# US 10,864,170 B2 · Polymeric bile acid nanocompositions targeting the pancreas and colon

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- Number: US 10,864,170 B2
- Document ID: US10864170B2
- Status: Granted
- Kind: B2
- Application number: 15/757,608
- Filed: 2016-09-02
- Published: 2018-08-30
- Granted: 2020-12-15
- Earliest claimed: 2015-09-04
- Assignees: Yale University
- Applicants: Yale University
- Inventors: Tarek M. Fahmy; Jung Seok Lee; Dongin Kim
- Web page: https://patentgrep.com/patent/US10864170B2

## CPC

- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 38/28: Insulins
- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61K 49/1824: {coated or functionalised nanoparticles (liposomes A61K49/1812; nanoemulsions A61K49/1806; micelles A61K49/1809)}
- A61K 51/1244: {microparticles or nanoparticles, e.g. polymeric nanoparticles}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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

Pharmaceutical composition containing poly(bile) acid (PBA) polymers for oral delivery of agent(s) show enhanced uptake by the pancreas, liver, and colon. These nanoparticles show significant retention in the pancreas and colon and are therefore useful for selective delivery. The examples demonstrate efficacy of oral administration of insulin to treat diabetes, and oral induction of tolerance by administration of insulin or ovalbumin in combination with rapamycin. Diabetic animals treated with the insulin or insulin with rapamycin showed normalization of blood glucose levels.

## Claims

### Claim 1

A formulation of nanoparticles comprising a polymeric matrix formed of polymers consisting of esterified bile acid monomers (PBA polymers),
wherein the bile acid monomers have a structure of Formula I,
wherein R1, R2, and R3 are independently hydrogen or —OH, and X is —OH or —O−,
or are selected from the group of taurine or glycine conjugates thereof consisting of glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurolitholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, glycolithocholic acid, glycochenodeoxycholic acid; or taurine conjugates of 3-alpha-7-alpha-12-alpha-22-xi-tetrahydroxy-5-beta-cholestan-26-oic acid or taurine conjugates of 3-alpha-12-alpha-22 xitrihydroxy-5-beta-cholestan-26-oic acid,
wherein the PBA polymers have a molecular weight between 500 Da and 250,000 Da,
wherein the nanoparticles comprise one or more therapeutic, prophylactic or diagnostic agents encapsulated within or entrapped in to the PBA polymers.

### Claim 2 (depends on 1)

The formulation of claim 1, wherein the nanoparticles are formed by emulsifying the PBA polymers.

### Claim 3 (depends on 1)

The formulation of claim 1 selectively taken up by the pancreas, liver, or colon after oral administration.

### Claim 4 (depends on 1)

The formulation of claim 1, wherein the nanoparticles further comprise one or more targeting moieties to specific cell types.

### Claim 5 (depends on 1)

The formulation of claim 1, wherein the agent is selected from the group consisting of proteins and peptides, sugars and polysaccharides, nucleic acids, lipids, small molecules having a molecular weight of less than 2000 Daltons, and combinations thereof.

### Claim 6 (depends on 5)

The formulation of claim 5, wherein the agent is selected from the group consisting of antigens, cytokines, hormones, anti-infectives, anti-proliferatives, anti-inflammatory agents, and immunomodulatory agents.

### Claim 7 (depends on 1)

The formulation of claim 1 for inducing tolerance, wherein the agent is a tolerogenic antigen selected from the group consisting of allergen, self-protein, and autoimmune antigen; a tolerogenic agent selected from the group consisting of TGF-beta, rapamycin and analogs thereof, retinoic acid, TLR agonists, cyclosporin, methotrexate, steroids, azathioprine, and tacrolimus; or a combination of the tolerogenic antigen and the tolerogenic agent.

### Claim 8 (depends on 1)

The formulation of claim 1, wherein the agent is insulin.

### Claim 9 (depends on 1)

The formulation of claim 1, wherein the agent is an anti-proliferative or chemotherapeutic agent for treatment of cancer.

### Claim 10 (depends on 1)

The formulation of claim 1 for non-invasively imaging pancreatic, liver, or colon inflammation in a subject in need thereof, wherein the agent is an imaging agent.

### Claim 11 (depends on 10)

The formulation of claim 10, wherein the nanoparticles comprise one or more imaging agent(s) selected from the group consisting of superparamagnetic iron oxide (SPIO), gadolinium, europium, diethylene triamine pentacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), gas, and positron-emitting radionuclides.

### Claim 12 (depends on 1)

The formulation of claim 1 in a liquid dosage form.

### Claim 13 (depends on 1)

A method of delivering a therapeutic, prophylactic or diagnostic agent, comprising orally administering to a subject in need thereof an effective amount of the formulation of claim 1.

### Claim 14 (depends on 13)

The method of claim 13 for treatment of type 1 or type 2 diabetes, wherein the agent in the formulation is insulin.

### Claim 15 (depends on 13)

The method of claim 13 for inducing tolerance, wherein the agent in the formulation comprises a tolerogenic antigen selected from the group consisting of allergen, self-protein, and autoimmune antigen; a tolerogenic agent selected from the group consisting of TGF-beta, rapamycin and analogs thereof, retinoic acid, TLR agonists, cyclosporin, methotrexate, steroids, azathioprine, and tacrolimus; or a combination of the tolerogenic antigen and the tolerogenic agent.

### Claim 16 (depends on 13)

The method of claim 13, wherein the agent in the formulation is selected from the group consisting of anti-inflammatory agents, anti-proliferatives and anti-infectives, wherein the subject has pancreatitis, colitis, or a proliferative disorder.

### Claim 17 (depends on 1)

A method of making the formulation of claim 1 comprising mixing the agent with the PBA polymers and forming the PBA polymers into nanoparticles.

### Claim 18 (depends on 17)

The method of claim 17 wherein the PBA polymers are in a solution.

### Claim 19 (depends on 17)

The method of claim 17 wherein the agent is added to the PBA polymers in powder or aggregated form.

### Claim 20 (depends on 1)

The formulation of claim 1 in a dosage form for oral administration to an individual in need thereof.

### Claim 21 (depends on 20)

The formulation of claim 20 wherein the dosage form is a tablet, capsule or powder.

### Claim 22 (depends on 1)

The formulation of claim 1 wherein the dosage form is a solution for nasal, pulmonary, rectal or vaginal administration.

### Claim 23 (depends on 7)

The formulation of claim 7, wherein the analogs of rapamycin are selected from the group consisting of everolimus, ridaforolimus, remsirolimus, umirolimus, and zotarolimus.

### Claim 24 (depends on 1)

The formulation of claim 1, wherein the PBA polymers have a structure of Formula VII,
wherein n is a number ranging from between 2-600.

### Claim 25 (depends on 1)

The formulation of claim 1, wherein the bile acid monomers are selected from the group consisting of cholic acid (CA), lithocholic acid (LCA), deoxycholic acid (DCA), cheno-deoxycholic acid (CDCA), and urso-deoxycholic acid (UDCA), and combinations thereof.