Treatment for intestinal aerobicization

Abstract

The present invention provides a medicament, kit and method that utilizes oxygen supply to prevent and / or treat intestinal inflammation and / or infection caused by anaerobic microorganisms. In some embodiments, the formulation is provided as a capsule within a capsule, so that the oxygen prodrug is separated from the catalyst until the formulation reaches the target site in the intestine. In some embodiments, the catalyst is provided in an excess amount of the oxygen prodrug. In some embodiments, the prodrug is in an inner capsule or coating, and a biological material (e.g., yeast, spirulina, chlorella, etc.) containing the catalyst surrounds the encapsulated prodrug, and the biological material is in a capsule or coating. The medicament, kit and method can be used to prevent and / or treat anaerobic bacterial infection in the intestinal lumen by intestinal aerobicization treatment.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 261,828, filed September 29, 2021, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure, in some embodiments, relates to an aerobic therapy for preventing and / or treating anaerobic infection. Specifically, certain embodiments relate to an intestinal aerobic therapy for preventing and treating intestinal (intestinal) anaerobic infection, although other tissues may also be treated. Summary of the Invention

[0003] In some embodiments, a formulation is provided for the prevention and / or treatment of anaerobic bacterial infection. The site of action may be the intestine or other tissue. In one embodiment, the formulation comprises or consists essentially of an agent that delivers oxygen to a target site (e.g., in the digestive tract, such as the intestine) in a patient and / or acts as a source of an amount of oxygen, where the amount of oxygen can create an aerobic environment at the target site and / or convert the anaerobic intestinal environment of the target site to an aerobic environment sufficient to inhibit the growth of anaerobic bacterial infection, reduce toxicity, or both. One, two or more agents can be used sequentially or simultaneously. The formulation can be adapted for oral delivery. In some embodiments, the oral formulation is in solid form (pills, such as tablets and caplets, capsules, etc.). Pills can be round, oval, oblong, disc-shaped, or other shapes suitable for administration (e.g., orally). Capsules can include gel, solid and / or liquid components. In one embodiment, solid formulations are particularly efficient in oxygen delivery.

[0004] In some embodiments, an oral formulation for providing oxygen to an intestinal region is provided, the oral formulation comprising a prodrug, a plurality of yeast cells comprising catalase, a first soluble coating surrounding the prodrug and isolating the prodrug from the plurality of yeast cells, a second soluble coating surrounding the plurality of yeast cells and the coated prodrug, and an insoluble, semi-permeable coating having a lumen, in which the plurality of coated yeast cells surrounding the coated prodrug are present. In some embodiments, the prodrug comprises sodium percarbonate and / or carbamide peroxide. In some embodiments, the catalase is configured to act on the prodrug and convert it to an active drug upon contact with the prodrug. In some embodiments, the catalase controls the rate of conversion of the prodrug to oxygen. In some embodiments, when the oral formulation is orally administered to a subject, the first and second soluble coatings dissolve in the intestinal region, allowing the prodrug and the plurality of yeast cells to contact each other. In some embodiments, contact of the plurality of yeast cells with the prodrug allows catalase from the yeast cells to convert the prodrug to oxygen, thereby providing oxygen to the intestinal region. In some embodiments, the oral formulation is in a solid form.

[0005] In some embodiments, the prodrug is present in an amount of 100-2000 mg. In some embodiments, the plurality of yeast cells is provided in an amount greater than that of the prodrug, e.g., 100-4000 mg. In some embodiments, the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation for at least 14 days at a temperature of 15-30° C. In further embodiments, the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation for at least 20 days, at least 25 days, at least 30 days, at least 35 days, or at least 40 days (or more) at a temperature of 20-25° C.

[0006] In some embodiments, the plurality of yeast cells comprises one or more yeast strains. In some embodiments, the plurality of yeast cells comprises baker's yeast. In some embodiments, the plurality of yeast cells is derived from a yeast strain selected from Saccharomyces cerevisiae, Saccharomyces exiguous, Schizosaccharomyces pombe, and combinations thereof.

[0007] In some embodiments, an oral formulation for supplying oxygen to the intestinal region is provided, comprising a prodrug, a catalyst configured to act on the prodrug and convert it to an active drug when it comes into contact with the prodrug, a first soluble coating surrounding the prodrug and separating the prodrug from the catalyst, a second soluble coating surrounding the catalyst and surrounding the coated prodrug, and an insoluble, semi-permeable coating having a lumen, in which the coated catalyst surrounding the coated prodrug is present. In some embodiments, the prodrug comprises sodium percarbonate. In some embodiments, the catalyst comprises catalase, which controls the rate of conversion of the prodrug to oxygen. In some embodiments, the catalyst is present in an amount approximately equal to or greater than the amount of the prodrug. In some embodiments, when orally administered to a subject, the first and second soluble coatings dissolve in the intestinal region, allowing the prodrug and the catalyst to contact each other. In some embodiments, the contact of the catalyst with the prodrug allows the catalyst to convert the prodrug to oxygen, thereby providing oxygen to the intestinal region. In some embodiments, the catalyst is provided by a plurality of eukaryotic unicellular microorganisms. In some embodiments, the prodrug is present in an amount of 100-2000 mg and the plurality of eukaryotic unicellular microorganisms is provided in an amount of 100-4000 mg. In some embodiments, the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation at a temperature of 15-30° C. for at least 14 days.

[0008] In some embodiments, the insoluble, semipermeable coating prevents catalase from diffusing out of the lumen and prevents intestinal digestive enzymes from diffusing into the lumen, in some embodiments, the insoluble, semipermeable coating allows water to diffuse into or out of the lumen and allows oxygen to diffuse out of the lumen.

[0009] In some embodiments, the oral formulation provides 2%-5% oxygen in at least the intestinal region for 24 hours or more after administration to a subject, hi some embodiments, the oral formulation provides 5%-10% oxygen in at least the intestinal region for 6 hours or more after administration to a subject.

[0010] In some embodiments, the first and second soluble coatings are not substantially dissolved by gastric acid after administration to a subject.In some embodiments, some dissolution may occur, but not to the extent that allows catalase and / or yeast cells to contact and act on the prodrug.In some embodiments, the intestinal region is in the small intestine.In some embodiments, the intestinal region is the large intestine.In some embodiments, other regions of the intestine are oxygenated.

[0011] In some embodiments, the first soluble coating comprises a gelatin capsule. In some embodiments, the second soluble coating comprises a gelatin capsule. In some embodiments, one or both of the first soluble coating and / or the second soluble coating comprise a gelatin capsule. In some embodiments, the gelatin is bovine gelatin. In some embodiments, the gelatin is porcine gelatin. In some embodiments, one or more of the first and second soluble coatings comprise a plant cellulose capsule. In some embodiments, the first soluble coating and / or the second soluble coating comprises an agar capsule. In some such embodiments, the agar is derived from seaweed. In some embodiments, the first soluble coating and / or the second soluble coating comprises an enteric coating comprising hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, diethyl phthalate and / or cellulose acetate phthalate. In some embodiments, the prodrug is provided in tablet form.

[0012] According to some embodiments, oxygenation of the intestinal region by administration of an oral formulation prevents and / or treats inflammatory bowel disease (IBD). According to some embodiments, oxygenation of the intestinal region by administration of an oral formulation prevents and / or treats intestinal anaerobic bacterial infection. In some such embodiments, the anaerobic bacteria comprises one or more of Clostridioides difficile, Clostridium perfringens, Clostridium botulinum, Clostridium butyricum, Clostridium baratii, Vibrio cholera, Escherichia coli, and Salmonella enteritidis.

[0013] In some embodiments, the oral formulation further comprises at least one additive.In some embodiments, the at least one additive is polyvinyl acetate and / or glyceryl behenate.In some embodiments, the oral formulation further comprises flavoring, sweetening, coloring and / or buffering agents.

[0014] In some embodiments, the formulation is suitable for daily administration to a subject for at least three days.

[0015] In some embodiments, the insoluble, semipermeable coating prevents catalase from diffusing out of the lumen and prevents intestinal digestive enzymes from diffusing into the lumen, allows water to diffuse into or out of the lumen, and allows oxygen to diffuse out of the lumen.

[0016] Also provided is an oral formulation for supplying oxygen to the intestinal region, comprising a prodrug comprising one or both of sodium percarbonate or carbamide peroxide, a biological material comprising catalase, a first soluble coating surrounding the prodrug and separating the prodrug from the biological material, a second soluble coating surrounding the biological material and the coated prodrug, and an insoluble, semi-permeable coating having a lumen, in which the coated biological material surrounding the coated prodrug is present. In some embodiments, when orally administered to a subject, the first and second soluble coatings dissolve in the intestinal region, allowing the prodrug and the biological material to contact each other. In some embodiments, contact between the biological material and the prodrug allows catalase from the biological material to convert the prodrug to oxygen, thereby supplying oxygen to the intestinal region. In some embodiments, the oral formulation is in a solid form.

[0017] In some embodiments, the biological material comprises a plurality of eukaryotic unicellular microorganisms, wherein the prodrug is present in an amount of 100-2000 mg, the plurality of eukaryotic unicellular microorganisms is provided in an amount of 100-4000 mg, and the oral formulation is capable of providing oxygen to the intestinal region following storage of the oral formulation for at least 14 days at a temperature of 15-30° C.

[0018] In some embodiments, the biological material comprises a plurality of cyanobacteria, wherein the prodrug is present in an amount of 100-2000 mg, and the plurality of cyanobacteria is provided in an amount of 100-4000 mg, and the oral formulation is capable of providing oxygen to the intestinal region following storage of the oral formulation for at least 14 days at a temperature of 15-30° C. In some embodiments, the plurality of cyanobacteria is a species selected from Arthrospira platensis, Arthrospira fusiformis, Arthrospira maxima, and combinations thereof.

[0019] In some embodiments, the biological material comprises fruit and / or plant material or derivatives thereof, wherein the prodrug is present in an amount of 100-2000 mg, the fruit or plant material or derivatives thereof is provided in an amount of 100-4000 mg, and the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation at a temperature of 15-30° C. for at least 14 days. In some embodiments, the biological material comprises plant material or derivatives thereof and is derived from a Brassicaceae plant. In some embodiments, the biological material comprises plant material or derivatives thereof and is derived from alfalfa, brussels sprouts, scallions, onions, broccoli, parsnips, zucchini, spinach, kale, radish, carrots, red peppers, turnips, cucumbers, celery, avocados, potatoes, and / or red cabbage. In some embodiments, the biological material comprises fruit material or derivatives thereof, and is derived from kiwi, peach, cherry, apricot, banana, watermelon, pineapple, apple and / or grapes.

[0020] Also provided is an oral formulation comprising an insoluble, semipermeable outer coating having a lumen, a prodrug comprising sodium percarbonate or carbamide peroxide disposed within the lumen, a first soluble coating surrounding the prodrug, a catalyst comprising catalase disposed within the lumen and surrounding the prodrug coated with the first soluble coating, and a second soluble coating surrounding the catalyst, wherein when orally administered to a subject, water from the intestine diffuses through the insoluble, semipermeable outer coating and dissolves the first and second soluble coatings, thereby allowing the catalyst to contact the prodrug and act on the prodrug to produce an enzyme, thereby providing oxygen to the intestinal region.

[0021] In some embodiments, the insoluble, semi-permeable coating prevents catalase from diffusing out of the lumen and prevents intestinal digestive enzymes from diffusing into the lumen, allows water to diffuse into or out of the lumen, and allows oxygen to diffuse out of the lumen. In some embodiments, the first soluble coating and / or the second soluble coating comprises a gelatin capsule. In some embodiments, the prodrug is in tablet form and is coated with a gelatin coating, and the second soluble coating comprises a gelatin capsule. In some embodiments, the prodrug comprises sodium percarbonate and is present in an amount of 100-2000 mg, the catalyst is provided by a plurality of yeast cells, and the plurality of yeast cells is present in an amount equal to or greater than the sodium percarbonate.

[0022] Also provided is a method of providing oxygen to the intestinal region to prevent and / or treat inflammatory bowel disease (IBD), comprising administering at least one dose of an oral formulation described herein.

[0023] Also provided is a method of providing oxygen to the intestinal region to prevent and / or treat intestinal anaerobic bacterial infection comprising administering at least one dose of the oral formulation described herein.

[0024] Also provided is the use of the oral formulations described herein for the treatment of inflammatory bowel disease (IBD) or intestinal anaerobic bacterial infection.

[0025] Also provided is the use of an oral formulation as described herein for use in the manufacture of a medicament for the treatment of inflammatory bowel disease (IBD) or an intestinal anaerobic bacterial infection.

[0026] In some embodiments, a method of providing oxygen to the intestinal region is provided comprising orally administering to a subject an oral formulation, the oral formulation comprising an insoluble, semipermeable outer coating having a lumen, a prodrug comprising sodium percarbonate or carbamide peroxide disposed within the lumen, a first soluble coating surrounding the prodrug, a catalyst comprising catalase disposed within the lumen and surrounding the prodrug coated with the first soluble coating, and a second soluble coating surrounding the catalyst.

[0027] In some embodiments, when orally administered to a subject, water from the intestine diffuses through the insoluble semipermeable outer coating and dissolves the first and second soluble coatings, allowing the catalyst to contact the prodrug and act on the prodrug to produce an enzyme, thereby providing oxygen to the intestinal region.In some embodiments, at least one further oral administration of the oral formulation is performed.

[0028] In some embodiments, the catalase is provided by a biological source.

[0029] In some embodiments, the biological material comprises a plurality of eukaryotic unicellular microorganisms. In some embodiments, the plurality of eukaryotic unicellular microorganisms comprises a plurality of yeast cells from one or more yeast strains. In some embodiments, the plurality of yeast cells comprises baker's yeast. In some embodiments, the plurality of yeast cells is from a yeast strain selected from Saccharomyces cerevisiae, Saccharomyces equigus, Schizosaccharomyces pombe, and combinations thereof.

[0030] In some embodiments, the biological material comprises a plurality of cyanobacteria, wherein the plurality of cyanobacteria is a species selected from Arthrospira platensis, Arthrospira fusiformis, Arthrospira maxima, and combinations thereof.

[0031] In some embodiments, the biological material comprises fruit and / or plant material or derivatives thereof. In some embodiments, the biological material comprises plant material or derivatives thereof and is derived from a Brassicaceae plant, wherein the biological material comprises plant material or derivatives thereof and is derived from alfalfa, brussels sprouts, scallions, onions, broccoli, parsnips, zucchini, spinach, kale, radish, carrots, red peppers, turnips, cucumbers, celery, avocados, potatoes, and / or red cabbage, and / or the biological material comprises fruit material or derivatives thereof and is derived from kiwi, peach, cherry, apricot, banana, watermelon, pineapple, apple, and / or grapes.

[0032] In some embodiments, the prodrug is present in an amount of 100-2000 mg, wherein the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation at a temperature of 15-30° C. for at least 14 days.

[0033] In some embodiments, the catalase, the biological material, the plurality of yeast cells, the plurality of cyanobacteria, and / or the fruit and / or plant material or derivatives thereof are provided in an amount of 100-4000 mg.

[0034] In some embodiments, the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation at a temperature of 20-25° C. for at least 20 days.

[0035] In some embodiments, when orally administered to a subject, the formulation provides 2%-5% oxygen in at least the intestinal region for 24 hours or more. In some embodiments, when orally administered to a subject, the formulation provides 5%-10% oxygen in at least the intestinal region for 6 hours or more.

[0036] In some embodiments, the intestinal region is within the small intestine or large intestine of a subject.

[0037] In some embodiments, the first soluble coating and / or the second soluble coating comprises a gelatin capsule, wherein the gelatin is optionally bovine or porcine gelatin.In some embodiments, one or more of the first and second soluble coatings comprises a plant cellulose capsule, or the first soluble coating and / or the second soluble coating comprises an agar capsule, wherein the agar is derived from seaweed.In some embodiments, the first soluble coating and / or the second soluble coating comprises an enteric coating comprising hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, diethyl phthalate and / or cellulose acetate phthalate.

[0038] In some embodiments, oxygenation of the intestinal region by administration of the oral formulation prevents and / or treats inflammatory bowel disease (IBD). In some embodiments, oxygenation of the intestinal region by administration of the oral formulation prevents and / or treats intestinal anaerobic bacterial infection.

[0039] In some embodiments, the insoluble, semipermeable coating prevents catalase from diffusing out of the lumen and prevents intestinal digestive enzymes from diffusing into the lumen, allows water to diffuse into or out of the lumen, and allows oxygen to diffuse out of the lumen, hi some embodiments, the insoluble, semipermeable coating is substantially the only portion of the oral formulation passed by the subject during a bowel movement following administration of the oral formulation.

[0040] In some embodiments, the oral formulations described herein do not require refrigeration or freezing to maintain stability prior to administration.

[0041] In further embodiments, the drug, such as the active pharmaceutical ingredient (API), can comprise or essentially consist of oxygen carrier molecules and / or oxygen-containing mixtures. The oxygen carrier molecules and / or oxygen-containing mixtures can comprise, for example, oxygen-binding biomolecules, oxygen cocktails, microemulsions of oxygen gas bubbles, microemulsions of oxygen gas foams, or perfluorocarbons (e.g., oxygen perfluorocarbon solutions). The drug can comprise or essentially consist of oxygen prodrugs or oxygen-generating compounds. The oxygen prodrugs or oxygen generators can comprise, for example, oxygen-generating metal peroxide salts, hydrogen peroxide complexes (e.g., hydrogen peroxide adducts, or organic molecules containing peroxide).

[0042] In some embodiments, the formulations described herein provide oxygen concentrations and / or amounts of at least (i) 2-5% oxygen (gas phase) for 24 hours or more, or (ii) 5-10% oxygen (gas phase) for 6 hours or more. In one embodiment, oxygen is increased by at least 20% at the target site for 1-24 hours or more. The formulations may be used prophylactically, administered once a day or several times a week. Conditions such as IBD may be significantly improved by the formulations described herein by treating (or preventing) the growth of anaerobic microorganisms that exacerbate IBD symptoms.

[0043] In some embodiments, a catalyst is also provided. In some embodiments, a formulation is provided in which the catalyst is encapsulated or otherwise contained in a diffusion control or regulation means. The API can also be encapsulated or otherwise contained in a diffusion control or regulation means. Such means include, for example, a material or a layer of material, such as a membrane, coating, or other material. In one embodiment, the material is permeable to water but impermeable to one or more solutes. For example, the material can be permeable to water but impermeable to solutes with molecular weights of >250, 500, 1000, 1500 Daltons or more. In one embodiment, either the catalyst (e.g., catalase) or the API is encapsulated or coated. In another embodiment, both are encapsulated or coated (e.g., individually). For example, in some embodiments, the catalyst and / or API are individually coated or encapsulated in granular or powder form. As an example, granules of catalyst and / or API are contained in a capsule or other housing, and each of the granules is coated (e.g., with one, two or more of an enteric coating, an osmotic coating and a barrier coating). Two or more layers of the same coating may also be used. In some embodiments, each granule is individually coated, and then the coated granules are contained in a capsule or other form. In other embodiments, each granule is individually coated, and no capsule or other housing is provided. In one embodiment, a group of granules is coated (e.g., 2-20 granules) and then optionally placed in a capsule or some other form.

[0044] In one embodiment, the diffusion control or regulation means (e.g., the material described herein) (i) allows the diffusion of water, electrolytes, specific solutes and / or oxygen throughout the material, (ii) prevents all, substantially all or most of the catalase (or other agent) from diffusing out of the material, and (iii) prevents all, substantially all or most of the digestive enzymes from diffusing into the material. In some embodiments, the agent comprises or consists essentially of an oxygen carrier molecule and / or an oxygen-containing mixture. In one embodiment, such catalyst (e.g., catalase) or other agent (e.g., API) is formulated in a capsule or tablet coated with a dialysis or osmosis membrane. In one embodiment, the pore size of the membrane is large enough to allow small molecules such as water, electrolytes, specific solutes and oxygen to diffuse through the membrane, but small enough to prevent the digestive enzymes from diffusing into the capsule or tablet while preventing catalase from diffusing out of the capsule or tablet. In one embodiment, the pore size is in the range of 1 nm to 100 μm (e.g., 10-250 nm, 100-500 nm, 500-1000 nm, 1-100 μm, and overlapping ranges therein) or 1 kilodalton to 100 kilodalton (e.g., 1-10 kD, 10-50 kD, 50-100 kD, and overlapping ranges therein). In one embodiment, less than about 1000 daltons are used (e.g., 10-100 daltons, 100-500 daltons, 250-750 daltons, 500-1000 daltons, and overlapping ranges therein). Coatings, membranes, or layers of other materials may be used, e.g., the functional pore size is smaller than the actual pore size due to layering. In some embodiments, the material comprises a polymer (e.g., a cellulosic compound).

[0045] In some embodiments, a formulation for preventing, treating, or both of at least one infection (e.g., intestinal anaerobic bacterial infection) is provided, the formulation comprising at least one agent that delivers oxygen to a target site (e.g., in the digestive tract, such as the intestine) and / or acts as a source of an amount of oxygen when orally administered to a subject, the amount of oxygen can create an aerobic environment at the target site and / or can convert the anaerobic intestinal environment of the target site into an aerobic environment sufficient to inhibit the growth of anaerobic bacterial infection, reduce toxicity, or both. The agent can comprise or essentially consist of an oxygen carrier molecule and / or an oxygen-containing mixture. The oxygen carrier molecule and / or the oxygen-containing mixture can comprise or essentially consist of an oxygen-binding biomolecule, an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foams, or an oxygen perfluorocarbon solution. The oxygen-binding biomolecule can comprise or essentially consist of one, two, or all of leghemoglobin, hemoglobin, and / or myoglobin. In some embodiments, the formulation further comprises one or more additional ingredients that enhance localization, enhance stability and / or reduce degradation of the agent described herein. The formulation may be designated as GRAS.

[0046] In some embodiments, the agent comprises or consists essentially of an oxygen prodrug or an oxygen generating compound or both. The oxygen prodrug or oxygen generator may comprise or consist essentially of an oxygen generating metal peroxide salt or hydrogen peroxide complex. The oxygen generating metal peroxide salt or hydrogen peroxide complex may comprise or consist essentially of carbamide peroxide, calcium peroxide, calcium hydroxide, magnesium peroxide, sodium percarbonate or endoperoxide or a combination thereof.

[0047] In some embodiments, the formulation comprises or consists essentially of a catalyst to control the rate of conversion of API (e.g., peroxide-containing prodrug) to oxygen.The catalyst can comprise or consist essentially of iodide, catalase, manganese dioxide, iron (III), silver or dichromate, or a combination thereof.Any catalyst can be administered in the same formulation as API or separately. In some embodiments, the formulation comprises about 100-3000 mg of API per dose (e.g., 100-500 mg, 250-2000 mg, 500-1000 mg, 500-1500 mg, 750-1000 mg, 800-1200 mg, 1000-2000 mg, and overlapping ranges therein) together with about 5-1000 Baker Units of any catalyst (e.g., 5-25 Baker Units, 10-100 Baker Units, 10-150 Baker Units, 25-50 Baker Units, 50-150 Baker Units, 150-300 Baker Units, 300-500 Baker Units, 250-750 Baker Units, 500-1000 Baker Units, and overlapping ranges therein). The formulation may be provided once daily, 2-6 times daily, or as needed. In one embodiment, the API comprises at least one of sodium percarbonate and carbamide peroxide, and the catalyst comprises catalase. In some embodiments, the ratio of API to catalyst (e.g., by weight) is about 1:1, 1:2, 1:3, 1:4, 4:1, 3:1, or 2:1. In one embodiment, the ratio of API:catalyst is 5:1 to 30:1 (e.g., 5 / 10 / 15 / 20 / 25 / 30:1). The formulation may also include any or more of inactive ingredients, such as gum acacia, rice flour, cellulose, stearates (e.g., magnesium stearate), gelatin, carbonates (e.g., calcium carbonate), and various other binders, additives, stabilizers, and pH balancers. The formulation may be provided as pills, such as tablets and caplets, capsules, and the like. The percentage of inactive ingredients in a dose (e.g., an oral dose by weight) is about 25 to 75%.Oral formulations or supplements can be divided into smaller pill sizes (and the like) for ease of administration (e.g., a dose or serving size can be two, three or more smaller pills, such as tablets and caplets, capsules, and the like, which can be partially or entirely in solid form).In some embodiments, the formulation is in a solid form for oral delivery, such as tablets, caplets, capsules, which can be coated or uncoated.Alternatively, gel and liquid oral formulations can be used.In some embodiments, administration by parenteral route is also provided.

[0048] Also provided are kits for the prevention, treatment, or both of at least one anaerobic infection (e.g., of the intestine or other area), comprising a formulation as described herein and instructions for use.

[0049] In some embodiments, a method is provided for the prevention, treatment, or both of at least one infection of a target site (e.g., an anaerobic infection of the digestive tract, such as the intestine). In one embodiment, the method comprises or consists essentially of administering (e.g., orally) a therapeutically effective amount of a formulation described herein to a subject (e.g., a patient) in need thereof, and delivering an amount of oxygen to the intestine (or other site in the body), where the amount of oxygen is provided in an amount sufficient to (i) create an aerobic environment at the target site, and / or (ii) convert the anaerobic intestinal environment of the target site to an aerobic environment that can inhibit the growth of, reduce toxicity of, or both of, an anaerobic bacterial infection. The administration method can be provided for hours, days, weeks, months, or more. The subject can be instructed to orally ingest the formulation 1-6 times a day for at least 3, 7, 10, or 14 days. The subject can be instructed to orally ingest the formulation 1-3 times a day for weeks, months, or more as a prophylaxis. In some embodiments, a solid formulation for oral delivery is provided, such as a pill and a capsule.

[0050] Anaerobic infections of the intestine (or other sites in the body) can be caused by Clostridioides difficile infections and / or food-borne infections. Food-borne infections can be caused by bacteria selected from the group consisting of one or more of Clostridium perfringens, botulism caused by Clostridium botulinum, Clostridium butyricum and Clostridium baratii, cholera caused by Vibrio cholerae, diarrheagenic Escherichia coli infections, and Salmonella enteritidis.

[0051] In some embodiments, an oral granule formulation for intestinal anaerobic bacterial infections is provided, comprising a plurality of granules or particles comprising a drug and a catalyst, a first coating on the outside of each granule, and a second coating between the first coating and the catalyst, wherein the drug is configured to act on the catalyst to produce oxygen, the catalyst controlling the rate of conversion of the drug to oxygen, the first coating being resistant to degradation in a low pH environment, and the second coating allowing water to contact and activate the catalyst upon at least partial degradation of the first coating.

[0052] In some embodiments, when orally administered to a subject, the agent provides oxygen to the subject's intestine to create an aerobic environment in the intestine sufficient to inhibit the growth of anaerobic bacterial populations that cause anaerobic bacterial infections in the intestine.

[0053] In some embodiments, the granules or particles are optionally contained in a capsule.

[0054] In some embodiments, the agent comprises sodium percarbonate or carbamide peroxide, or a combination thereof, hi some embodiments, the catalyst comprises catalase.

[0055] In some embodiments, the first coating further comprises a third coating, and the third coating is a barrier between the drug and the catalyst.In some embodiments, the first coating is resistant to degradation in the stomach of a subject, thereby allowing the granule to be delivered to the intestine without being substantially inactivated by gastric acid.In some embodiments, the granule or particle further comprises one or more binders, one or more dispersants, one or more glidants and / or plasticizers.In some embodiments, the oral formulation does not comprise tannin or tannin-like components.

[0056] In some embodiments, a solid form coated oral formulation for treating intestinal anaerobic bacterial infections comprising a drug and a catalyst is provided, wherein the drug comprises sodium percarbonate or carbamide peroxide, the catalyst comprises catalase, the catalase controls the rate of conversion of the drug to oxygen, and when orally administered to a subject, the drug provides oxygen to the intestine of the subject to create an aerobic environment in the intestine sufficient to inhibit the growth of anaerobic bacterial populations that cause anaerobic bacterial infections in the intestine, and the drug is provided as individually coated granules or granules, and the granules are optionally provided in a capsule.

[0057] In some embodiments, the anaerobic bacterial population comprises Clostridioides difficile.

[0058] In some embodiments, when orally administered to a subject, the agent provides 2-5% oxygen to at least a portion of the intestine for 24 hours or more, hi some embodiments, the agent provides 5-10% oxygen to at least a portion of the intestine for 6 hours or more.

[0059] In some embodiments, the catalase is contained within a material, which prevents at least a majority of the catalase from diffusing out of the material and prevents at least one intestinal digestive enzyme from diffusing into the material. In some embodiments, the catalase is encapsulated in a porous membrane that controls the diffusion of the catalase through the membrane.

[0060] In some embodiments, the agent is provided in the range of 250-2000 mg, hi some embodiments, the catalase is provided in the range of 10-150 Baker Units.

[0061] Some embodiments provide an oral formulation in solid form for treating intestinal anaerobic bacterial infection comprising a drug and a catalyst, wherein the catalyst controls the rate of conversion of the drug to oxygen, and when orally administered to a subject, the drug provides oxygen to the intestine of the subject to create an aerobic environment in the intestine sufficient to inhibit the growth of anaerobic bacterial populations that can cause anaerobic bacterial infection in the intestine, the anaerobic bacterial populations including Clostridioides difficile, and the oral formulation is in solid form.

[0062] In some embodiments, the agent comprises sodium percarbonate. In some embodiments, the agent comprises carbamide peroxide. In some embodiments, the catalyst comprises catalase. In some embodiments, the catalyst is encapsulated with a membrane that controls the diffusion of the catalyst through the membrane.

[0063] Also provided is a solid form oral formulation for treating intestinal anaerobic bacterial infection, comprising at least one agent that delivers oxygen or acts as a source of oxygen to the intestine when orally administered to a subject, wherein the at least one agent is in solid form, and the oxygen can create an aerobic environment in the intestine sufficient to treat the anaerobic bacterial infection by reducing the anaerobic bacterial population. In some embodiments, the oral formulation further comprises a catalyst that controls the conversion rate of the agent to oxygen. In some embodiments, the catalyst is coated with a material that prevents at least a majority of the catalyst from diffusing out of the material and prevents at least one nitrification enzyme located in the intestine from diffusing into the material. In some embodiments, the delivered oxygen increases the oxygen level in the intestine by at least 20% for 1 to 24 hours.

[0064] In some embodiments, the medicament comprises sodium percarbonate, in some embodiments, the medicament comprises carbamide peroxide, in some embodiments, the medicament is provided in the range of 250-2000 mg.

[0065] In some embodiments, an oral granule formulation for treating intestinal anaerobic bacterial infections is provided, comprising a plurality of granules or particles comprising a drug and a catalyst, a first coating on the outside of each granule, and a second coating between the first coating and the catalyst, wherein the drug comprises sodium percarbonate or carbamide peroxide, the catalyst comprises catalase, which controls the rate of conversion of the drug to oxygen, the first coating is resistant to degradation in a low pH environment, and the second coating allows water to contact and activate the catalyst upon at least partial degradation of the first coating; when orally administered to a subject, the drug provides oxygen to the intestines of the subject to create an aerobic environment in the intestines sufficient to inhibit the growth of anaerobic bacterial populations that cause anaerobic bacterial infections in the intestines, and the granules or particles are optionally contained in a capsule.

[0066] In some embodiments, the oral formulation further comprises a third coating, the third coating being a barrier between the drug and the catalyst. In some embodiments, the first coating is resistant to degradation in the stomach of a subject, thereby allowing the granule to be delivered to the intestine without being substantially inactivated by gastric acid. In some embodiments, the oral formulation further comprises one or more binders, one or more dispersants, one or more glidants and / or plasticizers. In some embodiments, the formulation does not contain tannin or tannin-like components. In some embodiments, the formulations, kits and methods described herein can be used for the treatment of inflammatory bowel disease (IBD) and / or prevention against the exacerbation of IBD. [Brief description of the drawings]

[0067] [Figure 1]Figure 1A is a diagrammatic representation of one non-limiting embodiment of a formulation for delivering oxygen by catalytic release of oxygen from an oxygen prodrug. Figure 1B is a diagrammatic representation of another non-limiting embodiment of a formulation for delivering oxygen by catalytic release of oxygen from an oxygen prodrug that includes multiple coatings.

[0068] [Diagram 2] FIG. 2 is a diagrammatic representation of the embodiment of FIG. 1A showing the capsule or tablet at the target site (eg, the intestine) after the enteric coating has dissolved.

[0069] [Diagram 3] Figure 3A is a diagrammatic representation of the embodiment of Figure 1A showing a capsule or tablet where the controlled release coating begins to dissolve and release hydrogen peroxide, which is efficiently converted to oxygen and water. Figure 3B is a diagrammatic representation of the non-limiting embodiment of Figure 1B showing an individually coated granule where the controlled release coating begins to dissolve and release hydrogen peroxide, which is efficiently converted to oxygen and water.

[0070] [Figure 4] FIG. 4 shows one non-limiting embodiment of the study design of a mouse model of Clostridioides difficile infection.

[0071] [Diagram 5] FIG. 5 shows the results of the experimental protocol depicted in FIG. 4 showing the survival rates of the three treatment groups: control treatment (vehicle), the antibiotic vancomycin (Vanc) and enteral aerobic treatment (EAT).

[0072] [Figure 6] FIG. 6 shows one non-limiting embodiment of a clinical observation scale.

[0073] [Figure 7]Figure 7 shows the results of the experimental protocol shown in Figure 4 and indicates the number of animals in each group (EAT, vehicle (nitrogen), vancomycin) that showed at least one clinical observation according to the observation scale shown in Figure 6 one week after inoculation (days 0-7) and two weeks after inoculation (days 8-14).

[0074] [Figure 8] FIG. 8 shows the results of the experimental protocol shown in FIG. 4, showing the number of animals with at least one clinical finding on a daily basis for each of the three treatment groups: control (nitrogen), vancomycin (Vanc), and EAT (oxygen).

[0075] [Figure 9] FIG. 9 shows the results of the experimental protocol depicted in FIG. 4, showing the total clinical scores for each of the three treatment groups: control (nitrogen), vancomycin (Vanc), and EAT (oxygen).

[0076] [Figure 10] FIG. 10 shows the results of the experimental protocol depicted in FIG. 4, showing daily weight change records for each of the three treatment groups: control (nitrogen), vancomycin, and EAT (LP oxy).

[0077] [Figure 11] FIG. 11 shows a non-limiting schematic structure of a capsule-within-a-capsule device (also referred to as a coating-within-a-coating).

[0078] [Figure 12] FIG. 12 shows a non-limiting schematic structure of an activated capsule-within-a-capsule in an environment where the inner and outer capsules have dissolved, such as the higher pH of the small intestine or colon.

[0079] [Figure 13] FIG. 13 shows a non-limiting schematic diagram showing a used device after all the prodrug has been converted to oxygen and water.

[0080] [Figure 14] FIG. 14 shows the results of stability studies of various formulations stored according to various conditions, according to embodiments herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0081] Some embodiments of the present disclosure provide an improved solution for treating anaerobic infections, overcoming certain shortcomings of existing therapies.

[0082] The intestinal lumen is a largely anaerobic environment. Its oxygen content is a complex and variable function of the amount of air swallowed during ingestion, how much of that air is delivered into the gut and how much is expelled, the oxygen consumption by intestinal aerobes and facultative anaerobes, and the possibility of minimal absorption through the intestinal villi. However, although intestinal anaerobes can be forced to tolerate brief periods of low oxygen tension, the intestinal lumen is primarily an anaerobic environment optimal for the growth of anaerobic bacteria.

[0083] This anaerobic environment can not only support the growth of virulent anaerobic pathogens, but also enhance their virulence in a variety of other ways. In addition to the development of antibiotic resistance in these pathogens, the function of some antibiotics is impaired under anaerobic conditions. Hypoxia is thought to cause inflammation in the intestine. Anaerobic conditions induce the expression of virulence factors in pathogenic bacteria and damage tight junctions between host epithelial cells that act as a barrier against invasive infections. Anaerobiosis can reduce host defense mechanisms.

[0084] As disclosed herein, aerobicization of the intestinal lumen can be used to prevent and treat anaerobic infectious and non-infectious conditions exacerbated by hypoxia in the distal gut.

[0085] Some embodiments of the present disclosure relate to compositions, kits and methods that utilize oxygen supply to prevent and / or treat infections in the intestine caused by anaerobic microorganisms.Some embodiments of the present disclosure relate to compositions, kits and methods that can be used to supply oxygen to the intestinal lumen to prevent and / or treat infections caused by anaerobic bacteria.In some embodiments, the present disclosure relates to compositions, kits and methods that can be used to prevent and / or treat anaerobic bacterial infections in the intestinal lumen by enteral aerobic therapy (EAT).

[0086] Some embodiments of the present disclosure overcome one or more concerns of existing oxygen delivery therapies. For example, hyperbaric oxygen therapy has shown some benefit in treating infections such as gas gangrene, showing both bacteriostatic and bactericidal effects. Because hemoglobin is fully saturated at normal pressure, the primary mechanism of hyperbaric oxygen therapy is to increase dissolved oxygen in plasma through high oxygen partial pressure, improving oxygen delivery. Although there may be direct effects on open wounds, hyperbaric oxygen administration is primarily through the respiratory system. Although studies have shown that hyperbaric oxygen affects the growth of intestinal bacteria, particularly reducing the growth of obligate anaerobes in mice, hyperbaric oxygen therapy has not been used as a treatment for intestinal infections caused by obligate anaerobic pathogens. In addition to lacking efficacy against intestinal infections, hyperbaric oxygen therapy has limitations in treating other hypoxic intestinal diseases. It requires expensive and specialized equipment, which is not readily available to many patients, even in developed countries. It reduces the therapeutic index of oxygen as a drug, narrowing the gap between safe and toxic doses. It also does not rapidly change intraluminal oxygen concentrations. In some embodiments, some of these problems are alleviated by the use of the agents described herein in combination with or in place of hyperbaric oxygen.

[0087] Intestinal aerobization treatment In some embodiments of the present disclosure, intestinal aerobicization treatment (EAT) provides one or more agents (e.g., compounds, etc.) to be delivered to a desired location and / or act as a source of oxygen. As used herein, the terms agent and compound may be used interchangeably. In some embodiments, one or more agents are delivered to an intestinal site or other tissue site in the digestive tract or elsewhere in the body and / or act as a source of oxygen. In some embodiments, one or more agents are delivered to an intestinal site and / or act as a source of oxygen in a controlled manner to consistently and / or substantially convert an anaerobic intestinal environment to an aerobic environment. This can be achieved by at least two technical methods. In some embodiments, EAT is achieved by an oxygen carrier molecule and an oxygen-containing mixture. In some embodiments, EAT is achieved by an oxygen prodrug or an oxygen-generating compound. In some embodiments, EAT is achieved by a combination of an oxygen carrier molecule and an oxygen-containing mixture and an oxygen prodrug or an oxygen-generating compound. In some embodiments, the intestinal site may be the lumen, the inner wall, or both of the intestine. In some embodiments, the intestine can be the small intestine, the large intestine, or both. In some embodiments, the intestinal site can be a portion of the upper GI tract, the lower GI tract, or both. In one embodiment, multiple sites of the gastrointestinal (GI) system are treated.

[0088] In some embodiments, the conversion of the anaerobic intestinal environment to an aerobic environment is measured by various methods, including measuring intestinal gas composition. In some embodiments, the oxygen concentration is increased by about 20% or more in the intestinal environment and / or aerobic enough to provide therapeutic benefit. In some embodiments, at least 3% oxygen (gas phase) is achieved for 24 hours or more. In some embodiments, at least 3-5%, 5-10%, 10-25% oxygen is achieved for at least 12, 18, 24, or 48 hours.

[0089] In some embodiments, converting an anaerobic intestinal environment at a target site (e.g., the intestine) to an aerobic environment is sufficient to inhibit the growth, reduce the virulence, or both, of an anaerobic bacterial infection.

[0090] In some embodiments, inhibition of growth and / or reduction in toxicity is measured using a glutamate dehydrogenase assay (consistent with C. diff growth), growth cultures, toxicity assays, ELISA or other tests.

[0091] In some embodiments, the conversion of the anaerobic intestinal environment of the target site (e.g., intestine) to an aerobic environment results in the inhibition of proliferation below the threshold.In some embodiments, the conversion of the anaerobic intestinal environment of the target site (e.g., intestine) to an aerobic environment results in the reduction of toxicity below the threshold.The threshold can be functional and confirmed by the reduction of symptoms in the subject.The threshold can be evaluated by quantitative and qualitative evaluation of the proliferation and activity of microorganisms.

[0092] In some embodiments, EAT is achieved using one or more agents that deliver oxygen and / or act as a source of oxygen, such as oxygen carrier molecules and oxygen-containing mixtures, including, but not limited to, oxygen-binding biomolecules (e.g., hemoglobin and / or myoglobin), oxygen cocktails, microemulsions of oxygen gas bubbles, microemulsions of oxygen gas foams, and perfluorocarbons (e.g., perfluorocarbon oxygen solutions).

[0093] In some embodiments, EAT is achieved by oxygen prodrugs or oxygen generating compounds, including, but not limited to, hydrogen peroxide, carbamide peroxide, calcium peroxide, magnesium peroxide, sodium percarbonate, and endoperoxides.

[0094] In some embodiments, the combination of one or more agents that deliver oxygen and / or act as oxygen source is provided.In some embodiments, the combination delivers oxygen and / or acts as oxygen source, and comprises one or more agents selected from the group consisting of oxygen carrier molecules and oxygen-containing mixtures, including but not limited to oxygen-binding biomolecules (e.g., hemoglobin and / or myoglobin), oxygen cocktails, microemulsions of oxygen gas bubbles, microemulsions of oxygen gas foams, and perfluorocarbons.

[0095] In some embodiments, the combination comprises one or more agents that deliver oxygen and / or act as a source of oxygen, and enhances one or more other agents that deliver oxygen and / or act as a source of oxygen. Enhancement can be additive or synergistic. In some embodiments, synergistic effect can also be achieved by using the agent described herein and one or more other types of antibacterial agents (e.g., antibiotics).

[0096] In some embodiments, synergistic or sustained response is observed to the combination of one or more agents that deliver oxygen and / or act as oxygen source.In some embodiments, "combination therapy" is intended to include sequential administration of one or more agents that deliver oxygen and / or act as oxygen source (wherein each agent that delivers oxygen and / or acts as oxygen source is administered at different times), as well as simultaneous or substantially simultaneous administration of these agents that deliver oxygen and / or act as oxygen source, or at least two agents that deliver oxygen and / or act as oxygen source.Simultaneous administration can be achieved, for example, by administering to subject a single dosage form, such as a liquid, pill (e.g. tablet or caplet) or capsule, with a fixed ratio of each agent that delivers oxygen and / or acts as oxygen source, or multiple single dosage forms for each agent that delivers oxygen and / or acts as oxygen source. Sequential or substantially simultaneous administration of each compound / agent that delivers oxygen and / or acts as a source of oxygen can be effected or achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, rectal, topical, intrathecal, intranasal, intraocular, intraperitoneal, and direct absorption through mucosal tissue. In some embodiments, formulations and compositions that include or consist essentially of one, two, three, or more of the agents described herein also include additives, coatings for local delivery, sustained release components, stabilizers, and other biologically active or inactive components to enhance the effect of the agents described in this disclosure (e.g., to enhance localization, enhance stability, reduce degradation, etc.). In one embodiment, the formulation includes or consists essentially of one or more active agents and one or more inactive agents. For example, in some embodiments, the agents described herein are coated with one or more of an enteric coating, a permeable coating, and a barrier coating. For example, in some embodiments, the agents described herein are coated with two or more of an enteric coating, a permeable coating, and a barrier coating.For example, in some embodiments, the agent described herein is coated with enteric coating, permeable coating and barrier coating.In some embodiments, the agent that delivers oxygen and / or acts as a source of oxygen is administered in combination (simultaneously or sequentially) with the prebiotic composition.In some embodiments, the agent that delivers oxygen and / or acts as a source of oxygen is administered in combination (simultaneously or sequentially) with the probiotic composition.

[0097] In some embodiments, the mixture of one or more agents that deliver oxygen and / or act as a source of oxygen can also be administered to patients as a simple mixture or in a pharmaceutical composition that is appropriately formulated.In some embodiments, combination therapy can be achieved by administering two or more agents that deliver oxygen and / or act as a source of oxygen, each of which is formulated and administered separately, or by administering two or more agents that deliver oxygen and / or act as a source of oxygen in one formulation.Other combinations are also included in combination therapy.For example, two agents that deliver oxygen and / or act as a source of oxygen can be formulated together with a separate formulation that contains a third compound / agent that delivers oxygen and / or acts as a source of oxygen, and administered in combination with them.Two or more agents that deliver oxygen and / or act as a source of oxygen in combination therapy can be administered simultaneously, but do not have to be. For example, administration of a first agent that delivers oxygen and / or acts as a source of oxygen (or a combination of agents that deliver oxygen and / or act as a source of oxygen) may precede administration of a second agent that delivers oxygen and / or acts as a source of oxygen (or a combination of agents that deliver oxygen and / or act as a source of oxygen) by minutes, hours, days, or weeks. Thus, two or more agents that deliver oxygen and / or act as a source of oxygen may be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable for two, three, four or more agents used in combination therapy to deliver oxygen and / or act as a source of oxygen to be present in the patient's body at the same time, although in other cases this need not be the case. In one embodiment, treatment with the agents described herein is provided on a chronic basis for certain vulnerable patient populations.In some embodiments, the oxygen concentration in tissues (including intestinal tissues) after treatment with the agents described herein is at least 25%, 50%, 75%, 2-fold, 3-5-fold, 10-fold or more compared to before treatment. In some embodiments, the growth and / or activity of anaerobic microorganisms is reduced by at least 50% within hours or days after treatment. Although treatment of the gastrointestinal (GI) tract is described herein, other tissues requiring oxygen supply may also be treated according to some embodiments.

[0098] In some embodiments, the formulation contains 100-3000 mg of API (e.g., oxygen prodrug) per dose (e.g., 100-200 mg, 150-250 mg, 250-500 mg, 100-500 mg, 500-1000 mg, 750-1000 mg, 800-1200 mg, 1000-2000 mg, and overlapping ranges therein) and 5-10,000 Baker Units of any catalyst (e.g., 5-25 Baker Units, 10-100 Baker Units, 25-50 Baker Units, 50-150 Baker Units, 150-300 Baker Units, 300-400 Baker Units, 400-500 Baker Units, 500-600 Baker Units, 600-700 Baker Units, 700-800 Baker Units, 800-900 Baker Units, 900-1000 Baker Units, 1000-1200 Baker Units, 1500-1000 Baker Units, 1600-1600 Baker Units, 1700-1800 Baker Units, 1800-2000 Baker Units, 1900-2000 Baker Units, 2100-2200 Baker Units, 2200-2400 Baker Units, 2300-2400 Baker Units, 2400-2600 Baker Units, 2500-2800 Baker Units, 2600-3000 Baker Units, 2700-3200 Baker Units, 2800-3600 Baker Units, 2900-4000 Baker Units, 3000-4000 and 5,000-750 Baker units, 500-1000 Baker units, 1000-2000 Baker units / catalyst gram, 2000-3000 Baker units / catalyst gram, 3000-4000 Baker units / catalyst gram, 4000-5000 Baker units / catalyst gram, 5000-6000 Baker units / catalyst gram, 6000-7000 Baker units / catalyst gram, 7000-8000 Baker units / catalyst gram, 8000-9000 Baker units / catalyst gram, 9000-10000 Baker units / catalyst gram, and overlapping ranges therein). The formulations may be provided once daily, two to six times daily or as needed. In some embodiments, the catalyst (e.g., catalase) is provided in the range of 100-2000 mg (e.g., 100-500 mg, 500-1000 mg, 500-1500 mg, 1000-2000 mg, and overlapping ranges therein). In some embodiments, the catalyst (e.g., catalase) is provided in the range of 2500-10000 IU (e.g., 2500-5000 IU, 5000-7500 IU, 7500-10000 IU, and overlapping ranges therein).

[0099] In some embodiments, the formulation includes 100-3000 mg of API (e.g., oxygen prodrug) per dose (e.g., 100-200 mg, 150-250 mg, 250-500 mg, 100-500 mg, 500-1000 mg, 750-1000 mg, 800-1200 mg, 1000-2000 mg, and overlapping ranges therein). In some embodiments, the catalase is provided by a biological material described herein. In some embodiments, the biological material is provided in a similar amount as the prodrug, e.g., 100-3000 mg per dose (e.g., 100-200 mg, 150-250 mg, 250-500 mg, 100-500 mg, 500-1000 mg, 750-1000 mg, 800-1200 mg, 1000-2000 mg, and overlapping ranges therein). In some embodiments, the biological material is provided in an amount greater than the prodrug, e.g., 3000-5000 mg (e.g., 3000-3500 mg, 3500-4000 mg, 4000-4500 mg, 4500-5000 mg and overlapping ranges therein). In some embodiments, the biological material is present in an amount such that there is an excess of catalase compared to the prodrug substrate (e.g., 5% excess, 10% excess, 25% excess, 50% excess, 100% excess, 200% excess, or more, inclusive of amounts in between).

[0100] In some embodiments, the catalyst (e.g., catalase) is at least 10 to 10,000 Baker units per gram of catalyst (e.g., 10 to 25 Baker units per gram of catalyst, 25 to 50 Baker units per gram of catalyst, 50 to 100 Baker units per gram of catalyst, 100 to 200 Baker units per gram of catalyst, 200 to 300 Baker units per gram of catalyst, 300 to 400 Baker units per gram of catalyst, 400 to 500 Baker units per gram of catalyst, 500 to 600 Baker units per gram of catalyst, 600 to 700 Baker units per gram of catalyst, 700 to 800 Baker units per gram of catalyst, 800 to 900 Baker units per gram of catalyst, 900 to 1000 Baker units per gram of catalyst, 100 to 200 Baker units per gram of catalyst, 200 to 300 Baker units per gram of catalyst, 300 to 400 Baker units per gram of catalyst, 400 to 500 Baker units per gram of catalyst, 500 to 600 Baker units per gram of catalyst, 600 to 700 Baker units per gram of catalyst, 700 to 800 Baker units per gram of catalyst, 800 to 900 Baker units per gram of catalyst, 100 to 1000 Baker units per gram of catalyst, 100 to 200 Baker units per gram of catalyst, 150 to 200 Baker units per gram of catalyst, 100 to 250 Baker units per gram of catalyst, 150 to 300 Baker units per gram of catalyst, 100 to 300 Baker units per gram of catalyst, 150 to 400 Baker units per gram of catalyst, 150 to 500 Baker units per Baker units per gram of catalyst are provided in ranges of 00 Baker units per gram of catalyst, 900-1000 Baker units per gram of catalyst, 1000-2000 Baker units per gram of catalyst, 2000-3000 Baker units per gram of catalyst, 3000-4000 Baker units per gram of catalyst, 4000-5000 Baker units per gram of catalyst, 5000-6000 Baker units per gram of catalyst, 6000-7000 Baker units per gram of catalyst, 7000-8000 Baker units per gram of catalyst, 8000-9000 Baker units per gram of catalyst, 9000-10000 Baker units per gram of catalyst, and overlapping ranges therein). One Baker unit shall have its ordinary meaning and shall refer to the amount of catalase that will decompose 264 mg of hydrogen peroxide under assay conditions of pH 7.0 and 25°C. In some embodiments, the ratio (e.g., weight ratio) of API to catalyst is 1:1, 1:2, 1:3, 1:4, 1:10, 1:20, 1:30, 1:40, 1:50, 1:75, 1:100, 1:200, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1. The formulation may also include any one or more of inactive ingredients, such as gum acacia, rice flour, cellulose, starch, stearates (e.g., magnesium stearate), gelatin, carbonates (e.g., calcium carbonate) and other binders, stabilizers, additives and pH balancers. In some embodiments, the starch is instant starch, modified starch or unmodified starch. Non-limiting sources of starch include corn, potato, rice, wheat and tapioca.In some embodiments, the ratio (e.g., weight ratio) of prodrug to inert component is 1:1, 1:2, 1:3, 1:4, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1. In some embodiments, the ratio (e.g., volume ratio) of prodrug to inert component is 1:1, 1:2, 1:3, 1:4, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1. In some embodiments, the ratio (e.g., weight ratio) of inert component to catalyst is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8. In some embodiments, the ratio (e.g., volume ratio) of inert component to catalyst is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0101] The formulation (e.g., supplement) may be provided in solid form as a tablet, capsule, caplet, etc., and may be divided into 2-4 smaller sub-doses to facilitate swallowing. In some embodiments, the formulation may be provided in solid form as multiple caplets within another capsule. In some embodiments, one or more inner capsules contain a prodrug. In some embodiments, an outer capsule encapsulates a catalyst that surrounds one or more inner capsules. In some embodiments, the formulation may be provided in solid form as nested layers of ingredients. In some embodiments, one or more inner coatings encapsulate a prodrug (optionally in tablet form). In some embodiments, an outer coating encapsulates a catalyst that surrounds a prodrug encapsulated within its own coating.

[0102] In one embodiment, the API comprises at least one of sodium percarbonate and carbamide peroxide, and the catalyst comprises catalase.In another embodiment, the API comprises at least one of sodium percarbonate and carbamide peroxide, and the catalyst is provided by one or more yeast types.In another embodiment, the API comprises at least one of sodium percarbonate and carbamide peroxide, and the catalyst is provided by spirulina.In another embodiment, the API comprises at least one of sodium percarbonate and carbamide peroxide, and the catalyst is provided by chlorella.

[0103] In some embodiments, the prodrug is capable of providing oxygen to the intestinal region after the oral formulation is stored for at least 20 days (e.g., 20, 25, 30, 35, 40, 45, 50, 55, 60 days, and overlapping ranges therein). In some embodiments, the prodrug is capable of providing oxygen to the intestinal region after the oral formulation is stored at about 22° C. for at least 5 days.

[0104] In some embodiments, after storing the oral formulation at room temperature, the prodrug can provide oxygen to the intestinal region.In some embodiments, room temperature can be defined as any temperature between 20°C and 29°C (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29°C, and overlapping ranges therein).In some embodiments, the formulation comprising the prodrug and catalyst is stable (e.g., maintains oxygen generating capacity) for at least 20, 25, 30, 35, 40, 45 days, or more (including overlapping ranges therein) upon refrigeration of the formulation.

[0105] In some embodiments, the formulation comprising the prodrug and catalyst is stable (e.g., maintains oxygen generating capacity) without refrigeration of the formulation for at least 0, 1, 2, 5, 7, 9, 10, 12, 15, 17, 20 days or more (including overlapping ranges therein).

[0106] In some embodiments, EAT is used to control the proliferation of gastrointestinal flora, intestinal flora or intestinal flora. In some embodiments, EAT is used to prevent and / or treat anaerobic infections, including but not limited to Clostridioides difficile infections, food-borne infections (e.g., food poisoning) caused by Clostridium perfringens, botulism caused by Clostridium botulinum, cholera caused by Clostridium butyricum and Clostridium baratii, diarrheagenic Escherichia coli infections, Salmonella enteritidis, inflammatory bowel disease, and other infections and / or diseases related to the gastrointestinal tract.

[0107] In some embodiments, EAT is used to prevent and / or treat the infection in the anaerobic compartment of the intestinal compartment.In some embodiments, EAT can be used to prevent and / or treat any infection in any anaerobic compartment of the body.

[0108] In some embodiments, EAT is used to prevent and / or treat human infection.In some embodiments, EAT is used to prevent and / or treat non-human primate infection.In some embodiments, EAT is used to prevent and / or treat other animal infection, including but not limited to dog, cat, cow, sheep, poultry, birds, livestock, pets, laboratory animals and / or commercially important animals.

[0109] In some embodiments, any of the formulations described herein may be formulated into one or more of extended release and delivery, delayed release and delivery, sustained release and delivery, and / or controlled release and delivery formulations.In some embodiments, oral formulations are provided in solid form (including pills, such as tablets and caplets).Pills can be round, oval, oblong, disc-shaped or other shapes suitable for administration, and can be fully or partially coated or uncoated.Capsules can contain gel, solid and / or liquid components.In one embodiment, solid formulations are particularly efficient in oxygen delivery.

[0110] In some embodiments, any of the formulations described herein may be formulated into one or more nanoparticle formulations. In some embodiments, the nanoparticles may be one or more of nanospheres, nanocylinders, nanoplates, nanoshells, nanorods, nanorice, nanofibers, nanowires, nanopyramids, nanoprisms, nanostars, nanocrescents, nanorings, and nanoantennas. In some embodiments, the dimensions of the nanoparticles may range from about 1 nm to about 100 nm. In some embodiments, the dimensions of the nanoparticles may range from about 100 nm to about 250 nm. In some embodiments, the dimensions of the nanoparticles may range from about 20 nm to about 1000 nm. In some embodiments, the dimensions of the nanoparticles may range from about 4 nm to about 6250 nm. In some embodiments, the dimensions of the nanoparticles are about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 750, 1000 nm, or a value within a range defined by any two of the above values. In some embodiments, the amount of pharmaceutical agent that can be incorporated within a nanoparticle depends on the size of the nanoparticle, such that the larger the size of the nanoparticle, the greater the amount of pharmaceutical agent that can be incorporated within the nanoparticle.

[0111] The route of administration of any of the formulations described herein can be determined by those skilled in the art depending on the situation.Several non-limiting routes of administration are possible, including parenteral, subcutaneous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral, intracavitary, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, intrarectal, buccal, sublingual, intranasal or transdermal.

[0112] Therapeutic Uses of Enteral Aerobic Therapy (EAT) In some embodiments, one or more therapeutic uses of EAT are described herein based on any of the compositions, kits and methods described herein.In some embodiments, two or more therapeutic uses of EAT can be used in combination as described herein.In some embodiments, one or more formulations are described that are used to deliver oxygen by one or more mechanisms.Any of the therapeutic uses of EAT can be applied based on any of the formulations described herein and can be used to deliver oxygen by any of the mechanisms described herein.

[0113] Clostridioides difficile infection (CDI) Clostridioides difficile (formerly known as Clostridium difficile) is an endospore-forming obligate anaerobic pathogen. C. difficile is a leading cause of hospital-acquired infections causing antibiotic-associated diarrhea, pseudomembranous colitis, toxic megacolon, sepsis, and death. There are an estimated 450,000 cases annually, half of which are community-acquired and half are in critically ill hospitalized patients, resulting in nearly 13,000 deaths annually and billions of dollars in excess healthcare costs.

[0114] Patients are susceptible to CDI when they are treated with broad-spectrum antibiotics that disrupt the body's healthy microflora (e.g., the normal microflora of the intestine). Commonly used antibiotics that predispose to CDI include clindamycin, fluoroquinolones, and cephalosporins, but CDI can appear as a complication of treatment with any antibiotic. CDI can be difficult to eradicate, as it often recurs even after successful treatment. There are only three antibiotics commonly used to treat CDI (metronidazole, vancomycin, and fidaxomicin), and treatment success rates are relatively low. The combination of high morbidity, mortality, economic burden, and ineffective treatment options urgently requires better therapies.

[0115] Many interesting strategies have been employed in the search for novel CDI therapies, which can be categorized into traditional therapeutic categories for treatment and / or prevention of infection: 1) small molecules that directly or indirectly target C. difficile, such as targeting toxins and inhibiting endospore growth; 2) passive and active immunotherapy that targets C. difficile or its disease-causing toxins; 3) bacteriology aimed at restoring microbiota balance. A patent review shows similar strategies: 1) anti-C. difficile small molecules; 2) passive and active immunotherapy / vaccination; 3) bacteriology; and 4) special diets / nutrients; 5) genetic / molecular biology; 6) phage therapy; and 7) antivirulence therapy.

[0116] EAT provides a safe and effective method to prevent and / or treat CDI. The active pharmaceutical ingredient (API) is oxygen, a safe molecule that exhibits an extremely high therapeutic index under normobaric conditions. Aerobic conditions are toxic to the vegetative state of C. difficile, which is forced to adopt a metabolic dormant spore state in order to survive. C. difficile endospores do not cause disease and do not compete with normal colonic flora, allowing the latter's synergistic protective function.

[0117] Importantly, there is no selective pressure for C. difficile to acquire resistance to oxygen because it is already resistant. It forms endospores to survive oxygen exposure. Endospore-forming Clostridia branched off from the bacterial evolutionary tree at roughly the same time as the Great Oxidation Event. Having survived in a toxic aerobic biosphere for 2.3 billion years by forming disease-free endospores, it is highly unlikely that it would evolve another resistance mechanism. Thus, some embodiments provide a safe and effective treatment with no or reduced tendency to select for resistance.

[0118] Foodborne infection (food poisoning) According to the CDC, foodborne infections cause 48 million infections, 128,000 hospitalizations, and 3,000 deaths annually. Many of these infections are caused by anaerobic conditions in the intestine that enhance pathogenicity. Below are some non-limiting examples:

[0119] Clostridium perfringens Clostridium perfringens is an endospore-forming, gram-positive pathogen that causes an estimated 1 million cases of foodborne illness annually in the United States.

[0120] Although the disease is generally self-limited, in some embodiments, EAT can be used as a safe and effective non-antibiotic means to hasten recovery and prevent hospitalization and mortality.

[0121] In some embodiments, any of the therapeutic applications of EAT may be applied based on any of the formulations described herein to deliver oxygen by any of the mechanisms described herein as a safe and effective non-antibiotic means to hasten recovery and prevent hospitalization and mortality.

[0122] Botulism Clostridium botulinum, Clostridium butyricum and Clostridium baratii are the causative bacteria that cause botulism. These organisms produce neurotoxins, which are among the most lethal toxins known. Hospitalization and treatment with antitoxins are the mainstay of treatment, although antibiotics may be administered to clear the toxin-producing infection. However, bacteria can rapidly develop resistance to antibiotics.

[0123] In some embodiments, EAT can be used as a replacement and / or supplement for antibiotics.In one embodiment, EAT and antibiotics act synergistically.As a non-limiting example, EAT can reduce the required dose or duration of antibiotics, thereby reducing the undesirable side effects of certain antibiotics.

[0124] In some embodiments, any of the therapeutic applications of EAT may be applied based on any of the formulations described herein and used to deliver oxygen by any of the mechanisms described herein as a replacement and / or adjunct to antibiotics.

[0125] cholera Cholera is caused by the foodborne facultative anaerobic pathogen Vibrio cholerae. The disease is rare in the United States but is a much greater problem in developing countries with poor sanitation systems. Hydration is the mainstay of treatment, and in severe cases parenteral hydration may be required, which is a challenge for many people living in developing countries with limited access to medical care. V. cholerae tolerates oxygen, but anaerobic conditions exacerbate its virulence.

[0126] In some embodiments, EAT may function as a convenient adjunct to maximize the onset of efficacy of antibiotic treatment and reduce the severity of the disease.

[0127] In some embodiments, any of the therapeutic applications of EAT may be applied based on any of the formulations described herein, and may be used to deliver oxygen by any of the mechanisms described herein to serve as a convenient adjunct to maximize the efficacy of antibiotic treatment and reduce the severity of the disease.

[0128] diarrheagenic E. coli Escherichia coli is a facultative anaerobe with many pathogenic strains, including those that cause severe food-borne infections, as well as V. cholerae.

[0129] Non-limiting examples of strains causing enteric infections include Shiga toxin-producing E. coli (STEC) (also known as verocytotoxin-producing E. coli (VTEC) or enterohemorrhagic E. coli (EHEC)), enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAEC), enteroinvasive E. coli (EIEC) and dispersive-adherent E. coli (DAEC).

[0130] EAT may be beneficial in intestinal infections caused by anaerobic bacteria, which are thought to exacerbate virulence.

[0131] In some embodiments, any of the therapeutic uses of EAT can be applied based on any of the formulations described herein. Some embodiments can be used to deliver oxygen by any of the mechanisms described herein to reduce the pathogenicity and / or render non-virulent facultative anaerobic strains.

[0132] Salmonella Salmonella are facultative anaerobes that cause disease and are more virulent under anaerobic conditions, where EAT may be beneficial. In the United States, Salmonella enteritidis is a significant cause of morbidity and mortality, with 1.35 million infections, 26,500 hospitalizations, and 420 deaths annually. Salmonella Typhi and Paratyphi are the causative agents of typhoid fever, which infects up to 21 million people worldwide each year.

[0133] In some embodiments, any of the therapeutic applications of EAT may be applied based on any of the formulations described herein and may be used to deliver oxygen by any of the mechanisms described herein to reduce the virulence and / or render these facultative anaerobic strains non-virulent.

[0134] Inflammatory bowel disease (IBD) Inflammatory bowel disease, Crohn's disease, and ulcerative colitis are diseases of chronic inflammation of the digestive tract. Approximately 1.6 million people in the United States suffer from IBD. Although the cause is unknown, these diseases are thought to be non-infectious in etiology. However, increasing evidence suggests that intestinal hypoxia may contribute to the pathogenesis of these diseases.

[0135] Thus, in some embodiments, IBD (e.g., one or more symptoms or recurrence) can be prevented and / or treated by EAT. In some embodiments, any of the therapeutic uses of EAT can be applied based on any of the formulations described herein, and can be used to deliver oxygen by any of the mechanisms described herein to prevent and / or treat IBD.

[0136] Oxygen Carriers Oxygen-binding biomolecules Hemoglobin and myoglobin are the two most major oxygen-carrying biomolecules known. Myoglobin is the main component of red meat and can be biochemically isolated from meat. Animal hemoglobin is more readily available for biochemical isolation from animal processing plants. Alternative production routes could be achieved by cloning and expression bioengineering.

[0137] Myoglobin and hemoglobin bind oxygen well in solution. In some embodiments, myoglobin and / or hemoglobin formulations are administered to patients in solution form. In some embodiments, other heme proteins are also provided. In one embodiment, leghemoglobin is used. In some embodiments (e.g., using leghemoglobin), beverages and supplements are provided with additional flavorings.

[0138] In some embodiments, the formulation is provided in a solution that minimizes and / or avoids denaturation by stomach acid.In some embodiments, the formulation is provided in a solution that minimizes and / or avoids premature and uncontrolled release of oxygen before the desired dose reaches the target (e.g., the intestinal target).One, two or more heme proteins can be used.

[0139] In some embodiments, a lyophilized formulation is provided. In some embodiments, the heme protein is lyophilized and formulated and encapsulated in a formulation that protects the heme protein from, for example, stomach acid upon oral administration. In some embodiments, the heme protein is lyophilized in a manner that is cost-effective and avoids oxygen loss in vacuum during lyophilization. One, two or more heme proteins can be used.

[0140] Hemoglobin and myoglobin bind oxygen very tightly, especially in the absence of 2,3-bisphosphoglyceric acid (2,3DPG), which is required at millimolar concentrations to release oxygen well at physiological pH.In some embodiments, hemoglobin (or other hemoprotein) is formulated with 2,3DPB.In some embodiments, oxygen is released when hemoprotein (e.g., myoglobin and / or hemoglobin) is digested.

[0141] In some embodiments, one or more hemoproteins are used to deliver oxygen in any of the formulations for any of the therapeutic uses of EAT described herein. In some embodiments, one or more formulations are used to deliver oxygen by hemoglobin, myoglobin, leghemoglobin or other hemoproteins. In some embodiments, one or more formulations are used to deliver oxygen by a combination of one, two or more hemoproteins and at least one digestive enzyme, such as a protease (e.g., trypsin, chymotrypsin, carboxypeptidase, etc.). According to one embodiment, such enzymes accelerate or otherwise control the release of oxygen.

[0142] In some embodiments of the formulation, the heme protein is formulated to avoid generation of digestion products of the heme protein in the feces to avoid false indications of gastrointestinal bleeding and / or to hinder evaluation of gastrointestinal bleeding in complex hospitalized patients.

[0143] In some embodiments of the formulation, the heme protein is formulated to have an enhanced oxygen binding capacity available for delivery to a target site (e.g., the intestine). In some embodiments of the formulation, the enhanced heme protein binding capacity allows for the use of small doses to deliver therapeutic doses of oxygen, e.g., about 0.25 mL to 50 mL of gaseous oxygen per gram of dry weight of heme protein. In some embodiments of the formulation, about 0.25 to 2, 2 to 5, 5 to 10, 10 to 25, or 25 to 50 mL of gaseous oxygen per gram of dry weight of heme protein, or a value within a range defined by any two of the preceding values, is delivered.

[0144] Oxygen Cocktail The oxygen cocktail is a microemulsion of oxygen gas bubbles (foam) that is administered orally. In some embodiments, a composition comprising a microemulsion of oxygen gas bubbles (foam) is used for EAT.

[0145] In some embodiments, oxygen cocktail is used to deliver oxygen in any of the formulations for any of the therapeutic uses of EAT described herein.In some embodiments of the formulation, oxygen cocktail is formulated to reduce and / or avoid the loss of oxygen by spurting.In some embodiments of the formulation, oxygen cocktail is formulated to be not stable to packaging and / or mass distribution, and therefore formulated or packaged as separate components that can be combined by the person administering the formulation to form oxygen cocktail.

[0146] Perfluorocarbon Perfluorocarbons (PFCs) large enough that they do not act as anesthetics have been tested for improving oxygen delivery by plasma. In some embodiments, these compounds dissolve oxygen well, with an estimated capacity of 30-40 mL of gaseous oxygen per 100 mL of PFC. Several PFC formulations have FDA and EMEA approval as oxygen carriers. One PFC has been FDA approved for use as a contrast or imaging agent (e.g., intestinal radiographic contrast agent). These compounds are relatively cheap to manufacture and extremely safe, but have the disadvantage of causing some fecal leakage. These compounds can be formulated and packaged in airtight pouches for oral administration.

[0147] In some embodiments, perfluorocarbon is used to deliver oxygen in any of the formulations for any of the therapeutic uses of EAT described herein. In some embodiments, the formulation comprises perfluorocarbon. In some embodiments, the formulation comprising perfluorocarbon has an oxygen capacity of about 30 mL to about 40 mL of gaseous oxygen per 100 mL of PFC. In some embodiments, about 0.25 mL to 50 mL of gaseous oxygen is delivered. In some embodiments, the formulation comprising perfluorocarbon is formulated to reduce and / or avoid oxygen loss due to gush and off-gassing in the hypoxic stomach, thereby providing controlled delivery of oxygen to the target site (e.g., intestine).

[0148] Oxygen Prodrugs Prodrugs are a well-known strategy for delivering drugs to targets. Oxygen-generating metal peroxide salts and hydrogen peroxide complexes are well known in the food, bioremediation, cosmetics and pharmaceutical industries. However, applicant is not aware of the formulations and delivery methods described herein for efficiently delivering oxygen (e.g., into the intestine) for the purposes described herein.

[0149] In some embodiments, the oxygen-generating metal peroxide salt and / or hydrogen peroxide complex is used to deliver oxygen in any of the formulations for any of the therapeutic applications of EAT described herein.In some embodiments, the oxygen-generating metal peroxide salt and / or hydrogen peroxide complex is in solid state.In some embodiments, the oxygen-generating metal peroxide salt and / or hydrogen peroxide complex is in liquid state.In some embodiments, the oxygen-generating metal peroxide salt and / or hydrogen peroxide complex is in semi-solid form.In some embodiments, the oxygen-generating metal peroxide salt and / or hydrogen peroxide complex is formulated and encapsulated using known techniques to release oxygen at the target site (e.g., intestinal lumen) without being affected by gastric acid.

[0150] In some embodiments, the agents described herein (e.g., oxygen-generating metal peroxide salts and / or hydrogen peroxide complexes) are formulated with an antibiotic. In one embodiment, rather than being co-formulated, such antibiotics are indicated for administration before, after, or simultaneously with the agents described herein. Non-limiting examples of antibiotics include penicillins, such as phenoxymethylpenicillin, flucloxacillin and amoxicillin, cephalosporins, such as cefaclor, cefadroxil and cephalexin, tetracyclines, such as tetracycline, doxycycline and lymecycline, aminoglycosides, such as gentamicin and tobramycin, macrolides, such as erythromycin, azithromycin and clarithromycin, clindamycin, sulfonamides and trimethoprim, such as cotrimoxazole, metronidazole and tinidazole, quinolones, such as ciprofloxacin, levofloxacin and norfloxacin, and nitrofurantoin. In some embodiments, the compositions and formulations described herein exclude tannins. In one embodiment, the composition and formulations described herein exclude one or more of gallic acid, epigallic acid, ellagitannin, punicalagin, tannic acid and pseudotannin.In one embodiment, the composition and formulations described herein exclude water-soluble tannin.In some embodiments, the composition and formulations described herein exclude phenols, for example polyphenols.

[0151] In some embodiments, the oxygen-generating metal peroxide salt and / or hydrogen peroxide complex is formulated with one or more of antibiotics, anthelmintics, antifungals, antimalarials, antiprotozoal drugs, antivirals, prebiotics and probiotics.In one embodiment, rather than in addition to co-formulation, such antibiotics are indicated to be administered before, after or simultaneously with the agents described herein.In some embodiments, the agent that delivers oxygen and / or acts as a source of oxygen is administered in combination (simultaneously or consecutively) with the prebiotic composition.In some embodiments, the agent that delivers oxygen and / or acts as a source of oxygen is administered in combination (simultaneously or consecutively) with the probiotic composition.

[0152] For example, clindamycin is a broad-spectrum antibiotic on the WHO's essential medicines list that is effective in treating some infections caused by community-acquired MRSA and, in combination with quinine, in the treatment of malaria. C. difficile-associated diarrhea, including fatal colitis, can result from treatment with any antibiotic, but administration of clindamycin is more strongly correlated with the development of CDI and carries a boxed warning from the FDA.

[0153] The rate of conversion of peroxide-containing prodrugs to oxygen can be controlled by the use of a catalyst. The catalyst promotes the decomposition of hydrogen peroxide into water and oxygen by disproportionation. There are many known catalysts for this reaction, including but not limited to iodide, catalase, manganese dioxide, iron(III), silver, and dichromate (Equation 1). [ka]

[0154] In some embodiments, the oxygen generating metal peroxide salts and / or hydrogen peroxide complexes may be formulated with one or more catalysts to achieve an enhanced rate of conversion to oxygen and / or to achieve a sustained rate of conversion to oxygen.

[0155] These reaction rates and the rate of release of oxygen can be further controlled by controlling solubility through modified (e.g., extended or sustained) release methods known in the art. In some embodiments, the oxygen-generating metal peroxide salts and / or hydrogen peroxide complexes can be formulated with one or more components that allow for sustained, extended, and / or controlled release and delivery of oxygen, for example, the oxygen-generating metal peroxide salts and / or hydrogen peroxide complexes can be formulated in nanoparticle formulations.

[0156] In addition to controlling the release rate of oxygen, the catalytic conversion mitigates the absorption of hydrogen peroxide, a reactive oxygen species (ROS), systemically by ensuring its complete conversion to oxygen. Thus, in some embodiments, a catalyst is provided.

[0157] Potassium iodide, included in the WHO essential medicines list, is available over the counter and is used for a variety of purposes, including expectorant, up to 600 mg four times a day for adults. It is also used for thyroid block during accidental nuclear exposure, thyroid protection in Graves' disease, and treatment of cutaneous / lymphatic cutaneous sporotrichosis. Iodide is a safe drug and is absorbed systemically via the intestinal sodium iodide symporter. In some embodiments, iodide is used to control the conversion rate of peroxide-containing prodrugs to oxygen. In some embodiments, the absorption of iodide prior to the conversion of peroxide to oxygen is completely mitigated by formulating iodide for sustained release and delivery, sustained release and delivery, and / or controlled release and delivery of oxygen, for example, encapsulating iodide in a hydrogel that controls solubility and / or slows diffusion. In some embodiments, iodide can be formulated with one or more components that allow sustained release and delivery, sustained release and delivery, and / or controlled release and delivery of oxygen, for example, iodide can be formulated in a nanoparticle formulation.

[0158] Catalase is a natural enzyme produced and used in the food industry to remove hydrogen peroxide after cleaning equipment and from milk before cheese production. It is also used to remove hydrogen peroxide after cleaning and disinfecting contact lenses. The enzyme is extremely efficient and diffusion rate limited.

[0159] In some embodiments, catalase or other catalyst is used to control the rate of conversion of peroxide-containing prodrugs to oxygen.In some embodiments, the decomposition of catalase before conversion of peroxide to oxygen is completely mitigated by formulating catalase for sustained release and delivery, sustained release and delivery, and / or controlled release and delivery of oxygen, for example, by encapsulating catalase in hydrogel that controls and / or slows decomposition, or by formulating catalase in nanoparticle formulation.

[0160] In some embodiments, the decomposition of the catalyst (such as catalase) before the decomposition of peroxide to oxygen is completed is completely mitigated by formulating the catalyst (e.g., catalase) in a capsule or tablet coated with a dialysis or permeable membrane. The pore size of this dialysis membrane is large enough to allow small molecules such as water, electrolytes, certain solutes and oxygen to largely diffuse through the membrane, but small enough to prevent catalase from diffusing out of the capsule or tablet and at the same time prevent digestive enzymes from diffusing into the capsule or tablet. In some embodiments, catalase is provided in a membrane or other coating that allows water, electrolytes, solutes and oxygen to diffuse but prevents most of the catalase from diffusing (while preventing digestive enzymes from diffusing). The membrane or coating can be provided in a single layer or multiple layers and can be made from one, two, three or more of functionalized cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate with different degrees of substitution. Other polymers include, but are not limited to, cellulose acetate acetoacetate, cellulose chloroacetate, cellulose acetate furoate, and dimethoxyethyl cellulose acetate. The catalyst, API, or both may be encapsulated, coated, or otherwise formulated within a means that controls or regulates diffusion. In some embodiments, the catalyst and API (or oxygen prodrug) are individually coated. For example, in some embodiments, the agent provided herein, including an API (or oxygen prodrug) and a catalyst, may include multiple layers of various components with a coating between each layer. See, for example, FIG. 1B. In this non-limiting embodiment, the agent includes an internal region of sodium carbonate hydrogen peroxide, which is a precursor of oxygen. This region is coated with a barrier coating and is separated from the enzyme that acts on sodium carbonate hydrogen peroxide to produce oxygen. In this embodiment, the enzyme includes catalase. The enzyme is separated from the outer enteric coating by a permeable coating.In some embodiments, the oxygen-generating agent described herein (e.g., granules contained in a capsule) is coated with one, two or more of an enteric coating, a permeable coating and a barrier coating.For example, in some embodiments, the agent described herein is coated with an enteric coating, a permeable coating and a barrier coating.In some embodiments where the agent is contained in a capsule, the capsule can be coated with one or more coatings as described herein.

[0161] In some embodiments, the agent described herein, including the API (or oxygen prodrug) and catalyst, can be provided as a capsule-in-capsule device, as shown in FIG. 11. In this non-limiting embodiment, the API (or oxygen prodrug, preferably sodium percarbonate or percarbamide) is contained in at least one inner capsule, preventing physical contact with the catalyst in the outer capsule. The outer capsule encapsulates the catalyst. In the intestine or colon, the indigenous pH value is higher than that in the stomach, so that the soluble capsule, enteric coating or other release control coating dissolves. In some embodiments, the insoluble semipermeable membrane remains intact, and the osmotic gradient allows water to enter the device, dissolving the catalyst (e.g., yeast, catalase) and oxygen prodrug (e.g., sodium percarbonate or percarbamide), initiating the catalytic conversion of hydrogen peroxide to water and oxygen. Oxygen then diffuses out of the device through the insoluble semipermeable membrane, as shown, for example, in FIG. 12.

[0162] In some embodiments, after all hydrogen peroxide is converted to oxygen and water, the sodium carbonate and oxygen diffuse away, leaving only the catalyst trapped within the device (if any) dissolved or suspended in the equilibrated intestinal fluid, for example as shown in Figure 13. In some embodiments, the spent shell is expelled by defecation. In some embodiments, the spent shell is known as a ghost capsule or ghost tablet.

[0163] In some embodiments, yeast, catalase or other catalyst surrounds the inner capsule. In some embodiments, the amount of catalyst provided in the outer capsule or tablet is sufficient to control the rate of conversion of the peroxide-containing prodrug to oxygen. In other embodiments, the amount of catalyst provided in the outer capsule or tablet is in excess to control the rate of conversion of the peroxide-containing prodrug to oxygen.

[0164] In some embodiments, the catalyst is provided as a dry powder. In other embodiments, the catalyst is provided as a suspension. In some embodiments, the catalyst is provided as a solution. The contents of the inner capsule are physically separated from the contents of the outer capsule (or coating) by the inner capsule (or coating). The physical separation of the contents of the inner capsule and the outer capsule stabilizes the formulation by preventing premature conversion of oxygen prodrugs.

[0165] In some embodiments, the inner and outer capsules are essentially enteric. In some embodiments, the inner and outer capsules are coated with an enteric coating using additives known to those skilled in the art to prevent dissolution in the acidic environment of the stomach. In some embodiments, the inner and / or outer capsules are coated with a controlled release coating. In some embodiments, the oxygen-generating agent described herein (e.g., capsule-in-a-capsule) is coated with one, two or more of an enteric coating and a controlled release coating. It should be understood that the embodiments referring to capsules can be implemented with a coating (e.g., a coating that is applied rather than a preformed shape) and vice versa.

[0166] In some embodiments, the outer capsule is coated with a dialysis or osmosis membrane whose pore size is large enough to allow large diffusion of small molecules such as water, electrolytes, certain solutes and oxygen through the membrane, but small enough to prevent catalase, yeast or macromolecules from diffusing out of the capsule.

[0167] In some embodiments, the drug, including the API (or oxygen prodrug), is compressed into a capsule and then coated with one, two or more of an enteric layer and a control layer. In some embodiments, the inner capsule is first coated with an enteric layer and then coated with a control layer. In other embodiments, the inner capsule is first coated with a control layer and then coated with an enteric layer. The coated inner capsule is then enveloped in an outer capsule containing a catalyst. In some embodiments, the outer capsule is coated with one, two or more of an enteric coating and a semipermeable coating. In some embodiments, the outer capsule is first coated with an enteric layer and then coated with a semipermeable layer. In some embodiments, the outer capsule is first coated with a semipermeable layer and then coated with an enteric layer.

[0168] In some embodiments, the enteric coating comprises a gelatin capsule. In some embodiments, the gelatin is bovine, porcine, or a combination thereof. In some embodiments, the enteric coating comprises agar, starch, or carrageenan. In other embodiments, the enteric coating is made of hydroxypropylmethylcellulose, crystalline cellulose, or other water-soluble / dispersible polymers. In some embodiments, the enteric coating comprises hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, diethyl phthalate, and / or cellulose acetate phthalate.

[0169] In some embodiments, the semipermeable coating comprises cellulose acetate, or a similar or equivalent suitable polymer, or a combination thereof.

[0170] catalyst Manganese dioxide is an insoluble heterogeneous peroxide for oxygen catalysis. Manganese dioxide has low toxicity and can be safe at catalytic concentrations. This catalyst is not digestible and has low bioavailability, making it an attractive formulation candidate. In addition to catalysis, manganese dioxide may have other beneficial effects on oxygen production.

[0171] In some embodiments, manganese dioxide is used to control the conversion rate of peroxide-containing prodrugs to oxygen.In some embodiments, manganese dioxide is provided in a mixture of crystal structures.In some embodiments, one or more of the mixture of manganese dioxide crystal structures catalyzes the reaction from peroxide to oxygen.In some embodiments, the mixture of manganese dioxide is enriched in the crystal structure that most efficiently catalyzes the reaction from peroxide to oxygen.

[0172] Another heterogeneous catalyst is metallic silver, which is commercially available in powder form. Silver(0) is less toxic at low concentrations for short periods of time.

[0173] In some embodiments, metallic silver is used to control the rate of conversion of peroxide-containing prodrugs to oxygen. In some embodiments of the formulation, metallic silver is formulated in a catalytic amount to catalyze the conversion of peroxide to oxygen.

[0174] Ferric iron also catalyzes the conversion of hydrogen peroxide to oxygen. Ferrous iron is oxidized to catalytically active ferric iron by hydrogen peroxide, so either oxidation state may be used in the formulation.

[0175] In some embodiments, ferric or ferrous is used to control the rate of conversion of peroxide-containing prodrugs to oxygen.In some embodiments, the formulations containing ferric ion, ferrous ion, or both are formulated to minimize and / or avoid the transient formation of hydroxyl radicals and other reactive oxygen species.

[0176] In some embodiments, at least one unicellular microorganism is used to catalyze the conversion of peroxide to oxygen. In some embodiments, the unicellular microorganism comprises a catalase that catalyzes the conversion of peroxide to oxygen. In other embodiments, the unicellular microorganism comprises iodide, manganese dioxide, iron(III), silver, or dichromate that can catalyze the conversion of peroxide to oxygen.

[0177] In some embodiments, the unicellular microorganism is yeast. In some embodiments, the yeast is baker's yeast. In some embodiments, the yeast is selected from Saccharomyces cerevisiae, Saccharomyces equigus, Saccharomyces eubayanus, Saccharomyces pastorianus, Schizosaccharomyces pombe, and combinations thereof. In some embodiments, the unicellular microorganism is Chlorella. In some embodiments, the Chlorella is selected from Chlorella pyrenoidosa, Chlorella vulgaris, Chlorella regularis, Chrolla protothecoides, Chlorella saccharophila, and combinations thereof. In some embodiments, the unicellular microorganism is Spirulina. In some embodiments, the Spirulina is selected from Arthrospira platensis, Arthrospira fusiformis, Arthrospira maxima, and combinations thereof. One or more combinations of the microorganisms described herein may be used depending on the embodiment.

[0178] hydrogen peroxide 1. Carbamide peroxide Carbamide peroxide (also known as Artizon, urea hydrogen peroxide, hydrogen peroxide urea, UHP, hyperol, percarbamide) is a white crystalline solid hydrogen peroxide-urea complex (CH6N2O3) available without prescription for topical applications including earwax removal, oral wound disinfection, and teeth whitening. It is inexpensive and readily available in large quantities. Since this prodrug is composed of a weak base, urea, and a weak acid, hydrogen peroxide, in some embodiments, the formulation does not contain additional buffering agents, relying instead on the intrinsic buffering capacity of intestinal fluids. In some embodiments, a buffering agent is used. Urea is used topically as a dermatological drug and orally in the urea breath test for H. pylori.

[0179] Urea is a natural product found in human blood at normal concentrations up to 7 mmol / L and is classified by the FDA as a medical food for the treatment of hyponatremia administered in amounts up to 60 g per day. Without being limited to any particular theory, the conversion yield is 119 mL of gaseous oxygen per gram of carbamide peroxide at standard temperature and pressure (STP).

[0180] In some embodiments, carbamide peroxide / urea is used to deliver oxygen in any of the formulations for any of the therapeutic uses of EAT described herein. In some embodiments, the formulations containing carbamide peroxide / urea deliver a blood urea concentration of about 10 to 100 mmol / L. In some embodiments, the formulations containing carbamide peroxide / urea provide about 120 mL of gaseous oxygen per gram of carbamide peroxide at standard temperature and pressure (STP). In some embodiments, the formulations containing carbamide peroxide / urea deliver a blood urea concentration of about 0.35 mmol / L to about 3.5 mmol / L. In some embodiments, the formulations containing carbamide peroxide / urea deliver a blood urea concentration of about 3.5 mmol / L to about 100 mmol / L. In some embodiments, the formulations containing carbamide peroxide / urea deliver a blood urea concentration of about 0.35 mmol / L to about 100 mmol / L. In some embodiments, the formulation comprising carbamide peroxide / urea provides from about 12 mL to about 60 mL of gaseous oxygen per gram of carbamide peroxide at STP. In some embodiments, the formulation comprising carbamide peroxide / urea provides from about 60 mL to about 120 mL of gaseous oxygen per gram of carbamide peroxide at STP. In some embodiments, the formulation comprising carbamide peroxide / urea provides from about 12 mL to about 120 mL of gaseous oxygen per gram of carbamide peroxide at STP. In some embodiments, the urea is provided in a dose of 1 to 25 g per day (e.g., 1 to 3, 3 to 5, 5 to 10 g) and can be provided once per day or multiple times per day.

[0181] 2. Calcium peroxide Calcium peroxide (CaO2) is a crystalline solid used in the food industry as a flour bleaching agent, a dough improver, and as a treatment for rice seed before sowing. It is also used as an oxygen-supplying agent in aquaculture, environmental bioremediation, and is being investigated for use in bioengineering. On contact with water, it decomposes into oxygen, water, and hydrogen peroxide. The ratio of products and the rate of reaction are highly dependent on the pH.

[0182] Calcium peroxide is inexpensive, manufactured on an industrial scale, and is readily available. Calcium peroxide preparations typically contain 25% calcium hydroxide.

[0183] In some embodiments, formulations containing calcium peroxide preparations are formulated with buffer salts for optimal therapeutic value and / or to avoid the potential development of milk-alkali syndrome (hypercalcemic metabolic alkalosis). In one embodiment, other additives may be included to reduce calcium hydroxide as a contaminant.

[0184] Without being limited to any particular theory, 1 g of 75% calcium peroxide can deliver 117 mL of gaseous oxygen at STP.

[0185] Calcium hydroxide is used in food manufacturing processes including, but not limited to, pickling, baking, century eggs, and corn grit production. Calcium is included on the WHO list of essential medicines.

[0186] In some embodiments, calcium peroxide preparations are used to deliver oxygen in any of the formulations for any of the therapeutic uses for EAT described herein. In some embodiments, the formulations comprising calcium peroxide preparations deliver about 120 mL of gaseous oxygen per gram of 75% calcium peroxide at STP. In some embodiments, the formulations comprising calcium peroxide preparations deliver about 12 mL to about 60 mL of gaseous oxygen per gram of 75% calcium peroxide at STP. In some embodiments, the formulations comprising calcium peroxide preparations deliver about 60 mL to about 120 mL of gaseous oxygen per gram of 75% calcium peroxide at STP. In some embodiments, the formulations comprising calcium peroxide preparations deliver about 12 mL to about 120 mL of gaseous oxygen per gram of 75% calcium peroxide at STP.

[0187] 3. Magnesium peroxide Magnesium peroxide (MgO2) has chemical properties similar to calcium peroxide. It is used as an oxygen generator in bioremediation applications. Like calcium, magnesium is a naturally occurring ion essential for normal human health.

[0188] Without being limited to any particular theory, 1 g of 99% pure magnesium peroxide can deliver 199 mL of gaseous oxygen at STP.

[0189] In some embodiments, magnesium peroxide is used to deliver oxygen in any of the formulations for any of the therapeutic uses of EAT described herein. In some embodiments, the formulations containing magnesium peroxide deliver about 40 mL to about 1000 mL of peroxide per gram of MgO2 of 99% purity at STP. In some embodiments, the formulations containing magnesium peroxide deliver about 40 mL to about 150 mL of peroxide per gram of MgO2 of 99% purity at STP. In some embodiments, the formulations containing magnesium peroxide deliver about 150 mL to about 750 mL of peroxide per gram of MgO2 of 99% purity at STP. In some embodiments, the formulations containing magnesium peroxide deliver about 650 mL to about 1050 mL of peroxide per gram of MgO2 of 99% purity at STP.

[0190] 4. Sodium percarbonate Without being limited to any particular theory, 1 g of solid sodium percarbonate (Na2CO3·1.5H2O2) can deliver 107 mL of oxygen gas at STP. It is inexpensive and produced on an industrial scale. It is used in laundry and dish detergents, deodorants, preservatives, and water purification (e.g., for home use). In some embodiments, potassium percarbonate is produced and used when sodium loading from administration is to be avoided. For example, in one embodiment, potassium carbonate is substituted for sodium carbonate in the synthesis of sodium percarbonate to produce potassium percarbonate (when a low sodium option is desired). Since bicarbonate is the primary buffer system in the human bloodstream, the carbonate component is extremely safe as excess is excreted from the lungs as carbon dioxide.

[0191] In some embodiments, sodium percarbonate is used to deliver oxygen in any of the formulations for any of the therapeutic uses for EAT described herein. In some embodiments, the formulation delivers about 10 mL to about 1000 mL of oxygen gas per gram of solid Na2CO3·1.5H2O2 at STP. In some embodiments, a formulation comprising Na2CO3·1.5H2O2 delivers about 50 mL to about 200 mL of oxygen gas per gram of solid Na2CO3·1.5H2O2 at STP. In some embodiments, a formulation comprising Na2CO3·1.5H2O2 delivers about 150 mL to about 600 mL of oxygen gas per gram of solid Na2CO3·1.5H2O2 at STP. In some embodiments, a formulation comprising Na2CO3·1.5H2O2 delivers about 550 mL to about 1050 mL of oxygen gas per gram of solid Na2CO3·1.5H2O2 at STP.

[0192] Table 1 shows a non-limiting example of the components of the oxygen generating compositions described herein. This non-limiting embodiment represents a configuration in which each granule of the capsule is individually coated with an enteric coating, a barrier coating, and a permeable coating. [Table 1]

[0193] Endoperoxide Endoperoxides are bicyclic organic peroxide compounds that release oxygen via a retro-Diels-Alder reaction.

[0194] Synthetic routes are known, but are necessarily more expensive than the solid hydrogen peroxide adducts described herein. Another potential drawback is that the release of oxygen produces aromatic compounds that can be absorbed systemically and produce toxic effects. In some embodiments, the production of aromatic compounds is mitigated by incorporating the endoperoxide into a non-bioavailable polymer.

[0195] In some embodiments, endoperoxides are used to deliver oxygen in any of the formulations for any of the therapeutic uses of EAT described herein.

[0196] Amount and timing of oxygen administration In embodiments, the EAT provides oxygen to the target site, e.g., the intestine or at least a portion thereof. In some embodiments, at least 3% oxygen (gas phase) is achieved for 24 hours or more. In some embodiments, at least 3-5%, 5-10%, 10-25% oxygen is achieved for at least 12, 18, 24, or 48 hours. In one embodiment, the oxygen concentration is increased by 20% or more (compared to pre-treatment levels) for at least 12 hours. In another embodiment, the oxygen concentration is increased by 50% or more (compared to pre-treatment levels) for at least 6 hours. Prophylactically, 1-5% oxygen (gas phase) is achieved for days, weeks, months, or more. In some embodiments, the desired oxygen level is achieved by repeated or continuous administration of the EAT compound or agent described herein, for example, 1, 2, 3, 4, or more times per day (single or multiple doses or portions per administration), and / or for 1, 2, 3, 4, 5, 6, 7 days or more, or for several weeks. In one embodiment, the API and / or catalyst is generally provided in a dose of 250-1500 mg per dose, and multiple doses per day may be provided. In one embodiment, the API and / or catalyst is provided in an amount that substantially achieves one or more of: providing at least 3% oxygen to a portion of the gastrointestinal tract for 12 hours or more; reducing the toxicity of undesirable (e.g., anaerobic) microorganisms; reducing the growth of undesirable (e.g., anaerobic) microorganisms; and / or converting an anaerobic environment to an aerobic environment in at least a portion of the gastrointestinal tract.

[0197] In some embodiments, a formulation is provided in which the catalase or other agent described herein is encapsulated or otherwise contained within a material (e.g., a membrane, coating or other material).In one embodiment, such a material (i) allows diffusion of water, electrolytes, specific solutes and / or oxygen throughout the material, (ii) prevents all, substantially all or most (e.g., at least 50, 60, 70, 80, 90, 95%) of the catalase (or other agent) from diffusing out of the material, and (iii) prevents all, substantially all or most (e.g., at least 50, 60, 70, 80, 90, 95%) of the digestive enzymes from diffusing into the material.In some embodiments, the agent comprises or essentially consists of an oxygen carrier molecule and / or an oxygen-containing mixture.In one embodiment, the material comprises pores that control diffusion.The catalyst, API or both can be encapsulated, coated or otherwise formulated within a means that controls or regulates diffusion. In some embodiments, the oxygen-generating agent provided herein (e.g., granules contained within a capsule) is coated with one or more of an enteric coating, a permeable coating, and a barrier coating. For example, in some embodiments, the agent provided herein is coated with two or more of an enteric coating, a permeable coating, and a barrier coating. EXAMPLES

[0198] The following are non-limiting examples according to some embodiments herein, and other variations are contemplated within the skill of the art. In any of the following examples, the aerobic environment may be maintained for 6, 12, 18, or 24 hours or more according to some embodiments.

[0199] Example 1 Oxygen Carrier A patient suffering from an anaerobic bacterial infection (e.g., of the digestive tract, e.g., intestine) is identified. The infection may be diagnosed, for example, by symptoms, signs, clinical presentation, biochemical laboratory tests, and / or pathogen identification. Optionally, the amount, growth rate, and / or toxicity level of the anaerobic bacteria are determined. A composition comprising at least one compound / agent that is an oxygen carrier molecule, e.g., an oxygen-binding biomolecule (e.g., hemoglobin and / or myoglobin) and / or an oxygen-containing mixture (e.g., an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foam, or a perfluorocarbon (e.g., a perfluorocarbon oxygen solution), is administered to the patient. In some embodiments, one or more perfluorocarbons are used. Optionally, the oxygen carrier molecule can be administered in combination with an oxygen prodrug or an oxygen-generating compound. The compound / agent is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, inhibit the amount, growth rate and / or toxicity of the anaerobic bacterial infection, resulting in an improvement in the patient's condition. Optionally, after administration of the composition, the amount, growth rate and / or toxicity level of the anaerobic bacteria is determined. Administration of the composition can be repeated until the amount or growth and / or toxicity level of the anaerobic bacteria falls below a predetermined threshold and / or the undesirable symptoms subside.

[0200] Example 2 Oxygen Prodrugs A patient suffering from an anaerobic bacterial infection (e.g., of the digestive tract, e.g., intestine) is identified. The infection may be diagnosed, for example, by symptoms, signs, clinical status (e.g., biochemical laboratory tests) and / or pathogen identification. Optionally, the amount, growth rate and / or toxicity level of the anaerobic bacteria is determined. A composition is administered to the patient, comprising at least one compound / agent that is an oxygen prodrug or oxygen generator (e.g., an oxygen-generating metal peroxide salt or hydrogen peroxide complex, e.g., carbamide peroxide, calcium peroxide, calcium hydroxide, magnesium peroxide, sodium percarbonate or an endoperoxide). Optionally, the oxygen prodrug or oxygen generator may be administered in combination with an oxygen carrier molecule. The agent is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, inhibiting the amount, growth rate and / or toxicity of the anaerobic bacterial infection, resulting in an improvement in the patient's condition. Optionally, after administration of the composition, the amount, growth rate and / or toxicity level of the anaerobic bacteria is determined. Administration of the composition may be repeated until the amount or growth of anaerobic bacteria and / or toxicity levels drop below a predetermined threshold and / or the undesirable symptoms subside.

[0201] Example 3 Clostridioides difficile infection and oxygen carriers A patient suffering from Clostridioides difficile infection (e.g., in the digestive tract, e.g., in the intestine) is identified. The infection may be diagnosed, for example, by symptoms, signs, clinical status (e.g., biochemical laboratory tests) and / or pathogen identification. Optionally, the amount, growth rate and / or toxicity level of anaerobic bacteria is determined. A composition is administered to the patient, comprising at least one compound / agent that is an oxygen carrier molecule, e.g., an oxygen-binding biomolecule (e.g., hemoglobin and / or myoglobin) and / or an oxygen-containing mixture (e.g., an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foams, or a perfluorocarbon). Optionally, the oxygen carrier molecule may be administered in combination with an oxygen prodrug or an oxygen-generating compound. An agent (e.g., a compound) is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, inhibit the amount, growth rate and / or toxicity of Clostridioides difficile, and result in an improvement in the patient's condition. Optionally, after administration of the composition, the amount, growth rate and / or toxicity level of the Clostridioides difficile bacteria is determined. Administration of the composition can be repeated until the amount or growth and / or toxicity level of the Clostridioides difficile bacteria falls below a predetermined threshold and / or the undesirable symptoms subside.

[0202] Example 4 Clostridioides difficile infection and oxygen prodrugs A patient suffering from Clostridioides difficile infection (e.g., of the digestive tract, e.g., intestine) is identified. The infection may be diagnosed, for example, by symptoms, signs, clinical status (e.g., biochemical laboratory tests) and / or pathogen identification. Optionally, the amount, growth rate and / or toxicity level of anaerobic bacteria is determined. A composition is administered to the patient, comprising at least one agent that is an oxygen prodrug or oxygen generator (e.g., an oxygen-generating metal peroxide salt or hydrogen peroxide complex, e.g., carbamide peroxide, calcium peroxide, calcium hydroxide, magnesium peroxide, sodium percarbonate or an endoperoxide). Optionally, the oxygen prodrug or oxygen generator may be administered in combination with an oxygen carrier molecule. The agent is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, inhibit the amount, growth rate and / or toxicity of Clostridioides difficile, and result in an improvement in the patient's condition. Optionally, after administration of the composition, the amount, growth rate and / or toxicity level of the Clostridioides difficile bacteria is determined. Administration of the composition can be repeated until the amount or growth and / or toxicity level of the Clostridioides difficile bacteria falls below a predetermined threshold and / or the undesirable symptoms subside.

[0203] Example 5 Food poisoning and oxygen carriers Identify a patient suffering from food poisoning due to a food-borne infection (e.g., of the digestive tract, e.g., intestinal) caused by anaerobic bacteria (e.g., botulism caused by Clostridium perfringens, Clostridium botulinum, Clostridium butyricum and Clostridium baratii, cholera caused by Vibrio cholerae, diarrheagenic Escherichia coli infection and Salmonella enteritidis). The infection may be diagnosed, for example, by symptoms, signs, clinical status (e.g., biochemical laboratory tests) and / or pathogen identification. Optionally, determine the amount, growth rate and / or toxicity level of the anaerobic bacteria. Administer to the patient a composition comprising at least one agent that is an oxygen carrier molecule, e.g., an oxygen-binding biomolecule (e.g., hemoglobin and / or myoglobin) and / or an oxygen-containing mixture (e.g., an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foams or a perfluorocarbon). Optionally, the oxygen carrier molecule may be administered in combination with an oxygen prodrug or oxygen generating compound. The agent is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, inhibit the amount, growth rate and / or toxicity of plant-borne infection of anaerobic bacteria, and result in an improvement in the patient's condition. Optionally, after administration of the composition, the amount, growth rate and / or toxicity level of food-borne anaerobic bacteria is determined. Administration of the composition can be repeated until the amount or growth and / or toxicity level of food-borne anaerobic bacteria falls below a predetermined threshold and / or the undesirable symptoms subside.

[0204] Example 6 Food poisoning and oxygen prodrugs Identify a patient suffering from food poisoning due to a food-borne infection (e.g., of the digestive tract, e.g., intestinal) caused by anaerobic bacteria (e.g., botulism caused by Clostridium perfringens, Clostridium botulinum, Clostridium butyricum and Clostridium baratii, cholera caused by Vibrio cholerae, diarrheagenic Escherichia coli infection and Salmonella enteritidis). The infection may be diagnosed, for example, by symptoms, signs, clinical status (e.g., biochemical laboratory tests) and / or pathogen identification. Optionally, determine the amount, growth rate and / or toxicity level of the anaerobic bacteria. Administer to the patient a composition comprising at least one agent that is an oxygen carrier molecule, e.g., an oxygen-binding biomolecule (e.g., hemoglobin and / or myoglobin) and / or an oxygen-containing mixture (e.g., an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foams or a perfluorocarbon). Optionally, the oxygen carrier molecule may be administered in combination with an oxygen prodrug or oxygen generating compound. The agent is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, inhibit the amount, growth rate and / or toxicity of plant-borne infection of anaerobic bacteria, and result in an improvement in the patient's condition. Optionally, after administration of the composition, the amount, growth rate and / or toxicity level of food-borne anaerobic bacteria is determined. Administration of the composition can be repeated until the amount or growth and / or toxicity level of food-borne anaerobic bacteria falls below a predetermined threshold and / or the undesirable symptoms subside.

[0205] Example 7 Inflammatory Bowel Disease (IBD) and Oxygen Carriers A patient suffering from IBD is identified and diagnosed, for example, by a person skilled in the art. A composition is administered to the patient, comprising at least one agent that is an oxygen carrier molecule, for example, an oxygen-binding biomolecule (for example, hemoglobin and / or myoglobin) and / or an oxygen-containing mixture (for example, an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foam, or a perfluorocarbon). Optionally, the oxygen carrier molecule can be administered in combination with an oxygen prodrug or an oxygen-generating compound. The agent is administered in an amount that can create an aerobic environment at the target site (for example, the intestinal lumen) of the patient, reduce the inflammatory process, and improve the patient's condition, for example, eliminate or improve IBD symptoms and signs, including recurrence. Daily administration can be used to prevent exacerbations.

[0206] Example 8 Inflammatory Bowel Disease (IBD) and Oxygen Prodrugs A patient suffering from IBD is identified and diagnosed, for example, by a person skilled in the art. The IBD patient may have an anaerobic bacterial infection (e.g., intestinal) that exacerbates the condition. Optionally, the amount, growth rate and / or toxicity level of the anaerobic bacteria is determined. The patient is administered a composition that includes at least one agent that is an oxygen carrier molecule, such as an oxygen-binding biomolecule (e.g., hemoglobin and / or myoglobin) and / or an oxygen-containing mixture (e.g., an oxygen cocktail, a microemulsion of oxygen gas bubbles, a microemulsion of oxygen gas foams, or a perfluorocarbon). Optionally, the oxygen carrier molecule can be administered in combination with an oxygen prodrug or an oxygen-generating compound. The agent is administered in an amount that can create an aerobic environment at the target site (e.g., intestinal lumen) of the patient, reduce the inflammatory process, and result in an improvement of the patient's condition, for example, elimination or improvement of IBD symptoms and signs. Daily administration can be used to prevent exacerbations.

[0207] Example 9. Formulations with constant catalyst concentration FIG. 1A diagrammatically represents an exemplary formulation for delivering oxygen by catalytic release of oxygen from an oxygen prodrug. In FIG. 1A, the thick solid line represents an enteric coated permeable membrane that encases the contents of a capsule or tablet. The oxygen prodrug is represented by an API encased in a controlled release coating (thin line around the API). The controlled release coating further serves to extend shelf life by preventing the API from contacting the catalase catalyst powder. The enteric coating prevents water from penetrating the capsule or tablet until the capsule or tablet reaches a target site such as the intestine. FIG. 1B represents a further embodiment of a formulation for delivering oxygen by catalytic release of oxygen from an oxygen prodrug. In FIG. 1B, the formulation is formed into granules for delivery such as in a capsule, and the outer solid line represents the enteric coating that surrounds the contents of each individual granule (for clarity, only one granule is shown in the figure). The oxygen prodrug, e.g., sodium carbonate hydrogen peroxide, is located in the center of the granule and is surrounded by a barrier coating. The barrier coating also serves to extend shelf life by preventing oxygen prodrugs from contacting enzyme catalysts such as catalase. The enteric coating prevents water from penetrating the capsule or tablet until it reaches the target site, such as the intestine. Located between the enteric coating and the catalyst is the osmotic coating (dashed line in FIG. 1B). The osmotic coating has a pore size large enough to allow water to pass through the coating under osmotic pressure and dissolve and activate the catalase catalyst. In one embodiment, catalase cannot diffuse through the osmotic coating because the pore size is too small, and catalase is maintained at a constant concentration (e.g., within individual granules). Catalase is not degraded by digestive enzymes because the pore size is too small for the digestive enzymes to diffuse into the granules.

[0208] Figure 2 shows a capsule or tablet at a target site (e.g., intestine) after dissolving, in one embodiment, leaving an exposed osmotic membrane, represented by a blurred line encasing the enteric coating, capsule or tablet contents. The pore size of the osmotic membrane is large enough for water to pass through the membrane according to osmotic pressure and dissolve and activate the catalase catalyst. In one embodiment, catalase cannot diffuse through the osmotic membrane because the pore size is too small, so that catalase is maintained at a constant concentration (e.g., in a capsule, caplet, tablet, etc.). Catalase is not degraded by digestive enzymes because the pore size is too small for the digestive enzymes to diffuse into the capsule or tablet. In Figure 2, the controlled release coating has not yet begun to dissolve, as represented by an intact line surrounding the API.

[0209] FIG. 3A shows a capsule or tablet in one embodiment in which the controlled release coating begins to dissolve and hydrogen peroxide begins to be released, which is efficiently converted to oxygen and water by catalase enzyme according to formula 1. The oxygen thus produced diffuses through the osmotic membrane and aerobicizes the intestinal lumen. In some embodiments, other tissue sites may be treated. Similarly, FIG. 3B shows a schematic diagram of an individual granule (or tablet, etc.) in which the enteric coating dissolves (e.g., after reaching the target site, such as the intestine), and water passes through the osmotic coating to activate catalase, which acts on sodium hydrogen peroxide carbonate (or other oxygen prodrug) to release hydrogen peroxide, which is efficiently converted to oxygen and water according to formula 1.

[0210] Example 10. Stability testing of various methods of formulating and storing catalyst and oxygen prodrug This experiment was designed to evaluate different formulations of prodrugs and catalysts, different storage conditions and structures of drug delivery vehicles, and their effect on the extension of the oxygen generating capacity of the prodrugs. The results of this experiment are shown in Figure 14. Some embodiments provided herein advantageously allow for a stable supply of oxygen. Further advantages are associated with some embodiments, including, but not limited to, relatively high accessibility to components, reduced manufacturing costs, and improved stability even at room temperature.

[0211] A 10:10:80 mixture containing 1000 Baker Units / gram of catalase:instant setting starch:sodium percarbonate by mass was prepared. The mixture was made by adding the individual components to a large glass vial and vortex mixing. Immediately after mixing, an aliquot containing 240 mg of sodium percarbonate was assayed for oxygen generating activity. In this first assay (i.e., time 0), 21.3 cc of gaseous oxygen was produced, defined as 100%. After storage at room temperature for 7 days, the assay was repeated. In the second assay, 17.4 cc of gaseous oxygen was produced, or 82% of the original volume. This mixture lost 18% of its oxygen generating capacity after 7 days at room temperature. This data is shown as Plot A (open squares) in Figure 14.

[0212] A mixture of 10% by weight 1000 Baker Units / gram catalase and 90% by weight sodium percarbonate was prepared by mixing the components with a mechanical vortex and stored at room temperature. Volumetric analysis immediately after mixing with an aliquot containing 260 mg of sodium percarbonate yielded 27.0 cc of gaseous oxygen, defined as 100% (time 0). Assays repeated 7 and 15 days after mixing revealed losses of 8% and 56%, respectively (see plot B (open circles)).

[0213] A 50:50 mass mixture of baker's yeast and sodium percarbonate was mixed in a mortar and pestle and stored in a glass vial at room temperature. Immediately after mixing (time 0), an aliquot containing 260 mg of sodium percarbonate was assayed for oxygen generating activity, yielding 27.0 cc of oxygen, defined as 100%. Over the course of the day, condensation of water was observed on the sides of the storage glass vial, consistent with an imbalance of hydrogen peroxide to water and oxygen. One day after mixing, only 1 cc (i.e., 4% of the original volume) was observed, representing a loss of 96% of oxygen generating capacity (plot C, open triangles). This indicates that hydrogen peroxide oxygen prodrug is lost, at least in part, due to contact of the prodrug with the catalyst during storage and / or due to storage temperature.

[0214] A mixture of 10% 1000 Baker Units / gram catalase and 90% sodium percarbonate was mixed by mechanical vortexing and stored refrigerated at 4°C. Volumetric analysis immediately after mixing with an aliquot containing 240 mg sodium percarbonate (time 0) yielded 21.3 cc of gaseous oxygen, defined as 100%. Multiple subsequent assays repeated up to 42 days after mixing showed no loss in oxygen generating capacity (plot D, black circles). These data indicate that the prodrug remains stable when refrigerated, even when exposed to a catalyst (compare plot B). In some embodiments, the oral formulations described herein are optionally stored below room temperature (e.g., about 4°C), resulting in enhanced stability / oxygen capacity maintenance. In some embodiments, the oral formulations described herein are optionally stored frozen (e.g., about -20°C), resulting in further enhanced stability / oxygen capacity maintenance.

[0215] Further experiments were performed to evaluate further improvements in the stability and long-term oxygen generating capacity of formulations according to embodiments disclosed herein, in which the catalyst and prodrug are separated from each other until they reach the desired site of action (such as the small or large intestine). The structure was designed to mimic the capsule-within-a-capsule structure described herein (or coated prodrug within a coated catalyst). Size 1 gelatin capsules were filled with sodium percarbonate and embedded in 100 grams of baker's yeast. This mimics a capsule-within-a-capsule structure in which the outer capsule contains the baker's yeast, surrounds the inner capsule, and is stored at room temperature (22°C). In this arrangement, the outer surface area of ​​the inner capsule is completely surrounded by the yeast, as would be the case if the yeast / catalyst were also encapsulated / coated. On day 0, 255 mg of sodium percarbonate from the inner capsule yielded 25.3 cc of gaseous oxygen, which is defined as 100%. Repeated testing showed a decline in activity up to 26 days after mixing. This data shows that, according to certain embodiments described herein, a mixture of prodrug (e.g., sodium percarbonate) is stable at room temperature for at least 20 days when the prodrug and catalyst (e.g., catalase) are compressed and stored in a capsule-in-capsule device at room temperature. This data also shows that a biological source of catalase, such as yeast, can be used to convert the prodrug to oxygen and water. Advantageously, yeast (or other microorganisms or biological sources of catalase) are renewable, and since yeast replicates naturally, the cost of goods can be substantially reduced. Furthermore, the stabilizing effect of yeast on the formulation causes an unexpectedly robust preservation of oxygen-generating capacity even at room temperature storage. This indicates that such formulations may be more effective at oxygenating the intestinal region of subjects living in environments where refrigeration is not readily available, thereby expanding the potential geographic areas where oxygenation therapy can be effectively (and cost-effectively) administered.

[0216] Example 11 Animal model efficacy of intestinal aerobicity There are two models of Clostridioides difficile infection that are commonly used to evaluate new treatments. Hamsters develop severe infections and high mortality rates when infected with CDI. Some experts prefer the mouse model because it behaves more like humans. CDI in mice is less severe, has lower mortality rates, and antibiotic control groups experience recurrent infections, just like in humans. The mouse CDI model was chosen to evaluate gut aerobicity because of its more human-like characteristics.

[0217] The implementation of gut aerobicity treatment presented several challenges in the mouse model. Administration of experimental compounds to rodents is typically performed by gavage with a solution of the test substance. However, dissolving the mixture before administration would result in premature loss of oxygen effervescence before entering the gut, which was not possible with gut aerobicity treatment. It is also uncertain whether rodents will reliably pass enteric-coated capsules or tablets from the stomach to the intestine. Furthermore, the pH gradient in rodents is shallower than in humans, suggesting that enteric coatings may not function reliably. Finally, the small size of capsules or tablets required for administration to rodents severely limits the dosage. Duodenal cannulated mice were used to directly aerate the model gut by infusing oxygen directly.

[0218] Thirty C57BL / 6 female mice (18–22 g) with exteriorized duodenal catheters and fitted with access button ports were purchased from Charles River Laboratories and housed singly in a temperature- and humidity-controlled room with a 12-h light cycle. Mice were divided into three groups of 10 mice each. All procedures used in these experimental protocols were in accordance with the Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, and the Office of Laboratory Animal Welfare.

[0219] Mice were pretreated with an antibiotic cocktail in their drinking water for 8 consecutive days. The antibiotic cocktail consisted of 1% glucose, 500 μg / mL kanamycin, 44 μg / mL gentamicin, 1062.5 units / mL colistin, 269 μg / mL metronidazole, 156 μg / mL ciprofloxacin, 100 μg / mL ampicillin, and 56 μg / mL vancomycin. The antibiotic cocktail and drinking water were changed every 2-3 days. Five days before infection, the antibiotic water was removed and the animals were given regular drinking water. Three days before infection, the animals were orally administered a single dose of clindamycin at 10 mg per kg in a volume of 10 mL / kg. According to some embodiments of the invention, other antibiotics and antibacterial agents may also be used. Other tissues within the digestive tract or at other sites may be treated.

[0220] On day 0 of the study, mice were orally administered 5 × 10 5 Mice were inoculated with a bacterial suspension of CFU of Clostridioides difficile ATCC 43255. Eight hours after inoculation, administration of vehicle, antibiotic control, and test article was initiated as follows: 10 mice in the vehicle, also known as infected control group received 80 μL / hr of 100% pure nitrogen gas via duodenal catheter. 10 mice in the infected control group received 50 mg / kg vancomycin via oral gavage once daily. 10 mice in the experimental group received 80 μL / hr of 100% oxygen test article via duodenal catheter. Administration continued for a total of 5 days from study day 0 to study day 4. Mice were followed for 14 days post-inoculation, and daily weights and clinical observations were recorded. Animals deemed significantly debilitated were euthanized. At the end of the study, all animals were humanely euthanized.

[0221] An experimental protocol according to one embodiment is shown in FIG.

[0222] Survival outcomes The infected (also known as vehicle, placebo, nitrogen) control group had a 30% mortality rate (70% survival rate). Both the EAT (also known as oxygen, test, experimental) group and the antibiotic (also known as vancomycin) control group had a 100% survival rate (no mortality). These results are shown in Figure 5.

[0223] Clinical cure results Only 70% of the infected control group recovered from CDI, reflecting the mortality of the groups. Figure 7 shows the number of animals in each group that showed at least one clinical observation according to the table in Figure 6, divided into the first week post-inoculation and the second week post-inoculation. These results can also be seen in Figure 8, which shows the number of animals with at least one clinical observation on a daily basis.

[0224] Also seen in Figures 7 and 8 is the clear rapid onset of vancomycin in the antibiotic control group. However, this strong initial efficacy did not translate into a high clinical cure. 70% of the animals in the antibiotic control group showed signs of infection two weeks after inoculation and treatment. Such recurrences are also seen in humans treated with antibiotics for CDI.

[0225] Figure 7 shows that EAT has a protective effect with fewer diseased animals compared to the infected control group, but not as early as the antibiotic control group. As will be seen in the next section, the diseased animals in the EAT group were not as sick as those in the infected control group. In Figure 8, it can be seen that the animals in the EAT group recovered rapidly. Most importantly, these findings indicate that there was no recurrent infection in the EAT group, i.e., a cure rate of 100%.

[0226] Clinical severity outcomes The data in Figure 9 confirm that animals treated with EAT were mildly ill and recovered rapidly compared to the infected controls, with a 100% cure rate compared to the infected and antibiotic controls. The daily weight change records shown in Figure 10 support these observations. The small drop in weight between days 5 and 9 in Figure 10 does not represent a relapse, as there were no clinical findings in the previous plot. The slower onset of action of EAT seen in these experiments is to be expected, as oxidative conditions are hostile to C. difficile, and the organism can tolerate higher oxygen tensions for short periods of time, 24-36 hours. The organism can survive at higher oxygen tensions, but it does not grow.

[0227] Tolerability In a separate experiment using the above conditions, the tolerance of bolus infusion of 100% oxygen gas was tested. No adverse effects were observed up to the maximum bolus tested, 200 μL every 6 hours (8 mL / kg per bolus; 32 mL / kg / day). In these efficacy experiments, no adverse effects were observed with infusion of nitrogen or oxygen gas (3.2 mL / kg / hour; 76.8 mL / kg / day). In fact, one asymptomatic animal in the nitrogen group and three animals in the oxygen group were vigorous enough to bite through the infusion line and have to be replaced.

[0228] Summary of Results These results demonstrate that aerobicization of the animal's intestines is well tolerated and creates a hostile environment for C. difficile. Intestinal aerobicization treatment reduces disease severity and promotes recovery, resulting in a 100% cure rate in a mouse CDI model. The vancomycin antibiotic control, while having a faster onset of action, only yielded a 30% cure rate, with 70% of animals showing clinical signs of relapse after completion of treatment. In other embodiments, a hostile environment for a desired organism other than or in addition to C. difficile is created.

[0229] Example 12 Testing of coated granules This experiment was designed to evaluate the stability and oxygen release of the oxygen generating formulation described herein. The experiment tested the oxygen release rate of granules at various stages of manufacture containing individual enteric, osmotic and barrier coatings (see, e.g., FIG. 1B). Individually coated granules were manufactured using the non-limiting ingredients and amounts shown in Table 2. [Table 2]

[0230] Test granules were made by application of an aqueous coating applied by fluidized bed coating. Granules were made with various coatings to compare the functionality of the coatings. Group 1 of granules was made with sodium percarbonate, a barrier coating and catalase. Group 2 of granules was made with sodium percarbonate, a barrier coating, catalase and a permeable coating. Group 3 of granules was made with sodium percarbonate, a barrier coating, catalase, a permeable coating and an enteric coating. For group 3, the total density of the granules was 0.95 g / cc. Individual granule densities are >1.0 g / cc based on observations during the experiment that the granules sink to the bottom of the aqueous solutions tested.

[0231] To mimic gastric conditions, 500 mg of Group 3 granules were placed in 50 mL of simulated gastric fluid (RICCAN Catalog No. 7108-16) in a volumetric meter (screw cap bottle with rubber stopper and tubing to a glass syringe) with stirring. No reaction was observed during the first 30 minutes. After 30 minutes, the previously sinking particles rose from the bottom of the test vessel and floated to the top of the solution, consistent with gas evolution. Very slow effervescence was observed as air bubbles over the next hour (total 1.5 hours), but released enough gas to be detected by the volumetric meter (<1 mL).

[0232] Further experiments were performed to mimic the conditions in which the administered oxygen generating formulation passed through the stomach and accumulated in the intestine. For this experiment, granules from groups 1 and 2 were tested in 100 mL of 100 mM pH 6.8 sodium phosphate buffer, and granules from group 3 were tested in 50 mL of pH 7.0 simulated intestinal fluid (RICCAN catalog number 7109.75-16). First, granules from each group were allowed to sink to the bottom of the test vessel. After about 20 minutes of stirring, foaming began. The granules then floated to the test medium and showed a solid foaming, which was measured by a volumetric meter. Foaming was completed within 75 minutes from the start of the experiment. The granules remained floating after complete foaming, but after standing overnight, the granules sank again to the bottom of the reaction vessel. The data are summarized in Table 3 below. [Table 3]

[0233] These data show that granules (or other forms of oxygen generating compositions) according to certain embodiments described herein can generate large amounts of oxygen. The addition of multiple coatings (e.g., enteric, permeable and barrier coatings) on individual granules reduces the percentage of the granule that corresponds to the active agent (or pre-active agent). Here, these data show that even if only 57% of a given granule is composed of the pre-enzyme component (here, as a non-limiting embodiment, sodium percarbonate), the resulting oxygen generation is close to 80% of the theoretical value. The use of multiple coatings (e.g., enteric, permeable and barrier coatings) on individual granules is also believed to provide additional stability of the granules in the target environment (e.g., the intestine), which may improve therapy by providing oxygen to the surrounding environment.

[0234] Although specific embodiments and examples have been described herein, aspects of the embodiments shown and described in this disclosure may be variously combined and / or modified to form further embodiments. Section headings used herein are provided merely to enhance readability and are not intended to limit the scope of the embodiments described in a particular section to the features or elements described in that section. Furthermore, although features may be described above as working in a particular combination, one or more features of the claimed combination may, in some cases, be excluded from the combination, and the combination may be claimed as a subcombination or a variation of the subcombination. For purposes of this disclosure, certain aspects, advantages, and novel features are described herein. Not necessarily all such advantages are achieved in accordance with a particular embodiment. Thus, for example, the disclosure may be implemented or performed in a manner that achieves one advantage or advantages taught herein without necessarily achieving other advantages taught or implied herein. The methods described herein need not be performed in the order described. The methods described herein include specific actions performed by the practitioner, but may also include, explicitly or implicitly, third-party instructions for these actions. Alternatively, the methods described herein may be performed with any agent suitable for performing the steps described. Various embodiments of the present disclosure are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be construed as an inflexible and undue limitation on the scope of the invention. The ranges described herein include not only the individual values ​​within the range, but also all overlaps, subranges, and combinations thereof. Phrases such as "up to," "at least," "greater than," "less than," "between," and the like, include the recited numerical value. Numbers preceded by terms such as "about" or "approximately" include the recited numerical value. For example, "approximately or about 30-50%" includes 30% and 50%. As used herein, the terms "generally" and "substantially" refer to values ​​close to the recited amount that perform a desired function or achieve a desired result.

Claims

1. 1. An oral formulation for treating enteric anaerobic bacterial infections, comprising a plurality of granules or particles containing a drug and a catalyst, a first coating on the outside of each granule, and a second coating between the first coating and the catalyst, The agent includes sodium percarbonate or carbamide peroxide, the catalyst comprises catalase; Catalase controls the rate of conversion of drugs to oxygen, the first coating is resistant to degradation in a low pH environment; the second coating allows water to contact and activate the catalyst upon at least partial decomposition of the first coating; When orally administered to a subject, the agent provides oxygen to the intestine of the subject, creating an aerobic environment in the intestine sufficient to inhibit the growth of anaerobic bacterial populations that cause anaerobic bacterial infections in the intestine; The granules or particles are optionally contained in a capsule. Oral formulation.

2. further comprising a third coating; the third coating is a barrier between the drug and the catalyst; The oral formulation according to claim 1.

3. the first coating is resistant to degradation in the subject's stomach, thereby allowing the granules to be delivered to the intestine without being substantially inactivated by stomach acid; The oral formulation according to claim 1 or 2.

4. further comprising one or more binders, one or more dispersants, one or more glidants, and / or plasticizers; The oral formulation of claim 1.

5. 10. The oral formulation of claim 1, wherein the formulation does not contain tannins or tannin-like components.

6. 10. The oral formulation of claim 1, wherein the granules or particles are contained in a capsule.

7. 2. The oral formulation of claim 1, wherein the anaerobic bacterial population is Clostridioides difficile.

8. the first coating is an enteric coating; the second coating is a porous osmotic coating having pores that control the diffusion of the catalyst through the porous osmotic coating and that allow water to contact and activate the catalyst upon at least partial decomposition of the first coating; The oral formulation of claim 1.

9. 10. The oral formulation of claim 1, wherein the drug is provided in the range of 250 to 2000 mg.

10. 10. The oral dosage form of claim 1, wherein the catalyst is provided in the range of 10 to 150 Baker units.

11. 10. The oral formulation of claim 1, wherein the formulation provides 2% to 5% oxygen in at least the intestinal region for 24 hours or more after administration to a subject.

12. 10. The oral formulation of claim 1, wherein the formulation provides 5% to 10% oxygen at least in the intestinal region for 6 hours or more after administration to a subject.

13. 10. The oral formulation of claim 1, wherein the oral formulation is in solid form.

14. 10. The oral formulation of claim 1, wherein the anaerobic bacterial population comprises one or more of Clostridioides difficile, Clostridium perfringens, Clostridium botulinum, Clostridium butyricum, Clostridium baratii, Vibrio cholera, Escherichia coli, and Salmonella enteritidis.

15. A kit comprising the oral formulation according to any one of claims 1 to 14 and instructions for use.

16. A prodrug, a prodrug, wherein the prodrug comprises sodium percarbonate; a catalyst configured to act on a prodrug and convert it into an active drug upon contact with the prodrug; the catalyst comprises catalase and controls the rate of conversion of the prodrug to oxygen; a catalyst, wherein the catalyst is present in an amount about equal to or greater than the amount of the prodrug; a first soluble coating surrounding the prodrug and separating the prodrug from the catalyst; a second soluble coating surrounding the catalyst and surrounding the coated prodrug; an insoluble, semipermeable coating having a lumen, wherein a coated catalyst is present within the lumen surrounding the coated prodrug; 1. An oral formulation for supplying oxygen to the intestinal region, comprising: Upon oral administration to a subject, the first and second soluble coatings dissolve in the intestinal region, allowing the prodrug and catalyst to contact each other; Contact of the catalyst with the prodrug allows the catalyst to convert the prodrug into oxygen, thereby providing oxygen to the intestinal region; The oral formulation is in solid form, Oral formulation.

17. 17. The oral formulation of claim 16, wherein the catalyst is provided by a plurality of eukaryotic unicellular microorganisms, the prodrug is present in an amount of 100-2000 mg, the plurality of eukaryotic unicellular microorganisms is provided in an amount of 100-4000 mg, and the oral formulation is capable of providing oxygen to the intestinal region after storage of the oral formulation at a temperature of 15-30° C. for at least 14 days.

18. 18. The oral formulation of claim 16 or 17, wherein the insoluble, semipermeable coating prevents catalase from diffusing out of the lumen and prevents intestinal digestive enzymes from diffusing into the lumen, allows water to diffuse into or out of the lumen, and allows oxygen to diffuse out of the lumen.

19. 17. The oral formulation of claim 16, wherein the first soluble coating and / or the second soluble coating comprises a gelatin capsule.

20. 17. The oral formulation of claim 16, wherein the prodrug is in tablet form and coated with a gelatin coating, and the second soluble coating comprises a gelatin capsule.

21. an insoluble, semipermeable outer coating having a lumen; a prodrug comprising sodium percarbonate or carbamide peroxide disposed within the lumen; a first soluble coating surrounding the prodrug; a catalyst comprising catalase disposed within the lumen and surrounding the prodrug coated with a first soluble coating; A second soluble coating surrounding the catalyst 1. An oral formulation for supplying oxygen to the intestinal region, comprising: Upon oral administration to a subject, water from the intestine diffuses through the insoluble, semipermeable outer coating and dissolves the first and second soluble coatings, allowing the catalyst to contact the prodrug and act on the prodrug to produce an enzyme, thereby providing oxygen to the intestinal region. Oral formulation.

22. 22. The oral formulation of claim 21, wherein the insoluble, semipermeable coating prevents catalase from diffusing out of the lumen and prevents intestinal digestive enzymes from diffusing into the lumen, allows water to diffuse into or out of the lumen, and allows oxygen to diffuse out of the lumen.

23. 23. The oral formulation of claim 21 or 22, wherein the first soluble coating and / or the second soluble coating comprises a gelatin capsule.

24. 23. The oral formulation of claim 21 or 22, wherein the prodrug is in tablet form and coated with a gelatin coating, and the second soluble coating comprises a gelatin capsule.

25. 22. The oral formulation of claim 21, wherein the prodrug comprises sodium percarbonate and is present in an amount of 100 to 2000 mg, and the catalyst is provided by a plurality of yeast cells, and the plurality of yeast cells is present in an amount equal to or greater than the sodium percarbonate.

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