Controlled release granulations of water-soluble active pharmaceutical ingredients

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,

R 1 is selected from hydrogen and C 1-6 alkyl; and

each of R 2 and R 3 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxycarbonyl, and C 3-6 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.

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

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

4. 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.

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

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

7. 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.

8. 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:

9. A pharmaceutical composition comprising the pharmaceutical granulation of claim 1 .

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

11. 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:

12. 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.

13. 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.

14. The pharmaceutical granulation of claim 1 , wherein,

the water-soluble polymer comprises ethylcellulose; and

the water-insoluble polymer comprises hydroxypropylcellulose.

15. 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.

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