# US 10,441,605 B2 · Oral cholestyramine formulation and use thereof

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- Number: US 10,441,605 B2
- Document ID: US10441605B2
- Status: Granted
- Kind: B2
- Application number: 15/449,781
- Filed: 2017-03-03
- Published: 2017-08-10
- Granted: 2019-10-15
- Earliest claimed: 2016-02-09
- Assignees: Albireo AB
- Applicants: Albireo AB
- Inventors: Per-Göran Gillberg; Nils Ove Gustafsson; Nils-Olof Lindberg; Jessica Elversson
- Web page: https://patentgrep.com/patent/US10441605B2

## CPC

- A61K 31/745: Polymers of hydrocarbons
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5036: {Polysaccharides, e.g. gums, alginate; Cyclodextrin}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61K 31/785: Polymers containing nitrogen
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/12: Antidiarrhoeals
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/06: Antihyperlipidemics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 invention relates to an oral formulation for targeted delivery of cholestyramine to the colon, comprising a plurality of cholestyramine pellets that are coated with a colon release coating. The invention also relates to the use of this formulation in the treatment of bile acid malabsorption.

## Claims

### Claim 1

An oral formulation for targeted delivery of cholestyramine to the colon, comprising:
a) a plurality of extruded and spheronized pellets, each extruded and spheronized pellet comprising cholestyramine and
i. at least 7% w/w of a vinylpyrrolidone-based polymer; or
ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or
iii. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 3% w/w of an acrylate copolymer; or
iv. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer, at least 1% w/w of an acrylate copolymer and at least 10% w/w microcrystalline cellulose;
wherein the vinylpyrrolidone-based polymer is selected from the group consisting of copovidone, povidone, and combinations thereof; wherein the pellets exhibit a friability of less than 2.1% as measured using the European Pharmacopoeia 8.0, test 2.9.7; and
b) a coating surrounding each extruded and spheronized pellet, wherein the coating is capable of targeting release of the cholestyramine in the colon.

### Claim 2 (depends on 1)

The formulation according to claim 1, wherein the coating is elastic.

### Claim 3 (depends on 1)

The formulation according to claim 1, wherein the coating comprises starch.

### Claim 4 (depends on 3)

The formulation according to claim 3, wherein the starch is resistant starch type 2 (RS2).

### Claim 5 (depends on 1)

The formulation according to claim 1, wherein the coating further comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

### Claim 6 (depends on 1)

The formulation according to claim 1, wherein the diameter of each of the uncoated extruded and spheronized pellets is from 1000 to 1400 μm.

### Claim 7 (depends on 1)

The formulation according to claim 1, wherein the uncoated extruded and spheronized pellet also comprises microcrystalline cellulose.

### Claim 8 (depends on 1)

The formulation according to claim 1, wherein the uncoated extruded and spheronized pellets are free of microcrystalline cellulose.

### Claim 9 (depends on 1)

The formulation according to claim 1, wherein each of the uncoated extruded and spheronized pellets comprise from 70% to 93% w/w cholestyramine.

### Claim 10 (depends on 9)

The formulation according to claim 9, wherein each of the uncoated extruded and spheronized pellets comprise at least 80% w/w cholestyramine.

### Claim 11 (depends on 10)

The formulation according to claim 10, wherein each of the uncoated extruded and spheronized pellets comprise at least 85% w/w cholestyramine and
i. at least 7% w/w of a vinylpyrrolidone-based polymer; or
ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or
iii. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 3% w/w of an acrylate copolymer.

### Claim 12 (depends on 1)

The formulation according to claim 1, wherein the formulation is capable of releasing more than 70% of the cholestyramine in the colon.

### Claim 13 (depends on 1)

The formulation according to claim 1, wherein the formulation is capable of releasing less than 30% of the cholestyramine in the small intestine.

### Claim 14 (depends on 1)

The formulation according to claim 1, wherein the formulation is contained within a capsule.

### Claim 15 (depends on 1)

The formulation according to claim 1, wherein the formulation is contained within a sachet.

### Claim 16

A method for treating bile acid malabsorption in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an oral formulation comprising:
a) a plurality of extruded and spheronized pellets, each extruded and spheronized pellet comprising cholestyramine and
i. at least 7% w/w of a vinylpyrrolidone-based polymer; or
ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or
iii. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 3% w/w of an acrylate copolymer; or
iv. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer, at least 1% w/w of an acrylate copolymer and at least 10% w/w microcrystalline cellulose;
wherein the vinylpyrrolidone-based polymer is selected from the group consisting of copovidone, povidone, and combinations thereof; wherein the pellets exhibit a friability of less than 2.1% as measured using the European Pharmacopoeia 8.0, test 2.9.7; and
b) a coating surrounding each extruded and spheronized pellet, wherein the coating is capable of targeting release of the cholestyramine in the colon.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the bile acid malabsorption is the result of ileal disease (Crohn's disease), ileal resection or ileal bypass, the result of overproduction of bile acids or defective feedback inhibition of hepatic bile acid synthesis, or the result of cholecystectomy, vagotomy, small intestinal bacterial overgrowth (SIBO), coeliac disease, pancreatic insufficiency (chronic pancreatitis, cystic fibrosis), pancreatic transplant, radiation enteritis, collagenous colitis, microscopic colitis, lymphocytic colitis, ulcerative colitis or irritable bowel syndrome (IBS-D).

### Claim 18

A method for treating bile acid diarrhoea in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an oral formulation comprising:
a) a plurality of extruded and spheronized pellets, each extruded and spheronized pellet comprising cholestyramine and
i. at least 7% w/w of a vinylpyrrolidone-based polymer; or
ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or
iii. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 3% w/w of an acrylate copolymer; or
iv. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer, at least 1% w/w of an acrylate copolymer and at least 10% w/w microcrystalline cellulose;
wherein the vinylpyrrolidone-based polymer is selected from the group consisting of copovidone, povidone, and combinations thereof; wherein the pellets exhibit a friability of less than 2.1% as measured using the European Pharmacopoeia 8.0, test 2.9.7; and
b) a coating surrounding each extruded and spheronized pellet, wherein the coating is capable of targeting release of the cholestyramine in the colon.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the patient is also administered an IBAT inhibitor via oral.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the patient has a cholestatic liver disease.

### Claim 21 (depends on 19)

The method according to claim 19, wherein the IBAT inhibitor is
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)-carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
or a pharmaceutically acceptable salt thereof.

### Claim 22

A process for the preparation of coated extruded and spheronized pellets comprising:
a) a plurality of extruded and spheronized pellets, each extruded and spheronized pellet comprising cholestyramine and
i. at least 7% w/w of a vinylpyrrolidone-based polymer; or
ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or
iii. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 3% w/w of an acrylate copolymer; or
iv. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer, at least 1% w/w of an acrylate copolymer and at least 10% w/w microcrystalline cellulose;
wherein the vinylpyrrolidone-based polymer is selected from the group consisting of copovidone, povidone, and combinations thereof; wherein the pellets exhibit a friability of less than 2.1% as measured using the Eurpoean Pharmacopoeia 8.0, test 2.9.7; and
b) a coating surrounding each extruded and spheronized pellet, wherein the coating is capable of targeting release of the cholestyramine in the colon,
the process comprising the steps of:
a) preparing the pellets in a method comprising:
i) mixing the dry ingredients;
ii) adding water, and optionally the acrylate copolymer, to obtain a wet mass;
iii) extruding the wet mass;
iv) spheronizing the extrudate; and
v) drying the obtained extruded and spheronized pellets, wherein the pellets exhibits a friability of less than 2.1% as measured using the European Pharmacopoeia 8.0, test 2.9.7; and
b) applying the coating to the extruded and spheronized pellets.