# US 12,109,186 B2 · Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,109,186 B2 - Document ID: US12109186B2 - Status: Granted - Kind: B2 - Application number: 18/531,095 - Filed: 2023-12-06 - Published: 2024-06-06 - Granted: 2024-10-08 - 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/US12109186B2 ## 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 formulation for the treatment of narcolepsy or a symptom thereof, comprising: (a) an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate; (b) microcrystalline cellulose spheres; (c) methacrylic acid and methyl methacrylate copolymer; (d) methacrylic acid and ethyl acrylate copolymer, (e) hydrogenated vegetable oil; and (f) an acidifying agent, wherein the weight ratio of the methacrylic acid and methyl methacrylate copolymer to the methacrylic acid and ethyl acrylate copolymer is about 2:1 (w/w), and wherein the formulation is designed to be administered orally only once nightly. ### Claim 2 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent is selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid, and mixtures thereof. ### Claim 3 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent is selected from the group consisting of malic acid, tartaric acid, and mixtures thereof. ### Claim 4 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent comprises 1.2% to 15% (w/w) of the formulation. ### Claim 5 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent comprises 1.2% to 10% (w/w) of the formulation. ### Claim 6 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent comprises 1.2% to 5% (w/w) of the formulation. ### Claim 7 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent comprises 1.6% to 3.2% (w/w) of the formulation. ### Claim 8 (depends on 1) The pharmaceutical formulation of claim 1, wherein the acidifying agent comprises about 1.6% (w/w) of the formulation. ### Claim 9 A pharmaceutical formulation for the treatment of narcolepsy or a symptom thereof, comprising: (a) an amount of gamma-hydroxybutyrate equivalent to 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g, or 12.0 g of sodium oxybate; (b) microcrystalline cellulose spheres; (c) methacrylic acid and methyl methacrylate copolymer; (d) methacrylic acid and ethyl acrylate copolymer, (e) hydrogenated vegetable oil; and (f) malic acid, wherein the weight ratio of the methacrylic acid and methyl methacrylate copolymer to the methacrylic acid and ethyl acrylate copolymer is about 2:1 (w/w), and wherein the formulation is designed to be administered orally only once nightly. ### Claim 10 A pharmaceutical formulation for the treatment of narcolepsy or a symptom thereof, comprising: an immediate release portion comprising gamma-hydroxybutyrate; a delayed release portion comprising gamma-hydroxybutyrate and a coating, the coating comprising: about 4.48% (w/w) methacrylic acid and methyl methacrylate copolymer; about 2.23% (w/w) methacrylic acid and ethyl acrylate copolymer; about 10.07% (w/w) hydrogenated vegetable oil; and an acidifying agent. ### Claim 11 A pharmaceutical formulation for the treatment of narcolepsy or a symptom thereof, comprising: an immediate release portion comprising gamma-hydroxybutyrate; and a delayed release portion comprising gamma-hydroxybutyrate and a coating, the coating comprising: about 0.318 g methacrylic acid and methyl methacrylate copolymer; about 0.159 g methacrylic acid and ethyl acrylate copolymer; and about 0.716 g hydrogenated vegetable oil; and malic acid, wherein the amount of gamma-hydroxybutyrate in the formulation is equivalent to 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g, or 12.0 g of sodium oxybate.