A method of administering a γ-hydroxybutyrate composition together with divalproex sodium.

Abstract

Provided is an oral pharmaceutical composition of gamma-hydroxybutyrate (GHB) suitable for co-administration with a dose of divalproex sodium (DVP) without substantially changing the dosage of either drug. Also provided is a therapeutic use of the composition for treating one or more symptoms of narcolepsy.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 010,974, filed on 16 April 2020.

[0002] The present invention relates to a composition for the treatment of narcolepsy, including any of the symptoms of narcolepsy (e.g., cataplexy, excessive daytime sleepiness, nocturnal sleep interruption, hypnagogic hallucinations, or sleep paralysis), comprising a unit dose of gamma-hydroxybutyrate suitable for administration with divalproex sodium. The present invention also relates to a modified-release formulation of gamma-hydroxybutyrate with improved pharmacokinetic (PK) properties when administered concomitantly with divalproex sodium. [Background technology]

[0003] Narcolepsy is a devastating disorder. Its main symptoms include excessive daytime sleepiness (EDS), cataplexy (sudden loss of muscle tone triggered by strong emotions, affecting approximately 60% of patients), hypnagogic hallucinations (HH), sleep paralysis (SP), and nighttime / nocturnal sleep disturbances (DNS). Aside from EDS, DNS is the most common symptom in narcolepsy patients.

[0004] One of the main treatments for narcolepsy is sodium oxybate, a neuroactive agent with various central nervous system (CNS) pharmacological properties. This species is endogenously present in many tissues, where it acts as a neurotransmitter on gamma-hydroxybutyrate (GHB) receptors (GHBR) and possesses neuromodulatory properties that significantly affect dopamine and gamma-aminobutyric acid (GABA). Studies suggest that sodium oxybate, in contrast to antidepressants, improves rapid eye movement sleep (REM sleep, REMS) in narcolepsy patients.

[0005] Sodium oxybate is also known as sodium 4-hydroxybutanoate or sodium γ-hydroxybutyrate salt, and has the following chemical structure. [ka]

[0006] Sodium oxybate is marketed in the United States as Xyrem®. The product is formulated as an immediate-release liquid solution, taken once immediately before bedtime and again approximately 2.5 to 4 hours later, in equal doses. Sleep onset can be dramatic and rapid, and patients are advised to sit up in bed when taking the medication. The most commonly reported side effects are confusion, depression, incontinence, and sleepwalking.

[0007] One of the significant drawbacks of Xyrem® is that the initial dose of Xyrem needs to be reduced when used in combination with divalproex sodium (DVP). Specifically, the Xyrem® label states, "In combination with divalproex sodium: an initial reduction of at least 20% in the Xyrem® dose is recommended." Following clinical trials for the co-administration of Xyrem and divalproex sodium, the following statement was added to the Xyrem label in Section 2.4. "When Xyrem is administered concomitantly with divalproex sodium, pharmacokinetic and pharmacodynamic interactions have been observed. In patients already stabilized on Xyrem, it is recommended that the addition of divalproex sodium should be accompanied by at least a 20% reduction in the overnight dose of Xyrem. In patients already taking divalproex sodium, it is recommended that prescribers use a lower starting dose of Xyrem when introducing it." A medical issue noted by the Xyrem® label and not addressed by prior art is the pharmacokinetic and pharmacodynamic interactions when Xyrem® is administered concomitantly with divalproex sodium. As stated in the drug interactions section of the Xyrem® prescribing information, "Concomitant use of Xyrem and divalproex sodium results in a mean 25% increase in systemic exposure to Xyrem (AUC ratio ranging from 0.8 to 1.7) and greater impairment in several tests of attention and working memory." In practice, prescribers should carefully monitor patient responses and adjust doses according to the concomitant use of Xyrem® and divalproex sodium. In addition, Jazz Pharmaceuticals' U.S. Patent No. 8,772,306 instructs that if a patient is receiving concomitant therapy with valproates, acids, salts, or mixtures thereof (e.g., divalproex sodium), the dose of GHB must be reduced by at least 5%.

[0008] Therefore, there is a need for a γ-hydroxybutyrate composition that can be administered co-administered with divalproex sodium without reducing the dose of γ-hydroxybutyrate and without compromising safety or efficacy. [Overview of the project] [Means for solving the problem]

[0009] In some embodiments, the disclosure includes a method for treating narcolepsy (e.g., one or more symptoms of narcolepsy) by administering a GHB composition in combination with divalproex sodium (DVP) without reducing the dose of GHB. For example, a method for treating a patient suffering from excessive daytime sleepiness (EDS), nocturnal sleep interruption (DNS), cataplexy, hypnagogic hallucinations, or sleep paralysis may include orally administering to the patient a pharmaceutical composition containing a total dose of GHB and co-administering a pharmaceutical composition containing a total dose of DVP. In some embodiments, the dose of the GHB composition is not reduced in response to the co-administration of DVP, and / or the dose of DVP is not reduced in response to the co-administration of the GHB composition. In other embodiments, if the dose of one or both GHB and DVP is reduced, such reduction is less than 5% of the total dose in response to the co-administration of DVP.

[0010] This specification further provides oral pharmaceutically active compositions of GHB for the treatment of narcolepsy (e.g., one or more symptoms of narcolepsy) which can be administered in combination with DVP. In some examples, the dose of the GHB composition is not reduced in response to the co-administration of DVP, and the dose of DVP is not reduced in response to the co-administration of the GHB composition. In other words, the doses of both the GHB composition and DVP are not reduced at all when administered concurrently. In other examples, the dose of one or both of the GHB composition and DVP is reduced by less than 5% of the total dose when administered concurrently.

[0011] Other aspects and variations of the present invention are fully described below. The present invention provides, for example, the following items: (Item 1) A method for treating a patient suffering from one or more symptoms of narcolepsy, wherein the method is The patient shall be orally administered the entire dose of the pharmaceutical composition containing γ-hydroxybutyrate (GHB), This includes co-administration of divalproex sodium (DVP), A method wherein the dose of the GHB composition is not reduced in response to the concomitant administration of DVP. (Item 2) The method according to item 1, wherein the combined administration of GHB and DVP provides a substantially bioequivalent PK profile compared to the administration of an equid dose of the GHB composition in the absence of the combined administration of DVP. (Item 3) The method according to item 1 or 2, wherein the GHB composition is administered once daily. (Item 4) The method according to any one of the preceding items, wherein the GHB composition is administered in a dose of 4.5 g, 6 g, 7.5 g, or 9 g. (Item 5) The method according to any one of the preceding items, wherein the dose of DVP is the total dose of DVP. (Item 6) The method according to any one of the preceding items, wherein the DVP is administered up to a maximum daily dose of 60 mg / kg / day. (Item 7) The method according to any one of the preceding items, wherein the dose of DVP is not reduced in response to the concomitant administration of the GHB composition. (Item 8) The aforementioned combined administration of GHB and DVP is C when GHB is administered in the absence of DVP. max AUC 0-last , and / or AUC inf C within 80% to 125% max AUC 0-last , and / or AUC inf A method according to any one of the preceding items, which provides the following: (Item 9) The method according to any one of the preceding items, wherein co-administration of the GHB composition with divalproex sodium results in an average increase of less than 25% in systemic exposure to the GHB composition. (Item 10) The method according to any one of the preceding items, wherein co-administration of the GHB composition with divalproex sodium does not result in a change in systemic exposure to the GHB composition. (Item 11) The combined administration of DVP and the aforementioned GHB composition in a 6g dose resulted in an average C25 concentration of 59 μg / mL to 97 μg / mL. max A method according to any one of the preceding items, which provides the following: (Item 12) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. 0-last A method according to any one of the preceding items, which provides the following: (Item 13) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. inf A method according to any one of the preceding items, which provides the following: (Item 14) The combined administration of DVP and the 6g dose of the GHB composition occurred over an average time interval of 0.3 to 3.5 hours. max A method according to any one of the preceding items, which provides the following: (Item 15) A method described in any one of the preceding items, which does not result in a significant reduction in safety or efficacy in the patient after concomitant administration. (Item 16) The method according to any one of the preceding items, wherein one or more of the symptoms of narcolepsy are selected from excessive daytime sleepiness (EDS), nocturnal sleep disruption (DNS), cataplexy, hypnagogic hallucinations, and sleep paralysis. (Item 17) A method for treating a patient suffering from one or more symptoms of narcolepsy, wherein the method is The patient shall be orally administered the entire dose of the pharmaceutical composition containing γ-hydroxybutyrate (GHB), This includes co-administration of divalproex sodium (DVP), A method wherein the dose of GHB is reduced to less than 5% in response to the concomitant administration of DVP. (Item 18) The method according to item 17, wherein the combined administration of GHB and DVP provides a substantially bioequivalent PK profile compared to administration of an equid dose of the GHB composition in the absence of the combined administration of DVP. (Item 19) The method according to item 17 or 18, wherein the GHB composition is administered once daily. (Item 20) The method according to any one of items 17 to 19, wherein the GHB composition is administered in doses of 4.5 g, 6 g, 7.5 g, or 9 g. (Item 21) The method according to any one of items 17 to 20, wherein the dose of DVP is the total dose of DVP. (Item 22) The method according to any one of items 17 to 21, wherein the DVP is administered up to a maximum daily dose of 60 mg / kg / day. (Item 23) The method according to any one of items 17 to 22, wherein the dose of DVP is not reduced in response to the concomitant administration of the GHB composition. (Item 24) The aforementioned combined administration of GHB and DVP is C when GHB is administered in the absence of DVP. max AUC 0-last , and / or AUC inf C within 80% to 125% max AUC 0-last , and / or AUC inf The method described in any one of items 17-23, which provides the following: (Item 25) The method according to any one of items 17 to 24, wherein co-administration of the GHB composition with divalproex sodium results in an average increase of less than 25% in systemic exposure to the GHB composition. (Item 26) The method according to any one of items 17 to 25, wherein co-administration of the GHB composition with divalproex sodium does not result in a change in systemic exposure to the GHB composition. (Item 27) The combined administration of DVP and the aforementioned GHB composition in a 6g dose resulted in an average C25 concentration of 59 μg / mL to 97 μg / mL. max The method described in any one of items 17 to 26, which provides the following: (Item 28) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. 0-last The method described in any one of items 17 to 27, which provides the following. (Item 29) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. inf The method described in any one of items 17-28, which provides the following: (Item 30) The combined administration of DVP and the 6g dose of the GHB composition occurred over an average time interval of 0.3 to 3.5 hours. max The method described in any one of items 17 to 29, which provides the following: (Item 31) A method according to any one of items 17 to 30, which does not result in a significant reduction in safety or efficacy in the patient after concomitant administration. (Item 32) The method according to any one of items 17 to 31, wherein one or more of the symptoms of narcolepsy are selected from excessive daytime sleepiness (EDS), nocturnal sleep disruption (DNS), cataplexy, hypnagogic hallucinations, and sleep paralysis. (Item 33) A method for treating a patient suffering from one or more symptoms of narcolepsy, wherein the method is The patient shall be orally administered the entire dose of the pharmaceutical composition containing γ-hydroxybutyrate (GHB), This includes co-administration of divalproex sodium (DVP), A method wherein the combined administration of GHB and DVP provides a substantially bioequivalent PK profile compared to the administration of an equid dose of the GHB composition in the absence of the combined administration of DVP. (Item 34) The method according to item 33, wherein the GHB composition is administered once daily. (Item 35) The method according to item 33 or 34, wherein the GHB composition is administered in doses of 4.5 g, 6 g, 7.5 g, or 9 g. (Item 36) The method according to any one of items 33 to 35, wherein the dose of DVP is the total dose of DVP. (Item 37) The method according to any one of items 33 to 36, wherein the dose of DVP is not reduced in response to the concomitant administration of the GHB composition. (Item 38) The method according to any one of items 33 to 37, wherein the DVP is administered up to a maximum daily dose of 60 mg / kg / day. (Item 39) The aforementioned combined administration of GHB and DVP is C when GHB is administered in the absence of DVP. max AUC 0-last , and / or AUC inf C within 80% to 125% max AUC 0-last , and / or AUC inf The method described in any one of items 33 to 38, which provides the following: (Item 40) The method according to any one of items 33 to 39, wherein co-administration of the GHB composition with divalproex sodium results in an average increase of less than 25% in systemic exposure to the GHB composition. (Item 41) The method according to any one of items 33 to 40, wherein co-administration of the GHB composition with divalproex sodium does not result in a change in systemic exposure to the GHB composition. (Item 42) The combined administration of DVP and the aforementioned GHB composition in a 6g dose resulted in an average C25 concentration of 59 μg / mL to 97 μg / mL. max The method described in any one of items 33 to 41, which provides the following: (Item 43) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. 0-last The method described in any one of items 33 to 42, which provides the following: (Item 44) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. inf The method described in any one of items 33 to 43, which provides the following: (Item 45) The combined administration of DVP and the 6g dose of the GHB composition occurred over an average time interval of 0.3 to 3.5 hours. max The method described in any one of items 33 to 44, which provides the following: (Item 46) The method described in any one of items 33 to 45, which does not result in a significant reduction in safety or efficacy in the patient after concomitant administration. (Item 47) The method according to any one of items 33 to 46, wherein one or more of the symptoms of narcolepsy are selected from excessive daytime sleepiness (EDS), nocturnal sleep disruption (DNS), cataplexy, hypnagogic hallucinations, and sleep paralysis. (Item 48) An oral pharmaceutical composition for the treatment of one or more symptoms of narcolepsy, containing γ-hydroxybutyrate (GHB), suitable for concomitant administration with divalproex sodium (DVP). (Item 49) The oral pharmaceutical composition according to item 48, wherein the dose of GHB is reduced to less than 5% in response to the concomitant administration of DVP. (Item 50) The oral pharmaceutical composition according to item 48 or 49, wherein the dose of GHB is not reduced in response to concomitant administration of DVP. (Item 51) An oral pharmaceutical composition according to any one of items 48 to 50, wherein the dose of DVP is not reduced in response to the concomitant administration of the GHB composition. (Item 52) An oral pharmaceutical composition according to any one of items 48 to 51, wherein the combined administration of GHB and DVP provides a substantially bioequivalent PK profile compared to the administration of an equid dose of the GHB composition in the absence of the said combined administration of DVP. (Item 53) The aforementioned combined administration of GHB and DVP is C when the GHB composition is administered in the absence of DVP. max AUC 0-last , and / or AUC inf C within 80% to 125% max AUC 0-last , and / or AUC inf An oral pharmaceutical composition according to any one of items 48 to 52, which provides... (Item 54) An oral pharmaceutical composition according to any one of items 48 to 53, wherein co-administration of the GHB composition with divalproex sodium results in an average increase of less than 25% in systemic exposure to the GHB composition. (Item 55) An oral pharmaceutical composition according to any one of items 48 to 54, wherein co-administration of the GHB composition with divalproex sodium does not result in a change in systemic exposure to the GHB composition. (Item 56) The oral pharmaceutical composition according to any one of items 48 to 55, wherein the GHB composition is suitable for administration once daily. (Item 57) An oral pharmaceutical composition according to any one of items 48 to 56, wherein the GHB composition is administered once daily in a dose of 4.5 g, 6 g, 7.5 g, or 9 g. (Item 58) An oral pharmaceutical composition according to any one of items 48 to 57, wherein the DVP is administered up to a maximum daily dose of 60 mg / kg / day. (Item 59) An oral pharmaceutical composition according to any one of items 48 to 58, wherein the dose of DVP is the total dose of DVP. (Item 60) The combined administration of DVP and the aforementioned GHB composition in a 6g dose resulted in an average C25 concentration of 59 μg / mL to 97 μg / mL. max An oral pharmaceutical composition according to any one of items 48 to 59, which provides... (Item 61) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. 0-last An oral pharmaceutical composition according to any one of items 48 to 60, which provides... (Item 62) The combined administration of DVP and the GHB composition at a dose of 6 g yielded an average AUC of 220 μg / mL·h to 512 μg / mL·h. inf An oral pharmaceutical composition according to any one of items 48 to 61, which provides... (Item 63) The combined administration of DVP and the 6g dose of the GHB composition occurred over an average time interval of 0.3 to 3.5 hours. max An oral pharmaceutical composition according to any one of items 48 to 62, which provides... (Item 64) An oral pharmaceutical composition according to any one of items 48 to 63, which does not result in a significant reduction in safety or efficacy in patients after concomitant administration. (Item 65) The oral pharmaceutical composition according to any one of items 48 to 64, wherein the composition does not include the Risk Assessment and Mitigation Strategy (REMS) Program Directive. (Item 66) An oral pharmaceutical composition according to any one of items 48 to 65, wherein the composition does not include a directive for monitoring drug interactions with γ-hydroxybutyrate (GHB) and divalproex sodium (DVP). (Item 67) An oral pharmaceutical composition according to any one of items 48 to 66, wherein one or more of the symptoms of narcolepsy is selected from excessive daytime sleepiness (EDS), nocturnal sleep disruption (DNS), cataplexy, hypnagogic hallucinations, and sleep paralysis. [Brief explanation of the drawing]

[0012] The accompanying drawings incorporated herein and constituting part of this specification illustrate several embodiments of the present invention and serve to illustrate the principles of the present invention together with the description.

[0013] [Figure 1A] These are mean concentration-time curves for 6g of FT218 administered alone and in the evening with DVP. [Figure 1B] These are a series of individual profiles in the mean concentration-time curve for 6g of FT218 administered alone and in the evening with DVP. [Figure 2A] This shows a comparison of the mean Tmax for 6g of FT218 administered in the evening, both alone and with DVP. [Figure 2B] This shows a comparison of the mean Cmax for 6g of FT218 administered in the evening, both alone and with DVP. [Figure 2C] This shows a comparison of the mean AUCinf for 6g of FT218 administered in the evening, both alone and with DVP. [Figure 3A] These are the mean concentration-time curves for DVP administered alone and in the evening with FT218. [Figure 3B] These are a series of individual profiles in the mean concentration-time curve for DVP administered alone and in the evening with FT218. [Figure 4A] These are mean concentration-time curves for 6g of FT218 administered alone and in the evening with DVP. [Figure 4B] These are a series of individual profiles in the mean concentration-time curve for 6g of FT218 administered alone and in the morning with DVP. [Figure 5A] This shows a comparison of the mean Tmax for 6g of FT218 administered alone and in the morning with DVP. [Figure 5B] This shows a comparison of the mean Cmax for 6g of FT218 administered alone and in the morning with DVP. [Figure 5C] This shows a comparison of the mean AUCinf for 6g of FT218 administered alone and in the morning with DVP. [Figure 6A] These are the mean concentration-time curves for DVP administered alone and in combination with FT218 during the morning. [Figure 6B] These are a series of individual profiles in the mean concentration-time curve for DVP administered alone and in combination with FT218 in the morning. [Figure 7] This is the mean concentration-time curve for 6g of FT218 administered alone or with DVP in either the morning (DDI#1) or evening (DDI#2). [Modes for carrying out the invention]

[0014] The present invention can be more readily understood by referring to the following detailed description of embodiments of the formulation, methods of treatment using some embodiments of the formulation, and examples contained therein.

[0015] Definitions and Use of Terms Where analysis or testing is required to understand a given characteristic or feature listed herein, it will be understood that, unless otherwise specified, such analysis or testing will be conducted in accordance with the applicable guidelines, draft guidance, regulations, and monographs of the U.S. Food and Drug Administration ("FDA") and the United States Pharmacopeia ("USP") applicable to medicinal products in the United States as of November 1, 2015. Clinical endpoints may be determined by referring to criteria adopted by the American Academy of Sleep Medicine, including the criteria published in C Iber, S Ancoli-Israel, A Chesson, SF Quan. The AASM Manual for the Scoring of Sleep and Associated Events. Westchester, IL: American Academy of Sleep Medicine; 2007.

[0016] Where pharmacokinetic comparisons are made between formulations described or claimed herein and reference products, it will be understood that the comparisons are to be made in suitably designed crossover studies; however, unless otherwise specified, crossover studies are not required. It will also be understood that comparisons may be made directly or indirectly. For example, even if a formulation has not been directly tested against a reference product, if it has been tested against a different formulation, it may still satisfy the requirement for a comparison with the reference product, and the comparison can be inferred from there.

[0017] As used herein and in the following claims, the singular “a,” “an,” and “the” refer to multiple subjects unless otherwise indicated by the context. Thus, for example, a reference to “components” includes mixtures of components, and a reference to “active agents” includes one or more active agents.

[0018] "Bioavailability" refers to the rate and extent to which the active ingredient or active site is absorbed from a drug and becomes available at the site of action.

[0019] "Relative Bioavailability," or "Rel BA," or "RBA" is the average AUC of a reference product for an equal total dose. inf The average AUC of the test product compared to the average AUC of the test product. inf This refers to the percentage of [amount]. Unless otherwise specified, relative bioavailability is the mean AUC observed for the same total dose of the test product without administration of divalproex sodium. inf The mean AUC observed for the total dose of the test product administered co-administered with divalproex sodium. inf This refers to the percentage.

[0020] "Bioequivalence" means the absence of significant differences in the rate and extent to which the active ingredient or active portion becomes available at the site of action in a pharmaceutically equivalent or pharmaceutically equivalent or pharmaceutically equivalent when administered under similar conditions and at the same molar dose in a properly designed study. In some embodiments, "range of bioequivalence" means that the test composition / state has a PK value within 80% to 125% of the PK value of the reference composition / state.

[0021] If a range is given by specifying a lower limit to the range separately from the upper limit, it will be understood that the range can be defined by selectively combining one of the lower limit variables with one of the mathematically and physically possible upper limit variables. Therefore, for example, if a formulation may contain 1 to 10 parts by weight of a particular ingredient, or 2 to 8 parts of a particular ingredient, it will be understood that the formulation may also contain 2 to 10 parts of the ingredient. Similarly, if a formulation may contain more than 1 or 2 parts by weight of an ingredient, and up to 10 or 9 parts by weight of an ingredient, it will be understood that the formulation may contain 1 to 10 parts by weight of an ingredient, 2 to 9 parts by weight of an ingredient, and so on. Unless otherwise specified, the boundaries of the range (the lower and upper limits of the range) are included within the claims.

[0022] Where used herein, the terms “about,” “substantially,” or “approximately” will compensate for variability acceptable in the pharmaceutical industry and variability inherent to pharmaceuticals, such as differences in product strength due to manufacturing variations and time-induced product degradation. This terminology allows for any modifications in pharmaceutical practice that enable a product to be assessed as bioequivalent to the listed strengths, as described in the FDA’s March 2003 Industry Guidance on Bioavailability and Bioequivalence Testing Guidelines for Orally Administered Pharmaceuticals – General Considerations.

[0023] As used herein, the terms “γ-hydroxybutyrate” or “GHB” refer, unless otherwise specified, to any pharmaceutical composition that releases free γ-hydroxybutyrate bases and free GHB bases into the patient’s bloodstream (including pharmaceutically acceptable salts of γ-hydroxybutyrate, prodrugs of γ-hydroxybutyrate, their hydrates, solvates, complexes, or tautomers, and combinations or mixtures thereof). γ-hydroxybutyrate may be selected from sodium salts of γ-hydroxybutyrate or sodium oxybate, potassium salts of γ-hydroxybutyrate, magnesium salts of γ-hydroxybutyrate, calcium salts of γ-hydroxybutyrate, lithium salts of γ-hydroxybutyrate, tetraammonium salts of γ-hydroxybutyrate, or any other pharmaceutically acceptable salt form of γ-hydroxybutyrate.

[0024] As used herein, the terms “divalproex sodium” or “DVP” may include divalproex sodium, divalproic acid, valproic acid, valproate, valproate acid or salt, or monocarboxylate transporter, unless otherwise specified.

[0025] As used herein, the terms “total dose” or “total dosage” refer to the total amount administered to a patient without co-administration. For example, the total dosage of a GHB composition refers to the total amount administered to a patient without co-administration of DVP, and the total dosage of DVP refers to the total amount administered to a patient without co-administration with a GHB composition.

[0026] "Pharmacologically acceptable" means useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes being acceptable for veterinary and human pharmaceutical use. The terms "formulation" or "composition" refer to the quantitative and qualitative characteristics of a pharmaceutical or dosage form prepared in accordance with the present invention.

[0027] As used herein, the dose and strength of gamma-hydroxybutyrate are expressed in equivalent grams (g) of sodium oxibate unless otherwise explicitly stated. Therefore, when considering doses of gamma-hydroxybutyrate other than the sodium salt of gamma-hydroxybutyrate, the listed dose or strength must be converted from sodium oxibate to the gamma-hydroxybutyrate being evaluated. Therefore, if a certain embodiment is said to provide a 4.5 g dose of γ-hydroxybutyrate, since the form of γ-hydroxybutyrate is not specified, it will be understood that the dose includes the weight of 4.5 g of sodium oxibate, 5.1 g of potassium γ-hydroxybutyrate (assuming 126.09 g / mol MW for sodium oxibate and 142.20 g / mol MW for potassium γ-hydroxybutyrate), and 3.7 g of free base (assuming 126.09 g / mol MW for sodium oxibate and 104.1 g / mol MW for the free base of γ-hydroxybutyrate), or any mixture of salts of γ-hydroxybutyrate that provides the same amount of GHB as 4.5 g of sodium oxibate.

[0028] As used herein, “microparticles” means any inconspicuous particles of a solid material. Particles may be made of a single material, or they may have a complex structure with a core and shell, or they may be made of several materials. The terms “microparticles,” “particles,” “microspheres,” and “pellets” are interchangeable and have the same meaning. Unless otherwise specified, microparticles are not limited to particles with a specific particle size or diameter and a volume-average diameter D(4,3) of less than 1 mm.

[0029] As used herein, the "volume-average diameter D(4,3)" is calculated according to the following formula: D(4,3)=Σ(d4i·ni) / Σ(d3i·ni) The diameter d of a given particle is the diameter of a rigid sphere having the same volume as the particle.

[0030] As used herein, the terms “composition,” “oral composition,” “oral pharmaceutical composition,” “finished composition,” “finished formulation,” or “formulation” are interchangeable and specify a composition of gamma-hydroxybutyrate comprising modified-release microparticles of gamma-hydroxybutyrate, immediate-release microparticles of gamma-hydroxybutyrate, and any other excipients. The composition may be described as sustained-release, delayed-release, or modified-release.

[0031] As used herein, “immediate release” means the release of the major portion of γ-hydroxybutyrate over a relatively short period, for example, at least 75% of AP being released in 0.75 hours, or 30 minutes.

[0032] As used herein, the “immediate-release (IR) portion” of a formulation includes a physically inconspicuous portion of the formulation, a mechanically inconspicuous portion of the formulation, and a pharmacokinetically inconspicuous portion of the formulation that gives or supports the defined IR pharmacokinetic properties. Therefore, for example, any formulation that releases the active ingredient at the rate and degree required for the immediate-release portion of the formulation of the present invention includes an “immediate-release portion,” even if the immediate-release portion is physically integrated into what would otherwise be considered a sustained-release formulation. Thus, the IR portion may be structurally inconspicuous from the MR portion or structurally prominent (i.e., integrated with the MR portion). In one embodiment, the IR portion and the MR portion are provided as particles, and in other embodiments, the IR portion and the MR portion are provided as particles inconspicuous to each other.

[0033] As used herein, “immediate-release formulation” or “immediate-release portion” means USP38 <711> This refers to a composition that, when tested in a dissolution apparatus 2 using the above method, in a 0.1N HCl dissolution medium at a temperature of 37°C and a paddle speed of 75 rpm, releases at least 80% of its γ-hydroxybutyrate in 1 hour.

[0034] Similarly, the “modified-release (MR) portion” includes that portion of a formulation or dosage form that imparts or supports specific MR pharmacokinetic characteristics, regardless of the physical formulation in which the MR portion is integrated. Modified-release drug delivery systems are designed to deliver a drug at a specific time, over a period of time after administration, or at a specific location within the body. The USP defines a modified-release system as one in which the course or location of drug release, or both, is selected to achieve therapeutic efficacy or convenience objectives that are not met by conventional IR dosage forms. More specifically, MR solid oral dosage forms include sustained-release (ER) and delayed-release (DR) products. DR products release the drug entirely at once, rather than immediately after administration. Typically, coatings (e.g., enteric coatings) are used to delay the release of the active ingredient until the dosage form has passed through the acidic medium of the stomach. ER products are formulated to make the drug available over a longer period after ingestion, thus allowing for a reduction in dosing frequency compared to drugs presented as conventional dosage forms, e.g., solutions or immediate-release dosage forms. For oral use, the term "sustained release" is usually interchangeable with "continuous release," "sustained-release," or "controlled release."

[0035] Traditionally, sustained-release systems have provided a constant drug release to maintain stable drug concentrations. However, for some drugs, zero-order delivery may not be optimal, and more complex and sophisticated systems have been developed to provide multi-phase delivery. Oral MR delivery systems can be distinguished among four categories: (1) delayed release using enteric coating, (2) site-specific or time-delayed release (e.g., for colonic delivery), (3) sustained release (e.g., zero-order, primary, and bi-phase release), and (4) programmed release (e.g., pulsating release, delayed sustained release). See page 34 of Gibaldi's *DRUG DELIVERY SYSTEMS IN PHARMACEUTICAL CARE*, *AMERICAN SOCIETY OF HEALTH-SYSTEM PHARMACISTS*, 2007, "Modified Oral Drug Delivery Systems," and page 469 of *DEVELOPING SOLID ORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE*, *Academic Press*, Elsevier, 2009, "Rational Design of Oral Modified-release Drug Delivery Systems." As used herein, in one embodiment, "modified-release formulation" or "modified-release portion" refers to a composition that releases its γ-hydroxybutyrate according to multiphase delivery, e.g., delayed sustained release, contained in a fourth class MR product. Thus, it differs from a delayed-release product classified as a first class MR product.

[0036] As used herein, the terms “coating,” “coating layer,” “coating film,” and “film coating,” and similar terms are interchangeable and have the same meaning. These terms refer to coatings applied to particles containing gamma-hydroxybutyrate that control the modified release of gamma-hydroxybutyrate.

[0037] "Similar PK profiles," "substantially similar PK profiles," or "equivalent bioavailability" refer to the mean AUC of the test product when administered co-administered with divalproex sodium. inf However, in a suitably designed crossover study, the mean AUC of the same dose of the test product administered alone was... inf This was 80% to 125% of the test product administered simultaneously with divalproex sodium, and the 8 hours (C) of the test product. 8h The mean plasma concentration in ) was the mean C of the reference product administered alone. 8h The maximum plasma concentration (C) of the test product was 40% to 130% of the total and / or administered concurrently with divalproex sodium. max ) when administered alone as a reference product C max This means it is between 50% and 140% of that.

[0038] As used herein, “dose-proportional” means that the increase in the administered dose is proportional to the AUC or C. max This occurs when accompanied by a proportional increase in the PK profile, such as those mentioned above.

[0039] "Combined PK profile" refers to the average AUC of the composition when administered concurrently with divalproex sodium. inf , mean plasma concentration (C) over 8 hours 8h ), and / or maximum plasma concentration (C max ) means.

[0040] "Standard PK profile" refers to the average AUC of the composition when administered alone (i.e., without co-administration with divalproex sodium). inf , mean plasma concentration (C) over 8 hours 8h ), and / or maximum plasma concentration (C max ) means.

[0041] One or more symptoms of narcolepsy include excessive daytime sleepiness (EDS), nocturnal sleep disruption (DNS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Type 1 narcolepsy (NT1) refers to narcolepsy characterized by excessive daytime sleepiness ("EDS") and cataplexy. Type 2 narcolepsy (NT2) refers to narcolepsy characterized by excessive daytime sleepiness without cataplexy. A diagnosis of narcolepsy (with or without cataplexy) may be confirmed by (i) a polysomnography (PSG) and multiple sleep latency test (MSLT) performed within the past two years, (ii) complete documented evidence from the PSG and MSLT from the Sleep Institute being available, (iii) current symptoms of narcolepsy, including current complaints of EDS (ESS greater than 10) for the past three months, (iv) a mean MWT of less than 8 minutes, (v) a mean number of cataplexy events of 8 per week in the baseline sleep / cataplexy diary, and / or (vi) the presence of cataplexy in the past three months and one or a combination of 28 events per week during the screening period.

[0042] Unless otherwise specified herein, the percentages, ratios, and numerical values ​​listed herein are based on weight, the averages and means are arithmetic mean, and all pharmacokinetic measurements based on body fluid measurements are based on plasma concentrations.

[0043] Where a composition is defined herein by its pharmacokinetic or solubility properties, it will be understood that, alternatively, a formulation may be defined as “means for” achieving the enumerated pharmacokinetic or solubility properties. Therefore, a formulation in which a modified release portion releases less than 20% of its γ-hydroxybutyrate in one hour may instead be defined as a formulation comprising “means for” or “modified release means for” releasing less than 20% of its γ-hydroxybutyrate in one hour. It will be further understood that a structure for achieving the enumerated pharmacokinetic or solubility properties is the structure described in the examples herein for achieving the enumerated pharmacokinetic or solubility properties.

[0044] Oral pharmaceutical composition for concomitant administration with divalproex sodium As prior art demonstrates, it is extremely difficult to find a sodium oxidate formulation that can be administered concomitantly with divalproex sodium without reducing the sodium oxidate dose. Furthermore, it is difficult to find a sodium oxidate formulation that possesses comparable pharmacokinetic properties to sodium oxidate formulations when administered concomitantly with divalproex sodium, without the concomitant administration of divalproex sodium. Prior art, including the labeling of Xyrem, clearly suggests moving away from the co-administration of sodium oxidate and divalproex sodium at full doses. Indeed, the labeling of Xyrem includes several statements recommending a reduction of at least 20% in the dose of Xyrem when administered concomitantly with divalproex sodium, based on clinical trials that found that "concomitant use of Xyrem with divalproex sodium resulted in an average 25% increase in systemic exposure to Xyrem."

[0045] The inventors have discovered a novel relationship between the in vivo absorption of gamma-hydroxybutyrate from modified release particles and the effect of divalproex sodium on gamma-hydroxybutyrate absorption, which for the first time allows for the full dose of a gamma-hydroxybutyrate composition that can be administered in combination with divalproex sodium to approximate the bioavailability of the same composition of gamma-hydroxybutyrate at the same dose without administration of divalproex sodium, and over a range of therapeutic doses. The dose of divalproex sodium administered may be the full dose administered without administration of gamma-hydroxybutyrate.

[0046] This specification provides oral pharmaceutical compositions for the treatment of narcolepsy, including one or more symptoms of narcolepsy (e.g., excessive daytime sleepiness (EDS), nocturnal sleep disruption (DNS), cataplexy, hypnagogic hallucinations, and / or sleep paralysis), comprising a unit dose of gamma-hydroxybutyrate suitable for concomitant administration with divalproex sodium. In various embodiments, the composition may contain gamma-hydroxybutyrate in a sustained-release formulation, a delayed-release formulation, or a modified-release formulation.

[0047] The Xyrem® label indicates that there is a drug-drug interaction between Xyrem® and divalproex sodium, which affects the bioavailability of Xyrem®, and consequently, it is recommended that the Xyrem® dose be reduced when administered co-administered with divalproex sodium. In addition, the Xyrem Risk Assessment and Mitigation Strategy (REMS) program is a monitoring component that requires specific risk mitigation measures for DDIs between Xyrem and divalproex sodium. The FDA has concluded that it cannot "extract" information regarding DDIs involving divalproex sodium from ANDA for sodium oxibate products that reference Xyrem®. Based on literature data regarding competitive exclusion pathways with GHB and divalproate, similar results were expected for Xyrem®. However, surprisingly, the γ-hydroxybutyrate composition can be administered co-administered with divalproex sodium without being significantly affected by divalproex sodium. The γ-hydroxybutyrate composition is a once-daily composition with two emission waves of GHB. While not limited to any particular theory, the two release waves of a γ-hydroxybutyrate composition may enable co-administration with divalproex sodium without reducing the GHB dose. For example, the first wave may behave similarly to reference Xyrem, but the second wave, by releasing the latter in the gastrointestinal tract, may skip some of the competition in the metabolic pathway and reduce the interaction effect with divalproex sodium.

[0048] In one embodiment, the γ-hydroxybutyrate composition may be administered co-administered with divalproex sodium without the need to reduce the dose of the γ-hydroxybutyrate composition at any point during administration. In one embodiment, divalproex sodium may be administered co-administered with the γ-hydroxybutyrate composition without the need to reduce the dose of divalproex sodium at any point during administration. For example, the γ-hydroxybutyrate composition may be administered to a patient who is already taking and needs divalproex sodium without reducing the dose of the γ-hydroxybutyrate composition compared to the dose that would be administered if the patient were not taking divalproex sodium. In another embodiment, divalproex sodium may be administered to a patient who is already taking and needs the γ-hydroxybutyrate composition without reducing the dose of the currently patented γ-hydroxybutyrate composition. Because the γ-hydroxybutyrate compositions of the present invention can be administered co-administered with divalproex sodium without reducing the dose of either composition, the need for a monitoring component may be reduced, or a monitoring component may not be present. For example, γ-hydroxybutyrate compositions may not require prescriber information / brochures and / or patient counseling information related to co-administration with divalproex sodium.

[0049] The Xyrem® label instructs that, when Xyrem® is administered alone, systemic exposure to gamma-hydroxybutyrate from Xyrem increases by more than 25% of total systemic exposure, and therefore Xyrem® should not be co-administered with divalproex sodium without reducing the dose of Xyrem® by 20%. Conversely, co-administration of the gamma-hydroxybutyrate composition of the present invention with divalproex sodium may result in a lower change in systemic exposure to the gamma-hydroxybutyrate composition compared to co-administration of Xyrem® and divalproex sodium. For example, co-administration of the gamma-hydroxybutyrate composition with divalproex sodium may result in an average increase of less than 25% in systemic exposure to the gamma-hydroxybutyrate composition. In some embodiments, co-administration of the gamma-hydroxybutyrate composition with divalproex sodium may result in an average increase of less than 15% in systemic exposure to the gamma-hydroxybutyrate composition. In other embodiments, co-administration of the gamma-hydroxybutyrate composition with divalproex sodium may result in an average increase of less than 5% in systemic exposure to the gamma-hydroxybutyrate composition. In at least one embodiment, the combined use of the γ-hydroxybutyrate composition with divalproex sodium may not result in a change in systemic exposure to the γ-hydroxybutyrate composition.

[0050] The Xyrem® label also clearly instructs that co-administration of Xyrem® with divalproex sodium may impair certain tests of attention and working memory. Surprisingly, co-administration of the γ-hydroxybutyrate composition with divalproex sodium may result in fewer side effects compared to co-administration of Xyrem® and divalproex sodium. For example, co-administration of the γ-hydroxybutyrate composition with divalproex sodium can reduce impairment in certain tests of attention and working memory compared to co-administration of Xyrem® and divalproex sodium. In other embodiments, patients cannot reduce their dosage without the risk of GHB overdose side effects.

[0051] Oral pharmaceutical compositions of gamma-hydroxybutyrate may be in a unit dose suitable for co-administration with divalproex sodium without reducing the dose of gamma-hydroxybutyrate for the treatment of narcolepsy or one or more symptoms of narcolepsy (e.g., one or more symptoms of narcolepsy selected from excessive daytime sleepiness (EDS), nocturnal sleep interruption (DNS), cataplexy, hypnagogic hallucinations, and sleep paralysis). In some embodiments, the oral pharmaceutical composition may be effective in human subjects who require treatment for narcolepsy, cataplexy, or excessive daytime sleepiness. In some embodiments, the human subject may be a human patient. In any of the embodiments provided herein, the formulation may be effective in treating narcolepsy type 1 or type 2. Treatment of narcolepsy may be defined as reducing excessive daytime sleepiness, reducing the frequency of cataplexy attacks, reducing nocturnal sleep interruption, reducing hypnagogic hallucinations, or reducing sleep paralysis. In various embodiments, the composition is sufficient to be administered once daily. For example, the composition may be sufficient for administration in the morning or evening when used in combination with divalproex sodium. The formulation is also effective in inducing at least 6 to 8 hours of continuous sleep. In one embodiment, the composition administered concurrently with divalproex sodium is effective in inducing at least 8 hours of continuous sleep. In various embodiments, the formulation is effective in inducing at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours of sleep. In other embodiments, the formulation is effective in inducing up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, or up to 10 hours of sleep.

[0052] A γ-hydroxybutyrate composition may have both an immediate-release moiety and a modified-release moiety. The release of γ-hydroxybutyrate from the immediate-release moiety is hardly inhibited and occurs almost immediately in a 0.1N hydrochloric acid solution. In contrast, the modified-release moiety can also release its γ-hydroxybutyrate almost immediately when fully triggered, although the release may not be triggered until a predetermined lag time, or the drug may be subjected to a suitable solution such as a phosphate buffer pH 6.8 solution. While we do not wish to be bound by either theory, it is thought that divalproex sodium may have little to no effect on the modified-release moiety of the composition because the γ-hydroxybutyrate from the modified-release moiety is absorbed in the posterior part of the gastrointestinal tract.

[0053] In any of these embodiments, the composition may include an immediate-release and a modified-release portion, the modified-release portion comprising a polymer supporting free carboxylic acid groups and γ-hydroxybutyrate particles coated with a hydrophobic compound having a melting point of 40°C or higher, the ratio of γ-hydroxybutyrate in the immediate-release portion and the modified-release portion being 10 / 90 to 65 / 35. The polymer containing free carboxylic acid groups may have a pH dissolution trigger of 5.5 to 6.97 and may be a methacrylic acid copolymer having a pH dissolution trigger of 5.5 to 6.97.

[0054] In various embodiments, the composition contains γ-hydroxybutyrate present in a unit dose of at least 4.5 g, at least 6.0 g, at least 7.5 g, or at least 9.0 g. In some embodiments, the oral pharmaceutically active composition of γ-hydroxybutyrate may be administered once daily in combination with a dose of divalproex sodium. In one embodiment, the once daily dose of γ-hydroxybutyrate is administered as a 6 g dose. The once daily dose of γ-hydroxybutyrate may be administered once overnight. In one embodiment, the once overnight dose of γ-hydroxybutyrate is administered as a 6 g dose. The dose range of divalproex sodium ER is 10 to 60 mg / kg body weight per day. In some embodiments, divalproex sodium is administered up to a daily dose of 60 mg / kg / day. In other embodiments, divalproex sodium is administered at a dose of 1250 mg / day.

[0055] Pharmacokinetics The compositions may provide substantially similar combined PK profiles and standard PK profiles when the γ-hydroxybutyrate compositions are administered at the same dose. In some embodiments, combined administration of γ-hydroxybutyrate and divalproex sodium provides substantially bioequivalent PK profiles compared to administration of an equal dose of the γ-hydroxybutyrate composition in the absence of combined administration of divalproex sodium.

[0056] In one embodiment, a γ-hydroxybutyrate composition administered co-administered with divalproex sodium can substantially approximate the bioavailability of an equidose γ-hydroxybutyrate composition without divalproex sodium across the entire therapeutic range of γ-hydroxybutyrate doses.

[0057] In one embodiment, there is no significant reduction in patient safety or efficacy after co-administration of the composition with divalproex sodium. For example, the safety profile for co-administration of the γ-hydroxybutyrate composition and divalproex sodium may be consistent with that known for sodium oxibate.

[0058] In another embodiment, the γ-hydroxybutyrate composition may enable co-administration with divalproex sodium without a reduction in the dose of γ-hydroxybutyrate, compared to the commercial treatment Xyrem® which requires at least a 5% reduction in the Xyrem® dose when co-administered with divalproex sodium. In some embodiments, the dose of the γ-hydroxybutyrate composition is reduced to less than 5% in response to co-administration of DVP.

[0059] In another embodiment, divalproex sodium may be administered concurrently with the γ-hydroxybutyrate composition without reducing the dose of divalproex sodium.

[0060] In other embodiments, the γ-hydroxybutyrate composition may be administered co-administered with divalproex without reducing the Xyrem® dose, and having an improved solubility and pharmacokinetic profile compared to the co-administration of Xyrem® and divalproex.

[0061] The γ-hydroxybutyrate compositions can also be defined by the concentration / time curves they produce when tested according to the examples. One embodiment of a γ-hydroxybutyrate composition produces a plasma concentration-vs-time curve when administered at a strength of 6 g in combination with divalproex sodium, substantially as shown in Figures 1A and 1B.

[0062] In one embodiment, the combined administration of the γ-hydroxybutyrate composition and divalproex sodium is as shown in Figure 2A, compared to the administration of the same dose of the γ-hydroxybutyrate composition alone. max to biologically equivalent T max In another embodiment, the combined administration of the γ-hydroxybutyrate composition and divalproex sodium is equivalent to the same dose of the γ-hydroxybutyrate composition alone, as shown in Figure 2B. max C is biologically equivalent to maxThe present invention provides the following: In one embodiment, the combined administration of the γ-hydroxybutyrate composition and divalproex sodium is shown in Figure 2C to be the same dose as the γ-hydroxybutyrate composition alone in terms of AUC. inf Bioequivalent AUC inf To provide.

[0063] In yet another embodiment, when divalproex sodium is administered co-administered once overnight at a strength of 6 g with a γ-hydroxybutyrate composition, substantially as shown in Figures 3A and 3B, it produces a plasma concentration-versus-time curve.

[0064] Another embodiment of the γ-hydroxybutyrate composition, substantially as shown in Figure 4, produces a plasma concentration-time curve when administered once overnight at a strength of 6 g in combination with divalproex sodium.

[0065] Formulations achieving this improved bioavailability can be described using several different pharmacokinetic parameters when administered co-administered with divalproex sodium. A γ-hydroxybutyrate composition administered once overnight in combination with divalproex sodium may achieve relative bioavailability exceeding 80%, 85%, 90%, or 95% compared to an equivalent dose of the γ-hydroxybutyrate composition administered without divalproex sodium.

[0066] In one embodiment, the AUC of the γ-hydroxybutyrate composition administered in combination with divalproex sodium inf When the same composition in the same dosage is administered alone, the AUC inf It can be substantially similar to the above. For example, when a γ-hydroxybutyrate composition is administered co-administered with divalproex sodium, the average AUC provided by the same dose of the γ-hydroxybutyrate composition as when administered without divalproex sodium is comparable to the average AUC provided by the same dose of the γ-hydroxybutyrate composition. inf The mean AUC is 80%-125%, 80%-100%, 90%-100%, 90%-115%, 100%-120%, or 110%-125%. infThis achieves the following: In at least one embodiment, when the γ-hydroxybutyrate composition is administered co-administered with divalproex sodium, the mean AUC provided by the same dose of the γ-hydroxybutyrate composition as when administered without divalproex sodium is achieved. inf The average AUC is approximately 117% of inf This can be achieved by comparing the release profiles and pharmacokinetic profiles of Examples 1-6.

[0067] Embodiments of the γ-hydroxybutyrate composition include immediate-release and modified-release portions, and a 6g dose formulation, when administered with divalproex sodium, exhibits an average AUC greater than 220hr*μg / mL. inf This can be achieved. In particular, the 6g dose of γ-hydroxybutyrate composition administered concurrently with divalproex has an average AUC greater than 250hr*μg / mL, 300hr*μg / mL, 350hr*μg / mL, 400hr*μg / mL, 450hr*μg / mL, 500hr*μg / mL, or less than 512hr*μg / mL. inf This can be achieved. For example, a 6g dose composition administered concurrently with divalproex sodium has an average AUC of approximately 366hr*μg / mL. inf It may have the following properties. In addition, the 6g dose of the composition may be administered once a day in the morning or evening.

[0068] AUC of the composition administered with DVP inf The AUC of the composition and DVP / composition (alone) is within the bioequivalent range of the same composition administered alone. inf The 90% confidence interval for the geometric mean ratio is approximately 111 to 122. In at least one embodiment, the ratio is approximately 116.52.

[0069] In one embodiment, C of a γ-hydroxybutyrate composition administered in combination with divalproex sodium max This is the case when the same dose of γ-hydroxybutyrate composition is administered alone. maxIt can be substantially similar to the above. In one embodiment, when the γ-hydroxybutyrate composition is administered simultaneously with divalproex sodium, the average C provided by the γ-hydroxybutyrate composition is equivalent to that provided by the same dose as when administered without divalproex sodium. max The average C is 80%-125%, 80%-100%, 90%-100%, 95%-110%, 100%-120%, or 110%-125%. max This achieves the average C25% of max The average C is approximately 98% of max This can be achieved by comparing the release profiles and pharmacokinetic profiles of Examples 1-6.

[0070] Embodiments of the γ-hydroxybutyrate composition include an immediate-release and a modified-release portion, and a 6g dose formulation, when administered with divalproex sodium, exhibits an average C2 concentration exceeding 59 μg / mL. max This can be achieved. For example, when a 6g dose of the formulation is administered concurrently with divalproex sodium, it can achieve an average C levels greater than 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, or less than 97 μg / mL. max This can be achieved. For example, a 6g dose composition administered concurrently with divalproex sodium has an average C of approximately 78 μg / mL. max It has the following properties. In addition, the 6g dose of the composition may be administered once a day in the morning or evening.

[0071] Composition C administered together with DVP max It is within the bioequivalent range of the same composition administered alone. In various examples, the composition and DVP / composition (alone) are C max The 90% confidence interval for the geometric mean ratio is approximately 91 to 106. In at least one embodiment, the ratio is approximately 98.46.

[0072] In one embodiment, the AUC of the γ-hydroxybutyrate composition co-administered with divalproex sodium 0-last may be substantially similar to the AUC 0-last when the same dose of the γ-hydroxybutyrate composition is administered alone. In some examples, when the γ-hydroxybutyrate composition is co-administered with divalproex sodium, the mean AUC 0-last provided by the equidose γ-hydroxybutyrate composition administered without divalproex sodium is 80% - 125%, 80% - 100%, 90% - 100%, 95% - 110%, or 100% - 125% of the mean AUC 0-last achieved. In at least one example, when the γ-hydroxybutyrate composition is co-administered with divalproex sodium, the mean AUC 0-last is about 117% of the mean AUC 0-last provided by the equidose γ-hydroxybutyrate composition administered without divalproex sodium. This can be seen by comparing the release profiles and pharmacokinetic profiles of Examples 1 - 6.

[0073] In various embodiments, the composition of 6 g dose of γ-hydroxybutyrate may be characterized by achieving a mean AUC 0-last exceeding 220 hr*μg / mL, 250 hr*μg / mL, 300 hr*μg / mL, 350 hr*μg / mL, 400 hr*μg / mL, 450 hr*μg / mL, 500 hr*μg / mL, or less than 512 hr*μg / mL when co-administered with divalproex sodium. For example, the composition of 6 g dose co-administered with divalproex sodium may have a mean AUC 0-last of about 366 hr*μg / mL. Additionally, the composition of 6 g dose may be administered once daily in the morning or evening.

[0074] The AUC of the composition administered with DVP 0-last is within the biologically equivalent range of the same composition administered alone. In various examples, the AUC 0-lastThe 90% confidence interval of the geometric mean ratio is from about 111 to about 122. In at least one embodiment, the ratio is about 116.67.

[0075] In one embodiment, a γ-hydroxybutyrate composition administered in combination with divalproex sodium can provide an average blood concentration (μg / ml) at 8 hours that is substantially similar to that of the γ-hydroxybutyrate composition at the same dosage when administered alone. In one example, when the γ-hydroxybutyrate composition is co-administered with divalproex sodium, the average C 8h is 40% - 60%, 60% - 80%, 80% - 125%, 80% - 100%, 90% - 100%, 90% - 100%, 115%, or 100% - 125% of the average C 8h is achieved. This can be seen by comparing the release profiles and pharmacokinetic profiles of Examples 1 - 6.

[0076] In various embodiments, a composition of 6 g dosage of γ-hydroxybutyrate, when co-administered with divalproex sodium, has an average C 8h that exceeds 1 μg / mL, 2 μg / mL, 4 μg / mL, 6 μg / mL, 8 μg / mL, 10 μg / mL, 12 μg / mL, 14 μg / mL, 16 μg / mL, 18 μg / mL, or 20 μg / mL. For example, a composition of 6 g dosage co-administered with divalproex sodium has an average C 8h of about 9.8 μg / mL. Additionally, the composition of 6 g dosage may be administered once daily in the morning or evening.

[0077] In one embodiment, the T max of a γ-hydroxybutyrate composition administered in combination with divalproex sodium is the T maxIt can be substantially similar to this. In some embodiments, when the γ-hydroxybutyrate composition is administered co-administered with divalproex sodium, the average T provided by an equivalent dose of the γ-hydroxybutyrate composition administered without divalproex sodium is comparable to that provided by an equivalent dose of the γ-hydroxybutyrate composition administered without divalproex sodium. max The average T is 60%-80%, 70%-90%, 80%-125%, 80%-100%, 90%-100%, 90%-115%, or 100%-125%. max This can be achieved by comparing the release profiles and pharmacokinetic profiles of Examples 1-6.

[0078] A γ-hydroxybutyrate composition may also be defined based on the time required to reach the maximum blood concentration of γ-hydroxybutyrate. Therefore, in additional embodiments, a γ-hydroxybutyrate composition may have an average T time of 0.3 to 3.5 hours. max This can be achieved. In various embodiments, when the γ-hydroxybutyrate composition is administered co-administered with divalproex sodium, an average T of approximately 0.5, 0.75 hours, 1.0 hour, 1.5 hours, 2.0 hours, 2.25 hours, 2.5 hours, 3 hours, or 3.5 hours can be achieved. max This can be achieved. For example, a 6g dose composition administered concurrently with divalproex sodium has a median T of approximately 2 hours. max It may have the following properties. In addition, the 6g dose of the composition may be administered once a day in the morning or evening.

[0079] In one embodiment, the composition has an AUC proportional to the dose when administered co-administered with divalproex sodium. inf The composition provides a dose-proportional C when administered simultaneously with divalproex sodium. max The composition provides the following. In various embodiments, the composition exhibits dose-proportional pharmacokinetics when administered once daily in combination with divalproex sodium. For example, the composition is administered once daily at a dose of 6 g. max C of the composition with a dose of 9 g max C is proportional to the dose, across once-daily doses of 4.5g, 7.5g, 6g, and 9g. maxThe composition may exhibit a predictable increase in plasma levels with increasing dose, consistent with the desired PK profile for a once-overnight sodium oxibate formulation.

[0080] Structural Embodiments The γ-hydroxybutyrate composition may be provided in any dosage form suitable for oral administration, including tablets, capsules, liquids, or orally dissolvable tablets, etc. In one embodiment, they are provided as dry microparticle formulations (i.e., granules, powders, coated particles, microparticles, pellets, microspheres, etc.) in pouches or other suitable inconspicuous packaging units. The microparticle formulations are mixed with tap water immediately before administration. In one embodiment, the composition may be mixed with 50 mL of water before administration. In another embodiment, the composition is an oral pharmaceutical composition.

[0081] In various embodiments, the composition contains γ-hydroxybutyrate in a unit dose of at least 4.5 g, at least 6.0 g, at least 7.5 g, or at least 9.0 g. In various embodiments, the composition contains γ-hydroxybutyrate in a unit dose greater than 4.5 g, greater than 6.0 g, greater than 7.5 g, or greater than 9.0 g. In one embodiment, the formulation contains 6 g of γ-hydroxybutyrate. In another embodiment, the formulation contains 7.5 g of γ-hydroxybutyrate. In yet another embodiment, the formulation contains 9 g of γ-hydroxybutyrate. In some embodiments, the dose of γ-hydroxybutyrate may be sufficient to administer the composition once daily.

[0082] In one embodiment, the formulation comprises an immediate-release portion and a modified-release portion, where (a) the modified-release portion comprises γ-hydroxybutyrate-coated microparticles, and (b) the ratio of γ-hydroxybutyrate in the immediate-release portion and the modified-release portion is 10 / 90 to 65 / 35.

[0083] In one embodiment, the formulation comprises an immediate-release portion and a modified-release portion, where (a) the modified-release portion comprises γ-hydroxybutyrate-coated microparticles, and (b) the ratio of γ-hydroxybutyrate in the immediate-release portion and the modified-release portion is 40 / 60 to 60 / 40.

[0084] In another embodiment, the formulation comprises an immediate-release and a modified-release portion, (a) the modified-release portion comprises γ-hydroxybutyrate-coated fine particles, (b) the coating of the γ-hydroxybutyrate-coated modified-release particles comprises a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher, and (c) the ratio of γ-hydroxybutyrate in the immediate-release portion and the modified-release portion is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40.

[0085] In one embodiment, the γ-hydroxybutyrate composition may comprise an immediate-release and a modified-release portion, a suspending agent or viscosity modifier, and an acidifying agent, wherein (a) the modified-release portion comprises γ-hydroxybutyrate-coated particles, (b) the coating comprises a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher, and (c) the ratio of γ-hydroxybutyrate in the immediate-release portion to the modified-release portion is 10 / 90 to 65 / 35.

[0086] In another embodiment, the formulation comprises an immediate-release and a modified-release portion, (a) the modified-release portion comprises γ-hydroxybutyrate-coated fine particles, (b) the coating of the γ-hydroxybutyrate-coated modified-release particles comprises a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher, (c) the weight ratio of the hydrophobic compound to the polymer supporting free carboxylic acid groups is 0.4 to 4, (d) the ratio of γ-hydroxybutyrate in the immediate-release portion and the modified-release portion is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40, and (e) the film coating is 10 to 50% of the weight of the fine particles.

[0087] In another embodiment, the formulation comprises an immediate-release and a modified-release portion, (a) the modified-release portion comprises particles coated with γ-hydroxybutyrate, (b) the coating of the modified-release particles of γ-hydroxybutyrate comprises a polymer supporting free carboxylic acid groups having a pH trigger of 5.5 to 6.97 and a hydrophobic compound having a melting point of 40°C or higher, (c) the weight ratio of the hydrophobic compound to the polymer supporting free carboxylic acid groups is 0.4 to 4, (d) the ratio of γ-hydroxybutyrate in the immediate-release portion and the modified-release portion is 10 / 90 to 65 / 35 or 40 / 60 to 60 / 40, and (e) the coating is 10 to 50% of the weight of the particles.

[0088] In one embodiment, the polymer supporting the free carboxylic acid group includes 100% poly(methacrylic acid, ethyl acrylate) 1:1, 0% poly(methacrylic acid, methyl methacrylate) 1:2 to 2% poly(methacrylic acid, ethyl acrylate) 1:1, and 98% poly(methacrylic acid, methyl methacrylate) 1:2, and the hydrophobic compound includes hydrogenated vegetable oil.

[0089] In one embodiment, the formulation includes an excipient to improve the viscosity and fluidity of the mixture of the particulate formulation and tap water. Thus, in addition to the immediate-release and modified-release particles of γ-hydroxybutyrate, the particulate formulation includes one or more suspending agents, viscosity modifiers, or lubricants.

[0090] The suspending agent or viscosity modifier may be selected from the group consisting of xanthan gum, medium viscosity sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, a mixture of microcrystalline cellulose and guar gum, medium viscosity hydroxyethylcellulose, agar, sodium alginate, a mixture of sodium alginate and calcium alginate, gellan gum, carrageenan gum, grade iota, kappa, or lambda, and medium viscosity hydroxypropyl methylcellulose.

[0091] Medium viscosity sodium carboxymethylcellulose corresponds to grades of sodium carboxymethylcellulose with a viscosity of over 200 mPa·s and less than 3100 mPa·s in a 2% aqueous solution at 25°C.

[0092] Medium viscosity hydroxyethylcellulose corresponds to a grade of hydroxyethylcellulose where the viscosity of a 2% aqueous solution at 25°C is greater than 250 mPa·s and less than 6500 mPa·s. Medium viscosity hydroxypropyl methylcellulose corresponds to a grade of hydroxypropyl methylcellulose where the viscosity of a 2% aqueous solution at 20°C is greater than 80 mPa·s and less than 3800 mPa·s.

[0093] In one embodiment, the suspending agent or viscosity modifier is xanthan gum, in particular Xantural 75™ from Kelco; hydroxyethylcellulose, in particular Natrosol 250M™ from Ashland; kappa-carrageenan gum, in particular Gelcarin PH812™ from FMC Biopolymer; and lambda-carrageenan gum, in particular Viscarin PH209™ from FMC Biopolymer.

[0094] In one embodiment, the γ-hydroxybutyrate composition contains 1 to 15% of a viscosity modifier or suspending agent. In other embodiments, the γ-hydroxybutyrate composition contains a viscosity modifier or suspending agent in an amount of 2 to 10%, 2 to 5%, or 2 to 3% of the formulation.

[0095] In one embodiment, the γ-hydroxybutyrate composition is in the form of a powder intended to be dispersed in water before administration, and further comprises xanthan gum, carrageenan gum, and 1 to 15% of a suspending agent or viscosity modifier selected from hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum.

[0096] In one embodiment, the γ-hydroxybutyrate composition is in the form of a powder intended to be dispersed in water before administration, and further comprises 1.2 to 15% of an acidifying agent selected from malic acid and tartaric acid, and 1 to 15% of a suspending agent or viscosity modifier selected from xanthan gum, carrageenan gum and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum.

[0097] In one embodiment, the γ-hydroxybutyrate composition comprises about 1% lambda-carrageenan gum or Viscarin PH209™, about 1% medium-viscosity grade hydroxyethylcellulose or Natrasol 250M™, and about 0.7% xanthan gum or Xantural 75™. For a 4.5g dose unit, these percentages are typically equivalent to about 50mg of xanthan gum (Xantural 75™), about 75mg of carrageenan gum (Viscarin PH209™), and about 75mg of hydroxyethylcellulose (Natrasol 250M™).

[0098] Alternative packages for a 4.5g dose of viscosity modifier or suspending agent include approximately 50mg of xanthan gum (Xantural 75™) and approximately 100mg of carrageenan gum (Gelcarin PH812™), or approximately 50mg of xanthan gum (Xantural 75™), approximately 75mg of hydroxyethylcellulose (Natrasol 250M™), and approximately 75mg of carrageenan gum (Viscarin PH109™).

[0099] In one embodiment, the γ-hydroxybutyrate composition further comprises a lubricant or flow enhancer in addition to the immediate-release and modified-release particles of γ-hydroxybutyrate. In various embodiments, the lubricant and flow enhancer are selected from the group consisting of salts of stearic acid, particularly magnesium stearate, calcium stearate, or zinc stearate, esters of stearic acid, particularly glyceryl monostearate or glyceryl palmitostearate, stearic acid, glycerol behenate, sodium stearyl fumarate, talc, and colloidal silicon dioxide. In one embodiment, the lubricant or flow enhancer is magnesium stearate. The lubricant or flow enhancer may be used in particulate formulations in an amount of 0.1 to 5%. In one embodiment, the amount of the lubricant or flow enhancer is about 0.5%. For example, the γ-hydroxybutyrate composition may contain about 0.5% magnesium stearate.

[0100] The γ-hydroxybutyrate composition may further contain an oxidizing agent. The acidifying agent helps ensure that the release profile of the formulation in 0.1N HCl remains substantially unchanged for at least 15 minutes after mixing, which is approximately the maximum length of time a patient might need before consuming a dose after mixing the formulation with tap water.

[0101] In one embodiment, the formulation is a powder and further comprises an acidifying agent and a suspending agent or viscosity modifier in the weight percentages listed herein.

[0102] The acidifying agent may be 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. In various embodiments, the acidifying agent is present in the formulation at concentrations of 1.2–15%, 1.2–10%, or 1.2–5%. In one embodiment, the acidifying agents are tartaric acid and malic acid. In another embodiment, the acidifying agent is malic acid.

[0103] When tartaric acid is used, it may be used in amounts of 1-10%, 2.5-7.5%, or about 5%. In various embodiments, the amount of malic acid in the γ-hydroxybutyrate composition is 1.2-15%, 1.2-10%, 1.2-5%, or 1.6% or 3.2%. In one embodiment, the amount of malic acid in the γ-hydroxybutyrate composition is about 1.6%.

[0104] The γ-hydroxybutyrate composition comprises an immediate-release portion and a modified-release portion of γ-hydroxybutyrate. In one embodiment, the formulation is a particulate formulation comprising a plurality of immediate-release γ-hydroxybutyrate particles and a plurality of modified-release γ-hydroxybutyrate particles. The molar ratios of γ-hydroxybutyrate in the immediate-release and modified-release portions are in the ranges of 0.11:1 to 1.86:1, 0.17:1 to 1.5:1, 0.25:1 to 1.22:1, 0.33:1 to 1.22:1, 0.42:1 to 1.22:1, 0.53:1 to 1.22:1, 0.66:1 to 1.22:1, 0.66:1 to 1.5:1, and 0.8:1 to 1.22:1. In one embodiment, the molar ratio of γ-hydroxybutyrate in the immediate-release and modified-release portions is approximately 1:1. The molar percentage of γ-hydroxybutyrate in the immediate-release portion relative to the total γ-hydroxybutyrate in the formulation is in the range of 10% to 65%, 15 to 60%, 20 to 55%, 25 to 55%, 30 to 55%, 35 to 55%, 40 to 55%, 40 to 60%, or 45 to 55%. In one embodiment, the molar percentage of γ-hydroxybutyrate in the immediate-release portion relative to the total γ-hydroxybutyrate in the formulation is in the range of 40% to 60%. In one embodiment, the molar percentage of γ-hydroxybutyrate in the immediate-release portion relative to the total γ-hydroxybutyrate in the formulation is approximately 50%. The molar percentage of γ-hydroxybutyrate in the modified-release portion relative to the total γ-hydroxybutyrate in the formulation is in the range of 90%-35%, 85-40%, 80-45%, 75-45%, 70-45%, 65-45%, 60-45%, 60-40%, or 55-45%. In one embodiment, the molar percentage of γ-hydroxybutyrate in the modified-release portion relative to the total γ-hydroxybutyrate in the formulation is in the range of 60%-40%. In one embodiment, the molar ratio of γ-hydroxybutyrate in the modified-release portion relative to the total γ-hydroxybutyrate in the formulation is approximately 50%.The weight percentage of IR particles relative to the total weight of IR particles and MR particles is in the range of 7.2% to 58.2%, 11.0% to 52.9%, 14.9% to 47.8%, 18.9% to 47.8%, 23.1% to 47.8%, 27.4% to 47.8%, 31.8% to 47.8%, 31.8% to 52.9%, or 36.4% to 47.8%. In other embodiments, the weight percentage of IR particles relative to the total weight of IR particles and MR particles is in the range of 5.9% to 63.2%, 9.1% to 58.1%, 12.4% to 53.1%, 19.9% ​​to 53.1%, 19.6% to 53.1%, 23.4% to 53.1%, 27.4% to 53.1%, or 27.4% to 58.1%. In one embodiment, the weight percentage of IR particles relative to the total weight of IR particles and MR particles is in the range of 31.7% to 53.1%.

[0105] In one embodiment, the finished formulation contains 80.75% w / w sodium oxybate and 4.25% w / w povidone. The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 50% of the sodium oxidate content in these particles. Modified release particles consist of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 50% of the sodium oxidate content in these particles. These particles are layered with 56.5% w / w sodium oxidate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0106] In one embodiment, the finished formulation contains 80.75% w / w sodium oxybate and 4.25% w / w povidone. The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, with 50% of the sodium oxidate contained in K30, and modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, with 50% of the sodium oxidate contained in K30, are layered with 56.5% w / w sodium oxidate mixed with 3% w / w Povidone® K30, and are finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0107] In one embodiment, the finished formulation contains 80.75% w / w sodium oxybate and 4.25% w / w povidone. The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 50% of the sodium oxidate content in these particles. Modified release particles consist of 11.3% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, with 50% of the sodium oxidate content in these particles. These particles are layered with 60.5% w / w sodium oxidate mixed with 3.2% w / w Povidone® K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 9.25% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0108] In one embodiment, the completed formulation contains 80.75% w / w sodium oxidate, 4.25% w / w Povidone® K30, and 50% of the sodium oxidate in immediate-release particles consisting of 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, and 11.3% w / w of the sodium oxidate in modified-release particles consisting of microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns. The material is layered with 60.5% w / w sodium oxibate, which contains 50% of the material and is mixed with 3.2% w / w Povidone® K30, and finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 9.25% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0109] In one embodiment, the finished formulation contains 80.75% w / w potassium salt of γ-hydroxybutyrate and 4.25% w / w povidone. The material contains 50% of the γ-hydroxybutyrate in immediate-release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of approximately 95 to 450 microns, and 50% of the γ-hydroxybutyrate in modified-release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of approximately 95 to 450 microns, layered with 56.5% w / w sodium oxibate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0110] In one embodiment, the finished formulation contains 80.75% w / w potassium salt of γ-hydroxybutyrate and 4.25% w / w povidone. The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, with 50% of the γ-hydroxybutyrate contained therein. Modified release particles consist of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns also contain 50% of the γ-hydroxybutyrate contained therein. These particles are layered with 56.5% w / w sodium oxibate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0111] In one embodiment, the completed formulation contains 80.75% w / w potassium salt of γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 16.7% of the γ-hydroxybutyrate in immediate-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of approximately 95 microns to approximately 450 microns; 80.75% w / w magnesium salt of γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 16.7% of the γ-hydroxybutyrate in immediate-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of approximately 95 microns to approximately 450 microns; 80.75% w / w calcium salt of γ-hydroxybutyrate, and 4.25% w / w Povidone The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, containing 16.7% of its γ-hydroxybutyrate, and modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 450 microns, containing 50% of its γ-hydroxybutyrate, are layered with 56.5% w / w sodium oxibate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0112] In one embodiment, the completed formulation contains 80.75% w / w potassium salt of γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 16.7% of its γ-hydroxybutyrate content in immediate-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of approximately 95 microns to approximately 170 microns; 80.75% w / w magnesium salt of γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 16.7% of its γ-hydroxybutyrate content in immediate-release particles consisting of 15% microcrystalline cellulose spheres having a volume average diameter of approximately 95 microns to approximately 170 microns; 80.75% w / w calcium salt of γ-hydroxybutyrate, and 4.25% w / w Povidone The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, containing 16.7% of its γ-hydroxybutyrate, and modified release particles consisting of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, containing 50% of its γ-hydroxybutyrate. These particles are layered with 56.5% w / w sodium oxibate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0113] In one embodiment, the finished formulation contains 80.75% w / w potassium salt of γ-hydroxybutyrate and 4.25% w / w povidone. The material contains 50% of the γ-hydroxybutyrate in immediate-release particles consisting of K30 and 15% microcrystalline cellulose spheres having a volume average diameter of approximately 95 to 450 microns, and 50% of the γ-hydroxybutyrate in modified-release particles consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of approximately 95 to 450 microns, layered with 56.5% w / w calcium salt of γ-hydroxybutyrate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0114] In one embodiment, the finished formulation contains 80.75% w / w potassium salt of γ-hydroxybutyrate and 4.25% w / w povidone. The immediate-release particles consist of K30 and 15% microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, containing 50% of its γ-hydroxybutyrate, and modified-release particles consisting of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of approximately 95 to 170 microns, containing 50% of its γ-hydroxybutyrate, are layered with 56.5% w / w calcium salt of γ-hydroxybutyrate mixed with 3% w / w Povidone® K30, and are finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% type C methacrylate copolymer (Eudragit® L100-55 or equivalent), and 8% type B methacrylate copolymer (Eudragit® S100 or equivalent).

[0115] Other features of the immediate discharge section The immediate release portion of the formulation can take any form capable of achieving immediate release of gamma-hydroxybutyrate upon ingestion. For example, if the formulation is a particulate formulation, the formulation may comprise granules, particles, or microparticles of gamma-hydroxybutyrate that rapidly dissolve, containing unmodified "raw" gamma-hydroxybutyrate, which are composed of a core covered by a layer loaded with gamma-hydroxybutyrate containing a binder such as povidone.

[0116] The IR granules or particles of gamma-hydroxybutyrate can be made using any manufacturing process suitable for generating the required particles, including the following. ● Aggregation of gamma-hydroxybutyrate sprayed in a molten state, such as the Glatt ProCell™ technique ● Extrusion and spheronization of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients ● Wet granulation of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients ● Compression molding of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients ● Granulation and spheronization of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients (spheronization is carried out, for example, in a fluid bed apparatus equipped with a rotor, particularly using the Glatt CPS™ technique) ● Spraying of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients, in a fluid bed type apparatus equipped with a zigzag filter, particularly using the Glatt MicroPx™ technique, or ● Spraying of gamma-hydroxybutyrate in a dispersion or in a solution in an aqueous or organic solvent on a core in a fluid bed apparatus optionally equipped with a fractionation tube or a Wurster tube, optionally with one or more physiologically acceptable excipients.

[0117] The immediate release portion of the formulation is in the form of microparticles comprising immediate release γ-hydroxybutyrate and an optional pharmaceutically acceptable excipient. In one embodiment, the immediate release microparticles of γ-hydroxybutyrate have a volume average diameter D(4,3) of 10 to 1000 microns. In other embodiments, the immediate release microparticles of γ-hydroxybutyrate have a volume average diameter D(4,3) of 95 to 600 microns. In additional embodiments, the immediate release microparticles of γ-hydroxybutyrate have a volume average diameter D(4,3) of 150 to 400 microns. In one embodiment, their volume average diameter is about 270 microns.

[0118] The immediate release particles of γ-hydroxybutyrate may comprise a core and a layer deposited on the core containing γ-hydroxybutyrate. The core may be any particle selected from the group consisting of the following. ● Crystals or spheres of lactose, sucrose (such as Compressuc™ PS from Tereos), microcrystalline cellulose (such as Avicel™ from FMC Biopolymer, Cellet™ from Pharmatrans, or Celphere™ from Asahi Kasei), sodium chloride, calcium carbonate (such as Omyapure™ 35 from Omya), sodium bicarbonate, dicalcium phosphate (such as Dicafos™ AC92-12 from Budenheim), or tricalcium phosphate (such as Tricafos™ SC93-15 from Budenheim); ● Composite spheres or granules, such as sugar spheres containing sucrose and starch (such as Suglets™ from NP Pharm), spheres of calcium carbonate and starch (such as Destab™ 90S Ultra 250 from Particle Dynamics), or spheres of calcium carbonate and maltodextrin (such as Hubercal™ CCG4100 from Huber).

[0119] The core may also contain other particles of pharmaceutically acceptable excipients, such as hydroxypropyl cellulose (e.g., Klucel® from Aqualon Hercules), guar gum particles (e.g., Grinsted® Guar from Danisco), or xanthan gum particles (e.g., Xantural® 180 from CP Kelco).

[0120] According to certain embodiments of the present invention, the core is a sugar sphere or microcrystalline cellulose sphere such as Cellets® 90, Cellets® 100, or Cellets® 127, or Celphere® CP203, Celphere® CP305, or Celphere® SCP100, all commercially available from Pharmatrans. In one embodiment, the core is a microcrystalline cellulose sphere. For example, the core may be Cellets® 127 from Pharmatrans.

[0121] In various embodiments, the core has an average volume diameter of approximately 95 to 450 microns, approximately 95 to 170 microns, or approximately 140 microns.

[0122] The layer deposited on the core contains an immediate-release γ-hydroxybutyrate. In one embodiment, the layer also contains a binder which may be selected from the group consisting of the following: ● Low molecular weight hydroxypropyl cellulose (such as Klucel® EF from Aqualon-Hercules); Low molecular weight hydroxypropyl methylcellulose (or hypromellose) (such as Methocel® E3 or E5 from Dow), or low molecular weight methylcellulose (for example, Methocel® A15 from Dow); ● Low molecular weight polyvinylpyrrolidone (or povidone) (e.g., Plasdone® K29 / 32 from ISP or Kollidon® 30 from BASF), vinylpyrrolidone and vinyl acetate copolymer (or copovidone) (e.g., Plasdone® S630 from ISP or Kollidon® VA64 from BASF); ● Dextrose, pregelatinized starch, maltodextrin; and mixtures thereof.

[0123] Low molecular weight hydroxypropyl cellulose corresponds to grades of hydroxypropyl cellulose having a molecular weight of less than 800,000 g / mol, 400,000 g / mol or less, or 100,000 g / mol or less. Low molecular weight hydroxypropyl methylcellulose (or hypromellose) corresponds to grades of hydroxypropyl methylcellulose whose solution viscosity is 1,000 mPa·s or less, 100 mPa·s or less, or 15 mPa·s or less at 2% aqueous solution and 20°C. Low molecular weight polyvinylpyrrolidone (or povidone) corresponds to grades of polyvinylpyrrolidone having a molecular weight of 1,000,000 g / mol or less, 800,000 g / mol or less, or 100,000 g / mol or less.

[0124] In some embodiments, the binder is selected from low molecular weight polyvinylpyrrolidone or povidone (e.g., Plasdone® K29 / 32 from ISP), low molecular weight hydroxypropyl cellulose (e.g., Klucel® EF from Aqualon-Hercules), low molecular weight hydroxypropyl methylcellulose or hypromellose (e.g., Methocel® E3 or E5 from Dow), and mixtures thereof.

[0125] In one embodiment, the binder is Povidone K30 or K29 / 32, in particular Plasdone® K29 / 32 from ISP. The binder may be present in amounts of 0-80%, 0-70%, 0-60%, 0-50%, 0-40%, 0-30%, 0-25%, 0-20%, 0-15%, 0-10%, or 1-9% based on the total weight of the immediate-release coating. In one embodiment, the binder is present in an amount of 5% based on the total weight of the immediate-release coating. In one embodiment, the amount of binder is 5% of the total mass of γ-hydroxybutyrate and binder.

[0126] The layer deposited on the core can represent at least 10% by weight of the total weight of the immediate-release particles of γ-hydroxybutyrate, and more than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight. In one embodiment, the layer deposited on the core represents about 85% of the weight of the immediate-release particles of γ-hydroxybutyrate.

[0127] According to one embodiment, the immediately released particles contain 80.75% w / w γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 15% microcrystalline cellulose spheres.

[0128] According to another embodiment, the immediately released particles comprise 80.75% w / w γ-hydroxybutyrate, 4.25% w / w povidone K30, and 15% microcrystalline cellulose spheres, each having a volume-average diameter of approximately 95 microns to approximately 450 microns.

[0129] In yet another embodiment, the immediately released particles comprise 80.75% w / w γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns.

[0130] According to one embodiment, the immediately released particles contain 80.75% w / w sodium oxidate, 4.25% w / w povidone K30, and 15% microcrystalline cellulose spheres.

[0131] According to another embodiment, the immediate-release particles comprise 80.75% w / w potassium salt of γ-hydroxybutyrate, 4.25% w / w Povidone K30, and 15% microcrystalline cellulose spheres.

[0132] According to another embodiment, the immediate-release particles comprise 80.75% w / w of calcium salt of γ-hydroxybutyrate, 4.25% w / w of Povidone K30, and 15% of microcrystalline cellulose spheres.

[0133] According to another embodiment, the immediate release particles comprise 80.75% w / w magnesium salt of γ-hydroxybutyric acid, 4.25% w / w Povidone K30, and 15% microcrystalline cellulose spheres.

[0134] According to another embodiment, the immediate release particles are produced by dissolving γ-hydroxybutyrate and Povidone K30 in a 40 / 60 w / w mixture of water / ethanol and spraying the resulting solution onto the surface of microcrystalline cellulose spheres.

[0135] Other features of the modified release portion The modified release portion can be any formulation that provides the desired in vitro dissolution profile of γ-hydroxybutyrate. The modified release portion may include modified release particles obtained by coating the immediate release particles of γ-hydroxybutyrate with a coating (or coating film) that inhibits the immediate release of γ-hydroxybutyrate. In one sub-embodiment, the modified release portion includes particles comprising (a) an inert core, (b) a coating, and (c) a layer of γ-hydroxybutyrate intervening between the core and the coating.

[0136] In one embodiment, the modified release portion includes a time-dependent release mechanism and a pH-dependent release mechanism.

[0137] In one embodiment, the coating film includes at least one polymer bearing free carboxylic acid groups and at least one hydrophobic compound characterized by a melting point of 40°C or higher.

[0138] Polymers supporting free carboxylic acid groups can be selected from (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 of type A, type B, or type C, cellulose derivatives supporting free carboxylic acid groups, cellulose phthalate acetate, cellulose succinate acetate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, cellulose trimellitate acetate, hydroxypropyl methylcellulose succinate acetate, polyvinyl phthalate acetate, zein, shellac, alginates, and mixtures thereof.

[0139] In one embodiment, the methacrylic acid copolymer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:1 or Eudragit® L100 or equivalent, poly(methacrylic acid, ethyl acrylate) 1:1 or Eudragit® L100-55 or equivalent, and poly(methacrylic acid, methyl methacrylate) 1:2 or Eudragit® S100 or equivalent.

[0140] In another embodiment, the coating comprises a polymer supporting free carboxylic acid groups, which are substantially ionized at pH 7.5.

[0141] Hydrophobic compounds with a melting point of 40°C or higher may be selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, yellow waxes, white waxes, microcrystalline waxes, lanolin, anhydrous milk fat, hard fat suppository bases, lauroyl macrogol glycerides, polyglyceryl diisostearates, glycerol diesters or triesters containing fatty acids, and mixtures thereof.

[0142] In various embodiments, hydrophobic compounds having a melting point of 40°C or higher are selected from the following group of products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated coconut oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimiristin, yellow wax, hard fats or fats useful as suppository bases, anhydrous milk fat, lanolin, glyceryl palmitate, glyceryl stearate, lauryl macrogol glyceride, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, omega-3 fatty acids, and mixtures thereof. For example, hydrophobic compounds may include hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimiristin, beeswax, hydrogenated poly-1-decene, carnauba wax, and mixtures thereof.

[0143] In practice, but not limited to these, hydrophobic compounds having a melting point of 40°C or higher may be selected from the group of products sold under the following trademarks: Dynasan(trademark), Cutina(trademark), Hydrobase(trademark), Dub(trademark), Castorwax(trademark), Croduret(trademark), Compritol(trademark), Sterotex(trademark), Luburitab(trademark), Apifil(trademark), Akofine(trademark), Softisan(trademark), Hydrocote(trademark), Livopol(trademark), Super Hartolan(TM), MGLA(TM), Corona(TM), Protalan(TM), Akosoft(TM), Akosol(TM), Cremao(TM), Massupol(TM), Novata(TM), Suppocire(TM), We cobee(TM), Witepsol(TM), Lanolin(TM), Incromega(TM), Estaram(TM), Suppoweiss(TM), Gelucire(TM), Precirol(TM), Emulcire(TM), Plurol diisostearique(TM), Geleol(TM), Hydrine(TM), Monthyle(TM), Kahlwax(TM), and mixtures thereof. In one embodiment, the hydrophobic compound having a melting point of 40°C or higher may be selected from the group of products sold under the following trademarks: Dynasan(trademark) P60, Dynasan(trademark) 114, Dynasan(trademark) 116, Dynasan(trademark) 118, Cutina(trademark) HR, Hydrobase(trademark) 66-68, Dub(trademark) HPH, Compritol(trademark) 888, Sterotex(trademark) NF, Sterotex(trademark) K, Luburitab(trademark), and mixtures thereof.

[0144] Particularly preferred coatings consist of a mixture of hydrogenated vegetable oil and methacrylate copolymer. The precise structure and amount of each component, as well as the amount of coating applied to the particles, control the release rate and release trigger. Eudragit® methacrylate copolymers, namely methacrylate-methyl methacrylate copolymer and methacrylate-ethyl acrylate copolymer, have pH-dependent solubility, and typically, the pH that triggers the release of the active ingredient from the microparticles is set by the selection and mixture of appropriate Eudragit® polymers. For γ-hydroxybutyrate-modified release microparticles, the theoretical pH that triggers release is 5.5–6.97 or 5.5–6.9. "pH trigger" refers to the minimum pH at which dissolution of the polymer occurs.

[0145] In certain embodiments, the coating comprises a hydrophobic compound having a melting point of 40°C or higher, and the polymer supporting the free carboxylic acid groups is present in weight ratios of 0.4-4, 0.5-4, 0.6-2.5, 0.67-2.5, 0.6-2.33, or 0.67-2.33. In one embodiment, the weight ratio is approximately 1.5.

[0146] Particularly preferred coatings consist of a mixture of hydrogenated vegetable oil and methacrylic acid copolymer having a theoretical pH of 6.5 to 6.97 that triggers release, in weight ratios of 0.4 to 4, 0.5 to 4, 0.6 to 2.5, 0.67 to 2.5, 0.6 to 2.33, or 0.67 to 2.33. In one embodiment, the weight ratio may be about 1.5.

[0147] The modified γ-hydroxybutyrate-releasing particles have a volume-average diameter of 100-1200 microns, 100-500 microns, or 200-800 microns. In one embodiment, the modified γ-hydroxybutyrate-releasing particles have a volume-average diameter of approximately 320 microns.

[0148] The coating can represent 10–50, 15–45, 20–40, or 25–35% by weight of the total weight of the coated modified release particles. In one embodiment, the coating represents 25–30% by weight of the total weight of the γ-hydroxybutyrate modified release particles.

[0149] In one embodiment, a coating layer of modified γ-hydroxybutyrate-releasing particles is obtained, particularly in a fluidized bed apparatus, by spraying a solution, suspension, or dispersion containing the aforementioned coating composition onto the immediate-releasing particles of γ-hydroxybutyrate, especially the aforementioned immediate-releasing particles of γ-hydroxybutyrate. In one embodiment, the coating is formed by spraying a solution of the coating excipient in hot isopropyl alcohol in a fluidized bed equipped with a Wurster or fractionation tube, according to an upward spray orientation or a downward spray orientation.

[0150] According to one embodiment, the modified γ-hydroxybutyrate-releasing particles consist of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, layered with 56.5% w / w γ-hydroxybutyrate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 8% methacrylate copolymer type B (Eudragit® S100 or equivalent), all percentages expressed based on the total weight of the final modified γ-hydroxybutyrate-releasing particles.

[0151] According to one embodiment, the modified γ-hydroxybutyrate-releasing particles consist of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, layered with 56.5% w / w γ-hydroxybutyrate mixed with 3% w / w Povidone® K30, and finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 8% methacrylate copolymer type B (Eudragit® S100 or equivalent), all percentages expressed based on the total weight of the final modified γ-hydroxybutyrate-releasing particles.

[0152] According to one embodiment, the γ-hydroxybutyrate-releasing particles consist of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, are layered with 56.5% w / w sodium oxidate mixed with 3% w / w Povidone® K30, and are finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 8% methacrylate copolymer type B (Eudragit® S100 or equivalent), all percentages expressed based on the total weight of the final modified-releasing particles of sodium oxidate.

[0153] According to one embodiment, the γ-hydroxybutyrate-releasing particles consist of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, are layered with 56.5% w / w sodium oxibate mixed with 3% w / w Povidone® K30, and are finally coated with a coating composition consisting of 18% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 4% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 8% methacrylate copolymer type B (Eudragit® S100 or equivalent), all percentages expressed based on the total weight of the final modified-releasing particles of sodium oxibate.

[0154] According to another embodiment, the γ-hydroxybutyrate-releasing particles consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, are layered with 60.5% w / w γ-hydroxybutyrate mixed with 3.2% w / w Povidone® K30, and are finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 9.25% methacrylate copolymer type B (Eudragit® S100 or equivalent).

[0155] According to another embodiment, the γ-hydroxybutyrate-releasing particles consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, are layered with 60.5% w / w γ-hydroxybutyrate mixed with 3.2% w / w Povidone® K30, and are finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 9.25% methacrylate copolymer type B (Eudragit® S100 or equivalent).

[0156] According to another embodiment, the γ-hydroxybutyrate-releasing particles consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, are layered with 60.5% w / w sodium oxibate mixed with 3.2% w / w Povidone® K30, and are finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 9.25% methacrylate copolymer type B (Eudragit® S100 or equivalent).

[0157] According to another embodiment, the γ-hydroxybutyrate-releasing particles consist of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, are layered with 60.5% w / w sodium oxibate mixed with 3.2% w / w Povidone® K30, and are finally coated with a coating composition consisting of 15% w / w hydrogenated vegetable oil (Lubritab® or equivalent), 0.75% methacrylate copolymer type C (Eudragit® L100-55 or equivalent), and 9.25% methacrylate copolymer type B (Eudragit® S100 or equivalent).

[0158] Packaging The γ-hydroxybutyrate composition may be supplied in sachets or stick packs containing microparticle formulations. The sachets may be available in several different doses, each containing γ-hydroxybutyrate in an amount equivalent to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g, and / or 12 g of sodium oxybate. Depending on the required dose, one or more of these sachets can be opened and their contents mixed with tap water to provide an overnight dose of γ-hydroxybutyrate.

[0159] Treatment method This specification provides a method for treating a human patient suffering from one or more symptoms of narcolepsy by orally administering a single daily dose to the human patient, wherein the total dose of the pharmaceutical composition contains γ-hydroxybutyrate in combination with divalproex sodium. In some embodiments, this method may be effective in doing so in a human patient who needs to treat a disorder including but not limited to narcolepsy. Treatment of narcolepsy may include improvement (e.g., reduction) of one or more symptoms such as cataplexy, excessive daytime sleepiness, nocturnal sleep interruption, hypnagogic hallucinations, or sleep paralysis. In some embodiments, the human patient may be a human subject. This specification further provides a method for doing so in a human subject who needs to treat a disorder treatable with γ-hydroxybutyrate, comprising orally administering a single daily dose of γ-hydroxybutyrate in combination with divalproex sodium in a human amount equivalent to 3.0 to 12.0 g of sodium oxybate in the composition. This specification further provides a method for treating narcolepsy type 1 and / or type 2 by orally administering a therapeutically effective dose of a γ-hydroxybutyrate formulation characterized by the novel γ-hydroxybutyrate pharmacokinetic properties of the composition when administered co-administered with divalproex sodium, without reducing the dose of γ-hydroxybutyrate administered without divalproex sodium. In one embodiment, the composition of the present invention is effective in treating narcolepsy type 1 or type 2, where treatment of narcolepsy is defined as reducing excessive daytime sleepiness, reducing the frequency of cataplexy attacks, reducing nocturnal sleep interruption, reducing hypnagogic hallucinations, or reducing sleep paralysis. The therapeutically effective dose may contain 3.0 to 12.0 g of sodium oxybate. In various embodiments, the therapeutically effective dose is 4.5, 6.0, 7.5, or 9.0 g of sodium oxybate. In one embodiment, the therapeutically effective dose is 6 g or 9 g of sodium oxybate. In various embodiments, the formulation comprises sodium oxibate present in a unit dose of at least 4.5 g, at least 6.0 g, at least 7.5 g, or at least 9.0 g.The effectiveness of the treatment can be measured by one or any combination of the following criteria: ● Increases mean sleep latency, as determined by the Maintaining Wakefulness Test (MWT). ● Improve the clinically-based impression (CGI) assessment of drowsiness. ● Reduce the number of cataplexy attacks (NCA) as determined from the cataplexy frequency items in sleep and symptom diaries. ● Reduces nocturnal sleep interruption (DNS), nocturnal event interruption, or adverse respiratory events as determined by polysomnography (PSG) measurement of sleep fragmentation. ● Reduces excessive daytime sleepiness (EDS) as measured by patient reports via the Epworth Sleepiness Scale (ESS). ● Reduces daytime sleepiness as measured by an alertness maintenance test based on EEG measurement of wakefulness. ● Reduces the transition from N / 2 to N / 3, and from REM sleep to wakefulness and N1 sleep (as determined by C Iber, S Ancoli-Israel, A Chesson, SF Quan. The AASM Manual for the Scoring of Sleep and Associated Events. Westchester, IL: American Academy of Sleep Medicine; 2007). ● Reduces the number of arousals or wakes obtained from polysomnography (PSG), as defined by the American Academy of Sleep Medicine. ●Improve sleep quality as determined from one or more of the following: (i) sleep and symptom diaries, (ii) visual continuous scale (VAS) and sleep diaries for sleep quality, and (iii) VAS for the refreshing nature of sleep. ● Reduces hypnagogic hallucinations (HH) or sleep paralysis (SP) symptoms in NT1 narcolepsy patients, as measured by sleep and symptom diaries.

[0160] In one embodiment, treatment using a composition administered concurrently with divalproex sodium is superior to an equidose of a composition administered without divalproex sodium, as measured by any one or a combination of the aforementioned criteria.

[0161] In some embodiments, the present method has been shown to include the treatment of narcolepsy type 1 or type 2, and compared to a drug regimen consisting of reducing the dose of sodium oxidate when administered in combination with divalproex sodium, a single daily dose of a therapeutically effective amount of the present formulation administered in combination with divalproex sodium does not require a reduction in the dose of sodium oxidate. [Examples]

[0162] Example 1. Formulation Tables 1a to 1d provide qualitative and quantitative compositions of sodium oxybate IR fine particles, MR fine particles, and mixtures of IR and MR fine particles. Figure 1 shows the physical structures of the fine particles representing the qualitative and quantitative compositions of IR and MR fine particles.

[0163] Briefly, sodium oxidate immediate-release (IR) fine particles were prepared as follows: 1615.0 g of sodium oxidate and 85.0 g of polyvinylpyrrolidone (Povidone K30-Plasdone® K29 / 32 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water. This solution was sprayed evenly onto 300 g of microcrystalline cellulose spheres (Cellets® 127) in a fluid-bed spray coater apparatus. IR fine particles with a volume-average diameter of approximately 270 microns were obtained.

[0164] Sodium oxidate-modified release (MR) fine particles were prepared as follows: 22.8 g of methacrylic acid copolymer type C (Eudragit® L100-55), 45.8 g of methacrylic acid copolymer type B (Eudragit® S100), and 102.9 g of hydrogenated cottonseed oil (Lubritab®) were dissolved in 1542.9 g of isopropanol at 78°C. The solution was sprayed evenly onto 400.0 g of the above sodium oxidate IR fine particles in a fluidized bed spray coater apparatus with an inlet temperature of 48°C, a spray rate of approximately 11 g / min, and a spray pressure of 1.3 bar. The MR fine particles were dried for 2 hours with the inlet temperature set to 56°C. MR fine particles with an average volume diameter of approximately 320 microns were obtained.

[0165] A finished composition containing a 50:50 mixture of MR and IR fine particles calculated based on sodium oxidate content was prepared as follows: 353.36 g of the above IR fine particles, 504.80 g of the above MR fine particles, 14.27 g of malic acid (D / L malic acid), 6.34 g of xanthan gum (Xantural® 75 from Kelco), 9.51 g of carrageenan gum (Viscarin® PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol® 250M from Ashland), and 4.51 g of magnesium stearate were mixed. 7.11 g of individual samples (corresponding to a 4.5 g dose of sodium oxidate, with half of the dose as the immediate-release fraction and the other half as the modified-release fraction) were weighed out. [Table 1a] [Table 1b] [Table 1c] [Table 1d]

[0166] Example 1bis. Alternative Formulation An alternative formulation to the formulation described in Example 1 is described in Example 1bis.

[0167] Sodium oxidate immediate-release (IR) microparticles were prepared by coating the IR microparticles described in Example 1 with a topcoat layer. The microparticles were prepared as follows: 170.0 ml of hydroxypropyl cellulose (Klucel® EF Pharm from Hercules) was solubilized in 4080.0 g of acetone. This solution was sprayed evenly over 1530.0 g of the IR microparticles from Example 1 in a fluidized bed spray coater. IR microparticles with a volume-average diameter of approximately 298 microns were obtained (see Table 1bis-a).

[0168] Sodium oxidate-modified release (MR) fine particles were prepared as described in Example 1 (see Table 1b).

[0169] A finished composition containing a 50:50 mixture of MR and IR fine particles based on sodium oxidate content was prepared as follows: 412.22 g of the above IR fine particles, 530.00 g of the above MR fine particles, 29.96 g of malic acid (D / L malic acid), 4.96 g of xanthan gum (Xantural® 75 from Kelco), 4.96 g of colloidal silicon dioxide (Aerosil® 200 from Degussa), and 9.92 g of magnesium stearate were mixed. 7.45 g of individual samples (corresponding to a 4.5 g dose of sodium oxidate, with half the dose in the immediate-release fraction and the other half in the modified-release fraction) were weighed (see Tables 1bis-b and 1bis-c). [Table 1-2a] [Table 1-2b] [Table 1-2c]

[0170] Compared to the completed composition described in Example 1, this alternative composition has the following characteristics: it contains the same MR microparticles and IR microparticles, but with a top coat, an increased amount of malic acid, only one suspending agent (xanthan gum), and the presence of a flow enhancer.

[0171] Example 2. In vivo pharmacokinetic study of FT218 with and without DVP. Pharmacokinetic studies were conducted in vivo in healthy human volunteers using the completed composition (FT218) from Example 1, administered co-administered with DVP. This study was designed to explain the magnitude of PK changes in FT218 when administered co-administered with divalproex sodium ER evening dose. Volunteers were 18-55 years old and weighed 19.1-28.0 kg / m². 2 A total of 24 healthy male subjects with a BMI participated in the study. One subject withdrew their consent on day 9 (before simultaneous administration), so n=23 received FT218 along with 1250 mg / day of divalproex sodium ER, and n=24 received FT218 without DVP.

[0172] This study included a three-period sequential design with a single dose of 6g of FT218 on day 1 (period 1), 1250mg of divalproex sodium ER once daily from days 2 to 11 (period 2), and simultaneous administration of FT218 and divalproex sodium ER on day 12 (period 3). All doses were administered in the evening, two hours after dinner. Overall, no serious safety issues were observed during this study, and no SAEs or AESIs occurred.

[0173] After administering 6 g of FT218 on the evening of day 1, quantifiable concentrations of GHB were observed in all subjects 10 minutes later (first sampling point). GHB concentrations increased, reaching a maximum geometric mean concentration of 71.2 μg / mL approximately 1 hour after administration. After reaching the peak concentration, GHB concentrations gradually decreased. Plasma concentrations of GHB remained quantifiable in all subjects for at least 8 hours after administration.

[0174] The concentration-time curves of FT218 with and without DVP are shown in Figures 1A and 1B. The derived PK parameters are summarized below (Table 2).

[0175] Co-administration of a single evening dose of 6g FT218 and divalproex sodium ER showed a decrease in GHB AUC. 0-t and AUC 0-inf This increased it by approximately 17%. max The 90% CI of the ratio of mean AUCs was within the standard bioequivalence range (80.00% to 125.00%), in compliance with bioequivalence standards. max The patient was not affected by the co-administration of divalproex sodium ER. max The results were similar regardless of whether or not divalproex sodium ER was administered concurrently. [Table 2]

[0176] Example 3. Comparison of FT218 with and without DVP To compare the effect of DVP on FT218, we performed T on FT218 alone and FT218 with DVP. max , C max , and AUC inf The mean values ​​were plotted together. The effect of DVP on FT218 is shown in Figures 2A, 2B, and 2C. Figure 2A shows the mean T for each patient when FT218 was administered alone and when it was administered concurrently with DVP. max The values ​​are shown. Figure 2B shows the average C for each patient when FT218 was administered alone and when it was administered concurrently with DVP. max The values ​​are shown. Figure 2C shows the mean AUC for each patient when FT218 was administered alone and when it was administered concurrently with DVP. inf The values ​​are shown. In comparison, the FT218 with DVP appears to behave similarly to the FT218 alone. Therefore, the FT218 appears to have a similar PK profile regardless of the presence or absence of DVP.

[0177] The point estimate (PE) and 90% confidence interval (CI) of the geometric mean ratio of FT218+DVP / FT218 (alone) are shown below (Table 3). max The 90% CI of the mean ratio of AUC was within the standard bioequivalence range (80.00% to 125.00%), in compliance with bioequivalence standards. The 90% CI of the T / R ratio was within the AUC 0-inf (T / R ratio [90%CI]:116.74[111.03~122.73]) and AUC 0-t The T / R ratio [90% CI] (116.67 [111.18~122.44]) did not include 100 and showed an increase in AUC of approximately 17%. C for both treatments max The results were similar (T / R ratio [90% CI]: 98.46 [91.58~105.85]). Therefore, C max AUC 0-last , and AUC 0-inf The 90% confidence interval for GHB is within the range of 80–125% bioequivalence. max The effects of both treatments were equivalent. This was confirmed by nonparametric statistical analysis. [Table 3]

[0178] Example 4. Comparison of DVP with and without FT218 After administering 1250 mg of divalproex sodium ER on the evening of day 11, the geometric mean concentration of valproic acid increased from 58.5 μg / mL at baseline to a maximum geometric mean concentration of 79.5 μg / mL 14 hours after administration. After reaching the peak concentration, the geometric mean concentration of valproic acid returned to 57.9 μg / mL 24 hours after administration.

[0179] After administration of 1250 mg of divalproex sodium ER on the evening of day 12, the geometric mean concentration of valproic acid increased from 57.9 μg / mL at baseline to a maximum geometric mean concentration of 77.0 μg / mL 14 hours after administration, in the presence of GHB levels. After reaching the peak concentration, the geometric mean concentration of valproic acid returned to 64.0 μg / mL 24 hours after administration.

[0180] On day 11 (without FT218) and day 12 (with FT218), both divalproex sodium ER treatments were administered. For subjects included in the statistical analysis (N=23), the C levels of valproic acid on both days were analyzed. max and AUC 0-24 The geometric mean of C was compared. max and AUC 0-24 The 90% CI of the mean ratio was within the standard bioequivalence range (80.00%–125.00%), adhering to bioequivalence criteria. AUC for both treatments 0-24 The results were similar (T / R ratio [90% CI]: 97.28 [94.59~100.04]). max Regarding this, the 90% CI of the T / R ratio does not include 100 (T / R ratio [90% CI]: 94.82 [91.03~98.76]), C max It showed a decrease of approximately 5%. Valproic acid t max The effects of both treatments were equivalent. This was confirmed by nonparametric statistical analysis.

[0181] To compare the effects of FT218 on DVP, the concentration-time curves for DVP monotherapy at a dose of 1250 mg (day 11) and DVP co-administration with FT218 (day 12) were plotted together.

[0182] Figure 3A shows the average PK profile of DVP with and without co-administration of FT218. Figure 3B shows the individual PK profiles of DVP with and without co-administration of FT218. This appears to show a similar DVP profile regardless of the presence or absence of FT218.

[0183] Example 5. Comparison with Xyrem® DDI research To compare the effect of DVP on FT218 and Xyrem®, we examined the geometric LS mean AUC of FT218 with and without DVP. inf The values ​​are the geometric LS mean AUC of Xyrem® with and without DVP from Xyrem's drug-drug interaction (DDI) studies. inf The values ​​were compared (Eller et al, 2013). Tables 4 and 5 below provide comparisons. Table 4 shows the C for 6g FT218 with 1250mg / day DVP. max and AUC inf However, regarding C for FT218 alone at a 6g dose max and AUC inf This indicates that the bioequivalence is within the range of 80% to 125%, while Table 5 shows the AUC of two 3g doses of Xyrem® with 1250mg / day DVP. inf However, AUC inf This demonstrates that the bioequivalence range is exceeded. Specifically, Xyrem administered with DVP without dose adjustment showed approximately 127% higher AUC than Xyrem alone. inf This resulted in Xyrem with DVP, while FT218 administered with DVP without dose adjustment yielded approximately 117% higher AUCinf for FT218 alone. Therefore, Xyrem with DVP is outside the limits of bioequivalence, while FT218 with DVP is within the limits of bioequivalence. [Table 4] [Table 5]

[0184] Example 6. In vivo pharmacokinetic study of FT218 with or without DVP administration in the morning. Pharmacokinetic studies were conducted in vivo in healthy human volunteers using the completed composition (FT218) from Example 1, administered concurrently with DVP. This study was an open-label, sequential trial to evaluate steady-state drug-drug interactions of divalproex sodium sustained-release (ER) with respect to the FT218 formulation administered as a single 6 g morning dose in healthy volunteers. A total of 22 healthy subjects participated in this study. All 22 subjects completed the study according to the protocol, and 21 subjects were evaluable for GHB PK statistical analysis. FT218 was administered in the morning, 2 hours after breakfast, with or without 1250 mg / day of divalproex sodium ER.

[0185] This study included a three-period sequential design with a single dose of 6g of FT218 on day 1 (period 1), 1250mg of divalproex sodium ER once daily from days 2 to 11 (period 2), and simultaneous administration of FT218 and divalproex sodium ER on day 12 (period 3). All doses were administered in the morning, two hours after breakfast. Overall, no serious safety issues were observed during this study, and no SAEs or AESIs occurred.

[0186] After administering 6g of FT218 on the morning of day 1, quantifiable levels of GHB were observed in all subjects 10 minutes later (first sampling point). After reaching the peak concentration, the GHB concentration gradually decreased. Plasma concentrations of GHB remained quantifiable in all subjects for at least 8 hours after administration.

[0187] The concentration-time curves of FT218 with and without DVP are shown in Figures 4A and 4B. The derived PK parameters are summarized below (Table 6).

[0188] C max The 90% CI of the ratio of mean AUCs was within the standard bioequivalence range (80.00% to 125.00%), in compliance with bioequivalence standards. maxThe patient was not affected by the co-administration of divalproex sodium ER. max The results were similar regardless of whether or not divalproex sodium ER was administered concurrently. [Table 6]

[0189] Example 7. Comparison of FT218 with and without DVP To compare the effect of DVP on FT218, we performed T on FT218 alone and FT218 with DVP. max , C max , and AUC inf The average values ​​were plotted together. The effect of DVP on FT218 is shown in Figures 5A, 5B, and 5C. Figure 5A shows the average T for each patient when FT218 was administered alone and when it was administered concurrently with DVP. max The values ​​are shown. Figure 5B shows the average C for each patient when FT218 was administered alone and when it was administered concurrently with DVP. max The values ​​are shown. Figure 5C shows the mean AUC for each patient when FT218 was administered alone and when it was administered concurrently with DVP. inf The values ​​are shown. In comparison, FT218 with DVP appears to behave similarly to FT218 alone. Therefore, FT218, with or without DVP, appears to have a similar PK profile when administered in the morning.

[0190] The point estimate (PE) and 90% confidence interval (CI) of the geometric mean ratio of FT218+DVP / FT218 (alone) are shown below (Table 7). max The 90% CI of the ratio of mean AUCs was within the standard bioequivalence range (80.00%–125.00%), adhering to bioequivalence criteria. The results show an approximately 18% increase in AUC between both treatments. max They were similar. Therefore, C max AUC 0-last , and AUC 0-inf The 90% confidence interval for this is within the range of 80–125% bioequivalence. [Table 7]

[0191] Example 8. Comparison of DVP with and without FT218 After administering 1250 mg of divalproex sodium ER on the morning of day 11, the geometric mean concentration of valproic acid increased to a maximum geometric mean concentration of 72.43 μg / mL.

[0192] On day 11 (without FT218) and day 12 (with FT218), both divalproex sodium ER treatments were administered. For subjects included in the statistical analysis (N=22), the C levels of valproic acid on both days were analyzed. max and AUC 0-24 The geometric mean of C was compared. max and AUC 0-24 The 90% CI of the mean ratio fell within the standard bioequivalence range (80.00%–125.00%), adhering to bioequivalence standards.

[0193] To compare the effects of FT218 on DVP, the concentration-time curves for DVP monotherapy at a dose of 1250 mg (day 11) and DVP co-administration with FT218 (day 12) were plotted together. Figure 6A shows the average PK profile of DVP with and without co-administration of FT218 in the morning. Figure 6B shows the individual PK profiles of DVP with and without co-administration of FT218 in the morning. This appears to show a similar DVP profile regardless of the presence or absence of FT218.

[0194] Example 9. Inter-study comparison of FT218 alone and in combination with DVP. Figure 7 shows the mean concentration-versus-time curves of FT218 administered alone and with DVP in two separate studies (DDI#1, DDI#2).

[0195] DDI#1 was an open-label sequential study to evaluate steady-state drug-drug interactions of divalproex sodium sustained-release (ER) with a single 6g morning dose of FT218 in healthy volunteers. In DDI#1, FT218 was administered in the morning, 2 hours after breakfast, with or without 1250 mg / day of divalproex sodium ER. Examples 6-8 show the results from DDI#1.

[0196] DDI#2 was an open-label sequential study to evaluate steady-state drug-drug interactions of divalproex sodium sustained-release (ER) with FT218 administered as a single 6g evening dose in healthy male volunteers. In DDI#2, FT218 was administered in the evening, 2 hours after dinner, with or without 1250 mg / day of divalproex sodium ER. Examples 2-4 show the results from DDI#2.

[0197] As shown in Figure 7, the comparison between DDI#1 and DDI#2 indicates that the interaction between FT218 and DVP has a similar effect on GHB concentration, regardless of the administration time. Therefore, FT218 may be administered once daily (morning or evening) concurrently with DVP without the need to reduce the FT218 dose.

[0198] Throughout this application, various publications are referenced. The entire disclosures of these publications are incorporated herein by reference to more fully describe the technical field to which the invention relates. It will be apparent to those skilled in the art that various modifications and variations can be made in the invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specifications and practices of the invention disclosed herein. This specification and the examples are intended to be merely illustrative, and the true scope and spirit of the invention are shown by the following claims.

Claims

1. A once-overnight oral composition containing gamma-hydroxybutyrate (GHB) for use in the treatment of GHB-treated diseases in human subjects already taking divalproex sodium ER (DVP), The aforementioned once-overnight oral composition comprises an immediate-release portion and a modified-release portion, the immediate-release portion comprising γ-hydroxybutyrate particles, and the modified-release portion comprising γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. A composition in which a single 6 g dose of divalproex sodium ER and the composition in a steady state increases the AUC by 18% with a 90% confidence interval (CI) within the range of 80-125% bioequivalence, compared to a single 6 g dose of the composition without divalproex sodium ER.

2. The composition according to claim 1, wherein the composition is effective in inducing at least six hours of sleep in the human subject.

3. The composition according to claim 1 or claim 2, wherein the composition is a particulate formulation that forms a suspension when mixed with water.

4. The composition according to any one of claims 1 to 3, wherein the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is 10 / 90 to 65 / 35.

5. The composition according to any one of claims 1 to 4, wherein the γ-hydroxybutyrate comprises 3.0 g to 12.0 g of sodium oxibate.

6. A once-overnight oral composition containing gamma-hydroxybutyrate (GHB) for use in the treatment of GHB-treated diseases in human subjects already taking divalproex sodium ER (DVP), The aforementioned once-overnight oral composition comprises an immediate-release portion and a modified-release portion, the immediate-release portion comprising γ-hydroxybutyrate particles, and the modified-release portion comprising γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. In a steady state, a single 6g dose of the divalproex sodium ER and the composition exhibits a bioequivalence of 80-125% compared to a single 6g dose of the composition without the divalproex sodium ER. ｍａｘ A composition that brings about a result.

7. The composition according to claim 6, wherein the composition is effective in inducing at least six hours of sleep in the human subject.

8. The composition according to claim 6 or claim 7, wherein the composition is a particulate formulation that forms a suspension when mixed with water.

9. The composition according to any one of claims 6 to 8, wherein the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is 10 / 90 to 65 / 35.

10. The composition according to any one of claims 6 to 9, wherein the γ-hydroxybutyrate comprises 3.0 g to 12.0 g of sodium oxibate.

11. A once-overnight oral composition containing gamma-hydroxybutyrate (GHB) for the treatment of human disorders treatable with GHB in humans already taking divalproex sodium ER (DVP), The composition comprises an immediate-release portion and a modified-release portion, the immediate-release portion comprising γ-hydroxybutyrate particles, and the modified-release portion comprising γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher, and each of the immediate-release portion and the modified-release portion contains a daily dose of γ-hydroxybutyrate in an amount equivalent to 0.5 g to 12.0 g of sodium oxibate. A composition in which administration of a dose of divalproex sodium ER and the composition in a steady state yields an AUC within the range of 80-125% bioequivalence compared to administration of a dose of the composition without divalproex sodium ER.

12. The composition according to claim 11, wherein the composition is effective in inducing at least six hours of sleep in the human subject.

13. The composition according to claim 11 or claim 12, wherein the composition is a particulate formulation that forms a suspension when mixed with water.

14. The composition according to any one of claims 11 to 13, wherein the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is 10 / 90 to 65 / 35.

15. The composition according to any one of claims 11 to 14, wherein the γ-hydroxybutyrate comprises 3.0 g to 12.0 g of sodium oxibate.

16. A once-overnight oral composition containing gamma-hydroxybutyrate (GHB) for the treatment of human disorders treatable with GHB in humans already taking divalproex sodium ER (DVP), The composition comprises an immediate-release portion and a modified-release portion, the immediate-release portion comprising γ-hydroxybutyrate particles, and the modified-release portion comprising γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. A composition in which, when administered in combination with divalproex sodium ER in a steady state, a single dose of 6 g of the composition does not require a reduction in the initial dose of the composition in adults.

17. The composition according to claim 16, wherein the composition is effective in inducing at least six hours of sleep in the human subject.

18. The composition according to claim 16 or claim 17, wherein the composition is a particulate formulation that forms a suspension when mixed with water.

19. The composition according to any one of claims 16 to 18, wherein the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is 10 / 90 to 65 / 35.

20. The composition according to any one of claims 16 to 19, wherein the γ-hydroxybutyrate comprises 3.0 g to 12.0 g of sodium oxibate.

21. A combination for treating narcolepsy, cataplexy, or excessive daytime sleepiness in human subjects, The formula contains a once-overnight dose of γ-hydroxybutyrate and a dose of divalproex sodium ER (DVP), The combination comprises an immediate-release portion and a modified-release portion, the immediate-release portion comprises γ-hydroxybutyrate particles, and the modified-release portion comprises γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. Combination therapy results in 50% to 140% higher plasma C compared to the use of gamma-hydroxybutyrate alone. ｍａｘ A combination that yields a value of and an AUC value of 80% to 125%.

22. The combination according to claim 21, wherein the bioavailability of the once-overnight dose of γ-hydroxybutyrate is not affected by its co-administration with the dose of divalproex sodium ER.

23. The combination according to claim 21 or 22, wherein neither the once-overnight dose of γ-hydroxybutyrate nor the dose of divalproex sodium ER is dose-adjusted for the combination.

24. The combination according to any one of claims 21 to 23, wherein the combination does not cause any impairment of attention or working memory in the human subject.

25. The aforementioned once-overnight dose of γ-hydroxybutyrate ｍａｘ However, the combination according to any one of claims 21 to 24 is approximately 2.0 hours.

26. The aforementioned once-overnight dose of γ-hydroxybutyrate C ｍａｘ The combination according to any one of claims 21 to 25, wherein the concentration is 78 μg / mL ± 19.

27. AUC of the aforementioned once-overnight dose of γ-hydroxybutyrate ０－ｌａｓｔ The combination according to any one of claims 21 to 26, wherein the concentration is 366 μg / mL·h ± 146.

28. AUC of the aforementioned once-overnight dose of γ-hydroxybutyrate ０－ｉｎｆ The combination according to any one of claims 21 to 27, wherein the concentration is 366 μg / mL·h ± 146.

29. The combination according to any one of claims 21 to 28, wherein the C8h of the once-overnight dose of γ-hydroxybutyrate is 9.8 μg / mL ± 10.

7.

30. The amount of γ-hydroxybutyrate used alone in the aforementioned once-night dose is C ｍａｘ The amount of γ-hydroxybutyrate used in combination, divided by the ratio of C to the aforementioned once-night dose. ｍａｘ The combination according to any one of claims 21 to 29, wherein the point estimate (PE) providing the geometric mean ratio is about 98.

46.

31. The combination according to any one of claims 21 to 30, wherein the combination does not affect the pharmacokinetics of divalproex sodium ER compared to the use of divalproex sodium ER alone.

32. The combination results in a T for divalproex sodium ER within the range of 80 to 125% bioequivalence relative to the T when divalproex sodium ER is used alone. ｍａｘ for divalproex sodium ER that is within the range of 80 to 125% bioequivalence relative to the T ｍａｘ A combination according to any one of claims 21 to 31.

33. The combination according to any one of claims 21 to 32, wherein the dose of divalproex sodium ER is 1250 mg.

34. For treating patients suffering from one or more symptoms of narcolepsy, The total dose of a pharmaceutical composition including the immediate-release portion and the modified-release portion; and Dosage of divalproex sodium ER (DVP) It is a combination of, The immediate release portion comprises γ-hydroxybutyrate (GHB) particles, and the modified release portion comprises γ-hydroxybutyrate particles coated with a coating containing a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. The dosage of the GHB composition is within the range of 80-125% bioequivalence to the same dosage of the γ-hydroxybutyrate composition used alone. ｍａｘ , C ｍａｘ , or AUC ｉｎｆ A combination that brings about a result.

35. The dosage of the GHB composition is shown in Figure 2A as T ｍａｘ In contrast, T within the range of 80-125% bioequivalence ｍａｘ The combination according to claim 34, which brings about the following:

36. The dosage of the GHB composition is shown in Figure 2B, C ｍａｘ In contrast, C within the range of 80-125% bioequivalence ｍａｘ The combination according to claim 34 or claim 35, which brings about the following:

37. The dose of the GHB composition, compared to the same dose of the γ-hydroxybutyrate composition administered alone, contains 5% C. ｍａｘ A combination according to any one of claims 34 to 36 that results in a reduction.

38. The dosage of the GHB composition is shown in Figure 2C as AUC ｉｎｆ In contrast, AUC within the range of 80-125% bioequivalence ｉｎｆ A combination according to any one of claims 34 to 37 that brings about the following:

39. The combination according to any one of claims 34 to 38, wherein the dose of the GHB composition is present in a unit dose of at least 4.5 g.

40. The combination according to any one of claims 34 to 38, wherein the dose of the GHB composition is present in a unit dose of at least 6.0 g.

41. The combination according to any one of claims 34 to 38, wherein the dose of the GHB composition is present in a unit dose of at least 7.5 g.

42. The combination according to any one of claims 34 to 38, wherein the dose of the GHB composition is present in a unit dose of at least 9.0 g.

43. A once-overnight oral formulation of γ-hydroxybutyrate for use in human subjects already taking divalproex sodium ER (DVP), The γ-hydroxybutyrate formulation comprises an immediate-release portion and a modified-release portion, The immediate release portion comprises γ-hydroxybutyrate particles, The modified release portion comprises particles of γ-hydroxybutyrate coated with a coating containing a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. The T of the modified release formulation ｍａｘ , C ｍａｘ , or AUC ｉｎｆ However, the formulation exhibits a bioequivalence of 80-125% to the modified-release formulation when administered in combination with divalproex sodium ER (DVP).

44. A composition comprising an immediate-release portion and a modified-release portion for treating narcolepsy, cataplexy, or excessive daytime sleepiness in human subjects, The immediate-release portion comprises γ-hydroxybutyrate particles, the modified-release portion comprises γ-hydroxybutyrate particles coated with a coating containing a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher, and each of the immediate-release portion and the modified-release portion comprises a once-overnight dose of γ-hydroxybutyrate. A composition characterized by being administered in combination with the dose of divalproex sodium ER (DVP).

45. A composition for treating narcolepsy, cataplexy, or excessive daytime sleepiness in human subjects, Includes the dose of divalproex sodium ER (DVP), The composition is administered in combination with a composition comprising an immediate-release portion and a modified-release portion, wherein the immediate-release portion comprises γ-hydroxybutyrate particles, and the modified-release portion comprises γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher, and each of the immediate-release portion and the modified-release portion comprises a once-overnight dose of γ-hydroxybutyrate.

46. A total dose of a pharmaceutical composition comprising an immediate-release portion and a modified-release portion for treating a patient suffering from one or more symptoms of narcolepsy, wherein the immediate-release portion comprises γ-hydroxybutyrate (GHB) particles, and the modified-release portion comprises γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher. The composition is characterized by being administered in combination with the dosage of divalproex sodium ER (DVP).

47. A composition comprising a dosage of divalproex sodium ER (DVP) for treating a patient suffering from one or more symptoms of narcolepsy, A composition administered in combination with a total dose of a pharmaceutical composition comprising an immediate-release portion and a modified-release portion, wherein the immediate-release portion comprises γ-hydroxybutyrate (GHB) particles, and the modified-release portion comprises γ-hydroxybutyrate particles coated with a coating comprising a polymer supporting free carboxylic acid groups and a hydrophobic compound having a melting point of 40°C or higher.

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