CN101163492A - Method of treating skin ulcers using oxidative reductive potential water solution - Google Patents

Method of treating skin ulcers using oxidative reductive potential water solution Download PDF

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CN101163492A
CN101163492A CN200680013725.8A CN200680013725A CN101163492A CN 101163492 A CN101163492 A CN 101163492A CN 200680013725 A CN200680013725 A CN 200680013725A CN 101163492 A CN101163492 A CN 101163492A
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solution
aqueous solution
patient
orp aqueous
burn
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CN101163492B (en
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H·阿里米
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Oculus Innovative Sciences Inc
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Oculus Innovative Sciences Inc
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Priority claimed from PCT/US2006/011251 external-priority patent/WO2006102680A2/en
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Abstract

A method of treating burns, preferably second and third degree burns, by administration of an oxidative reduction potential (ORP) water solution that is stable for at least twenty-four hours is provided.

Description

Utilize the method for oxidative reductive potential water solution treatment 2 degree and 3 degree burns
Quoting mutually of related application
Present patent application requires the priority of following U.S. Provisional Patent Application: 60/760 of submission on January 20th, 2006,635,60/760 of submission on January 20th, 2006,567,60/760 of submission on January 20th, 2006,645,60/760 of submission on January 20th, 2006,557,60/730 of submission on October 27th, 2005,743,60/676 of submission on May 2nd, 2005,883,60/667 of submission on March 31st, 2005,60/664 of submission on March 23rd, 101 and 2005,361, incorporate its full content into the application by reference at this.
Invention field
The present invention relates to by using oxidative reductive potential water solution treatment burn, the method for preferred 2 degree and 3 degree burns.
Background of invention
Oxidation-reduction potential (ORP) water (being also referred to as super oxidize water) can be used as the nontoxic disinfectant of removing under the multiple situation and comprise antibacterial, virus and spore with the elimination of micro-organisms.For example, ORP water can be applied at health care and medical instruments field, and surface and armarium are carried out disinfection.Advantageously, OPR water is environmentally safe, has therefore avoided the needs to the disposal operations of costliness.ORP water also can be applied to the terrified aspect of wound care, armarium sterilization, food sterilizing, hospital, user's household and antibiont.
Although ORP water is a kind of effective disinfectant, it has only extremely limited storage period, has only several hours usually.Because life-span of this weak point, must carry out the production of ORP water being adjacent to very much the place that ORP water is used as disinfectant.This just mean site of health care for example hospital must buy, place and safeguard the necessary equipment of ORP water of producing.In addition, can't to produce the ORP water of enough commercial size amounts be the disinfectant of site of health care to allow that it is widely used as to existing production technology.
Therefore, need in the time that prolongs, keep stable ORP water and the method for using this ORP water.The method that also needs the ORP water of more economical preparation commercial size amount.The invention provides the method for this OPR water and preparation and this ORP water of use.
As described in U.S. Patent Application Publication 2002/0160053A1, ORP water also has been used as the growth promoter of patient tissue cell.Infection is still a problem in the wound care, particularly along with the appearance of multiple antibiotics resistance antibacterial.These infection comprise for example Acinetobacter bauamnnii, staphylococcus aureus, Pseudomonas aeruginosa, escherichia coli etc.The compositions that contains ORP water that therefore, need be used for the burn treating prevention infection.By describing in invention that this provided, these and other advantage and other inventive features of the present invention will be conspicuous.
The invention summary
The invention provides a kind of method of the burn by using oxidation-reduction potential (ORP) aqueous solution treatment patient, wherein solution kept stable 24 hours at least.The present invention also relates to the method by the burn of using oxidative reductive potential water solution treatment patient, wherein solution comprises anode water and negative electrode water.In one embodiment, the used ORP aqueous solution of method of the present invention comprises one or more chlorine kinds.
The present invention also provides a kind of method impaired or injured tissues for the treatment of, this method comprise with the ORP aqueous solution contact of treatment effective dose impaired or injured tissues, wherein solution kept stable 24 hours at least.This method comprises treated tissue, described organizing damaged by surgical operation or injured tissues or must or do not damaged with the infringement of the relevant reason of operation, and described reason for example is burn, cutting, wearing and tearing, scraping, erythra, ulcer, stab, infection etc.
The present invention also provides the method for disinfecting surface, and this method comprises the ORP aqueous solution contact surface with the infection amount, and wherein solution kept stable 24 hours at least.The surface can be the combination on biological surface, abiotic surface or these surfaces, and it can be sterilized according to the present invention.Can comprise for example muscular tissue, skeletal tissue, organ-tissue, mucous membrane tissue and combination thereof in the biological surface of disinfectant according to the present invention.But abiotic surface comprises device, prosthetic appliance and the medical apparatus and instruments of for example underwent operative implantation.
Another aspect of the present invention comprises the preparation that comprises oxidative reductive potential water solution and thickening agent that is used for local application, and wherein preparation kept stable 24 hours at least.
The present invention also relates to pharmaceutical dosage form, it comprises the preparation that comprises oxidative reductive potential water solution and thickening agent and (2) sealed container that (1) is used for local application, and wherein preparation kept stable 24 hours at least.
In addition, the present invention relates to be used for the treatment of the method for patient's disease, comprise the preparation that comprises oxidation-reduction potential solution and thickening agent to patient's local application treatment effective dose, wherein preparation keeps stable at least about 24 hours.
The present invention also provides the method that promotes patient's wound healing, comprise to wound and use the preparation that comprises oxidative reductive potential water solution and thickening agent, wherein the amount of the preparation of being used is enough to promote wound healing, and wherein preparation keeps stable at least about 24 hours.
The present invention also provides the method for the disease that is used to prevent the patient, comprises the preparation that comprises oxidative reductive potential water solution and thickening agent to patient's local application treatment effective dose, and wherein preparation keeps stable at least about 24 hours.
Another aspect of the present invention comprises the device that is used to produce oxidative reductive potential water solution, comprise at least two electrolyzers, wherein each electrolyzer comprises anode chamber, cathode chamber and the salt solution chamber between anode chamber and cathode chamber, wherein the anode electrode and first film separate anode chamber and salt solution chamber, and the cathode electrode and second film separate cathode chamber with salt solution chamber.This device can comprise the recirculating system of the saline solution that is used to supply with salt solution chamber, so that allow control and keep salt ionic concentration.
The present invention also provides the method that is used to produce oxidative reductive potential water solution, comprise at least two electrolyzers are provided, wherein each electrolyzer comprises anode chamber, cathode chamber and the salt solution chamber between anode chamber and cathode chamber, wherein the anode electrode and first film separate anode chamber and salt solution chamber, and the cathode electrode and second film separate cathode chamber with salt solution chamber; The current of flow through anode chamber and cathode chamber are provided; The saline solution stream of the salt solution chamber that flows through is provided; Electric current is provided for simultaneously anode electrode and cathode electrode with the saline solution stream of the current of flow through anode chamber and cathode chamber and the salt solution chamber that flows through; And collection is by the oxidative reductive potential water solution of electrolyzer generation.
The present invention also relates to be used to produce the method for oxidative reductive potential water solution, comprise at least one electrolyzer is provided, wherein electrolyzer comprises anode chamber, cathode chamber and the salt solution chamber between anode chamber and cathode chamber, wherein the anode electrode and first film separate anode chamber and salt solution chamber, and the cathode electrode and second film separate cathode chamber with salt solution chamber; The current of flow through anode chamber and cathode chamber are provided; The saline solution stream of the salt solution chamber that flows through is provided; Electric current is provided for simultaneously anode electrode and cathode electrode with the saline solution stream of the current of flow through anode chamber and cathode chamber and the salt solution chamber that flows through; And collect the oxidative reductive potential water solution that generates by electrolyzer, wherein said solution comprises anode water and negative electrode water.
Brief Description Of Drawings
Fig. 1 is the sketch map that is used to produce three Room electrolyzers of oxidative reductive potential water solution of the present invention.
Fig. 2 for example understands three Room electrolyzers, and has described the ionic species that wherein generates.
Fig. 3 is the schematic flow diagram that is used to produce the method for oxidation-reduction potential water of the present invention.
Fig. 4 A-4C has described through the cell survival of the human skin fibroblast (HDF) of the ORP of example aqueous solution (MCN) and hydrogen peroxide (HP) processing, apoptosis and downright bad diagram and has compared.
Fig. 5 is that the diagram of 8-hydroxyl-2 '-deoxyguanosine (8-OHdG) adduct level in the HDF of the ORP of example aqueous solution (MCN) and the processing of 500 μ M hydrogen peroxide (HP) is compared.
Fig. 6 A-6B for example understands the expression of old and feeble relevant beta galactosidase in the chronic example ORP aqueous solution (MCN) that is exposed to low concentration and hydrogen peroxide (HP) back HDF.
Detailed Description Of The Invention
The invention provides the method for prevention or treatment patient's illness, described method comprises redox current potential (ORP) aqueous solution of effectively measuring to patient's administering therapeutic, and wherein said solution kept stable 24 hours at least. Illness can comprise for example medical conditions, disease, damage, allergy etc., and described illness can be treated with the ORP aqueous solution of the present invention.
In the context of the present invention, give the patient for example the effective amount for the treatment of used of animal (particularly people) should be enough to reasonably in the patient, realizing therapeutic or preventative reaction in the time frame. Utilize method well known in the art can determine easily dosage. Those skilled in the art will recognize that the concrete dosage level of any particular patient will depend on many factors. For example, can determine dosage according to age of the seriousness of the intensity of the concrete ORP aqueous solution that adopts, illness, patient's body weight, patient, patient's physical efficiency and the state of mind, general health condition, sex, diet etc. According to any adverse side effect size that a situation arises, nature and extent also can be determined dosage of using the concrete ORP aqueous solution and may occurring together. All wish in the case of any possible to keep adverse side effect minimum.
The factor that may need to take into consideration for concrete dosage can comprise such as biological utilisation degree, metabolism spectrum, use time, route of administration, drainage rate, the concrete pharmacokinetics of the ORP aqueous solution in concrete patient etc. Other factors can comprise such as the ORP aqueous solution with respect to the effectiveness of the concrete illness for the treatment of or validity, before the treatment process or during the serious degree etc. of the symptom that occurs. In some cases, by using one or more detection methods also can partly determine to consist of the effectively dosage of amount for the treatment of, for example can rational prediction go out the concrete ORP aqueous solution and be used for the treatment of or prevent the bioassay method of the clinical curative effect of concrete illness.
Can be individually or unite one or more other treatment agent and for example use the ORP aqueous solution of the present invention to the patient human therapy, for example in order to treat existing illness. Also can be individually or unite one or more other treatment agent to the patient for example the people prophylactically use the ORP aqueous solution of the present invention, described patient has been exposed to one or more pathogenic factors relevant with illness. For example, suitably prophylactically use the ORP aqueous solution of the present invention can for the patient who has been exposed to one or more microorganisms that cause infection (for example virus, bacterium and/or fungi), to suppress or to reduce the possibility that infects among the patient or reduce the serious degree of the infection that this kind exposure caused.
Those skilled in the art will know that the appropriate method that can obtain to use the ORP aqueous solution of the present invention, although can use more than one route of administration, specific approach can provide than another kind approach more fast with more efficiently reaction. Treat effective amount and can in individual patient, obtain the necessary dosage of the ORP aqueous solution " effectively level ". Treat effective amount for example can be defined as being administered to individual patient with the blood levels that obtains ORP water prevention of the present invention or treatment patient illness, organize the required amount of level in level and/or the cell.
When effective level was used as the preferred terminal point of administration, actual dosage and timetable can be different, depend on such as between individuality in the difference of the aspects such as pharmacokinetics, distribution, metabolism. When uniting the use ORP aqueous solution of the present invention with one or more treatment agent except the ORP aqueous solution of the present invention, effectively level also can be different, described treatment agent for example is one or more anti-infectives, one or more " moderator ", " conditioning agent " or " nertralizer " (for example United States Patent(USP) Nos. 5,334,383 and 5,622,848 is described), one or more anti-scorching agent etc.
Suitable indication can be used to determine and/or monitor effective level. For example, can determine effective level by direct analysis (for example analytical chemistry) or indirect analyze (for example clinical chemical indicant) to suitable patient's sample (for example blood and/or tissue). For example, by to also determining effective level such as the related indication direct or indirect observation that alleviates etc. of variation (such as the viral count in the virus infections), histopathology and immunochemical analyses, the illness of urinating metabolite concentration, illness mark of correlation thing.
Utilize any suitable method of using known in the art can use the used ORP water of the present invention. Can unite one or more pharmaceutically suitable carrier known in the art, medium, adjuvant, excipient or diluent and use the used ORP water of the present invention. Those skilled in the art can determine easily be used to the suitable preparation of using ORP water of the present invention and use method. According to the variation of other factors such as side effect, patient's general status etc., those skilled in the art can carry out the dosage adjustment of any necessity easily, so that more meet character or the serious degree of the illness for the treatment of.
ORP solution of the present invention can be administered to upper air flue with the form of steam or spraying. In addition, can use the ORP aqueous solution of the present invention by aerosolization, spraying or atomizing. When using the ORP aqueous solution of the present invention by aerosolization, spraying or atomizing, preferably use to about 10 microns droplet form as about 1 micron take diameter range.
The method and apparatus that is used for aerosolization, spraying and atomizing is being known in the art. For example the medical atomized device is used for the physiologically active liquid delivery of dosing is arrived the inspiratory airflow that sucks for acceptor. Referring to for example U.S. Patent No. 6,598,602. Can handle the medical atomized device, generate liquid droplet, described droplet has formed aerosol with sucking gas. In other cases, the medical atomized device can be used for little water droplet is expelled to the suction air-flow, providing the gas with suitable water content to acceptor, is when being provided by the auxiliary for example respirator of mechanical respiration, lung ventilator or anesthesia delivery system when sucking air-flow, and this is useful especially.
For example described the atomizer of example in WO95/01137, it has described a kind of handheld device, and its operation is injected the air-flow (suction air-flow) that passes through with the medical use liquid droplet, and the latter is generated by the suction effect of acceptor by mouth mask. In U.S. Patent No. 5, can see another example in 388,571, it has described a kind of positive airway pressure system, control and the reinforcement of breathing are provided for the patient with respiratory insufficiency, it comprises to the atomizer of patient's air flue and alveolar delivering liquid drug particles. U.S. Patent No. 5,312,281 have described a kind of ultrasonic ultrasonic delay line memory, its can atomize at low temperatures water or liquid, and it is reported the size that can regulate mist. In addition, U.S. Patent No. 5,287,847 have described the pneumatic atomizer with variable flow rate and output volume, can be used for to neonate, children and adult's delivering drugs aerosol. In addition, U.S. Patent No. 5,063,922 have described a kind of ultrasonic sprayer.
Method of the present invention also can be used for prevention or treatment is infected, and described infection can be treated with ORP aqueous solution of the present invention.Infection can by one or more infectious pathogens for example infective micro-organisms cause.These microorganisms can comprise for example virus, antibacterial and fungus.Virus can comprise that for example one or more are selected from the virus in the group of being made up of adenovirus, HIV, rhinovirus and influenza virus.Antibacterial can comprise that for example one or more are selected from the antibacterial in the group of being made up of escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus and mycobacterium tuberculosis.Fungus can comprise that for example one or more are selected from the fungus in the group of being made up of Candida albicans, bacillus subtilis and Bacillusathrophaeus.Method of the present invention also can be used for prevention or treatment inflammatory disease or anaphylaxis, and it can be treated with ORP aqueous solution of the present invention.
In addition, by handling and to control with ORP aqueous solution used according to the invention, reduce, the organism of killing or removing comprises for example Pseudomonas aeruginosa, escherichia coli, enterococcus hirae, Acinetobacter bauamnnii, acinetobacter, bacteroides fragilis, clostridium perfringen, enterococcus faecalis, enterococcus faecalis (the VRE of vancomycin resistance, MDR), hemophilus influenza, acid-producing Klebsiella bacterium, Klebsiella pneumonia, micrococcus luteus, proteus mirabilis, serratia marcesens, staphylococcus aureus, staphylococcus epidermidis, staphylococcus haemolyticus, staphylococcus hominis, staphylococcus saprophyticus, streptococcus pneumoniae, streptococcus pyogenes, Salmonella choleraesuis, Shigella dysenteriae, with other sensitive bacterials, and yeast trichophyton mentagrophytes for example, Candida albicans and Oidium tropicale.Also can control, reduce, kill or remove virus according to the present invention, comprise for example adenovirus, human immunodeficiency virus (HIV), rhinovirus, influenza virus (for example influenza virus A), hepatitis virus (for example hepatitis A virus (HAV)), coronavirus (causing for example severe acute respiratory syndrome (SARS)), rotavirus, bird flu virus, respiratory syncytial virus, herpes simplex virus, varicella zoster virus, rubella virus and other responsive virus with the ORP aqueous solution.
In another embodiment, method of the present invention comprises that intestinal uses ORP aqueous solution of the present invention outward.Intestinal is used outward and can be comprised that intravenous, subcutaneous, intramuscular or intraperitoneal use ORP aqueous solution of the present invention.One preferred embodiment in, the method according to this invention, intravenous is used ORP aqueous solution of the present invention, with the prevention or the treatment disease.Suitable disease can comprise for example viral myocarditis, multiple sclerosis and AIDS.Referring to for example United States Patent (USP) 5,334,383 and 5,622,848, it has described the method for using ORP aqueous solution treatment viral myocarditis, multiple sclerosis and AIDS through intravenous.
The present invention also provides the method impaired or injured tissues for the treatment of, described method comprise with the ORP aqueous solution of the present invention contact of treatment effective dose impaired or injured tissues.Can with any suitable method contact impaired or injured tissues so that treat impaired according to the present invention or injured tissues.For example, by making impaired with ORP aqueous solution of the present invention flushing tissue or injured tissues contacts with ORP water, can treat impaired according to the present invention or injured tissues.Perhaps (with in addition), can use ORP aqueous solution of the present invention with the form of steam or spraying or by aerosol effect described herein, spraying or atomizing, make impaired or injured tissues contacts with ORP water.
Method of the present invention can be used for the treatment of to be damaged or injured tissues by for example operation.For example, method of the present invention can be used for the treatment of be cut damage or injured tissues.In addition, method of the present invention can be used for the treatment of by operation on oral cavity, grafting operation, implant surgery, transplant operation, burns, amputation, radiation, chemotherapy and combination thereof damage or injured tissues.Operation on oral cavity can comprise for example for example root canal of dental operation, exodontia, gingiva operation etc.
Method of the present invention also comprise treatment by one or more burns, cutting, wearing and tearing, scraping, erythra, ulcer, stab and damage or injured tissues such as combination, these damages or damage are not necessarily caused by operation.Method of the present invention can also be used for the treatment of infected impaired or injured tissues or the impaired or injured tissues owing to infect.These infection can be caused that for example one or more are selected from the microorganism in the group of being made up of virus, antibacterial and fungus, and are as described herein by one or more infectious pathogens.
The present invention also provides a kind of method of disinfecting surface, and described method comprises the ORP aqueous solution contact surface of the present invention with the infection amount.The method according to this invention can be with any suitable method contact surface.For example, by can contact surface with ORP aqueous solution of the present invention flushing surface so that according to the present invention disinfecting surface.In addition, can be to the ORP aqueous solution of the present invention of surface applied steam or Sprayable or by aerosol effect described herein, spraying or atomizing contact surface so that according to the present invention disinfecting surface.In addition, can wipe to surface applied ORP aqueous solution of the present invention, as said with cleaning.By disinfecting surface, can remove the infective micro-organisms on surface according to the present invention.Perhaps (or in addition) can give surface applied ORP aqueous solution of the present invention, so that the barrier to infecting, the disinfecting surface according to the present invention in view of the above are provided.
Method of the present invention can be used for disinfecting surface, and described surface is biological, abiotic surface or its combination.Biological surface can comprise for example one or more endoceliac tissues, for example oral cavity, hole chamber, cranial cavity, abdominal cavity and thoracic cavity.Intraoral tissue comprises for example mouthful tissue, gingiva tissue, tongue tissue and throat tissue.Biological organization also can comprise muscular tissue, skeletal tissue, organ-tissue, mucosal tissue and combination thereof.Abiotic surface can comprise equipment, prosthesis apparatus and the medical apparatus and instruments that for example operation is implanted.The method according to this invention, for example, the surface of the internal that may be exposed at intra-operative, internal organs, muscle etc. can be sterilized, to keep the aseptic of surgical environments.
The present invention also provides the preparation that is used for topical, and it comprises oxidation-reduction potential (ORP) aqueous solution and thickening agent, and described preparation is prepared to provides enhanced effectiveness and stability.
The water yield that exists in the preparation of the present invention normally from about 10% weight of weight of formulation to about 95% weight.Preferably, the contained water yield is to about 90% weight from about 50% weight.
Preparation of the present invention preferably includes the ORP aqueous solution that comprises anode water and negative electrode water.Anode water is to generate in the anode chamber of the used electrolyzer of the present invention.Negative electrode water is to generate in the cathode chamber of electrolyzer.
The preparation that is used for topical according to the present invention also comprises thickening agent.Any suitable thickening may be used to produce the preparation with required viscosity, and described viscosity is higher with the ORP aqueous solution than single usually.Used thickening agent preferably with ORP aqueous solution and preparation in other optional component compatibility.Suitable thickening includes but not limited to polymer and hydroxyethyl-cellulose.Suitable polymers can be homopolymer or copolymer, and is optional crosslinked.Other suitable thickening are well known in the artly (for example to see 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)).
Preferred thickening is based on the polymerizing acrylic acid thing.More preferably, thickening agent be high-molecular weight, crosslinked, based on the polymerizing acrylic acid thing.These polymer have following formula:
This base polymer is sold with trade name Carbopol  by Noveon.Carbopol  polymer is used as the rheology dressing agent usually, as thickening agent, suspending agent and the stabilizing agent in various personal care products, medicine and the household cleaning agent.Can use the Carbopol  polymer of solid (for example powder) or liquid form.
Be applicable to that of the present invention can be homopolymer or copolymer based on the polymerizing acrylic acid thing.Suitable homopolymer can be preferably crosslinked with allyl sucrose or pi-allyl tetramethylolmethane.Suitable acrylic copolymer is by long-chain (C 10-C 30) alkyl acrylate modifies, and can be preferably and the pi-allyl tetramethylolmethane crosslinked.
In in order to obtain maximum viscosity and Carbopol  polymer.The Carbopol  polymer that is provided is the acidic molecular of doing, closely curl, and keeps coiled structure by hydrogen bond.In case when it was scattered in water or another kind of solvent, they begin aquation and part is separated curling.Realize that by Carbopol  polymer the most common way of maximum thickening power is that acidic polymer is transformed salify.By common alkali for example the neutralization of sodium hydroxide (NaOH) or triethanolamine (TEA) realize this point easily.This neutralization makes long-chain polymer " separate curling ", makes molecule expand into effective thickening form.
Suitable thickening will for preparation provide required viscosity and other features for example outward appearance, shear resistance, ion resistance and heat stability.For example for viscosity greater than for the suspension or emulsion (rather than clear gel) preparation of 3000 centipoises (cps), Carbopol  934 is preferred.Because its useful bioadhesion performance also can be used Carbopol  974P.
In order to produce the required viscosity of preparation, preparation of the present invention can comprise the thickening agent of any appropriate amount.The amount of thickening agent generally is that about 0.1% weight from weight of formulation is to about 50% weight.Preferably, the amount of thickening agent is to about 10% weight from about 0.1%.
In other words, based on ORP aqueous solution volume, normally about 0.1% weight/volume of the amount of thickening agent (mg/mL) is to about 50% weight/volume (mg/mL).Preferably, the amount of thickening agent is to about 10%w/v from about 0.1%w/v.
The amount of thickening agent generally is to 50mg/250mL ORP aqueous solution from about 0.1g/250mL.Preferably, the amount of the thickening agent of existence be from about 1mg/250mL to about 20mg/250mL ORP aqueous solution, and most preferably from about 3mg/250mL to about 15mg/250mL.
When use low concentration based on the polymerizing acrylic acid thing time, preparation flows easily quite smoothly.At higher concentration, preparation of the present invention have high viscosity and be pseudoplastic and be difficult to mobile.When applying shearing force by blender or pump, apparent viscosity lowers, and can pump preparation.
Preparation of the present invention can randomly comprise nertralizer.Any suitable nertralizer can be used to generate the required pH value of preparation.Suitable nertralizer comprises for example sodium hydroxide, triethanolamine, ammonia, potassium hydroxide, L-arginine, AMP-95, Neutrol TE, Tris Amino, Ethomeen, diisopropanolamine (DIPA) and triisopropanolamine.Other nertralizers are normally known in the art (to be seen, for example 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 nertralizer can be the liquid or solid form.
Preferably, when thickening agent is based on the polymerizing acrylic acid thing for example during Carbopol , use the nertralizer triethanolamine.Nertralizer has changed into gel with preparation.
Preparation of the present invention can comprise the nertralizer of any appropriate amount.Usually, the amount of nertralizer is that about 0.1% weight from weight of formulation is to about 50% weight.Preferably, the amount of nertralizer be from weight of formulation about 0.1% to about 10% weight.With regard to volume, the amount of contained nertralizer is to about 50% volume, based on the volume of ORP aqueous solution from about 1%.
When adding the nertralizer of liquid form, the amount of the nertralizer that is added can be to about 100mL/250mL ORP aqueous solution from about 1mL/250mL.Preferably, the amount of nertralizer is to about 90mg/250mL ORP aqueous solution from about 10mL/250mL.In addition, when nertralizer is solid form, can add nertralizer corresponding to the amount of solid of these amount of liquid.
Preparation can also comprise additional component for example coloring agent, aromatic, buffer agent, physiologically acceptable carrier and/or excipient etc.The example of suitable coloring agent includes but not limited to titanium dioxide, iron oxides, carbazole violet, chromium-cobalt-aluminum oxide, 4-two [(2-ethoxy) amino]-9, two (2-acrylic acid) ester copolymers of 10-amerantrone etc.Can use any suitable aromatic.
Can prepare preparation of the present invention with any suitable method.Can be by any means with the component of preparation for example ORP aqueous solution and thickening agent mix, generate uniform mixture.Preferably, utilize motorized agitator or other suitable device that component was mixed several minutes, to guarantee the uniformity.Usually from about 400rpm to about 1000rpm, component from about 500rpm to about 800rpm and more preferably preferably from about 500rpm to about 600rpm ground mix preparation.
Mixed sufficiently long a period of time of preparation, generating uniform mixture, the described time generally is after having made up all components about 1 minute to about 10 minutes.
When thickening agent was powder type, the thickening agent that can sieve was earlier smashed big agglomerate, so that allow the uniform preparation of preparation.
Can contain subsequently in the past and add for example triethanolamine of nertralizer in the preparation of ORP aqueous solution and thickening agent.As mentioned above, the adding of triethanolamine can allow thickening agent for example Carbopol  separate curlingly, generate preparation in view of the above with required viscosity.
Also can before or after for example Carbopol  is dissolved in ORP water with thickening agent, in mixture, add coloring agent or aromatic, but must be before neutralization procedure.
The physical property of preparation of the present invention usually be present in preparation in ORP aqueous solution identical.Even after the nertralizer that adds thickening agent and choose wantonly, still kept the performance of ORP aqueous solution.For example, ORP aqueous solution itself all is identical with stability of formulation that contains the ORP aqueous solution and pH value usually.Therefore, all features of ORP aqueous solution described herein all are applicable to preparation of the present invention.
For example, preparation of the present invention kept stable 24 hours usually at least, typically at least 2 days.More typically, preparation keeps stable at least about 1 week (for example 1 week, 2 weeks, 3 weeks, 4 weeks etc.), preferably at least about 2 months.More preferably, preparation kept stable 6 months after its preparation at least.Even more preferably, preparation kept stable 1 year and most preferably kept stable at least 3 years at least.
The pH value of preparation normally from about 6 to about 8.Preferably, the pH value of preparation is from about 6.2 to about 7.8, and most preferably is from about 7.4 to about 7.6.
Preparation of the present invention can anyly be suitable for using to the form of patient's local application, suitable form includes but not limited to gel, lotion, cream, paste, ointment etc., these forms all are known in the artly (to see for example Modern Pharmaceutics, 3rd ed., Banker etal.ed. (1996)).Gel generally is semisolid emulsion or the suspension with three dimensional structure.Preferably, preparation is a gel form.
Paste generally all is semisolid suspension, and it usually contains major part and is scattered in solid in aqueous or the fat carrier (for example from about 20% to about 50%).Lotion normally contains based on the carrier of water and the volatilizer milky liquid liquid of (surpassing 50%), and it has enough low can be toppled over the viscosity that (less than 30,000cps).Normally semisolid emulsion of ointment and cream or suspension, it can contain as the Hydrocarbon of a carrier part or Polyethylene Glycol and other volatile component.
When preparation of the present invention was gel form, under about room temperature (for example about 25 ℃), the range of viscosities of gel was from about 10,000 to about 100,000 centipoises (cps) (for example about 15,000cps, about 20,000cps, about 25,000cps, about 30,000cps, about 35,000cps, about 40,000cps, about 45,000cps, about 50,000 cps, about 55,000cps, about 60,000cps, about 65,000cps, about 70,000cps, about 75,000cps, about 80,000cps, about 85,000cps, about 90,000cps, about 95,000cps or its scope).
The pH value of gel normally from about 6.0 to about 8.0.When being higher than this pH value, the thickening agent for example viscosity of Carbopol  polymer can descend, and causes not satisfied topical preparation.Preferably, the pH value of gel is from about 6.4 to about 7.8, and more preferably is from about 7.4 to about 7.6.
Preparation of the present invention is suitable for local application and comprises people and/or animal to the patient, so that treat various diseases.Particularly, preparation can be applied to animal (for example mice, rat, pig, cattle, horse, Canis familiaris L., cat, rabbit, Cavia porcellus, hamster, bird) and people.Local application comprises and is applied in skin and mouth, intranasal, the bronchus and the route of administration of rectum.
In another embodiment, the present invention relates to comprise the preparation for treating patient's of ORP aqueous solution and thickening agent the method for disease by local application.
Disease below the treatable patient's of the present invention disease for example comprises: operation/explorative wound clean agent, skin pathogens sterilization (antibacterial for example, mycoplasma, virus, fungus, Protein virus), wound disinfection (for example war wound), promote wound healing, promote burn-healing, the treatment dermatophytes, psoriasis, the athlete foot, ear infection (for example swimmer's ear), trauma wounds, acute, chronic and the chronic infection (for example the diabetic foot infection is the latter's a example) in Asia, pressure ulcer, the skin wearing and tearing, wound through debridement, laser surface is rebuild, donor site/graft, the part of oozing out and the wound of holostrome, superficial injury (is scratched, cutting, wearing and tearing, little skin irritation) and on human or animal's body or other interior medical applications.The ulcer of being treated according to the present invention can have or not have abscess or slough exists.
In addition, the present invention relates to by use the method that the preparation that comprises oxidative reductive potential water solution and thickening agent promotes patient's wound healing to wound.The wound of being treated can be caused by any operation, ulcer or other modes.The ulcer that can be treated comprises for example diabetic foot ulcer.
The invention still further relates to the method for disease that comprises the preparation prevention patient of ORP aqueous solution and thickening agent by local application.For example, preparation (example gel form) can be used as the barrier of prevention infection on the open wound.Particularly, for example on the ulcer of foot of diabetics, described wound tends to take place the complication of neural and blood vessel on the surface that preparation (example gel form) can be applied to wound.Therefore the preparation of being used can provide the barrier to infecting, because these wounds are main doors that diabetics infects.
Preparation can be used to prevent patient's sexually transmitted disease (STD) to comprise for example infection.These infection that can be prevented comprise herpes, human immunodeficiency virus (HIV) and vaginal infection.When preparation was gel form, it can be used as spermicide.
Can use or the preparation of the present invention of administering therapeutic effective dose, so that the required therapeutical effect to antibacterial, virus and/or pathogenic bacteria is provided.The treatment effective dose causes the amount of the improved preparation of disease that treated or prevention in this expression.For example, when being used for the treatment of infection, the preparation of treatment effective dose has alleviated the degree that infects and/or has prevented further infection.Those skilled in the art understand, and the effectiveness by the preparation of the present invention that administered formulation obtained can be short-term (for example a couple of days) and/or secular (for example several months).
Can also one sufficiently long period of administered formulation, for example 1,2 or a couple of days, about 1 week or several weeks, up to observing required effect on one's body the patient.
Can use ORP aqueous solution or its preparation by any suitable manner.For example, a certain amount of preparation can be administered to the patient's who is treated surface, the patient smears it equably with the finger of oneself then.Perhaps, the medical personnel can be administered to preparation patient's tissue.Can use preparation with for example disposable wiping of suitable device or cloth.
Produce ORP water of the present invention by oxide-reduction method, described method can be called electrolysis or redox reaction, wherein with the chemical change in the electric energy generation aqueous solution.Pass through water by electric charge being transmitted to another point and electric energy is incorporated into and transmits from a point with the form of electric current.In order to take place and to keep electric current, must have charge carrier in the water, and must have the power that makes that carrier is moved.For metal and quasiconductor, charge carrier can be an electronics, and perhaps for solution, they can be cation and anion.
In the method that is used for preparing ORP aqueous solution of the present invention, in negative electrode generation reduction reaction, simultaneously in anode generation oxidation reaction.Special reduction and the oxidation reaction that is taken place described in International Application No. WO 03/048421A1.
As used herein, the water that generates at anode is called anode water, and the water that generates at negative electrode is called negative electrode water.Anode water contains the kind of the oxidation that generates from cell reaction, negative electrode water contains to come self-reacting reductive kind simultaneously.
Anode water generally has low pH value, and usually from about 1 to about 6.8.Anode water generally contains various forms of chlorine, comprises for example chlorine, chloride ion, hydrochloric acid and/or hypochlorous acid.Also can there be various forms of oxygen, randomly comprise for example oxygen, peroxide and/or ozone.Negative electrode water generally has high pH value, and usually from about 7.2 to about 11.Negative electrode water generally contains hydrogen, hydroxyl radical free radical and/or sodium ion.
ORP aqueous solution of the present invention can be tart, neutral or alkaline, and pH value generally is from about 1 to about 14.When this pH value, the ORP aqueous solution of appropriate amount can be administered to hard surface safely, and the object that contacts with the ORP aqueous solution of injured surface or injury human body skin for example not.ORP pH value of aqueous solution normally from about 3 to about 8.More preferably, the ORP pH value of aqueous solution is from about 6.4 to about 7.8, and most preferably, pH value is from about 7.4 to about 7.6.
The Eo+ of ORP aqueous solution of the present invention generally is to about+1350 millivolts (mV) from about-1000 millivolts (mV).This current potential is that solution is accepted or the measurement of the trend (being potential) of metastatic electron, its by the metal electrode perception and compare with reference electrode in the same solution.Can go out this current potential with measured by standard techniques, comprise for example by measuring the millivolt current potential of ORP aqueous solution with respect to the reference silver/silver chloride electrode of standard.The current potential of ORP water generally is from pact-400mV to pact+1300mV or pact+1150mV.Preferably, the current potential of ORP aqueous solution be from about 0mV to pact+1250mV, more preferably be to pact+1250mV from pact+500mV.Even more preferably, the current potential of ORP water of the present invention be from pact+800mV to pact+1100mV, and most preferably be to pact+1000mV from pact+800mV.
Can there be multiple different ionic species and other kinds in the ORP aqueous solution of the present invention.For example, the ORP aqueous solution can contain chlorine (for example free chlorine and combined chloride), and randomly contains ozone and peroxide (for example hydrogen peroxide).The existence of believing one or more these kinds makes the ORP aqueous solution have for example disinfecting power of antibacterial, fungus and virus of kill many kinds of microorganisms.
Free chlorine generally includes but is not limited to hypochlorous acid (HClO), hypochlorite ion (ClO -), sodium hypochlorite (NaOCl), chloride ion (Cl -), chlorite ion (ClO 2 -), dissolved chlorine (Cl 2) and other free radical chlorine kinds.The ratio of hypochlorous acid and hypochlorite ion depends on pH value.At pH value is 7.4 o'clock, and the hypochlorous acid level is to about 75ppm from about 25ppm.Temperature also influences the ratio of free chlorine component.
Combined chloride is the chlorine in the chemical combination with ammonia or organic amine (for example chloramines).The about at the most usually 20ppm of the content of combined chloride.
The chlorine and the optional ozone and the hydrogen peroxide of existing that in ORP aqueous solution of the present invention, can have any appropriate amount.Can determine the level of these components with methods known in the art.
Chloride content (comprising free chlorine and combined chloride) normally from about 5,000 ten thousand/(ppm) to about 200ppm.Preferably, chloride content arrives about 150ppm for about 80ppm.
Can determine chlorinity with methods known in the art, for example the DPD colorimetry (Lamotte Company, Chestertown, Maryland) or other known methods of setting up of Environmental Protection Department.In the DPD colorimetry, free chlorine and N, N-diethyl-p-phenylenediamine (PPD) (DPD) reaction generates yellow, uses the tintometer through calibration to determine intensity, and it provides 1,000,000/be the output result of unit.Further adding potassium iodide again can change into pink colour with solution, so that total chlorine numerical value to be provided.Deduct the content that free chlorine can determine combined chloride by total chlorine then.
The amount of the optional ozone that exists be from about 0.03ppm to about 0.2ppm, preferably from about 0.10ppm to about 0.16ppm.
In the ORP aqueous solution horizontal extent of the optional hydrogen peroxide that exists be from about 0.01ppm to about 200ppm, preferably from about 0.05ppm to about 100ppm.More preferably, the amount of contained hydrogen peroxide be from 0.1ppm to about 40ppm, most preferably be to 4ppm from about 1ppm.Optional peroxide (the H for example that exists 2O 2, H 2O 2 -And HO 2 -), its concentration is less than 0.12 millimolar concentration (mM).
Total weight range of the oxidation chemistry kind that the ORP aqueous solution is contained is about 2 millimolar concentrations (mM), and it comprises aforesaid chlorine kind, oxygen kind and other kinds that may be difficult to measure Cl for example -, ClO 3, Cl 2 -, and ClO xAlso can determine the level of contained oxidation chemistry kind by ESR spectral method (utilizing TemponeH) as the spin trapping molecule.
ORP aqueous solution of the present invention is general to keep stable at least about 24 hours, usually at least about 2 days.More common, it is stable at least about 1 week (for example 1 week, 2 weeks, 3 weeks, 4 weeks etc.) that the ORP aqueous solution keeps, and preferably at least about 2 months.More preferably, the ORP aqueous solution keeps stable at least about 6 months after its preparation.Even more preferably, it is stable at least about 1 year that the ORP aqueous solution keeps, and most preferably keep stable at least about 3 years.
As used herein, the stable general expression ORP aqueous solution of term keeps being suitable for the ability of one period fixed time of its desired use down at normal condition of storage (being room temperature) after its preparation, described purposes is for example decontamination, sterilization, sterilization, antimicrobial cleansing and wound clean.
When being stored in acceleration environment (usually from about 30 ℃ to about 60 ℃), it is stable at least about 90 days that ORP aqueous solution of the present invention also can keep, and preferably about 180 days.
The ionic species that solution is contained and the concentration of other kinds generally were maintained between the storage period of ORP aqueous solution.Typically, free chlorine and randomly the concentration of ozone and hydrogen peroxide be maintained at its initial concentration about 70% or higher, be maintained at least and prepared behind the ORP aqueous solution about 2 months.Preferably, these concentration be maintained at its initial concentration about 80% or higher, be maintained at least and prepared behind the ORP aqueous solution about 2 months.More preferably, these concentration be its initial concentration about 90% or higher, be maintained at least and prepared behind the ORP aqueous solution most preferably about 95% or higher about 2 months.
According to being exposed to after the ORP aqueous solution stability that the minimizing of the amount of contained organism in the sample also can determine ORP aqueous solution of the present invention.Use any suitable organism to comprise antibacterial, fungus, yeast or the viral mensuration that can carry out the reduction of organism concentration.Suitable organism includes but not limited to: escherichia coli, staphylococcus aureus, Candida albicans and Bacillus athrophaeus (before being called bacillus subtilis).The ORP aqueous solution both can be used as and can reduce about 4 the logarithm levels (10 of living microorganism concentration 4) low-level disinfectant, also can be used as and can reduce about 6 the logarithm levels (10 of living microorganism concentration 6) high-caliber disinfectant.
In one aspect of the invention, when measuring at least 2 months after preparing solution, after exposing 1 minute, the ORP aqueous solution can cause the organism total concentration to be reduced by at least about 4 logarithm levels (10 4).Preferably, when measuring at least 6 months after preparing solution, the ORP aqueous solution also can reach the minimizing of the organism concentration of this level.More preferably, when after preparing the ORP aqueous solution, measuring at least about 1 year, the ORP aqueous solution also can reach the minimizing of the organism concentration of this level, most preferably, when measuring at least about 3 years after preparing solution, the ORP aqueous solution also can reach the minimizing of the organism concentration of this level.
In another aspect of the present invention, after preparing the ORP aqueous solution, to measure at least 2 months, the ORP aqueous solution can make the concentration of living microorganism sample be reduced by at least about 6 logarithm levels (10 in exposing 1 minute 6), described microorganism is selected from the group of being made up of escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus and Candida albicans.Preferably, when at after the preparation at least 6 months and when more preferably measuring at least 1 year after preparation, the ORP aqueous solution can be realized this minimizing of escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus or Candida albicans.Preferably, when measuring at least 2 months the time after preparation, the ORP aqueous solution can make the concentration of these living microorganisms be reduced by at least about 7 logarithm levels (10 in exposing 1 minute 7).
When measuring at least 2 months after preparing the ORP aqueous solution, ORP aqueous solution of the present invention generally can make the living microorganism sample from initial concentration about 1 * 10 in exposing 1 minute 6To about 1 * 10 8It is about 0 microorganism/ml that individual microorganism/ml drops to final concentration, and described microorganism includes but not limited to escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus and Candida albicans.The minimizing of microorganism concn is in about 6 logarithm levels (10 6) to about 8 logarithm levels (10 8) between.Preferably, when at after the preparation at least 6 months and when more preferably measuring at least 1 year after preparation, the ORP aqueous solution can be realized the minimizing of this level of escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus or Candida albicans organism.
Perhaps, when measuring at least 2 months after preparing the ORP aqueous solution, ORP aqueous solution of the present invention can reduce about 6 logarithm levels (10 in the concentration that exposes in about 5 minutes the spore suspension of Bacillus athrophaeus spore 6).Preferably, when measuring at least about 6 months after preparation, and more preferably when measuring at least 1 year the time after preparation, the ORP aqueous solution can be realized this minimizing of Bacillus athrophaeus spore concentration.
When measuring at least 2 months after preparing the ORP aqueous solution, the ORP aqueous solution can also reduce about 4 logarithm levels (10 in the concentration that exposes in about 30 seconds the spore suspension of Bacillus athrophaeus spore 4).Preferably, when measuring at least about 6 months after preparation, and more preferably when measuring at least 1 year the time after preparation, the ORP aqueous solution can be realized the minimizing of the Bacillus athrophaeus spore concentration of this level.
When after preparing the ORP aqueous solution, measuring at least about 2 months, the ORP aqueous solution also can be in exposing about 5 to 10 minutes with fungal spore for example the concentration of Aspergillus niger spores reduce about 6 logarithm levels (10 6).Preferably, when measuring at least 6 months after preparation, and more preferably when measuring at least 1 year the time after preparation, the ORP aqueous solution can be realized the minimizing of the fungal spore concentration of this level.
In one embodiment, ORP aqueous solution of the present invention randomly comprises hydrogen peroxide (H 2O 2) and one or more chlorine kinds.Contained chlorine kind is free chlorine species preferably.Free chlorine species can be selected from by hypochlorous acid (HOCl), hypochlorite ion (OCl -), sodium hypochlorite (NaOCl), chlorite ion (ClO 2 -), chloride ion (Cl -), dissolved chlorine (Cl 2) and composition thereof the group formed.
The optional hydrogen peroxide that contains of ORP aqueous solution generally be from about 0.01ppm to about 200ppm, preferably from about 0.05ppm to about 100ppm.More preferably, the amount of contained hydrogen peroxide be from about 0.1ppm to about 40ppm, and most preferably from about 1ppm to about 4ppm.
The total amount of free chlorine species generally be from about 10ppm to about 400ppm, preferably from about 50ppm to about 200ppm, and most preferably from about 50ppm to about 80ppm.Hypochlorous amount generally is to about 35ppm from about 15ppm.The scope of the amount of sodium hypochlorite generally is to about 50ppm from about 25ppm.The chlorine dioxide level is generally all less than about 5ppm.
It is stable at least about 1 week that the ORP aqueous solution generally can keep.Preferably, it is stable at least about 2 months that the ORP aqueous solution can keep, and more preferably the ORP aqueous solution can keep stable at least about 6 months after its preparation.Even more preferably, the ORP aqueous solution can keep stablizing at least about 1 year and most preferably can keep stable at least about 3 years.
In this embodiment, the ORP pH value of aqueous solution generally is from about 6 to about 8.Preferably, the ORP pH value of aqueous solution is from about 6.2 to about 7.8, and most preferably is from about 7.4 to about 7.6.
Though do not want to limit the present invention, believe and control the ORP aqueous solution that pH value allows that formation is stable, wherein for example hypochlorous acid and hypochlorite ion coexistence of chlorine kind.
After preparation, ORP aqueous solution of the present invention or preparation can be transferred to sealed container, be used for distributing and be sold to the terminal use for example site of health care comprise hospital, sanitarium, doctor's office, Outpatient Surgical Center, dental clinic or the like.Pharmaceutical dosage form according to the present invention comprises and as described hereinly is used for the preparation of topical and to the sealed container of wherein inserting preparation.
Can use any suitable sealed container, it has kept the ORP aqueous solution that container adorns or the aseptic and the stability of preparation.Container can be made by any material compatible with ORP aqueous solution or formulation components (for example ORP aqueous solution or thickening agent).Container should be normally non-reacted, makes contained ion in the ORP aqueous solution that the reaction of any obvious degree not take place with container.
Preferably, container is to be made by plastics or glass.Plastics can be hard, make container can be stored on the thing frame.Perhaps, container can be flexible, for example Rou Xing sack.
Suitable plastic comprises polypropylene, polyester terephthalate (PET), polyolefin, cycloolefin, Merlon, ABS resin, polyethylene, polrvinyl chloride and composition thereof.Preferably, container comprises the polyethylene that is selected from the group of being made up of high density polyethylene (HDPE) (HDPE), low density polyethylene (LDPE) (LDPE) and linear low density polyethylene (LLDPE).Most preferably, container is made by high density polyethylene (HDPE).
Container preferably has allows distribution ORP aqueous solution or the opening of preparation to use to the patient.Sealed container opening in any suitable manner.For example, can be with reversing medicated cap or plug seal container.Randomly, can also use the foil seal opening.
The top gas of sealed container can be that air or other can or not contain the suitable gas of other component reaction in the preparation of ORP aqueous solution with the ORP aqueous solution.Suitable top gas comprises nitrogen, oxygen and composition thereof.
The present invention also provides the ORP aqueous solution that comprises anode water and negative electrode water.In the anode chamber of the used electrolyzer of the present invention, generate anode water.In the cathode chamber of electrolyzer, generate negative electrode water.
The amount of the negative electrode water that ORP aqueous solution of the present invention is contained generally is to about 90% liquor capacity from about 10% liquor capacity.Preferably, the amount of the negative electrode water that the ORP aqueous solution is contained be from about 10% volume to about 50% volume, more preferably be from about 20% liquor capacity to about 40% liquor capacity, and most preferably be to about 30% liquor capacity from about 20% liquor capacity.In addition, the amount of the contained anode water of ORP aqueous solution is to about 90% liquor capacity from about 50% liquor capacity.
Said, the ORP aqueous solution that contains anode water and negative electrode water can be tart, neutral or alkaline, and pH value generally is from about 1 to about 14.ORP pH value of aqueous solution normally from about 3 to about 8.Preferably, pH value is from about 6.4 to about 7.8, more preferably is from about 7.4 to about 7.6.
ORP aqueous solution of the present invention has purposes widely, as the active disinfectant of the undesired or deleterious material that exists in controling environment, abluent, cleaning agent, sterilization antiseptic etc.Can comprise biological example body and anaphylactogen with the material that the ORP aqueous solution is handled.
The ORP aqueous solution can be used as disinfectant, biocide, detergent, sterilization antiseptic and/or abluent.ORP aqueous solution of the present invention is applicable to following representative applications: medical science, stomatology and/or veterinary's equipment and device, food industry (for example crust, fruit, vegetable, meat), hospital/site of health care (for example crust), cosmetics industry (for example skin cleaner), household articles (for example floor, sales counter, crust), electronics industry (for example cleaning circuit, hard disk) and bio-terrorism (for example anthrax, infective micro-organisms).
The ORP aqueous solution also can be applied to people and/or animal, for example comprises following disease to treat various diseases: operation/open wound abluent, skin pathogens sterilization (for example directed toward bacteria, mycoplasma, virus, fungus, Protein virus), war wound sterilization, promote wound healing, promote burn-healing, treatment gastric ulcer, wound irrigation, dermatophytes, psoriasis, athlete foot, pink eye disease and other ocular infections, ear infection (for example swimmer's ear), lung/nose/sinus infection and on human or animal body or other interior medical applications.The purposes of ORP aqueous solution as the histiocyte growth promoter also described in U.S. Patent Application Publication 2002/0160053A1.
Though do not limit the present invention in any way, believe that the cellular component that the ORP aqueous solution has been removed the antibacterial that is in contact with it and destroyed antibacterial comprises albumen and DNA.
For example, when measuring at least 2 months after preparing the ORP aqueous solution, the ORP aqueous solution can be reduced by at least about 5 logarithm levels (10 in the concentration that exposes in 30 seconds the living microorganism sample 5), described living microorganism is selected from by Pseudomonas aeruginosa, escherichia coli, enterococcus hirae, Acinetobacter bauamnnii, acinetobacter, bacteroides fragilis, clostridium perfringen, enterococcus faecalis, enterococcus faecalis (the VRE of vancomycin resistance, MDR), hemophilus influenza, acid-producing Klebsiella bacterium, Klebsiella pneumonia, micrococcus luteus, proteus mirabilis, serratia marcesens, staphylococcus aureus, staphylococcus epidermidis, staphylococcus haemolyticus, staphylococcus hominis, staphylococcus saprophyticus, streptococcus pneumoniae, streptococcus pyogenes, the group that Candida albicans and Oidium tropicale are formed.
In one embodiment, when after preparing the ORP aqueous solution, measuring at least about 2 months, the ORP aqueous solution of using according to the present invention can be in exposing about 1 minute with the living microorganism sample from about 1 * 10 6To about 1 * 10 8The initial concentration of organism/ml reduces to the final concentration of about 0 organism/ml, and described living microorganism includes but not limited to escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus and Candida albicans.This reduces about 6 logarithm levels (10 corresponding to organism concentration 6) to about 8 logarithm levels (10 8).Preferably, when after preparation, measuring at least about 6 months, and more preferably when measuring about 1 year the time after preparation, the ORP aqueous solution can realize that organisms such as escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus or Candida albicans reduce about 10 6To about 10 8
Perhaps, when measuring at least about 2 months after preparing the ORP aqueous solution, the ORP aqueous solution of using according to the present invention can reduce about 6 logarithm levels (10 in the concentration that exposes in about 5 minutes the spore suspension of Bacillus athrophaeus spore 6).Preferably, when measuring at least about 6 months after preparation, and more preferably when measuring about 1 year the time after preparation, the ORP aqueous solution of using according to the present invention can realize that the concentration of Bacillus athrophaeus spore reduces about 10 6When measuring at least about 2 months after preparing the ORP aqueous solution, the ORP aqueous solution can also reduce about 4 logarithm levels (10 in the concentration that exposes in about 30 seconds the spore suspension of Bacillus athrophaeus spore 4).Preferably, when measuring at least about 6 months after preparation, and more preferably when measuring about 1 year the time after preparation, the ORP aqueous solution can be realized the minimizing of the Bacillus athrophaeus spore concentration of this level.
When after preparing the ORP aqueous solution, measuring at least about 2 months, the ORP aqueous solution also can be in exposing about 5 to 10 minutes with fungal spore for example the concentration of Aspergillus niger spores reduce about 6 logarithm levels (10 6).Preferably, when measuring at least 6 months after preparation, and more preferably when measuring at least 1 year the time after preparation, the ORP aqueous solution can be realized the minimizing of the fungal spore concentration of this level.
When after preparing the ORP aqueous solution, measuring at least about 2 months, the ORP aqueous solution of using according to the present invention can also be after exposing about 5 to 10 minutes with virus for example the concentration minimizing of HIV (human immunodeficiency virus) (HIV) and adenovirus above 3 logarithm levels (10 3).Preferably, when measuring at least about 6 months after preparation, and more preferably when measuring at least about 1 year after preparation, the ORP aqueous solution can realize that virus concentration reduces＞10 3
When measuring at least about 2 months after preparing the ORP aqueous solution, the ORP aqueous solution of using according to the present invention can also expose the growth that suppresses Mycobacterium bovis in about 5 minutes fully.Preferably, when measuring at least about 6 months after preparation, and more preferably when measuring at least about 1 year after preparation, the ORP aqueous solution can be realized the inhibition fully to mycobacteria concentration.
Therefore, include but not limited to antibacterial, fungus, yeast and virus by handling the organism that to control, reduce, kill or remove with the ORP aqueous solution.Susceptible bacteria includes but not limited to escherichia coli, staphylococcus aureus, Bacillus athrophaeus, streptococcus pyogenes, Salmonella choleraesuis, Pseudomonas aeruginosa, Shigella dysenteriae and other susceptible bacterias.Can comprise for example Candida albicans and trichophyton mentagrophytes with fungus and the yeast that the ORP aqueous solution is handled.The ORP aqueous solution also can be applied to virus, comprises for example adenovirus, HIV (human immunodeficiency virus) (HIV), rhinovirus, influenza virus (for example A type influenza virus), hepatitis virus (for example hepatitis A virus (HAV)), coronavirus (causing severe acute respiratory syndrome (SARS)), rotavirus, respiratory syncytial virus, herpes simplex virus, varicella zoster virus, rubella virus and other susceptible virus.
One preferred embodiment in, can use the patient that ORP aqueous solution of the present invention treatment suffers from 1 degree, 2 degree or 3 degree burns.Also can suffer from for example patient that makes up of 2 degree and 3 degree burns of combination burn with ORP aqueous solution treatment.1 degree burn involves epidermis or skin surface.2 degree burns involve epidermis and following corium.3 degree burns involve under epidermis, corium and the corium.More preferably, use the patient that the treatment of ORP aqueous solution suffers from 2 degree or 3 degree burns.The burn that is fit to the present invention's treatment can cause by various damages, for example comprises with fire, boiling liquid (for example water, milk etc.) or electrically contacts, and extend to about 0% to about 69% patient tissue usually.
Can use the ORP aqueous solution to the fire victim with arbitrary suitable manner.Can use the ORP aqueous solution partly by spraying, shower, immersion, wiping or in the mode at other moistening burn positions.Use the ORP aqueous solution with the amount that is enough to treat burn.Use ORP aqueous solution every day 1 time and every day more than 1 time preferably at least to burn.More preferably, use ORP aqueous solution every day 3 times to burn.
For example by toppling over from container or can directly using the ORP aqueous solution to burn area from the storage spraying.Can be with any suitable device to burn spraying.Preferably, with high pressure rinse equipment the ORP aqueous solution is sprayed onto burn site.
Be immersed in partially or completely in the ORP aqueous solution by burning, can soak burn.Can soak any suitable time period of burn.Generally speaking, burn is soaked in the ORP aqueous solution at least about 1 minute.Preferably, will burn and soak about 5 minutes to about 15 minutes.
Perhaps, can utilize with the water saturated base material of ORP for example gauze the ORP aqueous solution is administered to burn.Preferably, comprise spray application ORP aqueous solution with several different methods, spraying is also soaked burn.
Randomly can come dressing wrapping burn by using through the saturated wet wound dressing of ORP aqueous solution.Except wet wound dressing, randomly can cover the wrapping burn with dry gauze and stickiness covering.After using the ORP aqueous solution, can also use any suitable suave, emulsifiable paste, gel and/or ointment to burn surfaces.
In one embodiment, with ORP aqueous solution of the present invention the patient who suffers from the burn that needs treatment is carried out washing step.At first the ORP aqueous solution is sprayed onto on the burn with high pressure rinse equipment.Next, burn is immersed in one suitable period in the ORP aqueous solution.After soaking, and then to burn spray ORP aqueous solution.Then, allow that burn keeps moisture state at least about 5 minutes.At least every day, 1 burn to the patient carried out this treatment step, more preferably was every day 3 times preferred every day 2 times.In this embodiment, preferably using between the ORP aqueous solution not dressing burn surfaces.
Before using the ORP aqueous solution, preferably burn is carried out debridement treatment, so that remove Hyperkeratotic, downright bad and other unsound tissues, up to the tissue that exposes healthy appearance.In the debridement burn, the excision edge of wound is up to the bleeding tissue of health.After debridement, can remove the fragment of burn site.The ORP aqueous solution of using according to the present invention also can be with the rinse solution of hydrotherapy operation (hydrosurgery) equipment that acts on the skin ulcer debridement.Suitable hydrotherapy surgical apparatus can comprise JetOx or the gondola PulsaVac that VersaJet equipment that for example Smith and Nephew sell in the U.S., Debritom, DeRoyal that Medaxis sells in Europe sell at US and European.Believe the ORP aqueous solution can with described equipment collaboration effect, the microbial load by reducing the wound and avoid in the debridement process, forming infectious mist.Therefore, according to the present invention, can reduce the formation of course of infection and avoiding infection property mist with the debridement of under continuous flushing, burning of described equipment.
The ORP aqueous solution of using according to the present invention also can alleviate in the water and the rinse solution of the negative pressure equipment of increasing blood flow with acting on.Suitable negative pressure equipment can comprise for example V.A.C. that sells in the U.S. of Kinetic Concepts company of one or more vacuum aided wound closure equipment for example And V.A.C. Instill TMBelieve the ORP aqueous solution can with described equipment collaboration effect, by controlling inflammation-irritated process, reduce microbial load simultaneously.Therefore, according to the present invention, can under interruption or continuous flushing, use described equipment for open the burn, so that treat or prevention tissue infection or necrosis.
Randomly, also can utilize some auxiliary treatment according to the present invention, comprise biological engineering skin (Apligraf, Organogenesis, Inc., Canton), acellular skin sub ((Oasis Wound Matrix, Healthpoint), ultrasound wave uses displacement of ORP aqueous solution and local oxygen or hyperbaric oxygentherapy (for example high-voltaghe compartment, Vent-Ox system).
If desired, can unite skin graft and use the ORP aqueous solution, so that promote the healing of burn.
Using randomly of ORP solution can be united using of part and/or systemic antibiotics.Suitable antibiotic can include but not limited to penicillin, cephalosporin or other beta-lactams, Macrolide (for example erythromycin, 6-0-erythromycin and azithromycin), fluoroquinolones, sulfonamides, Tetracyclines, aminoglycosides, clindamycin, quinolones, metronidazole, vancomycin, chloromycetin, the effective derivant of its antibacterium and combination thereof.Suitable anti-infective can also comprise antifungal for example amphotericin B, fluconazol, flucytosine, ketoconazole, miconazole, its derivant and combination thereof.Suitable antiinflammatory can comprise for example one or more anti-inflammatory medicaments, for example one or more anti-inflammatory steroidals or one or more nonsteroidal anti-inflammatory drugs (NSAID).The anti-inflammatory medicaments of example can comprise that for example cyclophilins, FK are conjugated protein, anti-cytokine antibodies (for example anti-TNF), steroidal class and NSAID.
In yet another embodiment of the present invention, at first, spray the ORP aqueous solution with high pressure rinse equipment then to patient's 2 degree and/or 3 degree burn debridements.The amount that is used to clean the ORP aqueous solution of burn preferably is enough to remove fragment.To burn then and in the ORP aqueous solution, soak one suitable period.Next, with ORP aqueous solution spraying patient's burn, allow solution wetted one suitable period of burn, preferably from about 5 minutes to about 15 minutes.Repeat every day to spray and moistening about 3 times.Between the ORP aqueous solution is used, dressing burn surfaces not.
Can repeat burn is carried out high-pressure fog, optionally soak, spraying and moistening process with suitable interval.Preferably, repeat about 1 time weekly burn carried out high-pressure fog, optionally soak, spraying and moistening operation, and more preferably be about every day 1 time.Utilize ORP aqueous solution treatment burn can last till fully healing of burn, this need repeat this operation usually in a couple of days.Generally speaking, use the ORP aqueous solution every day, continue at least about 3 days.Usually, use the ORP aqueous solution every day, continue at least about 5 days, preferably at least about 7 days and more preferably at least about 10 days.Usually weigh the healing of burn by the speed of scar contracture and cutization.
The activity of the anaphylactogen that exists during ORP water of the present invention also is applicable to and controls environment.As used herein, anaphylactogen comprises that any except that antibacterial, fungus, yeast or virus can cause disadvantageous immunoreation or hypersensitive material in the human or animal of susceptible.Asthma is a kind of common physiological reaction after being exposed to one or more anaphylactogens.Anaphylactogen can be (promptly from that live or dead organism) or abiotic (for example non-living body such as the textile) of living, and may reside in environment for example in household and/or the working space.
Can be with the ORP water treatment comprise for example animal hair, scurf and feces, household dust, artemisiifolia, grass, tree, demodicid mite and pollen based on proteic household anaphylactogen.Zoo-anaphylactogen comprises the epithelium of cat for example, the epithelium of Canis familiaris L., the scurf of horse, the scurf of cattle, the scurf of Canis familiaris L., epithelium, Pluma Anseris domestica, the epithelium of mice, the urine of mice, the epithelium of rat and the urine of rat of Cavia porcellus.
The occupation anaphylactogen comprises that high molecular weight material for example is as native protein and low-molecular-weight chemical substance such as vulcabond and other materials of finding of plant-derived or animal proteinum usually in some textiles.Other chemical anaphylactogens that the working space may exist comprise for example acid anhydride, antibiotic, wood dust and dyestuff.Multiple protein can be that professional anaphylactogen comprises plant gum, enzyme, animal proteinum, insecticide, vegetable protein and beans.
At the Allergy of Korenblat and Wedner Theory and Practice (1992) and Middleton, other anaphylactogens that are suitable for the processing of ORP aqueous solution have been described among the Allergy Principles and Practice (1993) of Jr..
Have been found that the ORP aqueous solution of using according to the present invention does not in fact all have toxicity to normal structure and normal mammalian cell.The ORP aqueous solution of using according to the present invention can not cause the remarkable decline of eukaryotic cell viability, the remarkable increase of apoptosis, the remarkable acceleration of cell ageing and/or the significant oxidative dna damage of mammalian cell.Avirulence is useful especially, even may be surprising, because the disinfecting power of the ORP aqueous solution of using according to the present invention and the disinfecting power of hydrogen peroxide are roughly the same, but its to the toxicity of normal structure and normal mammalian cell but significantly less than hydrogen peroxide.These find to confirm for example to be applied to by the ORP aqueous solution of using according to the present invention safely, and mammal comprises the people.
For the ORP aqueous solution of using according to the present invention, after being exposed to about 30 minutes of ORP aqueous solution, the cells survival power rate is preferably at least about 65%, more preferably at least about 70%, still more preferably at least about 75%.In addition, reach about 30 minutes or during shorter time (for example after contacting about 30 minutes with the ORP aqueous solution or after contacting about 5 minutes) when contacting with the ORP aqueous solution, the ORP aqueous solution of using according to the present invention preferably at most only causes about 10% cell, more preferably at most only causes about 5% cell and still more preferably at most only cause about 3% cell to expose annexin V on its cell surface.In addition, the ORP aqueous solution of using according to the present invention preferably causes less than about 15% cell, more preferably less than about 10% cell, and still more preferably expresses the SA-beta galactosidase less than 5% cell after the chronic ORP of being exposed to aqueous solution.The ORP aqueous solution of using according to the present invention preferably causes the O-DNA adduct that causes with saline solution to form identical fractional O-DNA adduct and forms, for example be the O-DNA adduct that in the cell of under condition of equivalent, handling, normally causes of hydrogen peroxide form about below 20%, about below 10%, or about 5% or below.
The ORP aqueous solution of using according to the present invention can not cause significant RNA degraded.Therefore, that extract people's cell culture of 3 hours after being exposed to about 30 minutes of ORP aqueous solution or after exposing in about 30 minutes and can not demonstrate significant RNA degraded usually through the RNA of denaturing gel electrophoresis analysis, usually will represent two discrete bands, illustrate that the ORP aqueous solution of using according to the present invention makes RNA be kept perfectly basically corresponding to ribosome eucaryotic RNA (being 28S and 18S).Equally, after being exposed to ORP aqueous solution 30 minutes or expose the RNA that extracts people's cell culture after about 3 hours and can carry out reverse transcription and amplification (RT-PCR) composing type people GAPDH (glyceraldehyde-3-phosphate dehydrogenase) gene, on the gel electrophoresis of RT-PCR product, form strong GAPDH band.By contrast, handle the cell of identical time through HP and demonstrate significant RNA degraded and (if any) GAPDH RT-PCR product seldom.
For the required effect of killing antibacterial, killing the virus, killing pathogenic bacteria and/or anti-allergen is provided, can use or use the ORP aqueous solution of the present invention of any appropriate amount.
Can use the ORP aqueous solution in any suitable manner carries out disinfection and sterilizes.For example, in order to sterilize and sterilize armarium and dental equipment, equipment and ORP aqueous solution are kept in touch one sufficiently long period, so that the organism level that exists on the equipment is reduced to desired level.
For the sterilization and the sterilization of crust, can from the container that stores the ORP aqueous solution, the ORP aqueous solution be applied directly on the crust.For example, the ORP aqueous solution can be toppled over, sprayed or otherwise directly is administered on the crust.Then, can for example cloth, fabric or napkin be distributed to the ORP aqueous solution on the whole crust with suitable substrates.In hospital used, base material was preferably aseptic.Perhaps, can at first the ORP aqueous solution be administered to base material for example cloth, fabric or napkin.Then moistening base material is contacted with crust.Perhaps, can by as solution is distributed in the air saidly and the ORP aqueous solution is administered on the crust.The ORP aqueous solution can be applied to humans and animals by similar mode.
The present invention also provides cleaning to wipe, and comprises water-fast base material and ORP aqueous solution described herein, and wherein the ORP aqueous solution is formulated on the base material.Can or otherwise be applied to base material with ORP aqueous solution soaking, bag quilt, covering.Preferably, will clean wipe be assigned to the terminal use before, with ORP aqueous solution pretreating substrates.
The base material that cleaning is wiped can be any suitable water-fast absorbability or sorptive material.Multiple material can be as base material.It should have enough wet strengths, abrasivity, loft and porous, and base material should not influence the stability of ORP aqueous solution unfriendly.Example comprises non-woven substrate, textile substrate, hydroentangled base material and sponge.
Base material can have one or more layers.Each layer can have identical or different quality structures and abrasiveness.Different quality structures can be derived to use different combinations of materials or be derived from uses different production process or its combination.Base material should water-soluble or disintegrate in water.Base material provides carrier for the ORP aqueous solution is delivered to pending base material.
Base material can be single nonwoven sheet or a plurality of nonwoven sheet.Nonwoven sheet can be made by wood pulp, synthetic fibers, natural fiber and its admixture.The used suitable synthetic fibers of base material include but not limited to the mixture of polyester, artificial silk, nylon, polypropylene, polyethylene, other cellulosic polymers and these fibers.Non-woven material can comprise the non-woven fibre sheet material, and it comprises and melts and sprays, coform, air-laid, spins glutinous, wet laid, bonding-carded fibers net materials, hydroentangled (also being called spunlaced one-tenth cloth) material and combination thereof.These materials can comprise synthetic or natural fiber or its combination.Base material can randomly contain adhesive.
Suitable nonwoven, the example of water-fast base material comprise the admixture Hydraspun 8579 and the 70%Viscose/30%PES Code9881 of 100% cellulose WaddingGrade 1804,100% polypropylene needlepunch material NB 701-2.8-W/R, cellulose and synthetic fibers.At United States Patent (USP) 4,781,974,615,937,4,666,621 and 5,908,707, and other examples of all having described the non-woven substrate that is applicable to that cleaning is wiped among international patent application open WO98/03713, WO97/40814 and the WO96/14835.
Base material also can be made by textile material, for example cotton fiber, Cotton Gossypii/nylon admixture or other textiles.The regenerated cellulose, polyurethane foam etc. that are used to prepare sponge also are suitable for.
The liquid load ability of base material should be about 50%-1000% of its dry weight at least, preferably at least about 200%-800%.This is expressed as loading is about 1/2 to 10 times of base material weight.The weight of base material can not wait from every square metre about 0.01 to about 1000 grams, but is not limited to this, most preferably is to about 120 gram/m from about 25 2(being called " basis weight "), be formed into sheet or net usually, it can be cut, cross cutting or otherwise form suitable shape and size.Cleaning is wiped preferably to be had-wet tensile strength of Ding, and it from about 25 to about 250 newton/m, more preferably is about 75-170 newton/m preferably.
The ORP aqueous solution can be distributed, soaks, wraps quilt, cover or otherwise be applied to base material with any suitable method.For example, can handle the single part of base material with not commensurability ORP aqueous solution.Preferably, carry out ORP aqueous solution focusing on to the continuous net of substrate material.Whole substrate material net can be soaked in the ORP aqueous solution.Perhaps, when axle string base material net or even during generating non-woven substrate, can or be metered into online with the spraying of ORP aqueous solution.The manufacturer can soak in its container or wraps by a folded base material part that cuts and have a certain size respectively with the ORP aqueous solution.
Cleaning is wiped can randomly contain additional component, so that improve the performance that cleaning is wiped.For example, cleaning is wiped can also comprise polymer, surfactant, polysaccharide, polycarboxylate, polyvinyl alcohol, solvent, chelating agen, buffer, thickening agent, dyestuff, coloring agent, aromatic and its mixture, so that improve the performance that cleaning is wiped.These optional components should influence the stability of ORP aqueous solution sharply.At United States Patent (USP) 6,340, described cleaning in 663,6,649,584 and 6,624,135 and wiped the example that to choose the various components that comprise wantonly.
Can seal cleaning of the present invention individually with thermoplasticity outer package heat insulation or can be gluing (for example polyethylene, Mylar etc.) wipes.For more economical allotment, cleaning is wiped and can be packaged into a lot of one.By at first the multi-disc base material being positioned in the allotter, then substrate sheets is contacted with ORP aqueous solution of the present invention, can prepare cleaning and wipe.Perhaps, then moistening base material is installed in the allotter by using the ORP aqueous solution to base material in process of production, the cleaning that can form continuous net form formula is wiped.
Allotter includes but not limited to have closed jar or has closed basin.Closure on the allotter is the too early volatilization of isolating and avoiding liquid component for moistening wiping and external environment condition.
Allotter can be made by any suitable material all compatible with the ORP aqueous solution with base material.For example, allotter can be by plastics high density polyethylene (HDPE) for example, and polypropylene, Merlon, polyethylene terephthalate (PET), polrvinyl chloride (PVC) or other duroplastss are made.
The continuous net of wiping can pass the narrow and small opening of allotter top, most preferably passes closure.Need from net, to cut out the instrument of the wiping of Len req or size then.The blade, serrated knife blade or other instruments that net are cut into required size can be provided above allotter, and not limited example is the dual-use function that in fact narrow and small opening has blade.Perhaps, the continuous net of wiping can be scored, folds, segmentation, punching or part cut into unified or skimble-scamble size or length, and this has just eliminated the needs to sharp knife edges.In addition, wiping can be staggeredly placed, and makes that taking out a slice just directly manifests down a slice.
ORP aqueous solution of the present invention can by gaseous medium for example air be dispersed in the environment.The ORP aqueous solution can be dispersed in the air by any suitable manner.For example, the ORP aqueous solution can form the droplet of any suitable dimension and be distributed in the room.
Use for small-scale, can comprise that standpipe and pump use the ORP aqueous solution by spray bottle.Perhaps, the ORP aqueous solution can be wrapped in the aerosol container.Aerosol container generally comprises product to be applied, propellant, container and valve.Valve comprises actuator and soaks pipe.By the compressing actuator can applying container content.Various components in the aerosol container are all compatible with the ORP aqueous solution.Suitable propellant can comprise halocarbon, hydrocarbon or the halocarbon-hydrocarbon admixture of liquefaction or Compressed Gas for example carbon dioxide, nitrogen or-nitrous oxide.The aerosol system generates the droplet of magnitude range from about 0.15 μ m to about 5 μ m usually.
As being used for the treatment of the part that pulmonary and/or air flue infect or be used for the intake system of this class of health wound healing partly, can distribute the ORP aqueous solution with the form of aerosol.
For more massive application, can ORP be distributed in the air with any suitable device, include but not limited to humidifier, mist device, mister, aerosol apparatus, nebulizer, water jet and other spraying apparatus.These equipment are allowed and are used the ORP aqueous solution continuously.Can adopt aerosol apparatus at direct mist in nozzle place and water.The ORP aqueous solution can be converted to for example low-pressure steam of steam, and is released into air-spray.Can use for example ultrasonic humidifier of dissimilar humidifiers, seam humidifier or nebulizer and evaporation humidifier.
Be used to disperse the special installation of ORP aqueous solution can be integrated into aerating system, so that the extensive use of ORP aqueous solution in whole house or site of health care (for example hospital, nursing house etc.) is provided.
The present invention also provides the method for utilizing at least one electrolyzer to produce the ORP aqueous solution, and described electrolyzer comprises anode chamber, cathode chamber and the salt solution chamber between anode chamber and cathode chamber, and wherein the ORP aqueous solution comprises anode water and negative electrode water.Fig. 1 has shown the sketch map of three Room electrolyzers of the classics that the present invention is used.
Electrolyzer 100 has anode chamber 102, cathode chamber 104 and salt solution chamber 106.Salt solution chamber is between anode chamber 102 and cathode chamber 104.Anode chamber 102 has inlet 108 and outlet 110, so that allow that current are through anode chamber 102.Cathode chamber 104 has inlet 112 and outlet 114 equally, so that allow that current are through cathode chamber 104.Salt solution chamber 106 has inlet 116 and outlet 118.Electrolyzer 100 preferably includes and contains all components groove together.
By anode electrode 120 and anode ion exchange membrane 122 anode chamber 102 and salt solution chamber are separated.Anode electrode 120 can be adjacent to anode chamber 102, and film 122 is between anode electrode 120 and salt solution chamber 106.Perhaps, film 122 can be adjacent to anode chamber 102, and anode electrode 120 is between film 122 and salt solution chamber 106.
By cathode electrode 124 and cathode ion exchange film 126 cathode chamber 104 is separated with salt solution chamber.Cathode electrode 124 can be adjacent to cathode chamber 104, and film 126 is between cathode electrode 124 and salt solution chamber 106.Perhaps, film 126 can be adjacent to cathode chamber 104, and cathode electrode 124 is between film 122 and salt solution chamber 106.
Electrode normally is made of metal, allows between anode chamber and cathode chamber to apply voltage potential.Metal electrode is normally planar, and to have similar size and cross section surface long-pending to ion exchange membrane.Electrode is configured to make the most surfaces of ion exchange membrane all to be exposed to the water in their corresponding anode chambers and the cathode chamber.This allows that ionic species moves between salt solution chamber, anode chamber and cathode chamber.Preferably, electrode has a plurality of passage or holes that are distributed in equably on the electrode surface.
Potential source links to each other with cathode electrode 124 with anode electrode 120, makes to bring out oxidation reaction in the anode chamber 102 and the reduction reaction in the cathode chamber 104.
Electrolyzer 100 used ion exchange membranees 122 and 126 can be made of any suitable material, to allow ion exchange (for example chloride ion Cl-) between salt solution chamber 106 and the anode chamber 102 and the ion exchange (for example Na+) between salt solution chamber 106 and the cathode chamber 104.Anode ion exchange membrane 122 can be made by identical or different materials with cathode ion exchange film 126.Preferably, the anode ion exchange membrane comprises fluorinated polymer.Suitable fluorinated polymer for example comprises perfluorinated sulfonic acid polymer and copolymer for example perfluorinated sulfonic acid/PTFE copolymer and perfluorinated sulfonic acid/TFE copolymer.Ion exchange membrane can be made by monolayer material or multilayer material.
The anode chamber 102 of electrolyzer 100 and the water source of cathode chamber 104 can be any suitable water systems.Water can be from municipal water supply system or can be pretreated before being used for electrolyzer.Preferably, water is pretreated and be selected from the group of being made up of demineralized water, pure water, distilled water and deionized water.More preferably, pretreated water source is the ultra-pure water that obtains by reverse osmosis and UV line purification devices.
Used saline solution can be any aqueous saline solution in salt solution chamber 106, and it contains the suitable ionic species of producing the ORP aqueous solution.Preferably, saline solution is watersoluble chlorinated sodium (NaCl) saline solution, also often is called saline solution.Other suitable saline solution comprise for example for example potassium salt and bromine salt of potassium chloride, ammonium chloride and magnesium chloride and other halogen of other chloride salts.Saline solution can wrap saliniferous mixture.
Saline solution can have any suitable concentration.Saline solution can be saturated or spissated.Preferably, saline solution is saturated sodium chloride solution.
Fig. 2 has shown that it is believed that is the various ionic speciess that generate in three used Room electrolyzers of the present invention.Three Room electrolyzers 200 comprise anode chamber 202, cathode chamber 204 and salt solution chamber 206.Giving after anode 208 and negative electrode 210 apply suitable current, the contained ion of the saline solution of the salt solution chamber 206 that flows through moves respectively by anode ion exchange membrane 212 and cathode ion exchange film 214 and enters in the water of flow through anode chamber 202 and cathode chamber 204.
Cation is divided a word with a hyphen at the end of a line to from the saline solution 216 of the salt solution chamber 206 that flows through and is flowed through in the negative electrode water 218 of cathode chamber 204.Anion is divided a word with a hyphen at the end of a line to from the saline solution 216 of the salt solution chamber 206 that flows through and is flowed through the anode water 220 of anode chamber 202.
Preferably, saline solution 216 is to contain sodium ion (Na+) and the ionic sodium chloride of chloride ion (Cl-) (NaCl) aqueous solution.Positive Na+ ion is from saline solution 216 is divided a word with a hyphen at the end of a line negative electrode water 218.Minus Cl-ion is from saline solution 216 is divided a word with a hyphen at the end of a line anode water 220.
Sodium ion and chloride ion can also experience further reaction in anode chamber 202 and cathode chamber 204.For example, chloride ion can generate ClOn-and ClO-with contained various oxygen-carrying ions and other kinds (for example oxygen-derived free radicals, O2, the O3) reaction of anode water 220.Also can other reactions take place in anode chamber 202, comprise forming oxygen-derived free radicals, hydrion (H+), oxygen (O2) and randomly ozone (O3) and peroxide (for example hydrogen peroxide).In cathode chamber 204, can form hydrogen (H2), hydroxide ion (OH-), sodium hydroxide (NaOH) and other groups.
The present invention also provides and has utilized at least two three Room electrolyzers to produce the method and apparatus of ORP aqueous solution.Fig. 3 has shown the sketch map of the method for utilizing two electrolyzers production ORP aqueous solutions of the present invention.
Method 300 comprises two three Room electrolyzers, and concrete is first electrolyzer 302 and second electrolyzer 304.Water is shifted, pumps into or otherwise be assigned to the anode chamber 310 and cathode chamber 312 of the anode chamber 306 of first electrolyzer 302 and cathode chamber 308 and second electrolyzer 304 from water source 305.Method of the present invention can produce usually from about 1 liter/minute to about 50 liters/minute ORP aqueous solution.By utilizing additional electrolyzer can improve production capacity.For example, can with 3,4,5,6,7,8,9,10 or more a plurality of three Room electrolyzers increase the output of ORP aqueous solution of the present invention.
The anode water that anode chamber 306 and anode chamber 310 are produced is collected in the blending tank 314.A part of negative electrode water that cathode chamber 308 and cathode chamber 312 are produced is collected in the blending tank 314, and mixed with anode water.Outwell the negative electrode water of the remainder that this method produces.Before joining blending tank 314, negative electrode water can randomly pass through the processing of gas trap 316 and/or gas trap 318.Gas trap remove during the production process in negative electrode water formed gas hydrogen for example.
Blending tank 314 can randomly be connected with circulating pump 315, so that allow anode water and the part negative electrode water that mixes equably from electrolyzer 302 and 304.In addition, blending tank 314 can randomly comprise and is used to monitor the level of ORP aqueous solution and the suitable equipment of pH value.Through pump 317 the ORP aqueous solution can be shifted from blending tank 314 be applied to the blending tank position or near carry out disinfection or sterilize.Perhaps, the ORP aqueous solution can be assigned in the suitable containers, so that be transported to (for example warehouse, hospital etc.) at a distance.
Method 300 also comprises the saline solution blood circulation, so that saline solution is provided for the salt solution chamber 322 of first electrolyzer 302 and the salt solution chamber 324 of second electrolyzer 304.In salt cellar 320, prepare saline solution.Through pump 321 saline solution is transferred in salt solution chamber 322 and 324.Preferably, saline solution at first flows through salt solution chamber 322 successively, follows by salt solution chamber 324.Perhaps, saline solution can be pumped in two salt solution chamber simultaneously.
Before turning back to salt cellar 320, the saline solution heat exchanger 326 in the blending tank 314 of can flowing through is so that control the temperature of ORP aqueous solution as required.
Along with the ion in the saline solution in first electrolyzer 302 of time and second electrolyzer 304 is consumed.Can in blending tank 320, add extra ion source termly, be transferred to the ion of anode water and negative electrode water with replacement.Can keep the constant pH value of saline solution with extra ion source, described pH value is along with the time can be tended to descend (promptly becoming acidity).Extra ion source can be any suitable compound, comprises for example salt such as sodium chloride.Preferably, in blending tank 320, add sodium chloride, be transferred to sodium ion (Na+) in anode water and the negative electrode water with replacement.
In another embodiment, the invention provides the device that generates oxidative reductive potential water solution, described device comprises at least two three Room electrolyzers.Each electrolyzer comprises anode chamber, negative electrode water and the salt solution chamber of separating anode chamber and cathode chamber.This device comprises the anode water and the blending tank of a part by the negative electrode water of one or more electrolyzers generations that is used to collect the electrolyzer generation.Preferably, this device also comprises the salt blood circulation of saline solution recirculation of the salt solution chamber of permissible feed electrolyzer.
Invention that the following examples have been described illustration further, this not should be understood to constitute any restriction to invention scope certainly.
Embodiment 1-3
These embodiment have shown the specific characteristic of ORP aqueous solution of the present invention.According to the ORP aqueous sample among the methods analyst embodiment 1-3 described herein, to determine the physical property and the level of the ionic species that exists in each sample and other chemical species.The result of the chlorine dioxide that is obtained, ozone and hydrogen peroxide is dependent on the standard method of test that is used to measure these kinds; But the possibility of result indication also can produce the variety classes of positive test result.In addition, reported that chlorine dioxide, ozone and hydrogen peroxide can react with hypochlorite, caused their consumption and other kinds (for example HCl and O 2) generation.Table 1 has shown pH value, oxidation-reduction potential (ORP) and the existing ionic species of each ORP aqueous sample.
The physical features of table 1:ORP aqueous sample and contained ionic species
Embodiment 1 Embodiment 2 Embodiment 3
pH 7.45 7.44 7.45
ORP(mV) +879 +881 +874
Total Cl -(ppm) 110 110 120
In conjunction with Cl -(ppm) 5 6 6
The ORP aqueous solution has the suitable physical features of the sterilization of being applicable to, sterilization and/or cleaning.
Embodiment 4-10
These embodiment have showed the not commensurability bleach of adding in ORP aqueous solution of the present invention.Particularly, these embodiment have shown the antimicrobial acivity and the fabric bleaching ability of compositions.
Prepare 10%Clorox  liquid lime chloride with distilled water.Prepare following solution with 10% liquid lime chloride then: 80%ORP aqueous solution/20% bleach (embodiment 4); 60%ORP aqueous solution/40% bleach (embodiment 5); 40%ORP aqueous solution/60% bleach (embodiment 6); 20%ORP aqueous solution/80% bleach (embodiment 7); With 0%ORP aqueous solution/100% bleach (embodiment 8).Also compare, comprise 100%ORP aqueous solution/0% bleach (embodiment 9) and contain the ORP aqueous solution (embodiment 10) of 0.01%Tween20 detergent with two kinds of contrast solutions.Determine the physical features of these samples, particularly pH value, oxidation-reduction potential (ORP), total chlorine (Cl -) content, hypochlorous acid (HClO -) content, chlorine dioxide content and peroxide content, table 2 has shown these data.
The physical features of table 2:ORP aqueous solution/bleach compositions
pH ORP (mV) Total Cl - (ppm) HClO - (ppm)
Embodiment 4 8.92 +789 1248 62
Embodiment 5 9.20 +782 2610 104
Embodiment 6 9.69 +743 4006 80
Embodiment 7 9.86 +730 4800 48
Embodiment 8 9.80 +737 5000 50
Embodiment 9 7.06 +901 64 32
Embodiment 10 6.86 +914 51 26
Adding has stoped accurate mensuration to chlorine dioxide and peroxide level as a large amount of fluorion of the part of bleach, shown in labelling n.d..The chlorine dioxide that is obtained and the result of peroxide are dependent on the standard method of test that is used to measure these kinds; But the possibility of result indication also can produce the variety classes of positive test result.In addition, reported that chlorine dioxide, ozone and hydrogen peroxide can react with hypochlorite, caused their consumption and other kinds (for example HCl and O 2) generation.Shown in these embodiment, the hypochlorous acid level that adds or do not add in the ORP aqueous solution of bleach is similar.
Utilize bacillus subtilis black mutation spore (from SPS Medical of Rush, the ATCC#9372 that NewYork obtains) that the sample of embodiment 4-10 is carried out high spore counting mensuration.Spore suspension is concentrated (by evaporating in the aseptic cover) to per 100 microlitres 4 * 10 6Individual spore.Each sample mix with 100 microlitre spore suspension samples and 900 microlitre embodiment 4-10.As shown in table 3, with sample 1 to 5 fen clock time of incubation at room temperature.Shown in time, with 100 microlitres through the sample bed board of incubation to single TSA plate and 35 ℃ ± 2 ℃ following incubations 24 hours, determine the number of formed bacterium colony on each plate afterwards.Dull and stereotyped initial spore concentration＞1 * 10 that confirms of contrast 6Spore/100 microlitres.Table 3 has demonstrated the concentration (meansigma methods of twice mensuration) of different samples at the subtilis spore of different incubation time.
Table 3: subtilis spore concentration (spore/100 microlitres)
1 minute 2 minutes 3 minutes 4 minutes 5 minutes
Embodiment 4 ＞＞1000 411 1 0 2
Embodiment 5 ＞＞1000 1000 1 0 0
Embodiment 6 ＞＞1000 ＞＞1000 ＞1000 22 0
Embodiment 7 ＞＞1000 ＞＞1000 ＞1000 15 0
Embodiment 8 ＞＞1000 ＞＞1000 ＞1000 3 1
Embodiment 9 ＞＞1000 74 0 0 0
Embodiment 10 ＞＞1000 239 3 0 0
These results show, along with the increase of bleach concentration (10% aqueous liquid lime chloride), the decreased number of the bacillus spores of killing in incubation 2-3 minute the sample.But for 5 minutes sample of incubation, bleach concentration can not influence the killing action to bacillus spores.In addition, the result shows that in the OPR aqueous solution adding 0.01% detergent can not reduce spore and kill.
Sample with embodiment 4-10 carries out the fabric bleaching test.The fabric that is used for sample test is the child's T-shirt with navy blue dyestuff speckle of 100% artificial silk.2 square inches of dyed piece of cloth are put in the 50mL plastic tube.Cover every fabric with the solution example among the embodiment 4-10.Table 4 has shown up to having realized the spent time of full bleaching effect (it is definite to bleach by fabric).
Table 4: the time that the full bleaching fabric sample is spent
Embodiment Time
Embodiment 4 39 minutes
Embodiment
5 23 minutes
Embodiment 6 18 minutes
Embodiment 7 19 minutes
Embodiment 8 10 minutes
Embodiment 9 ＞6 hours
Embodiment
10 ＞6 hours
These embodiment show, during the concentration of the ORP aqueous solution in increasing compositions, realize that the spent time of full bleaching increases.
Embodiment 11
Present embodiment relates to the toxicology feature of ORP aqueous solution of the present invention.In these researchs, used the ORP aqueous solution of Microcyn 60 (or M60)-example of the present invention.
With regard to safety, as testing according to international standard (AAMI 1997, NV SOP 16G-44, PFEUM 2000), M60 does not have stimulation to skin or the conjunctiva of rabbit.In addition, the acute EXPERIMENT STUDY ON SUBCHRONIC of rat confirms that it is safe using Microcyn 60 by this approach.
Estimated the potential stimulation of Microcyn 60 at the main eye stimulation study of rabbit.The Microcyn 60 of 0.1mL volume is splashed in the right eye of 3 New Zealand white rabbit.The left eye of every animal is untreated in contrast.Observe eyes, and the 1st, 24,48 and 72 hour corneal ulcer or turbidity, iris inflammation, conjunctiva is rubescent or chemosis is marked.Also observe mortality rate and the unsound sign of all animals once a day.
The sign of whenever in any treated eye or contrast eye, all not observing eye irritation during the whole research.All animals all show as the clinical health state duration of research.These find that explanation Microcyn 60 can not cause male irritant reaction.
Also in rat, carried out acute EXPERIMENT STUDY ON SUBCHRONIC, to determine the potential toxicity on inhalation of Microcyn 60.10 Sprauge-Dawley albefaction rats are exposed to by undiluted Microcyn 60 formed aerosols 4 hours.The concentration that determines Microcyn 60 is 2.16mg/L.Expose observed animal continually the same day and observe once a day in 14 days afterwards all animals mortality rate and toxic clinical/behavior sign.At the 14th day all animals are implemented euthanasia, and carry out the cardinal principle necropsy.
All animals show very slight to slight piloerection and very slight activity minimizing in the time of 4 1/2 and 6 hours in exposure beginning back, but do not had symptom to next day, and all show clinical normal duration of research.1 male Mus did not have weight increase between the 0th to the 7th day.There do not have mortality rate and cardinal principle postmortem not to find to be visible unusual.The acute suction LD50 that estimates from this research is greater than 2.16mg/L.
In rabbit, carried out additional toxicologic study.In the right naris of 20 new zealand rabbits, send the super oxidize water of aerosol (1mL) by malleation equipment, totally 15,30,45 and 60 days every day 3 times.Any processing is not done in contrast nostril, left side.From 5 animals, obtain to be untreated and the nasal mucosa biopsy in the nostril that M60 handles at each time point.Under light microscopic and Electronic Speculum, observe these tissues then.The next day every animal carried out comprehensive medical inspection, note nasal obstruction, opsialgia, compressing, mucopurulent rhinorrhearhea and discomfort.It is rare, slight and of short duration that side effect is reported as.
The change of nasal mucosa appearred after 60 days using intranasal M60.In the time of the 60th day, the discrete inflammatory infiltration of the slight damage of epithelium, last subcutaneous area and the hypertrophy of body of gland and blood vessel have all appearred in all samples.Under Ultrastructural observation, we find to have occurred multiple different capsule sample and change mitochondrion cohesion distortion, the dissolving of part film in epithelial cell.Some epithelial cells separate, and the epithelium cilium almost disappears, and the space broadens in its film dissolving and the born of the same parents.Some cells separate with basement membrane.Lamina propria is a Mild edema.
This studies confirm that intranasal administration after 60 days M60 can stimulate nasal mucosa slightly.But this damage is very little and reversible, so intranasal administration M60 approach can be considered to safe.Although the fact of this foundation be use vasoconstrictor after the several years nasal mucosa can be subjected to serious damage, it still can return to normal behind these medicines of stopping using.This is possible, because the regenerated process of nasal mucosa depends on whether basal cell and basement membrane still are kept perfectly after damage.Contiguous basal cell can move to disease damage place along basement membrane, and covers the disease damage.Therefore, even some zones exist under the slight isolating situation of epithelial cell after M60 handles, and basement membrane is still survived, and the viable epithelial cell in adjacent lesion zone is to the region growing that lacks epithelium.In addition, also can use topical steroids, to promote the recovery of nasal mucosa 26S Proteasome Structure and Function.
Generally speaking, intranasal administration M605 days is safe in this group.It is slight and reversible that the pathologic mucosa changes.Therefore, can use the intranasal administration of M60 widely.
Embodiment 12
Present embodiment has been described activity, the stability of example ORP aqueous solution and has been lacked toxicity.
A kind of such ORP aqueous solution that this institute is used is called " Microcyn ", and it is introduced in Mexico market as antibiotic antiseptic recently.Microcyn is the super oxidizing solution with pH neutral, and according to the certificate that obtains from the healthy administration of Mexico, it has the activity of sterilization, sterilization and wound sterilization and anticorrosion.Microcyn is from the preparation of pure water and salt (NaCl), its have low concentration sodium (＜55ppm) and chlorine (＜80ppm), the pH value scope is from 7.2 to 7.8, the scope of oxidation-reduction potential is from 840mV to 960mV.The Microcyn that only prepares a concentration does not need activation or dilution.
Prepare this solution with the water that obtains through reverse osmosis, the electrochemical gradient that generates with high voltage and sodium chloride is handled then.By this way, connect controlled way and select in a plurality of chambers that generate electrochemical gradient therein formed reactive kind to generate Microcyn.The result is the solution that has obtained to have the free radical of controlled content, described free radical provide high oxidation-reduction potential (+840mV to+960mV), therefore solution have high antimicrobial acivity.
Hypochlorous acid and sodium hypochlorite are the contained the abundantest components of Microcyn, and the component that Microcyn also contains other low concentrations is hydrogen peroxide, ozone, chloride ion, hydride and sodium hydroxide etc. for example.Although the applicant is reluctant to be subjected to the restriction of particular theory, believes that sterilization must not depend on the amount of chlorine, but depend on the content of free radical, because the level of sodium among the Microcyn and chlorine is respectively less than 50 and 60ppm.In addition, compare with other super oxidizing solutions that document has been reported, Microcyn has neutral pH value (6.4-7.8), and it is non-corrosive, and the longest can storage-stable 2 years.All these features all make and can generate the super oxidizing solution that can be effective as high-caliber disinfectant and be applicable to abiotic surface and tissue.
The accelerated stability test has confirmed that Microcyn can be stored in the temperature conditions of extensive variation (from 4 to 65 ℃), and does not lose its antimicrobial activity in 2 years.This prolongation stability on shelf also is different from the super oxidizing solution of previous report, and the latter only uses just effective after preparation at once.In other words, even can under extreme conditions store and distribute Microcyn and do not lose its antimicrobial acivity, but other solution must be generated by the machine special and costliness in each hospital that wants to use this solution.However, business men is still recommended, and for activity and the constant effect that guarantees that it is unified, in case opened the container of Microcyn, should use in 30 days.
Therefore because only generate the Microcyn of a concentration, the variation of the volume that can only be used by per unit area skin changes the dosage of Microcyn.In toxicologic study, the dosage of giving the Microcyn of complete topical application is 0.05 and 0.07mL/cm 2Between, in acute dermal toxicity research and skin irritation research, dosage is up to 8.0mL/cm 2, inquiring into it in the research of the application of deep wound, the dosage of the Microcyn that is used is 0.09mL/cm 2
Carry out toxicologic study, wherein give complete topical application Microcyn, single administration exposes 4 to 24h.Estimate Microcyn and repeatedly use every day 1 time or 2 times totally 7 days at the rat deep wound.
On the intact skin of rabbit, carry out two researchs, estimate acute irritation effect and the dermal toxicity of Microcyn.Skin abnormality when in being exposed to any animal of Microcyn, all not finding clinical sign, skin irritation or postmortem.
Estimated to caused part of deep wound local application Microcyn and systemic-toxic feature with rat.Do not observe any unusual, the significant difference of blood biochemical or blood cell mathematic(al) parameter, postmortem is not observed unusually yet.The histopathology of skin irritation classification and wound and site of administration surrounding tissue does not all show through wound that Microcyn handles and any difference between the wound of the matched group that saline solution is handled.
Also estimated the general toxicity of Microcyn by the peritoneal injection of mice.To this, give 5 injected in mice single doses (50mL/kg) Microcyn through the intraperitoneal approach.Give 5 control mice injection single dose (50mL/kg) saline solutions (0.9% sodium chloride) in a like fashion.In this research, in any animal of accepting single intraperitoneal dosage Microcyn, all do not observe mortality rate or any systemic-toxic evidence, its LD 50Greater than 50mL/kg.
By oral route is used Microcyn to rat, so that allow the inherent toxic action in any inherence of its absorption and sign product.For this reason, giving 3 Sprague-Dawley by food meatus is that the albefaction rat is used single dose (4.98mL/kg).In being exposed to all animals of single oral dose Microcyn, all do not have mortality rate, do not have clinical sign or postmortem unusual.
Also estimated the probability that local application Microcyn causes eye irritation with rabbit.In all animals of the Microcyn of eyes approach local application, all do not observe eye irritation and any other clinical sign being exposed to.
Use Microcyn by inhalation route to rat, suck the possible acute toxicity that causes to measure.After exposing, all animals all demonstrate very slight or slight activity minimizing and piloerection, but they all are asymptomatic in next day.In the animal that is exposed to Microcyn through suction, do not observe mortality rate or postmortem is unusual.
The occlusion patch method (Buehler) of utilize modifying has been carried out evaluation to the probability of Microcyn sensitization skin on one's body Cavia porcellus.All do not observe stimulation in animals of control group after single treatment is attacked and the animal of being estimated (through inducing processing) after handling attack.Therefore, Microcyn can not cause sensitivity response.
Therefore, when by oral and inhalation route or by peritoneal injection Microcyn being applied to intact skin, the open skin wound in deep, conjunctival sac, Microcyn does not demonstrate the ill effect relevant with product.Also there are treatment 500 many cases to have the patient's of skin very of different nature and mucosa wound experience, fabulous antibiotic anticorrosion and esthetic result is arranged.Therefore, in this clinical trial, local application Microcyn effectively and better tolerates.
Microcyn is packaged in the transparent 240mL PET bottle.At room temperature preserve this product, if bottle is not opened, it can keep stable and reach 2 years on shelf.In case opened bottle, recommended all products in 90 days, to use up.Because its high biological safety, Microcyn can be introduced in the tank, does not pollute or corrosive danger.
Carried out the microbiological test of multinomial Microcyn in the U.S. and Mexico.In the exposure of a several seconds, can remove the antibacterial more than 90%.Table 5 has been summed up antibacterium and the antifungal activity that is shown according to this standard Microcyn.
Antibacterium and the antifungal activity of table 5.Microcyn
Antibacterial Numbering Action time (minimizing is lower than 99.999%)
Pseudomonas aeruginosa ATCC25619 1min
Staphylococcus aureus ATCC6538 1min
Escherichia coli ATCC11229 1min
Salmonella typhi CDC99 1min
Candida albicans ATCC 1min
Bacillus subtilis 9372
Low spore (10 4) 10min
High spore (10 6) 15min
According to PAHO[the whole America health organization]/the WHO scheme kills the spore activity test.
About viricidal activity, find that Microcyn has reduced human immunodeficiency virus's's (SF33 strain) viral load more than 3 logarithm levels in 5 minutes.Disappearance by cytopathic effect and antigen A gp24 in the virus test of handling through Microcyn has confirmed this point.Antiviral scheme (DIS/TSS-7/1981 November 12) according to Environmental Protection Agency is implemented these tests.
The nearest verified viricidal activity of Microcyn in the research that the U.S. carries out at HIV and poliovirus, the also verified activity of its anti-listerisa monocytogenes in mjme, MRSA and mycobacterium tuberculosis.Therefore, verified when as recommend use Microcyn the time, Microcyn can remove antibacterial, fungus, virus and spore after exposing 1 to 15 minute.
Embodiment 13
Present embodiment has shown the purposes of example ORP aqueous solution Microcyn as effective antimicrobial solutions.
Implemented external time-killed and wounded evaluation with the Microcyn oxidation-reduction potential water.Estimated the ability of the attack suspension of 50 kinds of different microbial strains of Microcyn antagonism, 25 kinds of American Type Culture Collections (ATCC) bacterial strain wherein, the clinical separation strain of 25 kinds of these same species, as Tentative Final Monograph, Federal Register, 17 June 1994, vol.59:116, pg.31444 is described.Be exposed to Microcyn after 30 seconds, 1 minute, 3 minutes, 5 minutes, 7 minutes, 9 minutes, 11 minutes, 13 minutes, 15 minutes and 20 minutes, determining every kind and attack percentage ratio and the Log10 minimizing that bacterial strain reduces from initial flora quantity.All agar bed boards all repeat twice, and the Microcyn concentration of being estimated is 99% (v/v).Carry out all tests according to Good Laboratory Practices (as described in 21C.F.R the 58th part).
Following table has been summed up in 30 seconds and has been exposed the mark minimizing above 5.0 Log 10Above-mentioned external time-kill result of evaluation of all test groups.
Table 6: sterilization in external 30 seconds
No. Microbial species Initial number (CFU/mL) Expose back quantity (CFU/mL) Log 10Reduce Reduce percentage ratio
1 Acinetobacter bauamnnii (ATCC#19003) 2.340×10 9 ＜1.00×10 3 6.3692 99.9999
2 Acinetobacter bauamnnii clinical separation strain BSLI#061901Ab3 1.8150×10 9 ＜1.00×10 3 6.2589 99.9999
3 Bacteroides fragilis (ATCC#43858) 4.40×10 10 ＜1.00×10 3 7.6435 99.9999
4 Bacteroides fragilis clinical separation strain BSLI#061901Bf6 2.70×10 10 ＜1.00×10 3 7.4314 99.9999
5 Candida albicans (ATCC#10231) 2.70×10 10 ＜1.00×10 3 6.3345 99.9999
6 Candida albicans clinical separation strain BSLI#042905Ca 5.650×10 9 ＜1.00×10 3 6.7520 99.9999
7 Clostridium perfringen (ATCC#29007) 1.2250×10 9 ＜1.00×10 3 6.0881 99.9999
8 Clostridium perfringen clinical separation strain BSLI#042905Ea 1.0150×10 9 ＜1.00×10 3 6.0065 99.9999
9 Enterococcus faecalis (ATCC#29212) 2.610×10 9 ＜1.00×10 3 6.4166 99.9999
10 Enterococcus faecalis clinical separation strain BSLI#061901Efs2 1.2850×10 9 ＜1.00×10 3 6.1089 99.9999
11 Enterococcus faecalis VRE, MDR (ATCC#51559) 3.250×10 9 ＜1.00×10 3 6.5119 99.9999
12 Enterococcus faecalis clinical separation strain BSLI#061901Efm1 1.130×10 9 ＜1.00×10 3 6.0531 99.9999
13 Escherichia coli (ATCC#11229) 5.00×10 8 ＜1.00×10 3 5.6990 99.9998
14 Escherichia coli clinical separation strain BSLI#042905Ec1 3.950×10 8 ＜1.00×10 3 5.5966 99.9997
15 Escherichia coli (ATCC#25922) 6.650×10 8 ＜1.00×10 3 5.8228 99.9998
16 Escherichia coli clinical separation strain BSLI#042905Ec2 7.40×10 8 ＜1.00×10 3 5.8692 99.9998
17 Hemophilus influenza (ATCC#8149) 1.5050×10 9 ＜1.00×10 4 5.1775 99.9993
18 Hemophilus influenza clinical separation strain BSLI#072605Hi 1.90×10 9 ＜1.00×10 4 5.2788 99.9995
19 Acid-producing Klebsiella bacterium MDR (ATCC#15764) 1.120×10 9 ＜1.00×10 3 6.0492 99.9999
20 Acid-producing Klebsiella bacterium clinical separation strain BSLI#061901Ko1 1.810×10 9 ＜1.00×10 3 6.2577 99.9999
21 Klebsiella pneumonia ozena subspecies (ATCC#29019) 1.390×10 9 ＜1.00×10 3 6.1430 99.9999
22 Klebsiella pneumonia clinical separation strain BSLI#061901Kpn2 9.950×10 8 ＜1.00×10 3 5.9978 99.9999
23 Micrococcus luteus (ATCC#7468) 6.950×10 8 ＜1.00×10 3 5.8420 99.9999
24 Micrococcus luteus clinical separation strain BSLI#061901M12 1.5150×10 9 ＜1.00×10 3 6.1804 99.9999
25 Proteus mirabilis (ATCC#7002) 1.5950×10 9 ＜1.00×10 3 6.2028 99.9999
26 Proteus mirabilis clinical separation strain BSLI#061901Pm2 2.0950×10 9 ＜1.00×10 3 6.3212 99.9999
27 Pseudomonas aeruginosa (ATCC#15442) 6.450×10 8 ＜1.00×10 3 5.8096 99.9999
28 Pseudomonas aeruginosa clinical separation strain BSLI#072605Pa 1.3850×10 9 ＜1.00×10 3 6.1414 99.9999
29 Pseudomonas aeruginosa (ATCC#27853) 5.550×10 8 ＜1.00×10 3 5.7443 99.9999
30 Pseudomonas aeruginosa clinical separation strain BSLI#061901Pa2 1.1650×10 9 ＜1.00×10 3 6.0663 99.9999
31 Serratia marcesens (ATCC#14756) 9.950×10 8 ＜1.00×10 3 5.9978 99.9999
32 Serratia marcesens clinical separation strain BSLI#042905Sm 3.6650×10 9 ＜1.00×10 3 6.5641 99.9999
33 Staphylococcus aureus (ATCC#6538) 1.5050×10 9 ＜1.00×10 3 6.1775 99.9999
34 Staphylococcus aureus clinical separation strain BSLI#061901Sa1 1.250×10 9 ＜1.00×10 3 6.0969 99.9999
35 Staphylococcus aureus (ATCC#29213) 1.740×10 9 ＜1.00×10 3 6.2405 99.9999
36 Staphylococcus aureus clinical separation strain BSLI#061901Sa2 1.1050×10 9 ＜1.00×10 3 6.0434 99.9999
37 Staphylococcus epidermidis (ATCC#12228) 1.0550×10 9 ＜1.00×10 3 6.0233 99.9999
38 Staphylococcus epidermidis clinical separation strain BSLI#072605Se 4.350×10 8 ＜1.00×10 3 5.6385 99.9998
39 Staphylococcus haemolyticus (ATCC#29970) 8.150×10 8 ＜1.00×10 3 5.9112 99.9999
40 Staphylococcus haemolyticus clinical separation strain BSLI#042905Sha 8.350×10 8 ＜1.00×10 3 5.9217 99.9999
41 Staphylococcus hominis (ATCC#27844) 2.790×10 8 ＜1.00×10 3 5.4456 99.9996
42 Staphylococcus hominis clinical separation strain BSLI#042905Sho 5.20×10 8 ＜1.00×10 3 5.7160 99.9998
43 Staphylococcus saprophyticus (ATCC#35552) 9.10×10 8 ＜1.00×10 3 5.9590 99.9999
44 Staphylococcus saprophyticus clinical separation strain BSLI#042905Ss 1.4150×10 9 ＜1.00×10 3 6.1508 99.9999
45 Streptococcus pneumoniae (ATCC#33400) 2.1450×10 9 ＜1.00×10 4 5.3314 99.9995
46 Streptococcus pyogenes (ATCC#19615) 5.20×10 9 ＜1.00×10 3 6.7160 99.9999
47 Streptococcus pyogenes clinical separation strain BSLI#061901Spy7 2.5920×10 9 ＜1.00×10 3 6.4141 99.9999
For 3 kinds of bacterial strains of residue that table 6 does not comprise, reduce less than 5.0Log although measure its microorganism 10But Microcyn has also demonstrated the antimicrobial acivity that resists these 3 kinds of bacterial strains.More specifically, the exposure in 30 seconds of Microcyn is made streptococcus pneumoniae (clinical separation strain; BSLI#072605Spnl) quantity reduces above 4.5Log 10, this is the detection limit of this strain.In addition, when attacking with Oidium tropicale (ATCC#750), Microcyn makes the microorganism minimizing surpass 3.0Log after exposing for 30 seconds 10, in addition, when attacking with Oidium tropicale (BSLI#042905Ct), Microcyn makes the microorganism minimizing surpass 3.0Log after exposing 20 minutes 10
The example results of this external time-kill evaluation shows that the Microcyn oxidation-reduction potential water has fast the antimicrobial acivity of (being all less than 30 seconds in the most applications) anti-wide spectrum aggressivity microorganism.Be exposed to this product in 30 seconds, the microbial biomass of 47 kinds of bacterial strains in 50 kinds of Gram-positives, Gram-negative and barmses being estimated has all reduced 5.0Log 10More than.
Embodiment 14
Present embodiment has shown example ORP aqueous solution Microcyn and HIBICLENS The comparison of the antimicrobial acivity of chlorhexidine gluconate solution 4.0% (w/v) and 0.9% sodium choride irrigation (USP).
Utilize HIBICLENS Chlorhexidine gluconate solution 4.0% (w/v) and aseptic 0.9% sodium choride irrigation (USP) be as with reference to product, carries out external time-kill and wound evaluation as embodiment 13 is described.The suspension that is used in the specially appointed 10 kinds of American Type Culture Collections of Tentative Final Monograph (ATCC) bacterial strain is estimated every kind with reference to product.Analyze collected data then, and the reduction activation of microorganism of the Microcyn that is write down with embodiment 13 compares.
The level that the 5 kinds of quantity of attacking bacterial strains that make the Microcyn oxidation-reduction potential water reduce with to HIBICLENS Chlorhexidine gluconate solution is observed is on close level.Microcyn and HIBICLENS Strain below all makes its microorganism reduce 5.0Log after exposing for 30 seconds 10More than: escherichia coli (ATCC#11229 and ATCC#25922), Pseudomonas aeruginosa (ATCC#15442 and ATCC#27853) and serratia marcesens (ATCC#14756).In addition, shown in top table 5, Microcyn demonstrates the antimicrobial acivity of fabulous anti-micrococcus luteus (ATCC#7468), has reduced 5.8420Log after exposing in 30 seconds 10, still, directly compare HIBICLENS Anti-micrococcus luteus (ATCC#7468) activity be impossible because after exposing for 30 seconds, HIBICLENS The detection limit that makes the minimizing of bacterial strain quantity reach test (is to have surpassed 4.8Log in this instantiation 10).It should be noted that 0.9% aseptic sodium chloride rinse solution only makes 6 kinds discussed above to attack each micro organism quantity of bacterial strains and reduce less than 0.3Log after fully exposing 20 minutes 10
Attack bacterial strain for 4 kinds of tests: for enterococcus faecalis (ATCC#29212), staphylococcus aureus (ATCC#6538 and ATCC#29213) and the staphylococcus epidermidis (ATCC#12228), the Microcyn oxidation-reduction potential water provides and compares HIBICLENS With the higher antimicrobial acivity of sodium chloride flushing.Below table summed up external time of these 4 kinds of strains-killed and wounded the result that the microorganism of evaluation reduces:
Table 7: the result relatively sterilizes
Microbe species Open-assembly time Log 10Reduce
Microcyn HIBICLENS The NaCl flushing
Enterococcus faecalis (ATCC#29212) 30 seconds 6.4166 1.6004 0.3180
1 minute 6.4166 2.4648 0.2478
3 minutes 6.4166 5.2405 0.2376
5 minutes 6.4166 5.4166 0.2305
7 minutes 6.4166 5.4166 0.2736
9 minutes 6.4166 5.4166 0.2895
11 minutes 6.4166 5.4166 0.2221
13 minutes 6.4166 5.4166 0.2783
15 minutes 6.4166 5.4166 0.2098
20 minutes 6.4166 5.4166 0.2847
Staphylococcus aureus (ATCC#6538) 30 seconds 6.1775 1.1130 0.0000
1 minute 6.1775 1.7650 0.0191
3 minutes 6.1775 4.3024 0.0000
5 minutes 6.1775 5.1775 0.0000
7 minutes 6.1775 5.1775 0.0000
9 minutes 6.1775 5.1775 0.0000
11 minutes 6.1775 5.1775 0.0267
13 minutes 6.1775 5.1775 0.0000
15 minutes 6.1775 5.1775 0.0191
20 minutes 6.1775 5.1775 0.0000
Staphylococcus aureus (ATCC#29213) 30 seconds 6.2405 0.9309 0.0000
1 minute 6.2405 1.6173 0.0000
3 minutes 6.2405 3.8091 0.0460
5 minutes 6.2405 5.2405 0.0139
7 minutes 6.2405 5.2405 0.0000
9 minutes 6.2405 5.2405 0.0113
11 minutes 6.2405 5.2405 0.0283
13 minutes 6.2405 5.2405 0.0000
15 minutes 6.2405 5.2405 0.0000
20 minutes 6.2405 5.2405 0.0615
Staphylococcus epidermidis (ATCC#12228) 30 seconds 5.6385 5.0233 0.0456
1 minute 5.6385 5.0233 0.0410
3 minutes 5.6385 5.0233 0.0715
5 minutes 5.6385 5.0233 0.0888
7 minutes 5.6385 5.0233 0.0063
9 minutes 5.6385 5.0233 0.0643
11 minutes 5.6385 5.0233 0.0211
13 minutes 5.6385 5.0233 0.1121
15 minutes 5.6385 5.0233 0.0321
20 minutes 5.6385 5.0233 0.1042
The result of this more external time-kill and wound evaluation confirms that the Microcyn oxidation-reduction potential water not only shows and HIBICLENS The antimicrobial acivity of suitable Chinese People's Anti-Japanese Military and Political College enterobacteria (ATCC#11229 and ATCC#25922), Pseudomonas aeruginosa (ATCC#15442 and ATCC#27853), serratia marcesens (ATCC#14756) and micrococcus luteus (ATCC#7468), but also the treatment of more effectively anti-enterococcus faecalis (ATCC#29212), staphylococcus aureus (ATCC#6538 and ATCC#29213) and staphylococcus epidermidis (ATCC#12228) is provided.As shown in table 7, Microcyn has shown antimicrobial effect (promptly less than 30 seconds) more fast in some strains.In addition, Microcyn exposes the minimizing of the bigger overall microorganism that has caused listed all strains of table 7.
Embodiment 15
Present embodiment provides and has been applicable to the of the present invention preparation of local application to the patient.Preparation comprises following component:
Component Quantity
ORP aqueous solution 250mL
Carbopol  polymer powder (thickening agent) 15g
Triethanolamine (nertralizer) 80mL
Embodiment 16
Present embodiment provides and has been applicable to the of the present invention preparation of local application to the patient.Preparation comprises following component:
Component Quantity
ORP aqueous solution 1000mL
Carbopol  polymer powder (thickening agent) 15g
Triethanolamine (nertralizer) 80mL
Embodiment 17
Present embodiment provides and has been applicable to the of the present invention preparation of local application to the patient.Preparation comprises following component:
Component Quantity
ORP aqueous solution 250mL
Carbopol  polymer powder (thickening agent) 7g
Triethanolamine (nertralizer) 12mL
Embodiment 18
Present embodiment has been described the production of the preparation of the present invention that comprises ORP aqueous solution and thickening agent.
With the ORP aqueous solution be poured into suitable containers for example glass beaker or the bottle in.Through scalping (or filter screen), it allows rapid screening with Carbopol  974P polymer, can smash all big coagulas simultaneously.Add polymer Carbopol  974P then as thickening agent.Slowly add Carbopol  polymer, avoiding the formation of grumeleuse, and therefore avoid long mixing cycle.
Mixed solution apace during adding Carbopol  polymer makes powder at room temperature dissolve.In solution, add the nertralizer triethanolamine then, and mix, up to obtaining even gel with motorized agitator or other suitable device.Adding nertralizer in Carbopol  polymer composition makes preparation become gel.
Embodiment 19
Present embodiment has been described particularly 2 degree and the 3 degree purposes of burning of burn that ORP aqueous solution of the present invention is used for the treatment of the child fire victim.
64 routine child fire victims have accepted the treatment of ORP aqueous solution altogether.Seminar is compared with the matched group of being made up of the 64 routine patients that accept traditional burn treating equally.Seminar comprises following patient: the patient of the patient of 1 example, 1 degree fire victim, 6 examples, 1 degree and 2 degree burn combinations, 38 examples, 2 degree fire victims, 4 examples, 3 degree burns, 15 examples, 2 degree and 3 degree burn combinations.In addition, seminar is made up of the patient with following burn percentage ratio (scope of promptly burning): patient, 1 examples that patient, 4 examples that patient, 8 examples that patient, 11 examples that patient, 27 examples that 10 examples have 0 to 9% a burn scope have 10 to 19% burn scopes have 20 to 29% burn scopes have 30 to 39% burn scopes have 40 to 49% burn scopes have the patient that 50 to the 59% burn patients of scopes and 3 examples have 60 to 69% burn scopes.All every example burn has been carried out debridement at first.By high pressure rinse equipment spray application solution.Then,, and make its moistening burn 5 to 15 minutes, repeat this process 3 times every day by spray application solution.Using between the solution not dressing burn.
In the cultivation of getting, have only 6 examples after the patient of ORP aqueous solution treatment had been in hospital 7-15 days, positive the cultivation to occur, and matched group have 22 examples in order to determine burn surfaces whether to have microorganism.Residue patient in seminar's (58 example) and the matched group (42 example) cultivation that all is negative.
Table 8 listed the positive in seminar and the matched group cultivate in existing microorganism.
Table 8: burn microorganism
Matched group ％ Seminar ％
Staphylococcus aureus enterobacter cloacae Pseudomonas aeruginosa Candida albicans Klebsiella amounts to 56.0 8.0 19.0 12.0 5.0 100.0 Staphylococcus aureus enterobacter cloacae staphylococcus haemolyticus amounts to 57.1 28.2 14.2 100.0
According to the character of every patient's burn, the frequency of using the ORP aqueous solution is different.Seminar and matched group have been made table by the burn rank with average time in hospital day.For 1 degree burn, the average time in hospital day of seminar (6 routine patient) is 4.6 days, and matched group (45 routine patient) is 19.2 days.For 2 degree burns, the average time in hospital day of seminar (44 routine patient) is 10.6 days, and matched group (9 routine patient) is 26.9 days.For 3 degree burns, the average time in hospital day of seminar (14 routine patient) is 29.5 days, and matched group (10 routine patient) is 39.8 days.Generally speaking, use ORP aqueous solution of the present invention for the child fire victim and make average stay length drop to 14.9 days, descended 48% from 28.6 days.Table 9 has been listed the average hospital days based on the relative seminar of burn scope matched group.
Table 9: hospital stays
The burn scope The length of stay matched group Length of stay seminar
0-9％ 10-19％ 20-29％ 30-39％ 40-49％ 50-59％ 60-69％ Not 16.1 11.7 8.6 40.2 32.3 0 (not having the treatment patient) 34.3 6.9 8.2 22.7 16.8 26.5 55 68.0
By present embodiment as seen, ORP aqueous solution of the present invention can be applied to the child fire victim valuably, causes the decline of length of stay.
Embodiment 20
Present embodiment has been described and has been used ORP aqueous solution of the present invention and non-administration of antibiotics for the child fire victim.
58 routine patients antibiotic therapy all of no use to microorganism culturing feminine gender after being in hospital 7-15 days in the seminar described in the embodiment 19 in the above.This group patient's average time in hospital day is 12.3 days.In matched group, 46 routine patients have also used antibiotic except using the ORP aqueous solution.22 examples among these patients have been observed male microorganism culturing, and these average time in hospital days of using antibiotic patient are 28.6 days.
As shown in this embodiment, ORP aqueous solution of the present invention can be applied to the child fire victim and not conventional use antibiotic valuably.
Embodiment 21
Present embodiment has shown the effect to the viability of human diploid fibroblasts (HDF) of example ORP aqueous solution and hydrogen peroxide (HP).In order to study this potential toxicity, with external ORP aqueous solution and the hydrogen peroxide (HP) of being exposed to of HDF.Known HP is deleterious to eukaryotic cell, has increased apoptosis and necrosis and has reduced cell survival.In the present embodiment, cell survival, apoptosis and the necrosis of the HDF that is exposed to pure ORP aqueous solution and 880mM HP (concentration that antibacterial application adopted of HP) 5 minutes and 30 minutes have been measured.
Obtain the HDF culture from 3 different foreskins, compiling it also, cold preservation is used for this research together.Diploid cell is only used in all tests.In cell cycle analysis, the DNA diploidy is defined in and exists CV smaller or equal to 7% single G0-G1 peak and corresponding G2/M peak at least in 20,000 collected total incident.Fig. 4 A-4C has described the result, and wherein describing open-assembly time with informal voucher and secret note respectively is 5 and 30 minutes result.Utilize: A) 7-aminoactinomycin D (7AAD), B) annexin V-FITC and C) when carrying out these parameters by flow cytometry to identical cell mass, iodate third ingot analyzes.Fig. 4 A-4C has described percent value, with meansigma methods ± SD (n=3) expression.
Cell survival after being exposed to ORP aqueous solution and HP5 minute is respectively 75% and 55% (Fig. 4 A).If exposure is extended to 30 minutes, cell survival further is reduced to 60% and 5% respectively.The ORP aqueous solution obviously by necrosis induction cell death because in the flow cytometry of two time points, all there is 15% cell to mix iodate third ingot (Fig. 4 C).Though do not want to be subjected to the constraint of any particular theory, this possibility of result is because the inductive osmosis of hypotonicity (13mOsm) of Microcyn because cell is only kept with the ORP aqueous solution, is not added somatomedin or ion.As if apoptosis is not the mechanism of ORP aqueous solution inducing cell death, because have only 3% to expose annexin V (label of apoptosis) (Fig. 4 B) through the cell that the ORP aqueous solution was handled on its cell surface.This percentage ratio is in fact similar to the result who is measured at matched group.On the contrary, HP has induced 20% and 75% to handle the necrosis of cell and 15% and 20% apoptosis after exposing 5 minutes and 30 minutes respectively.These results show that together (undiluted) ORP aqueous solution is to the toxicity of the HDF HP far below antibiotic concentration.
Embodiment 22
Present embodiment has been described example ORP aqueous solution with respect to the effect of hydrogen peroxide (HP) to the damage of the O-DNA among the HDF and dna adduct 8-hydroxyl-2 '-deoxyguanosine (8-OHdG) formation.The label of the oxidative damage at the specific residue place that known intracellular 8-OHdG adduct formation is DNA.In addition, high-caliber this adduct and mutation in the cell, carcinogenic and cell ageing is relevant.
Fig. 5 has shown in control treatment, ORP aqueous solution and has handled and HP handles 30 minutes levels of contained 8-OHdG adduct in the DNA of HDF sample afterwards.After exposure (T0, informal voucher) or extract DNA attacking after date 3 hours (T3, secret note) at once.Dna digestion, and according to catalogue ELISA kit measurement 8-OHdG adduct.Numerical value (ng/mL) is represented with meansigma methods ± SD (n=3).Compare with the control cells of incubation after 30 minutes, the ORP aqueous solution exposes 30 minutes does not increase the formation of handling intracellular adduct.Opposite, the processing (handling 30 minutes with 500 μ M HP) of the HP of high dilution (low to the inferior HP concentration (500 μ M HP) that causes death and do not have therapeutical effect) makes the quantity comparison of 8-OHdG adduct increase about 25 times according to the quantity in the cell of handling or the ORP aqueous solution is handled.
If after being exposed to the ORP aqueous solution, cell to be stayed replenished among the DMEM 3 hours, the cell of handling through the ORP aqueous solution can reduce the level of 8-OHdG adduct.Although allow to have 3 hours identical convalescent period, the cell of handling through HP still has comparison according to the high about 5 times adduct of cell that handled or that the ORP aqueous solution was handled.In a word, these results have confirmed can not induce significant DNA oxidative damage to the acute exposure of ORP aqueous solution.These results show that also the ORP aqueous solution all unlikely induces mutation or carcinogenesis in external or body.
Embodiment 23
Present embodiment has been described the chronic exposure of the example ORP aqueous solution of low concentration and the HP effect to HDF.Known eremacausis stress can inducing cell cross presenility.In order to simulate the oxidative stress of prolongation, during 20 population doublings, former generation HDF culture is exposed to chronically the HP concentration (5 μ M) of the ORP aqueous solution (10%) or the non-lethality of low concentration.Relevant in the expression that had before had been found that the SA-beta galactosidase and active and the body with external aging course.In the present embodiment, be exposed to the expression of ORP aqueous solution or HP1 month post analysis SA-beta galactosidase continuously at HDF.Fig. 6 has shown the result.Analyze the expression (the dyeing pattern of example is seen little figure A) of SA-beta galactosidase by the number of counting 20 blue cells in the field of microscope.Little figure B shows that having only HP to handle has quickened the aging of cell, shown in the cell number (n=3) of overexpression SA-beta galactosidase.The chronic processing of low dosage HP has increased the expression of the SA-β-Gal in 86% cell, and this proteic overexpression is not induced in the processing of ORP aqueous solution.Can reach a conclusion from this embodiment, promptly the ORP aqueous solution is not the derivant of too early cell ageing.
Embodiment 24
Present embodiment has been described the result of the toxicity research that utilizes example ORP aqueous solution.
In mice, carry out acute general toxicity research, so that determine the possible general toxicity of example ORP aqueous solution Microcyn 60.Give the Microcyn 60 of injection single dose (50mL/kg) in 5 mouse peritoneums.Give the saline (0.9% sodium chloride) of 5 control mice injection single doses (50mL/kg).After injection at once, the injection back mortality rate and the untoward reaction of observing all animals in 4 hours, observed every day then 1 time totally 7 days.All animals of weighing also before injection, weighing was once once more in the 7th day.During studying, all there is not mortality rate.The clinical manifestation of all animals during whole research is all normal.All animals have all increased body weight.The acute intraperitoneal LD50 of the Microcyn 60 that estimates from this research is greater than 50mL/kg.Present embodiment has confirmed that Microcyn 60 lacks significant toxicity, and it should be safe using for therapeutic of the present invention.
Embodiment 25
Present embodiment has been described the research of implementing for the potential cytogenetics toxicity of measuring example ORP aqueous solution.
Utilize example ORP aqueous solution (Microcyn 10%) to carry out micronucleus test, to estimate the mutation probability of giving injection ORP aqueous solution in the mouse peritoneum.Micronucleus test is used to identify the material of the damage of the chromosome of the polychromatic erythrocyte that causes Mus or MA in the mammalian body.This damage has caused the formation of " micronucleus ", and this is a kind of cell inner structure that contains laggard,lagging chromosome fragment or isolated whole chromosome.ORP aqueous solution research comprises 3 groups, every group of 10 mice (5 male/5 female): test group (using the ORP aqueous solution), negative control group (using 0.9%NaCl solution) and positive controls (but using the cyclophosphamide solution of mutation).Test group and negative control group have been accepted peritoneal injection (12.5mL/kg) ORP aqueous solution or 0.9%NaCl solution respectively, altogether continuous 2 days (the 1st and 2 day).The positive control mice accepted at the 2nd day the single intraperitoneal injection cyclophosphamide (8mg/mL, 12.5mL/kg).After injection, observe any untoward reaction of all mices at once.All animals are all acted normally during whole research clinically, all do not find toxicity sign in arbitrary group.At the 3rd day, weigh for all animals, and put to death animal.
From put to death mice, downcut femur, take out bone marrow, every mice is all prepared duplicate bone marrow smear.Under amplifying, reads 40X the bone marrow sheet of every animal.At least 200 red blood cell determinations go out the polychromatic erythrocyte (PCE) of every mice and the ratio of NE (NCE) by counting altogether, and this is the index of bone marrow toxicity.2000 PCE that can mark of every minimum evaluation of mice then calculate the incidence rate of the polychromatic erythrocyte of micronucleus.With statistical package (Statview 5.0, SAS Institute Inc., USA) Mann in and Whitney the check (5% dangerous threshold value) data are carried out statistical analysis.
When with their corresponding negative controls relatively the time, the positive control mice has the significantly lower PCE/NCE ratio of statistics (male Mus: 0.77 pair 0.90, female Mus: 0.73 pair 1.02), has demonstrated the toxicity of cyclophosphamide to the bone marrow handled.But, between the PCE/NCE ratio of mice that the ORP aqueous solution was handled and negative control, do not have statistically-significant difference.Equally, the mice that the positive control mice was handled than ORP aqueous solution (male Mus: 11.0 pairs 1.4, female Mus: 12.6 pairs 0.8) and negative control (male Mus: 11.0 pairs 0.6, female Mus: 12.6 pairs 1.0) have the significantly polychromatic erythrocyte with micronucleus of higher number of statistics.In mice that the ORP aqueous solution was handled and negative control mice, have between the polychromatic erythrocyte number of micronucleus and do not have statistically-significant difference.
Present embodiment has confirmed that Microcyn 10% does not induce toxicity or mutagenesis after the injection in giving mouse peritoneum.
Embodiment 26
Originally studies confirm that example ORP aqueous solution Dermacyn lacks toxicity.
Carry out this research according to the ISO10993-5:1999 standard, cause Cytotoxic probability to determine example ORP aqueous solution Dermacyn.The filter paper that will contain 0.1mL Dermacyn is placed into the agarose surface, directly is pressed on the monolayer l cell (L-929).There is 5%CO 2, after 37 ℃ of following incubations 24 hours, the cell toxicant damage of the sample of observation post's preparation.Observed result and positive and negative control sample are compared.The sample that contains Dermacyn does not show any lysis or toxic evidence, and the positive and negative control have the performance of expection.
According to this research, conclusion is that Dermacyn can not produce cytotoxicity to l cell.
Embodiment 27
Carry out this research with 16 rats, with the local tolerance of estimating example ORP aqueous solution Dermacyn with and to the histopathologic effect of the wound bed in the holostrome skin wound healing model.Wound is made in both sides the object rat.In agglutination, take off the skin biopsy (for example handling and saline treatment through Dermacyn respectively) on left side or right side.
The veterinary pathologist that authenticates through committee is estimated the Masson trichrome and the II Collagen Type VI stained at the surgical wound position that Dermacyn and saline treatment cross.The degree of appearance, inflammation and the skin ulcer of the newborn epidermis in the quantity that 2 Collagen Type VIs as the connective tissue proliferation performance in the evaluation section are expressed, fibroblast morphology and collagen formation, the cross section.
The result shows that rat tolerates Dermacyn well.In the skin biopsy of either side wound (handling and saline treatment through Dermacyn respectively), all there is not the sick damage of the relevant histopathology of treatment.Between the wound location of saline treatment and Dermacyn processing, do not have relevant histopathology difference, illustrate that Dermacyn handles by fine tolerance.The significant difference that does not have 2 Collagen Type VIs to express between the wound location of saline treatment and Dermacyn processing illustrates that Dermacyn does not have ill effect to fibroblast or to the generation of the collagen during wound healing processing.
Embodiment 28
This research can be used to confirm that the used example ORP aqueous solution Dermacyn of the present invention is as Versajet TM(Smith﹠amp; Nephew) replace solution of hydro-peening system is used for the treatment of the safety and the curative effect of the slough (ulcer) of ankle far-end, and compares with standard scheme.
This be perspective, at random the contrast, double-blind study.The selected about 30 routine patients (about 20 examples are organized at Dermacyn, and about 10 examples are at matched group) of research.The crowd of this research is the patient who suffers from ulcer of the lower limb (for example diabetic foot ulcer, venous stasis ulcer).In the time of the 0th day, the patient of all qualified selected researchs must satisfy the selected and exclusion standard of all research.Inclusion criteria is: patient age was more than or equal to 18 years old; Patient's ulcer of the lower limb manifests slough and is candidate through the mechanicalness debridement of hydro-peening system; Patient's ulcer is positioned at the ankle far-end; Patient's ulcer surface area is more than or equal to 1.0cm 2Patient's ulcer extends through corium and enters subcutaneous tissue (granulation tissue can occur), and may expose muscle or tendon, but does not have getting involved of bone and/or joint capsule; Ankle-arm index (ABI) of the patient who is measured to through Doppler is more than or equal to 0.8, and perhaps patient's toe is pressed more than or equal to 40mmHg.
Exclusion standard is: the clinical evidence of gangrene appears in any position of patient's treatment limbs; The ulcer of estimating the patient during studying needs cut or amputation; The patient has the sign of following systemic inflammatory response syndrome (SIRS); The total surface area of patient's ulcer is less than 1cm 2The patient has one or more medical conditions (comprising kidney, liver, blood, nerve or immunological diseases), makes researcher think that the patient is not suitable for this research; The patient is known active excessive drinking or drug dependence; The patient is accepting oral or intestinal outer glucocorticoid, immunosuppressant or cytotoxic agent, needs these medicines during perhaps being expected at research; The patient is known to chlorine allergy; Patient's the ulcer osteomyelitis that occurred together; And the patient suffers from any meeting and seriously hinders the patient to finish the disease of the ability of this research.
After signing Informed Consent Form and satisfying selected and exclusion standard, the patient is arrived wherein a group of following treatment by random packet (2: 1 random packet): the treatment group: with hydro-peening systemic application Dermacyn, add the hydrogel wound dressing scheme of using; Matched group: saline (with the standard care of hydro-peening system) adds the hydrogel wound dressing scheme of using.
Each patient to Dermacyn will accept during patient's wound is carried out the mechanicalness debridement through Versajet hydro-peening systemic application research product D ermacyn by random packet.Normal pressure device on the Versajet will be used to be positioned at the diabetic foot ulcer of ankle far-end.After debridement, Dermacyn is applied on the wound, present in an amount at least sufficient to rinse out all fragments on the wound bed.Cover wound with aerogel dressing.When each change of dressing, irrigate and with new aerogel dressing covering wound with Dermacyn.Per 3 days more change dressings once, unless researcher has other different explanations.During making a house call weekly, determine the clinical response factor (the CFR) (minimizing of (1) wound antibacterial; (2) wound area dwindles; (3) generation of granulation tissue).
Each control patients all will be accepted through Versajet hydro-peening systemic application reference product (saline solution) during patient's wound is carried out the mechanicalness debridement.After debridement, saline is applied on the wound, present in an amount at least sufficient to rinse out all fragments on the wound bed.Cover wound with aerogel dressing.When each change of dressing, irrigate the wound with salt solution and with new aerogel dressing covering wound.Per 3 days more change dressings once, unless researcher has other different explanations.During making a house call weekly, determine the clinical response factor.
When making a house call weekly, can carry out the wound debridement.Before wound is estimated, fall any slough with the hydro-peening System Cleaning.Rinse out fragment on the ulcer with Dermacyn or saline (depending on random packet).Between making a house call, the patient will irrigate with Dermacyn or saline (depending on random packet) when each change of dressing.When making a house call, after debridement, all take the photo of wound at every turn.
Main curative effect terminal point is: the minimizing of (1) wound antibacterial; (2) wound area dwindles; (3) generation of granulation tissue.To in the research all by the patient of random packet evaluate safety all.Note treatment to urgent and serious adverse events.
Embodiment 29
This research will confirm that example ORP aqueous solution Dermacyn is used for the treatment of the safety and the curative effect of the slough in the ulcer of the lower limb as the replace solution of Jet-Ox ND rinse-system, and compare with Jet-Ox ND system used standard scheme.
Slough in the chronic wounds is removed by the hydro-peening of controlled Sterile Saline by Jet-Ox ND system, and does not damage following health tissues.This research will replace saline with Dermacyn, estimate that this can provide identical hydro-peening effect, can also reduce the bacterial load in the wound that may suppress wound closure.
Study 20 routine patients (random packet becomes 10 routine Dermacyn patients and 10 routine control patients).Inclusion criteria is: patient age was greater than 18 years old; The patient has the following ulcer of lower limb knee that slough occurs, and is the candidate that carries out the mechanicalness debridement with Jet-Ox ND rinse-system; Before screening is made a house call, patient's ulcer exists＞and 30 days; Ulcer surface area＞1cm 2Ulcer extends through corium and enters subcutaneous tissue (granulation tissue can occur), and may expose muscle or tendon, but does not have the bone and/or the joint capsule of exposure; The patient's who is measured to through Doppler ankle/arm index＞0.8 and/or patient's toe pressure＞40mmHg; Can touch patient's dorsal artery of foot and/or beating of posterior tibial artery.
Exclusion standard is as follows: the patient of kidney, liver, blood, nerve or immune function depression includes human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) (AIDS); Wherein researcher thinks that the patient is not suitable for participating in this research; Wound with following infection clinical sign; The gangrene at any position of treatment limb; Ulcer manifests skeleton (can visit and skeleton) or has potential myelitic other evidences of ulcer spot; Estimate that infected ulcer will be by amputation or excision during treating; Serious malnutrition is shown in albumin＜2.0; Known excessive drinking or drug dependence; The patient is accepting oral or the outer glucocorticoid of intestinal, immunosuppressant or cell toxicity medicament, Coumarins, heparin or expectation need these medicines during treating; And the patient is known to chlorine allergy.
Each individuality is all by one group in random packet to the two treatment group: Dermacyn or saline.Target ulcer will be accepted the mechanicalness debridement, bind up a wound afterwards with Dermacyn or normal saline washing wound, and with the aerogel dressing dressing.The wound biopsy of taking-up center is used for quantitative culture, and the chamber of experimentizing research (suitable hematology, serum chemistry and pregnancy check), the research of Noninvasive peripheral vessels, medical history and physical examination, ulcer are followed the trail of and the ulcer photo.
Jet-Ox ND rinse-system can be applied with Dermacyn or saline, hydrogel and dressing wrapper material.The guidance that provides family to use.Make a house call and comprise screening, go into group (the 0th day) and random packet, make a house call weekly and carry out debridement, take pictures and estimate.Minimizing by (1) wound antibacterial during the research; (2) wound area dwindles; (3) curative effect is estimated in the generation of granulation tissue.To in the research all by the patient of random packet evaluate safety all.Note treatment to urgent and serious adverse events.
To comprise that publication, patent application and patent all incorporate the application at these all lists of references of quoting by reference, degree is all incorporated every piece of list of references into the application by reference and is listed in full in this article as indicating individually and particularly at this.
Term " one " and " being somebody's turn to do " and in describing context of the present invention (particularly the context of claims in) below similar use that refers to be interpreted as encompasses singular and plural number, unless other different explanations arranged in this article or clearly negate.Term " comprises ", " having ", " comprising " and " containing " are interpreted as open-ended term (i.e. expression " including but not limited to "), unless other different explanations are arranged.Only be intended as individually in the statement of this logarithm value scope that expression drops on the stenography of each the independent numerical value within the scope, unless at this other different explanations are arranged, and each independent numerical value all is integrated in the description, individually stated at this as them.Can carry out all methods described herein by any suitable order, negate unless have to have in other different explanations or the context clearly at this.Any and all embodiment or only plan to illustrate invention better in the example languages (for example " for example ") that this provided, the scope that is not intended to limit the present invention is unless there is different requirements.It is that to put into practice the present invention institute requisite that all language in the description not should be understood to indicate the element of any failed call.
Described preferred embodiment of the present inventionly at this, comprised the best pattern of the known realization of inventor invention.After reading above-mentioned description, the variation of those preferred implementations will be conspicuous for persons skilled in the art.The inventor expects that those of skill in the art can adopt these variations suitably, and the inventor plans can use and put into practice invention in the different mode of this concrete described mode.Therefore, the present invention includes all modifications and the equivalent of the theme of in appended claims, being stated that applicable law allows.In addition, present invention resides in any combination of the above-mentioned element in all possible variation, negate unless have to have in other different explanations or the context clearly at this.

Claims (40)

1. the method for the treatment patient's 2 degree or 3 degree burns comprises the oxidative reductive potential water solution of using the amount that is enough to treat described burn to the patient, and the pH of wherein said solution is about 6.4 to about 7.8, and it keeps stable at least 1 week.
2. the process of claim 1 wherein that described solution keeps stable at least about 2 months.
3. it is stable at least about 1 year that the method for claim 2, wherein said solution keep.
4. the method for claim 3, wherein pH is from about 7.4 to about 7.6.
5. the method for the treatment patient's 2 degree or 3 degree burns comprises the oxidative reductive potential water solution of using the amount that is enough to treat described burn to the patient, and the pH of wherein said solution is about 6.4 to about 7.8, and described solution comprises anode water and negative electrode water.
6. the method for claim 5, the amount of wherein contained negative electrode water account for about 10% volume of liquor capacity to about 50% volume.
7. the method for claim 6, the amount of wherein contained negative electrode water account for about 20% volume of liquor capacity to about 40% volume.
8. the method for claim 6, the amount of wherein contained anode water account for about 50% volume of liquor capacity to about 90% volume.
9. the process of claim 1 wherein by the burn described solution of spray is used solution to the patient.
10. the method for claim 9, wherein by with high pressure rinse equipment to the burn described solution of spray and use solution to the patient.
11. the method for claim 9 was wherein burnt 5 minutes with solution wetted at least.
12. the method for claim 11 was wherein burnt 15 minutes with solution wetted at least.
13. the process of claim 1 wherein and use solution to the patient every day at least.
14. the method for claim 13 is wherein used solution 3 times to the patient every day.
15. treatment patient's 2 degree or the method for 3 degree burns comprise the oxidative reductive potential water solution of using the amount that is enough to treat described burn to the patient, wherein said solution comprises at least about a kind of free chlorine species, and it is stable at least about 2 months that wherein said solution keeps.
16. the method for claim 15, wherein free chlorine species is selected from the group of being made up of hypochlorous acid, hypochlorite ion, sodium hypochlorite, chlorite ion, chloride ion, dissolved chlorine and composition thereof.
17. the method for claim 15, wherein the amount of free chlorine species is to about 400ppm from about 10ppm.
18. the method for claim 17, wherein free chlorine species is a hypochlorous acid, and its content is to about 35ppm from about 15ppm.
19. the method for claim 17, wherein free chlorine species is a sodium hypochlorite, and its content is to about 50ppm from about 25ppm.
20. the method for claim 15 is wherein by using solution to the burn described solution of spray to the patient.
21. the method for claim 20 is wherein by using solution to the burn described solution of spray to the patient with high pressure rinse equipment.
22. the method for claim 20 was wherein burnt 5 minutes with described solution wetted at least.
23. the method for claim 22 was wherein burnt 15 minutes with described solution wetted at least.
24. the method for claim 15, wherein use solution to the patient every day at least.
25. the method for claim 24 is wherein used solution 3 times to the patient every day.
26. treatment patient's 2 degree or the method for 3 degree burns, comprise the oxidative reductive potential water solution of using the amount that is enough to treat described burn to the patient, the hypochlorous acid of wherein said solution packet content from about 15ppm to about 35ppm and the sodium hypochlorite of amount from about 25ppm to about 50ppm, and the stable pH at least about 1 week and described solution of wherein said solution maintenance is from about 6.2 to about 7.8.
27. the method for claim 26, wherein said solution kept stable 2 months at least.
28. the method for claim 26 is wherein by using solution to the burn described solution of spray to the patient.
29. the method for claim 28 is wherein by using solution to the burn described solution of spray to the patient with high pressure rinse equipment.
30. the method for claim 28 is wherein burnt at least about 5 minutes with solution wetted.
31. the method for claim 30 is wherein burnt at least about 15 minutes with solution wetted.
32. the method for claim 26, wherein use solution to the patient every day at least.
33. the method for claim 32 is wherein used solution 3 times to the patient every day.
34. treatment patient's 2 degree or the method for 3 degree burns, comprise (1) with high pressure to burn spray oxidation-reduction potential (ORP) aqueous solution; (2) randomly with ORP aqueous solution soaking burn; (3) to burn spray ORP aqueous solution; (4) make the moistening burn of ORP aqueous solution, the pH of wherein said solution is from about 6.4 to about 7.8, and it keeps stable at least about 2 months.
35. the method for claim 34 was wherein carried out the debridement treatment to burn before spray.
36. claim 1,5,15,26 and 34 method are not wherein given patient's administration of antibiotics during the treatment burn.
37. the method for claim 34 also comprises patient's application skins based upon bidding graft.
38. the method for claim 34, wherein repeating step every day (3)-(4) is 3 times.
39. the method for claim 34, wherein fully heal up to burn in repeating step (1)-(4).
40. the method for claim 34 also comprises the administration of antibiotics to the patient.
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EP1863502B1 (en) 2005-03-23 2018-09-12 Sonoma Pharmaceuticals, Inc. Method of treating skin ulcers using oxidative reductive potential water solution
WO2007085021A2 (en) 2006-01-20 2007-07-26 Oculus Innovative Sciences, Inc. Methods of treating or preventing peritonitis with oxidative reductive potential water solution
CN102481357A (en) * 2009-05-11 2012-05-30 奥古露丝创新科学公司 Methods of treating or preventing influenza associated illness with oxidative reductive potential water solutions
BRPI1011886B1 (en) 2009-06-15 2022-05-03 Invekra, S.A.P.I De C.V Low pH antimicrobial solution
CA2913137A1 (en) 2013-05-22 2014-11-27 Oculus Innovative Sciences, Inc. Stabilized hypochlorous acid solution and use thereof
US20150099010A1 (en) * 2013-10-07 2015-04-09 Reoxcyn Discoveries Group, Inc Redox signaling gel formulation
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CN101608411B (en) * 2008-06-19 2010-12-08 杨黎明 Process for manufacturing paper pulp by using oxidation-reduction potential water and biological enzyme
CN109475396A (en) * 2016-07-22 2019-03-15 皇家飞利浦有限公司 The administration of oral care antibacterial agent
CN109475396B (en) * 2016-07-22 2021-07-16 皇家飞利浦有限公司 Administration of oral care antibacterial agents

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