# US 10,369,111 B2 · Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents

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- Number: US 10,369,111 B2
- Document ID: US10369111B2
- Status: Granted
- Kind: B2
- Application number: 15/874,543
- Filed: 2018-01-18
- Published: 2018-08-09
- Granted: 2019-08-06
- Earliest claimed: 2013-03-14
- Assignees: Therabiome, LLC
- Applicants: Therabiome, LLC
- Inventors: Mohan Kabadi; Jerome J. Schentag
- Web page: https://patentgrep.com/patent/US10369111B2

## CPC

- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/4816: {Wall or shell material}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 35/741: Probiotics (probiotic yeast, e.g. saccharomyces A61K36/06)
- A61K 35/744: Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K 35/745: Bifidobacteria
- A61K 35/747: Lactobacilli, e.g. L. acidophilus or L. brevis
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 31/04: Antibacterial agents
- 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

## Abstract

The present invention relates to the development of a targeted delivery system for the oral delivery of probiotics or therapeutic agent for various indications, including and not 5 limited to active and prophylaxis treatment of Clostridium difficile infection, antibiotic associated diarrhea, irritable bowel syndrome, Crohn's disease, intestinal flora replacement, supplemental flora treatments for patients taking antibiotics, and for restoration of balance and signaling between the intestinal microbiome and the intestinal cells in patients under treatment of metabolic syndrome manifestations, specifically 10 diabetes, insulin resistance, obesity, hyperlipidemia and hypertension. The present invention restores altered probiotic organism imbalances that are characteristic of said diseases among others as well as defines a platform technology development for site specific delivery of probiotic organisms in the GI tract of a 15 mammal, most specifically the ileum and/or right colon of a human subject.

## Claims

### Claim 1

A method of treating a gastrointestinal disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of an oral formulation comprising:
a biodegradable first capsule comprising a probiotic formulation targeted to the proximal colon, wherein the first capsule comprises a reverse enteric coating that solubilizes in a pH of about 6.2 to about 6.5; and
a biodegradable second capsule that includes the first capsule and a probiotic formulation targeted to the ileum, wherein the second capsule comprises an enteric coating that solubilizes in a pH of about 7 to 8,
wherein upon administration to the subject, the second capsule releases the first capsule and the probiotic formulation targeted to the ileum in the ileum and once released, the first capsule releases the probiotic formulation targeted to the proximal colon in the proximal colon.

### Claim 2 (depends on 1)

The method of claim 1, wherein the gastrointestinal disorder is a Clostridium difficile disorder.

### Claim 3 (depends on 2)

The method of claim 2, wherein the Clostridium difficile disorder is associated with one or more of a Clostridium difficile infection, an imbalance of Clostridium difficile in the ileum or colon of the subject, diarrhea, inflammation, colitis, fever, or dysbiosis.

### Claim 4 (depends on 1)

The method of claims 1, wherein the probiotic formulation targeted to the proximal colon and the probiotic formulation targeted to the ileum each comprise a live bacterial suspension comprising a bacteria selected from the genus Lactobacillus and Bifidobacterium.

### Claim 5 (depends on 1)

The method of claims 1, wherein the gastrointestinal disorder is an irritable bowel disease associated with dysbiosis.

### Claim 6 (depends on 1)

The method of claim 1, wherein the oral formulation is administered in combination with a statin, linaclotide, an ileal brake hormone releasing substance, or an anti-inflammatory agent.

### Claim 7 (depends on 1)

The method of claim 1, wherein the enteric coating comprises one or more polymers each selected from the group consisting of copolymers of methacrylic acid, and copolymers of methacrylic acid and methyl methacrylate.

### Claim 8 (depends on 1)

The method of claim 1, wherein the biodegradable first capsule and the biodegradable second capsule each comprise hydroxypropylmethyl cellulose.

### Claim 9 (depends on 1)

The method of claim 1, wherein the biodegradable first capsule and the biodegradable second capsule are each band sealed.

### Claim 10

A method of treating a gastrointestinal disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of a capsule-in-capsule formulation comprising:
an inner biodegradable capsule contained within an outer biodegradable capsule, wherein
the inner capsule contains an inner probiotics formulation and is coated with a reverse enteric coating that solubilizes in a pH of about 6.2 to about 6.5; and
the outer capsule contains the inner capsule and an outer probiotics formulation, and is coated with an enteric coating that solubilizes in a pH of about 7 to 8.

### Claim 11 (depends on 10)

The method of claim 10, wherein the gastrointestinal disorder is a Clostridium difficile disorder.

### Claim 12 (depends on 10)

The method of claims 10, wherein the gastrointestinal disorder is an irritable bowel disease associated with dysbiosis.

### Claim 13 (depends on 10)

The method of claims 10, wherein the reverse enteric coating comprises dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer (2:1:1).

### Claim 14 (depends on 10)

The method of claims 10, wherein the enteric coating comprises poly (methacrylic acid-co-methyl-methacrylate) 1:1 copolymer and poly(methacrylic acid-co-methyl-methacrylate) 1:2 copolymer.

### Claim 15 (depends on 10)

The method of claims 10, wherein the reverse enteric coating comprises 5 mg/cm2 to 10 mg/cm2 of dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer (2:1:1) copolymer and the enteric coating comprises 5 mg/cm2 to 10 mg/cm2 of poly(methacrylic acid-co-methyl-methacrylate) 1:1 copolymer and poly(methacrylic acid-co-methyl-methacrylate) 1:2 copolymer in a 75/25 ratio.

### Claim 16 (depends on 10)

The method of claims 10, wherein the reverse enteric coating and the enteric coating each have a thickness of 60 μm to 180 μm.

### Claim 17 (depends on 10)

The method of claims 10, wherein the inner capsule and outer capsule each comprise hydroxypropylmethyl cellulose.

### Claim 18 (depends on 10)

The method of claims 10, wherein the inner capsule is a size no. 3 hydroxypropylmethyl cellulose capsule.

### Claim 19 (depends on 10)

The method of claims 10, wherein the outer capsule is a size no. 0 hydroxypropylmethyl cellulose capsule.

### Claim 20 (depends on 10)

The method of claims 10, wherein the inner capsule and outer capsule each are each band sealed.