Modified release pharmaceutical composition comprising gamma-hydroxybutyrate

Abstract

The present invention relates to modified release formulations of gamma-hydroxybutyrate comprising an immediate release component, a delayed release component, and one or more stabilizing agents and / or lipophilic surfactants. The stabilizing agents and / or lipophilic surfactants may be present in the immediate release component, the delayed release component, or both.

Description

[0001] MODIFIED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING GAMMA-HYDROXYBUTYRATE

[0002] FIELD OF THE INVENTION:

[0003] The present invention relates to modified release pharmaceutical compositions of gamma-hydroxybutyrate and process for preparing thereof.

[0004] BACKGROUND OF THE INVENTION:

[0005] Sodium oxybate is also known as sodium 4-hydroxybutanoate, or gammahydroxybutyric acid sodium salt, and has the following chemical structure:

[0006] Sodium oxybate is a central nervous system (CNS) depressant used to treat cataplexy or excessive daytime sleepiness associated with narcolepsy. It is an endogenous cerebral inhibitory neurotransmitter and a metabolite of the inhibitory neurotransmitter GABA.

[0007] In 2002, Sodium oxybate liquid solution was approved in the United States as Xyrem® twice-nightly solution. The product is formulated as immediate release liquid solution taken once immediately before bed, and a second time approximately 2.5 to 4 hours later, in equal doses. The requirement to take Xyrem® twice each night is a substantial inconvenience to narcolepsy patients. The patient must typically set an alarm to take the second dose, which can interrupt ongoing productive sleep. Several efforts have been made to provide a once-nightly modified release dosage form of sodium oxybate.

[0008] In 2023, Sodium oxybate for extended-release oral suspension was approved in the United States as Lumryz®. The product is formulated as powder for extended-release oral suspension containing 4.5g, 6g, 7.5g, or 9g of sodium oxybate per packet to be administered once daily as a single dose at bedtime.

[0009] U.S. Pat. No. 8,193,211 Liang et al developed a pulse-release once-daily oral pharmaceutical dosage form of gamma-hydroxybutyrate salt with an immediate release component and several delayed release components. These formulations are tested in dogs alongside an immediate release formulation to compare the relative pharmacokinetics (PK) of these formulations. By encapsulating the gamma-hydroxybutyrate salt in an enteric / delayed release coating the AUC of the gamma-hydroxybutyrate salt decreased significantly.

[0010] U.S. Pat. No. 10,272,062 Megret et al developed a once daily modified release formulation of gamma-hydroxybutyrate that optimize the bioavailability of the gamma-hydroxybutyrate, and roughly approximate the bioavailability of an equal dose of an immediate release liquid solution of sodium oxybate administered twice nightly. The formulation preferably comprises immediate release and modified release portions, wherein the modified release portion comprises gamma hydroxybutyrate particles coated by a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40° C 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, lauryl macrogol glycerides, polyglyceryl diisostearate, diesters or triesters of glycerol with a fatty acid, and mixtures thereof.

[0011] The present inventors have developed alternative modified release pharmaceutical compositions of gamma-hydroxybutyrate and processes for the preparation thereof, which are easier to commercially operate and cost-effective. One such process involves the use of stabilizer in the modified release composition to prevent drug migration between layers and to increase the stability and shelf life of the multi-coated pharmaceutical formulation. Another such process involves the use of lipophilic surfactant in the modified release composition to achieve the desired dissolution profile and bioavailability which were also found to be comparable with the marketed formulation.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS:

[0013] FIG. 1 is a graph illustrating the percentage of drug release versus time for topcoated modified-release pellets in 0.1N HC1 followed by phosphate buffer.

[0014] FIG. 2 is a graph depicting comparative dissolution profiles (% drug release versus time) of the test product (Ex-7) and the marketed product (Lumryz) in 0. IN HC1 followed by phosphate buffer.

[0015] SUMMARY OF INVENTION:

[0016] According to an aspect of the present invention there is provided a modified release formulation of gamma-hydroxybutyrate comprising an immediate release component, a delayed release component, and one or more stabilizing agents and / or lipophilic surfactants, wherein the stabilizing agents and / or lipophilic surfactants are present in the immediate release component, the delayed release component or both.

[0017] According to another aspect of the present invention there is provided a modified release pharmaceutical composition comprising:

[0018] (1) an immediate release component comprising gamma-hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;

[0019] (2) a delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant. According to another aspect of the present invention there is provided a modified release formulation of gamma-hydroxybutyrate comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant and (d) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer.

[0020] According to another aspect of the present invention there is provided a delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0021] According to another aspect of the present invention there is provided a powder formulation comprising:

[0022] (1) an immediate release (IR) component comprising gamma- hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;

[0023] (2) a delayed release component comprising: (a) a core comprising gamma- hydroxybutyrate and optional stabilizer; and (b) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; and

[0024] (3) an extra-granular portion comprising one or more pharmaceutically acceptable excipients.

[0025] In one aspect, the present invention provides a modified release formulations of gamma-hydroxybutyrate (GHB) that are administered once daily at bedtime.

[0026] In another aspect, the present invention provides a modified release formulations of gamma-hydroxybutyrate comprising an immediate release component, and a delayed release component. In yet another aspect, the present invention provides a delayed release component comprising (a) a core comprising gamma-hydroxybutyrate, and one or more optional stabilizers; and (b) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0027] In another aspect, the present invention provides a delayed release component comprising (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant having a hydrophilic-lipophilic balance (HLB) of less than 25.

[0028] In yet another aspect, the present invention provides a delayed release component comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and lipophilic surfactants selected from stearic acid, palmitic acid and their glycerol esters and salts.

[0029] In another aspect, the present invention provides a delayed release component comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; (c) a drug layer comprising gamma- hydroxybutyrate and an optional stabilizer; (d) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (e) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0030] In another aspect, the present invention provides a delayed release component comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; (c) a drug layer comprising gamma- hydroxybutyrate and an optional stabilizer; (d) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (e) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant having a hydrophilic-lipophilic balance (HLB) of less than 25.

[0031] In yet another aspect, the present invention provides a modified release formulations of gamma-hydroxybutyrate comprising an immediate release (IR) component and a delayed release (DR) component, wherein the IR component and DR component are present as a single particle / bead or as separate particles / beads.

[0032] In another aspect, the present invention provides a modified release composition comprising multiple delayed release particles / beads and immediate release particles / beads of gamma-hydroxybutyrate in a single dosage form.

[0033] In another aspect, the present invention provides an immediate release particle / bead comprising gamma-hydroxybutyrate optionally with one or more stabilizers, lipophilic surfactants and one or more pharmaceutically acceptable excipients.

[0034] In another aspect, the present invention provides a modified release composition comprising multiple delayed release particles beads of gamma- hydroxybutyrate coated by an immediate release drug layer of gamma- hydroxybutyrate, where in both the layers are separated by one or more separating layers.

[0035] In another aspect, the present invention provides a modified release formulation comprising: (a) a delayed release component comprising gamma- hydroxybutyrate; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a drug layer comprising gamma- hydroxybutyrate and an optional stabilizer. In another aspect, the present invention provides a modified release formulation comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; (d) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (e) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer.

[0036] In another aspect, the present invention provides a modified release formulation comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; (c) a drug layer comprising gamma- hydroxybutyrate and an optional stabilizer; (d) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; (e) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; (f) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (g) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer.

[0037] In yet another aspect of the present invention, the immediate release component can be part of a delayed release unit or may be a separate immediate release component and the ratio of gamma-hydroxybutyrate in the immediate release portion to the delayed release portion ranges from 40:60 to 60:40.

[0038] In yet another aspect, the present invention provides a modified release formulations of gamma-hydroxybutyrate designed for once-nightly administration at bedtime, exhibiting improved dissolution profiles and reduced sodium content compared to an immediate release liquid solution of sodium oxybate administered twice nightly. In yet another aspect, the present invention provides a modified release composition of gamma-hydroxybutyrate further combined with one or more pharmaceutically excipients to prepare a dosage form.

[0039] DETAILED DESCRIPTION:

[0040] As used herein, the term “gamma-hydroxybutyrate” or “GHB” unless otherwise specified, refers to gamma hydroxy-butyric acid, a pharmaceutically acceptable salt of gamma-hydroxybutyric acid, and combinations thereof. gamma-hydroxybutyric acid salts can be selected from the sodium salt of gamma-hydroxybutyric acid or sodium oxybate, the potassium salt of gammahydroxybutyric acid or potassium oxybate, the magnesium salt of gammahydroxybutyric acid or magnesium oxybate, the calcium salt of gammahydroxybutyric acid or calcium oxybate, or any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid.

[0041] The term “immediate release” or “IR” or “Immediate release component” or “Immediate release particle” refers to a formulation that releases GHB almost immediately in 0.1N hydrochloric acid dissolution medium.

[0042] The term “modified release (MR)” encompasses any mode of release that is different from an immediate release.

[0043] The term “delayed release” or “DR” or “delayed release component” or “delayed release particle” refers to a formulation that releases GHB until a predetermined lag-time or the drug is subjected to a suitable dissolution medium such as a phosphate buffer pH 6.8 dissolution medium.

[0044] The term beads, particles, pellets, micro particles as used herein include a plurality of core pellets that in certain embodiments are substantially spherical beads. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0045] As set forth herein, an embodiment provides modified release pharmaceutical formulations of gamma-hydroxybutyrate (GHB) comprising an immediate release component, and a delayed release component.

[0046] In one embodiment, the present invention provides modified release formulations of gamma-hydroxybutyrate comprising an immediate release (IR) component and a delayed release (DR) component, wherein the IR component and DR component are present as a single particle / bead or as separate particles / beads.

[0047] In another embodiment, the present invention provides a modified release composition comprising multiple delayed release particles / beads and immediate release particles / beads of gamma-hydroxybutyrate in a single dosage form.

[0048] The dosage form comprising the formulation of present invention are in the form of beads, granules, powders, sachets, pouches, sprinkles, solutions and suspensions.

[0049] In another embodiment, the present invention provides modified release formulation of gamma-hydroxybutyrate comprising an immediate release component, a delayed release component, and one or more stabilizing agents and / or lipophilic surfactants, wherein the stabilizing agents and / or lipophilic surfactants are present in the immediate release component, delayed release component or both.

[0050] Stabilizing agents are used in the composition to prevent drug migration between layers in the pharmaceutical composition to achieve the desired release profile and improving the overall stability and shelf life of the multi-layered pharmaceutical formulation. A lipophilic surfactant is used in the composition to achieve the desired release profile of the drug from the formulation. The immediate release component can form part of a modified release unit dosage form or may be a separate immediate release component wherein the ratio of gamma-hydroxybutyrate in the immediate release portion to the modified release portion ranges from 40:60 to 60:40.

[0051] In one embodiment, the dosage form of the present invention comprising an immediate release component in the form of a core comprising gammahydroxybutyric acid present together with (or separated contained from) one or more delayed release components.

[0052] In another embodiment, the immediate release component is present in the form of a core comprising gamma-hydroxybutyric acid, optionally together with one or more stabilizers, lipophilic surfactants and one or more pharmaceutically acceptable excipients.

[0053] The core can include a drug containing core or a drug coated inert nonpareil bead core in which the drug core or drug layer can also contain. The drug containing core can be prepared by combining GHB, optionally together with one or more stabilizers, lipophilic surfactants and one or more pharmaceutically acceptable excipients.

[0054] In another embodiment, the immediate release component is present in the form of a core comprising gamma-hydroxybutyric acid, an optional stabilizer, an optional lipophilic surfactant having a hydrophilic-lipophilic balance (HLB) of less than 25 and one or more pharmaceutically acceptable excipients.

[0055] Processes that are used to produce formulations of this embodiment comprising a drug-containing core include solution or dry powder drug layering, compression coating, hot melt coating, supercritical fluid coating, electrostatic spray coating, agglomeration, granulation, pelletization, roller compaction, tablet compression, wet granulation with extrusion and spheronization, hot melt extrusion, and injection molding. In another embodiment, the drug containing core is coated with an overcoat, the overcoat can be a moisture barrier coat, a protection coat, a seal coat, a taste-masking coat, a flavor coat, a polish coat, a color coat, or any other cosmetic coats. Suitable coating materials for such an overcoat are known in the art, including, but are not limited to, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, microcrystalline cellulose carrageenan, and ethylcellulose and one or more pharmaceutically acceptable excipients.

[0056] In certain embodiments, the immediate release component of a modified release dosage is provided as a coating over a delayed release component as described herein.

[0057] An Immediate release component formed as a coating over a delayed release component as disclosed herein is applied as an overcoat according to conventional coating methods comprising GHB, an optional stabilizer and one or more pharmaceutically acceptable excipients, from a coating solution that utilizes an alcohol and water solvent, where desired or necessary based on the drug to be delivered from the IR component and delayed release component included in such an integrated dosage form, the outer surface of the IR component may then be coated with a film coating layer.

[0058] One embodiment of the present invention is a modified release dosage form comprising delayed release component of GHB, wherein each of the delayed release component is composed of (a) a core comprising gammahydroxybutyrate, optionally one or more stabilizers; and (b) a delayed release layer comprising pH dependent polymer and lipophilic surfactant.

[0059] In one embodiment, the total quantity of GHB in the delayed release component is present in the form of drug core or inert core coated with single drug layer or as multiple layers between the core and separating layer or separating layer and delayed release layer. These multiple layers of drug usually prevent dose dumping of GHB in the modified release formulation and achieve the desired release profile.

[0060] In another embodiment of the present invention, there is provided a modified release dosage form comprising (a) a core comprising gammahydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0061] Core comprising gamma-hydroxybutyrate and stabilizer as used here in the present invention is a drug containing core along with stabilizer or a drug coated inert non-pareil bead core in which the drug core or drug layer along with stabilizer can also contain, or the drug layer coated with a layer of stabilizer.

[0062] Stabilizing agents (stabilizer) as used here in the present invention prevent drug migration between layers in the pharmaceutical composition and to achieve the desired release profile. A lipophilic surfactant as used in the composition provides the desired release profile of the drug from the formulation.

[0063] Stabilizing agents defined herein include basic inorganic salts" of sodium, potassium, magnesium and / or calcium. Preferred are basic inorganic salts of magnesium and / or calcium. More preferred are basic inorganic salts of magnesium. Examples of the basic inorganic salts of sodium include sodium carbonate and sodium hydrogen carbonate. Examples of the basic inorganic salts of potassium include potassium carbonate and potassium hydrogen carbonate. Examples of the basic inorganic salt of magnesium include magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium aluminometasilicate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite and alumina magnesium hydroxide, preferably magnesium oxide, magnesium hydroxide, magnesium carbonate etc. Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide, etc. More preferably, the "basic inorganic salt" includes magnesium oxide, magnesium hydroxide and magnesium carbonate, etc.

[0064] Delayed release layer comprising lipophilic surfactant as used here in the present invention is a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant or a delayed release layer comprising a pH dependent polymer coated with one or more layers of Surfactant.

[0065] Lipophilic surfactants are defined herein as having a hydrophilic- lipophilic balance (HLB) of less than 25, preferably less than 20. Here, HLB is an empirical formula showing the relationship between the hydrophilic group and the lipophilic group of a surface active amphiphilic molecule such as a surfactant. This is used as an index of a surfactant, and its value is about 1 to about 45. The higher the HLB, the higher the water solubility of the surfactant. A lipophilic surfactant component may be required for the purpose of desirably releasing the drug from the formulation.

[0066] In one embodiment, the melting point of the lipophilic surfactant is from about 25°C. to about 100°C., preferably from about 35°C. to about 85°C., more preferably from 40°C. to about 80°C. The lipophilic surfactants suitable for the drug delivery system of the present invention include the following fatty acids, alcohols (C 6 -C 24, preferably C io -C 24, more preferably C 14 -C 24 are), for example, octanoic acid, decanoic, undecanoic, lauric, myristic, palmitic, stearic, oleic acids, linoleic acid isotearic acid, alcohols like palmitic alcohol, stearyl alcohol, olayl alcohol, lauric alcohol; the fatty acids can also be mixed with alcohols, such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol; with ethers, such as poly( ethylene glycol) 450. Among the lipophilic surfactants described above, those suitable as “release controlling” components include, but are not limited to: Stearic acid, palmitic acid and its glycerol and salts, and mixtures thereof.

[0067] In one embodiment, the present invention provides a delayed release component comprising (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0068] In another embodiment, the present invention provides a delayed release component comprising (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant having a hydrophilic-lipophilic balance (HLB) of less than 25.

[0069] In another embodiment, the present invention provides a delayed release component comprising (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; (c) a drug layer comprising gamma- hydroxybutyrate and an optional stabilizer; (d) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (e) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0070] In one embodiment, pH dependent coating materials for the delayed release coating in the present invention and the lipophilic surfactant components are combined in a single layer like in form of a matrix. A particular mixture of lipophilic surfactant and a pH dependent polymeric coating controls the release rate and release triggers.

[0071] The pH dependent polymeric coating materials include, but are not limited to, methacrylate-based coating materials such as polymers of methacrylic acid and methacrylates (e.g. Eudragit L 100-55, Eudragit L 30-D55, Eudragit L 100, Eudragit S 100, Eudragit FS 30 D), cellulose-based coating materials such as cellulose acetate phthalate, carboxymethyl ethylcellulose, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, Shellac -based coating materials such as Emcoat 120N and Marcoat 125, and other enteric coating polymers such as polyvinyl acetate phthalate.

[0072] The separating layers can optionally act as a controlled / delayed release coat to control the rate of release of gamma-hydroxybutyric acid salts from the immediate release core, allowing for site specific and controlled / delayed release of gamma-hydroxybutyric acid salts in the GI tract of a subject.

[0073] Suitable coating materials for the separating layer in the present invention include, but are not limited to, cellulosic polymers such as ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, or other water-based or solvent-based coating materials; optional stabilizers or surfactants as described herein and one or more pharmaceutically acceptable excipients.

[0074] In one embodiment, one or more pharmaceutically acceptable excipients as used in the composition, include, but are not limited to diluents (such as microcrystalline cellulose, starch, mannitol), binders (such as povidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose), disintegrants (such as croscarmellose sodium, crospovidone, sodium starch glycolate) lubricants (such as stearates) and glidants (such as colloidal silicon dioxide, talc).

[0075] The separating layers can also be multiple layers and acts as barrier layers of different coating materials. For example, the separating layers can have an Opadry AMB initial coat, an ethylcellulose secondary layer surrounding the initial coat, and a stabilzer or lipophilic surfactant based tertiary coat surrounding the secondary coat. The separating layers can be water-based coatings, or organic solventbased coatings. Preferably, the barrier coat is organic solvent-based coating such as an alcohol or alcohol- water or ketone based coating.

[0076] In certain embodiments, an overcoat is provided as a coating over a drug layer, separating layer or delayed release layer, the overcoat can be a moisture barrier coat, a protection coat, a seal coat, a taste-masking coat, a flavor coat, a polish coat, a color coat, or any other cosmetic coats. Suitable coating materials for such an overcoat are known in the art, including, but are not limited to, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, microcrystalline cellulose carrageenan, and ethylcellulose and one or more pharmaceutically acceptable excipients.

[0077] The pharmaceutically acceptable excipients as used here in the coating layers include, but are not limited to solvents, plasticizers (e.g. PEG, triethyl citrate, dibutyl sebacate), binding agents (e.g. polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose) anti-tack agents (e.g. Talc, colloidal silica), anti-foam agents, colorants, fillers / extenders, flavorants, and surfactants (e.g. sodium lauryl sulfate).

[0078] In another embodiment, the present invention provides a delayed release component comprising (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant having a hydrophilic-lipophilic balance (HLB) of less than 25.

[0079] In another embodiment, the present invention provides a modified release composition comprising multiple delayed release particles beads of gamma- hydroxybutyrate coated by an immediate release drug layer of gamma- hydroxybutyrate, where in both the layers are separated by one or more separating layers.

[0080] In one embodiment, the present invention provides a modified release formulation comprising: (a) a delayed release component comprising gammahydroxybutyrate; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (d) a drug layer comprising gammahydroxybutyrate and optional stabilizer selected from basic inorganic salt.

[0081] In another embodiment, the present invention provides a modified release composition comprising:

[0082] (1) an IR component comprising gamma-hydroxybutyrate and one or more pharmaceutically acceptable excipients;

[0083] (2) a delayed release component comprising gamma-hydroxybutyrate and one or more pharmaceutically acceptable excipients.

[0084] In another embodiment, the present invention provides a modified release composition comprising:

[0085] (1) an IR component comprising gamma-hydroxybutyrate and one or more pharmaceutically acceptable excipients;

[0086] (2) a delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; and (b) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0087] In another embodiment, the present invention provides a modified release composition comprising:

[0088] (1) an IR component comprising gamma-hydroxybutyrate, optional stabilizer and one or more pharmaceutically acceptable excipients;

[0089] (2) a delayed release component comprising: (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; and (b) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant. In another embodiment, the present invention provides a modified release composition comprising:

[0090] (1) an immediate release (IR) component comprising gamma-hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;

[0091] (2) a delayed release component comprising: (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

[0092] In another embodiment, the present invention provides a modified release composition comprising:

[0093] (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer;

[0094] (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants;

[0095] (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; and

[0096] (d) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer.

[0097] In another embodiment, the present invention provides a modified release composition comprising:

[0098] (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer;

[0099] (b) one or more separating layers comprising an optional stabilizer and / or lipophilic surfactant;

[0100] (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant;

[0101] (d) one or more separating layers comprising optional stabilizer and / or lipophilic surfactant; and

[0102] (e) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer. In another embodiment, the present invention provides a modified release composition comprising:

[0103] (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer;

[0104] (b) one or more separating layers comprising an optional stabilizer and / or lipophilic surfactant;

[0105] (c) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer;

[0106] (d) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants;

[0107] (e) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant;

[0108] (f) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and

[0109] (g) a drug layer comprising gamma-hydroxybutyrate and an optional stabilizer selected from basic inorganic salt.

[0110] In another embodiment, one or more seal coatings of different coating materials are provided between the drug layer and separating layer, separating layer and delayed release layer, delayed release layer and drug layer, over the drug layer. These coatings can be a barrier coat, a protection coat, a seal coat a taste-masking coat, a flavor coat, a polish coat, a color coat, or any other cosmetic coats comprising one or more pharmaceutically acceptable excipients.

[0111] In one embodiment, the modified release pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients selected from the group comprising of diluents, binders, disintegrants, surfactants, lubricants and glidants.

[0112] In another embodiment, the final size of the particles is 3 to 1000 microns (at best 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 microns, etc.). In another embodiment, the final size of the pharmaceutical particles is 10-500 microns. In one embodiment, the final size of the pharmaceutical particles is 50-600 microns. In another embodiment, the final size of the pharmaceutical particles is 100-900 microns.

[0113] In one embodiment of the present invention, the modified release composition of the present invention is combined with one or more pharmaceutically acceptable excipients to prepare a dosage form.

[0114] In another embodiment, the dosage form comprising the formulation of the present invention is in the form of micro particles, beads, granules, microspheres, powders, sachets, pouches, sprinkles, solutions and suspensions.

[0115] In another embodiment the present invention provides a powder formulation comprising:

[0116] (1) an immediate release (IR) component comprising gamma-hydroxybutyrate and one or more pharmaceutically acceptable excipients;

[0117] (2) a delayed release component comprising gamma-hydroxybutyrate and one or more pharmaceutically acceptable excipients; and

[0118] (3) an extra-granular portion comprising one or more pharmaceutically acceptable excipients.

[0119] In another embodiment, the present invention provides a powder formulation comprising:

[0120] (1) an immediate release (IR) component comprising gamma- hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;

[0121] (2) a delayed release component comprising: (a) a core comprising gamma- hydroxybutyrate and optional stabilizer; and (b) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; and (3) an extra-granular portion comprising one or more pharmaceutically acceptable excipients.

[0122] In another embodiment, the present invention provides a powder formulation comprising:

[0123] (1) an immediate release (IR) component comprising gamma-hydroxybutyrate, optional stabilizer and one or more pharmaceutically acceptable excipients;

[0124] (2) a delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; and

[0125] (3) an extra-granular portion comprising one or more pharmaceutically acceptable excipients.

[0126] In another embodiment, the present invention provides a powder formulation comprising:

[0127] (1) an immediate release (IR) component comprising gamma-hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;

[0128] (2) a delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; and

[0129] (3) an extra-granular portion comprising one or more pharmaceutically acceptable excipients selected from suspending or viscosifying agents, acidifying agents and combinations thereof.

[0130] The viscosifying agents are selected from the group consisting of hydroxypropyl cellulose, xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose hydroxypropyl methyl cellulose, and mixtures thereof.

[0131] The acidifying agents are 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;

[0132] In another embodiment, the powder dosage form as provided here in is intended to be dispersed in water prior to administration.

[0133] In a particular embodiment, one or more pharmaceutically acceptable excipients as disclosed here in the present invention include but not limited to binders, lubricants, anti-adherents, glidants, granulating aids, fillers, disintegrants, antioxidants, stabilizers, preservatives, neutralizing agents, buffering agents, tonicifiers, moisture absorbents, colorants, flavorants, sweeteners, sugars, and taste-masking agents, suspending agents, thickening agents, gelling agents, solvents, solubilizers, surfactants, absorption enhancers, emulsifying agents, and combinations thereof.

[0134] Examples of these pharmaceutically acceptable excipients in the component of the present invention include, but are not limited to, binders / fillers: microcrystalline cellulose, silicified microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, starch, pregelatinized starch, starch paste, lactose, mannitol, sorbitol, xylitol, sucrose, calcium phosphate, calcium carbonate, ethylcellulose, methylcellulose, and Acacia; lubricants / anti- adherents / glidants / granulating aids: talc, sodium lauryl fumarate, fumed silicon dioxide, colloidal silica, titanium dioxide, kaolin, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, and sodium lauryl sulfate; disintegrants: sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, and alginic acid; antioxidants / preservatives: riboflavin, tocopherol, vitamin E TPGS, BHT, BHA, cysteine and derivatives, ascorbates, sorbates, benzoates, propionates, bicarbonates, thiosulfates, metabisulfites, EDTA, carrageen, gums and benzyl alcohol; neutralizing agents: acids such as malic acid, citric acid, tartaric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, polyacids, acidic ionic resins, and other acidic excipients; suspending agents / thickening agents / gelling agents: mineral oils, vegetable oils, silicon dioxide, various gums such as xanthan gum, locust bean gum, gum Arabic, alginates, Carbopols, polyvinyl alcohols, carrageenan, gelatin, starches; or mixtures thereof.

[0135] EXAMPLES: The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0136] The active ingredient specified in the example is non-limiting and can be replaced with other active salts of GHB and combinations thereof.

[0137] Example-1: Delayed Release Pharmaceutical Compositions

[0138] *Ab indicates Absent

[0139] Brief Manufacturing process:

[0140] • MCC spheres were sifted and coated with a drug solution formed by mixing sodium oxybate, povidone K30 and magnesium oxide in a solvent mixture of methanol and water to form drug coated IR pellets.

[0141] • The drug coated pellets were further layered with different coating solutions as per example- 1 to form delayed release pellets. Example-2: Dissolution data of DR pellets

[0142] The dissolution test was performed using the delayed release pellets prepared as described in Example- 1. The dissolution conditions and results are summarized below: Dissolution media:

[0143] Acid stage: 0.1 N HC1, 900 mL

[0144] Apparatus: USP Dissolution Apparatus 2 (paddle)

[0145] Agitation speed: 100 rpm Temperature: 37 ± 0.5 °C

[0146] Duration: 2 hours (acid stage)

[0147] As demonstrated by the above data, the compositions exhibit no drug release during the 2-hour acid stage.

[0148] Example-3: IR pellets

[0149] Brief Manufacturing process:

[0150] • MCC spheres were sifted and coated with a drug solution formed by mixing sodium oxybate, povidone K30 and magnesium oxide in a solvent mixture of methanol and water to form drug coated IR pellets.

[0151] • The drug coated pellets were further layered with different coating solutions as per example-3 to form IR coated pellets. Example-4: Modified Release Pharmaceutical Compositions

[0152] Ex-4e: *Formulations of Ex-4e were further mixed with IR pellets of Ex-3 to form a modified release dosage form. Brief Manufacturing process:

[0153] The delayed release pellets of Example- 1 (la- Id) were further coated with various coating solutions as described in Example-4 to produce modified release composition. Example-5: Dissolution Data of Modified Release Composition:

[0154] The dissolution test was conducted using the modified release dosage form prepared as described in Example-4. The dissolution conditions and sampling time points are summarized below:

[0155] Dissolution Media:

[0156] Acid stage: 0.1 N HC1, 900 mL

[0157] Buffer stage: Phosphate buffer (pH 6.0), 900 mL

[0158] Apparatus: USP Dissolution Apparatus 2 (paddle)

[0159] Agitation Speed: 100 rpm

[0160] Temperature: 37 ± 0.5 °C

[0161] Sampling Time Points: 0.25 hr. and 2 hr. during acid stage; subsequent sampling in buffer stage

[0162] A graph illustrating the dissolution data is shown in FIG. 1. As depicted, the formulations exhibit a modified release profile. Example-6:

[0163] Extra granular Material:

[0164] Brief Manufacturing process:

[0165] The Extra granular material was formed by granulating Hydroxypropyl cellulose with methanol, followed by drying and lubricating with extra granular Magnesium stearate.

[0166] Example-7: Powder composition

[0167] Brief Manufacturing process:

[0168] The top-coated pellets of Example-4 were combined with the extra-granular material of Example-6 to prepare a powder for oral suspension.

[0169] Example-8:

[0170] Comparative Dissolution Profile:

[0171] A comparative dissolution test was performed to evaluate the test product prepared according to Example-7 against the marketed product Lumryz® (sodium oxybate). The dissolution conditions and sampling time points are as follows:

[0172] Dissolution Media:

[0173] Acid stage: 0.1 N HC1, 900 mL

[0174] Buffer stage: Phosphate buffer (pH 6.0), 900 mL

[0175] Apparatus: USP Dissolution Apparatus 2 (paddle)

[0176] Agitation Speed: 100 rpm

[0177] Sampling Time Points: 0.25 hour and 2 hours during acid stage; subsequent sampling in buffer stage

[0178] A graph illustrating the dissolution data is shown in FIG. 2. As depicted, the test product demonstrates pharmaceutical equivalence to the marketed product, Lumryz®.

[0179] While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims

CLAIMS:

1. A modified release formulation of gamma-hydroxybutyrate comprising an immediate release component, a delayed release component, and one or more stabilizing agents and / or lipophilic surfactants, wherein the stabilizing agents and / or lipophilic surfactants are present in the immediate release component, the delayed release component or both.

2. The modified release formulation of gamma-hydroxybutyrate as claimed in claim 1 , wherein the stabilizing agents are selected from basic inorganic salts of sodium, potassium, magnesium and / or calcium.

3. The modified release formulation of gamma-hydroxybutyrate of as claimed in claim 1, wherein the lipophilic surfactants have a hydrophilic-lipophilic balance (HLB) of less than 25.

4. A modified release pharmaceutical composition comprising:(1) an immediate release (IR)component comprising gamma- hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;(2) a delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

5. The modified release pharmaceutical composition of gamma- hydroxybutyrate as claimed in claim 4, wherein the core comprising gamma- hydroxybutyrate is either an active drug core or an inert core coated with a drug layer.

6. A modified release formulation of gamma-hydroxybutyrate comprising: (a) a core comprising gamma-hydroxybutyrate and an optional stabilizer (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant and (d) a drug layer comprising gamma- hydroxybutyrate and an optional stabilizer.

7. A delayed release component comprising (a) a core comprising gamma- hydroxybutyrate and an optional stabilizer; (b) one or more separating layers comprising optional stabilizers and / or lipophilic surfactants; and (c) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant.

8. A powder formulation comprising:(1) an immediate release (IR) component comprising gamma- hydroxybutyrate, an optional stabilizer and one or more pharmaceutically acceptable excipients;(2) a delayed release component comprising: (a) a core comprising gamma- hydroxybutyrate and optional stabilizer; and (b) a delayed release layer comprising a pH dependent polymer and a lipophilic surfactant; and(3) an extra-granular portion comprising one or more pharmaceutically acceptable excipients.

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