Controlled release compositions of gamma-hydroxybutyric acid derivatives

Abstract

To provide a pharmaceutical granulate having a functional coating surrounding a core containing 4 - ((L-valyl) oxy) butanoic acid.SOLUTION: A pharmaceutical composition comprising: (a) an immediate-release component, wherein the immediate-release component comprises a plurality of immediate-release granules, wherein the immediate-release granules comprise more than 80% by weight of 4 - ((L-valyl) oxy) butanoic acid, wherein the% by weight is based on the total weight of the immediate-release granules; and (b) a modified-releasecomponent, wherein the modified-releasecomponent comprises a plurality of modified-release granules, wherein the modified-release granules comprise a core and a modified-release coating covering the core, the core comprises greater than 80 wt% of 4 - ((L-valyl) oxy) butanoic acid, wherein the wt% is based on the total weight of the core.SELECTED DRAWING: Figure 20

Description

[Technical Field]

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 087,515, filed October 5, 2020, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to pharmaceutical granulations of 4-((L-valyl)oxy)butanoic acid having a functional coating. The coated pharmaceutical granulations can be used in modified-release (synonymous with "modified release") oral compositions. [Background technology]

[0003] In certain treatment methods, it is necessary to administer a high dose of a pharmaceutically active ingredient. In order to minimize the amount of oral pharmaceutical composition administered to a patient in such treatment, it is desirable that the pharmaceutical composition contains a high content of a pharmaceutically active ingredient and minimizes the amount of pharmaceutical excipients.

[0004] Oral modified release dosage forms can contain granules coated with a functional coating that provides a desired release profile in the gastrointestinal tract.

[0005] A modified-release composition containing a pharmaceutical granule that has a high bulk density of an active pharmaceutical ingredient and is suitable for once- or twice-daily administration is desired. To improve palatability, the pharmaceutical granule desirably has a low average particle size, such as 200 μm to 400 μm. Summary of the Invention

[0006] According to the present invention, a modified-release pharmaceutical granule comprises a plurality of coated granules, the granules comprising a core and a modified-release coating surrounding the core, the modified-release coating comprising 50% to 85% by weight of a matrix polymer and 10% to 20% by weight of an antistatic agent, the weight percentages being based on the total weight of the modified-release coating. The pharmaceutical granules are characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, the PSD being determined by sieve analysis, and the cores comprising greater than 90% by weight of 4-((L-valyl)oxy)butanoic acid, the weight percentages being based on the total weight of the cores.

[0007] According to the present invention, the pharmaceutical composition comprises a pharmaceutical granulate according to the present invention.

[0008] According to the present invention, a method for coating a granule comprises applying a coating composition to a pharmaceutical granule comprising a plurality of granules comprising 4-((L-valyl)oxy)butanoic acid, the coating composition comprising 6% to 14% by weight of solids, 0% to 20% by weight of water, and 70% to 95% by weight of ethanol, the weight percentages being based on the total weight of the coating formulation.

[0009] According to the present invention, the pharmaceutical composition comprises an immediate release (IR) (synonymous with "immediate release") component (synonymous with "constituent"), the immediate release component comprising 1.2 g equivalents to 4.0 g equivalents of gamma-hydroxybutyrate, a modified release (MR) component, the modified release component comprising 3 g equivalents to 9 g equivalents of gamma-hydroxybutyrate, and the modified release granule according to the present invention.

[0010] According to the present invention, a method for treating fatigue or excessive daytime sleepiness associated with narcolepsy in a patient comprises orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention.

[0011] According to the present invention, a method of treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient comprises orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention.

[0012] According to the present invention, the kit comprises a pharmaceutical composition according to the present invention. [Brief explanation of the drawings]

[0013] Those skilled in the art will understand that the drawings described herein are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0014] [Figure 1] 1 shows the particle size distribution of granules containing a hydroxypropyl methylcellulose seal coating as described in Example 1. [Figures 2A-2E] 1 shows scanning electron microscope (SEM) images of seal-coated granules at different magnifications as described in Example 1. [Figure 3] 1 shows the particle size distribution of granules containing a hydroxypropyl cellulose seal coating as described in Example 2. [Figures 4A-4E] 1 shows SEM images of seal-coated granules at different magnifications as described in Example 2. [Figure 5] 1 shows the particle size distribution of coated granules containing 40% wg ethyl cellulose / hydroxypropyl cellulose functional coating as described in Example 3. [Figure 6] 1 shows the dissolution profile of 4-((L-valyl)oxy)butanoic acid from granules containing ethyl cellulose / hydroxypropyl cellulose functional coatings representing different % wg as described in Example 3. [Figures 7A-7D] 1 shows SEM images of 40% wg coated granules at three different magnifications as described in Example 3. [Figure 7E] 1 shows an SEM image of a cross section of a 40% wg coated granule as described in Example 3. [Figure 8] 1 shows the particle size distribution of coated granules containing 40% wg ethyl cellulose / hydroxypropyl cellulose functional coating as described in Example 4. [Figure 9] 1 shows the dissolution profile of 4-((L-valyl)oxy)butanoic acid from granules containing ethyl cellulose / hydroxypropyl cellulose functional coatings representing different % wg as described in Example 4. [Figures 10A-10D] 1 shows SEM images of 40% wg coated granules at different magnifications as described in Example 4. [Figure 10E] 1 shows an SEM image of a cross section of a 40% wg coated granule as described in Example 4. [Figure 11] 1 shows the particle size distribution of coated granules containing 40% wg ethyl cellulose / hydroxypropyl cellulose functional coating as described in Example 5. [Figure 12] 1 shows the dissolution profile of 4-((L-valyl)oxy)butanoic acid from granules containing ethyl cellulose / hydroxypropyl cellulose functional coatings representing different % wg as described in Example 5. [Figures 13A-13D] 1 shows SEM images of 40% wg coated granules at different magnifications as described in Example 5. [Figure 13E] 1 shows an SEM image of a cross section of a 40% wg coated granule as described in Example 5. [Figure 14] 1 shows the particle size distribution of coated granules containing 40% wg ethyl cellulose functional coating as described in Example 6. [Figure 15]1 shows the dissolution profile of the active pharmaceutical ingredient from granules containing ethylcellulose functional coatings representing different % wg as described in Example 6. [Figures 16A-16D] 1 shows SEM images of 40% wg coated granules at different magnifications as described in Example 6. [Figure 16E] 1 shows an SEM image of a cross section of a 40% wg coated granule as described in Example 8. [Figure 17] 1 shows the mean plasma concentrations of Compound (1) following oral administration of an immediate release (IR) or three modified release (MR1-MR3) compositions of Compound (1) to fasted healthy subjects. [Figure 18] 1 shows mean plasma gamma-hydroxybutyrate concentrations following oral administration of an immediate release (IR) or three modified release (MR1-MR3) compositions of Compound (1) to fasted healthy subjects. [Figure 19] 1 shows the mean plasma concentrations of Compound (1) following oral administration of two controlled-release formulations of Compound (1) to fasted healthy subjects. [Figure 20] 1 shows mean plasma gamma-hydroxybutyrate concentrations following oral administration of two controlled-release compositions of Compound (1) to fasted healthy subjects. DETAILED DESCRIPTION OF THE INVENTION

[0015] For purposes of the following detailed description, it should be understood that the embodiments provided by the present disclosure may assume various alternative variations and step sequences, unless expressly indicated to the contrary. Furthermore, other than as examples of any operations, or where otherwise indicated, all numbers expressing quantities of ingredients used in the specification and claims, for example, should be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques.

[0016] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0017] It should also be understood that any numerical range recited herein is intended to include all subranges subsumed therein. For example, a range of "1 to 10" is intended to include all subranges between (and including) the recited minimum of 1 and the recited maximum of 10, i.e., minimums of 1 or greater and maximums of 10 or less.

[0018] "Functional coatings" include immediate-release coatings, controlled-release coatings, modified-release coatings, sustained-release coatings, pH-release coatings, pulsatile-release coatings, timed-release coatings, and delayed-release coatings. Functional coatings are configured to provide desired properties to granules containing 4-((L-valyl)oxy)butanoic acid, such as a desired release profile in the gastrointestinal tract after oral administration.

[0019] "Fast-release" refers to a pharmaceutical composition that releases substantially all of the pharmaceutically active ingredient into a patient's gastrointestinal tract within less than one hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. For example, a fast-release dosage form can release more than 90%, more than 95%, or more than 98% of the pharmaceutically active ingredient in the pharmaceutical composition into the gastrointestinal tract within less than one hour, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. Fast-release pharmaceutical compositions may be suitable for administering pharmaceutically active ingredients that are absorbed into the systemic circulation from the upper gastrointestinal tract.

[0020] "Modified-release" pharmaceutical compositions include controlled-release formulations, delayed-release compositions, sustained-release compositions, extended-release compositions, timed-release compositions, pulsatile-release compositions, and pH-dependent release compositions. These compositions are intended to release an active pharmaceutical ingredient from the pharmaceutical composition at a desired rate and / or at a desired time and / or at a specific location or locations in the gastrointestinal tract and / or at a specific pH in the gastrointestinal tract after oral administration by a patient. The USP defines a modified-release system as one in which the time course or location of drug release, or both, is selected to achieve a therapeutic efficacy or convenience objective not met by immediate-release dosage forms. Modified-release oral dosage forms may contain sustained-release and delayed-release components. Delayed-release dosage forms release the drug all at once rather than immediately after administration. Modified-release compositions may include delayed release using enteric coatings, site-specific or timed release, such as for colonic delivery, sustained release, including compositions capable of providing, for example, zero-order, first-order, or biphasic release profiles, and programmed release, such as pulsatile release and delayed-release.

[0021] "Sustained release" pharmaceutical compositions and coatings provide a dissolution rate over an extended period of time after oral administration. A granulation comprising granules with a sustained release coating may be referred to as a sustained release granulation. A pharmaceutical composition comprising a sustained release granulation may be referred to as a sustained release pharmaceutical composition.

[0022] "pH-release" pharmaceutical compositions and coatings provide an enhanced dissolution rate at a designated pH.

[0023] "Pulsatile release" pharmaceutical compositions and coatings exhibit an increase in dissolution rate at intervals where the release interval can be determined by time, exposure to an internal stimulus, or exposure to an external stimulus. Examples of pulsatile release systems include capsule systems, osmotic systems, systems with erodible membranes, and systems with rupturable coatings. Examples of stimuli include temperature, chemicals, electrical stimuli, and magnetic stimuli.

[0024] "Timed-release" pharmaceutical compositions and coatings have a dissolution rate that is a function of time. Time-release pharmaceutical compositions or coatings include, for example, delayed-release, sustained-release, and extended-release pharmaceutical compositions and coatings.

[0025] "Delayed release" pharmaceutical compositions and coatings provide an increased dissolution rate at a designated time after administration.

[0026] "Immediate release component" refers to a component of a pharmaceutical composition that includes immediate release microparticles provided by the present disclosure.

[0027] "Modified-release component" refers to a component of a pharmaceutical composition that includes modified-release microparticles provided by the present disclosure.

[0028] "Controlled release pharmaceutical composition" refers to a pharmaceutical composition comprising immediate release microparticles provided by the present disclosure and modified release microparticles provided by the present disclosure.

[0029] The terms "granules" and "microparticles" are used interchangeably.

[0030] "Patient" refers to a mammal, for example, a human.

[0031] "Pharmaceutically acceptable" refers to that which is listed, approved, or approvable by a regulatory agency of the Federal or State government, or in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0032] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include inorganic acids and acid addition salts formed with one or more protonatable functional groups, such as primary, secondary, or tertiary amines, in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts can also be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid. Salts may be formed with 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Salts may be formed when one or more acidic protons present in the parent compound are replaced by coordination with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a combination thereof, or an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts may be hydrochlorides. Pharmaceutically acceptable salts may be sodium salts. For compounds with two or more ionizable groups, a pharmaceutically acceptable salt can include one or more counterions, such as a disalt, e.g., a dihydrochloride salt.

[0033] The term "pharmaceutically acceptable salts" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. When a specific pharmaceutically acceptable salt is disclosed, it is understood that the specific salt (e.g., hydrochloride) is an example of a salt, and that other salts may be formed using techniques known to those skilled in the art. Additionally, using techniques generally known in the art, those skilled in the art will be able to convert a pharmaceutically acceptable salt to the corresponding compound, free base, and / or free acid.

[0034] "Percent weight gain" or % wg, such as a "35% wg" coating, refers to a coated granule or granule in which the weight of the coated granule or granule is the indicated percent (%) greater than the weight of the uncoated granule or granule. For example, a 35% wg particle has a coating that increases the weight of the uncoated particle by 35%. For example, for a granule with an initial weight of 100 gm, adding a 35% wg coating increases the weight of the granule to 135 gm. The coating comprises 25.9 wt% of the total weight of the granule.

[0035] Dissolution profiles were measured using a USP Type 2 dissolution apparatus and sodium acetate buffer solution at pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm.

[0036] Values ​​that are "bioequivalent" are those that exhibit substantially similar pharmacokinetic profiles and / or therapeutic effects. max or AUC. Bioequivalence can be demonstrated by several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamic, clinical, and in vitro studies. Bioequivalence can be determined by a number of factors, including loading dose, steady-state dose, initial or steady-state concentration of the drug, biological half-life, elimination rate, area under the curve (AUC), clearance, peak blood or plasma concentration (C max ), time to peak concentration (T max), bioavailability, and efficacy. max A value may be bioequivalent to the reference pharmacokinetic value if the geometric mean of is between 80% and 125% (e.g., 90% confidence interval) of the reference pharmacokinetic value.

[0037] Similar or bioequivalent pharmacokinetic profiles are defined as the mean AUC 0-inf However, the mean AUC in a well-designed crossover study 0-inf and the 8-hour C of the pharmaceutical composition is 80% to 125% of the 8h The mean plasma concentration at 8 hours C of the reference composition 8h a pharmacokinetic profile that is 40% to 130% of the mean plasma concentration at 200 mg / dL, and / or a maximum plasma concentration (C max ) is the C of the reference composition max This refers to a pharmacokinetic profile that is 50% to 140% of the original dose.

[0038] "Fed state" refers to the period immediately following ingestion of a meal up to two hours after ingestion. The fed state can include periods less than two hours after eating.

[0039] "Fasted state" refers to the period 8 hours after ingestion of a meal.

[0040] A "prodrug" refers to a derivative of a drug molecule that requires conversion within the body to provide the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs can typically be obtained by attaching a promoiety to the parent drug via a functional group.

[0041] "Curing" a disease refers to eliminating the disease or disorder or eliminating the symptoms of the disease or disorder.

[0042] "Treating" or "treatment" of a disease or disorder refers to reducing the severity of one or more clinical symptoms of the disease or disorder, delaying the onset of one or more clinical symptoms of the disease or disorder, and / or reducing one or more clinical symptoms of the disease or disorder.

[0043] "Treating" or "treatment" of a disease or disorder refers to inhibiting a disease or disorder or one or more clinical symptoms of a disease or disorder, preventing the onset of a disease or disorder or one or more clinical symptoms of a disease or disorder, alleviating a disease or disorder or one or more clinical symptoms of a disease or disorder, causing regression of a disease or disorder or one or more clinical symptoms of a disease or disorder, and / or stabilizing a disease or disorder or one or more clinical symptoms of a disease or disorder; "treating" or "treatment" of a disease or disorder refers to producing a clinically beneficial effect without curing the underlying disease or disorder.

[0044] A "therapeutically effective amount" refers to the amount of a compound, such as an active pharmaceutical ingredient, that, when administered to a patient for treating a disease, or at least one of the clinical symptoms of the disease, is sufficient to affect such treatment of the disease or its symptoms. A "therapeutically effective amount" can vary depending, for example, on the compound, the disease and / or symptoms of the disease, the severity of the disease, and / or symptoms of the disease or disorder, the age, weight, and / or health of the patient being treated, and the judgment of the prescribing physician. The therapeutically effective amount in any given case can be ascertained by one of ordinary skill in the art or can be determined by routine experimentation.

[0045] A "therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. A therapeutically effective dose may vary from compound to compound and from patient to patient, and may depend on factors such as the condition of the patient and the route of delivery. A therapeutically effective dose may be determined according to routine pharmacological procedures known to those skilled in the art.

[0046] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a patient. The vehicle can be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0047] Reference is now made to pharmaceutical granules having functional coatings, methods of making the coated pharmaceutical granules, and pharmaceutical compositions comprising the coated pharmaceutical granules. The disclosed coated pharmaceutical granules, compositions comprising the coated pharmaceutical granules, and methods of making the coated pharmaceutical granules are not intended to limit the scope of the claims. On the contrary, the claims are intended to cover all alternatives, modifications, and equivalents.

[0048] 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyric acid. When administered orally, 4-((L-valyl)oxy)butanoic acid is absorbed from the gastrointestinal tract and metabolized into the systemic circulation to release gamma-hydroxybutyric acid. Gamma-hydroxybutyric acid can be used to treat diseases and disorders such as narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0049] The coated pharmaceutical granules provided by the present disclosure can be used to provide a modified release form of 4-((L-valyl)oxy)butanoic acid after oral administration to a patient. The coated pharmaceutical granules contain 4-((L-valyl)oxy)butanoic acid, a hygroscopic, highly water-soluble active pharmaceutical ingredient that is susceptible to hydrolysis. The coated pharmaceutical granules can be used to provide a modified release oral pharmaceutical composition. The coated pharmaceutical granules can be used to orally administer high doses of 4-((L-valyl)oxy)butanoic acid.

[0050] The controlled-release granulations provided by the present disclosure can be prepared by coating granules containing 4-((L-valyl)oxy)butanoic acid. The granules containing 4-((L-valyl)oxy)butanoic acid can be uncoated or can include a seal coating.

[0051] The uncoated pharmaceutical granulation provided by the present disclosure may include a plurality of granules, and the granules may comprise greater than 90 wt. % 4-((L-valyl)oxy)butanoic acid, where the wt. % is based on the total weight of the granules, and the uncoated pharmaceutical granulation may be characterized by a particle size distribution (PSD) (D50) of 150 μm to 400 μm, 150 μm to 350 μm, 150 μm to 300 μm, 200 μm to 400 μm, 200 μm to 300 μm, 250 μm to 350 μm, or 225 μm to 275 μm, where the PSD is determined by sieve analysis, and the wt. % is based on the total weight of the pharmaceutical granulation.

[0052] The uncoated granules may contain a high load of 4-((L-valyl)oxy)butanoic acid. For example, the granules may contain more than 90 wt%, more than 93 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, or more than 99 wt%, 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules. The uncoated granules may contain, for example, 90 wt% to 99.5 wt%, 95 wt% to 99.5 wt% of a gamma-hydroxybutyric acid derivative, 96 wt% to 99 wt%, 97 wt% to 99 wt%, or 98 wt% to 99 wt% of 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules.

[0053] 4-((L-valyl)oxy)butanoic acid has the structure of formula (1). [ka]

[0054] 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyric acid (GHB) having the structure of formula (2). [ka]

[0055] After administration, such as oral administration, 4-((L-valyl)oxy)butanoic acid is metabolized in the systemic circulation to release gamma-hydroxybutyric acid in the patient's plasma. 4-((L-valyl)oxy)butanoic acid provides oral bioavailability of gamma-hydroxybutyric acid in patients greater than 60%F.

[0056] Pharmaceutical compositions provided by the present disclosure include pharmaceutical granulations comprising granules of 4-((L-valyl)oxy)butanoic acid coated with a functional coating.

[0057] Prior to being formed into granules, the 4-((L-valyl)oxy)butanoic acid may have a low bulk density.

[0058] 4-((L-valyl)oxy)butanoic acid can have a bulk density of, for example, less than 0.20 g / mL, less than 0.30 g / mL, less than 0.40 g / mL, or less than 0.50 g / mL.

[0059] 4-((L-valyl)oxy)butanoic acid can have a bulk density of, for example, 0.15 g / mL to 0.33 g / mL, 0.16 g / mL to 0.32 g / mL, 0.17 g / mL to 0.31 g / mL, 0.18 g / mL to 0.30 g / mL, 0.19 g / mL to 0.29 g / mL, or 0.20 g / mL to 0.28 g / mL.

[0060] The 4-((L-valyl)oxy)butanoic acid can have a particle size distribution characterized, for example, by a D10 of 1 μm to 3 μm, a D50 of 6.5 μm to 8.5 μm, and a D90 of 15 μm to 17 μm, where the particle size distribution is measured by laser diffraction.

[0061] The 4-((L-valyl)oxy)butanoic acid can have a particle size distribution characterized by a D50 of, for example, 5 μm to 15 μm, 6 μm to 14 μm, 7 μm to 13 μm, 8 μm to 12 μm, or 9 μm to 11 μm, where the particle size distribution is measured by laser diffraction.

[0062] 4-((L-valyl)oxy)butanoic acid can be jet milled to reduce particle size.

[0063] Uncoated granules containing 4-((L-valyl)oxy)butanoic acid can be prepared using MicroPX® micropelletization technology (Glatt GmbH).

[0064] For high dose pharmaceutical compositions of 4-((L-valyl)oxy)butanoic acid, it may be useful for the uncoated and coated granules to have a small average diameter to improve palatability, especially when reconstituted as a suspension before administration.

[0065] The uncoated pharmaceutical granulation of 4-((L-valyl)oxy)butanoic acid can be characterized by a PSD (D50) of, for example, 75 μm to 450 μm, 100 μm to 400 μm, 150 μm to 350 μm, 200 μm to 350 μm, 200 μm to 300 μm, 250 μm to 350 μm, or 225 μm to 275 μm.

[0066] The uncoated granules may contain a high load of 4-((L-valyl)oxy)butanoic acid. For example, the uncoated granules may contain more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, or more than 99 wt%, 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules. The uncoated granules may contain, for example, 95 wt% to 99.5 wt% 4-((L-valyl)oxy)butanoic acid, 96 wt% to 99 wt%, 97 wt% to 99 wt%, or 98 wt% to 99 wt% 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the uncoated granules.

[0067] The uncoated granules or granules provided by the present disclosure can contain, for example, more than 85% by weight of 4-((L-valyl)oxy)butanoic acid, 1% to 10% by weight of an antistatic agent such as magnesium silicate (talc), and 1% to 10% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, where the weight percentages are based on the total weight of the granules or granules. The uncoated granules or granules provided by the present disclosure can contain, for example, more than 90% by weight of 4-((L-valyl)oxy)butanoic acid, 2% to 8% by weight of an antistatic agent such as magnesium silicate (talc), and 2% to 8% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, where the weight percentages are based on the total weight of the granules or granules. The uncoated granules or granulations provided by the present disclosure can contain, for example, greater than 90% by weight of 4-((L-valyl)oxy)butanoic acid, 3% to 7% by weight of an antistatic agent such as magnesium silicate (talc), and 3% to 7% by weight of a water-soluble polymer such as hydroxypropylmethylcellulose, the weight percentages being based on the total weight of the granules or granulations.

[0068] The uncoated granules provided by the present disclosure can be characterized by a sphericity of 0.90 to 1, such as 0.91 to 0.99, or 0.92 to 0.98, where the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated granules provided by the present disclosure can be characterized by a sphericity of, for example, greater than 0.90, greater than 0.91, greater than 0.92, greater than 0.93, greater than 0.94, or greater than 0.95.

[0069] The uncoated granules provided by the present disclosure can include a plurality of granules characterized by a mode sphericity of 0.90 to 1, such as 0.91 to 0.99, or 0.92 to 0.98, where the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated granules provided by the present disclosure can include a plurality of granules characterized by an average sphericity of, for example, greater than 0.94, greater than 0.95, greater than 0.96, greater than 0.97, greater than 0.98, or greater than 0.99.

[0070] The uncoated granules provided by the present disclosure are solid and characterized by a substantially homogeneous composition throughout the granule.

[0071] The pharmaceutical granules provided by the present disclosure can include a seal coating. The pharmaceutical granules including the seal coating can be used as immediate-release pharmaceutical granules.

[0072] The pharmaceutical granulation provided by the present disclosure can include a seal coating that covers the granules that include 4-((L-valyl)oxy)butanoic acid.

[0073] The seal coating can include any water soluble polymer, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, or any water soluble polymer disclosed herein.

[0074] The seal coating may include an antistatic agent such as talc, magnesium stearate, or a combination thereof.

[0075] The seal coating can include, for example, 65% to 95% by weight of the water soluble polymer, e.g., 70% to 90% by weight, or 75% to 85% by weight of the water soluble polymer, and 5% to 35% by weight of the antistatic agent, e.g., 10% to 30% by weight, or 15% to 25% by weight of the antistatic agent, the weight percentages being based on the total weight of the seal coating.

[0076] The seal coating can have a thickness of, for example, 0.5 μm to 4 μm, 1 μm to 3.5 μm, 1 μm to 3 μm, or 1 μm to 2.5 μm.

[0077] Examples of methods for coating granules containing 4-((L-valyl)oxy)butanoic acid in a seal coat are provided in Examples 1 and 2.

[0078] Figures 1 and 3 show the particle size distribution of the seal-coated granulation.

[0079] Figures 2A-2D show, at various magnifications, 4-((L-valyl)oxy)butanoic acid-containing granules with a 1.3 μm (+ / - 0.27 μm) thick seal coating of hydroxypropyl methylcellulose and talc. Figure 2E shows a cross-section of a 4-((L-valyl)oxy)butanoic acid-containing granule with a seal coating of hydroxypropyl methylcellulose and talc.

[0080] Figures 4A-4D show, at various magnifications, 4-((L-valyl)oxy)butanoic acid-containing granules with a 2.23 μm (+ / - 0.34 μm) thick seal coating of hydroxypropyl cellulose and talc. Figure 4E shows a cross-section of a 4-((L-valyl)oxy)butanoic acid granule with a seal coating of hydroxypropyl cellulose and talc.

[0081] The coated pharmaceutical granules provided by the present disclosure can include a plurality of granules coated with a functional coating. The functional coating can include, for example, a modified release coating, such as a controlled-release coating, a sustained-release coating, a pH-release coating, a pulsatile-release coating, a timed-release coating, or a delayed-release coating. The functional coating can be configured, for example, to release 4-((L-valyl)oxy)butanoic acid from the coated granules over a intended period of time after ingestion and / or within an intended region of the gastrointestinal tract.

[0082] The coated pharmaceutical granules provided by the present disclosure can include one or more functional coatings.

[0083] Each of the one or more functional coatings can independently have an average thickness of, for example, less than 50 μm, less than 40 μm, less than 30 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. Each of the one or more functional coatings can independently have an average thickness of, for example, 5 μm to 50 μm, 5 μm to 40 μm, 5 μm to 30 μm, 5 μm to 20 μm, 5 μm to 15 μm, or 5 μm to 10 μm.

[0084] The coated granules or coated granules can contain, for example, more than 50 wt. % 4-((L-valyl)oxy)butanoic acid, more than 55 wt. %, more than 60 wt. %, more than 70 wt. %, more than 80 wt. %, or more than 85 wt. % 4-((L-valyl)oxy)butanoic acid, where the weight percent is based on the total weight of the coated granules or coated granules.

[0085] The coated granule or coated granules comprising a plurality of coated granules can comprise, for example, 50% to 85% by weight of 4-((L-valyl)oxy)butanoic acid, 55% to 80% by weight, 60% to 80% by weight, 65% to 80% by weight, or 70% to 75% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the coated granule or coated granule.

[0086] The coated granules or coated granules can contain, for example, less than 50 wt. % of the functional coating, less than 40 wt. % of the functional coating, less than 30 wt. % of the functional coating, less than 20 wt. % of the functional coating, or less than 10 wt. % of the functional coating, where the weight % is based on the total weight of the coated granules or coated granules. The coated granules or coated granules can contain, for example, 10 wt. % to 50 wt. % of the functional coating, 10 wt. % to 45 wt. % of the functional coating, 15 wt. % to 40 wt. % of the functional coating, or 15 wt. % to 35 wt. % of the functional coating, where the weight % is based on the total weight of the coated granules. The coated granules containing 4-((L-valyl)oxy)butanoic acid can have a thick coating to reduce the release rate of 4-((L-valyl)oxy)butanoic acid and / or increase the storage stability of 4-((L-valyl)oxy)butanoic acid by minimizing or preventing moisture intrusion.

[0087] The coated granules or coated granules can contain, for example, more than 50 wt. % 4-((L-valyl)oxy)butanoic acid, more than 55 wt. %, more than 60 wt. %, more than 70 wt. %, more than 80 wt. %, or more than 85 wt. % 4-((L-valyl)oxy)butanoic acid, where the weight percent is based on the total weight of the coated granules or coated granules.

[0088] The coated granule or coated granules comprising a plurality of coated granules can comprise, for example, 50% to 90% by weight of 4-((L-valyl)oxy)butanoic acid, 55% to 85% by weight, 60% to 85% by weight, 65% to 85% by weight, or 70% to 80% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentages are based on the total weight of the coated granule or coated granule.

[0089] The functional coating can include a matrix polymer or a combination of matrix polymers. The matrix polymer and / or pore-forming polymer combination can be selected to provide a desired release profile of 4-((L-valyl)oxy)butanoic acid in the gastrointestinal tract.

[0090] The functional coating can include, for example, 55% to 95% by weight of matrix polymer, 60% to 90% by weight, 65% to 90% by weight, 70% to 85% by weight, or 75% to 85% by weight of matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0091] The functional coating can include a matrix polymer or a combination of matrix polymers that can be selected to provide a desired release profile of 4-((L-valyl)oxy)butanoic acid in the gastrointestinal tract.

[0092] The functional coating can include, for example, 55% to 95% by weight of matrix polymer, 60% to 90% by weight, 65% to 90% by weight, 70% to 85% by weight, or 75% to 85% by weight of matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0093] The functional coating can include, for example, less than 95 wt. % matrix polymer, less than 90 wt. %, less than 85 wt. %, less than 80 wt. %, less than 75 wt. %, less than 70 wt. %, or less than 60 wt. % matrix polymer, where the wt. % is based on the total weight of the functional coating.

[0094] The functional coating can include, for example, greater than 50% matrix polymer, greater than 55% by weight, greater than 60% by weight, greater than 65% by weight, greater than 70% by weight, greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, or greater than 90% by weight matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0095] The matrix polymer can include a water insoluble polymer or a combination of water insoluble polymers.

[0096] Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl acetate, polyacrylates, and polymethacrylates.

[0097] The water-insoluble polymer, such as ethyl cellulose, can have an average molecular weight of, for example, 25,000 daltons to 300,000 daltons, such as 50,000 daltons to 200,000 daltons, 50,000 daltons to 150,000 daltons, or 50,000 daltons to 100,000 daltons.

[0098] A water-insoluble polymer such as ethyl cellulose can have a viscosity of less than 100 mPa×sec, less than 75 mPa×sec, less than 50 mPa×sec, less than 25 mPa×sec, less than 20 mPa×sec, or less than 15 mPa×sec, as determined using a Brookfield viscometer in, for example, an 80:20 mixture of toluene / ethanol.

[0099] Examples of suitable ethylcellulose polymers include Aqualon® T10 Pharm, N7 Pharm, N10 Pharm, N14 Pharm, N22 Pharm, N50 Pharm, and N100 Pharm polymers available from Ashland. Other examples of suitable ethylcellulose polymers include Ethocel® Standard 7, Standard 10, Standard 14, and Standard 20 polymers available from DuPont.

[0100] The matrix polymer can comprise, for example, 90% to 100% by weight of the water-insoluble polymer, 91% to 99% by weight, 82% to 98% by weight, or 93% to 97% by weight, where the weight percentages are based on the total weight of the matrix polymer. The matrix polymer can comprise, for example, more than 90% by weight of the water-insoluble polymer, more than 92% by weight, more than 94% by weight, more than 96% by weight, or more than 98% by weight, where the weight percentages are based on the total weight of the matrix polymer. The matrix polymer can comprise, for example, less than 100% by weight of the water-insoluble polymer, less than 98% by weight, less than 96% by weight, less than 94% by weight, or less than 92% by weight, where the weight percentages are based on the total weight of the matrix polymer.

[0101] The matrix polymer can include a pore-forming polymer. Examples of pore-forming polymers include water-soluble polymers, swelling or expanding polymers such as carbomers, and polymers soluble in gastric juice, such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methacrylic acid-methyl methacrylate copolymer, and polyvinyl acetate phthalate. The pore-forming polymer can increase the permeability of the functional coating under intended conditions.

[0102] The matrix polymer can include a water-soluble polymer or a combination of water-soluble polymers.

[0103] Examples of suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, copovidone, and poloxamer.

[0104] Water-soluble polymers such as hydroxypropyl cellulose can have an average molecular weight of, for example, less than 1,000,000 daltons, less than 800,000 daltons, less than 600,000 daltons, less than 400,000 daltons, less than 200,000 daltons, less than 100,000 daltons, or less than 50,0000 daltons.

[0105] Water-soluble polymers such as hydroxypropyl cellulose can have a viscosity of less than 7,000 mPa×sec, less than 5,000 mPa×sec, less than 3,000 mPa×sec, or less than 1,000 mPa×sec, as determined, for example, using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0106] Examples of suitable hydroxypropyl cellulose polymers include Klucel® HF Pharm, MF Pharm, GF Pharm JF Pharm, LF Pharm, EF Pharm, and ELF Pharm polymers available from Ashland.

[0107] Examples of suitable hydroxypropyl methylcellulose polymers include Pharmacoat® 603, 645, 606, and 615 polymers available from Shin-Etsu Chemical Co.

[0108] The matrix polymer can include, for example, 0 to 15 wt. % of the water-soluble polymer, 0 to 10 wt. % of the water-soluble polymer, 1 to 8 wt. % of the water-soluble polymer, or 2 to 6 wt. % of the water-soluble polymer, where the weight % is based on the total weight of the matrix polymer. The matrix polymer can include, for example, more than 0 wt. % of the water-soluble polymer, more than 2 wt. % of the water-soluble polymer, more than 4 wt. % of the water-soluble polymer, more than 6 wt. % of the water-soluble polymer, or more than 8 wt. % of the water-soluble polymer, where the weight % is based on the total weight of the matrix polymer. The matrix polymer can include, for example, less than 10 wt. % of the water-soluble polymer, less than 8 wt. % of the water-soluble polymer, less than 6 wt. % of the water-soluble polymer, or less than 2 wt. % of the water-soluble polymer, where the weight % is based on the total weight of the matrix polymer.

[0109] The matrix polymer can comprise, for example, 90% to 100% by weight of a water-insoluble polymer and 0% to 10% by weight of a water-soluble polymer, 92% to 98% by weight of a water-insoluble polymer and 2% to 8% by weight of a water-soluble polymer, or 94% to 96% by weight of a water-insoluble polymer and 4% to 6% by weight of a water-soluble polymer, the weight percentages being based on the total weight of the matrix polymer.

[0110] The functional coating can be applied to the granules provided by the present disclosure by any suitable method, such as spraying a solution, suspension, or dispersion of the functional coating onto the granules in a fluidized bed apparatus.

[0111] In addition to the matrix polymer or combination of matrix polymers, the functional coating can include, for example, a plasticizer, an antistatic agent, an antiblocking agent, a colorant or pigment, a flow promoter, a viscosity modifier, or a combination of any of the foregoing.

[0112] The functional coating may include an antistatic agent or a combination of antistatic agents.

[0113] Antistatic agents are useful to minimize or prevent granule agglomeration during application of the functional coating.

[0114] Examples of suitable antistatic agents include talc, magnesium stearate, and silicon dioxide.

[0115] The functional coating can include, for example, 5 wt % to 25 wt % of the antistatic agent, e.g., 8 wt % to 22 wt %, or 10 wt % to 20 wt %, where the weight percentage is based on the total weight of the functional coating. The functional coating can include, for example, less than 25 wt %, less than 23 wt %, less than 18 wt %, or less than 15 wt % of the antistatic agent, where the weight percentage is based on the total weight of the functional coating. The functional coating can include, for example, more than 5 wt %, more than 8 wt %, more than 12 wt %, more than 16 wt %, or more than 20 wt % of the antistatic agent, where the weight percentage is based on the total weight of the functional coating.

[0116] The functional coatings provided by the present disclosure are free of plasticizers such as dibutyl sebacate, polyethylene glycol, triacetin, and triethyl citrate.

[0117] The functional coating provided by the present disclosure can include, for example, 70% to 95% by weight of a matrix polymer and 5% to 30% by weight of an antistatic agent, where the weight percentages are based on the total weight of the functional coating.

[0118] The functional coating provided by the present disclosure can include, for example, 75% to 90% by weight of a matrix polymer and 10% to 25% by weight of an antistatic agent, the weight percentages being based on the total weight of the functional coating.

[0119] The functional coating provided by the present disclosure can include, for example, 80% to 90% by weight of a matrix polymer and 10% to 12% by weight of an antistatic agent, where the weight percentages are based on the total weight of the functional coating.

[0120] In the functional coatings provided by the present disclosure, the matrix polymer can include hydroxypropyl cellulose and hydroxypropyl methylcellulose, and the antistatic agent can include magnesium stearate, talc, or a combination thereof.

[0121] A functional coating, such as a modified-release coating of the present disclosure, can include, for example, 72% to 92% by weight of a water-insoluble polymer, such as ethyl cellulose, 0.5% to 4% by weight of a water-soluble polymer, such as hydroxypropyl methyl cellulose, and 11% to 22% by weight of an antistatic agent, such as magnesium stearate, where the weight percentages are based on the total weight of the functional coating. A functional coating, such as a modified-release coating of the present disclosure, can include, for example, 74% to 90% by weight of a water-insoluble polymer, such as ethyl cellulose, 1% to 3.5% by weight of a water-soluble polymer, such as hydroxypropyl methyl cellulose, and 13% to 20% by weight of an antistatic agent, such as magnesium stearate, where the weight percentages are based on the total weight of the functional coating. A functional coating, such as a modified release coating of the present disclosure, can include, for example, 76% to 88% by weight of a water-insoluble polymer, such as ethyl cellulose, 1% to 3.0% by weight of a water-soluble polymer, such as hydroxypropyl methylcellulose, and 14% to 18% by weight of an antistatic agent, such as magnesium stearate, where the weight percentages are based on the total weight of the functional coating.

[0122] The modified-release granules or granules provided by the present disclosure may include, for example, a core and a modified-release coating surrounding the core. The core may include, for example, 85% to 95% by weight of 4-((L-valyl)oxy)butanoic acid, 1% to 9% by weight, such as 3% to 7% by weight, of a water-soluble polymer such as hydroxypropylmethylcellulose, and 1% to 9% by weight, such as 3% to 7% by weight, of an antistatic agent such as magnesium stearate, where the weight percentages are based on the total weight of the core. The modified-release coating surrounding the core may include, for example, 77% to 87% by weight of a water-insoluble polymer such as ethylcellulose, 0.1% to 5% by weight of a water-soluble polymer such as hydroxypropylmethylcellulose, and 11% to 21% by weight, such as 14% to 18% by weight, of an antistatic agent such as magnesium stearate, where the weight percentages are based on the total weight of the modified-release coating.

[0123] The modified-release granulations provided by the present disclosure can be configured to provide a single nighttime dose, once-daily dosing (QD), twice-daily dosing (BID), three-times-daily dosing (TID), or four-times-daily dosing (QID). For example, the modified-release granulations can release substantially 100% of the 4-((L-valyl)oxy)butanoic acid over a 24-hour duration, a 12-hour duration, an 8-hour duration, or a 4-hour duration.

[0124] For example, the modified-release granules can exhibit dissolution profiles substantially as shown, for example, in Figures 6, 9, 12, and 16. For example, the modified-release granules can exhibit dissolution profiles that are bioequivalent to any of the dissolution profiles shown, for example, in Figures 6, 9, 12, and 16.

[0125] The modified-release granules may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm, in which, for example, less than 80% of the 4-((L-valyl)oxy)butanoic acid is released from the modified-release granules within 2 hours, less than 70% by weight, less than 60% by weight, less than 50% by weight, or less than 40% by weight of the 4-((L-valyl)oxy)butanoic acid is released from the modified-release granules within 2 hours, and more than 60% by weight, more than 70% by weight, or more than 80% by weight of the 4-((L-valyl)oxy)butanoic acid is released from the modified-release granules within 6 hours, wherein the weight percentages are based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granules.

[0126] The controlled-release granules may exhibit a dissolution profile, when determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm, in which 30 wt % to 80 wt %, such as 35 wt % to 75 wt %, or 40 wt % to 70 wt %, of 4-((L-valyl)oxy)butanoic acid is released from the controlled-release granules within 2 hours, where the wt % is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granules.

[0127] The controlled-release granules may exhibit a dissolution profile, when determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm, in which 50 wt % to 90 wt %, such as 65 wt % to 85 wt %, or 70 wt % to 80 wt %, of 4-((L-valyl)oxy)butanoic acid is released from the controlled-release granules within 4 hours, where the wt % is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granules.

[0128] The controlled-release granules may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm, in which 60 wt % to 100 wt %, such as 65 wt % to 95 wt %, or 70 wt % to 90 wt %, of 4-((L-valyl)oxy)butanoic acid is released from the controlled-release granules within 6 hours, where the wt % is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granules.

[0129] The modified-release granules may exhibit a dissolution profile, when determined using a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm, wherein 30% to 80% of the 4-((L-valyl)oxy)butanoic acid is released from the modified-release granules within 2 hours, 50% to 90% by weight of the 4-((L-valyl)oxy)butanoic acid is released from the modified-release granules within 4 hours, and 60% to 100% by weight of the 4-((L-valyl)oxy)butanoic acid is released from the composition within 6 hours, wherein the weight percentages are based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granules.

[0130] The controlled-release granules may exhibit a dissolution profile, when determined using a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm, in which 25 wt% to 70 wt% of the 4-((L-valyl)oxy)butanoic acid is released from the controlled-release granules within 2 hours, 50 wt% to 85 wt% of the 4-((L-valyl)oxy)butanoic acid is released from the controlled-release granules within 4 hours, and 60 wt% to 85 wt% of the 4-((L-valyl)oxy)butanoic acid is released from the controlled-release granules within 6 hours, wherein the weight percentages are based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granules.

[0131] The modified-release granulation can exhibit a dissolution profile that is bioequivalent to any of the dissolution profiles shown in FIGS.

[0132] The coated granules provided by the present disclosure can have a water content of, for example, less than 2 wt.%, less than 1.5 wt.%, less than 1 wt.%, less than 0.5 wt.%, or less than 0.25 wt.%, where the wt.% is based on the total weight of the coated granule.

[0133] The coated granules provided by the present disclosure can have a water content of, for example, 0.1 wt % to 2 wt %, 0.1 wt % to 1 wt %, or 0.2 wt % to 0.6 wt %, where the wt % is based on the total weight of the coated granule.

[0134] The coated pharmaceutical granulation can have a bulk density of, for example, greater than 0.55 g / mL, greater than 0.60 g / mL, greater than 0.65 g / mL, greater than 0.70 g / mL, or greater than 0.75 g / mL.

[0135] The coated pharmaceutical granules can have a bulk density of, for example, 0.55 g / mL to 0.80 g / mL, 0.60 g / mL to 75 g / mL, or 0.60 g / mL to 0.70 g / mL.

[0136] Bulk density can be determined using a bulk density cylinder.

[0137] The coated pharmaceutical granules provided by the present disclosure can be characterized by a PSD (D50) of 150 μm to 400 μm, for example, 150 μm to 350 μm, 175 μm to 325 μm, 200 μm to 300 μm, 250 μm to 350 μm, or 225 μm to 275 μm.

[0138] Examples of particle size distributions for coated granules provided by the present disclosure are shown in Figures 5, 8, 11, and 15.

[0139] The particle size distribution can be determined by laser diffraction or sieve analysis.

[0140] The functional coating provided by the present disclosure can be coated onto the granulation using any suitable equipment and process. Examples of suitable coating methods include the Wurster fluidized bed film coating process, the compression coating process, and the phase inversion process.

[0141] The functional coating can be applied to an uncoated granulation or to a granulation that includes a seal coating provided by the present disclosure.

[0142] Examples of coating compositions are provided in the Experimental Examples. Coating composition refers to a composition that is applied to uncoated or seal-coated granulation to provide a coated granulation.

[0143] The functional coating composition can comprise more than 70 wt%, more than 75 wt%, more than 80 wt%, more than 85 wt%, or more than 90 wt% of a non-alcoholic solvent such as ethanol or acetone, where the weight percent is based on the total weight of the functional coating solution / suspension composition used to coat the granules.

[0144] The functional coating composition can include, for example, less than 20 wt. % water, less than 15 wt. %, less than 10 wt. %, or less than 5 wt. % water, where the wt. % is based on the functional coating solution / suspension composition used to coat the granules.

[0145] For highly water-soluble and hygroscopic pharmaceutical active ingredients, such as 4-((L-valyl)oxy)butanoic acid, it may be useful to minimize the amount of water in the functional coating composition. Reducing the level of water in the functional coating solution / suspension composition can result in static electricity that can cause problems in the coating process.

[0146] The functional coating solution / suspension composition can include, for example, a solids content of less than 20 wt%, less than 18 wt%, less than 16 wt%, less than 14 wt%, less than 12 wt%, less than 10 wt%, less than 8 wt%, or less than 6 wt%, where the weight percentage is based on the functional coating solution / suspension composition.

[0147] The functional coating composition can include a solids content of 2 wt% to 20 wt%, 4 wt% to 16 wt%, 4 wt% to 12 wt%, 6 wt% to 14 wt%, or 6 wt% to 10 wt%, where the wt% is based on the functional coating composition.

[0148] Examples of coating process conditions using a Wurster column inserted into a fluidized bed coating apparatus are provided in the Experimental Examples.

[0149] The granulations provided by the present disclosure can include immediate release granulations.

[0150] The immediate release granulation can include a plurality of uncoated granules or a plurality of granules including a seal coating.

[0151] An immediate-release granulation comprising a plurality of uncoated or seal-coated granules can comprise greater than 90% by weight of 4-((L-valyl)oxy)butanoic acid provided by the present disclosure, such as 4-((L-valyl)oxy)butanoic acid. The immediate-release granulation comprising uncoated or seal-coated granules can completely dissolve in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, less than 5 minutes, or less than 4 minutes when tested in a USP Type 2 dissolution apparatus at a pH 4.5 buffer solution, a temperature of 37° C., and a paddle speed of 100 rpm.

[0152] The immediate-release granules can comprise a plurality of coated or seal-coated granules having an immediate-release functional coating. The immediate-release granules comprising a plurality of coated granules can comprise greater than 80% by weight of 4-((L-valyl)oxy)butanoic acid. The immediate-release granules comprising coated granules can completely dissolve in, for example, less than 25 minutes, less than 20 minutes, less than 18 minutes, less than 16 minutes, less than 14 minutes, or less than 12 minutes when tested in a USP Type 2 dissolution apparatus at a pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 100 rpm. The immediate-release granules comprising coated granules can release greater than 80% of the 4-((L-valyl)oxy)butanoic acid in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes when tested in a USP Type 2 dissolution apparatus at a pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 100 rpm. The coated immediate-release granules can include a coating comprising a water-soluble polymer such as, for example, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol. The coated immediate-release granules can include a coating comprising an antistatic agent such as talc, magnesium stearate, or silicon dioxide.

[0153] The pharmaceutical composition provided by the present disclosure can include a combination of an immediate-release granule and a controlled-release granule, for example, in a weight percent ratio of 4-((L-valyl)oxy)butanoic acid as the immediate-release granule to 4-((L-valyl)oxy)butanoic acid as the controlled-release granule of 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:2 to 1:3.

[0154] The pharmaceutical compositions provided by the present disclosure can include the coated granules provided by the present disclosure.

[0155] The pharmaceutical composition can comprise any suitable dosage form for oral administration.

[0156] Examples of suitable oral dosage forms include tablets, capsules, caplets, sachets, bottles, stick packs, dispersions, and suspensions.

[0157] Oral dosage forms provided by the present disclosure can contain, for example, 0.1 grams to 20 grams of 4-((L-valyl)oxy)butanoic acid, 0.1 grams to 15 grams, 0.1 grams to 12 grams, 0.1 grams to 10 grams, 0.2 grams to 8 grams, 0.5 grams to 5 grams, 1 gram to 4.5 grams, or 1.5 grams to 4 grams of 4-((L-valyl)oxy)butanoic acid. Oral dosage forms can contain, for example, more than 0.5 grams, more than 1 gram, more than 2 grams, more than 3 grams, more than 4 grams, more than 6 grams, or more than 8 grams, more than 10 grams, more than 14 grams, or more than 18 grams of 4-((L-valyl)oxy)butanoic acid.

[0158] Oral compositions provided by the present disclosure can include oral suspensions of coated granules having a modified-release functional coating provided by the present disclosure. Oral compositions can include modified-release granules and immediate-release granules provided by the present disclosure.

[0159] Oral compositions can include a combination of immediate-release and modified-release granulations provided by the present disclosure.

[0160] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid over a period of time.

[0161] For example, oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid over a period of 3 hours, 6 hours, 8 hours, or 10 hours.

[0162] Oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid over a period of 4 to 12 hours, 4 to 10 hours, or 4 to 8 hours.

[0163] Oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid for a period of 1 hour to 12 hours after oral administration, 2 hours to 10 hours after oral administration, or 4 hours to 8 hours after oral administration.

[0164] The oral compositions provided by the present disclosure can be once-a-nightly compositions, in which a patient can administer a dose of 4-((L-valyl)oxy)butanoic acid before bed and sleep through the night, such as for 6 or 8 hours, without administering a second dose during the night.

[0165] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient.

[0166] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral composition.

[0167] The oral compositions provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid greater than 10 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the modified release oral composition.

[0168] The oral compositions provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid greater than 15 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the modified release oral composition.

[0169] The oral compositions provided by the present disclosure may provide a therapeutically effective amount of C of gamma-hydroxybutyric acid in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral composition. max Against C min The ratio can be provided from less than 3 or less than 2.

[0170] Oral compositions provided by the present disclosure can include a gamma-hydroxybutyric acid derivative of formula (2), for example, 0.5 g equivalent of gamma-hydroxybutyric acid, 1 g equivalent, 2 g equivalent, 3 g equivalent, 4 g equivalent, 5 g equivalent, 6 g equivalent, 7 g equivalent, 8 g equivalent, 9 g equivalent, 10 g equivalent, 11 g equivalent, or 12 g equivalent of gamma-hydroxybutyric acid.

[0171] The pharmaceutical compositions provided by the present disclosure can be included in kits that can be used to administer the compounds to patients for therapeutic purposes. The kits can include pharmaceutical compositions containing immediate-release and controlled-release components suitable for administration to a patient, as well as instructions for administering the pharmaceutical compositions to a patient. The kits can be used, for example, to treat sleep disorders. The kits can include immediate-release and controlled-release components, pharmaceutically acceptable vehicles for administering the immediate-release and controlled-release components, and instructions for administering the pharmaceutical compositions to a patient.

[0172] Oral compositions provided by the present disclosure can be provided, for example, as sachets containing the coated granules provided by the present disclosure. The sachets can be provided with different doses of 4-((L-valyl)oxy)butanoic acid, such as 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 10 g, 12 g, 15 g, or 20 g of 4-((L-valyl)oxy)butanoic acid. The coated granules can be combined, for example, with water, to provide an orally ingestible dosage form.

[0173] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0174] The instructions supplied with the kit may be printed and / or supplied, for example, as an electronically readable medium, video cassette, audio tape, flash memory device, or may be published on an internet website or distributed as an electronic communication to the patient and / or healthcare provider.

[0175] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) exhibited a mean t 1 / 2 , 0.9 hours average T max , mean C of 16 μg / mL max , mean AUC of 16h × μg / mL 0-6 , AUC of 16h × μg / mL 0-inf , and a CL / F of 48 L / h).

[0176] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 0.8 to 1.0 hours max , mean C of 14μg / mL to 18μg / mL max , mean AUC of 14h×μg / mL to 18h×μg / mL 0-6 , AUC of 14h×μg / mL to 18h×μg / mL 0-inf and a CL / F of 44 L / h to 52 L / h.

[0177] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 0.85 to 0.95 hours max , mean C of 15μg / mL to 17μg / mL max , mean AUC of 15h×μg / mL to 17h×μg / mL 0-6 , AUC of 15h×μg / mL to 17h×μg / mL 0-infand a CL / F of 446 L / h to 50 L / h.

[0178] Following oral administration of MR1 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , mean T of 1.6 hours max , 4μg / mL mean C max , mean AUC of 9h × μg / mL 0-6 , mean AUC of 9h × μg / mL 0-inf and an average CL / F of 838 L / h.

[0179] Following oral administration of 7.25 g of Compound (1) in the MR1 composition to a group of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 1.4 to 1.8 hours max , mean C of 2μg / mL to 6μg / mL max , mean AUC of 7h×μg / mL to 11h×μg / mL 0-6 , mean AUC of 7h×μg / mL to 11h×μg / mL 0-inf and a CL / F of 818 L / h to 858 L / h.

[0180] Following oral administration of 7.25 g of Compound (1) in the MR1 composition to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 1.5 to 1.7 hours max , mean C of 3μg / mL to 5μg / mL max , mean AUC of 8h×μg / mL to 10h×μg / mL 0-6 , mean AUC of 8h×μg / mL to 10h×μg / mL 0-inf and a CL / F of 828 L / h to 848 L / h.

[0181] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , mean T of 1.4 hours max , 6 μg / mL mean C max , mean AUC of 10h × μg / mL 0-6 , mean AUC of 10h × μg / mL 0-inf and an average CL / F of 762 L / h.

[0182] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 1.2 to 1.6 hours max , mean C of 4μg / mL to 8μg / mL max , mean AUC of 8h×μg / mL to 12h×μg / mL 0-6 , mean AUC of 8h×μg / mL to 12h×μg / mL 0-inf and a CL / F of 720 L / h to 800 L / h.

[0183] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 1.3 to 1.5 hours max , mean C of 5μg / mL to 7μg / mL max , mean AUC of 9h×μg / mL to 11h×μg / mL 0-6 , mean AUC of 9h×μg / mL to 11h×μg / mL 0-inf and a CL / F of 740 L / h to 780 L / h.

[0184] Following oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) exhibited a mean t 1 / 2 , 1.1 hour average T max , 5μg / mL mean C max, mean AUC of 10h × μg / mL 0-6 , mean AUC of 10h × μg / mL 0-inf and an average CL / F of 801 L / h.

[0185] Following oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 0.9 to 1.3 hours max , mean C of 3μg / mL to 7μg / mL max , mean AUC of 8h×μg / mL to 12h×μg / mL 0-6 , mean AUC of 8h×μg / mL to 12h×μg / mL 0-inf and a CL / F of 760 L / h to 840 L / h.

[0186] Following oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) showed a mean t 1 / 2 , average T of 1.0 to 1.2 hours max , mean C of 4μg / mL to 6μg / mL max , mean AUC of 9h×μg / mL to 11h×μg / mL 0-6 , mean AUC of 9h×μg / mL to 11h×μg / mL 0-inf and a CL / F of 780 L / h to 820 L / h.

[0187] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was determined to be 0.6 hours after a mean t 1 / 2 , 1.3 hour average T max , mean C of 86 μg / mL max , mean AUC of 239 h × μg / mL 0-6 , mean AUC of 246 h × μg / mL 0-inf and an average CL / F of 31 L / h.

[0188] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibited a mean t 1 / 2 , average T of 1.1 to 1.5 hours max , mean C of 76μg / mL to 96μg / mL max , mean AUC of 219h×μg / mL to 259h×μg / mL 0-6 , mean AUC of 226h×μg / mL to 266h×μg / mL 0-inf and a CL / F of 21 L / h to 41 L / h.

[0189] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibited a mean t 1 / 2 , average T of 1.2 to 1.4 hours max , mean C of 81μg / mL to 91μg / mL max , mean AUC of 229h×μg / mL to 249h×μg / mL 0-6 , mean AUC of 236h×μg / mL to 256h×μg / mL 0-inf and a CL / F of 26 L / h to 36 L / h.

[0190] Following oral administration of 7.25 g of the MR1 composition containing Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate exhibited a mean t 1 / 2 , mean T of 2.4 hours max , mean C of 27 μg / mL max , mean AUC of 86h × μg / mL 0-6 , mean AUC of 95h × μg / mL 0-inf and an average CL / F of 95 L / h.

[0191] Following oral administration of 7.25 g of the MR1 composition containing Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibited a mean t 1 / 2, mean T of 2.2 to 2.6 hours max , mean C of 17μg / mL to 37μg / mL max , mean AUC of 76h×μg / mL to 96h×μg / mL 0-6 , mean AUC of 75h×μg / mL to 115h×μg / mL 0-inf and a CL / F of 85 L / h to 105 L / h.

[0192] Following oral administration of 7.25 g of the MR1 composition containing Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibited a mean t 1 / 2 , average T of 2.3 to 2.5 hours max , mean C of 22 μg / mL to 32 μg / mL max , mean AUC of 81h×μg / mL to 91h×μg / mL 0-6 , mean AUC of 85h×μg / mL to 105h×μg / mL 0-inf and a CL / F of 90 L / h to 100 L / h.

[0193] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate showed a mean t 1 / 2 , mean T of 2.4 hours max , mean C of 36 μg / mL max , mean AUC of 112h × μg / mL 0-6 , mean AUC of 120h × μg / mL 0-inf and an average CL / F of 72 L / h.

[0194] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibited a mean t 1 / 2 , mean T of 2.2 to 2.6 hours max , mean C of 34μg / mL to 38μg / mL max , mean AUC of 102h×μg / mL to 122h×μg / mL 0-6, mean AUC of 110h×μg / mL to 130h×μg / mL 0-inf and a CL / F of 62 L / h to 82 L / h.

[0195] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t 1 / 2 , average T of 2.3 to 2.5 hours max , mean C of 35μg / mL to 37μg / mL max , mean AUC of 107h×μg / mL to 117h×μg / mL 0-6 , mean AUC of 125h×μg / mL to 135h×μg / mL 0-inf and a CL / F of 67 L / h to 77 L / h.

[0196] Following oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was determined to be 0.05 g / L at a mean t of 1.0 hour. 1 / 2 , mean T of 1.9 hours max , 30 μg / mL mean C max , mean AUC of 102h × μg / mL 0-6 , mean AUC of 110h × μg / mL 0-inf and an average CL / F of 79 L / h.

[0197] Following oral administration of 7.25 g of the MR3 composition containing Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibited a mean t 1 / 2 , mean T of 1.7 to 2.1 hours max , mean C of 26 μg / mL to 34 μg / mL max , mean AUC of 82h×μg / mL to 122h×μg / mL 0-6 , mean AUC of 90h×μg / mL to 130h×μg / mL 0-inf and a CL / F of 69 L / h to 89 L / h.

[0198] Following oral administration of 7.25 g of the MR3 composition containing Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t 1 / 2 , average T of 1.8 to 2.0 hours max , mean C of 28μg / mL to 32μg / mL max , mean AUC of 92h×μg / mL to 112h×μg / mL 0-6 , mean AUC of 100h×μg / mL to 120h×μg / mL 0-inf and a CL / F of 74 L / h to 84 L / h.

[0199] Following oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 5.9. max Ratio, mean AUC of 15.0 0-inf Ratio, mean AUC of 16.2 0-6 The plasma pharmacokinetic profile was characterized by a mean C value of 4.9 to 6.9, which refers to the ratio of γ-hydroxybutyrate values ​​to Compound (1) values. After oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C value of 4.9 to 6.9. max Ratio, mean AUC of 14.0 to 16.0 0-inf Ratio, mean AUC of 15.2 to 17.2 0-6 The ratio can be characterized as the ratio of γ-hydroxybutyrate values ​​to Compound (1) values. After oral administration of an IR composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C of 5.4 to 6.4. max Ratio, mean AUC of 14.5-15.5 0-inf Ratio, mean AUC of 15.7–16.7 0-6 The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0200] Following oral administration of MR1 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 6.6 maxRatio, mean AUC of 10.0 0-inf Ratio, mean AUC of 9.8 0-6 The plasma pharmacokinetic profile was characterized by a mean C ratio of 6.2 to 7.0, which refers to the ratio of γ-hydroxybutyrate values ​​to Compound (1) values. Following oral administration of MR1 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C ratio of 6.2 to 7.0. max Ratio, mean AUC of 9.0-11.0 0-inf Ratio, mean AUC of 9.4 to 10.2 0-6 The ratio can be characterized as the ratio of γ-hydroxybutyrate to Compound (1). After oral administration of MR1 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C of 6.4 to 6.8. max Ratio, mean AUC of 9.5-10.5 0-inf Ratio, mean AUC of 9.6-10.0 0-6 The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0201] Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 6.3 max Ratio, mean AUC of 11.9 0-inf Ratio, mean AUC of 11.5 0-6 The plasma pharmacokinetic profile was characterized by a mean C ratio of 5.9 to 6.7, which refers to the ratio of gamma-hydroxybutyrate values ​​to Compound (1) values. Following oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C ratio of 5.9 to 6.7. max Ratio, mean AUC of 11.5 to 12.3 0-inf Ratio, mean AUC of 11.1 to 11.9 0-6 The ratio can be characterized as the ratio of γ-hydroxybutyrate values ​​to Compound (1) values. After oral administration of MR2 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C of 6.1 to 6.5. max Ratio, mean AUC of 11.7 to 12.1 0-inf Ratio, mean AUC of 11.3–11.70-6 The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0202] Following oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 6.5. max Ratio, mean AUC of 11.4 0-inf Ratio, mean AUC of 11.4 0-6 The plasma pharmacokinetic profile was characterized by a mean C value of 6.1 to 6.9 after oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects. max Ratio, mean AUC of 11.0 to 11.8 0-inf Ratio, mean AUC of 11.0 to 11.8 0-6 The ratio can be characterized as the ratio of γ-hydroxybutyrate to Compound (1). After oral administration of MR3 composition containing 7.25 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a mean C of 6.3 to 6.7. max Ratio, mean AUC of 11.2–11.6 0-inf Ratio, mean AUC of 11.2–11.6 0-6 The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0203] The pharmaceutical composition may include an immediate release component and a controlled release component.

[0204] The immediate release component can include any of the immediate release microparticles disclosed herein.

[0205] The regulatory component can include any of the regulatory microparticles or combinations of regulatory microparticles disclosed herein.

[0206] The pharmaceutical compositions provided by the present disclosure may contain, for example, 10% by weight to 50% by weight of compound (1) in the IR component and 50% by weight to 90% by weight in the MR component, 20% by weight to 40% by weight of compound (1) in the IR component and 60% by weight to 80% by weight of γ-hydroxybutyrate in the MR component, or 25% by weight to 35% by weight of compound (1) in the IR component and 65% by weight to 75% by weight of compound (1) in the MR component, where the weight percentages are based on the total weight of compound (1) in the pharmaceutical composition.

[0207] Pharmaceutical compositions provided by the present disclosure can contain, for example, more than 10% by weight of compound (1) in the IR component and less than 90% by weight of compound (1) in the MR component, more than 20% by weight of compound (1) in the IR component and less than 80% by weight of compound (1) in the MR component, more than 30% by weight of compound (1) in the IR component and less than 70% by weight of compound (1) in the MR component, or more than 40% by weight of compound (1) in the IR component and less than 60% by weight of compound (1) in the MR component, where the weight percentages are based on the total weight of compound (1) in the pharmaceutical composition.

[0208] The pharmaceutical compositions provided by the present disclosure can have a weight ratio of compound (1) in the IR component to compound (1) in the MR component of, for example, 1:1.4 to 1:3.4, 1:1.6 to 1:3.2, 1:1.8 to 1:3.0, 1:2.0 to 1:2.8, or 1.22 to 1:2.6.

[0209] The pharmaceutical compositions provided by the present disclosure can have a weight ratio of Compound (1) in the IR component to Compound (1) in the MR component of, for example, greater than 1:1.4, greater than 1:1.6, greater than 1:1.8, greater than 1:2.0, greater than 1:2.2, greater than 1:2.4, or greater than 1:2.6.

[0210] Pharmaceutical compositions provided by the present disclosure can contain, for example, 2.0 g to 6.0 g of compound (1) in the IR component, 2.25 g to 5.75 g, 2.5 g to 5.5 g, 2.75 g to 5.25 g, 3.0 g to 5.0 g, 3.25 g to 4.75 g, or 3.5 g to 4.5 g of compound (1) in the IR component.

[0211] The pharmaceutical composition can contain, for example, 8 g to 12 g of compound (1) in the MR component, 8.5 g to 11.5 g, 9 g to 11 g, 9.25 g to 10.75 g, or 9.5 g to 10.5 g of compound (1) in the MR component.

[0212] The pharmaceutical composition may contain, for example, 2.0 g to 6.0 g of compound (1) in the IR component, 2.25 g to 5.75 g, 2.5 g to 5.5 g, 2.75 g to 5.25 g, 3.0 g to 5.0 g, 3.25 g to 4.75 g, or 3.5 g to 4.5 g of compound (1) in the IR component, and 8 g to 12 g of compound (1) in the MR component, or 8.5 g to 11.5 g, 9 g to 11 g, 9.25 g to 10.75 g, or 9.5 g to 10.5 g of compound (1) in the MR component.

[0213] Pharmaceutical compositions provided by the present disclosure can contain, for example, 9.5 g to 22 g of Compound (1), 10 g to 20 g of Compound (1), 12 g to 18 g of Compound (1), or 14 g to 16 g of Compound (1). Pharmaceutical compositions provided by the present disclosure can contain, for example, more than 9 g of Compound (1), more than 10 g, more than 12 g, more than 14 g, more than 16 g, more than 18 g, or more than 20 g of Compound (1).

[0214] Pharmaceutical compositions provided by the present disclosure can comprise, for example, 10% to 50% by weight of gamma-hydroxybutyrate equivalents in the IR component and 50% to 90% by weight in the MR component, 20% to 40% by weight of gamma-hydroxybutyrate equivalents in the IR component and 60% to 80% by weight of gamma-hydroxybutyrate in the MR component, or 25% to 35% by weight of gamma-hydroxybutyrate equivalents in the IR component and 65% to 75% by weight of gamma-hydroxybutyrate equivalents in the MR component, where the weight % equivalents are based on the total weight % of gamma-hydroxybutyrate equivalents in the pharmaceutical composition.

[0215] Pharmaceutical compositions provided by the present disclosure can comprise, for example, greater than 10% by weight of gamma-hydroxybutyrate equivalents in the IR component and less than 90% by weight of gamma-hydroxybutyrate equivalents in the MR component; greater than 20% by weight of gamma-hydroxybutyrate equivalents in the IR component and less than 80% by weight of gamma-hydroxybutyrate equivalents in the MR component; greater than 30% by weight of gamma-hydroxybutyrate equivalents in the IR component and less than 70% by weight of gamma-hydroxybutyrate equivalents in the MR component; or greater than 40% by weight of gamma-hydroxybutyrate equivalents in the IR component and less than 60% by weight of gamma-hydroxybutyrate equivalents in the MR component, where the weight % equivalents are based on the total gamma-hydroxybutyrate equivalents in the pharmaceutical composition.

[0216] Pharmaceutical compositions provided by the present disclosure can have a weight ratio of γ-hydroxybutyrate equivalents in the IR component to γ-hydroxybutyrate equivalents in the MR component of, for example, 1:1.5 to 1:3.5, 1:1.7 to 1:3.3, 1:1.9 to 1:3.1, 1:2.1 to 1:2.9, or 1.23 to 1:2.7.

[0217] Pharmaceutical compositions provided by the present disclosure can have a weight ratio of gamma-hydroxybutyrate equivalents in the IR component to gamma-hydroxybutyrate equivalents in the MR component of, for example, greater than 1:1.5, greater than 1:1.7, greater than 1:1.9, greater than 1:2.1, greater than 1:2.3, greater than 1:2.5, or greater than 1:2.7.

[0218] Pharmaceutical compositions provided by the present disclosure can include, for example, 1.1 g to 3.1 g of gamma-hydroxybutyrate equivalents in the IR component, 1.2 g to 3.0 g, 1.3 g to 2.9 g, or 1.4 g to 2.8 g of gamma-hydroxybutyrate equivalents in the IR component.

[0219] The pharmaceutical composition can contain, for example, 4.1 g to 6.1 g of gamma-hydroxybutyrate equivalents in the MR component, 4.2 g to 6.0 g, 4.3 g to 5.9 g, 4.4 g to 6.8 g, or 4.5 g to 6.7 g of gamma-hydroxybutyrate equivalents in the MR component.

[0220] The pharmaceutical composition can comprise, for example, 1.1 g to 3.1 g of gamma-hydroxybutyrate equivalents in the IR component and 4.1 g to 6.1 g of gamma-hydroxybutyrate equivalents in the MR component; 1.4 g to 2.8 g of gamma-hydroxybutyrate equivalents in the IR component and 4.3 g to 5.9 g of gamma-hydroxybutyrate equivalents in the MR component; 1.6 g to 2.6 g of gamma-hydroxybutyrate equivalents in the IR component and 4.5 g to 5.7 g of gamma-hydroxybutyrate equivalents in the MR component; or 1.8 g to 2.2 g of gamma-hydroxybutyrate equivalents in the IR component and 4.7 g to 5.5 g of gamma-hydroxybutyrate equivalents in the MR component.

[0221] Pharmaceutical compositions provided by the present disclosure can contain, for example, 6.5 g to 18 g of compound (1), 8 g to 16 g of gamma-hydroxybutyrate equivalents, 10 g to 14 g of compound (1), or 11 g to 13 g of gamma-hydroxybutyrate equivalents. Pharmaceutical compositions provided by the present disclosure can contain, for example, more than 9 g of gamma-hydroxybutyrate equivalents, more than 6.5 g, more than 8 g, more than 10 g, more than 12 g, more than 14 g, or more than 16 g of gamma-hydroxybutyrate equivalents.

[0222] 4-((L-valyl)oxy)butanoic acid (1) Methods for determining the plasma pharmacokinetic profiles for γ-hydroxybutyrate and 4-((L-valyl)oxy)butanoic acid (1) following administration to fasted healthy subjects are provided in the experimental examples.

[0223] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) was 0.01 g with a mean t of 1.1 hours. 1 / 2 , mean T of 1.4 hours max , 15μg / mL mean C max , mean AUC of 25h × μg / mL 0-6 , mean AUC of 27h × μg / mL 0-inf and an average CL / F of 556 L / h.

[0224] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) exhibited a mean t 1 / 2 , average T of 1.3 to 1.5 hours max , mean C of 12μg / mL to 18μg / mL max , mean AUC of 20h×μg / mL to 30h×μg / mL 0-6 , mean AUC of 22h×μg / mL to 32h×μg / mL 0-inf and a CL / F of 536 L / h to 576 L / h.

[0225] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) exhibited a mean t 1 / 2 , average T of 1.35 to 1.45 hours max , mean C of 14μg / mL to 16μg / mL max , mean AUC of 22h×μg / mL to 28h×μg / mL 0-6 , mean AUC of 24h×μg / mL to 30h×μg / mL 0-inf and a CL / F of 546 L / h to 566 L / h.

[0226] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate was 0.01 mg / kg, with a mean t 1 / 2 , mean T of 2.7 hours max , mean C of 108 μg / mL max , mean AUC of 400h × μg / mL 0-6 , mean AUC of 534 h × μg / mL 0-inf and an average CL / F of 32 L / h.

[0227] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t 1 / 2 , mean T of 2.5 to 2.9 hours max , mean C of 88μg / mL to 128μg / mL max , mean AUC of 380h×μg / mL to 420h×μg / mL 0-6 , mean AUC of 514h×μg / mL to 554h×μg / mL 0-inf and a CL / F of 22 L / h to 42 L / h.

[0228] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t of 1.05 hours to 1.15 hours. 1 / 2 , mean T of 2.6 to 2.8 hours max , mean C of 98μg / mL to 118μg / mL max , mean AUC of 390h×μg / mL to 410h×μg / mL 0-6 , mean AUC of 524h×μg / mL to 544h×μg / mL 0-inf and a CL / F of 27 L / h to 37 L / h.

[0229] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 8.0. max ratio, and a mean AUC of 19.3 0-inf The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0230] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 7.0 to 9.0. max ratio, and mean AUC of 18.3 to 20.3 0-inf The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0231] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of Compound (1) and an MR1 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 7.5 to 8.5. max ratio, and mean AUC of 18.8 to 19.8 0-inf The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0232] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the Compound (1) plasma pharmacokinetic profile exhibited a mean t 1 / 2 , 1.3 hour average T max , mean C of 12 μg / mL max , mean AUC of 20h × μg / mL 0-6 , mean AUC of 21h × μg / mL 0-inf and an average CL / F of 700 L / h).

[0233] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) exhibited a mean t 1 / 2 , average T of 1.1 to 1.5 hours max , mean C of 10 μg / mL to 14 μg / mL max, mean AUC of 16h×μg / mL to 24h×μg / mL 0-6 , mean AUC of 11h×μg / mL to 31h×μg / mL 0-inf and a CL / F of 660 L / h to 740 L / h.

[0234] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of Compound (1) exhibited a mean t 1 / 2 , average T of 1.2 to 1.4 hours max , mean C of 11 μg / mL to 13 μg / mL max , mean AUC of 18h×μg / mL to 22h×μg / mL 0-6 , mean AUC of 16h×μg / mL to 26h×μg / mL 0-inf and a CL / F of 680 L / h to 720 L / h.

[0235] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t 1 / 2 , mean T of 2.2 hours max , mean C of 83 μg / mL max , mean AUC of 322h × μg / mL 0-6 , mean AUC of 386 h × μg / mL 0-inf , and an average CL / F of 43 L / h).

[0236] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t 1 / 2 , mean T of 2.0 to 2.4 hours max , mean C of 73μg / mL to 93μg / mLmax , mean AUC of 302h×μg / mL to 342h×μg / mL 0-6 , mean AUC of 366h×μg / mL to 406h×μg / mL 0-inf and a CL / F of 33 L / h to 53 L / h.

[0237] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t of 0.85 hours to 0.95 hours. 1 / 2 , mean T of 2.1 to 2.3 hours max , mean C of 78μg / mL to 88μg / mL max , mean AUC of 312h×μg / mL to 332h×μg / mL 0-6 , mean AUC of 376h×μg / mL to 396h×μg / mL 0-inf and a CL / F of 38 L / h to 48 L / h.

[0238] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 7.8. max ratio, and a mean AUC of 18.3 0-inf The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0239] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 6.8 to 8.8. max ratio, and mean AUC of 17.3 to 19.3 0-inf The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0240] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of Compound (1) and an MR2 composition containing 10 g of Compound (1) to a population of fasted healthy subjects, the plasma pharmacokinetic profile showed a mean C of 7.3 to 8.3. max ratio, and mean AUC of 17.8 to 18.8 0-inf The ratio can be characterized as a ratio, which refers to the ratio of the gamma-hydroxybutyrate value to the Compound (1) value.

[0241] For the combined release compositions provided by the present disclosure, 8 hours after oral administration of a combined release composition comprising 10 g to 20 g of Compound (1) to a population of fasted healthy subjects, the concentration of gamma-hydroxybutyrate in the plasma of the subjects is less than 40 μg / mL, less than 30 μg / mL, or less than 20 μg / mL.

[0242] For the combined release compositions provided by the present disclosure, after oral administration of a combined release composition containing 10 g to 20 g of Compound (1) to a population of fasted healthy subjects, the AUC of gamma-hydroxybutyrate in the plasma of the subjects was inf is the AUC of gamma-hydroxybutyrate after oral administration of (a) the immediate-release component inf and (b) AUC of gamma-hydroxybutyrate after oral administration of the modified-release formulation. inf exceeds the total of

[0243] For the combined release compositions provided by the present disclosure, 6 to 8 hours after oral administration of a combined release composition comprising 10 g to 20 g of Compound (1) to a population of fasted healthy subjects, the concentration of gamma-hydroxybutyrate in the plasma of the subjects exceeds the sum of the gamma-hydroxybutyrate concentration 6 to 8 hours after oral administration of (a) the immediate-release component and (b) the modified-release component to a population of fasted healthy subjects.

[0244] For the combined release compositions provided by the present disclosure, following oral administration of a combined release composition comprising 10 g to 20 g of Compound (1) to a population of healthy, fasted subjects, the concentration 6 to 8 hours after administration exceeds the concentration of gamma-hydroxybutyrate in the plasma of the subjects following administration of the modified release component alone.

[0245] For the combined release compositions provided by the present disclosure, the mean gamma-hydroxybutyrate AUC after oral administration of the immediate-release component and the modified-release component to a population of fasted healthy subjects 0-inf is the mean gamma-hydroxybutyrate AUC after oral administration of the immediate-release component alone 0-inf and mean gamma-hydroxybutyrate AUC after oral administration of the modified-release component alone 0-inf and the sum of ...

[0246] For the combined release compositions provided by the present disclosure, the mean Compound (1) AUC after oral administration of the immediate-release component and the modified-release component to a population of fasted healthy subjects was 0-inf is the mean Compound (1) AUC after oral administration of the immediate-release component alone 0-inf and the mean Compound (1) AUC after oral administration of the controlled-release component alone. 0-inf is the same as the sum of ...

[0247] For the combined release compositions provided by the present disclosure, the mean gamma-hydroxybutyrate AUC after oral administration of a combined release composition comprising an immediate-release component comprising 4.11 g of Compound (1) and a modified-release component comprising 10 g of Compound (1) to a population of fasted healthy subjects was 0-inf is the mean gamma-hydroxybutyrate AUC after oral administration of 7.25 g of the immediate-release formulation containing Compound (1) alone. 0-inf and the mean gamma-hydroxybutyrate AUC after oral administration of 7.25 g of the modified-release formulation containing Compound (1) alone. 0-inf exceeds the total of

[0248] For the combined release compositions provided by the present disclosure, the mean Compound (1) AUC after oral administration of a combined release composition comprising an immediate-release component comprising 4.52 g of Compound (1) and a modified-release component comprising 10 g of Compound (1) to a population of fasted healthy subjects was 0-inf is the mean Compound (1) AUC after oral administration of 7.25 g of the immediate-release formulation alone containing Compound (1). 0-inf and the mean Compound (1) AUC after oral administration of 7.25 g of the modified-release formulation containing Compound (1) alone. 0-inf is substantially the same as the sum of

[0249] The immediate-release component provided by the present disclosure can exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) shown in Figure 17 or gamma-hydroxybutyrate shown in Figure 18. The immediate-release component provided by the present disclosure can exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) provided in Table 6 or gamma-hydroxybutyrate provided in Table 7.

[0250] The modified-release components provided by the present disclosure can exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) shown in Figure 17 or gamma-hydroxybutyrate shown in Figure 18. The modified-release components provided by the present disclosure can exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) provided in Table 6 or gamma-hydroxybutyrate provided in Table 7.

[0251] Pharmaceutical compositions provided by the present disclosure, such as combined release compositions, can exhibit plasma pharmacokinetic profiles that are bioequivalent to the plasma pharmacokinetic profiles for compound (1) shown in Figure 19 or gamma-hydroxybutyrate shown in Figure 20. Pharmaceutical compositions provided by the present disclosure, such as combined release compositions, can exhibit plasma pharmacokinetic profiles that are bioequivalent to the plasma pharmacokinetic profiles for compound (1) provided in Table 10 or gamma-hydroxybutyrate provided in Table 11.

[0252] Pharmaceutical compositions provided by the present disclosure can be used to treat, for example, narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia.

[0253] The pharmaceutical compositions provided by the present disclosure can be used to treat, for example, REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety.

[0254] The pharmaceutical compositions provided by the present disclosure can be used, for example, to enhance cognitive function in neurodegenerative disorders, for example, the pharmaceutical compositions provided by the present disclosure can be used to enhance cognitive function in patients with Parkinson's disease or Alzheimer's disease.

[0255] The pharmaceutical compositions provided by the present disclosure can be used to treat narcolepsy, such as type 1 or type 2 narcolepsy. Treatment of narcolepsy is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplexy attacks. In various embodiments, the composition is sufficient for once-daily administration. For example, the composition may be administered in the morning or evening less than two hours after a meal. The pharmaceutical composition may also be effective for inducing sleep for at least 6 to 8 consecutive hours. A pharmaceutical composition administered less than two hours after a meal is effective for inducing sleep for at least 8 consecutive hours. The pharmaceutical composition may be effective for inducing sleep for at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours. The pharmaceutical composition may be effective for inducing sleep for up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, or up to 10 hours.

[0256] The pharmaceutical compositions and compositions provided by the present disclosure can be used to treat symptoms associated with sleep disorders, drug abuse, alcohol and opioid withdrawal, decreased growth hormone levels, anxiety, analgesia, neurological disorders such as Parkinson's disease, Alzheimer's disease, and depression, endocrine disorders, tissue hypoxia or anoxia such as in stroke or myocardial infarction, or elevated intracranial pressure levels.

[0257] The pharmaceutical compositions provided by the present disclosure can be used to treat diseases or conditions treatable by administering gamma-hydroxybutyric acid, such as, for example, fibromyalgia and sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucinations, sleep arousals, insomnia, and nocturnal myoclonus.

[0258] The pharmaceutical compositions provided by the present disclosure can be used to treat sleep disorders associated with viral diseases such as COVID-19 infection.

[0259] The pharmaceutical compositions provided by the present disclosure can be used to alleviate pain and improve function in patients with fibromyalgia syndrome, and to alleviate excessive daytime sleepiness and fatigue in patients with Parkinson's disease, improve myoclonus and essential tremor, and reduce tardive dyskinesia and bipolar disorder.

[0260] The pharmaceutical compositions provided by the present disclosure can be used to improve cognitive function in patients suffering from neurological disorders such as Parkinson's disease and Alzheimer's disease.

[0261] The pharmaceutical compositions and compositions provided herein can be used to treat a patient suffering from a neurodegenerative disease or a condition or disorder associated with an autonomic nervous system disorder, such as Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy, motor neuron disease, Creutzfeldt-Jakob disease, primary progressive aphasia, or progressive supranuclear palsy. Other examples of neurodegenerative diseases include Alpers' disease, Batten disease, cerebro-oculofacial-skeletal syndrome, corticobasal degeneration, Gerstmann-Straussler-Scheinker disease, kuru, Leigh's disease, unilateral crural muscular atrophy, multiple system atrophy, opsoclonus-myoclonus, prion disease, progressive multifocal leukoencephalopathy, leukoencephalopathy striatonigral degeneration, and transmissible spongiform encephalopathies.

[0262] 4-((L-valyl)oxy)butanoic acid, which is metabolized after administration to provide gamma-hydroxybutyric acid in the systemic circulation, can be used to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia.

[0263] 4-((L-valyl)oxy)butanoic acid can be used to treat REM sleep behavior disorder, convulsive dystonia, symptoms of schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, symptoms of Alzheimer's disease, symptoms of Parkinson's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety.

[0264] 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyric acid that provides oral bioavailability of gamma-hydroxybutyric acid in the systemic circulation of a patient after oral administration.

[0265] 4-((L-valyl)oxy)butanoic acid and pharmaceutical compositions thereof can be used to treat diseases known to be or determined to be treated by administering gamma-hydroxybutyric acid.

[0266] 4-((L-valyl)oxy)butanoic acid and pharmaceutical compositions thereof can be used to treat diseases that are known to be or have been determined to be treated by administering γ-hydroxybutyric acid and one or more additional therapeutic agents.

[0267] 4-((L-valyl)oxy)butanoic acid and pharmaceutical compositions can be used to treat excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0268] The methods provided by the present disclosure include providing a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation of a patient, comprising administering to the patient 4-((L-valyl)oxy)butanoic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0269] The pharmaceutical compositions provided by the present disclosure can further include one or more pharmaceutically active compounds in addition to 4-((L-valyl)oxy)butanoic acid. Such compounds can be provided to treat a disease being treated with 4-((L-valyl)oxy)butanoic acid, or to treat a disease, disorder, or condition other than that being treated with 4-((L-valyl)oxy)butanoic acid.

[0270] 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof can be used in combination with at least one other therapeutic agent. 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof can be administered to a patient along with another compound for treating a bacterial infection in the patient. 4-((L-valyl)oxy)butanoic acid and the at least one other therapeutic agent can function additively or synergistically. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle containing 4-((L-valyl)oxy)butanoic acid, or can be included in a separate pharmaceutical composition or vehicle. Thus, the methods provided by the present disclosure further include, in addition to administering 4-((L-valyl)oxy)butanoic acid, administering one or more therapeutic agents effective to treat a different disease, disorder, or condition other than the disease being treated with gamma-hydroxybutyric acid. The methods provided by the present disclosure include the administration of 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof and one or more other therapeutic agents, provided that the combined administration does not interfere with the therapeutic effectiveness of 4-((L-valyl)oxy)butanoic acid and / or gamma-hydroxybutyric acid and / or does not result in adverse combined effects.

[0271] A pharmaceutical composition comprising 4-((L-valyl)oxy)butanoic acid may be administered concurrently with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as or in a different pharmaceutical composition from the pharmaceutical composition comprising 4-((L-valyl)oxy)butanoic acid, and 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition thereof may be administered before or after the administration of the other therapeutic agent. In certain embodiments of combination therapy, the combination therapy may involve alternating between the administration of 4-((L-valyl)oxy)butanoic acid and a pharmaceutical composition comprising another therapeutic agent, such as to minimize adverse drug effects associated with a particular drug. When 4-((L-valyl)oxy)butanoic acid is administered concurrently with another therapeutic agent that could potentially produce adverse drug effects, including, for example, toxicity, the other therapeutic agent may be administered at a dose below the threshold at which an adverse drug reaction is elicited.

[0272] Pharmaceutical compositions comprising 4-((L-valyl)oxy)butanoic acid can be administered with one or more substances to, for example, enhance, regulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of 4-((L-valyl)oxy)butanoic acid. For example, to enhance the therapeutic efficacy of 4-((L-valyl)oxy)butanoic acid or a pharmaceutical composition comprising 4-((L-valyl)oxy)butanoic acid, it can be co-administered with one or more active agents to increase absorption or diffusion and / or transport of 4-((L-valyl)oxy)butanoic acid from the gastrointestinal tract to the systemic circulation, or to inhibit the degradation of 4-((L-valyl)oxy)butanoic acid in the patient's blood. Pharmaceutical compositions comprising 4-((L-valyl)oxy)butanoic acid can be co-administered with active agents that have pharmacological effects that enhance the therapeutic efficacy of 4-((L-valyl)oxy)butanoic acid or γ-hydroxybutyric acid.

[0273] Aspects of the present invention The present invention is further defined by the following aspects.

[0274] Embodiment 1. A pharmaceutical granulation comprising a plurality of coated granules, the granules comprising a core and a functional coating surrounding the core, the pharmaceutical granulation characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, the PSD determined by sieve analysis, and the cores comprising greater than 90 wt. % 4-((L-valyl)oxy)butanoic acid, the wt. % being based on the total weight of the cores.

[0275] Aspect 2. The pharmaceutical granulation of Aspect 1, wherein the pharmaceutical granulation comprises 60% to 90% by weight of 4-((L-valyl)oxy)butanoic acid, the weight percentages being based on the total weight of the pharmaceutical granulation.

[0276] Aspect 3. The pharmaceutical granulation of Aspect 1 or 2, wherein the functional coating comprises a modified release coating.

[0277] Aspect 4. The pharmaceutical granulation of any one of Aspects 1-3, wherein the functional coating comprises 50% to 85% by weight of the matrix polymer, the weight percentage being based on the total weight of the functional coating.

[0278] Embodiment 5. The pharmaceutical granulation of embodiment 4, wherein the matrix polymer comprises a water-insoluble polymer.

[0279] Embodiment 6. The pharmaceutical granulation of embodiment 5, wherein the water-insoluble polymer comprises ethyl cellulose.

[0280] Embodiment 7. The pharmaceutical granulation of any one of embodiments 1 to 6, wherein the functional coating comprises 0% to 10% by weight of a pore-forming polymer, wherein the weight percent is based on the total weight of the matrix polymer.

[0281] Embodiment 8. The pharmaceutical granulation of embodiment 7, wherein the pore-forming polymer comprises a water-soluble polymer.

[0282] Embodiment 9. The pharmaceutical granulation of embodiment 8, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

[0283] Embodiment 10. The pharmaceutical granulation of any one of embodiments 1 to 9, wherein the functional coating comprises 10% to 20% by weight of an antistatic agent, the weight percentage being based on the total weight of the functional coating.

[0284] Aspect 11. The pharmaceutical granulation of Aspect 10, wherein the antistatic agent comprises talc, magnesium stearate, or a combination thereof.

[0285] Aspect 12. The pharmaceutical granulation of any one of Aspects 1 to 11, wherein the functional coating comprises 50% to 85% by weight of the matrix polymer and 10% to 20% by weight of the antistatic agent, the weight percentages being based on the total weight of the functional coating.

[0286] Embodiment 13. The pharmaceutical granule of any one of embodiments 1 to 12, wherein the core represents 65% to 85% by weight of the total weight of the coated granule, and the functional coating represents 15% to 40% by weight of the total weight of the coated granule.

[0287] Embodiment 14. The pharmaceutical granulation according to any one of embodiments 1 to 13, wherein the functional coating has a thickness of 5 μm to 30 μm.

[0288] Aspect 15. The pharmaceutical granulation of any one of aspects 1 to 14, wherein the pharmaceutical granulation has a water content of less than 2% by weight, the weight percentage being based on the total weight of the pharmaceutical granulation.

[0289] Embodiment 16. The pharmaceutical granulation of any one of embodiments 1 to 15, further comprising a seal coating surrounding the core, wherein the functional coating surrounds the seal coating.

[0290] Aspect 17. The pharmaceutical granulation of Aspect 16, wherein the seal coating comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and talc, or hydroxypropyl methylcellulose and talc.

[0291] Aspect 18. The pharmaceutical granulation of aspect 17, wherein the pharmaceutical granulation comprises 2% to 15% by weight of a seal coating.

[0292] Aspect 19. The pharmaceutical granulation of any one of Aspects 1 to 18, wherein 30% to 80% by weight of 4-((L-valyl)oxy)butanoic acid is released from the granulation within 2 hours when tested in a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37° C. and a paddle speed of 100 rpm, wherein the weight percentage is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granulation.

[0293] Aspect 20. The pharmaceutical granulation of any one of Aspects 1 to 19, wherein 50% to 90% by weight of 4-((L-valyl)oxy)butanoic acid is released from the granulation within 4 hours when tested in a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37° C. and a paddle speed of 100 rpm, wherein the weight percentage is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granulation.

[0294] Aspect 21. The pharmaceutical granulation of any one of Aspects 1 to 20, wherein 60% to 100% by weight of 4-((L-valyl)oxy)butanoic acid is released from the granulation within 6 hours when tested in a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37° C. and a paddle speed of 100 rpm, wherein the weight percentage is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the granulation.

[0295] Aspect 22. A pharmaceutical composition comprising the pharmaceutical granulation according to any one of Aspects 1 to 21.

[0296] Aspect 23. The pharmaceutical composition according to aspect 22, wherein the pharmaceutical composition is an oral composition.

[0297] Aspect 24. The pharmaceutical composition of aspect 23, wherein the pharmaceutical composition comprises a modified oral composition.

[0298] Aspect 25. The pharmaceutical composition of aspect 23 or 24, wherein the oral composition comprises a modified release portion, wherein the modified release portion comprises a pharmaceutical granulation, and wherein the pharmaceutical composition further comprises an immediate release portion.

[0299] Aspect 26. The pharmaceutical composition according to aspect 25, wherein the immediate-release portion dissolves in water in less than 5 minutes.

[0300] Aspect 27. The pharmaceutical composition according to any one of Aspects 23 to 26, wherein the oral composition is a BID composition.

[0301] Embodiment 28. The pharmaceutical composition of any one of embodiments 23 to 27, wherein the oral composition is a QD composition.

[0302] Aspect 29. The pharmaceutical composition of any one of Aspects 22 to 28, wherein the pharmaceutical composition comprises the equivalent of 500 mg to the equivalent of 12 g of 4-((L-valyl)oxy)butanoic acid.

[0303] Aspect 30. The pharmaceutical composition of any one of aspects 22 to 29, wherein the pharmaceutical composition comprises a sustained release oral composition, a delayed release composition, an immediate release composition, or a combination of any of the foregoing.

[0304] Aspect 31. The pharmaceutical composition of any one of Aspects 22 to 30, wherein the pharmaceutical composition comprises a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid for treating a disorder in a patient, the disorder being selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0305] Aspect 32. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of Aspects 22-31, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0306] Embodiment 33. The method of embodiment 32, wherein the disease is cataplexy associated with narcolepsy.

[0307] Embodiment 34. The method of embodiment 32, wherein the disease is excessive daytime sleepiness associated with narcolepsy.

[0308] Embodiment 35. The method of embodiment 32, wherein the disease is excessive daytime sleepiness in patients with Parkinson's disease.

[0309] Embodiment 36. The method of embodiment 32, wherein the disease is chronic fatigue in patients with Parkinson's disease.

[0310] Embodiment 37. The method of any one of embodiments 32 to 36, wherein administering comprises oral administration.

[0311] Embodiment 38. A method of coating a granulation, comprising: applying a coating composition to a pharmaceutical granulation comprising a plurality of granules comprising 4-((L-valyl)oxy)butanoic acid, wherein the coating composition comprises 6% to 14% by weight of solids, 0% to 20% by weight of water, and 70% to 95% by weight of ethanol, wherein the weight percentages are based on the total weight of the coating composition.

[0312] Aspect 39. The method of aspect 38, wherein the solid comprises a matrix polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, or a combination thereof, and an antistatic agent selected from talc, magnesium stearate, or a combination thereof.

[0313] Embodiment 40. The method of embodiment 38 or 39, wherein applying comprises spraying. [Example]

[0314] Embodiments provided by the present disclosure are further illustrated by reference to the following examples, which describe coated pharmaceutical granules comprising 4-((L-valyl)oxy)butanoic acid, coated pharmaceutical granules comprising 4-((L-valyl)oxy)butanoic acid, oral modified-release pharmaceutical compositions, and methods of making the coated pharmaceutical granules and granules provided by the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

[0315] General method Pharmacokinetic analysis Plasma concentrations of compound (1) and γ-hydroxybutyrate in healthy human subjects were measured using liquid chromatography-tandem mass spectrometry and evaluated using Phoenix™ WinNonlin® version 8.1 (Pharsight Corporation, USA) and Microsoft® Excel® 2016 (Microsoft Corporation, USA).

[0316] Dissolution Profile The dissolution profile for the modified-release microparticles was determined using a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37° C. and a paddle speed of 75 rpm. The dissolution profile for the release of Compound (1) from the modified-release microparticles is shown in FIG.

[0317] Example 1 Water-based, seal-coated, immediate-release granules of 4-((L-valyl)oxy)butanoic acid Seal-coated immediate-release (IR) granulations were prepared by spray coating uncoated IR granulations of 4-((L-valyl)oxy)butanoic acid granules.

[0318] Uncoated IR granulation containing 4-((L-valyl)oxy)butanoic acid was prepared using MicroPX® micropelletization technology (Glatt GmbH). The uncoated IR granulation had an average granule size (D50) of 225 μm to 275 μm. The uncoated IR granulation contained 90 wt. % 4-((L-valyl)oxy)butanoic acid, 5 wt. % USP magnesium silicate, and 5 wt. % hypromellose (hydroxypropyl methylcellulose), where the wt. % is based on the total weight of the IR granulation.

[0319] The composition used to provide the seal coat contained 14.2 wt. % hydroxypropyl methylcellulose (Pharmacoat® 603), 2.1 wt. % talc, and 85.6 wt. % water, the weight percentages being based on the total weight of the seal coat composition.

[0320] The composition was spray coated onto uncoated IR granulation to give a seal coat having a thickness of 2.23 (+ / - 0.34) μm.

[0321] The particle size distribution of the particles is shown in Figure 1, SEM images of the seal-coated granules are shown in Figures 2A-2D, and an SEM image of a cross section of a seal-coated granule is shown in Figure 2E.

[0322] Example 2 Acetone-based seal-coated immediate-release granules of 4-((L-valyl)oxy)butanoic acid Seal-coated IR granulation was prepared by spray coating an uncoated granulation of 4-((L-valyl)oxy)butanoic acid granules.

[0323] Uncoated IR granules containing 4-((L-valyl)oxy)butanoic acid were prepared using MicroPX® micropelletization technology (Glatt GmbH). The uncoated IR granules had an average granule size (D50) of 225 μm to 275 μm. The uncoated IR granules had a 4-((L-valyl)oxy)butanoic acid content of greater than 90% by weight.

[0324] The composition used to provide the seal coat contained 5.4 wt. % hydroxypropyl cellulose (Klucel® EF), 2.1 wt. % talc, and 92.5 wt. % acetone, the weight percentages being based on the total weight of the seal coat composition.

[0325] The composition was spray coated onto the uncoated granulation to give a seal coat having a thickness of 1.30 (+ / - 0.27) μm.

[0326] The particle size distribution of the seal-coated IR particles is shown in Figure 3, SEM images of the seal-coated granules are shown in Figures 4A-4D, and an SEM image of a cross-section of a seal-coated granule is shown in Figure 4E.

[0327] Example 3 Granules of 4-((L-valyl)oxy)butanoic acid with a modified release coating (1) A granulation containing granules having 98.5% by weight of 4-((L-valyl)oxy)butanoic acid and characterized by an average granule particle size (D50) of 225 μm to 275 μm was used to prepare a granulation having a modified-release (MR) coating.

[0328] The composition of the modified release coating is provided in Table 1. [Table 1]

[0329] The modified release coating was applied at 20% wg and 40% wg.

[0330] For the coated granulation with 40% wg, the bulk density was 0.70 g / mL and the (loss on drying) LOD was 0.55%. The thickness of the modified release coating at 40 wg% was 10.26 μm + / - 1.46 μm (standard).

[0331] The particle size distribution is shown in Figure 5, and the dissolution profile is shown in Figure 6. SEM images of the 40% wg coated granules at different magnifications are shown in Figures 7A-7D, and a cross-section of the coating is shown in Figure 7E.

[0332] Example 4 Granules of 4-((L-valyl)oxy)butanoic acid with a modified release coating (2) A granulation containing granules having 98.5% by weight of 4-((L-valyl)oxy)butanoic acid and characterized by a granule particle size of 225 μm to 275 μm was used.

[0333] The components of the modified release coating composition are provided in Table 2. [Table 2]

[0334] The processing conditions for applying the modified release coating are provided in Table 3. [Table 3]

[0335] The modified release coating was applied at 20% wg and 40% wg.

[0336] For the coated granulation with 40% wg, the bulk density was 0.63 g / mL and the LOD was 0.37%. The modified release coating thickness at 40% wg was 10.16 μm + / - 2.80 μm (standard).

[0337] The particle size distribution is shown in Figure 8 and the dissolution profile is shown in Figure 9. SEM images of the 40% wg coated granules at different magnifications are shown in Figures 10A-10D, and a cross-section of the coating is shown in Figure 10E.

[0338] Example 5 Granules of 4-((L-valyl)oxy)butanoic acid with a modified release coating (3) A granulation containing granules having 98.5% by weight of 4-((L-valyl)oxy)butanoic acid and characterized by a granule particle size of 200 μm to 425 μm was used.

[0339] The process conditions for applying the modified release coating were the same as those in Example 3.

[0340] The composition of the modified release coating is provided in Table 4. [Table 4]

[0341] The modified release coatings were applied at 20% wg, 30% wg, 35% wg, and 40% wg.

[0342] For the coated granulation with 40% wg, the bulk density was 0.68 g / mL and the LOD was 0.69%. The modified release coating thickness at 40% wg was 11.58 μm + / - 1.45 μm (standard).

[0343] The particle size distribution is shown in Figure 11 and the dissolution profile is shown in Figure 12. SEM images of the 40% wg coated granules at different magnifications are shown in Figures 13A-13D and a cross-section of the coating is shown in Figure 13E.

[0344] Example 6 Coated granules (4) The seal coated granulation of Example 1 was used as the starting material.

[0345] The process conditions for applying the modified release coating were the same as those for Examples 3-5.

[0346] The components of the modified release coating composition are provided in Table 5. [Table 5]

[0347] The modified release coating was applied at 20% wg and 40% wg.

[0348] For the coated pharmaceutical granulation with 40% wg, the bulk density was 0.64 g / mL and the LOD was 0.45%. The functional coating thickness at 40% wg was 15.03 μm + / - 2.24 μm (typical).

[0349] The particle size distribution is shown in Figure 14 and the dissolution profile is shown in Figure 15. SEM images of the 40% wg coated granules at different magnifications are shown in Figures 16A-16D and a cross section of the coating is shown in Figure 16E.

[0350] Example 7 Pharmacokinetics of immediate-release and modified-release compositions The pharmacokinetics of compound (1) and gamma-hydroxybutyrate were determined following oral administration of immediate-release or modified-release components to fasted healthy subjects.

[0351] To prepare the immediate-release component, the immediate-release microparticles prepared according to Example 1 were added to 30 mL of water and gently stirred to dissolve the immediate-release microparticles. The uncoated IR granulation had an average granule particle size (D50) of 225 μm to 275 μm. The IR granulation contained 90 wt% 4-((L-valyl)oxy)butanoic acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose, where the wt% is based on the total weight of the IR granulation. Water was added to bring the total volume to 250 mL to obtain the immediate-release component to be taken by the subject.

[0352] To prepare the modified-release compositions, the modified-release microparticles prepared according to Example 5 were added to 30 mL of water and gently mixed. Ora-Plus® (30 mL) was added, the contents gently mixed, and the subject ingested. Additional water, up to a total volume of 250 mL, was used to rinse the container and administer to the subject. MR1 granulation had a 60% wg coating, MR2 granulation had a 40% wg coating, and MR3 granulation had a 50% wg coating. The modified-release coatings contained 81.7 wt% ethylcellulose, 2.0 wt% hypromellose, and 16.3 wt% magnesium stearate, where the wt% are based on the total weight of the coating.

[0353] Each component contained 7.25 g of Compound (1) (equivalent to 3.172 g of gamma-hydroxybutyrate).

[0354] The plasma pharmacokinetic profiles for Compound (1) and γ-hydroxybutyrate following oral administration of immediate-release (IR) or modified-release (MR1-MR3) compositions to fasted healthy subjects are shown in Figure 17 for Compound (1) and Figure 18 for γ-hydroxybutyrate. The results represent the mean and standard deviation based on results for 7-8 subjects.

[0355] Pharmacokinetic parameters for Compound (1) and γ-hydroxybutyrate following oral administration of compositions containing IR and MR microparticles are provided in Tables 6 and 7, respectively. These results represent the mean and standard deviation based on results for 7-8 subjects. [Table 6] [Table 7]

[0356] C max ratio, AUC 0-inf Ratio, and AUC 0-8The ratios are shown in Table 8 and refer to the ratio of the gamma-hydroxybutyrate value to the corresponding Compound (1) value. [Table 8]

[0357] Example 8 Pharmacokinetics of Combined Release Compositions The pharmacokinetics of a combined release (CR) composition containing immediate release microparticles (IR component) and modified release microparticles (MR component) were determined.

[0358] The amounts of microparticles used to prepare the combined release compositions (CR1 and CR2) are summarized in Table 9. [Table 9]

[0359] To prepare the combined release composition, the amount of immediate-release microparticles was dissolved in 30 mL of water.Then, the dose of controlled-release microparticles was added and gently stirred.Thirty (30) mL of Ora-Plus®, an oral suspension vehicle, was added, and the mixture was gently stirred.The subject then drank the solution.The subject repeatedly rinsed the cup with up to 250 mL of water and drank the solution.

[0360] The plasma pharmacokinetic profiles for Compound (1) and γ-hydroxybutyrate after oral administration of combined release compositions (CR1 and CR2) to fasted healthy subjects are shown in Figures 19 and 20, respectively. The results represent the mean and standard deviation based on 12 subjects.

[0361] A summary of the pharmacokinetic parameters for Compound (1) and γ-hydroxybutyrate after oral administration of the combined release composition to fasted healthy subjects is provided in Tables 10 and 11. These results reflect the average values ​​obtained for 12 subjects. [Table 10] [Table 11]

[0362] C for combined release compositions max ratio, AUC 0-inf Ratio, and AUC 0-8 The ratios are shown in Table 12 and refer to the ratio of the gamma-hydroxybutyrate value to the corresponding Compound (1) value. [Table 12]

[0363] It should be noted that there are alternative ways of implementing the embodiments disclosed herein. Accordingly, the present embodiments should be considered as illustrative and not restrictive. Moreover, the claims are not limited to the details given herein, but are entitled to their full scope and equivalents.

Claims

1. 1. A modified release pharmaceutical granulation comprising a plurality of coated granules, the coated granules comprising a core and a modified release coating surrounding the core; the modified release coating comprising: 80% to 90% by weight of a matrix polymer; 10% to 20% by weight of an antistatic agent; The weight percentages are based on the total weight of the modified release coating, A modified release pharmaceutical granulation, wherein the core comprises greater than 85% by weight of 4-((L-valyl)oxy)butanoic acid, the weight percentage being based on the total weight of the core.

2. 2. The pharmaceutical granulation of claim 1, wherein the pharmaceutical granulation is characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, the PSD being determined by sieve analysis.

3. 3. The pharmaceutical granule of claim 1, wherein the pharmaceutical granule comprises 50% to 90% by weight of 4-((L-valyl)oxy)butanoic acid, the weight percentages being based on the total weight of the pharmaceutical granule.

4. The pharmaceutical granule according to any one of claims 1 to 3, wherein the matrix polymer comprises a water-insoluble polymer.

5. 5. The pharmaceutical granulation of claim 4, wherein the water-insoluble polymer comprises ethyl cellulose.

6. 6. The pharmaceutical granulation of any one of claims 1 to 5, wherein the matrix polymer comprises 0% to 10% by weight of a pore-forming polymer, the weight percentage being based on the total weight of the matrix polymer.

7. The pharmaceutical granulation of claim 6 , wherein the pore-forming polymer comprises a water-soluble polymer.

8. 8. The pharmaceutical granulation of claim 7, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

9. The pharmaceutical granulation of any one of claims 1 to 8, wherein the antistatic agent comprises talc, magnesium stearate, or a combination thereof.

10. the core represents 65% to 85% by weight of the total weight of the coated granules, 10. The pharmaceutical granule according to any one of claims 1 to 9, wherein the modified release coating represents from 15% to 40% by weight of the total weight of the coated granule.

11. 11. The pharmaceutical granulation according to any one of claims 1 to 10, wherein the modified release coating has a thickness of from 5 μm to 30 μm.

12. 12. The pharmaceutical granule of any one of claims 1 to 11, wherein the pharmaceutical granule has a water content of less than 2% by weight, the weight percentage being based on the total weight of the pharmaceutical granule.

13. 13. The pharmaceutical granulation of any one of claims 1 to 12, further comprising a seal coating surrounding the core, wherein the modified release coating surrounds the seal coating.

14. The seal coating Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Hydroxypropyl cellulose and talc, or 14. The pharmaceutical granulation of claim 13, comprising hydroxypropyl methylcellulose and talc.

15. 15. The pharmaceutical granule of claim 13 or 14, wherein the pharmaceutical granule comprises 2% to 15% by weight of the seal coating, the weight percentage being based on the total weight of the pharmaceutical granule.

16. 16. The pharmaceutical granulation of any one of claims 1 to 15, wherein 30% to 80% of the 4-((L-valyl)oxy)butanoic acid is released from the pharmaceutical granulation within 2 hours when tested in a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm.

17. 17. The pharmaceutical granulation of any one of claims 1 to 16, wherein 50% to 90% of the 4-((L-valyl)oxy)butanoic acid is released from the pharmaceutical granulation within 4 hours when tested in a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm.

18. 18. The pharmaceutical granulation of any one of claims 1 to 17, wherein 60% to 100% of the 4-((L-valyl)oxy)butanoic acid is released from the pharmaceutical granulation within 6 hours when tested in a USP Type 2 dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm.

19. 19. The pharmaceutical granulation of any one of claims 1 to 18, wherein the modified release pharmaceutical granulation exhibits a dissolution profile that is bioequivalent to the dissolution profiles shown in any one of Figures 6, 12, and 15 when tested in a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

20. 19. The pharmaceutical granulation of any one of claims 1 to 18, wherein the modified release pharmaceutical granulation exhibits a dissolution profile that is bioequivalent to the dissolution profiles shown in any one of Figures 6, 12, and 15 when tested in a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

21. The pharmaceutical granule according to any one of claims 1 to 20, wherein the pharmaceutical granule does not contain a plasticizer.

22. A pharmaceutical composition comprising the pharmaceutical granule according to any one of claims 1 to 20.

23. 23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is an oral composition.

24. The oral composition comprises: A controlled release component, wherein the controlled release portion comprises the pharmaceutical granulation; 24. The pharmaceutical composition of claim 22 or 23, comprising an immediate-release component.

25. 25. The pharmaceutical composition of claim 24, wherein the immediate-release component dissolves in water in less than 5 minutes.

26. The pharmaceutical composition according to any one of claims 23 to 25, wherein the oral composition is a BID formulation.

27. The pharmaceutical composition of any one of claims 23 to 25, wherein the oral composition is a QD formulation.

28. 28. The pharmaceutical composition of any one of claims 22 to 27, wherein the pharmaceutical composition comprises 500 mg equivalent to 12 g equivalent of 4-((L-valyl)oxy)butanoic acid.

29. 29. The pharmaceutical composition of any one of claims 22 to 28, wherein the pharmaceutical composition comprises a sustained release oral composition, a delayed release composition, an immediate release composition, or a combination of any of the foregoing.

30. 30. The pharmaceutical composition according to any one of claims 22 to 29, comprising a therapeutically effective amount of 4-((L-valyl)oxy)butanoic acid for treating a disease in a patient, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

31. 31. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 22 to 30, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

32. 32. The method of claim 31, wherein the disease is cataplexy associated with narcolepsy.

33. 32. The method of claim 31, wherein the disorder is excessive daytime sleepiness associated with narcolepsy.

34. 32. The method of claim 31, wherein the disorder is excessive daytime sleepiness in patients with Parkinson's disease.

35. 32. The method of claim 31, wherein the disorder is chronic fatigue in patients with Parkinson's disease.

36. 36. The method of any one of claims 31 to 35, wherein administering comprises oral administration.

37. 37. The method of claim 36, wherein the administration is oral and the administration is in a fasted state.

38. The method of claim 36, wherein the administration is oral and / or administered in a fed state.

39. 1. A method for coating a granulation, comprising applying a coating composition to a pharmaceutical granulation comprising a plurality of granules comprising 4-((L-valyl)oxy)butanoic acid, wherein the coating composition comprises: 6% to 14% by weight solids; 0% to 20% by weight of water; 70% to 95% by weight of ethanol; The method wherein the weight percentage is based on the total weight of the coating formulation.

40. The solid is a matrix polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, or a combination thereof; and an antistatic agent selected from talc, magnesium stearate, or a combination thereof.

41. The method of any one of claims 39 to 40, wherein applying comprises spraying.

42. 1. A pharmaceutical composition comprising: an immediate release (IR) component, said immediate release component comprising from 1.2 g equivalent of gamma-hydroxybutyrate to 4.0 g equivalent of gamma-hydroxybutyrate; A modified release (MR) component, wherein the modified release component comprises: a modified release (MR) component comprising the equivalent of 3 g to 9 g of gamma-hydroxybutyrate; A pharmaceutical composition comprising the modified release granule of any one of claims 1 to 21.

43. 43. The pharmaceutical composition of claim 42, wherein the immediate-release component and the modified-release component each comprise 4-((L-valyl)oxy)butanoic acid.

44. 44. The pharmaceutical composition of claim 42 or 43, wherein the gamma-hydroxybutyrate equivalent is in the form of gamma-((L-valyl)oxy)butanoic acid.

45. the immediate-release component comprises 10% to 50% by weight of the 4-((L-valyl)oxy)butanoic acid; the controlled-release component comprises 50% to 90% by weight of the 4-((L-valyl)oxy)butanoic acid; 45. The pharmaceutical composition of claim 43 or 44, wherein the weight percentages are based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

46. the immediate release component comprises 2 g to 7 g of 4-((L-valyl)oxy)butanoic acid in the form 46. ​​The pharmaceutical composition of any one of claims 43 to 45, wherein the modified release component comprises 7 g to 15 g of 4-((L-valyl)oxy)butanoic acid.

47. the immediate release component comprises between 1 g equivalent and 4 g equivalent of gamma-hydroxybutyrate; 47. The pharmaceutical composition of any one of claims 42 to 46, wherein the modified release component comprises 3.5g equivalents to 8.5g equivalents of gamma-hydroxybutyrate.

48. 48. The pharmaceutical composition of any one of claims 42 to 47, wherein the weight ratio of gm equivalents of gamma-hydroxybutyrate in the immediate-release component to the gm equivalents of gamma-hydroxybutyrate in the modified-release component is from 1.5 to 3.

5.

49. 49. The pharmaceutical composition of any one of claims 42 to 48, wherein the immediate release component comprises a plurality of immediate release microparticles.

50. 50. The pharmaceutical composition of claim 49, wherein the immediate-release microparticles comprise greater than 90% by weight of 4-((L-valyl)oxy)butanoic acid, wherein the weight percentage is based on the total weight of the immediate-release microparticles.

51. 51. The pharmaceutical composition of claim 49 or 50, wherein the rapid-release microparticles have a volume-average diameter D(4.3) of 200 μm to 500 μm.

52. 52. The pharmaceutical composition of any one of claims 42 to 51, wherein the immediate release component comprises a solution suitable for oral administration.

53. 53. The pharmaceutical composition of any one of claims 42 to 52, wherein the modified release component comprises a plurality of modified release microparticles.

54. 54. The pharmaceutical composition of any one of claims 42 to 53, wherein the modified release component comprises a suspension of modified release microparticles suitable for oral administration.

55. 55. The pharmaceutical composition of claim 53 or 54, wherein the modified release microparticle comprises a core and a modified release coating surrounding the core.

56. 56. The pharmaceutical composition of claim 55, wherein the core comprises greater than 85% by weight of 4-((L-valyl)oxy)butanoic acid, wherein the weight percentage is based on the total weight of the core.

57. 56. The pharmaceutical composition of claim 55, wherein the core comprises greater than 90% by weight of 4-((L-valyl)oxy)butanoic acid, wherein the weight percentage is based on the total weight of the core.

58. 58. The pharmaceutical composition of any one of claims 55 to 57, wherein the core comprises immediate release macroparticles comprising 4-((L-valyl)oxy)butanoic acid.

59. 59. The pharmaceutical composition of any one of claims 53 to 58, wherein the modified release microparticles comprise 10% to 50% by weight of the modified release coating, wherein the weight percentage is based on the total weight of the modified release microparticles.

60. the modified release microparticles comprising: 24% to 34% by weight of the modified release coating (MR2); 28% to 38% by weight of the modified release coating (MR3), or 32% to 42% by weight of said modified release coating (MR1); 60. The pharmaceutical composition of any one of claims 53 to 59, wherein the weight percentages are based on the total weight of the modified release microparticles.

61. Following oral administration of 7.25 g of an IR component containing 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid showed a mean t １／２ , average T of 0.8 to 1.0 hours ｍａｘ , mean C of 14 μg / mL to 18 μg / mL ｍａｘ , mean AUC of 14h×μg / mL to 18h×μg / mL ０－６ , AUC of 14h×μg / mL to 18h×μg / mL ０－ｉｎｆ and a CL / F of 44 L / h to 52 L / h).

62. Following oral administration of an IR composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate showed a mean t １／２ , average T of 1.1 to 1.5 hours ｍａｘ , mean C of 76 μg / mL to 96 μg / mL ｍａｘ , AUC of 219h×μg / mL to 259h×μg / mL ０－６ , AUC of 226h×μg / mL to 266h×μg / mL ０－ｉｎｆ and a CL / F of 21 L / h to 41 L / h.

63. Following oral administration of an IR composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a C of 4.9 to 6.

9. ｍａｘ Ratio, and AUC of 14-26 ０－ｉｎｆ 63. The pharmaceutical composition of any one of claims 42 to 62, characterized by a ratio, said ratio referring to the ratio of gamma-hydroxybutyrate value to 4-((L-valyl)oxy)butanoic acid value.

64. Following oral administration of a modified release (MR1) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid showed a mean t １／２ , mean T of 1.4 to 1.8 hours ｍａｘ , mean C of 2 μg / mL to 6 μg / mL ｍａｘ , mean AUC of 7h×μg / mL to 11h×μg / mL ０－６ , mean AUC of 7h×μg / mL to 11h×μg / mL ０－ｉｎｆ and an average CL / F of 818 L / h to 858 L / h.

65. Following oral administration of a modified-release (MR1) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t １／２ , mean T of 2.2 to 2.6 hours ｍａｘ , mean C of 17 μg / mL to 37 μg / mL ｍａｘ , mean AUC of 76h×μg / mL to 96h×μg / mL ０－６ , mean AUC of 75h×μg / mL to 115h×μg / mL ０－ｉｎｆ and an average CL / F of 85 L / h to 105 L / h.

66. Following oral administration of a modified release (MR1) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a C of 6.2 to 7.

2. ｍａｘ Ratio, and AUC of 9.0 to 11.0 ０－ｉｎｆ 66. The pharmaceutical composition of any one of claims 42 to 65, characterized by a ratio, wherein said ratio refers to the ratio of the gamma-hydroxybutyrate value to the 4-((L-valyl)oxy)butanoic acid value.

67. Following oral administration of a modified release (MR2) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid showed a mean t １／２ , mean T of 1.2 to 1.6 hours ｍａｘ , mean C of 4 μg / mL to 8 μg / mL ｍａｘ , mean AUC of 8h×μg / mL to 12h×μg / mL ０－６ , mean AUC of 8h×μg / mL to 12h×μg / mL ０－ｉｎｆ and an average CL / F of 720 L / h to 800 L / h.

68. Following oral administration of a modified release (MR2) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t １／２ , mean T of 2.2 to 2.6 hours ｍａｘ , mean C of 34 μg / mL to 38 μg / mL ｍａｘ , mean AUC of 102h×μg / mL to 122h×μg / mL ０－６ , mean AUC of 110h×μg / mL to 130h×μg / mL ０－ｉｎｆ and an average CL / F of 62 L / h to 82 L / h.

69. Following oral administration of a modified release (MR2) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a C of 5.9 to 6.

7. ｍａｘ ratio, and AUC of 11.5 to 12.3 ０－ｉｎｆ 69. The pharmaceutical composition of any one of claims 42 to 68, characterized by a ratio, wherein said ratio refers to the ratio of the gamma-hydroxybutyrate value to the 4-((L-valyl)oxy)butanoic acid value.

70. Following oral administration of a modified-release (MR3) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid showed a mean t １／２ , average T of 0.9 to 1.3 hours ｍａｘ , mean C of 3 μg / mL to 7 μg / mL ｍａｘ , mean AUC of 8h×μg / mL to 12h×μg / mL ０－６ , mean AUC of 10h×μg / mL to 12h×μg / mL ０－ｉｎｆ and an average CL / F of 760 L / h to 840 L / h.

71. Following oral administration of a modified-release (M3) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of gamma-hydroxybutyrate showed a mean t １／２ , mean T of 1.7 to 2.1 hours ｍａｘ , mean C of 26 μg / mL to 34 μg / mL ｍａｘ , mean AUC of 82h×μg / mL to 122h×μg / mL ０－６ , mean AUC of 90h×μg / mL to 130h×μg / mL ０－ｉｎｆ and an average CL / F of 69 L / h to 89 L / h.

72. Following oral administration of a modified release (MR3) composition containing 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a C of 6.1 to 6.

9. ｍａｘ ratio, and AUC of 11.0 to 11.8 ０－ｉｎｆ 72. The pharmaceutical composition of any one of claims 42 to 71, characterized by a ratio, wherein said ratio refers to the ratio of the gamma-hydroxybutyrate value to the 4-((L-valyl)oxy)butanoic acid value.

73. 73. The pharmaceutical composition of any one of claims 42-72, wherein after oral administration of an immediate release (IR) composition comprising 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate are bioequivalent to the plasma pharmacokinetic profiles presented in Tables 6 and 7 or shown in Figures 17 and 18.

74. 74. The pharmaceutical composition of any one of claims 42-73, wherein after oral administration of a modified release (M1) composition comprising 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate are bioequivalent to those presented in Tables 6 and 7 or shown in Figures 17 and 18.

75. 75. The pharmaceutical composition of any one of claims 42-74, wherein after oral administration of a modified release (M2) composition comprising 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate are bioequivalent to those presented in Tables 6 and 7 or shown in Figures 17 and 18.

76. 75. The pharmaceutical composition of any one of claims 43-74, wherein after oral administration of a modified release (M3) composition comprising 7.25 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate are bioequivalent to those presented in Tables 6 and 7 or shown in Figures 17 and 18.

77. the immediate-release component comprises 2 g to 8 g of 4-((L-valyl)oxy)butanoic acid; 77. The pharmaceutical composition of any one of claims 42 to 76, wherein the modified release component comprises 8 g to 16 g of 4-((L-valyl)oxy)butanoic acid in the form

78. the immediate-release component comprises 20% to 40% by weight of 4-((L-valyl)oxy)butanoic acid; the modified-release component comprises 60% to 80% by weight of 4-((L-valyl)oxy)butanoic acid; 78. The pharmaceutical composition of any one of claims 42-77, wherein the weight percentages are based on the total weight of 4-((L-valyl)oxy)butanoic acid.

79. 79. The pharmaceutical composition of any one of claims 42 to 78, wherein the weight ratio of 4-((L-valyl)oxy)butanoic acid in the immediate-release component to 4-((L-valyl)oxy)butanoic acid in the modified-release component is from 1:2 to 1:

3.

80. to a group of fasting healthy subjects, the IR component comprising 4.1 g of 4-((L-valyl)oxy)butanoic acid; and the modified release (MR1) component comprising 10 g of 4-((L-valyl)oxy)butanoic acid, After oral administration of the pharmaceutical composition to a population of patients, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid exhibits a mean t １／２ , average T of 1.3 to 1.5 hours ｍａｘ , mean C of 12 μg / mL to 18 μg / mL ｍａｘ , mean AUC of 20h×μg / mL to 30h×μg / mL ０－６ , mean AUC of 22h×μg / mL to 32h×μg / mL ０－ｉｎｆ and an average CL / F of 536 L / h to 576 L / h.

81. to a group of fasting healthy subjects, an IR component comprising 4.1 g of 4-((L-valyl)oxy)butanoic acid; and a modified release (MR1) component comprising 10 g of 4-((L-valyl)oxy)butanoic acid, After oral administration of the pharmaceutical composition to a population of patients, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibits a mean t １／２ , mean T of 2.5 to 2.9 hours ｍａｘ , mean C of 88 μg / mL to 128 μg / mL ｍａｘ , mean AUC of 380h×μg / mL to 420h×μg / mL ０－６ , mean AUC of 514h×μg / mL to 554h×μg / mL ０－ｉｎｆ and an average CL / F of 22 L / h to 42 L / h.

82. to a group of fasting healthy subjects, an IR component comprising 4.1 g of 4-((L-valyl)oxy)butanoic acid; and a modified release (MR1) component comprising 10 g of 4-((L-valyl)oxy)butanoic acid, After oral administration of the pharmaceutical composition to a population of patients, the plasma pharmacokinetic profile exhibits a C of 7.0 to 9.

0. ｍａｘ Ratio, and AUC of 18.3 to 20.3 ０－ｉｎｆ 82. The pharmaceutical composition of claim 80 or 81, characterized by a ratio, said ratio referring to the ratio of a gamma-hydroxybutyrate value to a corresponding 4-((L-valyl)oxy)butanoic acid value.

83. 80. The pharmaceutical composition of any one of claims 42-79, wherein after oral administration of 7.25 g of a combined release (CR1) composition comprising 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate is bioequivalent to the plasma pharmacokinetic profiles presented in Tables 10 and 11 or shown in Figures 19 and 20.

84. to a group of fasting healthy subjects, an IR component comprising 4.5 g of 4-((L-valyl)oxy)butanoic acid; and a combined release composition (CR2) comprising: After oral administration of the pharmaceutical composition to a population of patients, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid exhibits a mean t １／２ , average T of 1.1 to 1.5 hours ｍａｘ , mean C of 10 μg / mL to 14 μg / mL ｍａｘ , mean AUC of 16h×μg / mL to 24h×μg / mL ０－６ , mean AUC of 11h×μg / mL to 31h×μg / mL ０－ｉｎｆ and an average CL / F of 660 L / h to 740 L / h.

85. to a group of fasting healthy subjects, an IR component comprising 4.5 g of 4-((L-valyl)oxy)butanoic acid; and a combined release composition (CR2) comprising: After oral administration of the pharmaceutical composition to a population of patients, the plasma pharmacokinetic profile of gamma-hydroxybutyrate exhibits a mean t １／２ , mean T of 2.0 to 2.4 hours ｍａｘ , mean C of 73 μg / mL to 93 μg / mL ｍａｘ , mean AUC of 302h×μg / mL to 342h×μg / mL ０－６ , mean AUC of 366h×μg / mL to 406h×μg / mL ０－ｉｎｆ and an average CL / F of 33 L / h to 53 L / h.

86. After oral administration of a combined release composition (CR2) comprising an IR component comprising 4.5 g of 4-((L-valyl)oxy)butanoic acid, and Following oral administration of 10 g of a modified release (MR2) component comprising 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile exhibited a C of 6.8 to 8.

8. ｍａｘ Ratio, and AUC of 16.3 to 20.3 ０－ｉｎｆ 86. The pharmaceutical composition of claim 84 or 85, characterized by a ratio, said ratio referring to the ratio of gamma-hydroxybutyrate value to the corresponding 4-((L-valyl)oxy)butanoic acid value.

87. 80. The pharmaceutical composition of any one of claims 42-79, wherein after oral administration of 7.25 g of a combined release (CR2) composition comprising 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butanoic acid and gamma-hydroxybutyrate is bioequivalent to the plasma pharmacokinetic profiles presented in Tables 10 and 11 or shown in Figures 19 and 20.

88. 88. The pharmaceutical composition of any one of claims 42-87, wherein 6 hours after oral administration of the pharmaceutical composition to a population of fasted healthy subjects, the concentration of gamma-hydroxybutyrate in the plasma of the subjects is less than 15 μg / mL, less than 10 μg / mL, or less than 5 μg / mL.

89. After oral administration of 10 g to 20 g of a pharmaceutical composition comprising 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the concentration of gamma-hydroxybutyrate in the plasma of the subjects is determined by: (a) the AUC of the gamma-hydroxybutyrate after oral administration of the immediate-release component to the population of fasted healthy subjects; ｉｎｆ and (b) the AUC of gamma-hydroxybutyrate after oral administration of the modified-release component. ｉｎｆ The pharmaceutical composition of any one of claims 42 to 88, wherein the total amount of

90. 90. The pharmaceutical composition of any one of claims 42-89, wherein 6 to 8 hours after oral administration of a pharmaceutical composition comprising 10 g to 20 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects, the concentration of gamma-hydroxybutyrate in the plasma of the subjects exceeds the sum of (a) the concentration of gamma-hydroxybutyrate 6 to 8 hours after oral administration of the immediate-release component and (b) the concentration of gamma-hydroxybutyrate 6 to 8 hours after oral administration of the modified-release component to the population of fasted healthy subjects.

91. 91. The pharmaceutical composition of any one of claims 42-90, wherein after oral administration of a pharmaceutical composition comprising 10 g to 20 g of 4-((L-valyl)oxy)butanoic acid to a population of healthy, fasted subjects, the concentration 6 to 8 hours after administration exceeds the concentration of gamma-hydroxybutyrate in the plasma of the subjects after administration of the modified-release component alone.

92. The mean gamma-hydroxybutyrate AUC following oral administration of the immediate release component and the modified release component to a population of fasted healthy subjects. ０－ｉｎｆ the mean gamma-hydroxybutyrate AUC after oral administration of the immediate-release component alone ０－ｉｎｆ and the mean gamma-hydroxybutyrate AUC after oral administration of the controlled-release component alone. ０－ｉｎｆ The pharmaceutical composition of any one of claims 42 to 91, wherein the total amount of

93. the mean 4-((L-valyl)oxy)butanoic acid AUC following oral administration of the immediate release component and the modified release component to a population of subjects; ０－ｉｎｆ the mean 4-((L-valyl)oxy)butanoic acid AUC after oral administration of the immediate-release component alone ０－ｉｎｆ and the mean 4-((L-valyl)oxy)butanoic acid AUC after oral administration of the controlled-release component alone. ０－ｉｎｆ The pharmaceutical composition according to any one of claims 42 to 92, wherein the total of

94. The mean gamma-hydroxybutyrate AUC following oral administration of a pharmaceutical composition comprising an immediate-release component comprising 4.52 g of 4-((L-valyl)oxy)butanoic acid and a modified-release component comprising 10 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects. ０－ｉｎｆ The mean gamma-hydroxybutyrate AUC after oral administration of 7.25 g of an immediate-release component containing 4-((L-valyl)oxy)butanoic acid alone ０－ｉｎｆ and the mean gamma-hydroxybutyrate AUC after oral administration of 7.25 g of a modified-release formulation containing 4-((L-valyl)oxy)butanoic acid alone. ０－ｉｎｆ The pharmaceutical composition of any one of claims 42 to 92, wherein the total amount of

95. The mean 4-((L-valyl)oxy)butanoic acid AUC following oral administration of a pharmaceutical composition comprising an immediate-release component comprising 4.52 g of 4-((L-valyl)oxy)butanoic acid and a modified-release component comprising 10 g of 4-((L-valyl)oxy)butanoic acid to a population of fasted healthy subjects. ０－ｉｎｆ the mean 4-((L-valyl)oxy)butanoic acid AUC after oral administration of 7.25 g of an immediate-release component containing 4-((L-valyl)oxy)butanoic acid alone ０－ｉｎｆ and the mean 4-((L-valyl)oxy)butanoic acid AUC after oral administration of 7.25 g of a modified-release formulation containing 4-((L-valyl)oxy)butanoic acid alone. ０－ｉｎｆ The pharmaceutical composition according to any one of claims 42 to 93, wherein the total amount of

96. 96. A method of treating fatigue or excessive daytime sleepiness associated with narcolepsy in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42 to 95.

97. 96. A method of treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42-95.

98. 96. A method of treating symptoms associated with narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient, the method comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42-95.

99. 96. A method of treating REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42 to 95.

100. 96. A method of treating symptoms associated with REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42-95.

101. 100. A method of treating a sleep disorder associated with a bacterial infection in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42 to 95.

102. 102. The method of claim 101, wherein the bacterial infection is a COVID-19 infection.

103. 96. A method of enhancing cognitive function in patients with neurological disorders, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 42 to 95.

104. 104. The method of any one of claims 97-103, wherein administering comprises QD administering.

105. 104. The method of any one of claims 97-103, wherein administering comprises BID administration.

106. 104. The method of any one of claims 97-103, wherein administering comprises administering once a night.

107. A kit comprising the pharmaceutical composition of any one of claims 42 to 95.

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