Compositions of bile acids and phenylbutyrate compounds

Abstract

This invention relates to compositions comprising phenylbutyrate compounds and bile acids, and methods for processing such compositions.

Description

[Technical Field]

[0001] Cross-referencing of related applications

[0002] This application claims priority to U.S. Patent Application No. 16 / 940,102, filed July 27, 2020, which claims priority to U.S. Patent Application No. 62 / 948,756, filed December 16, 2019, and U.S. Patent Application No. 63 / 030,793, filed May 27, 2020, each of which is incorporated herein by reference in its entirety.

[0003] This article generally relates to pharmaceutical compositions and methods of manufacturing such pharmaceutical compositions. [Previous Technology]

[0004] The flowability of powders and other bulk solids is an important consideration during the manufacture of pharmaceutical compositions. Furthermore, the particle size distribution also affects the downstream processing and packaging of pharmaceutical products. Certain active pharmaceutical ingredients exhibit poor flowability, and there is a demand for pharmaceutical compositions with improved physical properties, including improved flowability. [Summary of the Invention]

[0005] This invention relates to compositions comprising phenylbutyrate compounds and bile acids, and to methods for processing the compositions disclosed herein.

[0006] In one aspect, the text provides a composition comprising: (a) about 15% to about 45% w / w phenylbutyrate compound; (b) about 5% to about 15% w / w bile acids; (c) about 8% to about 24% w / w dextrate; (d) about 1% to about 6% w / w sugar alcohol; and (e) about 22% to about 35% maltodextrin, wherein the phenylbutyrate compound and the bile acids have a weight ratio of about 3:1. In some specific examples, the composition comprises about 8% to about 12% w / w bile acids. In some specific examples, the bile acids are hydrophilic bile acids. In certain specific examples, 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 certain specific examples, the bile acid is TURSO. In certain specific examples, the compositional system comprises about 9.7% w / w TURSO. In certain specific examples, the compositional system comprises about 25% to about 35% w / w phenylbutyrate compound. In certain specific instances, the phenylbutyrate compound is selected from the group consisting of: 4-phenylbutyric acid (4-PBA), glyceryl tri-(4-phenylbutyrate), phenylacetic acid, 2-(4-methoxyphenoxy)acetic acid (2-POAA-OMe), 2-(4-nitrophenoxy)acetic acid (2-POAA-NO2), and 2-(2-naphthyloxy)acetic acid (2-NOAA) and their pharmaceutically acceptable salts. In certain specific instances, the phenylbutyrate compound is a pharmaceutically acceptable salt of 4-PBA. In certain specific instances, the pharmaceutically acceptable salt of 4-PBA is sodium phenylbutyrate. In some specific instances, the composition system includes approximately 29.2% w / w sodium phenylbutyrate. In some specific instances, the composition system includes approximately 10% to approximately 20% w / w glucose conjugate.In some specific examples, the composition system includes about 15.6% w / w glucose conjugate. In some specific examples, the composition system includes about 2% to about 5% w / w sugar alcohol. In some specific examples, the sugar alcohol is selected from the group consisting of sorbitol, xylitol, and mannitol. In some specific examples, the sugar alcohol is sorbitol. In some specific examples, the composition system includes about 3.9% w / w sorbitol. In some specific examples, the composition system includes about 25% to about 32% w / w maltodextrin. In some specific examples, the maltodextrin is pea maltodextrin. In some specific examples, the composition further includes sucralose. In some specific examples, the composition system includes about 0.5% to about 5% w / w sucralose. In some specific examples, the composition system includes about 1% to about 3% w / w sucralose. In some specific examples, the composition further comprises one or more flavoring agents. In some specific examples, the composition comprises about 2% to about 15% w / w of one or more flavoring agents. In some specific examples, the composition comprises about 5% to about 10% w / w of flavoring agents.

[0007] In some specific examples, the composition further comprises about 0.05% to about 2% w / w porous silica. In some specific examples, the composition comprises about 0.05% to about 1.5% w / w porous silica. In some specific examples, the porous silica has a higher H2O adsorption capacity compared to fumed silica at about 20% or higher relative humidity. In some specific examples, the porous silica has a higher H2O adsorption capacity compared to fumed silica at about 90% or higher relative humidity. In some specific examples, the porous silica has an H2O adsorption capacity of about 5% to about 40% by weight at about 50% relative humidity. In some specific examples, the porous silica has an H2O adsorption capacity of about 30% to about 40% by weight at about 50% relative humidity. In some specific examples, the porous silica exhibits higher porosity compared to fumed silica systems at approximately 20% or higher relative humidity. In some specific examples, the porous silica exhibits higher porosity compared to fumed silica systems at approximately 90% or higher relative humidity. In some specific examples, the porous silica system has an average pore volume of approximately 0.1 cc / gm to approximately 2.0 cc / gm. In some specific examples, the porous silica system has an average pore volume of approximately 0.2 to approximately 0.8 cc / gm. In some specific examples, the porous silica system has a bulk density of approximately 100 g / L to approximately 600 g / L. In some specific examples, the porous silica system has a bulk density of approximately 400 g / L to approximately 600 g / L.

[0008] In some specific examples, the composition further comprises about 0.5% to about 5% w / w of a buffer. In some specific examples, the buffer is sodium phosphate. In some specific examples, the sodium phosphate is disodium hydrogen phosphate. In some specific examples, the composition comprises about 2.7% w / w of disodium hydrogen phosphate. In some specific examples, the composition further comprises about 0.05% to about 1% w / w of one or more lubricants. In some specific examples, 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 oil. In some specific examples, the one or more lubricants are sodium stearyl fumarate. In some specific examples, the composition comprises about 0.5% w / w of sodium stearyl fumarate.

[0009] In some specific instances, the constituent system has a Carr's index of about 25 or lower. In some specific instances, the constituent system has a Carr's index of about 20 or lower. In some specific instances, the constituent system has a Carr's index of about 12 or lower.

[0010] In certain specific instances, the text provides a composition comprising: approximately 29.2% w / w sodium phenylbutyrate; approximately 9.7% w / w TURSO; approximately 15.6% w / w glucose conjugate; approximately 3.9% w / w sorbitol; approximately 1.9% w / w sucralose; approximately 28.3% w / w maltodextrin; approximately 7.3% w / w flavoring agent; approximately 0.1% w / w silicon dioxide; approximately 2.7% w / w sodium phosphate; and approximately 0.5% w / w sodium stearate fumarate.

[0011] In another aspect, the present invention provides a method for processing a compound, the method comprising: (i) rolling a premixed composition comprising sodium phenylbutyrate and TURSO, wherein the sodium phenylbutyrate and TURSO have a weight ratio of about 3:1, thereby forming a pressed premix; and (ii) granulating the pressed premix to form particles having a Karl Fischer index of about 12 or lower. In some specific examples, the premixed composition comprises about 15% to about 45% w / w sodium phenylbutyrate and about 5% to about 15% w / w TURSO. In some specific examples, the method further comprises, prior to step (i), mixing a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form a premixed composition. In some specific examples, the first and second compositions are mixed for 1 hour or less. In some specific examples, the first and second compositions are mixed for 30 minutes or less. In some specific examples, the first and second components are mixed at a speed of about 10 rpm to about 20 rpm. In some specific examples, the speed is about 15 rpm. In some specific examples, step (i) includes rolling the premixed component by applying a pressing force of about 5 kN / cm to about 15 kN / cm. In some specific examples, the pressing force is about 8 kN / cm to about 12 kN / cm. In some specific examples, the pressing force is about 10 kN / cm.

[0012] In certain specific instances of the method described herein, step (i) comprises rolling the premixed composition between at least two rollers having a gap width of about 1 mm to about 5 mm. In certain specific instances, the gap width is about 2 mm to about 3 mm. In certain specific instances, step (i) comprises rolling the premixed composition between at least two rollers having a rolling speed of about 4 rpm to about 12 rpm. Step (i) comprises rolling the premixed composition at a temperature of about 10°C to about 30°C. In certain specific instances, the method comprises cooling the premixed composition to a temperature of about 12°C to about 18°C.

[0013] In certain specific examples of the method described herein, step (ii) includes granulating the compressed premix using a granulation screen having a diameter of about 0.8 mm to about 2 mm. In certain specific examples, the diameter is about 1.5 mm. In certain specific examples, the method includes sieving the first and second compositions before mixing them. In certain specific examples, the granules have a bulk density of about 0.2 g / mL to about 1.0 g / mL. In certain specific examples, the bulk density is about 0.5 g / mL to about 0.7 g / mL. In certain specific examples, the granules have a knockdown of about 0.5 g / mL to about 1.2 g / mL. In certain specific examples, the knockdown is about 0.7 g / mL to about 0.9 g / mL. In certain specific examples, the granules have a Karl Fischer index of about 10 or less. In certain specific examples, the dissolution time for releasing about 75% of the TURSO in the granules is between about 0.5 and about 15 minutes. In some specific instances, the dissolution time of approximately 75% of the TURSO released from the particles is between approximately 0.5 and approximately 5 minutes. In some specific instances, the dissolution time of approximately 75% of the sodium phenylbutyrate released from the particles is between approximately 0.5 and approximately 15 minutes. In some specific instances, the dissolution time of approximately 75% of the sodium phenylbutyrate released from the particles is between approximately 0.5 and approximately 5 minutes.

[0014] In certain specific instances of any of the methods described herein, the composition further comprises: about 8% to about 24% w / w of a glucose conjugate; about 1% to about 6% w / w of a sugar alcohol; and about 22% to about 35% w / w of maltodextrin. In certain specific instances, the composition comprises: about 29.2% w / w of sodium phenylbutyrate; about 9.7% w / w of TURSO; about 15.6% w / w of a glucose conjugate; about 3.9% w / w of sorbitol; about 1.9% w / w of sucralose; about 28.3% w / w of maltodextrin; about 7.3% w / w of a flavoring agent; about 0.1% w / w of silicon dioxide; about 2.7% w / w of sodium phosphate; and about 0.5% w / w of sodium stearate fumarate.

[0015] Unless otherwise defined, all technical terms, symbols and other scientific terms or terms used herein are intended to have the general meaning as understood by one skilled in the art to which this application pertains. In some cases, terms of general understanding are defined herein for clarification and / or for quick reference, and such definitions included herein are not necessarily construed as representing a material difference from the general understanding of the definitions in this art.

[0016] When range values ​​are provided, it should be understood that the intermediate values, unless explicitly stated in the text to the tenths place of the lower limit, are intended to be included within this document as well as the upper and lower limits of the range and any other intermediate values ​​described or described in the range. Where restrictions are specifically excluded from any stated range, the upper and lower limits of these smaller ranges may be independently included in the smaller range and are also included within this document. When a range includes one or two restrictions, the range excluding any one or both of the restrictions included is also included within this document.

[0017] Certain ranges in the text are indicated by the term "approximately" preceding numerical values. The term "approximately" is used in the text to provide literal support for a precise number that follows, and to indicate proximity or nearness to the number placed after this term. In determining whether a number is close to or approximately a particular number, a number that is not listed may, in the context it represents, provide a number substantially equal to the particular number.

[0018] It should be understood that, for clarity, certain features of this text described in individual concrete instances and combinations of single concrete instances may also be provided. Conversely, for brevity, various features of this text described in the content of a single concrete instance may also be provided individually or in any suitable sub-combination. All combinations of concrete instances belonging to this text are specifically included in and disclosed herein as each and every combination is individually and explicitly disclosed herein. Furthermore, all sub-combinations of various concrete instances and their elements are also specifically included in and disclosed herein as each and every sub-combination is individually and explicitly disclosed herein.

[0019] Although similar or equivalent methods and materials described herein may be used to practice or test the invention, suitable methods and materials are those listed below. All publications, patent applications and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods and examples are illustrative only and are not intended to be limiting.

Implementation Method

[0020] Active pharmaceutical ingredients, such as bile acids and phenylbutyrate compounds, may exhibit poor flowability, which affects downstream processing, including mixing, scaling up, and packaging of powdered pharmaceutical products. Aggregation of powdered substances can also affect the uniformity of contents and downstream processing. This document provides formulations containing bile acids and phenylbutyrate compounds and methods for manufacturing such formulations, which exhibit improved flowability, uniformity, stability, and reduced aggregation of the final particulate product. Therefore, this document provides a composition comprising: (a) about 15% to about 45% w / w of a phenylbutyrate compound (e.g., any phenylbutyrate compound described herein or known in the art); (b) about 5% to about 15% w / w of a bile acid (e.g., any bile acid described herein or known in the art); (c) about 8% to about 24% w / w of a glucose conjugate (e.g., any glucose conjugate described herein or known in the art); (d) about 1% to about 6% w / w of a sugar alcohol (e.g., any sugar alcohol described herein or known in the art); and (e) about 22% to about 35% maltodextrin, wherein the phenylbutyrate compound and the bile acid have a weight ratio of about 3:1. The compositions herein may have a Karl quotient of about 25 or less, about 20 or less, or about 12 or less. In certain specific instances of any composition described herein, the composition is water-soluble.

[0021] The manufacturing method provided herein is partly based on a dry granulation method. The present invention has discovered a method for producing processed compositions with improved flowability and stability compared to individual active pharmaceutical ingredients. Therefore, the present invention provides a method for processing a composition comprising: (i) rolling a premixed composition comprising sodium phenylbutyrate and TURSO, wherein the sodium phenylbutyrate and TURSO have a weight ratio of approximately 3:1, thereby forming a pressed premix; and (ii) granulating the pressed premix to form particles having a Karl Fischer index of approximately 12 or lower. The method described herein may also include, prior to step (i), mixing a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form the premixed composition. Karl Fischer index

[0022] In certain specific instances of any composition described herein, the composition system has a Cartesian index of about 25 or less. For example, the composition may have a Cartesian index of 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 certain specific instances, the composition system has a Cartesian index of 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 more than about 38.

[0023] The Karl index (or Karl compressibility index) of a composition indicates the compressibility (or the tendency of the composition to be compressed) and flowability of the substance. In some cases, the Karl index is related to the bulk density and tap compaction of the substance. Bulk density is a property of a substance (e.g., powders and granules) and can be measured by dividing the mass of the particles in the substance by the total volume they occupy. The total volume may include the particle volume, the interparticle void volume, and / or the internal pore volume. For powdered substances, the bulk density can be determined based on the density of the particles in the powder and the spatial arrangement of the particles. Tap compaction is typically the increase in bulk density obtained after a specific pressing process, such as mechanical tapping or vibration of a container containing the substance.

[0024] The bulk density and tapping density of a composition containing powder or granules can be measured using methods known in the art. For example, the bulk density of a powder can be the ratio between the mass and volume of an untackled sample. The bulk density of a powder can also be determined by measuring the volume of a known weight of powder sample that may have passed through a sieve into a container (e.g., a graduated cylinder), or by measuring the mass of a known volume of powder that has passed through a volumetric meter into a container. Tapping density can be obtained, for example, by mechanically tapping a container containing a sample (e.g., a graduated cylinder or a measuring instrument). The Karl index of a substance can be calculated based on the bulk density and tapping density, for example, according to the formula C=100(1-pB / pT) (where C represents the Karl index, pB represents the bulk density, and pT represents the tapping density). Other methods for determining the Carr index of a substance can be found in, for example, 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 fluidity of a substance. For example, a higher Carr index (a greater difference between bulk density and tapped density) may indicate lower fluidity. The Hausner ratio, which can be expressed as H = pT / pB, or the ratio of tapped density to bulk density, may also be related to the fluidity of a substance.

[0026] Other flow indices for measuring the flowability of a substance can also be estimated in this text, such as the angle of repose. The angle of repose of particulate matter can be expressed as the steepest slope of an uncompressed substance, measured from a horizontal plane on which the substance can be filled without collapsing (see, for example, Mehta et al. Prog. Phys. 57 (1994) 383–416). An example method for measuring the angle of repose of a substance can be found, for example, Beakawi et al., Powder Technology 330 (2018) 397–417. For powders that can be defined as small particulate matter, which are aggregated and suspended in a gas, the definition of the angle of repose can be related to Hausnerbi (see, for example, Beddow Part. Part. Syst. Charact. 12 (4): 213, 1995), and the powder is flowable at angles greater than the angle of repose. The angle of repose can also indicate the cohesiveness of particulate matter, with respect to the Carr classification of flowability as shown below. illustrate Angle of rest Very free flow <30° Free flow 30-38° Still Flowable 38-45° Cohesion 45-55° Highly cohesive (non-fluid) >55° bile acids

[0027] This document 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). The bile acids described herein may include naturally occurring surfactants having a cholanonic acid-derived core, typically substituted with a 3α-hydroxy group at the C6, C7, or C12 position of the sterol core, and, where desired, substituted with other hydroxyl groups. Suitable bile acids include (but are not limited to) taurine diol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (also known as chenodiol or deoxychenocholic acid), cholic acid, porcine deoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, porcine cholic acid, taurocene chenodeoxycholic acid, taurocene deoxycholic acid, glycine ursodeoxycholic acid, taurolic acid, glycocholic acid, cholic acid or their analogs, derivatives or prodrugs. In some specific instances, the bile acid is a hydrophilic bile acid, including (but not limited to) TURSO, UDCA, chenodeoxycholic acid, cholic acid, porcine deoxycholic acid, lithocholic acid and glycine ursodeoxycholic acid. Pharmaceutically acceptable salts or solvates of any bile acid described herein are also included. Bile acid derivatives are also included, including but not limited to derivatives formed by the hydroxyl and carboxyl groups of bile acids with other functional groups, such as hydrogen and amino groups. TURSO and taurine deoxycholic acid (TUDCA) are used interchangeably in this article.

[0028] The bile acids mentioned herein may be TURSO as shown in Formula I (with the carbon marked to help understand the substituted parts).

[0029] The composition described herein may include about 5% to about 15% w / w (e.g., any subrange of the range described herein) of TURSO. In some specific instances, the composition comprises about 9.7% TURSO. The TURSO of any composition described herein may have a Cartesian index of about 22 to about 26 (e.g., about 23, 24, or 25).

[0030] The bile acids mentioned herein may be UDCA as shown in Formula II (with the indicated carbon to help understand the possible substitutions).

[0031] Physiologically relevant bile acid derivatives, such as compounds having a hydrogen at position 3 or 7 in the chemical formula TURSO or UDCA substituted with any combination of steric chemical shifts of the hydroxyl group at position 3 or 7, are applicable to the compositions of the present invention.

[0032] Any amino acid conjugate of bile acids described herein or known in this art, or a pharmaceutically acceptable salt thereof, is also applicable to the compositions described herein. The amino acid in the conjugate may be, but is not limited to, taurine, glycine, glutamine, aspartic acid, methionine, or carbocysteine. For example, compounds of formula III are included herein: III where R is -H or a C1-C4 alkyl group; R1 is -CH2-SO3R3 and R2 is -H; or R1 is -COOH and R2 is -CH2-CH2-CONH2, -CH2-CONH2, -CH2-CH2-SCH3, or -CH2-S-CH2-COOH; and R3 is -H or a basic amino acid residue, or a pharmaceutically acceptable salt, analogue, derivative, prodrug, or mixture thereof. Phenylacetate compounds

[0033] This document 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 phenylbutyrate compound. The phenylbutyrate compound described herein includes phenylbutyrates (low molecular weight aromatic carboxylic acids) that are free acids (4-phenylbutyrate (4-PBA), 4-phenylbutyric acid, or phenylbutyric acid) and their pharmaceutically acceptable salts, cocrystals, polyforms, hydrates, solvates, derivatives, or prodrugs. The phenylbutyrate compounds described herein also include analogs of 4-PBA, including (but not limited to) triglycerides (4-phenylbutyrate), phenylacetic acid (an active metabolite of 4-PBA), 2-(4-methoxyphenoxy)acetic acid (2-POAA-OMe), 2-(4-nitrophenoxy)acetic acid (2-POAA-NO2), and 2-(2-naphthoxy)acetic acid, and their pharmaceutically acceptable salts. The structures of 4-PBA analogs can be found, for example, Zhang et al., Br J Pharmacol 2013 Oct; 170(4): 822–834. Phenylbutyrate compounds also include physiologically relevant types of 4-PBA, such as, but not limited to, those having any deuterium-substituted hydrogen in the structure of 4-PBA. Physiologically acceptable salts of 4-PBA include, for example, sodium, potassium, magnesium, and calcium salts.

[0034] In certain specific instances, this document provides a composition comprising about 15% to about 45% w / w (e.g., any sub-range of any range described herein). In certain specific instances, the composition comprises about 29.2% sodium phenylbutyrate. The sodium phenylbutyrate of any composition described herein may have a Karl quotient of about 35 or higher (e.g., about 36, 37, 38, 39, or 40 or higher). Sodium phenylbutyrate has the following structure: IV

[0035] In certain circumstances, the combination of bile acids (e.g., TURSO) and phenylbutyrate compounds (e.g., sodium phenylbutyrate) has a synergistic effect when administered to a subject for the treatment of symptoms associated with one or more neurodegenerative diseases. Examples of 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, multiple infarct dementia, Creutzfeldt-Jakob's disease, Lewy body dementia, mixed dementia, and frontotemporal dementia. For example, the combination of bile acids and phenylbutyrate compounds can induce a mathematically synergistic increase in neuronal activity in a linear model of severe oxidative damage (H₂O₂-mediated toxicity). These combination therapies are disclosed in U.S. Patent Nos. 9,872,865 and 10,251,896.

[0036] In some specific examples, the phenylbutyrate compound and bile acid system in the compositions provided herein have a weight ratio between about 1:1 and about 4:1 (e.g., 2:1 or 3:1). In some specific examples, the phenylbutyrate compound and bile acid system in the compositions provided herein have a weight ratio of about 3:1. Glucose binding agent

[0037] Certain specific examples of any composition 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). This text covers both anhydrous and hydrated glucose conjugates. Glucose conjugates described herein may include mixtures of sugars developed from the controlled enzymatic hydrolysis of starch. Certain specific examples of any composition described herein include hydrated glucose conjugates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra). Sugar alcohols

[0038] Certain specific examples of any composition described herein include 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 sugar alcohol. Sugar alcohols may be derived from sugars and contain a hydroxyl group (-OH) attached to each carbon atom. Disaccharides and monosaccharides can form sugar alcohols. Sugar alcohols may be naturally occurring or produced by the hydrogenation of sugars. Example sugar alcohols include, but are not limited to, sorbitol, xylitol, and mannitol. In certain specific examples, the composition system includes 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). Maltodextrin

[0039] Certain specific examples of any composition described herein include 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) of maltodextrin. Maltodextrin, when dissolved in solution, can form elastic helices capable of retaining active ingredients (e.g., any phenylbutyrate compounds and bile acids described herein), thereby masking the taste of the active ingredients. The term encompasses maltodextrin manufactured from any suitable source, including, but not limited to, pea, rice, cassava, corn, and potato. In certain specific examples, the maltodextrin is pea maltodextrin. In certain specific examples, the composition comprises about 28.3% w / w pea maltodextrin. For example, pea maltodextrin derived from Roquette (KLEPTOSE® LINECAPS) can be used. Sucralose

[0040] Certain specific examples of any composition described herein further include sucralose. In certain specific examples, the composition described herein includes 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) of sucralose. Other sugar substitutes covered herein include, but are not limited to, aspartame, neotame, acesulfame potassium, saccharin, and advantame. Flavoring agents

[0041] Certain specific examples of any composition described herein further include one or more flavoring agents. In certain specific examples, the composition described herein includes 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 flavoring agents. Flavoring agents may include substances that impart flavor to other substances or alter the properties of the composition by affecting its taste. Flavoring agents can be used to mask unpleasant tastes without affecting their physical and chemical stability and can be selected based on the taste of the incorporated drug. Suitable flavoring agents include, but are not limited to, natural flavoring substances, artificial flavoring substances, and flavor mimicry. In certain specific examples, a mixture of flavoring agents is used. For example, the composition described herein may include two or more (e.g., two, three, four, five, or more) flavoring agents. The flavoring agents described herein are water-soluble and stable in water. Suitable flavoring agents may be selected based on taste testing. For example, multiple different flavoring agents can be added to a composition for taste testing. Example flavoring agents include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, cherry, and mixed berry flavor powders). In some specific instances, any composition system described herein includes about 0.5% to about 1.5% w / w (e.g., about 1% w / w) of mixed berry flavor powder. In some specific instances, any composition system described herein includes about 5% to about 7% w / w (e.g., about 6.3% w / w) of a masking flavor agent. Suitable masking flavor agents are available from, for example, Firmenich. Silicon dioxide.

[0042] Certain specific examples of the compositions provided herein further include silicon dioxide. The addition of silicon dioxide to the compositions can prevent or reduce agglomeration of the composition components. Silicon dioxide can be used as an anti-caking agent, disintegrant, or flow aid. In certain specific examples, the compositions described herein include about 0.05% to about 2% w / w (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% w / w) porous silicon dioxide. Porous silica, for example, may exhibit higher H2O adsorption capacity and / or higher porosity compared to fumed silica at about 20% or higher relative humidity (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher). In some specific examples, the porous silica has an H2O adsorption capacity of about 5% to about 40% (e.g., about 20% to about 40%, or about 30% to about 40%) by weight at about 50% relative humidity. The porous silica may also exhibit higher porosity compared to fumed silica at about 20% or higher relative humidity (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher). In some specific examples, the porous silica system 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 specific examples, the porous silica system has an average pore capacity 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 certain specific instances, the porous silica system 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 certain specific instances, the compositional system described herein includes about 0.05% to about 2% w / w (e.g., any subrange of the range described herein) of Syloid® 63FP (WR Grace). Buffers and Lubricants

[0043] Certain specific examples of any composition described herein further include one or more buffers. In certain specific examples, the composition includes 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 buffer. The buffer may include a weak acid or weak base that maintains the acidity and pH of the composition close to a selected value after the addition of another acid or base. Suitable buffers are known in the art. In certain specific examples, the buffer in the composition provided herein is a phosphate, such as sodium phosphate (e.g., disodium hydrogen phosphate hydrate). For example, the composition may include about 2.7% w / w disodium hydrogen phosphate.

[0044] Certain specific examples of any composition described herein further include one or more lubricants. In certain specific examples, 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. Example lubricants include, but are not limited to, sodium stearate, magnesium stearate, stearic acid, metal stearate salts, talc, waxes and high-melting-point glyceryl esters, colloidal silica, polyethylene glycol, alkyl sulfates, glyceryl behenate, and hydrogenated oils. Other lubricants are known in the art. In certain specific examples, the composition comprises about 0.05% to about 1% w / w (e.g., any sub-range of the range described herein) of sodium stearate. For example, the composition may include about 0.5% w / w sodium stearate fumarate.

[0045] Additional suitable sweeteners or flavor maskers may also be included in the components described herein, such as (but not limited to) xylitol, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, steviol glycosides, partially hydrolyzed starch, and corn syrup solids. Water-soluble artificial sweeteners are included herein, such as soluble saccharin salts (e.g., sodium or calcium saccharin salts), cyclamate salts, acesulfame potassium (acesulfame K), and saccharin and aspartame-based sweeteners in free acid form, such as methyl L-aspartate, Alitame®, or Neotame®. The amount of sweetener or flavor masker may vary depending on the desired amount of sweetener or flavor masker selected for a particular final component.

[0046] In addition to the reagents described above, the compositions described herein may also cover pharmaceutically acceptable adhesives. Examples include cellulose derivatives, including microcrystalline cellulose, cellulose, and low-substituted hydroxypropyl cellulose (e.g., LH 22, LH 21, LH 20, LH 32, LH 31, LH 30); starches, including potato starch; croscarmellose sodium (i.e., croscarmellose sodium salt; e.g., Ac-Di-Sol®); alginate or alginate; insoluble polyvinylpyrrolidone (e.g., Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); and sodium carboxymethyl starch (e.g., Primogel® and Explotab®).

[0047] Additional fillers, diluents, or binders may be incorporated, 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, LH 22, LH 21, LH 20, LH 32, LH 31. (LH30), dextrin, maltodextrin (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. Pharmaceutical ingredients.

[0048] Any of the components described herein may be formulated as a pharmaceutical composition or used in a pharmaceutical composition. These components may be formulated or adapted for administration of the drug via any route, such as any route approved by the Food and Drug Administration (FDA), such as (but not limited to) oral, non-enteral, or transdermal delivery. Example methods are described in FDA's CDER Data Standards Manual, version 004 (available at fda.give / cder / dsm / DRG / drg00301.html).

[0049] In certain specific instances, the constituent systems described herein are used to treat or prevent symptoms associated with one or more neurodegenerative diseases in subjects who require such treatment. Examples of neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), Parkinson's disease, Huntington's disease, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob's disease, Lewy body dementia, mixed dementia, and frontotemporal dementia.

[0050] Any composition described herein may be formulated as a pharmaceutical composition further comprising one or more additional therapeutic agents. Examples of 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®), anticholinergic drugs, and psychiatric drugs, such as, but not limited to, antidepressants, antipsychotics, anxiolytics / hypnotics, mood stabilizers, and stimulants. Any known anticholinergic drugs may be covered in this text, including (but not limited to) glycopyrrolate, scopolamine, atropine, belladonna alkaloids, benztropine mesylate, cogentin, clidinium, cyclopentolate, darifenacin (Enablex), dicylomine, fesoterodine (Toviaz), flavoxate (Urispas), glycopyrrolate, and homatropine bromate. Hydrobromide, hyoscyamine (Levsinex), ipratropium (Atrovent), orphenadrine, oxybutynin (Ditropan XL), propantheline (Probanthine), scopolamine, methscopolamine, solifenacin (VESIcare), tiotropium (Spiriva), tolterodine (Detrol), trihexyphenidyl, trospium, and diphenhydramine (Benadryl).The text covers any known antidepressants as additional therapeutic agents, including (but not limited to) selective serotonin inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators and stimulants, serotonin antagonists and reuptake inhibitors, norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors, and NMDA receptor antagonists.

[0051] The pharmaceutical compositions described herein may further include any pharmaceutically acceptable carriers, adjuvants, and / or mediators. A pharmaceutically acceptable carrier or adjuvant is one that can be administered to a patient without destroying its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic dose of the active compound. Examples of pharmaceutically acceptable carriers include saline, solvents, dispersants, coatings, antibacterial and antifungal agents, isotonics, and absorption delayers, similar to those used in pharmaceutical administration. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to improve the stability of the formulated compound or its delivery form. The term "non-enteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0052] Any therapeutic composition disclosed herein may be formulated for sale within the United States, imported into the United States, and / or exported from the United States. The pharmaceutical composition may be included in a container, package, or dispenser together with instructions for use. In some cases, the present invention provides a kit comprising bile acids and phenylbutyrate compounds. This kit may also include instructions for use provided to physicians and / or patients, syringes, needles, boxes, bottles, vials, etc. Dosage and method of administration.

[0053] Pharmaceutical compositions are typically formulated to be compatible with their desired route of administration. Examples of routes of administration include non-enteral, such as intravenous, intramuscular, subcutaneous, oral (e.g., inhalation or via feeding tube), transdermal (topical), mucosal, and rectal administration.

[0054] Pharmaceutical compositions may be in the form of solutions or powders for inhalation and / or intranasal administration. These compositions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in this art. Sterile injectable preparations may also be sterile injectable solutions or suspensions dissolved in non-toxic, non-enteric acceptable diluents or solvents, such as solutions dissolved in 1,3-butanediol. Acceptable mediators and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are conventionally used as solvents or suspending agents.

[0055] Pharmaceutical formulations can be administered orally in any orally acceptable dosage form, including (but not limited to) powders, capsules, tablets, emulsions, suspensions, dispersions, and solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. For oral administration in capsule form, diluents that can be used include lactose and dried corn starch. When suspensions and / or emulsions are administered orally, the active ingredient can be combined with emulsifiers and / or suspending agents to suspend or dissolve in the oil phase. If necessary, a colorant may be added. Solid formulations can be reconstituted with aqueous solvents (e.g., water, aqueous saline solution) to prepare aqueous formulations. As used herein, the term "aqueous solvent" means a liquid comprising at least 50% (e.g., at least 60%, 70%, 80%, 90%, or at least 95%) water. In some specific instances, the aqueous solvent is water.

[0056] Alternatively or additionally, the pharmaceutical composition may be administered by nasal spray or inhalation. These compositions are prepared according to techniques known in the art of pharmaceutical formulations and may be prepared into a solution soluble in saline solution using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and / or other solubilizers or dispersants known in the art.

[0057] In certain specific instances, any of the components described herein are substantially dissolved in water before being administered to the object. The components described herein may be administered to an object in need once, twice, three or more times a day.

[0058] In certain specific instances, the bile acid (e.g., TURSO) of the composition is administered in an amount of about 0.5 to about 5 grams per day (e.g., about 0.5 to about 4.5, about 0.5 to about 3.5, about 1 to about 3, or about 2 grams). In certain specific instances, the bile acid is TURSO and is administered in an amount of about 2 grams per day, for example, 1 gram twice a day. In certain specific instances, the bile acid is administered in an amount of about 10 mg / kg to about 50 mg / kg based on 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).

[0059] In certain specific instances, the phenylbutyrate compound of the composition (e.g., sodium phenylbutyrate) is administered in an amount of about 0.5 to about 10 grams per day (e.g., about 1 to about 10, about 2 to about 9, about 3 to about 8, about 5 to about 7, or, for example, about 6 grams). In certain specific instances, the bile acid is sodium phenylbutyrate and is administered in an amount of about 6 grams per day, for example, 3 grams twice a day. In certain specific instances, the phenylbutyrate compound is administered in an amount of about 10 mg / kg to about 400 mg / kg based on 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).

[0060] In some specific instances, the composition is administered once or twice daily, and each administration comprises about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate. In some specific instances, the composition is administered once daily, and each administration comprises about 2 grams of TURSO and about 6 grams of sodium phenylbutyrate.

[0061] The composition may be supplied to an object in need 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 certain specific instances, the composition may be supplied to an object in need for less than about 6 months (e.g., less than about 5, 4, 3, 2, or 1 month). Treatment Method

[0062] This article further relates to a method for processing or manufacturing pharmaceutical formulations based on dry granulation. The method provided herein is a method for processing a composition, which includes: (i) rolling a premixed composition comprising sodium phenylbutyrate and TURSO, wherein the sodium phenylbutyrate and TURSO have a weight ratio of about 3:1, thereby forming a pressed premix; and granulating the pressed premix to form particles having a Karl Fischer index of about 12 or lower.

[0063] The premix may include about 15% to about 45% w / w (e.g., any sub-range of the range described herein) of sodium phenylbutyrate and about 5% to about 15% w / w (e.g., any sub-range of the range described herein) of TURSO.

[0064] Certain specific examples of any method of processing the composition described herein further include, prior to step (i), mixing a first composition comprising sodium phenylbutyrate and a second composition comprising TURSO to form a premixed composition.

[0065] Prior to mixing, a step of sieving the first component, comprising sodium phenylbutyrate, and the second component, comprising TURSO, may be performed. This sieving can be performed by any conventional sieving method known to those skilled in the art.

[0066] The first and second components are mixed for about 1 hour or less (e.g., about 55, 50, 45, 40, 35, 30, or 25 minutes or less), and / or at a mixing speed of about 10 rpm to about 20 rpm (e.g., about 12 rpm to about 18 rpm, about 14 to about 16, or about 15 rpm). The mixing speed and mixing time can be adjusted to achieve a substantially homogeneous mixture of components. The mixing speed can be fixed or adjusted during mixing. In some specific instances, the first and second components are mixed for about 30 minutes or less (e.g., about 29, 28, 27, or 26 minutes or less, or about 25 minutes or about 15 minutes) to produce lower particle abrasion compared to components mixed for more than 30 minutes, which is therefore more desirable. Suitable mixing apparatus and parameters are known in the art. For example, any apparatus typically used in the pharmaceutical industry for the homogeneous mixing of two or more components includes V-type mixers, container mixers, and rotary drum mixers. Mixer capacities can be 50 L, 100 L, 200 L, 250 L, or larger. The components can also be ground at suitable grinding speeds before, during, and after mixing. Suitable grinding equipment and parameters are known in this art.

[0067] The term "roller compacting" refers to a method in which powder is pressed and compressed into a compact or tape between two counter-rotating rollers. Rolling can be performed using any suitable rolling mill known to the skilled craftsman. For example, a MACRO-PACTOR® or MINI-PACTOR® from Gerteis can be used. The step of granulating compacts or tapes into granules includes milling / sieving the compacts or tapes to the desired particle size, and can be performed using a rolling mill that integrates rolling and milling functions, or on separate equipment. "Pelletizing" and "milling" are used interchangeably herein and can refer to methods of breaking solid matter into smaller fragments, such as by grinding, crushing, or cutting.

[0068] A rolling mill can generally be composed of three main units: a feeding system that transports powder to the rolling zone between the rollers; a rolling unit in which the powder is pressed into strips by applying force between two counter-rotating rollers; and a size reduction unit for grinding the strips into the desired particle size.

[0069] Several operating parameters can be adjusted / controlled to modify product particle size, including compaction force, gap width, and granulation screen size. Compaction force can be expressed in kN / cm, which refers to the force per cm of shaft width. Gap width refers to the width of the gap between two rollers. When the gap width increases, the constant force applied by the rollers must be transmitted through a thicker powder strip, and therefore the strip may have lower strength and may produce smaller, weaker particles after rolling. Further explanation of rolling process variables can be found, for example, Freeman et al. Asian Journal of Pharmaceutical Sciences 11: 516-527, 2016.

[0070] The pressing force used in step (i) may be from about 5 kN / cm to about 15 kN / cm (e.g., from about 7 kN / cm to about 13 kN / cm, from about 8 kN / cm to about 12 kN / cm, or from about 9 kN / cm to about 11 kN / cm, e.g., about 10 kN / cm). In some specific instances of the method described herein, step (i) may include rolling the premixed composition between at least two rollers 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 rollers may have a rotational speed of from about 4 rpm to about 12 rpm (e.g., about 5, 6, 7, 8, 9, 10, or 11 rpm). Rolling may be performed at a temperature that prevents the composition from melting or agglomerating. For example, the premixed composition can be rolled at a temperature of 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). For this purpose, a cooling unit with a temperature 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 rolling mill. For example, the rollers can have a temperature of about 10°C to about 30°C (e.g., any subrange of the range described herein).

[0071] In certain specific instances of any of the methods described herein, step (ii) includes granulating the compressed premix to form granules. A granulation 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. These methods may also include the step of sieving the granules to at least a suitable mesh size.

[0072] The method described herein may further include a final mixing step, which includes mixing the particles for 10 minutes or less, or 5 minutes or less.

[0073] The particles prepared by the method of the present invention may have a bulk density of 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 particles can be determined using methods known in the art, for example, by pouring the particles into a graduated cylinder of a suitable size.

[0074] The particles prepared by the method of the present invention have a tapping density of about 0.5 g / mL to about 1.2 g / mL, or about 0.7 g / mL to about 0.9 g / mL. The tapping density of the particles can be determined using methods known in the art, for example, by compressing the particles using a tapped volumeter, increasing the amount by 100 taps until the volume change is less than 5%.

[0075] The particles prepared by the method described herein may have improved flowability (e.g., reflected in Karl Fischer index, Hausner ratio, rest angle, or bulk density and / or tap compaction) compared to the premixed composition of step (i). The particles may also have improved flowability compared to the first composition comprising sodium phenylbutyrate and / or the second composition comprising TURSO. In some specific examples, the particles prepared by the method of the present invention have a Karl Fischer index of about 12 or lower (e.g., a Karl Fischer index of about 1 to 12, such as about 11, 10, 9, 8, 7, 6, or about 5). Compared to the Karl Fischer index of the premixed composition from step (i), the treatment method described herein may reduce the Karl Fischer index of the particles formed in step (ii) by at least about 3 (e.g., at least about 4, 5, 6, 7, 8, or 10).

[0076] In certain specific examples of any method of processing the composition provided herein, the dissolution time of about 75% of TURSO in the particles formed in step (iii) is between about 0.5 and about 15 minutes (e.g., between about 0.5 and about 10 minutes, between about 0.5 and about 8 minutes, or between about 0.5 and about 5 minutes). In certain specific examples, the dissolution time of about 75% of sodium phenylbutyrate in the particles formed in step (iii) is between about 0.5 and about 15 minutes (e.g., between about 0.5 and about 10 minutes, between about 0.5 and about 8 minutes, or between about 0.5 and about 5 minutes). The dissolution time of the compound can be determined using methods known in the art.

[0077] In certain specific examples of any method of processing a composition provided herein, the composition further comprises about 8% to about 24% w / w (e.g., any sub-range of the range described herein); about 1% to about 6% w / w (e.g., any sugar alcohol described herein or known in the art, such as sorbitol); and about 22% to about 35% w / w (e.g., any sub-range of the range described herein). The composition may further include about 0.5% to about 5% w / w (e.g., any sub-range of the range described herein), about 2% to about 15% w / w (e.g., any sub-range of the range described herein), one or more flavoring agents, about 0.05% to about 2% w / w (e.g., any sub-range of the range described herein), porous silica, about 0.5% to about 5% w / w (e.g., any sub-range of the range described herein), a buffer (e.g., any buffer described herein or known in the art, such as sodium phosphate), and / or about 0.05% to about 1% w / w (e.g., any sub-range of the range described herein), one or more lubricants (e.g., any lubricant described herein or known in the art, such as sodium stearate). Examples

[0078] Further specific examples are disclosed in more detail in the following examples, which are provided by way of illustration and are not intended to limit the scope of this document or the scope of the claims in any way. Example 1: Flow optimization by changing the type of sorbitol, glucose binder and sodium phosphate.

[0079] The following examples are used to develop and optimize formulations and related methods for manufacturing final dosage forms and taste-blind placebos containing dual-active pharmaceutical ingredients (API, TURSO, and NaPB). Formulation development includes using various excipients to optimize the flowability, activity, and taste masking of the mixture, as well as using excipients and processing techniques to control humidity. Placebo formulations that mimic the active formulation in both appearance and taste are developed using similar methods.

[0080] Because the two APIs were found to have poor flowability, which may increase the difficulty of automated processing during scale-up and manufacturing, flow optimization was achieved by mixing the API with an excipient that has better flowability, serving the dual purpose of improving mixing flow and masking API odor. Materials and Equipment

[0081] Table 1: Materials used for qualitative flow characteristics Material brand grade Manufacturer Manufacturer batch number # TURSO -- -- Prodotti Chimici E Alimentari SpA 2015010026 NaPB -- -- Sri Krishna Pharmaceuticals limited SPB013 / 14-15 Sodium dihydrogen phosphate monohydrate -- ACS Fisher Chemical 116745 Anhydrous sodium disodium phosphate -- ACS Amresco 2934C448 glucose binding agent Emdex NF JRS Pharma EX13K42DX Sorbitol Neosorb P110 USP / NF / EP / JP Roquette US061 Sucralose -- HPLC Sigma Life Science BCBH2029V Colloidal silicon dioxide Aerosil 200 USP / NF / EP / JP Spectrum RM-08L13 magnesium stearate Ligamed MF-2-K USP / NF / EP / JP Peter Greven C401433

[0082] Table 2: Equipment equipment Manufacturer model sieve oscillator WS Tyler RX86 screen Fischer Scientific E-11 Spec Tighten the volumetric gauge Erweka SVM22 LOD Denver Instruments IR-30

[0083] Table 3: Mixtures with varying amounts of sorbitol and glucose binding agents Target weight (x2 bags) Material batch number# Ingredients# % of ingredients A B C A B C TURSO 2015010026 2 2 2 14.7 12.8 11.3 NaPB (Sri Krishna Pharmaceuticals limited) SPB013 / 14-15 6 6 6 44 38.4 34 Sodium dihydrogen phosphate monohydrate (Fisher Chemical) 116745 0.56 0.56 0.56 4.1 3.58 3.17 Anhydrous disodium hydrogen phosphate (Amresco) 2934C448 0.784 0.784 0.784 5.75 5.01 4.44 Hydrated glucose binder (Emdex NF) EX13K42DX 3.2 4.8 6.4 23.5 30.7 36.3 Sorbitol (Neosorb p110) US061 0.8 1.2 1.6 5.86 7.67 9.07 Sucralose (Sigma Life Science, 69293-100g) BCBH2029V 0.02 0.02 0.02 0.15 0.13 0.11 Aerosil 200 (Evonik) RM-08L13 0.16 0.16 0.16 1.17 1.02 0.91 Magnesium stearate (Peter Greven, Ligamed MF-2-k) C401433 0.12 0.12 0.12 0.88 0.77 0.68 total: 13.64 15.64 17.644 100 100 100 results

[0084] Compounds A, B, and C, containing different amounts of sorbitol and glucose binding agents, were prepared. The compound mixtures were then subjected to the following analyses: Particle size distribution.

[0085] Sample mixtures were analyzed using a WS Tyler RX86 sieve shaker with mesh sizes of #60, 80, 100, 140, 200, 325, or 400. 10 g of each API was placed in the top sieve and stirred for 5 minutes. The amount of API collected on each sieve was then measured and recorded. The particle size distributions of NaPB and TURSO are shown in Figure 1. Hausner ratio and Carr exponent.

[0086] The bulk density of each API and the mixture was calculated by slowly pouring the powder into a 25 mL graduated cylinder. Using a tapping volumetric gauging meter, the amount was increased by 100-tap increments until the volume change was less than 5%, and the tapping density was calculated. Then, the Hausner ratio and Karl index were calculated using the bulk density and tapping density. The Karl indexes for the API and formulation AC are shown in Table 4 below. Formulation C was selected based on flow characteristics. In addition to measuring compressibility, the Karl index can also be used to determine the flowability of a substance. A high Karl index (large difference between bulk density and tapping density) indicates that the substance has stronger intermolecular forces that reduce flowability. Acceptable flowability (as measured by the packaging equipment used) is a Karl index of at least 25, with a Karl index below 20 being preferred.

[0087] Table 4: Karl Fischer Index of API and Mixture Liquidity Carr index NaPB TURSO Blend A Blend B Blend C excellent <10 -- -- -- -- -- good 11-15 -- -- -- -- -- ordinary 16-20 -- -- -- -- 19.2 qualified 21-25 -- 24.2 21.5 23.1 -- Difference 26-31 -- -- -- -- -- Very bad 32-37 -- -- -- -- -- Very, very bad >38 39.2 -- -- -- -- Angle of rest

[0088] Next, the flowability of formulation C was measured using the angle of repose, by allowing the powder to fall from a funnel at a fixed height onto a flat surface. The angle of repose for formulation C was determined to be 31.1°. The flowability corresponding to a specific range of angles of repose is shown in Table 5 below for reference.

[0089] Table 5: Angle of Repose and Flow Angle of rest Liquidity 25-30 excellent 31-35 good 36-40 ordinary 41-45 qualified 46-55 Poor – Must vibrate 56-65 Very bad >66 Very, very poor aggregate buildup

[0090] After being stored in a sealed bottle for about one week, slight aggregation of the mixture was observed. Results of the LOD test of the sorbitol and glucose binder showed no significant water absorption, which is unlikely to be the cause of the aggregation.

[0091] Due to the fact that the anhydrous form is more hygroscopic than the heptahydrate form, the anhydrous disodium hydrogen phosphate in the formulation was replaced with disodium hydrogen phosphate heptahydrate before the final formulation was determined. Formulation selection

[0092] As measured by the angle of repose and the Karl Fischer index, the amount of sorbitol and glucose binder in formulation C was selected due to the significant improvement in fluidity. Example 2: Flavor Masking Optimization

[0093] In order to manufacture a delicious dosage form that can be taken by patients who may have mobility impairments, powders for reconstructing the dosage form were selected and the taste masking effects of various sweeteners and flavorings were investigated. Materials

[0094] Table 6: Materials used for flavor masking optimization Material batch number# Manufacturer TURSO 2015010026 Prodotti Chimici E Alimentari SpA NaPB SPB013 / 14-15 Sri Krishna Pharmaceuticals Sodium dihydrogen phosphate monohydrate 116745 Fisher Chemical Anhydrous disodium hydrogen phosphate 2934C448 Amresco Hydrated glucose binder (Emdex NF) EX13K42DX JRS Pharma Sorbitol (Neosorb p110) US061 Roquette Sucralose (69293-100g) BCBP3048V Sigma Life Science Aerosil 200 RM-08L13 Evonik 26-04-0026SD1 Peach Flavored Powder (Nat & Art) 021716 Edgar A. Weber & Co. 28-05-0050SD1 Peach Flavor Powder (MWNI) 010616 Edgar A. Weber & Co. 28-98-0014SD1 Strawberry Flavor Powder (MWNI) 012516 Edgar A. Weber & Co. 30-86-0184SD1 Strawberry Flavored Powder (Art) 072815 Edgar A. Weber & Co. 20-85-4724SD1 Orange Flavor Powder (Nat) 021716 Edgar A. Weber & Co. 26-01-0120SD2 Orange Flavor Powder (Nat & Art) 080715 Edgar A. Weber & Co. 26-03-0039SD1 Mango Flavored Powder (Nat & Art) 021716 Edgar A. Weber & Co. 28-11-0058SD1 Mango Flavored Powder (MWNI) 011916 Edgar A. Weber & Co. 30-98-0057SD1 Apple Flavored Powder (Art) 072915 Edgar A. Weber & Co. 22-97-0119SD2 Apple Flavored Powder (WONF) 030216 Edgar A. Weber & Co. F4538 Grape Flavor Powder (Art) 45383316 Foote & Jenks Hawaiian Punch Flavor Powder (Nat) 158D12 Prinova Blue raspberry flavored powder (Nat & Art) 113D01 Prinova Mixed Berry Flavor Powder (Nat) 118D01 Prinova Cherry Flavored Powder (Nat & Art) 186D01 Prinova 28-03-0212SD1 Mixed Berry Flavor Powder (MWNI) 031516 Edgar A. Weber & Co. Kleptose Linecaps Maltodextrin E436F Roquette's results showed that sucralose content was optimized.

[0095] Flavor masking was performed using different amounts of sucralose to create formulations C (formulations C1 to C3). The composition of formulations C1-C3 is shown in Table 7. Formulation C1 was selected based on optimal flavor masking performance.

[0096] Table 7: Composition of Sucralose Compound Material (Ingredient C) Type C1 (0.5% sucralose) C1 percentage Type C2 (0.3% sucralose) C2 percentage Type C3 (0.1% sucralose) C3 percentage TURSO 1.0000 14.74% 1.0000 14.77% 1.0000 14.80% NaPB 3.0000 44.21% 3.0000 44.30% 3.0000 44.39% Sodium dihydrogen phosphate monohydrate 0.2800 4.13% 0.2800 4.13% 0.2800 4.14% Anhydrous disodium hydrogen phosphate 0.3920 5.78% 0.3920 5.79% 0.3920 5.80% hydrated glucose binder 1.6000 23.58% 1.6000 23.63% 1.6000 23.67% Sorbitol 0.4000 5.89% 0.4000 5.91% 0.4000 5.92% Aerosil 200 0.0800 1.18% 0.0800 1.18% 0.0800 1.18% Subtotal: 6.7520 99.50% 6.7520 99.70% 6.7520 99.90% Sucralose 0.0339 0.50% 0.0203 0.30% 0.0068 0.10% total: 6.7859 100.00% 6.7723 100.00% 6.7588 100.00% Seasoning Options

[0097] Prepare bulk active mixtures and dissolve each unit dose in approximately 250 mL of water. In addition to Kleptose Linecaps maltodextrin, add several flavoring agents at different concentrations until the desired flavor masking level is achieved. Select the final concentrations of flavoring agents and sweeteners based on flavor optimization. Maltodextrin-based formulations and updates.

[0098] In order to maintain the formulation at a total material of approximately 10g of added flavoring agent and maltodextrin, all other materials (except API) were adjusted and formulation C1 was further modified. Furthermore, considering that the anhydrous form is more hygroscopic than the heptahydrate form, the anhydrous disodium hydrogen phosphate in the formulation was replaced with disodium hydrogen phosphate heptahydrate. The modified formulation C1 is shown in Table 8 below.

[0099] Table 8. Modified formulation C1 Materials (Modified formulation (C1)) Composition % (w / w) Modified formulation C1-1 sachet (0.5% sucralose) TURSO 9.35% 1 NaPB 28.06% 3 Sodium dihydrogen phosphate monohydrate 2.62% 0.28 Disodium hydrogen phosphate heptahydrate 6.92% 0.74 hydrated glucose binder 14.96% 1.6 Sorbitol 3.74% 0.4 Aerosil 200 0.75% 0.08 Sucralose 0.50% 0.0535 Mixed berry flavor (0.14% w / v) 3.10% 0.331223 Subtotal: 70.00% 7.484723 Kleptose Linecaps (maltodextrin) 30.00% 3.207738429 total: 100.00% 10.69246143

[0100] It is worth noting that the liquidity is still stronger than that of the API, indicating that the modified formulation has been successful in improving liquidity. The Cartesian index of C1 for the modified formulation is 22.3, with a rest angle of 34.4. The liquidity coefficients for specific rest angle ranges are shown in Table 5 above for reference; the liquidity coefficients for specific Cartesian index ranges are shown in Table 9.

[0101] Table 9. Carr Index and Liquidity Carr index Liquidity <10 excellent 11-15 good 16-20 ordinary 21-25 qualified 26-31 Difference 32-37 Very bad >38 Very, very bad results

[0102] The amounts of specific flavoring agents, maltodextrin, and sucralose added were measured to determine the optimal flavor masking. Furthermore, the addition of these agents did not affect the flowability improvement achieved in Example 1. Example 3: Aggregation Detection and Prevention Materials and Equipment

[0103] Table 10: Active and Stable Materials Material brand grade Manufacturer Manufacturer batch number # TURSO -- -- Prodotti Chimici E Alimentari SpA 2015010026 NaPB -- -- Sri Krishna Pharmaceuticals SPB026 / 14-15 Sodium dihydrogen phosphate monohydrate -- ACS Amresco 1575C229 Disodium hydrogen phosphate heptahydrate -- ACS Amresco 3606C403 hydrated glucose binder Emdex NF JRS Pharma EX13K42DX Sorbitol Neosorb P110 USP / NF / EP / JP Roquette US061 Sucralose HPLC Sigma Life Science BCBP3048V Colloidal silicon dioxide Aerosil 200 USP / NF / EP / JP Spectrum 1DK0436 Maltodextrin Lab4118 Kleptose Linecaps EP Roquette E436F Mixed Berry Flavor Powder (MWNI) 28-03-0212SD1 -- Edgar A. Weber & Co. 031516

[0104] Table 11: Equipment used for manufacturing active and stable approvals equipment Manufacturer model mixer Bohle LM40 w / 5L bin

[0105] Table 12: Equipment used for analyzing nonconforming batches equipment Manufacturer model LOD Denver Instruments IR-30 Stability test chamber Environmental Specialties ES2000 / ES2000 Reach-in Results

[0106] Storing the mixture in a sealed Bohle Blender 5L cabinet for ~36 hours resulted in aggregated and difficult-to-disperse mixture. To prevent aggregation and further improve the stability of the mixture, the aggregated mixture was manually removed and placed in a 50°C drying oven for loss on drying (LOD) testing. Loss on drying (LOD) testing

[0107] After drying at 50°C for 2 hours, the degree of moisture absorption was determined by LOD testing on the recovered aggregated mixture (PD2016-015-33B). The results were compared with those of the non-aggregated mixture stored in a sealed bottle (PD2016-015-29A). The LOD test results are shown in Table 13.

[0108] Table 13. LOD of active mixtures Mixture approval document Sample weight (g) Drying weight loss % Time (min) PD2016-015-33B (Aggregation) 2.044 5.72 7.7 2.215 5.6 4.7 2.121 6.22 7.1 2.09 6.22 10 PD2016-015-29A 2.234 4.59 6.9 2.205 4.63 7.4 Dynamic Vapor Adsorption (DVS) Detection

[0109] Samples of NaPB, TURSO, and the modified formulation C1 mixture were subjected to DVS analysis to determine the weight increase due to humidity. The DVS isotherms for NaPB and TURSO are shown in Figures 2 and 3, respectively. The results showed that NaPB exhibited significant weight fluctuations above 45% RH. These changes were also reflected in the active mixture (as shown in Figure 4) and are believed to have caused the observed aggregation. Individual and combined effects of humidity on APIs.

[0110] The samples of NaPB, TURSO and their mixture were stored in open vials at 25°C / 60%RH for ~60 hours, after which the vials were removed and the observations were recorded.

[0111] Aggregation occurs in mixtures containing two APIs due to moisture absorption. NaPB exhibits mass fluctuations of up to 50%, and the aggregation caused by moisture absorption presents difficulties in handling and administration, potentially altering efficacy. Furthermore, the aggregated material may restrict its mixing and flowability during processing. Since aggregation is only observed when the two APIs are mutually exposed to moisture, it is necessary to prevent moisture absorption or isolate the APIs to reduce aggregation. The following experiments were conducted with the goal of reducing aggregation. Balancing and rolling materials and equipment.

[0112] Table 14. Materials used in equilibrium studies Material brand grade Manufacturer Manufacturer batch number # TURSO -- -- Prodotti Chimici E Alimentari SpA 2015010026 NaPB -- -- Sri Krishna Pharmaceuticals SPB026 / 14-15 Sodium dihydrogen phosphate monohydrate -- ACS Amresco 1575C229 Disodium hydrogen phosphate heptahydrate -- ACS Amresco 3606C403 hydrated glucose binder Emdex NF JRS Pharma EX13K42DX Sorbitol Neosorb P110 USP / NF / EP / JP Roquette US782 Colloidal silicon dioxide Aerosil 200 USP / NF / EP / JP Spectrum 1DK0436 Maltodextrin Lab4118 Kleptose Linecaps EP Roquette E436F Mixed Berry Flavor Powder (MWNI) 28-03-0212SD1 -- Edgar A. Weber & Co. 031516

[0113] Table 15 Equipment used for equilibrium studies equipment Manufacturer model mixer Bohle LM40 w / 5L tank Comil Conical grinder Quadro 197 Screen (#30 mesh) Fischer Scientific E-11 Spec Rolling mill Gerteis Mini-Pactor heat sealing machine Midwest Pacific MP-12 Karl Fischer Coulometer Mettler Toledo DL32 fuel gauge balance

[0114] API Equilibration: To test whether equilibration prevents subsequent aggregation, APIs are equilibrated under ambient conditions. In short, APIs are equilibrated in two non-separate trays. Samples are taken at T = 0, 1, 2, 3, 4, and 24 hours and sealed in headspace vials for Karl Fischer titration analysis. This study is conducted to determine the moisture absorption rate of each API and whether pre-equilibrated APIs exhibit lower aggregation due to reduced moisture absorption after mixing.

[0115] Water content analysis by Karl Fischer titration: Water content of each sample was analyzed using Karl Fischer titration. Equilibrium was determined when RSDE < 10% between two consecutive time points.

[0116] Mixing parameters: Mix each batch for 20 minutes, grind, and then mix again at 25 RPM for 20 minutes. For grinding, operate a Quadro Comil equipped with a 1016 conical screen with fan-shaped mesh at 30% power. Fill with particle-free test bags. Rolling.

[0117] Dry granulation was performed by rolling the active mixture. The remaining mixture was rolled at 7.5 and 10 kN. Test bags for each granulation condition were filled to observe the behavior of granulated and non-granulated samples in the packaging over time. Table 16 below shows the rolling parameters used.

[0118] Table 16: Rolling Parameters parameter Setting value Extrusion pressure 7.5 / 10kN Rolling speed 3RPM Gap 2.5mm Granulation screen 2.0mm Granulation speed 10 / 20 RPM

[0119] Results from the equilibrium study showed that the equilibrium surprisingly had no significant effect on the API moisture content. All mixtures and particles aggregated over time; however, 10 kN particles showed the least aggregation and the best recovery from the bag, indicating that rolling surprisingly resulted in a significant improvement in preventing aggregation. Example 4: Study on silica treatment for aggregation prevention

[0120] Studies were also conducted to determine whether aggregation was due to the interaction between the two APIs and whether porous silica could reduce aggregation by controlling the surrounding water vapor. Tables 17 and 18 below show the materials used for individual API treatment and silica studies.

[0121] Table 17: Materials used for individual API processing / silicon dioxide research Material brand grade Manufacturer Manufacturer batch number # TURSO -- -- 2016020063 Prodotti Chimici E Alimentari SpA NaPB -- -- SPB013 / 14-15 Sri Krishna Pharmaceuticals Anhydrous disodium hydrogen phosphate -- ACS 2934C448 Amresco hydrated glucose binder Emdex NF EX13K42DX JRS Pharma Sorbitol Neosorb P110 USP / NF / EP / JP US782 Roquette Sucralose (69293-100g) HPLC BCBP3048V Sigma Life Science Colloidal silicon dioxide Aerosil 200 USP / NF / EP / JP 1DK0436 Spectrum Silicon dioxide Syloid 244FP USP / NF 5210156995 Grace Maltodextrin Lab4118 Kleptose Linecaps EP E436F Roquette Mixed Berry Flavor Powder (MWNI) 28-03-0212SD1 -- 031516 Edgar A. Weber & Co. Sodium stearate Pruv NF 1298X JRS Pharma Silicon dioxide Syloid 63FP USP / NF 5210151493 Grace

[0122] Table 18: Equipment used for individual API processing / silicon dioxide research equipment Manufacturer model Rolling mill Gerteis Mini-Pactor Tighten the volumetric gauge Erweka SVM22 heat sealing machine Midwest Pacific MP-12 Mesh screen vibrator WS Tyler RX86 screen Fischer Scientific E-11 Spec

[0123] Each API was separately mixed with the excipient and rolled to determine whether the proximity of two APIs in the mixture or particles would cause aggregation. The resulting particles were then mixed and stirred before being filled into test bags. The bulk density and tapping compactness of each mixture were measured before rolling. For this experiment, all silica systems were used at 1% w / w. Aerosil 200 was used as a negative control, while Syloid 244FP and Syloid 63FP systems were used to remove moisture from the APIs to determine whether the APIs would aggregate under reduced local moisture content. The flowability of the mixtures is shown in Table 19 below.

[0124] Table 19: Flowability of Silicon Dioxide Mixtures 1% Aerosil 200 1% Syloid 244FP 1% Syloid 244FP (TURSO) Bulk density (g / mL) 0.4906 0.5313 0.6429 Knock density (g / mL) 0.6500 0.6846 0.8372 Hausnabi 1.3250 1.2885 1.3023 Carr index 24.5283 22.3881 23.2143 1% Syloid 244FP (NaPB) 1% Syloid 63FP (TURSO) 1% Syloid 63 FP (NaPB) Bulk density (g / mL) 0.5517 0.6032 0.5079 Knock density (g / mL) 0.6809 0.8130 0.6400 Hausnabi 1.2340 1.3478 1.2600 Carr index 18.9655 25.8065 20.6349 Particle size distribution

[0125] Particle size distribution was used as a measure of aggregation because aggregated particles should be unable to pass through smaller mesh sieves, thus favoring larger particles. Sieve shaker analysis was performed at T=7 days for each experimental condition. The results are shown in Figure 5. (Station angle)

[0126] The relative degree of aggregation under each condition was determined using flowability measured at the angle of repose. Since decreased flowability is observed in aggregated samples, a lower angle of repose should indicate a lower degree of aggregation and better recyclability of the final product packaging. The angle of repose measurements at T=4 for each test condition are used (Table 20).

[0127] Table 20: Angle of rest at T=4 Liquidity Angle of rest Aerosil 200 (without RC) Syloid 244FP (without RC) Syloid 244FP (10kN) Aerosil 200 (10kN) Syloid 63FP (individual, 10kN) Syloid 244FP (individual, 10kN) excellent 25-30 -- -- -- -- -- -- good 31-35 35.69 35.71 34.38 33.05 31.83 34.05 ordinary 36-40 -- -- -- -- -- -- qualified 41-45 -- -- -- -- -- -- Poor - Must vibrate 46-55 -- -- -- -- -- -- Very bad 56-65 -- -- -- -- -- -- Very, very bad >66 -- -- -- -- -- --result

[0128] Originally, the formulation used a silicon dioxide form, Aerosil 200, which produced a stationary angle of 35.69. Replacing this with Syloid 63FP and rolling with a 10 kN extrusion pressure resulted in an 11% improvement in flowability. Surprisingly, different Syloid products, such as Syloid 244FP, did not produce the same improvement. Due to these experimental results, Aerosil 200 was removed from the formulation and replaced with Syloid 63FP, and rolling was added to the process. Given the detrimental effects of aggregation on processing, an 11% improvement represents significant and remarkable progress. Example 5: Manufacturing Stability of Active Formulations / Molded Parts

[0129] Active formulation mixing and rolling: Tables 21 and 22 show the materials and equipment used for active formulation mixing and rolling. Table 23 shows the active formulations.

[0130] Table 21 Material brand grade Manufacturer Manufacturer batch number # TURSO -- -- Prodotti Chimici E Alimentari SpA 2016020063 NaPB -- -- Sri Krishna Pharmaceuticals limited SPB011 / 15-16 Anhydrous disodium hydrogen phosphate -- ACS Amresco 3536C204 glucose binding agent Emdex NF JRS Pharma EX15J37D Sorbitol Neosorb P110 USP / NF / EP / JP Roquette US453 Sucralose -- HPLC Sigma Life Science BCBP3048V Silicon dioxide Syloid 63FP USP / NF Grace 5210151493 maltodextrin Kleptose Linecaps EP Roquette E436F Mixed Berry Flavor Powder (MWNI) 28-03-0212SD1 -- Edgar A. Weber & Co. 1609834 Sodium stearate Pruv NF JRS Pharma 1298X

[0131] Table 22 equipment Manufacturer model Screen (#30 mesh) Fischer Scientific E-11 Spec Mixer (w / 20L bin) Bohle LM40 Comil Conical grinder Quadro 197 Rolling mill Gerteis Mini-Pactor heat sealing machine Midwest Pacific MP-12

[0132] Table 23 Materials (Active Mixture - 1 Salt) Components % (w / w) Active mixture - x1 (unit: grams) TURSO 10.29% 1.0000 NaPB 30.86% 3.0000 Anhydrous disodium hydrogen phosphate 2.88% 0.2800 hydrated glucose binder 16.46% 1.6000 Sorbitol 4.11% 0.4000 Syloid 63FP (1%) 1.00% 0.0971 Sucralose (0.5%) 0.50% 0.0485 Sodium stearate fumarate (0.5%) 0.50% 0.0485 Mixed berry flavor powder (0.14% w / v) 3.41% 0.3312 Subtotal: 70.00% 6.8053 Kleptose Linecaps (30%) 30.00% 2.9166 total: 100.00% 9.7219

[0133] Weigh all materials, sieve (#30 mesh), and layer them into a 20 L mixer tank. Mix at 25 RPM for 30 minutes. Remove the contents of the mixer and grind using a Quadro Comil equipped with a 1016 fan-shaped drum sieve at 30% speed. After grinding, return the mixture to the mixer tank and mix again at 25 RPM for 30 minutes. During the last 30 minutes of mixing, take samples of homogeneity at 10-minute intervals and analyze the API content by HPLC. Once the RSD is shown to be >5% and the drug loading is within 90 to 110%, roll the mixture using the parameters shown in Table 24 below. A batch was successfully manufactured under these parameters.

[0134] Table 24: Rolling Parameters parameter Setting value Extrusion pressure 7.5 / 10kN Rolling speed 3RPM Gap 2.5mm Granulation screen 2.0 mm Granulation speed 10 / 20 RPM Example 6: Further Flavor Optimization

[0135] While the flavor optimization in Example 2 substantially improved the taste, a series of follow-up experiments were conducted to determine whether the taste could be further improved. Additional flavoring agents.

[0136] A range of novel flavorings, including mango, strawberry, masking flavorings, and mixed berry flavorings, were tested. Following further taste testing, the combination of the masking flavoring and the mixed berry flavoring was determined to be the most suitable API flavor masking. The results were substantially superior to formulation C1 developed during the initial formulation development phase. Additional sucralose.

[0137] After changing the flavoring agent, the amount of sucralose was further adjusted and taste tests were conducted. It was determined that additional sucralose would be used to further enhance / mask the flavor of the API, and the amount of sucralose was adjusted to 200 mg per unit dose. Formulation D

[0138] With the above changes, the blend was modified into blend D (Table 25) with improved flavor characteristics.

[0139] Table 25: Blending Material D Material mg per unit dose weight% NaPB 3000.000 29.2% TURSO 1000.000 9.7% Hydrated glucose binder NF (EMDEX NON GMO) 1600.000 15.6% Sorbitol NF (NEOSORB P110) 400,000 3.9% Sucralose NF / PH.EUR 200,000 1.9% Silicon dioxide NF (Syloid 63FP)-CTM 97.200 0.09% Maltodextrin NF / PH.EUR. (Kleptose) 2916.000 28.3% Mixed Berry Flavor Powder (MWNI) 102.000 1.0% Taste masking 644.000 6.3% Anhydrous disodium hydrogen phosphate USP 280,000 2.7% Sodium stearate fumarate NF / EP / JP 48.600 0.5%

[0140] These results show that changing the amount of sucralose and replacing the flavoring agent can exceed the flavor masking provided by formulation C1. Since formulation C1 was previously believed to be optimal, this change represents a significant improvement. Example 7: Processing and Manufacturing

[0141] Next, several processing steps, including premixing, pressing, and final mixing, were performed for optimization. The stirring during the premixing stage can affect the homogeneity of the mixture used for downstream pressing and the properties of the premix, and therefore optimization was performed. Specifically, three individual batches, CCZHB, CCZHC, and CCZHD, were subjected to different stirring times as shown in Table 26. An A&M mixer equipped with a 197S Quadro Comil with a 16-quart V-Shell, a 062R comil screen, and a Gerteis Macro-pactor was used. Mixture homogeneity, flow index, bulk density and tap compaction, particle size distribution (PSD), rebuilding time, and dissolution were used as readings. Mixture homogeneity (BU) samples were taken from each batch at 10 different locations using the 16-quart V-Shell (see Figure 6). Table 27 summarizes the BU results for all three batches. The average value of PB ranged from 98.1% to 99.8%, while that of TUDCA was 98.1% to 99.3%. The RSD of PB ranged from 0.5% to 1.1%, while that of TUDCA was 1.3% to 1.9%. Figure 7 shows the PSD graph of the sample after premixing.

[0142] Table 26 batch number# Stirring time at 25 rpm Number of rotations CCZHB 15 minutes 375 RPM CCZHC 25 minutes and 48 seconds 645 turns (used for mixed time in registration approval) CCZHD 36 minutes and 36 seconds 915 turns

[0143] Table 27: Results of uniformity of mixtures from batches CCZHB, CCZHC and CCZHD Sample location API percentage (%) PB TUDCA CCZHB CCZHC CCZHD CCZHB CCZHC CCZHD Top 1 98.6 99.2 98.4 96.7 97.1 96.6 Top 2 98.2 99.7 98.0 101.1 103.4 98.2 3 above 97.9 100.6 100.5 97.6 99.5 101.7 4 above 98.8 100.9 97.4 98.3 99.8 95.7 Middle 1 97.2 100.1 97.6 98.1 97.7 95.9 Middle 2 97.6 99.8 99.1 98.5 98.9 97.8 Middle 3 98.3 99.9 99.5 99.9 99.1 97.4 Middle 4 98.0 100.8 99.4 98.9 100.3 99.3 Below 1 98.2 98.7 99.9 97.9 99.4 99.4 2 below 98.5 98.7 100.0 97.9 98.2 99.0 average 98.1 99.8 99.0 98.5 99.3 98.1 Minimum 97.2 98.7 97.4 96.7 97.1 95.7 maximum 98.8 100.9 100.5 101.1 103.4 101.7 %RSD 0.5 0.8 1.1 1.3 1.7 1.9

[0144] A 250 g sample of the composition mixture was obtained for physical qualitative analysis, including PSD, bulk density, tapped density and flow index. Table 28 shows the physical test results obtained for all three batches (premix and final mixture).

[0145] Table 28 premix Final mixture TEST CCYNH CCPKP CCZHB CCZHC CCZHD CCYNH CCPKP CCZHB CCZHC CCZHD PSD 10 (2000μm) 0 0 0 0 0 0.06 0.06 0.07 0.18 0.18 14 (1400μm) 0.12 0.12 2.96 0.16 0.22 17.12 14.84 15.62 22.09 19.47 18 (1000μm) 1.34 1.22 3.99 2.49 1.32 20.34 17.94 16.89 21.02 20.45 30 (600μm) 6.04 5.48 66.23 55.20 5.39 19.13 16.30 18.48 19.47 18.61 40 (425μm) 9.88 9.65 21.24 37.35 13.63 8.42 8.82 8.79 7.85 8.01 80 (180 μm) 55.87 45.27 4.77 4.80 52.40 16.26 16.96 18.97 13.87 13.21 PAN (˂180μm) 26.75 38.26 0.81 0.00 27.04 18.67 25.08 21.18 15.52 20.07 total% 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Bulk density (g / mL) 0.46 0.48 0.47 0.48 0.49 0.63 0.67 0.63 0.63 0.63 Knock density (g / mL) 0.75 0.83 0.75 0.76 0.76 0.83 0.87 0.89 0.79 0.82 Flow index (mm) 28 26 34 26 26 14 14 9 9 12

[0146] Next, the dissolution and reconstruction times of these three batches were analyzed. The results are shown in Tables 29 to 31.

[0147] Table 29: Dissolution data of TUDCA in the premixing study Time: (minutes) / Approval document 5 15 30 45 60 75 Average percentage of release CCZHB 92 96 96 96 96 97 CCZHC 89 97 98 98 98 98 CCZHD 92 97 97 97 97 97

[0148] Table 30: PBA dissociation data in premixing study Time: (minutes) / Approval document 5 15 30 45 60 75 Average percentage of release CCZHB 94 97 97 97 97 97 CCZHC 91 99 99 99 100 100 CCZHD 93 98 98 98 98 98

[0149] Table 31: Reconstruction Time of Batch CCZHB, CCZHC and CCZHD Approval document Time (minutes:seconds) CCZHB 13:04 CCZHC 11:03 CCZHD 11:57

[0150] No statistically significant differences were observed in the homogeneity, dissolution, or reconstruction time of the mixtures among the three batches. However, significant differences were observed in the PSD of the three batches after premixing. The PSD of the premixes of CCZHB and CCZHC, which were premixed for shorter times, showed coarser material. This indicates that increasing the mixing time results in more particle loss. Therefore, a shorter premixing time is preferred.

[0151] In the compression step, several compression parameters, such as roller gap, compression force, and granulation screen size, can affect the physical properties of the final particles 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. Compression speed, another factor that may affect physical properties, was evaluated during the final mixing study. Bulk mixtures (batch CDCVY) premixed based on the aforementioned determined premixing parameters were divided into 12 sub-batches, and each sub-batch was rolled and granulated using a set of different compression forces (5-15 kN / cm), roller gaps (2-3 mm), and grading screen sizes (1 to 2 mm) (Table 32). For each sub-batch, the physical properties, dissolution, and reconstitution time of the final mixture were evaluated. Tables 33 and 34 show the physical properties obtained for all 12 sub-batches.

[0152] Table 32: Rolling and Granulation Parameters test# Mesh screen (mm) Gap (mm) Force applied (kN / cm) 1 1 3 15 2 1 3 5 3 1.5 2.5 10 4 2 3 15 5 2 3 5 6 1.5 2.5 10 7 1 2 15 8 1 2 5 9 1.5 2.5 10 10 2 2 5 11 2 2 15 12 1.5 2.5 10

[0153] Table 33: Sub-lots 1 to 6 Final Mixture Detection Sub-batch #1 Sub-batch #2 Sub-batch #3 Sub-batch #4 Sub-batch #5 Sub-batch #6 PSD 10 (2000μm) 0.05 0.03 0.04 0.28 0.12 0.04 14 (1400μm) 0.11 0.26 2.21 28.33 13.00 1.99 18 (1000μm) 0.86 0.51 21.85 24.62 17.38 22.97 30 (600μm) 25.38 22.48 24.46 17.96 16.80 24.70 40 (425μm) 17.01 15.02 10.68 7.20 8.58 10.38 80 (180μm) 30.08 30.90 19.70 11.10 20.66 19.53 PAN (˂180μm) 26.51 30.80 21.06 10.51 23.46 20.39 total% 100.00 100.00 100.00 100.00 100.00 100.00 Bulk density (g / mL) 0.62 0.57 0.63 0.63 0.60 0.63 Knock density (g / mL) 0.82 0.81 0.80 0.80 0.79 0.81 Flow index (mm) 9 14 8 9 12 9

[0154] Table 34: Sub-lots 7 to 12 premix Final Mixture Detection Sub-batch #7 Sub-batch #8 Sub-batch #9 Sub-batch #10 Sub-batch #11 Sub-batch #12 PSD 10 (2000μm) 0.06 0.10 0.14 0.17 0.46 0.14 14 (1400μm) 0.22 0.28 2.00 17.60 27.58 2.53 18 (1000μm) 0.92 0.79 21.13 19.08 22.83 24.26 30 (600μm) 28.94 25.98 23.37 17.11 17.82 25.65 40 (425μm) 17.16 15.30 10.85 8.29 7.85 10.68 80 (180μm) 28.96 30.15 20.95 19.84 13.34 18.98 PAN (˂180μm) 23.74 27.40 21.56 17.91 10.12 17.76 Total % 100.00 100.00 100.00 100.00 100.00 100.00 Bulk density (g / mL) 0.64 0.59 0.61 0.60 0.61 0.62 Knock density (g / mL) 0.82 0.81 0.77 0.78 0.78 0.79 Flow index (mm) 9 12 9 14 9 9

[0155] Figures 8 to 10 show the particle size distribution under granulation screens of 1.00 mm, 1.5 mm and 2.0 mm, respectively; the combined result is shown in Figure 11.

[0156] The above physical property data were input into the Minitab v. 18 statistical program and the optimal rolling parameters were determined using a statistical model based on the following reaction target group. These reaction targets related to particle size distribution were selected to achieve a narrow PSD for downstream packaging activities.

[0157] Table 35 reaction Target Particle size distribution Materials >1400 μm NMT 10% 425 μm < material < 1400 μm 45% ≤ Material ≤ 65% Materials <425 μm NMT 45% Reconstruction time NMT 15 minutes TUDCA dissolution Q=75% → Individual values ​​NLT 85% @15 minutes PB dissociation Q=75% à Individual values ​​NLT 85% @15 minutes

[0158] Based on statistical analysis, significant differences were observed in the PSD of 12 sub-batches of the final mixture. In the overall statistical analysis, bulk density and flow index showed moderately significant differences. Results from knock-tightness showed no significant differences. Since the physical properties of the final mixture are important factors for downstream packaging, a homogeneous particle size distribution is preferred. To achieve the above reaction objectives, the optimal pressing parameters for the predictive model were considered to be a roller gap width of approximately 2 mm to approximately 3 mm, a pressing force of approximately 5 to 15 kN / cm (target: 10.0 kN / cm), and a grading screen size of approximately 1.5 mm. Reconstruction time and dissolution curves were also presented.

[0159] Because compression force can affect the physical properties of the particles and the extent and rate of drug release, reconstitution time and dissolution data were further evaluated. Tables 36-38 present reconstitution time and average dissolution data for 12 sub-batches. Dissolution data for TUDCA and sodium phenylbutyrate in each of the 12 sub-batches are shown in Figures 12 and 13, respectively.

[0160] Table 36: Reconstruction Time Sub-approval Time: (minutes:seconds) #1 9:14 #2 8:30 #3 10:23 #4 13:19 #5 10:56 #6 12:06 #7 13:12 #8 9:27 #9 13:09 #10 13:57 #11 16:31 #12 13:26

[0161] Table 37: Dissolution Data of TUDCA Time: (minutes) / sub-batch 5 15 30 45 60 75 release% #1 85 98 99 99 99 99 #2 88 97 98 98 98 98 #3 86 97 98 98 98 98 #4 89 99 99 99 99 99 #5 90 100 98 100 100 100 #6 90 99 101 101 101 101 #7 83 97 98 98 98 98 #8 89 97 98 98 97 98 #9 94 100 101 101 101 101 #10 91 100 101 101 101 101 #11 92 101 101 101 101 101 #12 89 100 101 101 101 101

[0162] Table 38: Dissolution Data of PB Time: (minutes) / sub-batch 5 15 30 45 60 75 release% #1 85 98 98 98 98 98 #2 87 97 97 97 97 97 #3 85 97 97 97 97 97 #4 90 99 99 99 99 99 #5 86 96 97 97 97 97 #6 87 98 98 98 98 98 #7 84 97 98 98 98 98 #8 88 97 97 97 97 97 #9 92 98 99 99 99 99 #10 92 100 101 101 101 101 #11 93 101 101 101 101 101 #12 86 96 96 96 97 97

[0163] Generally significant differences in rebuild time were observed between different sub-lots. All 12 sub-lots met the bulk product specification of NMT (not exceeding) 20 minutes. To establish a more sensitive limit, a rebuild time of NMT = 15 minutes was entered into the statistical program as a response target. For this response target, no significant differences were observed between sub-lots, except for sub-lot #11, which had the longest rebuild time of approximately 16 to 17 minutes.

[0164] The dissociation data were not strongly affected by the detection parameters. Both the TUDCA dissociation % release and PB dissociation % release figures were completed after 15 minutes. The dissociation % release results were completely above the target limit of Q=75% @ 15 minutes. Figures 12 and 13 show the dissociation curves for the sub-batch.

[0165] To assess whether lower temperatures would affect the physical properties of the particles, a cooling temperature unit of 15 ± 2°C was introduced into the rolling mill. A reduction in agglomeration and aggregation was observed from the added cooling unit. Final mixing optimization...

[0166] The mixing time during the final mixing step can affect the homogeneity and final physical properties of the mixture, which are crucial for downstream packaging and are therefore optimized. Table 39 shows the different times and corresponding rotation numbers used. The homogeneity and physical properties of the mixture are evaluated. BU samples are obtained from the location shown in Figure 14. BU results are shown in Tables 40 to 42.

[0167] Table 39 series Mixing time at a constant speed of 20.5 rpm Number of rotations 1 0 minutes 0 turns 2 3 minutes 61.5 turns (similar to the 60 turns used for registration approval documents, which represents a mixed time) 3 5 minutes 102.5 rpm

[0168] Table 40: Batch CDCWH Premix Sample location % PBA % TUDCA Top 1 100.1 92.7 Top 2 100.3 98.8 3 above 99.3 100.9 Middle 1 98.7 97.3 Middle 2 100.0 101.3 3 in the middle 98.5 98.1 4 in the middle 101.1 98.2 Below 1 98.9 98.8 2 below 98.0 99.6 3 below 99.6 98.9 average 99.5 98.5 Minimum 98.0 92.7 maximum 101.1 101.3 % RSD 1.0 2.4

[0169] Sufficient uniformity of the premix was achieved, with an average value of 99.5% for PB and 98% for TUDCA, while the %RSD values ​​of the two active pharmaceutical ingredients were all below 2.5%.

[0170] Table 41: Batch of CDWH Compressed Granules Sample location Container #1 Container #2 Container #1 Container #2 % PBA % TUDCA Above 94.5 96.0 96.7 98.5 middle 95.5 95.2 97.3 99.2 Below 98.0 94.0 97.0 98.2 average 96.0 95.1 97.0 98.2 Minimum 94.5 94.0 96.7 98.2 maximum 98.0 96.0 97.3 99.2 % RSD 1.9 1.1 0.3 0.5 Overall average 95.5 97.8 Overall minimum 94.0 96.7 Overall maximum 98.0 99.2 Overall RSD 1.5 1.0

[0171] After rolling, sufficient uniformity was achieved, with the overall average value of PB being 95.5% and TUDCA being 97.8%, while the %RSD values ​​of the two active pharmaceutical ingredients were less than 2.0%.

[0172] Table 42: Final Mixture of Batch CDCWH Sample location % PBA % TUDCA No mixing Mix for 3 minutes Mix for 5 minutes No mixing Mix for 3 minutes Mix for 5 minutes Top 1 98.3 100.6 95.8 100.0 96.9 96.9 Top 2 103.6 98.6 101.6 99.8 96.9 99.4 3 above 98.8 99.2 100.0 99.5 98.9 97.6 4 above 99.6 101.3 99.9 97.9 99.4 98.5 Middle 1 101.3 99.7 98.7 98.3 98.8 98.7 Middle 2 95.4 96.3 99.2 98.4 94.2 96.7 3 in the middle 100.4 99.3 98.4 99.1 98.2 96.2 4 in the middle 100.5 98.8 102.4 98.6 97.3 98.0 Below 1 94.0 100.2 101.1 95.4 97.8 98.6 2 below 98.5 99.3 99.2 98.3 97.8 99.0 average 99.0 99.3 99.6 98.5 97.6 98.0 Minimum 94.0 96.3 95.8 95.4 94.2 96.2 maximum 103.6 101.3 102.4 100.0 99.4 99.4 % RSD 2.8 1.3 1.9 1.3 1.5 1.1

[0173] No significant differences in mix uniformity were observed with different final mixing times. Sufficient final mix uniformity was achieved; the average value for PBA ranged from 99.0% to 99.6%, while that for TUDCA ranged from 97.6% to 98.5%. The %RSD for PBA ranged from 1.3% to 2.8%, while that for TUDCA ranged from 1.1% to 1.5%. Although the individual values ​​for mix uniformity at various locations were entirely within the recommended range of 85% to 115%, a larger change in BU results was observed compared to mixing for 3 or 5 minutes without final mixing.

[0174] A 250 g sample of the composition mixture was obtained for physical qualitative analysis. Table 43 shows the results of the physical tests. There were no significant differences in PSD, bulk density, and knockdown; however, there were significant differences in flow index. Improved flowability was observed under no-mixing conditions. Shorter mixing times also resulted in coarser material. Therefore, no final mixing was determined to be the preferred condition.

[0175] Table 43: Physical Qualitative Batch CDWH Detection Final Mixture No mixing Mix for 3 minutes Mix for 5 minutes PSD (%) 10 (2000µm) 0 0 0 14 (1400µm) 1.16 1.34 1.30 18 (1000µm) 18.31 17.70 17.08 30 (600µm) 23.73 22.18 22.14 40 (425µm) 11.59 10.43 10.53 80 (180µm) 21.38 20.40 21.07 PAN (<180µm) 23.83 27.95 27.88 total 100.00 100.00 100.00 Bulk density (g / mL) 0.60 0.62 0.63 Knock density (g / mL) 0.82 0.83 0.85 Flow integer (mm) 9 16 14

[0176] Table 44: PSD Batch CDWH Particle size distribution Target No mixing Mix for 3 minutes Mix for 5 minutes Materials >1400 µm NMT 10% 1.16 1.34 1.30 425 µm < material < 1400 µm 45% < Material < 65% 53.63 50.31 49.75 Material < 425 µm NMT 45% 45.21 48.38 48.95 Dissolution and Reconstitution Time

[0177] No statistical significance was observed in the dissolution and reconstruction times (Tables 45 to 47). Table 48 shows a group of preferred physical properties of bulk products.

[0178] Table 45: TUDCA dissolution data chart (batch CDWH) Time: (minutes) / mixing time 5 15 30 45 60 75 Average release % No mixing 89 96 96 96 96 96 Mix for 3 minutes 90 97 97 97 97 97 Mix for 5 minutes 87 95 96 96 96 95

[0179] Table 46: PBA dissolution data chart (batch CDWH) Time: (minutes) / mixing time 5 15 30 45 60 75 Average release % No mixing 90 95 95 95 95 95 Mix for 3 minutes 93 98 98 98 98 98 Mix for 5 minutes 90 98 98 98 98 98

[0180] Table 47: Reconstruction Time (Batch CDCWH) Mixing time Time (minutes) No mixing 16 Mix for 3 minutes 15 Mix for 5 minutes 15

[0181] Table 48 Particle size distribution Target Material > 1400 µm 425 µm < Material < 1400 µm Material < 425 µm *NMT 10% 45% < Material < 65% NMT 50% Volume density 0.5 – 0.7 g / mL Tightness 0.7 – 0.9 g / mL Flow Index **NLT 16 mm * NMT: Not exceeding** NLT: Not less than

[0182] The above optimization study revealed better processing conditions for improving flowability and reducing the amount of fine particles in the final product that are considered detrimental to flowability. It determined that: i. a premixing time of approximately 375 rpm, ii. a compaction force between 5 and 15 kN / cm, a gap width between approximately 1.0 mm and approximately 5.0 mm, a rolling speed of approximately 4 to approximately 12 rpm, and a granulation screen size of approximately 1.5 mm, and iii. no final mixing, resulting in improved product properties, including flowability. These improvements collectively yielded a Karl Fischer index of approximately 8 to 9, representing a significant and remarkable improvement compared to the previously developed formulation (~20 Karl Fischer index). Statistical analysis

[0183] Perform statistical analysis on the results from the suppression research. The input settings are as follows: factor Minimum middle maximum Mesh size (mm) 1.0 1.5 2.0 Gap width (mm) 2.0 2.5 3.0 Extrusion pressure (kN / cm) 5.0 10.0 15.0

[0184] Analyze the following physical reactions: % remaining on a 10-mesh sieve, % remaining on a 14-mesh sieve, % remaining on an 18-mesh sieve, % remaining on a 30-mesh sieve, % remaining on a 40-mesh sieve, % remaining on an 80-mesh sieve, % Pan, bulk density, knock density, and flow index. Results – Particle size distribution reaction

[0185] A good or very good model was found for the particle size distribution reaction (% remaining on the 10-mesh sieve, % remaining on the 14-mesh sieve, % remaining on the 18-mesh sieve, % remaining on the 30-mesh sieve, % remaining on the 40-mesh sieve, % remaining on the 80-mesh sieve and % Pan).

[0186] In all these models, the major effects of screen size and extrusion pressure, as well as the interaction effect of screen forces, were statistically significant with ≥95% confidence. The curvature effect was also significant in all PSD reaction models, except for the percentage and percentage Pan remaining on the 10-mesh screen. The presence of the curvature term in the model indicates that at least one major factor has a secondary effect on the reaction. In the model, the major effect of the gap width on the percentage and percentage Pan remaining on the 30-mesh screen was statistically significant with ≥95% confidence.

[0187] In the model, the coefficients for the percentages remaining on a 10-mesh sieve, 14-mesh sieve, and 180-mesh sieve are positive for sieve size, while the coefficients for the percentages remaining on a 30-mesh sieve, 40-mesh sieve, 80-mesh sieve, and % Pan are negative. This indicates that increasing the sieve size tends to increase the amount of larger particles in the pressed mixture and decrease the amount of smaller particles.

[0188] Similarly, the model coefficient for extrusion pressure is positive for the percentages remaining on the 10-mesh sieve, 14-mesh sieve, 18-mesh sieve, 30-mesh sieve, and 40-mesh sieve, while the coefficient is negative for the percentages remaining on the 80-mesh sieve and % Pan. This shows that increasing extrusion pressure also tends to increase the amount of larger particles in the compressed mixture and decrease the amount of smaller particles.

[0189] The model coefficient for gap width is negative for the percentage remaining on a 10-mesh sieve and the percentage remaining on a 30-mesh sieve. For the percentage remaining on a 14-mesh sieve, the percentage remaining on an 18-mesh sieve, the percentage remaining on a 40-mesh sieve, and the percentage remaining on an 80-mesh sieve, the coefficient is close to zero. The gap width coefficient is positive for the percentage of Pan particles. Therefore, increasing the gap width may reduce the amount of larger particles in the pressed mixture and increase the amount of smaller particles.

[0190] This paper also found a good predictive model for bulk density and flow index. Example 8: Study on degradation by external forces

[0191] External degradation studies were also conducted on each API and the final formulation containing two APIs (referred to as "AMX bagged powder"). This study included samples of PB (sodium phenylbutyrate) API, TURSO API, placebo, and AMX bagged powder under heat, heat and humidity, light, oxidation, acid, or alkali conditions (Table 49).

[0192] Table 49 sample Pressure conditions Details of pressure conditions Observed degradation % PB API TURSO API AMX in bags (bulk) PB API (4500 mg / sample), TURSO API (1500 mg / sample), placebo mixture, and AMX sachet powder (4500 mg PB and 1500 mg TURSO per sample). hot 85°C for 10 days none none PB: ~8% TURSO: ~19% Hot and humid Each sample was treated at 85°C with 1.0 mL of water for 10 days. none 100% PB: ~4% TURSO: ~10% Oxidation 10 mL of 3% H2O2 per sample none 3% PB: None; TURSO: ~2% acid Each sample was treated with 10 mL of 1.0 N HCl at 50°C for 3 days. none none none Each sample was treated with 10 mL of 1.0 N HCl at 50°C for 7 days. none ~ 3% none alkali Each sample was treated with 10 mL of 1.0N NaOH at 50°C for 3 days. none ~5% none Each sample was treated with 10 mL of 1.0N NaOH at 50°C for 7 days. none ~17% none Light 1 x ICH conditions (white light NLT 1.2 million lux hours and UV light NLT 200 W hours / m) 2 ) none none none

[0193] The analysis results of the control group and the pressure sample are summarized in Table 50. The relative mass balance deficit values ​​are seriesd in Table 51.

[0194] PB API did not degrade under any external degradation conditions. TURSO API did not degrade under heat and light. Slight degradation was observed on day 7 under acidic conditions and on day 3 under oxidizing and alkaline conditions. On day 7, TURSO API degraded by ~17% under alkaline conditions. TURSO API completely denatured or precipitated in solution under heat and humidity conditions, as no TURSO peak was detected in the analytical sample solution. The placebo mixture exposed to external degradation conditions did not produce any interfering peaks in terms of residence time of the active peak.

[0195] PB and TURSO in the AMX bagged powder did not degrade under acidic, alkaline, and light conditions. PB in the bag did not degrade under oxidizing conditions, but degraded by approximately 8% and 4% under heat and humid conditions, respectively. TURSO in the bag degraded slightly under oxidizing conditions and by 19% and 10% under heat and humid conditions, respectively. Furthermore, surprisingly, under humid conditions, TURSO degraded much less in the bag compared to the complete degradation observed in the TURSO API sample.

[0196] Table 50 sample result Comparison hot Hot and humid Oxidation 3 days of acid 3 days of alkali 7 days of acidity Alkali 7 days Light contrast Light PB API %PB 99.2 98.9 99.3 98.6 99.1 98.9 99.7 99.8 99.9 98.3 Remaining PB% 99.7 100.1 99.4 99.9 99.7 100.5 100.6 99.3 PB peak purity qualified qualified qualified qualified qualified qualified qualified qualified qualified qualified in conclusion No significant degradation No significant degradation No significant degradation No significant degradation No significant degradation No significant degradation No significant degradation No significant degradation TUDCA API %TUDCA 100.2 100.6 No TUDCA peak was detected; the solution appeared white and turbid. 97.1 100.0 95.1 97.2 82.8 96.4 99.5 Remaining TUDCA% 100.4 0% 96.9 99.8 94.9 97.0 82.6 103.2 TUDCA peak purity Unqualified Unqualified N / A (no peak) Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified in conclusion No significant degradation Completely reduced / Sample precipitation may have occurred 3% degradation No significant degradation 5% degradation 3% degradation 17% degradation No significant degradation placebo %PB ND ND ND ND ND ND ND ND ND ND %TUDCA ND ND ND ND ND ND ND ND ND ND in conclusion The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. The activity did not cause any disruption during its duration. AMX-0035 Powder Bag %PB 99.1 90.8 94.7 98.5 98.9 99.0 98.9 99.2 99.2 99.6 %TUDCA 97.2 78.4 87.1 95.2 96.1 97.4 97.1 97.1 96.8 97.1 Remaining PB% 91.6 95.6 99.4 99.8 99.9 99.8 100.1 100.4 Remaining TUDCA% 80.7 89.6 97.9 98.9 100.2 99.2 99.9 100.3 PB peak purity qualified qualified qualified qualified qualified qualified qualified qualified qualified qualified TUDCA peak purity Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified Unqualified in conclusion ~8% PB and ~19% TUDCA degradation ~8% PB and ~10% TUDCA degradation PB - No significant degradation TUDCA - ~2% No significant degradation No significant degradation No significant degradation No significant degradation No significant degradation* Two additional samples were prepared and analyzed after exposure to the same heat and humidity conditions for 3 and 7 days (85°C, 1.0 mL water). The results confirmed that the TUDCA samples were completely degraded under these exposure conditions. Only 1.30% TUDCA was detected in the sample on day 3 (ref: PDS-NB-16454, page 019).

[0197] Table 51 sample result Comparison hot Hot and humid Oxidation 3 days of acid 3 days of alkali 7 days of acidity Alkali 7 days Light contrast Light PB API Efficacy % 99.2 98.9 99.3 98.6 99.1 98.9 99.7 99.8 99.0 98.3 Total RS% 2.07 3.93 1.18 3.13 1.18 1.11 1.14 1.10 0.96 0.74 mass balance 101.27 102.83 100.48 101.73 100.28 100.01 100.84 100.90 99.96 99.04 %RMBD N / A 101.5 99.2 100.5 99.0 98.8 99.6 99.6 N / A 99.1 TUDCA API Efficacy % 100.2 100.6 ND 97.1 100.0 95.1 97.2 82.8 96.4 99.5 Total RS% 0.22 0.28 ND 1.36 0.23 0.22 0.20 0.18 0.22 0.24 sum 100.42 100.88 0.00 98.46 100.23 95.32 97.4 82.98 96.62 99.74 %RMBD N / A 100.5 0.0 98.0 99.8 94.9 97.0 82.6 N / A 103.2 Placebo AMX-0035 sachets / powder PB effectiveness % 99.1 90.8 94.7 98.5 98.9 99.0 98.9 99.2 99.2 99.6 Total PB purity % 0.78 12.12 2.90 2.01 1.14 2.28 1.10 2.42 0.86 0.81 PB total 99.88 102.92 97.60 100.51 100.04 101.28 100.0 101.62 100.06 100.41 %RMBD N / A 103.0 97.7 100.6 100.2 101.4 100.1 101.7 N / A 100.3 TUDCA effectiveness % 97.2 78.4 87.1 95.2 96.1 97.4 96.4 97.1 96.8 97.1 Total TUDCA purity % 1.19 1.33 1.20 1.64 1.31 1.19 1.31 1.20 1.21 1.18 TUDCA sum 98.39 79.73 88.30 96.84 97.41 98.59 97.71 98.30 98.01 98.28 %RMBD N / A 81.0 89.7 98.4 99.0 100.2 99.3 99.9 N / A 100.3 Example 9: The effect of cooling unit on mixing properties

[0198] A placebo batch (lot number # CFSMM) was prepared in which a cooling unit (15 ± 2°C) was added to the rolling mill. The temperature of the rolls (nip area) ranged from 16.0 to 24.1°C throughout the batch production. The particle temperature ranged from 24.8 to 29.0°C throughout the batch production. No accumulation was observed on the rotating 1.5 mm screen throughout the batch production. Tables 52 and 53 and Figures 15 and 16 show the physical properties of the premix and the pressed particles. As shown in Table 53, the flow index of batch CFSMM was reduced (i.e., improved fluidity) compared to batch CDZGW prepared without a cooling unit. These results indicate that the cooling rolling mill is advantageous for the processing conditions.

[0199] Table 52: Results of Premixed Materials Particle size distribution Ingredients: 100g of premix reserve% placebo Real placebo-scale expansion - FEAS 2000 KG Net Aperture (micrometers) Batch number: CDZGW (360 kg) Batch No.: CFSMM Premix 1 Batch number: CFSMM premix D 2 Batch number: CFSMM premix D 3 Batch number: CFSMM premix D 4 Batch number: CFSMM premix D 5 Batch number: CFSMM premix D 6 10 2000 0.00 0.00 0.01 0.00 0.00 0.00 0.00 14 1400 0.00 0.08 0.20 0.13 0.05 0.00 0.00 18 1000 0.03 0.97 0.80 1.40 1.12 0.64 0.50 30 600 0.41 2.18 2.58 3.08 2.82 2.62 2.75 40 425 4.20 6.57 7.28 8.17 8.45 7.58 7.49 80 180 53.22 51.62 52.16 53.03 51.53 52.10 50.93 PAN <180 42.14 38.58 36.97 34.19 36.03 37.06 38.33 total -- 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Body density and knock-tightness Ingredients: 100g of premix Unit of measurement: g / mL placebo Real-world placebo-scale expansion - FEAS 2000 KG Batch number: CDZGW (360 kg) Batch number: CFSMM premix D 1 Batch Number: CFSMM Premix D 2 Batch number: CFSMM premix D 3 Batch number: CFSMM premix D 4 Batch number: CFSMM premix D 5 Batch number: CFSMM premix D 6 Volume density 0.63 0.60 0.63 0.64 0.63 0.64 0.63 Tightness 0.83 0.78 0.81 0.78 0.79 0.81 0.81 Flow Index Ingredients: 50g of premix Unit of measurement: mm placebo AMX-0035 Real Placebo-Scale Amplification - FEAS 2000 KG Batch number: CDZGW (360 kg) Batch number: CFSMM premix D1 Batch number: CFSMM premix D2 Batch number: CFSMM premix D3 Batch number: CFSMM premix D4 Batch number: CFSMM premix D5 Batch number: CFSMM premix D6 Flow Index 5 9 7 6 8 9 12

[0200] Table 53: Results of Particle Compression Particle size distribution Materials: 100 grams of compressed granules reserve% placebo AMX-0035 Real Placebo-Scale Amplification - FEAS 2000 KG Net Aperture (micrometers) Batch number: CDZGW (360 kg) Batch number # CFSMM start Batch number # CFSMM Slot 1 and later Batch number # CFSMM slot box 2 and later Batch number # CFSMM slot box 3 and later Batch number # CFSMM slot 4 and later Batch number # CFSMM slot 5 and later Batch number # CFSMM ends Batch number # CFSMM composition 10 2000 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 14 1400 0.75 0.23 0.19 0.30 0.27 0.12 0.42 0.51 0.15 18 1000 16.60 11.72 7.85 10.22 9.42 5.39 14.33 14.99 9.60 30 600 22.20 19.92 17.10 19.42 17.49 12.15 20.57 21.66 17.61 40 425 11.31 11.83 11.82 12.64 11.75 9.38 10.88 11.25 11.17 80 180 23.38 27.85 29.95 29.04 30.29 30.34 25.25 24.82 29.36 PAN <180 25.76 28.45 33.09 28.38 30.78 42.62 28.55 26.77 32.11 total -- 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Body density and knock-tightness Materials: 100 grams of compressed granules Unit of measurement: g / mL placebo AMX-0035 TRUE PLACEBO SCALE-UP - FEAS 2000 KG Batch number: CDZGW (360 kg) Batch number # CFSMM start Batch number # CFSMM Slot 1 and later Batch number # CFSMM slot box 2 and later Batch number # CFSMM slot box 3 and later Batch number # CFSMM slot 4 and later Batch number # CFSMM slot 5 and later Batch number # CFSMM ends Batch number # CFSMM composition Volume density 0.63 0.68 0.67 0.65 0.66 0.68 0.67 0.67 0.68 Tightness 0.88 0.91 0.91 0.86 0.88 0.91 0.88 0.88 0.88 Flow Index Materials: 50 grams of compressed granules Unit of measurement: mm placebo AMX-0035 Real Placebo-Scale Amplification - FEAS 2000 KG Batch number: CDZGW (360 kg) Batch number # CFSMM start Batch number # CFSMM Slot 1 and later Batch number # CFSMM slot box 2 and later Batch number # CFSMM slot box 3 and later Batch number # CFSMM slot 4 and later Batch number # CFSMM slot 5 and later Batch number # CFSMM ends Batch number # CFSMM composition Flow Index 14 8 10 12 12 12 10 10 10 [Simplified Explanation of the Diagram]

[0201] Figure 1 shows the particle size distribution of sodium phenylbutyrate and TURSO.

[0202] Figure 2 is a DVS isotherm of sodium phenylbutyrate adsorption (Sorb) and desorption (Desorb).

[0203] Figure 3 is a DVS isotherm of TURSO adsorption and desorption.

[0204] Figure 4 is a DVS isotherm diagram showing the adsorption and desorption of the active mixture.

[0205] Figure 5 shows the particle size distribution of mixtures containing different types of silicon dioxide.

[0206] Figure 6 shows the location of the 16 Quart V-Shell where the mixing uniformity sample was obtained.

[0207] Figure 7 shows the particle size distribution of various samples after premixing.

[0208] Figure 8 shows the particle size distribution of various samples after granulation using a 1.0 mm mesh sieve.

[0209] Figure 9 shows the particle size distribution of various samples after granulation using a 1.5 mm mesh screen.

[0210] Figure 10 shows the particle size distribution of various samples after granulation using a 2.0 mm mesh sieve.

[0211] Figure 11 shows the combined results from Figures 8 to 10.

[0212] Figure 12 is a graph showing the dissolution curves of TUDCA in each sub-batch.

[0213] Figure 13 is a graph showing the dissolution curves of sodium phenylbutyrate in each sub-batch.

[0214] Figure 14 shows the location where the mixing uniformity sample was obtained for the final mixing analysis.

[0215] Figure 15 shows the particle size distribution of the premix in the placebo approval.

[0216] Figure 16 shows the particle size distribution of the compressed particles in the placebo approval.

Claims

1. A composition comprising: (a) 15% to 45% w / w phenylbutyric acid (4-PBA) or a pharmaceutically acceptable salt thereof; (b) 5% to 15% w / w taurursodiol (TURSO); (c) 10% to 20% w / w dextrate; (d) 2% to 5% w / w sorbitol; and (e) 22% to 35% maltodextrin, wherein the 4-PBA or a pharmaceutically acceptable salt thereof and TURSO are in a 3:1 weight ratio.

2. As in claim 1, the composition comprises 8% to 12% w / w TURSO.

3. The composition of claim 1 comprises 25% to 35% w / w 4-PBA or a pharmaceutically acceptable salt thereof.

4. As in claim 1, the composition includes 9.7% w / w TURSO.

5. The composition of claim 1, wherein the composition comprises sodium phenylbutyrate.

6. The composition of claim 4, comprising 29.2% w / w sodium phenylbutyrate.

7. The composition of claim 1, comprising 15.6% w / w glucose conjugate.

8. The composition of claim 1, comprising 3.9% w / w sorbitol.

9. The composition of claim 1 comprises 25% to 32% w / w maltodextrin.

10. The composition of claim 1 further includes sucralose.

11. The composition of claim 10 includes 1% to 3% w / w sucralose.

12. The composition of claim 1 further includes one or more flavoring agents.

13. The composition of claim 12, comprising 5% to 10% w / w of flavoring agent.

14. The composition of claim 1 further comprises 0.05% to 2% w / w porous silicon dioxide.

15. The composition of claim 14, comprising 0.05% to 1.5% w / w porous silicon dioxide.

16. The composition of claim 14 or 15, wherein the porous silica system has an average pore capacity of 0.1 cc / gm to 2.0 cc / gm.

17. The composition of claim 16, wherein the porous silica system has an average pore capacity of 0.2 cc / gm to 0.8 cc / gm.

18. The composition of claim 1 further comprises 0.5% to 5% w / w sodium phosphate.

19. The composition of claim 1 further comprises 0.05% to 1% w / w of one or more lubricants.

20. The composition of claim 19, wherein the one or more lubricants are selected from the group consisting of: sodium stearate, magnesium stearate, stearic acid, polyethylene glycol, glyceryl behenate, and hydrogenated oil.

21. As in claim 1, the constituent parts include: 29.2% w / w sodium phenylbutyrate; 9.7% w / w TURSO; 15.6% w / w glucose binding agent; 3.9% w / w sorbitol; 1.9% w / w sucralose; 28.3% w / w maltodextrin; 7.3% w / w flavoring agent; 0.07% to 0.9% w / w silicon dioxide; 2.7% w / w sodium phosphate; and 0.5% w / w sodium stearate fumarate.

22. A method for processing a composition, the method comprising: (i) Rolling a premixed composition comprising sodium phenylbutyrate and TURSO, the premixed composition comprising: 15% to 45% w / w sodium phenylbutyrate, 5% to 15% w / w TURSO, 10% to 20% w / w sucralose, 2% to 5% w / w sorbitol, and 22% to 35% w / w maltodextrin, wherein the sodium phenylbutyrate and TURSO are in a 3:1 weight ratio, thereby forming a pressed premix; and (ii) granulating the pressed premix using a granulation screen having a diameter of 0.8 mm to 2 mm.

23. The method of claim 22, wherein step (i) comprises rolling the premixed composition by applying a compressive force of 5 kN / cm to 15 kN / cm.

24. The method of claim 22, wherein step (i) comprises rolling the premixed composition between at least two rollers having a gap width of 1 mm to 5 mm, and / or wherein step (i) comprises rolling the premixed composition between at least two rollers having a rolling speed of 4 rpm to 12 rpm, and / or wherein step (i) comprises rolling the premixed composition at a temperature of 10°C to 30°C.

25. The method of claim 22, wherein the particles have a bulk density of 0.2 g / mL to 1.0 g / mL.

26. The method of claim 22, wherein the particles have a tapped density of 0.5 g / mL to 1.2 g / mL.

27. The method of claim 22, wherein the constituent system comprises: 29.2% w / w sodium phenylbutyrate; 9.7% w / w TURSO; 15.6% w / w glucose binding agent; 3.9% w / w sorbitol; 1.9% w / w sucralose; 28.3% w / w maltodextrin; 7.3% w / w flavoring agent; 0.07% to 0.9% w / w silicon dioxide; 2.7% w / w sodium phosphate; and 0.5% w / w sodium stearate fumarate.

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