# US 10,246,461 B2 · Dosage form compositions comprising an inhibitor of bruton's tyrosine kinase

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- Number: US 10,246,461 B2
- Document ID: US10246461B2
- Status: Granted
- Kind: B2
- Application number: 15/442,774
- Filed: 2017-02-27
- Published: 2017-08-31
- Granted: 2019-04-02
- Earliest claimed: 2016-02-29
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Chen Mao; Dawen Kou; Po-Chang Chiang
- Web page: https://patentgrep.com/patent/US10246461B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 9/10: Dispersions; Emulsions
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 309/04: containing only one sulfo group
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention relates generally to pharmaceutical tablet compositions comprising fumaric acid and the compound (S)-2-(3′-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-2′-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one free base that is an inhibitor of Bruton's tyrosine kinase. The invention further relates to amorphous solid dispersions comprising at least one polymer and the Bruton's kinase inhibitor free base compound. The invention further relates to crystalline mesylate salts, crystalline chloride salts and crystalline sulfate salts of the Bruton's kinase inhibitor free base compound. In some aspects, the crystalline salts are single polymorphs.

## Claims

### Claim 1

A tablet composition comprising:
(i) from about 25 mg to about 300 mg of a free base of structure (I):
and
(ii) fumaric acid, wherein the weight ratio of the free base of structure (I) to fumaric acid is from about 1:5 to about 3:1.

### Claim 2 (depends on 1)

The composition of claim 1 wherein the compound (I) free base content is from about 100 mg to about 300 mg, and wherein the composition comprises from about 15 wt. % to about 30 wt. % compound (I) free base.

### Claim 3 (depends on 1)

The composition of claim 1 wherein the fumaric acid content is from about 10 wt. % to about 30 wt. %.

### Claim 4 (depends on 1)

The composition of claim 1 wherein the weight ratio of the compound (I) free base to fumaric acid is from about 1:2 to about 2:1.

### Claim 5 (depends on 1)

The composition of claim 1 further comprising at least one pharmaceutically acceptable excipient selected from fillers, binders, disintegrants, lubricants and glidants.

### Claim 6 (depends on 1)

The composition of claim 1 wherein the fumaric acid is present as an extra-granular component.

### Claim 7 (depends on 5)

The composition of claim 5 comprising:
(i) from about 20 wt. % to about 25 wt. % of the free base of structure (I);
(ii) from about 15 wt. % to about 25 wt. % fumaric acid;
(iii) filler;
(iv) lubricant; and
(v) from about 1 wt. % to about 5 wt. % disintegrant,
wherein the weight ratio of the free base of structure (I) to fumaric acid is from about 1:1.5 to about 1.5:1.

### Claim 8 (depends on 7)

The composition of claim 7 wherein the weight ratio of the free base of structure (I) to fumaric acid is from about 1:1.2 to about 1.2:1.

### Claim 9 (depends on 7)

The composition of claim 7 wherein:
(i) the tablet comprises and intra-granular component and an extra-granular component;
(ii) the disintegrant is present as an intra-granular component and as an extra-granular component; and
(iii) the fumaric acid is present as an extra-granular component.

### Claim 10 (depends on 9)

The composition of claim 9 wherein:
(i) the filler comprises lactose monohydrate and microcrystalline cellulose;
(ii) the disintegrant comprises croscarmellose sodium; and
(iii) the lubricant comprises magnesium stearate.

### Claim 11 (depends on 1)

A method of treating a condition selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders in an achlorhydric patient, the method comprising administering the pharmaceutical composition of claim 1 to a patient in need of such treatment.