# US 11,026,939 B2 · High dosage valbenazine formulation and compositions, methods, and kits related thereto

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- Number: US 11,026,939 B2
- Document ID: US11026939B2
- Status: Granted
- Kind: B2
- Application number: 17/074,278
- Filed: 2020-10-19
- Published: 2021-02-04
- Granted: 2021-06-08
- Earliest claimed: 2017-09-21
- Assignees: Neurocrine Biosciences, Inc.
- Applicants: Neurocrine Biosciences, Inc.
- Inventors: Richard Alexander Moore, Jr.; Gregory A. McClelland; Christopher F. O{grave over ( )}Brien
- Web page: https://patentgrep.com/patent/US11026939B2

## CPC

- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 9/4858: {Organic compounds}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 25/00: Drugs for disorders of the nervous system
- 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

Solid pharmaceutical compositions with high drug loading are provided. A formulation useful for the solid pharmaceutical composition includes valbenazine, or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, isomalt, hydroxypropyl methylcellulose, partially pregelatinized maize starch, and magnesium stearate.

## Claims

### Claim 1

A unit dosage form comprising:
(S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate;
silicified microcrystalline cellulose;
isomalt;
hydroxypropyl methylcellulose;
partially pregelatinized maize starch; and
magnesium stearate;
wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level ranging from about 20 mg to 160 mg as measured as the free base, and
(S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of at least 30% by weight of the total weight of the unit dosage form.

### Claim 2 (depends on 1)

The unit dosage form of claim 1, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 20 mg as measured as the free base.

### Claim 3 (depends on 1)

The unit dosage form of claim 1, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 40 mg as measured as the free base.

### Claim 4 (depends on 1)

The unit dosage form of claim 1, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 60 mg as measured as the free base.

### Claim 5 (depends on 1)

The unit dosage form of claim 1, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 80 mg as measured as the free base.

### Claim 6 (depends on 1)

The unit dosage form of claim 1, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 100 mg as measured as the free base.

### Claim 7 (depends on 1)

The unit dosage form of claim 1, wherein the unit dosage form is suitable for oral administration.

### Claim 8 (depends on 1)

The unit dosage form of claim 1, wherein the unit dosage form is formulated for dosing once daily.

### Claim 9 (depends on 1)

The unit dosage form of claim 1, wherein the unit dosage form is in a capsule form.

### Claim 10 (depends on 9)

The unit dosage form of claim 9, wherein the capsule is a size 3 capsule or smaller.

### Claim 11 (depends on 9)

The unit dosage form of claim 9, wherein the capsule is a size 2 capsule or smaller.

### Claim 12 (depends on 9)

The unit dosage form of claim 9, wherein the capsule is a size 1 capsule or smaller.

### Claim 13 (depends on 9)

The unit dosage form of claim 9, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 40 mg as measured as the free base and the capsule is a size 2 capsule or smaller.

### Claim 14 (depends on 9)

The unit dosage form of claim 9, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 60 mg as measured as the free base and the capsule is a size 2 capsule or smaller.

### Claim 15 (depends on 9)

The unit dosage form of claim 9, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 80 mg as measured as the free base and the capsule is a size 1 capsule or smaller.

### Claim 16 (depends on 1)

The unit dosage form of claim 1, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate has a d(0.9) particle size distribution less than 100 μm.

### Claim 17 (depends on 1)

The unit dosage form of claim 1, wherein said dosage form comprises:
about 40 wt % of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate;
about 25 wt % of silicified microcrystalline cellulose;
about 20 wt % of isomalt;
about 5 wt % of hydroxypropyl methylcellulose;
about 7.5 wt % of partially pregelatinized maize starch;
about 2.5 wt % of magnesium stearate; and
the unit dosage form is in a capsule form that is a size 1 capsule or smaller.

### Claim 18 (depends on 17)

The unit dosage form of claim 17, wherein the capsule is a size 2 capsule or smaller.

### Claim 19 (depends on 17)

The unit dosage form of claim 17, wherein the unit dosage form is suitable for oral administration.

### Claim 20 (depends on 17)

The unit dosage form of claim 17, wherein the unit dosage form is formulated for dosing once daily.

### Claim 21 (depends on 17)

The unit dosage form of claim 17, wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate has a d(0.9) particle size distribution less than 100 μm.

### Claim 22 (depends on 1)

A method of treating a hyperkinetic movement disorder in a patient in need thereof, comprising administering to the patient the unit dosage form of claim 1.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the hyperkinetic movement disorder is tardive dyskinesia.

### Claim 24 (depends on 22)

The method according to claim 22, wherein the hyperkinetic movement disorder is chorea.

### Claim 25 (depends on 24)

The method according to claim 24, wherein chorea is associated with Huntington's disease.

### Claim 26 (depends on 17)

A method of treating a hyperkinetic movement disorder in a patient in need thereof, comprising administering to the patient the unit dosage form of claim 17.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the hyperkinetic movement disorder is tardive dyskinesia.

### Claim 28 (depends on 26)

The method according to claim 26, wherein the hyperkinetic movement disorder is chorea.

### Claim 29 (depends on 28)

The method according to claim 28, wherein chorea is associated with Huntington's disease.