (2) a sealed container, wherein the formulation is stable for at least twenty-four hours.

[0017] Additionally, the invention is directed to a method for treating a condition in a patient comprising topically administering to a patient a therapeutically effective amount of a formulation comprising an oxidative reductive potential solution and a thickening agent, wherein the formulation is stable for at least about twenty-four hours.

[0018] The invention further provides a method for promoting wound healing in a patient comprising applying to a wound a formulation comprising an oxidative reductive potential water solution and a thickening agent, wherein the formulation is administered in an amount sufficient to promote wound healing, and wherein the formulation is stable for at least about twenty-four hours.

[0019] The invention additionally provides a method for preventing a condition in a patient comprising topically administering to a patient a therapeutically effective amount of a formulation comprising an oxidative reductive potential water solution and a thickening agent, wherein the formulation is stable for at least about twenty-four hours.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 is a schematic diagram of a three-chambered electrolysis cell for producing an oxidative reductive potential water solution of the present invention.

[0021] FIG. 2 illustrates a three-chambered electrolysis cell and depicts ionic species generated therein.

[0022] FIG. 3 is a schematic flow diagram of a process for producing an oxidative reductive potential water of the present invention.

[0023] FIG. 4A-4C depicts a graphical comparison of cell viability, apoptosis and necrosis in human dermal fibroblasts (HDFs) treated with an exemplary ORP water solution (MCN) versus hydrogen peroxide (HP).

[0024] FIG. 5 is a graphical comparison of the levels of 8-hydroxy-2’-deoxiguanosine (8-OHdG) adducts in HDFs treated with an exemplary ORP water solution (MCN) versus 500 .mu.M hydrogen peroxide (HP).

[0025] FIG. 6A-6B illustrate the expression of a senescence associated with .beta.-galactosidase in HDFs after chronic exposure to low concentrations of an exemplary ORP water solution (MCN) versus hydrogen peroxide (HP).

[0026] FIGS. 7A-B are graphical depictions of the patient groups and outcomes in the root canal study.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention provides a method of preventing or treating a condition in a patient, which method comprises administering to the patient a therapeutically effective amount of an oxidative reductive potential (ORP) water solution, wherein the solution is stable for at least twenty-four hours. The condition can include, e.g., medical conditions, illnesses, injuries, allergies, and the like, which are treatable with the ORP water solution of the present invention.

[0028] The therapeutically effective amount administered to the patient, e.g., an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic or prophylactic response in the patient over a reasonable time frame. The dose can be readily determined using methods that are well known in the art. One skilled in the art will recognize that the specific dosage level for any particular patient will depend upon a variety of factors. For example, the dose can be determined based on the strength of the particular ORP water solution employed, the severity of the condition, the body weight of the patient, the age of the patient, the physical and mental condition of the patient, general health, sex, diet, and the like. The size of the dose also can be determined based on the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular ORP water solution. It is desirable, whenever possible, to keep adverse side effects to a minimum.

[0029] Factors, which can be taken into account for a specific dosage can include, for example, bioavailability, metabolic profile, time of administration, route of administration, rate of excretion, pharmacodynamics associated with a particular ORP water solution in a particular patient, and the like. Other factors can include, e.g., the potency or effectiveness of the ORP water solution with respect to the particular condition to be treated, the severity of the symptoms presented prior to or during the course of therapy, and the like. In some instances, what constitutes a therapeutically effective amount also can be determined, in part, by the use of one or more of the assays, e.g., bioassays, which are reasonably clinically predictive of the efficacy of a particular ORP water solution for the treatment or prevention of a particular condition.

[0030] The ORP water solution of the present invention can be administered therapeutically, alone or in combination with one or more other therapeutic agents, to a patient, e.g., a human, e.g., to treat an existing condition. The ORP water solution of the present invention also can be administered prophylactically, alone or in combination with one or more other therapeutic agents, to a patient, e.g., a human, that has been exposed to one or more causative agents associated with the condition. For example, the ORP water solution of the invention can be suitably administered to a patient that has been exposed to one or more infection-causing microorganisms (e.g., viruses, bacteria and/or fungi) prophylactically to inhibit or decrease the likelihood of infection in a patient, or decrease the severity of an infection that develops as a result of such exposure.

[0031] One skilled in the art will appreciate that suitable methods of administering the ORP water solution of the present invention are available, and, although more than one route of administration can be used, a particular route can provide a more immediate and more effective reaction than another route. The therapeutically effective amount can be the dose necessary to achieve an “effective level” of the ORP water solution in an individual patient. The therapeutically effective amount can be defined, for example, as the amount required to be administered to an individual patient to achieve a blood level, tissue level, and/or intracellular level of the ORP water of the present invention to prevent or treat the condition in the patient.

[0032] When the effective level is used as a preferred endpoint for dosing, the actual dose and schedule can vary depending, for example, upon interindividual differences in pharmacokinetics, distribution, metabolism, and the like. The effective level also can vary when the ORP water solution of the present invention is used in combination with one or more therapeutic agents other than the ORP water solution of the present invention, e.g., one or more anti-infective agents, one or more “moderating,” “modulating” or “neutralizing agents,” e.g., as described in U.S. Pat. Nos. 5,334,383 and 5,622,848, one or more anti-inflammatory agents, and the like.

[0033] An appropriate indicator can be used for determining and/or monitoring the effective level. For example, the effective level can be determined by direct analysis (e.g., analytical chemistry) or by indirect analysis (e.g., with clinical chemistry indicators) of appropriate patient samples (e.g., blood and/or tissues). The effective level also can be determined, for example, by direct or indirect observations such as, e.g., the concentration of urinary metabolites, changes in markers associated with the condition (e.g., viral count in the case of a viral infection), decrease in the symptoms associated with the conditions, and the like.

[0034] The ORP water of the present invention can be administered using any suitable method of administration known in the art. The ORP water of the present invention can be administered in combination with one or more pharmaceutically acceptable carriers, vehicles, adjuvants, excipients, or diluents, which are known in the art. One skilled in the art can easily determine the appropriate formulation and method of administration for administering the ORP water in accordance with the present invention. Any necessary adjustments in dose can be readily made by a skilled practitioner to address the nature or severity of the condition being treated in view of other factors, such as, e.g., side effects, changes in the patient’s overall condition, and the like.

[0035] In one embodiment, the condition is an upper respiratory condition, which is treatable by the ORP water solution of the present invention. Any suitable method of administration can be employed for the treatment or prevention of an upper respiratory condition in accordance with the present invention. Preferably, the ORP solution is administered to the upper airway, e.g., so as to contact one or more upper airway tissues associated with the upper respiratory condition. The ORP solution of the present invention can be administered to the upper airway as a steam or a spray. In addition, the ORP water solution of the present invention can be administered by aerosolization, nebulization or atomization. When the ORP water solution of the invention is administered by aerosolization, nebulization or atomization, it is preferably administered in the form of droplets having a diameter in the range of from about 1 micron to about 10 microns.

[0036] Methods and devices, which are useful for aerosolization, nebulization and atomization, are well known in the art. Medical nebulizers, for example, have been used to deliver a metered dose of a physiologically active liquid into an inspiration gas stream for inhalation by a recipient. See, e.g., U.S. Pat. No. 6,598,602. Medical nebulizers can operate to generate liquid droplets, which form an aerosol with the inspiration gas. In other circumstances medical nebulizers may be used to inject water droplets into an inspiration gas stream to provide gas with a suitable moisture content to a recipient, which is particularly useful where the inspiration gas stream is provided by a mechanical breathing aid such as a respirator, ventilator or anaesthetic delivery system.

[0037] An exemplary nebulizer is described, for example, in WO 95/01137, which describes a hand held device that operates to eject droplets of a medical liquid into a passing air stream (inspiration gas stream), which is generated by a recipient’s inhalation through a mouthpiece. Another example can be found in U.S. Pat. No. 5,388,571, which describes a positive-pressure ventilator system which provides control and augmentation of breathing for a patient with respiratory insufficiency and which includes a nebulizer for delivering particles of liquid medication into the airways and alveoli of the lungs of a patient. U.S. Pat. No. 5,312,281 describes an ultrasonic wave nebulizer, which atomizes water or liquid at low temperature and reportedly can adjust the size of mist. In addition, U.S. Pat. No. 5,287,847 describes a pneumatic nebulizing apparatus with scalable flow rates and output volumes for delivering a medicinal aerosol to neonates, children and adults. Further, U.S. Pat. No. 5,063,922 describes an ultrasonic atomizer.

[0038] The method of the present invention can be used for preventing or treating an upper respiratory condition, which affects one or more upper respiratory airway tissues, particularly nasal tissue, sinus tissue, and lung tissue. Such upper respiratory conditions can include, for example, a sinusitis (e.g., a rhinosinusitis, an acute sinusitis, a chronic sinusitis, and the like), a pharyngitis, an asthma, and the like, which are preventable or treatable with the ORP solution of the present invention.

[0039] Chronic sinusitis typically refers to inflammation of the sinuses that continues for at least 3 weeks, but often continues for months or even years. Allergies are frequently associated with chronic sinusitis. In addition, patients with asthma have a particularly high frequency of chronic sinusitis. Inhalation of airborne allergens (substances that provoke an allergic reaction), such as dust, mold, and pollen, often set off allergic reactions (allergic rhinitis) that, in turn, may contribute to sinusitis. People who are allergic to fungi can develop a condition called “allergic fungal sinusitis.” Damp weather or pollutants in the air and in buildings also can affect people subject to chronic sinusitis.

[0040] Like acute sinusitis, chronic sinusitis is more common in patients with immune deficiency or abnormalities of mucus secretion or movement (e.g., immune deficiency, HIV infection, cystic fibrosis, Kartagener’s syndrome). In addition, some patients have severe asthma, nasal polyps, and severe asthmatic responses to aspirin and aspirin-like medications (so-called non-steroidal anti-inflammatory drugs, or NSAIDs). These latter patients have a high frequency of chronic sinusitis.

[0041] A doctor can diagnose sinusitis by medical history, physical examination, X-rays, and if necessary, MRIs or CT scans (magnetic resonance imaging and computed tomography). After diagnosing sinusitis and identifying a possible cause, a doctor can prescribe a course of treatment that will reduce the inflammation and relieve the symptoms. Treating acute sinusitis typically requires re-establishing drainage of the nasal passages, controlling or eliminating the source of the inflammation, and relieving the pain. Doctors generally recommend decongestants to reduce the congestion, antibiotics to control a bacterial infection, if present, and pain relievers to reduce the pain.

[0042] When treatment with drugs fails, surgery may be the only alternative for treating chronic sinusitis, e.g., removal of adenoids, removal of nasal polyps, repair of a deviated septum, endoscopic sinus surgery, and the like. It is believed that the administration of ORP water in accordance with the method of the present invention can be used for treating chronic sinusitis as an alternative to potentially avoid more aggressive therapies, such as antibiotics and surgery.

[0043] With regard to pharyngitis, it is estimated that worldwide, 1 to 2% of all visits to doctors’ offices, clinics and emergency rooms are because of pharyngitis. In the United States and Mexico, pharyngitis/tonsillitis accounts for a reported 15 and 12 million consultations per year, respectively. It has been established that these cases are caused by various bacteria and viruses. On the one hand we know that pharyngitis and tonsillitis caused by group A .beta.-hemolytic Streptococcus significantly raise the risk of rheumatic fever in poor populations. On the other hand, it is believed that only 5 to 15% of pharyngitis cases are caused by this bacterium, and that the rest of the acute cases are due to bacteria and viruses of little epidemiological relevance. The latter cases tend to be self-limiting in a few days and do not leave sequelae.

[0044] It has been verified that a great number of doctors worldwide prescribe antibiotics indiscriminately for acute pharyngitis. This occurs in a daily practice, often because patients tend to request powerful antibiotics. Unfortunately, it is difficult to establish an accurate diagnosis of streptococcal pharyngitis/tonsillitis clinically and the cost/benefit ratio of treating acute pharyngitis/tonsillitis with antibiotics is questionable. In some countries, such as Mexico, the waste of government resources to cover the cost of antibiotics, in addition to working days missed, represent a significant loss with respect to the national budget.

[0045] It is believed that the administration of ORP water in accordance with the method of the present invention can be useful for the adjuvant treatment of acute pharyngitis/tonsillitis. The empirical treatment of acute pharyngitis/tonsillitis may begin with administering an ORP water solution in accordance with the present invention, and, depending on evolution or the result of the rapid test for Streptococcus, antibiotics may be initiated from 48-72 hours thereafter only if needed. The method of the present invention may thus allow the use of antibiotics to be deferred, and, at the same time, reduce the symptomatology of the patient and accelerate the patient’s recovery if the pharyngitis/tonsillitis is not from group A Streptococcus. The adjuvant use of an ORP water solution of the present invention with antibiotics for the treatment of streptococcal pharyngitis/tonsillitis also may shorten the period of clinical response and decrease the incidence of recurrences.

[0046] The method of the present invention also can be used for the prevention or treatment of an infection, which is treatable with the ORP water solution of the present invention. The infection can be caused by one or more infectious pathogens such as, for example, infectious microorganisms. Such microorganisms can include, for example, viruses, bacteria, and fungi. The viruses can include, e.g., one or more viruses selected from the group consisting of adenoviruses, HIV, rhinoviruses, and flu viruses. The bacteria can include, e.g., one or more bacteria selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobaterium tuberculosis. The fungi can include, e.g., one or more fungi selected from the group consisting of Candida albicans, Bacillus subtilis and Bacillus athrophaeus. The method of the present invention also can be used for the prevention or treatment of inflammatory conditions or allergic reactions, which are treatable with the ORP water solution of the invention.

[0047] In addition, organisms that can be controlled, reduced, killed or eradicated by treatment with the ORP water solution used in accordance with the invention include, e.g., Pseudomonas aeruginosa, Escherichia coli, Enterococcus hirae, Acinetobacter baumannii, Acinetobacter species, Bacteroides fragilis, Enterobacter aerogenes, Enterococcus faecalis, Vancomycin resistant-Enterococcus faecium (VRE, MDR), Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Micrococcus luteus, Proteus mirabilis, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Salmonella choleraesuis, Shigella dysenteriae, and other susceptible bacteria, as well as yeasts, e.g., Trichophyton mentagrophytes, Candida albicans and Candida tropicalis. The ORP water solution can also be used in accordance with the invention to control, reduce, kill or eradicate viruses including, e.g., adenovirus, human immunodeficiency virus (HIV), rhinovirus, influenza (e.g., influenza A), hepatitis (e.g., hepatitis A), coronavirus (responsible for, e.g., Severe Acute Respiratory Syndrome (SARS)), rotavirus, avian flu virus, respiratory syncytial virus, herpes simplex virus, varicella zoster virus, rubella virus, and other susceptible viruses.

[0048] In another embodiment, the method of the present invention comprises parenterally administering the ORP water solution of the invention. Parenteral administration can include administering the ORP water solution of the invention intravenously, subcutaneously, intramuscularly, or intraperitoneally. In a preferred embodiment, the ORP water solution of the present invention is administered intravenously to prevent or treat a condition in accordance with the method of the present invention. Suitable conditions can include, e.g., viral myocarditis, multiple sclerosis, and AIDS. See, e.g., U.S. Pat. Nos. 5,334,383 and 5,622,848, which describe methods of treating viral myocarditis, multiple sclerosis, and AIDS via intravenous administration of ORP water solutions.

[0049] The present invention additionally provides a method of treating impaired or damaged tissue, which method comprises contacting the impaired or damaged tissue with a therapeutically effective amount of the ORP water solution of the present invention. Any suitable method can be used for contacting the impaired or damaged tissue, so as to treat the impaired or damaged tissue in accordance with the present invention. For example, the impaired or damaged tissue can be treated in accordance with the invention by irrigating the tissue with the ORP water solution of the invention, so as to contact the impaired or damaged tissue with the ORP water. Alternatively (and additionally), the ORP water solution of the present invention can be administered as a steam or a spray, or by aerosolization, nebulization or atomization, as described herein, so as to contact the impaired or damaged tissue with the ORP water.

[0050] The method of the present invention can be used in the treatment of tissues, which have been impaired or damaged, e.g., by surgery. For instance, the method of the present invention can be used for treating tissues, which have been impaired or damaged by an incision. In addition, the method of the present invention can be used for treating tissues, which have been impaired or damaged by oral surgery, graft surgery, implant surgery, transplant surgery, cauterization, amputation, radiation, chemotherapy, and combinations thereof. The oral surgery can include, for example, dental surgery such as, e.g., root canal surgery, tooth extraction, gum surgery, and the like.

[0051] The method of the present invention also includes treating tissues, which have been impaired or damaged by one or more burns, cuts, abrasions, scrapes, rashes, ulcers, puncture wounds, combinations thereof, and the like, which are not necessarily caused by surgery. The method of the present invention also can be used for treating impaired or damaged tissue, which is infected, or tissue impaired or damaged due to infection. Such infection can be caused by one or more infectious pathogens, such as, e.g., one or more microorganisms selected from the group consisting of viruses, bacteria, and fungi, as described herein.

[0052] The present invention further provides a method of disinfecting a surface, which method comprises contacting the surface with an anti-infective amount of the ORP water solution of the present invention. In accordance with the method of the present invention, the surface can be contacted using any suitable method. For example, the surface can be contacted by irrigating the surface with the ORP water solution of the invention, so as to disinfect the surface in accordance with the invention, for example during a root canal procedure. Additionally, the surface can be contacted by applying the ORP water solution of the present invention to the surface as a steam or a spray, or by aerosolization, nebulization or atomization, as described herein, so as to disinfect the surface in accordance with the invention. Further, the ORP water solution of the present invention can be applied to the surface with a cleaning wipe, as described herein. By disinfecting a surface in accordance with the present invention, the surface may be cleansed of infectious microorganisms. Alternatively (or additionally), the ORP water solution of the present invention can be applied to the surface to provide a barrier to infection, thereby disinfecting a surface in accordance with the present invention.

[0053] The method of the present invention can be used for disinfecting a surface, which is biological, inanimate, or a combination thereof. Biological surfaces can include, for example, tissues within one or more body cavities such as, for example, the oral cavity, the sinus cavity, the cranial cavity, the abdominal cavity, and the thoracic cavity. Tissues within the oral cavity include, e.g., mouth tissue, gum tissue, tongue tissue, and throat tissue. The biological tissue also can include muscle tissue, bone tissue, organ tissue, mucosal tissue, and combinations thereof. Inanimate surfaces include, for example, surgically implantable devices, prosthetic devices, and medical devices. In accordance with the method of the present invention, the surfaces of internal organs, viscera, muscle, and the like, which may be exposed during surgery, can be disinfected, e.g., to maintain sterility of the surgical environment.

[0054] The present invention also provides formulations for topical administration comprising an oxidative reductive potential (ORP) water solution and a thickening agent which are prepared to provide enhanced efficacy and stability.

[0055] The amount of water present the formulations of the invention is generally from about 10% by weight to about 95% by weight, based on the weight of the formulation. Preferably, the amount of water present is from about 50% by weight to about 90% by weight.

[0056] The formulations of the invention preferably include an ORP water solution comprising anode water and cathode water. Anode water is produced in the anode chamber of the electrolysis cell used in the present invention. Cathode water is produced in the cathode chamber of the electrolysis cell.

[0057] The formulation for topical administration according to the present invention further comprises a thickening agent. Any suitable thickening agent may be used to produce a formulation having the desired viscosity which is generally greater than the ORP water solution alone. The thickening agent utilized is compatible with the ORP water solution and other optional components in the formulation. Suitable thickening agents include, but are not limited to, polymers and hydroxyethylcellulose. Suitable polymers may be homopolymers or copolymers and are optionally crosslinked. Other suitable thickening agents are generally known in art (see, e.g., Handbook of Cosmetic and Personal Care Additives, 2nd ed., Ashe et al. eds. (2002), and Handbook of Pharmaceutical Excipients, 4th ed., Rowe et al. eds. (2003)).

[0058] Preferred thickening agents are acrylic acid-based polymers. More preferably, the thickening agents are high molecular weight, crosslinked, acrylic acid-based polymers. These polymers have the following general structure:

STR00001

[0059] Such polymers are sold under the tradename Carbopol.RTM. by Noveon. Carbopol.RTM. polymers are generally supplied as rheology modifiers for use thickeners, suspending agents, and stabilizers in a variety of personal care products, pharmaceuticals, and household cleaners. Carbopol.RTM. polymers may be used in either solid (e.g., powder) or liquid form.

[0060] The acrylic acid-based polymers suitable for use in the invention may be homopolymers or copolymers. Suitable homopolymers may be crosslinked, preferably with allyl sucrose or allylpentaerythritol. Suitable copolymers of acrylic acid are modified by long chain (C.sub.10-C.sub.30) alkyl acrylates and may be crosslinked, preferably with allylpentaerythritol.

[0061] Carbopol.RTM. polymers are neutralized in order to achieve maximum viscosity. As supplied, Carbopol.RTM. polymers are dry, tightly coiled acidic molecules, held in a coiled structure by hydrogen bonds. Once dispersed in water, or another solvent, they begin to hydrate and partially uncoil. The most common way to achieve maximum thickening from Carbopol.RTM. polymers is by converting the acidic polymer into a salt. This is easily achieved by neutralizing with a common base such as sodium hydroxide (NaOH) or triethanolamine (TEA). This neutralization “uncoils” the long chain polymer, swelling the molecule into an effective thickening form.

[0062] Suitable thickening agents will yield the desired viscosity for the formulation, as well as other characteristics, such as appearance, shear resistance, ion resistance, and thermal stability. For example, Carbopol.RTM. 934 is preferred for a formulation that is either a suspension or emulsion (rather than a clear gel) with a viscosity greater than 3000 centipoise (cps). Carbopol.RTM. 974P may alternatively be used for its advantageous bioadhesive properties.

[0063] Any suitable amount of a thickening agent is present in the formulation of the invention to yield the desired viscosity for the formulation. Generally, the amount of thickening agent is from about 0.1% by weight to about 50% by weight, based on the weight of the formulation. Preferably, the amount of thickening agent is from about 0.1% to about 10% by weight.

[0064] In other terms, the amount of thickening agent based on the volume of the ORP water solution is generally from about 0.1% weight/volume (mg/mL) to about 50% weight/volume (mg/mL). Preferably, the amount of thickening agent is from about 0.1% w/v to about 10% w/v.

[0065] The amount of thickening agent generally is from about 0.1 g/250 mL to about 50 mg/250 mL of the ORP water solution. Preferably, the amount of thickening agent present is from about 1 mg/250 mL to about 20 mg/250 mL of the ORP water solution and, most preferably, from about 3 mg/250 mL to about 15 mg/250 mL.

[0066] When acrylic acid-based polymers are used at low concentrations, the formulation flows easily with a slippery feel. At higher concentrations, the formulation of the invention has a high viscosity and is pseudoplastic and resistant to flow. When shear force is applied by a mixer or pump, the apparent viscosity is reduced, and the formulation may be pumped.

[0067] The formulation of the invention may optionally include a neutralizing agent. Any suitable neutralizing agent may be used to yield the desired pH of the formulation. Suitable neutralizing agents include, for example, sodium hydroxide, triethanolamine, ammonia, potassium hydroxide, L-arginine, AMP-95, Neutrol TE, Tris Amino, Ethomeen, di-isopropanolamine, and tri-isopropanolamine. Other neutralizing agents are generally known in the art (see, e.g., Handbook of Cosmetic and Personal Care Additives, 2nd ed., Ashe et al. eds. (2002), and Handbook of Pharmaceutical Excipients, 4th ed., Rowe et al. eds. (2003)). Suitable neutralizing agents may be either in liquid or solid form.

[0068] Preferably, the neutralizer triethanolamine used when the thickening agent is an acrylic acid-based polymer such as Carbopol.RTM.. The neutralizing agent converts the formulation into a gel.

[0069] Any suitable amount of neutralizing agent may be included in the formulation of the invention. Generally, the amount of neutralizing agent is from about 0.1% by weight to about 50% by weight, based on the weight of the formulation. Preferably, the amount of neutralizing agent is from about 0.1% to about 10% by weight, based on the weight of the formulation. On a volume basis, the amount of neutralizing agent is present in an amount of about 1% to about 50% by volume, based on the volume of the ORP water solution.

[0070] When added in liquid form, the neutralizing may be added in an amount of from about 1 mL/250 mL to about 100 mL/250 mL of the ORP water solution. Preferably, the amount of neutralizing agent is from about 10 mL/250 mL to about 90 mg/250 mL of the ORP water solution.

[0071] The formulation may further contain additional components such as colorants, fragrances, buffers, physiologically acceptable carriers and/or excipients, and the like. Examples of suitable colorants include, but are not limited to, titanium dioxide, iron oxides, carbazole violet, chromium-cobalt-aluminum oxide, 4-Bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester copolymers, and the like. Any suitable fragrance can be used.

[0072] The formulation of the invention may be prepared by any suitable means. The components of the formulation, such as the ORP water solution and thickening agent, may be mixed together in any manner to yield a homogenous mixture. Preferably, the components are mixed together for several minutes using an electric mixture or other suitable device to ensure uniformity. The components of the formulation are generally mixed from about 400 rpm to about 1000 rpm, preferably from about 500 rpm to about 800 rpm, and more preferably from about 500 rpm to about 600 rpm.

[0073] The formulation is mixed for a sufficient period of time to yield a homogenous mixture, generally from about 1 minute to about 10 minutes after all of the components have been combined.

[0074] When the thickening agent is in the form of a power, it may first be sieved to break up large agglomerates to allow for the preparation of a homogenous formulation.

[0075] A neutralizing agent, such as triethanolamine, may subsequently be added to the formulation containing the ORP water solution and thickening agent. As noted above, the addition of triethanolamine may allow the thickening agent, such as Carbopol.RTM., to uncoil and, thus, yield a formulation having the desired viscosity.

[0076] A colorant or fragrance may also be added to the mixture either before or after the thickening agent, such as Carbopol.RTM., is dissolved into the ORP water, but before the neutralization step.

[0077] The physical properties of the formulation of the invention are typically the same as those of the ORP water solution present in the formulation. The properties of the ORP water solution remain even after the addition of a thickening agent and optional neutralizing agent. For example, the stability and pH of the ORP water solution itself and the formulation containing the ORP water solution are generally the same. Accordingly, all of the characteristics of the ORP water solution described herein apply to the formulation of the invention.

[0078] For example, the formulation of the invention is generally stable for at least twenty-hours, and typically at least two days. More typically, the formulation is stable for at least one week (e.g., one week, two weeks, three weeks, four weeks, etc.), and preferably at least two months. More preferably, the formulation is stable for at least six months after its preparation. Even more preferably, the formulation is stable for at least one year, and most preferably for at least three years.

[0079] The pH of the formulation is generally from about 6 to about 8. Preferably, the pH of the formulation is from about 6.2 to about 7.8, more preferably from about 7.2 to about 7.5, and most preferably from about 7.4 to about 7.6.

[0080] The formulation of the invention may be used any form suitable for topical administration to a patient. A suitable form includes, but is not limited to, gel, lotion, cream, paste, ointment, and the like, which forms are known in the art (see, e.g., Modern Pharmaceutics, 3rd ed., Banker et al. ed. (1996)). Gels are typically a semisolid emulsion or suspension that has a three-dimensional structure. Preferably, the formulation is in the form of a gel.

[0081] Pastes are generally semisolid suspensions that often contain a large portion of solids (e.g., 20% to 50%) dispersed in an aqueous or fatty vehicle. Lotions are typically liquid emulsions containing a water-based vehicle and volatiles (more than 50%) and that have a sufficiently low viscosity (less than 30,000 cps) to be poured. Ointments and creams are generally semisolid emulsions or suspensions that may contain hydrocarbons or polyethylene glycols as part of the carrier along with other volatile components.

[0082] When the formulation of the invention is in the form of a gel, the viscosity of the gel is in the range of from about 10,000 to about 100,000 centipoise (cps) (e.g., about 15,000 cps, about 20,000 cps, about 25,000 cps, about 30,000 cps, about 35,000 cps, about 40,000 cps, about 45,000 cps, about 50,000 cps, about 55,000 cps, about 60,000 cps, about 65,000 cps, about 70,000 cps, about 75,000 cps, about 80,000 cps, about 85,000 cps, about 90,000 cps, about 95,000 cps, or ranges thereof) when measured at room temperature (about 25.degree. C.).

[0083] The pH of the gel is typically in the range of from about 6.0 to about 8.0. Above this pH, the viscosity of the thickening agent, such as the Carbopol.RTM. polymer, may decrease leading to an unsatisfactory topical formulation. Preferably, the pH of the gel is from about 6.4 to about 7.8, more preferably from about 7.2 to about 7.5, and more preferably, from about 7.4 to about 7.6.

[0084] The formulation of the invention is suitable for topical administration to a patient, including a human and/or animal, to treat a variety of conditions. Specifically, the formulation may be applied to animals (e.g., mice, rats, pigs, cows, horses, dogs, cats, rabbits, guinea pigs, hamsters, birds) and humans. Topical administration includes application to the skin as well as oral, intranasal, intrabronchial, and rectal routes of administration.

[0085] In another embodiment, the invention is directed to a method for treating a condition in a patient by topically administering a formulation comprising an ORP water solution and a thickening agent.

[0086] Conditions in a patient that may be treated according to the invention include, for example, the following: surgical/open wound cleansing agent; skin pathogen disinfection (e.g., for bacteria, mycoplasmas, virus, fungi, prions); wound disinfection (e.g., battle wounds); wound healing promotion; burn healing promotion; treatment of skin fungi; psoriasis; athlete’s foot; ear infections (e.g., swimmer’s ear); traumatic wounds; acute, subchronic and chronic infections (e.g. diabetic foot infections being an example of the latter), pressure ulcers, derma-abrasion, debrided wounds, laser re-surfacing, donor sites/grafts, exuding partial and full thickness wounds, superficial injuries (lacerations, cuts, abrasions, minor skin irritations) and other medical applications on or in the human or animal body. Ulcers treated according to the invention may or may not have abscesses or necrotic tissue present.

[0087] Additionally, the invention is directed to a method for promoting wound healing in a patient by applying to a wound a formulation comprising an oxidative reductive potential water solution and a thickening agent. The wound to be treated may be caused by any surgery, ulcer or other means. Ulcers that may be treated include, for example, diabetic foot ulcers.

[0088] The invention further relates to a method for preventing a condition in a patient by topically administering a formulation comprising an ORP water solution and a thickening agent. For example, the formulation (e.g., in the form of a gel) can be used as a barrier on open wounds to prevent infection. Specifically, the formulation (e.g., in the form of a gel) can be applied to the surface of a wound, such as a foot ulceration in a diabetic, who is prone to neurological and vascular complications. The formulation applied thusly can provide a barrier to infection, since these wounds are the principal portal for infection for diabetic patients.

[0089] The formulation may be used to prevent sexually transmitted diseases in a patient including, for example, infections. Such infections that may be prevented include herpes, human immunodeficiency virus (HIV) and vaginal infections. When the formulation is in the form of a gel, it may be used as a spermicide.

[0090] The formulation of the invention may be used or applied in a therapeutically effective amount to provide the desired therapeutic effect on bacteria, viruses, and/or germs. As used herein, a therapeutically effective amount refers to an amount of the formulation that results in an improvement of the condition being treated or to be prevented. For example, when used to treat an infection, a therapeutically effective amount of the formulation reduces the extent of the infection and/or prevents further infection. As is appreciated by one skilled in the art, the efficacy of the formulation of the invention resulting from administering the formulation may be short-term (i.e., a few days) and/or long-term (e.g., months).

[0091] The formulation may further be applied over a sufficient period of time, for example, about one, about two, several days, one week, or several weeks, until the desired effect on the patient is observed.

[0092] The formulation may be applied in any suitable manner. For example, a quantity of the formulation may be applied to the surface of the patient to be treated and then evenly spread using the patient’s own fingers. Alternatively, a health care provider may apply the formulation to the patient’s tissue. A suitable implement, for example, a disposable wipe or cloth, may be used to apply the formulation.

[0093] The ORP water of the present invention is produced by an oxidation-reduction process, which can be referred to as an electrolytic or redox reaction, in which electrical energy is used to produce chemical change in an aqueous solution. Electrical energy is introduced into and transported through water by the conduction of electrical charge from one point to another in the form of an electrical current. In order for the electrical current to arise and subsist there must be charge carriers in the water, and there must be a force that makes the carriers move. The charge carriers can be electrons, as in the case of metal and semiconductors, or they can be positive and negative ions in the case of solutions.

[0094] A reduction reaction occurs at the cathode while an oxidation reaction occurs at the anode in the process for preparing an ORP water solution according to the invention. The specific reductive and oxidative reactions that occur are described in International Application WO 03/048421 A1.

[0095] As used herein, water produced at an anode is referred to as anode water and water produced at a cathode is referred to as cathode water. Anode water contains oxidized species produced from the electrolytic reaction while cathode water contains reduced species from the reaction.

[0096] Anode water generally has a low pH typically of from about 1 to about 6.8. Anode water generally contains chlorine in various forms including, for example, chlorine gas, chloride ions, hydrochloric acid and/or hypochlorous acid. Oxygen in various forms is optionally present including, for example, oxygen gas, peroxides, and/or ozone. Cathode water generally has a high pH typically of from about 7.2 to about 11. Cathode water generally contains hydrogen gas, hydroxyl radicals, and/or sodium ions.

[0097] The ORP water solution of the invention may be acidic, neutral or basic, and generally has a pH of from about 1 to about 14. At this pH, the ORP water solution can safely be applied in suitable quantities to hard surfaces without damaging the surfaces or harming objects, such as human skin, that comes into contact with the ORP water solution. Typically, the pH of the ORP water solution is from about 3 to about 8. More preferably, the pH of the ORP water solution is from about 6.4 to about 7.8, even more preferably from about 7.2 to about 7.5, and most preferably, the pH is from about 7.4 to about 7.6.

[0098] The ORP water solution of the present invention generally has an oxidation-reduction potential of from about -1000 millivolts (mV) to about +1350 millivolts (mV). This potential is a measure of the tendency (i.e., the potential) of a solution to either accept or transfer electrons that is sensed by a metal electrode and compared with a reference electrode in the same solution. This potential may be measured by standard techniques including, for example, by measuring the electrical potential in millivolts of the ORP water solution relative to standard reference silver/silver chloride electrode. The ORP water generally has a potential from about -400 mV to +1150 mV. Preferably, the ORP water solution has a potential from about 0 mV to about +1250 mV, and more preferably from about +500 mV to about +1250 mV. Even more preferably, the ORP water of the present invention has a potential from about +800 mV to about +1100 mV, even more preferably from about +800 mV to about +1000 mV, and most preferably from about +850 mV to about +1000 mV.

[0099] Various ionic and other species may be present in the ORP water solution of the invention. For example, the ORP water solution may contain chlorine (e.g., free chlorine and bound chlorine), and optionally, ozone and peroxides (e.g., hydrogen peroxide). The presence of one or more of these species is believed to contribute to the disinfectant ability of the ORP water solution to kill a variety of microorganisms, such as bacteria and fungi, as well as viruses.

[0100] Free chlorine typically includes, but is not limited to, hypochlorous acid (HClO), hypochlorite ions (ClO.sup.-), sodium hypochlorite (NaOCl), chloride ion (Cl.sup.-), chlorite ions (ClO.sub.2.sup.-), dissolved chlorine gas (Cl.sub.2), and other radical chlorine species. The ratio of hypochlorous acid to hypochlorite ion is dependent upon pH. At a pH of 7.4, hypochlorous acid levels are from about 25 ppm to about 75 ppm. Temperature also impacts the ratio of the free chlorine component.

[0101] Bound chlorine is chlorine in chemical combination with ammonia or organic amines (e.g., chloramines). Bound chlorine is generally present in an amount up to about 20 ppm.

[0102] Chlorine, and, optionally ozone and hydrogen peroxide may present in the ORP water solution of the invention in any suitable amount. The levels of these components may be measured by methods known in the art.

[0103] Typically, the total chlorine content, which includes both free chlorine and bound chlorine, is from about 50 parts per million (ppm) to about 200 ppm. Preferably, the total chlorine content is about 80 ppm to about 150 ppm.

[0104] The chlorine content may be measured by methods known in the art, such as the DPD colorimeter method (Lamotte Company, Chestertown, Md.) or other known methods established by the Environmental Protection Agency. In the DPD colorimeter method, a yellow color is formed by the reaction of free chlorine with N,N-diethyl-p-phenylenediamine (DPD) and the intensity is measured with a calibrated calorimeter that provides the output in parts per million. Further addition of potassium iodide turns the solution a pink color to provide the total chlorine value. The amount of bound chlorine present is then determined by subtracting free chlorine from the total chlorine.

[0105] Typically, chlorine dioxide is present in an amount of from about 0.01 ppm to about 5 ppm, preferably from about 1.0 ppm to about 3.0 ppm, and more preferably from about 1.0 ppm to about 1.5 ppm.

[0106] Ozone is optionally present in an amount of from about 0.03 ppm to about 0.2 ppm, and preferably from about 0.10 ppm to about 0.16 ppm. Hydrogen peroxide levels in the ORP water solution are optionally in the range of about 0.01 ppm to about 200 ppm, and preferably between about 0.05 ppm and about 100 ppm. More preferably, hydrogen peroxide is present in an amount between about 0.1 ppm and about 40 ppm, and most preferably between about 1 ppm and 4 ppm. Peroxides (e.g., H.sub.2O.sub.2, H.sub.2O.sub.2.sup.- and HO.sub.2.sup.-) are generally present in a concentration of less than 0.12 milliMolar (mM).

[0107] The total amount of oxidizing chemical species present in the ORP water solution is in the range of about 2 millimolar (mM) which includes the aforementioned chlorine species, oxygen species, and additional species that may be difficult to measure such as Cl.sup.-, ClO.sub.3, Cl.sub.2.sup.-, and ClO.sub.x. The level of oxidizing chemical species present may also be measured by ESR spectroscopy (using Tempone H as the spin trap molecule).

[0108] The ORP water solution of the invention is generally stable for at least about twenty-four hours, and typically at least about two days. More typically, the water solution is stable for at least about one week (e.g., about one week, about two weeks, about three weeks, about four weeks, etc.), and preferably at least about two months. More preferably, the ORP water solution is stable for at least about six months after its preparation. Even more preferably, the ORP water solution is stable for at least about one year, and most preferably for at least about three years.

[0109] As used herein, the term stable generally refers to the ability of the ORP water solution remain suitable for its intended use, for example, in decontamination, disinfection, sterilization, anti-microbial cleansing, and wound cleansing, for a specified period of time after its preparation under normal storage conditions (i.e., room temperature).

[0110] The ORP water solution of the invention is also stable when stored under accelerated conditions, typically about 30.degree. C. to about 60.degree. C., for at least about 90 days, and preferably about 180 days.

[0111] The concentrations of ionic and other species present solution are generally maintained during the shelf-life of the ORP water solution. Typically, the concentrations of free chlorine, and, optionally, ozone and hydrogen peroxides are maintained at about 70% or great from their initial concentration for at least about two months after preparation of the ORP water solution. Preferably, these concentrations are maintained at about 80% or greater of their initial concentration for at least about two months after preparation of the ORP water solution. More preferably, these concentrations are at about 90% or greater of their initial concentration for at least about two months after preparation of the ORP water solution, and most preferably, about 95% or greater.

[0112] The stability of the ORP water solution of the invention may be determined based on the reduction in the amount of organisms present in a sample following exposure to the ORP water solution. The measurement of the reduction of organism concentration may be carried out using any suitable organism including bacteria, fungi, yeasts, or viruses. Suitable organisms include, but are not limited to, Escherichia coli, Staphylococcus aureus, Candida albicans, and Bacillus athrophaeus (formerly B. subtilis). The ORP water solution is useful as both a low-level disinfectant capable of an about four log (10.sup.4) reduction in the concentration of live microorganisms and a high-level disinfectant capable of an about six log (10.sup.6) reduction in concentration of live microorganisms.

[0113] In one aspect of the invention, the ORP water solution is capable of yielding at least an about four log (10.sup.4) reduction in total organism concentration following exposure for one minute, when measured at least two months after preparation of the solution. Preferably, the ORP water solution is capable of such a reduction of organism concentration when measured at least about six months after preparation of the solution. More preferably, the ORP water solution is capable of such a reduction of organism concentration when measured at least about one year after preparation of the ORP water solution, and most preferably when measured at least three years after preparation of the ORP water solution.

[0114] In another aspect of the invention, the ORP water solution is capable of at least an about six log (10.sup.6) reduction in the concentration of a sample of live microorganisms selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans within one minute of exposure, when measured at least two months after preparation of the ORP water solution. Preferably, the ORP water solution is capable of achieving this reduction of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus or Candida albicans organisms when measured at least about six months after preparation, and more preferably at least about one year after preparation. Preferably, the ORP water solution is capable of at least an about seven log (10.sup.7) reduction in the concentration of such live microorganism within about one minute of exposure, when measured at least about two months after preparation.

[0115] The ORP water solution of the invention is generally capable of reducing a sample of live microorganisms including, but not limited to, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, from an initial concentration of from about 1.times.10.sup.6 to about 1.times.10.sup.8 organisms/ml to a final concentration of about zero organisms/ml within about one minute of exposure, when measured at least about two months after preparation of the ORP water solution. This is from an about six log (10.sup.6) to an about eight log (10.sup.8) reduction in organism concentration. Preferably, the ORP water solution is capable of achieving this reduction of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus or Candida albicans organisms when measured at least about six months after preparation, and more preferably at about least one year after preparation.

[0116] Alternatively, the ORP water solution is capable of an about six log (10.sup.6) reduction in the concentration of a spore suspension of Bacillus athrophaeus spores within about five minutes of exposure, when measured at least about two months after preparation of the ORP water solution. Preferably, the ORP water solution is capable of achieving this reduction in the concentration of Bacillus athrophaeus spores when measured at least about six months after preparation, and more preferably at least about one year after preparation.

[0117] The ORP water solution is further capable of an about four log (10.sup.4) reduction in the concentration of a spore suspension of Bacillus athrophaeus spores within about thirty (30) seconds of exposure, when measured at least about two months after preparation of the ORP water solution. Preferably, the ORP water solution is capable of achieving this reduction in the concentration of Bacillus athrophaeus spores when measured at least six months after preparation, and more preferably at least one year after preparation.

[0118] The ORP water solution is also capable of an about six log (10.sup.6) reduction in the concentration of fungal spores, such as Aspergillis niger spores, within about five to about ten minutes of exposure, when measured at least two months after preparation of the ORP water solution. Preferably, the ORP water solution is capable of achieving this reduction in the concentration of fungal spores when measured at least about six months after preparation, and more preferably at about least one year after preparation.

[0119] In one embodiment, the ORP water solution of the invention optionally comprises hydrogen peroxide (H.sub.2O.sub.2) and one or more chlorine species. Preferably, the chlorine species present is a free chlorine species. The free chlorine species may be selected from the group consisting of hypochlorous acid (HOCl), hypochlorite ions (OCl.sup.-), sodium hypochlorite (NaOCl), chlorite ions (ClO.sub.2.sup.-), chloride ion (Cl.sup.-), dissolved chlorine gas (Cl.sub.2), and mixtures thereof.

[0120] Hydrogen peroxide is optionally present in the ORP water solution generally in the range of from about 0.01 ppm to about 200 ppm, and preferably from about 0.05 ppm to about 100 ppm. More preferably, hydrogen peroxide when optionally, is present in an amount from about 0.1 ppm and to about 40 ppm, and most preferably from about 1 ppm to about 4 ppm.

[0121] The total amount of free chlorine species is generally from about 10 ppm to about 400 ppm, preferably from about 50 ppm to about 200 ppm, and most preferably from about 50 ppm to about 80 ppm. The amount of hypochlorous acid is in the generally from about 15 ppm to about 35 ppm. The amount of sodium hypochlorite is generally in the range from about 25 ppm to about 50 ppm.

[0122] The ORP water solution comprising one or more chlorine species is stable as described herein. Generally, the ORP water solution is stable for at least about one week. Preferably, the ORP water solution is stable for at least about two months, more preferably, the ORP water solution is stable for at least about six months after its preparation. Even more preferably, the ORP water solution is stable for at least about one year, and most preferably for at least about three years.

[0123] The pH of the ORP water solution in this embodiment is generally from about 6 to about 8. Preferably, the pH of the ORP water solution is from about 6.2 to about 7.8, and most preferably from about 7.4 to about 7.6. An exemplary ORP water solution of the present invention can comprise, e.g., from about 15 ppm to about 35 ppm hypochlorous acid, from about 25 ppm to about 50 ppm sodium hypochlorite, a pH of from about 6.2 to about 7.8, and is stable for at least about one week.

[0124] While in no way limiting the present invention, it is believed that the control of pH permits a stable ORP water solution in which hydrogen peroxide and chlorine species, such as, by way of example, hypochlorous acid and hypochlorite ions, coexist.

[0125] Following its preparation, the ORP water solution or the formulation of the invention may be transferred to a sealed container for distribution and sale to end users such as, for example, health care facilities including hospitals, nursing homes, doctor offices, outpatient surgical centers, dental offices, and the like. The pharmaceutical dosage form according to the present invention comprises the formulation for topical administration as described herein and a sealed container into which the formulation is placed.

[0126] Any suitable sealed container may be used that maintains the sterility and stability of the ORP water solution or formulation held by the container. The container may be constructed of any material that is compatible with the ORP water solution or the components of the formulation, for example, the ORP water solution and the thickening agent. The container should be generally non-reactive so that the ions present in the ORP water solution do not react with the container to any appreciable extent.

[0127] Preferably, the container is constructed of plastic or glass. The plastic may be rigid so that the container is capable of being stored on a shelf. Alternatively, plastic may be flexible, such as a flexible bag.

[0128] Suitable plastics include polypropylene, polyester terephthalate (PET), polyolefin, cycloolefin, polycarbonate, ABS resin, polyethylene, polyvinyl chloride, and mixtures thereof. Preferably, the container comprises polyethylene selected from the group consisting of high-density polyethylene (HDPE), low-density polyethylene (LDPE), and linear low-density polyethylene (LLDPE). Most preferably, the container is high density polyethylene.

[0129] The container has an opening to permit dispensing of the ORP water solution or formulation for administration to a patient. The container opening may be sealed in any suitable manner. For example, the container may be sealed with a twist-off cap or stopper. Optionally, the opening may be further sealed with a foil layer.

[0130] The headspace gas of the sealed container may be air or other suitable gas that does not react with the ORP water solution or other components of a formulation containing the ORP water solution. Suitable headspace gases included nitrogen, oxygen, and mixtures thereof.

[0131] The invention further provides an ORP water solution comprising anode water and cathode water. Anode water is produced in the anode chamber of the electrolysis cell used in the present invention. Cathode water is produced in the cathode chamber of the electrolysis cell.

[0132] Cathode water is generally present in the ORP water solution of the solution in an amount of from about 10% by volume to about 90% by volume of the solution. Preferably, cathode water is present in the ORP water solution in an amount of from about 10% by volume to about 50% by volume, more preferably of from about 20% by volume to about 40% by volume of the solution, and most preferably of from about 20% by volume to about 30% by volume of the solution. Additionally, anode water may be present in the ORP water solution in an amount of from about 50% by volume to about 90% by volume of the solution.

[0133] As noted herein, the ORP water solution containing both anode water and cathode water can be acidic, neutral or basic, and generally has a pH of from about 1 to about 14. Typically, the pH of the ORP water solution is from about 3 to about 8. Preferably, the pH is about 6.4 to about 7.8, and more preferably from about 7.4 to about 7.6.

[0134] The ORP water solution of the invention has a wide variety of uses as a disinfectant, cleanser, cleaner, antiseptic and the like to control the activity of unwanted or harmful substances present in the environment. Substances that may be treated with the ORP water solution include, for example, organisms and allergens.

[0135] The ORP water solution may be used as a disinfectant, sterilization agent, decontaminant, antiseptic and/or cleanser. The ORP water solution of the invention is suitable for use in the following representative applications: medical, dental and/or veterinary equipment and devices; food industry (e.g., hard surfaces, fruits, vegetables, meats); hospitals/health care facilities (e.g., hard surfaces); cosmetic industry (e.g., skin cleaner); households (e.g., floors, counters, hard surfaces); electronics industry (e.g., cleaning circuitry, hard drives); and bio-terrorism (e.g., anthrax, infectious microbes).

[0136] The ORP water solution may also be applied to humans and/or animals to treat various conditions including, for example, the following: surgical/open wound cleansing agent; skin pathogen disinfection (e.g., for bacteria, mycoplasmas, virus, fungi, prions); battle wound disinfection; wound healing promotion; burn healing promotion; treatment of stomach ulcers; wound irrigation; skin fungi; psoriasis; athlete’s foot; pinkeye and other eye infections; ear infections (e.g., swimmer’s ear); lung/nasal/sinus infections; and other medical applications on or in the human or animal body. The use of ORP water solutions as a tissue cell growth promoter is further described in U.S. Patent Application Publication 2002/0160053 A1.

[0137] While in no way limiting the present invention, it is believed that the ORP water solution eradicates the bacteria with which it contacts as well as destroying the bacterial cellular components including proteins and DNA.

[0138] For instance, the ORP water solution is capable of at least about five log (10.sup.5) reduction in the concentration of a sample of live microorganism selected from the group consisting of Pseudomonas aeruginosa, Escherichia coli, Enterococcus hirae, Acinetobacter baumannii, Acinetobacter species, Bacteroides fragilis, Enterobacter aerogenes, Enterococcus faecalis, Vancomycin Resistant-Enterococcus faecium (VRE, MDR), Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Micrococcus luteus, Proteus mirabilis, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Candida albicans and Candida tropicalis, within 30 seconds of exposure, when measured at least two months after preparation of the ORP water solution.

[0139] In one embodiment, the ORP water solution administered in accordance with the invention can reduce a sample of live microorganisms including, but not limited to, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, from an initial concentration of from about 1.times.10.sup.6 to about 1.times.10.sup.8 organisms/ml to a final concentration of about zero organisms/ml within about one minute of exposure when measured at least about two months after preparation of the ORP water solution. This corresponds to from about a six log (10.sup.6) to about an eight log (10.sup.8) reduction in organism concentration. Preferably, the ORP water solution is capable of achieving an about 10.sup.6-about 10.sup.8 reduction of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus or Candida albicans organisms when measured at least about six months after preparation, and more preferably when measured at least about one year after preparation.

[0140] Alternatively, the ORP water solution administered in accordance with the present invention can produce about a six log (10.sup.6) reduction in the concentration of a spore suspension of Bacillus athrophaeus spores within about five minutes of exposure when measured at least about two months after preparation of the ORP water solution. Preferably, the ORP water solution administered in accordance with the invention can achieve about a 10.sup.6 reduction in the concentration of Bacillus athrophaeus spores when measured at least about six months after preparation, and more preferably when measured at least about one year after preparation. The ORP water solution is further capable of an about four log (10.sup.4) reduction in the concentration of a spore suspension of Bacillus athrophaeus spores within about thirty (30) seconds of exposure, when measured at least two months after preparation of the ORP water solution. Preferably, the ORP water solution is capable of achieving this reduction in the concentration of Bacillus athrophaeus spores when measured at least about six months after preparation, and more preferably at least one about year after preparation.

[0141] The ORP water solution is also capable of an about six log (10.sup.6) reduction in the concentration of fungal spores, such as Aspergillis niger spores, within about five to about ten minutes of exposure, when measured at least two months after preparation of the ORP water solution. Preferably, the ORP water solution is capable of achieving this reduction in the concentration of fungal spores when measured at least six months after preparation, and more preferably at least one year after preparation.

[0142] The ORP water solution administered in accordance with the invention further can produce more than 3 log (10.sup.3) reduction in the concentration of viruses, such as Human Immunodeficiency Virus (HIV) and adenovirus, after from an about five to an about ten minutes exposure when measured at least about two months after preparation of the ORP water solution. Preferably, the ORP water solution can achieve a >10.sup.3 reduction in the concentration of viruses when measured at least about six months after preparation, and more preferably when measured at least about one year after preparation.

[0143] The ORP water solution administered in accordance with the invention further can completely inhibit the growth of Mycobacterium bovis with an about five minutes exposure when measured at least about two months after preparation of the ORP water solution. Preferably, the ORP water solution can achieve the total inhibition in the concentration of Mycobacteria when measured at least about six months after preparation, and more preferably when measured at least about one year after preparation.

[0144] Accordingly, organisms that can be controlled, reduced, killed or eradicated by treatment with the ORP water solution include, but are not limited to, bacteria, fungi, yeasts, and viruses. Susceptible bacteria include, but are not limited to, Escherichia coli, Staphylococcus aureus, Bacillus athrophaeus, Streptococcus pyogenes, Salmonella choleraesuis, Pseudomonas aeruginosa, Shingella dysenteriae, and other susceptible bacteria. Fungi and yeasts that may be treated with the ORP water solution include, for example, Candida albicans and Trichophyton mentagrophytes. The ORP water solution may also be applied to viruses including, for example, adenovirus, human immunodeficiency virus (HIV), rhinovirus, influenza (e.g., influenza A), hepatitis (e.g., hepatitis A), coronavirus (responsible for Severe Acute Respiratory Syndrome (SARS)), rotavirus, respiratory syncytial virus, herpes simplex virus, varicella zoster virus, rubella virus, and other susceptible viruses.

[0145] In a preferred embodiment, the ORP water solution of the invention can be utilized in a variety of dental applications. First, the ORP water solution can be administered to patients for the routine disinfection of the oral cavity as part of an on-going program of oral hygiene. Second, the ORP water solution can be used to irrigate and/or disinfect oral tissues, tooth surfaces, cavities, or a tooth canal during oral or maxillo-facial procedures. Third, the ORP water solution can be administered to treat patients with damage to the oral tissues caused by, for example, oral or maxillo-facial procedures or disease. Finally, the ORP water solution can be used to disinfect objects related to dentistry, including, for example, dental instruments, irrigation lines of a dental office irrigation system, and dentures.

[0146] The use of antiseptic solutions, such as chlorhexidine, hydrogen peroxide, and bleach, in dental applications is known in the art. Current oral antiseptic solutions suffer from several disadvantages. Significantly, these oral antiseptics have high toxicity and can damage healthy tissue, resulting in a delay in healing time. Also, due to high toxicity, these oral antiseptics cannot be used for prolonged periods of time. Other adverse side affects include distortion of taste and staining of teeth. Conversely, ORP water solution is neither toxic nor irritating and offers an improved approach to treatment and disinfection with oral antiseptic solutions.

[0147] In one embodiment, the ORP water solution can be administered to patients for the routine disinfection of the oral cavity as part of an on-going program of oral hygiene. The ORP water solution reduces levels of a wide spectrum of oral micro-organisms present in the oral cavity, thereby decreasing the occurrence of infectious diseases. The ORP water solution is administered to patients in any suitable manner. Preferably, the ORP water solution is administered as a mouthrinse or mouthwash. Preferably, patients rinse for at least about 30 seconds, more preferably for at least about one minute, and most preferably for at least about two minutes. Patients rinse daily, for example, or twice a day, or three times a day. Preferably, patients should rinse with ORP water solution after meals. Patients should brush and floss their teeth daily in combination with rinsing with ORP water solution. Patients can, for example, brush and floss their teeth before rinsing with the ORP water solution.

[0148] The reduction in oral microbial flora upon rinsing with the ORP water solution can be monitored. Oral microbioal flora levels are measured by culturing bacteriological swabs taken from the buccal mucosa. First, a baseline bacteriological swab is taken. The immediate reduction in oral microbial flora upon rinsing with ORP water solution can be determined by taking bacteriological swabs about ten minutes after rinsing and about fifteen minutes after rinsing. The long term reduction in oral microbial flora after a regimen of rinsing can also determined. For example, bacteriological swabs can be taken after one month of rinsing with the ORP water solution.

[0149] In a second embodiment, the ORP water solution can also be used as an irrigant and/or disinfectant during oral or maxillo-facial procedures. The ORP water solution can be used as the irrigant in ultrasonic scaling. Ultrasonic scaling is a procedure for the treatment of periodontal disease that removes plaque above and below the gum line. The ultrasonic scaler is operated in conjunction with a coolant or irrigant, and the cavitational activity within the solution contributes to the disruption and removal of plaque. Typically, the irrigant is water. The use of ORP water solution instead of water can slow the recolonization of microbes after removal of plaque. The treatment can be monitored with an assessment of inflammation, bleeding and pocket depths. The ultrasonic scaling with ORP water solution as the irrigant can be combined with other follow up treatments. The patient should brush and floss teeth daily. Preferably, the ultrasonic scaling is combined with the outpatient administration of ORP water solution in the form of a rinse. The patient rinses with ORP water solution for at least about two months or preferably at least about three months after the ultrasonic scaling procedure.

[0150] The ORP water solution is used an irrigant to cleanse and disinfect a cavity or a tooth canal during tooth restoration. Treatment for tooth decay or cavities consists of removing the decayed material and replacing it with restorative, or filling, material. First, the decayed material is removed by drilling. Next, the tooth is prepared for filling, including the steps of cleaning and disinfecting the dentin surface and/or enamel. The ORP water solution can be used as an irrigating solution to wash away debris such as debrided tooth material. Alternatively, the ORP water solution can be used to disinfect the dentin surface and/or enamel prior to filling. The ORP water solution can be applied by spraying the surface or moistening the surface with a brush or sponge. Similarly, the ORP water solution can be used as an irrigating solution during endodontic, or root canal, therapy. Endodontic therapy is required if the patient has a bacterial infection in a tooth’s nerve tissue. Endodontic therapy consists of making an access hole to the pulp chamber with a drill, cleaning out the interior of the tooth, filling and sealing the interior of the tooth with root canal filling material, and filling in the access hole. As part of the cleaning step, irrigants are used to dissolve and flush out debris. The ORP water solution can be used as the irrigant during endodontic therapy. Alternatively, the ORP water solution can be used to disinfect the interior tooth after cleaning and prior to filling.

[0151] The ORP water solution is used as an irrigant and/or antiseptic during tooth extraction. After the tooth is extracted, the socket is irrigated with the ORP water solution to dissolve and flush out debris. The socket can be irrigated for at least about 30 seconds, or at least about one minute, or at least about two minutes, or longer if required. Preferably, the ORP water solution is used when the tooth is extracted due to an abscess or periodontal disease.

[0152] The ORP water solution is used as an irrigant and/or intraoperative antiseptic during maxillo-facial surgeries. Two recurrent problems in maxillo-facial surgery are bleeding and infection. The ORP water solution reduces bleeding in the surgical field. The ORP water solution also decreases post-operative healing time.

[0153] The ORP water solution is administered to patients undergoing maxillo-facial surgeries in any suitable manner. The ORP water solution can be administered immediately before, during, or immediately after the surgery. For example, the entire oral cavity can be rinsed once, twice, or three times prior to an incision. Preferably, the oral cavity is rinsed twice. The ORP water solution can be used to irrigate the operation site. Preferably, the ORP water solution is used to the flush operation site prior to suturing. The operation site can be irrigated for at least one minute, or at least two minutes, or at least three minutes, or longer if required.

[0154] In a third embodiment, the ORP water solution may be administered to patients with oral tissues damaged by disease or an oral or maxillo-facial procedure. Preferably, the ORP water solution is administered to patients suffering from periodontal diseases. Periodontal disease is a chronic bacterial infection that affects the gums and bone supporting the teeth and is one of the leading causes of tooth loss. Disease causing bacteria are present in the plaque above and below the gum line. Examples of periodontal diseases include gingivitis, or inflammation of the gingival tissues, and periodontitis, an inflammatory disease of the periodontium. Treatment with ORP water solution results in arresting the infection. There is also a reduction or elimination of inflammation and bleeding. Furthermore, in many cases, treatment with ORP water solution results in bone regeneration, halting the loss of periodontal attachment.

[0155] The ORP water solution is administered to patients suffering from periodontal diseases in any suitable manner. Preferably, the ORP water solution is administered as a mouthrinse or mouthwash. Preferably, patients rinse for at least about 30 seconds, more preferably for at least about one minute, and most preferably for at least about two minutes. Patients rinse daily, or twice a day, or preferably three times a day. Preferably, patients should rinse with ORP water solution after meals. Patients should brush and floss their teeth daily in combination with rinsing with ORP water solution. The treatment of periodontal disease using the ORP water solution may continue until the disease is resolved. Depending on the progression of the disease, the ORP water solution can be administered for at least about one month, or preferably about two months, or more preferably about three months, or longer. The administration of the ORP water solution can be combined with other treatments for periodontal diseases. Such treatments include mechanical removal of plaque and calculus and administration of antibiotics. Preferably, administration of the ORP water solution is combined with mechanical removal of plaque and calulus. Preferably, administration of the ORP water solution is not combined with antibiotics.

[0156] The ORP water solution can also be administered to patients with oral mucosal lesions or ulcers. Lesions are accompanied by pain and redness, and can impair chewing and swallowing. The lesions or ulcers have many causes. For example, denture stomatitis are lesions caused by wearing dentures. Patients who are immuno-compromised are also more likely to develop oral mucosal lesions or ulcers. Oral candidiasis, a fungal infection of the mucous membrane, causes lesions around the mouth. Oral mucositis is a common side effect experienced by patients undergoing cancer treatment, such as chemotherapy, radiation, or bone marrow transplant.

[0157] The ORP water solution is administered to patients suffering from oral mucosal lesions or ulcers in any suitable manner. Preferably, the ORP water solution is administered as a mouthrinse or mouthwash. Preferably, patients rinse for at least about 30 seconds, more preferably for at least about one minute, and most preferably for at least about two minutes. Patients rinse daily, or twice a day, or more preferably three times a day. The treatment of oral mucosal lesions or ulcers using the ORP water solution may continue until the lesions or ulcers are healed. Depending on the progression of the disease, the ORP water solution can be administered for about two weeks, for example, or about three weeks, or about four weeks, or about two months, or longer. The administration of the ORP water solution may be prophylactic in patients who are susceptible to oral mucosal lesions or ulcers.

[0158] The ORP water solution can be administered to patients to promote healing of oral tissues injured, for example, by dental procedures, oral surgery, or maxillo-facial surgery. The ORP water solution can be administered as post-operative follow up to such procedures or surgeries. Patients exhibit decreased healing time as compared to standard treatment without ORP water solution.

[0159] The ORP water solution is administered to patients after undergoing an oral or maxillo-facial procedure in any suitable manner. Preferably, the ORP water solution is administered as a mouthrinse or mouthwash. Preferably, patients rinse for at least about 30 seconds, more preferably for at least about one minute, and most preferably for at least about two minutes. Patients rinse daily, or preferably twice a day, or more preferably three times a day. The ORP water solution can be administered for about one week, or for about two weeks, or for about one month, or for about three months, or longer if necessary. The ORP water solution can be administered in combination with NSAID. The ORP water solution can also be administered in combination with antibiotics. Preferably, no antibiotic is administered.

[0160] The ORP water solution may be applied to disinfect and sterilize dental equipment. For example, to disinfect and sterilize dental instruments, the instrument is maintained in contact with the ORP water solution for a sufficient period of time to reduce the level of organisms present on the equipment to a desired level. To disinfect and sterilize dental office irrigation lines, for example, the irrigation lines are flushed with the ORP water solution. The reduction in bacteria levels can be measured by taking bacterial cultures before and after flushing the lines.

[0161] The ORP water solution may be applied to disinfect and sterilize dentures. For example, to disinfect and sterilize dental dentures, the dentures are maintained in contact with the ORP water solution for a sufficient period of time to reduce the level of organisms present on the equipment to a desired level. The dentures are maintained in contact with the ORP water solution in any suitable manner. For example, the dentures can be soaked in the ORP water solution. Alternatively, the dentures can be scrubbed with ORP water solution and a brush.

[0162] The ORP water solution administered in accordance with the present invention also can be used as the irrigation solution for hydrosurgery devices that are used to debride oral lesions. Suitable hydrosurgery devices can include, for example, the VersaJet devices sold in the United States by Smith and Nephew, Debritom in Europe by Medaxis, JetOx in the United States and Europe by DeRoyal or PulsaVac in Italy. It is believed that the ORP water solution can act synergistically with the device by reducing the microbial load in the oral lesions and by avoiding the formation of infectious mists during the debridement procedure. Thus the device may be used to debride an oral lesion with continuous irrigation, reduce the infection process and avoid the formation of infectious mists in accordance with the present invention.

[0163] The ORP water solution administered in accordance with the present invention also can be used as the irrigation solution for negative pressure devices that are used to reduce edema and increase the blood flow. Suitable negative pressure devices can include, e.g., one or more vacuum assisted wound closure devices such as, e.g., the V.A.C..RTM. and V.A.C..RTM. Instill.TM. devices sold in the United States by Kinetic Concepts, Inc. It is believed that the ORP water solution can act synergistically with the device by controlling the inflammatory-allergic process while reducing the microbial load. Thus the device may be applied to an open oral lesion with intermittent or continuous irrigation to treat or prevent tissue infection or necrosis in accordance with the present invention.

[0164] The administration of ORP solution can optionally be combined with the administration of topical and/or systemic antibiotics. Suitable antibiotics can include, without limitation, penicillin, cephalosporins or other .beta.-lactams, macrolides (e.g., erythromycin, 6-O-methylerythromycin, and azithromycin), fluoroquinolones, sulfonamides, tetracyclines, aminoglycosides, clindamycin, quinolones, metronidazole, vancomycin, chloramphenicol, antibacterially effective derivatives thereof, and combinations thereof. Suitable anti-infective agents also can include antifungal agents such as, for example, amphotericin B, fluconazole, flucytosine, ketoconazole, miconazole, derivatives thereof, and combinations thereof. Suitable anti-inflammatory agents can include, e.g., one or more anti-inflammatory drugs, e.g., one or more anti-inflammatory steroids or one or more non-steroidal anti-inflammatory drugs (NSAIDs). Exemplary anti-inflammatory drugs can include, e.g., cyclophilins, FK binding proteins, anti-cytokine antibodies (e.g. anti-TNF), steroids, and NSAIDs.

[0165] It has been found that the ORP water solution administered in accordance with the invention is virtually free of toxicity to normal tissues and normal mammalian cells. The ORP water solution administered in accordance with the invention causes no significant decrease in the viability of eukaryotic cells, no significant increase in apoptosis, no significant acceleration of cell aging and/or no significant oxidative DNA damage in mammalian cells. The non-toxicity is particularly advantageous, and perhaps even surprising, given that the disinfecting power of the ORP water solution administered in accordance with the invention is roughly equivalent to that of hydrogen peroxide, yet is significantly less toxic than hydrogen peroxide is to normal tissues and normal mammalian cells. These findings demonstrate that the ORP water solution administered in accordance with the present invention is safe for use, e.g., in mammals, including humans.

[0166] For the ORP water solution administered in accordance with the invention, the cell viability rate is preferably at least about 65%, more preferably at least about 70%, and still more preferably at least about 75% after an about 30 minute exposure to the ORP water solution. In addition, the ORP water solution administered in accordance with the invention preferably causes only up to about 10% of cells, more preferably only up to about 5% of cells, and still more preferably only up to about 3% of cells to expose Annexin-V on their cellular surfaces when contacted with the ORP water solution for up to about thirty minutes or less (e.g., after about thirty minutes or after about five minutes of contact with the ORP water solution). Further, the ORP water solution administered in accordance with the invention preferably causes less than about 15% of cells, more preferably less than about 10% of cells, and still more preferably less than about 5% of cells to express the SA-.beta.-galactosidase enzyme after chronic exposure to the OPR water solution. The ORP water solution administered in accordance with the invention preferably causes caused the same fraction of the oxidative DNA adduct formation caused by saline solution, e.g., less than about 20% of the oxidative DNA adduct formation, less than about 10% of the oxidative DNA adduct formation, or about 5% or less of the oxidative DNA adduct formation normally caused by hydrogen peroxide in cells treated under equivalent conditions.