# US 11,304,906 B2 · Controlled release granulations of water-soluble active pharmaceutical ingredients

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- Number: US 11,304,906 B2
- Document ID: US11304906B2
- Status: Granted
- Kind: B2
- Application number: 17/350,939
- Filed: 2021-06-17
- Published: 2021-12-23
- Granted: 2022-04-19
- Earliest claimed: 2020-06-18
- Assignees: Xwpharma Ltd.
- Applicants: Xwpharma Ltd.
- Inventors: Sami Karaborni; Daniel M. Canafax; Jia-Ning Xiang; William W. Xiang; James Tien; Nicolas D. Kirkland
- Web page: https://patentgrep.com/patent/US11304906B2

## CPC

- 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 9/1611: {Inorganic compounds}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- 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 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/223: of alpha-aminoacids
- A61K 31/225: Polycarboxylic acids
- 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)

## Abstract

Pharmaceutical granulations having a functional coating surrounding a core containing a water-soluble active pharmaceutical ingredient are disclosed. The functional coating provides for immediate release or controlled release of the active pharmaceutical ingredient. The pharmaceutical granulations can be used in oral pharmaceutical compositions.

## Claims

### Claim 1

A pharmaceutical granulation for once a day dosing comprising a plurality of coated granules, wherein,
the coated granules comprise a core and a controlled release coating surrounding the core;
the core comprises from 90.0 wt % to 99.5 wt % of a compound of Formula (2):
or a pharmaceutically acceptable salt thereof, wherein,
R1 is selected from hydrogen and C1-6 alkyl; and
each of R2 and R3 is independently selected from hydrogen, C1-6 alkyl, C1-6 alkoxycarbonyl, and C3-6 cycloalkoxycarbonyl;
wherein wt % is based on the total weight of the core;
the coated granules are characterized by a particle size distribution (PSD) (D50) from 150 μm to 500 μm, wherein the particle size distribution is determined by laser diffraction;
the coated granules comprise from 50 wt % to 95 wt % of the compound of Formula (2), wherein wt% is based on the total weight of the coated granules;
the controlled release coating comprises:
from 60 wt % to 85 wt % of a matrix polymer, wherein the matrix polymer comprises:
from 92 wt % to 98 wt % of a water-insoluble polymer; and
from 2 wt % to 8 wt % of a water-soluble polymer,
wherein wt % is based on the total weight of the matrix polymer;
from 10 wt % to 20 wt % of talc; and
from 3 wt % to 13 wt % of dibutyl sebacate,
wherein wt % is based on the total weight of the controlled release coating; and
the controlled release coating has a thickness from 5 μm to 40 μm.

### Claim 2 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the water-insoluble polymer comprises ethylcellulose.

### Claim 3 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the water soluble polymer comprises hydroxypropyl cellulose.

### Claim 4 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the coated granules comprise:
from 55 wt % to 90 wt % of the core; and
from 10 wt % to 45 wt % of the controlled release coating,
wherein wt % is based on the total weight of the coated granules.

### Claim 5 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the controlled release coating has a thickness from 5 μm to 30 μm.

### Claim 6 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the compound of Formula (2) has an aqueous solubility greater than 100 mg/mL.

### Claim 7 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the compound of Formula (2) is selected from:
4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid;
4-(glycyloxy)butanoic acid;
4-((D-valyl)oxy)butanoic acid;
4-((L-alanyl)oxy)butanoic acid;
4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;
4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;
4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;
4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid;
4-((L-valyl)oxy)butanoic acid;
a pharmaceutically acceptable salt of any of the foregoing; and
a combination of any of the foregoing.

### Claim 8 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the compound of Formula (2) comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof:

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the pharmaceutical granulation of claim 1.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises from 500 mg equivalents to 12 g equivalents of γ-hydroxybutyric acid.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9, wherein the compound of Formula (2) comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof:

### Claim 12 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (2) for treating excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in a patient with Parkinson's disease, fatigue in a patient with multiple sclerosis, or fibromyalgia.

### Claim 13 (depends on 9)

A method of providing a therapeutically effective amount of γ-hydroxybutyric acid in the systemic circulation of a patent for treating a disease comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 9 for treating the disease, wherein the disease is selected from excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in a patient with Parkinson's disease, fatigue in a patient with multiple sclerosis, and fibromyalgia.

### Claim 14 (depends on 1)

The pharmaceutical granulation of claim 1, wherein,
the water-soluble polymer comprises ethylcellulose; and
the water-insoluble polymer comprises hydroxypropylcellulose.

### Claim 15 (depends on 1)

The pharmaceutical granulation of claim 1, wherein the core is characterized by:
an average sphericity greater than 0.90, wherein sphericity is determined using wet dispersion particle shape methods or by dynamic image analysis; and
a friability value less than 2 wt %, wherein friability is determined using a sonic sifter.

### Claim 16 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises an oral suspension.