Gamma-hydroxybutyrate compositions with improved pharmacokinetics in eating state

Abstract

Sodium hydroxybutyrate oral pharmaceutical compositions having improved pharmacokinetic properties when administered less than two hours after eating and therapeutic uses thereof are provided.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080016490.8 (application date: February 28, 2020, invention name: γ-hydroxybutyrate composition with improved pharmacokinetics in the fed state).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 812,699 filed on March 1, 2019 and U.S. Provisional Application No. 62 / 857,008 filed on June 4, 2019. Technical Field

[0004] The present invention relates to a composition for treating narcolepsy, cataplexy or excessive daytime sleepiness, comprising a unit dose of gamma-hydroxybutyrate, suitable for administration less than two hours after eating. The present invention also relates to a modified release formulation of gamma-hydroxybutyrate with improved pharmacokinetic (PK) properties in the fed state and its therapeutic use. Background Art

[0005] Narcolepsy is a devastating and disabling disease. The main symptoms are excessive daytime sleepiness (EDS), cataplexy (a sudden loss of muscle tone triggered by strong emotions, seen in about 60% of patients), hypnagogic hallucinations (HH), sleep paralysis (SP) and nocturnal sleep disturbances (DNS). In addition to EDS, DNS is the most common symptom in patients with narcolepsy.

[0006] Sodium oxybate is one of the main treatments for narcolepsy. The exact mechanism by which sodium oxybate works is unclear, but it is thought to work by promoting SWS (delta sleep) and consolidating nighttime sleep. Sodium oxybate administered before sleep at night increases stage 3 and 4 sleep and increases sleep latency while decreasing the frequency of sleep onset REM phases (SOREMPs). Other mechanisms that have not yet been elucidated may also be involved.

[0007] Sodium hydroxybate is also known as sodium 4-hydroxybutyrate or sodium salt of gamma-hydroxybutyrate and has the following chemical structure:

[0008]

[0009] Sodium oxybate is used in the United States Commercially available. The product is formulated as an immediate-release liquid solution that is taken once in equal doses immediately before bedtime and a second dose approximately 2.5 to 4 hours later. Sleep onset may be violent and rapid, and patients are advised to sit up in bed while taking doses. The most commonly reported side effects are nausea, dizziness, vomiting, drowsiness, enuresis, and tremor.

[0010] A serious disadvantage of is the requirement to take the first dose at least 2 hours after eating. The label clearly recommends taking the first dose of It should be taken at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate." The medical concern that the label warns of and that is not addressed by the prior art is the adverse effect of food on GHB absorption. The Risk Management Plan states, “Because food can significantly reduce the bioavailability of sodium oxybate, patients should try to eat and take the first dose of sodium oxybate several hours before bedtime. Patients should try to minimize variability in dosing timing relative to meals.” (See https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2002 / 21196lbl.pdf). In practice, the food effect barrier of the prior art presents a variety of unresolved issues for patients, as eating several hours before bedtime is not always possible. Likewise, despite best efforts, patients may experience variability in dosing timing relative to meals due to unforeseen schedule changes, travel, etc. As a result, the food effect issues of the prior art inevitably lead to reduced patient compliance, reduced efficacy, and reduced safety. Furthermore, because GHB is a known drug of abuse, food effect issues and an inherently greater risk of abuse, including accidental abuse.

[0011] Scientific studies have shown that after a high-fat meal, intestinal uptake of GHB may be significantly reduced due to inhibition of anion transporters such as monocarboxylate transporters (MCTs). MCTs are transporters that determine systemic GHB absorption, renal clearance, and distribution. Recent studies have shown that MCT-mediated intestinal absorption of GHB occurs in a concentration- and proton gradient-dependent manner and occurs through a carrier-mediated process along the length of the intestine. MCT-mediated intestinal absorption of GHB is important for its pharmacological activity because more than 99% of GHB is ionized and cannot diffuse across cell membranes at physiological pH.

[0012] Therefore, there is a need for compositions of gamma-hydroxybutyrate that can be administered less than two hours after a meal without compromising safety or efficacy. Summary of the invention

[0013] In one aspect, the present disclosure encompasses an oral pharmaceutical composition for treating narcolepsy, cataplexy, or excessive daytime sleepiness that can be administered less than two hours after a meal. For example, a composition comprising gamma-hydroxybutyrate can be a unit dose suitable for administration less than two hours after a meal. In other aspects, the composition may be suitable for once daily administration. In some aspects, the composition provides an average AUC of 100 mg / kg when administered less than two hours after a meal. inf and / or average C max is the mean AUC of the composition when administered at least two hours after a meal inf or average C max When administered less than two hours after a meal, the composition can provide the same effect as taking the composition in equally divided doses at least two hours after a meal at t0 and t1. 4h AUC of an equivalent dose of sodium oxybate immediate-release liquid solution administered inf or C max Bioequivalence AUC inf and / or C max In some aspects, a 6 g dose of the composition administered less than two hours after a meal has been shown to achieve a mean AUC of greater than 240 hr*μ / mL inf and at least 2 hours after a meal in equally divided doses at t0 and t 4h Administration of an equal dose of sodium oxybate immediate-release liquid solution provided the mean C max Average C from 50% to 140% max .

[0014] Further provided herein is a method of treating narcolepsy and related disorders and symptoms in a patient in need thereof by administering an oral pharmaceutical composition of gamma-hydroxybutyrate less than two hours after eating. In one aspect, the composition can be administered once daily. In some aspects, the composition can be administered after eating in the morning or evening. In other aspects, sleep comprises at least six consecutive hours.

[0015] In other aspects, a method of treating hypersomnia and related disorders and symptoms in a patient in need thereof may comprise administering an oral pharmaceutical composition comprising gamma-hydroxybutyrate once daily, wherein the composition is dose proportional. max The dosage may be proportional on one or more of the 4.5 g, 7.5 g and 9 g doses of the composition.

[0016] Also provided herein is an oral pharmaceutical composition and method for treating narcolepsy, cataplexy or excessive daytime sleepiness. The oral pharmaceutical composition comprises a unit dose of gamma-hydroxybutyrate suitable for once-daily administration, wherein most adverse events (AEs) occur during the Tmax period (at C maxIn another aspect, compositions and methods for treating narcolepsy, cataplexy or excessive daytime sleepiness are provided. The composition comprises a unit dose of gamma-hydroxybutyrate, suitable for once daily administration, wherein at C max During the time period, most adverse events (AEs) occurred during T max In some embodiments of this aspect, the oral pharmaceutical composition administered less than two hours after eating may result in fewer AEs than the oral pharmaceutical composition administered at least two hours after eating. The oral pharmaceutical composition of some embodiments is administered in equally divided doses at t0 and t 4h The invention may have a more favorable safety profile (ie, fewer AEs) than an equivalent dose of an immediate-release liquid solution of sodium oxybate administered.

[0017] Other aspects and iterations of the invention are described more fully below. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0019] Figure 1A The qualitative and quantitative structure of the immediate release (IR) microparticles of γ-hydroxybutyrate of Example 1 is described.

[0020] Figure 1B The qualitative and quantitative structure of the modified release (MR) microparticles of gamma-hydroxybutyrate of Example 1 are described.

[0021] Figure 2A is a graph showing the mean concentration over time of 6 g FT218 administered in the fed and fasted states.

[0022] Figure 2B is a series of individual curves plotting the mean concentration versus time for 6 g FT218 administered in the fed and fasted states.

[0023] Figure 3A Figure 2 is a graph of simulated concentration changes over time for IR microparticles of 3 g FT218 administered under fed and fasted conditions.

[0024] Figure 3B Figure 2 is a graph of simulated concentrations over time for 6 g of FT218 administered under fed and fasted conditions and for the IR and MR microparticle fractions of FT218.

[0025] Figure 4A It is a single dose of 4.5g The concentration changes over time in the fed state, fasting state and 2 hours after meal.

[0026] Figure 4BThis is a graph showing the concentration changes over time of a 6g dose of FT218 in the fed state, fasting state and 2 hours after a meal.

[0027] Figure 5A Two 3 g doses are shown in the fed state. and a graph showing the expected concentration versus time for a 6 g dose of FT218.

[0028] Figure 5B Two 3 g doses administered two hours after a meal are shown. and a graph showing the expected concentration versus time for a 6 g dose of FT218.

[0029] Figure 5C Two 3 g doses are shown administered in the fasting state. and a graph showing the expected concentration versus time for a 6 g dose of FT218.

[0030] Fig. 6A Two 4.5 g doses are shown in the fed state. and a graph showing the expected concentration versus time for a 9 g dose of FT218.

[0031] Figure 6B Two 4.5 g doses administered two hours after a meal are shown. and a graph showing the expected concentration versus time for a 9 g dose of FT218.

[0032] Figure 6C Two 4.5 g doses are shown for administration in the fasting state. and a graph showing the expected concentration versus time for a 9 g dose of FT218.

[0033] Fig. 7A Shown 6g FT218 and 6g Postprandial AUC changes over time.

[0034] Figure 7B Shown 6g FT218 and 6g After meal C max Changes over time.

[0035] Figure 8 The graph showing the change in plasma concentration of FT218 over time when the dose was increased from 4.5 g to 9 g per night. DETAILED DESCRIPTION

[0036] The present invention may be understood more readily by reference to the following detailed description of examples of formulations, methods of treatment using some examples of the formulations, and the Examples contained therein.

[0037] Definition and Use of Terms

[0038] Unless otherwise indicated, when analysis or testing is required to understand a given property or characteristic described herein, it is understood that the analysis or testing was performed in accordance with applicable guidance, draft guidance, regulations, and monographs of the U.S. Food and Drug Administration ("FDA") and the United States Pharmacopeia ("USP") applicable to drug products in effect in the United States on November 1, 2015. Clinical endpoints may be judged by reference to the criteria adopted by the American Academy of Sleep Medicine, including those published in the following literature: CIber, 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.

[0039] When a pharmacokinetic comparison is made between a formulation described or claimed herein and a reference product, it is understood that the comparison is made in a crossover trial of appropriate design, but it is also understood that a crossover trial is not required unless otherwise specified. It is also understood that the comparison may be made directly or indirectly. For example, even if a formulation is not tested directly against a reference formulation, a comparison with the reference formulation may still be satisfied if it has been tested against a different formulation, and a comparison with the reference formulation may be derived therefrom.

[0040] As used in this specification and the claims that follow, the singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "an ingredient" includes a mixture of ingredients, reference to "an active pharmaceutical agent" includes more than one active pharmaceutical agent, and so forth.

[0041] "Bioavailability" means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

[0042] "Relative bioavailability" or "Rel BA" or "RBA" means the average AUC of a test product given equal total doses. inf Average AUC relative to the reference product inf Unless otherwise stated, relative bioavailability means the mean AUC observed for the full dose of the test product when the total dose is equal. inf Compared to two doses four hours apart 1 / 2-dose of the immediate-release liquid solution observed mean AUC inf percentage.

[0043] "Bioequivalence" means that in appropriately designed studies, the rate and extent to which the active ingredient or active moiety in a pharmaceutical equivalent or pharmaceutical substitute becomes available at the site of drug action does not differ significantly when administered at the same molar dose under similar conditions.

[0044] When providing scope by separating the lower end of the specified range from the upper end of the scope, it should be understood that the scope can be defined by selectively combining any one of the lower end variables with any one of the upper end variables, which is both mathematically and physically possible. Therefore, for example, if the preparation can contain a specific component of 1 to 10 weight portions, or a specific component of 2 to 8 weight portions, it should be understood that the preparation can also contain the described composition of 2 to 10 weight portions. In a similar manner, if the preparation can contain a composition greater than 1 or 2 weight portions and a composition of at most 10 or 9 weight portions, it should be understood that the preparation can include a composition of 1 to 10 weight portions, a composition of 2 to 9 weight portions, etc., unless otherwise stated, otherwise the boundary of the scope (the lower end and the upper end of the scope) is included in the scope claimed.

[0045] In a similar manner, when various sub-embodiments of a high-level (i.e., main) embodiment are described herein, it should be understood that the sub-embodiments of the high-level embodiment can be combined to define another sub-embodiment. Thus, for example, when a main embodiment contains sub-embodiments 1, 2, and 3, it should be understood that the main embodiment can be further limited by any one of sub-embodiments 1, 2, and 3 or any combination of sub-embodiments 1, 2, and 3 that is mathematically and physically possible. In a similar manner, it should be understood that the main embodiments described herein can be combined in any manner that is mathematically and physically possible, and the invention extends to such combinations.

[0046] The term "about" or "substantially" or "approximately" when used herein will compensate for the variability allowed in the pharmaceutical industry and inherent in drug products, such as differences in product strength due to manufacturing variations and time-induced product degradation. The term allows for any variation in pharmaceutical practice that will allow the product being evaluated to be considered bioequivalent to the stated strength, as described in the FDA's March 2003 BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS.

[0047] Unless otherwise indicated, the term "γ-hydroxybutyrate" or GHB as used herein refers to the free base of γ-hydroxybutyrate, the pharmaceutically acceptable salt of γ-hydroxybutyric acid, and combinations thereof, hydrates, solvates, complexes or tautomer forms thereof. The γ-hydroxybutyrate may be selected from the sodium salt of γ-hydroxybutyric acid or sodium oxybutyrate, the potassium salt of γ-hydroxybutyric acid, the magnesium salt of γ-hydroxybutyric acid, the calcium salt of γ-hydroxybutyric acid, the lithium salt of γ-hydroxybutyric acid, the tetraammonium salt of γ-hydroxybutyric acid or any other pharmaceutically acceptable salt form of γ-hydroxybutyric acid.

[0048] "Pharmaceutically acceptable" means a substance that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and contains substances that are acceptable for veterinary as well as human pharmaceutical use. The term "formulation" or "composition" refers to the quantitative and qualitative characteristics of a pharmaceutical product or dosage form prepared according to the present invention.

[0049] As used herein, the doses and strengths of gamma-hydroxybutyrate are expressed in terms of the equivalent weight of sodium oxybate - grams (g), unless otherwise specifically stated. Therefore, when considering a dose of gamma-hydroxybutyrate other than the sodium salt of gamma-hydroxybutyrate, the dose or strength must be converted from sodium oxybate to the gamma-hydroxybutyrate being evaluated. Thus, if an embodiment is said to provide a 4.5 g dose of gamma-hydroxybutyrate, because the form of the gamma-hydroxybutyrate is not specified, it is understood that the dose encompasses a 4.5 g dose of sodium oxybate, a 5.1 g dose of potassium gamma-hydroxybutyrate (assuming sodium oxybate is 126.09 g / mol MW and potassium gamma-hydroxybutyrate is 142.20 g / mol MW), and a 3.7 g dose of free base (assuming sodium oxybate is 126.09 g / mol MW and the free base of gamma-hydroxybutyrate is 104.1 g / mol MW), or by weight of any mixture of salts of gamma-hydroxybutyrate that provides the same amount of GHB as 4.5 g of sodium oxybate.

[0050] As used herein, "microparticles" means any discrete particles of a solid material. The particles may be made of a single material or may have a complex structure with a core and a shell and be made of multiple materials. The terms "microparticles", "particles", "microspheres" or "pellets" are interchangeable and have the same meaning. Unless otherwise specified, microparticles have no specific particle size or diameter and are not limited to particles having a volume average diameter D(4,3) of 1 mm or less.

[0051] As used herein, the "volume average diameter D(4,3)" is calculated according to the following formula:

[0052] D(4,3)=∑(d4i·ni) / ∑(d3 i·ni)

[0053] where the diameter d of a given particle is the diameter of a hard sphere having the same volume as the particle.

[0054] As used herein, the terms "composition", "oral composition", "oral pharmaceutical composition", "finished composition", "finished formulation" or "formulation" are interchangeable and refer to a composition of γ-hydroxybutyrate that includes modified release microparticles of γ-hydroxybutyrate, immediate release microparticles of γ-hydroxybutyrate and any other excipients. The composition may be described as extended release, delayed release or modified release.

[0055] As used herein, "fast release" means that a major portion of the gamma-hydroxybutyrate is released within a relatively short period of time, for example, at least 75% of the AP is released within 0.75 hours, such as within 30 minutes.

[0056] As used herein, the "immediate release (IR) portion" of a formulation includes physically discrete portions of a formulation, mechanically discrete portions of a formulation, and pharmacodynamically discrete portions of a formulation that contribute to or support a defined IR pharmacokinetic profile. Thus, for example, any formulation that releases an active ingredient at a rate and to an extent desired for the immediate release portion of a formulation of the invention comprises an "immediate release portion," even if the immediate release portion is physically integrated into what might be considered an extended release formulation. Thus, the IR portion may be structurally discrete relative to the MR portion or structurally non-discrete (i.e., integrated with the MR portion). In one embodiment, the IR portion and the MR portion are provided as particles, while in other embodiments, the IR portion and the MR portion are provided as particles separate from each other.

[0057] As used herein, "immediate release formulation" or "immediate release portion" refers to a formulation that is administered according to USP 38 <711> A composition that releases at least 80% of its gamma-hydroxybutyrate within 1 hour when tested in dissolution apparatus 2 in 0.1 N HCl dissolution medium at a temperature of 37°C and a paddle speed of 75 rpm.

[0058] As used herein, "dose dumping" is understood to refer to the immediate and undesired release of dose after oral ingestion. In one embodiment, dose dumping can be the rapid release of gamma-hydroxybutyrate in the presence of alcohol.

[0059] In a similar manner, a "modified release (MR) portion" comprises a portion of a formulation or dosage form that contributes to or supports a specific MR pharmacokinetic profile, regardless of the physical formulation into which the MR portion is incorporated. Modified release drug delivery systems are designed to deliver a drug at a specific time or within a certain period of time after administration, or at a specific location in the body. The USP defines a modified release system as a system that selects the time course or location of drug release, or both, to achieve therapeutic effectiveness or convenience goals that cannot be achieved with traditional IR dosage forms. More specifically, MR solid oral dosage forms include extended release (ER) and delayed release (DR) products. DR products release the drug immediately after administration, rather than immediately after administration. Typically, a coating (e.g., enteric coating) is used to delay the release of the drug substance until the dosage form has passed the acidic medium of the stomach. ER products are formulated to make the drug available for an extended period of time after ingestion, so the dosing frequency is reduced compared to drugs proposed as conventional dosage forms (e.g., solutions or immediate release dosage forms). For oral applications, the term "extended release" is generally interchangeable with "sustained release", "extended release" or "controlled release".

[0060] Traditionally, extended release systems provide a constant release of drug to maintain a steady concentration of the drug. 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. Four categories of oral MR delivery systems can be distinguished: (1) delayed release using enteric coatings, (2) site-specific or timed release (e.g., for colonic delivery), (3) extended release (e.g., zero-order, first-order, biphasic release, etc.), and (4) programmed release (e.g., pulsatile, delayed extended release, etc.) See Gibaldi, DRUG DELIVERY SYSTEMS IN PHARMACEUTICAL CARE, American Society of Health-System Pharmacists, 2007, p. 34, “Modified Oral Drug Delivery Systems” and DEVELOPING SOLID ORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Academic Press, Elsevier, 2009, p. 469, “Rational Design of Oral Modified-release Drug Delivery Systems”. As used herein, in one embodiment, a "modified release formulation" or "modified release portion" refers to a composition that releases its gamma-hydroxybutyrate according to a multi-phase delivery release, such as a delayed extended release, included in the fourth category of MR products. Therefore, it is different from the delayed release products classified as first category MR products.

[0061] As used herein, the terms "coating", "coating layer", "coating film", "film coating" and similar terms are interchangeable and have the same meaning. The terms refer to a coating applied to particles comprising γ-hydroxybutyrate, which controls the modified release of γ-hydroxybutyrate.

[0062] As used herein, "meal state" or "meal mode" includes the feeding state, 2 hours after meal and fasting mode. "Feeding state" or "feeding mode" includes the time period from immediately after meal to up to two hours after meal. The feeding state may include the time period less than two hours after meal. "Fasting state" or "fasting mode" includes the time period after 8 hours after meal. "2 hours after meal" includes the time between the feeding state and the fasting state. For example, "2 hours after meal" may include the time period between at least 2 hours and 8 hours after meal. In all pharmacokinetic tests described herein, unless otherwise stated, the dosage form or initial dosage form (if the dosing regimen needs to be administered more than once) is administered less than two hours after meal, about two hours after meal, or more than 8 hours after meal. For example, the dosage form can be administered less than two hours after consuming a standardized dinner, about two hours after consuming a standardized dinner, or more than 8 hours after consuming a standardized dinner. A standardized dinner may include 25.5% fat, 19.6% protein, and 54.9% carbohydrates.

[0063] "Similar PK profiles", "substantially similar PK profiles" or "comparable bioavailability" means that in an appropriately designed crossover study, the mean AUC of the test product is inf is the average AUC of the reference product inf The mean plasma concentration (C 8h ) is the mean plasma concentration of the reference product at 8 hours (C 8h ) from 40% to 130% of the total plasma concentration (C max ) is the C of the reference product max From 50% to 140%.

[0064] As used herein, "dose proportional" occurs when an increase in the administered dose is accompanied by an increase in the PK profile, such as AUC or C max When the proportion of increases.

[0065] "Fed state PK profile" means the mean AUC of a composition when administered less than two hours after a meal. inf , the average plasma concentration (C 8h ) and / or maximum plasma concentration (C max ).

[0066] "2-hour postprandial administration PK profile" means the mean AUC of the composition when administered at least two hours after a meal. inf , the average plasma concentration (C 8h ) and / or maximum plasma concentration (C max ).

[0067] Hypersomnia type 1 (NT1) refers to hypersomnia characterized by excessive daytime sleepiness ("EDS") and cataplexy. Hypersomnia type 2 (NT2) refers to hypersomnia characterized by excessive daytime sleepiness ("EDS") without cataplexy. The diagnosis of hypersomnia (with or without cataplexy) can be confirmed by one or more of the following combinations: (i) nocturnal polysomnography (PSG) and multiple sleep latency test (MSLT) performed within the past 2 years; (ii) complete written evidence confirming the diagnosis of sleep laboratory PSG and MSLT must be available; (iii) current symptoms of hypersomnia including: current complaint of EDS (ESS greater than 10) within the past 3 months, (iv) mean MWT less than 8 minutes, (v) average number of cataplexy events per week in the baseline sleep / cataplexy diary, and / or (vi) 28 events per week during the past 3 months when cataplexy occurred and during the screening period.

[0068] As used herein, "adverse event" (AE) or "treatment-emergent adverse event" (TEAE) means an adverse event self-reported by a patient administering a composition associated with an AE. AE or TEAE may include, but are not limited to, gastrointestinal disturbances, nervous system disturbances, drowsiness, dizziness, nausea, headache, feeling drunk, vomiting and / or fatigue.

[0069] Unless otherwise indicated herein, percentages, ratios and values ​​described herein are based on weight; averages and means are arithmetic means; and all pharmacokinetic measurements based on measurements in body fluids are based on plasma concentrations.

[0070] It should be understood that when a composition is defined herein by its pharmacokinetic or dissolution properties, the formulation may alternatively be defined as a "means" for achieving the pharmacokinetic or dissolution properties. Thus, 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 a "means" or "modified release means" for releasing less than 20% of its γ-hydroxybutyrate in one hour. It will be further understood that the structure for achieving the pharmacokinetic or dissolution properties is the structure described in the examples herein for achieving the pharmacokinetic or dissolution properties.

[0071] Oral pharmaceutical composition for administration less than two hours after eating

[0072] As shown in the prior art, it is extremely difficult to find a formulation that can be administered less than 2 hours after a meal and has comparable pharmacokinetic properties to an immediate release liquid solution of sodium oxybate administered twice nightly at least 2 hours after a meal.

[0073] The present inventors have discovered a new relationship between in vivo gamma-hydroxybutyrate absorption of modified release particles and the effect of food on gamma-hydroxybutyrate absorption that for the first time enables gamma-hydroxybutyrate compositions administered less than 2 hours after a meal to approach the bioavailability of a twice-nightly average immediate-release liquid solution of sodium oxybate administered at least 2 hours after a meal, and this is true across a therapeutic dose range.

[0074] Provided herein is an oral pharmaceutical composition for treating narcolepsy, cataplexy, or excessive daytime sleepiness, comprising a unit dose of gamma-hydroxybutyrate, suitable for administration less than two hours after a meal. In various embodiments, the composition may comprise gamma-hydroxybutyrate in an extended release formulation, a delayed release formulation, or a modified release formulation.

[0075] Surprisingly, the composition can be administered at any time after eating without being significantly affected by the food effect. In one embodiment, the composition can be administered less than two hours after eating. For example, the composition can be administered simultaneously with food, or can be administered immediately after eating, at least 15 minutes after eating, at least 30 minutes after eating, at least 1 hour after eating, at least 1.5 hours after eating, or less than 2 hours after eating.

[0076] The composition can provide a substantially similar fed state PK profile and a 2-hour post-meal administration PK profile. For example, the AUC of the composition administered less than two hours after a meal is inf The AUC may be similar to that when the same composition is administered at least 2 hours after a meal. inf In another example, the C of the composition administered less than two hours after eating max The same composition may be administered at least two hours after a meal. max Basically similar.

[0077] In one embodiment, when the composition is administered less than two hours after eating, the average AUC that can be achieved is inf The mean AUC provided by the composition is comparable to that provided by administration of an equivalent dose at least two hours after a meal. inf In some embodiments, when the composition is administered less than two hours after a meal, the mean AUC that can be achieved is inf is the average AUC provided by an equal dose of the composition administered at least two hours after a meal inf From 50% to 120%, from 60% to 120%, from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80% to 100%, from 90% to 100%, from 50% to 95% or from 60% to 90%.

[0078] In one embodiment, when the composition is administered less than two hours after eating, the average C max The mean C provided by the composition is equal to that provided by administration of the same dose at least two hours after a meal. max In some embodiments, when the composition is administered less than two hours after eating, the average C max is the average C provided by an equal dose of the composition administered at least two hours after a meal max From 50% to 140%, from 60% to 120%, from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80% to 100%, from 90% to 100%, from 50% to 95% or from 60% to 90%.

[0079] The composition can provide substantially similar fed state PK profiles and fasted state PK profiles. In one example, the AUC of the composition administered less than two hours after a meal is inf The AUC may be similar to that when the same composition is administered in the fasting state. inf In yet another example, the C of the composition administered less than two hours after a meal is max The C of the same composition administered in the fasting state may be max Basically similar.

[0080] In one embodiment, when the composition is administered less than two hours after eating, the average AUC that can be achieved is inf The mean AUC provided by the composition is the same as that provided by administration of the same dose in the fasting state. inf In some embodiments, when the composition is administered less than two hours after a meal, the mean AUC that can be achieved is inf is the average AUC provided by an equal dose of the composition administered in the fasting state inf From 50% to 120%, from 60% to 120%, from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80% to 100%, from 90% to 100%, from 50% to 95%, or from 60% to 90%. In one embodiment, when the composition is administered less than two hours after a meal, it can achieve a mean AUC with a 90% CI of inf The composition is within the 80%-125% bioequivalence range of an equivalent dose of the composition administered in the fasted state, and has no effect margin. In some examples, the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach infIn other examples, the composition provides an average AUC of 80% to 95% when administered less than two hours after a meal. inf is the mean AUC of the composition when administered on an empty stomach inf In at least one instance, AUC last (Eating) and AUC last The ratio of (fasting) can be about 86, with a 90% CI of 79.9-92.6. In at least one embodiment, the AUC inf (Eating) and AUC inf The (fasting) ratio may be about 86.1, with a 90% CI of 80.0-92.7.

[0081] In one embodiment, when the composition is administered less than two hours after eating, the average C max The average C provided by the composition is equal to that provided by administration of the same dose in the fasting state. max In some embodiments, when the composition is administered less than two hours after eating, the average C max is the average C provided by an equal dose of the composition administered in the fasting state max From 50% to 140%, from 60% to 120%, from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80% to 100%, from 90% to 100%, from 50% to 95%, or from 60% to 90%. In one embodiment, when the composition is administered less than two hours after a meal, it can achieve a mean C with a 90% CI of max The composition is within the 80%-125% bioequivalence range of an equal dose of the composition administered in the fasting state, and has no effect margin. In some examples, the composition provides a mean C of 1.5-1.0 when administered less than two hours after a meal. max is the average C of the composition when administered on an empty stomach max In other examples, the composition provides an average C of 55% to 80% when administered less than two hours after a meal. max is the average C of the composition when administered on an empty stomach max In at least one instance, C max (Eating) and C max The (fasting) ratio may be about 66.6 with a 90% CI of 58.2-76.5.

[0082] In one embodiment, the composition provides a dose-proportional amount of C max In additional embodiments, the composition does not provide dose dumping.

[0083] In one embodiment, a composition of gamma-hydroxybutyrate administered less than two hours after a meal can optimize the bioavailability of gamma-hydroxybutyrate and approximately approximate the bioavailability of equal doses of an immediate-release liquid solution of sodium oxybate administered twice nightly, with the first dose administered at least two hours after a meal.

[0084] In some embodiments, over the entire therapeutic range of sodium oxybate doses, a composition of gamma-hydroxybutyrate administered less than two hours after a meal can substantially approach or exceed the bioavailability of an equivalent dose of an immediate release solution of sodium oxybate administered twice nightly at least two hours after a meal.

[0085] In other embodiments, a composition of gamma-hydroxybutyrate administered less than two hours after a meal may produce very low residual drug levels in the bloodstream of most patients up to 8 hours after administration, but still similar to the residual drug levels observed after two equal doses of sodium oxybate immediate-release liquid solution are administered nightly at least two hours after a meal.

[0086] In one embodiment, after administration of the composition, there is no significant reduction in safety or efficacy for the patient. In another embodiment, based on the new pharmacokinetic profile, the composition of γ-hydroxybutyrate can improve the therapeutic efficacy and safety profile of γ-hydroxybutyrate when administered less than two hours after eating. For example, administration of the γ-hydroxybutyrate composition less than two hours after eating can result in fewer AEs compared to administration of the γ-hydroxybutyrate composition at least two hours after eating or in the fasting state.

[0087] In some embodiments, the dose is divided equally between t0 and t 4h The gamma-hydroxybutyrate composition has a more favorable safety profile than an equivalent dose of sodium oxybate immediate-release liquid solution administered in C max During the time period, most adverse events (AEs) may occur during T max In one example, with an immediate release formulation that requires multiple daily administrations (such as ) in multiple T max and C max In contrast, since the gamma-hydroxybutyrate composition is administered once daily, it can have only one T per day. max and a C max Thus, compared to the immediate release formulation, there is only one T max and a C max May result in fewer AEs. In another embodiment, the C of the gamma-hydroxybutyrate composition max Can be The first peak of C max and the second peak C maxThe gamma-hydroxybutyrate composition C max May be lower than the C of an equivalent dose of an immediate-release formulation max , such that administration of the γ-hydroxybutyrate composition may result in fewer AEs than administration of an immediate-release formulation. Thus, once daily administration of the γ-hydroxybutyrate composition may be more effective than administration of equally divided doses at t0 and t 4h Administration of an equivalent dose of sodium oxybate immediate-release liquid solution resulted in fewer AEs. In other embodiments, the onset of action of the composition in the fed state may be earlier than

[0088] With immediate-release sodium oxybate (eg, ) formulations, the gamma-hydroxybutyrate compositions can provide a significant improvement in the safety profile for patients with narcolepsy, cataplexy, or excessive daytime sleepiness by reducing the amount of adverse events (AEs) within an 8 hour, 12 hour, 16 hour, 20 hour, 24 hour, and / or 48 hour period following administration of the gamma-hydroxybutyrate composition. In particular, compared to immediate-release sodium oxybate (e.g., ) formulation, the gamma-hydroxybutyrate composition resulted in fewer adverse events and less C in the 8, 12, 16, 20, 24, and 48 hour time periods. max time period. Since AE seems likely to be related to C max Closely related, thanks to the C of the gamma-hydroxybutyrate composition max Time period ratio short, and therefore with immediate-release sodium oxybate (e.g. ) formulations, the gamma-hydroxybutyrate composition may also have fewer AEs over an 8 hour, 12 hour, 16 hour, 20 hour, 24 hour, and / or 48 hour period. ) or any sodium oxybate composition that needs to be administered more frequently than once daily, the gamma-hydroxybutyrate composition may have a superior safety profile and / or reduced AEs.

[0089] In yet another embodiment, a gamma-hydroxybutyrate composition administered less than two hours after a meal can produce a similar pharmacokinetic profile while potentially administering a reduced dose compared to an immediate-release liquid solution of sodium oxybate administered twice nightly at least two hours after a meal.

[0090] In another embodiment, a commercial treatment In contrast, the composition of gamma-hydroxybutyrate may allow administration less than two hours after eating.

[0091] In other embodiments, the composition of gamma-hydroxybutyrate can be administered less than two hours after a meal, or can be administered in the fed or fasted state, and has improved dissolution and pharmacokinetic characteristics compared to an immediate-release liquid solution of sodium oxybate administered twice nightly at least two hours after a meal.

[0092] In one embodiment, the composition provides an AUC of inf and AUC inf Bioequivalence, such as Figure 4A , 5A , 5B, 6A, 6B, 7A or 7B. In another embodiment, the composition provides C max Less than The Second C max ,like Figure 4A , 5A , 5B, 6A, 6B, 7A or 7B. In one embodiment, when administered less than two hours after a meal, the composition C max Can be The First C max and The Second C max In yet another embodiment, the composition provides C max Basically less than C max ,like Figure 4A , 5A , 5B, 6A, 6B, 7A or 7B. The composition provides C max Maybe C max 10%-60% less, such as Figure 4A , 5A , 5B, 6A, 6B, 7A or 7B. The composition provides a C between when the composition is administered at least two hours after a meal and when the composition is administered less than two hours after a meal. max Changes than Xyrem C max The change is small, 10%-60%, such as free Figure 4A , 5A , 5B, 6A, 6B, 7A and 7B. The AUC provided by the composition may be The AUC is more proportional to the dose, as Figure 4A , 5A , 5B, 6A, 6B, 7A or 7B.

[0093] In particular, it has been shown that a 6 g dose of a gamma-hydroxybutyrate composition administered less than two hours after a meal achieves a mean AUC of greater than 230 hr*μg / mL. infand in equal doses at to and t 4h Equivalent doses of sodium oxybate immediate-release liquid solution administered provided a mean C max Average C from 50% to 140% max , wherein the first dose is administered at least two hours after eating a standardized meal. For example, a 6 g dose of the composition administered less than two hours after eating may have an average AUC of about 242 hr*μg / mL inf and an average C of about 64 μg / mL max In addition, a 9 g dose of the gamma-hydroxybutyrate composition administered less than two hours after a meal can achieve an average AUC greater than 400 hr*μg / mL inf and may be in equally divided doses at to and t 4h Equivalent doses of sodium oxybate immediate-release liquid solution administered provided a mean C max Average C from 50% to 140% max , wherein the first dose is administered at least two hours after a standardized meal. This can be seen by comparing the release profiles and pharmacokinetic profiles in Examples 1-7.

[0094] The composition of γ-hydroxybutyrate can have an immediate release and a modified release portion. The release of γ-hydroxybutyrate from the immediate release portion is virtually uninhibited and is released almost immediately in a 0.1N hydrochloric acid dissolution medium. In contrast, although the modified release portion can also release its γ-hydroxybutyrate almost immediately when fully triggered, the release is not triggered until a predetermined lag time or the drug is subjected to a suitable dissolution medium such as a phosphate buffer dissolution medium at pH 6.8. Without wishing to be bound by any theory, it is believed that food has no or little effect on the modified release portion of the composition because the γ-hydroxybutyrate from the modified release portion is absorbed by the latter part of the gastrointestinal tract.

[0095] Several different pharmacokinetic parameters can be used to describe formulations that achieve this improved bioavailability in the fed state. One embodiment of a γ-hydroxybutyrate composition comprises an immediate release and a modified release portion, wherein when a 6 g dose of the formulation is administered less than two hours after a meal, an average AUC of greater than 230, 240, 245, 300, 325, 340, 375, 400, 425, or 450 hr*μg / mL can be achieved. inf In one embodiment, a 6 g dose of the composition has a mean AUC greater than 230 hr*μg / mL inf In one embodiment, a 6 g dose of the composition has a mean AUC of about 242 hr*μg / mL inf For example, when the composition is administered less than two hours after a meal, it achieves an average AUC infis the average AUC provided by an equal dose of the composition administered at least two hours after a meal inf From 50% to 120%, from 60% to 120%, from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80% to 100%, from 90% to 100%, from 50% to 95% or from 60% to 90%.

[0096] One embodiment of a γ-hydroxybutyrate composition comprises an immediate release and a modified release portion, wherein a mean C of greater than 55, 60, 65, or 70 μg / mL is achieved when a 6 g dose of the formulation is administered less than two hours after a meal. max For example, a 6 g dose of the composition has an average Cmax of about 64 μg / mL. One embodiment of a γ-hydroxybutyrate composition comprising an immediate release and a modified release portion can achieve an average Cmax of about 64 μg / mL when a 6 g dose of the formulation is administered less than two hours after a meal. max It is given in equally divided doses at t0 and t2 hours after a standardized meal. 4h An equivalent dose of sodium oxybate immediate-release liquid solution (e.g., ) provides the average C max From 50% to 140%, from 60% to 140%, from 70% to 140%, from 75% to 135%, from 80% to 135%, from 80% to 130%, from 90% to 110%, from 50% to 95% or from 60% to 90%. In one embodiment, a 6 g dose of the composition has a dosage of about two hours after a standardized meal in equally divided doses at t0 and t 4h An equivalent dose of sodium oxybate immediate-release liquid solution (e.g., ) average C max An average C from 60% to 90% or from 60% to 140% max In other embodiments, the average C max The drug is administered in equally divided doses at t0 and t2 at least 2 hours after a meal. 4h The average C of the first peak of an equal dose of sodium oxybate immediate-release liquid solution administered max From 100% to 150%, and the average C max The drug is administered in equally divided doses at t0 and t2 at least 2 hours after a meal. 4h The average C of the second peak of an equal dose of sodium oxybate immediate-release liquid solution administered max From 80% to 100%.

[0097] One embodiment of a γ-hydroxybutyrate composition comprises an immediate release and a modified release portion, wherein when a 9 g dose of the formulation is administered less than two hours after a meal, an average AUC of greater than 350, 400, 450, 500, 525, or 550 hr*μg / mL is achieved infIn one embodiment, a 9 g dose of the composition may have a mean AUC greater than 400 hr*μg / mL inf .

[0098] One embodiment of a gamma-hydroxybutyrate composition comprising an immediate release and a modified release portion may have an average C max It is given in equally divided doses at t0 and t2 hours after a standardized meal. 4h An equivalent dose of sodium oxybate immediate-release liquid solution (e.g., ) provides the average C max From 50% to 140%, from 60% to 140%, from 70% to 140%, from 75% to 135%, from 80% to 135%, from 80% to 130%, from 90% to 110%, from 50% to 95% or from 60% to 90%. In one embodiment, a 9 g dose of the composition may have a dose of 100 g taken at t0 and t1 in equally divided doses about two hours after a standardized meal. 4h An equivalent dose of sodium oxybate immediate-release liquid solution (e.g., ) provides the average C max An average C from 60% to 90% or from 60% to 120% max .

[0099] One embodiment of a gamma-hydroxybutyrate composition, when administered at a strength of 6 g less than two hours after a standardized evening meal, produces a plasma concentration profile over time substantially as follows: Figure 2A shown.

[0100] Another embodiment of the gamma-hydroxybutyrate composition, when administered once nightly at a strength of 6 g less than two hours after a meal, produces a plasma concentration profile over time substantially as follows: Figure 4B shown.

[0101] Yet another embodiment of the gamma-hydroxybutyrate composition produces a plasma concentration profile over time substantially as follows when administered once nightly at a strength of 6 g less than two hours after a meal: Figure 5A shown.

[0102] One embodiment of a gamma-hydroxybutyrate composition, when administered once nightly at a strength of 9 g less than two hours after a meal, produces a plasma concentration profile over time substantially as follows: Fig. 6A shown.

[0103] Another embodiment of the gamma-hydroxybutyrate composition produces an AUC curve substantially as follows when administered once nightly at a strength of 6 g between 0 and 4 hours after a meal: Fig. 7A shown.

[0104] Another embodiment of the gamma-hydroxybutyrate composition produces C when administered once nightly at a strength of 6 g between 0 and 4 hours after a standardized evening meal. max The curve is basically Figure 7B shown.

[0105] In any of these embodiments, the formulation is effective for treating type 1 or type 2 hypersomnia. Treatment of hypersomnia is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplexy attacks. In various embodiments, the composition is sufficient to be administered once daily. For example, the composition may be sufficient to be administered less than 2 hours after eating in the morning or evening. The formulation is also effective in inducing sleep for at least 6 to 8 consecutive hours. In one embodiment, the composition administered less than two hours after eating effectively induces sleep for at least 8 consecutive hours. In various embodiments, the formulation effectively induces sleep for at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours. In other embodiments, the formulation effectively induces sleep for up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, or up to 10 hours.

[0106] In any of these embodiments, the composition may include an immediate release portion and a modified release portion, wherein the modified release portion includes gamma-hydroxybutyrate particles coated with a polymer carrying free carboxyl groups and a hydrophobic compound having a melting point equal to or greater than 40° C., and the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35. The polymer including free carboxyl groups may have a pH dissolution trigger value of 5.5 to 6.97, and may be a methacrylic acid copolymer having a pH dissolution trigger value of from 5.5 to 6.97.

[0107] Structural embodiment

[0108] A variety of techniques for formulating modified release dosage forms are known, including, for example, those described in U.S. Pat. No. 8,101,209 to Legrand et al. ("Legrand"). Legrand provides a system that ensures that the active ingredient is indeed released from the modified release dosage form through a dual mechanism of "time-dependent" and "pH-dependent" release. Legrand does not describe any dosage form for delivering sodium oxybate or other forms of gamma-hydroxybutyrate that are administered less than two hours after a meal.

[0109] In various embodiments, the composition of any embodiment herein can be used in any meal state.Especially, the composition can be used in the fed state, at least two hours after eating or in the fasting state.In one embodiment, the composition is used in the fed state less than two hours after eating.For example, the composition can be used when eating, immediately after eating, up to 30 minutes after eating, at least 30 minutes after eating, up to 45 minutes after eating, up to 1 hour after eating, up to 1.25 hours after eating, up to 1.5 hours after eating, up to 1.75 hours after eating, up to 1.8 hours after eating, up to 1.9 hours after eating, or up to 1.95 hours after eating.In certain embodiments, the composition can be used less than two hours after eating a standardized dinner.

[0110] In one embodiment, the composition of γ-hydroxybutyrate may include an immediate release portion and a modified release portion, wherein: (a) the modified release portion includes coated particles of γ-hydroxybutyrate; (b) the coating includes a polymer carrying a free carboxyl group and a hydrophobic compound having a melting point equal to or greater than 40°C; and (c) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35.

[0111] In one embodiment, the composition of γ-hydroxybutyrate may comprise an immediate release portion and a modified release portion, a suspending agent or a viscosity increasing agent, and an acidulant, wherein: (a) the modified release portion comprises coated particles of γ-hydroxybutyrate; (b) the coating comprises a polymer carrying a free carboxyl group and a hydrophobic compound having a melting point equal to or greater than 40°C; and (c) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35.

[0112] In one embodiment, the composition of γ-hydroxybutyrate may comprise an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated particles of γ-hydroxybutyrate; (b) the coating comprises a polymer carrying free carboxyl groups and a hydrophobic compound having a melting point equal to or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxyl groups is from 0.4 to 4; (d) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35; and (e) the coating accounts for from 10% to 50% of the weight of the particles.

[0113] In one embodiment, the composition of γ-hydroxybutyrate may comprise an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated particles of γ-hydroxybutyrate; (b) the coating comprises a polymer carrying a free carboxyl group with a pH trigger value from 5.5 to 6.97 and a hydrophobic compound having a melting point equal to or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying a free carboxyl group is from 0.4 to 4; (d) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35; and (e) the coating accounts for from 10% to 50% of the weight of the particles.

[0114] In one embodiment, the composition of γ-hydroxybutyrate may include an immediate release portion and a modified release portion, wherein: (a) the modified release portion includes coated particles of γ-hydroxybutyrate; (b) the coating includes a methacrylic acid copolymer carrying a free carboxyl group with a pH trigger value from 5.5 to 6.97 and a hydrophobic compound with a melting point equal to or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying a free carboxyl group is from 0.4 to 4; (d) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35; and (e) the coating accounts for from 10% to 50% of the weight of the particles.

[0115] In various embodiments, the gamma-hydroxybutyrate may be present in the composition at a dose of 4.5 g, 6.0 g, 7.5 g, or 9.0 g. In some embodiments, the dose of gamma-hydroxybutyrate may be sufficient to administer the composition once daily.

[0116] Pharmacokinetics

[0117] As mentioned in the definition section of this document, each sub-embodiment can be used to further characterize and limit each aforementioned main embodiment. In addition, more than one of the following sub-embodiments can be combined and used to further characterize and limit each aforementioned main embodiment in any way that is mathematically and physically possible.

[0118] In one embodiment, the oral pharmaceutical composition of γ-hydroxybutyrate can be a unit dose suitable for administration less than two hours after eating for the treatment of narcolepsy, cataplexy or excessive daytime sleepiness. Without being limited by a particular theory, the composition may include a modified release portion that delays the release of a portion of the γ-hydroxybutyrate until the composition reaches the small intestine, so that the intake of food has a limited effect on the absorption of γ-hydroxybutyrate.

[0119] In one embodiment, the oral pharmaceutical composition of gamma-hydroxybutyrate can be a unit dosage suitable for once-daily administration for the treatment of narcolepsy, cataplexy, or excessive daytime sleepiness. In one example, the composition can exhibit rapid initial absorption comparable to twice-nightly IR sodium oxybate. In another example, the composition can exhibit lower overall C max In other examples, the composition can provide a similar mean blood concentration (ug / ml) at 8 hours as IR sodium oxybate twice nightly.

[0120] In various embodiments, the composition provides substantially similar fed state PK profiles and 2-hour postprandial administration PK profiles. In some embodiments, 4.5 g, 7.5 g, and / or 9 g doses may exhibit a PK profile consistent with the PK profile required for once-night administration. In various embodiments, when administered once daily, 2 hours postprandially, the composition exhibits dose-proportional pharmacokinetics. In one embodiment, the composition provides C max In proportion to the dosage. For example, the composition provides C max The composition provides an AUC proportional to the dose at once daily doses of 4.5 g, 7.5 g, and 9 g. In one embodiment, the composition provides an AUC proportional to the dose. For example, a 6 g dose of C max With a dose of 9g of composition C max In another embodiment, the composition is proportional to the dosage by a factor of about 1 to about 1.3. In one example, C max The AUC may be proportional to the dose by a factor of about 1. In another example, the AUC may be proportional to the dose by a factor of about 1.3. In certain examples, the increase in AUC may be slightly more than proportional. As the dose increases, the composition may exhibit a predictable increase in plasma levels consistent with the desired PK profile of a once-night sodium oxybate formulation.

[0121] In one embodiment, a controlled-release sodium oxybate composition once nightly may exhibit a lower total C compared to sodium oxybate twice nightly. max and similar total AUC. In one embodiment, the once nightly composition safety profile can be consistent with what is known about sodium oxybate.

[0122] In one embodiment, the composition does not provide dose dumping. For example, ingestion of alcohol does not result in an immediate release of gamma-hydroxybutyrate.

[0123] In another embodiment, there is no significant reduction in safety or efficacy for the patient after administration of the composition less than two hours after eating. is increased so that when administered in a fed state, the Cmax Less than the second dose After C max In other embodiments, when administered in the fed state, the composition is For example, when administered in a fed state, the C max Higher than the first dose After C max .

[0124] In one embodiment, the composition provides an AUC of inf and AUC inf Bioequivalence, if selected from Figure 4A , 5A , 5B, 6A, 6B and 7A. In one embodiment, the composition provides C max Less than C max , if selected from Figure 4A , 5A , 5B, 6A, 6B, 7A and 7B. In one embodiment, the composition provides C max Basically less than C max , if selected from Figure 4A , 5A , 5B, 6A, 6B and 7B. In one embodiment, the composition provides C max Compare C max 10%-60% less, such as selected Figure 4A , 5A , 5B, 6A, 6B and 7B. In one embodiment, the composition provides an AUC of The AUC is more proportional to the dose, such as Figure 4A , 5A , 5B, 6A, 6B and 7A.

[0125] In various embodiments, a 6 g dose of a gamma-hydroxybutyrate composition may be characterized as having been shown to achieve a mean AUC of greater than 230, 240, 245, 250, 255, 260, 275, 300, 325, or 350 hr*μg / mL when administered once less than two hours after a meal. inf The mean AUC for this 6 g dose was infThe upper limit can be set to 300 or 350hr*μg / mL. In these embodiments, a 6g dose of the composition can be administered less than two hours after eating. For example, a 6g dose of the composition can be administered once a day in the morning or evening. In other embodiments, a 6g dose of the composition can be administered in a fed state.

[0126] In additional embodiments, a 6 g dose of a gamma-hydroxybutyrate composition may be characterized as having been shown to achieve an average C of greater than 50, 55, 60, 65, 70, 75, 80, 85, or 90 μg / mL when administered once less than two hours after a meal. max The average C for this 6g dose max The upper limit can be set to 75 or 90 μg / mL. In these embodiments, the composition of the 6g dose can be administered less than two hours after eating. For example, the composition of the 6g dose can be administered once a day in the morning or evening. In other embodiments, the composition of the 6g dose can be administered in the fed state.

[0127] In additional embodiments, a 6 g dose of a gamma-hydroxybutyrate composition administered less than two hours after a meal can be characterized as having been shown to achieve an average C max , which consists of two equally divided doses at t0 and t2 at least 2 hours after a standardized meal. 4h Equivalent doses of γ-hydroxybutyrate immediate-release liquid solution administered provided an average C max From 50% to 140%, from 60% to 140%, from 70% to 140%, from 75% to 135%, from 80% to 135%, or from 80% to 130%. In these embodiments, a 6g dose of the composition can be administered less than two hours after eating. For example, a 6g dose of the composition can be administered once daily in the morning or evening. In other embodiments, a 6g dose of the composition can be administered in a fed state.

[0128] In various embodiments, a 6 g dose of a γ-hydroxybutyrate composition may be characterized as having been shown to achieve a mean AUC of greater than 1, 2, 3, 4, 5, or 6 μg / mL when administered once less than two hours after a meal. 8h The mean AUC for this 6 g dose was 8h The upper limit can be set to 5 or 6 μg / mL. In these embodiments, a 6g dose of the composition can be administered less than two hours after eating. For example, a 6g dose of the composition can be administered once a day in the morning or evening. In other embodiments, a 6g dose of the composition can be administered in a fed state.

[0129] In various embodiments, a 6 g dose of a γ-hydroxybutyrate composition may be characterized as having been shown to achieve an average AUC of greater than 150, 175, 200, 225, 250, 300, or 350 hr*μg / mL when administered once less than two hours after a meal. 0-8 The mean AUC for this 6 g dose was 0-8 The upper limit can be set to 300 or 350hr*μg / mL. In these embodiments, a 6g dose of the composition can be administered less than two hours after eating. For example, a 6g dose of the composition can be administered once a day in the morning or evening. In other embodiments, a 6g dose of the composition can be administered in a fed state.

[0130] In various embodiments, a 6 g dose of a γ-hydroxybutyrate composition may be characterized as having been shown to achieve an average AUC of greater than 150, 175, 200, 225, 250, 300, or 350 hr*μg / mL when administered once less than two hours after a meal. 0-t The mean AUC for this 6 g dose was 0-t The upper limit can be set to 300 or 350hr*μg / mL. In these embodiments, a 6g dose of the composition can be administered less than two hours after eating. For example, a 6g dose of the composition can be administered once a day in the morning or evening. In other embodiments, a 6g dose of the composition can be administered in a fed state.

[0131] In various embodiments, a 6g dose of a gamma-hydroxybutyrate composition may be characterized as having been shown to achieve an average %AUC greater than 0.1%, 0.2%, or 0.3% when administered once less than two hours after eating. In these embodiments, the 6g dose of the composition may be administered less than two hours after eating. For example, the 6g dose of the composition may be administered once daily in the morning or evening. In other embodiments, the 6g dose of the composition may be administered in the fed state.

[0132] In various embodiments, a 6 g dose of a γ-hydroxybutyrate composition can be characterized as having been shown to achieve a t of greater than 0.5, 1, 1.5, 2, or 2.5 hours when administered once less than two hours after a meal. max In these embodiments, the 6 g dose of the composition can be administered less than two hours after eating. For example, the 6 g dose of the composition can be administered once daily in the morning or evening. In other embodiments, the 6 g dose of the composition can be administered in a fed state.

[0133] In various embodiments, a 6 g dose of a γ-hydroxybutyrate composition can be characterized as having been shown to achieve an average t of greater than 0.5, 1, or 1.5 hours when administered once less than two hours after a meal. 1 / 2In these embodiments, the 6 g dose of the composition can be administered less than two hours after eating. For example, the 6 g dose of the composition can be administered once daily in the morning or evening. In other embodiments, the 6 g dose of the composition can be administered in a fed state.

[0134] In one embodiment, a 6 g dose of the composition administered less than two hours after a meal can achieve an average AUC greater than 230 hr·μg / mL inf and are given in equally divided doses at least 2 hours after a meal at t0 and t 4h Equivalent doses of sodium oxybate immediate-release liquid solution administered provided a mean C max Average C from 50% to 140% max .

[0135] In various embodiments, a 9 g dose of a gamma-hydroxybutyrate composition administered less than two hours after a meal can be characterized as having been shown to achieve a mean AUC of greater than 350, 400, 450, 460, 470, 480, 490, 500, 525, 550, 575, or 600 hr*μg / mL. inf The mean AUC for this 9 g dose was inf The upper limit can be set to 550 or 600hr*μg / mL. In these embodiments, a 9g dose of the composition can be administered less than two hours after eating. For example, a 9g dose of the composition can be administered once a day in the morning or evening. In other embodiments, a 9g dose of the composition can be administered in a fed state.

[0136] In additional embodiments, a 9 g dose of the gamma-hydroxybutyrate composition administered less than two hours after a meal may be characterized as having an average C of greater than 60, 65, 70, 75, 80, 85, 90, 95, or 100 μg / mL. max The average C for this 9g dose max The upper limit can be set to 125 or 100 μg / mL. In these embodiments, the 9g dose of the composition can be administered less than two hours after eating. For example, the 9g dose of the composition can be administered once a day in the morning or evening. In other embodiments, the 9g dose of the composition can be administered in the fed state.

[0137] In additional embodiments, a 9 g dose of a gamma-hydroxybutyrate composition administered less than two hours after a meal can be characterized as having an average C max , which was administered at least 2 hours after a standardized meal in two equally divided doses at t0 and t 4h Equivalent doses of γ-hydroxybutyrate immediate-release liquid solution administered provided an average C maxFrom 50% to 120% or from 60% to 120%. In these embodiments, the 9g dose of the composition can be administered less than two hours after eating. For example, the 9g dose of the composition can be administered once a day in the morning or evening. In other embodiments, the 9g dose of the composition can be administered in a fed state.

[0138] In one embodiment, a 9 g dose of the composition administered less than two hours after a meal can achieve an average AUC greater than 500 hr·μg / mL inf and were given in equally divided doses at t0 and t2 at least 2 hours after a standardized evening meal. 4h Administration of an equal dose of sodium oxybate immediate-release liquid solution provided a mean Cmax ranging from 50% to 120% of the mean C max .

[0139] Further embodiments can also be defined based on the pharmacokinetics of the composition of gamma-hydroxybutyrate compared to an immediate release solution of gamma-hydroxybutyrate. Thus, in additional embodiments, when compared to taking the composition of gamma-hydroxybutyrate in equally divided doses at least two hours after a standardized meal at t0 and t 4h The gamma-hydroxybutyrate composition administered less than two hours after a meal can achieve a relative bioavailability (RBA) of greater than 80%, 85%, 90%, or 95% when compared to an equal dose of sodium oxybate immediate-release liquid solution administered at least two hours after a standardized meal. For example, when compared to an equal dose of sodium oxybate administered at least two hours after a standardized meal in equally divided doses at t0 and t1. 4h The 6 g and 9 g doses of the formulation administered less than two hours after a meal may have an RBA of greater than 80%, 85%, or 90% when compared to an equivalent dose of an immediate release liquid solution of sodium oxybate administered.

[0140] The γ-hydroxybutyrate composition may also be defined by the concentration / time curve it produces when tested according to the examples. Thus, in other embodiments, a 6 g or 9 g dose of the γ-hydroxybutyrate composition administered less than two hours after a meal may achieve substantially the same concentration as described herein, respectively. Figure 5A and 6A In other embodiments, the composition can be implemented substantially as described herein. Figure 2A , 3B Or the time / concentration curve shown in 4B.

[0141] The γ-hydroxybutyrate composition can also be defined based on the time required to reach a maximum blood concentration of γ-hydroxybutyrate. Thus, in additional embodiments, the γ-hydroxybutyrate composition can achieve an average T of 0.5 to 2.5 hours. maxIn various embodiments, the composition of gamma-hydroxybutyrate can achieve an average T of about 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, or 2.5 hours when administered less than two hours after a meal. max . Median T in any of the above ranges max The lower limit may alternatively be set to 0.5 or 1.0 hour.

[0142] In another embodiment, a 6 g dose of the composition can achieve a mean AUC greater than 230 hr·μg / mL when administered less than two hours after a meal. inf and an average C greater than 60 μg / mL max .

[0143] In another embodiment, a 9 g dose of the formulation can achieve a mean AUC greater than 400 hr·μg / mL when administered less than two hours after a meal. inf and an average C greater than 60 μg / mL max .

[0144] In one embodiment, when administered once daily 2 hours after a meal, the 4.5 g, 7.5 g and 9 g doses of the composition may exhibit similar overall mean pharmacokinetic profiles. In some embodiments, when administered once daily 2 hours after a meal, the 4.5 g, 7.5 g and 9 g doses of the composition may exhibit similar overall mean pharmacokinetic profiles. Figure 8 The average pharmacokinetic profile shown. In one example, the composition at doses of 4.5 g, 7.5 g, and 9 g may exhibit a median T between 1.5 and 2 hours. max ( Figure 8 In one embodiment, the composition of 4.5 g, 7.5 g and 9 g dosages can achieve an average C from 42.9 to 84.5 g / mL at increasing dosages. max In C max Afterwards, blood levels may gradually decrease overnight. In one example, when administered once daily 2 hours after a meal, the composition can achieve an average AUC of 191, 358, and 443 μg.h / mL at 4.5, 7.5, and 9 g doses, respectively. inf In one embodiment, when administered once daily 2 hours after a meal, the composition may exhibit average concentrations of 4.8, 19.7, and 25.5 g / mL at 8 hours for 4.5, 7.5, and 9 g doses, respectively.

[0145] Structural embodiment

[0146] The composition of γ-hydroxybutyrate can be provided in any dosage form suitable for oral administration, including tablets, capsules, liquids, orally dissolving tablets, etc. In one embodiment, they are provided as dry granular preparations (i.e., granules, powders, coated granules, microparticles, pellets, microspheres, etc.) in pouches or other suitable discrete packaging units. The granular preparation will be mixed with tap water shortly before administration. In one embodiment, the composition can be mixed with 50 mL of water before administration. In another embodiment, the composition is an oral pharmaceutical composition.

[0147] In various embodiments, the composition comprises gamma-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 various embodiments, the composition comprises gamma-hydroxybutyrate present in a unit dose of 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 comprises 6 g of gamma-hydroxybutyrate. In another embodiment, the formulation comprises 9 g of gamma-hydroxybutyrate.

[0148] In one embodiment, the formulation comprises an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated microparticles of γ-hydroxybutyrate; and (b) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35.

[0149] In one embodiment, the formulation comprises an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated microparticles of γ-hydroxybutyrate; and (b) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is 40 / 60 to 60 / 40.

[0150] In another embodiment, the formulation comprises an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated microparticles of γ-hydroxybutyrate; (b) the coating of the modified release particles of γ-hydroxybutyrate comprises a polymer carrying a free carboxyl group and a hydrophobic compound having a melting point equal to or greater than 40°C; and (c) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35 or from 40 / 60 to 60 / 40.

[0151] In another embodiment, the formulation comprises an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated microparticles of γ-hydroxybutyrate; (b) the coating of the modified release particles of γ-hydroxybutyrate comprises a polymer carrying free carboxyl groups and a hydrophobic compound having a melting point equal to or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxyl groups is from 0.4 to 4; (d) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35 or from 40 / 60 to 60 / 40; and (e) the film coating accounts for from 10% to 50% of the weight of the microparticles.

[0152] In another embodiment, the formulation comprises an immediate release portion and a modified release portion, wherein: (a) the modified release portion comprises coated particles of γ-hydroxybutyrate; (b) the coating of the modified release particles of γ-hydroxybutyrate comprises a polymer carrying free carboxyl groups with a pH trigger value from 5.5 to 6.97 and a hydrophobic compound having a melting point equal to or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxyl groups is from 0.4 to 4; (d) the ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 10 / 90 to 65 / 35 or from 40 / 60 to 60 / 40; and (e) the coating accounts for from 10% to 50% of the weight of the particles.

[0153] In one embodiment, the polymer carrying free carboxyl groups includes 100% poly(methacrylic acid, ethyl acrylate) 1:1 and 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.

[0154] In one embodiment, the formulation includes excipients to improve the viscosity and pourability of the mixture of the granular formulation with tap water. Thus, in addition to the immediate release and modified release granules of gamma-hydroxybutyrate, the granular formulation also includes one or more suspending agents or viscosity enhancers or lubricants.

[0155] The suspending agent or viscosity increasing agent 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 grade iota, kappa or lambda and medium viscosity hydroxypropyl methylcellulose.

[0156] Medium viscosity sodium carboxymethyl cellulose corresponds to a grade of sodium carboxymethyl cellulose having a viscosity greater than 200 mPa·s and less than 3100 mPa·s in a 2% aqueous solution at 25°C.

[0157] Medium viscosity hydroxyethyl cellulose corresponds to a grade of hydroxyethyl cellulose having a viscosity greater than 250 mPa·s and less than 6500 mPa·s in a 2% aqueous solution at 25° C. Medium viscosity hydroxypropyl methyl cellulose corresponds to a grade of hydroxypropyl methyl cellulose having a viscosity greater than 80 mPa·s and less than 3800 mPa·s in a 2% aqueous solution at 20° C.

[0158] In one embodiment, the suspending agent or viscosity increasing agent is xanthan gum, particularly Xantural 75 from Kelco. TM , hydroxyethylcellulose, especially Natrosol 250M from Ashland TM , kappa carrageenan, especially Gelcarin PH812 from FMC Biopolymer TM , and lambda carrageenan, especially Viscarin PH209 from FMC Biopolymer TM .

[0159] In one embodiment, the composition of γ-hydroxybutyrate includes from 1% to 15% of a viscosity enhancer or suspending agent. In other embodiments, the composition of γ-hydroxybutyrate includes a viscosity enhancer or suspending agent in an amount from 2% to 10%, from 2% to 5%, or from 2% to 3% of the formulation.

[0160] In one embodiment, the composition of gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water before administration, and further comprises from 1% to 15% of a suspending agent or viscosity increasing agent selected from xanthan gum, carrageenan and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan.

[0161] In one embodiment, the composition of gamma-hydroxybutyrate is in the form of a powder intended to be dispersed in water before administration, and further comprises: from 1.2% to 15% of an acidulant selected from malic acid and tartaric acid; and from 1% to 15% of a suspending agent or viscosity increasing agent selected from xanthan gum, carrageenan and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan.

[0162] In one embodiment, the composition of gamma-hydroxybutyrate includes about 1% lambda carrageenan or Viscarin PH209. TM , about 1% medium viscosity grade hydroxyethyl cellulose or Natrosol 250M TM and about 0.7% xanthan gum or Xantural 75 TMFor a 4.5 g dosage unit, these percentages would typically equal about 50 mg xanthan gum (Xantural 75™), about 75 mg carrageenan (Viscarin PH209™), and about 75 mg hydroxyethylcellulose (Natrasol 250M™).

[0163] For the 4.5 g dose, alternative packages of viscosity enhancing or suspending agents contain about 50 mg xanthan gum (Xantural 75™) and about 100 mg carrageenan (Gelcarin PH812™), or about 50 mg xanthan gum (Xantural 75™), about 75 mg hydroxyethylcellulose (Natrasol 250M™), and about 75 mg carrageenan (Viscarin PH109™).

[0164] In one embodiment, in addition to the immediate release and modified release particles of γ-hydroxybutyrate, the composition of γ-hydroxybutyrate further includes a lubricant or a glidant. In various embodiments, the lubricant and glidant are selected from the group consisting of: stearates (especially magnesium stearate, calcium stearate or zinc stearate), stearates (especially monostearate glyceryl or palmitate glyceryl), stearic acid, behenic acid glyceryl, sodium stearyl fumarate, talc and colloidal silicon dioxide. In one embodiment, the lubricant or glidant is magnesium stearate. The lubricant or glidant is used in a granular formulation in an amount from 0.1% to 5%. In one embodiment, the amount of the lubricant or glidant is about 0.5%. For example, the composition of γ-hydroxybutyrate may contain about 0.5% magnesium stearate.

[0165] The composition of γ-hydroxybutyrate may further comprise an acidulant. The acidulant helps ensure that the release profile of the formulation in 0.1 N HCl remains substantially unchanged for at least 15 minutes after mixing, which is about the maximum time a patient may need before consuming a dose after mixing the formulation with tap water.

[0166] In one embodiment, the formulation is a powder and further comprises an acidifying agent and a suspending agent or viscosity increasing agent in the weight percentages described herein.

[0167] The acidulant 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 acidulant is present in the formulation in an amount from 1.2% to 15%, 1.2% to 10%, or 1.2% to 5%. In one embodiment, the acidulant is tartaric acid and malic acid. In another embodiment, the acidulant is s-malic acid.

[0168] When tartaric acid is used, it can be employed in an amount from 1% to 10%, from 2.5% to 7.5%, or about 5%. In various embodiments, the amount of malic acid in the gamma-hydroxybutyrate composition is from 1.2% to 15%, from 1.2% to 10%, from 1.2% to 5%, or from 1.6% or 3.2%. In one embodiment, the amount of malic acid in the gamma-hydroxybutyrate composition is about 1.6%.

[0169] The composition of γ-hydroxybutyrate comprises an immediate release portion and a modified release portion of γ-hydroxybutyrate, and in one embodiment, the formulation is a granular formulation comprising a plurality of immediate release γ-hydroxybutyrate particles and a plurality of modified release γ-hydroxybutyrate particles. The molar ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is from 0.11:1 to 1.86:1, from 0.17:1 to 1.5:1, from 0.25:1 to 1.22:1, from 0.33:1 to 1.22:1, from 0.42:1 to 1.22:1, from 0.53:1 to 1.22:1, from 0.66:1 to 1.22:1, from 0.66:1 to 1.5:1, from 0.8:1 to 1.22:1. In one embodiment, the molar ratio of γ-hydroxybutyrate in the immediate release portion and the modified release portion is about 1:1. The molar percentage of γ-hydroxybutyrate in the immediate release portion relative to the total amount of γ-hydroxybutyrate in the formulation is in the range of from 10% to 65%, from 15% to 60%, from 20% to 55%, from 25% to 55%, from 30% to 55%, from 35% to 55%, from 40% to 55%, from 40% to 60%, or from 45% to 55%. In one embodiment, the molar percentage of γ-hydroxybutyrate in the immediate release portion relative to the total amount of γ-hydroxybutyrate in the formulation is from 40% to 60%. In one embodiment, the molar percentage of γ-hydroxybutyrate in the immediate release portion relative to the total amount of γ-hydroxybutyrate in the formulation is about 50%. The molar percentage of γ-hydroxybutyrate in the modified release portion relative to the total amount of γ-hydroxybutyrate in the formulation is in the range of from 90% to 35%, from 85% to 40%, from 80% to 45%, from 75% to 45%, from 70% to 45%, from 65% to 45%, from 60% to 45%, from 60% to 40%, or from 55% to 45%. In one embodiment, the molar percentage of γ-hydroxybutyrate in the modified release portion relative to the total amount of γ-hydroxybutyrate in the formulation is from 60% to 40%. In one embodiment, the molar ratio of γ-hydroxybutyrate in the modified release portion relative to the total amount of γ-hydroxybutyrate in the formulation is about 50%. The weight percentage of IR particles relative to the total weight of IR particles and MR particles ranges from 7.2% to 58.2%, from 11.0% to 52.9%, from 14.9% to 47.8%, from 18.9% to 47.8%, from 23.1% to 47.8%, from 27.4% to 47.8%, from 31.8% to 47.8%, from 31.8% to 52.9% or from 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 from 5.9% to 63.2%, from 9.1% to 58.1%, from 12.4% to 53.1%, from 19.9% ​​to 53.1%, from 19.6% to 53.1%, from 23.4% to 53.1%, from 27.4% to 53.1%, or from 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 from 31.7% to 53.1%.

[0170] In one embodiment, the finished formulation includes 50% of the sodium oxybate content in immediate release granules, the immediate release granules consisting of 80.75% w / w sodium oxybate, 4.25% w / w povidone K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns; and 50% of the sodium oxybate content in modified release granules, the modified release granules consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3% w / w povidone K30. TM K30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0171] In one embodiment, the finished formulation includes 50% of the sodium oxybate content in immediate release granules, the immediate release granules consisting of 80.75% w / w sodium oxybate, 4.25% w / w povidone K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns; and 50% of the sodium oxybate content in modified release granules, the modified release granules consisting of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3% w / w povidone K30. TM K30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0172] In one embodiment, the finished formulation includes 50% of the sodium oxybate content in immediate release granules, the immediate release granules consisting of 80.75% w / w sodium oxybate, 4.25% w / w povidone K30 and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns; and 50% of the sodium oxybate content in modified release granules, the modified release granules consisting of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3.2% w / w povidone K30. TM K30 60.5% w / w sodium oxybate layered, and finally 15% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 9.25% of type B methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0173] In one embodiment, the finished formulation comprises 50% of the sodium oxybate content in immediate release granules consisting of 80.75% w / w sodium oxybate, 4.25% w / w povidone™ K30, and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns; and 50% of the sodium oxybate content in modified release granules consisting of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3.2% w / w povidone™ K30. TM K30 60.5% w / w sodium oxybate layered, and finally 15% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 9.25% of type B methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0174] In one embodiment, the finished formulation includes 50% of the γ-hydroxybutyrate content in immediate-release granules, the immediate-release granules consisting of 80.75% w / w of γ-hydroxybutyrate potassium salt, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns; and 50% of the γ-hydroxybutyrate content in modified-release granules, the modified-release granules consisting of 10.5% w / w of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3% w / w of povidone K30. TMTMK30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TMTM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TMTM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TMTM S100 or equivalent) is coated.

[0175] In one embodiment, the finished formulation comprises 50% of the γ-hydroxybutyrate content in immediate-release granules, wherein the immediate-release granules are composed of 80.75% w / w of γ-hydroxybutyrate potassium salt, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns; and 50% of the γ-hydroxybutyrate content in modified-release granules, wherein the modified-release granules are composed of 10.5% w / w of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3% w / w of povidone K30. TMTM K30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TMTM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TMTM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TMTM S100 or equivalent) is coated.

[0176] In one embodiment, the finished formulation comprises 16.7% γ-hydroxybutyrate in immediate-release granules composed of 80.75% w / w potassium salt of γ-hydroxybutyrate, 4.25% w / w povidone K30, and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns; 16.7% γ-hydroxybutyrate in immediate-release granules composed of 80.75% w / w magnesium salt of γ-hydroxybutyrate, 4.25% w / w povidone K30, and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns. The invention relates to an immediate-release granule composed of cellulose spheres; 16.7% of the gamma-hydroxybutyric acid content in an immediate-release granule composed of 80.75% w / w of gamma-hydroxybutyric acid calcium salt, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns; and 50% of the gamma-hydroxybutyrate content in the following modified-release granules: the modified-release granules are composed of 10.5% w / w of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3% w / w of povidone K30. TMK30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0177] In one embodiment, the finished formulation includes 16.7% of the γ-hydroxybutyrate content in the immediate-release granules, which are composed of 80.75% w / w of γ-hydroxybutyrate potassium salt, 4.25% w / w of povidone K30 and 15% of microcrystalline cellulose spheres with a volume average diameter of about 95 microns to about 170 microns; 16.7% of the γ-hydroxybutyrate content in the immediate-release granules, which are composed of 80.75% w / w of γ-hydroxybutyrate magnesium salt, 4.25% w / w of povidone K30 and 15% of microcrystalline cellulose spheres with a volume average diameter of about 95 microns to about 170 microns. 70 micron microcrystalline cellulose spheres; 16.7% gamma-hydroxybutyrate content in immediate-release granules, the immediate-release granules consisting of 80.75% w / w gamma-hydroxybutyrate calcium salt, 4.25% w / w povidone K30 and 15% microcrystalline cellulose spheres with a volume average diameter of about 95 microns to about 170 microns; and 50% gamma-hydroxybutyrate content in modified-release granules, the modified-release granules consisting of 10.5% w / w microcrystalline cellulose spheres with a volume average diameter of about 95 microns to about 170 microns, mixed with 3% w / w povidone TM K30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TMTM S100 or equivalent) is coated.

[0178] In one embodiment, the finished formulation comprises 50% of the γ-hydroxybutyrate content in immediate-release granules, wherein the immediate-release granules are composed of 80.75% w / w of γ-hydroxybutyrate potassium salt, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns; and 50% of the γ-hydroxybutyrate content in modified-release granules, wherein the modified-release granules are composed of 10.5% w / w of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3% w / w of povidone K30. TMK30 56.5% w / w of gamma-hydroxybutyric acid calcium salt layered, and finally 18% w / w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0179] In one embodiment, the finished formulation includes 50% of the γ-hydroxybutyrate content in immediate-release granules, wherein the immediate-release granules are composed of 80.75% w / w of potassium salt of γ-hydroxybutyrate, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns; and 50% of the γ-hydroxybutyrate content in modified-release granules, wherein the modified-release granules are composed of 10.5% w / w of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3% w / w of povidone K30. TMTM K30 56.5% w / w of calcium salt of gamma-hydroxybutyrate, and finally 18% w / w of hydrogenated vegetable oil (Lubritab TMTM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TMTM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TMTM S100 or equivalent) is coated.

[0180] Other characteristics of the immediate-release portion

[0181] The immediate release portion of the formulation may be in any form that enables immediate release of γ-hydroxybutyrate when ingested. For example, when the formulation is a granular formulation, the formulation may include unmodified "raw" γ-hydroxybutyrate, rapidly dissolving γ-hydroxybutyrate granules, granules or microparticles comprising a core covered by a γ-hydroxybutyrate loading layer containing a binder, such as povidone.

[0182] The IR granules or particles of gamma-hydroxybutyrate may be made using any manufacturing process suitable for producing the desired particles, including:

[0183] Agglomeration of gamma-hydroxybutyrate sprayed in the molten state, such as Glatt ProCell TMTM technology,

[0184] extrusion and spheronization of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients,

[0185] wet granulation of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients,

[0186] compacting gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients,

[0187] Granulation and spheronization of the gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients, the spheronization being carried out, for example, in a fluidized bed apparatus equipped with a rotor, in particular using a Glatt CPS TMTM technology,

[0188] Spraying of gamma-hydroxybutyrate, optionally with one or more physiologically acceptable excipients, for example in a fluidized bed type apparatus equipped with a zigzag filter, in particular using a Glatt MicroPx TMTM Technology, or

[0189] - The gamma-hydroxybutyrate, optionally together with one or more physiologically acceptable excipients, is sprayed onto the cores in the form of a dispersion or a solution in an aqueous or organic solvent, for example in a fluidized bed apparatus, optionally equipped with a partition tube or a Wurster tube.

[0190] The immediate-release portion of the formulation is in the form of microparticles comprising immediate-release γ-hydroxybutyrate and optional pharmaceutically acceptable excipients. 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 other 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.

[0191] The immediate-release granules of γ-hydroxybutyrate may comprise a core and a layer containing γ-hydroxybutyrate deposited on the core. The core may be any granule selected from the group consisting of:

[0192] Lactose, sucrose (such as Compressuc from Tereos TM PS), microcrystalline cellulose (such as Avicel from FMC Biopolymer TM , Cellet from Pharmatrans TM Or Celphere from Asahi Kasei TM ), sodium chloride, calcium carbonate (such as Omyapure TM35), sodium bicarbonate, dicalcium phosphate (such as Dicafos from Budenheim TM AC 92-12) or tricalcium phosphate (such as Tricafos from Budenheim TM SC93-15) crystals or spheres;

[0193] Composite spheres or granules, for example sugar spheres comprising sucrose and starch (such as Suglets from NP Pharm TM ), calcium carbonate and starch spheres (such as Destab from Particle Dynamics TM 90S Ultra250) or calcium carbonate and maltodextrin spheres (such as Hubercal TM CCG4100).

[0194] The core may also include other pharmaceutically acceptable excipient particles, such as hydroxypropylcellulose particles (such as Klucel from Aqualon Hercules TM ), guar gum particles (such as Grinsted TM Guar gum), xanthan gum particles (such as Xantural TM 180).

[0195] According to a particular embodiment of the invention, the core is a sugar sphere or a microcrystalline cellulose sphere, such as Cellets sold by Pharmatrans. TM 90. Cellets TM 100 or Cellets TM 127, also or Celphere TM CP 203, Celphere TM CP305, Celphere TM SCP 100. In one embodiment, the core is a microcrystalline cellulose sphere. For example, the core may be Cellets from Pharmatrans TM 127.

[0196] In various embodiments, the core has an average volume diameter of about 95 to about 450 microns, about 95 to about 170 microns, or about 140 microns.

[0197] The layer deposited on the core includes immediate release γ-hydroxybutyrate. In one embodiment, the layer further includes a binder, which can be selected from the group consisting of:

[0198] Low molecular weight hydroxypropyl cellulose (such as Klucel from Aqualon-Hercules TM ), low molecular weight hydroxypropyl methylcellulose (or hypromellose) (such as Methocel TM E3 or E5) or low molecular weight methylcellulose (such as Methocel TM A15);

[0199] Low molecular weight polyvinyl pyrrolidone (or povidone) (such as Plasdone from ISP TM K29 / 32 or Kollidon from BASF TM 30), vinyl pyrrolidone and vinyl acetate copolymer (or copolyvidone) (such as Plasdone from ISP TM :S630 or Kollidon from BASF TM VA 64);

[0200] • Glucose, pregelatinized starch, maltodextrin; and mixtures thereof.

[0201] Low molecular weight hydroxypropyl cellulose corresponds to a grade of hydroxypropyl cellulose having a molecular weight of less than 800,000 g / mol, less than or equal to 400,000 g / mol, or less than or equal to 100,000 g / mol. Low molecular weight hydroxypropyl methylcellulose (or hypromellose) corresponds to a grade of hydroxypropyl methylcellulose having a solution viscosity of less than or equal to 1000 mPa·s, less than or equal to 100 mPa·s, or less than or equal to 15 mPa·s for a 2% aqueous solution at 20° C. Low molecular weight polyvinyl pyrrolidone (or povidone) corresponds to a grade of polyvinyl pyrrolidone having a molecular weight of less than or equal to 1,000,000 g / mol, less than or equal to 800,000 g / mol, or less than or equal to 100,000 g / mol.

[0202] In some embodiments, the binder is selected from low molecular weight polyvinyl pyrrolidone or povidone (e.g., Plasdone from ISP). TM K29 / 32), low molecular weight hydroxypropyl cellulose (e.g., Klucel from Aqualon-Hercules TM EF), low molecular weight hydroxypropyl methylcellulose or hypromellose (e.g., Methocel TM E3 or E5) and mixtures thereof.

[0203] In one embodiment, the binder is povidone K30 or K29 / 32, especially Plasdone from ISP TMK29 / 32. Based on the total weight of the immediate-release coating, the binder can be present in an amount of 0% to 80%, 0% to 70%, 0% to 60%, 0% to 50%, 0% to 40%, 0% to 30%, 0% to 25%, 0% to 20%, 0% to 15%, 0% to 10%, or from 1% to 9% of the binder. 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 the binder is 5% of the binder in the total mass of gamma-hydroxybutyrate and the binder.

[0204] The layer deposited on the core may account for at least 10% by weight of the total weight of the γ-hydroxybutyrate immediate-release granules, and even greater than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% by weight of the total weight of the γ-hydroxybutyrate immediate-release granules. In one embodiment, the layer deposited on the core accounts for about 85% of the weight of the γ-hydroxybutyrate immediate-release granules.

[0205] According to one embodiment, the immediate release granules include 80.75% w / w of gamma-hydroxybutyrate, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres.

[0206] According to another embodiment, the immediate release granules include 80.75% w / w gamma-hydroxybutyrate, 4.25% w / w povidone K30, and 15% microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns.

[0207] According to yet another embodiment, the immediate release granules include 80.75% w / w of gamma-hydroxybutyrate, 4.25% w / w of povidone K30, and 15% of microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns.

[0208] According to one embodiment, the immediate release granules include 80.75% w / w sodium oxybate, 4.25% w / w povidone K30, and 15% microcrystalline cellulose spheres.

[0209] According to another embodiment, the immediate release granules include 80,75% w / w of potassium salt of gamma-hydroxybutyrate, 4.25% w / w of povidone K30 and 15% of microcrystalline cellulose spheres.

[0210] According to another embodiment, the immediate release granules include 80,75% w / w of gamma-hydroxybutyric acid calcium salt, 4.25% w / w of povidone K30 and 15% of microcrystalline cellulose spheres.

[0211] According to another embodiment, the immediate release granules include 80,75% w / w of magnesium salt of gamma-hydroxybutyrate, 4.25% w / w of povidone K30 and 15% of microcrystalline cellulose spheres.

[0212] According to another embodiment, the immediate release granules are manufactured by dissolving gamma-hydroxybutyrate and povidone K30 in a mixture of water / ethanol 40 / 60 w / w and spraying the resulting solution onto the surface of microcrystalline cellulose spheres.

[0213] Modifying other properties of the release moiety

[0214] The modified release portion can be any formulation that provides the desired in vitro dissolution profile of γ-hydroxybutyrate. The modified release portion can comprise modified release particles obtained by coating γ-hydroxybutyrate immediate release particles with a coating (or coating film) that inhibits the immediate release of γ-hydroxybutyrate. In a sub-embodiment, the modified release portion comprises particles comprising: (a) an inert core; (b) a coating; and (c) a layer comprising γ-hydroxybutyrate between the core and the coating.

[0215] In one embodiment, the modified release moiety includes a time-dependent release mechanism and a pH-dependent release mechanism.

[0216] In one embodiment, the coating film comprises at least one polymer carrying free carboxyl groups, and at least one hydrophobic compound characterized by a melting point equal to or greater than 40°C.

[0217] The polymer carrying free carboxyl groups can be selected from: (meth)acrylic acid / (meth)acrylic acid alkyl ester copolymers or methacrylic acid and methyl methacrylate copolymers or methacrylic acid and ethyl acrylate copolymers or methacrylic acid copolymers A, B or C types, cellulose derivatives carrying free carboxyl groups, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginates and mixtures thereof.

[0218] In one embodiment, the methacrylic acid copolymer is selected from poly (methacrylic acid, methyl methacrylate) 1:1 or Eudragit TM L100 or equivalent, poly(methacrylic acid, ethyl acrylate) 1:1 or Eudragit TM L100-55 or equivalent and poly(methacrylic acid, methyl methacrylate) 1:2 or Eudragit TM S100 or equivalent.

[0219] In another embodiment, the coating comprises a polymer carrying free carboxyl groups, wherein the free carboxyl groups are substantially ionized at pH 7.5.

[0220] The hydrophobic compound having a melting point equal to or greater than 40° C. can be selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, wax yellow, wax white, wax microcrystals, lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogol glycerides, polyglyceryl distearate, diesters or triesters of glycerol and fatty acids, and mixtures thereof.

[0221] In various embodiments, the hydrophobic compound having a melting point of 40° C. or greater is selected from the group of the following products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimyristin, yellow wax, hard fat or fat that can be used as a suppository base, anhydrous milk fat, lanolin, stearyl palmitin, stearyl glyceride, lauroyl macrogol glyceride, polyglyceryl distearate, diethylene glycol monostearate, ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof. For example, the hydrophobic compound may include hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimyristin, beeswax, hydrogenated poly-1-decene, carnauba wax, and mixtures thereof.

[0222] In practice (but not exclusively), the hydrophobic compound having a melting point equal to or higher than 40° C. may be selected from the group of products sold under the following trademarks: Dynasan TM , Cutina TM 、Hydrobase TM 、Dub TM 、Castorwax TM Croduret TM 、Compritol TM 、Sterotex TM 、Lubritab TM 、Apifil TM 、Akofine TM Softisan TM 、Hydrocote TM , Livopol TM 、Super Hartolan TM MGLA TM , Corona TM 、Protalan TM 、Akosoft TM , Akosol TM , Cremao TM 、Massupol TM 、Novata TM 、Suppocire TM 、Wecobee TM、Witepsol TM , Lanolin TM Incromega TM , Estaram TM 、Suppoweiss TM , Gelucire TM 、Precirol TM , Emulcire TM , Plurol diisostéarique TM , Geleol TM 、Hydrine TM Monthyle TM , Kahlwax TM and mixtures thereof. In one embodiment, the hydrophobic compound having a melting point equal to or higher than 40° C. can be selected from the group of products sold under the following trademarks: Dynasan TM P60、Dynasan TM 114. Dynasan TM 116. Dynasan TM 118. Cutina TM HR, Hydrobase TM 66-68, Dub TM HPH、Compritol TM 888, Sterotex TM NF, Sterotex TM K. Lubritab TM and mixtures thereof.

[0223] A particularly suitable coating consists of a mixture of hydrogenated vegetable oil and methacrylic acid copolymer.The exact structure and amount of each component and the amount of coating applied to the particle controls the release rate and release trigger. Methacrylic acid copolymers, namely methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer, have pH-dependent solubility: usually, the pH that triggers the release of the active ingredient from the microparticles is determined by appropriate The pH of the polymer is determined by the choice and mixture of polymers. In the case of gamma-hydroxybutyrate modified release microparticles, the theoretical pH for triggering release is from 5.5 to 6.97 or from 5.5 to 6.9. "pH trigger" means the lowest pH at which the polymer dissolves.

[0224] In a specific embodiment, the coating comprises a hydrophobic compound having a melting point equal to or greater than 40° C., and the polymer carrying free carboxyl groups is present in a weight ratio of from 0.4 to 4, from 0.5 to 4, from 0.6 to 2.5, from 0.67 to 2.5, from 0.6 to 2.33, or from 0.67 to 2.33. In one embodiment, the weight ratio is about 1.5.

[0225] Particularly suitable coatings are composed of a mixture of hydrogenated vegetable oil and methacrylic acid copolymer, the theoretical pH of which triggers release is from 6.5 to 6.97, and the weight ratio is from 0.4 to 4, from 0.5 to 4, from 0.6 to 2.5, from 0.67 to 2.5, from 0.6 to 2.33 or from 0.67 to 2.33. In one embodiment, the weight ratio can be about 1.5.

[0226] The modified release particles of gamma-hydroxybutyrate have a volume average diameter of from 100 to 1200 microns, from 100 to 500 microns, or from 200 to 800 microns. In one embodiment, the modified release particles of gamma-hydroxybutyrate have a volume average diameter of about 320 microns.

[0227] The coating may comprise 10% to 50%, 15% to 45%, 20% to 40%, or 25% to 35% by weight of the total weight of the coated modified release particle. In one embodiment, the coating comprises 25% to 30% by weight of the total weight of the modified release particle of gamma-hydroxybutyrate.

[0228] In one embodiment, the coating layer of the modified release granules of γ-hydroxybutyrate is obtained by spraying a solution, suspension or dispersion comprising the coating composition as defined above onto the immediate release granules of γ-hydroxybutyrate, especially the immediate release granules of γ-hydroxybutyrate as described above, in particular in a fluidized bed apparatus. In one embodiment, the coating is formed by spraying a solution of the coating excipient in hot isopropanol in a fluidized bed equipped with a Wurster or a partitioned tube and according to an upward spray orientation or a bottom spray orientation.

[0229] According to one embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3% w / w povidone TM K30 with 56.5% w / w gamma-hydroxybutyrate, and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TMThe granules are coated with a coating composition consisting of S100 or equivalent), and all percentages are expressed based on the total weight of the final modified-release granules of γ-hydroxybutyrate.

[0230] According to one embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3% w / w povidone TM K30 with 56.5% w / w gamma-hydroxybutyrate, and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM The granules are coated with a coating composition consisting of S100 or equivalent), and all percentages are expressed based on the total weight of the final modified-release granules of γ-hydroxybutyrate.

[0231] According to one embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3% w / w povidone TM K30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM The coating is performed with a coating composition consisting of S100 or equivalent), and all percentages are expressed based on the total weight of the final modified-release granules of sodium oxybate.

[0232] According to one embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 10.5% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3% w / w povidone TM K30 was layered with 56.5% w / w sodium oxybate and finally with 18% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 4% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 8% B-type methacrylic acid copolymer (Eudragit TM The coating is performed with a coating composition consisting of S100 or equivalent), and all percentages are expressed based on the total weight of the final modified-release granules of sodium oxybate.

[0233] According to another embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3.2% w / w povidone TM K30 60.5% w / w of gamma-hydroxybutyrate layered, and finally with 15% w / w of hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 9.25% of type B methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0234] According to another embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3.2% w / w povidone TM K30 60.5% w / w of gamma-hydroxybutyrate layered, and finally with 15% w / w of hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 9.25% of type B methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0235] According to another embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 450 microns, mixed with 3.2% w / w povidone TM K30 was layered with 60.5% w / w sodium oxybate and finally with 15% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 9.25% of type B methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0236] According to another embodiment, the modified release particles of gamma-hydroxybutyrate are composed of 11.3% w / w microcrystalline cellulose spheres having a volume average diameter of about 95 microns to about 170 microns, mixed with 3.2% w / w povidone TMK30 was layered with 60.5% w / w sodium oxybate and finally with 15% w / w hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% C-type methacrylic acid copolymer (Eudragit TM L100-55 or equivalent) and 9.25% of type B methacrylic acid copolymer (Eudragit TM S100 or equivalent) is coated.

[0237] Package

[0238] The composition of gamma-hydroxybutyrate can be provided in the form of a sachet or a stick package including a granular formulation. These sachets can be provided in several different doses to include 0.5g, 1.0g, 1.5g, 3.0g, 4.5g, 6.0g, 7.5g, 9.0g, 10.5g and / or 12g of sodium oxybate equivalent gamma-hydroxybutyrate. Depending on the desired dose, one or more sachets can be opened and the contents thereof mixed with tap water to provide a nighttime dose of gamma-hydroxybutyrate.

[0239] Treatment

[0240] Further provided herein is a method for treating a disorder treatable with γ-hydroxybutyrate in a human subject in need thereof, comprising orally administering to the human being a single bedtime daily dose of a composition equivalent to 3.0 to 12.0 g of sodium oxybate in less than two hours after eating. Further provided herein is a method for treating hypersomnia (type 1 and / or type 2) by oral administration of a therapeutically effective amount of a γ-hydroxybutyrate preparation before bedtime, the γ-hydroxybutyrate preparation being characterized by a novel γ-hydroxybutyrate pharmacokinetic property of the composition when administered less than two hours after eating. In one embodiment, the composition of the present invention is effective for treating type 1 or type 2 hypersomnia, wherein the treatment of hypersomnia is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplexy attacks. The therapeutically effective amount may include 3.0 to 12.0 g equivalents of sodium oxybate. In various embodiments, the therapeutically effective amount is 4.5, 6.0, 7.5 or 9.0 g of sodium oxybate. In one embodiment, the therapeutically effective amount is 6 g or 9 g of sodium oxybate. In various embodiments, the formulation comprises 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 of sodium oxybate. The effectiveness of the treatment can be measured by one or any combination of the following criteria:

[0241] Increased mean sleep latency, as determined by the Maintenance of Wakefulness Test (MWT)

[0242] Improved Clinical Global Impression (CGI) scores for sleepiness

[0243] Reduction in the number of cataplexy episodes (NCA) as determined by the cataplexy frequency item in the sleep and symptom daily diary

[0244] Reduction in nocturnal disrupted sleep (DNS), nocturnal disordered events, or adverse breathing events as determined by polysomnography (PSG) measures of sleep fragmentation

[0245] Reduction in excessive daytime sleepiness (EDS), as measured by the Epworth Sleepiness Scale (ESS) based on patient report

[0246] Reduced daytime sleepiness, based on EEG measures of wakefulness as determined by the Maintenance of Wakefulness Test

[0247] • Reduced PSG transitions from N / 2 to N / 3, and REM sleep to wakefulness and N1 sleep (as determined by: CIber, S Ancoli-Israel, A Chesson, SF Quan. AASM Manual for Scoring Sleep and Related Events. Westchester, IL: American Academy of Sleep Medicine; 2007).

[0248] Reduced number of awakenings or arousals, as obtained from a PSG as defined by the American Academy of Sleep Medicine

[0249] Improved sleep quality as measured by one or more of the following: (i) sleep and symptom daily diaries, (ii) sleep quality and sleep diary visual analogue scales (VAS), and (iii) sleep freshness VAS

[0250] Reduction of hypnagogic hallucinations (HH) or sleep paralysis (SP) symptoms in patients with NT1 hypersomnia, as measured by a sleep and symptom daily diary

[0251] In one embodiment, treatment with the composition administered less than two hours after a meal is superior to an equal dose of sodium oxybate immediate-release liquid solution administered twice nightly, with the second dose administered 4 hours after the first dose, as determined by any one or combination of the foregoing criteria.

[0252] The invention further provides a method of treating hypersomnia type 1 or type 2, wherein administration of a single daily bedtime dose of a therapeutically effective amount of a formulation of the invention has been shown to produce less confusion, less depressive syndrome, less incontinence, less nausea, or less sleepwalking compared to a dosing regimen consisting of administering half the dose at t0 and the other half the dose at t4h of an immediate release liquid solution of sodium oxybate.

[0253] Examples

[0254] Example 1. Formulation

[0255] Tables 1a-1d provide the qualitative and quantitative compositions of sodium oxybate IR microparticles, MR microparticles, and mixtures of IR and MR microparticles. The physical structure of the microparticles is depicted in Figure 1, showing the qualitative and quantitative compositions of the IR and MR microparticles.

[0256] Briefly, sodium oxybate immediate release (IR) microparticles were prepared as follows: 1615.0 g sodium oxybate and 85.0 g polyvinyl pyrrolidone (Povidone K30-Plasdone from ISP) were mixed with TM K29 / 32) was dissolved in 1894.3 g of anhydrous ethanol and 1262.9 g of water. In a fluidized bed spray coater, the solution was completely sprayed onto 300 g of microcrystalline cellulose beads (Cellets TM 127). IR microparticles with a volume average diameter of about 270 microns were obtained.

[0257] Sodium oxybate modified release (MR) microparticles were prepared as follows: 22.8 g of type C methacrylic acid copolymer (Eudragit TM L100-55), 45.8g B-type methacrylic acid copolymer (Eudragit TM S100), 102.9g hydrogenated cottonseed oil (Lubritab TM ) was dissolved in 1542.9 g of isopropanol. The solution was sprayed completely onto 400.0 g of the above sodium oxybate IR microparticles in a fluidized bed spray coater apparatus at an inlet temperature of 48° C., a spray rate of about 11 g / min and an atomization pressure of 1.3 bar. The MR microparticles were dried for two hours, with the inlet temperature set at 56° C. MR microparticles with an average volume diameter of about 320 microns were obtained.

[0258] A finished composition containing a 50:50 mixture of MR and IR microparticles calculated based on their sodium oxybate content was prepared by mixing 353.36 g of the above IR microparticles, 504.80 g of the above MR microparticles, 14.27 g of malic acid (D / L malic acid), 6.34 g of xanthan gum (Xantural Gum from Kelco) and 100 g of IR microparticles. TM 75), 9.51 g carrageenan (Viscarin from FMC Biopolymer TM PH209), 9.51 g hydroxyethyl cellulose (Natrosol from Ashland TM 250M) and 4.51 g of magnesium stearate were mixed. A single sample of 7.11 g (corresponding to a 4.5 g dose of sodium oxybate, half of which was the immediate release portion and half of which was the modified release portion) was weighed.

[0259] Table 1a: Composition of IR microparticles

[0260]

[0261] Table 1b: Composition of MR particles

[0262]

[0263]

[0264] Table 1c: Qualitative finished product composition

[0265]

[0266] Table 1d: Quantitative finished product composition

[0267]

[0268] Example 1-2. Alternative formulations

[0269] An alternative formulation to that of Example 1 is described in Example 1-bis.

[0270] Sodium oxybate immediate release (IR) microparticles were prepared by coating the IR microparticles described in Example 1 with a topcoat. The microparticles were prepared as follows: 170.0 hydroxypropyl cellulose (Klucel TM EF Pharm) was dissolved in 4080.0 g of acetone. In a fluidized bed spray coater, the solution was sprayed completely onto 1530.0 g of the IR microparticles of Example 1. IR microparticles having a volume average diameter of about 298 μm were obtained (see Table 1-bis-a).

[0271] Sodium oxybate modified release (MR) microparticles were prepared as described in Example 1 (see Table 1b).

[0272] A finished composition containing a 50:50 mixture of MR and IR microparticles based on their sodium oxybate content was prepared as follows: 412.22 g of the above IR microparticles, 530.00 g of the above MR microparticles, 29.96 g malic acid (D / L malic acid), 4.96 g xanthan gum (Xantural Gum from Kelco) and 1.5 g xanthan gum (Xantural Gum from Kelco) were added. TM 75), 4.96 g colloidal silicon dioxide (Aerosil from Degussa TM 200) and 9.92 g of magnesium stearate were mixed. A single sample of 7.45 g (corresponding to a 4.5 g dose of sodium oxybate, half of which was the immediate release portion and half of which was the modified release portion) was weighed (see Tables 1-bis-b and 1-bis-c).

[0273] Table 1-bis-a: Composition of IR particles

[0274]

[0275] Table 1-bis-b: Qualitative finished product composition

[0276]

[0277] Table 1-bis-c: Quantitative finished product composition

[0278]

[0279]

[0280] Compared to the finished composition described in Example 1, this alternative composition has the following characteristics: same MR microparticles, same IR microparticles but with a topcoat, increased amounts of malic acid, only one suspending agent (xanthan gum) and the presence of a glidant.

[0281] Example 2. In vivo pharmacokinetic study of the finished composition according to Example 1 (6 g FT218 in fed and fasted states)

[0282] Pharmacokinetic testing was performed in healthy human volunteers. The test product produced at a larger scale with the finished composition of Example 1 (FT218) was administered at a dose of 6 g. FT218 was administered to 16 healthy volunteers, and the first group n=14 administered FT218 in the fed state and the second group n=13 administered FT218 in the fasted state. A 4.5 g test sample was manufactured as described in Table 1c, and it was assumed that the amount was adjusted to a 6 g dose. Figure 2A and 2B The concentration profiles of FT218 over time are shown in the fed and fasted states. The derived PK parameters are summarized in Table 2 below, and Table 3 provides the percentage ratios of the geometric means between the fed and fasted states. Figure 2A Table 3 shows that the C max (Eating) / C max (fasting) = 66.7%, and AUC (fed) / AUC (fasting) = 86%. Therefore, the AUC is within the bioequivalence range of 80-125%, and there is no effect margin, so food has no effect on the total exposure of the composition. Food appears to have no or little effect on the absorption of MR particles in the latter half of the gastrointestinal tract.

[0283] Table 2. Mean PK parameters

[0284]

[0285] Table 3. Effects of food on FT218

[0286]

[0287]

[0288] Example 3. Simulated data demonstrating the effect of food on the IR fraction, MR fraction, and FT218 in the fed and fasted states

[0289] To illustrate the effect of food on FT218 and the IR and MR fractions of FT218 for a 9 g dose, concentration profiles over time were simulated. Figure 3A The predicted negative effect of food on the IR fraction of microparticles alone was shown at a single 3 g dose. Figure 3A Display C max (Eating) / C max (fasting) = 40%, and AUC (fed) / AUC (fasting) = 70%. Food appears to have a similar effect on the IR particles of FT218 as on Similar effects, such as comparison Figure 3A and Figure 4A As seen in Figure 2, the concentration of Xyrem changes over time in the fed and fasted states.

[0290] Figure 3B It was shown that the predicted negative food effects were reduced in the MR fraction of the microparticles and in the entire FT218 formulation compared to the IR fraction of the microparticles. Figure 3B Display FT218 C max (Eating) / C max (fasting) = 55%, and AUC (fed) / AUC (fasting) = 80%. Therefore, food appears to have little or no effect on MR particle absorption in the latter half of the gastrointestinal tract.

[0291] Example 4. Effects of 100 mg / kg / day on the stomach, 2 hours after a meal, and on the fasting stomach Comparison with FT218

[0292] Food for FT218 and The impact of Figure 4A and 4B Data digitized from the NDA dossier for Xyrem 21-196. Figure 4A Display 4.5g single dose The concentration change curves over time in the fed state, fasting state and 2 hours after meal. Figure 4B The concentration curve of 6g FT218 in the fed state, fasting state and 2 hours after meal is shown. As the meal time is closer to administration, C max and AUC decreased, while T max In contrast, FT218 showed Same behavior, but the effect of meal timing seems to be reduced. Administration with and 2 h after a meal appears to have similar PK characteristics (comparison between studies). The derived PK parameters are summarized below (Table 4).

[0293] Table 4. Mean PK parameters

[0294]

[0295] a: Provide means to study OMC-SXB-8.

[0296] Example 5. Effects of 100 mg / kg of glutathione on the stomach in the fed, 2-hour postprandial and fasting states Comparison with FT218

[0297] To compare the effects of food on FT218 and The effect of two 3g doses of The concentrations of FT218 were plotted over time together with a single 6 g dose.

[0298] Figure 5A Shown in eating state The expected concentration variation of FT218 over time. The 4.5 g data (linearized to a 3 g dose and multiplied by a correction factor of 0.7) from the NDA review (Study OMC-SXB-11) were extrapolated to the fed state. like Figure 5A As shown, during the first dose, There is a risk of lack of efficacy, and FT218 has a shorter onset of action than Early, and FT218's C max Lower than The second peak C max Therefore, administration of FT218 in the fed state can reduce Related security issues.

[0299] Figure 5B Shows that the drug is taken two hours after a meal. and the expected concentration variation curve of FT218 over time. Data were extrapolated from the PK FT218-1602BA study. This study was a randomized, 2-treatment, 2-period, 2-sequence crossover study. The two treatments were: FT218 6g administered 2 hours after dinner and 2*3Xyrem first dose administered 2 hours after dinner and second dose administered 4 hours after first dose. 28 subjects were included.

[0300] like Figure 5B As shown, the C of FT218max Between The first peak C max and the second peak C max Therefore, administration of FT218 two hours after a meal can reduce Related security issues. Figure 5C Shows that the drug was administered on an empty stomach The expected concentration variation curves of FT218 and FT218 over time were simulated using the numerical superposition method. data.

[0301] Based on food effect and dose proportionality data, In contrast, the food effect of FT218 on C max The predictability of FT218 may be better than Table 5 provides the results of the experiments in the fed state, two hours after meal and fasting state. The expected PK parameters of FT218 (2x3g dose) and FT218 (6g dose) were analyzed.

[0302] Table 5. Estimated PK parameters

[0303]

[0304] Example 6. Effects of 1 mg / kg / day on the stomach, 2 hours after a meal, and on the stomach Comparison with FT218

[0305] To compare the effects of food on FT218 and The expected effect of two 4.5 g doses of The concentrations of FT218 were plotted over time together with a single 9 g dose.

[0306] Fig. 6A Shown in eating state The expected concentration-time curve of FT218. The FT218 data comes from a dose proportionality study. Data from NDA file for .

[0307] The mean concentration-time curve of FT218 is the observed data of the dose proportionality study at 9 g 2 hours after meal. Fig. 6A As shown, during the first dosing period, There is a risk of lack of efficacy, and FT218 has a shorter onset of action than Early, and FT218's C max Lower than The second peak Cmax Therefore, administration of FT218 in the fed state can reduce Related security issues.

[0308] Figure 6B Shows that the drug is taken two hours after a meal. and the expected concentration variation curve of FT218 over time. Figure 6B As you can see, FT218's C max Between The first peak C max and the second peak C max Therefore, administration of FT218 two hours after a meal can reduce Related security issues. Figure 6C Shown in fasting state and the expected concentration variation curve of FT218 over time. The FT218 fasting data were extrapolated based on the 4.5 g data (dose linearity assumption and multiplied by a correction factor of 1.2).

[0309] Based on food effect and dose proportionality data, In contrast, the food effect of FT218 on C max The predictability of FT218 may be better than Table 6 provides the results of the experiments in the fed state, two hours after meal and fasting state. The expected PK parameters of FT218 (2x4.5g dose) and FT218 (9g dose) were analyzed.

[0310] Table 6. Estimated PK parameters

[0311]

[0312] Example 7. AUC and Cmax in the fed state Comparison with FT218PK curve

[0313] To compare the effects of administration time, the time course of 6 g FT218 and AUC and C max picture. Fig. 7A Display 6g FT218 and 6g The relationship between AUC and postprandial time. Figure 7B Display 6g FT218 and 6g C max The relationship between the time of meal and the time of day. PK parameters were calculated based on the mean PK profile. The circulating levels of FT218 may vary throughout the night compared to each individual. More consistent, because the linear profile of FT218 is more constant overall (less fluctuations). In addition, circulating levels of GHB are less affected by meals (from a fed state to a fasted state). For example, taking FT218 during a meal, 1 hour after a meal, or 2 hours after a meal may result in a similar PK profile. This may reduce constraints on patients.

[0314] Example 8. Pharmacokinetics and dose proportionality of FT218 once-nightly dosing

[0315] In order to evaluate the PK of FT218 administered in single doses of 4.5g, 7.5g and 9g, compare the PK parameters of the three doses, and estimate the dose ratio, an open-label, single-dose, 3-continuous-period study was conducted in 20 healthy volunteers. Subjects received 3 separate single doses (no titration) of FT218 at bedtime, two hours after dinner, in the order of 4.5g, 7.5g and 9g, with a minimum washout period of 7 days between each dose. The dose ratio between the three doses was evaluated using the power method. ANOVA was used for sensitivity analysis.

[0316] In the PK pilot study and in the present study, the variability of concentrations of FT218 and twice-nightly sodium oxybate IR at 8 and 10 hours post-dose (when patients typically awaken) was compared in terms of standard deviation.

[0317] This study was conducted in 20 healthy volunteers (12 males and 8 females). All subjects completed sessions 1 (4.5 g) and 2 (7.5 g), and 12 subjects completed session 3 (9 g).

[0318] For the three doses, the mean pharmacokinetics showed similar overall characteristics, with a median T max Between 1.5 and 2 hours ( Figure 8 ). With the increase of dose, the average C max Increased from 42.9 to 84.5 μg / mL. max After 4.5, 7.5 and 9 g doses, the mean AUC inf The mean concentrations at 8 hours were 4.8, 19.7 and 25.5 μg / mL for the 4.5, 7.5 and 9 g doses, respectively.

[0319] Table 7 provides the concentration variability of sodium oxybate and FT218 at 8 and 10 h post-dose twice-nightly in the PK pilot study and the dose proportionality study.

[0320] Table 7. Concentrations of sodium oxybate and FT218 at 8 and 10 hours after twice-nightly dosing

[0321]

[0322]

[0323] BQL: Concentration below the limit of quantitation.

[0324] Regardless of the algorithm used to treat concentrations below the limit of quantitation, mean concentrations of FT218 at 8 and 10 h post-dosing were at least as low as those of the twice-nightly sodium oxybate IR (Table 7). In addition, the variability of concentrations was similar.

[0325] Applying the power method, C max The slope estimate of AUC was 1.02, and the confidence interval was centered at 1.00 (90% CI: 0.76-1.28). inf , the estimate was 1.34 (90% CI: 1.19-1.48), indicating a slightly more than proportional increase in AUC. These results were consistent with the results of the ANOVA sensitivity analysis.

[0326] Thirteen subjects (65%) reported a total of 31 treatment-emergent adverse events (TEAEs). During the 4.5g period, 7 / 20 (35%) subjects experienced 8 TEAEs (mainly headache 5 / 8). During the 7.5g period, 4 / 20 (20%) subjects experienced 7 TEAEs (mainly gastrointestinal disorders 4 / 7). During the 9g period, 6 / 12 (50%) subjects experienced 16 TEAEs (mainly gastrointestinal disorders 8 / 16). One of them, nervous system disorder (sedation) was a SAE. In terms of the intensity of TEAEs, 2 / 31 TEAEs (all in the 9g period) were judged to be severe, 10 / 31 (4 in the 4.5g period, 3 in the 7.5g period, and 3 in the 9g period) were judged to be moderate, and 19 / 31 were judged to be mild. All TEAEs were resolved before the end of the study.

[0327] FT218 achieved a blood level profile consistent with a single CR dose when administered at bedtime. max The safety profile was consistent with that known for sodium oxybate, and most AEs were mild to moderate in severity, even without titration.

[0328] Example 9. TEAEs of FT218 in the fed and fasted states

[0329] Table 8 provides a summary of TEAEs for the 6 g dose of FT218 in the fed and fasted states.

[0330] Table 8. Adverse events of FT218

[0331]

[0332] As can be seen in Table 8, administration of 6 g FT218 in the fed state resulted in fewer TEAEs compared to administration of 6 g FT218 in the fasted state.

[0333] In addition, the pharmacokinetic-adverse event (AE) relationships of FT218 were evaluated. A total of 129 healthy volunteers received single doses of FT218 between 4.5-9g. Six single-dose, randomized, crossover studies were used to evaluate the pharmacokinetics of 4.5, 6, 7.5, and 9g FT218 in healthy volunteers. Grid plots, "spaghetti" plots, and scatter plots of each γ-hydroxybutyrate concentration and index at the time of AE listed by system, organ, or category (SOC) were created to identify any PK-AE relationships.

[0334] Most AEs (especially neurological and gastrointestinal SOCs) were in C max The time period occurs during T max The time period for FT218 was approximately 1.5-2 hours after administration. These AEs are known AEs associated with sodium oxybate. There does not appear to be a clear correlation between individual plasma GHB concentration levels and AEs between subjects. Individual AEs were not significantly different from the average population C in the data set. max and AUC inf Distribute evenly above and below.

[0335] Throughout this application, various publications are cited. The disclosures of these publications are incorporated herein by reference in their entirety for the purpose of more fully describing the present state of the art to which the invention pertains. It will be apparent to those skilled in the art that various modifications and variations may be made to the invention without departing from the scope or spirit of the invention. In view of the specification and practice of the invention disclosed herein, other embodiments of the invention will be apparent to those skilled in the art. This specification and examples are intended to be exemplary only, and the true scope and spirit of the invention are represented by the appended claims.

[0336] In summary, the present invention includes but is not limited to the following items:

[0337] 1. An oral pharmaceutical composition for treating narcolepsy, cataplexy or excessive daytime sleepiness, comprising a unit dose of gamma-hydroxybutyrate, suitable for administration less than two hours after a meal.

[0338] 2. An oral pharmaceutical composition according to claim 1, wherein the composition is suitable for administration with food, immediately after eating, up to 30 minutes after eating, up to 1 hour after eating, up to 1.5 hours after eating, or up to 2 hours after eating.

[0339] 3. The oral pharmaceutical composition according to item 1 or 2, wherein the composition is administered once a day.

[0340] 4. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition is suitable for evening administration.

[0341] 5. An oral pharmaceutical composition according to any one of items 1 to 3, wherein the composition is suitable for morning administration.

[0342] 6. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition comprises γ-hydroxybutyrate in an extended release or delayed release dosage form.

[0343] 7. An oral pharmaceutical composition according to any one of items 1 to 5, wherein the composition comprises γ-hydroxybutyrate in a modified release formulation.

[0344] 8. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides substantially similar fed state PK profile and 2-hour post-prandial administration PK profile.

[0345] 9. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides a mean AUC of inf is the mean AUC when the composition is administered at least two hours after a meal inf 50%-120% of.

[0346] 10. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 50%-120% of.

[0347] 11. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 80%-95%.

[0348] 12. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 85%-90% of.

[0349] 13. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides an average C of max is the average C when the composition is administered at least two hours after a meal max 50%-120% of.

[0350] 14. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides an average C of max is the average C of the composition when administered on an empty stomach max 50%-120% of.

[0351] 15. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides an average C max is the average C of the composition when administered on an empty stomach max 55%-80%.

[0352] 16. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides an average C max is the average C of the composition when administered on an empty stomach max 60%-75%.

[0353] 17. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides a dose-proportional C max .

[0354] 18. An oral pharmaceutical composition according to any of the preceding items, wherein the composition does not provide dose dumping.

[0355] 19. An oral pharmaceutical composition according to any one of the preceding items, wherein the safety or efficacy to the patient is not significantly reduced after administration.

[0356] 20. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides an AUC of inf Take at least 2 hours after a meal in equally divided doses at t0 and t 4h AUC of an equivalent dose of sodium oxybate immediate-release liquid solution administered inf Bioequivalence.

[0357] 21. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides C max Less than 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max .

[0358] 22. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides C max Less than 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max .

[0359] 23. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides C max Than at least 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max 10%-60% smaller.

[0360] 24. An oral pharmaceutical composition according to any one of the preceding items, wherein the composition provides C max Than less than 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max 10%-60% smaller.

[0361] 25. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides a C of between 1.5 and 2.0 when the composition is administered at least two hours after a meal and less than two hours after a meal. max change, said change being greater than the change in the dose at t0 and t2 taken at least two hours after a meal in equally divided doses 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max The variation is 10%-60% smaller.

[0362] 26. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides a C of between 1.5 and 2.0 when the composition is administered at least two hours after a meal and less than two hours after a meal. max changes compared to the changes observed in equally divided doses at t0 and t2 hours after a meal. 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max The variation is 10%-60% smaller.

[0363] 27. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides an AUC comparable to that of the AUC of t0 and t2 in equally divided doses at least two hours after a meal. 4h The AUC for equivalent doses of sodium oxybate immediate release liquid solution administered was more proportional to dose.

[0364] 28. An oral pharmaceutical composition according to any of the preceding items, wherein the composition provides an AUC comparable to that of the AUC of 1.0% at t0 and t1 in equally divided doses less than two hours after a meal. 4h The AUC for equivalent doses of sodium oxybate immediate release liquid solution administered was more proportional to dose.

[0365] 29. An oral pharmaceutical composition according to any one of items 20 to 28, wherein the dosage is divided equally between t0 and t 4h The equivalent dose of sodium oxybate immediate release liquid solution administered is

[0366] 30. An oral pharmaceutical composition for treating narcolepsy, cataplexy or excessive daytime sleepiness comprising a unit dose of gamma-hydroxybutyrate, wherein the absorption of the gamma-hydroxybutyrate in the gastrointestinal tract is not substantially altered by the presence of food.

[0367] 31. An oral pharmaceutical composition comprising a unit dose of gamma-hydroxybutyrate suitable for administration less than two hours after a meal.

[0368] 32. An oral pharmaceutical composition according to claim 31, wherein the composition comprises γ-hydroxybutyrate in a modified release formulation.

[0369] 33. An oral pharmaceutical composition according to item 31 or 32, wherein the formulation is administered during meals, immediately after meals, up to 30 minutes after meals, up to 1 hour after meals, up to 1.5 hours after meals, or up to 2 hours after meals.

[0370] 34. An oral pharmaceutical composition according to any one of items 31 to 33, wherein the composition is suitable for once-daily administration.

[0371] 35. An oral pharmaceutical composition according to any one of items 31 to 34, wherein the composition is suitable for evening administration.

[0372] 36. An oral pharmaceutical composition according to any one of items 31 to 34, wherein the composition is suitable for morning administration.

[0373] 37. An oral pharmaceutical composition according to any one of items 31 to 36, wherein the composition is effective in inducing sleep for at least eight consecutive hours.

[0374] 38. An oral pharmaceutical composition according to any one of items 31 to 37, wherein a 6 g dose of the composition administered less than two hours after a meal has a mean AUC greater than 230 hr*μg / mL inf and at least 2 hours after a meal in equally divided doses at t0 and t 4hEquivalent doses of sodium oxybate immediate-release liquid solution administered provided a mean C max The average C from 50% to 140% max .

[0375] 39. An oral pharmaceutical composition according to claim 38, wherein the average C max The drug is administered in equally divided doses at t0 and t2 at least 2 hours after a meal. 4h Administration of an equal dose of sodium oxybate immediate-release liquid solution provided the mean C max From 80% to 140%.

[0376] 40. An oral pharmaceutical composition according to claim 38, wherein the average C max The drug is administered in equally divided doses at t0 and t2 at least 2 hours after a meal. 4h The mean C of the first peak of an equal dose of sodium oxybate immediate-release liquid solution administered max From 100% to 150%.

[0377] 41. An oral pharmaceutical composition according to claim 38, wherein the average C max The drug is administered in equally divided doses at t0 and t2 at least 2 hours after a meal. 4h The mean C of the second peak of an equal dose of sodium oxybate immediate-release liquid solution administered max From 80% to 100%.

[0378] 42. An oral pharmaceutical composition according to claim 38, wherein the average C max It is about 50 μg / mL to about 82 μg / mL.

[0379] 43. An oral pharmaceutical composition according to claim 42, wherein the average C max It is about 64μg / mL.

[0380] 44. An oral pharmaceutical composition according to claim 38, wherein when the formulation is administered about 30 minutes after eating, the mean AUC inf It is about 242hr*μg / mL.

[0381] 45. An oral pharmaceutical composition according to claim 38, wherein when the formulation is administered about 2 hours after a meal, the mean AUC inf It is about 273hr*μg / mL.

[0382] 46. ​​A method of treating narcolepsy and related disorders and symptoms in a patient in need thereof, comprising:

[0383] The oral pharmaceutical composition comprising gamma-hydroxybutyrate is administered less than two hours after eating.

[0384] 47. A method according to claim 46, wherein the composition is administered once daily.

[0385] 48. A method according to claim 47, wherein the composition is administered in the evening after eating.

[0386] 49. A method according to claim 47, wherein the composition is administered in the morning after eating.

[0387] 50. A method according to any one of items 46 to 49, wherein the composition is administered during a meal, immediately after a meal, up to 30 minutes after a meal, up to 1 hour after a meal, up to 1.5 hours after a meal, or up to 2 hours after a meal.

[0388] 51. A method according to any one of items 46 to 50, wherein the composition is effective to induce sleep for at least six consecutive hours.

[0389] 52. A method according to any one of items 46 to 51, wherein the composition is effective to induce sleep for at least eight consecutive hours.

[0390] 53. A method according to any one of items 46 to 52, wherein the composition is effective to induce sleep for at least ten consecutive hours.

[0391] 54. A method according to any one of items 46 to 53, wherein the composition comprises gamma-hydroxybutyrate in an extended release or delayed release formulation.

[0392] 55. A method according to any one of items 46 to 53, wherein the composition comprises gamma-hydroxybutyrate in a modified release formulation.

[0393] 56. A method according to any one of items 46 to 55, wherein the composition provides a substantially similar fed state PK profile and a 2-hour post-prandial administration PK profile.

[0394] 57. The method according to any one of items 46 to 56, wherein the composition provides a mean AUC of inf is the mean AUC when the composition is administered at least two hours after a meal inf 50%-120% of.

[0395] 58. The method according to any one of items 46 to 57, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 50%-120% of.

[0396] 59. The method according to any one of items 46 to 58, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 80%-95%.

[0397] 60. The method according to any one of items 46 to 59, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 85%-90% of.

[0398] 61. The method according to any one of items 46 to 60, wherein the composition provides an average C of max is the average C when the composition is administered at least two hours after a meal max 50%-120% of.

[0399] 62. The method according to any one of items 46 to 61, wherein the composition provides an average C of max is the average C of the composition when administered on an empty stomach max 50%-120% of.

[0400] 63. The method according to any one of items 46 to 62, wherein the composition provides an average C of max is the average C of the composition when administered on an empty stomach max 55%-80%.

[0401] 64. The method according to any one of items 46 to 63, wherein the composition provides an average C of max is the average C of the composition when administered on an empty stomach max 60%-75%.

[0402] 65. The method according to any one of items 46 to 64, wherein the composition provides a dose-balanced C max .

[0403] 66. The method of any one of items 46 to 65, wherein the composition does not provide dose dumping.

[0404] 67. A method according to any one of items 46 to 66, wherein there is no significant reduction in safety or efficacy to the patient after administration.

[0405] 68. The method according to any one of items 46 to 67, wherein the composition provides an AUC of inf Take at least 2 hours after a meal in equally divided doses at t0 and t 4h AUC of an equivalent dose of sodium oxybate immediate-release liquid solution administered inf Bioequivalence.

[0406] 69. A method according to any one of items 46 to 68, wherein the composition provides C max Less than 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max .

[0407] 70. A method according to any one of items 46 to 69, wherein the composition provides C max Less than 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max .

[0408] 71. A method according to any one of items 46 to 70, wherein the composition provides C max Than at least 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max 10%-60% smaller.

[0409] 72. A method according to any one of items 46 to 71, wherein the composition provides C max Than less than 2 hours after a meal in equally divided doses at t0 and t 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max 10%-60% smaller.

[0410] 73. The method of any one of items 46 to 72, wherein the composition provides a C between when the composition is administered at least two hours after a meal and when the composition is administered less than two hours after a meal. max change, said change being greater than the change in the dose at t0 and t2 taken at least two hours after a meal in equally divided doses 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max The variation is 10%-60% smaller.

[0411] 74. The method of any one of items 46 to 73, wherein the composition provides a C between when the composition is administered at least two hours after a meal and when the composition is administered less than two hours after a meal. maxchanges compared to the changes observed in equally divided doses at t0 and t2 hours after ingestion. 4h Administer an equal dose of sodium oxybate immediate-release liquid solution of the C max The variation is 10%-60% smaller.

[0412] 75. The method according to any one of items 46 to 74, wherein the composition provides an AUC comparable to that of the AUC of the test sample at t0 and t2 in equally divided doses at least two hours after a meal. 4h The AUC for equivalent doses of sodium oxybate immediate release liquid solution administered was more proportional to dose.

[0413] 76. The method according to any one of items 46 to 75, wherein the amount of the mixture is divided equally between t0 and t 4h The equivalent dose of sodium oxybate immediate release liquid solution administered is

[0414] 77. A method according to any one of items 46 to 76, wherein a 6 g dose of the composition administered has been shown to achieve a mean AUC of greater than 230 hr*μg / mL inf and at least 2 hours after a meal in equally divided doses at t0 and t 4h Administration of an equal dose of sodium oxybate immediate-release liquid solution provided the mean C max Average C from 50% to 140% max .

[0415] 78. A method according to claim 77, wherein the average C max It is given in equal doses at t0 and t2 hours after a meal. 4h Administration of an equal dose of sodium oxybate immediate-release liquid solution provided the mean C max From 80% to 140%.

[0416] 79. A method according to any one of items 77 to 78, wherein the average C max The drug is administered in equally divided doses at t0 and t2 at least 2 hours after a meal. 4h The mean C of the first peak of an equal dose of sodium oxybate immediate-release liquid solution administered max From 100% to 150%.

[0417] 80. A method according to any one of items 77 to 79, wherein the average C max It is given in equal doses at t0 and t2 hours after a meal. 4h The mean C of the second peak of an equal dose of sodium oxybate immediate-release liquid solution administered max From 80% to 100%.

[0418] 81. A method according to any one of items 77 to 80, wherein the average C max It is about 50 μg / mL to about 82 μg / mL.

[0419] 82. A method according to item 81, wherein the average C max It is about 64μg / mL.

[0420] 83. The method according to any one of items 77 to 82, wherein when the formulation is administered about 30 minutes after a meal, the mean AUC inf It is about 242hr*μg / mL.

[0421] 84. The method according to any one of items 77 to 82, wherein when the formulation is administered about 2 hours after a meal, the mean AUC inf It is about 273hr*μg / mL.

[0422] 85. An oral pharmaceutical composition for treating narcolepsy, cataplexy or excessive daytime sleepiness comprising a unit dose of gamma-hydroxybutyrate suitable for once daily administration, wherein the composition is dose proportional.

[0423] 86. An oral pharmaceutical composition according to item 85, wherein the composition is suitable for evening administration.

[0424] 87. An oral pharmaceutical composition according to item 85, wherein the composition is suitable for morning administration.

[0425] 88. An oral pharmaceutical composition according to any one of items 85 to 87, wherein the composition is dose proportional over the 4.5g, 7.5g and 9g doses of the composition.

[0426] 89. An oral pharmaceutical composition according to any one of items 85 to 88, wherein the C of the composition max This is proportional on the 4.5g, 7.5g and 9g doses of the composition.

[0427] 90. An oral pharmaceutical composition according to any one of items 85 to 89, wherein the composition is proportional to dose by a factor of 1 to 1.3.

[0428] 91. An oral pharmaceutical composition according to any one of items 88 to 90, wherein at increasing doses, the median T max Between about 1.5 and 2 hours.

[0429] 92. An oral pharmaceutical composition according to any one of items 88 to 97, wherein at increasing doses, the average C max Between about 42.9 and 84.5 μg / mL.

[0430] 93. An oral pharmaceutical composition according to any one of items 88 to 92, wherein for the 4.5, 7.5 and 9 g doses, the mean AUC inf Approximately 191, 358 and 443 μg.h / mL respectively.

[0431] 94. An oral pharmaceutical composition according to any one of items 88 to 93, wherein the average concentration at 8 hours is about 4.8, 19.7 and 25.5 μg / mL for the 4.5, 7.5 and 9 g doses, respectively.

[0432] 95. A method of treating narcolepsy and related disorders and symptoms in a patient in need thereof, comprising:

[0433] An oral pharmaceutical composition comprising gamma-hydroxybutyrate is administered once daily, wherein the composition is dose proportional.

[0434] 96. A method according to claim 95, wherein the composition is applied in the evening.

[0435] 97. A method according to claim 95, wherein the composition is applied in the morning.

[0436] 98. A method according to any one of items 95 to 97, wherein the composition is dose proportional over the 4.5g, 7.5g and 9g doses of the composition.

[0437] 99. A method according to any one of items 95 to 98, wherein the C of the composition max Proportional on the 4.5g, 7.5g and 9g doses of the composition.

[0438] 100. A method according to any one of items 95 to 99, wherein the composition is proportional to the dose by a factor of 1 to 1.3.

[0439] 101. The method according to any one of items 98 to 100, wherein at increasing doses, the median T max Between about 1.5 and 2 hours.

[0440] 102. The method of any one of items 98 to 101, wherein at increasing doses, the mean C max Between about 42.9 and 84.5 μg / mL.

[0441] 103. The method of any one of items 98 to 102, wherein for the 4.5, 7.5 and 9 g doses, the mean AUC inf Approximately 191, 358 and 443 μg.h / mL respectively.

[0442] 104. The method of any one of items 98 to 103, wherein the mean concentrations over 8 hours are about 4.8, 19.7 and 25.5 μg / mL for the 4.5, 7.5 and 9 g doses, respectively.

[0443] 105. An oral pharmaceutical composition for treating narcolepsy, cataplexy or excessive daytime sleepiness, comprising a unit dose of gamma-hydroxybutyrate, suitable for once daily administration, wherein in C max During the time period, most adverse events (AEs) occurred during T max nearby.

[0444] 106. An oral pharmaceutical composition according to item 105, wherein most AEs occur 1.5-2 hours after administration.

[0445] 107. The oral pharmaceutical composition according to item 105 or 106, wherein administration of the oral pharmaceutical composition less than two hours after a meal results in fewer AEs than administration of the oral pharmaceutical composition at least two hours after a meal.

[0446] 108. An oral pharmaceutical composition according to any one of items 105 to 107, wherein the oral pharmaceutical composition is administered in equal doses at t0 and t 4h The safety profile of sodium oxybate was more favorable than that of an immediate-release liquid solution of sodium oxybate administered at an equivalent dose.

[0447] 109. An oral pharmaceutical composition according to any one of items 105 to 108, wherein the oral pharmaceutical composition is administered once daily with equal divided doses at t0 and t 4h Administration of an equivalent dose of sodium oxybate immediate-release liquid solution resulted in fewer AEs.

[0448] 110. A method of treating narcolepsy and related disorders and symptoms in a patient in need thereof, comprising:

[0449] A pharmaceutical composition comprising gamma-hydroxybutyrate is administered once daily, wherein the majority of AEs are in the C max The time period occurs during T max nearby.

[0450] 111. The method according to claim 110, wherein most AEs occur 1.5-2 hours after administration.

[0451] 112. The method according to item 110 or 111, wherein administration of the oral pharmaceutical composition less than two hours after a meal results in fewer AEs than administration of the oral pharmaceutical composition at least two hours after a meal.

[0452] 113. The method according to any one of items 110 to 112, wherein the oral pharmaceutical composition is administered in equal doses at t0 and t 4h The safety profile of sodium oxybate was more favorable than that of an immediate-release liquid solution of sodium oxybate administered at an equivalent dose.

[0453] 114. The method according to any one of items 110 to 113, wherein the oral pharmaceutical composition is administered once daily with equal divided doses at t0 and t 4h Administration of an equivalent dose of sodium oxybate immediate-release liquid solution resulted in fewer AEs.

[0454] 115. A method according to any one of items 110 to 114, wherein the amount of AE is reduced over a period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours and / or 48 hours after administration of the oral pharmaceutical composition compared to an equal dose of an immediate-release sodium oxybate formulation administered more frequently than once daily.

[0455] 116. A method of reducing the amount of adverse events (AEs) in a patient suffering from narcolepsy, cataplexy, or excessive daytime sleepiness, comprising:

[0456] An oral pharmaceutical composition comprising gamma-hydroxybutyrate is administered once daily, wherein the gamma-hydroxybutyrate composition has a lower C than an equal dose of an immediate-release sodium oxybate formulation administered more frequently than once daily. max Time period.

[0457] 117. The method of claim 116, wherein administration of the gamma-hydroxybutyrate composition results in fewer adverse events and less C in an 8 hour, 12 hour, 16 hour, 20 hour, 24 hour, and / or 48 hour period compared to an immediate-release sodium oxybate formulation administered more frequently than once daily. max Time period.

[0458] 118. The method of claim 116 or 117, wherein the gamma-hydroxybutyrate composition has a superior safety profile compared to an immediate-release sodium oxybate formulation administered more frequently than once daily.

Claims

1. An oral pharmaceutical composition for treating narcolepsy, cataplexy or excessive daytime sleepiness, comprising a unit dose of gamma-hydroxybutyrate, suitable for administration less than two hours after a meal.

2. An oral pharmaceutical composition according to claim 1, wherein the composition is suitable for administration with food, immediately after eating, up to 30 minutes after eating, up to 1 hour after eating, up to 1.5 hours after eating, or up to 2 hours after eating.

3. The oral pharmaceutical composition according to claim 1 or 2, wherein the composition is administered once daily.

4. An oral pharmaceutical composition according to any one of the preceding claims, wherein the composition is suitable for evening administration.

5. The oral pharmaceutical composition according to any one of claims 1 to 3, wherein the composition is suitable for morning administration.

6. An oral pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises gamma-hydroxybutyrate in an extended release or delayed release dosage form.

7. An oral pharmaceutical composition according to any one of claims 1 to 5, wherein the composition comprises gamma-hydroxybutyrate in a modified release formulation.

8. An oral pharmaceutical composition according to any one of the preceding claims, wherein the composition provides a substantially similar fed state PK profile and a 2-hour postprandial administration PK profile.

9. An oral pharmaceutical composition according to any one of the preceding claims, wherein the composition provides a mean AUC of 0.040 when administered less than two hours after a meal. inf is the mean AUC when the composition is administered at least two hours after a meal inf 50%-120% of.

10. An oral pharmaceutical composition according to any one of the preceding claims, wherein the composition provides a mean AUC of inf is the mean AUC of the composition when administered on an empty stomach inf 50%-120% of.

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