# US 11,896,572 B2 · Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

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- Number: US 11,896,572 B2
- Document ID: US11896572B2
- Status: Granted
- Kind: B2
- Application number: 18/231,581
- Filed: 2023-08-08
- Published: 2023-11-30
- Granted: 2024-02-13
- Earliest claimed: 2016-07-22
- Assignees: Flamel Ireland Limited
- Applicants: Flamel Ireland Limited
- Inventors: Jordan Dubow; Hervé Guillard; Claire Mégret; Jean-François Dubuisson
- Web page: https://patentgrep.com/patent/US11896572B2

## CPC

- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/10: Dispersions; Emulsions
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/5078: {with drug-free core}
- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K 9/5089: {Processes}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61P 25/00: Drugs for disorders of the nervous system
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- 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

Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.

## Claims

### Claim 1

A pharmaceutical composition comprising:
immediate release particles, each of which comprises:
a core consisting of microcrystalline cellulose; and
a sodium oxybate loaded layer covering the core and containing a binder comprising povidone, wherein the immediate release particles have a volume mean diameter of 150 to 400 microns;
delayed release particles having a pH trigger, each delayed release particle comprising:
a core consisting of microcrystalline cellulose;
a sodium oxybate loaded layer covering the core of each delayed release particle and containing a binder comprising povidone; and
a coating covering the sodium oxybate loaded layer of each delayed release particle, wherein the coating consists essentially of hydrogenated vegetable oil, methacrylic acid copolymer type C and methacrylic acid copolymer type B, wherein a weight ratio of the hydrogenated vegetable oil to the copolymers types B and C is from 0.4 to 4, and wherein the coating is from 10 to 50% of the weight of the delayed release particles, and wherein the delayed release particles have a volume mean diameter of 200 to 800 microns;
a suspending or viscosifying agent comprising 2% to 5% by weight of the composition, the suspending or viscosifying agent being a mixture of xanthan gum, carrageenan and hydroxyethylcellulose; and
an acidifying agent comprising 1.2% to 5% by weight of the composition, the acidifying agent being malic acid,
wherein the composition comprises from 3.0 to 12.0 g of sodium oxybate,
wherein a ratio of sodium oxybate in the immediate release particles and the delayed release particles is from 40/60 to 60/40,
wherein the composition is in the form of a powder that is intended to be suspended in water prior to oral administration, and
wherein the suspending or viscosifying agent and the acidifying agent are separate from the immediate release particles and the delayed release particles.