# US 2022/0031802 A1 · Low-Dose Stable Formulations of Linaclotide

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- Number: US 2022/0031802 A1
- Document ID: US20220031802A1
- Status: Published application
- Kind: A1
- Application number: 17/503,601
- Filed: 2021-10-18
- Published: 2022-02-03
- Earliest claimed: 2013-12-11
- Assignees: Ironwood Pharmaceuticals, Inc.; Forest Laboratories Holdings Limited
- Applicants: Ironwood Pharmaceuticals, Inc.; Forest Laboratories Holdings Limited
- Inventors: Yun Mo; Caroline Kurtz
- Web page: https://patentgrep.com/patent/US20220031802A1

## CPC

- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 9/1611: {Inorganic compounds}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- 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 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/2886: {having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer (of the type active core-drug layer-inactive layer A61K9/209)}
- 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 9/4825: {Proteins, e.g. gelatin (gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816)}
- A61K 9/485: {Inorganic compounds}
- A61K 9/4858: {Organic compounds}
- 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 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}
- 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 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 35/00: Antineoplastic 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 stable pharmaceutical compositions comprising linaclotide or pharmaceutically acceptable salts thereof, as well as to various methods and processes for the preparation and use of the compositions.

## Claims

### Claim 1

A low dose pharmaceutical composition comprising linaclotide, Ca2+ and histidine.

### Claim 2 (depends on 1)

The low dose pharmaceutical composition of claim 1, wherein the composition has a molar ratio of Ca2+:histidine of less than 2:1.

### Claim 3 (depends on 1, 2)

The composition of claim 1 or claim 2, wherein the composition further comprises a polymer.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the polymer is selected from polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) or a mixture thereof.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the composition comprises Ca2+ and histidine in a molar ratio of Ca2+:histidine between about 1:1 and 1:3.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the composition comprises Ca2+ and histidine in a molar ratio of Ca2+:histidine about 1:2.

### Claim 7

A pharmaceutical composition comprising linaclotide; Ca2+; histidine; and polyvinyl alcohol (PVA), wherein the molar ratio of Ca2+:histidine:linaclotide is between 30-80:80-120:1.

### Claim 8 (depends on 7)

The pharmaceutical composition of claim 7, wherein the Ca2+ is provided as CaCl2.

### Claim 9 (depends on 8)

A unit dosage form comprising the pharmaceutical composition of claim 8.

### Claim 10 (depends on 7)

The unit dosage form of claim 7, wherein the linaclotide is present in the pharmaceutical composition in an amount between 1 μg to 100 μg.

### Claim 11 (depends on 10)

The unit dosage form of claim 10, wherein the linaclotide is presented in an amount of 72 μg.

### Claim 12 (depends on 10)

The unit dosage form of claim 10, wherein the linaclotide is presented in an amount of 36 μg.

### Claim 13 (depends on 7)

The unit dosage form of claim 7, wherein the CaCl2 is present in an amount of 180 or 360 μg.

### Claim 14 (depends on 7)

The unit dosage form of claim 7, wherein the histidine is present in an amount of 380 or 760 μg.

### Claim 15 (depends on 7)

The unit dosage form of claim 7, wherein the PVA is present in an amount of 840 or 1670 μg.

### Claim 16

A pharmaceutical composition comprising coated beads, wherein the beads are coated with a coating solution comprising linaclotide, wherein the coating solution comprises:
linaclotide;
Ca2+;
histidine; and
polyvinyl alcohol (PVA),
wherein the molar ratio the of Ca2+:histidine:linaclotide is between 30-80:80-120:1.

### Claim 17 (depends on 16)

A unit dosage form comprising the pharmaceutical composition of claim 16.

### Claim 18 (depends on 17)

The unit dosage form of claim 17, wherein the linaclotide is present in the pharmaceutical composition in an amount between 1 μg to 100 μg.

### Claim 19 (depends on 17)

The unit dosage form of claim 17, wherein the linaclotide is present in an amount of 72 μg.

### Claim 20 (depends on 17)

The unit dosage form of claim 17, wherein the Ca2+ is provided as CaCl2) in an amount of 180 or 360 μg.

### Claim 21 (depends on 17)

The unit dosage form of claim 17, wherein the histidine is present in an amount of 380 or 760 μg.

### Claim 22 (depends on 390)

The unit dosage form of claim 390, wherein the PVA is present in an amount of 840 or 1670 μg.

### Claim 23 (depends on 16)

The pharmaceutical composition of claim 16, wherein the beads comprise microcrystalline cellulose.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)

A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of claims 1-23.

### Claim 25 (depends on 24)

The method of claim 24, wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, chronic constipation, opioid induced constipation and dyspepsia.

### Claim 26 (depends on 25)

The method of claim 25, wherein the gastrointestinal disorder is chronic constipation.

### Claim 27 (depends on 25)

The method of claim 25, wherein the gastrointestinal disorder is irritable bowel syndrome with constipation.

### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)

A method of making the composition of claims 1-23, comprising combining linaclotide with CaCl2 and histidine, wherein the composition has a molar ratio of CaCl2:histidine of less than 1.1.

### Claim 29 (depends on 28)

A composition prepared by the method of claim 28.

### Claim 30 (depends on 29)

A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of claim 29.

### Claim 31 (depends on 30)

The method of claim 30, wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, chronic constipation, opioid induced constipation and dyspepsia.

### Claim 32 (depends on 30)

The method of claim 30, wherein the gastrointestinal disorder is chronic constipation.

### Claim 33 (depends on 30)

The method of claim 30, wherein the gastrointestinal disorder is irritable bowel syndrome with constipation.