Pharmacokinetics of combined release formulations of gamma-hydroxybutyrate derivatives

Abstract

The present invention provides pharmaceutical compositions and methods for treating fatigue or excessive daytime sleepiness associated with narcolepsy. [Solution] A pharmaceutical composition comprising an immediate-release component containing 4-((L-valyl)oxy)butanoic acid and a controlled-release component containing 4-((L-valyl)oxy)butanoic acid, as well as the pharmacokinetics of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate after oral administration of the pharmaceutical composition are disclosed.

Description

[Technical Field]

[0001] This application asserts the interests under Section 119(e) of U.S. Patent Provisional Patent Application No. 63 / 163,096, filed on 19 March 2021, which is incorporated in its entirety by reference.

[0002] This application relates to U.S. Publication No. 2022 / 0023247, U.S. Publication No. 2021 / 0393537A1, and U.S. Publication No. 2021 / 0393529A1.

[0003] This disclosure relates to a pharmaceutical composition containing 4-((L-valyl)oxy)butanoic acid, and to the pharmacokinetics of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate after oral administration of the pharmaceutical composition. [Background technology]

[0004] Sodium gamma-hydroxybutyrate is approved by the United States Food and Drug Administration for the treatment of sudden muscle weakness and excessive daytime sleepiness associated with narcolepsy. Sodium gamma-hydroxybutyrate is the sodium salt of gamma-hydroxybutyrate. [Overview of the project]

[0005] According to the present invention, a pharmaceutical composition comprises an immediate-release (IR) component containing 1.5 g to 3.5 g of γ-hydroxybutyrate equivalents, and a regulated-release (MR) component containing 3 g to 9 g of γ-hydroxybutyrate equivalents.

[0006] According to the present invention, a method for treating fatigue or excessive daytime sleepiness associated with narcolepsy in a patient comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0007] 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 comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0008] According to the present invention, a method for treating symptoms associated with narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0009] According to the present invention, a method for treating in patients REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety disorder comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0010] According to the present invention, a method for treating in patients symptoms associated with REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety disorder comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0011] According to the present invention, a method for treating a sleep disorder associated with a bacterial infection in a patient comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0012] According to the present invention, a method for enhancing cognitive function in a patient with neurological impairment comprises orally administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a patient requiring 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 provided herein are for illustrative purposes only. The drawings are not intended to limit the scope of this disclosure.

[0015] [Figure 1] The dissolution profiles of the controlled-release microparticles provided by this disclosure are shown. [Figure 2A] The mean plasma concentrations of compound (1) after oral administration of the immediate-release component and three controlled-release components of compound (1) to fasted, healthy subjects are shown. [Figure 2B] The mean plasma γ-hydroxybutyrate concentrations in fasted, healthy subjects after oral administration of the immediate-release component of compound (1) and three controlled-release formulations. [Figure 3] This table shows the mean plasma concentrations of compound (1) after oral administration of the combined release formulation to fasted, healthy subjects. [Figure 4] This table shows the mean plasma γ-hydroxybutyrate concentrations in fasted, healthy subjects after oral administration of the combined release formulation. [Figure 5] The mean γ-hydroxybutyrate plasma concentrations are shown after oral administration of the compound (1) combination release formulation to fasted, healthy subjects. [Figure 6]The mean γ-hydroxybutyrate plasma concentrations are shown after oral administration of the different doses of the combined release formulations provided by this disclosure, as described in Example 5, to fasted, healthy subjects. [Modes for carrying out the invention]

[0016] For the purposes of the following detailed description, it should be understood that the embodiments provided by this disclosure may be subject to various alternative modifications and process sequences, unless expressly designated to be contrary. Furthermore, except for any example of the operation, or where otherwise shown, all numbers representing the quantities of components used in the specification and claims should be understood in all examples as being modified by the term “approximately.” Thus, unless shown to be contrary, the numerical parameters described in the following specification and appended claims are approximations that may vary depending on the desired characteristics obtained by the invention. At the very least, and without attempting to limit the application of the equivalent view to the claims, each numerical parameter should be interpreted in light of at least the reported significant number of digits and by applying the usual rounding technique.

[0017] Although the numerical ranges and parameters describing the broad scope of this invention are approximations, the numerical values ​​described in specific examples are reported as accurately as possible. However, any numerical value inherently contains a certain error that inevitably arises from the standard deviation observed in each of its test measurements.

[0018] Furthermore, it should be understood that any numerical range listed herein is intended to include all subranges contained within it. For example, the range "1 to 10" is intended to include all subranges between (and including) the stated minimum value of 1 and the stated maximum value of 10, i.e., a minimum value of 1 or greater and a maximum value of 10 or less.

[0019] "Immediate release" refers to a composition that, when tested in a USP38 dissolution apparatus 2 at a temperature of 37°C and a paddle speed of 75 rpm in a 0.1 N HCl dissolution medium, releases at least 80% of compound (1) within 1 hour.

[0020] Immediate-release compositions or formulations can release substantially all of their pharmaceutically active ingredients into the patient's gastrointestinal tract within less than one hour after oral administration, such as within 50 minutes, 40 minutes, 30 minutes, 20 minutes, or 10 minutes. For example, an immediate-release dosage form can release more than 90%, 95%, or 98% of the pharmaceutically active ingredient, such as compound (1) in the pharmaceutical composition, into the gastrointestinal tract within less than one hour after oral administration, such as within 50 minutes, 40 minutes, 30 minutes, 20 minutes, or 10 minutes. Immediate-release pharmaceutical compositions may be suitable for administering pharmaceutically active ingredients that are absorbed into the systemic circulation from the upper gastrointestinal tract.

[0021] "Controlled-release" pharmaceutical compositions and formulations may include controlled-release formulations, delayed-release formulations, sustained-release formulations, prolonged-release formulations, time-delayed-release formulations, pulsating-release formulations, and pH-dependent-release formulations. These formulations are intended to release the pharmaceutically active ingredient from the pharmaceutical composition at a desired rate and / or time, and / or at specific locations or multiple locations in the gastrointestinal tract, and / or at a specific pH in the gastrointestinal tract, after oral administration by the patient. The USP defines a controlled-release system as one in which the time course and / or location of drug release is selected to achieve therapeutic efficacy or convenience objectives that cannot be met by immediate-release formulations. Controlled-release oral formulations may include sustained-release and delayed-release components. Delayed-release formulations release the drug all at once, rather than immediately after administration. Modified-release formulations may include delayed-release formulations using enteric coatings, site-specific or time-delayed-release formulations such as those for colonic delivery, sustained-release formulations that can provide zero-order, primary, or biphasic release profiles, and programmed-release formulations such as pulsating-release and delayed-sustained-release.

[0022] "Sustained release" pharmaceutical compositions and coatings provide a long-term dissolution rate after oral administration. Granules containing microparticles with a sustained release coating may be referred to as sustained release granules. A pharmaceutical composition containing sustained release granules may be referred to as a sustained release pharmaceutical composition.

[0023] "Bioequivalent" refers to a formulation and / or pharmaceutical composition that is therapeutically equivalent to a reference product when administered under the same conditions in a pharmacokinetic evaluation that complies with FDA guidance regarding bioequivalence testing, regardless of the biopharmaceutical class.

[0024] Values that are "bioequivalent" refer to pharmacokinetic values such as C max or AUC that exhibit substantially similar pharmacokinetic profiles and / or therapeutic effects. Bioequivalence can be demonstrated by several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamic, clinical, and in vitro studies. Bioequivalence can be demonstrated using any suitable pharmacokinetic measurement, or a combination of pharmacokinetic measurements known in the art, including loading dose, steady state dose, initial or steady state concentration of the drug, biological half-life, elimination rate, area under the curve (AUC), clearance, peak blood or plasma concentration (C max ), time to peak concentration (T max ), bioavailability, and efficacy. In some embodiments, when the geometric mean of the AUC and / or C max is between 80% and 125% (e.g., 90% confidence interval) of the reference pharmacokinetic value, the value is bioequivalent to the reference pharmacokinetic value.

[0025] A similar or bioequivalent pharmacokinetic profile is one in which the mean AUC of the pharmaceutical composition 0-inf is between 80% and 125% of the mean AUC 0-inf in a well-designed crossover study, and the mean plasma concentration of the pharmaceutical composition at 8-hour C 8h is between 40% and 130% of the mean plasma concentration of the reference composition at 8-hour C 8h , and / or the maximum plasma concentration (C max) is C of the reference composition max This refers to a pharmacokinetic profile that is between 50% and 140% of the total.

[0026] "Feeding state" refers to the period immediately following a meal, up to two hours after ingestion. The feeding state may also include the period less than two hours after eating.

[0027] "Fasting" refers to the period of eight hours following food intake.

[0028] "Patient" refers to a mammal, such as a human.

[0029] "Pharmacologically acceptable" means approved or appropriable as defined by a federal or state regulatory body, or as defined in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in animals, more specifically in humans.

[0030] A "pharmaceutically acceptable salt" refers to a salt of a parent compound that has the desired pharmacological activity. Such salts include inorganic acids, as well as acid addition salts formed by one or more protonable controlled release groups, such as primary, secondary, or tertiary amines, in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts can be formed from organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc. Salts can be formed when one or more acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or combinations thereof, or by coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. A pharmaceutically acceptable salt may be a hydrochloride salt. A pharmaceutically acceptable salt may also be a sodium salt. For compounds having two or more ionizable groups, a pharmaceutically acceptable salt may contain one or more counterions, such as a dichloride salt.

[0031] The term “pharmaceutically acceptable salt” includes hydrates and other solvates, as well as salts in crystalline or amorphous forms. Where a particular pharmaceutically acceptable salt is disclosed, it should be understood that the particular salt (e.g., hydrochloride) is an example of a salt, and other salts may be formed using techniques known to those skilled in the art. In addition, using techniques generally known in the art, those skilled in the art may convert pharmaceutically acceptable salts to the corresponding compounds, free bases, and / or free acids.

[0032] A “prodrug” refers to a derivative of a drug molecule that requires conversion in the body to deliver an active drug. Prodrugs are often pharmacologically inactive until they are converted to the parent drug, though this is not always the case. Prodrugs can typically be obtained by attaching a pro-moiety (as defined herein) to a drug via a controlled-release group.

[0033] To "cure" a disease means to eliminate the disease or disorder, or to eliminate the symptoms of the disease or disorder.

[0034] "Treating" or "treating" a disease or disorder means reducing the severity of one or more clinical symptoms of the disease or disorder, delaying the onset of one or more clinical symptoms of the disease or disorder, and / or alleviating one or more clinical symptoms of the disease or disorder; "Treating" or "treating" a disease or disorder means inhibiting one or more clinical symptoms of the disease or disorder, preventing the onset of one or more clinical symptoms of the disease or disorder, alleviating one or more clinical symptoms of the disease or disorder, causing regression of one or more clinical symptoms of the disease or disorder, and / or stabilizing one or more clinical symptoms of the disease or disorder; and "Treating" or "treating" a disease or disorder means producing a clinically beneficial effect without curing the underlying disease or disorder.

[0035] The “therapeutic dose” refers to the amount of compound (1) or γ-hydroxybutyrate, or other pharmaceutically active ingredient, that is sufficient to have such an effect on the treatment of a disease or at least one of its clinical symptoms when administered to a patient. The “therapeutic dose” may vary, for example, depending on the compound, the disease and / or symptoms of the disease, the severity of the disease, and / or the symptoms of the disease or disorder, the age, weight, and / or health of the patient being treated, and the judgment of the prescribing physician. The therapeutic dose in any given case may be determined by a person skilled in the art, by routine experimentation, or based on the judgment of the prescribing physician or healthcare professional.

[0036] The "therapeutic effective dose" refers to the dose that provides effective treatment for a disease or disorder in a patient. The therapeutic effective dose of compound (1) or γ-hydroxybutyrate may vary from patient to patient and may depend on factors such as the patient's medical condition, the severity of the disease, and the route of delivery. The therapeutic effective dose may be determined according to routine pharmacological procedures known to those skilled in the art.

[0037] "Vehicle" refers to a diluent, excipient, or carrier administered to the patient along with the compound. The vehicle may be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0038] "Percent weight increase" or "35%wg" coating, where "%wg" is used, refers to coated microparticles where the weight of the coated microparticles is 35% greater than the weight of the uncoated microparticles.

[0039] The dissolution profile is measured using a USP Type 2 dissolution apparatus, sodium acetate buffer solution, at a temperature of 37°C and a paddle speed of 75 rpm, with a pH of 4.5.

[0040] "C max " refers to the maximum plasma concentration.

[0041] "C tC6 refers to the plasma concentration at time t, where t is the duration after administration. For example, C6 refers to the plasma concentration of the analyte 6 hours after administration.

[0042] "T max This refers to the time it takes to reach the maximum plasma concentration.

[0043] AUC 0-tlast " refers to the area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration.

[0044] AUC 0-inf " refers to the area under the plasma concentration-time curve from time 0 to infinite time, and is called AUC. 0-tlast and C last It is calculated as the sum of / λz and / λz.

[0045] AUC 0-τ " refers to the area under the plasma concentration-time curve during the dosing interval τ. For example, the interval can be 6 hours or 8 hours after administration.

[0046] "λz" refers to the apparent terminal vanishing rate constant.

[0047] "T 1 / 2 This refers to the elimination half-life related to the terminal slope (λz) of the semi-logarithmic drug concentration-time curve, and is calculated as 0.693 / λz.

[0048] "CL / F" refers to the apparent systemic clearance of a drug from plasma, calculated as follows: CL / F = Dose / AUC 0-inf .

[0049] This document refers to microparticles containing 4-((L-valyl)oxy)butanoic acid, pharmaceutical compositions containing 4-((L-valyl)oxy)butanoic acid, and the pharmacokinetics of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate after oral administration of pharmaceutical compositions containing 4-((L-valyl)oxy)butanoic acid to fasted healthy subjects. The disclosed microparticles, pharmaceutical compositions, and pharmacokinetics are not intended to limit the scope of the claims. On the contrary, the claims are intended to encompass all substitutes, modifications, and equivalents.

[0050] Sodium oxibate (sodium gamma-hydroxybutyrate) is approved by the U.S. Food and Drug Administration for the treatment of muscle fatigue and excessive daytime sleepiness associated with narcolepsy. Sodium oxibate is available from Jazz Pharmaceuticals under the trademark name Xyrem®. Sodium oxibate is administered orally and is a salt form of the pharmaceutically active ingredient gamma-hydroxybutyrate, also known as gamma-hydroxybutyrate and oxibate. Sodium oxibate and gamma-hydroxybutyrate have the structures of formula (2a) and formula (2b), respectively. [ka] [ka]

[0051] 4-((L-valyl)oxy)butanoic acid (compound (1)) is a prodrug of γ-hydroxybutyrate, which, after oral administration, is metabolized to provide γ-hydroxybutyrate to the patient's plasma. 4-((L-valyl)oxy)butanoic acid has the structure of formula (1). [ka]

[0052] One gram of compound (1) contains 0.512 g of γ-hydroxybutyrate equivalents. For example, 4.5 g of compound (1) contains 2.3 g of γ-hydroxybutyrate equivalents, and 10 g of compound (1) contains 5.2 g of γ-hydroxybutyrate equivalents.

[0053] Compound (1) corresponds to 0.62 g of sodium gamma-hydroxybutyrate. For example, 4.5 g of compound (1) corresponds to 2.79 g of sodium gamma-hydroxybutyrate, and 4.5 g of sodium gamma-hydroxybutyrate corresponds to 7.26 g of compound (1).

[0054] The pharmaceutical compositions provided by this disclosure may include immediate-release components, controlled-release components, and combinations thereof.

[0055] The immediate-release (IR) component may include microparticles containing a compound (1) configured to dissolve immediately upon contact with gastrointestinal fluid or in an oral pharmaceutical composition.

[0056] The regulated-release (MR) component may include microparticles containing a compound (1) configured to dissolve in gastrointestinal fluid over time.

[0057] The combined release (CR) pharmaceutical compositions provided by this disclosure may include immediate-release components and controlled-release components. The pharmaceutical compositions provided by this disclosure may include, for example, 3 g to 6 g of compound (1) in the IR component and 6 g to 16 g of compound (1) in the MR component, 3 g to 6 g in the IR component and 7 g to 13 g in the MR component, 3 g to 6 g in the IR component and 8 g to 12 g in the MR component, 3 g to 6 g in the IR component and 9 g to 11 g in the MR component, or 3.5 g to 5.5 g of compound (1) in the IR component and 9 g to 11 g of compound (1) in the MR component.

[0058] The pharmaceutical compositions provided by this disclosure may, for example, contain compound (1) in the IR component in a weight ratio of compound (1) 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, 1:2.3 to 1:2.7, or 1:2.4 to 1:2.7.

[0059] The pharmaceutical compositions provided by this disclosure may, for example, contain 20% to 40% by weight of compound (1) in the IR component, 22% to 38% by weight, 24% to 36% by weight, 26% to 36% by weight, or 28% to 34% by weight of compound (1) in the IR component, where the weight percentage is based on the total weight of compound (1) in the pharmaceutical composition.

[0060] The pharmaceutical compositions provided by this disclosure may, for example, contain 60% to 80% by weight of compound (1) in the MR component, 62% to 78% by weight of compound (1) in the MR component, or 65% to 75% by weight of compound (1), where the weight percentage is based on the total weight of compound (1) in the pharmaceutical composition.

[0061] The pharmaceutical compositions provided by this disclosure may contain, for example, compound (1) in the immediate-release component in a molar ratio of compound (1) in the controlled-release component to compound (1) in the controlled-release component, such as 1:1 to 1:10, 1:1 to 1:9, 1:1.5 to 1:8.5, 1:2 to 1:8, 1:2.5 to 1:7.5, 1:3 to 1:1.7, 1:3.5 to 1:6.5, or 1:4 to 1:6.

[0062] The pharmaceutical compositions provided by this disclosure may include, for example, mole percentages of compound (1) in immediate components of 5% to 40%, 10% to 35%, 15% to 30%, or 20% to 25%, based on the total number of moles of compound (1) in the pharmaceutical composition.

[0063] The pharmaceutical compositions provided by this disclosure may include, for example, molar percentages of compound (1) in the controlled-release component of 95% to 69%, 90% to 65%, 85% to 60%, 80% to 55%, or 75% to 60%, based on the total number of moles of compound (1) in the pharmaceutical composition.

[0064] The pharmaceutical compositions provided by this disclosure may, for example, contain 1.5g to 3g of γ-hydroxybutyrate equivalents in the IR component and 3g to 8g of γ-hydroxybutyrate equivalents in the MR component, 1.5g to 3g in the IR component and 3.5g to 6.5g in the MR component, 1.5g to 3g in the IR component and 4g to 6g in the MR component, 1.5g to 3g in the IR component and 4.5g to 15.5g in the MR component, or 1.7g to 52.8g of compound (1) in the IR component and 4.5g to 5.5g of γ-hydroxybutyrate equivalents in the MR component.

[0065] The pharmaceutical compositions provided by this disclosure may, for example, contain a weight ratio of the γ-hydroxybutyrate equivalent in the IR component to the γ-hydroxybutyrate equivalent 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, 1:2.3 to 1:2.7, or 1:2.4 to 1:2.7.

[0066] The pharmaceutical compositions provided by this disclosure may, for example, contain 20% to 40% by weight of γ-hydroxybutyrate equivalents in the IR component, 22% to 38% by weight, 24% to 36% by weight, 26% to 36% by weight, or 28% to 34% by weight of γ-hydroxybutyrate equivalents in the IR component, where the weight percentage is based on the total weight of γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0067] The pharmaceutical compositions provided by this disclosure may, for example, contain 60% to 80% by weight of γ-hydroxybutyrate equivalents in the MR component, 62% to 78% by weight, or 65% to 75% by weight of γ-hydroxybutyrate equivalents in the MR component, where the weight percentage is based on the total weight of γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0068] The pharmaceutical compositions provided by this disclosure may contain, for example, a molar ratio of the γ-hydroxybutyrate equivalent in the immediate-release component to the γ-hydroxybutyrate equivalent in the controlled-release component of 1:1 to 1:10, 1:1 to 1:9, 1:1.5 to 1:8.5, 1:2 to 1:8, 1:2.5 to 1:7.5, 1:3 to 1:1.7, 1:3.5 to 1:6.5, or 1:4 to 1:6.

[0069] The pharmaceutical compositions provided by this disclosure may include, for example, molar percentages of γ-hydroxybutyrate equivalents in immediate components of 5% to 40%, 10% to 35%, 15% to 30%, or 20% to 25%, based on the total γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0070] The pharmaceutical compositions provided by this disclosure may include, for example, molar percentages of γ-hydroxybutyrate equivalents in the controlled-release components of 95% to 69%, 90% to 65%, 85% to 60%, 80% to 55%, or 75% to 60%, based on the total number of moles of γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0071] The pharmaceutical compositions provided by this disclosure may, for example, contain 2 to 6 g of sodium γ-hydroxybutyrate equivalents in the IR component and 6 to 16 g of sodium γ-hydroxybutyrate equivalents in the MR component, 2 to 6 g in the IR component and 7 to 15 g in the MR component, 3 to 6 g in the IR component and 8 to 14 g in the MR component, 2 to 6 g in the IR component and 9 to 14 g in the MR component, or 1.2 to 3.8 g of sodium γ-hydroxybutyrate equivalents in the IR component and 3.8 to 9.0 g of sodium γ-hydroxybutyrate equivalents in the MR component.

[0072] The immediate-release components provided by this disclosure may include immediate-release microparticles. The immediate-release microparticles may include uncoated microparticles or microparticles with an immediate-release coating.

[0073] The controlled-release components provided in this disclosure may include controlled-release microparticles. The controlled-release microparticles may include uncoated microparticles containing a controlled-release coating. The controlled-release microparticles may include microparticles containing an immediate-release coating and an overlying controlled-release coating.

[0074] The uncoated, immediate-release microparticles provided by this disclosure may include pharmaceutical active ingredients, binders, and antistatic agents.

[0075] Uncoated immediate-release microparticles may include, for example, compound (1) in greater than 90% by weight, greater than 92% by weight, greater than 94% by weight, greater than 96% by weight, or greater than 98% by weight, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles. Uncoated immediate-release microparticles provided by this disclosure may include, for example, compound (1) in 90% to 99.9% by weight, 91% to 99.5% by weight, 92% to 99% by weight, 93% to 98.5% by weight, 94% to 98% by weight, or 94.5% to 97.5% by weight, where the weight percentage is based on the total weight of the immediate-release microparticles.

[0076] Uncoated immediate-release microparticles may contain a binder or a combination of binders.

[0077] Uncoated immediate-release microparticles may contain, for example, less than 1% by weight of binder, less than 0.8% by weight, less than 0.6% by weight, less than 0.4% by weight, or less than 0.2% by weight of binder, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles. Uncoated immediate-release microparticles may contain, for example, 0.1% to 1.0% by weight of binder, 0.2% to 0.9% by weight, 0.2% to 0.8% by weight, 0.25% to 0.75% by weight, or 0.3% to 0.7% by weight of binder, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles.

[0078] Uncoated microparticles may contain, for example, less than 3% by weight of binder, less than 2.5% by weight, less than 2% by weight, less than 1.5% by weight, or less than 1% by weight of binder, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles.

[0079] Uncoated immediate-release microparticles may contain any suitable binder. Examples of suitable binders include natural binders such as starch, pregelatinized starch, sodium alginate, and gelatin; synthetic binders such as polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polymethacrylate, sodium carboxymethylcellulose, and polyethylene glycol; and sugars such as modified cellulose, hydroxypropylcellulose, sorbitol, xylitol, and mannitol.

[0080] Other suitable binders include acacia, copovidone, carbomer, corn starch, pregelatinized starch, calcium carboxymethylcellulose, calcium glycolate, carmellosum calcium, sodium carboxymethylcellulose, carmellose sodium, ceratonia, chitosan hydrochloride, dextrate, dextrin, ethylcellulose, liquid glucose, guar galatomannan, guar gum, hydroxyethylcellulose, microcrystalline cellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropyl starch, hypromellose / hydroxypropylmethylcellulose, inulin, aluminum magnesium silicate, maltodextrin, methylcellulose, polyethylene glycol, polyethylene oxide, povidone, sodium alginate, starch, pregelatinized starch, sucrose, compressed sugar, zein, gelatin, polymethacrylate, sorbitol, glucose, and sodium alginate.

[0081] Uncoated, immediately released microparticles may contain an antistatic agent or a combination of antistatic agents.

[0082] Uncoated immediate-release microparticles may contain, for example, less than 3% by weight, less than 2.5% by weight, less than 2% by weight of antistatic agent, less than 1.25% by weight, less than 1% by weight, less than 0.75% by weight, less than 0.5% by weight, or less than 0.25% by weight of antistatic agent, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles. Uncoated immediate-release microparticles may contain, for example, 0.1% to 3.0% by weight of antistatic agent, 0.2% to 2% by weight, 0.5% to 1.50% by weight, or 0.75% to 1.25% by weight of antistatic agent, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles.

[0083] The uncoated, immediately released microparticles may contain any suitable antistatic agent.

[0084] Suitable antistatic agents include hydrophilic silica, talc, magnesium stearate, sodium stearyl fumarate, and any combination of the above.

[0085] The antistatic agent may include, for example, hydrophilic fumed silica such as Aerosil® 200 (Evonik Industries).

[0086] The uncoated immediate-release microparticles may, for example, contain 95.0% to 99.5% by weight of compound (1), 0.1% to 1.0% by weight of a binder, and 0.1% to 2.0% by weight of an antistatic agent, where the weight percentages are based on the total weight of the uncoated immediate-release microparticles.

[0087] The uncoated immediate-release microparticles may, for example, contain 98% to 99% by weight of compound (1), 0.25% to 0.75% by weight of a binder, and 0.5% to 1.5% by weight of an antistatic agent, where the weight percentages are based on the total weight of the uncoated immediate-release microparticles.

[0088] The uncoated immediate-release microparticles may, for example, contain 98.25% to 98.75% by weight of compound (1), 0.33% to 0.65% by weight of a binder, and 0.74% to 1.25% by weight of an antistatic agent, where the weight percentages are based on the total weight of the uncoated immediate-release microparticles.

[0089] In addition to pharmaceutical active ingredients, binders, and antistatic agents, uncoated immediate-release microparticles may contain one or more excipients, such as flow regulators, lubricants, disintegrants, fillers, compression aids, surfactants, diluents, colorants, buffers, flow enhancers, and any combination thereof.

[0090] Uncoated immediate-release microparticles may contain, for example, less than 3% by weight of one or more excipients, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight of one or more excipients, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles. Uncoated immediate-release microparticles may contain, for example, one or more excipients in amounts of 0% to 3% by weight, 0.1% to 3% by weight, 0.5% to 2% by weight, or 1% to 2% by weight of one or more excipients, where the weight percentage is based on the total weight of the uncoated immediate-release microparticles.

[0091] Suitable flow control agents or flow accelerators include magnesium stearate, fumed silica (colloidal silicon dioxide), starch, and talc.

[0092] Suitable lubricants include magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, diesel fuel, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, zinc stearate, and any combination of the above.

[0093] Suitable disintegrants include citric acid, croscarmellose sodium, colloidal silicone dioxide, crospovidone, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and any combination of the above.

[0094] The surfactant may include ionic or nonionic surfactants. Suitable anionic surfactants include sodium doxate (sodium dioctyl sulfosuccinate), sodium lauryl sulfate, and any combination thereof. Suitable nonionic surfactants include polyoxyethylene alkyl ethers, polyoxyethylene stearate, poloxamer, polysorbate, sorbitan ester, glyceryl monooleate, and any combination thereof.

[0095] Suitable fillers and compression aids include lactose, calcium carbonate, calcium sulfate, compressed sugar, dextrose, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, sucrose, and any combination of the above.

[0096] The uncoated immediate-release microparticles provided by this disclosure may feature a sphericity of 0.90 to 1, such as 0.91 to 0.99 or 0.92 to 0.98, and the sphericity of the uncoated immediate-release microparticles provided by this disclosure may feature a sphericity of 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.

[0097] The uncoated immediate-release microparticles provided by this disclosure may include a plurality of microparticles characterized by mode sphericities of 0.90 to 1, such as 0.91 to 0.99 or 0.92 to 0.98, where sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated immediate-release microparticles provided by this disclosure may include a plurality of microparticles characterized by mean sphericities 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.

[0098] The uncoated immediate-release microparticles provided by this disclosure are solid and feature a substantially homogeneous composition throughout the uncoated immediate-release microparticles. The homogeneous composition refers to a composition that does not have internal structures such as layers or core / shell, and the composition is the same throughout the microparticles by less than ±5% by weight, less than ±2% by weight, or less than ±1% by weight.

[0099] For high doses of pharmaceutically active ingredients, especially when reconstituted as a suspension before administration, it may be useful for microparticles to have a small average diameter to improve palatability.

[0100] The various uncoated, immediately-released microparticles provided by this disclosure may feature particle size distributions (PSD)(D50) of, for example, 75 μm to 450 μm, 100 μm to 400 μm, 150 μm to 350 μm, 175 μm to 325 μm, 200 μm to 300 μm, or 225 μm to 275 μm.

[0101] Multiple uncoated, immediately released microparticles may feature PSD(D10) sizes of, for example, 50 μm to 150 μm, 60 μm to 140 μm, 70 μm to 120 μm, or 80 μm to 110 μm.

[0102] Multiple uncoated, immediately released microparticles may be characterized by PSD(D90) of, for example, 450 μm to 750 μm, 475 μm to 725 μm, 500 μm to 700 μm, 525 μm to 675 μm, or 550 μm to 650 μm.

[0103] Multiple uncoated, immediately released microparticles can be characterized, for example, by PSD(D10) of 50 μm to 150 μm, PSD(D50) of 220 μm to 320 μm, and PSD(D90) of 480 μm to 560 μm.

[0104] Multiple uncoated, immediately released microparticles can be characterized, for example, by PSD(D10) of 60 μm to 140 μm, PSD(D50) of 230 μm to 310 μm, and PSD(D90) of 490 μm to 550 μm.

[0105] Multiple uncoated, immediately released microparticles can be characterized, for example, by PSD(D10) of 70 μm to 130 μm, PSD(D50) of 240 μm to 300 μm, and PSD(D90) of 500 μm to 540 μm.

[0106] The particle size distribution can be determined by laser diffraction or sieve analysis.

[0107] Multiple uncoated, immediately released microparticles can have bulk densities of, for example, greater than 0.60 g / mL, greater than 0.90 g / mL, greater than 1.10 g / mL, greater than 1.30 g / mL, or greater than 1.50 g / mL.

[0108] Multiple uncoated, immediately released microparticles can have bulk densities of, for example, 0.60 g / mL to 1.60 g / mL, 0.70 g / mL to 1.50 g / mL, 0.80 g / mL to 1.40 g / mL, or 1.00 g / mL to 1.20 g / mL.

[0109] Bulk density can be determined using a bulk density cylinder.

[0110] Smooth microparticle surfaces facilitate the ability to coat microparticles with thin, continuous functional coatings having substantially uniform thickness. Coating quality can be important for regulated or controlled-release formulations. For example, rough and / or porous surfaces tend to require significantly larger amounts of functional coating to achieve a release profile comparable to that of smooth surfaces. In addition, coating rough and / or porous surfaces can result in a variety of dissolution or release profiles.

[0111] Multiple uncoated, immediately-release microparticles may be characterized by a loss on drying (LOD) of, for example, 0.92–0.98, 0.93–0.97, or 0.94–0.96. The LOD represents the removal of water incorporated into the microparticles during the preparation of the uncoated microparticles. The LOD is determined by thermogravimetric analysis.

[0112] Multiple uncoated, immediately released microparticles provided by this disclosure may be characterized by abrasion values ​​of 0% to 2%, such as less than 2%, less than 1%, or less than 0.5%. Microparticles with low abrasion are easier to coat than microparticles with high abrasion. Abrasion is defined as the number of microparticles with a diameter of less than 75 μm produced by feeding granules through an acoustic sieve operated at an amplitude of 8 corresponding to 3,600 sound energy pulses per minute for at least 2 minutes.

[0113] Multiple uncoated, immediately released microparticles provided by this disclosure may have, for example, a degree of abrasion of 1.02%, the degree of abrasion being determined using an ultrasonic sieve.

[0114] A method for producing uncoated, immediately-released microparticles provided in this disclosure is disclosed in U.S. Patent Publication No. 2021 / 039357A1.

[0115] The immediate-release component may contain immediate-release microparticles, or the immediate-release formulation can be prepared by dissolving the immediate-release microparticles in a solution suitable for oral administration.

[0116] Immediately released microparticles can have an average particle size distribution (PSD) (D50) of 150 μm to 400 μm, 150 μm to 350 μm, 150 μm to 300 μm, or 150 μm to 250 μm, and the PSD is determined by sieve analysis.

[0117] Immediately released microparticles can have, for example, a volume-average diameter D(4,3) of 200 μm to 500 μm or 250 μm to 450 μm.

[0118] The core of the immediate-release microparticles may contain more than 90% by weight of compound (1), such as more than 92% by weight, more than 94% by weight, more than 96% by weight, more than 98% by weight, or more than 99% by weight, where the weight percentage is based on the total weight of the core of the immediate-release microparticles.

[0119] Immediately released microparticles may include a thin protective coating, such as a seal coating.

[0120] Immediate-release microparticles may include multiple uncoated immediate-release microparticles. Immediate-release microparticles may contain more than 90% by weight of compound (1), where the weight percentage is based on the total weight of the microparticles. When tested in a USP Type 2 dissolution apparatus at a pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 75 rpm, the immediate-release uncoated microparticles can 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.

[0121] Immediately released microparticles may have an immediate-release coating such as a seal coating. Immediately released microparticles may contain more than 80% by weight of compound (1). 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 75 rpm, the immediate-release microparticles can 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 75 rpm, the immediate-release microparticles can release more than 80% of compound (1) in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes.

[0122] The coated immediate-release microparticles may include coatings containing water-soluble polymers such as hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol. The coated immediate-release microparticles may also include coatings containing antistatic agents such as talc, magnesium stearate, or silicon dioxide.

[0123] The immediate-release microparticles can be dissolved in a solution suitable for oral administration.

[0124] The controlled-release component may include controlled-release microparticles. For example, the controlled-release component may include controlled-release microparticles suspended in a solution suitable for oral administration.

[0125] The controlled-release microparticles include a controlled-release coating. Controlled-release microparticles containing 4-((L-valyl)oxy)butanoic acid (1), methods for preparing controlled-release microparticles, and properties of controlled-release microparticles are disclosed in U.S. Patent Publication No. 2021 / 0393537A1 and U.S. Patent Publication No. 2021 / 0393529A1.

[0126] Controlled-release microparticles may include uncoated immediate-release microparticles having a controlled-release coating. Controlled-release microparticles may also include immediate-release microparticles having a seal coating, and a controlled-release coating covering the seal coating.

[0127] A controlled emission coating can have an average thickness of, for example, less than 300 μm, less than 200 μm, less than 150 μm, less than 100 μm, less than 50 μm, less than 25 μm, less than 20 μm, less than 10 μm, or less than 5 μm. A controlled emission coating can have an average thickness of, for example, 5 μm to 300 μm, 5 μm to 200 μm, 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 20 μm, or 5 μm to 15 μm.

[0128] Controlled-release microparticles may include, for example, a controlled-release coating of less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, or less than 10% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles. Dosage forms containing a highly water-soluble pharmaceutically active ingredient such as compound (1) may have a thick coating to increase the storage stability of the pharmaceutically active ingredient by reducing the release rate of the pharmaceutically active ingredient and / or minimizing or preventing the infiltration of moisture.

[0129] The controlled-release microparticles may contain, for example, more than 60% by weight of compound (1), more than 70% by weight, more than 80% by weight of compound (1), or more than 85% by weight of compound (1), where the weight percentage is based on the total weight of the controlled-release microparticles.

[0130] The controlled-release microparticles may contain, for example, 60% to 85% by weight of compound (1), for example, 65% to 80% by weight, or 70% to 75% by weight of compound (1), where the weight percentage is based on the total weight of the controlled-release microparticles.

[0131] Controlled-release microparticles may include, for example, a controlled-release coating of 5% to 40% by weight, 10% to 35% by weight, 15% to 30% by weight, or 20% to 25% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles. Controlled-release microparticles may include, for example, a controlled-release coating of more than 5% by weight, more than 10% by weight, more than 15% by weight, more than 20% by weight, more than 25% by weight, or more than 30% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles. Controlled-release microparticles may include, for example, a controlled-release coating of less than 40% by weight, less than 35% by weight, less than 30% by weight, less than 25% by weight, less than 20% by weight, less than 15% by weight, or less than 10% by weight, where the weight percentage is based on the total weight of the controlled-release coating.

[0132] The controlled-release microparticles may include, for example, 60% to 95% by weight of uncoated immediate-release microparticles, 65% to 90% by weight, 70% to 85% by weight, or 75% to 80% by weight of uncoated immediate-release microparticles, where the weight percentage is based on the total weight of the controlled-release microparticles. The controlled-release microparticles may also include, for example, more than 60% by weight of uncoated immediate-release microparticles, more than 65% by weight, more than 70% by weight, more than 75% by weight, more than 80% by weight, more than 85% by weight, or more than 90% by weight of immediate-release microparticles, where the weight percentage is based on the total weight of the controlled-release microparticles.

[0133] The controlled release coating may include, for example, a matrix polymer, an antistatic agent, and a plasticizer.

[0134] The controlled-release coating may include a matrix polymer or a combination of matrix polymers. The combination of matrix polymers and / or pore-forming polymers may be selected to provide a desired release profile of compound (1) into the gastrointestinal tract.

[0135] The controlled release coating may contain, for example, 60% to 85% by weight of a matrix polymer, 65% to 80% by weight, or 70% to 80% by weight of a matrix polymer, where the weight percentage is based on the total weight of the controlled release coating.

[0136] The controlled release coating may contain, for example, less than 85% by weight of the matrix polymer, less than 80% by weight, less than 75% by weight, less than 70% by weight, or less than 65% by weight of the matrix polymer, where the weight percentage is based on the total weight of the controlled release coating.

[0137] The controlled release coating may contain, for example, more than 60% by weight of the matrix polymer, more than 65% by weight, more than 70% by weight, more than 75% by weight, or more than 80% by weight of the matrix polymer, where the weight percentage is based on the total weight of the controlled release coating.

[0138] The matrix polymer may include a water-insoluble polymer or a combination of water-insoluble polymers.

[0139] Suitable examples of water-insoluble polymers include ethylcellulose and polyvinyl acetate, polyacrylates, and polymethacrylates.

[0140] Water-insoluble polymers such as ethylcellulose can have number-average molecular weights of, for example, 25,000 to 300,000 daltons, 50,000 to 200,000 daltons, 50,000 to 150,000 daltons, or 50,000 to 100,000 daltons.

[0141] Water-insoluble polymers such as ethylcellulose may have viscosities of less than 100 mPa×sec, less than 75 mPa×sec, less than 50 mPa×sec, less than 25 mPa×sec, less than 20 mPa×sec, or less than 15 mPa×sec, as determined, for example, using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0142] 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.

[0143] The matrix polymer may, for example, contain 90% to 100% by weight of a water-insoluble polymer, 91% to 99% by weight, 82% to 98% by weight, or 93% to 97% by weight of a water-insoluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer may, for example, contain more than 90% by weight of a water-insoluble polymer, more than 92% by weight, more than 94% by weight, more than 96% by weight, or more than 98% by weight of a water-insoluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer may, for example, contain less than 100% by weight of a water-insoluble polymer, less than 98% by weight, less than 96% by weight, less than 94% by weight, or less than 92% by weight of a water-insoluble polymer, where the weight percentage is based on the total weight of the matrix polymer.

[0144] The matrix polymer may include pore-forming polymers. Examples of pore-forming polymers include water-soluble polymers, swelling or expanding polymers such as carbomers, and polymers soluble in gastric juice, such as cellulose phthalate acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate copolymer, and polyvinyl acetate phthalate. Pore-forming polymers can increase the permeability of the controlled release coating under intended conditions.

[0145] The matrix polymer may include a water-soluble polymer or a combination of water-soluble polymers.

[0146] Suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, copovidone, and poloxamer.

[0147] Water-soluble polymers such as hydroxypropylcellulose may have a number 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 500,000 daltons.

[0148] Water-soluble polymers such as hydroxypropylcellulose may have viscosities of less than 7,000 mPa×sec, less than 5,000 mPa×sec, less than 3,000 mPa×sec, or less than 1,000 mPa×sec, as determined, for example, using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0149] Suitable examples of hydroxypropyl cellulose polymers include Klucel® HF Pharm, MF Pharm, GF Pharm, JF Pharm, LF Pharm, EF Pharm, and ELF Pharm polymers, which are available from Ashland.

[0150] Suitable examples of hydroxypropyl methylcellulose polymers include Pharmacoat® 603, 645, 606, and 615 polymers, available from Shin-Etsu Chemical Co.

[0151] The matrix polymer may include, for example, 90% to 100% by weight of a water-insoluble polymer and 0% to 10% by weight, 1% to 8% by weight, or 2% to 6% by weight of a water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer may include, for example, more than 0% by weight of a water-soluble polymer, more than 2% by weight, more than 4% by weight, more than 6% by weight, or more than 8% by weight of a water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer may include, for example, less than 10% by weight of a water-soluble polymer, less than 8% by weight, less than 6% by weight, less than 4% by weight, or less than 2% by weight of a water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer, and the weight percentage is based on the total weight of the matrix polymer.

[0152] The matrix polymer may include, for example, 90% to 100% by weight of a water-insoluble polymer and 0% to 10% by weight of a water-soluble polymer, 92% to 98% by weight of a water-insoluble polymer and 2% to 8% by weight of a water-soluble polymer, or 94% to 96% by weight of a water-insoluble polymer and 4% to 6% by weight of a water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer.

[0153] The controlled release coating can be applied to the immediate release microparticles provided by this disclosure by any preferred method, such as spraying a solution, suspension, or dispersion of the controlled release coating onto the immediate release microparticles in a fluidized bed apparatus.

[0154] In addition to the matrix polymer or a combination of matrix polymers, the controlled release coating may include, for example, plasticizers, antistatic agents, anti-tack agents, colorants or pigments, flow promoters, viscosity modifiers, or any combination of the above.

[0155] The controlled emission coating may include an antistatic agent or a combination of antistatic agents.

[0156] Antistatic agents are useful for minimizing or preventing the aggregation of microparticles during the application of controlled-release coatings.

[0157] Suitable examples of antistatic agents include talc (magnesium silicate), magnesium stearate, and silicon dioxide. For example, the antistatic agent may include talc.

[0158] A controlled emission coating may contain, for example, 10% to 20% by weight of an antistatic agent, for example, 12% to 18% by weight, or 14% to 16% by weight of an antistatic agent, with the weight percentage being based on the total weight of the controlled emission coating. A controlled emission coating may contain, for example, less than 20% by weight of an antistatic agent, less than 18% by weight, less than 16% by weight, less than 14% by weight, or less than 12% by weight of an antistatic agent, with the weight percentage being based on the total weight of the controlled emission coating. A controlled emission coating may contain, for example, more than 10% by weight of an antistatic agent, more than 12% by weight, more than 14% by weight, more than 16% by weight, or more than 18% by weight of an antistatic agent, with the weight percentage being based on the total weight of the controlled emission coating.

[0159] The controlled release coating may contain a plasticizer or a combination of plasticizers.

[0160] Plasticizers are useful for providing a modified release coating having a uniform thickness.

[0161] Examples of suitable plasticizers include dibutyl sebacate, polyethylene glycol, triacetin, and triethyl citrate.

[0162] The modified release coating can include, for example, 0 wt% to 14 wt% plasticizer, such as 2 wt% to 12 wt%, or 4 wt% to 10 wt% plasticizer, based on the total weight of the modified release coating. The modified release coating can include, for example, less than 14 wt% plasticizer, less than 12 wt%, less than 12 wt%, less than 8 wt%, less than 6 wt%, or less than 4 wt% plasticizer, based on the total weight of the modified release coating. The modified release coating can include, for example, more than 0 wt% plasticizer, more than 2 wt%, more than 4 wt%, more than 6 wt%, more than 8 wt%, more than 10 wt%, or more than 12 wt% plasticizer, based on the total weight of the modified release coating.

[0163] The modified release coating provided by the present disclosure can include, for example, 60 wt% to 85 wt% matrix polymer, 10 wt% to 20 wt% antistatic agent, and 0 wt% to 14 wt% plasticizer, based on the total weight of the modified release coating.

[0164] The modified release coating provided by the present disclosure can include, for example, 65 wt% to 80 wt% matrix polymer, 12 wt% to 18 wt% antistatic agent, and 2 wt% to 12 wt% plasticizer, based on the total weight of the modified release coating.

[0165] The modified release coating provided by the present disclosure can include, for example, 70 wt% to 80 wt% matrix polymer, 14 wt% to 16 wt% antistatic agent, and 4 wt% to 10 wt% plasticizer, based on the total weight of the modified release coating.

[0166] In a controlled release coating, the matrix polymer can include ethylcellulose and hydroxypropylcellulose, the plasticizer can include dibutyl sebacate, and the antistatic agent can include talc.

[0167] In a controlled release coating, the matrix polymer can include ethylcellulose and hydroxypropylcellulose, the antistatic agent can include magnesium stearate, and the plasticizer can be absent.

[0168] The coated immediate release microparticles can include a seal coating covering the immediate release microparticles containing the pharmaceutically active ingredient. The controlled release coating can cover the seal coat.

[0169] The seal coating can increase the storage stability of the coated microparticles by minimizing the ingress of moisture into the pharmaceutically active ingredient, thereby reducing the hydrolysis of the pharmaceutically active ingredient. The seal coating can also minimize the negative interaction between the controlled release coating and the pharmaceutically active ingredient, thereby reducing the hydrolysis of the pharmaceutically active ingredient such as compound (1) and increasing the storage stability of the coated microparticles.

[0170] The seal coating can include a water-soluble polymer such as hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, polyvinylpyrrolidone, or polyethylene glycol.

[0171] The seal coating can have an average thickness of, for example, 0.5 μm to 5 μm, 1 μm to 4 μm, or 1 μm to 3 μm. The seal coating can have an average thickness of, for example, less than 5 μm, less than 4 μm, less than 3 μm, less than 2 μm, or less than 1 μm.

[0172] The seal coating can be applied to immediately released microparticles such that the %wg is less than 15%wg, less than 10%wg, less than 8%wg, less than 6%wg, or less than 4%wg, where %wg is based on the weight of the uncoated immediately released microparticles. The seal coating can be applied to microparticles such that the %wg is between 1%wg and 15%wg, 1%wg and 10%wg, 2%wg and 8%wg, or 4%wg and 6%wg, where %wg is based on the weight of the uncoated immediately released microparticles.

[0173] In coated immediate-release microparticles including a seal coating containing a water-soluble polymer, the controlled-release coating may not contain the water-soluble polymer.

[0174] The controlled-release microparticles provided by this disclosure may have, for example, a water content of less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.5% by weight, or less than 0.25% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles.

[0175] The controlled-release microparticles provided by this disclosure may have, for example, a water content of 0.1% to 2% by weight, 0.1% to 1% by weight, or 0.2% to 0.5% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles.

[0176] The controlled-release microparticles may have bulk densities 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.

[0177] The controlled-release microparticles can have bulk densities 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.

[0178] Bulk density can be determined using a bulk density cylinder.

[0179] The controlled-release microparticles provided by this disclosure may have, for example, a water content of less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.5% by weight, or less than 0.25% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles.

[0180] The controlled-release microparticles provided by this disclosure may have, for example, a water content of 0.1% to 2% by weight, 0.1% to 1% by weight, or 0.2% to 0.5% by weight, where the weight percentage is based on the total weight of the controlled-release microparticles.

[0181] The controlled-release microparticles may have bulk densities 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.

[0182] The controlled-release microparticles can have bulk densities 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.

[0183] Bulk density can be determined using a bulk density cylinder.

[0184] The controlled-emission microparticles provided by this disclosure may be characterized by, for example, PSD(D50) particles of sizes ranging from 150 μm to 350 μm, 175 μm to 325 μm, 200 μm to 300 μm, or 225 μm to 275 μm.

[0185] The controlled-release microparticles may be characterized by PSD(D10) of, for example, 50 μm to 150 μm, 60 μm to 140 μm, 70 μm to 120 μm, or 80 μm to 110 μm.

[0186] Uncoated microparticles can be characterized by PSD(D90) of, for example, 450 μm to 750 μm, 475 μm to 725 μm, 500 μm to 700 μm, 525 μm to 675 μm, or 550 μm to 650 μm.

[0187] The controlled-release microparticles can be characterized, for example, by a PSD (D10) of 50 μm to 150 μm such as 60 μm to 140 μm, a PSD (D50) of 230 μm to 310 μm, and a PSD (D90) of 490 μm to 550 μm.

[0188] The controlled-release microparticles can be characterized, for example, by a PSD (D10) of 70 μm to 130 μm, a PSD (D50) of 240 μm to 300 μm, and a PSD (D90) of 500 μm to 540 μm.

[0189] The particle size distribution can be determined by laser diffraction or sieving analysis.

[0190] The controlled-release microparticles (MR1) provided by the present disclosure can be characterized by a dissolution profile in which 70% to 90% of compound (1) is released into the dissolution medium within 2 hours, 85% to 100% within 4 hours, and more than 95% within 6 hours when determined using a USP Type 2 dissolution apparatus at a temperature of 37 °C and a paddle speed of 75 rpm using a buffer solution at pH 4.5.

[0191] The controlled-release microparticles (MR1) provided by the present disclosure can be characterized by a dissolution profile in which 75% to 85% of compound (1) is released into the dissolution medium within 2 hours, 90% to 100% within 4 hours, and more than 95% within 6 hours when determined using a USP Type 2 dissolution apparatus at a temperature of 37 °C and a paddle speed of 75 rpm using a buffer solution at pH 4.5.

[0192] The controlled-release microparticles (MR2) provided by the present disclosure can be characterized by a dissolution profile in which 45% to 65% of compound (1) is released into the dissolution medium within 2 hours, 70% to 90% within 4 hours, 80% to 100% within 6 hours, and more than 90% within 8 hours when determined using a USP Type 2 dissolution apparatus at a temperature of 37 °C and a paddle speed of 75 rpm using a buffer solution at pH 4.5.

[0193] The controlled-release microparticles (MR2) provided by this disclosure may be characterized by a dissolution profile in which, when determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 75 rpm, 50% to 60% of compound (1) is released into the dissolution medium within 2 hours, 75% to 85% within 4 hours, 85% to 95% within 6 hours, and more than 90% within 8 hours.

[0194] The controlled-release microparticles (MR3) provided by this disclosure may be characterized by a dissolution profile in which, when determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution, at a temperature of 37°C and a paddle speed of 75 rpm, 25% to 45% of compound (1) is released into the dissolution medium within 2 hours, 60% to 80% within 4 hours, 70% to 90% within 6 hours, 80% to 100% within 8 hours, and over 90% within 12 hours.

[0195] The controlled-release microparticles (MR3) provided by this disclosure may be characterized by a dissolution profile in which, when determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution, at a temperature of 37°C and a paddle speed of 75 rpm, 30% to 40% of compound (1) is released into the dissolution medium within 2 hours, 65% to 75% within 4 hours, 75% to 85% within 6 hours, 85% to 95% within 8 hours, and more than 90% within 12 hours.

[0196] When controlled-release microparticles are determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution, a temperature of 37°C, and a paddle speed of 75 rpm, the controlled-release microparticles can release, for example, 25% of compound (1) in less than 2 hours, 50% of compound (1) in 1 to 4 hours, 75% of compound (1) in 1.5 to 6 hours, and more than 85% of compound (1) into the dissolution medium.

[0197] When the controlled release of microparticles is determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 75 rpm, for example, more than 20% of compound (1) can be released in 2 hours, more than 50% in 4 hours or less, more than 70% in 6 hours or less, more than 80% in 8 hours or less, and more than 90% in 10 hours or less.

[0198] After oral administration of an IR formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 0.45 hours. 1 / 2 , 0.6 hours average T max , average C18 μg / mL max , average AUC of 16h × μg / mL 0-6 , AUC of 16h × μg / mL 0-inf (and / or may be characterized by a CL / F of 501 L / h).

[0199] In a group of fasted, healthy subjects, after oral administration of an IR formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average time of 0.35 to 0.55 hours. 1 / 2 , average T of 0.5 to 0.7 hours max , average C16μg / mL~20μg / mL max , average AUC of 14h×μg / mL to 18h×μg / mL 0-6 AUC of 14h×μg / mL to 18h×μg / mL 0-inf , and / or may be characterized by a CL / F of 480 L / h to 520 L / h.

[0200] In a group of fasted, healthy subjects, after oral administration of an IR formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.4 to 0.5 hours. 1 / 2 , average T of 0.55 hours to 0.65 hours max , average C 17μg / mL~19μg / mL max , average AUC of 15h×μg / mL to 17h×μg / mL 0-6 AUC of 15h×μg / mL to 17h×μg / mL 0-inf, and / or may be characterized by a CL / F of 490 L / h to 510 L / h.

[0201] After oral administration of an MR1 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 0.87 hours. 1 / 2 , 1.3 hours average T max , average C 8 μg / mL max , average AUC of 15h × μg / mL 0-6 , average AUC of 15h × μg / mL 0-inf It can be characterized by, and / or an average CL / F of 514 L / h.

[0202] In a group of fasted, healthy subjects, after oral administration of an MR1 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.7 to 1.1 hours. 1 / 2 , average T of 1.1 to 1.5 hours max , average C 0.6 μg / mL to 1.0 μg / mL max , average AUC of 13h×μg / mL to 17h×μg / mL 0-6 , average AUC of 13h×μg / mL to 17h×μg / mL 0-inf It may be characterized by an average CL / F of 495 L / h to 535 L / h.

[0203] In a group of fasted, healthy subjects, after oral administration of an MR1 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.8 to 1.0 hours. 1 / 2 , average T of 1.2 to 1.4 hours max , average C 0.7 μg / mL to 0.9 μg / mL max , average AUC of 14h×μg / mL to 16h×μg / mL 0-6 , average AUC of 14h×μg / mL to 16h×μg / mL 0-inf It can be characterized by an average CL / F of 505 L / h to 525 L / h.

[0204] After oral administration of an MR2 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 0.82 hours. 1 / 2 , 1.6 hours average T max , 5 μg / mL average C max , average AUC of 12h × μg / mL 0-6 , average AUC of 12h × μg / mL 0-inf It can be characterized by, and / or an average CL / F of 642 L / h.

[0205] In a group of fasted, healthy subjects, after oral administration of an MR2 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.6 to 1.0 hours. 1 / 2 , average T max , average C of 3 μg / mL to 7 μg / mL max , average AUC of 10h×μg / mL to 14h×μg / mL 0-6 , average AUC of 10h×μg / mL to 14h×μg / mL 0-inf It may be characterized by an average CL / F of 620 L / h to 660 L / h.

[0206] In a group of fasted, healthy subjects, after oral administration of an MR2 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.7 to 0.9 hours. 1 / 2 , average T max , average C of 4μg / mL~6μg / mL max , average AUC of 9h×μg / mL to 11h×μg / mL 0-6 , average AUC of 11h×μg / mL to 13h×μg / mL 0-inf It may be characterized by an average CL / F of 630 L / h to 650 L / h.

[0207] After oral administration of an MR3 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was as follows: 1 / 2 , 2.3 hours average T max , average C3.7μg / mLmax , average AUC of 10h × μg / mL 0-6 , average AUC of 11h × μg / mL 0-inf It may be characterized by an average CL / F of 715 L / h.

[0208] In a group of fasted, healthy subjects, after oral administration of an MR3 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.8 to 1.2 hours. 1 / 2 , average T of 2.1 to 2.5 hours max , average C of 3.5 μg / mL to 3.9 μg / mL max , average AUC of 8h×μg / mL to 12h×μg / mL 0-6 , average AUC of 9h×μg / mL to 13h×μg / mL 0-inf It may be characterized by an average CL / F of 695 L / h to 735 L / h.

[0209] In a group of fasted, healthy subjects, after oral administration of an MR3 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of compound (1) was observed over an average of 0.9 to 1.1 hours. 1 / 2 , average T max , average C of 3.6 μg / mL to 3.8 μg / mL max , average AUC of 9h×μg / mL to 11h×μg / mL 0-6 , average AUC of 10h×μg / mL to 12h×μg / mL 0-inf It can be characterized by an average CL / F of 705 L / h to 725 L / h.

[0210] In a group of fasted, healthy subjects, after oral administration of an IR formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 0.66 hours. 1 / 2 , 0.9 hours average T max , average C 83 μg / mL max , average AUC of 167h × μg / mL 0-6 , AUC of 168h × μg / mL 0-inf It may be characterized by a CL / F of 48.5 L / h.

[0211] After oral administration of an IR formulation containing 7.25 g of compound (1) to a group of healthy fasted subjects, the pharmacokinetic profile of γ-hydroxybutyrate has an average t of 0.45 hours to 0.85 hours 1 / 2 , an average T of 0.7 hours to 1.1 hours max , an average C of 75 μg / mL to 96 μg / mL max , an average AUC of 147 h×μg / mL to 187 h×μg / mL 0-6 , an AUC of 150 h×μg / mL to 190 h×μg / mL 0-inf , and / or a CL / F of 38 L / h to 58 L / h.

[0212] After oral administration of an IR formulation containing 7.25 g of compound (1) to a group of healthy fasted subjects, the pharmacokinetic profile of γ-hydroxybutyrate has an average t of 0.55 hours to 0.75 hours 1 / 2 , an average T of 0.9 hours to 1.0 hours max , an average C of 80 μg / mL to 90 μg / mL max , an average AUC of 157 h×μg / mL to 177 h×μg / mL 0-6 , an AUC of 160 h×μg / mL to 180 h×μg / mL 0-inf , and / or a CL / F of 43 L / h to 53 L / h.

[0213] After oral administration of an MR1 formulation containing 7.25 g of compound (1) to a group of healthy fasted subjects, the pharmacokinetic profile of γ-hydroxybutyrate has an average t of 0.85 hours 1 / 2 , an average T of 1.7 hours max , an average C of 42 μg / mL max , an average AUC of 116 h×μg / mL 0-6 , an average AUC of 120 h×μg / mL 0-inf , and / or an average CL / F of 82 L / h.

[0214] In a group of fasted, healthy subjects, after oral administration of an MR1 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 0.65 to 1.05 hours. 1 / 2 , average T max , average C 32μg / mL~52μg / mL max , average AUC of 96h×μg / mL to 136h×μg / mL 0-6 , average AUC of 100h×μg / mL to 140h×μg / mL 0-inf It can be characterized by an average CL / F of 62 L / h to 102 L / h.

[0215] In a group of fasted, healthy subjects, after oral administration of an MR1 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.75 to 0.95 hours. 1 / 2 , average T of 1.6 to 1.8 hours max , average C 37μg / mL~47μg / mL max , average AUC of 106h×μg / mL to 126h×μg / mL 0-6 , average AUC of 110h×μg / mL to 130h×μg / mL 0-inf It can be characterized by an average CL / F of 72 L / h to 92 L / h.

[0216] In a group of fasted, healthy subjects, after oral administration of an MR2 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was as follows: 1 / 2 , 2.3 hours average T max , average C25μg / mL max , average AUC of 73h × μg / mL 0-6 , average AUC of 76h × μg / mL 0-inf It can be characterized by, and / or an average CL / F of 119 L / h.

[0217] In a group of fasted, healthy subjects, after oral administration of an MR2 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 0.8 to 1.2 hours. 1 / 2, average T of 2.1 to 2.5 hours max , average C 23μg / mL~27μg / mL max , average AUC of 63h×μg / mL to 83h×μg / mL 0-6 , average AUC of 66h×μg / mL to 86h×μg / mL 0-inf It may be characterized by an average CL / F of 100 L / h to 140 L / h.

[0218] In a group of fasted, healthy subjects, after oral administration of an MR2 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 0.9 to 1.1 hours. 1 / 2 , average T max , average C 24μg / mL~26μg / mL max , average AUC of 68h×μg / mL to 78h×μg / mL 0-6 , average AUC of 71h×μg / mL to 81h×μg / mL 0-inf It may be characterized by an average CL / F of 110 L / h to 130 L / h.

[0219] In a group of fasted, healthy subjects, after oral administration of an MR3 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 1.5 hours. 1 / 2 , 3.0 hours average T max , average C16 μg / mL max , average AUC of 49h × μg / mL 0-6 , average AUC of 55h × μg / mL 0-inf It can be characterized by, and / or an average CL / F of 146 L / h.

[0220] In a group of fasted, healthy subjects, after oral administration of an MR3 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 1.3 to 1.7 hours. 1 / 2 , average T of 2.8 hours to 3.2 hours max , average C14μg / mL~18μg / mL max , average AUC of 45h×μg / mL to 53h×μg / mL 0-6, average AUC of 51h×μg / mL to 59h×μg / mL 0-inf It can be characterized by an average CL / F of 136 L / h to 156 L / h.

[0221] In a group of fasted, healthy subjects, after oral administration of an MR3 formulation containing 7.25 g of compound (1), the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 1.4 to 1.6 hours. 1 / 2 , average T of 2.9 hours to 3.1 hours max , average C15μg / mL~17μg / mL max , average AUC of 47h×μg / mL to 51h×μg / mL 0-6 , average AUC of 53h×μg / mL to 57h×μg / mL 0-inf It can be characterized by an average CL / F of 141 L / h to 151 L / h.

[0222] After oral administration of an IR formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.9 C max Ratio, and AUC of 11.3 0-inf The ratio is characterized by the following: After oral administration of an IR formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 3.9–5.9 C max Ratio, and AUC between 10.3 and 12.3 0-inf The ratio can be characterized. After oral administration of an IR formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.4 to 5.4 C max Ratio, and AUC between 10.8 and 11.8. 0-inf The ratio can be a defining characteristic.

[0223] After oral administration of an MR1 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 5.2 C max Ratio, and AUC of 7.6 0-infThe pharmacokinetic profile is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR1 formulation containing 7.25 g of compound (1) to a fasted population of healthy subjects, the pharmacokinetic profile was 5.0–5.4 C max Ratio and AUC of 7.2-8.0 0-inf The pharmacokinetic profile is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR1 formulation containing 7.25 g of compound (1) to a fasted population of healthy subjects, the pharmacokinetic profile was 5.1-5.3 C max Ratio and AUC of 7.4-7.8 0-inf It is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0224] After oral administration of an MR2 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.9 C max Ratio, and AUC of 6.3 0-inf The pharmacokinetic profile is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR2 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.5–5.3 C max Ratio and AUC of 5.9-6.7 0-inf Characterized by a ratio, this ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR2 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.7–5.1 C max Ratio and AUC of 6.1-6.5 0-inf It is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0225] After oral administration of an MR3 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.4 C. max Ratio, and AUC of 5.2 0-infThe pharmacokinetic profile is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR3 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.0–4.8 C max Ratio and AUC of 4.8-5.6 0-inf The pharmacokinetic profile is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR3 formulation containing 7.25 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.2–4.6 C max Ratio and AUC of 5.0-5.4 0-inf It is characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0226] The pharmaceutical composition may contain an immediate-release component and a regulatory component.

[0227] The immediate-release component may include any of the immediate-release microparticles disclosed herein.

[0228] The controlled-release component may include any of the controlled microparticles disclosed herein, or any combination of controlled-release microparticles.

[0229] The pharmaceutical compositions provided by this disclosure may, for example, contain 10% to 50% by weight of compound (1) in the IR component and 90% to 50% by weight of γ-hydroxybutyrate in the MR component, 20% to 40% by weight of compound (1) in the IR component and 80% to 60% by weight of γ-hydroxybutyrate in the MR component, or 25% to 35% by weight of compound (1) in the IR component and 75% to 65% by weight of compound (1) in the MR component, where the weight percentage is based on the total weight of compound (1) in the pharmaceutical composition.

[0230] The pharmaceutical compositions provided by this disclosure may include, for example, a compound (1) in an IR component at more than 10% by weight and a compound (1) in an MR component at less than 90%, a compound (1) in an IR component at more than 20% by weight and a compound (1) in an MR component at less than 80%, a compound (1) in an IR component at more than 30% by weight and a compound (1) in an MR component at less than 70%, or a compound (1) in an IR component at more than 40% by weight and a compound (1) in an MR component at less than 60%, where the weight percentage is based on the total weight of compound (1) in the pharmaceutical composition.

[0231] The pharmaceutical compositions provided by this disclosure may have a weight ratio of compound (1) in the IR component to compound (1) in the MR component, for example, 1:1.5 to 1:3.5, 1:1.7 to 1:3.3, 1:1.9 to 1:3.1, 1:2.1 to 1:2.9, or 1:2:3 to 1:2.7.

[0232] The pharmaceutical compositions provided by this disclosure may have a weight ratio of compound (1) in the IR component to compound (1) in the MR component, for example, greater than 1:1.5, greater than 1:1.7, greater than 1:1.9, greater than 1:2.1, greater than 1:2.3, greater than 1:2.5, or greater than 1:2.7.

[0233] The pharmaceutical compositions provided by this disclosure may, for example, include 2.5 g to 7.0 g of compound (1) in the IR component, or 2.75 g to 6.5 g, 3 g to 6 g, 3.25 g to 5.75 g, 3.5 g to 5.5 g, 3.75 g to 5.25 g, or 4 g to 6 g of compound (1) in the IR component.

[0234] The pharmaceutical composition may, for example, contain 7g to 15g of compound (1) in the MR component, or 7.5g to 14g, 8g to 13g, 8.5g to 12g, or 9g to 11g of compound (1) in the MR component.

[0235] The pharmaceutical composition may include, for example, 2.5g to 7g of compound (1) in the IR component and 7g to 15g of compound (1) in the MR component; 3g to 6g of compound (1) in the IR component and 8g to 14g of compound (1) in the MR component; 3.5g to 5.5g of compound (1) in the IR component and 9g to 13g of compound (1) in the MR component; or 4g to 5g of compound (1) in the IR component and 9g to 12g of compound (1) in the MR component.

[0236] The pharmaceutical compositions provided by this disclosure may include, for example, 9.5 g to 22 g of compound (1), 10 g to 20 g of compound (1), 12 g to 18 g of compound (1), or 14 g to 16 g of compound (1). The pharmaceutical compositions provided by this disclosure may include, for example, more than 9 g of compound (1), more than 10 g, more than 12 g, more than 14 g, more than 16 g, more than 18 g, or more than 20 g of compound (1).

[0237] The pharmaceutical compositions provided by this disclosure may, for example, contain 10% to 50% by weight of γ-hydroxybutyrate equivalents in the IR component and 50% to 90% by weight in the MR component, 20% to 40% by weight of γ-hydroxybutyrate equivalents in the IR component and 60% to 80% by weight of γ-hydroxybutyrate in the MR component, or 25% to 35% by weight of γ-hydroxybutyrate equivalents in the IR component and 65% to 75% by weight of γ-hydroxybutyrate equivalents in the MR component, where the weight % of γ-hydroxybutyrate equivalents is based on the total weight % of γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0238] The pharmaceutical compositions provided by this disclosure may, for example, contain more than 10% by weight of γ-hydroxybutyrate equivalents in the IR component and less than 90% of γ-hydroxybutyrate equivalents in the MR component, more than 20% by weight of γ-hydroxybutyrate equivalents in the IR component and less than 80% of γ-hydroxybutyrate equivalents in the MR component, more than 30% by weight of γ-hydroxybutyrate equivalents in the IR component and less than 70% of γ-hydroxybutyrate equivalents in the MR component, or more than 40% by weight of γ-hydroxybutyrate in the IR component and less than 60% of γ-hydroxybutyrate equivalents in the MR component, where the weight % γ-hydroxybutyrate equivalent is based on the total γ-hydroxybutyrate equivalent in the pharmaceutical composition.

[0239] The pharmaceutical compositions provided by this disclosure may have a weight ratio of γ-hydroxybutyrate equivalent in the IR component to γ-hydroxybutyrate equivalent in the MR component, for example, 1.0:1.5 to 1.0:3.5, 1.0:1.7 to 1.0:3.3, 1.0:1.9 to 1.0:3.1, 1.0:2.1 to 1.0:2.9, or 1.0:2.3 to 1:2.7.

[0240] The pharmaceutical compositions provided by this disclosure may have a weight ratio of γ-hydroxybutyrate equivalent in the IR component to γ-hydroxybutyrate equivalent in the MR component, for example, greater than 1.0:1.5, greater than 1.0:1.7, greater than 1.0:1.9, greater than 1.0:2.1, greater than 1.0:2.3, greater than 1.0:2.5, or greater than 1.0:2.7.

[0241] The pharmaceutical compositions provided by this disclosure may, for example, contain 1 g to 4 g of γ-hydroxybutyrate equivalents in the IR component, or 1.5 g to 3.5 g, 1.75 g to 3.25 g, or 2.0 g to 3.0 g of γ-hydroxybutyrate equivalents in the IR component.

[0242] The pharmaceutical composition may, for example, contain 3g to 9g of γ-hydroxybutyrate equivalents in the MR component, or 3.5g to 8.5g, 4g to 8g, 4.5g to 7.5g, or 5g to 8g of γ-hydroxybutyrate equivalents in the MR component.

[0243] For example, a pharmaceutical composition may contain 1 g to 4 g of γ-hydroxybutyrate equivalents in the IR component and 3 g to 9 g of γ-hydroxybutyrate equivalents in the MR component; 1.5 g to 3.5 g of γ-hydroxybutyrate equivalents in the IR component and 3.5 g to 8.5 g of γ-hydroxybutyrate equivalents in the MR component; 1.75 g to 3.25 g of γ-hydroxybutyrate equivalents in the IR component and 4.5 g to 7.5 g of γ-hydroxybutyrate equivalents in the MR component; or 2 g to 3 g of γ-hydroxybutyrate equivalents in the IR component and 5 g to 8 g of γ-hydroxybutyrate equivalents in the MR component.

[0244] The pharmaceutical compositions provided by this disclosure may include, for example, 6.5 g to 18 g of γ-hydroxybutyrate equivalents, 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 compositions provided by this disclosure may include, 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.

[0245] A method for determining the pharmacokinetic profiles of γ-hydroxybutyrate and 4-((L-valyl)oxy)butanoic acid (1) after oral administration of 4-((L-valyl)oxy)butanoic acid (1) to fasted healthy subjects is provided in experimental examples.

[0246] After oral administration of a combined releasing formulation (CR1) containing an IR component with 4.5 g of compound (1) and an MR1 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed at an average time of 0.71 hours. 1 / 2, 0.6 hours average T max , average C20 μg / mL max , average AUC of 30h × μg / mL 0-6 , average AUC of 31h × μg / mL 0-inf It can also be characterized by an average CL / F of 493 L / h.

[0247] After oral administration of a combined releasing formulation (CR1) containing an IR component with 4.5 g of compound (1) and an MR1 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 0.6 to 0.8 hours. 1 / 2 , average T of 0.5 to 0.7 hours max , average C of 10 μg / mL to 30 μg / mL max , average AUC of 20h×μg / mL to 40h×μg / mL 0-6 , average AUC of 20h×μg / mL to 40h×μg / mL 0-inf It may be characterized by an average CL / F of 440 L / h to 540 L / h.

[0248] After oral administration of a combined releasing formulation (CR1) containing an IR component with 4.5 g of compound (1) and an MR1 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 0.65 to 0.75 hours. 1 / 2 , average T of 0.55 hours to 0.65 hours max , average C15μg / mL~25μg / mL max , average AUC of 25h×μg / mL to 35h×μg / mL 0-6 , average AUC of 25h×μg / mL to 435h×μg / mL 0-inf It may be characterized by an average CL / F of 470 L / h to 510 L / h.

[0249] After oral administration of a combined releasing formulation (CR1) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate over an average of 0.70 hours was observed.1 / 2 , 1.8 hours average T max , average C 99 μg / mL max , 379h × μg / mL average AUC 0-6 , 407h × μg / mL average AUC 0-inf It may be characterized by an average CL / F of 395 L / h.

[0250] After oral administration of a combined releasing formulation (CR1) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 0.6 to 0.8 hours. 1 / 2 , average T of 1.6 to 2.0 hours max , average C of 80 μg / mL to 120 μg / mL max , average AUC of 340h×μg / mL to 420h×μg / mL 0-6 , average AUC of 360h×μg / mL to 440h×μg / mL 0-inf It may be characterized by an average CL / F of 360 L / h to 440 L / h.

[0251] After oral administration of a combined releasing formulation (CR1) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.65 to 0.75 hours. 1 / 2 , average T of 1.7 to 1.9 hours max , average C 90μg / mL~110μg / mL max , average AUC of 360h×μg / mL to 400h×μg / mL 0-6 , average AUC of 380h×μg / mL to 420h×μg / mL 0-inf It may be characterized by an average CL / F of 380 L / h to 420 L / h.

[0252] After oral administration of a combined releasing formulation (CR1) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR1 component to a fasted, healthy subject population, the pharmacokinetic profile was 5.3 C max Ratio, and AUC of 13.3 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0253] After oral administration of a combined releasing formulation (CR1) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR1 component to a fasted, healthy subject population, the pharmacokinetic profile was 4.5–6.5 C max Ratio, and AUC between 11.5 and 15.5. 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0254] After oral administration of a combined releasing formulation (CR1) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR1 component to a fasted, healthy subject population, the pharmacokinetic profile was 4.7–6.3 C max Ratio, and AUC between 12.5 and 14.5. 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0255] After oral administration of a combined releasing formulation (CR2) containing an IR component with 4.5 g of compound (1) and an MR2 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average time of 0.89 hours. 1 / 2 , 0.8 hours average T max , average C17μg / mL max , average AUC of 26h × μg / mL 0-6 , average AUC of 26h × μg / mL 0-inf It may be characterized by an average CL / F of 570 L / h.

[0256] After oral administration of a combined releasing formulation (CR2) containing an IR component with 4.5 g of compound (1) and an MR2 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average time of 0.7 to 1.1 hours. 1 / 2 , average T of 0.7 hours to 0.9 hours max , average C15μg / mL~19μg / mL max , average AUC of 22h×μg / mL to 30h×μg / mL 0-6 , average AUC of 22h×μg / mL to 30h×μg / mL 0-inf It may be characterized by an average CL / F of 530 L / h to 610 L / h.

[0257] After oral administration of a combined releasing formulation (CR2) containing an IR component with 4.5 g of compound (1) and an MR2 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 0.8 to 1.0 hours. 1 / 2 , average T of 0.75 hours to 0.85 hours max , average C 16μg / mL~18μg / mL max , average AUC of 24h×μg / mL to 28h×μg / mL 0-6 , average AUC of 24h×μg / mL to 28h×μg / mL 0-inf It may be characterized by an average CL / F of 550 L / h to 590 L / h.

[0258] After oral administration of a combined releasing formulation (CR2) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR2 component to a fasted, healthy subject population, the pharmacokinetic profile of γ-hydroxybutyrate over an average of 0.92 hours was observed. 1 / 2 , 1.3 hours average T max , average C 75 μg / mL max , average AUC of 307h × μg / mL 0-6 , average AUC of 342h × μg / mL 0-inf It may be characterized by an average CL / F of 525 L / h.

[0259] After oral administration of a combined releasing formulation (CR2) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR2 component to a fasted, healthy subject population, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average of 0.8 to 1.0 hours. 1 / 2 , average T of 1.1 to 1.5 hours max , average C65μg / mL~85μg / mL max , average AUC of 290h×μg / mL to 330h×μg / mL 0-6 , average AUC of 320h×μg / mL to 360h×μg / mL 0-inf It can be characterized by an average CL / F of 505 L / h to 545 L / h.

[0260] After oral administration of a combined releasing formulation (CR2) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR2 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.85 to 0.95 hours. 1 / 2 , average T of 1.2 to 1.4 hours max , average C of 70 μg / mL to 80 μg / mL max , average AUC of 300h×μg / mL to 320h×μg / mL 0-6 , average AUC of 330h×μg / mL to 350h×μg / mL 0-inf It can be characterized by an average CL / F of 515 L / h to 535 L / h.

[0261] After oral administration of a combined releasing formulation (CR2) containing an IR component with 4.5 g of compound (1) and an MR2 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.9 C max Ratio, and AUC of 12.7 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0262] After oral administration of a combined releasing formulation (CR2) containing an IR component with 4.5 g of compound (1) and an MR2 component with 10 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile was 4.7–5.1 C max Ratio, and AUC of 11-15 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0263] After oral administration of a combined releasing formulation (CR2) containing 4.5 g of compound (1) as an IR component and 10 g of compound (1) as an MR2 component to a fasted, healthy subject population, the pharmacokinetic profile was 4.8–5.0 C max Ratio, and AUC of 12-14 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0264] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed at an average time of 1.1 hours. 1 / 2 , 1.0 hour average T max , average C19μg / mL max , average AUC of 32h × μg / mL 0-6 , average AUC of 34h × μg / mL 0-inf It can be characterized by, and / or an average CL / F of 569 L / h.

[0265] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 1.0 to 1.2 hours. 1 / 2 , average T of 0.9 hours to 1.1 hours max , average C15μg / mL~23μg / mL max , average AUC of 28h×μg / mL to 36h×μg / mL0-6 , average AUC of 30h×μg / mL to 38h×μg / mL 0-inf It may be characterized by an average CL / F of 550 L / h to 590 L / h.

[0266] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 1.05 to 1.15 hours. 1 / 2 , average T of 0.95 hours to 1.05 hours max , average C17μg / mL~21μg / mL max , average AUC of 30h×μg / mL to 32h×μg / mL 0-6 , average AUC of 32h×μg / mL to 36h×μg / mL 0-inf It may be characterized by an average CL / F of 560 L / h to 580 L / h.

[0267] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was as follows: 1 / 2 , 1.7 hours average T max , average C 96 μg / mL max , average AUC of 334h × μg / mL 0-6 , Average AUC of 389h × μg / mL 0-inf It may be characterized by an average CL / F of 55 L / h.

[0268] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.9 to 1.1 hours. 1 / 2 , average T max , average C 85 μg / mL to 105 μg / mL max, average AUC of 314h×μg / mL to 354h×μg / mL 0-6 , average AUC of 370h×μg / mL to 410h×μg / mL 0-inf It can be characterized by an average CL / F of 45 L / h to 65 L / h.

[0269] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.95 to 1.05 hours. 1 / 2 , average T of 1.6 to 1.8 hours max , average C 90μg / mL~100μg / mL max , average AUC of 324h×μg / mL to 344h×μg / mL 0-6 , average AUC of 380h×μg / mL to 400h×μg / mL 0-inf It can be characterized by an average CL / F of 50 L / h to 60 L / h.

[0270] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a fasted, healthy subject population, the pharmacokinetic profile was 5.3 C max Ratio, and AUC of 11.6 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0271] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile was 5.0–5.6 C max Ratio, and AUC of 10-14 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0272] After oral administration of a combined releasing formulation (CR3) containing 4.5 g of compound (1) in the IR component and 13.5 g of compound (1) in the MR1 component to a group of fasted, healthy subjects, the pharmacokinetic profile was 5.1–5.5 C max Ratio, and AUC of 11-13 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0273] After oral administration of a combined releasing formulation (CR4) containing an IR component with 6 g of compound (1) and an MR2 component with 12 g of compound (1) to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was as follows: 1 / 2 , 1.0 hour average T max , average C19μg / mL max , average AUC of 31h × μg / mL 0-6 , average AUC of 34h × μg / mL 0-inf It may be characterized by an average CL / F of 554 L / h.

[0274] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a group of fasted, healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average of 1.0 to 1.2 hours. 1 / 2 , average T of 1.0 to 1.2 hours max , average C17μg / mL~21μg / mL max , average AUC of 29h×μg / mL to 33h×μg / mL 0-6 , average AUC of 32h×μg / mL to 36h×μg / mL 0-inf It can be characterized by an average CL / F of 535 L / h to 575 L / h.

[0275] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a fasted population of healthy subjects, the pharmacokinetic profile of compound (1) was observed over an average time of 1.05 to 1.15 hours. 1 / 2 , average T of 1.05 hours to 1.15 hours max , average C18μg / mL~20μg / mL max , average AUC of 30h×μg / mL to 32h×μg / mL 0-6 , average AUC of 33h×μg / mL to 35h×μg / mL 0-inf It can be characterized by an average CL / F of 545 L / h to 565 L / h.

[0276] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was as follows: 1 / 2 , 2.2 hours average T max , average C 92 μg / mL max , average AUC of 332h × μg / mL 0-6 , Average AUC of 404h × μg / mL 0-inf It may be characterized by an average CL / F of 55.4 L / h.

[0277] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.8 to 1.0 hours. 1 / 2 , average T of 2.0 to 2.4 hours max , average C 88μg / mL~96μg / mL max , average AUC of 310h×μg / mL to 350h×μg / mL 0-6 , average AUC of 380h×μg / mL to 420h×μg / mL 0-inf It can be characterized by an average CL / F of 51 L / h to 59 L / h.

[0278] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was observed over an average time of 0.85 to 0.95 hours. 1 / 2 , average T of 2.1 to 2.3 hours max , average C 90μg / mL~94μg / mL max , average AUC of 320h×μg / mL to 340h×μg / mL 0-6 , average AUC of 390h×μg / mL to 410h×μg / mL 0-inf It can be characterized by an average CL / F of 53 L / h to 57 L / h.

[0279] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a fasted, healthy subject population, the pharmacokinetic profile was 6.0 C max Ratio, and AUC of 12.0 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0280] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a fasted, healthy subject population, the pharmacokinetic profile was 4-8 C max Ratio, and AUC of 10-14 0-inf The compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0281] After oral administration of a combined releasing formulation (CR4) containing 6 g of compound (1) in the IR component and 12 g of compound (1) in the MR2 component to a fasted, healthy subject population, the pharmacokinetic profile was 5-7 C max Ratio, and AUC of 11-13 0-infThe compound can be characterized by a ratio, which refers to the ratio of the γ-hydroxybutyrate value to the value of the corresponding compound (1).

[0282] With respect to the combined release formulations provided by this disclosure, the concentration of γ-hydroxybutyrate in the plasma of subjects can be less than 15 μg / mL, less than 10 μg / mL, or less than 5 μg / mL six hours after oral administration of a combined release formulation containing 10 g to 20 g of compound (1) to a population of fasted, healthy subjects.

[0283] With respect to the combined release formulations provided by this disclosure, after oral administration of a combined release formulation containing 10 g to 20 g of compound (1) to a fasted healthy subject population, the γ-hydroxybutyrate concentration in the subjects' plasma was as follows: (a) AUC of γ-hydroxybutyrate after oral administration of the immediate-release component to a fasted healthy subject population. inf (b) AUC of γ-hydroxybutyrate after oral administration of the controlled-release component inf It may exceed the sum of the above.

[0284] With respect to the combined release formulations provided by this disclosure, the plasma γ-hydroxybutyrate concentration of subjects may exceed the sum of (a) the γ-hydroxybutyrate concentration 6 to 8 hours after oral administration of the combined release formulation containing 10 g to 20 g of compound (1) to a fasted, healthy subject population.

[0285] With respect to the combined release formulations provided by this disclosure, after oral administration of a combined release formulation containing 10 g to 20 g of compound (1) to a population of healthy, fasted subjects, the concentration 6 to 8 hours after oral administration may exceed the concentration of γ-hydroxybutyrate in the subjects' plasma after administration of the controlled release component alone.

[0286] The combined release formulations provided in this disclosure have been measured in a population of fasted, healthy subjects, with respect to the mean γ-hydroxybutyrate AUC after oral administration of the immediate-release and controlled-release components. 0-inf This is the mean γ-hydroxybutyrate AUC after oral administration of the immediate-release component alone. 0-inf And the mean γ-hydroxybutyrate AUC after oral administration of the controlled-release component alone. 0-inf It may exceed the sum of the above.

[0287] The combined release formulations provided in this disclosure shall have an average compound (1) AUC after oral administration of the immediate-release and controlled-release components to a population of subjects. 0-inf This is the average compound (1) AUC after oral administration of the immediate-release component alone. 0-inf And the average compound (1) AUC after oral administration of the controlled-release component alone. 0-inf This is essentially the same as the sum of the two.

[0288] The combined release formulation provided in this disclosure is used to measure the mean γ-hydroxybutyrate AUC after oral administration of the combined release formulation, which comprises an immediate-release component containing 4.52 g of compound (1) and a controlled-release component containing 10 g of compound (1), to a population of fasted, healthy subjects. 0-inf This is the mean γ-hydroxybutyrate AUC after oral administration of the immediate-release component alone containing 7.25 g of compound (1). 0-inf And the mean γ-hydroxybutyrate AUC after oral administration of the controlled-release component alone containing 7.25 g of compound (1). 0-inf It exceeds the sum of the above.

[0289] The combined release formulation provided in this disclosure is based on the mean compound (1) AUC after oral administration of the combined release formulation, which comprises an immediate-release component containing 4.52 g of compound (1) and a controlled-release component containing 10 g of compound (1), to a population of fasted, healthy subjects. 0-inf This is the average compound (1) AUC after oral administration of the immediate-release component containing 7.25 g of compound (1) alone. 0-infThe average compound (1) AUC after oral administration of the controlled-release component containing 7.25 g of compound (1) alone. 0-inf This is essentially the same as the sum of the two.

[0290] The combined release formulations provided by this disclosure may include immediate-release components and controlled-release components.

[0291] The immediate-release component may include uncoated microparticles containing compound (1) or sealed coated microparticles containing compound (1).

[0292] The immediate-release component may include a solution containing compound (1).

[0293] The controlled-release component may include uncoated or sealed-coated microparticles containing a compound (1) having a controlled-release coating covering the microparticles. The controlled-release microparticles may include, for example, a controlled-release coating of 5% wg to 50% wg.

[0294] The combined release formulations provided by this disclosure may include, for example, more than 5 g of compound (1), more than 8 g, more than 12 g, more than 16 g, or more than 20 g of compound (1). The combined release formulations provided by this disclosure may include, for example, 5 g to 20 g of compound (1), 7 g to 18 g, 9 g to 16 g, or 11 g to 16 g of compound (1).

[0295] In the combined release formulations provided by this disclosure, the immediate-release component may contain 2.5 g to 6.5 g of compound (1), such as 3.5 g to 5.5 g, and the controlled-release component may contain 12.5 g to 16.5 g of compound (1), such as 12.5 g to 15.5 g.

[0296] In the combined release formulations provided by this disclosure, the weight ratio of compound (1) in the immediate-release component to the compound in the controlled-release component may be, for example, 0.3 to 0.6, 0.35 to 0.55, or 0.40 to 0.50.

[0297] In the combined release formulations provided by this disclosure, 15% to 45% by weight of compound (1) may be present in the immediate-release compound, forming 20% ​​to 40% by weight, or 25% to 35% by weight, where the weight percentage is based on the total weight of compound (1) in the combined release formulation.

[0298] Following oral administration of the combined releasing formulation provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents (11.3 g to 17.7 g of compound (1)), to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profiles showed mean T1 / 2 hours of <2.4 hours, <2.2 hours, <2.0 hours, <1.8 hours, and <1.6 hours. max It is characterized by the following.

[0299] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile showed an average T1 time of 1.4 to 2.4 hours, 1.5 to 2.2 hours, 1.6 to 2.0 hours, or 1.7 to 1.9 hours. max It is characterized by the following.

[0300] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profiles were <100 μg / mL, <95 μg / mL, <90 μg / mL, <85 μg / mL, or <80 μg / mL on average. max It is characterized by the following.

[0301] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profiles were 75 μg / mL to 105 μg / mL, 80 μg / mL to 100 μg / mL, or 85 μg / mL to 95 μg / mL (mean C1). max It is characterized by the following.

[0302] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile showed a mean AUC of >250 h×μg / mL, >275 h×μg / mL, >300 h×μg / mL, >325 h×μg / mL, >350 h×μg / mL, >400 h×μg / mL, or >425 h×μg / mL to a population of fasted patients. 0-6h It is characterized by the following.

[0303] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile showed mean AUCs of 250 h×μg / mL to 425 h×μg / mL, 275 h×μg / mL to 400 h×μg / mL, 300 h×μg / mL to 375 h×μg / mL, or 325 h×μg / mL to 375 h×μg / mL. 0~6h It is characterized by the following.

[0304] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile is characterized by mean C6 levels of less than 36 μg / mL, less than 34 μg / mL, less than 32 μg / mL, less than 30, less than 28 μg / mL, less than 26 μg / mL, less than 24 μg / mL, less than 22 μg / mL, less than 20 μg / mL, or less than 18 μg / mL.

[0305] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile is characterized by mean C6 of 18 μg / mL to 36 μg / mL, 20 μg / mL to 34 μg / mL, 22 μg / mL to 32 μg / mL, or 24 μg / mL to 30 μg / mL.

[0306] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profiles are characterized by mean C8 values ​​of <20 μg / mL, <16 μg / mL, <12 μg / mL, <10 μg / mL, <8 μg / mL, or <4 μg / mL.

[0307] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile is characterized by mean C8 of 4 μg / mL to 20 μg / mL, 6 μg / mL to 18 μg / mL, 8 μg / mL to 16 μg / mL, or 10 μg / mL to 14 μg / mL.

[0308] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profiles were <10 μg / mL, <8 μg / mL, <6 μg / mL, <4 μg / mL, or <2 μg / mL mean C10. 10h It is characterized by the following.

[0309] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profiles were 0 μg / mL to 8 μg / mL, 0 μg / mL to 6 μg / mL, 0 μg / mL to 4 μg / mL, or 0 μg / mL to 2 μg / mL (mean C). 10h It is characterized by the following.

[0310] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile is characterized by plasma γ-hydroxybutyrate concentrations of >10 μg / mL, >15 μg / mL, >20 μg / mL, >25 μg / mL, or >30 μg / mL at 5 to 7 hours, such as 6 hours.

[0311] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile is characterized by plasma γ-hydroxybutyrate concentrations of 10 μg / mL to 30 μg / mL, 15 μg / mL to 30 μg / mL, 20 μg / mL to 30 μg / mL, 22 μg / mL to 28 μg / mL, or 24 μg / mL to 26 μg / mL at 5 to 7 hours, such as 6 hours.

[0312] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was less than 4, less than 3, or less than 2 C. max / C 5h It is characterized by ratios.

[0313] Following oral administration of the combined release formulations provided herein to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was 1.5–4, 1.5–3.5, or 2–3 C. max / C 5h It is characterized by ratios.

[0314] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was greater than 2, greater than 4, greater than 6, greater than 8, or greater than 10 C max / C 6h It is characterized by ratios.

[0315] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was 2–10, 2–8, or 4–6 C. max / C 6h It is characterized by ratios.

[0316] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was greater than 5, greater than 10, greater than 15, or greater than 20 C max / C 8h It is characterized by ratios.

[0317] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was 5 to 20 or 10 to 15 C. max / C 6h It is characterized by ratios.

[0318] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile shows an AUC greater than 0.6, greater than 0.8, greater than 1.0, or greater than 1.2. 0-8h / AUC inf It is characterized by ratios.

[0319] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile was 0.6 to 1.2 or 0.8 to 1.0 AUC. 0-8h / AUC inf It is characterized by ratios.

[0320] Following oral administration of the combined releasing formulations provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the pharmacokinetic profile of plasma γ-hydroxybutyrate showed an AUC greater than 250 h×μg / mL, greater than 300 h×μg / mL, greater than 350 h×μg / mL, or greater than 400 h×μg / mL. inf It is characterized by the following.

[0321] Following oral administration of the combined releasing formulation provided by this disclosure, containing 7 g to 11 g of γ-hydroxybutyrate equivalents, to a fasted patient population, the plasma γ-hydroxybutyrate pharmacokinetic profile showed an AUC of 250 h×μg / mL to 450 h×μg / mL, or 300 h×μg / mL to 400 h×μg / mL. inf It is characterized by the following.

[0322] In any of the combined release formulations described above, the combined release formulation may contain 14.5 g of compound (1), corresponding to 9 g of γ-hydroxybutyrate equivalents, having 4.5 g of compound (1) in the immediate-release component and 10 g of compound (1) in the controlled-release component.

[0323] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate showed an average T1 time of 2.0 to 3.2 hours, such as 2.2 to 3.0 hours or 2.4 to 2.8 hours. max It can be characterized by the following.

[0324] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was 94 μg / mL to 114 μg / mL, with mean C1 levels ranging from 96 μg / mL to 112 μg / mL, 98 μg / mL to 110 μg / mL, 100 μg / mL to 108 μg / mL, or 102 μg / mL to 106 μg / mL. max It can be characterized by the following.

[0325] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted population of healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate showed a mean AUC of 430 hours × μg / mL to 490 hours × μg / mL, 440 hours × μg / mL to 480 hours × μg / mL, or 450 hours × μg / mL to 470 hours × μg / mL. inf It can be characterized by the following.

[0326] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted, healthy subject population, the pharmacokinetic profile of γ-hydroxybutyrate showed a mean AUC of 360 hours × μg / mL to 420 hours × μg / mL, 370 hours × μg / mL to 410 hours × μg / mL, or 380 hours × μg / mL to 400 hours × μg / mL. 0~6 It can be characterized by the following.

[0327] Following oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted, healthy subject population, the pharmacokinetic profile of γ-hydroxybutyrate may be characterized by an average C6 of 25 μg / mL to 55 μg / mL, 30 μg / mL to 50 μg / mL, or 35 μg / mL to 45 μg / mL.

[0328] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted population of healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate may be characterized by an average C8 of 5 μg / mL to 15 μg / mL, 7 μg / mL to 13 μg / mL, or 9 μg / mL to 11 μg / mL.

[0329] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate was less than 4 μg / mL, or less than 5 μg / mL, such as less than 2 μg / mL. 10 It can be characterized by the following.

[0330] After oral administration of a combined release formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted, healthy subject population, the pharmacokinetic profile of γ-hydroxybutyrate was 9.5-10.5, with an average C of 9-11. max The / C8 ratio can be a distinguishing feature.

[0331] After oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a group of fasted, healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate showed an average T1 time of 2.0 to 3.2 hours. max , average C 94μg / mL~114μg / mL max , average AUC of 430 hours × μg / mL to 490 hours × μg / mLinf , average AUC of 360 hours × μg / mL to 420 hours × μg / mL 0-6 Average C6 for 25 μg / mL to 55 μg / mL, average C8 for 5 μg / mL to 15 μg / mL, average C for less than 5 μg / mL 10 , and / or C 9-11 max The / C8 ratio can be a distinguishing feature.

[0332] Following oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted population of healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate may be characterized by plasma γ-hydroxybutyrate levels greater than 25 μg / mL at at least 8 hours, at least 7 hours, at least 6 hours, at least 5 hours, or at least 4 hours.

[0333] Following oral administration of a combined releasing formulation containing 4.5 g of compound (1) in the IR component and 10 g of compound (1) in the MR component to a fasted population of healthy subjects, the pharmacokinetic profile of γ-hydroxybutyrate may be characterized by plasma γ-hydroxybutyrate at 2-8 hours, 2-7 hours, 2-6 hours, 2-5 hours, 2-4 hours, 4-6 hours, or 5-6 hours.

[0334] The immediate-release components provided in this disclosure can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profiles of compound (1) shown in Figure 2A or γ-hydroxybutyrate shown in Figure 2B.

[0335] The regulated-release components provided in this disclosure can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profiles of compound (1) shown in Figure 2A or γ-hydroxybutyrate shown in Figure 2B.

[0336] The combined release formulations provided by this disclosure can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profile for γ-hydroxybutyrate shown in Figure 5.

[0337] The combined release formulations provided by this disclosure can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profile for γ-hydroxybutyrate shown in Figure 6.

[0338] The combined release formulations provided by this disclosure can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profile for γ-hydroxybutyrate shown in Figure 4.

[0339] The pharmaceutical compositions provided by this disclosure, such as combined release formulations, can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profiles of compound (1) provided in Table 6 or γ-hydroxybutyrate shown in Table 7. Table 6 shows the mean plasma γ-hydroxybutyrate concentrations of compound (1) after oral administration of various combined release (CR) formulations, such as those described in Example 4. Table 7 shows the mean plasma concentrations of γ-hydroxybutyrate after oral administration of various combined release (CR) formulations, such as those described in Example 4.

[0340] The pharmaceutical compositions provided by this disclosure, such as combined release formulations, can exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profiles of compound (1) provided in Table 3 or γ-hydroxybutyrate shown in Table 4. Figure 3 shows the mean plasma γ-hydroxybutyrate concentrations of compound (1) after oral administration of various combined release (CR) formulations, such as those described in Example 4. Figure 4 shows the mean plasma concentrations of γ-hydroxybutyrate after oral administration of various combined release (CR) formulations, such as those described in Example 4.

[0341] The pharmaceutical compositions provided by this disclosure, such as combined release formulations, may exhibit pharmacokinetic profiles that are bioequivalent to the pharmacokinetic profiles for γ-hydroxybutyrate as shown in Figure 6 or summarized in Table 10.

[0342] The dosages of the pharmaceutical compositions provided herein may be suitable for any dosage used to treat a disease or symptoms of a disease in a patient.

[0343] The dosages of the pharmaceutical compositions provided by this disclosure may include, for example, 6 g to 22 g of compound (1), 8 g to 20 g, 10 g to 20 g, 12 g to 20 g, 14 g to 20 g, or 14 g to 18 g of compound (1).

[0344] The doses of the pharmaceutical compositions provided by this disclosure may include, for example, more than 6 g of compound (1), more than 8 g, more than 10 g, more than 12 g, more than 14 g, more than 18 g, or more than 20 g of compound (1).

[0345] The dosages of the pharmaceutical compositions provided by this disclosure may include, for example, 3 g to 12 g of γ-hydroxybutyrate equivalents, 4 g to 11 g, 5 g to 10 g, or 6 g to 9 g of γ-hydroxybutyrate equivalents.

[0346] The doses of the pharmaceutical compositions provided by this disclosure may include, for example, more than 3 g of γ-hydroxybutyrate equivalents, more than 5 g, more than 7 g, more than 9 g, or more than 9 g of γ-hydroxybutyrate equivalents.

[0347] The pharmaceutical compositions provided by this 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 controlled-release component suitable for administration to a patient, as well as instructions for administering the pharmaceutical composition to a patient. The kit may be used, for example, to treat sleep disorders. The kit may include an immediate-release component and a controlled-release component, a pharmaceutically acceptable vehicle for administering the immediate-release component and the controlled-release component, and instructions for administering the pharmaceutical composition to a patient.

[0348] The pharmaceutical composition may be contained in a container, pack, or dispenser, along with instructions for administration.

[0349] The user instructions provided with the kit may be printed and / or supplied, for example, on electronically readable media, videocassettes, audiotapes, or flash memory devices, or made public on an internet website, or distributed to patients and / or healthcare providers as electronic communications.

[0350] The pharmaceutical compositions provided by this disclosure can be used, for example, to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia.

[0351] The pharmaceutical compositions provided by this disclosure can be used, for example, to treat REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety disorders.

[0352] The pharmaceutical compositions provided herein can be used, for example, to enhance cognitive function in neurodegenerative disorders. For example, the pharmaceutical compositions provided herein can be used for enhanced cognitive function in patients with Parkinson's disease or Alzheimer's disease.

[0353] The pharmaceutical compositions provided by this disclosure can be used to treat narcolepsy, such as type 1 or type 2 narcolepsy. Treatment of narcolepsy is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplexy attacks. In various embodiments, the composition is sufficient to be administered once daily. For example, the composition may be sufficient to be administered in the morning or evening less than two hours after a meal. The formulation is also effective in inducing at least 6 to 8 hours of continuous sleep. In one embodiment, the composition administered less than two hours after a meal is effective in inducing at least 8 hours of continuous sleep. In various embodiments, the formulation is effective in inducing at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours of sleep. In other embodiments, the formulation is effective in inducing up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, or up to 10 hours of sleep.

[0354] The pharmaceutical compositions and formulations provided herein can be used to treat symptoms associated with neurological disorders such as sleep disorders, drug abuse, alcohol and opioid withdrawal, decreased growth hormone levels, anxiety, insensitivity to pain, Parkinson's disease, Alzheimer's disease, and depression, endocrine disorders, hypoxia or anoxia of tissues such as stroke or myocardial infarction, or elevated intracranial pressure levels.

[0355] The pharmaceutical compositions provided by this disclosure can be used to treat diseases or conditions that can be treated by administering gamma-hydroxybutyrate, such as fibromyalgia, sleep apnea, sleep time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucinations, sleep-wake cycles, insomnia, and nocturnal myoclonus.

[0356] The pharmaceutical compositions provided herein can be used to treat sleep disorders associated with viral diseases such as COVID-19 infection.

[0357] The pharmaceutical compositions provided herein can be used to alleviate pain and improve function in patients with fibromyalgia syndrome, and to alleviate excessive daytime sleepiness and fatigue in patients with Parkinson's disease, thereby improving myoclonus and essential tremor, and reducing tardive dyskinesia and bipolar disorder.

[0358] The pharmaceutical compositions provided herein can be used to improve cognitive function in patients suffering from neurological disorders such as Parkinson's disease and Alzheimer's disease.

[0359] The pharmaceutical compositions and formulations provided herein may be used to treat conditions or disorders in patients associated with neurodegenerative diseases or autonomic nervous system disorders, the neurodegenerative diseases being selected from, for example, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, spinal muscular atrophy, motor neuron disease, Creutzfeldt-Jakob disease, primary progressive aphasia, and progressive supranuclear palsy.

[0360] Other examples of neurodegenerative diseases include Alpers disease, Batten disease, cerebroophthalmoscoskeletal syndrome, corticobasal degeneration, Gerstmann-Streussler-Scheinker disease, Kuru disease, Leigh disease, unilateral lower leg muscular atrophy, multiple system atrophy, opsoclonus-myoclonus, prion diseases, progressive multifocal leukoencephalopathy, leukoencephalopathy, striatonigral degeneration, and infectious spongiform encephalopathy. [Examples]

[0361] Embodiments provided by this disclosure are further illustrated with reference to the following examples, which describe microparticles containing compound (1), immediate-release and controlled-release components containing compound (1), pharmaceutical compositions containing compound (1), and the pharmacokinetics of compound (1) and γ-hydroxybutyrate after oral administration of the pharmaceutical compositions to fasted healthy subjects. It will be apparent to those skilled in the art that many modifications to both materials and methods can be made without departing from the scope of this disclosure. It should be noted that alternative methods exist for carrying out the embodiments disclosed herein. Therefore, these embodiments should be considered illustrative and not limiting. Furthermore, the claims are not limited to the details given herein, and the full scope thereof and its equivalents are reserved.

[0362] General method Plasma concentrations of compound (1) and γ-hydroxybutyrate in the plasma of healthy human subjects were measured using liquid chromatography-tandem mass spectrometry and evaluated using Phoenix® WinNonlin® version 8.1 (Pharsight Corporation, USA) and Microsoft® Excel® 2016 (Microsoft Corporation, USA).

[0363] Example 1 Oral preparations Table 1 provides the components of immediate-release (IR) microparticles and three controlled-release (MR1, MR2, and MR3) microparticles containing compound (1). [Table 1]

[0364] To prepare immediate-release microparticles, compound (1) was first pulverized and then mixed with colloidal SiO2 and hydroxypropyl cellulose. Water was added and mixed to obtain wet granules. The wet granules were co-pulverized by passing them through a screen to form wet lumps. The wet lumps were granulated by adding water to form granules, which were then mixed to form microparticles. The microparticles were dried at 40°C for 12 to 24 hours. The dried microparticles were classified by size. Microparticles with a size of 200 μm to 500 μm (D4,3) were separated and used for pharmacokinetic studies.

[0365] The immediate-release microparticles contained 98.5% by weight of compound (1)4-((L-valyl)oxy)butanoic acid, where the weight percentage is based on the total weight of the immediate-release microparticles.

[0366] To prepare the controlled-release microparticles, a coating mixture was first prepared by mixing ethyl alcohol, ethyl cellulose, hydroxypropyl cellulose, water, magnesium silicate (hydrated), and dibutyl sebacate to provide a coating suspension. The coating suspension was sprayed onto immediate-release microparticles to different thicknesses to provide three controlled-release microparticles for use in pharmacokinetic studies.

[0367] After coating, the immediately released microparticles showed a weight increase of 20%, 30%, and 40% for the MR1 (20% wg), MR2 (30% wg), and MR3 (40% wg) controlled-release microparticles, respectively.

[0368] Example 2 Dissolution Profile The dissolution profile for controlled-release microparticles was determined using a buffer solution with a pH of 4.5, at a temperature of 37°C, and a paddle speed of 75 rpm, using a USP Type 2 dissolution apparatus. The dissolution profile for the release of compound (1) from controlled-release microparticles is shown in Figure 1.

[0369] Example 3 Pharmacokinetics of immediate-release and controlled-release components The pharmacokinetics of compound (1) and γ-hydroxybutyrate were determined after oral administration of either an immediate-release component or a controlled-release component to fasted, healthy subjects.

[0370] To prepare the immediate-release formulation, the immediate-release microparticles prepared according to Example 1 were added to 30 mL of water and gently stirred to dissolve the immediate-release microparticles. Water was added to bring the total volume to 250 mL to obtain the immediate-release oral formulation to be administered to the subject.

[0371] To prepare the controlled-release formulation, controlled-release microparticles prepared according to Example 1 were added to 30 mL of water and gently stirred. Ora-Plus® (30 mL) was added, the contents were gently stirred, and the suspension was ingested by the subjects. The container was rinsed with an additional volume of water up to 250 mL in total volume and again ingested by the subjects.

[0372] Each formulation contained 7.25 g of compound (1) (equivalent to 3.172 g of γ-hydroxybutyrate).

[0373] The pharmacokinetic profiles of compound (1) and γ-hydroxybutyrate after oral administration of immediate-release (IR) and controlled-release (MR1-MR3) formulations to fasted, healthy subjects are shown in Figure 2A for compound (1) and Figure 2B for γ-hydroxybutyrate. These results represent the mean and standard deviation based on data from 10-12 subjects.

[0374] The pharmacokinetic parameters for compound (1) and γ-hydroxybutyrate after oral administration of IR and MR microparticles are provided in Tables 2 and 3, respectively. These results represent the mean and standard deviation based on data from 10 to 12 subjects. [Table 2] [Table 3]

[0375] C max ratio, AUC 0-inf Ratio and AUC 0-8 The ratios are shown in Table 4, and the ratio refers to the ratio obtained by dividing the γ-hydroxybutyrate value by the value of the corresponding compound (1). For example, C max The ratio is (C max (GHB) / C max (Equivalent to Compound 1)) [Table 4]

[0376] Example 4 Pharmacokinetics of combined release formulations The pharmacokinetics of combined release (CR) formulations containing immediate-release and controlled-release components were determined.

[0377] Table 5 summarizes the amounts of compound (1) in the immediate-release and controlled-release components used to prepare the combined release formulations (CR1-CR4). [Table 5]

[0378] To prepare the combined release formulation, immediate-release microparticles were dissolved in 30 mL of water. Then, controlled-release microparticles were added and gently stirred. 30 mL of the oral suspension vehicle, Ora-Plus®, was added and the suspension was gently stirred. The subjects then drank the suspension. The subjects repeatedly rinsed the cup with up to 250 mL of water and drank the solution.

[0379] The pharmacokinetic profiles of compound (1) and γ-hydroxybutyrate after oral administration of the combined release formulations (CR1-CR4) to fasted, healthy subjects are shown in Figures 3 and 4, respectively. The pharmacokinetic profile of γ-hydroxybutyrate is shown in Figure 5. These results represent the mean and standard deviation based on 10-12 subjects.

[0380] Tables 6 and 7 provide a summary of specific pharmacokinetic parameters for compound (1) and γ-hydroxybutyrate after oral administration of the combined release formulation to fasted, healthy subjects. These results reflect the mean values ​​obtained from 10–12 subjects. [Table 6] [Table 7]

[0381] C for combined release formulations max ratio, AUC 0-inf Ratio and AUC 0-8 The ratios are shown in Table 8, and the ratio refers to the ratio obtained by dividing the γ-hydroxybutyrate value by the value of the corresponding compound (1). [Table 8]

[0382] Example 5 Pharmacokinetics of Regulated-Release Microparticles Controlled-release microparticles were prepared by applying a controlled-release coating to immediate-release microparticles.

[0383] Immediate-release microparticles containing 4-((L-valyl)oxy)butanoic acid were prepared using MicroPX® micropelletization technology (Glatt GmbH). The immediate-release microparticles had an average granule size (D50) of 225 μm to 275 μm. The immediate-release microparticles contained 90 wt% 4-((L-valyl)oxy)butanoic acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose (hydroxypropyl methylcellulose), where wt% is based on the total weight of the immediate-release microparticles.

[0384] As described in Example 1, a controlled-release coating was applied to immediate-release microparticles to provide controlled-release microparticles. A 20% wg solution was provided after coating.

[0385] Immediate-release microparticles (IR components) and controlled-release microparticles (MR components) were combined and administered orally with water to 12 fasted, healthy subjects described in Example 4 at doses of 5.8 g, 8.7 g, 11.6 g, and 14.5 g of compound (1). The amounts of compound (1) in the IR and MR components are provided in Table 9. [Table 9]

[0386] Specific pharmacokinetic parameters are provided in Table 10, and the γ-hydroxybutyrate pharmacokinetic profile is shown in Figure 6. [Table 10]

[0387] It should be noted that alternative methods exist for carrying out the embodiments disclosed herein. Therefore, these embodiments should be considered illustrative and not restrictive. Furthermore, the claims are not limited to the details given herein, and the full scope of those claims and their equivalents is reserved.

Claims

1. A first component selected from a solution containing 4-((L-valyl)oxy)butanoic acid and immediate-release granules containing 4-((L-valyl)oxy)butanoic acid, and Second component containing regulated release granules A pharmaceutical composition comprising the regulated release granules: A core containing more than 80% by weight of 4-((L-valyl)oxy)butanoic acid based on the total weight of the core, and Controlled emission coating surrounding the core A pharmaceutical composition comprising the above, wherein the molar ratio of 4-((L-valyl)oxy)butanoic acid in the first component to 4-((L-valyl)oxy)butanoic acid in the second component is 1:1 to 1:

10.

2. The aforementioned immediate-release granules are: 4-((L-valyl)oxy)butanoic acid exceeding 80% by weight, Binder, and Antistatic agent A pharmaceutical composition according to claim 1, comprising:

3. The aforementioned controlled release coating is: Water-soluble polymers, Water-insoluble polymer, Plasticizers, and Antistatic agent The pharmaceutical composition according to claim 1, further comprising:

4. The pharmaceutical composition according to claim 1, wherein the first component is the immediate-release granules.

5. The pharmaceutical composition is a suspension, The first component is a solution, The controlled release particles are suspended in the solution. The pharmaceutical composition according to claim 1.

6. A first component selected from a solution containing 4-((L-valyl)oxy)butanoic acid and immediate-release granules, The aforementioned immediate-release granules contain 4-((L-valyl)oxy)butanoic acid, The first component, which is either uncoated or includes an immediate-release coating, and A second component comprising regulated release granules, wherein the regulated release granules are: A core containing 4-((L-valyl)oxy)butanoic acid, and Controlled emission coating surrounding the core The second component includes A pharmaceutical composition containing, The first component comprises 5 mol% to 40 mol% of 4-((L-valyl)oxy)butanoic acid, The second component comprises 60 mol% to 90 mol% of 4-((L-valyl)oxy)butanoic acid, Here, mol% is based on the total number of moles of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition. Pharmaceutical composition.

7. The aforementioned immediate-release granules are: 4-((L-valyl)oxy)butanoic acid exceeding 80% by weight, Binder, and Antistatic agent The pharmaceutical composition according to claim 6, comprising:

8. The aforementioned controlled release coating is: Water-soluble polymers, Water-insoluble polymer, Plasticizers, and Antistatic agent The pharmaceutical composition according to claim 6, further comprising:

9. The pharmaceutical composition according to claim 6, wherein the first component is the immediate-release granules.

10. The pharmaceutical composition is a suspension, The first component is a solution, The controlled release particles are suspended in the solution. The pharmaceutical composition according to claim 6.

11. A first component selected from a solution containing 4-((L-valyl)oxy)butanoic acid and immediate-release granules, The aforementioned immediate-release granules contain 4-((L-valyl)oxy)butanoic acid, The first component, which is either uncoated or includes an immediate-release coating, and A second component comprising regulated release granules, wherein the regulated release granules are: A core containing 4-((L-valyl)oxy)butanoic acid, and Controlled emission coating surrounding the core The second component includes A pharmaceutical composition containing, The first component comprises 10% to 50% by weight of 4-((L-valyl)oxy)butanoic acid, The second component comprises 50% to 90% by weight of 4-((L-valyl)oxy)butanoic acid, Here, the weight percent is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition. Pharmaceutical composition.

12. The pharmaceutical composition according to claim 11, wherein the weight ratio of 4-((L-valyl)oxy)butanoic acid in the immediate-release component to 4-((L-valyl)oxy)butanoic acid in the controlled-release component is 1:1.5 to 1:3.

5.

13. The aforementioned controlled release coating is: Water-soluble polymers, Water-insoluble polymer, Plasticizers, and Antistatic agent The pharmaceutical composition according to claim 11, further comprising:

14. The pharmaceutical composition according to claim 11, wherein the first component is the immediate-release granules.

15. The pharmaceutical composition is a suspension, The first component is a solution, The controlled release particles are suspended in the solution. The pharmaceutical composition according to claim 11.

16. 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, A pharmaceutical composition according to any one of claims 1 to 15 for the treatment of idiopathic hypersomnia or fibromyalgia.

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