Composition of bile acid and phenylbutyric acid compound

Abstract

To provide a composition containing phenylbutyric acid compound and bile acid, and a method for processing the composition.SOLUTION: A composition contains: (a) approximately 15% to approximately 45w / w% of phenylbutyric acid compound; (b) approximately 5% to approximately 15w / w% of bile acid; (c) approximately 8% to approximately 24w / w% of dextrate; (d) approximately 1% to approximately 6w / w% of sugar alcohol; and (e) approximately 22% to approximately 35% of maltodextrin, where a weight ratio between the phenylbutyric acid compound and the bile acid is approximately 3:1.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 16 / 940,102, filed July 27, 2020, U.S. Provisional Patent Application No. 62 / 948,756, filed December 16, 2019, and U.S. Provisional Patent Application No. 63 / 030,793, filed May 27, 2020, all of which are incorporated herein by reference in their entirety.

[0002] Technical Field FIELD OF THE INVENTION The present invention relates generally to pharmaceutical compositions and methods for making same. [Background technology]

[0003] The flow properties of powders and other bulk solids are an important consideration in the manufacture of pharmaceutical compositions. In addition, particle size distribution also affects downstream processing and packaging of pharmaceutical products. Some drug substances have poor flow properties, and there is a need for improved pharmaceutical compositions with improved physical properties, including improved flow properties. Summary of the Invention

[0004] The present invention relates to compositions comprising phenylbutyric acid compounds and bile acids, as well as methods of processing the compositions disclosed herein.

[0005] In one aspect, the present specification provides a composition comprising: (a) about 15% to about 45% by weight of a phenylbutyric acid compound; (b) about 5% to about 15% by weight of a bile acid; (c) about 8% to about 24% by weight of a dextrate; (d) about 1% to about 6% by weight of a sugar alcohol; and (e) about 22% to about 35% by weight of a maltodextrin, wherein the weight ratio of the phenylbutyric acid compound to the bile acid is about 3:1. In some embodiments, the composition comprises about 8% to about 12% by weight of the bile acid. In some embodiments, the bile acid is a hydrophilic bile acid. In some embodiments, the bile acid is selected from the group consisting of taurursodiol (TURSO, also known as tauroursodeoxycholic acid (TUDCA)), ursodeoxycholic acid (UDCA), chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, lithocholic acid, and glycoursodeoxycholic acid. In some embodiments, the bile acid is TURSO. In some embodiments, the composition comprises about 9.7% by weight of TURSO. In some embodiments, the composition comprises about 25% to about 35% by weight of a phenylbutyric acid compound. In some embodiments, the phenylbutyrate compound is selected from the group consisting of 4-phenylbutyric acid (4-PBA), glycerol tri-(4-phenylbutyrate), phenylacetic acid, 2-(4-methoxyphenoxy)acetic acid (2-POAA-OMe), 2-(4-nitrophenoxy)acetic acid (2-POAA-NO), and 2-(2-naphthyloxy)acetic acid (2-NOAA), and pharmaceutically acceptable salts thereof. In some embodiments, the phenylbutyrate compound is a pharmaceutically acceptable salt of 4-PBA. In some embodiments, the pharmaceutically acceptable salt of 4-PBA is sodium phenylbutyrate. In some embodiments, the composition comprises about 29.2 w / w% sodium phenylbutyrate. In some embodiments, the composition comprises about 10% to about 20 w / w% dextrates. In some embodiments, the composition comprises about 15.6 w / w% dextrates. In some embodiments, the composition comprises about 2% to about 5% w / w of a sugar alcohol. In some embodiments, the sugar alcohol is selected from the group consisting of sorbitol, xylitol, and mannitol. In some embodiments, the sugar alcohol is sorbitol. In some embodiments, the composition comprises about 3.9% w / w of sorbitol.In some embodiments, the composition comprises about 25% to about 32% w / w of maltodextrin. In some embodiments, the maltodextrin is pea maltodextrin. In some embodiments, the composition further comprises sucralose. In some embodiments, the composition comprises about 0.5% to about 5% w / w of sucralose. In some embodiments, the composition comprises about 1% to about 3% w / w of sucralose. In some embodiments, the composition further comprises one or more flavoring agents. In some embodiments, the composition comprises about 2% to about 15% w / w of one or more flavoring agents. In some embodiments, the composition comprises about 5% to about 10% w / w of a flavoring agent.

[0006] In some embodiments, the composition further comprises about 0.05% to about 2 wt.% porous silica. In some embodiments, the composition comprises about 0.05% to about 1.5 wt.% porous silica. In some embodiments, the porous silica has a higher HO adsorption capacity at about 20% or higher humidity than fumed silica. In some embodiments, the porous silica has a higher HO adsorption capacity at about 90% or higher humidity than fumed silica. In some embodiments, the porous silica has a moisture absorption capacity of about 50% humidity of about 5% to about 40% by weight. In some embodiments, the porous silica has a moisture absorption capacity of about 50% humidity of about 30% to about 40% by weight. In some embodiments, the porous silica has a higher porosity at about 20% or higher humidity than fumed silica. In some embodiments, the porous silica has a higher porosity at about 90% or higher humidity than fumed silica. In some embodiments, the porous silica has an average pore volume of about 0.1 cc / gm to about 2.0 cc / gm. In some embodiments, the porous silica has an average pore volume of about 0.2 to about 0.8 cc / gm. In some embodiments, the porous silica has a bulk density of about 100 g / L to about 600 g / L. In some embodiments, the porous silica has a bulk density of about 400 g / L to about 600 g / L.

[0007] In some embodiments, the composition further comprises about 0.5% to about 5% w / w of a buffering agent. In some embodiments, the buffering agent is sodium phosphate. In some embodiments, the sodium phosphate is dibasic sodium phosphate. In some embodiments, the composition comprises about 2.7% w / w of dibasic sodium phosphate. In some embodiments, the composition further comprises about 0.05% to about 1% w / w of one or more lubricants. In some embodiments, the one or more lubricants are selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, polyethylene glycol, glyceryl behenate, and hydrogenated oils. In some embodiments, the one or more lubricants is sodium stearyl fumarate. In some embodiments, the composition comprises about 0.5% w / w of sodium stearyl fumarate.

[0008] In some embodiments, the composition has a Carr index of about 25 or less. In some embodiments, the composition has a Carr index of about 20 or less. In some embodiments, the composition has a Carr index of about 12 or less.

[0009] In some aspects, provided herein is a composition comprising about 29.2 w / w% sodium phenylbutyrate, about 9.7 w / w% TURSO, about 15.6 w / w% dextrates, about 3.9 w / w% sorbitol, about 1.9 w / w% sucralose, about 28.3 w / w% maltodextrin, about 7.3 w / w% flavorings, about 0.1 w / w% silicon dioxide, about 2.7 w / w% sodium phosphate, and about 0.5 w / w% sodium stearyl fumarate.

[0010] In another aspect, provided herein is a method of processing a composition, the method comprising: (i) roller-compacting a preblend composition comprising sodium phenylbutyrate and TURSO in a weight ratio of about 3:1 to form a compressed preblend; and (ii) granulating the compressed preblend to form granules having a Carr index of about 12 or less. In some embodiments, the preblend composition comprises about 15% to about 45% w / w of sodium phenylbutyrate and about 5% to about 15% w / w of TURSO. In some embodiments, the method further comprises, prior to step (i), blending a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form a preblend composition. In some embodiments, the blending time for the first and second compositions is 1 hour or less. In some embodiments, the blending time for the first and second compositions is 30 minutes or less. In some embodiments, the blending speed for the first and second compositions is about 10 rpm to about 20 rpm. In some embodiments, the speed is about 15 rpm. In some embodiments, step (i) comprises roller compacting the preblend composition at a compaction force of about 5 kN / cm to about 15 kN / cm. In some embodiments, the compaction force is about 8 kN / cm to about 12 kN / cm. In some embodiments, the compaction force is about 10 kN / cm.

[0011] In some embodiments of the methods described herein, step (i) comprises roller compacting the preblend composition between at least two rotating rolls having a gap width of about 1 mm to about 5 mm. In some embodiments, the gap width is about 2 mm to about 3 mm. In some embodiments, step (i) comprises roller compacting the preblend composition between at least two rotating rolls having a roll speed of about 4 rpm to about 12 rpm. Step (i) comprises roller compacting the preblend composition at about 10°C to about 30°C. In some embodiments, the method comprises cooling the preblend composition to about 12°C to about 18°C.

[0012] In some embodiments of the methods described herein, step (ii) comprises granulating the compressed preblend using a granulating screen having a diameter of about 0.8 mm to about 2 mm. In some embodiments, the diameter is about 1.5 mm. In some embodiments, the method comprises sieving the first and second compositions prior to blending them. In some embodiments, the bulk density of the granules is about 0.2 g / mL to about 1.0 g / mL. In some embodiments, the bulk density is about 0.5 g / mL to about 0.7 g / mL. In some embodiments, the tapped density of the granules is about 0.5 g / mL to about 1.2 g / mL. In some embodiments, the tapped density is about 0.7 g / mL to about 0.9 g / mL. In some embodiments, the Carr index of the granules is about 10 or less. In some embodiments, the dissolution time to release about 75% of the TURSO in the granules is about 0.5 to about 15 minutes. In some embodiments, the dissolution time to release about 75% of the TURSO in the granules is about 0.5 to about 5 minutes. In some embodiments, the dissolution time to release about 75% of the sodium phenylbutyrate in the granules is about 0.5 to about 15 minutes. In some embodiments, the dissolution time to release about 75% of the sodium phenylbutyrate in the granules is about 0.5 to about 5 minutes.

[0013] In some embodiments of the methods described herein, the composition further comprises about 8% to about 24% (w / w) dextrates, about 1% to about 6% (w / w) sugar alcohol, and about 22% to about 35% (w / w) maltodextrin. In some embodiments, the composition comprises about 29.2% (w / w) sodium phenylbutyrate, about 9.7% (w / w) TURSO, about 15.6% (w / w) dextrates, about 3.9% (w / w) sorbitol, about 1.9% (w / w) sucralose, about 28.3% (w / w) maltodextrin, about 7.3% (w / w) flavorings, about 0.1% (w / w) silicon dioxide, about 2.7% (w / w) sodium phosphate, and about 0.5% (w / w) sodium stearyl fumarate.

[0014] Unless otherwise defined, all terms, notations, and other scientific or technical terms used herein are intended to have the meanings commonly understood by one of ordinary skill in the art to which this application pertains. In some cases, for clarity and / or ready reference, terms with commonly understood meanings are defined herein, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference with respect to what is generally understood in the art.

[0015] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range, to one decimal place of the unit of the lower limit, unless the context clearly dictates otherwise, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. When the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0016] Ranges are presented herein with numerical values ​​preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as numbers that are near or approximately the number it precedes. In determining whether a number is near or approximately a specifically recited number, the near or approximately unrecited number may be a number that, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0017] It will be understood that certain features of the present disclosure that are described, for clarity, in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present disclosure that are described in the context of a single embodiment may also be provided separately or in any suitable subcombination. All combinations of the embodiments belonging to the present disclosure are specifically encompassed by this disclosure and are disclosed herein just as if each and every combination were individually and explicitly disclosed herein. In addition, all subcombinations of the various embodiments and elements thereof are also specifically encompassed by this disclosure and are disclosed herein just as if each and every such subcombination were individually and explicitly disclosed herein.

[0018] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated in their entirety. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows the particle size distribution of sodium phenylbutyrate and TURSO. [Figure 2] FIG. 2 is a DVS isotherm plot of the adsorption and desorption of sodium phenylbutyrate. [Figure 3] Figure 3 shows the DVS isotherm plot of the adsorption and desorption of TURSO. [Figure 4] FIG. 4 is a DVS isothermal plot showing the adsorption and desorption of the active blend. [Figure 5] FIG. 5 shows the particle size distribution of blends with different silica systems. [Figure 6] FIG. 6 shows the location of the 16 quart V-shell where the blend uniformity samples were taken. [Figure 7] Figure 7 shows the particle size distribution of the various samples after pre-blending. [Figure 8] Figure 8 shows the particle size distribution of various samples after granulation with a screen size of 1.0 mm. [Figure 9] Figure 9 shows the particle size distribution of various samples after granulation with a screen size of 1.5 mm. [Figure 10] Figure 10 shows the particle size distribution of various samples after granulation with a screen size of 2.0 mm. [Figure 11] FIG. 11 shows a combination of the results of FIGS. [Figure 12] FIG. 12 shows the dissolution profiles of various sub-batches of TUDCA. [Figure 13] FIG. 13 shows the dissolution profiles of various sub-batches of sodium phenylbutyrate. [Figure 14] FIG. 14 shows the locations where blend uniformity samples were taken for final blending analysis. [Figure 15] Figure 15 shows the particle size distribution of the preblend for the placebo batch. [Figure 16] Figure 16 shows the particle size distribution of the compressed granules of the placebo batch. DETAILED DESCRIPTION OF THE INVENTION

[0020] Drug substances, such as bile acids and phenylbutyric acid compounds, can have poor flow properties that affect downstream processing, including, among other things, blending, scale-up, and packaging of powdered pharmaceuticals. Agglomeration of powder materials can also affect content uniformity and downstream processing. The present invention provides formulations containing bile acids and phenylbutyric acid compounds, and methods for producing the same, with improved flow properties, uniformity, stability, and reduced agglomeration of the final granules. Accordingly, the present invention provides a composition comprising: (a) about 15% to about 45% by weight of a phenylbutyric acid compound (e.g., any of the phenylbutyric acid compounds described herein or known in the art); (b) about 5% to about 15% by weight of a bile acid (e.g., any of the bile acids described herein or known in the art); (c) about 8% to about 24% by weight of a dextrate (e.g., any of the dextrates described herein or known in the art); (d) about 1% to about 6% by weight of a sugar alcohol (e.g., any of the sugar alcohols described herein or known in the art); and (e) about 22% to about 35% by weight of maltodextrin, wherein the weight ratio of the phenylbutyric acid compound to the bile acid is about 3:1. The compositions of the present invention may have a Carr index of about 25 or less, about 20 or less, or about 12 or less. In some embodiments of the compositions described herein, the compositions are water-soluble.

[0021] The manufacturing methods provided herein are based in part on a dry granulation process. The inventors have discovered a method for processing a composition that results in improved flow characteristics and stability compared to the active pharmaceutical composition alone. Accordingly, the present disclosure provides a method for processing a composition, the method comprising: (i) roller-compacting a preblend composition comprising sodium phenylbutyrate and TURSO in a weight ratio of about 3:1 to form a compressed preblend; and (ii) granulating the compressed preblend to form granules having a Carr index of about 12 or less. The methods described herein may also include, prior to step (i), blending a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form a preblend composition.

[0022] Carr index In some embodiments of the compositions described herein, the Carr index of the composition is about 25 or less. For example, the Carr index of the composition may be about 21 to about 25 (e.g., about 22, 23, or 24), about 16 to about 20 (e.g., about 17, 18, or 19), about 11 to about 15 (e.g., about 12, 13, or 14), or about 10 or less (e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1). In some embodiments, the Carr index of the composition is about 26 to about 31 (e.g., about 27, 28, 29, or 30), about 32 to about 37 (e.g., about 32, 33, 34, 35, or 36), or greater than about 38.

[0023] The Carr index (or Carr compressibility index) of a composition can indicate the compressibility (or tendency of a composition to be compressed) and flowability of a material. In some cases, the Carr index is related to the bulk density and tapped density of a material. Bulk density is a property of materials, such as powders and granules, and can be measured by dividing the mass of particles in the material by the total volume occupied. The total volume may include particle volume, interparticle void volume, and / or internal pore volume. For powder materials, bulk density can be determined by both the density of the particles and the spatial arrangement of the particles in the powder. Tapped density is usually the increase in bulk density reached after a specified compression process, such as mechanically tapping or vibrating a container containing the material.

[0024] The bulk density and tapped density of a composition containing a powder or granules can be measured by methods known in the art. For example, the bulk density of a powder can be the ratio between the mass and volume of an untapped sample. The bulk density of a powder can also be determined by measuring the volume of a powder sample of known weight, which may have passed through a sieve into a container (e.g., a graduated cylinder), or by measuring the mass of a powder of known volume passed through a volumetric meter into a container. Tapped density can be obtained, for example, by mechanically tapping a container (e.g., a measuring cylinder or vessel) containing the sample. The Carr index of a material can be calculated, for example, by: Formula C=100(1-pB / pT) (C represents the Carr index, pB represents the bulk density, and pT represents the tapped density) Additional methods for determining the Carr index of a material can be found, for example, in ASTM-D6393, Standard test method for bulk solids characterization by Carr indices, J. ASTM Int. 04.09 (2014); and RE Riley, HH Hausner, Effect of particle size distribution on the friction in a powder mass, Int. J. Powder Metall. 6 (1970) 17-22.

[0025] The Carr index can indicate the flowability of a material. For example, a high Carr index (large difference between bulk density and tapped density) can be associated with poor flowability. The Hausner ratio, or the ratio of tapped density to bulk density, expressed as H=pT / pB, can also be related to the flowability of a material.

[0026] Additional flow indices for measuring the flowability of a material, such as the angle of repose, are also contemplated in this invention. The angle of repose of a granular material can be represented by the steepest slope of unconstrained material measured from a horizontal plane onto which the material can be piled without collapsing (see, e.g., Mehta et al. Prog. Phys. 57 (1994) 383-416). A representative method for measuring the angle of repose of a material can be found, for example, in Beakawi et al., Powder Technology 330 (2018) 397-417. For powders that can be defined as small granular materials depending on their cohesion and suspension in gas, the definition of the angle of repose can be related to the Hausner ratio (see, e.g., Beddow Part. Part. Syst. Charact. 12 (4): 213, 1995), where the powder can flow at angles greater than the angle of repose. The angle of repose can also indicate the cohesiveness of a granular material, with reference to the Carr classification of flowability, as follows:

[0027] [Table A]

[0028] bile acids The present invention provides a composition comprising about 5% to about 15% w / w (e.g., about 6% to about 14%, about 7% to about 13%, about 8% to about 12%, about 8% to about 11%, about 9% to about 10%, or about 9.7% w / w) of a bile acid. The bile acid described herein can include naturally occurring surfactants having a nucleus derived from cholanic acid, typically substituted at the C6, C7, or C12 position of the sterol nucleus with a 3α-hydroxyl group, and optionally with other hydroxyl groups. Suitable bile acids include, but are not limited to, taurursodiol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (also referred to as "chenodiol" or "cheno acid"), cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, cholic acid, or analogs, derivatives, or prodrugs thereof. In some embodiments, the bile acid is a hydrophilic bile acid, including, but not limited to, TURSO, UDCA, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, lithocholic acid, and glycoursodeoxycholic acid. Pharmaceutically acceptable salts or solvates of the bile acids described herein are also contemplated. Bile acid derivatives are also contemplated, including, but not limited to, derivatives formed at the hydroxyl and carboxylic acid groups of bile acids with other functional groups, such as halogens and amino groups. TURSO and taursodeoxycholic acid (TUDCA) are used interchangeably herein.

[0029] Bile acids described herein can be TURSOs as shown in Formula I (with labeled carbons to aid in understanding where substitutions may be made).

[0030] [ka]

[0031] The compositions described herein can include about 5% to about 15% w / w (e.g., within this range) of TURSO. In some embodiments, the compositions include about 9.7% TURSO. The Carr index for TURSO of the compositions described herein can be about 22 to about 26 (e.g., about 23, 24, or 25).

[0032] The bile acid described herein can be UDCA, as shown in Formula II (with labeled carbons to aid in understanding where substitutions may be made).

[0033] [ka]

[0034] Physiologically relevant bile acid derivatives, such as compounds having any combination of hydrogen substitution at the 3- or 7-position in the TURSO or UDCA formula and / or a shift in the stereochemistry of the hydroxyl group at the 3- or 7-position, are suitable for use in the compositions of the present invention.

[0035] Any amino acid conjugate of a bile acid, or a pharmaceutically acceptable salt thereof, described herein or known in the art is also suitable for the presently described compositions. The amino acid in the conjugate can be, but is not limited to, taurine, glycine, glutamine, asparagine, methionine, or carbocysteine. For example, included in the present invention is a compound of formula III:

[0036] [ka]

[0037] wherein R is —H or C1-C4 alkyl, R1 is —CH2—SO3R3, and R2 is —H; or R1 is —COOH, R2 is -CH2-CH2-CONH2, -CH2-CONH2, -CH2-CH2-SCH3 or -CH2-S-CH2-COOH, and R3 is -H or a residue of a basic amino acid. or a pharmaceutically acceptable salt, analog, derivative, prodrug or mixture thereof.

[0038] Phenylbutyric acid compounds The present invention provides a composition comprising about 15% to about 45% w / w (e.g., about 20% to about 40%, about 25% to about 35%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w / w) of a phenylbutyric acid compound. The phenylbutyric acid compound described herein includes phenylbutyric acid (a low molecular weight aromatic carboxylic acid) as the free acid (4-phenylbutyrate (4-PBA), 4-phenylbutyric acid, or phenylbutyric acid), as well as pharmaceutically acceptable salts, cocrystals, polymorphs, hydrates, solvates, conjugates, derivatives, or prodrugs thereof. The phenylbutyrate compounds described herein also include analogs of 4-PBA, including, but not limited to, glycerol tri-(4-phenylbutyrate), phenylacetic acid (the active metabolite of 4-PBA), 2-(4-methoxyphenoxy)acetic acid (2-POAA-OMe), 2-(4-nitrophenoxy)acetic acid (2-POAA-NO), and 2-(2-naphthyloxy)acetic acid (2-NOAA), as well as pharmaceutically acceptable salts thereof. Structures of 4-PBA analogs can be found, for example, in Zhang et al., Br J Pharmacol 2013 Oct; 170(4): 822-834. Phenylbutyrate compounds also include physiologically relevant 4-PBA species, including, but not limited to, any substitution of hydrogen with deuterium in the 4-PBA structure. Physiologically acceptable salts of 4-PBA include, for example, sodium, potassium, magnesium, and calcium salts.

[0039] In some embodiments, the present invention provides compositions comprising about 15% to about 45% w / w (e.g., within this range) sodium phenylbutyrate. In some embodiments, the compositions comprise about 29.2% sodium phenylbutyrate. The sodium phenylbutyrate of the compositions described herein may have a Carr index of about 35 or greater (e.g., about 36, 37, 38, 39, or 40 or greater). Sodium phenylbutyrate has the following structure:

[0040] [ka]

[0041] It has.

[0042] In some cases, a combination of a bile acid (e.g., TURSO) and a phenylbutyric acid compound (e.g., sodium phenylbutyrate) has synergistic efficacy when administered to a subject to treat one or more symptoms associated with a neurodegenerative disease. Representative neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), Parkinson's disease, Huntington's disease, stroke, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies, mixed dementia, and frontotemporal dementia. The combination of a bile acid and a phenylbutyric acid compound can induce a mathematically synergistic increase in neuronal viability in a strong oxidative injury model (hydrogen peroxide-mediated toxicity) as determined by linear modeling, for example. Such combination therapies are disclosed in U.S. Patent Nos. 9,872,865 and 10,251,896.

[0043] In some embodiments, the weight ratio of the phenylbutyric acid compound to the bile acid in the compositions provided herein is about 1:1 to about 4:1 (e.g., 2:1 or 3:1). In some embodiments, the weight ratio of the phenylbutyric acid compound to the bile acid in the compositions provided herein is about 3:1.

[0044] Dextrate Some embodiments of the compositions described herein include about 8% to about 24% w / w (e.g., about 9% to about 23%, about 10% to about 22%, about 10% to about 20%, about 11% to about 21%, about 12% to about 20%, about 13% to about 19%, about 14% to about 18%, about 14% to about 17%, about 15% to about 16%, or about 15.6 w / w%) dextrates. Anhydrous and hydrated dextrates are contemplated herein. Dextrates of the present invention can include a mixture of sugars developed from the controlled enzymatic hydrolysis of starch. Some embodiments of the compositions described herein include hydrated dextrates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra).

[0045] sugar alcohols Some embodiments of the compositions described herein contain about 1% to about 6% w / w (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w / w) of a sugar alcohol. Sugar alcohols can be derived from sugars and can contain one hydroxyl group (—OH) attached to each carbon atom. Disaccharides and monosaccharides can form sugar alcohols. Sugar alcohols can be natural or can be produced by hydrogenation of sugars. Representative sugar alcohols include, but are not limited to, sorbitol, xylitol, and mannitol. In some embodiments, the compositions contain about 1% to about 6% w / w (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w / w) of sorbitol.

[0046] Maltodextrin Some embodiments of the compositions described herein comprise about 22% to about 35% w / w (e.g., about 22% to about 33%, about 24% to about 31%, about 25% to about 32%, about 26% to about 30%, or about 28% to about 29% w / w, e.g., about 28.3% w / w) maltodextrin. Maltodextrin forms a flexible helix that, when solubilized in solution, allows for encapsulation of an active ingredient (e.g., any of the phenylbutyric acid compounds and bile acids described herein), thereby masking the taste of the active ingredient. Maltodextrins produced from suitable sources, including, but not limited to, pea, rice, tapioca, corn, and potato, are contemplated herein. In some embodiments, the maltodextrin is pea maltodextrin. In some embodiments, the composition comprises about 28.3% w / w pea maltodextrin. For example, pea maltodextrin obtained from Rockete (KLEPTOSE® LINECAPS) can be used.

[0047] Sucralose Some embodiments of the compositions described herein further comprise sucralose. In some embodiments, the compositions described herein comprise about 0.5% to about 5% w / w (e.g., about 1% to about 4%, about 1% to about 3%, or about 1% to about 2%, e.g., about 1.9% w / w) sucralose. Other sugar substitutes contemplated herein include, but are not limited to, aspartame, neotame, acesulfame potassium, saccharin, and advantame.

[0048] Flavoring agents Some embodiments of the compositions described herein further comprise one or more flavoring agents. In some embodiments, the compositions described herein comprise about 2% to about 15% w / w (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w / w) of a flavoring agent. Flavoring agents can include substances that impart the flavor of another substance or affect its taste, thereby altering the characteristics of the composition. Flavoring agents can be used to mask unpleasant flavors without affecting physical and chemical stability and can be selected based on the taste of the drug to be incorporated. Suitable flavoring agents include, but are not limited to, natural flavoring agents, artificial flavoring agents, and imitation flavors. In some embodiments, a blend of flavoring agents is used. For example, the compositions described herein can include two or more flavoring agents (e.g., two, three, four, five, or more). The flavoring agents described herein can be soluble and stable in water. The selection of a suitable flavoring agent can be based on taste testing. For example, multiple different flavoring agents can be added separately to the composition and taste tested. Exemplary flavoring agents include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, raspberry, cherry, or mixed berry flavor powder). In some embodiments, any of the compositions described herein contains about 0.5% to about 1.5 wt. / wt. % (e.g., about 1 wt. / wt. %) mixed berry flavor powder. In some embodiments, the compositions described herein contain about 5% to about 7 wt. / wt. % (e.g., about 6.3 wt. / wt. %) masking flavor. Suitable masking flavors can be obtained, for example, from Firmenich.

[0049] silica Some embodiments of the compositions provided herein further comprise silicon dioxide (or silica). The addition of silica to a composition can prevent or reduce aggregation of the composition's components. Silica can serve as an anti-caking agent, adsorbent, disintegrant, or glidant. In some embodiments, the compositions described herein comprise about 0.05% to about 2 wt. % (e.g., about 0.05% to about 1.5%, about 0.07% to about 1.2%, or about 0.08% to about 0.1%, e.g., 0.09 wt. %) of porous silica. The porous silica can have a higher HO absorption capacity and / or a higher porosity than fumed silica, for example, at humidity levels of about 20% or higher (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher). In some embodiments, the porous silica has a moisture absorption capacity of about 5% to about 40% by weight (e.g., about 20% to about 40% or about 30% to about 40%) at about 50% humidity. The porous silica can have a higher porosity than fumed silica at humidity levels of about 20% or higher (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher). In some embodiments, the porous silica has an average particle size of about 2 μm to about 10 μm (e.g., about 3 μm to about 9 μm, about 4 μm to about 8 μm, about 5 μm to about 8 μm, or about 7.5 μm). In some embodiments, the porous silica has an average pore volume of about 0.1 cc / gm to about 2.0 cc / gm (e.g., about 0.1 cc / gm to about 1.5 cc / gm, about 0.1 cc / gm to about 1 cc / gm, about 0.2 cc / gm to about 0.8 cc / gm, about 0.3 cc / gm to about 0.6 cc / gm, or about 0.4 cc / gm). In some embodiments, the porous silica has a bulk density of about 50 g / L to about 700 g / L (e.g., about 100 g / L to about 600 g / L, about 200 g / L to about 600 g / L, about 400 g / L to about 600 g / L, about 500 g / L to about 600 g / L, about 540 g / L to about 580 g / L, or about 560 g / L). In some embodiments, the compositions described herein include about 0.05% to about 2% w / w (eg, any subrange within this range) of Syloid® 63FP (WR Grace).

[0050] Buffers and lubricants Some embodiments of the compositions described herein further comprise one or more buffering agents. In some embodiments, the compositions comprise about 0.5% to about 5% w / w (e.g., about 1% to about 4%, about 1.5% to about 3.5%, or about 2% to about 3%, e.g., about 2.7% w / w) of a buffering agent. The buffering agent can comprise a weak acid or base that maintains the acidity or pH of the composition at or near a selected value after the addition of another acid or base. Suitable buffering agents are known in the art. In some embodiments, the buffering agent in the compositions provided herein is a phosphate, such as sodium phosphate (e.g., dibasic sodium phosphate anhydrous). For example, the composition can comprise about 2.7% w / w of dibasic sodium phosphate.

[0051] Some embodiments of the compositions described herein further comprise one or more lubricants. In some embodiments, the composition comprises about 0.05% to about 1 w / w% (e.g., about 0.1% to about 0.9%, about 0.2% to about 0.8%, about 0.3% to about 0.7%, or about 0.4% to about 0.6%, e.g., about 0.5 w / w%) of a lubricant. Representative lubricants include, but are not limited to, sodium stearyl fumarate, magnesium stearate, stearic acid, metal stearates, talc, high melting temperature waxes and glycerides, colloidal silica, polyethylene glycol, alkyl sulfates, glyceryl behenate, and hydrogenated oils. Additional lubricants are known in the art. In some embodiments, the composition comprises about 0.05% to about 1 w / w% (e.g., a range within this range) of sodium stearyl fumarate. For example, the composition may comprise about 0.5 w / w% of sodium stearyl fumarate.

[0052] Additional suitable sweeteners or flavoring agents may also be included in the compositions described herein, such as, but not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, steviol glycosides, partially hydrolyzed starch, and corn syrup solids. Water-soluble artificial sweeteners, such as soluble saccharin salts (e.g., sodium or calcium saccharin salts), cyclamates, acesulfame potassium (acesulfame K), and the free acid forms of saccharin and aspartame-based sweeteners, such as L-aspartyl-phenylalanine methyl ester, Alitame®, or Neotame®, are contemplated herein. The amount of sweetener or flavoring agent may vary depending on the desired amount of sweetener or flavoring agent selected for a particular final composition.

[0053] In addition to those mentioned above, pharmaceutically acceptable binders are also contemplated for the compositions described herein. Examples include cellulose derivatives, including microcrystalline cellulose and low-substituted hydroxypropyl cellulose (e.g., LH22, LH21, LH20, LH32, LH31, and LH30); starches, including potato starch; croscarmellose sodium (i.e., cross-linked carboxymethylcellulose sodium salt; e.g., Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g., Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, and Polyplasdone® XL-10); and sodium carboxymethyl starch (e.g., Primogel® and Explotab®).

[0054] Additional fillers, diluents or binders, such as polyols, sucrose, sorbitol, mannitol, Erythritol®, Tagatose®, lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floc®), microcrystalline cellulose (e.g. various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka-Floc®), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted) (e.g., L-HPC-CH31, L-HPC-LH11, LH22, LH21, LH20, LH32, LH31, LH30), dextrins, maltodextrins (e.g., Lodex® 5 and Lodex® 10), starch or modified starch (including potato starch, corn starch, and rice starch), sodium chloride, sodium phosphate, calcium sulfate, and calcium carbonate may also be incorporated.

[0055] Pharmaceutical Composition Any of the compositions described herein can be formulated as or for use in a pharmaceutical composition. Such compositions can be formulated or adapted for administration to a subject via any route, e.g., a route approved by the Food and Drug Administration (FDA), including, but not limited to, oral, parenteral, or transdermal delivery. Exemplary methods are described in the FDA's CDER Data Standards Manual, Version 004 (available at fda.give / cder / dsm / DRG / drg00301.html).

[0056] In some embodiments, the compositions described herein are used to treat or prevent one or more symptoms associated with a neurodegenerative disease in a subject in need thereof, including, but not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), Parkinson's disease, Huntington's disease, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies, mixed dementia, and frontotemporal dementia.

[0057] Any of the compositions described herein may be formulated as a pharmaceutical composition further comprising one or more additional therapeutic agents. Exemplary additional therapeutic agents include riluzole (C8H5F3N2OS, sold under the trade names Rilutek® and Tiglutik®), edaravone (sold under the trade names Radicava® and Radicut®), mexiletine (sold under the trade names Mexitil and NaMuscla), a combination of dextromethorphan and quinidine (Nuedexta®), anticholinergics, and psychiatric medications, including, but not limited to, antidepressants, antipsychotics, anxiolytic / hypnotics, mood stabilizers, and stimulants. Known anticholinergic agents are contemplated by the present invention, including, but not limited to, glycopyrrolate, scopolamine, atropine (Atropene), belladonna alkaloids, benztropine mesylate (Cogentin), clidinium, cyclopentolate (Cyclodyl), darifenacin (Enablex), dicylomine, fesoterodine (Tobias), flavoxate (Ulyspas), glycopyrrolate, homatropine hydrobromide, hyoscyamine (Revcinex), ipratropium (Atrovent), orphenadrine, oxybutynin (Ditropan XL), propantheline (Probansain), scopolamine, methscopolamine, solifenacin (Vesicare), tiotropium (Spiriva), tolterodine (Detrol), trihexyphenidyl, trospium, and diphenhydramine (Benadryl). Known antidepressants, including but not limited to selective serotonin inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators and stimulators, serotonin antagonists and reuptake inhibitors, norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors, and NMDA receptor antagonists, are contemplated as additional therapeutic agents herein.

[0058] The pharmaceutical compositions described herein may further comprise any pharmaceutically acceptable carrier, adjuvant, and / or vehicle. A pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient and is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the active compound without destroying its pharmacological activity. Representative pharmaceutically acceptable carriers include saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents, which are compatible with pharmaceutical administration. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral, as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0059] Any of the therapeutic compositions disclosed herein may be formulated for sale in, import into, and / or export from the United States. The pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration. In some aspects, the present invention provides kits comprising a bile acid and a phenylbutyric acid compound. The kit may also include instructions for the physician and / or patient, syringes, needles, boxes, bottles, vials, etc.

[0060] Dosage and Administration Pharmaceutical compositions are typically formulated to be compatible with their intended route of administration, examples of which include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., via inhalation or feeding tube), transdermal (topical), transmucosal, and rectal administration.

[0061] The pharmaceutical compositions may be in the form of solutions or powders for inhalation and / or nasal administration. Such compositions may be formulated by techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media.

[0062] Pharmaceutical compositions can be orally administered in any orally acceptable dosage form, including, but not limited to, powders, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase containing an emulsifying and / or suspending agent. If desired, a coloring agent may be added. Aqueous formulations can be prepared by reconstituting a solid formulation in an aqueous solvent (e.g., water, saline solution). As used herein, the term "aqueous solvent" refers to a liquid containing at least 50% water (e.g., at least 60%, 70%, 80%, 90%, or at least 95%). In some embodiments, the aqueous solvent is water.

[0063] Alternatively, or additionally, pharmaceutical compositions may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0064] In some embodiments, any of the compositions described herein is substantially dissolved in water prior to oral administration to a subject. The compositions of the present invention can be administered to a subject in need thereof once a day, twice a day, or three or more times a day.

[0065] In some embodiments, the bile acid (e.g., TURSO) of the composition is administered in an amount of about 0.5 to about 5 g per day (e.g., about 0.5 to about 4.5, about 0.5 to about 3.5, about 1 to about 3, e.g., about 2 g). In some embodiments, the bile acid is TURSO and is administered in an amount of about 2 g per day, e.g., 1 g administered twice daily. In some embodiments, the bile acid is administered at about 10 mg / kg to about 50 mg / kg of the subject's body weight (e.g., about 10 mg / kg to about 40 mg / kg, about 10 mg / kg to about 30 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, or about 13 mg / kg to about 15 mg / kg).

[0066] In some embodiments, the phenylbutyrate compound (e.g., sodium phenylbutyrate) of the composition is administered in an amount of about 0.5 to about 10 g per day (e.g., about 1 to about 10, about 2 to about 9, about 3 to about 8, about 5 to about 7, e.g., about 6 g). In some embodiments, the bile acid is sodium phenylbutyrate and is administered in an amount of about 6 g per day, e.g., 3 g administered twice daily. In some embodiments, the phenylbutyrate compound is administered at about 10 mg / kg to about 400 mg / kg of the subject's body weight (e.g., about 10 mg / kg to about 300 mg / kg, about 10 mg / kg to about 200 mg / kg, about 10 mg / kg to about 100 mg / kg, about 10 mg / kg to about 80 mg / kg, about 30 mg / kg to about 80 mg / kg, or about 30 mg / kg to about 50 mg / kg).

[0067] In some embodiments, the composition is administered once daily or twice daily, each administration containing about 1 g of TURSO and about 3 g of sodium phenylbutyrate. In some embodiments, the composition is administered once daily, each administration containing about 2 g of TURSO and about 6 g of sodium phenylbutyrate.

[0068] The composition can be administered to a subject in need thereof for at least about 6 months (e.g., at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 16, 18, 20, 21, 22, 23, or 24 months). In some embodiments, the composition is administered to a subject in need thereof for less than about 6 months (e.g., less than about 5, 4, 3, 2, or 1 month).

[0069] Processing method The present invention also relates to a method of processing or manufacturing a pharmaceutical formulation based on dry granulation. Provided herein is a method of processing a composition, comprising: (i) roller compacting a preblend composition comprising sodium phenylbutyrate and TURSO in a weight ratio of about 3:1 to form a compressed preblend; and (ii) granulating the compressed preblend to form granules having a Carr index of about 12 or less.

[0070] The preblend composition can include about 15% to about 45% w / w (e.g., a range within this range) sodium phenylbutyrate and about 5% to about 15% w / w (e.g., a range within this range) TURSO.

[0071] Some embodiments of the methods of processing the compositions described herein further include, prior to step (i), blending a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form a preblend composition.

[0072] The step of sieving the first composition comprising sodium phenylbutyrate and the second composition comprising TURSO may be carried out prior to blending, and such a step may be carried out using conventional sieving means known to those skilled in the art.

[0073] The first and second compositions may be blended for about 1 hour or less (e.g., about 55, 50, 45, 40, 35, 30, or 25 minutes or less) and / or at a blending speed of about 10 rpm to about 20 rpm (e.g., about 12 rpm to about 18 rpm, about 14 to about 16, e.g., about 15 rpm). The blending time and blending speed can be adjusted to achieve an essentially homogeneous mixture of the components. The blending speed can be either fixed or adjusted during blending. In some embodiments, blending the first and second compositions for about 30 minutes or less (e.g., about 29, 28, 27, or 26 minutes or less, e.g., about 25 minutes or about 15 minutes) results in less particle attrition and is more desirable than blending the compositions for more than 30 minutes. Suitable blending equipment and parameters are known in the art. Any equipment commonly utilized in the pharmaceutical industry for uniformly blending two or more components can be used, including, for example, V-shaped blenders, double cone blenders, bin (container) blenders, and rotary drum blenders. The capacity of the blender can be 50 L, 100 L, 200 L, 250 L, or more. Before, during, or after blending, the composition may be milled at a suitable milling speed. Suitable milling equipment and parameters are known in the art.

[0074] The term "roller compacting" refers to the process of forcing and compressing a powder between two counter-rotating rolls into a solid compacted body or ribbon. Roller compaction can be performed using any suitable roller compactor known to those skilled in the art. For example, a MACRO-PACTOR® or MINI-PACTOR® manufactured by Gerteis can be used. Granulating the solid compacted body or ribbon into granules involves crushing / sieving the compacted body or ribbon to the desired granule size and can be performed by a roller compactor that integrates roller compaction and crushing functions, or can be performed in separate equipment. "Granulation" and "crushing" are used interchangeably herein and can refer to the process of breaking a solid material into small pieces, for example, by grinding, crushing, or cutting.

[0075] A roller compactor can generally consist of three main units: a feed system that conveys the powder to the compaction area between the rolls; a compaction unit that applies force to compress the powder into a ribbon between two counter-rotating rolls; and a size reduction unit that breaks the ribbon down to a desired particle size.

[0076] Several operating parameters, including compaction force, gap width, and granulation screen size, can be adjusted / controlled to modify the product granules. Compaction force is measured in kN / cm, which refers to the force per cm of roll width. Gap width refers to the width of the gap between the two rotating rollers. As the gap width increases, a given force applied by the rollers must be transmitted through a thicker ribbon of powder; therefore, the ribbon may have lower strength, likely resulting in smaller, weaker granules after the milling process. Additional descriptions of roller compaction processing variables can be found, for example, in Freeman et al., Asian Journal of Pharmaceutical Sciences 11:516-527, 2016.

[0077] The compression force used in step (i) can be about 5 kN / cm to about 15 kN / cm (e.g., about 7 kN / cm to about 13 kN / cm, about 8 kN / cm to about 12 kN / cm, or about 9 kN / cm to about 11 kN / cm, e.g., about 10 kN / cm). In some embodiments of the methods described herein, step (i) can include roller compacting the preblend composition between at least two rotating rolls having a gap width of about 1 mm to about 5 mm, about 2 mm to about 4 mm, or about 2 mm to about 3 mm. The roll speed of the rotating rolls can be about 4 rpm to about 12 rpm (e.g., about 5, 6, 7, 8, 9, 10, or 11 rpm). The roller compaction can be carried out at a temperature that prevents the composition from melting or agglomerating. For example, the preblend composition can be roller compacted at about 10°C to about 30°C (e.g., about 12°C to about 30°C, about 12°C to about 20°C, or about 12°C to about 18°C, about 15°C to about 25°C, about 20°C to about 30°C, or about 24°C to about 29°C). A cooling unit set at about 10°C to about 20°C (e.g., about 12°C to about 18°C, or about 13°C to about 17°C) can be added to the roller compactor for this purpose. The rotating rolls can be, for example, about 10°C to about 30°C (e.g., any subrange within this range).

[0078] In some embodiments of the methods described herein, step (ii) includes granulating the compressed preblend to form granules. A granulating screen having a diameter of about 0.8 mm to about 2 mm (e.g., about 1 mm to about 1.8 mm, about 1.2 mm to about 1.7 mm, about 1.4 mm to about 1.6 mm, or, for example, about 1.5 mm) can be used. The method can also include sieving the granules through at least one suitable mesh size.

[0079] The method described herein may further comprise a final blending step after step (ii), which may include blending the granules for up to 10 minutes or up to 5 minutes.

[0080] The bulk density of the granules produced by the method of the present invention may be about 0.2 g / mL to about 1.0 g / mL (e.g., about 0.2 g / mL to about 0.9 g / mL, about 0.3 g / mL to about 0.8 g / mL, or about 0.5 g / mL to about 0.7 g / mL). The bulk density of the granules may be measured by methods known in the art, for example, by pouring the granules into a graduated cylinder of an appropriate size.

[0081] The tap density of the granules produced by the methods of the present invention may be from about 0.5 g / mL to about 1.2 g / mL, or from about 0.7 g / mL to about 0.9 g / mL. The tap density of the granules may be measured by methods known in the art, for example, using a tap volumeter in which the powder is compressed using 100 taps until the volume change is less than 5%.

[0082] The granules produced by the methods described herein can have improved flowability (e.g., as reflected by Carr index, Hausner ratio, angle of repose, or bulk and / or tapped density) compared to the preblend composition of step (i). The granules can also have improved flowability compared to the first composition comprising sodium phenylbutyrate and / or the second composition comprising TURSO. In some embodiments, the Carr index of the granules produced by the methods of the present invention is about 12 or less (e.g., about 1 to 12, e.g., about 11, 10, 9, 8, 7, 6, or about 5). The processing methods described herein can result in a decrease of at least about 3 (e.g., at least about 4, 5, 6, 7, 8, or 10) in the Carr index of the granules formed in step (ii) compared to the Carr index of the preblend composition from step (i).

[0083] In some embodiments of the methods of processing the compositions provided herein, the dissolution time to release about 75% of the TURSO in the granules formed in step (iii) is about 0.5 to about 15 minutes (e.g., about 0.5 to about 10 minutes, about 0.5 to about 8 minutes, or about 0.5 to about 5 minutes). In some embodiments, the dissolution time to release about 75% of the sodium phenylbutyrate in the granules formed in step (iii) is about 0.5 to about 15 minutes (e.g., about 0.5 to about 10 minutes, about 0.5 to about 8 minutes, or about 0.5 to about 5 minutes). The dissolution time of a compound may be determined by methods known in the art.

[0084] In some embodiments of the methods of processing the compositions provided herein, the composition further comprises about 8% to about 24% w / w (e.g., a range within this range) dextrates, about 1% to about 6% w / w (e.g., a range within this range) sugar alcohol (e.g., a sugar alcohol described herein or known in the art, e.g., sorbitol), and about 22% to about 35% w / w (e.g., a range within this range) maltodextrin. The composition may further comprise about 0.5% to about 5 w / w% (e.g., a range within this range) sucralose, about 2% to about 15 w / w% (e.g., a range within this range) of one or more flavoring agents, about 0.05% to about 2 w / w% (e.g., a range within this range) of porous silica, about 0.5% to about 5 w / w% (e.g., a range within this range) of a buffering agent (e.g., a buffering agent described herein or known in the art, e.g., sodium phosphate), and / or about 0.05% to about 1 w / w% (e.g., a range within this range) of one or more lubricants (e.g., a lubricating agent described herein or known in the art, e.g., sodium stearyl fumarate). [Example]

[0085] Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not intended to limit the scope of the invention or the claims in any way.

[0086] Example 1 Flow optimization by varying the type of sorbitol, dextrates, and sodium phosphate The following experiments were conducted to develop and optimize the formulation and associated processes for producing the final drug product containing the two active pharmaceutical ingredients (APIs, in this application, TURSO and NaPB) and a taste-blind placebo. Formulation development included optimizing blend flow characteristics with various excipients, taste masking of the active and placebo blends, and moisture control with excipients and processing techniques. Using the same methodology, a placebo formulation was developed to mimic the appearance and taste of the active drug product.

[0087] These APIs have poor flowability, which increases the difficulty of automation when scaled up. Therefore, flowability was optimized by blending the API with excipients that have good flowability for two purposes: improving blend flow for manufacturing and masking the taste of the API.

[0088] Materials and Equipment

[0089] [Table 1]

[0090] [Table 2]

[0091] [Table 3]

[0092] result Formulations A, B, and C containing varying amounts of sorbitol and dextrates were prepared and then subjected to the following analyses:

[0093] Particle size distribution The sample blends were analyzed using a WSTyler RX86 sieve shaker equipped with 60, 80, 100, 140, 200, 325, or 400 mesh screens. Ten grams of each API was placed on the top sieve and shaken for 5 minutes, after which the amount of API collected in each sieve was measured and recorded. The particle size distributions for NaPB and TURSO are shown in Figure 1.

[0094] Hausner ratio and Carr index For each API and blend, bulk density was calculated by gently pouring the powder into a 25 mL graduated cylinder. Tapped density was calculated using a tap volumeter, compressing the powder with 100 taps until the volume change was less than 5%. The bulk and tapped densities were then used to calculate the Hausner ratio and Carr index. The Carr indexes for API and Formulations A-C are shown in Table 4. Formulation C was selected based on its flowability. In addition to being a measure of compressibility, the Carr index may also be used to determine the flow properties of a material. A higher Carr index (a larger difference between bulk density and tapped density) indicates that the material has stronger intermolecular forces that reduce flowability. Acceptable flow properties (determined by the packaging equipment used) are a minimum Carr index below 25, with a Carr index below 20 being preferred.

[0095] [Table 4]

[0096] angle of repose The flowability of Formulation C was measured using the angle of repose, which was determined by dropping the powder from a funnel of a certain height onto a flat surface. The angle of repose was calculated from the radius of the bottom of the stack and the height. The angle of repose of Formulation C was 31.1. For reference, the flowability corresponding to a specific range of angles of repose is shown in Table 5.

[0097] [Table 5]

[0098] Blend Agglomeration After approximately one week of storage in a sealed bottle, slight clumping was observed in the blend. Loss on Drying (LOD) testing of sorbitol and dextrates indicated that neither absorbed significant amounts of water, making them unlikely to cause clumping.

[0099] Prior to finalization of the formulation, the dibasic sodium phosphate in the formulation was changed from anhydrous to heptahydrate due to concerns that the anhydrous form was more hygroscopic than the heptahydrate form.

[0100] Selection of formulation The amounts of sorbitol and dextrates in Formulation C were chosen because of the significant improvement in flow properties as measured by angle of repose and Carr index.

[0101] Example 2: Taste masking optimization In order to produce a palatable dosage form that can be consumed by patients who may have motor impairments, the reconstitution powder was investigated with a variety of sweeteners and flavor masking.

[0102] material

[0103] [Table 6]

[0104] result Optimizing the amount of sucralose For taste masking, formulations C (formulations C1-C3) were prepared with varying amounts of sucralose. The compositions of formulations C1-C3 are shown in Table 7. Formulation C1 was selected based on its best taste masking performance.

[0105] [Table 7]

[0106] Flavor selection A bulk active blend was prepared and dissolved in approximately 250 mL of water per dosage unit. In addition to Kleptose Linecaps maltodextrin, several flavoring agents were added at various concentrations until the desired level of taste masking was achieved. Final flavor and sweetener concentrations were selected based on taste optimization.

[0107] Maltodextrin and updated formulations Formulation C1 was further modified by adjusting all other ingredients (except API) to achieve a formulation with approximately 10 g of total material after the addition of flavorings and maltodextrin. Additionally, the dibasic sodium phosphate in the formulation was changed from anhydrous to heptahydrate due to concerns that the anhydrous form was more hygroscopic than the heptahydrate form. The modified Formulation C1 is shown in Table 8.

[0108] [Table 8]

[0109] Notably, the flowability was still significantly better than that of the API, suggesting that the modification of this formulation was successful in improving flowability. The Carr index of the modified formulation C1 was 22.3, and the angle of repose was 34.4. For reference, Table 5 shows the flowability corresponding to a specific range of angle of repose, and Table 9 shows the flowability corresponding to a specific range of Carr index.

[0110] [Table 9]

[0111] result The addition of specific flavoring agents and maltodextrin, as well as the amount of sucralose, was tested to ensure optimal taste masking. Furthermore, the addition of these agents did not affect the flow improvement achieved in Example 1.

[0112] Example 3: Detection and prevention of aggregation Materials and Equipment

[0113] [Table 10]

[0114] [Table 11]

[0115] [Table 12]

[0116] result After storing the blend in a sealed 5 LBin Bohle blender for approximately 36 hours, clumping occurred, making the blend difficult to dispense. To prevent clumping and further improve blend stability, the clumped blend was manually removed and placed in a drying oven at 50°C for loss on drying (LOD) testing.

[0117] Loss on Drying (LOD) Test After drying at 50°C for approximately 2 hours, LOD testing was performed on the recovered agglomerated blend (PD2016-015-33B) to determine the extent of water uptake. The results were compared to the non-agglomerated blend (PD2016-015-29A) that had been stored in a sealed bottle. The results of the LOD testing are shown in Table 13.

[0118] [Table 13]

[0119] Dynamic Vapor Sorption (DVS) Test DVS testing of samples of NaPB, TURSO, and the modified formulation C1 blend was performed to determine the extent of weight gain with humidity. DVS isotherm plots for NaPB and TURSO are shown in Figures 2 and 3, respectively. NaPB exhibited significant mass fluctuations above 45% humidity. These mass changes were also reflected in the active blend (as shown in Figure 4) and were believed to contribute to the observed aggregation.

[0120] Effect of humidity on individual APIs and API combinations NaPB, TURSO and blends of both were stored in unstoppered vials at 25°C / 60% humidity for approximately 60 hours, after which the vials were removed and observed.

[0121] A blend containing two APIs experienced aggregation due to moisture uptake. The up to 50% variation in mass of NaPB and aggregation made processing and dosing difficult, as moisture uptake altered potency and the aggregated material limited its ability to blend and flow during processing. Since aggregation was observed only when both APIs were exposed to moisture, preventing moisture uptake or separating the APIs was necessary to reduce aggregation. The following experiments were performed with the goal of reducing aggregation.

[0122] Equalization and roller compaction Materials and Equipment

[0123] [Table 14]

[0124] [Table 15]

[0125] Equilibration API Equilibration: To test whether equilibration can prevent subsequent aggregation, the APIs were equilibrated to ambient conditions. Briefly, the APIs were spread on two separate trays and allowed to equilibrate. Samples were taken after 0, 1, 2, 3, 4, and 24 hours and sealed in headspace vials for analysis by Karl Fischer titration. This experiment was performed to determine the moisture uptake rate for each API and to determine whether aggregation of the pre-equilibrated APIs would be reduced due to reduced water uptake after blending.

[0126] Analysis of water content by Karl Fischer titration: Each sample was analyzed for water content by Karl Fischer titration. Equilibration was determined when the RSD between two consecutive time points was less than 10%.

[0127] Blending parameters: Each batch was blended for 20 minutes, milled, and then blended for an additional 20 minutes at 25 RPM. For milling, a Quadrocomill fitted with a corrugated 1016 conical mesh screen was operated at 30% power. Degranulated test sachets were filled.

[0128] Roller compaction Dry granulation by roller compaction of the active blend was carried out. The remaining blend was roller compacted at 7.5 and 10 kN. Test sachets for each granulation condition were filled to observe the behavior of the granulated and non-granulated samples within the package over time. Table 16 shows the roller compaction parameters used.

[0129] [Table 16]

[0130] The results of the equilibration experiments surprisingly demonstrated that equilibration had no significant effect on the moisture content of the API. All blends and granules agglomerated over time; however, the 10 kN granules had the least agglomeration and the highest recovery from the sachet, suggesting that roller compaction surprisingly provided a significant improvement in preventing agglomeration.

[0131] Example 4 Silica treatment to prevent aggregation Experiments were also conducted to determine whether aggregation was due to interactions between the two APIs and whether localized moisture control using porous silica could reduce aggregation. Tables 17 and 18 show the materials used for silica treatment of the APIs.

[0132] [Table 17]

[0133] [Table 18]

[0134] Each API was blended and roller-compacted separately from the excipients to determine whether the proximity of the two APIs in the blend or granules caused agglomeration. The resulting granules were then recombined and blended before being filled into test sachets. The bulk and tapped densities of each blend were measured before roller-compaction. All silicas were used at 1 w / w% in this experiment. Aerosil 200 was used as a negative control, while Syloid 244FP and Syloid 63FP were used to remove moisture from the API to determine whether the API would agglomerate due to localized moisture reduction. The flow properties of the blends are shown in Table 19.

[0135] [Table 19]

[0136] Particle size distribution Particle size distribution was used as a measure of agglomeration because agglomerated particles would not be able to pass through a fine sieve, resulting in a distribution biased towards larger particles. Sieve shaker analysis was performed for each test condition at T=7 days. The results are shown in Figure 5.

[0137] angle of repose The relative degree of agglomeration was determined for each condition by flowability, as assessed by the angle of repose. Agglomerated samples were expected to have reduced flowability, so a smaller angle of repose would likely result in less agglomeration and higher recovery of the final product from the package. Angle of repose measurements were made at T=4 for each test condition (Table 20).

[0138] [Table 20]

[0139] result Initially, when Aerosil 200, a form of silica, was used in the formulation, the angle of repose was 35.69. Substituting this material with syloid 63FP and roller compacting at a compaction force of 10 kN improved flowability by 11%. Surprisingly, a different syloid product, syloid 244FP, did not produce a similar improvement. As a result of these experiments, Aerosil 200 was replaced with syloid 63 FP and roller compaction was added to the process. Considering the detrimental effect of agglomeration on processing, an 11% improvement was a significant and surprising advance.

[0140] Example 5 Preparation of Stability / Tooling Batches for Active Formulation Active Formulation Blending and Roller Compaction: The materials and equipment used for active formulation blending and roller compaction are listed in Tables 21 and 22. Table 23 lists the active formulations.

[0141] [Table 21]

[0142] [Table 22]

[0143] [Table 23]

[0144] All materials were weighed, sieved (#30 mesh), layered into a 20 L blender bin, and blended at 25 RPM for 30 minutes. The blender contents were removed and milled using a QuadroCorMill equipped with a 1016 corrugated mesh conical screen operating at 30% speed. After milling, the blend was returned to the blender bin and blended at 25 RPM for an additional 30 minutes. During the final 30 minutes of blending, blend uniformity samples were taken at 10-minute intervals and analyzed for API content by HPLC. If the RSD was greater than 5% and the drug loading was within 90-110%, the blend was roller compacted using the parameters shown in Table 24. Under these parameters, the batch was successfully manufactured.

[0145] [Table 24]

[0146] Example 6 Further flavor optimization Although the flavor optimization in Example 2 substantially improved taste, a follow-up set of experiments was conducted to determine whether taste could be improved even further.

[0147] Additional flavoring agents New flavors were tested, including mango, strawberry, masking flavor, and mixed berry flavor. After additional taste testing, it was determined that the combination of masking flavor and mixed berry flavor was optimal for masking the taste of the API. The result was a substantial improvement over Formulation C1, which was developed early in formulation development.

[0148] Additional Sucralose After changing the flavoring agent, the amount of sucralose was further adjusted and taste testing was performed. The additional sucralose further improved / masked the taste of the API, and the amount of sucralose was revised to 200 mg per unit dose.

[0149] Formulation D Following the above changes, the formulation was changed to Formulation D (Table 25) which has improved taste characteristics.

[0150] [Table 25]

[0151] These results demonstrated that by varying the amount of sucralose and changing the flavoring, it was possible to exceed the taste masking provided by Formulation C1, a surprising improvement since Formulation C1 was considered optimal.

[0152] Example 7 Processing and Manufacturing Several processes, including preblending, compression, and final blending, were optimized. The blending duration in the preblending stage was optimized because it can affect blend uniformity and preblend properties for downstream compression. Specifically, three batches, CCZHB, CCZHC, and CCZHD, were tested at various blending times, as shown in Table 26. A 16-quart V-shell blender, a 197S QuadroCorMill with a 062R CorMill screen, and an A&M blender with a Gerteis macropactor were used. Data were obtained for blend uniformity, flow index, bulk and tapped density, particle size distribution (PSD), reconstitution time, and dissolution. Blend uniformity (BU) samples were taken from each batch at 10 different locations in the 16-quart V-shell (see Figure 6). Table 27 summarizes the BU results for all three batches. Average values ​​ranged from 98.1 to 99.8% for PB and 98.1 to 99.3% for TUDCA. The RSD was 0.5-1.1% for PB and 1.3-1.9 for TUDCA. Figure 7 is a graph showing the PSD of the samples after preblending.

[0153] [Table 26]

[0154] [Table 27]

[0155] A 250g sample of the composite blend was obtained to determine the physical properties such as PSD, bulk density, tapped density and flow index. Table 28 shows the physical testing results obtained for all three batches (preblends and final blends).

[0156] [Table 28]

[0157] The three batches were then analyzed for dissolution and reconstitution times, and the results are shown in Tables 29-31.

[0158] [Table 29]

[0159] [Table 30]

[0160] [Table 31]

[0161] No statistically significant differences in blend uniformity, dissolution, or reconstitution time were observed for the three batches. However, significant differences were observed in the PSD of the three batches after preblending. The PSD of the CCZHB and CCZHC preblends with shorter blending times indicated coarser materials. This suggests that increasing blending time increases particle attrition. Therefore, shorter preblending times are preferred.

[0162] During the compression process, several compression parameters, such as roller gap, compression force, and granulation screen size, can affect the physical properties of the final granules and the extent and rate of drug release. Therefore, these parameters were optimized and their effects on dissolution, physical properties, and reconstitution time were evaluated. Compaction speed, another factor that can affect physical properties, was evaluated in parallel during the final blending experiments. The bulk blend (Lot CDCVY) preblended based on the optimal preblending parameters determined above was divided into 12 subbatches, and each subbatch was roller-compacted and granulated using different sets of parameters for compression force (5-15 kN / cm), roller gap (2-3 mm), and screen size (1-2 mm) (Table 32). The physical properties, dissolution, and reconstitution time of the final blend were evaluated for each subbatch. The physical test results obtained for all 12 subbatches are shown in Tables 33 and 34.

[0163] [Table 32]

[0164] [Table 33]

[0165] [Table 34]

[0166] 8 to 10 show the particle size distributions after granulation using granulation screen sizes of 1.00 mm, 1.5 mm, and 2.0 mm, respectively, and the combined results are shown in FIG.

[0167] The above physical data was entered into a Minitab v.18 statistical program and a statistical model was used to determine optimal compression parameters based on the following set of response-targets: The response-target for particle size distribution was selected to achieve a narrow PSD for downstream packaging.

[0168] [Table 35]

[0169] Based on statistical analysis, significant differences in PSD were observed for all 12 subbatches in the final blend. Bulk density and flow index showed moderately significant differences in the overall statistical analysis. No significant differences were observed in the tapped density results. Because the physical properties of the final blend are important factors for downstream packaging, a homogeneous particle size distribution is preferred. To achieve the above response-target, the optimal compression parameters based on the predictive model were determined to be a roller gap width of approximately 2 mm to approximately 3 mm, a compression force of approximately 5 to 15 kN / cm (target: 10.0 kN / cm), and a granulation screen size of approximately 1.5 mm.

[0170] Reconstitution Time and Dissolution Profile Because the compression process can affect the physical properties of the granules and therefore the extent and rate of drug release, the reconstitution times and dissolution profiles were further investigated. The reconstitution times and average dissolution profiles for the 12 subbatches are shown in Tables 36-38. The dissolution profiles of TUDCA and sodium phenylbutyrate for each subbatch are shown in Figures 12 and 13, respectively.

[0171] [Table 36]

[0172] [Table 37]

[0173] [Table 38]

[0174] Moderately significant differences in reconstitution times were observed between the different subbatches. All 12 subbatches met the bulk product specification of NMT (no more than) 20 minutes (within 20 minutes). To establish a higher limit, a reconstitution time of NMT = 15 minutes was entered into the statistical program as the response target. At this response target, no significant differences were observed between the subbatches except for subbatch number 11, which had the longest reconstitution time at approximately 16-17 minutes.

[0175] The dissolution profiles were not significantly affected by the parameters tested. The % dissolution release of both TUDCA and PB appeared to be complete after 15 minutes. The % dissolution release results significantly exceeded the target of Q=75% at 15 minutes. Figures 12 and 13 show the dissolution profiles of the sub-batches.

[0176] To investigate whether lower temperatures could affect the physical properties of the granules, a cooling unit at 15±2°C was added to the roller compactor, which reduced agglomeration.

[0177] Final Blending Optimization The blending time during the final blending step was optimized as it can affect blend uniformity and final blend physical properties, which are important for downstream packaging. Table 39 shows the various durations and corresponding rotation speeds tested. Blend uniformity and physical properties were investigated. BU samples were taken from the locations shown in Figure 14. BU results are shown in Tables 40-42.

[0178] [Table 39]

[0179] [Table 40]

[0180] Adequate preblend homogeneity was achieved with mean values ​​of 99.5% for PB and 98% for TUDCA, and %RSD values ​​were less than 2.5% for both drug substances.

[0181] [Table 41]

[0182] After roller compaction, the overall mean homogeneity was 95.5% for PB and 97.8% for TUDCA, indicating that adequate homogeneity was achieved, with %RSD values ​​less than 2.0% for both drug substances.

[0183] [Table 42]

[0184] No significant differences in blend uniformity were observed for different final blending durations. Adequate final blend uniformity was achieved, with mean values ​​ranging from 99.0 to 99.6% for PBA and 97.6 to 98.5% for TUDCA. %RSDs ranged from 1.3 to 2.8% for PBA and 1.1 to 1.5% for TUDCA. Compared to blending for 3 or 5 minutes, there was more variability in the BU results when no final blending was performed; however, individual values ​​at each position were within the recommended range for blend uniformity (85% to 115%).

[0185] A 250g sample of the composite blend was obtained for physical property study. Table 43 shows the results of the physical testing. There were no significant differences in PSD, bulk density, and tapped density, but there was a significant difference in the flow index. The no-blending condition improved the flow index. A short blending time resulted in a coarse material. Therefore, no final blending was determined to be the preferred condition.

[0186] [Table 43]

[0187] [Table 44]

[0188] Dissolution and reconstitution time No statistical significance was observed in either dissolution or reconstitution (Tables 45-47). Table 48 shows the favorable physical characteristics of the bulk product.

[0189] [Table 45]

[0190] [Table 46]

[0191] [Table 47]

[0192] [Table 48]

[0193] Previous optimization experiments have revealed favorable conditions for improving flow properties and reducing the amount of fines in the final product that may be detrimental to flow. i. A pre-blending time corresponding to approximately 375 revolutions; ii. A compression force of 5 to 15 kN / cm, a gap width of approximately 1.0 mm to approximately 5.0 mm, a roller speed of approximately 4 to approximately 12 rpm, and a granulation screen size of approximately 1.5 mm; and iii. The omission of final blending was found to improve product properties, including flowability. These improvements resulted in a Carr index of approximately 8 to 9, a significant and surprising improvement over the original formulation (Carr index of approximately 20).

[0194] statistical analysis The results of the compression experiments were statistically analyzed. The input settings were as follows:

[0195] [Table B]

[0196] The % retention at 10 mesh, % retention at 14 mesh, % retention at 18 mesh, % retention at 30 mesh, % retention at 40 mesh, % retention at 80 mesh, total % (% Pan), bulk density, tap density and flow index were analyzed.

[0197] Results - particle size distribution For each of the particle size distribution results (% retention at 10 mesh, % retention at 14 mesh, % retention at 18 mesh, % retention at 30 mesh, % retention at 40 mesh, % retention at 80 mesh and total), a good or very good model was found.

[0198] The main effects of screen size and pushing force, as well as the interaction effect of screen force, were statistically significant at 95% or greater confidence in each of these models. The curvature effect was also significant in the model for each PSD except for % Retained and % Total at 10 mesh. The presence of a curvature term in a model indicates that at least one of the main factors has a quadratic effect on the response. The gap width main effect was statistically significant at 95% or greater confidence in the models for % Retained and % Total at 30 mesh.

[0199] The model coefficients for screen size were positive for the % retained at 10 mesh, % retained at 14 mesh, and % retained at 18 mesh, but negative for the % retained at 30 mesh, % retained at 40 mesh, % retained at 80 mesh, and % total, indicating that increasing screen size tends to increase the amount of large particles and decrease the amount of small particles in the compacted blend.

[0200] Similarly, the model coefficients for compression force were positive for the models for % Retained at 10 mesh, % Retained at 14 mesh, % Retained at 18 mesh, % Retained at 30 mesh, and % Retained at 40 mesh, but negative for the models for % Retained at 80 mesh and % Total, indicating that increasing compression force tends to increase the amount of large particles and decrease the amount of small particles in the compressed blend.

[0201] The model coefficient for gap width was negative for % retention at 10 mesh and % retention at 30 mesh. This coefficient was approximately equal to zero for % retention at 14 mesh, 18 mesh, 40 mesh, and 80 mesh. The gap width coefficient was positive for total %. Therefore, increasing the gap width may decrease the amount of large particles and increase the amount of small particles in the compacted blend.

[0202] Good predictive models were also found for bulk density and flow index.

[0203] Example 8 Forced Decomposition Forced degradation of each API and the final formulation containing the two APIs (referred to as "AMX powder in sachets") was conducted. The experiments involved stressing samples of PB (sodium phenylbutyrate), TURSO, placebo, and AMX powder in sachets with heat, heat-humidity, light, oxidation, acid, or base conditions (Table 49).

[0204] [Table 49]

[0205] Analytical results for the control and stressed samples are summarized in Table 50. Relative Mass Balance Deficit values ​​are shown in Table 51.

[0206] PB did not degrade under any of the forced degradation conditions tested. TURSO did not degrade under heat or light conditions. TURSO degraded slightly under acidic conditions by day 7 and under oxidative and basic conditions by day 3. TURSO degraded approximately 17% under basic conditions by day 7. No TURSO peak was detected in the assay sample solution, suggesting that TURSO under heat-humidity conditions either completely changed properties or precipitated in solution. Exposure of the placebo mixture to forced degradation conditions did not produce peaks that interfered with the retention time of the active peak.

[0207] The PB and TURSO of the AMX powder in the sachets did not decompose under acid, base, or light conditions. The PB in the sachets did not decompose under oxidative conditions, but decomposed by approximately 8% and 4%, respectively, under heat and heat-humidity conditions. The TURSO in the sachets decomposed slightly under oxidative conditions and by 19% and 10%, respectively, under heat and heat-humidity conditions. Furthermore, surprisingly, the degree of TURSO decomposition under heat-humidity conditions was much smaller in the sachets than the complete decomposition of TURSO.

[0208] [Table 50]

[0209] [Table 51]

[0210] Example 9 Effect of Cooling Unit on Blend Properties A cooling unit (15±2°C) was added to the roller compactor to produce a placebo batch (Lot No. CFSMM). The roller (nip area) temperature ranged from 16.0 to 24.1°C throughout the batch. The granule temperature ranged from 24.8 to 29.0°C throughout the batch. No buildup was observed on the rotary 1.5 mm screen throughout the batch. The physical properties of the preblend and compacted granules are shown in Tables 52 and 53 and Figures 15 and 16. As shown in Table 53, Lot CFSMM exhibited a reduced flow index (i.e., improved flow characteristics) compared to the flow index of Lot CDZGW, which was produced without the cooling unit. These results suggest that cooling the roller compactor may be beneficial to processing conditions.

[0211] [Table 52]

[0212] [Table 53]

Claims

1. (a) about 15% to about 45% w / w of a phenylbutyric acid compound; (b) about 5% to about 15% w / w of bile acids; (c) about 8% to about 24 w / w% dextrates; (d) about 1% to about 6% w / w of a sugar alcohol; and (e) about 22% to about 35% maltodextrin; Including, A composition wherein the weight ratio of said phenylbutyric acid compound to said bile acid is about 3:

1.

2. 10. The composition of claim 1, comprising about 8% to about 12% w / w of bile acids.

3. The composition of claim 1 , wherein the bile acid is a hydrophilic bile acid.

4. 2. The composition of claim 1, wherein the bile acid is selected from the group consisting of taurursodiol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, lithocholic acid, and glycoursodeoxycholic acid.

5. The composition of claim 4, wherein the bile acid is TURSO.

6. 6. The composition of claim 5, comprising about 9.7 w / w% TURSO.

7. 10. The composition of claim 1, comprising about 25% to about 35% w / w of a phenylbutyric acid compound.

8. The phenylbutyric acid compounds include 4-phenylbutyric acid (4-PBA), glycerol phenylbutyrate (glycerol tri-(4-phenylbutyrate)), phenylacetic acid, 2-(4-methoxyphenoxy)acetic acid (2-POAA-OMe), 2-(4-nitrophenoxy)acetic acid (2-POAA-NO ２ 2. The composition of claim 1, wherein the compound is selected from the group consisting of 2-(2-naphthyloxy)acetic acid (2-NOAA), and 2-(2-naphthyloxy)acetic acid (2-NOAA), and pharmaceutically acceptable salts thereof.

9. The composition of claim 8, wherein the phenylbutyric acid compound is a pharmaceutically acceptable salt of 4-PBA.

10. 10. The composition of claim 9, wherein the pharmaceutically acceptable salt of 4-PBA is sodium phenylbutyrate.

11. 11. The composition of claim 10, comprising about 29.2 w / w% sodium phenylbutyrate.

12. 10. The composition of claim 1, comprising about 10% to about 20% w / w of dextrates.

13. 13. The composition of claim 12, comprising about 15.6 w / w% dextrates.

14. 10. The composition of claim 1, comprising about 2% to about 5% w / w of a sugar alcohol.

15. 2. The composition of claim 1, wherein the sugar alcohol is selected from the group consisting of sorbitol, xylitol, and mannitol.

16. 16. The composition of claim 15, wherein the sugar alcohol is sorbitol.

17. 17. The composition of claim 16, comprising about 3.9% w / w sorbitol.

18. 10. The composition of claim 1, comprising about 25% to about 32% w / w of maltodextrin.

19. 2. The composition of claim 1, wherein the maltodextrin is pea maltodextrin.

20. 10. The composition of claim 1, further comprising sucralose.

21. 21. The composition of claim 20, comprising about 0.5% to about 5% w / w of sucralose.

22. 22. The composition of claim 21, comprising about 1% to about 3% w / w of sucralose.

23. The composition of claim 1 further comprising one or more flavoring agents.

24. 24. The composition of claim 23, comprising from about 2% to about 15% w / w of one or more flavoring agents.

25. 25. The composition of claim 24, comprising about 5% to about 10% w / w of a flavoring agent.

26. 10. The composition of claim 1, further comprising about 0.05% to about 2 w / w% porous silica.

27. 27. The composition of claim 26, comprising about 0.05% to about 1.5 w / w% porous silica.

28. 28. The composition of claim 27, wherein the porous silica has a higher moisture absorption capacity at humidity levels of about 20% or greater than that of fumed silica.

29. 29. The composition of claim 28, wherein the porous silica has a higher moisture absorption capacity at humidity levels of about 90% or greater than that of fumed silica.

30. 28. The composition of claim 27, wherein the porous silica has a moisture absorption capacity of about 5% to about 40% by weight at about 50% humidity.

31. 31. The composition of claim 30, wherein the porous silica has a moisture absorption capacity of about 30% to about 40% by weight at about 50% humidity.

32. 28. The composition of claim 27, wherein the porous silica has a higher porosity at a humidity of about 20% or higher than that of fumed silica.

33. 33. The composition of claim 32, wherein the porous silica has a higher porosity at a humidity of about 90% or higher than that of fumed silica.

34. 28. The composition of claim 27, wherein the porous silica has an average pore volume of from about 0.1 cc / gm to about 2.0 cc / gm.

35. 35. The composition of claim 34, wherein the porous silica has an average pore volume of about 0.2 to about 0.8 cc / gm.

36. 28. The composition of claim 27, wherein the porous silica has a bulk density of about 100 g / L to about 600 g / L.

37. 37. The composition of claim 36, wherein the porous silica has a bulk density of about 400 g / L to about 600 g / L.

38. 10. The composition of claim 1, further comprising about 0.5% to about 5% w / w of a buffering agent.

39. 39. The composition of claim 38, wherein the buffering agent is sodium phosphate.

40. 40. The composition of claim 39, wherein the sodium phosphate is dibasic sodium phosphate.

41. 41. The composition of claim 40, comprising about 2.7% w / w of dibasic sodium phosphate.

42. 10. The composition of claim 1, further comprising about 0.05% to about 1 w / w% of one or more lubricants.

43. 43. The composition of claim 42, wherein the one or more lubricants are selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, polyethylene glycol, glyceryl behenate, and hydrogenated oils.

44. 44. The composition of claim 43, wherein the one or more lubricants is sodium stearyl fumarate.

45. 45. The composition of claim 44, comprising about 0.5% w / w of sodium stearyl fumarate.

46. 10. The composition of claim 1, wherein the composition has a Carr index of about 25 or less.

47. 47. The composition of claim 46, wherein the composition has a Carr index of about 20 or less.

48. 48. The composition of claim 47, wherein the composition has a Carr index of about 12 or less.

49. about 29.2 w / w% sodium phenylbutyrate; Approximately 9.7 w / w% TURSO; about 15.6 w / w% dextrates; about 3.9 w / w% sorbitol; about 1.9 w / w% sucralose; Approximately 28.3 w / w% maltodextrin; about 7.3 w / w% flavoring agent; about 0.1 w / w% silicon dioxide; About 2.7 w / w% sodium phosphate; and Approximately 0.5 w / w% sodium stearyl fumarate A composition comprising:

50. 1. A method of treating a composition, comprising: (i) roller compacting a preblend composition comprising sodium phenylbutyrate and TURSO in a weight ratio of about 3:1 to form a compacted preblend; and (ii) granulating the compressed preblend to form granules having a Carr index of about 12 or less. A method comprising:

51. 51. The method of claim 50, wherein the preblend composition comprises about 15% to about 45% w / w of sodium phenylbutyrate and about 5% to about 15% w / w of TURSO.

52. 51. The method of claim 50, further comprising, prior to step (i), blending a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form a preblend composition.

53. 53. The method of claim 52, wherein the first and second compositions are blended for one hour or less.

54. 54. The method of claim 53, wherein the first and second compositions are blended for 30 minutes or less.

55. 53. The method of claim 52, wherein the blending speed of the first and second compositions is from about 10 rpm to about 20 rpm.

56. 56. The method of claim 55, wherein the speed is about 15 rpm.

57. 51. The method of claim 50, wherein step (i) comprises roller compacting the preblend composition at a compaction force of from about 5 kN / cm to about 15 kN / cm.

58. 58. The method of claim 57, wherein the compressive force is from about 8 kN / cm to about 12 kN / cm.

59. 59. The method of claim 58, wherein the compressive force is about 10 kN / cm.

60. 51. The method of claim 50, wherein step (i) comprises roller compacting the preblend composition between at least two rotating rolls having a gap width of from about 1 mm to about 5 mm.

61. 61. The method of claim 60, wherein the gap width is between about 2 mm and about 3 mm.

62. 51. The method of claim 50, wherein step (i) comprises roller compacting the preblend composition between at least two rotating rolls having a roll speed of from about 4 rpm to about 12 rpm.

63. 51. The method of claim 50, wherein step (i) comprises roller compacting the preblend composition at about 10°C to about 30°C.

64. 64. The method of claim 63, comprising cooling the preblend composition to about 12°C to about 18°C.

65. 51. The method of claim 50, wherein step (ii) comprises granulating the compressed preblend using a granulating screen having a diameter of from about 0.8 mm to about 2 mm.

66. 66. The method of claim 65, wherein the diameter is about 1.5 mm.

67. 53. The method of claim 52, further comprising sieving the first and second compositions prior to blending.

68. 51. The method of claim 50, wherein the bulk density of the granules is from about 0.2 g / mL to about 1.0 g / mL.

69. 69. The method of claim 68, wherein the bulk density is from about 0.5 g / mL to about 0.7 g / mL.

70. 51. The method of claim 50, wherein the tap density of the granules is from about 0.5 g / mL to about 1.2 g / mL.

71. 71. The method of claim 70, wherein the tap density is from about 0.7 g / mL to about 0.9 g / mL.

72. 51. The method of claim 50, wherein the granules have a Carr index of about 10 or less.

73. 51. The method of claim 50, wherein the dissolution time to release about 75% of the TURSO in the granules is from about 0.5 to about 15 minutes.

74. 74. The method of claim 73, wherein the dissolution time to release about 75% of the TURSO in the granules is about 0.5 to about 5 minutes.

75. 51. The method of claim 50, wherein the dissolution time to release about 75% of the sodium phenylbutyrate in the granules is from about 0.5 to about 15 minutes.

76. 76. The method of claim 75, wherein the dissolution time to release about 75% of the sodium phenylbutyrate in the granules is about 0.5 to about 5 minutes.

77. The composition comprises: about 8% to about 24 w / w% dextrates; about 1% to about 6% w / w of a sugar alcohol; and about 22% to about 35% w / w of maltodextrin 51. The method of claim 50, further comprising:

78. The composition comprises: about 29.2 w / w% sodium phenylbutyrate; Approximately 9.7 w / w% TURSO; about 15.6 w / w% dextrates; about 3.9 w / w% sorbitol; about 1.9 w / w% sucralose; Approximately 28.3 w / w% maltodextrin; about 7.3 w / w% flavoring agent; about 0.1 w / w% silicon dioxide; About 2.7 w / w% sodium phosphate; and Approximately 0.5 w / w% sodium stearyl fumarate 51. The method of claim 50, comprising:

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