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WO2025019857A1 - Compositions thérapeutiques de traitement de biofilms - Google Patents

Compositions thérapeutiques de traitement de biofilms Download PDF

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Publication number
WO2025019857A1
WO2025019857A1 PCT/US2024/038961 US2024038961W WO2025019857A1 WO 2025019857 A1 WO2025019857 A1 WO 2025019857A1 US 2024038961 W US2024038961 W US 2024038961W WO 2025019857 A1 WO2025019857 A1 WO 2025019857A1
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Prior art keywords
biofilm
solution
source
composition
charged
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Derek Hill
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Az Solutions LLC
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Az Solutions LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present disclosure relates to a charged biofilm formula and related compositions, methods of their manufacturing and use.
  • Biofilms The majority of bacterial life in nature resides not as free-floating planktonic cells, but as members of surface-bound communities called biofilms. Biofilms or biofilm-like substances can also be formed by other microorganisms, including fungi and viruses. Biofilms can form on biotic surfaces including human, animal, or plant tissue, or abiotic surfaces including soil, implanted medical devices, surgical instruments, or river stones. Bacterial biofilms are estimated to cause upwards of about 75% of infectious diseases in humans including wound infections, urinary tract and ear infections, and many nosocomial and chronic infections. Conventional antibiotic treatments are currently the prevailing treatment method for biofilm infections even though biofilms exhibit wide-spread anti-microbial resistance.
  • a system for treating a biofilm infection may include a delivery device housing a composition having a source of ions in the amount of about 25-225 mM, a source of an oxidizing agent in the amount of about 25-225 mM, and a source of Vitamin C in the amount of about 1 mM to 10 mM.
  • the source of ions may be a zinc compound.
  • the source of an oxidizing agent may be a chlorite forming solution.
  • the delivery device may include a compartment. The source of an oxidizing agent, and the source of Vitamin C may be combined in the compartment prior to use to generate the composition.
  • compositions to a site of a biofilm infection by the delivery device may inhibit growth and metabolism of microorganisms when applied to the site of the biofilm infection.
  • the Vitamin C component may be ascorbic acid.
  • the composition may additionally include chlorhexidine gluconate.
  • a system for treating a biofilm infection may include a disposable cloth having a non-woven fabric, wherein the cloth is saturated with an aqueous solution including a source of ions in the amount of about 25-225 mM, a source of an oxidizing agent in the amount of about 25-225 mM, and a source of Vitamin C in the amount of about 1 mM to 10 mM.
  • Applying the disposable cloth to a site of a biofilm infection may transfer the aqueous solution to the site of the biofilm infection.
  • the disposable cloth may be further saturated with one or more of a softener, a lotion, a perfume, a surfactant, or a preservative.
  • the disposable cloth may be biodegradable.
  • the aqueous solution may have a pH value of about 4.8 to 5.2.
  • a system for treating a biofilm infection may have a delivery device including a compartment housing a first composition comprising a source of ions in the amount of about 20-60 mM, and a syringe housing a second composition including a source of an oxidizing agent in the amount of about 600-1300 mM, wherein the second composition is delivered to the compartment by injection and wherein the first and second compositions mix together within the compartment to form a mixed solution.
  • the compartment may be a single bag.
  • the source of ions may be a zinc compound.
  • the source of an oxidizing agent may be a chlorite forming solution.
  • the first composition may further include a Vitamin C component.
  • the first composition may further include succinic acid.
  • the second composition may further include succinic acid.
  • the mixed solution may have a pH value of from about 4.5 to about 5.0.
  • the description of a group or class of materials as suitable or preferred for a given purpose in connection with the disclosure implies that mixtures of any two or more of the members of the group or class are equally suitable or preferred; description of constituents in chemical terms refers to the constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among the constituents of a mixture once mixed; the first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation and applies mutatis mutandis to normal grammatical variations of the initially defined abbreviation; and, unless expressly stated to the contrary, measurement of a property is determined by the same technique as previously or later referenced for the same property.
  • the term “about” means that the amount or value in question may be the specific value designated or some other value in its neighborhood. Generally, the term “about” denoting a certain value is intended to denote a range within +/- 5% of the value. As one example, the phrase “about 100” denotes a range of 100+/- 5, i.e. the range from 95 to 105. Generally, when the term “about” is used, it can be expected that similar results or effects according to the disclosure can be obtained within a range of +/- 5% of the indicated value.
  • fee term “and/or” means feat either all or only one of fee elements of said group may be present.
  • a and/or B shall mean “only A, or only B, or both A and B”.
  • fee case of “only A” the term also covers fee possibility feat B is absent, i.e. “only A, but not B' ⁇
  • the terms “one or more” and “at least one” include “plurality” as a subset.
  • the term “substantially,” “generally,” or “about” may be used herein to describe disclosed or claimed embodiments.
  • the term “substantially” may modify a value or relative characteristic disclosed or claimed in the present disclosure. In such instances, “substantially” may signify that the value or relative characteristic it modifies is within ⁇ 0%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5% or 10% of the value or relative characteristic.
  • integer ranges explicitly include all intervening integers.
  • the integer range 1-10 explicitly includes 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • the range 1 to 100 includes 1, 2, 3, 4. . . . 97, 98, 99, 100.
  • intervening numbers that are increments of the difference between the upper limit and the lower limit divided by 10 can be taken as alternative upper or lower limits. For example, if the range is 1.1. to 2.1 the following numbers 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 can be selected as lower or upper limits.
  • concentrations, temperature, and reaction conditions e.g., pressure, pH, flow rates, etc.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 50 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • concentrations, temperature, and reaction conditions e.g., pressure, pH, flow rates, etc.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 30 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • concentrations, temperature, and reaction conditions e.g., pressure, pH, flow rates, etc.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 10 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • Bio films are complex microbial communities composed of either a single species or multiple species of bacteria which aggregate and adhere to a biological or non-biological surface.
  • the bacterial cells themselves secrete extracellular polymeric substances (EPS) to form a matrix in which the cells become embedded. While the chemical composition of the matrix is dynamic and complex, it may generally include polysaccharides, proteins, lipids, metal ions, and extracellular DNA (eDNA).
  • Biofilms are thus accumulations of microorganisms of mono- or polymicrobial aggregates which are encased in the matrix and form clusters.
  • Non-biological (abiotic) surfaces to which biofilms adhere may include practically any surface including soil, rocks, household surfaces, industrial pipes, surgical tools, medical instruments, medical devices, and the like.
  • Biofilms may include human, animal or plant tissues including skin, teeth, mucosa or roots. Biofilms can also form on materials used on or in the human body such as contact lenses, implants, catheters, and the like. Some of the most well-known examples of biofilms are dental plaque or the chronic lung infections observed in cystic fibrosis patients.
  • biofilms The microbial community in a biofilm functions synergistically.
  • the various microorganisms cooperate, support, and protect one another through close proximity, substrate exchanges, distribution of metabolic products, removal of toxic end products, and the like.
  • the biofilm matrix also serves as a source of protection for the bacterial cells and may shield them from damage by physical force, the host immune system, UV radiation, protozoan predation, and anti-microbials.
  • biofilms contain a layer of dormant or slow-growing bacteria which are resistant to antibiotics, as many antibiotics function by targeting processes essential for active growth.
  • Bacterial cells in biofilms may also produce virulence factors, toxins, and immune modulators that aid in evasion of the host immune defenses, thus rendering them very difficult to eradicate.
  • biofilm bacteria are more resistant than planktonic free-floating bacteria to biocides such as bleach or acids.
  • biofilms Due to the protection conferred by the matrix, and the cooperative nature of the microbial community, biofilms are a significant medical challenge. Biofilms are notoriously resistant to antibiotics and other treatments and are responsible for a majority of surgical site infections and chronic infections worldwide. Hence, there is an urgent need to develop successful treatment options for biofilms.
  • a formulation or composition is disclosed herein.
  • the formulation or composition may be a therapeutic or treatment composition.
  • the composition may be a biofilm therapeutic composition.
  • the composition may be configured as a biofilm reducer or a composition capable of minimizing, reducing, removing, diminishing, or eliminating biofilm presence, microorganism count, or both.
  • the composition may be applied to surgical sites, body cavities, organs, tissues, abscesses, and acute or chronically occurring wounds, bum wounds, graft sites (e.g., skin grafts), or a combination thereof.
  • the composition may be used to treat infections of any kind, such as, but not limited to, infections of the skin, soft tissues, organs, body cavities, surgical sites, etc.
  • the composition may be used to manage, control, minimize, treat, and/or remove microorganisms, gram positive and gram negative bacteria, aerobic and anaerobic bacteria, viruses, fungi, or any other organisms/microorganisms having infectious properties.
  • the composition may be a solution or a chemical mixture where one substance dissolves in another.
  • the solution may be an aqueous solution.
  • the solution may include a source of first ions; a source of second ions; and water.
  • the solution may optionally include a buffer and/or a degradation inhibitor.
  • the solution may also optionally include a surfactant.
  • the first ions may be metal ions and the second ions may be non-metal ions.
  • the first ions may be Zn 2+ , Ag + , Cu 2+ , Au + , or the like.
  • the second ions may be, for example, CICh' ions.
  • the composition may include two or more separate components (e.g., component (A) and component (B)) that may be mixed prior to use.
  • the components may include one or more ionic chemical compositions having free available ions.
  • the buffer may include, but is not limited to, succinate.
  • the solution including the (A) component may be a solution forming Zn 2+ , Ag + or Cu 2+ ions.
  • zinc compounds that form solutions with free available zinc ions include, but are not limited to, zinc chloride, zinc acetate, zinc lactate, zinc salicylate, zinc sulfate, zinc nitrate, zinc stearate, zinc gluconate, zinc ammonium sulfate, zinc chromate, zinc citrate, zinc dithionate, zinc fluorosilicate, zinc tartrate, zinc formate, zinc iodide, zinc phenol sulfonate, zinc succinate, zinc glycerophosphate, or other zinc halides.
  • copper compounds that form solutions with free available copper ions include, but are not limited to copper acetate, copper formate, copper citrate, copper lactate, copper oxalate, copper propionate, copper benzoate, copper succinate, copper malonate, copper stearate, copper gluconate, copper ammonium sulfate, copper chromate, copper dithionate, copper fluorosilicate, copper tartrate, copper iodide, copper nitrate, copper phenol sulfonate, copper salicylate, copper sulfate, copper glycerophosphate, or other copper halides.
  • silver compounds that form solutions with free available silver ions include, but are not limited to silver sulfate, silver oxide, silver acetate, silver nitrate, silver citrate, silver chloride, silver lactate, silver phosphate, silver stearate, silver thiocyanate, silver saccharinate, silver anthranilate, silver carbonate, or other silver halides.
  • the solutions providing the ions, or mixed with such solution may have preferred solubility for the specific ion selected, as well as provide an effective concentration of ions without permitting the redox potential to fall to unwanted levels.
  • the solution including the (B) component may be a solution forming CIO2' ions.
  • the (B) component may increase the oxidation-reduction (redox) potential (or Eh).
  • the (B) component may act as an oxidizing agent.
  • the ions in the solution having the (B) component may oxidize the ions present in the solution having the (A) component, charging them and thereby increasing the concentration of charged ions.
  • chlorite present in the (B) solution may oxidize the zinc present in the (A) solution such that the concentration of Zn 2+ ions increases.
  • the combining of the two solutions (component (A) and component (B)) may produce a charged formula containing an efficacious concentration of charged ions.
  • component (A) and component (B) may produce a charged formula containing an efficacious concentration of charged ions.
  • ZnCh and NaCICh may be used as two solutions to produce an efficacious concentration of charged zinc ions (Zn 2+ ).
  • the biofilm therapeutic composition formed by combining the solutions may be referred to as a “charged biofilm formula.”
  • the two solutions may be combined in a container to form a charged compound having free available ions and at least one redox raising component.
  • the container may be a compartment, bowl, bottle, tube, can, jar, package, packet, pouch, tank, vessel, vial, or the like.
  • the NaCICh contributed by component (B) may raise the redox potential by acting as an oxidant.
  • the charged zinc ions inhibit the growth and metabolism of microorganisms including, for example, gram positive and gram negative bacteria, fungi, viruses, or their combination.
  • the chlorite of the NaClCh (sodium chlorite) additionally has antimicrobial properties and has been used for disinfection and control of bacterial fouling, as well as controlling taste, odor, and oxidation of metal ions. It is important to control the pH of the solution including component (B) as sodium chlorite may produce chlorine dioxide when combined with acid. Elevated levels of chlorine dioxide may harm red blood cells and may combine with amino acids to produce potentially mutagenic compounds. Thus, maintaining a neutral or basic pH of the (B) component providing NaCICh allows for the maintenance of safe levels of chlorine dioxide. Additional components, such as, but not limited to, hydrogen peroxide, may be included in the charged biofilm formula to help stabilize the ions, and control the pH of the separate solutions, and of the charged biofilm formula.
  • the metabolism and growth of microorganisms at sites of infections may increase when the oxidation-reduction (redox) potential (Eh) of the infection site is decreased.
  • redox oxidation-reduction
  • a decrease in oxygen at the infection site may decrease the redox potential of that site.
  • Other changes in the biological and chemical properties of the infection site may also lead to a reduction in the redox potential of that site.
  • the metabolism and growth of harmful microorganisms including but not limited to bacteria, fungi or viruses, may be decreased, thus preventing, minimizing, and/or curing an infection.
  • the metabolism and growth of the microorganisms may be prevented by increasing the oxidation-reduction (redox) potential (or Eh) of the wound site by irrigating the wound or infected area. Irrigation may help eradicate and/or prevent the formation of bio films at the wound site.
  • Biofilms are resistant to host defenses and antibiotics. Cells within biofilms may also leave the biofilm and seed new sites of infection in other areas of host tissue. In addition to curing infection at the site of the biofilm, preventing or eradicating biofilm growth or production may therefore eliminate infection, inoculation, colonization, or other pathology at secondary sites.
  • the charged biofilm formula may include a Vitamin C component.
  • the Vitamin C may be any form of Vitamin C such as, but not limited to, ascorbic acid, ascorbates such as mineral ascorbates, flavonoids, or mixtures or variations thereof having antioxidant properties.
  • the Vitamin C component may have wound healing properties in addition to the antioxidant properties. In some instances, the Vitamin C component may have antimicrobial properties.
  • the Vitamin C component may be included in either or both solutions prior to charging, or may be included in a separate solution to be combined with the charged biofilm formula.
  • the Vitamin C component may be included in any effective concentration, as determined by the type of Vitamin C component and the solutions provided.
  • the Vitamin C component may be about 1 mM to 10 mM, about 2 to 7 mM, or about 3 to 5 mM concentration of an ionically charged zinc solution.
  • the Vitamin C component may be about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mM concentration of an ionically charged zinc solution. Yet it is important to regulate the amount of Vitamin C carefully, as Vitamin C is capable of neutralizing chlorite by reducing it to chloride.
  • the charged biofilm formula may include additional vitamins, including, but not limited to, Vitamin A, Vitamin D, Vitamin E, Vitamin Bi- 6, Vitamin B12, and others and mixtures thereof.
  • additional vitamins including, but not limited to, Vitamin A, Vitamin D, Vitamin E, Vitamin Bi- 6, Vitamin B12, and others and mixtures thereof.
  • B Vitamins may provide prophylactic properties against potential host tissue toxicity and/or oxidative damage of components in the charged biofilm formula.
  • the charged biofilm formula may also include chlorhexidine gluconate to prevent biofilm formation.
  • the chlorhexidine gluconate may be provided in any effective amount in the charged biofilm formula.
  • the chlorhexidine gluconate may be about 0.01 to 2, 0.05 to 1.8, or 0.1 to 0.5% of the charged biofilm formula by volume.
  • the chlorhexidine gluconate may be about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95 or 2 vol.% of the charged biofilm formula.
  • the charged biofilm formula may alternatively or additionally include cetylpyridinium chloride, an antiseptic to kill bacteria and microorganisms in tissue and wounds.
  • the chlorohexidine gluconate and/or the cetylpyridinium chloride may be included in either or both solutions prior to combining to form the charged biofilm formula, or may be included in a separate solution to be added to the charged biofilm formula.
  • the addition of chlorohexidine gluconate and/or the cetylpyridinium chloride provides additional antimicrobial properties to the charged biofilm formula, specifically to aid in preventing biofilm formation.
  • the charged biofilm formula may include at least one antibiotic agent, antiviral agent, antifungal agent, other antimicrobial agent, or combinations thereof, in either or both solutions prior to combining to form the charged biofilm formula.
  • the antibiotic agent, antiviral agent, antifungal agent, other antimicrobial agent, or combinations thereof may otherwise be provided in a separate solution to be added to the charged biofilm formula.
  • the antibiotic agent, antiviral agent, antifungal agent, other antimicrobial agent, or combinations thereof may be selected specifically for the type of wound, surgical site, infection, or tissue to be irrigated/treated.
  • the charged biofilm formula may also include a protein such as a transforming growth factor beta (TGF-P) protein to promote wound healing.
  • TGF-P transforming growth factor beta
  • the TGF-P additive may be any of three isoforms of TGF-P (pi, P2, p3) or a combination thereof.
  • the charged biofilm formula may also include a peptide such as a proinsulin C- peptide to decrease inflammation.
  • the charged biofilm formula may also include a pain-relieving agent, including but not limited to an anesthetic, or analgesic, and/or combinations thereof.
  • a pain-relieving agent including but not limited to an anesthetic, or analgesic, and/or combinations thereof.
  • anesthetics include epinephrine, bupivacaine hydrochloride, epinephrine bitartrate, lidocaine, benzocaine, prilocaine, the like, or a combination thereof.
  • analgesics include acetaminophen, ibuprofen, aspirin, naproxen, naproxen sodium, diclofenac, and the like.
  • the solutions forming the charged biofilm formula may be stored separately and combined immediately prior to use. Once components (A) and (B) have been mixed, the charged biofilm formula may lose its charge over time as the free available ions are reduced. Within a given period of time after mixing, the charged biofilm formula may no longer be able to raise the redox potential of the infection site (or inhibit lowering of the redox potential).
  • the solutions are stored separately at either neutral, acidic or basic pH, and combined at the time of use. For example, storing sodium chlorite at a neutral or basic pH prevents any significant formation of chlorine dioxide. Storing zinc chloride at an acidic pH ensures the availability of zinc ions, and once the solution has been applied, allows for the conversion of sulfur anions to the acidic forms, resulting in a higher Eh at the infection site.
  • the charged biofilm formula may be applied by first combining two solutions, for example solution (A) and solution (B), retained in separate compartments in a charging portion to form the charged formula, and then by applying or distributing the formula via methods commonly known in the art.
  • the charged biofilm formula disclosed herein may be used at various types of infection sites to increase the redox potential to decrease metabolism and growth of bacteria in the wound or tissue, and also to decrease or eradicate the formation of biofilms.
  • the charged biofilm formula may be applied via any mechanism appropriate for the type of biomaterial present at the infected site. Examples of suitable dispensing, application or delivery mechanisms are disclosed in U.S. Patent Application 15/686,612, which is herein incorporated in its entirety.
  • the charged biofilm formula may be applied to an infection site on the skin, for example, at a wound that is not healing due to infection with biofilm forming bacteria.
  • the formula may include a dual-chambered container with a pump such that the 2 (or more) solutions sire combined immediately before use to form the charged biofilm formula, which can then be applied by pumping an effective amount onto the infected area or onto a bandage to be placed on the infected area.
  • the charged biofilm formula may be delivered through aerosolization for treatment of pulmonary infections such as pneumonia, particularly nosocomial or hospital- acquired pneumonia, bronchitis or other respiratory infections.
  • the device for distributing the aerosolized charged biofilm formula may include, but is not limited to, a nebulizer, atomizer, mister, or other aerosol dispensing device.
  • the charged biofilm formula may be distributed via a catheter (e.g., an indwelling catheter, or a catheter solely for irrigation) to the bladder and/or urethra to treat and/or prevent urinary tract infections or bacterial colonization.
  • a catheter e.g., an indwelling catheter, or a catheter solely for irrigation
  • the charged biofilm formula may be delivered via hydrogel.
  • a hydrogel is a three-dimensional hydrophilic polymeric biphasic network arranged to absorb and retain one or more fluids without the structural network being dissolved. Hydrogels may deliver fluids, drugs, and biological molecules to delivery sites in human and animal bodies and tissues.
  • the hydrogels designed to deliver the formula disclosed herein may be of a suitable composition, including but not limited to polysaccharide-based hydrogels that include chitosan, cellulose, dextran, starch, hyaluronic acid (HA) and the like; protein-based hydrogels that include collagen, gelatin, albumin and the like; poloxamers; poly (ethylene imine)-poly (ethylene glycol) methacrylate (PEI-PEGMA); polyvinyl-alcohol (PVA); or other such suitable materials or combinations thereof. Additionally, injectable hydrogel microspheres are contemplated as an example of a suitable delivery mechanism for the formula.
  • colloidal gels may be used for delivery of the charged biofilm formula to sites of infection.
  • Colloidal microgels are also contemplated as an example of a suitable delivery mechanism for the charged biofilm formula.
  • the charged biofilm formula may be deliverable via another route such as a disposable cloth also known as wipes or wet wipes.
  • Wet wipes typically include a cloth made from a non-woven fabric saturated with a solution. In this case, the cloth may be saturated with the charged formula disclosed herein.
  • the charged formula may be included as an aqueous solution within the wipes or a hydrogel within the wipes.
  • the fabric of the wipes may be a natural or synthetic textile.
  • Non-limiting example fabrics may include fibers of polyester, polypropylene, polyethylene, cotton, rayon, bamboo, the like, or a combination thereof.
  • the fabric may be a non-woven fabric made directly from short fibers, long fibers, or both assembled in individual sheets. The bonding of the fibers together may be facilitated chemically, mechanically, via heat, via solvent, or a combination thereof.
  • the fabric may also include one or more of the following components: softeners, lotions, perfumes, surfactants such as amphoteric surfactants, preservatives such as methylisothiazolinone, gluconolactone, the like, or their combination, pH buffers.
  • the wet wipes may be flushable, sewer-safe, septic-safe, or a combination thereof.
  • the wet wipes may be biodegradable or compostable.
  • Intravenous treatments are also contemplated as suitable delivery methods for the charged biofilm formula.
  • Both zinc and sodium chlorite are suitable for intravenous delivery in humans as are C-peptide, Vitamin C (and other Vitamins), and other substances described above that are contemplated as being included in the charged biofilm formula.
  • the charged biofilm formula may be applied to infection sites including but not limited to surgical sites, body cavities, tissues, organs, abscesses, acute or chronically occurring wounds, bum wounds, graft sites (e.g., skin grafts) or any other biological tissue that is infected with microorganisms.
  • the charged biofilm formula may be used to treat infections of any kind, and to manage, control, minimize, treat, and/or remove microorganisms, gram positive and gram negative bacteria, aerobic and anaerobic bacteria, viruses, fungi, or any other organisms/microorganisms having infectious properties.
  • the charged biofilm formula may also be applied onto body sites prone to odor generation due to presence of bacteria or fungi.
  • Non-limiting example odor generation sites may include areas in proximity of sweat glands in the dermis such as armpits, inner thighs, small of the back, palms of the hands, soles of the feet, forehead, etc.
  • the secretion from the sweat glands typically includes a fluid, sweat, which contains proteins, lipids, and steroids. While sweat is naturally odorless, the skin microbiota metabolize the fluid which results in a production of malodorous byproducts causing unwanted body odor.
  • Example of the skin microbiota producing body odor include aerobes, anaerobes, and fungi, such as Corynebacterium, Staphylococcus, Cutibacterium genera, Candida species, Aspergillus species, and Malassezia species.
  • the charged biofilm formula may suppress, reduce, or minimize bacterial presence on the sites and thus reduce odor generation.
  • the odor generation minimization or suppression by the charged biofilm formula may also apply to the infectious sites such as wounds discussed herein.
  • Non-limiting examples of bacterial species that may be treated using the charged biofilm formula include ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter species, or their combination.
  • Non-limiting examples of infections that are suitable for topical treatment with the charged biofilm formula include oral candidiasis and vaginal yeast infections caused by yeast such as Candida albicans', dandruff caused by Malassezia yeasts; ringworm or tinea caused by fungi including Trichophyton, Microsporum, or Epidermophyton,' intertrigo caused by Streptococcus or Corynebacterium minutissimum, fungi such as Candida albicans, or viruses; sores (cold and anogenital) and herpetic whitlow caused by the Herpes simplex virus; and rashes caused by the Varicella zoster virus.
  • yeast such as Candida albicans', dandruff caused by Malassezia yeasts
  • ringworm or tinea caused by fungi including Trichophyton, Microsporum, or Epidermophyton,' intertrigo caused by Streptococcus or Corynebacterium minutissimum, fungi such
  • the topical treatment is also suitable for the above-mentioned skin microbiota including aerobic and anaerobic bacteria and fungi, such as Corynebacterium, Staphylococcus, Cutibacterium genera, and Malassezia, Aspergillus, and Candida species.
  • the charged biofilm formula may be used to treat surgical sites, wounds, or infections as well as odor generating sites in or on human bodies.
  • the charged biofilm formula may also be used at infection sites as well as odor generating sites on or in animal bodies in the veterinary setting, as animals are subject to similar infection risks from open wounds, surgeries, and exposure to microorganisms.
  • the ions present in the solution comprising component (A) may be provided by ZnCh solution.
  • the concentration of the ZnCh in component (A) may be at least about 25 mM to about 225 mM, or at least about 50 mM to about 150 mM.
  • the concentration of the ZnCh in component (A) may be at least about, at most about, or about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225 mM. In a non-limiting example, the concentration of ZnCh in component (A) may be at least about 100 mM.
  • the Eh increasing component present in the solution comprising component (B) may be provided by NaCICh (sodium chlorite) solution.
  • the concentration of NaCICh in component (B) may be at least about 25 mM to about 225 mM, or at least about 75 mM to about 175 mM.
  • the concentration of NaCICh in component (B) may be at least about, at most about, or about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225 nM.
  • the concentration of NaCICh may be at least about 100 mM.
  • the ratio of the source of ions to the Eh increasing component may be about 1 : 1 such as about 50:50 mM, 100:100 mM, or 200:200 mM. Other ratios are also contemplated, for example 1 :2, 1 :3, or 1 :4 for the source of ions to the Eh increasing component or vice versa.
  • Component A may also be referred to as solution A.
  • Component B may also be referred to as Solution B.
  • Components A and B may include buffers.
  • the buffer of either of Solution A and/or Solution B may include succinate or succinic acid in the amount of about 5 to 10 mM.
  • the buffer may include 5, 6, 7, 8, 9, or 10 mM of succinate or succinic acid.
  • the Eh increasing component present in the solution comprising component (B) may also be referred to as a source of an oxidizing agent.
  • component or solution (B) may be provided in a more concentrated form.
  • the source of the oxidizing agent may be present in the solution comprising component or solution (B) at a concentration of about 500 to 1300 mM.
  • the source of the oxidizing agent may be present at a concentration of 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, or 1300 mM.
  • the solution comprising component A may have a about value ranging from about
  • the solution comprising component A may have a pH value of about, at least about, or at most about 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.
  • the pH values may have an error of+/- 0.1.
  • the solution comprising component B may have a pH value ranging from about 7.4 to about 10.6.
  • the solution comprising component B may have a pH value of about, at least about, or at most about 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, or 10.6.
  • the pH values may have an error of +/- 0.1.
  • the pH values of combined solutions according to various disclosed embodiments may be from about 4.4 to about 5.3.
  • the pH value of a combined solution according to various embodiments may be about, at least about, or at most about 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or 5.3.
  • the pH values may have an error of +/- 0.1.
  • Example 1 Charged biofilm formula
  • Example 1 A charged biofilm formula of Example 1 was prepared by mixing Solution A and Solution B at the site of treatment immediately prior to use. The composition is shown in Table 1 :
  • Example 2 Charged biofilm formula
  • a charged biofilm formula of Example 2 was prepared by mixing Solution A and
  • Example 3 Testing the effect of the charged biofilm formula on Candida albicans yeast colonies
  • the composition of Example 3 was prepared to include 50 mM ZnCh (“Z50”and 50 mM NaClCh (“C50”) with either 0 (“A00”), 3 (“A03”) or 10 (“A10”) mM ascorbic acid.
  • the zinc chloride and ascorbic acid were provided by the solution of component (A) and the sodium chlorite was provided by the solution of component (B).
  • the solutions were mixed immediately prior to treatment, and the log value of yeast colonies killed was measured 1 (Tl) or 2 (T2) minutes after treatment. Complete eradication (CE) of yeast colonies was obtained within 1 minute after treatment. Italics denote a value higher than log 3. Results are shown in Table 3 below. “CE” denotes “Complete Eradication.”
  • Example 4 Testing the effect of the charged biofilm formula on ESKAPE pathogen biofilm bacteria
  • Tl, T5, T15, and T30 signify 1, 5, 15 or 30 minutes after treatment with the charged biofilm formula.
  • Z50, Z75, Z100, and Z125 signify the concentration (mM) of ZnCh in the solution including component (A).
  • C75, C100, C125, and C150 signify the concentration (mM) of NaCIChin the solution including component (B). Solutions A and B were mixed immediately prior to treatment.
  • the log value of the bacterial colonies killed was recorded at the indicated times after treatment.
  • Bold font indicates a log value of less than 1. Underlined with da ⁇ she ⁇ indicates a log value between 1 and 2. Underlined with solid line indicates a log value between 2 and 3. Italics indicates a value higher than 3.
  • CE denotes “Complete Eradication.”
  • a log value of at least 2.0 for bacterial biofilm colonies killed is considered to be a biologically and medically meaningful reduction/ eradication of biofilm bacteria.
  • a treatment that successfully reduces/eradicates biofilm bacterial colonies within 5 minutes is considered to be a biologically and medically practical and effective treatment.
  • Example 4 The performance of Example 4 (with a formulation in which component (A) included 100 mM ZnCh and 3.0 mM Ascorbic Acid and component (B) included 100 mM NaCICh) was additionally compared to other formulas intended for infection prevention/elimination.
  • the log values of bacterial colonies killed at 5 minutes after treatment were measured for biofilm bacteria treated with Example 4, Surgiphor, Irrisept, Prontosan, or for Povidone iodine 0.35%.
  • ENF7 denotes Enterococcus faecium.
  • StA8 denotes Staphylococcus aureus
  • KIP6 denotes Klebsiella pneumoniae
  • AcB6 denotes Acinetobacter baumannii
  • PsA3 denotes Pseudomonas aeruginosa.
  • PVP-I denotes Povidone iodine 0.35%.
  • Example 4 was more effective at reducing biofilm bacteria than the other formulas.
  • the test results are shown in Table 11.
  • Example 5 Testing the efficiency of the charged biofilm formula at various exposure times
  • Example 6 A pig wound study
  • sixteen fullthickness wounds were generated on the back of a pig, using a custom-designed 2.0 cm-diameter trephine.
  • the wounds were treated in groups of 4.
  • the wounds in group D were treated with sterile saline (as a control); group A with a formulation of the charged biofilm formula having 50 mM ZnCh and 50 mM NaCICh; group B with a formulation of the charged biofilm formula having 100 mM ZnCh and 100 mM NaCICh; and group C with a formulation of the charged biofilm formula having 125 mM ZnCh and 125 mM NaCICh.
  • the wounds were exposed to the charged bio film formula or saline on Days 0, 1, and 2. The formula was left in the wounds, and the wounds were evaluated for signs of adverse reaction.
  • Neutrophils were scored as follows: 0 absent, 1 scattered, 2 clustered or nodular, 3 diffuse sheets; Edema 0 absent, 1 minimal, 2 mild, 3 moderate, 4 severe; Hemorrhage: 0 absent, 1 minimal, 2 mild, 3 moderate, 4 severe; Necrosis: 0 absent, 1 minimal, 2 mild, 3 moderate, 4 severe; Granulation tissue filling of wound bed: 0 no granulation tissue filling wound, 1 -1-25% filled, 2 -26-50% filled, 3 -51-75% filled, 4 -76-100% filled; Granulation tissue maturation: 0 no collagen deposition, 1 scanty collagen deposition as loose, poorly organized stroma, 2 more notable collagen deposition than score 1 - majority of stroma is loose and poorly organized with collagen fibers predominantly oriented parallel and perpendicular to the skin surface, 3 more notable collagen deposition than score 2 - majority of stroma is dense and organized with collagen fibers oriented parallel to the skin surface, 4 more notable collagen deposition than
  • Example 7 Combined C50 Z50 AO Solution
  • Example 7 The solution according to Example 7 was prepared as described below. Using an Analytical Balance, the following were weighed out to give the desired concentrations listed in the tables below.
  • Solution 1 0.0884 g (0.0886 g) succinic acid, 0.1758g (0.1753 g) sodium chloride, and 0.6822 g (0.6815 g) of zinc chloride was added to a 100 mL volumetric flask containing about 50 mL of distilled water. The volume of the solution was brought to about 95 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 100 mL beaker. Using a pH Meter and magnetic stir plate, the pH of the solution was adjusted to 4.00 at 22.0°C (pH 4.0) using 1% and 10% sodium hydroxide and hydrochloric acid. The solution was returned to the 100 mL volumetric flask and brought to 100 ml with distilled water. The solution was thoroughly mixed, then filtered through a 0.2 micron filter and stored while being protected from light.
  • Solution 2 0.0887 g (0.0886 g) succinic acid and 0.1742 g (0.1753 g) sodium chloride was added to a 100 mL volumetric flask containing about 50 mL of distilled water. The volume of the solution was brought to about 95 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 100 mL beaker. 0.4538 g (0.4522 g) of sodium chlorite was weighed out and added to the 100 mL beaker.
  • Solution 1 0.0894 g (0.0886 g) succinic acid, 0.0522 g (0.0528 g) ascorbic acid, 0.1754 g (0.1753 g) sodium chloride, and 1.3627 g (1.3630 g) of zinc chloride was added to a 100 mL volumetric flask containing about 50 mL of distilled water. The volume of the solution was brought to about 95 mL using distilled water. The solution was mixed thoroughly until all component were dissolved, then the solution was transferred to a 100 mL beaker.
  • the pH of the solution was adjusted to 4.00 at 22.2°C (pH 4.0) using 1% and 10% sodium hydroxide and gydrochloric acid.
  • the solution was returned to the 100 mL volumetric flask and brought to 100 ml with distilled water. The solution was thoroughly mixed, then filtered through a 0.2 micron filter and stored protected from light.
  • Solution 2 0.0871 g (0.0886 g) succinic acid and 0.1777 g (0.1753 g) sodium chloride was added to a lOOmL volumetric flask containing about 50 mL of distilled water. The volume of the solution was brought to about 95 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 100 mL beaker. 0.9088 g (0.9044 g) of sodium chlorite was weighed out and added to the 100 mL beaker.
  • the pH of the solution was immediately adjusted to 7.46 at 20.2°C (pH 7.5) using 1% and 10% sodium hydroxide and hydrochloric acid.
  • the solution was returned to the 100 mL volumetric flask and brought to 100 ml with distilled water. The solution was thoroughly mixed, then filtered through a 0.2 micron filter and stored protected from light.
  • Final Solution Immediately before use, Solution 1 and Solution 2 were mixed in a 1 : 1 ratio to form a final solution of with the concentrations of 7.5 mM succinic acid, 30 mM sodium chloride, 1.5 mM ascorbic acid, 50 mM zinc chloride, and 40 mM sodium chlorite.
  • the final pH of the mixed solutions may vary in the range of 4.8-5.2.
  • Example 9 Combined C625 Z26.04 AO Solution
  • Example 9 The solution according to Example 9 was prepared as described below. Using an Analytical Balance, the following were weighed out to give the desired concentrations listed in the tables below.
  • Solution 1 0.8855 g (0.8857 g) succinic acid, 1.7535 g (1.7532 g) sodium chloride, and 3.552 g (3.5493 g) of zinc chloride was added to a 1000 mL volumetric flask containing about 500 mL of distilled water. The volume of the solution was brought to about 990 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 1000 L beaker. Using a pH meter and magnetic stir plate, the pH of the solution was adjusted to 4.40 at 21.0°C (pH 4.4) using 1% and 10% sodium hydroxide and hydrochloric acid.
  • Solution 2 0.1788 g (0.1771 g) succinic acid and 0.3521 g (0.3506 g) sodium chloride was added to a 200 mL volumetric flask containing about 100 mL of distilled water. The volume of the solution was brought to about 185 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 250 mL beaker.
  • Example 10 Combined C1250 Z52.1 Al.5625 Solution
  • Example 10 The solution according to Example 10 was prepared as described below. Using an Analytical Balance, the following were weighed out to give the desired concentrations listed in the tables below.
  • Solution 1 0.8872 g (0.8857 g) succinic acid, 0.2752 g (0.2752 g) ascorbic acid, 1.7546 g (1.7532 g) sodium chloride, and 7.1014 g (7.1012 g) of zinc chloride was added to a 1000 mL volumetric flask containing about 500 mL of distilled water. The volume of the solution was brought to about 990 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 1000 mL beaker.
  • the pH of the solution was adjusted to 4.40 at 21.2°C (pH 4.4) using 1% and 10% sodium hydroxide and hydrochloric acid.
  • Solution was returned to the 1000 mL volumetric flask and brought to 1000 ml with distilled water. Solution was thoroughly mixed, then filtered through a 0.2 micron filter and stored protected from light.
  • Solution 2 0.1792 g (0.1771 g) succinic acid and 0.3527 g (0.3506 g) sodium chloride was added to a 200 mL volumetric flask containing about 100 mL of distilled water. The volume of the solution was brought to about 175 mL using distilled water. The solution was mixed thoroughly until everything was dissolved, then the solution was transferred to a 250 mL beaker. 22.6262 g (22.6100 g) of sodium chlorite was weighed out and added to the 250 mL beaker.
  • a charged biofilm formula of Example 11 was prepared by adding 20 ml of
  • Solution B to 430 ml of Solution A.
  • the pH of the charged biofilm formula was around 4.7.
  • Solution A was prepared by combining 7.5 mM succinic acid, 30 mM sodium chloride, and 26.16 mM zinc chloride. The pH was adjusted to 4.3 using 1% and 10% sodium hydroxide and hydrochloric acid in water.
  • Solution B was prepared by combining 7.5 nM succinic acid, 30 nM sodium chloride, and 562.5 mM sodium chlorite in water. The pH was adjusted to 10.3 using 1% and 10% sodium hydroxide and hydrochloric acid.
  • Example 12 Preparation of a charged biofilm formula
  • a charged biofilm formula of Example 12 was prepared by adding 20 ml of Solution B to 430 ml of Solution A.
  • the pH of the charged biofilm formula was around 4.9.
  • Solution A was prepared by combining 7.5 mM succinic acid, 30 mM sodium chloride, and 52.33 mM zinc chloride. The pH was adjusted to 4.3 using 1% and 10% sodium hydroxide and hydrochloric acid in water.
  • Solution B was prepared by combining 7.5 nM succinic acid, 30 nM sodium chloride, and 1125 mM sodium chlorite in water. The pH was adjusted to 10.3 using 1% and 10% sodium hydroxide and hydrochloric acid.
  • Example 13 Preparation of a charged biofilm formula
  • a charged biofilm formula of Example 13 was prepared by adding 50 ml of Solution B to 450 ml of Solution A.
  • the pH of the charged biofilm formula was around 4.6.
  • Solution A was prepared by combining 7.5 mM succinic acid, 30 mM sodium chloride, and 27.78 mM zinc chloride. The pH was adjusted to 4.2 using 1% and 10% sodium hydroxide and hydrochloric acid in water.
  • Solution B was prepared by combining 7.5 nM succinic acid, 30 nM sodium chloride, and 250 mM sodium chlorite in water. The pH was adjusted to 10.0 using 1% and 10% sodium hydroxide and hydrochloric acid.
  • Example 14 Preparation of a charged biofilm formula
  • a charged biofilm formula of Example 14 was prepared by adding 50 ml of Solution B to 450 ml of Solution A.
  • the pH of the charged biofilm formula was around 5.0.
  • Solution A was prepared by combining 7.5 mM succinic acid, 30 mM sodium chloride, and 55.56 mM zinc chloride. The pH was adjusted to 4.2 using 1% and 10% sodium hydroxide and hydrochloric acid in water.
  • Solution B was prepared by combining 7.5 nM succinic acid, 30 nM sodium chloride, and 500 mM sodium chlorite in water. The pH was adjusted to 10.3 using 1% and 10% sodium hydroxide and hydrochloric acid.

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Abstract

L'invention concerne un système de traitement de biofilms comprenant un dispositif d'administration contenant une composition renfermant une source d'ions dans une quantité d'environ 25 à 225 mM, une source d'un agent oxydant dans une quantité d'environ 25 à 225 mM et une source de vitamine C dans une quantité d'environ 1 mM à 10 mM, la composition étant conçue pour éliminer les biofilms.
PCT/US2024/038961 2023-07-20 2024-07-22 Compositions thérapeutiques de traitement de biofilms Pending WO2025019857A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
US20150210964A1 (en) * 2014-01-24 2015-07-30 The Procter & Gamble Company Consumer Product Compositions
US20160030476A1 (en) * 2013-03-14 2016-02-04 Iasis Molecular Sciences Compositions, Methods And Devices For Promoting Wound Healing And Reducing Infection
WO2016154051A1 (fr) * 2015-03-20 2016-09-29 University Of Florida Research Foundation, Inc. Polythérapie pour le traitement de maladies infectieuses
US20190388465A1 (en) * 2018-06-25 2019-12-26 Triumph Pharmaceuticals Inc. Methods of inhibiting microbial infections using zinc-containing compositions
US20220354953A1 (en) * 2021-07-20 2022-11-10 Pinnacle Biologics, Inc. Photodynamic therapy compositions and methods of treatment therein

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160030476A1 (en) * 2013-03-14 2016-02-04 Iasis Molecular Sciences Compositions, Methods And Devices For Promoting Wound Healing And Reducing Infection
US20150210964A1 (en) * 2014-01-24 2015-07-30 The Procter & Gamble Company Consumer Product Compositions
WO2016154051A1 (fr) * 2015-03-20 2016-09-29 University Of Florida Research Foundation, Inc. Polythérapie pour le traitement de maladies infectieuses
US20190388465A1 (en) * 2018-06-25 2019-12-26 Triumph Pharmaceuticals Inc. Methods of inhibiting microbial infections using zinc-containing compositions
US20220354953A1 (en) * 2021-07-20 2022-11-10 Pinnacle Biologics, Inc. Photodynamic therapy compositions and methods of treatment therein

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