# US 2018/0021284 A1 · 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 2018/0021284 A1 - Document ID: US20180021284A1 - Status: Published application - Kind: A1 - Application number: 15/655,924 - Filed: 2017-07-21 - Published: 2018-01-25 - Earliest claimed: 2016-07-22 - Assignees: Flamel Ireland Limited - Applicants: Flamel Ireland Limited - Inventors: Claire Mégret; Hervé Guillard; Jean-François DUBUISSON - Web page: https://patentgrep.com/patent/US20180021284A1 ## CPC - A61K 31/22: of acyclic acids, e.g. pravastatin - 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 9/5015: {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 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/20: Hypnotics; Sedatives - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - 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 (canceled) ### Claim 2 A modified release formulation of gamma-hydroxybutyrate, wherein a 7.5 g dose of the formulation has been shown to achieve a mean AUCinf of greater than 340 hr*microgram/mL, and a mean C8h that is from 50% to 130% of the mean C8h provided by an equal dose of immediate release liquid solution of sodium oxybate administered at to and t4h in equally divided doses approximately two hours after a standardized evening meal. ### Claim 3 (canceled) ### Claim 4 A modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: a) the formulation releases at least 80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm, b) the formulation releases from 10% to 65%, of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm, and c) the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm. ### Claim 5 (canceled) ### Claim 6 (canceled) ### Claim 7 (canceled) ### Claim 8 A modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: a) said immediate release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm; b) said modified release portion releases less than 20% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm; c) said modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm; and d) said modified release portion releases greater than 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm. ### Claim 9 (canceled) ### Claim 10 (canceled) ### Claim 11 (canceled) ### Claim 12 (canceled) ### Claim 13 (canceled) ### Claim 14 (canceled) ### Claim 15 (canceled) ### Claim 16 (canceled) ### Claim 17 (canceled) ### Claim 18 (canceled) ### Claim 19 (canceled) ### Claim 20 (canceled) ### Claim 21 (canceled) ### Claim 22 (depends on 4) The formulation of claim 4, comprising immediate release and modified release portions, wherein said modified release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm. ### Claim 23 (canceled) ### Claim 24 (canceled) ### Claim 25 (canceled) ### Claim 26 (depends on 4) The formulation of claim 4, wherein the formulation achieves an in vitro dissolution profile: a) measured in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm, characterized by the percentage of gamma-hydroxybutyrate dissolved being: (i) from 40% to 65% at 1 hour, (ii) from 40% to 65% at 3 hours, (iii) from 47% to 85% at 8 hours, (iv) greater or equal to 60% at 10 hours, (v) greater or equal to 80% at 16 hours, and b) measured in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm, characterized by the percentage of gamma-hydroxybutyrate dissolved being: (i) from 43% to 94% at 0.25 hour, (ii) greater or equal to 65% at 0.35 hour, and (iii) greater or equal to 88% at 1 hour. ### Claim 27 (canceled) ### Claim 28 (depends on 4) The formulation of claim 4, wherein a 7.5 g dose of the formulation has been shown to achieve a mean AUCinf of greater than 340 hr·microgram/mL, and a mean C8h that is from 50% to 130% of the mean C8h provided by an equal dose of immediate release liquid solution of sodium oxybate administered at to and t4h in equally divided doses approximately two hours after a standardized evening meal. ### Claim 29 (canceled) ### Claim 30 (canceled) ### Claim 31 (canceled) ### Claim 32 (canceled) ### Claim 33 (depends on 4) The formulation of claim 4, wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 40/60 to 60/40. ### Claim 34 (canceled) ### Claim 35 (depends on 4) The formulation of claim 4, wherein: a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; b) the coating of said modified release particles of gamma-hydroxybutyrate comprises a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40° C.; and c) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35. ### Claim 36 (depends on 4) The formulation of claim 4, wherein: a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; b) the coating of said modified release particles of gamma-hydroxybutyrate comprises a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40° C.; c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups to is from 0.4 to 4; d) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and e) the coating is from 10 to 50% of the weight of the particles. ### Claim 37 (depends on 4) The formulation of claim 4, wherein: a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; b) the coating of said modified release particles of gamma-hydroxybutyrate comprises a polymer carrying free carboxylic groups having a pH trigger of from 5.5 to 6.97 and a hydrophobic compound having a melting point equal or greater than 40° C.; c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4; d) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and e) the coating is from 10 to 50% of the weight of the particles. ### Claim 38 (canceled) ### Claim 39 (depends on 35) The formulation of claim 35 wherein the polymer carrying free carboxylic groups is selected from the group consisting of: (meth)acrylic acid/alkyl (meth)acrylate copolymers or methacrylic acid and methyl methacrylate copolymers or methacrylic acid and ethyl acrylate copolymers or methacrylic acid copolymers type A, B or C, cellulose derivatives carrying free carboxylic groups, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate carboxymethylethyl cellulose, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginate, and mixtures thereof. ### Claim 40 (depends on 35) The formulation of claim 35 wherein the polymer carrying free carboxylic groups is selected from the group consisting of copolymers of methacrylic acid and ethyl acrylate 1:1, copolymers of methacrylic acid and methylmethacrylate 1:2, and mixtures thereof. ### Claim 41 (depends on 35) The formulation of claim 35 wherein the hydrophobic compound is selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, wax yellow, wax white, wax microcrystalline, lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogol glycerides, polyglyceryl diisostearate, diesters or triesters of glycerol with a fatty acid, and mixtures thereof. ### Claim 42 (depends on 35) The formulation of claim 35 wherein the hydrophobic compound is selected from the group consisting of hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimyristin, yellow wax, hard fat or fat that is useful as suppository bases, anhydrous dairy fats, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogol glycerides, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof. ### Claim 43 (depends on 35) The formulation of claim 35 wherein the hydrophobic compound is selected from the group consisting of hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimyristin, beeswax, hydrogenated poly-1 decene, carnauba wax, and mixtures thereof. ### Claim 44 (depends on 35) The formulation of claim 35 wherein: a) the polymer carrying free carboxylic groups comprises from 100% poly (methacrylic acid, ethyl acrylate) 1:1 and 0% poly (methacrylic acid, methylmethacrylate) 1:2 to 2% poly (methacrylic acid, ethyl acrylate) 1:1 and 98% poly (methacrylic acid, methylmethacrylate) 1:2; and b) the hydrophobic compound comprises hydrogenated vegetable oil. ### Claim 45 (canceled) ### Claim 46 (canceled) ### Claim 47 (depends on 34) The formulation of claim 34 in the form of a powder that is intended to be dispersed in water prior to administration, further comprising an acidifying agent and a suspending or viscosifying agent. ### Claim 48 (canceled) ### Claim 49 (depends on 34) The formulation of claim 34 in the form of a powder that is intended to be dispersed in water prior to administration, further comprising from 1 to 15% of a viscosifying or suspending agent. ### Claim 50 (canceled) ### Claim 51 (canceled) ### Claim 52 (canceled) ### Claim 53 (canceled) ### Claim 54 (canceled) ### Claim 55 (canceled) ### Claim 56 (depends on 4) The formulation of claim 4 wherein a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose of the formulation or any combination thereof has been shown to achieve a ratio of mean AUC8h to mean AUCinf of greater than 0.80 when administered once approximately two hours after a standardized evening meal. ### Claim 57 (canceled) ### Claim 58 (canceled) ### Claim 59 (canceled) ### Claim 60 (depends on 4) The formulation of claim 4 wherein the modified release portion and the immediate release portion comprise structurally discreet modified release particles and immediate release particles. ### Claim 61 (depends on 4) The formulation of claim 4 wherein the modified release portion and the immediate release portion comprise structurally indiscreet particles. ### Claim 62 (canceled) ### Claim 63 (canceled) ### Claim 64 (depends on 4) The formulation of claim 4 in a dosage form selected from the group consisting of tablets, powders and capsules. ### Claim 65 (depends on 4) The formulation of claim 4 wherein the gamma-hydroxybutyrate is in the form of sodium oxybate. ### Claim 66 (depends on 4) The formulation of claim 4 in the form of a powder. ### Claim 67 (depends on 4) The formulation of claim 4 effective to treat narcolepsy Type 1 or Type 2, wherein said treatment of narcolepsy is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplectic attacks. ### Claim 68 (depends on 4) The formulation of claim 4 effective to induce sleep for eight consecutive hours. ### Claim 69 (canceled) ### Claim 70 (canceled) ### Claim 71 (canceled) ### Claim 72 (canceled) ### Claim 73 (depends on 4) The formulation of claim 4, wherein the formulation releases greater than 60% of its gamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. ### Claim 74 (depends on 8) The formulation of claim 8, wherein said modified release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.