# US 12,109,244 B2 · Enteric aerobization therapy

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- Number: US 12,109,244 B2
- Document ID: US12109244B2
- Status: Granted
- Kind: B2
- Application number: 18/109,785
- Filed: 2023-02-14
- Published: 2023-06-22
- Granted: 2024-10-08
- Earliest claimed: 2021-09-29
- Assignees: Lpoxy Therapeutics, Inc.
- Applicants: Lpoxy Therapeutics, Inc.
- Inventors: Larry D. Sutton
- Web page: https://patentgrep.com/patent/US12109244B2

## CPC

- A61K 36/06: Fungi, e.g. yeasts
- A61K 36/064: Saccharomycetales, e.g. baker's yeast
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/28: Dragees; Coated pills or tablets {, e.g. with film or compression coating (A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209)}
- A61K 9/4825: {Proteins, e.g. gelatin (gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816)}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 31/327: Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
- A61K 33/40: Peroxides
- A61K 35/742: Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
- A61K 35/748: Cyanobacteria, i.e. blue-green bacteria or blue-green algae, e.g. spirulina (algae, microalgae or microphytes A61K36/02)
- A61K 36/31: Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
- A61K 38/44: Oxidoreductases (1)
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 31/02: Local antiseptics
- A61P 31/04: Antibacterial agents
- A61P 39/00: General protective or antinoxious agents
- C12N 9/0065: {acting on hydrogen peroxide as acceptor (1.11)}
- C12Y 111/01006: Catalase (1.11.1.6)
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Agents, kits, and methods that utilize oxygenation to prevent and/or treat intestinal inflammation and/or infections caused by anaerobic microorganisms are provided. In several embodiments, the formulations are provided as a capsule within a capsule in order to separate an oxygen prodrug from a catalyst until the formulation is at a target site within the intestine. In several embodiments, the catalyst is provided in an excess of the oxygen prodrug. In several embodiments, the prodrug is within an inner capsule or coating and a biological material comprising a catalyst (e.g., yeast, spirulina, chlorella, etc.) surrounds the encapsulated prodrug and the biological material is within a capsule or coating. The agents, kits, and methods can be utilized to prevent and/or treat anaerobic bacterial infections of the intestinal lumen by enteric aerobization therapy.

## Claims

### Claim 1

An oral formulation for oxygenating an intestinal region of a subject, comprising:
an oxygen prodrug;
a plurality of yeast cells comprising an enzyme configured to act on the prodrug and convert it to an active agent upon contacting the prodrug,
wherein the enzyme controls the rate of conversion of the prodrug to oxygen;
a first soluble coating surrounding the oxygen prodrug and separating the oxygen prodrug from the plurality of yeast cells;
a second soluble coating surrounding the plurality of yeast cells and the coated oxygen prodrug;
an insoluble, semipermeable coating having a lumen, wherein the coated plurality of yeast cells surrounding the coated oxygen prodrug resides within the lumen, and
an enteric coating surrounding the oral formulation,
wherein the insoluble, semipermeable coating has a pore size that prevents a majority of the enzyme from diffusing across the coating out of the lumen and prevents a majority of digestive enzymes from diffusing across the coating into the lumen,
wherein the pore size is sufficient to allow water from an intestinal region to diffuse across any portion of the semipermeable coating to contact the oxygen prodrug and to allow oxygen to be generated to diffuse across any portion of the semipermeable coating into the intestinal region of the subject,
wherein when orally administered to the subject, the first and second soluble coating dissolve within the intestinal region and allow the oxygen prodrug and plurality of yeast cells to contact one another,
wherein the contacting of the plurality of yeast cells and the oxygen prodrug allows the enzyme from the yeast cells to convert the oxygen prodrug to oxygen, thereby oxygenating the intestinal region, and
wherein the oral formulation is in solid form.

### Claim 2 (depends on 1)

The oral formulation of claim 1, wherein the oxygen prodrug is present in an amount between 100 and 2000 mg, wherein the plurality of yeast cells is provided in an amount between 100 and 4000 mg, and wherein the oral formulation is capable of oxygenating the intestinal region after storage of the oral formulation for at least 14 days at a temperature between 15 and 30° C.

### Claim 3 (depends on 2)

The oral formulation of claim 2, wherein the oral formulation is capable of oxygenating the intestinal region after storage of the oral formulation for at least 20 days at a temperature between 2° and 25° C.

### Claim 4 (depends on 1)

The oral formulation of claim 1, wherein the plurality of yeast cells comprises one or more strains of yeast, wherein the prodrug comprises sodium percarbonate or carbamide peroxide; enzyme is catalase.

### Claim 5 (depends on 1)

The oral formulation of claim 1, wherein the plurality of yeast cells comprises a yeast strain selected from Saccharomyces cerevisiae, Saccharomyces exiguous, Schizosaccharomyces pombe, and combinations thereof.

### Claim 6 (depends on 1)

The oral formulation of claim 1, wherein the insoluble, semipermeable coating prevents the enzyme from diffusing out of the lumen, also 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.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The oral formulation of claim 1, wherein the first and second soluble coatings do not dissolve in stomach acid after being administered to a subject.

### Claim 9 (depends on 1)

The oral formulation of claim 1, wherein one or more of the first and the second soluble coating comprises:
a gelatin capsule, wherein the gelatin is bovine or porcine gelatin,
a vegetable cellulose capsule,
an agar-agar capsule, wherein the agar-agar is derived from seaweed, or
an enteric coating comprising hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, diethyl phthalate, and/or cellulose acetate phthalate.

### Claim 10 (depends on 1)

The oral formulation of claim 1, wherein oxygenation of the intestinal region by administration of the oral formulation prevents and/or treats an inflammatory bowel disorder (IBD) and/or prevents and/or treats an intestinal anaerobic bacterial infection.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 1)

The oral formulation of claim 1, further comprising at least one excipient, wherein the at least one excipient is polyvinyl acetate and/or glyceryl behenate, and optionally further comprising a flavorant.

### Claim 13

An oral formulation for oxygenating an intestinal region of a subject, comprising:
an oxygen prodrug;
a biological material comprising an enzyme suitable to act on the oxygen prodrug and convert it to oxygen upon contacting the oxygen prodrug,
a first soluble coating surrounding the prodrug and separating the oxygen prodrug from the biological material;
a second soluble coating surrounding the biological material and the coated oxygen prodrug;
an insoluble, semipermeable coating having a lumen, wherein the coated biological material surrounding the coated oxygen prodrug resides within the lumen, and
an enteric coating surrounding the oral formulation,
wherein the insoluble, semipermeable coating has a pore size that prevents a majority of the enzyme from diffusing across the coating out of the lumen and prevents a majority of digestive enzymes from diffusing across the coating into the lumen,
wherein the pore size is sufficient to allow water from an intestinal region to diffuse across any portion of the semipermeable coating to contact the oxygen prodrug and to allow oxygen to be generated to diffuse across any portion of the semipermeable coating into intestinal region of the subject,
wherein when orally administered to the subject, the first and second soluble coating dissolve within the intestinal region and allow the oxygen prodrug and biological material to contact one another,
wherein the contacting of the biological material and the oxygen prodrug allow the enzyme from the biological material to convert the oxygen prodrug to oxygen, thereby oxygenating the intestinal region, and
wherein the oral formulation is in solid form.

### Claim 14 (depends on 13)

The oral formulation of claim 13, wherein the biological material comprises a plurality of eukaryotic, single-celled microorganisms, wherein the oxygen prodrug is present in an amount between 100 and 2000 mg, wherein the plurality of eukaryotic, single-celled microorganisms is provided in an amount between 100 and 4000 mg, and wherein the oral formulation is capable of oxygenating the intestinal region after storage of the oral formulation for at least 14 days at a temperature between 15 and 30° C.

### Claim 15 (depends on 13)

The oral formulation of claim 13, wherein the biological material comprises a plurality of yeast cells selected from Saccharomyces cerevisiae, Saccharomyces exiguous, Schizosaccharomyces pombe, and combinations thereof.

### Claim 16 (depends on 13)

The oral formulation of claim 13, wherein the biological material comprises a plurality of cyanobacteria, wherein the oxygen prodrug is present in an amount between 100 and 2000 mg, wherein the plurality of cyanobacteria is provided in an amount between 100 and 4000 mg, wherein the oral formulation is capable of oxygenating the intestinal region after storage of the oral formulation for at least 14 days at a temperature between 15 and 30° C., and wherein the plurality of cyanobacteria are of a species selected from Arthrospira platensis, Arthrospira fusiformis, Arthrospira maxima, and combinations thereof.

### Claim 17 (depends on 13)

The oral formulation of claim 13, wherein the biological material comprises fruit and/or vegetable material or a derivative thereof, wherein the oxygen prodrug is present in an amount between 100 and 2000 mg, wherein the fruit or vegetable material or derivative thereof is provided in an amount between 100 and 4000 mg, and wherein the oral formulation is capable of oxygenating the intestinal region after storage of the oral formulation for at least 14 days at a temperature between 15 and 30° C.

### Claim 18 (depends on 17)

The oral formulation of claim 17, wherein the biological material comprises:
vegetable material or a derivative thereof and is from a cruciferous vegetable;
vegetable material or a derivative thereof and is from alfalfa, Brussel sprouts, young sprouts of dark green plants, leeks, onions, broccoli, parsnips, zucchini, spinach, kale, radishes, carrots, red peppers, turnips, cucumbers, celery, avocado, potato, and/or red cabbage; or
fruit material or a derivative thereof and is from kiwi, peaches, cherries, apricots, bananas, watermelon, pineapple, apples and/or grapes.

### Claim 19 (depends on 13)

The oral formulation of claim 13, wherein the oxygen prodrug comprises sodium percarbonate and is present in an amount between 100 and 2000 mg, wherein the enzyme comprises catalase and is provided by a plurality of yeast cells, and wherein the plurality of yeast cells are present in an amount equal to, or in excess of, the sodium percarbonate.

### Claim 20 (depends on 13)

The oral formulation of claim 13, wherein one or more of the first and the second soluble coating comprises:
a gelatin capsule, wherein the gelatin is bovine or porcine gelatin,
a vegetable cellulose capsule,
an agar-agar capsule, wherein the agar-agar is derived from seaweed, or
an enteric coating comprising hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, diethyl phthalate, and/or cellulose acetate phthalate.