Controlled release granules for water-soluble active pharmaceutical ingredients

Abstract

Disclosed is a pharmaceutical granule having a functional coating surrounding a core containing a water-soluble active pharmaceutical ingredient. The functional coating provides immediate or controlled release of the active pharmaceutical ingredient. The pharmaceutical granule can be used in an oral pharmaceutical composition.

Description

[Technical field]

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 059,514, filed July 31, 2020, and U.S. Provisional Patent Application No. 63 / 040,780, filed June 18, 2020, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates to pharmaceutical granulations of water-soluble active pharmaceutical ingredients having a functional coating. The coated pharmaceutical granulations can be used in controlled release oral formulations. [Background technology]

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

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

[0005] It is desirable to have a controlled release formulation containing a pharmaceutical granulation having a high bulk density of the active pharmaceutical ingredient suitable for once or twice daily dosing.To improve palatability, it is desirable for the pharmaceutical granulation to have a low average particle size, such as less than 500 μm. Summary of the Invention

[0006] In accordance with the present invention, the pharmaceutical granulation comprises a plurality of coated granules, the coated granules comprising a core and a functional coating surrounding the core, the core comprising 90% or more by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a water solubility greater than 100 mg / mL, the weight percentage being based on the total weight of the core, and the functional coating comprising a plasticizer.

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

[0008] According to the present invention, a method for providing a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation to treat a disease comprises administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention to treat the disease.

[0009] According to the present invention, a method of treating a disease in a patient, where the disease is known to be treated by administering gamma-hydroxybutyric acid, comprises administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention for treating the disease.

[0010] According to the present invention, a method of coating a pharmaceutical granule comprises applying a coating composition to a pharmaceutical granule comprising a plurality of granules, the coating composition comprising 4% to 12% by weight solids, greater than 10% by weight water, and 75% to 92% by weight ethanol, the weight percentages being based on the total weight of the coating composition, and the granules comprising a core comprising 90% or more by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a water solubility greater than 100 mg / mL, the weight percentages being based on the total weight of the core. Although overlapping with other descriptions, the present invention and its preferred embodiments are described below, however, the present invention is not limited to the following. [1] 1. A pharmaceutical granulation comprising a plurality of coated granules, The coated granule comprises a core and a functional coating surrounding the core, the core comprises greater than 85% by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a water solubility greater than 100 mg / mL, the weight percentage being based on the total weight of the core; The pharmaceutical granulation, wherein the functional coating comprises a plasticizer. [2] The pharmaceutical granule according to [1], wherein the pharmaceutical granule contains 50% by weight to 90% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the pharmaceutical granule. [3] The pharmaceutical granule according to [1] or [2], wherein the functional coating comprises a controlled release coating. [4] The pharmaceutical granule according to any one of [1] to [3], wherein the functional coating comprises 60% by weight to 85% by weight of a matrix polymer, the weight percentage being based on the total weight of the functional coating. [5] The pharmaceutical granule according to [4], wherein the matrix polymer comprises a water-insoluble polymer. [6] The pharmaceutical granule according to [5], wherein the water-insoluble polymer comprises ethyl cellulose. [7] The pharmaceutical granule according to any one of [1] to [6], wherein the functional coating comprises 0.5% by weight to 20% by weight of a water-soluble polymer, the weight percentage being based on the total weight of the matrix polymer. [8] The pharmaceutical granule according to [7], wherein the water-soluble polymer comprises hydroxypropyl cellulose. [9] The pharmaceutical granulation according to any one of [4] to [8], wherein the matrix polymer comprises 92% by weight to 98% by weight of a water-insoluble polymer and 2% by weight to 8% by weight of a water-soluble polymer, the weight percentages being based on the total weight of the matrix polymer.

[10] The pharmaceutical granule according to any one of [1] to [9], wherein the functional coating comprises 3 wt% to 13 wt% of the plasticizer, the weight% being based on the total weight of the functional coating.

[11] The pharmaceutical granule according to

[10] , wherein the plasticizer comprises dibutyl sebacate.

[12] The pharmaceutical granule according to any one of [1] to

[11] , wherein the functional coating comprises 10% by weight to 20% by weight of an antistatic agent, the weight percentage being based on the total weight of the functional coating.

[13] The pharmaceutical granule according to

[12] , wherein the antistatic agent comprises talc.

[14] The functional coating comprises: 60% to 85% by weight of a matrix polymer; 10% to 20% by weight of an antistatic agent, and Contains 3% to 13% by weight of a plasticizer; The pharmaceutical granule according to any one of [1] to

[13] , wherein the weight percentage is based on the total weight of the functional coating.

[15] The coated granules are 55% to 90% by weight of the core, and 10% to 45% by weight of said functional coating; The pharmaceutical granule according to any one of [1] to

[14] , wherein the weight percentage is based on the total weight of the coated granules.

[16] The pharmaceutical granule according to any one of [1] to

[15] , wherein the functional coating has a thickness of 5 μm to 30 μm.

[17] The pharmaceutical granule according to any one of [1] to

[16] , wherein the pharmaceutical granule has a moisture content of less than 1% by weight, the weight percentage being based on the total weight of the pharmaceutical granule.

[18] the coated granule comprises a seal coating surrounding the core; The pharmaceutical granule according to any one of [1] to

[17] , wherein the functional coating surrounds the seal coating.

[19] The pharmaceutical granule described in

[18] , wherein the seal coating comprises hydroxypropyl cellulose.

[20] The pharmaceutical granule according to

[18] or

[19] , wherein the coated granule comprises 2% by weight to 15% by weight of the seal coating, the weight percentage being based on the total weight of the granule.

[21] The pharmaceutical granule according to any one of

[18] to

[20] , wherein the seal coating has a thickness of 0.5 μm to 5 μm.

[22] The pharmaceutical granule according to any one of [1] to

[21] , wherein the active pharmaceutical ingredient has a water solubility of more than 100 mg / mL.

[23] The pharmaceutical granule according to any one of [1] to

[21] , wherein the active pharmaceutical ingredient has a water solubility of 100 mg / mL to 1,000 mg / mL.

[24] The pharmaceutical granule according to any one of [1] to

[23] , wherein the active pharmaceutical ingredient comprises γ-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof.

[25] The pharmaceutical granule according to any one of [1] to

[23] , wherein the active pharmaceutical ingredient comprises a derivative of γ-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof.

[26] The active pharmaceutical ingredient is a compound of formula (2): [C1] JPEG0007682215000001.jpg2895 or a pharma- ceutically acceptable salt thereof, wherein: R 1 But hydrogen and C 1-6 alkyl, R 2 and R 3 Each of these is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-6 The pharmaceutical granule according to any one of [1] to

[23] , wherein each of the cycloalkoxycarbonyls is independently selected from cycloalkoxycarbonyls.

[27] The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing, and The pharmaceutical granule according to any one of [1] to

[23] , selected from any combination of the above.

[28] The pharmaceutical granule according to any one of [1] to

[23] , wherein the active pharmaceutical ingredient comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharma- ceutical acceptable salt thereof: [C2] JPEG0007682215000002.jpg2989

[29] The pharmaceutical granule according to any one of [1] to

[28] , wherein the coated granules are characterized by a particle size distribution (PSD) (D50) of 150 μm to 500 μm, and the particle size distribution is determined by laser diffraction.

[30] The pharmaceutical granule according to any one of [1] to

[29] , wherein 35% to 85% of the active pharmaceutical ingredient is released from the pharmaceutical granule within 2 hours 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.

[31] The pharmaceutical granule according to any one of [1] to

[30] , wherein 70% to 95% of the active pharmaceutical ingredient is released from the pharmaceutical granule within 4 hours 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.

[32] The pharmaceutical granule according to any one of [1] to

[31] , wherein 80% to 100% of the active pharmaceutical ingredient is released from the pharmaceutical granule within 6 hours 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.

[33] A pharmaceutical composition comprising the pharmaceutical granule according to any one of [1] to

[32] .

[34] The pharmaceutical composition described in

[33] , wherein the pharmaceutical composition is an oral formulation.

[35] The pharmaceutical composition described in

[34] , wherein the oral formulation comprises an oral suspension.

[36] The pharmaceutical composition comprises: a controlled release portion, the controlled release portion comprising the pharmaceutical granulation; and The pharmaceutical composition according to any one of

[31] to

[35] , comprising an immediate release portion, a sustained release portion, or a combination thereof.

[37] the immediate release portion comprises immediate release granules, The immediate release granule comprises a seal coating surrounding a core, The pharmaceutical composition according to any one of

[31] to

[36] , wherein the core contains more than 85% by weight of the active pharmaceutical ingredient.

[38] The pharmaceutical composition according to any one of

[31] to

[37] , wherein the pharmaceutical composition is a BID formulation.

[39] The pharmaceutical composition according to any one of

[31] to

[38] , wherein the pharmaceutical composition is a QD formulation.

[40] The pharmaceutical composition according to any one of

[31] to

[39] , wherein the pharmaceutical composition contains 500 mg equivalent to 12 g equivalent of γ-hydroxybutyric acid.

[41] The pharmaceutical composition according to any one of

[31] to

[39] , wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof, a derivative of gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof, a compound of formula (2) or a pharma- ceutically acceptable salt thereof, or any combination of the foregoing.

[42] The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing; or The pharmaceutical composition according to any one of

[31] to

[39] , comprising any combination of the above.

[43] The pharmaceutical composition according to any one of

[31] to

[39] , wherein the active pharmaceutical ingredient comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharma- ceutical acceptable salt thereof: [C3] JPEG0007682215000003.jpg2888

[44] The pharmaceutical composition according to any of

[40] to

[43] , comprising a therapeutically effective amount of the active pharmaceutical ingredient for treating excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[45] A method for providing a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation for treating a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount for treating the disease of a pharmaceutical composition described in any of

[40] to

[44] .

[46] A method for treating a disease in a patient, the disease being known to be treated by administration of gamma-hydroxybutyric acid, the method comprising administering to a patient in need of such treatment a therapeutically effective amount for treating the disease of a pharmaceutical composition described in any one of

[40] to

[44] .

[47] The method of

[45] or

[46] , wherein after administration to the patient, the pharmaceutical composition provides a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation of the patient to treat the disease.

[48] The method according to any one of

[45] to

[47] , wherein administering includes oral administration.

[49] The method according to any of

[45] to

[48] , wherein the disease is selected from excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, and fibromyalgia.

[50] 1. A method of coating a pharmaceutical granule comprising applying a coating composition to a pharmaceutical granule comprising a plurality of granules, the coating composition comprising: 4% to 12% by weight solids; More than 10% by weight of water, and Contains 75% to 92% by weight of ethanol; Wt% is based on the total weight of the coating composition; The granules are A core containing at least 90% by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient has an aqueous solubility of greater than 100 mg / mL; The method, wherein the weight percentage is based on the total weight of the core.

[51] 50. The method of claim 50, wherein the solid comprises 3% to 13% by weight of a plasticizer, the weight percentage being based on the total weight of the solid.

[52] 60% to 85% by weight of a matrix polymer, and 10% to 20% by weight of an antistatic agent, The method of claim 50 or 51, wherein the weight percentage is based on the total weight of the solid.

[53] The method according to any one of

[50] to

[52] , wherein the granules comprise a seal coating surrounding the core.

[54] The method according to any one of

[50] to

[53] , wherein the applying includes spraying.

[55] The method according to any of

[50] to

[54] , wherein the method includes drying the applied coating composition. [Brief description of the drawings]

[0011] Those skilled in the art will understand that the drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure.

[0012] [Figure 1] FIG. 2 shows the dissolution profile of an active pharmaceutical ingredient from granules having a coating of methacrylic acid-methyl acrylate copolymer as described in Example 1.

[0013] [Diagram 2] FIG. 1 shows the dissolution profile of an active pharmaceutical ingredient from granules having a coating of ethyl cellulose and hydroxypropyl cellulose as described in Example 2.

[0014] [Diagram 3] FIG. 1 shows the dissolution profile of an active pharmaceutical ingredient from granules having a coating of methacrylic acid-methyl acrylate copolymer as described in Example 3.

[0015] [Figure 4]1 shows the dissolution profile of an active pharmaceutical ingredient from granules having a coating of ethyl cellulose and hydroxypropyl cellulose as described in Example 4.

[0016] [Diagram 5] FIG. 1 shows the dissolution profile of active pharmaceutical ingredients from granules having coatings of ethyl cellulose and hydroxypropyl cellulose as described in Examples 2 and 4.

[0017] [Figure 6] 1 shows the dissolution profile of an active pharmaceutical ingredient from granules having a coating of ethyl cellulose and hydroxypropyl cellulose as described in Example 5.

[0018] [Figure 7A-7C] 1 shows SEM images of granules coated with a 35% wg ethyl cellulose / hydroxypropyl cellulose coating as described in Example 6 at three different magnifications.

[0019] [Figure 8] FIG. 1 shows the dissolution profile of active pharmaceutical ingredients from granules having ethyl cellulose / hydroxypropyl cellulose coatings representing different % wg as described in Example 6.

[0020] [Figure 9A-9C] 1 shows SEM images of granules coated with a 35% wg ethyl cellulose / hydroxypropyl cellulose coating as described in Example 7 at three different magnifications.

[0021] [Figure 10] FIG. 1 shows the dissolution profile of active pharmaceutical ingredients from granules having ethyl cellulose / hydroxypropyl cellulose coatings representing different % wg as described in Example 7.

[0022] [Figure 11]1 shows particle size distribution of coated granules containing a 35% wg ethyl cellulose / hydroxypropyl cellulose coating as described in Example 7.

[0023] [Figures 12A-12C] 1 shows SEM images of granules coated with a 6% wg ethyl cellulose / hydroxypropyl cellulose seal coating as described in Example 8 at three different magnifications.

[0024] [Figures 13A-13C] 1 shows SEM images of granules coated with a 35% wg ethyl cellulose / hydroxypropyl cellulose coating as described in Example 9 at three different magnifications.

[0025] [Figure 14] FIG. 1 shows the dissolution profile of active pharmaceutical ingredients from granules having ethyl cellulose / hydroxypropyl cellulose coatings representing different % wg as described in Example 9.

[0026] [Figure 15] 1 shows particle size distribution of coated granules containing a 35% wg ethyl cellulose / hydroxypropyl cellulose coating as described in Examples 7, 8, and 9.

[0027] [Figure 16] 1 shows the dissolution profile of active pharmaceutical ingredients from granules having a 20% wg ethylcellulose / hydroxypropylcellulose coating as described in Examples 7, 8, and 9.

[0028] [Figure 17] 1 shows the dissolution profile of active pharmaceutical ingredients from granules having a 30% wg ethylcellulose / hydroxypropylcellulose coating as described in Examples 7, 8, and 9.

[0029] [Figure 18] 1 shows the dissolution profile of active pharmaceutical ingredients from granules having a 35% wg ethylcellulose / hydroxypropylcellulose coating as described in Examples 7, 8, and 9.

[0030] [Figure 19] 1 shows particle size distribution for uncoated pharmaceutical granulations prepared as described in Example 1.

[0031] [Figures 20A-20D] 1 shows SEM images at different magnifications of the uncoated pharmaceutical granulation described in Example 1.

[0032] [Figure 21] 1 illustrates the process conditions used to apply the functional coatings described in Examples 2-9 to the uncoated pharmaceutical granulation described in Example 1.

[0033] [Figure 22] FIG. 1 shows the dissolution profile of active pharmaceutical ingredients from granules with different % wg ethyl cellulose / hydroxypropyl cellulose coatings as described in Example 10. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] For the purposes of the following detailed description, it should be understood that the embodiments provided by the present disclosure may assume various alternative variations and sequences of steps, unless expressly specified to the contrary. Moreover, other than in any operating example, or where otherwise indicated, all numbers expressing amounts of ingredients used in the specification and claims, for example, should be understood as being modified in all instances by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending on the desired properties obtained by the present invention. At the very least, and without any attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0035] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible, however, any numerical values ​​inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0036] It is also to be understood that any numerical range recited herein is intended to include all subranges subsumed therein. For example, a range of "1 to 10" is intended to have all subranges between (and including) the recited minimum of 1 and the recited maximum of 10, i.e., minimums of 1 or greater and maximums of 10 or less.

[0037] "Immediate release" refers to a pharmaceutical composition that releases substantially all of the active pharmaceutical ingredient into the patient's digestive tract within less than 1 hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. For example, an immediate release dosage form can release more than 90%, more than 95%, or more than 98% of the active pharmaceutical ingredient in the pharmaceutical composition into the digestive tract within less than 1 hour, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. An immediate release pharmaceutical composition may be suitable for administering an active pharmaceutical ingredient that is absorbed into the systemic circulation from the upper part of the digestive tract.

[0038] "Controlled release" pharmaceutical compositions include modified, delayed, extended, sustained, timed, pulsatile, and pH-dependent release formulations. These formulations are intended to release the active pharmaceutical ingredient from the pharmaceutical composition at a desired rate and / or at a desired time and / or at a specific location or locations in the gastrointestinal tract and / or at a specific pH in the gastrointestinal tract after oral administration by a patient. The United States Pharmacopeia defines a modified release system as one in which the time course or location of drug release, or both, is selected to achieve a therapeutic efficacy or convenience objective not met by immediate release dosage forms. Controlled release pharmaceutical compositions may include extended and delayed release components. Delayed release pharmaceutical compositions are those that release the drug all at once, rather than immediately after oral administration. Modified release formulations may include delayed release using enteric coatings, site-specific or timed release, such as for colonic delivery, sustained release, including formulations that can provide, for example, zero-order, first-order, or biphasic release profiles, and programmed release, such as pulsatile and delayed sustained release.

[0039] "Alkoxy" refers to the radical -OR where R is alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups include, for example, C 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 It may be alkoxy, ethoxy or methoxy.

[0040] "Alkyl" refers to a saturated, branched, or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkyl groups include, for example, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 The alkyl group can be methyl, ethyl, n-propyl, iso-propyl, or tert-butyl.

[0041] "Cycloalkyl" refers to a saturated cyclic alkyl radical. Cycloalkyl groups include, for example, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 5-6 Cycloalkyl may be cyclopropyl, cyclopentyl, or cyclohexyl. Cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0042] "Alkoxycarbonyl" refers to the radical -C(=O)-OR, where R is 1-6 Alkyl, e.g., C 1-4 Alkyl or C 1-3 For example, R may be selected from methyl, ethyl, n-propyl, iso-propyl, and tert-butyl.

[0043] "Cycloalkoxycarbonyl" refers to the radical -C(=O)-OR, where R is 3-8 Cycloalkyl, e.g., C 4-7 Cycloalkyl or C 4-6 R may be, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0044] "Coating" refers to a dry layer applied to a granule. "Coating composition" refers to a material applied to a granulation to provide a coating. The coating composition comprises solids and solvents, including water. After the coating composition is applied to the granulation and the coated granulation is dried, the coating comprises the solids of the coating composition.

[0045] The terms "granulation" and "granules" are used interchangeably. A granulation comprises a plurality of granules. However, for the sake of clarity, expressions such as "coated granules" also refer to "coated granulations" and "coated granules" refer to "coated granules".

[0046] The particle size distribution parameter D90 refers to the point in the size distribution of a sample that contains up to 90% of the total volume of the material in the sample. For example, for a D90 of 400 μm, 90% of the sample volume has a size of 400 μm or less, and D50 is the size that contains less than 50% of the total volume of the material in the sample. Similarly, D10 refers to the size that contains less than 10% of the total volume of the material in the sample. The volume distribution of a sample can be determined by laser diffraction or sieve analysis.

[0047] "Patient" refers to a mammal, for example a human.

[0048] "Pharmaceutically acceptable" refers to that which is approved or approvable by a regulatory agency of the Federal or State government, or in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0049] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include inorganic acids as well as acid addition salts formed with one or more protonatable functional groups, such as primary, secondary, or tertiary amines in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts can also be formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, and the like. , 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Salts can be formed when one or more acidic protons present in the parent compound are replaced by coordination with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a combination thereof, or an organic base, such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine. The pharmaceutically acceptable salt can be a hydrochloride salt. The pharmaceutically acceptable salt can be a sodium salt. For compounds with two or more ionizable groups, a pharma- ceutically acceptable salt can contain one or more counterions, such as a di-salt, e.g., a dihydrochloride salt.

[0050] The term "pharmaceutically acceptable salts" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. When a specific pharmaceutically acceptable salt is disclosed, it is to be understood that the specific salt (e.g., hydrochloride) is an example of a salt, and other salts can be formed using techniques known to those skilled in the art. In addition, those skilled in the art will be able to convert a pharmaceutically acceptable salt to the corresponding compound, free base, and / or free acid using techniques generally known in the art.

[0051] "Percent weight gain" or "% wg," such as in the expression "35% wg," refers to the weight gain of a granule or granulation after application of a coating. For example, 35% wg refers to a coated granule or coated granulation in which the weight of the coated granule or coated granulation is 35% more than the weight of the uncoated granule or uncoated granulation.

[0052] The dissolution profile was measured using a USP Type 2 dissolution apparatus and a sodium acetate buffer solution at pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm.

[0053] "Active pharmaceutical ingredient" refers to an active drug substance or a compound that is converted to an active drug substance, such as a prodrug, after administration.

[0054] "Prodrug" refers to a derivative of a parent drug molecule that requires conversion in the body to provide an active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs can typically be obtained by attaching a promoiety to the parent drug via a functional group.

[0055] "Curing" a disease refers to eliminating the disease or disorder, or eliminating the symptoms of the disease or disorder.

[0056] "Treating" or "treatment" of a disease or disorder refers to inhibiting a disease or disorder or one or more clinical symptoms of a disease or disorder, preventing the onset of a disease or disorder or one or more clinical symptoms of a disease or disorder, alleviating a disease or disorder or one or more clinical symptoms of a disease or disorder, causing regression of a disease or disorder or one or more clinical symptoms of a disease or disorder, reducing the severity of one or more clinical symptoms of a disease or disorder, delaying the onset of one or more clinical symptoms of a disease or disorder, and / or stabilizing a disease or disorder or one or more clinical symptoms of a disease or disorder. "Treating" or "treatment" of a disease or disorder refers to producing a clinically beneficial effect without curing the underlying disease or disorder.

[0057] A "therapeutically effective amount" refers to an amount of a compound, such as an active pharmaceutical ingredient, that, when administered to a patient for treating a disease or at least one of the clinical symptoms of the disease, is sufficient to affect such treatment of the disease or its symptoms. A "therapeutically effective amount" may vary depending, for example, on the compound, the disease and / or symptoms of the disease, the severity of the disease, and / or symptoms of the disease or disorder, the age, weight, and / or health of the patient being treated, and the judgment of the prescribing physician. The therapeutically effective amount in any given case can be ascertained by one of ordinary skill in the art or can be determined by routine experimentation.

[0058] "Therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. Therapeutically effective doses may vary from compound to compound and from patient to patient, and may depend on factors such as the condition of the patient and the route of delivery. Therapeutically effective doses may be determined in accordance with routine pharmacological procedures known to those skilled in the art.

[0059] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a patient. The vehicle can be a pharma- ceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0060] Reference is now made to pharmaceutical granules having functional coatings, methods for making coated pharmaceutical granules, and pharmaceutical compositions comprising coated pharmaceutical granules. The disclosed coated pharmaceutical granules, compositions comprising coated pharmaceutical granules, and methods for making coated pharmaceutical granules are not intended to limit the scope of the claims. On the contrary, the claims are intended to encompass all alternatives, modifications, and equivalents.

[0061] The coated pharmaceutical granules provided by the present disclosure can be used to provide a controlled release of an active pharmaceutical ingredient after oral administration to a patient. The coated pharmaceutical granules contain hygroscopic and highly water-soluble active pharmaceutical ingredients. Water-soluble active pharmaceutical ingredients may be susceptible to hydrolysis. The coated pharmaceutical granules can be used in oral pharmaceutical compositions. The coated pharmaceutical granules can be used to orally administer high doses of active pharmaceutical ingredients.

[0062] Coated pharmaceutical granulations or coated granules comprise a coating surrounding a core.

[0063] Uncoated pharmaceutical granulations are disclosed in U.S. Patent Application No. 17 / 350,478, filed June 17, 2021, which is incorporated by reference in its entirety.

[0064] The uncoated pharmaceutical granules provided by the present disclosure may include a plurality of granules, the granules including, for example, 90% or more by weight of the active pharmaceutical ingredient, for example, more than 90% by weight of the active pharmaceutical ingredient, and the pharmaceutical granules may be characterized by a particle size distribution (PSD) (D50) from 150 μm to 500 μm, 150 μm to 450 μm, 150 μm to 400 μm, 150 μm to 350 μm, 150 μm to 300 μm, 200 μm to 300 μm, or 150 μm to 250 μm, the particle size distribution being determined by sieve analysis, and the weight percentage is based on the total weight of the pharmaceutical granules. The uncoated granules may have a particle size distribution D50 of less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, or less than 200 μm, the PSD being determined by sieve analysis.

[0065] The uncoated granules can contain, for example, 90% to 99.5% by weight of the active pharmaceutical ingredient, 90% to 99% by weight, 92% to 99% by weight, 95% to 99% by weight, or 98% to 99% by weight of the active pharmaceutical ingredient, the weight percentages being based on the total weight of the uncoated granules. The uncoated granules can contain, for example, greater than 90% by weight of the active pharmaceutical ingredient, greater than 92% by weight, greater than 94% by weight, greater than 96% by weight, greater than 98% by weight, or greater than 99% by weight of the active pharmaceutical ingredient, the weight percentages being based on the total weight of the uncoated granules.

[0066] The uncoated granules can be characterized, for example, by a particle size distribution (D50) of 225 μm to 275 μm, the particle size distribution being determined by sieve analysis.

[0067] The uncoated granules can be characterized, for example, by a particle size distribution (D10) of 50 μm to 150 μm, and a particle size distribution (D90) of 450 μm to 750 μm, the particle size distribution being determined by sieve analysis.

[0068] The uncoated granules can be characterized, for example, by a particle size distribution (D10) of 80 μm to 120 μm, and a particle size distribution (D90) of 510 μm to 650 μm, the particle size distribution being determined by sieve analysis.

[0069] The uncoated granules can be characterized by a particle size distribution (D10) of 106 μm, a particle size distribution (D50) of 267 μm, and a particle size distribution (D90) of 533 μm, the particle size distribution being determined by sieve analysis.

[0070] The uncoated granules can be characterized by a particle size distribution (D50) of, for example, less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, or less than 200 μm, as determined by sieve analysis.

[0071] In addition to the active pharmaceutical ingredient, the uncoated granules may further comprise binders and antistatic agents.

[0072] The uncoated granules can, for example, comprise 90% or more by weight of the pharma- ceutical active ingredient, for example, greater than 90% by weight of the pharma- ceutical active ingredient, 0.1% to 5% by weight of a binder, and 0.1% to 5% by weight of an antistatic agent, the weight percentages being based on the total weight of the pharmaceutical granulation.

[0073] The uncoated granules can contain, for example, 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of a binder, and 0.5% to 1.5% by weight of an antistatic agent, the weight percentages being based on the total weight of the uncoated granules.

[0074] The uncoated granules can contain, for example, 98.5% by weight of the active pharmaceutical ingredient, 0.5% by weight of the binder, and 1.0% by weight of the antistatic agent, the weight percentages being based on the total weight of the uncoated granules.

[0075] The uncoated granules may include a binder or combination of binders.

[0076] The uncoated granules can contain, for example, less than 6 wt.%, less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.8 wt.%, less than 0.6 wt.%, less than 0.4 wt.%, or less than 0.2 wt.% of the binder, the weight percentage being based on the total weight of the uncoated granules. The uncoated granules can contain, for example, 0.1 wt.% to 6.0 wt.%, 0.1 wt.% to 5.0 wt.%, 0.1 wt.% to 4.0 wt.%, 0.1 wt.% to 3.0 wt.%, 0.1 wt.% to 2.0 wt.%, 0.1 wt.% to 1.0 wt.%, 0.2 wt.% to 0.9 wt.%, 0.2 wt.% to 0.8 wt.%, 0.25 wt.% to 0.75 wt.%, or 0.3 wt.% to 0.7 wt.% of the binder, the weight percentage being based on the total weight of the uncoated granules.

[0077] The uncoated granules can contain, for example, less than 1.5 wt. % binder, less than 1.2 wt. %, less than 1.0 wt. %, less than 0.8 wt. %, or less than 0.6 wt. % binder, where the weight percentage is based on the total weight of the uncoated granules.

[0078] The binder may include a water-soluble polymer.

[0079] Examples of suitable binders include natural binders such as starch, pregelatinized starch, sodium alginate, and gelatin; synthetic binders such as polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polymethacrylates, sodium carboxymethylcellulose, and polyethylene glycol; and sugars such as modified celluloses, hydroxypropylcellulose, sorbitol, xylitol, and mannitol.

[0080] Examples of other suitable binders include acacia, copovidone, carbomer, corn starch, pregelatinized starch, calcium carboxymethyl cellulose, calcium glycolate cellulose, carmellosum calcium, sodium carboxymethyl cellulose, sodium carmellose, seriatonia, chitosan hydrochloride, dextrate, dextrin, ethyl cellulose, liquid glucose, guar galatomannan, guar gum, hydroxyethyl cellulose, microcrystalline cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, hypromellose / hydroxypropyl methyl cellulose, Methocel®, inulin, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyethylene glycol, polyethylene oxide, povidone, sodium alginate, starch, pregelatinized starch, sucrose, compressed sugar, zein, gelatin, polymethacrylate, sorbitol, glucose, and sodium alginate.

[0081] The binder can include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or a combination thereof.

[0082] In an uncoated pharmaceutical granule, the binder can include hydroxypropyl methyl cellulose. In certain uncoated pharmaceutical granules, the binder does not include hydroxypropyl methyl cellulose.

[0083] In an uncoated pharmaceutical granule, the binder can include hydroxypropyl cellulose.

[0084] The uncoated granules can include an anti-static agent or a combination of anti-static agents.

[0085] The uncoated granules can contain, for example, less than 6 wt. %, less than 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2.5 wt. %, less than 2.0 wt. %, less than 1.25 wt. %, less than 1 wt. %, less than 0.75 wt. %, less than 0.5 wt. %, or less than 0.25 wt. %, of the antistatic agent, where the weight percentage is based on the total weight of the uncoated granules. The uncoated granules can contain, for example, 0.1 wt. % to 2.0 wt. %, 0.2 wt. % to 1.8 wt. %, 0.5 wt. % to 1.50 wt. %, or 0.75 wt. % to 1.25 wt. %, of the antistatic agent, where the weight percentage is based on the total weight of the uncoated granules.

[0086] The uncoated granules may contain a suitable antistatic agent.

[0087] Examples of suitable antistatic agents include silica, talc, magnesium stearate, sodium stearyl fumarate, and combinations of any of the foregoing.

[0088] The antistatic agent can include silica, such as hydrophilic silica, such as hydrophilic fumed silica.

[0089] In uncoated pharmaceutical granulations, the antistatic agent can include hydrophilic fumed silica.

[0090] Antistatic agents can include hydrophilic fumed silica, such as, for example, Aerosil® fumed silica from Evonik Industries, Cab-o-sil® fumed silica from Cabot Corporation, or HDK® fumed silica from Brenntag Solutions Group.

[0091] Antistatic agents can include Aerosil® 200 available from Evonik Industries.

[0092] Hydrophilic fumed silica is 100m 2 / g~300m 2 / g, e.g., 175m 2 / g~225m 2 / g specific surface area (based on BET, pH value of 3.7-4.5 in 4% aqueous dispersion, loss on drying for 2 hours at 105 °C of 1.5% or less, packed density of about 40 g / L-60 g / L, and pyrophoric material of more than 99.8% SiO 2 It may have a content.

[0093] In certain granulations, the antistatic agent comprises talc. Pharmaceutical grade talc is available, for example, from Imerys Talc and Elementis PLC.

[0094] In certain uncoated granules, the antistatic agent does not include talc. In certain uncoated granules, the binder does not include hydroxypropyl methylcellulose and the antistatic agent does not include talc.

[0095] In addition to the active pharmaceutical ingredient, binder, and antistatic agent, the granules can include one or more excipients, such as, for example, flow control agents, lubricants, disintegrants, fillers, compression aids, surfactants, diluents, colorants, buffers, glidants, and combinations of any of the foregoing.

[0096] Uncoated granules can 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 granule. Granules can contain, for example, 0% to 3% by weight of one or more excipients, 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 granule.

[0097] Examples of suitable flow control agents or glidants include magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, and combinations of any of the foregoing.

[0098] Examples of suitable lubricants include magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, zinc stearate, and combinations of any of the foregoing.

[0099] Examples of suitable disintegrants include croscarmellose sodium citrate, colloidal silicone dioxide, crospovidone, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and combinations of any of the foregoing.

[0100] The surfactant may include ionic surfactant or non-ionic surfactant.Suitable examples of ionic surfactant include sodium docusate (dioctyl sulfosuccinate sodium salt), sodium lauryl sulfate, and any combination of the above.Suitable examples of non-ionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamer, polysorbate, sorbitan ester, glyceryl monooleate, and any combination of the above.

[0101] Examples of suitable fillers and compression aids include lactose, calcium carbonate, calcium sulfate, compression sugar, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, sucrose, and combinations of any of the foregoing.

[0102] The uncoated pharmaceutical granulation comprises a plurality of uncoated granules. A functional coating and an optional seal coat can be applied to the uncoated pharmaceutical granulation to form a coated pharmaceutical granulation. The coated granulation comprises a plurality of coated granules. The coated granule comprises a functional coating surrounding the uncoated granules and can be referred to as a core of the coated granule.

[0103] The uncoated pharmaceutical granules provided by the present disclosure include a plurality of granules, which can include, for example, greater than 85% by weight of the active pharmaceutical ingredient, greater than 90% by weight, or greater than 95% by weight of the active pharmaceutical ingredient, where the weight percentage is based on the total weight of the uncoated granules, and the uncoated pharmaceutical granules are characterized, for example, by a particle size distribution (D50, median diameter) of 150 μm to 450 μm.

[0104] The uncoated granules can contain a high loading of active pharmaceutical ingredient or a combination of high loading of active pharmaceutical ingredients. For example, the uncoated granules can contain more than 85% by weight, more than 90% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, or more than 99% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the uncoated granules. The uncoated granules can contain, for example, 85% to 99.5% by weight of the active pharmaceutical ingredient, 90% to 99.5% by weight, 95% to 99.5% by weight, 96% to 99% by weight, 97% to 99% by weight, or 98% to 99% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the uncoated granules.

[0105] The uncoated granules can contain active pharmaceutical ingredients that have high water solubility.

[0106] For example, the active pharmaceutical ingredient can have a water solubility of greater than 100 mg / mL, greater than 150 mg / mL, greater than 200 mg / mL, greater than 250 mg / mL, greater than 300 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, greater than 500 mg / mL, greater than 600 mg / mL. The active pharmaceutical ingredient can have a water solubility of, for example, 100 mg / mL to 600 mg / mL, 200 mg / mL to 500 mg / mL, or 250 mg / mL to 450 mg / mL.

[0107] Water solubility is determined by high pressure liquid chromatography (HPLC).

[0108] Examples of active pharmaceutical ingredients with aqueous solubilities greater than 100 mg / mL include acetohydroxamic acid, aliskiren, amifostine, aminocaproic acid, aminolevulinic acid, aminophylline, ascorbic acid, benzethonium, benzphetamine, betasol, bretylium, bromotheophylline, brompheniramine, bronopol, bupropion hydrochloride, folinic acid, captopril, carbamoylcholine, chloral hydrate, cidofovir, citrulline, clavulanic acid, clindamycin, and rifabutin. Codeine phosphate, cycloserine, cysteamine, cytarabine, d-glucose, dinoprost tromethamine, d-serine, dyphylline, edetic acid, emtricitabine, esketamine hydrochloride, arketamine hydrochloride, ethambutol hydrochloride, ferrous bisglycinate, flurazepam, fomepizole, framycetin, gabapentin, gamma-aminobutyric acid, gemifloxacin, gentamicin, gluconic acid, gluconolactone, glucosamine, glutathione, ibandronate, ibutilide, isoniazid, ketamine, Torolac, lactitol, lactose, lactulose, levamisole hydrochloride, levetiracetam, levocarnitine, lisdexamfetamine, mannitol, metformin hydrochloride, methenamine, methimazole, methyl aminolevulinate, migalastat hydrochloride, miglustat, nalmefene hydrochloride, naltrexone hydrochloride, neostigmine bromide, netilmicin, nicotinamide, nicotine, nitrofural, norfloxacin, ornithine, oxycodone, penicillamine, pentoxyverine , phenformin, phenylephrine, phenylpropanolamine, pidolic acid, piperazine, piracetam, pregabalin, procarbazine hydrochloride, promethazine hydrochloride, pyridoxine, pyruvic acid, ranitidine hydrochloride, rolitetracycline, ropinirole, scopolamine, selenomethionine, sodium ascorbate, sodium oxybate, terbutaline, thiamine hydrochloride, tobramycin, tranexamic acid, tromethamine salts, valacyclovir, and venlafaxine hydrochloride.

[0109] An active pharmaceutical ingredient having a water solubility greater than 100 mg / mL can include salt forms, hydrates, and / or solvates of a parent active pharmaceutical ingredient having a water solubility greater than 100 mg / mL, where the parent active pharmaceutical ingredient has a water solubility less than 100 mg / mL.

[0110] The active pharmaceutical ingredient can include gamma-hydroxybutyric acid or a derivative of gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt of any of the foregoing. Gamma-hydroxybutyric acid has the structure of formula (1): [ka]

[0111] Derivatives of γ-hydroxybutyric acid have the structure of formula (2): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is hydrogen and C 1-6 alkyl, R 2 and R 3 Each of 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-8 cycloalkoxycarbonyl.

[0112] In the compound of formula (2), R 1 is hydrogen and C 1-3 It may be selected from alkyl.

[0113] In the compound of formula (2), R 1 may be selected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl.

[0114] In the compound of formula (2), R 1 can be hydrogen.

[0115] In the compound of formula (2), R 1 can be methyl.

[0116] In the compound of formula (2), R 1 can be iso-propyl.

[0117] In the compound of formula (2), R 2 and R 3 At least one of the groups is hydrogen and C 1-3 It may be selected from alkyl.

[0118] In the compound of formula (2), R 2 and R 3 each independently represents hydrogen and C 1-3 It may be selected from alkyl.

[0119] In the compound of formula (2), R 2 and R 3 Each of may be hydrogen.

[0120] In the compound of formula (2), R 1 is hydrogen and C 1-3 alkyl, R 2 is C 1-6 Alkoxycarbonyl and C 5-6 cycloalkoxycarbonyl.

[0121] In the compound of formula (2), R 2 and R 3 each may be hydrogen; R 1 is hydrogen and C 1-3 It may be selected from alkyl.

[0122] In the compound of formula (2), R 2 and R 3 each may be hydrogen; R 1may be selected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl.

[0123] In the compound of formula (2), R 2 and R 3 each may be hydrogen; R 1 may be selected from hydrogen, methyl, and iso-propyl.

[0124] In the compound of formula (2), R 1 The carbon atom to which is attached may be in the (R)-configuration.

[0125] In the compound of formula (2), R 1 The carbon atom to which is attached may be in the (S)-configuration.

[0126] The compound of formula (2) 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing, and Any combination of the foregoing may be selected.

[0127] The compound of formula (2) can be 4-((L-valyl)oxy)butanoic acid (2a) or a pharma- ceutically acceptable salt thereof: [ka]

[0128] The compound of formula (2) can be 4-(glycyloxy)butanoic acid (2b) or a pharma- ceutically acceptable salt thereof: [ka]

[0129] The compound of formula (2) can be 4-((L-alanyl)oxy)butanoic acid (2c) or a pharma- ceutically acceptable salt thereof: [ka]

[0130] The compounds of formulae (2)-(2c) are prodrugs of gamma-hydroxybutyric acid and, upon oral administration, provide gamma-hydroxybutyric acid in the blood of a patient. The compounds of formulae (2)-(2c) exhibit a relative oral bioavailability of gamma-hydroxybutyric acid in a patient of greater than 10%F, greater than 20%F, greater than 30%F, greater than 40%F, greater than 50%F, or greater than 60%F.

[0131] Prior to being formed into granules, the active pharmaceutical ingredient may have a low bulk density.

[0132] The active pharmaceutical ingredient can have a bulk density of, for example, less than 0.20 g / mL, less than 0.30 g / mL, less than 0.40 g / mL, less than 0.50 g / mL, less than 0.6 g / mL, less than 0.7 g / mL, less than 0.8 g / mL, or less than 1.0 g / mL.

[0133] The active pharmaceutical ingredient can have a bulk density of, for example, 0.15 g / mL to 1.0 g / mL, 0.15 g / mL to 8 g / mL, 0.15 g / mL to 0.6 g / mL, 0.15 g / mL to 0.4 g / mL, 0.15 g / mL to 0.33 g / mL, 0.16 g / mL to 0.32 g / mL, 0.17 g / mL to 0.31 g / mL, 0.18 g / mL to 0.30 g / mL, 0.19 g / mL to 0.29 g / mL, or 0.20 g / mL to 0.28 g / mL.

[0134] An active pharmaceutical ingredient may be, for example, 200m 2 / kg~1200m 2 / kg, e.g., 400m 2 / kg~1000m 2 The active pharmaceutical ingredient may have a specific surface area of, for example, 200 m / kg, the specific surface area being determined using laser diffraction. 2 / kg over 400m 2 / kg over 600m 2 / kg over 800m 2 / kg or more than 1200m 2 / kg, the specific surface area being determined using laser diffraction.

[0135] The active pharmaceutical ingredient may have a particle size distribution characterized, for example, by a D10 of 1 μm to 3 μm, a D50 of 6.5 μm to 8.5 μm, and a D90 of 15 μm to 17 μm, the particle size distribution being measured by laser diffraction.

[0136] The active pharmaceutical ingredient can, for example, have a particle size distribution substantially as shown in any one of FIGS.

[0137] The active pharmaceutical ingredient can be jet milled to reduce particle size.

[0138] The jet milled active pharmaceutical ingredient can have a particle size distribution of, for example, less than 30 μm, less than 25 μm, less than 20 μm, or less than 15 μm.

[0139] The uncoated pharmaceutical granules or uncoated granules can comprise, for example, 95.0% to 99.5% by weight of the active pharmaceutical ingredient, 0.1% to 1.0% by weight of a binder, and 0.1% to 2.0% by weight of an antistatic agent, the weight percentages being based on the total weight of the uncoated pharmaceutical granules or uncoated granules.

[0140] The uncoated pharmaceutical granules or uncoated granules can comprise, for example, 98% to 99% by weight of the active pharmaceutical ingredient, 0.25% to 0.75% by weight of a binder, and 0.5% to 1.5% by weight of an antistatic agent, the weight percentages being based on the total weight of the uncoated pharmaceutical granules or uncoated granules.

[0141] The uncoated pharmaceutical granules or uncoated granules can contain, for example, 98.25% to 98.75% by weight of the active pharmaceutical ingredient, 0.33% to 0.65% by weight of a binder, and 0.74% to 1.25% by weight of an antistatic agent, the weight percentages being based on the total weight of the uncoated pharmaceutical granules or uncoated granules.

[0142] The uncoated pharmaceutical granules or uncoated granules can comprise, for example, 85.0% to 99.5% by weight of the active pharmaceutical ingredient, 0.1% to 8.0% by weight of a binder, and 0.1% to 8.0% by weight of an antistatic agent, the weight percentages being based on the total weight of the uncoated pharmaceutical granules or uncoated granules.

[0143] The uncoated pharmaceutical granules or granules can contain, for example, 85.0% to 95.0% by weight of the active pharmaceutical ingredient, 2.0% to 7.0% by weight of a binder, and 2.0% to 7.0% by weight of an antistatic agent, the weight percentages being based on the total weight of the uncoated pharmaceutical granules or uncoated granules.

[0144] Uncoated pharmaceutical granules or particles can contain, for example, 87.0% to 93.0% by weight of the pharmaceutical active ingredient, 3.0% to 7.0% by weight of the binder, and 3.0% to 7.0% by weight of the anti-static agent, where the percentages by weight are based on the total weight of the uncoated pharmaceutical granules or uncoated particles.

[0145] The uncoated granules can consist of a pharmaceutical active ingredient, a binder, and an anti-static agent. In addition to the pharmaceutical active ingredient, the uncoated granules can consist of a binder composed of hydroxypropyl cellulose and / or an anti-static agent composed of talc. The uncoated granules can consist of a pharmaceutical active ingredient selected from the compounds of formula (2), a binder composed of hydroxypropyl cellulose, and an anti-static agent composed of talc. The uncoated granules can have a trace amount of water. In certain pharmaceutical compositions and granules, the pharmaceutical active ingredient does not include 4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable salt thereof:

[0146] The uncoated particles provided by the present disclosure can be characterized by a sphericity of 0.90 to 1, such as 0.91 to 0.99, or 0.92 to 0.98, etc., and the sphericity is determined using the wet dispersion particle shape method or by dynamic image analysis. The uncoated particles provided by the present disclosure can be characterized by a sphericity 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.

[0147] The uncoated pharmaceutical granules provided by the present disclosure can contain a plurality of granules characterized by a mode sphericity of 0.90 to 1, such as 0.91 to 0.99, or 0.92 to 0.98, etc., and the sphericity is determined using the wet dispersion particle shape method or by dynamic image analysis. The uncoated pharmaceutical granules provided by the present disclosure can contain a plurality of granules characterized by an average sphericity 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.

[0148] The uncoated granules provided by the present disclosure are solid and characterized by a substantially homogeneous composition throughout the granule.

[0149] For high doses of active pharmaceutical ingredient, especially when reconstituted as a suspension before administration, it may be useful for the granules to have a small average diameter to improve palatability.

[0150] The uncoated pharmaceutical granules provided by the present disclosure can be characterized by a particle size distribution (D50) of, for example, 75 μm to 500 μm, 75 μm to 450 μm, 75 μm to 450 μm, 100 μm to 400 μm, 150 μm to 350 μm, for example, 175 μm to 325 μm, 200 μm to 300 μm, or 225 μm to 275 μm. The uncoated pharmaceutical granules provided by the present disclosure can be characterized by a particle size distribution (D50) of, for example, less than 400 μm, less than 360 μm, or less than 320 μm.

[0151] The uncoated pharmaceutical granules can be characterized by a particle size distribution (D10) of, for example, 50 μm to 150 μm, 60 μm to 140 μm, 70 μm to 120 μm, 80 μm to 110 μm, 50 μm to 150 μm, or 50 μm to 200 μm. The uncoated pharmaceutical granules can be characterized by a particle size distribution (D10) of, for example, less than 200 μm, less than 160 μm, or less than 120 μm.

[0152] The uncoated pharmaceutical granules can be characterized by a particle size distribution (D90) of, for example, 450 μm to 800 μm, 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. The uncoated pharmaceutical granules can be characterized by a particle size distribution (D90) of, for example, less than 800 μm, less than 700 μm, less than 600 μm, or less than 500 μm.

[0153] The uncoated pharmaceutical granules can be characterized, for example, by a particle size distribution (D10) of 50 μm to 150 μm, a particle size distribution (D50) of 220 μm to 320 μm, and a PSD (D90) of 480 μm to 560 μm. The uncoated granules can be characterized, for example, by a particle size distribution D50 of less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm to less than 250 μm, or less than 200 μm.

[0154] The uncoated pharmaceutical granulation can be characterized, for example, by a particle size distribution (D10) of 60 μm to 140 μm, a particle size distribution (D50) of 230 μm to 310 μm, and a particle size distribution (D90) of 490 μm to 550 μm.

[0155] The uncoated pharmaceutical granulation can be characterized, for example, by a particle size distribution (D10) of 70 μm to 130 μm, a particle size distribution (D50) of 240 μm to 300 μm, and a particle size distribution (D90) of 500 μm to 540 μm.

[0156] An example of a particle size distribution for an uncoated granulation provided by the present disclosure is shown in FIG.

[0157] The particle size distribution can be determined by laser diffraction or sieve analysis.

[0158] The uncoated pharmaceutical granulation can have a bulk density of, for example, greater than 0.40 g / mL, greater than 0.50 g / mL, 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.

[0159] The uncoated pharmaceutical granulation can have a bulk density of, for example, 0.40 g / mL to 1.60 g / mL, 0.40 g / mL to 1.20 g / mL, 0.40 g / mL to 0.80 g / mL, 0.50 g / mL to 1.60 g / mL, 0.50 g / mL to 1.40 g / mL, 0.50 g / mL to 1.20 g / mL, 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.

[0160] The uncoated pharmaceutical granulation can have a bulk density 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.

[0161] Bulk density can be determined using a bulk density cylinder.

[0162] The uncoated pharmaceutical granules or granules can have a bulk density of, for example, 0.5 g / mL to 1.0 g / mL, 0.5 g / mL to 0.9 g / mL, 0.5 g / mL to 0.8 g / mL, 0.5 g / mL to 0.7 g / mL, or 0.6 g / mL to 0.7 g / mL. The uncoated pharmaceutical granules or granules can have a bulk density of, for example, greater than 0.5 g / mL, greater than 0.6 g / mL, greater than 0.7 g / mL, greater than 0.8 g / mL, or greater than 0.9 g / mL.

[0163] Scanning electron micrograph (SEM) images of examples of uncoated granules provided by the present disclosure are shown in Figures 20A-20D at magnifications of 110x, 220x, 1,000x, and 2,000x, respectively. The uncoated granules shown in Figures 20A-20D are characterized by a substantially smooth surface.

[0164] A smooth granule surface facilitates the ability to coat the granules with a thin continuous functional coating having a substantially uniform thickness. The quality of the coating can be important for controlled release formulations. For example, rough and / or porous surfaces tend to require significantly higher amounts of functional coating to achieve a release profile comparable to that of smooth surfaces. In addition, coating of rough and / or porous surfaces can result in different dissolution or release profiles.

[0165] The uncoated pharmaceutical granules provided by the present disclosure can be characterized by, for example, a loss on drying (LOD) of 0.92-0.98, 0.93-0.97, or 0.94-0.96. The LOD represents the removal of water incorporated into the granule during preparation of the uncoated pharmaceutical.

[0166] The LOD is determined by thermogravimetric analysis.

[0167] The uncoated pharmaceutical granulations provided by the present disclosure can be characterized, for example, by a friability value of 0% to 2%. Granules with low friability are easier to coat than those with high friability. Friability is defined as the amount of granules with a diameter less than 75 μm produced by subjecting the granulation to a sonic sieve operated at an amplitude of 8, corresponding to 3,600 sonic energy pulses per minute, for at least 2 minutes.

[0168] The uncoated pharmaceutical granulation provided by the present disclosure can have, for example, a friability of 1.02%, where the friability is determined using sonic sieving.

[0169] A method for making uncoated pharmaceutical granules containing a high loading of a highly water-soluble active pharmaceutical ingredient is disclosed in U.S. patent application Ser. No. 17 / 350,478, filed June 17, 2021.

[0170] The coated pharmaceutical granules provided by the present disclosure can include a plurality of uncoated granules coated with a functional coating. The functional coating can include, for example, an immediate release coating, a controlled release coating, a modified release coating, a sustained release coating, a pH release coating, a pulsatile release coating, a timed release coating, or a delayed release coating. The functional coating can be configured, for example, to release the active pharmaceutical ingredient from the coated granule or core over an intended period of time after ingestion and / or within an intended region of the gastrointestinal tract.

[0171] The coated pharmaceutical granules provided by the present disclosure can include one or more functional coatings.

[0172] Each of the one or more functional coatings can independently 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 40 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 10 μm, or less than 5 μm. Each of the one or more functional coatings can independently have an average thickness of, for example, from 5 μm to 300 μm, from 5 μm to 200 μm, from 5 μm to 100 μm, from 5 μm to 50 μm, from 5 μm to 40 μm, from 5 μm to 30 μm, from 5 μm to 25 μm, from 5 μm to 20 μm, or from 5 μm to 15 μm.

[0173] The coated granules can include, for example, less than 50% by weight of the functional coating, less than 45% by weight of the functional coating, less than 40% by weight, less than 30% by weight, less than 20% by weight, or less than 10% by weight of the functional coating, where the weight percentages are based on the total weight of the coated granules.

[0174] The coated granules can include, for example, 1 wt % to 50 wt % of the functional coating, 5 wt % to 50 wt %, 10 wt % to 45 wt %, or 15 wt % to 40 wt % of the functional coating, the weight percentages being based on the total weight of the coated granule.

[0175] Dosage forms containing highly water-soluble active pharmaceutical ingredients may have thick coatings to reduce the release rate of the active pharmaceutical ingredient and / or increase the storage stability of the active pharmaceutical ingredient by minimizing or preventing the ingress of moisture.

[0176] The coated granules or coated granules can contain, for example, more than 50% by weight of the active pharmaceutical ingredient, more than 55% by weight, more than 60% by weight, more than 70% by weight, more than 80% by weight, or more than 85% by weight of the active pharmaceutical ingredient, the weight percentages being based on the total weight of the coated granules or coated granules.

[0177] A coated granule or a coated granulation comprising a plurality of coated granules can comprise, for example, 50% to 95% by weight of the active pharmaceutical ingredient, 55% to 90% by weight, 60% to 85% by weight, 65% to 80% by weight, or 70% to 75% by weight of the active pharmaceutical ingredient, the weight percentages being based on the total weight of the coated granule or coated granulation.

[0178] The coated granules may comprise a core, i.e., an uncoated granule, and a functional coating surrounding the core. The coated granules may comprise, for example, 55% to 90% by weight of the core and 10% to 45% by weight of the functional coating, the weight percentages being based on the total weight of the coated granule. The coated granules may comprise, for example, 60% to 85% by weight of the core and 15% to 40% by weight of the functional coating, the weight percentages being based on the total weight of the coated granule.

[0179] The functional coating may comprise a matrix polymer or a combination of matrix polymers. The combination of matrix polymers may comprise a water-insoluble polymer and / or a water-soluble or pore-forming polymer. The combination of matrix polymers may be selected to provide a desired release profile of the active pharmaceutical ingredient in the gastrointestinal tract.

[0180] The functional coating can include, for example, 55% to 85% by weight matrix polymer, 60% to 85% by weight, 65% to 80% by weight, or 70% to 80% by weight matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0181] The functional coating can include, for example, less than 85 wt % matrix polymer, less than 80 wt %, less than 75 wt %, less than 70 wt %, or less than 65 wt % matrix polymer, where the weight percentage is based on the total weight of the functional coating.

[0182] The functional coating can include, for example, greater than 60% matrix polymer, greater than 65% by weight, greater than 70% by weight, greater than 75% by weight, or greater than 80% by weight matrix polymer, where the weight percentages are based on the total weight of the functional coating.

[0183] The matrix polymer can include a water insoluble polymer or a combination of water insoluble polymers.

[0184] Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl acetate, polyacrylates, and polymethacrylates.

[0185] The water insoluble polymer can be ethyl cellulose.

[0186] A water insoluble polymer such as ethyl cellulose can have an average molecular weight of, for example, 25,000 daltons to 300,000 daltons, such as, for example, 50,000 daltons to 200,000 daltons, 50,000 daltons to 150,000 daltons, or 50,000 daltons to 100,000 daltons.

[0187] Water insoluble polymers such as ethyl cellulose can have a viscosity of less than 100 mPa×sec, less than 75 mPa×sec, less than 50 mPa×sec, less than 25 mPa×sec, less than 20 mPa×sec, or less than 15 mPa×sec, as determined, for example, using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0188] 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, Standard 20 polymers available from Dupont.

[0189] The functional coating can include, for example, 65% to 100% by weight of a water insoluble polymer, 65% to 90% by weight, or 70% to 80% by weight of a water insoluble polymer, where the weight percentages are based on the total weight of the functional coating. The functional coating can include, for example, more than 65% by weight of a water insoluble polymer, such as ethyl cellulose, more than 70% by weight, more than 75% by weight, or more than 80% by weight of a water insoluble polymer, where the weight percentages are based on the total weight of the functional coating.

[0190] The matrix polymer can include, for example, 85% to 100% by weight of the water-insoluble polymer, 90% to 100% by weight, 92% to 98% by weight, 91% to 99% by weight, 92% to 98% by weight, or 93% to 97% by weight of the water-insoluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer can include, for example, more than 85% by weight of the water-insoluble polymer, more than 90% by weight, more than 92% by weight, more than 94% by weight, more than 96% by weight, or more than 98% by weight of the water-insoluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer can include, for example, less than 100% by weight of the water-insoluble polymer, less than 98% by weight, less than 96% by weight, less than 94% by weight, less than 92% by weight, less than 90% by weight, or less than 85% by weight of the water-insoluble polymer, where the weight percentage is based on the total weight of the matrix polymer.

[0191] The matrix polymer may comprise a pore-forming polymer or a combination of pore-forming polymers. Pore-forming polymer refers to a water-soluble polymer.

[0192] Examples of pore-forming agents include water-soluble polymers, swelling or expanding polymers such as carbomers, and polymers soluble in gastric juices, such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid-methyl methacrylate copolymers, and polyvinyl acetate phthalate. Pore-forming polymers can increase the permeability of the functional coating under intended conditions.

[0193] The matrix polymer can include a water soluble polymer or a combination of water soluble polymers.

[0194] Examples of suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, crospovidone, and poloxamer.

[0195] Water soluble polymers such as hydroxypropylcellulose can have, for example, an average molecular weight of less than 1,000,000 daltons, less than 800,000 daltons, less than 600,000 daltons, less than 400,000 daltons, less than 200,000 daltons, less than 100,000 daltons, or less than 50,0000 daltons.

[0196] Water-soluble polymers such as hydroxypropyl cellulose can have a viscosity of less than 7,000 mPa×sec, less than 5,000 mPa×sec, less than 3,000 mPa×sec, or less than 1,000 mPa×sec, as determined, for example, using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0197] Examples of suitable hydroxypropyl cellulose polymers include Klucel® HF Pharm, MF Pharm, GF Pharm JF Pharm, LF Pharm, EF Pharm, and ELF Pharm polymers available from Ashland.

[0198] Examples of suitable hydroxypropyl methylcellulose polymers include Pharmacoat® 603, 645, 606, and 615 polymers, available from Shin-Etsu Chemical Co.

[0199] The matrix polymer can include, for example, 0% to 20% by weight of water-soluble polymer, 0% to 10% by weight, 0.5% to 20% by weight, 1% to 10% by weight, 1% to 8% by weight, 2% to 7% by weight, 2% to 6% by weight, or 4% to 6% by weight of water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer can include, for example, more than 0% by weight of water-soluble polymer, more than 2% by weight, more than 4% by weight, more than 6% by weight, more than 8% by weight, more than 10% by weight, or more than 15% by weight of water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer. The matrix polymer can include, for example, less than 20% by weight, less than 15% by weight, less than 10% by weight of 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 water-soluble polymer, where the weight percentage is based on the total weight of the matrix polymer. In certain functional coatings, the matrix polymer does not include a water-soluble polymer, such as hydroxypropyl cellulose.

[0200] The matrix polymer can comprise, for example, 90% to 100% by weight of the water-insoluble polymer and 0% to 10% by weight of the water-soluble polymer, 92% to 98% by weight of the water-insoluble polymer and 2% to 8% by weight of the water-soluble polymer, or 94% to 96% by weight of the water-insoluble polymer and 4% to 6% by weight of the water-soluble polymer, the weight percentages being based on the total weight of the matrix polymer.

[0201] The functional coating can include, for example, 65% to 90% by weight of a water insoluble polymer and 1% to 10% by weight of a water soluble polymer, 70% to 85% by weight of a water insoluble polymer and 2% to 8% by weight of a water soluble polymer, or 72% to 83% by weight of a water insoluble polymer and 3% to 7% by weight of a water soluble polymer, the weight percentages being based on the total weight of the functional coating.

[0202] In addition to the matrix polymer or combination of matrix polymers, the functional coating can include, for example, a plasticizer, an antistatic agent, an antiblocking agent, a colorant or pigment, a flow enhancer, a viscosity modifier, or a combination of any of the foregoing.

[0203] The functional coating may include an antistatic agent or a combination of antistatic agents.

[0204] Antistatic agents can be useful to minimize or prevent agglomeration of granules during application of the functional coating.

[0205] Examples of suitable antistatic agents include talc, magnesium stearate, and silicon dioxide.

[0206] The antistatic agent may include talc.

[0207] The antistatic agent can include magnesium stearate. In certain functional coatings, the antistatic agent does not include magnesium stearate.

[0208] The functional coating can include, for example, 10 wt% to 20 wt% of the antistatic agent, for example, 12 wt% to 18 wt%, or 14 wt% to 16 wt%, of the antistatic agent, where the weight percentage is based on the total weight of the functional coating. The functional coating can include, for example, less than 20 wt%, less than 18 wt%, less than 16 wt%, less than 14 wt%, or less than 12 wt%, of the antistatic agent, where the weight percentage is based on the total weight of the functional coating. The functional coating can include, for example, more than 10 wt%, more than 12 wt%, more than 14 wt%, more than 16 wt%, or more than 18 wt%, of the antistatic agent, where the weight percentage is based on the total weight of the functional coating.

[0209] The functional coating can include a plasticizer or combination of plasticizers.

[0210] Plasticizers can be useful to provide a functional coating with a uniform thickness.

[0211] Examples of suitable plasticizers include dibutyl sebacate, polyethylene glycol, triacetin, and triethyl citrate.

[0212] The plasticizer may include dibutyl sebacate.

[0213] In certain functional coatings, the functional coating does not include a plasticizer.

[0214] The functional coating can include, for example, 0% to 14% by weight of plasticizer, for example, 2% to 12% by weight, or 4% to 10% by weight of plasticizer, where the weight percentage is based on the total weight of the functional coating. The functional coating can include, for example, less than 14% by weight of plasticizer, less than 12% by weight, less than 12% by weight, less than 8% by weight, less than 6% by weight, or less than 4% by weight of plasticizer, where the weight percentage is based on the total weight of the functional coating. The functional coating can include, for example, more than 0% by weight of plasticizer, more than 2% by weight, more than 4% by weight, more than 6% by weight, more than 8% by weight, more than 10% by weight, or more than 12% by weight of plasticizer, where the weight percentage is based on the total weight of the functional coating.

[0215] A functional coating provided by the present disclosure can include, for example, 60% to 85% by weight of a matrix polymer, 10% to 20% by weight of an antistatic agent, and 0% to 14% by weight of a plasticizer, the weight percentages being based on the total weight of the functional coating.

[0216] A functional coating provided by the present disclosure can include, for example, 65% to 80% by weight of a matrix polymer, 12% to 18% by weight of an antistatic agent, and 2% to 12% by weight of a plasticizer, the weight percentages being based on the total weight of the functional coating.

[0217] A functional coating provided by the present disclosure can include, for example, 70% to 80% by weight of a matrix polymer, 14% to 16% by weight of an antistatic agent, and 4% to 10% by weight of a plasticizer, the weight percentages being based on the total weight of the functional coating.

[0218] Functional coatings provided by the present disclosure can include, for example, a water insoluble polymer such as ethyl cellulose, a water soluble polymer such as hydroxypropyl cellulose, an antistatic agent such as talc, and a plasticizer such as dibutyl sebacate.

[0219] The pharmaceutical granulation provided by the present disclosure can include a seal coating. The pharmaceutical granulation including the seal coating can be used as an immediate release pharmaceutical granulation.

[0220] The coated granules provided by the present disclosure can include a seal coat that covers the granules that include the active pharmaceutical ingredient. A functional coating can cover the seal coat.

[0221] The seal coat can increase the storage stability of the coated granulation by minimizing the ingress of moisture into the active pharmaceutical ingredient, thereby reducing hydrolysis of the active pharmaceutical ingredient. The seal coat can also increase the storage stability of the coated granulation by minimizing negative interactions between the functional coating and the active pharmaceutical ingredient, thereby reducing hydrolysis of the active pharmaceutical ingredient.

[0222] The seal coat may comprise a water soluble polymer such as, for example, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol.

[0223] The seal coat may comprise a water soluble polymer such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, or any of the water soluble polymers disclosed herein.

[0224] The seal coat may include an antistatic agent such as talc, magnesium stearate, or a combination thereof.

[0225] The seal coat may include, for example, hydroxypropyl cellulose, hydroxypropyl cellulose and talc, or hydroxypropyl methylcellulose and talc.

[0226] The seal coat can, for example, comprise 65% to 95% by weight of the water soluble polymer, e.g., 70% to 90% by weight, or 75% to 85% by weight of the water soluble polymer, and 5% to 35% by weight of the antistatic agent, e.g., 10% to 30% by weight, or 15% to 25% by weight of the antistatic agent, the weight percentages being based on the total weight of the seal coating.

[0227] The seal coat 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 coat 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.

[0228] The seal coat can be applied to the granulation 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. The seal coat can be applied to the granulation such that the %wg is 1%wg to 15%wg, 1%wg to 10%wg, 2%wg to 8%wg, or 4%wg to 6%wg.

[0229] In certain coated granulations, including a seal coating that includes a water-soluble polymer, the functional coating does not contain a water-soluble polymer.

[0230] The seal coat can be applied to the uncoated granules using any suitable method, such as by spraying a solution, suspension, or dispersion of the functional coating onto the granules in a fluid bed apparatus.

[0231] The functional coating can be applied to the uncoated granules provided by the present disclosure, or to the granules including the seal coat, by any suitable method, such as by spraying a solution, suspension, or dispersion of the functional coating onto the granules in a fluid bed apparatus.

[0232] The controlled release granulations provided by the present disclosure can include granules having a functional coating provided by the present disclosure.

[0233] The controlled release granulations provided by the present disclosure can be configured to provide one nighttime dose, once daily dose (QD), twice daily dose (BID), three times daily dose (TID), or four times daily dose (QID). For example, the controlled release granulations can release substantially 100% of the active pharmaceutical ingredient over a 24 hour duration, a 12 hour duration, an 8 hour duration, or a 4 hour duration.

[0234] For example, the controlled release granulation can exhibit a dissolution profile substantially as shown in, for example, FIG.

[0235] The controlled release granulation may exhibit a dissolution profile, when determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which less than 80% of the active pharmaceutical ingredient is released from the controlled release granulation within 2 hours, less than 70%, less than 60%, less than 50%, or less than 40% of the active pharmaceutical ingredient is released from the controlled release granulation within 2 hours, and more than 80% or more than 90% of the active pharmaceutical ingredient is released from the controlled release granulation within 6 hours.

[0236] The controlled release granulation may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which 35%-85%, e.g., 35%-80%, 40%-75%, or 45%-70% of the active pharmaceutical ingredient is released from the controlled release granulation within 2 hours.

[0237] The controlled release granulation may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which 70%-95%, e.g., 70%-90%, or 75%-85% of the active pharmaceutical ingredient is released from the controlled release granulation within 4 hours.

[0238] The controlled release granulation may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which 80%-100%, for example 85%-95%, of the active pharmaceutical ingredient is released from the controlled release granulation within 6 hours.

[0239] The controlled release granulation may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which 35%-85% of the active pharmaceutical ingredient is released from the controlled release granulation within 2 hours, 70%-95% of the active pharmaceutical ingredient is released from the controlled release granulation within 4 hours, and 80%-100% of the active pharmaceutical ingredient is released from the formulation within 6 hours.

[0240] The controlled release granulation may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which 35%-80% of the active pharmaceutical ingredient is released from the controlled release granulation within 2 hours, 70%-90% of the active pharmaceutical ingredient is released from the controlled release granulation within 4 hours, and 80%-100% of the active pharmaceutical ingredient is released from the formulation within 6 hours.

[0241] The controlled release granules may exhibit a dissolution profile, as determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 75 rpm, in which 45%-70% of the active pharmaceutical ingredient is released from the controlled release granules within 2 hours, 75%-85% of the active pharmaceutical ingredient is released from the controlled release granules within 4 hours, and 85%-95% of the active pharmaceutical ingredient is released from the controlled release granules within 6 hours.

[0242] The coated granules provided by the present disclosure can have a water content of, for example, less than 2 wt%, less than 1.5 wt%, less than 1 wt%, less than 0.5 wt%, or less than 0.25 wt%, where the weight percentage is based on the total weight of the granule.

[0243] The coated granules provided by the present disclosure can have a water content of, for example, 0.1 wt % to 2 wt %, 0.1 wt % to 1 wt %, or 0.2 wt % to 0.5 wt %, where the weight % is based on the total weight of the granule.

[0244] The coated pharmaceutical granulation can have a bulk density of, for example, greater than 0.55 g / mL, greater than 0.60 g / mL, greater than 0.65 g / mL, greater than 0.70 g / mL, or greater than 0.75 g / mL.

[0245] The coated pharmaceutical granules can have a bulk density of, for example, 0.55 g / mL to 0.80 g / mL, 0.60 g / mL to 0.75 g / mL, or 0.60 g / mL to 0.70 g / mL.

[0246] Bulk density can be determined using a bulk density cylinder.

[0247] The coated pharmaceutical granules provided by the present disclosure can be characterized, for example, by a particle size distribution (D50) of, for example, 150 μm to 350 μm, e.g., 175 μm to 325 μm, 200 μm to 300 μm, or 225 μm to 275 μm.

[0248] The coated pharmaceutical granules can be characterized by a particle size distribution (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.

[0249] The uncoated pharmaceutical granules can be characterized by a particle size distribution (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.

[0250] The coated pharmaceutical granules can be characterized, for example, by a particle size distribution (D10) of 50 μm to 150 μm, e.g., a particle size distribution (D50) of 230 μm to 310 μm, and a particle size distribution (D90) of 490 μm to 550 μm.

[0251] The coated pharmaceutical granules can be characterized, for example, by a particle size distribution (D10) of 70 μm to 130 μm, a particle size distribution (D50) of 240 μm to 300 μm, and a particle size distribution (D90) of 500 μm to 540 μm.

[0252] An example of a particle size distribution for an uncoated granulation provided by the present disclosure is shown in FIG.

[0253] For example, in a coated pharmaceutical granulation, 12.9% of the coated granules may have a particle size less than 300 μm, 83.8% of the coated granules may have a particle size between 300 μm and 600 μm, and 3.3% of the coated granules may have a particle size between 600 μm and 1190 μm.

[0254] The particle size distribution can be determined by laser diffraction or sieve analysis.

[0255] The functional and seal coatings provided by the present disclosure can be coated onto the granulation using any suitable equipment and process. Examples of suitable coating methods include the Wurster fluidized bed film coating process and the phase inversion process.

[0256] Examples of coating compositions are provided in the Experimental Examples. Coating composition refers to a composition that is applied to an uncoated granulation to provide a coated granulation.

[0257] The functional coating composition can include more than 70 wt. % alcohol solvent, more than 75 wt. %, more than 80 wt. %, more than 85 wt. %, or more than 90 wt. % alcohol solvent, such as ethanol, where the weight percentage is based on the total weight of the functional coating solution / suspension composition.

[0258] The functional coating composition can include, for example, less than 20% water, less than 15% water, less than 10% water, or less than 5% water by weight, where the weight percentages are based on the functional coating solution / suspension composition.

[0259] For highly water-soluble and hygroscopic active pharmaceutical ingredients, it may be useful to minimize the amount of water in the functional coating composition. Reducing the level of water in the functional coating solution / suspension composition may result in increased static electricity that may complicate the coating process.

[0260] The functional coating solution / suspension composition can, for example, comprise a solids content of less than 20 wt%, less than 18 wt%, less than 16 wt%, less than 14 wt%, less than 12 wt%, less than 10 wt%, less than 8 wt%, or less than 6 wt%, where the weight percentages are based on the functional coating solution / suspension composition.

[0261] The functional coating composition can include a solids content of 2 wt% to 20 wt%, 4 wt% to 16 wt%, 4 wt% to 12 wt%, or 6 wt% to 10 wt%, where the weight percentages are based on the functional coating composition.

[0262] The functional coating composition can include, for example, 3 wt% to 10 wt% solids, 4 wt% to 13 wt% water, and 75 wt% to 90 wt% alcohol solvent, such as ethanol, where the wt% are based on the total weight of the functional coating composition.

[0263] Examples of coating process conditions using a Wurster column inserted into a fluidized bed coating apparatus are provided in the Experimental Examples.

[0264] The granulations provided by the present disclosure can include immediate release granulations.

[0265] The immediate release granulation can include a plurality of uncoated granules. The immediate release granulation including a plurality of uncoated granules can include more than 90% by weight of the active pharmaceutical ingredient provided by the present disclosure, such as the compound of formula (2). The immediate release granulation including uncoated granules can be completely dissolved, for example, in less than 10 minutes, less than 8 minutes, less than 6 minutes, less than 5 minutes, or less than 4 minutes when tested in a USP type 2 dissolution apparatus at a pH 4.5 buffer solution, a temperature of 37° C., and a paddle speed of 75 rpm.

[0266] The immediate release granules can include a plurality of coated granules having an immediate release functional coating. The immediate release granules including a plurality of coated granules can include more than 80% by weight of the active pharmaceutical ingredient provided by the present disclosure, such as the compound of formula (2). The immediate release granules including the coated granules 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 at a temperature of 37° C. and a paddle speed of 75 rpm in a buffer solution of pH 4.5. The immediate release granules including the coated granules can release more than 80% of the active pharmaceutical ingredient in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes when tested in a USP type 2 dissolution apparatus at a temperature of 37° C. and a paddle speed of 75 rpm in a buffer solution of pH 4.5. The coated immediate release granules can include a coating that includes a water soluble polymer, such as, for example, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol. The coated immediate release granules can include a coating that includes an antistatic agent, such as talc, magnesium stearate, or silicon dioxide.

[0267] The pharmaceutical composition provided by the present disclosure can include a combination of immediate release granules and controlled release granules. The pharmaceutical composition can include, for example, a weight ratio of the compound of formula (2) as the immediate release granules and the compound of formula (2) as the controlled release granules of 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:2 to 1:3.

[0268] The pharmaceutical compositions provided by the present disclosure can include the coated granules provided by the present disclosure.

[0269] The pharmaceutical composition may comprise any suitable dosage form for oral administration.

[0270] Examples of suitable oral dosage forms include tablets, capsules, caplets, sachets, bottles, stick packs, dispersions, and suspensions.

[0271] Pharmaceutical compositions provided by the present disclosure can include suspensions for oral administration.

[0272] Oral dosage forms provided by the present disclosure can contain, for example, 0.1 grams to 20 grams of active pharmaceutical ingredient, 0.1 grams to 15 grams, 0.1 grams to 12 grams, 0.1 grams to 10 grams, 0.2 grams to 8 grams, 0.5 grams to 5 grams, 1 gram to 4.5 grams, or 1.5 grams to 4 grams of active pharmaceutical ingredient. Oral dosage forms can contain, for example, more than 0.5 grams, more than 1 gram, more than 2 grams, more than 3 grams, more than 4 grams, more than 6 grams, or more than 8 grams, more than 10 grams, more than 14 grams, or more than 18 grams of active pharmaceutical ingredient.

[0273] Oral formulations provided by the present disclosure can include oral suspensions of coated granules having a controlled release functional coating provided by the present disclosure. Oral formulations can include controlled release granules and immediate release granules provided by the present disclosure.

[0274] The oral formulation may include a combination of immediate release and controlled release granulations provided by the present disclosure.

[0275] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of an active pharmaceutical ingredient over a period of time.

[0276] For example, oral formulations provided by the present disclosure may provide a therapeutically effective amount of the active pharmaceutical ingredient for a period of 3 hours, 6 hours, 8 hours, or 10 hours.

[0277] Oral formulations provided by the present disclosure can provide a therapeutically effective amount of the active pharmaceutical ingredient over a period of 4 to 12 hours, 4 to 10 hours, or 4 to 8 hours.

[0278] Oral formulations provided by the present disclosure can provide a therapeutically effective amount of the active pharmaceutical ingredient for a period of 1 hour to 12 hours after oral administration, 2 hours to 10 hours after oral administration, or 4 hours to 8 hours after oral administration.

[0279] The oral formulations provided by the present disclosure can be once-a-nightly formulations, in which a patient can administer a dose of the active pharmaceutical ingredient before going to bed and sleep through the night, such as 6 or 8 hours, without administering a second dose during the night.

[0280] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient.

[0281] The oral formulations provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyric acid in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the controlled release oral formulation.

[0282] The oral formulations provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid of greater than 10 μg / mL for greater than 4 hours, greater than 6 hours, greater than 8 hours, or greater than 10 hours after oral administration of the controlled release oral formulation.

[0283] The oral formulations provided by the present disclosure can provide plasma concentrations of gamma-hydroxybutyric acid of greater than 15 μg / mL for greater than 4 hours, greater than 6 hours, greater than 8 hours, or greater than 10 hours after oral administration of the controlled release oral formulation.

[0284] The oral formulations provided by the present disclosure provide a therapeutically effective amount of C of γ-hydroxybutyrate in the plasma of a patient for a period of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the controlled release oral formulation. 最大 Against C 最小 The ratio can be provided from less than 3 or less than 2.

[0285] Oral formulations provided by the present disclosure can include a γ-hydroxybutyric acid derivative of formula (2), for example, 0.5 g equivalent of γ-hydroxybutyric acid, 1 g equivalent, 2 g equivalent, 3 g equivalent, 4 g equivalent, 5 g equivalent, 6 g equivalent, 7 g equivalent, 8 g equivalent, 9 g equivalent, 10 g equivalent, 11 g equivalent, or 12 g equivalent of γ-hydroxybutyric acid.

[0286] The oral formulations provided by the present disclosure can be provided, for example, as sachets containing the coated granules provided by the present disclosure. The sachets can be provided with different doses of the active pharmaceutical ingredient, for example, 0.5g, 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 11g, 10g, 12g, 15g, or 20g of the active pharmaceutical ingredient. The coated granules can be combined, for example, with water, to provide an orally ingestible dosage form.

[0287] Gamma-hydroxybutyric acid and gamma-hydroxybutyric acid derivatives of formula (2) can be used to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and fibromyalgia. Gamma-hydroxybutyric acid and gamma-hydroxybutyric acid derivatives of formula (2) can be used to treat REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety.

[0288] The compound of formula (2) is a prodrug of gamma-hydroxybutyric acid that provides oral bioavailability of gamma-hydroxybutyric acid in the systemic circulation of a patient following oral administration.

[0289] Efficacy of treatment may be measured by one or more of the following criteria: an increase in mean sleep latency as determined by the Maintenance of Wakefulness Test (MWT); an improvement in the Clinical Global Impression (CGI) rating of sleepiness; a reduction in the number of cataplexy attacks (NCA) as determined from the cataplexy frequency item of a sleep and symptom diary; a reduction in nocturnal sleep disturbance (DNS), nocturnal disturbance events, or adverse respiratory events as determined by a polysomnographic (PSG) measure of sleep fragmentation; a reduction in excessive daytime sleepiness (EDS) as measured by patient report on the Epworth Sleepiness Scale (ESS); a reduction in daytime sleepiness as measured by the Maintenance of Wakefulness Test based on an EEG measure of wakefulness; a reduction in PSG transition from N / 2 to N / 3 and waking REM sleep and N1 sleep as determined as described in the AASM Manual for the Scoring of Sleep and Associated Events; a reduction in the number of awakenings or arousals as determined from PSG as defined by the National Institutes of Health (NIH) and / or the National Institutes of Health (NIH); (i) improved sleep quality as determined using a sleep and symptom diary, (ii) a visual analog scale (VAS) for sleep quality and the sleep diary, and / or (iii) a VAS for quality sleep; and a reduction in hypnagogic hallucinations (HH) or sleep paralysis (SP) symptoms in NT1 narcolepsy patients as measured by a sleep and symptom diary.

[0290] The compounds of formula (2) and pharmaceutical compositions thereof can be used to treat diseases known or determined to be treated by γ-hydroxybutyric acid.

[0291] The compounds of formula (2) and pharmaceutical compositions thereof can be used to treat diseases known or determined to be treated by γ-hydroxybutyric acid and one or more additional therapeutic agents.

[0292] The compounds of formula (2) and pharmaceutical compositions can be used to treat excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0293] The methods provided by the present disclosure include providing a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation of a patient comprising administering to the patient a compound of formula (2) or a pharma- ceutical composition thereof.

[0294] The pharmaceutical compositions provided by the present disclosure can further comprise one or more active pharmaceutical compounds in addition to the compound of formula (2). Such compounds can be provided to treat the disease being treated with the compound of formula (2) or to treat a disease, disorder, or condition other than the disease being treated with the compound of formula (2).

[0295] The compound of formula (2) or its pharmaceutical composition can be used in combination with at least one other therapeutic agent. The compound of formula (2) or its pharmaceutical composition can be administered to a patient together with another compound for treating bacterial infection in the patient. The at least one other therapeutic agent can be a different compound encompassed by formula (2). The compound of formula (2) and the at least one other therapeutic agent can function additively or synergistically. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle that includes the compound of formula (2), or can be included in a separate pharmaceutical composition or vehicle. Thus, the method provided by the present disclosure further comprises, in addition to administering the compound of formula (2), administering one or more therapeutic agents that are effective in treating a different disease, disorder, or condition other than the disease treated with gamma-hydroxybutyric acid. The methods provided by the present disclosure include administration of a compound of formula (2) or a pharmaceutical composition thereof and one or more other therapeutic agents, provided that the combined administration does not interfere with the therapeutic effectiveness of the compound of formula (2) and / or gamma-hydroxybutyric acid and / or does not result in adverse combined effects.

[0296] The pharmaceutical composition comprising the compound of formula (2) may be administered simultaneously with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as the pharmaceutical composition comprising the compound of formula (2) or may be a different pharmaceutical composition. The compound of formula (2) or its pharmaceutical composition may be administered before or after the administration of the other therapeutic agent. In certain embodiments of combination therapy, the combination therapy may include alternating between the administration of the compound of formula (2) and a pharmaceutical composition comprising another therapeutic agent to minimize adverse drug effects associated with a particular drug. When the compound of formula (2) is administered simultaneously with another therapeutic agent that may potentially cause adverse drug effects, including, for example, toxicity, the other therapeutic agent may be administered at a dose below the threshold at which an adverse drug reaction is induced.

[0297] A pharmaceutical composition comprising a compound of formula (2) may be administered with one or more substances, for example, to enhance, regulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of the compound of formula (2). For example, to enhance the therapeutic efficacy of the compound of formula (2), the compound of formula (2) or a pharmaceutical composition comprising a compound of formula (2) may be co-administered with one or more active agents to increase the absorption or diffusion and / or transport of the compound of formula (2) from the gastrointestinal tract to the systemic circulation, or inhibit the degradation of the compound of formula (2) in the blood of a patient. A pharmaceutical composition comprising a compound of formula (2) may be co-administered with an active agent that has a pharmacological effect of enhancing the therapeutic efficacy of the compound of formula (2) or gamma-hydroxybutyric acid.

[0298] Aspects of the invention The present invention is further defined by the following aspects.

[0299] Aspect 1. A pharmaceutical granulation comprising a plurality of coated granules comprising a core and a functional coating surrounding the core, wherein the pharmaceutical granulation is characterized by a particle size distribution (PSD) (D50) of 150 μm to 400 μm, the particle size distribution being determined by sieve analysis, and the core comprises greater than 90% by weight of an active pharmaceutical ingredient, the weight % being based on the total weight of the core.

[0300] Aspect 2. The pharmaceutical granulation of aspect 1, wherein the pharmaceutical granulation comprises 60% to 85% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the pharmaceutical granulation.

[0301] Aspect 3. The pharmaceutical granulation of aspect 1 or 2, wherein the functional coating comprises a controlled release coating.

[0302] Aspect 4. The pharmaceutical granulation of any one of aspects 1 to 3, wherein the functional coating comprises 60% to 85% by weight of matrix polymer, the weight percentage being based on the total weight of the functional coating.

[0303] Embodiment 5. The pharmaceutical granulation of embodiment 4, wherein the matrix polymer comprises a water insoluble polymer.

[0304] Embodiment 6. The pharmaceutical granulation of embodiment 5, wherein the water-insoluble polymer comprises ethyl cellulose.

[0305] Embodiment 7. The pharmaceutical granulation according to any one of embodiments 1 to 6, wherein the functional coating comprises 0% to 10% by weight of a pore-forming polymer, the weight % being based on the total weight of the polymer.

[0306] Embodiment 8. The pharmaceutical granulation of embodiment 7, wherein the pore-forming polymer comprises a water-soluble polymer.

[0307] Aspect 9. The pharmaceutical granulation of aspect 8, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

[0308] Aspect 10. The pharmaceutical granulation of any one of aspects 1 to 9, wherein the functional coating comprises 0% to 14% by weight of a plasticizer, the weight percentage being based on the total weight of the functional coating.

[0309] Aspect 11. The pharmaceutical granulation of aspect 10, wherein the plasticizer comprises dibutyl sebacate.

[0310] Aspect 12. The pharmaceutical granulation of any one of aspects 1 to 11, wherein the functional coating comprises 10% by weight to 20% by weight of an antistatic agent, the weight percentage being based on the total weight of the functional coating.

[0311] Aspect 13. The pharmaceutical granulation of aspect 12, wherein the antistatic agent comprises talc.

[0312] Aspect 14. The pharmaceutical granulation of aspect 12 or 13, wherein the functional coating comprises 60% to 85% by weight of a matrix polymer, 10% to 20% by weight of an antistatic agent, and 0% to 14% by weight of a plasticizer, the weight percentages being based on the total weight of the functional coating.

[0313] Aspect 15. A pharmaceutical granule according to any one of aspects 1 to 14, wherein the core represents 65% by weight to 85% by weight of the total weight of the coated granule and the functional coating represents 15% by weight to 35% by weight of the total weight of the coated granule.

[0314] Aspect 16. A pharmaceutical granulation according to any one of aspects 1 to 15, wherein the functional coating has a thickness of 5 μm to 20 μm.

[0315] Aspect 17. The pharmaceutical granule according to any one of aspects 1 to 16, wherein the pharmaceutical granule has a moisture content of less than 1% by weight, the weight percentage being based on the total weight of the pharmaceutical granule.

[0316] Embodiment 18. The pharmaceutical granulation of any one of embodiments 1 to 17, further comprising a seal coating surrounding the core, wherein the functional coating surrounds the seal coating.

[0317] Aspect 19. The pharmaceutical granulation of aspect 18, wherein the seal coating comprises hydroxypropyl cellulose.

[0318] Aspect 20. The pharmaceutical granulation of aspect 18 or 19, wherein the granules comprise 2% to 15% by weight of a seal coating.

[0319] Aspect 21. The pharmaceutical granulation according to any one of aspects 1 to 20, wherein 35% to 80% of the active pharmaceutical ingredient is released from the formulation within 2 hours 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.

[0320] Aspect 22. The pharmaceutical granulation according to any one of aspects 1 to 20, wherein 70% to 90% of the active pharmaceutical ingredient is released from the formulation within 4 hours 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.

[0321] Aspect 23. The pharmaceutical granulation according to any one of aspects 1 to 20, wherein 80% to 100% of the active pharmaceutical ingredient is released from the formulation within 6 hours 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.

[0322] Aspect 24. A pharmaceutical granulation according to any one of aspects 1 to 23, wherein the active pharmaceutical ingredient has a water solubility of greater than 100 mg / mL.

[0323] Aspect 25. A pharmaceutical granulation according to any one of aspects 1 to 23, wherein the active pharmaceutical ingredient has a water solubility of 100 mg / mL to 1,000 mg / mL.

[0324] Aspect 26. The pharmaceutical granule according to any one of Aspects 1 to 25, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof.

[0325] Aspect 27. The pharmaceutical granule according to any one of Aspects 1 to 26, wherein the active pharmaceutical ingredient comprises a derivative of gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof.

[0326] Aspect 28. The active pharmaceutical ingredient is a compound of formula (2): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But hydrogen and C 1-6 alkyl, R 2 and R 3 Each of these is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-6 28. The pharmaceutical granulation according to any one of aspects 1 to 27, wherein the aryl group is independently selected from cycloalkoxycarbonyl.

[0327] Aspect 29. The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing, and 29. The pharmaceutical granulation according to embodiment 28, selected from any combination of the foregoing.

[0328] Aspect 30. The pharmaceutical granulation according to aspect 28, wherein the active pharmaceutical ingredient comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharma- ceutically acceptable salt thereof: [ka]

[0329] Aspect 31. A pharmaceutical composition comprising the pharmaceutical granule according to any one of aspects 1 to 30.

[0330] Aspect 32. The pharmaceutical composition according to aspect 31, wherein the pharmaceutical composition is an oral formulation.

[0331] Aspect 33. The pharmaceutical composition according to aspect 31 or 32, wherein the pharmaceutical composition is a controlled release formulation.

[0332] 34. The pharmaceutical composition comprises: A controlled release portion, the controlled release portion comprising the pharmaceutical granule according to claim 1; 34. The pharmaceutical composition according to any one of aspects 31 to 33, wherein pharmaceutical composition n further comprises an immediate release portion, a sustained release portion, or a combination thereof.

[0333] Aspect 35. The pharmaceutical composition according to any one of aspects 31 to 34, wherein the pharmaceutical composition is a BID formulation.

[0334] Embodiment 36. The pharmaceutical composition according to any one of embodiments 31 to 34, wherein the pharmaceutical composition is a QD formulation.

[0335] Aspect 37. The pharmaceutical composition according to any one of aspects 31 to 36, wherein the pharmaceutical composition comprises 500 mg equivalents to 12 g equivalents of gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof.

[0336] Aspect 38. The pharmaceutical composition according to any one of aspects 31 to 37, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof, a derivative of gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof, a compound of formula (2) or a pharma- ceutically acceptable salt thereof, or any combination of the foregoing.

[0337] Aspect 39. The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing, and 39. The pharmaceutical composition according to embodiment 38, selected from any combination of the foregoing.

[0338] Aspect 40. A pharmaceutical composition according to aspect 38 or 39, wherein the pharmaceutical composition comprises a therapeutically effective amount of an active pharmaceutical ingredient for treating excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0339] Aspect 41. A method of providing a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation of the patent, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to aspect 38 or 39 for treating a disease.

[0340] Aspect 42. A method of treating a disease in a patient, the disease being known to be treated by administering gamma-hydroxybutyric acid, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to aspect 38 or 39.

[0341] Aspect 43. A method of treating a disease in a patient, the disease being known to be treated by administering gamma-hydroxybutyric acid, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to aspect 38 or 39.

[0342] Embodiment 44. The method according to any one of embodiments 41 to 43, wherein the pharmaceutical composition, after administration to a patient, provides a therapeutically effective amount of gamma-hydroxybutyric acid in the patient's systemic circulation to treat a disease.

[0343] Embodiment 45. The method of any one of embodiments 41 to 44, wherein administering comprises oral administration.

[0344] Embodiment 46. The method of any one of embodiments 41 to 45, wherein the disease is selected from excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, and fibromyalgia.

[0345] Aspect 47. A method of coating a pharmaceutical granulation comprising applying a coating formulation to the pharmaceutical granulation comprising a plurality of granules comprising an active pharmaceutical ingredient, the coating formulation comprising 4% to 12% by weight solids, 3% to 7% by weight water, and 82% to 92% by weight ethanol.

[0346] Embodiment 48. The method of embodiment 47, wherein applying comprises spraying.

[0347] Aspect 49. The method of aspect 47 or 48, wherein the granules comprise an active pharmaceutical ingredient having a water solubility of more than 100 mg / mL.

[0348] Aspect 1A. A pharmaceutical granulation comprising a plurality of coated granules, the coated granules comprising a core and a functional coating surrounding the core, the core comprising greater than 85% by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a water solubility greater than 100 mg / mL, the weight percentage being based on the total weight of the core, and the functional coating comprising a plasticizer.

[0349] Aspect 2A. The pharmaceutical granulation of Aspect 1A, wherein the pharmaceutical granulation comprises 50% to 90% by weight of the active pharmaceutical ingredient, the weight percentage being based on the total weight of the pharmaceutical granulation.

[0350] Aspect 3A. The pharmaceutical granulation of Aspect 1A or 2A, wherein the functional coating comprises a controlled release coating.

[0351] Aspect 4A. The pharmaceutical granulation of any one of Aspects 1A-3A, wherein the functional coating comprises 60% to 85% by weight of matrix polymer, the weight percentage being based on the total weight of the functional coating.

[0352] Embodiment 5A. The pharmaceutical granulation of embodiment 4A, wherein the matrix polymer comprises a water insoluble polymer.

[0353] Aspect 6A. The pharmaceutical granulation of Aspect 5A, wherein the water-insoluble polymer comprises ethyl cellulose.

[0354] Aspect 7A. The pharmaceutical granulation of any one of Aspects 1A-6A, wherein the functional coating comprises 0.5% to 20% by weight of the water soluble polymer, the weight percentage being based on the total weight of the matrix polymer.

[0355] Aspect 8A. The pharmaceutical granulation of Aspect 7A, wherein the water soluble polymer comprises hydroxypropyl cellulose.

[0356] Aspect 9A. The pharmaceutical granulation of any one of Aspects 4A-8A, wherein the matrix polymer comprises 92% to 98% by weight of the water insoluble polymer, and 2% to 8% by weight of the water soluble polymer, the weight percentages being based on the total weight of the matrix polymer.

[0357] Aspect 10A. The pharmaceutical granulation of any one of Aspects 1A-9A, wherein the functional coating comprises 3% to 13% by weight of a plasticizer, the weight percentage being based on the total weight of the functional coating.

[0358] Embodiment 11A. The pharmaceutical granulation of Embodiment 10A, wherein the plasticizer comprises dibutyl sebacate.

[0359] Aspect 12A. The pharmaceutical granulation of any one of Aspects 1A-11A, wherein the functional coating comprises 10% to 20% by weight of an antistatic agent, the weight percentage being based on the total weight of the functional coating.

[0360] Aspect 13A. The pharmaceutical granulation of Aspect 12A, wherein the antistatic agent comprises talc.

[0361] Aspect 14A. The pharmaceutical granulation of any one of Aspects 1A-13A, wherein the functional coating comprises 60% to 85% by weight of a matrix polymer, 10% to 20% by weight of an antistatic agent, and 3% to 13% by weight of a plasticizer, the weight percentages being based on the total weight of the functional coating.

[0362] Aspect 15A. A pharmaceutical granulation according to any one of Aspects 1A to 14A, wherein the coated granule comprises 55% to 90% by weight of the core and 10% to 45% by weight of the functional coating, the weight percentages being based on the total weight of the coated granule.

[0363] Embodiment 16A. A pharmaceutical granulation according to any one of embodiments 1A to 15A, wherein the functional coating has a thickness of 5 μm to 30 μm.

[0364] Aspect 17A. The pharmaceutical granule of any one of Aspects 1A-16A, wherein the pharmaceutical granule has a moisture content of less than 1% by weight, the weight % being based on the total weight of the pharmaceutical granule.

[0365] Embodiment 18A. The pharmaceutical granulation of any one of embodiments 1A-17A, wherein the coated granule comprises a seal coating surrounding a core, and the functional coating surrounds the seal coating.

[0366] Aspect 19A. The pharmaceutical granulation of Aspect 18A, wherein the seal coating comprises hydroxypropyl cellulose.

[0367] Aspect 20A. The pharmaceutical granulation of Aspect 18A or 19A, wherein the coated granule comprises 2% to 15% by weight of a seal coating, the weight percentage being based on the total weight of the granule.

[0368] Embodiment 21A. A pharmaceutical granulation according to any one of embodiments 18A to 20A, wherein the seal coating has a thickness of 0.5 μm to 5 μm.

[0369] Aspect 22A. A pharmaceutical granulation according to any one of Aspects 1A-21A, wherein the active pharmaceutical ingredient has a water solubility of greater than 100 mg / mL.

[0370] Aspect 23A. A pharmaceutical granulation according to any one of Aspects 1A to 21A, wherein the active pharmaceutical ingredient has a water solubility of 100 mg / mL to 1,000 mg / mL.

[0371] Aspect 24A. The pharmaceutical granulation of any one of Aspects 1A-23A, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharma-ceutically acceptable salt thereof.

[0372] Aspect 25A. The pharmaceutical granulation of any one of Aspects 1A-23A, wherein the active pharmaceutical ingredient comprises a derivative of gamma-hydroxybutyric acid or a pharma-ceutically acceptable salt thereof.

[0373] Aspect 26A. The active pharmaceutical ingredient is a compound of formula (2): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But hydrogen and C 1-6 alkyl, R 2 and R 3 Each of these is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, and C 3-6 The pharmaceutical granulation of any one of Aspects 1A-23A, wherein the aryl group is independently selected from cycloalkoxycarbonyl.

[0374] Aspect 27A. The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing, and The pharmaceutical granulation according to any one of Aspects 1A to 23A, selected from any combination of the foregoing.

[0375] Aspect 28A. The pharmaceutical granulation of any one of Aspects 1A-23A, wherein the active pharmaceutical ingredient comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharma- ceutically acceptable salt thereof: [ka]

[0376] Aspect 29A. A pharmaceutical granulation according to any one of Aspects 1A to 28A, wherein the coated granules are characterized by a particle size distribution (PSD) (D50) of 150 μm to 500 μm, the particle size distribution being determined by laser diffraction.

[0377] Aspect 30A. The pharmaceutical granulation of any one of Aspects 1A to 29A, wherein 35% to 85% of the active pharmaceutical ingredient is released from the pharmaceutical granulation within 2 hours 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.

[0378] Aspect 31A. The pharmaceutical granulation of any one of Aspects 1A to 30A, wherein 70% to 95% of the active pharmaceutical ingredient is released from the pharmaceutical granulation within 4 hours 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.

[0379] Aspect 32A. The pharmaceutical granule according to any one of Aspects 1A to 31A, wherein 80% to 100% of the pharmaceutical active ingredient is released from the pharmaceutical granule within 6 hours when tested in a USP Type 2 dissolution apparatus at a temperature of 37°C and a paddle speed of 75 rpm in a buffer solution at pH 4.5.

[0380] Aspect 33A. A pharmaceutical composition comprising the pharmaceutical granule according to any one of Aspects 1A to 32A.

[0381] Aspect 34A. The pharmaceutical composition according to Aspect 33A, wherein the pharmaceutical composition is an oral formulation.

[0382] Aspect 35A. The pharmaceutical composition according to Aspect 34A, wherein the oral formulation comprises an oral suspension.

[0383] Aspect 36A. The pharmaceutical composition according to any one of Aspects 31A to 35A, wherein the pharmaceutical composition is a controlled release portion, and the controlled release portion comprises a controlled release portion containing the pharmaceutical granule and an immediate release portion, a sustained release portion, or a combination thereof.

[0384] Aspect 37A. The pharmaceutical composition according to any one of Aspects 3A1 to 36A, wherein the immediate release portion comprises immediate release granules, the immediate release granules comprise a seal coating surrounding a core, and the core comprises more than 85% by weight of the pharmaceutical active ingredient.

[0385] Aspect 38A. The pharmaceutical composition according to any one of Aspects 31A to 37A, wherein the pharmaceutical composition is a BID formulation.

[0386] Aspect 39A. The pharmaceutical composition according to any one of Aspects 31A to 38A, wherein the pharmaceutical composition is a QD formulation.

[0387] Aspect 40A. The pharmaceutical composition according to any one of Aspects 31A to 39A, wherein the pharmaceutical composition comprises 500 mg equivalent to 12 g equivalent of γ-hydroxybutyric acid.

[0388] Aspect 41A. The pharmaceutical composition of any one of Aspects 31A-39A, wherein the active pharmaceutical ingredient comprises gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof, a derivative of gamma-hydroxybutyric acid or a pharma- ceutically acceptable salt thereof, a compound of formula (2) or a pharma- ceutically acceptable salt thereof, or a combination of any of the foregoing.

[0389] Aspect 42A. The active pharmaceutical ingredient is 4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid, 4-(glycyloxy)butanoic acid, 4-((D-valyl)oxy)butanoic acid, 4-((L-alanyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid, 4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid, 4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid, 4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid, 4-((L-valyl)oxy)butanoic acid, A pharma- ceutically acceptable salt of any of the foregoing; or A pharmaceutical composition according to any one of aspects 31A to 39A, comprising any combination of the foregoing.

[0390] Aspect 43A. A pharmaceutical composition according to any one of aspects 31A-39A, wherein the active pharmaceutical ingredient comprises 4-((L-valyl)oxy)butanoic acid (2a) or a pharma- ceutically acceptable salt thereof: [ka]

[0391] Aspect 44A. The pharmaceutical composition of any one of Aspects 40A-42A, wherein the pharmaceutical composition comprises a therapeutically effective amount of an active pharmaceutical ingredient for treating excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0392] Aspect 45A. A method of providing a therapeutically effective amount of gamma-hydroxybutyric acid in the systemic circulation of a patient to treat a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount for treating the disease of a pharmaceutical composition described in any one of aspects 40A-43A.

[0393] Aspect 46A. A method of treating a disease in a patient, the disease being known to be treated by administering gamma-hydroxybutyric acid, comprising administering to a patient in need of such treatment a therapeutically effective amount for treating the disease of a pharmaceutical composition described in any one of aspects 40 to 43A.

[0394] Aspect 47A. The method of aspect 45A or 46A, wherein the pharmaceutical composition, after administration to a patient, provides a therapeutically effective amount of gamma-hydroxybutyric acid in the patient's systemic circulation to treat the disease.

[0395] Embodiment 48A. The method of any one of embodiments 45A to 47A, wherein administering comprises oral administration.

[0396] Aspect 49A. The method of any one of aspects 45A-48A, wherein the disease is selected from excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, and fibromyalgia.

[0397] Aspect 50A. A method of coating a pharmaceutical granulation comprising applying a coating composition to a pharmaceutical granulation comprising a plurality of granules, the coating composition comprising 4% to 12% by weight solids, greater than 10% by weight water, and 75% to 92% by weight ethanol, the weight percentages being based on a total weight of the coating composition, and the granules comprising a core comprising 90% or more by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a water solubility greater than 100 mg / mL, the weight percentages being based on a total weight of the core.

[0398] Embodiment 51A. The method of embodiment 50A, wherein the solid comprises 3% to 13% by weight of the plasticizer, the weight percentage being based on the total weight of the solid.

[0399] Embodiment 5A1. The method of embodiment 49A or 50A, comprising: 60% to 85% by weight of a matrix polymer; and 10% to 20% by weight of an antistatic agent, where the weight percentages are based on the total weight of solids.

[0400] Embodiment 52A. The method of any one of embodiments 49A-51A, wherein the granule comprises a seal coating surrounding a core.

[0401] Embodiment 53A. The method of any one of embodiments 49A-52A, wherein applying comprises spraying.

[0402] Embodiment 54A. The method of any one of embodiments 49A-53A, wherein the method includes drying the applied coating composition. EXAMPLES

[0403] Embodiments provided by the present disclosure are further illustrated with reference to the following examples, which describe uncoated pharmaceutical granules, uncoated pharmaceutical particles, coated pharmaceutical granules, coated pharmaceutical particles, oral controlled-release pharmaceutical compositions, and methods for making the coated pharmaceutical granules and particles provided by the present disclosure. It will be apparent to those skilled in the art that many changes can be made to both the materials and methods without departing from the scope of the present disclosure.

[0404] Example 1 Granules of pharmaceutical active ingredient Granules of pharmaceutical active ingredient were prepared as described in Examples 7-9 of U.S. Patent Application No. 17 / 350,478.

[0405] The pharmaceutical active ingredient used to prepare the pharmaceutical granules was the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, which had a purity of 99.3%.

[0406] The pharmaceutical active ingredient with a bulk density of 0.263 g / mL was passed through a Comil® equipped with a 0.056-inch screen. The pharmaceutical active ingredient was stored in a dry environment before simultaneous milling.

[0407] The components of the dry mixture were, in weight percent, 98.5% pharmaceutical active ingredient, 0.5% binder, and 1% anti-static agent.

[0408] Distilled water (4.7 wt%) was added to the dry mixture using a two-fluid spray nozzle with the pump and spray air set to 4 psi.

[0409] The granules were held in a 4-liter jacketed bowl throughout the process.

[0410] Wet granulation was carried out for 9.7 minutes at a mixer speed of 850 rpm and a chopper speed of 3,600 rpm.

[0411] The wet granulation was wet massed for up to 60 minutes with a mixer speed of 547 rpm and a chopper speed of 1,800 rpm while the temperature of the wet granulation was maintained at 23.1° C. to 23.6° C. A cooler was attached to the intestine to maintain a temperature below 25° C. during wet massing.

[0412] The granulation was characterized by a bulk density of granules between 0.68 g / mL and 0.714 g / mL and a friability of about 1.02%.

[0413] Uncoated pharmaceutical granules having a granule size of 200 μm to 425 μm were used to prepare the coated pharmaceutical granules described in the examples.

[0414] Example 2 Coated granules (2) The components of the functional coating formulation are shown in Table 1. [Table 1]

[0415] The granulation was coated with the functional coatings listed in Table 1 using a Wurster column inserted in the fluidized bed. The coating conditions are shown in Figure 21. The functional coatings were applied to achieve 10% wg or 20% wg.

[0416] The dissolution profile of the granulations was determined using a USP Type 2 dissolution apparatus at a buffer solution of pH 4.5, a temperature of 37° C. and a paddle speed of 75 rpm. The dissolution profile is shown in Figure 1. The designation 20% wg(1) and 20% wg(2) refers to two separate experiments using granulations with a 20% wg coating.

[0417] Example 3 Coated granules (3) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0418] The components of the functional coating formulation are shown in Table 2. [Table 2]

[0419] The granulation was coated with the functional coatings listed in Table 2 using a Wurster column inserted into the fluidized bed. The coating conditions are shown in Figure 21. The functional coatings were applied to achieve 10% wg or 20% wg. Static charge buildup increased during the coating process and agglomerates began to form at approximately 10% wg.

[0420] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus at a temperature of 37° C. and a paddle speed of 75 rpm in a buffer solution of pH 4.5. The dissolution profile is shown in Figure 2. The designation 20% wg(1) and 20% wg(2) refers to two separate experiments using granulations with a 20% wg coating.

[0421] Example 4 Coated granules (4) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0422] The components of the functional coating formulation are shown in Table 3. [Table 3]

[0423] The granulation was coated with the functional coatings listed in Table 3 using a Wurster column inserted in the fluidized bed. The coating conditions are shown in Figure 21. The functional coatings were applied to achieve a granulation with 20% wg. Static charge build-up increased during the coating process.

[0424] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus at a temperature of 37° C. and a paddle speed of 75 rpm in a buffer solution of pH 4.5. The dissolution profile is shown in Figure 3. The designation 30% wg(1) and 30% wg(2) refers to two separate experiments using granulations with a 30% wg coating.

[0425] Example 5 Coated granules (5) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0426] The components of the functional coating formulation are shown in Table 4. [Table 4]

[0427] In this coating formulation, the ratio of ethyl cellulose (insoluble) to hydroxypropyl cellulose (soluble) was increased to 95:5 wt / wt to extend the release time without increasing the %wg, and the talc content was increased from 20% to 30% by weight of the polymer to reduce static buildup.

[0428] The granulation was coated with the functional coatings listed in Table 4 using a Wurster column inserted in the fluidized bed. The coating conditions are shown in Figure 21. The functional coatings were applied to achieve granulations with 20% wg and 30% wg.

[0429] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus at a temperature of 37° C. and a paddle speed of 75 rpm in a buffer solution of pH 4.5. The dissolution profile is shown in Figure 4. The designation 30% wg(1) and 30% wg(2) refers to two separate experiments using granulations with a 30% wg coating.

[0430] The dissolution profiles of the granules with ethyl cellulose / hydroxypropyl cellulose (EC / HPC) functional coatings of Examples 2 and 4 are compared in FIG.

[0431] Example 6 Coated granules(6) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0432] The components of the functional coating formulation are shown in Table 5. [Table 5]

[0433] In this coating formulation, the talc content was set at 20% of the polymer and the water content was increased to 12% by weight of the solvent.

[0434] The granulation was coated with the functional coatings listed in Table 5 using a Wurster column inserted in the fluidized bed. The coating conditions are shown in Figure 21. The functional coatings were applied to achieve granulations with 20% wg, 25% wg, and 35% wg. Significant agglomeration was evident.

[0435] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 75 rpm. The dissolution profile is shown in FIG.

[0436] Example 7 Coated granules(7) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0437] The components of the functional coating formulation are shown in Table 6. [Table 6]

[0438] In this coating formulation, the talc content was set at 20% of the polymer and the water content was 10% by weight of the solvent.

[0439] The granulation was coated with the functional coatings listed in Table 6 using a Wurster column inserted into the fluidized bed. Coating conditions are shown in Figure 21. The spray rate was reduced and the surrounding air was humidified to avoid over-humidification. The functional coatings were applied to achieve granulations with 20% wg, 30% wg, and 35% wg. Minimal agglomeration was present. SEM images of the granulations with 35% wg functional coating are shown in Figures 7A-7C at magnifications of 27x, 110x, and 1000x, respectively.

[0440] The moisture content of the uncoated granules was 1.24% by weight and for the coated granules it was 0.23% by weight.

[0441] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 75 rpm. The dissolution profile is shown in FIG.

[0442] Example 8 Coated granules(8) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0443] In this coating formulation and process, conditions were similar to Example 6, except the batch size was increased from 425 g to 500 g.

[0444] The components of the functional coating formulation are shown in Table 7. [Table 7]

[0445] The granulation was coated with the functional coating described in Table 7 using a Wurster column inserted in the fluidized bed. The coating conditions are shown in Figure 21. The functional coating was applied to achieve granulations with 20% wg, 30% wg, and 35% wg. There was minimal clumping. SEM images of the granulation with 35% wg functional coating are shown in Figures 9A-9C at magnifications of 27x, 110x, and 340x, respectively.

[0446] The moisture content of the wet uncoated granulation was 2.42 wt%, the moisture content of the dried uncoated granulation was 0.21 wt%, and the moisture content of the 35% wg coated granulation was 0.25 wt%.

[0447] The dissolution profile of the granulation was determined using 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 dissolution profile is shown in FIG.

[0448] The particle size distribution of the granules with a 35% wg coating is shown in FIG.

[0449] Example 9 Coated granules(9) A granulation was used containing granules having 98.5% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by a granule size of 200 μm to 425 μm.

[0450] In this example, the granulation was first coated with a hydroxypropyl cellulose seal coat followed by the functional coating. The seal coat was applied at 5% wg and the components of the seal coat formulation are shown in Table 8. [Table 8]

[0451] The processing conditions for applying the seal coat are shown in FIG. 21(9A).

[0452] The components of the functional coating formulation are shown in Table 9. [Table 9]

[0453] The granules were coated with the functional coatings listed in Table 9 using a Wurster column inserted in the fluidized bed. The application conditions for the functional coatings are shown in Figure 21 (9B). The functional coatings were applied to achieve granules with 20% wg, 30% wg, and 35% wg. Minimal clumping was present. SEM images of the granules with 30% wg functional coating are shown in Figures 12A-12C at magnifications of 50x, 130x, and 500x, respectively. SEM images of the granules with 35% wg functional coating are shown in Figures 13A-13C at magnifications of 27x, 110x, and 340x, respectively.

[0454] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus at a buffer solution of pH 4.5, a temperature of 37° C. and a paddle speed of 75 rpm. The dissolution profile is shown in FIG.

[0455] The particle size distributions of the granules with 35% wg coating of Examples 7, 8, and 9 are compared in FIG.

[0456] The dissolution profiles for granules with 20% wg, 30% wg, and 35% wg functional coatings of Examples 7, 8, and 9, respectively, are compared in Figures 16-18.

[0457] Example 10 Coated granules (10) A granulation was used containing granules having 90.0% by weight of the compound of formula (2a), 4-((L-valyl)oxy)butanoic acid, characterized by a particle size of 225 μm to 400 μm. Uncoated granulations containing 4-((L-valyl)oxy)butanoic acid were prepared using MicroPX® micropelletization technology (Glatt GmbH). [Table 10]

[0458] The components of the functional coating formulation are shown in Table 11. [Table 11]

[0459] The granulation was coated with the functional coatings listed in Table 11 using a Wurster column inserted in the fluidized bed. The application conditions for the functional coatings are listed in Table 12. [Table 12]

[0460] The functional coating was applied to achieve coated granulations with 20% wg, 25% wg, and 30% wg of functional coating.

[0461] The coated granulation with 20% wg functional coating had a bulk density of 0.629 g / mL. Particle size distribution as shown in Table 13. [Table 13]

[0462] In the coated pharmaceutical granulation, 12.9% of the coated granules can have a particle size less than 300 μm, 83.8% of the coated granules can have a particle size between 300 μm and 600 μm, and 3.3% of the coated granules can have a particle size between 600 μm and 1190 μm.

[0463] The dissolution profile of the granulation was determined using a USP Type 2 dissolution apparatus at a buffer solution of pH 4.5, a temperature of 37° C. and a paddle speed of 75 rpm. The dissolution profile is shown in FIG.

[0464] Example 11 Water-based, seal-coated granules of 4-((L-valyl)oxy)butanoic acid A seal coated granulation was prepared by spray coating an uncoated granulation of 4-((L-valyl)oxy)butanoic acid granules.

[0465] Uncoated granules containing 4-((L-valyl)oxy)butanoic acid were prepared using MicroPX® micropelletization technology (Glatt GmbH). The uncoated granules had a mean particle size (D50) of 225 μm to 275 μm.

[0466] The composition used to provide the seal coat contained 14.2% by weight hydroxypropyl methylcellulose (Pharmacoat® 603), 2.1% by weight talc, and 85.6% by weight water, the weight percentages being based on the total weight of the seal coat composition.

[0467] The composition was spray coated onto the uncoated granulation to give a seal coat having a thickness of 2.23 (+ / - 0.34) μm.

[0468] Example 12 Acetone-based seal-coated granulation of 4-((L-valyl)oxy)butanoic acid Uncoated granules of 4-((L-valyl)oxy)butanoic acid were spray-coated to prepare sealed-coated granules.

[0469] Uncoated granules containing 4-((L-valyl)oxy)butanoic acid were prepared using the MicroPX® micro-pelletization technology (Glatt GmbH). The uncoated granules had an average particle size (D50) of 225 μm to 275 μm.

[0470] The composition used to provide the seal coat contained 5.4 wt% hydroxypropyl cellulose (Klucel® EF), 2.1 wt% talc, and 92.5 wt% acetone, where wt% is based on the total weight of the seal coat composition.

[0471] The composition was spray-coated onto the uncoated granules to obtain a seal coating having a thickness of 1.30 (+ / -0.27) μm.

[0472] It should be noted that there are alternative ways to implement the embodiments disclosed herein. Accordingly, this embodiment should be regarded as illustrative and not restrictive. Further, the claims are not limited to the details given herein, but have the full scope thereof and equivalents thereof.

Claims

1. 1. A pharmaceutical granulation comprising a plurality of coated granules, The coated granule comprises a core and a controlled release coating surrounding the core, The core is 90% to 99.5% by weight of a compound of formula (2a): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The weight percentages are based on the total weight of the core; and The controlled release coating comprises: 60% to 85% by weight of a matrix polymer, 92% to 98% by weight of ethyl cellulose, and Contains 2% to 8% by weight of hydroxypropyl cellulose; the matrix polymer, wherein the weight percentages are based on the total weight of the matrix polymer; 10% to 20% by weight of talc, and containing 3% to 13% by weight of dibutyl sebacate; the weight percentages are based on the total weight of the controlled release coating; and A pharmaceutical granulation, wherein said coated granules are characterized by a particle size distribution (PSD) (D50) of 150 μm to 500 μm, said particle size distribution being determined by laser diffraction.

2. 2. The pharmaceutical granule of claim 1, wherein the coated granule comprises 50% to 95% by weight of the compound of formula (2a), the weight percentage being based on the total weight of the coated granule.

3. The core is an average sphericity of greater than 0.90, wherein said average sphericity is determined by dynamic image analysis; and / or A friability value of less than 2% by weight, wherein the friability is determined using sonic sieving; The pharmaceutical granule according to claim 1, characterized in that

4. the core has a bulk density of 0.5 g / mL to 1.0 g / mL; and / or The pharmaceutical granulation has a bulk density of 0.55 g / mL to 0.80 g / mL; 2. The medical granulation of claim 1, wherein the bulk density is determined using a bulk density cylinder.

5. The coated granules are 55% to 90% by weight of said core, and 10% to 45% by weight of said controlled release coating; 2. The pharmaceutical granule of claim 1, wherein the weight percentage is based on the total weight of the coated granule.

6. A pharmaceutical composition comprising the pharmaceutical granule of claim 1.

7. 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises 500 mg equivalent to 12 g equivalent of gamma-hydroxybutyric acid.

8. The pharmaceutical composition comprises: a controlled release portion, the controlled release portion comprising the pharmaceutical granulation; and 7. The pharmaceutical composition of claim 6, comprising an immediate release portion, a sustained release portion, or a combination thereof.

9. 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises an oral formulation comprising a suspension of pharmaceutical granulation.

10. 10. A pharmaceutical granule according to claim 1 or a pharmaceutical composition according to claim 6 for treating a disease in a patient, wherein the disease is selected from excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, and fibromyalgia.

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