Modified release composition of gamma-hydroxybutyric acid derivatives

Abstract

A pharmaceutical granule having a functional coating surrounding a core containing 4-((L-valyl)oxy)butanoic acid is disclosed. The functional coating provides immediate release or modified release of 4-((L-valyl)oxy)butanoic acid. The pharmaceutical granule may be used in an oral pharmaceutical composition.

Description

Technology Field

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

[0002] field

[0003] The present disclosure relates to a 4-(( having a functional coating L This relates to pharmaceutical granules of valyl(oxy)butanoic acid. Coated pharmaceutical granules can be used in modified release oral compositions. Background Technology

[0004] In certain treatment methods, it is necessary to administer a high dose of a pharmaceutically active ingredient. To minimize the amount of oral pharmaceutical composition administered to the patient in such treatments, it is desirable for the pharmaceutical composition to contain a high content of the pharmaceutically active ingredient and for the amount of pharmaceutical excipients to be minimized.

[0005] Oral modified-release dosage forms may contain granules coated with a functional coating that provides a desired release profile in the gastrointestinal tract.

[0006] A modified release composition is desired that contains pharmaceutical granules having a high bulk density of active pharmaceutical ingredients and is suitable for administration once or twice daily. To improve palatability, it is desirable that the pharmaceutical granules have a low average particle size, such as 200 μm to 400 μm. Prior art literature

[65535] (Patent Document 1) US 8529954 B2

[0007] According to the present invention, a modified release pharmaceutical granule comprises a plurality of coated granules, wherein the granule comprises a core and a modified release coating surrounding the core, wherein the modified release coating comprises: 50 wt% to 85 wt% of a matrix polymer; and 10 wt% to 20 wt% of an antistatic agent; wherein the weight% is based on the total weight of the modified release coating. The pharmaceutical granule is characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, wherein the PSD is determined by sieve analysis; and the core comprises more than 90 wt% of 4-((L-valyl)oxy)butanoic acid, wherein the wt% is based on the total weight of the core.

[0008] According to the present invention, a pharmaceutical composition comprises a pharmaceutical granule according to the present invention.

[0009] According to the present invention, a method for coating granules is 4-(( L - The method comprises the step of applying a coating composition to a pharmaceutical granule formulation comprising a plurality of granules including valyl(oxy)butanoic acid, wherein the coating composition comprises: 6 wt% to 14 wt% solids; 0 wt% to 20 wt% water; and 70 wt% to 95 wt% ethanol, wherein wt% is based on the total weight of the coating formulation.

[0010] According to the present invention, a pharmaceutical composition comprises: an immediate-release (IR) component, wherein the immediate-release component is 1.2 g-equivalents of γ-hydroxybutyrate to 4.0 g-equivalents of γ-hydroxybutyrate; and a modified-release (MR) component, wherein the modified-release component is 3 g-equivalents of γ-hydroxybutyrate to 9 g-equivalents of γ-hydroxybutyrate; and a modified-release granule according to the present invention.

[0011] According to the present invention, a method for treating fatigue or excessive daytime sleepiness associated with narcolepsy in a patient comprises the step of orally administering a therapeutically effective amount of a pharmaceutical composition according to the present invention to a patient requiring such treatment.

[0012] According to the present invention, a method for 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 who requires such treatment comprises the step of orally administering a therapeutically effective amount of a pharmaceutical composition according to the present invention to a patient who requires such treatment.

[0013] According to the present invention, the kit comprises a pharmaceutical composition according to the present invention. Brief explanation of the drawing

[0014] Those skilled in the art will understand that the drawings described herein are for illustrative purposes only. The drawings are not intended to limit the scope of the disclosure. Figure 1 shows the particle size distribution of granules containing a hydroxypropylmethyl cellulose sealing coating as described in Example 1. Figures 2a to 2e show scanning electron microscope (SEM) images of seal-coated granules at different magnifications as described in Example 1. Figure 3 shows the particle size distribution of granules containing a hydroxypropyl cellulose sealing coating as described in Example 2. Figures 4a to 4e show SEM images of seal-coated granules at different magnifications as described in Example 2. Figure 5 shows the particle size distribution of coated granules containing a 40 %wg ethylcellulose / hydroxypropyl cellulose functional coating as described in Example 3. FIG. 6 shows 4-(( from granules containing ethylcellulose / hydroxypropyl cellulose functional coatings exhibiting different %wg as described in Example 3 L - Shows the solubility profile of valyl(oxy)butanoic acid. Figures 7a to 7d show SEM images of 40 %wg coated granules at different magnifications as described in Example 3. Figure 7e shows an SEM image of a cross-section of a 40 %wg coated granule as described in Example 3. Figure 8 shows the particle size distribution of coated granules containing a 40 %wg ethylcellulose / hydroxypropyl cellulose functional coating as described in Example 4. FIG. 9 shows 4-(( from granules containing ethylcellulose / hydroxypropyl cellulose functional coatings exhibiting different %wg as described in Example 4 L - Shows the solubility profile of valyl(oxy)butanoic acid. Figures 10a to 10d show SEM images of 40 %wg coated granules at different magnifications as described in Example 4. Figure 10e shows an SEM image of a cross-section of a 40 %wg coated granule as described in Example 4. Figure 11 shows the particle size distribution of coated granules containing a 40 %wg ethylcellulose / hydroxypropyl cellulose functional coating as described in Example 5. FIG. 12 shows 4-(( from granules containing ethylcellulose / hydroxypropyl cellulose functional coatings exhibiting different %wg as described in Example 5 L - Shows the solubility profile of valyl(oxy)butanoic acid. Figures 13a to 13d show SEM images of 40 %wg coated granules at different magnifications as described in Example 5. Figure 13e shows an SEM image of a cross-section of a 40 %wg coated granule as described in Example 5. Figure 14 shows the particle size distribution of coated granules containing a 40% wg ethylcellulose functional coating as described in Example 6. FIG. 15 shows the dissolution profile of an active pharmaceutical ingredient from granules containing an ethylcellulose functional coating with different %wg values ​​as described in Example 6. FIGS. 16a to 16d show SEM images of 40 %wg coated granules at different magnifications as described in Example 6. Figure 16e shows an SEM image of a cross-section of a 40 %wg coated granule as described in Example 8. FIG. 17 shows the average plasma concentration of compound (1) after oral administration of the immediate release (IR) composition of compound (1) or three modified release (MR1 to MR3) compositions to healthy fasting subjects. FIG. 18 shows the average plasma γ-hydroxybutyrate concentration after oral administration of the immediate-release (IR) composition of compound (1) or three modified-release (MR1 to MR3) compositions to healthy fasting subjects. FIG. 19 shows the average plasma concentration of compound (1) after two controlled-release compositions of compound (1) were orally administered to healthy fasting subjects. FIG. 20 shows the average plasma γ-hydroxybutyrate concentration after oral administration of two controlled-release compositions of compound (1) to healthy fasting subjects. Specific details for implementing the invention

[0015] For the purposes of the detailed description below, it should be understood that the embodiments provided by this disclosure may assume various alternative variations and sequences of steps, except as expressly contrary. Furthermore, in any operating example, or unless otherwise indicated, all numbers expressing the amount of a component used, for example, in the specification and claims, should be understood as being modified by the term “about” in all cases. Accordingly, unless otherwise indicated, the numerical parameters described in the following specification and appended claims are approximations that may vary depending on the preferred characteristics obtained by the invention. At least, without attempting to limit the application of the equivalence principle to the scope of the claims, each numerical parameter should be interpreted in light of at least the reported significant digits and by applying conventional rounding techniques.

[0016] Although the numerical ranges and parameters describing the broad scope of the invention are approximations, the figures presented in specific embodiments are reported as accurately as possible. However, all figures inherently contain certain errors resulting from the standard variance found in the corresponding test measurements.

[0017] Additionally, it should be understood that any numerical range cited herein is intended to include all sub-ranges contained therein. For example, the range “1 to 10” is intended to include all sub-ranges between (and including) the cited minimum value 1 and the cited maximum value 10, that is, all sub-ranges having a minimum value of 1 or greater and a maximum value 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, time-release coatings, and delayed-release coatings. Functional coatings provide a desired release profile in the gastrointestinal tract after oral administration, such as 4-(( L- It is configured to provide desired properties to granules containing valyl(oxy)butanoic acid.

[0019] "Immediate release" refers to a pharmaceutical composition that releases substantially all of the pharmaceutically active ingredient into the patient's gastrointestinal tract in less than one hour after oral administration, e.g., in less than 50 minutes, in less than 40 minutes, in less than 30 minutes, in less than 20 minutes, or in less than 10 minutes after oral administration. For example, an immediate-release formulation may release more than 90%, in more than 95%, or in more than 98% of the pharmaceutically active ingredient in the pharmaceutical composition into the gastrointestinal tract in less than one hour after oral administration, e.g., in less than 50 minutes, in less than 40 minutes, in less than 30 minutes, in less than 20 minutes, or in less than 10 minutes. An immediate-release pharmaceutical composition may be suitable for administering a pharmaceutically active ingredient that is absorbed into the systemic circulation from the upper gastrointestinal tract.

[0020] "Modified release" pharmaceutical compositions include controlled-release compositions, delayed-release compositions, extended-release compositions, sustained-release compositions, time-release compositions, pulsatile-release compositions, and pH-dependent-release compositions. These compositions are intended to release a pharmaceutical active ingredient from the pharmaceutical composition at a desired rate and / or at a desired time and / or at specific locations or sites within the gastrointestinal tract and / or at a specific pH within the gastrointestinal tract following oral administration by a patient. The USP defines a modified-release system as a system in which the time pathway or location of drug release, or both, is selected to achieve goals of therapeutic effect or convenience that are not met by immediate-release formulations. Modified-release oral formulations may include extended-release and delayed-release components. A delayed-release formulation is a form that releases the drug all at once at a time other than immediately after administration. Modified release compositions may include delayed release using an enteric coating, site-specific or time-dependent release such as for colon delivery, extended release including compositions capable of providing zero-order, first-order, or biphasic release profiles, and programmed release such as pulsatile and delayed extended release.

[0021] "Sustained-release" pharmaceutical compositions and coatings provide a dissolution rate over an extended period after oral administration. Granules comprising granules having a sustained-release coating may be referred to as sustained-release granules. Pharmaceutical compositions comprising sustained-release granules may be referred to as sustained-release pharmaceutical compositions.

[0022] "pH-releasing" pharmaceutical compositions and coatings provide an increased dissolution rate at the intended pH.

[0023] "Pulsating release" pharmaceutical compositions and coatings exhibit an increased dissolution rate at intervals, wherein the release interval may be determined by time, exposure to an internal stimulus, or exposure to an external stimulus. Examples of pulsating release systems include capsular systems, osmotic systems, systems having erosible membranes, and systems having ruptureable coatings. Examples of stimuli include temperature, chemicals, electrical stimulation, and magnetic stimulation.

[0024] "Time-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 the intended time after administration.

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

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

[0028] "Controlled-release pharmaceutical composition" refers to a pharmaceutical composition comprising immediately-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 mammals, for example, humans.

[0031] The term "pharmaceuticalally acceptable" refers to that which is approved or acceptable by federal or state regulatory agencies for use in animals, particularly in humans, or is listed in the United States Pharmacopoeia or other generally accepted pharmacopoeias.

[0032] "Pharmaceutically acceptable salts" refers to salts of a compound that possess the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed of an inorganic acid and one or more protic functional groups, such as primary, secondary, or tertiary amines in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, etc. Salts are organic acids, e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, 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, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphosulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, It may be formed by lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc. A salt may be formed when one or more acidic protons present in the parent compound are replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a combination thereof; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucarmine, etc. Pharmaceutically acceptable salts may be hydrochloride salts. Pharmaceutically acceptable salts may be sodium salts. In a compound having two or more ionizable groups, pharmaceutically acceptable salts may include one or more counterions, e.g., bi-salts, e.g., dihydrochloride salts.

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

[0034] "Percentage increase in weight" or "%wg," such as in a "35 %wg" coating, refers to coated granules or granules in which the weight of the coated granules or granules is greater than the weight of the uncoated granules or granules by the indicated percentage (%). For example, 35 %wg particles have a coating that increases the weight of the uncoated particles by 35%. For example, for granules with an initial weight of 100 gm, adding a 35 %wg coating increases the weight of the granules to 135 gm. The coating comprises 25.9 wt% of the total weight of the granules.

[0035] The dissolution profile was measured using a USP Type 2 dissolution device and sodium acetate buffer solution at pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

[0036] The "bioequivalence" value is C, which indicates substantially similar pharmacokinetic profiles and / or therapeutic effects. max Or it refers to pharmacokinetic values ​​such as AUC. Bioequivalence can be demonstrated by various in vivo and in vitro methods. These methods may include, for example, pharmacokinetics, pharmacodynamics, clinical, and in vitro studies. Bioequivalence is demonstrated by the loading dose, steady-state dose, initial or steady-state concentration of the drug, biological half-life, elimination rate, area under the curve (AUC), clearance, and peak concentration in blood or plasma (C). max), time to peak concentration (T max ), bioavailability, and efficacy may be demonstrated using any suitable pharmacokinetic measurement or combination of pharmacokinetic measurements known in the art. Values ​​may be demonstrated using AUC and / or C max If the geometric mean of is between 80% and 125% of the reference pharmacokinetic value (e.g., in a 90% confidence interval), it may be bioequivalent to the reference pharmacokinetic value.

[0037] The average AUC of the pharmaceutical composition is a pharmacokinetic profile of similar or bioequivalent properties. 0-inf The average AUC of the reference composition in a suitably designed crossover test 0-inf It is 80% to 125% of, and the average plasma concentration C of the pharmaceutical composition at 8 hours 8h a. Average plasma concentration C of the reference composition at 8 hours 8h 40% to 130% of, or the maximum plasma concentration of the pharmaceutical composition (C max ) is C of the reference composition max It refers to a pharmacokinetic profile that is 50% to 140% of .

[0038] "Eating state" refers to the period from immediately after eating up to 2 hours after eating. The eating state may include a period of less than 2 hours after eating.

[0039] "Fasting state" refers to the period 8 hours after a meal.

[0040] "Prodrugs" refer to derivatives of drug molecules that require modification within the body to provide an active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until they are converted into a parent drug. Prodrugs can typically be obtained by attaching a promotye to a parent drug through a functional group.

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

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

[0043] "Treating" or "treating" a disease or disorder refers to suppressing the disease or disorder, or one or more clinical symptoms of the disease or disorder, stopping the development of the disease or disorder, or one or more clinical symptoms of the disease or disorder, alleviating the disease or disorder, or one or more clinical symptoms of the disease or disorder, causing regression of the disease or disorder, or one or more clinical symptoms of the disease or disorder, or causing stabilization of the disease or disorder, and "treating" or "treating" a disease or disorder refers to producing a clinically beneficial effect without curing the underlying disease or disorder.

[0044] "Therapeutic effective dose" refers to an amount of a compound, such as a pharmaceutically active ingredient, that is sufficient to affect such treatment of the disease or at least one of its clinical symptoms when administered to a patient to treat the disease or at least one of its clinical symptoms. The "therapeutic effective dose" may vary depending, for example, on the compound, the disease and / or symptoms of the disease, the severity of the symptoms of the disease and / or disorder, the age, weight, and / or health of the patient to be treated, and the judgment of the prescribing physician. In any given example, the therapeutic effective dose may be identified by a person skilled in the art or determined by routine experimentation.

[0045] "Therapeutic effective dose" refers to the dose that provides effective treatment for a disease or disorder in a patient. The therapeutic effective dose may vary by compound and by patient, and may depend on factors such as the patient's pathological condition and delivery route. The therapeutic effective dose may be determined according to ordinary pharmacological procedures known to those skilled in the art.

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

[0047] Now, reference is made to pharmaceutical granules having a functional coating, a method for manufacturing coated pharmaceutical granules, and a pharmaceutical composition comprising coated pharmaceutical granules. The disclosed coated pharmaceutical granules, the composition comprising said coated pharmaceutical granules, and the method for manufacturing said coated pharmaceutical granules are not intended to limit the scope of the claims. On the contrary, the scope of the claims is intended to include all alternatives, modifications, and equivalents.

[0048] 4-(( L -Valyl)oxy)butyric acid is a precursor drug of γ-hydroxybutyric acid. When administered orally, 4-(( L -Valyl)oxy)butyric acid is absorbed in the gastrointestinal tract and metabolized in the systemic circulation to release γ-hydroxybutyric acid. γ-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, after oral administration to a patient, 4-(( L It can be used to provide modified release of -valyl)oxy)butanoic acid. Coated pharmaceutical granules are 4-(( LIt contains valyl(oxy)butanoic acid, which is a pharmaceutical active ingredient that is highly hygroscopic, highly water-soluble, and easily hydrolyzed. Coated pharmaceutical granules can be used to provide modified-release oral pharmaceutical compositions. Coated pharmaceutical granules provide high doses of 4-( L - It can be used for oral administration of valyl(oxy)butanoic acid.

[0050] The modified release granules provided by the present disclosure are 4-(( L It can be manufactured by coating granules containing valyl)oxy)butanoic acid. 4-(( L- Granules containing valyl(oxy)butanoic acid may be uncoated or may include a sealing coating.

[0051] The uncoated pharmaceutical granules provided by the present disclosure may comprise a plurality of granules, wherein the granules comprise more than 90 wt% of 4-(( L - It may contain valyl(oxy)butanoic acid, where wt% is based on the total weight of the granules; the uncoated pharmaceutical granules 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 PSD is determined by sieve analysis; and wt% is based on the total weight of the pharmaceutical granules.

[0052] Uncoated granules are high-loading 4-(( L - May contain valyl)oxy)butanoic acid. For example, the granules 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% of 4-(( L- It may contain valyl)oxy)butanoic acid, wherein wt% is based on the total weight of the uncoated granules. The uncoated granules are, for example, 90 wt% to 99.5 wt%, 95 wt% to 99.5 wt% of a γ-hydroxybutyric acid derivative, 96 wt% to 99 wt%, 97 wt% to 99 wt%, or 98 wt% to 99 wt% of a 4-(( L - May contain valyl(oxy)butanoic acid, where wt% is based on the total weight of uncoated granules.

[0053] 4-(( L - Valyl)oxy)butanoic acid has the structure of the following chemical formula (1):

[0054]

[0055] 4-(( L -Valyl)oxy)butyric acid is a precursor drug of γ-hydroxybutyric acid (GHB) having the structure of the following chemical formula (2):

[0056]

[0057] After administration, such as oral administration, 4-(( L -Varyl)oxy)butyric acid is metabolized in the systemic circulation to release γ-hydroxybutyric acid in the patient's plasma. 4-(( L -Valyl)oxy)butyric acid provides oral bioavailability of γ-hydroxybutyric acid in patients with more than 60% F.

[0058] The pharmaceutical composition provided by the present disclosure is 4-(( coated with a functional coating L - It includes pharmaceutical granules containing granules of valyl(oxy)butanoic acid.

[0059] Before forming into granules 4-(( L Valyl(oxy)butanoic acid can have a low bulk density.

[0060] 4-(( L- Valyl)oxy)butyric acid may 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.

[0061] 4-(( L -Valyl)oxy)butanoic acid may 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.

[0062] 4-(( L -Valyl)oxy)butanoic acid may have a particle size distribution characterized, for example, D10 of 1 μm to 3 μm, D50 of 6.5 μm to 8.5 μm, and D90 of 15 μm to 17 μm, wherein the particle size distribution is measured by laser diffraction.

[0063] 4-(( L - Valyl)oxy)butanoic acid may 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, wherein the particle size distribution is measured by laser diffraction.

[0064] 4-(( L Valyl(oxy)butanoic acid can be jet milled to reduce particle size.

[0065] 4-(( L Uncoated granules containing valyl(oxy)butanoic acid can be manufactured using MicroPX® micropelletization technology (Glatt GmbH).

[0066] 4-(( LIn the case of high-dose pharmaceutical compositions of valyl(oxy)butanoic acid, particularly when reconstituted as a suspension before administration, it may be useful to have small average diameters of uncoated granules and coated granules to improve palatability.

[0067] 4-(( L Uncoated pharmaceutical granules of valyl)oxy)butanoic acid may 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, wherein the PSD is determined by sieve analysis or laser diffraction.

[0068] Uncoated granules are high-loading 4-(( L - May contain valyl)oxy)butanoic acid. For example, uncoated granules 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% of 4-(( L - May contain valyl)oxy)butanoic acid, where wt% is based on the total weight of the uncoated granules. The uncoated granules are, for example, 95 wt% to 99.5 wt% of 4-(( L -Valyl)oxy)butanoic acid, 96 wt% to 99 wt%, 97 wt% to 99 wt%, or 98 wt% to 99 wt% of 4-(( L - May contain valyl(oxy)butanoic acid, where wt% is based on the total weight of uncoated granules.

[0069] The uncoated granules or granules provided by the present disclosure are, for example, more than 85 wt% of 4-(( L-Valyl)oxy)butanoic acid, 1 wt% to 10 wt% of an antistatic agent, such as magnesium silicate (talc), and 1 wt% to 10 wt% of a water-soluble polymer, such as hydroxypropylmethyl cellulose, wherein wt% is based on the total weight of the granules or granulated product. The uncoated granules or granulated products provided by the present disclosure may, for example, contain more than 90 wt% of 4-(( L -Valyl)oxy)butanoic acid, 2 wt% to 8 wt% of an antistatic agent, such as magnesium silicate (talc), and 2 wt% to 8 wt% of a water-soluble polymer, such as hydroxypropylmethyl cellulose, wherein wt% is based on the total weight of the granules or granulated product. The uncoated granules or granulated products provided by the present disclosure may, for example, contain more than 90 wt% of 4-(( L - It may contain valyl)oxy)butanoic acid, 3 wt% to 7 wt% of an antistatic agent, such as magnesium silicate (talc), and 3 wt% to 7 wt% of a water-soluble polymer, such as hydroxypropylmethyl cellulose, wherein wt% is based on the total weight of the granules or granulated product.

[0070] The uncoated granules provided by the present disclosure may be characterized by a sphericity of, for example, 0.90 to 1, e.g., 0.91 to 0.99, or 0.92 to 0.98, wherein the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated granules provided by the present disclosure may 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.

[0071] The uncoated granules provided by the present disclosure may comprise a plurality of granules characterized by a mode sphericity of, for example, 0.90 to 1, e.g., 0.91 to 0.99, or 0.92 to 0.98, wherein the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated granules provided by the present disclosure may comprise 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.

[0072] The uncoated granules provided by the present disclosure are solid and feature a substantially homogeneous composition throughout the granules.

[0073] The pharmaceutical granules provided by the present disclosure may include a sealing coating. Pharmaceutical granules including a sealing coating may be used as immediate-release pharmaceutical granules.

[0074] The pharmaceutical granules provided by the present disclosure are 4-(( L It may include sealing coating granules containing valyl(oxy)butanoic acid.

[0075] The sealing coating may comprise a water-soluble polymer such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or any water-soluble polymer disclosed herein.

[0076] The sealing coating may include an antistatic agent, such as talc, magnesium stearate, or a combination thereof.

[0077] The sealing coating comprises, for example, 65 wt% to 95 wt% of a water-soluble polymer, e.g., 70 wt% to 90 wt%, or 75 wt% to 85 wt% of a water-soluble polymer; and 5 wt% to 35 wt% of an antistatic agent, e.g., 10 wt% to 30 wt%, or 15 wt% to 25 wt% in the case of an antistatic agent, wherein wt% is based on the total weight of the sealing coating.

[0078] The sealing coating may 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.

[0079] Examples of a method for coating granules containing 4-((L-valyl)oxy)butanoic acid as a sealing coat are provided in Examples 1 and 2.

[0080] Figures 1 and 3 show the particle size distribution of sealed-coated granules.

[0081] FIGS. 2a to 2d show 4-(( with a 1.3 μm (+ / -0.27 μm) thick sealing coating of hydroxypropylmethylcellulose and talc at various magnifications. L - It shows granules containing valyl)oxy)butanoic acid. FIG. 2e shows 4-(( L - Shows a cross-sectional view of granules containing valyl(oxy)butanoic acid.

[0082] FIGS. 4a to 4d show 4-(( with a 2.23 μm (+ / -0.34 μm) thick sealing coating of hydroxypropyl cellulose and talc at various magnifications. L - It shows granules containing valyl)oxy)butanoic acid. Fig. 4e shows 4-(( L - Shows a cross-sectional view of valyl(oxy)butanoic acid granules.

[0083] The coated pharmaceutical granules provided by the present disclosure may comprise a plurality of granules coated with a functional coating. The functional coating may comprise a modified release coating, such as, for example, a controlled-release coating, a sustained-release coating, a pH-release coating, a pulsed-release coating, a time-release coating, or a delayed-release coating. The functional coating is 4-(( L - It may be configured to release valyl(oxy)butanoic acid, and may be released, for example, during the intended period after ingestion and / or in the intended area of ​​the gastrointestinal tract.

[0084] The coated pharmaceutical granules provided by the present disclosure may include one or more functional coatings.

[0085] Each of one or more functional coatings may 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 one or more functional coatings may 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.

[0086] Coated granules or coated granules, for example, exceeding 50 wt% of 4-(( L -Valyl)oxy)butyric acid, greater than 55 wt%, greater than 60 wt%, greater than 70 wt%, greater than 80 wt%, or greater than 85 wt% of 4-(( L - May contain valyl(oxy)butanoic acid, where wt% is based on the total weight of the coated granules or coated granule preparation.

[0087] A coated granule preparation comprising coated granules or a plurality of coated granules is, for example, 50 wt% to 85 wt% of 4-(( L-Valyl)oxy)butanoic acid, 55 wt% to 80 wt%, 60 wt% to 80 wt%, 65 wt% to 80 wt%, or 70 wt% to 75 wt% of 4-(( L - May contain valyl(oxy)butanoic acid, where wt% is based on the total weight of the coated granules or coated granule preparation.

[0088] Coated granules or coated granules may comprise, for example, less than 50 wt% of a functional coating, less than 40 wt% of a functional coating, less than 30 wt%, less than 20 wt%, or less than 10 wt% of a functional coating, wherein wt% is based on the total weight of the coated granules or coated granules. Coated granules or coated granules may comprise, for example, 10 wt% to 50 wt% of a functional coating, 10 wt% to 45 wt%, 15 wt% to 40 wt%, or 15 wt% to 35 wt% of a functional coating, wherein wt% is based on the total weight of the coated granules. 4-(( L Coated granules containing -valyl)oxy)butanoic acid are 4-(( L - By reducing the release rate of valyl)oxy)butanoic acid and / or minimizing or preventing moisture penetration, 4-(( L - Valyl(oxy)butanoic acid can have a thick coating to increase storage stability.

[0089] Coated granules or coated granules, for example, exceeding 50 wt% of 4-(( L -Valyl)oxy)butyric acid, greater than 55 wt%, greater than 60 wt%, greater than 70 wt%, greater than 80 wt%, or greater than 85 wt% of 4-(( L - May contain valyl(oxy)butanoic acid, where wt% is based on the total weight of the coated granules or coated granule preparation.

[0090] A coated granule preparation comprising coated granules or a plurality of coated granules is, for example, 50 wt% to 90 wt% of 4-(( L -Valyl)oxy)butanoic acid, 55 wt% to 85 wt%, 60 wt% to 85 wt%, 65 wt% to 85 wt%, or 70 wt% to 80 wt% of 4-(( L - May contain valyl(oxy)butanoic acid, where wt% is based on the total weight of the coated granules or coated granule preparation.

[0091] The functional coating may include a matrix polymer or a combination of matrix polymers. A combination of matrix polymers and / or pore-forming polymers in the gastrointestinal tract 4-(( L - Valyl)oxy)butanoic acid can be selected to provide a desired release profile.

[0092] The functional coating may comprise, for example, 55 wt% to 95 wt% of a matrix polymer, 60 wt% to 90 wt%, 65 wt% to 90 wt%, 70 wt% to 85 wt%, or 75 wt% to 85 wt% of a matrix polymer, wherein wt% is based on the total weight of the functional coating.

[0093] The functional coating may include a matrix polymer or a combination of matrix polymers. A combination of matrix polymers in the gastrointestinal tract 4-(( L - Valyl)oxy)butanoic acid can be selected to provide a desired release profile.

[0094] The functional coating may comprise, for example, 55 wt% to 95 wt% of a matrix polymer, 60 wt% to 90 wt%, 65 wt% to 90 wt%, 70 wt% to 85 wt%, or 75 wt% to 85 wt% of a matrix polymer, wherein wt% is based on the total weight of the functional coating.

[0095] The functional coating may comprise, for example, less than 95 wt% of the 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% of the matrix polymer, where wt% is based on the total weight of the functional coating.

[0096] The functional coating may comprise, for example, more than 50% of the matrix polymer, more than 55 wt%, more than 60 wt%, more than 65 wt%, more than 70 wt%, more than 75 wt%, more than 80 wt%, more than 85 wt%, or more than 90 wt% of the matrix polymer, where wt% is based on the total weight of the functional coating.

[0097] The matrix polymer may include a water-insoluble polymer or a combination of water-insoluble polymers.

[0098] Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl acetate, polyacrylate, and polymethacrylate.

[0099] Water-insoluble polymers such as ethylcellulose may have an average molecular weight of, for example, 25,000 daltons to 300,000 daltons, e.g., 50,000 daltons to 200,000 daltons, 50,000 daltons to 150,000 daltons, or 50,000 daltons to 100,000 daltons.

[0100] Water-insoluble polymers, such as ethylcellulose, may have a viscosity of, for example, 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 an 80:20 mixture of toluene and ethanol.

[0101] 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.

[0102] The matrix polymer may comprise, for example, 90 wt% to 100 wt% of a water-insoluble polymer, 91 wt% to 99 wt%, 82 wt% to 98 wt%, or 93 wt% to 97 wt% of a water-insoluble polymer, wherein wt% is based on the total weight of the matrix polymer. The matrix polymer may comprise, for example, more than 90 wt% of a water-insoluble polymer, more than 92 wt%, more than 94 wt%, more than 96 wt%, or more than 98 wt% of a water-insoluble polymer, wherein wt% is based on the total weight of the matrix polymer. The matrix polymer may comprise, for example, less than 100 wt% of water-insoluble polymer, less than 98 wt%, less than 96 wt%, less than 94 wt%, or less than 92 wt% of water-insoluble polymer, where wt% is based on the total weight of the matrix polymer.

[0103] The matrix polymer may 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 fluid, such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methacrylate-methyl methacrylate copolymer, and polyvinyl acetate phthalate. The pore-forming polymer may increase the permeability of the functional coating under intended conditions.

[0104] The matrix polymer may include a water-soluble polymer or a combination of water-soluble polymers.

[0105] Examples of suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, copovidone, and poloxamer.

[0106] Water-soluble polymers, such as hydroxypropyl cellulose, may 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 50,000 daltons.

[0107] Water-soluble polymers such as hydroxypropyl cellulose may have a viscosity of, for example, 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 measured using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0108] 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.

[0109] Examples of suitable hydroxypropylmethyl cellulose polymers include Pharmacoat® 603, 645, 606, and 615 polymers available from Shin-Etsu Chemical Co.

[0110] The matrix polymer may comprise, for example, 0 wt% to 15 wt% of a water-soluble polymer, 0 wt% to 10 wt%, 1 wt% to 8 wt%, or 2 wt% to 6 wt% of a water-soluble polymer, wherein wt% is based on the total weight of the matrix polymer. The matrix polymer may comprise, for example, more than 0 wt% of a water-soluble polymer, more than 2 wt%, more than 4 wt%, more than 6 wt%, or more than 8 wt% of a water-soluble polymer, wherein wt% is based on the total weight of the matrix polymer. The matrix polymer may comprise, for example, less than 10 wt% of a water-soluble polymer, less than 8 wt%, less than 6 wt%, less than 4 wt%, or less than 2 wt% of a water-soluble polymer, wherein wt% is based on the total weight of the matrix polymer.

[0111] The matrix polymer may comprise, for example, 90 wt% to 100 wt% of a water-insoluble polymer and 0 wt% to 10 wt% of a water-soluble polymer, 92 wt% to 98 wt% of a water-insoluble polymer and 2 wt% to 8 wt% of a water-soluble polymer, or 94 wt% to 96 wt% of a water-insoluble polymer and 4 wt% to 6 wt% of a water-soluble polymer, wherein wt% is based on the total weight of the matrix polymer.

[0112] A functional coating may 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 fluid bed apparatus.

[0113] In addition to a matrix polymer or a combination of matrix polymers, the functional coating may include, for example, a plasticizer, an antistatic agent, an anti-sticking agent, a colorant or pigment, a lubricant, a viscosity modifier, or a combination of any of the above.

[0114] The functional coating may include an antistatic agent or a combination of antistatic agents.

[0115] Antistatic agents are useful for minimizing or preventing the aggregation of granules during the application of functional coatings.

[0116] Examples of suitable antistatic agents include talc, magnesium stearate, and silicon dioxide.

[0117] The functional coating may comprise, for example, 5 wt% to 25 wt% of an antistatic agent, e.g., 8 wt% to 22 wt%, or 10 wt% to 20 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating. The functional coating may comprise, for example, less than 25 wt% of an antistatic agent, less than 23 wt%, less than 18 wt%, or less than 15 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating. The functional coating may comprise, for example, more than 5 wt% of an antistatic agent, more than 8 wt%, more than 12 wt%, more than 16 wt%, or more than 20 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating.

[0118] The functional coating provided by the present disclosure does not contain plasticizers such as dibutyl sebacate, polyethylene glycol, triacetin, and triethyl citrate.

[0119] The functional coating provided by the present disclosure may comprise, for example, 70 wt% to 95 wt% of a matrix polymer and 5 wt% to 30 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating.

[0120] The functional coating provided by the present disclosure may comprise, for example, 75 wt% to 90 wt% of a matrix polymer and 10 wt% to 25 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating.

[0121] The functional coating provided by the present disclosure may comprise, for example, 80 wt% to 90 wt% of a matrix polymer and 10 wt% to 12 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating.

[0122] In the functional coating provided by the present disclosure, the matrix polymer may comprise hydroxypropyl cellulose and hydroxypropylmethyl cellulose, and the antistatic agent may comprise magnesium stearate, talc, or a combination thereof.

[0123] A functional coating, such as a modified release coating of the present disclosure, may comprise, for example, 72 wt% to 92 wt% of a water-insoluble polymer such as ethyl cellulose, 0.5 wt% to 4 wt% of a water-soluble polymer such as hydroxypropylmethyl cellulose, and 11 wt% to 22 wt% of an antistatic agent such as magnesium stearate, wherein wt% is based on the total weight of the functional coating. A functional coating, such as a modified release coating of the present disclosure, may comprise, for example, 74 wt% to 90 wt% of a water-insoluble polymer such as ethyl cellulose, 1 wt% to 3.5 wt% of a water-soluble polymer such as hydroxypropylmethyl cellulose, and 13 wt% to 20 wt% of an antistatic agent such as magnesium stearate, wherein wt% is based on the total weight of the functional coating. A functional coating, such as a modified release coating of the present disclosure, may comprise, for example, 76 wt% to 88 wt% of a water-insoluble polymer such as ethyl cellulose, 1 wt% to 3.0 wt% of a water-soluble polymer such as hydroxypropylmethyl cellulose, and 14 wt% to 18 wt% of an antistatic agent such as magnesium stearate, wherein wt% is based on the total weight of the functional coating.

[0124] The modified release granules or granules provided by the present disclosure may comprise, for example, a core and a modified release coating surrounding the core. The core is, for example, 85 wt% to 95 wt% of 4-(( L - It may comprise valyl)oxy)butanoic acid, 1 wt% to 9 wt%, for example 3 wt% to 7 wt%, a water-soluble polymer, for example hydroxypropylmethyl cellulose, and 1 wt% to 9 wt%, for example 3 wt% to 7 wt%, an antistatic agent, for example magnesium stearate, where wt% is based on the total weight of the core; and the modified emission coating surrounding the core may comprise, for example, 77 wt% to 87 wt%, a water-insoluble polymer, for example ethyl cellulose, 0.1 wt% to 5 wt%, a water-soluble polymer, for example hydroxypropylmethyl cellulose, and 11 wt% to 21 wt%, for example 14 wt% to 18 wt%, an antistatic agent, for example magnesium stearate, where wt% is based on the total weight of the modified emission coating.

[0125] The modified release granules provided by the present disclosure may be configured to provide a single night dose, a once-daily dose (QD), a twice-daily dose (BID), a three-daily dose (TID), or a four-daily dose (QID). For example, the modified release granules may provide substantially 100% of 4-(( over a duration of 24 hours, 12 hours, 8 hours, or 4 hours. L - It can release valyl(oxy)butanoic acid.

[0126] For example, the modified release granules may exhibit a dissolution profile substantially as shown in, for example, FIGS. 6, 9, 12, and 16. For example, the modified release granules may exhibit a dissolution profile that is biologically equivalent to any dissolution profile shown in, for example, FIGS. 6, 9, 12, and 16.

[0127] Modified release granules, as determined using a USP Type 2 dissolution device in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm, for example, less than 80% 4-(( L -Valyl)oxy)butanoic acid is released from the modified release granules within 2 hours, and less than 70 wt%, less than 60 wt%, less than 50 wt%, or less than 40 wt% 4-(( L -Valyl)oxy)butanoic acid is released from the modified release granules within 2 hours; and 4-(( L -Valyl)oxy)butanoic acid can represent the dissolution profile released from modified release granules within 6 hours, where wt% is 4-( L - Based on the total weight of valyl(oxy)butanoic acid.

[0128] Modified release granules are 30 wt% to 80 wt%, e.g. 35 wt% to 75 wt%, or 40 wt% to 70 wt% of 4-(( as 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. L -Valyl)oxy)butanoic acid can represent the dissolution profile released from modified release granules within 2 hours, where wt% is 4-(( L - Based on the total weight of valyl(oxy)butanoic acid.

[0129] Modified release granules are 50 wt% to 90 wt%, e.g. 65 wt% to 85 wt%, or 70 wt% to 80 wt% of 4-(( as 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. L-Valyl)oxy)butanoic acid can represent the dissolution profile released from modified release granules within 4 hours, where wt% is 4-(( L - Based on the total weight of valyl(oxy)butanoic acid.

[0130] The modified release granules are 60 wt% to 100 wt%, e.g. 65 wt% to 95 wt%, or 70 wt% to 90 wt% of 4-(( as 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. L -Valyl)oxy)butanoic acid can represent the dissolution profile released from modified release granules within 6 hours, where wt% is 4-(( L - Based on the total weight of valyl(oxy)butanoic acid.

[0131] The modified release granules contain 30% to 80% of 4-(( as 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. L -Valyl)oxy)butanoic acid is released from the modified release granules within 2 hours, and 50 wt% to 90 wt% of 4-(( L -Valyl)oxy)butanoic acid is released from the modified release granules within 4 hours, and 60 wt% to 100 wt% of 4-(( L -Valyl)oxy)butanoic acid can exhibit a dissolution profile in which it is released from the composition within 6 hours, where wt% is 4-(( L - Based on the total weight of valyl(oxy)butanoic acid.

[0132] The modified release granules contain 25 wt% to 70 wt% of 4-(( as 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. L-Valyl)oxy)butanoic acid is released from the modified release granules within 2 hours, and 50 wt% to 85 wt% of 4-(( L -Valyl)oxy)butanoic acid is released from the modified release granules within 4 hours, and 60 wt% to 85 wt% of 4-(( L -Valyl)oxy)butanoic acid can represent the dissolution profile released from modified release granules within 6 hours, where wt% is 4-(( L - Based on the total weight of valyl(oxy)butanoic acid.

[0133] The modified release granules may exhibit a dissolution profile that is biologically equivalent to any of the dissolution profiles shown in Figures 9 and 12.

[0134] The coated granules provided by the present disclosure may have a moisture 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 wt% is based on the total weight of the coated granules.

[0135] The coated granules provided by the present disclosure may have a moisture 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 wt% is based on the total weight of the coated granules.

[0136] Coated pharmaceutical granules may 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.

[0137] Coated pharmaceutical granules may 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.

[0138] Bulk density can be determined using a bulk density cylinder.

[0139] The coated pharmaceutical granules provided by the present disclosure may be characterized by PSD (D50) of, for example, 150 μm to 400 μm, e.g. 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.

[0140] Examples of particle size distributions for coated granules provided by the present disclosure are shown in FIGS. 5, 8, 11 and 15.

[0141] The particle size distribution can be determined by laser diffraction or sieve analysis.

[0142] The functional coating provided by the present disclosure can be coated onto granules using any suitable equipment and process. Examples of suitable coating methods include the Wurster fluid bed film coating process, the compression coating process, and the phase inversion process.

[0143] The functional coating may be applied to uncoated granules or granules comprising a sealing coating provided by the present disclosure.

[0144] Examples of coating compositions are provided in the experimental examples. A coating composition refers to a composition applied to an uncoated granule or a seal-coated granule to provide a coated granule.

[0145] The functional coating composition may contain more than 70 wt%, more than 75 wt%, more than 80 wt%, more than 85 wt%, or more than 90 wt% of a non-aqueous solvent, such as ethanol or acetone, wherein wt% is based on the total weight of the functional coating solution / suspension composition used to coat the granules.

[0146] The functional coating composition may contain, for example, less than 20 wt% water, less than 15 wt%, less than 10 wt%, or less than 5 wt% water, where wt% is based on the functional coating solution / suspension composition used to coat the granules.

[0147] 4-(( L In the case of highly water-soluble and hygroscopic pharmaceutical active ingredients such as valyl(oxy)butanoic acid, it may be useful to minimize the amount of water in the functional coating composition. Reducing the water level in the functional coating solution / suspension composition can lead to static electricity, which may cause problems in the coating process.

[0148] The functional coating solution / suspension composition may contain, for example, 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% of solid content, wherein wt% is based on the functional coating solution / suspension composition.

[0149] The functional coating composition may include, for example, a solid 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%, wherein wt% is based on the functional coating composition.

[0150] An example of coating process conditions using a Wurster column inserted into a fluidized bed coating apparatus is provided in the experimental example.

[0151] The granules provided by the present disclosure may include immediate-release granules.

[0152] Immediate-release granules may comprise a plurality of uncoated granules or a plurality of granules comprising a sealing coating.

[0153] Immediate-release granules comprising a plurality of uncoated or seal-coated granules 4-((L -4-(provided by the present disclosure, such as valyl)oxy)butanoic acid L - It may contain more than 90% by weight of valyl(oxy)butanoic acid. Immediate-release granules containing uncoated or seal-coated granules may be completely dissolved 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 in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

[0154] Immediate-release granules may comprise a plurality of coated or sealing coated granules having an immediate-release functional coating. Immediate-release granules comprising a plurality of coated granules contain more than 80 weight% of 4-(( L - May contain valyl)oxy)butanoic acid. Immediate-release granules containing coated granules may be completely dissolved 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 in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm. Immediate-release granules containing coated granules may be completely dissolved in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes, with more than 80% of 4-(( L - It may release valyl(oxy)butanoic acid. The coated immediate-release granules may include a coating comprising a water-soluble polymer such as, for example, hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, polyvinylpyrrolidone, or polyethylene glycol. The coated immediate-release granules may include a coating comprising an antistatic agent such as talc, magnesium stearate, or silicon dioxide.

[0155] The pharmaceutical compositions provided by the present disclosure may comprise a combination of immediate-release granules and modified-release granules. The pharmaceutical composition may comprise, for example, 4-((L-valyl)oxy)butanoic acid as the modified-release granule to 4-(( L - May contain a wt% ratio of valyl(oxy)butanoic acid.

[0156] The pharmaceutical composition provided by the present disclosure may include a coated granule provided by the present disclosure.

[0157] The pharmaceutical composition may include any dosage form suitable for oral administration.

[0158] Examples of suitable oral administration forms include tablets, capsules, caplets, sachets, bottles, stick packs, dispersions, and suspensions.

[0159] The oral dosage forms provided by the present disclosure are, for example, 0.1 g to 20 g of 4-(( L -Valyl)oxy)butyric acid, 0.1 gram to 15 grams, 0.1 gram to 12 grams, 0.1 gram to 10 grams, 0.2 gram to 8 grams, 0.5 gram to 5 grams, 0.5 gram to 5 grams, 1 gram to 4.5 grams, or 1.5 gram to 4 grams of 4-(( L - May contain valyl)oxy)butanoic acid. Oral dosage forms are, for example, greater than 0.5 g, greater than 1 g, greater than 2 g, greater than 3 g, greater than 4 g, greater than 6 g, or greater than 8 g, greater than 10 g, greater than 14 g, or greater than 18 g of 4-(( L - May contain valyl(oxy)butanoic acid.

[0160] The oral composition provided by the present disclosure may comprise an oral suspension of coated granules having a modified release functional coating provided by the present disclosure. The oral composition may comprise modified release granules and immediate release granules provided by the present disclosure.

[0161] The oral composition may include a combination of immediate-release granules and modified-release granules provided by the present disclosure.

[0162] The oral composition provided by the present disclosure is 4-(( L - It can provide a therapeutically effective amount of valyl(oxy)butanoic acid.

[0163] For example, the oral composition provided by the present disclosure is 4-(( over a period of 3, 6, 8, or 10 hours L - It can provide a therapeutically effective amount of valyl(oxy)butanoic acid.

[0164] The oral composition provided by the present disclosure is 4-(( L - It can provide a therapeutically effective amount of valyl(oxy)butanoic acid.

[0165] The oral composition provided by the present disclosure is administered over a period of 1 to 12 hours after oral administration, 2 to 10 hours after oral administration, or 4 to 8 hours. L - It can provide a therapeutically effective amount of valyl(oxy)butanoic acid.

[0166] The oral composition provided by the present disclosure may be a once-night composition. In the case of a once-night composition, the patient 4-(( L - After administering a dose of valyl(oxy)butanoic acid, one can sleep for 6 or 8 hours overnight without needing to administer a second dose during the night.

[0167] The oral composition provided by the present disclosure can provide a therapeutically effective amount of γ-hydroxybutyric acid in the patient's plasma.

[0168] The oral composition provided by the present disclosure may provide a therapeutically effective amount of γ-hydroxybutyric acid in the patient's plasma for a period of 4, 6, 8, or 10 hours after oral administration of the modified release oral composition.

[0169] The oral composition provided by the present disclosure may provide a plasma concentration of γ-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.

[0170] The oral composition provided by the present disclosure may provide a plasma concentration of γ-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.

[0171] The oral composition provided by the present disclosure [reduces] the C of γ-hydroxybutyric acid in the patient's plasma for a duration of 4, 6, 8, or 10 hours after oral administration of the modified release composition min C regarding max A therapeutically effective dose of β can be provided in less than 3 or less than 2.

[0172] The oral composition provided by the present disclosure may include a derivative of γ-hydroxybutyric acid of formula (2), for example, 0.5 g-equivalent of γ-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 γ-hydroxybutyric acid.

[0173] The pharmaceutical composition provided by the present disclosure may be included in a kit that can be used to administer the compound to a patient for therapeutic purposes. The kit may include a pharmaceutical composition comprising an immediate-release component and a modified-release component suitable for administration to a patient, and instructions for administering the pharmaceutical composition to the patient. The kit may be used, for example, to treat sleep disorders. The kit may include an immediate-release component and a modified-release component, a pharmaceutically acceptable vehicle for administering the immediate-release component and the modified-release component, and instructions for administering the pharmaceutical composition to the patient.

[0174] The oral composition provided by the present disclosure may be provided, for example, as a chassé containing the coated granules provided in the present disclosure. The chassé may contain 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 -Varyl)oxy)butanoic acid and various dosages of 4-(( L - It may be provided as valyl(oxy)butanoic acid. Coated granules may be combined with water, for example, to provide an orally ingestible dosage form.

[0175] The pharmaceutical composition may be contained in a container, pack, or dispenser along with instructions for administration.

[0176] Instructions provided with the kit may be provided, for example, in print and / or on electronic-readable media, video cassettes, audio tapes, or flash memory devices, or may be published on an internet website or distributed to patients and / or healthcare providers as electronic communications.

[0177] After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t of 0.4 hours1 / 2 , average T of 0.9 hours max , average C of 16 μg / mL max , average AUC of 16 h × μg / mL 0-6 , AUC of 16 h × μg / mL 0-inf It can be characterized by , and 48 L / h of CL / F).

[0178] After orally administering an IR composition containing 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.3 to 0.5 hours 1 / 2 , average T of 0.8 to 1.0 hours max , average C of 14 μg / mL to 18 μg / mL max , average AUC of 14 h × μg / mL to 18 h × μg / mL 0-6 , AUC of 14 h×μg / mL to 18 h×μg / mL 0-inf and may be characterized by a CL / F of 44 L / h to 52 L / h.

[0179] After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.35 to 0.45 hours 1 / 2 , average T of 0.85 to 0.95 hours max , average C of 15 μg / mL to 17 μg / mL max , average AUC of 15 h × μg / mL to 17 h × μg / mL 0-6 , AUC of 15 h × μg / mL to 17 h × μg / mL 0-inf and may be characterized by a CL / F of 446 L / h to 50 L / h.

[0180] After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t of 0.7 hours 1 / 2 , average T of 1.6 hoursmax , average C of 4 μg / mL max , average AUC of 9 h × μg / mL 0-6 , average AUC of 9 h × μg / mL 0-inf It can be characterized by , and CL / F of 838 L / h.

[0181] After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.5 to 9 hours. 1 / 2 , average T of 1.4 to 1.8 hours max , average C of 2 μg / mL to 6 μg / mL max , average AUC of 7 h × μg / mL to 11 h × μg / mL 0-6 , average AUC of 7 h × μg / mL to 11 h × μg / mL 0-inf and can be characterized by an average CL / F of 818 L / h to 858 L / h.

[0182] After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.6 to 0.8 hours 1 / 2 , average T of 1.5 to 1.7 hours max , average C of 3 μg / mL to 5 μg / mL max , average AUC of 8 h × μg / mL to 10 h × μg / mL 0-6 , average AUC of 8 h × μg / mL to 10 h × μg / mL 0-inf and can be characterized by an average CL / F of 828 L / h to 848 L / h.

[0183] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t of 0.7 hours 1 / 2 , average T of 1.4 hours max , average C of 6 μg / mLmax , average AUC of 10 h × μg / mL 0-6 , average AUC of 10 h × μg / mL 0-inf It can be characterized by , and CL / F of 762 L / h.

[0184] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.5 to 0.9 hours. 1 / 2 , average T of 1.2 to 1.6 hours max , average C of 4 μg / mL to 8 μg / mL max , average AUC of 8 h × μg / mL to 12 h × μg / mL 0-6 , average AUC of 8 h × μg / mL to 12 h × μg / mL 0-inf and can be characterized by an average CL / F of 720 L / h to 800 L / h.

[0185] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.4 to 0.8 hours 1 / 2 , average T of 1.3 to 1.5 hours max , average C of 5 μg / mL to 7 μg / mL max , average AUC of 9 h × μg / mL to 11 h × μg / mL 0-6 , average AUC of 9 h × μg / mL to 11 h × μg / mL 0-inf and can be characterized by an average CL / F of 740 L / h to 780 L / h.

[0186] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t of 0.8 hours 1 / 2 , average T of 1.1 hours max , average C of 5 μg / mL max, average AUC of 10 h × μg / mL 0-6 , average AUC of 10 h × μg / mL 0-inf It can be characterized by , and CL / F of 801 L / h.

[0187] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.6 to 1.0 hours. 1 / 2 , average T of 0.9 to 1.3 hours max , average C of 3 μg / mL to 7 μg / mL max , average AUC of 8 h × μg / mL to 12 h × μg / mL 0-6 , average C of 8 h × μg / mL to 12 h × μg / mL 0-inf and can be characterized by an average CL / F of 760 L / h to 840 L / h.

[0188] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t of 0.7 to 0.9 hours. 1 / 2 , average T of 1.0 to 1.2 hours max , average C of 4 μg / mL to 6 μg / mL max , average AUC of 9 h × μg / mL to 11 h × μg / mL 0-6 , average AUC of 9 h × μg / mL to 11 h × μg / mL 0-inf , and can be characterized by an average CL / F of 780 L / h to 820 L / h.

[0189] After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.6 hours 1 / 2 , average T of 1.3 hours max , average C of 86 μg / mL max, average AUC of 239 h × μg / mL 0-6 , average AUC of 246 h × μg / mL 0-inf It can be characterized by , and CL / F of 31 L / h.

[0190] After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.4 to 0.8 hours 1 / 2 , average T of 1.1 to 1.5 hours max , average C of 76 μg / mL to 96 μg / mL max , average AUC of 219 h×μg / mL to 259 h×μg / mL 0-6 , average AUC of 226 h×μg / mL to 266 h×μg / mL 0-inf It can be characterized by an average CL / F of 21 L / h to 41 L / h.

[0191] After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.5 to 0.7 hours. 1 / 2 , average T of 1.2 to 1.4 hours max , average C of 81 μg / mL to 91 μg / mL max , average AUC of 229 h×μg / mL to 249 h×μg / mL 0-6 , average AUC of 236 h×μg / mL to 256 h×μg / mL 0-inf and can be characterized by an average CL / F of 26 L / h to 36 L / h.

[0192] After orally administering the MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 1.1 hours. 1 / 2 , average T of 2.4 hours max , average C of 27 μg / mLmax , average AUC of 86 h × μg / mL 0-6 , average AUC of 95 h × μg / mL 0-inf It can be characterized by , and CL / F of 95 L / h.

[0193] After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.9 to 1.3 hours. 1 / 2 , average T of 2.2 to 2.6 hours max , average C of 17 μg / mL to 37 μg / mL max , average AUC of 76 h×μg / mL to 96 h×μg / mL 0-6 , average AUC of 75 h × μg / mL to 115 h × μg / mL 0-inf and can be characterized by an average CL / F of 85 L / h to 105 L / h.

[0194] After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was an average t of 1.0 to 1.2 hours. 1 / 2 , average T of 2.3 to 2.5 hours max , average C of 22 μg / mL to 32 μg / mL max , average AUC of 81 h×μg / mL to 91 h×μg / mL 0-6 , average AUC of 85 h×μg / mL to 105 h×μg / mL 0-inf and can be characterized by an average CL / F of 90 L / h to 100 L / h.

[0195] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.9 hours 1 / 2 , average T of 2.4 hours max , average C of 36 μg / mLmax , average AUC of 112 h × μg / mL 0-6 , average AUC of 120 h × μg / mL 0-inf It can be characterized by , and CL / F of 72 L / h.

[0196] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was an average t of 0.8 to 1.0 hours 1 / 2 , average T of 2.2 to 2.6 hours max , average C of 34 μg / mL to 38 μg / mL max , average AUC of 102 h×μg / mL to 122 h×μg / mL 0-6 , average AUC of 110 h×μg / mL to 130 h×μg / mL 0-inf and can be characterized by an average CL / F of 62 L / h to 82 L / h.

[0197] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.85 to 0.95 hours. 1 / 2 , average T of 2.3 to 2.5 hours max , average C of 35 μg / mL to 37 μg / mL max , average AUC of 107 h×μg / mL to 117 h×μg / mL 0-6 , average AUC of 125 h×μg / mL to 135 h×μg / mL 0-inf and can be characterized by an average CL / F of 67 L / h to 77 L / h.

[0198] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t at 1.0 hour. 1 / 2 , average T of 1.9 hours max, average C of 30 μg / mL max , average AUC of 102 h × μg / mL 0-6 , average AUC of 110 h × μg / mL 0-inf It can be characterized by , and CL / F of 79 L / h.

[0199] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.9 to 1.1 hours. 1 / 2 , average T of 1.7 to 2.1 hours max , average C of 26 μg / mL to 34 μg / mL max , average AUC of 82 h×μg / mL to 122 h×μg / mL 0-6 , average AUC of 90 h×μg / mL to 130 h×μg / mL 0-inf and can be characterized by an average CL / F of 69 L / h to 89 L / h.

[0200] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was an average t of 0.95 to 1.05 hours 1 / 2 , average T of 1.8 to 2.0 hours max , average C of 28 μg / mL to 32 μg / mL max , average AUC of 92 h×μg / mL to 112 h×μg / mL 0-6 , average AUC of 100 h × μg / mL to 120 h × μg / mL 0-inf and can be characterized by an average CL / F of 74 L / h to 84 L / h.

[0201] After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile was a mean C of 5.9 max R, mean AUC of 15.0 0-infB, and a mean AUC of 16.2 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 4.9 to 6.9. max R, average AUC of 14.0 to 16.0 0-inf R, and average AUC of 15.2 to 17.2 0-6 The ratio may be characterized, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an IR composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 5.4 to 6.4. max R, average AUC of 14.5 to 15.5 0-inf R, and average AUC of 15.7 to 16.7 0-6 The ratio can be characterized as such, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0202] After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile was a mean C of 6.6 max R, mean AUC of 10.0 0-inf B, and a mean AUC of 9.8 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 6.2 to 7.0. max R, average AUC of 9.0 to 11.0 0-inf B, and average AUC of 9.4 to 10.2 0-6It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an MR1 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 6.4 to 6.8. max R, average AUC of 9.5 to 10.5 0-inf R, and average AUC of 9.6 to 10.0 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1).

[0203] After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile was an average C value of 6.3 max R, mean AUC of 11.9 0-inf B, and an average AUC of 11.5 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 5.9 to 6.7. max R, average AUC of 11.5 to 12.3 0-inf B, and average AUC of 11.1 to 11.9 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an MR2 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 6.1 to 6.5. max R, average AUC of 11.7 to 12.1 0-inf B, and average AUC of 11.3 to 11.7 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1).

[0204] After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile was 6.5 with an average C max R, mean AUC of 11.4 0-inf B, and a mean AUC of 11.4 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 6.1 to 6.9. max R, average AUC of 11.0 to 11.8 0-inf R, and average AUC of 11.0 to 11.8 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1). After orally administering an MR3 composition containing 7.25 g of compound (1) to a group of healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 6.3 to 6.7. max R, average AUC of 11.2 to 11.6 0-inf B, and average AUC of 11.2 to 11.6 0-6 It is characterized by a ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the value of compound (1).

[0205] The pharmaceutical composition may include an immediate-release component and a modified component.

[0206] The immediate-release component may include any immediate-release microparticle disclosed herein.

[0207] The modified component may include any modified microparticle or combination of modified microparticles disclosed herein.

[0208] The pharmaceutical composition provided by the present disclosure may comprise, for example, 10 wt% to 50 wt% of compound (1) in the IR component, 50 wt% to 90 wt% of the MR component, 20 wt% to 40 wt% of compound (1) in the IR component, and 60 wt% to 80 wt% of γ-hydroxybutyrate in the MR component, or 25 wt% to 35 wt% of compound (1) in the IR component and 65 wt% to 75 wt% of compound (1) in the MR component, wherein wt% is based on the total weight of compound (1) in the pharmaceutical composition.

[0209] The pharmaceutical composition provided by the present disclosure may comprise, for example, more than 10 wt% of compound (1) in the IR component and less than 90 wt% of compound (1) in the MR component, more than 20 wt% of compound (1) in the IR component and less than 80% of compound (1) in the MR component, more than 30 wt% of compound (1) in the IR component and less than 70% of compound (1) in the MR component, or more than 40 wt% of compound (1) in the IR component and less than 60% of compound (1) in the MR component, wherein wt% is based on the total weight of compound (1) in the pharmaceutical composition.

[0210] The pharmaceutical composition provided by the present disclosure may have, for example, a weight ratio of compound (1) in the IR component to compound (1) in the MR component of 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.

[0211] The pharmaceutical composition provided by the present disclosure may have, for example, a weight ratio of compound (1) in the IR component to compound (1) in the MR component of 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.

[0212] The pharmaceutical composition provided by the present disclosure may include, for example, 2.0 g to 6.0 g of a 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 a compound (1) in the IR component.

[0213] The pharmaceutical composition may include, 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.

[0214] The pharmaceutical composition may comprise, for example, 2.0 g to 6.0 g of a 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 a compound (1) in the IR component, 8 g to 12 g of a compound (1) in the IR 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 a compound (1) in the IR component.

[0215] The pharmaceutical composition provided by the present disclosure may include, for example, a compound (1) of 9.5 g to 22 g, a compound (1) of 10 g to 20 g, a compound (1) of 12 g to 18 g, or a compound (1) of 14 g to 16 g. The pharmaceutical composition provided by the present disclosure may include, for example, a compound (1) of more than 9 g, a compound (1) of more than 10 g, a compound of more than 12 g, a compound of more than 14 g, a compound of more than 16 g, a compound of more than 18 g, or a compound (1) of more than 20 g.

[0216] The pharmaceutical composition provided by the present disclosure may comprise, for example, 10 wt% to 50 wt% of γ-hydroxybutyrate equivalents in an IR component and 50 wt% to 90 wt% in an MR component, 20 wt% to 40 wt% of γ-hydroxybutyrate equivalents in an IR component and 60 wt% to 80 wt% of γ-hydroxybutyrate equivalents in an MR component, or 25 wt% to 35 wt% of γ-hydroxybutyrate equivalents in an IR component and 65 wt% to 75 wt% of γ-hydroxybutyrate equivalents in an MR component, wherein the wt% equivalents are based on the total wt% of γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0217] The pharmaceutical composition provided by the present disclosure may comprise, for example, an equivalent of γ-hydroxybutyrate of more than 10 wt% in the IR component and an equivalent of γ-hydroxybutyrate of less than 90 wt% in the MR component, an equivalent of γ-hydroxybutyrate of more than 20 wt% in the IR component and an equivalent of γ-hydroxybutyrate of less than 80 wt% in the MR component, an equivalent of γ-hydroxybutyrate of more than 30 wt% in the IR component and an equivalent of γ-hydroxybutyrate of less than 70 wt% in the MR component, or an equivalent of γ-hydroxybutyrate of more than 40 wt% in the IR component and an equivalent of γ-hydroxybutyrate of less than 60 wt% in the MR component, wherein the wt% equivalent is based on the total equivalent of γ-hydroxybutyrate in the pharmaceutical composition.

[0218] The pharmaceutical composition provided by the present disclosure may have, for example, a weight ratio of γ-hydroxybutyrate equivalents in the IR component to γ-hydroxybutyrate equivalents in the MR component of 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.

[0219] The pharmaceutical composition provided by the present disclosure may have, for example, a weight ratio of γ-hydroxybutyrate equivalents in the IR component to γ-hydroxybutyrate equivalents in the MR component of 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.

[0220] The pharmaceutical composition provided by the present disclosure may include, for example, 1.1 g to 3.1 g of γ-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 γ-hydroxybutyrate equivalents in the IR component.

[0221] The pharmaceutical composition may include, for example, 4.1 g to 6.1 g of γ-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 γ-hydroxybutyrate equivalents in the MR component.

[0222] The pharmaceutical composition may comprise, for example, 1.1 g to 3.1 g of γ-hydroxybutyrate equivalents in the IR component and 4.1 g to 6.1 g of γ-hydroxybutyrate equivalents in the MR component; 1.4 g to 2.8 g of γ-hydroxybutyrate equivalents in the IR component and 4.3 g to 5.9 g of γ-hydroxybutyrate equivalents in the MR component; 1.6 g to 2.6 g of γ-hydroxybutyrate equivalents in the IR component and 4.5 g to 5.7 g of γ-hydroxybutyrate equivalents in the MR component; or 1.8 g to 2.2 g of γ-hydroxybutyrate equivalents in the IR component and 4.7 g to 5.5 g of γ-hydroxybutyrate equivalents in the MR component.

[0223] The pharmaceutical composition provided by the present disclosure may comprise, for example, 6.5 g to 18 g of compound (1), 8 g to 16 g of γ-hydroxybutyrate equivalents, 10 g to 14 g of compound (1), or 11 g to 13 g of γ-hydroxybutyrate equivalents. The pharmaceutical composition provided by the present disclosure may comprise, for example, more than 9 g of γ-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 γ-hydroxybutyrate equivalents.

[0224] 4-(( to healthy fasting subjects L - After administration of γ-hydroxybutyrate and 4-(( LA method for determining the plasma pharmacokinetic profile of valyl)oxy)butanoic acid (1) is provided in the experimental example.

[0225] After orally administering 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 group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t of 1.1 hours. 1 / 2 , average T of 1.4 hours max , average C of 15 μg / mL max , average AUC of 25 h × μg / mL 0-6 , average AUC of 27 h × μg / mL 0-inf It can be characterized by , and CL / F of 556 L / h.

[0226] After orally administering a complex 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 group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t at 1.0 to 1.2 hours. 1 / 2 , average T of 1.3 to 1.5 hours max , average C of 12 μg / mL to 18 μg / mL max , average AUC of 20 h × μg / mL to 30 h × μg / mL 0-6 , average AUC of 22 h×μg / mL to 32 h×μg / mL 0-inf and can be characterized by an average CL / F of 536 L / h to 576 L / h.

[0227] After orally administering a complex 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 group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t of 1.05 to 1.15 hours. 1 / 2 , average T of 1.35 to 1.45 hoursmax , average C of 14 μg / mL to 16 μg / mL max , average AUC of 22 h×μg / mL to 28 h×μg / mL 0-6 , average AUC of 24 h × μg / mL to 30 h × μg / mL 0-inf and can be characterized by an average CL / F of 546 L / h to 566 L / h.

[0228] After orally administering a complex-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 healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at a mean t at 1.1 hours 1 / 2 , average T of 2.7 hours max , average C of 108 μg / mL max , average AUC of 400 h × μg / mL 0-6 , average AUC of 534 h × μg / mL 0-inf It can be characterized by , and CL / F of 32 L / h.

[0229] After orally administering a complex-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 healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 1.0 to 1.2 hours. 1 / 2 , average T of 2.5 to 2.9 hours max , average C of 88 μg / mL to 128 μg / mL max , average AUC of 380 h×μg / mL to 420 h×μg / mL 0-6 , average AUC of 514 h×μg / mL to 554 h×μg / mL 0-inf and can be characterized by an average CL / F of 22 L / h to 42 L / h.

[0230] After orally administering a complex-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 healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t between 1.05 and 1.15 hours. 1 / 2 , average T of 2.6 to 2.8 hours max , average C of 98 μg / mL to 118 μg / mL max , average AUC of 390 h×μg / mL to 410 h×μg / mL 0-6 , average AUC of 524 h×μg / mL to 544 h×μg / mL 0-inf and can be characterized by an average CL / F of 27 L / h to 37 L / h.

[0231] After orally administering 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 healthy fasting subjects, the plasma pharmacokinetic profile was a mean C of 8.0 max B, and a mean AUC of 19.3 0-inf The ratio can be characterized, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0232] After orally administering 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 healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 7.0 to 9.0. max B, and average AUC of 18.3 to 20.3 0-inf The ratio can be characterized, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0233] After orally administering a complex 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 healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 7.5 to 8.5 max R, and average AUC of 18.8 to 19.8 0-inf The ratio can be characterized, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0234] After orally administering a complex 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 group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was at an average t at 1.0 hour. 1 / 2 , average T of 1.3 hours max , average C of 12 μg / mL max , average AUC of 20 h × μg / mL 0-6 , average AUC of 21 h × μg / mL 0-inf It can be characterized by a CL / F of , and 700 L / h).

[0235] After orally administering 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 group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t at 0.9 to 1.1 hours. 1 / 2 , average T of 1.1 to 1.5 hours max , average C of 10 μg / mL to 14 μg / mL max , average AUC of 16 h × μg / mL to 24 h × μg / mL 0-6 , average AUC of 11 h × μg / mL to 31 h × μg / mL 0-inf and can be characterized by an average CL / F of 660 L / h to 740 L / h.

[0236] After orally administering a complex 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 group of healthy fasting subjects, the plasma pharmacokinetic profile of compound (1) was an average t at 0.95 to 1.05 hours. 1 / 2 , average T of 1.2 to 1.4 hours max , average C of 11 μg / mL to 13 μg / mL max , average AUC of 18 h × μg / mL to 22 h × μg / mL 0-6 , average AUC of 16 h × μg / mL to 26 h × μg / mL 0-inf and can be characterized by an average CL / F of 680 L / h to 720 L / h.

[0237] After orally administering a complex-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 healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at a mean t at 0.9 hours 1 / 2 , average T of 2.2 hours max , average C of 83 μg / mL max , average AUC of 322 h × μg / mL 0-6 , average AUC of 386 h × μg / mL 0-inf It can be characterized by a CL / F of , and 43 L / h).

[0238] After orally administering a complex-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 healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.8 to 1.0 hours. 1 / 2 , average T of 2.0 to 2.4 hours max , average C of 73 μg / mL to 93 μg / mL max, average AUC of 302 h×μg / mL to 342 h×μg / mL 0-6 , average AUC of 366 h×μg / mL to 406 h×μg / mL 0-inf and can be characterized by an average CL / F of 33 L / h to 53 L / h.

[0239] After orally administering a complex-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 healthy fasting subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate was at an average t of 0.85 to 0.95 hours. 1 / 2 , average T of 2.1 to 2.3 hours max , average C of 78 μg / mL to 88 μg / mL max , average AUC of 312 h×μg / mL to 332 h×μg / mL 0-6 , average AUC of 376 h×μg / mL to 396 h×μg / mL 0-inf and can be characterized by an average CL / F of 38 L / h to 48 L / h.

[0240] After orally administering 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 healthy fasting subjects, the plasma pharmacokinetic profile was a mean C of 7.8 max B, and a mean AUC of 18.3 0-inf The ratio can be characterized, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0241] After orally administering 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 healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 6.8 to 8.8 maxB, and average AUC of 17.3 to 19.3 0-inf The ratio can be characterized, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0242] After orally administering a complex 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 healthy fasting subjects, the plasma pharmacokinetic profile had an average C value of 7.3 to 8.3 max R, and average AUC of 17.8 to 18.8 0-inf The ratio can be characterized, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0243] For the complex-release composition provided by the present disclosure, at 8 hours after orally administering a complex-release composition containing 10 g to 20 g of compound (1) to a healthy fasting subject group, the concentration of γ-hydroxybutyrate in the subject's plasma is less than 40 μg / mL, less than 30 μg / mL, or less than 20 μg / mL.

[0244] In the case of the complex-release composition provided by the present disclosure, after orally administering a complex-release composition comprising 10 g to 20 g of compound (1) to a healthy fasting subject group, the AUC of γ-hydroxybutyrate in the subject's plasma inf is: (a) AUC of γ-hydroxybutyrate after oral administration of the immediate-release component inf ; and (b) AUC of γ-hydroxybutyrate after oral administration of the modified-release component to a healthy fasting subject population inf It is greater than the sum of .

[0245] For a complex-release composition provided by the present disclosure comprising 10 g to 20 g of compound (1) and administered orally to a healthy fasting subject population between 6 and 8 hours thereafter, the concentration of γ-hydroxybutyrate in the subject’s plasma is greater than the sum of: (a) the concentration of γ-hydroxybutyrate between 6 and 8 hours after oral administration of the immediate-release component; and (b) the concentration of γ-hydroxybutyrate between 6 and 8 hours after oral administration of the modified-release component to the healthy fasting subject population. .

[0246] In the case of the complex-release composition provided by the present disclosure, after orally administering a complex-release composition containing 10 g to 20 g of compound (1) to a healthy fasting subject group, the concentration at 6 to 8 hours after administration is greater than the concentration of γ-hydroxybutyrate in the subject's plasma after administration of the modified-release component alone.

[0247] For the combined-release composition provided by the present disclosure, the average γ-hydroxybutyrate AUC after oral administration of the immediate-release component and the modified-release component to a population of healthy fasting subjects 0-inf Mean γ-hydroxybutyrate AUC after oral administration of the immediate-release component alone 0-inf Mean γ-hydroxybutyrate AUC after single oral administration of the modified-release component 0-inf It is greater than the sum of the sums.

[0248] In the case of a combined release composition provided by the present disclosure, the average compound (1) AUC after oral administration of the immediate release component and the modified release component to a group of subjects 0-inf The average compound (1) AUC after oral administration of the immediate-release component alone 0-inf Average compound (1) AUC after single oral administration of modified release component 0-inf It is substantially the same as the sum of the agreements.

[0249] For the composite release composition provided by the present disclosure, the average γ-hydroxybutyrate AUC after orally administering a composite 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 group of healthy fasting subjects 0-inf The average γ-hydroxybutyrate AUC after single oral administration of an immediate-release component containing 7.25 g of compound (1) 0-inf Average γ-hydroxybutyrate AUC after single oral administration of a modified release component containing 7.25 g of compound (1) 0-inf It is greater than the sum of.

[0250] For the composite release composition provided by the present disclosure, the average compound (1) AUC after orally administering a composite 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 group of healthy fasting subjects 0-inf The average compound (1) AUC after single oral administration of an immediate-release component containing 7.25 g of compound (1) 0-inf Average compound (1) AUC after single oral administration of a modified release component containing 7.25 g of compound (1) 0-inf It is substantially the same as the sum of.

[0251] The immediate-release component provided by the present disclosure may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) as shown in FIG. 17, or for γ-hydroxybutyrate as shown in FIG. 18. The immediate-release component provided by the present disclosure may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) as provided in Table 6, or for γ-hydroxybutyrate as provided in Table 7.

[0252] The modified release component provided by the present disclosure may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) as shown in FIG. 17, or for γ-hydroxybutyrate as shown in FIG. 18. The modified release component provided by the present disclosure may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) as provided in Table 6, or for γ-hydroxybutyrate as provided in Table 7.

[0253] Pharmaceutical compositions provided by the present disclosure, such as complex-release compositions, may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) as shown in FIG. 19, or for γ-hydroxybutyrate as shown in FIG. 20. Pharmaceutical compositions provided by the present disclosure, such as complex-release compositions, may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile for compound (1) as provided in Table 10, or for γ-hydroxybutyrate as provided in Table 11.

[0254] The pharmaceutical composition provided by the present disclosure may 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, and fibromyalgia.

[0255] The pharmaceutical composition provided by the present disclosure may be used to treat, for example, REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress disorder, insomnia associated with post-traumatic stress disorder, and anxiety.

[0256] The pharmaceutical compositions provided in the present disclosure may be used, for example, to improve cognitive function in neurodegenerative disorders. For example, the pharmaceutical compositions provided in the present disclosure may be used to improve cognitive function in patients with Parkinson's disease or Alzheimer's disease.

[0257] The pharmaceutical composition provided by the present disclosure may 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. In various embodiments, the composition is sufficient for administration once daily. For example, the composition may be sufficient for administration in the morning or at night within 2 hours after a meal. The pharmaceutical composition may also be effective in inducing at least 6 to 8 consecutive hours of sleep. A pharmaceutical composition administered within 2 hours after a meal is effective in inducing at least 8 consecutive hours of sleep. The pharmaceutical composition may be effective in inducing at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours of sleep. The pharmaceutical composition may be effective in inducing up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, or up to 10 hours of sleep.

[0258] The pharmaceutical compositions and compositions provided by the present disclosure may be used to treat sleep disorders, drug abuse, alcohol and opioid withdrawal, decreased growth hormone levels, anxiety, pain, symptoms associated with neurological disorders such as Parkinson's disease, Alzheimer's disease and depression, endocrine disorders, tissue hypoxia or anoxia such as stroke or myocardial infarction, or increased levels of intracranial pressure.

[0259] The pharmaceutical composition provided by the present disclosure can be used to treat diseases or conditions that can be treated by administering γ-hydroxybutyric acid, such as, for example, fibromyalgia and sleep disorders, such as apnea, sleep timing disorder, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnotic hallucinations, sleep awakening, insomnia, and nocturnal muscle atrophy.

[0260] The pharmaceutical composition provided by the present disclosure can be used to treat sleep disorders associated with viral diseases such as COVID-19 infection.

[0261] The pharmaceutical composition provided by the present disclosure can be used for pain relief and functional improvement in patients with fibromyalgia syndrome, and for relief of excessive daytime sleepiness and fatigue in patients with Parkinson's disease, improvement of clonic and essential tremor, and reduction of tardive dyskinesia and bipolar disorder.

[0262] The pharmaceutical composition provided by the present disclosure can be used to improve cognitive function in patients with neurological disorders such as Parkinson's disease and Alzheimer's disease.

[0263] The pharmaceutical compositions and compositions provided by the present disclosure may be used to treat a neurodegenerative disease or a pathological condition or disorder associated with a neurodegenerative disease in a patient, wherein the neurodegenerative disease is selected from, for example, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewybody disease, Parkinson's disease, spinal muscular atrophy, motor neuron disease, Creutzfeldt-Jakob disease, primary progressive aphasia, and progressive supranuclear palsy. Other examples of neurodegenerative diseases include Alper's disease, Batten disease, brain-ocular-facial-skeletal syndrome, corticobasal degeneration, Gerstmann-Straussler-Scheinker disease, Kuru disease, Leigh disease, monosomal muscular atrophy, multiple systemic atrophy, myotonic muscular atrophy, prion disease, progressive multifocal leukemia, leukoencephalopathy, striatal desquamation, and infectious spongiform encephalopathy.

[0264] 4-(( L - Valyl)oxy)butanoic acid 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, and fibromyalgia.

[0265] 4-(( L - Valyl)oxy)butanoic acid can be used to treat, for example, REM sleep behavior disorder, convulsive dystonia, symptoms of schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headaches, symptoms of Alzheimer's disease, symptoms of Parkinson's disease, essential tremor, post-traumatic stress disorder, insomnia associated with post-traumatic stress disorder, and anxiety.

[0266] 4-(( L- Valyl)oxy)butyric acid is a precursor drug of γ-hydroxybutyric acid that provides oral bioavailability of γ-hydroxybutyric acid in the patient's circulatory system after oral administration.

[0267] 4-(( L - Valyl)oxy)butyric acid and its pharmaceutical compositions can be used to treat diseases known or determined to be treated by administering γ-hydroxybutyric acid.

[0268] 4-(( L - Valyl)oxy)butyric acid and its pharmaceutical compositions may be used to treat diseases known or determined to be treated by administering γ-hydroxybutyric acid and one or more additional therapeutic agents.

[0269] 4-(( L - Valyl)oxy)butanoic acid and pharmaceutical compositions may 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, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0270] The method provided by the present disclosure is for a patient 4-(( L - The step of providing a therapeutically effective amount of γ-hydroxybutyric acid in the patient's systemic circulation, comprising the step of administering valyl)oxy)butyric acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0271] The pharmaceutical composition provided by the present disclosure is 4-(( L -In addition to valyl)oxy)butanoic acid), it may additionally contain one or more pharmaceutically active compounds. These compounds are 4-(( L -Treat diseases treated with valyl)oxy)butanoic acid or 4-( (LIt may be provided to treat diseases, disorders, or conditions other than those treated with valyl(oxy)butanoic acid.

[0272] 4-(( L -Valyl)oxy)butanoic acid) or a pharmaceutical composition thereof may be used in combination with at least one other therapeutic agent. 4-(( L -Valyl)oxy)butanoic acid or pharmaceutical compositions thereof may be administered to a patient in combination with other compounds to treat bacterial infections in the patient. 4-(( L -Valyl)oxy)butanoic acid) and at least one other therapeutic agent may act additionally or synergistically. At least one additional therapeutic agent is 4-(( L - It may be included in the same pharmaceutical composition or vehicle comprising valyl)oxy)butanoic acid or may be included in a separate pharmaceutical composition or vehicle. Accordingly, the method provided by the present disclosure 4-(( L In addition to the step of administering -valyl)oxy)butyric acid, it further comprises the step of administering one or more therapeutic agents effective for treating different diseases, disorders, or conditions other than the disease treated with γ-hydroxybutyric acid. The method provided by the present disclosure 4-(( L - Includes administration of valyl)oxy)butanoic acid or a pharmaceutical composition thereof and one or more other therapeutic agents, provided that concomitant administration is 4-(( L - Limited to cases where it does not impair the therapeutic efficacy of valyl)oxy)butyric acid and / or γ-hydroxybutyric acid or produce harmful combination effects.

[0273] 4-(( L A pharmaceutical composition containing -valyl)oxy)butanoic acid is 4-(( L - May be administered concurrently with the administration of another therapeutic agent that may be part of the same pharmaceutical composition as containing valyl)oxy)butanoic acid, or among other pharmaceutical compositions 4-(( L-Valyl)oxy)butanoic acid or a pharmaceutical composition thereof may be administered before or after the administration of another therapeutic agent. In certain embodiments of combination therapy, the combination therapy is 4-(( to minimize adverse drug effects associated with a specific drug L - It may include the step of alternately administering a pharmaceutical composition comprising valyl)oxy)butanoic acid and other therapeutic agents. 4-(( L - When valyl)oxy)butanoic acid is administered concurrently with other therapeutic agents that may potentially produce adverse drug effects, such as toxicity, the other therapeutic agents may be administered at a dose that falls below the threshold at which adverse drug reactions are induced.

[0274] 4-(( L A pharmaceutical composition comprising -valyl)oxy)butanoic acid comprises one or more substances, for example, 4-(( L - It may be administered to improve, modulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of valyl)oxy)butanoic acid. For example, 4-(( L -Valyl)oxy)butanoic acid or 4-(( L - To enhance the therapeutic efficacy of a pharmaceutical composition containing valyl)oxy)butanoic acid, administered in combination with one or more active agents from the gastrointestinal tract 4-(( L -Increase the absorption or diffusion and / or transport of valyl)oxy)butyric acid, or 4-(( in the patient's blood L -Inhibits the decomposition of valyl(oxy)butyric acid. 4-(( L A pharmaceutical composition containing -valyl)oxy)butanoic acid is 4-(( L - It may be administered in combination with an activator having a pharmacological effect that enhances the therapeutic efficacy of valyl)oxy)butyric acid or γ-hydroxybutyric acid.

[0275] Aspects of the present invention

[0276] The present invention is further defined by the following aspects.

[0277] Aspect 1. A pharmaceutical granule formulation comprising a plurality of coated granules, wherein the granules comprise a core and a functional coating surrounding the core; the pharmaceutical granule formulation is characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, wherein the PSD is determined by sieve analysis; and the core comprises more than 90 wt% of 4-(( L A pharmaceutical granule containing valyl(oxy)butanoic acid, wherein wt% is based on the total weight of the core.

[0278] Aspect 2. In Aspect 1, the pharmaceutical granules comprise 60 wt% to 90 wt% of 4-(( L A pharmaceutical granule containing valyl(oxy)butanoic acid, wherein wt% is based on the total weight of the pharmaceutical granule.

[0279] Aspect 3. A pharmaceutical granule comprising a release coating modified from a functional coating, in any one of Aspects 1 to 2.

[0280] Aspect 4. A pharmaceutical granule, wherein in any one of aspects 1 to 3, the functional coating comprises 50 wt% to 85 wt% of a matrix polymer, wherein wt% is based on the total weight of the functional coating.

[0281] Aspect 5. A pharmaceutical granule according to Aspect 4, wherein the matrix polymer comprises a water-insoluble polymer.

[0282] Aspect 6. A pharmaceutical granule according to Aspect 5, wherein the water-insoluble polymer comprises ethylcellulose.

[0283] Aspect 7. A pharmaceutical granule, wherein in any one of aspects 1 to 6, the functional coating comprises 0 wt% to 10 wt% of a pore-forming polymer, wherein wt% is based on the total weight of the matrix polymer.

[0284] Aspect 8. A pharmaceutical granule according to Aspect 7, wherein the pore-forming polymer comprises a water-soluble polymer.

[0285] Aspect 9. A pharmaceutical granule according to Aspect 8, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

[0286] A pharmaceutical granule, wherein in any one of Aspects 1 to 9, the functional coating comprises 10 wt% to 20 wt% of an antistatic agent, wherein wt% is based on the total weight of the functional coating.

[0287] Aspect 11. A pharmaceutical granule according to Aspect 10, wherein the antistatic agent comprises talc, magnesium stearate, or a combination thereof.

[0288] Aspect 12. A pharmaceutical granule, wherein in any one of Aspects 1 to 11, the functional coating comprises 50 wt% to 85 wt% of a matrix polymer; and 10 wt% to 20 wt% of an antistatic agent; wherein wt% is based on the total weight of the functional coating.

[0289] A pharmaceutical granule, wherein in any one of Aspects 1 to 12, the core represents 65 wt% to 85 wt% of the total weight of the coated granule; and the functional coating represents 15 wt% to 40 wt% of the total weight of the coated granule.

[0290] Aspect 14. A pharmaceutical granule, wherein in any one of aspects 1 to 13, the functional coating has a thickness of 5 μm to 30 μm.

[0291] Aspect 15. In any one of aspects 1 to 14, the pharmaceutical granule has a water content of less than 2 wt%, wherein wt% is based on the total weight of the pharmaceutical granule.

[0292] Aspect 16. Any one of aspects 1 to 15, further comprising a sealing coating surrounding a core, wherein the functional coating surrounds the sealing coating, a pharmaceutical granule.

[0293] Aspect 17. A pharmaceutical granule according to Aspect 16, wherein the sealing coating comprises hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxypropyl cellulose and talc; or hydroxypropylmethyl cellulose and talc.

[0294] Aspect 18. A pharmaceutical granule according to Aspect 17, wherein the pharmaceutical granule comprises a sealing coating of 2 wt% to 15 wt%.

[0295] Aspect 19. In any one of Aspects 1 to 18, 30 wt% to 80 wt% of 4-(( L- Valyl)oxy)butanoic acid is released from the granules within 2 hours, where wt% is 4- in the granules ( L - A pharmaceutical granule based on the total weight of valyl(oxy)butanoic acid.

[0296] Aspect 20. In any one of Aspects 1 to 19, 50 wt% to 90 wt% of 4-(( L- Valyl)oxy)butanoic acid is released from the granules within 4 hours, where wt% is 4-(( in the granules L - A pharmaceutical granule based on the total weight of valyl(oxy)butanoic acid.

[0297] Aspect 21. In any one of Aspects 1 to 20, 60 wt% to 100 wt% of 4-(( L- Valyl)oxy)butanoic acid is released from the granules within 6 hours, where wt% is 4-(( in the granules L - A pharmaceutical granule based on the total weight of valyl(oxy)butanoic acid.

[0298] Aspect 22. A pharmaceutical composition comprising any one of the pharmaceutical granules of Aspects 1 to 21.

[0299] Aspect 23. A pharmaceutical composition according to Aspect 22, wherein the pharmaceutical composition is an oral composition.

[0300] Aspect 24. A pharmaceutical composition according to Aspect 23, wherein the oral composition comprises a modified release composition.

[0301] Aspect 25. Any one of Aspects 23 to 24, wherein the oral composition comprises a modified release portion, wherein the modified release portion comprises a pharmaceutical granule; and the pharmaceutical composition further comprises an immediate release portion.

[0302] Aspect 26. A pharmaceutical composition according to Aspect 25, wherein the immediate release portion dissolves in water within 5 minutes.

[0303] Aspect 27. A pharmaceutical composition in any one of Aspects 23 to 26, wherein the oral composition is a BID composition.

[0304] Aspect 28. A pharmaceutical composition in any one of Aspects 23 to 27, wherein the oral composition is a QD composition.

[0305] Aspect 29. In any one of Aspects 22 to 28, the pharmaceutical composition has 4-((500 mg equivalents to 12 g equivalents L- A pharmaceutical composition comprising valyl)oxy)butanoic acid.

[0306] Aspect 30. A pharmaceutical composition in 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 above.

[0307] Aspect 31. In any one of Aspects 22 to 30, the pharmaceutical composition has a therapeutically effective amount of 4-(( L- A pharmaceutical composition comprising valyl(oxy)butanoic acid, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0308] A method for treating a disease in a patient, comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of Aspects 22 to 31 to a patient requiring such treatment, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0309] Aspect 33. A method in which the disease in Aspect 32 is cataplexy associated with narcolepsy.

[0310] Aspect 34. A method in which the disease in Aspect 32 is excessive daytime sleepiness associated with narcolepsy.

[0311] Aspect 35. A method in which the disease in Aspect 32 is excessive daytime sleepiness in a patient with Parkinson's disease.

[0312] Aspect 36. A method in which the disease in Aspect 32 is chronic fatigue in a patient with Parkinson's disease.

[0313] Aspect 37. A method in any one of aspects 32 to 36, wherein the administration includes oral administration.

[0314] Side 38. 4-(( L-A method for coating granules comprising the step of applying a coating composition to a plurality of granules comprising valyl(oxy)butanoic acid, wherein the coating composition comprises: 6 wt% to 14 wt% solids; 0 wt% to 20 wt% water; and 70 wt% to 95 wt% ethanol, wherein wt% is based on the total weight of the coating composition.

[0315] Aspect 39. The method of Aspect 38, wherein the solid comprises: a matrix polymer selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, or a combination thereof; and an antistatic agent selected from talc, magnesium stearate, or a combination thereof.

[0316] Side 40. A method in any one of sides 38 to 39, wherein the application includes spraying.

[0317] Examples

[0318] The embodiments provided by the present disclosure are 4-(( L -Coated pharmaceutical granules containing valyl)oxy)butanoic acid, 4-( (L Coated pharmaceutical granules comprising valyl(oxy)butanoic acid, orally modified release pharmaceutical compositions, and methods for preparing the coated pharmaceutical granules and granules provided by the present disclosure are further illustrated with reference to the following examples. It will be apparent to those skilled in the art that many variations of both materials and methods may be made without departing from the scope of the present disclosure.

[0319] general method

[0320] Pharmacokinetic analysis

[0321] The plasma concentrations of compound (1) and γ-hydroxybutyrate in the plasma of healthy human subjects were measured using liquid chromatography tandem mass spectrometry, and Phoenix TMIt was evaluated using WinNonlin® version 8.1 (Pharsight Corporation, USA) and Microsoft® Excel® 2016 (Microsoft Corporation, USA).

[0322] Dissolution profile

[0323] The dissolution profile for the modified emitting microparticles was determined using a USP Type 2 dissolution apparatus with a buffer solution at pH 4.5 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 emitting microparticles is shown in FIG. 1.

[0324] Example 1

[0325] 4-(( L - Aqueous seal-coated immediate-release granules of valyl(oxy)butanoic acid

[0326] Sealed coated immediate-release (IR) granules 4-(( L It was prepared by spray-coating valyl)oxy)butanoic acid granules onto uncoated IR granules.

[0327] 4-(( L Uncoated granules containing -valyl)oxy)butanoic acid were manufactured using MicroPX® micropelletization technology (Glatt GmbH). The uncoated IR granules had an average granule diameter (D50) of 225 μm to 275 μm. The uncoated IR granules contained 90 wt% 4-(( L - Contains valyl)oxy)butanoic acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose (hydroxypropylmethylcellulose), where wt% is based on the total weight of the IR granules.

[0328] The composition used to provide the sealing coat contains 14.2 wt% hydroxypropylmethylcellulose (Pharmacoat® 603), 2.1 wt% talc, and 85.6 wt% water, where wt% is based on the total weight of the sealing coat composition.

[0329] The composition was spray-coated onto uncoated IR granules to provide a sealing coating with a thickness of 2.23 (+ / -0.34) μm.

[0330] The particle size distribution of the particles is shown in Fig. 1, SEM images of the seal-coated granules are shown in Figs. 2a to 2d, and SEM images of the cross-sectional view of the seal-coated granules are shown in Fig. 2e.

[0331] Example 2

[0332] 4-(( L - Acetone-based seal-coated immediate-release granules of valyl(oxy)butanoic acid

[0333] Sealed coated IR granules 4-(( L It was prepared by spray-coating uncoated granules of valyl(oxy)butanoic acid granules.

[0334] 4-(( L Uncoated granules containing -valyl)oxy)butanoic acid were manufactured using MicroPX® micropelletization technology (Glatt GmbH). The uncoated IR granules had an average granule diameter (D50) of 225 μm to 275 μm. The uncoated IR granules contained more than 90 wt% of 4-(( L - It has a valyl(oxy)butanoic acid content.

[0335] The composition used to provide the sealing coat contains 5.4 wt% hydroxypropyl cellulose (Klucel® EF), 2.1 wt% talc, and 92.5 wt% acetone, where wt% is based on the total weight of the sealing coat composition.

[0336] The composition was spray-coated onto uncoated granules to provide a sealing coating with a thickness of 1.30 (+ / -0.27) μm.

[0337] The particle size distribution of the seal-coated IR particles is shown in Fig. 3, SEM images of the seal-coated granules are shown in Figs. 4a to 4d, and SEM images of the cross-sectional view of the seal-coated granules are shown in Fig. 4e.

[0338] Example 3

[0339] 4-(( with modified emission coating (1) L - Granules of valyl oxybutanoic acid

[0340] 98.5 wt% of 4-(( L A granule with a modified release (MR) coating was prepared using a granule characterized by containing valyl)oxy)butanoic acid and having an average granule diameter (D50) of 225 μm to 275 μm.

[0341] The components of the modified emission coating are provided in Table 1.

[0342]

[0343] Modified emission coatings were applied at 20 %wg and 40 %wg.

[0344] For the 40 %wg coated granules, the bulk density was 0.70 g / mL (loss on drying) and the LOD was 0.55%. The thickness of the modified release coating at 40 wg% was 10.26 μm + / -1.46 μm (std).

[0345] The particle size distribution is shown in Fig. 5, and the dissolution profile is shown in Fig. 6. SEM images of 40 %wg coated granules are shown at different magnifications in Figs. 7a to 7d, and a cross-sectional view of the coating is shown in Fig. 7e.

[0346] Example 4

[0347] 4-(( with modified emission coating (2) L - Granules of valyl oxybutanoic acid

[0348] 98.5 wt% of 4-(( L- A granulated preparation containing granules characterized by granule diameters of 225 μm to 275 μm and containing valyl(oxy)butanoic acid was used.

[0349] The components of the modified emission coating composition are provided in Table 2.

[0350]

[0351] Process conditions for applying the modified emission coating are provided in Table 3.

[0352]

[0353] Modified emission coatings were applied at 20 %wg and 40 %wg.

[0354] For the 40 %wg coated granules, the bulk density was 0.63 g / mL and the LOD was 0.37%. The thickness of the modified release coating at 40 %wg was 10.16 μm + / -2.80 μm (std).

[0355] The particle size distribution is shown in Fig. 8, and the dissolution profile is shown in Fig. 9. SEM images of 40 %wg coated granules are shown at different magnifications in Figs. 10a to 10d, and a cross-sectional view of the coating is shown in Fig. 10e.

[0356] Example 5

[0357] 4-(( with modified emission coating (3) L - Granules of valyl oxybutanoic acid

[0358] 98.5 wt% of 4-(( L- A granulated preparation containing granules characterized by granule diameters of 200 μm to 425 μm having valyl(oxy)butanoic acid was used.

[0359] The process conditions for applying the modified emission coating were the same as those for Example 3.

[0360] The components of the modified emission coating are provided in Table 4.

[0361]

[0362] Modified emission coatings were applied at 20 %wg, 30 %wg, 35 %wg, and 40 %wg.

[0363] For the 40 %wg coated granules, the bulk density was 0.68 g / mL and the LOD was 0.69%. The thickness of the modified release coating at 40 %wg was 11.58 μm + / -1.45 μm (std).

[0364] The particle size distribution is shown in Fig. 11, and the dissolution profile is shown in Fig. 12. SEM images of 40 %wg coated granules are shown at different magnifications in Figs. 13a to 13d, and a cross-sectional view of the coating is shown in Fig. 13e.

[0365] Example 6

[0366] Coated granules (4)

[0367] The sealed coated granules of Example 1 were used as the starting material.

[0368] The process conditions for applying the modified emission coating were the same as those for Examples 3 to 5.

[0369] The components of the modified emission coating composition are provided in Table 5.

[0370]

[0371] Modified emission coatings were applied at 20 %wg and 40 %wg.

[0372] For the 40 %wg coated pharmaceutical granules, 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 (std).

[0373] The particle size distribution is shown in FIG. 14, and the dissolution profile is shown in FIG. 15. SEM images of 40 %wg coated granules are shown at different magnifications in FIG. 16a to 16d, and a cross-sectional view of the coating is shown in FIG. 16e.

[0374] Example 7

[0375] Pharmacokinetics of immediate-release and modified-release compositions

[0376] The pharmacokinetics of compound (1) and γ-hydroxybutyrate were determined after oral administration of the immediate-release component or modified-release component to healthy fasting subjects.

[0377] To prepare the immediate-release component, the immediate-release microparticles prepared according to Example 1 were added to 30 mL of water and gently shaken to dissolve the immediate-release microparticles. The uncoated IR granules had an average granule diameter (D50) of 225 μm to 275 μm. The IR granules contained 90 wt% 4-(( L It contains valyl)oxy)butanoic acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose, where wt% is based on the total weight of the IR granules. Water is added to make the total volume 250 mL to provide an immediate-release component, which was ingested by a subject.

[0378] To prepare the modified release composition, the modified release microparticles prepared according to Example 5 were added to 30 mL of water and gently shaken. Ora-Plus® (30 mL) was added, the contents were gently shaken, and the subject drank. The container was rinsed with additional water up to a total volume of 250 mL and ingested by the subject. MR1 granules had a 60% wg coating, MR2 granules had a 40 wg% coating, and MR3 granules had a 50% wg coating. The modified release coating contained 81.7 wt% ethylcellulose, 2.0 wt% hypromellose, and 16.3 wt% magnesium stearate, where wt% is based on the total weight of the coating.

[0379] Each component contained 7.25 g of compound (1) (3.172 g-equivalent γ-hydroxybutyrate).

[0380] Plasma pharmacokinetic profiles of compound (1) and γ-hydroxybutyrate after oral administration of immediate release (IR) or modified release (MR1 to MR3) compositions to healthy fasting subjects are shown in FIG. 17 for compound (1) and in FIG. 18 for γ-hydroxybutyrate. The results represent the mean and standard deviation based on results for 7 to 8 subjects.

[0381] Pharmacokinetic parameters for compound (1) and γ-hydroxybutyrate after oral administration of compositions containing IR and MR microparticles are provided in Tables 6 and 7, respectively. The results represent the mean and standard deviation based on the results for 7 to 8 subjects.

[0382]

[0383]

[0384] C max B, AUC 0-inf B, and AUC 0-8The ratios are shown in Table 8, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0385]

[0386] Example 8

[0387] Pharmacokinetics of complex release compositions

[0388] The pharmacokinetics of a composite release (CR) composition containing immediate-release microparticles (IR component) and modified-release microparticles (MR component) were determined.

[0389] The amount of microparticles used to prepare the composite release compositions (CR1 and CR2) is summarized in Table 9.

[0390]

[0391] To prepare the complex release composition, an amount of immediate-release microparticles was dissolved in 30 mL of water. Then, a dose of modified-release microparticles was added and the mixture was gently shaken. 30 mL of the oral suspension vehicle Ora-Plus® was added and the mixture was gently shaken. Then, the subjects drank the solution. The subjects repeatedly rinsed the cup with up to 250 mL of water and drank the solution.

[0392] Plasma pharmacokinetic profiles for compound (1) and γ-hydroxybutyrate after oral administration of the combined release compositions (CR1 and CR2) to healthy fasting subjects are shown in FIGS. 19 and 20, respectively. The results represent the mean and standard deviation based on 12 subjects.

[0393] A summary of pharmacokinetic parameters for compound (1) and γ-hydroxybutyrate after oral administration of the complex-release composition to healthy fasting subjects is provided in Tables 10 and 11. The results reflect the mean values ​​obtained for 12 subjects.

[0394]

[0395] C for a composite release composition max B, AUC 0-inf B and AUC 0-8 The ratios are presented in Table 12, where the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0396]

[0397] It should be noted that alternative methods for implementing the embodiments disclosed herein exist. Accordingly, the embodiments disclosed herein should be regarded as exemplary rather than restrictive. Furthermore, the claims are not limited to the details provided herein and have the full scope and equivalents.

Claims

Claim 1 A modified release pharmaceutical granule formulation comprising a plurality of coated granules, wherein the granules comprise a core and a modified release coating surrounding the core; the modified release coating comprises 72 wt% to 92 wt% ethylcellulose; and 0.5 wt% to 4 wt% hydroxypropylcellulose; and 11 wt% to 22 wt% antistatic agent, wherein the antistatic agent comprises talc, magnesium stearate, or a combination thereof; wherein wt% is based on the total weight of the modified release coating, and the core comprises more than 85 wt% 4-(( L- A modified release pharmaceutical granule comprising valyl(oxy)butanoic acid, wherein wt% is based on the total weight of the core, and the modified release pharmaceutical granule is characterized by an average particle size (D50) of 150 μm to 400 μm, wherein D50 is determined by sieve analysis. Claim 2 A modified release pharmaceutical granule according to claim 1, wherein the core comprises 65 wt% to 85 wt% of the total weight of the coated granule; and the modified release coating comprises 15 wt% to 40 wt% of the total weight of the coated granule. Claim 3 A modified release pharmaceutical granule according to claim 1, wherein the modified release coating has a thickness of 5 μm to 30 μm. Claim 4 The modified release pharmaceutical granules of claim 1, wherein the modified release pharmaceutical granules have a water content of less than 2 wt%, where wt% is based on the total weight of the modified release pharmaceutical granules. Claim 5 As an immediate-release (IR) component, 2 g to 8 g of 4-(( L- An immediate-release component comprising valyl)oxy)butanoic acid; and as a modified-release (MR) component, 8 g to 16 g of 4-(( L A pharmaceutical composition comprising a modified release component comprising - valyl)oxy)butanoic acid; and a modified release pharmaceutical granule of any one of claims 1 to 4. Claim 6 A pharmaceutical composition according to claim 5, wherein the immediate-release component comprises a plurality of immediate-release microparticles. Claim 7 In paragraph 5, 4-(( immediately released microparticles exceeding 90 wt% L- A pharmaceutical composition comprising valyl(oxy)butanoic acid, wherein wt% is based on the total weight of immediately released microparticles. Claim 8 A pharmaceutical composition according to claim 5, wherein the immediate-release microparticles have a volume average diameter D (4.3) of 200 μm to 500 μm. Claim 9 A pharmaceutical composition according to claim 5, wherein the immediate-release microparticles have an average particle diameter (D50) of 75 μm to 450 μm determined by sieve analysis or laser diffraction. Claim 10 In paragraph 5, the immediate release component is 20 wt% to 40 wt% of 4-(( L - Containing valyl)oxy)butanoic acid; the modified releasing component comprises 60 wt% to 80 wt% of 4-(( L - Contains valyl)oxy)butanoic acid, where wt% is 4-(( L A pharmaceutical composition based on the total weight of valyl(oxy)butanoic acid. Claim 11 In paragraph 5, among the immediately released components, 4-(( L -Valyl)oxy)butanoic acid versus 4-(( among modified releasing components L A pharmaceutical composition having a weight ratio of valyl)oxy)butanoic acid of 1:2 to 1:

3. Claim 12 A pharmaceutical composition according to claim 5, wherein the immediate-release component comprises a solution suitable for oral administration. Claim 13 A pharmaceutical composition according to claim 12, wherein the modified release component comprises modified release granules suspended in the solution. Claim 14 A pharmaceutical granule preparation for the treatment of narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness with narcolepsy, excessive daytime sleepiness with Parkinson's disease, excessive daytime sleepiness with multiple sclerosis, cataplexy with narcolepsy, fatigue, fatigue with Parkinson's disease, fatigue with multiple sclerosis, or fibromyalgia. Claim 15 In claim 1, a pharmaceutical granule for the treatment of REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress disorder, insomnia with post-traumatic stress disorder, or anxiety. Claim 16 In claim 1, a pharmaceutical granule for the treatment of a sleep disorder with a bacterial infection. Claim 17 In paragraph 1, a pharmaceutical granule preparation for the treatment of neurodegenerative disorders. Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete Claim 52 delete Claim 53 delete Claim 54 delete Claim 55 delete Claim 56 delete Claim 57 delete Claim 58 delete Claim 59 delete Claim 60 delete Claim 61 delete Claim 62 delete Claim 63 delete Claim 64 delete Claim 65 delete Claim 66 delete Claim 67 delete Claim 68 delete Claim 69 delete Claim 70 delete Claim 71 delete Claim 72 delete Claim 73 delete Claim 74 delete Claim 75 delete Claim 76 delete Claim 77 delete Claim 78 delete Claim 79 delete Claim 80 delete Claim 81 delete Claim 82 delete Claim 83 delete Claim 84 delete Claim 85 delete Claim 86 delete Claim 87 delete Claim 88 delete Claim 89 delete Claim 90 delete Claim 91 delete Claim 92 delete Claim 93 delete Claim 94 delete Claim 95 delete Claim 96 delete Claim 97 delete Claim 98 delete Claim 99 delete Claim 100 delete Claim 101 delete Claim 102 delete Claim 103 delete Claim 104 delete Claim 105 delete Claim 106 delete Claim 107 delete

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