# US 2016/0256397 A1 · Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor

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- Number: US 2016/0256397 A1
- Document ID: US20160256397A1
- Status: Published application
- Kind: A1
- Application number: 15/060,010
- Filed: 2016-03-03
- Published: 2016-09-08
- Earliest claimed: 2015-03-03
- Assignees: Pharmacyclics, Inc.
- Applicants: Pharmacyclics LLC
- Inventors: Ching W. Chong; Robert Kuehl; Heow Tan; Harisha Atluri
- Web page: https://patentgrep.com/patent/US20160256397A1

## CPC

- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- 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 9/2095: {Tabletting processes}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- 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

Described herein are pharmaceutical formulations of Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one. Also disclosed are methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

## Claims

### Claim 1

A high-load solid tablet formulation comprising ibrutinib and one or more pharmaceutically acceptable excipients, wherein ibrutinib is a compound with the structure of Compound 1,
and wherein the high-load solid tablet formulation comprises at least 50% w/w of ibrutinib.

### Claim at position 2

-3. (canceled)

### Claim 4 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the high-load solid tablet formulation comprises about 60% w/w to about 80% w/w of ibrutinib.

### Claim at position 4

-6. (canceled)

### Claim 7 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the one or more excipients are selected from the group consisting of diluents, binders, disintegrating agents, lubricants, glidants, and surfactants.

### Claim 8

(canceled)

### Claim 9 (depends on 7)

The high-load solid tablet formulation of claim 7, wherein
the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, and talc;
the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum;
the binder is hydroxypropyl cellulose or polyvinylpyrrolidone;
the surfactant is sodium lauryl sulfate;
the glidant is silica (colloidal silicon dioxide); and
the lubricant is magnesium stearate.

### Claim at position 8

-35. (canceled)

### Claim 36 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the excipients comprise lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide and magnesium stearate.

### Claim 37 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the formulation comprises intragranular and extragranular excipients; and the intragranular excipients comprise lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

### Claim 38 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein
the intragranular excipients comprise:
lactose in an amount from about 5% w/w to about 20% w/w, about 8% w/w to about 15% w/w, or about 8% w/w to about 14% w/w;
microcrystalline cellulose in an amount from about 5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about 15% w/w;
croscarmellose sodium in an amount from about 0 to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w to about 4% w/w; and
hydroxypropyl cellulose in an amount from about 0 to about 2% w/w, about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1% w/w; and
the extragranular excipients comprise
croscarmellose sodium in an amount from about 0 to about 5% w/w, about 2% w/w to about 5% w/w, or about 2% w/w to about 5% w/w;
sodium lauryl sulfate in an amount from about 0 to about 10% w/w, about 4% w/w to about 8% w/w, or about 5% w/w to about 6% w/w;
colloidal silicon dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and
magnesium stearate in an amount from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.

### Claim 39 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the formulation comprises intragranular and extragranular excipients; and the intragranular excipients comprise lactose, sodium lauryl sulfate, polyvinylpyrrolidone and croscarmellose sodium; and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

### Claim 40 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein
the intragranular excipients comprise:
lactose in an amount from about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
polyvinylpyrrolidone in an amount from about 0% w/w to about 5% w/w, or about 1% w/w to about 3% w/w;
croscarmellose sodium in an amount from about 1% w/w to about 10% w/w, or about 3% w/w to about 7% w/w; and
sodium lauryl sulfate in an amount from about 0% w/w to about 2% w/w, or about 0.5% w/w to about 1.5% w/w; and
the extragranular excipients comprise
croscarmellose sodium in an amount from about 0% w/w to about 5% w/w, or about 1% w/w to about 3% w/w;
sodium lauryl sulfate in an amount from about 0% w/w to about 10% w/w or about 0% w/w to about 4% w/w;
microcrystalline cellulose in an amount from about 1% w/w to about 10% w/w, or about 2% w/w to about 5% w/w;
colloidal silicon dioxide in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and
magnesium stearate in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.

### Claim 41 (depends on 1)

The high-load solid tablet formulation of claim 1, comprising:
a) about 69% w/w to about 71% w/w of ibrutinib,
b) about 13% w/w to about 15% w/w of lactose monohydrate,
c) about 2% w/w to about 5% w/w of microcrystalline cellulose,
d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,
e) about 6% w/w to about 8% w/w of croscarmellose sodium,
f) about 1% w/w to about 4% w/w of sodium lauryl sulfate,
g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and
h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

### Claim 42 (depends on 1)

The high-load solid tablet formulation of claim 1, comprising:
a) about 70% w/w of ibrutinib,
b) about 14% w/w of lactose monohydrate,
c) about 5% w/w of microcrystalline cellulose,
d) about 2% w/w of polyvinylpyrrolidone,
e) about 7% w/w of croscarmellose sodium,
f) about 1% w/w of sodium lauryl sulfate,
g) about 0.5% w/w of colloidal silicon dioxide, and
h) about 0.5% w/w of magnesium stearate.

### Claim 43 (depends on 1)

The high-load solid tablet formulation of claim 1, comprising:
a) about 70% w/w of ibrutinib,
b) about 14% w/w of lactose monohydrate,
c) about 2% w/w of microcrystalline cellulose,
d) about 2% w/w of polyvinylpyrrolidone,
e) about 7% w/w of croscarmellose sodium,
f) about 4% w/w of sodium lauryl sulfate,
g) about 0.5% w/w of colloidal silicon dioxide, and
h) about 0.5% w/w of magnesium stearate.

### Claim 44 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the formulation comprises:
a) about 65% w/w to about 75% w/w of ibrutinib,
b) about 14% w/w to about 18% w/w of lactose monohydrate,
c) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,
d) about 0.5% w/w to about 1.5% w/w of sodium lauryl sulfate,
e) about 5% w/w to about 15% w/w of crospovidone,
f) about 0.3% w/w to about 0.7% w/w of colloidal silicon dioxide, and
g) about 0.3% w/w to about 0.7% w/w of magnesium stearate.

### Claim 45 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the formulation comprises:
a) about 59% w/w to about 61% w/w of ibrutinib,
b) about 13% w/w to about 15% w/w of lactose,
c) about 13% w/w to about 15% w/w of microcrystalline cellulose,
d) about 4% w/w to about 6% w/w of croscarmellose sodium,
e) about 5% w/w to about 7% w/w of sodium lauryl sulfate,
f) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and
g) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

### Claim 46 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the formulation comprises:
a) about 59% w/w to about 61% w/w of ibrutinib,
b) about 13% w/w to about 14% w/w of lactose,
c) about 13% w/w to about 14% w/w of microcrystalline cellulose,
d) about 2% w/w to about 3% w/w of croscarmellose sodium (intragranular),
e) about 0.8% w/w to about 1.2% w/w of hydroxypropyl cellulose,
f) about 2% w/w to about 3% w/w of croscarmellose sodium (extragranular),
g) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate,
h) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and
i) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

### Claim 47 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the formulation comprises:
a) about 69% w/w to about 71% w/w of ibrutinib,
b) about 8% w/w to about 9% w/w of lactose,
c) about 8% w/w to about 9% w/w of microcrystalline cellulose,
d) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (intragranular),
e) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (extragranular),
g) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate,
h) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and
i) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

### Claim 48 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein ibrutinib is in an amount of about 420 or about 560 mg.

### Claim 49 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the high-load solid tablet formulation is used for one tablet once a day dosing.

### Claim 50 (depends on 1)

The high-load solid tablet formulation of claim 1, wherein the high-load solid tablet formulation is prepared using a process comprising a wet granulation method.

### Claim 51 (depends on 1)

A method of treating a disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of the high-load solid tablet formulation of claim 1.

### Claim 52 (depends on 1)

A process for preparing the high-load solid tablet formulation of claim 1, wherein the process comprises a wet granulation method.

### Claim at position 26

-54. (canceled)