Claims for Patent: 12,097,175

Summary for Patent: 12,097,175

Title:	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
Abstract:	Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.
Inventor(s):	Claire Mégret, Hervé Guillard, Jean-François DUBUISSON
Assignee:	Flamel Ireland Ltd
Application Number:	US18/368,403
Patent Claims:	1. A pharmaceutical formulation comprising a single bedtime daily dose of gamma-hydroxybutyrate (GHB) equivalent to from 3.0 g to 12.0 g of sodium oxybate, wherein the formulation comprises: an immediate release (IR) portion comprising GHB; and a delayed release (DR) portion comprising particles, each of the particles comprising GHB and a coating covering the GHB of each particle, wherein the coating comprises: a polymer carrying free carboxylic groups and 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., wherein a weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4, wherein the coating is from 10 to 50% of the weight of the delayed release particles, and wherein the GHB of the IR portion is the same as or different from the GHB of the DR portion. 2. The formulation of claim 1, wherein the IR portion comprises particles comprising GHB. 3. The formulation of claim 1, wherein the IR portion is an immediate release liquid solution comprising GHB. 4. The formulation of claim 1, wherein the IR portion is coated on the coating of the DR portion. 5. The formulation of claim 1, wherein the IR portion is structurally indiscreet from the DR portion. 6. The formulation of claim 1, wherein the GHB of one or both the IR and DR portions of the formulation comprises at least one salt of GHB. 7. The formulation of claim 6, wherein the at least one salt of GHB is selected from the sodium salt of GHB, the potassium salt of GHB, the magnesium salt of GHB, the calcium salt of GHB, the lithium salt of GHB, the tetra ammonium salt of GHB, and any other pharmaceutically acceptable salt forms of GHB. 8. The formulation of claim 7, wherein the GHB of one or both the IR and DR portions of the formulation comprises sodium oxybate. 9. The formulation of claim 1, wherein the GHB of one or both the IR and DR portions of the formulation comprises the free base of GHB, a pharmaceutically acceptable salt of GHB, hydrates, solvates, complexes, tautomers forms, and combinations thereof. 10. The formulation of claim 1, 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 methylmethacrylate copolymers or methacrylic acid and ethyl acrylate copolymers or methacrylic acid copolymers type A, B or C, 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. 11. The formulation of claim 1, wherein the polymer carrying free carboxylic groups is methacrylic acid copolymers type A, B or C. 12. The formulation of claim 11, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.3 g of methacrylic acid copolymer type B. 13. The formulation of claim 11, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.2 g of methacrylic acid copolymer type C. 14. The formulation of claim 1, further comprising an acidifying agent separate from the IR portion and the DR portion. 15. The formulation of claim 14, 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. 16. The formulation of claim 15, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.1 g to 0.2 g of malic acid. 17. The formulation of claim 1, further comprising a binding agent. 18. The formulation of claim 17, wherein the binding agent is selected from the group consisting of low molecular weight polyvinylpyrrolidone or povidone, low molecular weight hydroxypropyl cellulose, low molecular weight hydroxypropyl methylcellulose or hypromellose and mixtures thereof. 19. The formulation of claim 17, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.2 g of povidone. 20. The formulation of claim 1, wherein the hydrophobic compound is selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, wax yellow, wax white, wax microcrystalline, lanolin, anhydrous dairy fat, hard fat suppository base, lauroyl macrogol glycerides, polyglyceryl diisostearate, diesters or triesters of glycerol with a fatty acid, and mixtures thereof. 21. The formulation of claim 20, 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, yellow wax, anhydrous milk fats, lanolin, glyceryl palmitostearate, glyceryl stearate, diethylene glycol monostearate, ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof. 22. The formulation of claim 20, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.6 g to 0.7 g of hydrogenated vegetable oil. 23. The formulation of claim 1, further comprising a suspending or viscosifying agent separate from the IR portion and the DR portion. 24. The formulation of claim 23, wherein the suspending or viscosifying agent are selected from the group consisting of microcrystalline cellulose, xanthan gum, medium viscosity sodium carboxymethyl cellulose, mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose, mixtures of microcrystalline cellulose and guar gum, medium viscosity hydroxyethyl cellulose, agar, sodium alginate, mixtures of sodium alginate and calcium alginate, gellan gum, carrageenan gum grade iota, kappa or lambda, medium viscosity hydroxypropylmethyl cellulose, and combinations thereof. 25. The formulation of claim 24, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.8 g of microcrystalline cellulose. 26. The formulation of claim 24, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.1 g xanthan gum. 27. The formulation of claim 24, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.1 g hydroxyethylcellulose. 28. The formulation of claim 24, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, and the formulation comprises approximately 0.1 g carrageenan gum. 29. The formulation of claim 1, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, 0.8 g microcrystalline cellulose, 0.2 g povidone, 0.7 g hydrogenated vegetable oil, 0.2 g methacrylic acid copolymer C, 0.3 g methacrylic acid copolymer type B, and 0.1 g malic acid. 30. The formulation of claim 1, wherein the formulation comprises an amount of GHB equivalent to 4.5 g of sodium oxybate, 0.8 g microcrystalline cellulose, 0.2 g povidone, 0.6 g hydrogenated vegetable oil, 0.2 g methacrylic acid copolymer C, 0.3 g methacrylic acid copolymer type B, 0.2 g malic acid, and 0.3 g hydroxypropyl cellulose.