Dispersions of etradiam

Abstract

The solid dispersion comprises from 20% by weight to 40% by weight of etradient and from 60% by weight to 80% by weight of a polymer selected from the group consisting of HPMCAS, PVPPA, CAP, HPMC E3, HPMCP, PVP, and a polyethylene caprolactam-polyvinyl acetate-PEG graft copolymer. A process for preparing the composition by spray drying. The composition is useful for the treatment of cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 375,574, filed on September 14, 2022, and U.S. Provisional Patent Application No. 63 / 387,672, filed on December 15, 2022. The contents of each of the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] Provided herein are solid dispersions and semisolid dispersions of edradinam and compositions thereof. Background Art

[0004] Adenosine is a purine nucleoside compound that contains a complex of adenine and a ribose molecule (ribofuranose). Adenosine occurs naturally in mammals and plays an important role in several biochemical processes, including energy transfer (such as adenosine triphosphate and adenosine monophosphate) and signal transduction (such as cyclic adenosine monophosphate). Adenosine also plays a role in processes related to vasodilation (including cardiac vasodilation) and acts as a neuromodulator (i.e., it is thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is also used as a therapeutic antiarrhythmic agent to treat, for example, supraventricular tachycardia. Tumors evade host responses by suppressing immune function and promoting tolerance, and adenosine has been shown to play an important role in mediating tumor evasion of the immune system. By A 2A R and A 2B Adenosine signaling of R, expressed on a variety of immune cell subsets and endothelial cells, has been shown to play an important role in protecting tissues during inflammatory responses. Thus, under certain conditions, adenosine protects tumors from immune destruction (see, e.g., Fishman, P et al., (2009) Handb Exp Pharmacol 193:399-441).

[0005] Adenosine receptors are a class of purinergic G protein-coupled receptors that use adenosine as an endogenous ligand. The four types of adenosine receptors in humans are called A1, A 2A , A 2B and A3. Modulation of A1 has been proposed for the management and treatment of, for example, neurological disorders, asthma, and heart and kidney failure; A 2A Antagonists are used to control and treat, for example, Parkinson's disease; modulation of A 2B For the management and treatment of, for example, chronic lung diseases, including asthma; and modulation of A3 has been proposed for the management and treatment of, for example, asthma and chronic obstructive pulmonary disease, glaucoma, cancer, and stroke.

[0006] Historically, adenosine receptor modulators have been non-selective. This is acceptable in certain indications, such as parenteral administration of adenosine, an endogenous agonist for all four adenosine receptors in cardiac tissue, for the treatment of severe tachycardia. However, the use of subtype selective adenosine receptor agonists and antagonists offers the possibility of achieving desired results while minimizing or eliminating side effects.

[0007] Eltrodinam (also known as AB928) is reported to be a subtype-selective adenosine receptor antagonist. 2A R and A 2B It is a potent antagonist of R with a potency of less than 10 nM for both receptors. Summary of the invention

[0008] Provided herein are solid dispersions comprising about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of a polymer (w / w) selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS) and copovidone (PVP-VA).

[0009] Also provided are its dosage form, granules, composition, pharmaceutical composition and tablet; its use method; and a method for preparing the solid dispersion.

[0010] Other aspects and iterations of the disclosure are provided in further detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Shown is the x-ray powder diffraction (XRPD) pattern of crystalline edradinam.

[0012] Figure 2A A schematic diagram of a solvent shift dissolution experiment is shown. The API (i.e., starting drug substance) is dissolved in DMSO and then dosed to a solution of fasted state simulated intestinal fluid (FaSSIF) and a polymer. Aliquots are sampled at various time points and analyzed by HPLC.

[0013] Figure 2B is a graph depicting the results of a solvent shift dissolution experiment at 25% drug load. Etradinam solubility (µg / mL) is on the y-axis and time (minutes) is on the x-axis. As summarized in the legend, the polymers tested included CAP, HPMCE3LV, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCP, PVP, PVP-VA, and soluplus. A control sample without polymer is also plotted.

[0014] Figure 2Cis a graph depicting the results of a solvent shift dissolution experiment at 50% drug load. Etradinam solubility (µg / mL) is on the y-axis and time (minutes) is on the x-axis. As summarized in the legend, the polymers tested included CAP, HPMCE3LV, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCP, PVP, PVP-VA, and soluplus. A control sample without polymer is also plotted.

[0015] Figure 3A and Figure 3B shows reversibility ( Figure 3A ) or non-reversible ( Figure 3B ) mode.

[0016] Figure 4 XRPD patterns of SDI particles and starting drug substance (ie, AB928) are shown.

[0017] Figure 5 is a graph depicting the non-sinking dissolution of SDI granules (see legend) and starting drug substance ("AB928 API"). The vertical line (denoted in the legend as "Gastric Transition (0.1N HCl→FaSSIF)" depicts the time of gastric transition, i.e., the change from 0.1N HCl to FaSSIF.

[0018] Figure 6 Shown are XRPD patterns of 25:75 AB928:HPMCAS-M SDI and 40:60 AB928:HPMCAS-M SDI after stabilization for 12 weeks in an open or closed container at 25°C / 60% relative humidity ("RH") ("25 / 60") or 40°C / 75% RH ("40 / 75").

[0019] Figure 7 Shown are XRPD patterns of 25:75 AB928:PVP-VA SDI and 40:60 AB928:PVP-VA SDI after stabilization for 12 weeks at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75") in either an open or closed container.

[0020] Figure 8Shown are the XRPD patterns of 25:75 AB928:HPMCAS-M SDI, 30:70 AB928:HPMCAS-M SDI, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI after stabilization for 6 months in a closed container at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75").

[0021] Fig.9A and Fig. 9B The results of 25:75 AB928:HPMCAS-M SDI, 30:70 AB928:HPMCAS-M SDI, 35:65 AB928:HPMCAS-M SDI and 40:60 AB928:HPMCAS-M SDI at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75") in an open container ( Fig.9A ) or a sealed container ( Fig. 9B ) MDSC pattern after stabilization for 6 months.

[0022] Fig.10 is a graph depicting the non-sinking dissolution of 25:75 AB928:HPMCAS-M SDI, 30:70 AB928:HPMCAS-M SDI, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI at t = 0 d (manufacturing time). The vertical line (denoted as "Gastric Transition (0.1N HCl→FaSSIF)" in the legend depicts the time of gastric transition, i.e., the change from 0.1N HCl to FaSSIF.

[0023] Fig.11 is a graph depicting the non-sinking dissolution of 25:75 AB928:HPMCAS-M SDI, 30:70 AB928:HPMCAS-M SDI, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI after stabilization in a closed container for 6 months at 25°C / 60% RH or 40°C / 75% RH. The vertical line (denoted in the legend as "Gastric Transition (0.1N HCl→FaSSIF)" depicts the time of gastric transition, i.e., the change from 0.1N HCl to FaSSIF.

[0024] Fig. 12A A graph depicting tabletability is shown, Fig. 12B shows a graph depicting compactability, Fig. 12C shows a graph depicting compactability, Fig.12DShown is a graph depicting the disintegration time of 25:75 AB928:HPMCAS-M SDI tablets ("25% HPMCAS-M SDI tablets") and 40:60 AB928:HPMCAS-M SDI tablets ("40% HPMCAS-M SDI tablets").

[0025] Fig.13A A graph depicting tabletability is shown, Fig. 13B shows a graph depicting compactability, Fig. 13C shows a graph depicting compactability, Fig.13D Shown is a graph depicting the disintegration time of 25:75 AB928:PVP-VA SDI tablets ("25% PVP-VA SDI tablets") and 40:60 AB928:PVP-VA SDI tablets ("40% PVP-VA SDI tablets").

[0026] Fig.14 is a graph depicting the non-sinking dissolution of tablets containing 25:75 AB928:HPMCAS-M SDI or 25:75 AB928:PVP-VA at t=0 or after stabilization for 3 months (3M) in a closed container at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75").

[0027] Fig.15 is a graph depicting the non-sinking dissolution of tablets containing 40:60 AB928:HPMCAS-M SDI or 40:60 AB928:PVP-VA after stabilization in a closed container at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75") for 0 or 3 months.

[0028] Fig.16 is a graph depicting the non-sinking dissolution of tablets containing 25:75 AB928:HPMCAS-M SDI or 40:60 AB928:HPMCAS-M SDI after 0 or 12 months of stability in a closed container at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75").

[0029] Fig.17A is a graph depicting AB928 plasma concentration (y-axis) over time (x-axis) following oral administration of AB928 capsules ("Capsule Control") or one of three AB928 tablet formulations with HPMCAS SDI (see legend).

[0030] Fig. 17Bis a graph depicting AB928 plasma concentration (y-axis) over time (x-axis) following oral administration of AB928 capsules ("Capsule Control") or one of three AB928 tablet formulations with PVP-VA SDI (see legend).

[0031] Fig.18 Figure 1 is a graph depicting the box-and-whisker plot, median, and Cmax of plasma etraconazole after a single dose of 150 mg of etraconazole with and without multiple doses of 200 mg. In the figure, the upper and lower limits of the box represent the third and first quartiles, respectively, and the center line represents the median. The solid circle represents the mean. The upper and lower whiskers of the box-and-whisker plot represent the maximum and minimum observed values ​​within the 1.5-fold interquartile range, respectively. The open circles represent the individual parameter values.

[0032] Fig.19 Shown is an x-ray powder diffraction (XRPD) pattern of a crystalline form of phosphate salt of etradinam ("phosphate salt Form I").

[0033] Fig. 20 Shown is an x-ray powder diffraction (XRPD) pattern of a crystalline form of phosphate salt of etradinam ("phosphate salt Form II").

[0034] Fig.21 Shown is the x-ray powder diffraction (XRPD) pattern of crystalline edradinan fumarate. DETAILED DESCRIPTION

[0035] The present disclosure provides dispersions comprising edredinam or a pharmaceutically acceptable salt thereof, compositions thereof, and pharmaceutical compositions thereof (such as tablets). It is contemplated that the dispersions, compositions, and pharmaceutical compositions provided herein may exhibit improved drug solubility, improved bioavailability, and / or elimination or reduction of food effects (e.g., as compared to edredinam or a pharmaceutically acceptable salt thereof in crystalline form). Also provided herein are methods for preparing dispersions and methods of using the dispersions. The dispersions of edredinam disclosed herein can be formulated to have a high drug load, for example, up to and including 50% (w / w) edredinam.

[0036] I. Definitions

[0037] Unless otherwise defined, all technical terms, symbols and other scientific terms or technical terms used herein are intended to have the meanings commonly understood by those skilled in the art to which the present disclosure belongs. It should be understood that various aspects of the disclosure described herein include aspects of "comprising", "consisting of" and "consisting essentially of". The terms "comprising", "including" and "having" are intended to be inclusive and mean that additional elements other than the listed elements may be present. The term "consisting essentially of" means that specific additional components may be present, i.e., those components that do not have a substantial impact on the basic characteristics of the compound or composition.

[0038] In addition, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a particle" includes reference to one or more particles and equivalents thereof known to those skilled in the art.

[0039] The term "about" used herein has its original meaning "approximately" and provides literal support for the exact number preceding it and the number close to or approximating the number preceding the term. In general, the term "about" refers to the common error range of the corresponding value that is easily known to those skilled in the art. If the approximate degree is not otherwise clear according to the context, "about" means within ± 10% of the value provided, or rounded to the nearest significant figure, including the value provided in all cases. In the case of providing a range, they include the boundary values.

[0040] Also as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as no combination when interpreted as an alternative ("or"). Similarly, a phrase in the form "A / B" or in the form "A and / or B" means (A), (B), or (A and B); a phrase in the form "at least one of A, B, and C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0041] As used herein, the term "% w / w" refers to the weight of a component based on the total weight of the composition in which it is contained. For example, if component A is present in an amount of 50% w / w in 100 mg of the composition, component A is present in an amount of 50 mg.

[0042] The "Dv50" value is the size at which 50% of the total volume of the material in the sample is present. The "Dv90" value is the size at which 90% of the total volume of the material in the sample is present.

[0043] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid, depending on the temperature. Typically, such materials do not produce a characteristic X-ray diffraction pattern and, although exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, which is characterized by a change of state, usually a secondary change (glass transition).

[0044] As used herein, the term "polymer matrix" is defined to mean a composition comprising one or more polymers wherein the active agent is dispersed or included within the matrix.

[0045] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, etc.), and salts derived from relatively nontoxic organic acids (such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, maleic acid, oxalic acid, trans-cinnamic acid, etc.). Also included are salts of amino acids, such as arginine salts, etc., and salts of organic acids (such as glucuronic acid or galactonic acid, etc.) (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0046] The term "disintegrant" refers to a substance that, when added to a solid formulation, promotes its disintegration or disintegration after administration and allows the release of the active ingredient as effectively as possible to allow its rapid dissolution. Non-limiting examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid.

[0047] The term "filler" (also referred to as a diluent) refers to a compound used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize the compound. Non-limiting examples of diluents include starches, sugars, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compactable sugars, dicalcium phosphate dihydrate, mannitol, microcrystalline cellulose, and tricalcium phosphate.

[0048] The term "glidant" as used herein is intended to mean a pharmaceutical agent in tablet and capsule formulations to improve flowability during tablet compaction and produce an anti-caking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0049] The term "lubricant" refers to an excipient that is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It aids in the release of the tablet from the die and can improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silicon dioxide, fats or talc; and solubilizers such as fatty acids, including lauric acid, oleic acid, and C8 / C 10 fatty acid.

[0050] The term "coating" or "film coating" refers to a thin, uniform film on the surface of a substrate (e.g., a tablet). Film coatings are particularly useful for protecting active ingredients from photolytic degradation. Non-limiting examples of film coatings include polyvinyl alcohol-based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate film coatings.

[0051] The term “non-functional coating” refers to a coating that may improve product appearance, handling and / or stability of a substrate (e.g., tablet) but has no measurable effect on the biopharmaceutical properties of the substrate.

[0052] The terms "patient" and "subject" are used interchangeably herein to refer to a human or a non-human animal (eg, a mammal).

[0053] The term "administering" or the like, when applied to, for example, a subject, a cell, a tissue, an organ, or a biological fluid, refers to contacting, for example, a dispersion, a composition, or a pharmaceutical composition described herein with a subject, a cell, a tissue, an organ, or a biological fluid. In the case of cells, administration includes contacting an agent with a cell (e.g., in vitro or ex vivo), as well as contacting an agent with a fluid, wherein the fluid is in contact with the cell.

[0054] The term "treat" refers to a process of action that temporarily or permanently eliminates, reduces, suppresses, alleviates, improves, or prevents the worsening of at least one symptom associated with the disease, disorder, or condition to which the term applies. Treatment includes, for example, inhibiting (e.g., preventing the development or further development of a disease, disorder, or condition or clinical symptoms associated therewith) active disease, improving the quality of life, and / or prolonging the survival of a subject.

[0055] The terms "prevent" and the like refer to a process of action that is initiated in a manner (e.g., before the onset of a disease, disorder, condition, or symptom thereof) to temporarily or permanently prevent, suppress, inhibit, or reduce the risk of a subject developing a disease, disorder, condition, etc. (as determined by, for example, the absence of clinical symptoms) or to delay the onset thereof, which is typically in the case of a subject susceptible to a particular disease, disorder, or condition. In some cases, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its progression to a harmful or other undesirable state. Prevention also refers to a process of action that is initiated in a subject after the subject has been treated for a disease, disorder, condition, or symptom associated therewith, in order to prevent the recurrence of the disease, disorder, condition, or symptom.

[0056] II. Etrodinam

[0057] Etradinam (also known as AB928) is a novel target for the adenosine 2a receptor (A 2a R) and adenosine 2b receptor (A 2b R). Its chemical name is 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile, and its structural formula is as follows:

[0058] .

[0059] Eltrodinam and its pharmaceutically acceptable salts can take a variety of forms, including but not limited to amorphous forms, crystalline forms, mixtures of crystalline forms, and mixtures of amorphous forms and crystalline forms. In various embodiments of the present disclosure (e.g., compositions, dispersions, granules, tablets, etc.), Eltrodinam or its pharmaceutically acceptable salt can be in an amorphous form, a crystalline form, or any mixture thereof. The crystalline forms of Eltrodinam include those described in WO 2020 / 018680, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, crystalline Eltrodinam can be Type I of WO 2020 / 018680. In some embodiments, crystalline Eltrodinam can be Type II of WO 2020 / 018680. In some embodiments, crystalline Eltrodinam can be Type III of WO 2020 / 018680.

[0060] Methods for preparing edradinam are known in the art. See, for example, WO 2018 / 136700, WO 2020 / 018680, and WO 2020 / 247789, the disclosures of which are incorporated herein by reference in their entirety.

[0061] III. Dispersion of edrolidine and preparation method thereof

[0062] Dispersion

[0063] Disclosed herein is a dispersion of edradinam or a pharmaceutically acceptable salt thereof that is solid or semi-solid at a temperature below 40°C.

[0064] As used herein, a dispersion of edrolidine or a pharmaceutically acceptable salt thereof refers to a dispersion (i.e., distribution) of an active agent, such as edrolidine or a pharmaceutically acceptable salt thereof, in a matrix. As used herein, a "solid dispersion" refers to a dispersion that is solid at a temperature below 40°C, while a "semi-solid dispersion" refers to a dispersion that is semi-solid at a temperature below 40°C. In some embodiments, the solid dispersion described herein is solid at 25°C. In some embodiments, the semi-solid dispersion described herein is in a semi-solid state at 25°C.

[0065] For the avoidance of doubt, a semi-solid state is a state between a solid and a liquid. Although similar to a solid in some respects, such as being able to support its own weight and retain its shape, a semi-solid also has some properties of a liquid, such as conforming its shape to an object to which pressure is applied and the ability to flow under pressure. The dispersions of the present disclosure may also be characterized by, for example, MDSC, XRPD, scanning electron microscopy (SEM), non-sinking dissolution, Karl Fischer titration, assays, impurities, and non-sinking dissolution.

[0066] The matrix of the dispersion comprises at least one hydrophilic polymer (e.g., 1, 2, 3, 4 or more polymers; or 1 to 4 polymers; or 1 to 3 polymers). In some embodiments, the matrix comprises or consists essentially of one polymer. In some embodiments, the matrix comprises or consists essentially of a mixture of polymers. The polymer can be synthetic or natural. Non-limiting examples of suitable polymers can include polyethylene glycol polymers (e.g., PEG 400, PEG 1500, PEG4000, etc.), cellulose-based polymers (e.g., HPMC, HPMCAS, HPMCP, CAP, etc.), and vinyl pyrrolidone-based polymers (e.g., povidone ("PVP"), copovidone ("PVP-VA"), Soluplus ® wait).

[0067] The matrix may also include one or more additional components, including but not limited to one or more antioxidants, one or more surfactants, one or more solubilizers, or any combination thereof. Non-limiting examples of suitable antioxidants include ascorbic acid, BHT, tocosolane, and vitamin E. Non-limiting examples of suitable surfactants include inulin, inutec, poloxamer, tocopherol, Compritol ® Surfactants (e.g. Compritol ® 888 ATO, etc.), Gelucire ® Surfactants (such as Gelucire ® 44 / 14, etc.), and Kolliphor ® Surfactants (e.g. Kolliphor ® HS 15, Kolliphor ® RH40, etc.), polysorbates (e.g., polysorbate 20, polysorbate 80, etc.), egg lecithin, and soybean lecithin. The solvent and / or water used to prepare the dispersion may also be present in the dispersion, although typically it is present in a small amount (e.g., preferably less than 5 wt %, less than 4 wt %, less than 3 wt %, or less than 2 wt %).

[0068] Thus, the dispersion of the present disclosure comprises edroldinam or a pharmaceutically acceptable salt thereof and a polymer. Furthermore, in some embodiments, the dispersion of the present invention may consist essentially of (i) edroldinam or a pharmaceutically acceptable salt thereof and (ii) a polymer, a polymer mixture, or a mixture of a polymer and a surfactant. For the avoidance of doubt, a dispersion consisting essentially of (A) and (B) allows for the presence of materials that do not affect the basic properties of the dispersion, such as small amounts of impurities, related substances of A and / or B, residual solvents, and water.

[0069] In some embodiments, the present disclosure provides a solid dispersion comprising edredinam or a pharmaceutically acceptable salt thereof and a polymer. In some embodiments, the solid dispersion comprises (i) edredinam or a pharmaceutically acceptable salt thereof and (ii) a polymer, a polymer mixture, or a mixture of a polymer and a surfactant. In some embodiments, the solid dispersion consists essentially of (i) edredinam or a pharmaceutically acceptable salt thereof and (ii) a polymer, a polymer mixture, or a mixture of a polymer and a surfactant. Non-limiting examples of suitable polymers include cellulose-based polymers (e.g., HPMC, HPMCAS, HPMCP, CAP, etc.) and vinyl pyrrolidone-based polymers (e.g., povidone, copovidone, soluplus, etc.). In some embodiments, the solid dispersion of the present disclosure comprises or consists essentially of edredinam or a pharmaceutically acceptable salt thereof and a polymer selected from HPMCAS and copovidone.

[0070] On the other hand, the present invention provides a semi-solid dispersion comprising edredinam or a pharmaceutically acceptable salt thereof and a polymer. In some embodiments, the semi-solid dispersion comprises (i) edredinam or a pharmaceutically acceptable salt thereof and (ii) a polymer, a polymer mixture, or a mixture of a polymer and a surfactant. In some embodiments, the semi-solid dispersion consists essentially of (i) edredinam or a pharmaceutically acceptable salt thereof and (ii) a polymer, a polymer mixture, or a mixture of a polymer and a surfactant. Non-limiting examples of suitable polymers include cellulose-based polymers (e.g., HPMC, HPMCAS, HPMCP, CAP, etc.) and vinyl pyrrolidone-based polymers (e.g., povidone, copovidone, soluplus, etc.). In a specific example, the solid dispersion of the present invention comprises or consists essentially of edredinam or a pharmaceutically acceptable salt thereof and one or more polyethylene glycol polymers.

[0071] Provided herein are solid dispersions comprising about 25% to about 50% (w / w) of edredinam and about 50% to about 75% (w / w) of a polymer. In some embodiments, the polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose E3 (HPMC E3), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl pyrrolidone (PVP), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ® ).

[0072] Provided herein are solid dispersions comprising about 20% to about 40% (w / w) of edredinam and about 60% to about 80% (w / w) of a polymer selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS), copolyvidone (PVP-VA), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose E3 (HPMC E3), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ® ).

[0073] Provided herein are solid dispersions comprising about 25% to about 50% (w / w) of edradinam and about 50% to about 75% (w / w) of a polymer (w / w) selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS) and copovidone.

[0074] Provided herein are solid dispersions comprising about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of a polymer (w / w) selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS) and copovidone.

[0075] Provided herein are solid dispersions comprising about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of a polymer (w / w) selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS) and copovidone.

[0076] Provided herein are solid dispersions comprising about 35% to about 50% (w / w) of edredinam or a pharmaceutically acceptable salt thereof, and about 65% to about 50% (w / w) of a polymer (w / w) selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS) and copovidone.

[0077] In some embodiments, such solid dispersions comprise from about 25% to about 40% (w / w) edradinam.

[0078] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) eltrodinam; or about 25% to about 30% (w / w) eltrodinam. In some embodiments, the solid dispersions comprise about 25% to about 35% (w / w) eltrodinam. In some embodiments, the solid dispersions comprise about 25% to about 30% (w / w) eltrodinam.

[0079] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) of eltrodinam; or about 27% to about 33% (w / w) of eltrodinam; or about 31.5% to about 38.5% (w / w) of eltrodinam; or about 36% to about 44% (w / w) of eltrodinam. In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) of eltrodinam; or about 27% to about 33% (w / w) of eltrodinam; or about 31.5% to about 38.5% (w / w) of eltrodinam.

[0080] In some embodiments, the solid dispersions comprise about 22.5% to about 27.5% (w / w) eltrodinam. In some embodiments, the solid dispersions comprise about 27% to about 33% (w / w) eltrodinam. In some embodiments, the solid dispersions comprise about 31.5% to about 38.5% (w / w) eltrodinam. In some embodiments, the solid dispersions comprise about 36% to about 44% (w / w) eltrodinam.

[0081] In some embodiments, the solid dispersions comprise about 20% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 22.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 25% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 27% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 27.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 30% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 31.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 33% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 32.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 35% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 36% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 37.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 38.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 40% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 42.5% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 44% (w / w) of eltrodinam. In some embodiments, the solid dispersions comprise about 45% (w / w) of eltrodinam.

[0082] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) eltrodinam and about 65% to about 75% polymer; or about 25% to about 30% (w / w) eltrodinam and about 70% to about 75% (w / w) polymer. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) eltrodinam and about 65% to about 75% polymer. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) eltrodinam and about 70% to about 75% (w / w) polymer.

[0083] In some embodiments, the solid dispersion comprises about 25% eltrodinam and about 75% (w / w) polymer. In some embodiments, the solid dispersion comprises about 30% eltrodinam and about 70% (w / w) polymer. In some embodiments, the solid dispersion comprises about 35% eltrodinam and about 65% (w / w) polymer. In some embodiments, the solid dispersion comprises about 40% eltrodinam and about 60% (w / w) polymer.

[0084] In some embodiments, the solid dispersion is characterized by a single glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g ); and / or a crystallinity of no more than 5% or no more than 1%.

[0085] In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 75°C to about 100°C. g ); or a crystallinity of no more than 5%. In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g ); or a crystallinity of no more than 3%. In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g ); or a crystallinity not exceeding 1%.

[0086] In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 50°C to about 150°C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T g ).g It can be determined by modulated differential scanning calorimetry (MDSC).

[0087] In some embodiments, the solid dispersion is characterized by no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% crystallinity. In some embodiments, the solid dispersion is characterized by no more than 5% crystallinity. In some embodiments, the solid dispersion is characterized by no more than 3% crystallinity. In some embodiments, the solid dispersion is characterized by no more than 1% crystallinity. In some embodiments, crystallinity refers to the amount of crystalline edredinam relative to the total SDI.

[0088] Crystallinity can be determined, for example, by x-ray powder diffraction (XRPD). In some embodiments, the solid dispersion is characterized by a crystallinity below the XRPD limit of quantitation (LOQ). In some embodiments, the solid dispersion is characterized by a crystallinity below the XRPD limit of detection (LOD). In some embodiments, where crystallinity is determined by XRPD, crystallinity refers to the amount of crystalline edredinam relative to the total API.

[0089] In some embodiments, the solid dispersion is characterized by a single melting temperature (T m ); and / or an x-ray powder diffraction (XRPD) diffraction pattern lacking discrete peaks. In some embodiments, the solid dispersion is characterized by a single melting temperature (T m ); or an x-ray powder diffraction (XRPD) diffraction pattern lacking discrete peaks.

[0090] In some embodiments, the polymer is HPMCAS.In some embodiments, the polymer is copovidone.

[0091] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) of eltrodinam and about 65% to about 75% copovidone; or about 25% to about 30% (w / w) of eltrodinam and about 70% to about 75% (w / w) copovidone. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) of eltrodinam and about 65% to about 75% copovidone. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) of eltrodinam and about 70% to about 75% (w / w) copovidone.

[0092] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) of eltrodinam and about 60% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[0093] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) eltrodinam and about 65% to about 75% (w / w) hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[0094] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0095] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity of not more than 5% or not more than 1%.

[0096] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0097] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity not exceeding 5%.

[0098] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0099] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity not exceeding 3%.

[0100] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0101] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity not exceeding 1%.

[0102] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) of edradinam and about 65% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0103] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°Cg ); or a crystallinity of not more than 5% or not more than 1%.

[0104] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) of edradinam and about 65% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0105] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity not exceeding 5%.

[0106] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) of edradinam and about 65% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0107] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity not exceeding 3%.

[0108] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) of edradinam and about 65% to about 75% (w / w) of hydroxypropylmethylcellulose acetate succinate (HPMCAS),

[0109] wherein the solid dispersion is characterized by a single glass transition temperature (T) of about 75°C to about 85°C g ); or a crystallinity not exceeding 1%.

[0110] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) eltrodinam and about 65% to about 75% HPMCAS; or about 25% to about 30% (w / w) eltrodinam and about 70% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) eltrodinam and about 65% to about 75% HPMCAS. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) eltrodinam and about 70% to about 75% (w / w) HPMCAS.

[0111] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) of eltrodinam and about 65% to about 75% HPMCAS. In some embodiments, the solid dispersion comprises about 27% to about 33% (w / w) of eltrodinam and about 65% to about 75% (w / w) of HPMCAS. In some embodiments, the solid dispersion comprises about 31.5% to about 38.5% (w / w) of eltrodinam and about 65% to about 75% (w / w) of HPMCAS. In some embodiments, the solid dispersion comprises about 36% to about 44% (w / w) of eltrodinam and about 65% to about 75% (w / w) of HPMCAS.

[0112] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) of eltrodinam and about 70% to about 75% (w / w) of HPMCAS. In some embodiments, the solid dispersion comprises about 27% to about 33% (w / w) of eltrodinam and about 70% to about 75% (w / w) of HPMCAS. In some embodiments, the solid dispersion comprises about 31.5% to about 38.5% (w / w) of eltrodinam and about 70% to about 75% (w / w) of HPMCAS. In some embodiments, the solid dispersion comprises about 36% to about 44% (w / w) of eltrodinam and about 70% to about 75% (w / w) of HPMCAS.

[0113] In some embodiments, the solid dispersion comprises about 25% (w / w) eltrodinam and about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 30% (w / w) eltrodinam and about 70% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 35% (w / w) eltrodinam and about 65% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 40% (w / w) eltrodinam and about 60% (w / w) HPMCAS.

[0114] In some embodiments, the HPMCAS can be any commercially available grade of HPMCAS. In some embodiments, the HPMCAS comprises an acetyl content of about 5% to about 14%, a succinyl content of about 4% to about 18%, a methoxy content of about 20% to about 26%, and a hydroxypropoxy content of about 5% to about 10%. In some embodiments, the HPMCAS comprises an acetyl content of about 7% to about 11%, a succinyl content of about 10% to about 14%, a methoxy content of about 21% to about 25%, and a hydroxypropoxy content of about 5% to about 9%.

[0115] In some embodiments, the solid dispersion is characterized by a single T g In some embodiments, the solid dispersion comprising edradinam and HPMCAS is characterized by a single glass transition temperature (T g ); and / or a crystallinity of no more than 5% or no more than 1%. In some embodiments, the solid dispersion comprising edradinam and HPMCAS is characterized by a single glass transition temperature (T) of about 75°C to about 85°C. g ); or a crystallinity of no more than 5%. In some embodiments, the solid dispersion comprising edradinam and HPMCAS is characterized by a single glass transition temperature (T) of about 75°C to about 85°C. g ); or a crystallinity of no more than 3%. In some embodiments, the solid dispersion comprising edradinam and HPMCAS is characterized by a single glass transition temperature (T) of about 75°C to about 85°C. g ); or a crystallinity of no more than 1%. In some embodiments, the solid dispersion is characterized by the absence of other melting or crystallization events; and / or the XRPD diffraction pattern lacks discrete peaks. In some embodiments, the solid dispersion is characterized by the absence of other melting or crystallization events; or the XRPD diffraction pattern lacks discrete peaks.

[0116] In some embodiments, the solid dispersions described herein are tested in AUC by non-sinking dissolution testing. 35-210 The solid dispersion described herein has at least a 3-fold increase in FaSSIF (minutes*µgA / mL) compared to crystalline edredinam. Non-sinking dissolution testing can be performed as described herein. In some embodiments, the solid dispersion described herein has a 3-fold increase in AUC by non-sinking dissolution testing. 35-210 FaSSIF (minutes*µgA / mL) increased by approximately 4-fold, 5-fold, 6-fold, and 7-fold compared to crystalline edredinam.

[0117] In some embodiments, the solid dispersion as described herein has a total impurity amount (% area) of less than 2% as measured by HPLC. In some embodiments, the solid dispersion as described herein has a total impurity amount (% area) of less than 1% as measured by HPLC. The impurity analysis performed by HPLC can be performed as described herein. In some embodiments, the solid dispersion or tablet has a total impurity amount (% area) of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% as measured by HPLC. In some embodiments, the tablet has a total impurity amount (% area) of less than 1% as measured by HPLC. In some embodiments, the solid dispersion or tablet has a total impurity amount (area %) of less than 0.5% as measured by HPLC.

[0118] Some embodiments provide solid dispersions that are physically stable, chemically stable, and / or have a stable in vitro dissolution profile when stored in a sealed or open package for 3 months or longer (e.g., 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months) at 25°C and 60% relative humidity (long-term stability testing) or 40°C and 75% relative humidity (accelerated stability testing). Stability can be assessed by a variety of analytical methods, including XRPD, MDSC, HPLC for edredinam and impurities, and non-sinking dissolution testing.

[0119] In some embodiments, the solid dispersion is characterized by (i) a single glass transition temperature (Tg) of about 75°C to about 85°C when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity; g ), or another T as described herein g , as measured by MDSC, (ii) there are no other melting or crystallization events as measured by MDSC, (iii) the XRPD diffraction pattern lacks discrete peaks, (iv) the crystallinity does not exceed 5%, or does not exceed 1%, or is below the LOQ or LOD of XRPD, or (v) any combination of (i) to (iv).

[0120] In some embodiments, the amount of edredinam measured by a non-sinking dissolution test at 210 minutes when stored in a sealed or open package for 3 months or more at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity is 25°C and 60% relative humidity and / or 40°C and 75% relative humidity. 210; µgA / mL) differs by no more than about 25% from the value measured at 0 months. In some embodiments, the amount of edredinam measured by a non-sinking dissolution test at 210 minutes when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity is 210 ; µgA / mL) differs by no more than about 15% from the value measured at 0 months. In some embodiments, the amount of edredinam measured by a non-sinking dissolution test at 210 minutes when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity is 210 ; µgA / mL) differs by no more than about 12% from the value measured at 0 months. In some embodiments, the amount of edredinam measured by a non-sinking dissolution test at 210 minutes when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity is 210 ; µgA / mL) differs by no more than 10% from the value measured at 0 months. In some embodiments, the amount of edredinam measured by a non-sinking dissolution test at 210 minutes when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity is 210 ; µgA / mL) did not differ by more than 5% from the value measured at 0 months.

[0121] In some embodiments, the AUC is measured when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity. 35-210 FaSSIF The amount of etradinam in FaSSIF measured (minutes*gA / mL) does not vary by more than about 25% from the value measured at 0 months. In some embodiments, when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity, the amount of etradinam measured in FaSSIF (minutes*gA / mL) does not vary by more than about 25% from the value measured at 0 months. 35-210 FaSSIF The amount of etradinam in FaSSIF measured (minutes*gA / mL) does not vary by more than about 15% from the value measured at 0 months. In some embodiments, when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity, the amount of etradinam measured in FaSSIF (minutes*gA / mL) does not vary by more than about 15% from the value measured at 0 months. 35-210 FaSSIF The amount of etradinam in FaSSIF measured (minutes*gA / mL) does not vary by more than about 10% from the value measured at 0 months. In some embodiments, when stored in a sealed or open package for 3 months or longer at 25°C and 60% relative humidity and / or 40°C and 75% relative humidity, the amount of etradinam measured in FaSSIF (minutes*gA / mL) does not vary by more than about 10% from the value measured at 0 months.35-210 FaSSIF The amount of edredinam measured in FaSSIF (minutes*gA / mL) did not differ by more than approximately 5% from the value measured at 0 months.

[0122] In some embodiments, the solid dispersion, when stored in a sealed package at 25° C. and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months:

[0123] (i) the amount of etradinam in the solid dispersion is from about 90% to about 110% of the value measured at 0 months;

[0124] (ii) the solid dispersion has a total impurity amount (% area) of less than or equal to 2%, or less than or equal to 1%, as measured by high performance liquid chromatography (HPLC);

[0125] (iii) The solid dispersion was characterized by a single T by modulated differential scanning calorimetry (MDSC). g and optionally a single melting temperature (T m );

[0126] (iv) the solid dispersion is characterized by an XRPD diffraction pattern lacking discrete peaks;

[0127] (v) Passed the non-sinking dissolution test at 210 minutes (C 210 (µgA / mL) or AUC 35-210 FaSSIF The amount of edredinam measured at the end of the study period (minutes*µgA / mL) does not differ by more than 15% from the value measured at 0 months; or

[0128] (vi) Any combination of (i) to (v).

[0129] In some embodiments the solid dispersion when stored in a sealed package at 25°C and 60% relative humidity for 6 months, 12 months, 18 months, 24 months or 36 months:

[0130] (i) the amount of etradinam in the solid dispersion is from about 90% to about 110% of the value measured at 0 months;

[0131] (ii) the solid dispersion has a total impurity amount (% area) of less than or equal to 2%, or less than or equal to 1%, as measured by high performance liquid chromatography (HPLC);

[0132] (iii) The solid dispersion was characterized by a single T by modulated differential scanning calorimetry (MDSC). g and optionally a single melting temperature (T m );

[0133] (iv) the solid dispersion is characterized by an XRPD diffraction pattern lacking discrete peaks; or

[0134] (v) Any combination of (i) to (iv).

[0135] In some embodiments, provided herein are samples comprising one or more dispersions as described herein. In some embodiments, provided herein are samples comprising one or more solid dispersions as described herein. Such samples may exhibit one or more characteristics, such as those of the solid dispersions described herein.

[0136] Some embodiments provide particles, wherein such particles comprise a solid dispersion as described herein.Such particles may exhibit one or more properties, such as those of the solid dispersion described herein.

[0137] The solid dispersions described herein can be prepared according to the methods described herein. In some embodiments, the solid dispersions described herein are formed by spray drying.

[0138] Some embodiments provide spray-dried particles, wherein such particles are formed by spray drying and comprise a solid dispersion as described herein.Such spray-dried particles may exhibit one or more properties, such as those of the solid dispersions described herein.

[0139] In some embodiments, the spray-dried particles comprise a solid dispersion as described herein, wherein the spray-dried particles are characterized by a Dv90 of less than 150µm or a Dv50 of less than 50µm. In some embodiments, the spray-dried particles are characterized by a Dv90 of less than 150µm. In some embodiments, the spray-dried particles are characterized by a Dv50 of less than 50µm. In some embodiments, the spray-dried particles are characterized by a Dv90 of about 80µm to about 130µm; and / or a Dv50 of about 25µm to about 40µm. In some embodiments, the spray-dried particles are characterized by a Dv90 of about 80µm to about 130µm. In some embodiments, the spray-dried particles are characterized by a Dv50 of about 25µm to about 40µm.

[0140] In some embodiments, provided herein are samples comprising one or more particles as described herein. Such samples may exhibit one or more characteristics, such as those of the solid dispersion as described herein and / or the particles as described herein.

[0141] Method for preparing dispersion

[0142] Provided herein are methods of making the dispersions as described herein.

[0143] In some embodiments, the dispersion as described herein can be prepared according to methods known in the art. Non-limiting examples known in the art for preparing solid dispersions include, but are not limited to, spray drying, melt extrusion, freeze drying, and solution evaporation. In some embodiments, a method for preparing a solid dispersion comprising edrodinam is provided herein, the method comprising: mixing edrodinam, a polymer as described herein, and a solvent to produce a spray solution; and spray drying the spray solution to produce the solid dispersion. The term "spray solution" as used herein may also be referred to as a "solution" or a "feed solution."

[0144] Some embodiments provide a method for preparing a solid dispersion comprising edradinam, the method comprising:

[0145] mixing edradinam, a polymer selected from HPMCAS and copovidone, and a solvent to produce a spray solution; and

[0146] The spray solution is spray dried to produce the solid dispersion.

[0147] In some embodiments, the solid dispersion undergoes further drying to produce a dry powder having a moisture content of less than about 1% (w / w).

[0148] Some embodiments provide a method for preparing a spray-dried particle comprising a solid dispersion as described herein, the method comprising:

[0149] mixing edradinam, a polymer selected from HPMCAS and copovidone, and a solvent to produce a spray solution; and

[0150] The spray solution is spray dried to produce the spray-dried particles.

[0151] In some embodiments, the weight ratio of edradinam to polymer is 25:75 to 40:60.

[0152] Some embodiments provide a method for preparing a spray-dried particle comprising a solid dispersion as described herein, the method comprising:

[0153] mixing edradinam, HPMCAS, and a solvent to produce a spray solution; and

[0154] The spray solution is spray dried to produce the spray-dried particles.

[0155] In some embodiments, the weight ratio of edradinam to HPMCAS is 25:75 to 40:60.

[0156] In some embodiments, the spray solution is prepared at a solids loading of 8% to 13%.

[0157] In some embodiments, the spray-dried particles undergo further drying to produce a dry powder having a moisture content of less than about 1% (w / w).

[0158] In some embodiments, the spray drying step comprises atomizing the spray solution into a drying chamber having an outlet temperature of about 38°C to about 46°C, a gas-to-liquid ratio of about 0.5 to about 0.7, and a relative saturation (total) of about 15% to about 23%.

[0159] IV. Compositions and Pharmaceutical Compositions

[0160] Provided herein are compositions comprising a semi-solid dispersion or a solid dispersion as described herein, a particle as described herein, a spray-dried particle as described herein, or a sample thereof.

[0161] The dispersion of edradinam described herein may be in the form of a composition suitable for administration to a subject.

[0162] Some embodiments provide a pharmaceutical composition comprising a dispersion of edradinam as described herein and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients.

[0163] In some embodiments, edrolidine or a pharmaceutically acceptable salt thereof is present in a therapeutically acceptable amount.The pharmaceutical composition can be used in the methods of the present disclosure; thus, for example, the pharmaceutical composition can be administered to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.

[0164] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein. In addition, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds as described herein to treat or prevent the diseases, disorders and conditions contemplated by the present disclosure.

[0165] Pharmaceutical compositions comprising dispersions described herein may be in a form suitable for oral use, for example, in the form of tablets, capsules, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents and preservatives, in order to provide pharmaceutically excellent and palatable preparations. Tablets, capsules, etc. contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binding agents, such as starch, gelatin or gum arabic, and lubricants, such as magnesium stearate, stearic acid or talc.

[0166] Tablets, capsules etc. suitable for oral administration can be non-coated or coated by known technology to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action.For example, time-delay materials can be adopted, such as glyceryl monostearate or glyceryl distearate.They can also be coated by technology known in the art to form osmotic therapeutic tablets for controlled release.Additional agents include biodegradable or biocompatible particles or polymeric substances, such as polyester, polyamino acid, hydrogel, polyvinyl pyrrolidone, polyanhydride, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate or lactide / glycolide copolymer, polylactide / glycolide copolymer or ethylene vinyl acetate copolymer, so as to control the delivery of the composition used.For example, oral medicaments can be embedded in by coagulation technology or interfacial polymerization, respectively by using hydroxymethyl cellulose or gelatin-microcapsule or poly (methyl methacrylate) microcapsule prepared in the microcapsule, or embedded in the colloidal drug delivery system. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles and liposomes. Methods for preparing the above formulations will be apparent to those skilled in the art.

[0167] Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium phosphate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0168] Aqueous suspensions contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin) or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate) or condensation products of ethylene oxide with long chain fatty alcohols (e.g., for heptadecaethyleneoxycetanol) or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate) or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0169] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil), or in a mineral oil (e.g., liquid paraffin). Oily suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (e.g., those described above) and flavoring agents can be added to provide a palatable oral preparation.

[0170] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0171] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid paraffin) or a mixture of these. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0172] In some embodiments, the pharmaceutical composition comprises a dispersion comprising a therapeutically effective amount of edredinam or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically and physiologically acceptable formulations. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl paraben, ethyl paraben or n-propyl paraben), emulsifiers, suspending agents, dispersants, solvents, fillers, expanders, detergents, buffers, vehicles, diluents and / or adjuvants. For example, a suitable vehicle may be a physiological saline solution or citrate buffered saline, which may be supplemented with other materials commonly found in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is another exemplary vehicle. Those skilled in the art should readily recognize that a variety of buffers may be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases or mixtures thereof. As an example, the buffer component can be a water-soluble material such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS) and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0173] After the pharmaceutical composition has been formulated, it can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is in a disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector (similar to, for example, an EpiPen). ® )), while in other embodiments multiple-use containers (e.g., multiple-use vials) are provided.

[0174] The formulation can also include a carrier to protect the composition from rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time-delay material, such as glyceryl monostearate or glyceryl stearate, can be used alone or in combination with a wax. Any drug delivery device can be used to deliver the dispersion or composition described herein, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the technician.

[0175] Depot injections, which are usually administered subcutaneously or intramuscularly, can also be used to release the dispersion or composition disclosed herein over a defined period of time. Depot injections are usually solid or oil-based and usually contain at least one of the formulation components described herein. Those of ordinary skill in the art are familiar with the possible formulations and uses of depot injections.

[0176] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. The suspension may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Acceptable diluents, solvents and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL ™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used to prepare injections. Prolonged absorption of a particular injectable formulation may be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).

[0177] The present disclosure contemplates administration of the dispersion or composition described herein in the form of a suppository for rectal administration. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0178] The dispersions or compositions described herein can be in the form of any other suitable pharmaceutical composition currently known or developed in the future (eg, a spray for nasal use or inhalation use).

[0179] Some embodiments provide a dosage form comprising a semi-solid dispersion as described herein. In some embodiments, the dosage form is a tablet or a capsule. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a capsule. Some embodiments provide a capsule comprising a semi-solid dispersion as described herein.

[0180] Some embodiments provide a dosage form comprising a solid dispersion as described herein. Some embodiments provide a tablet comprising a solid dispersion as described herein.

[0181] Some embodiments provide dosage forms comprising the spray-dried particles as described herein.

[0182] In some embodiments, the dosage form is a tablet or a capsule. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a capsule. Exemplary tablets and capsules are described herein.

[0183] Exemplary compositions

[0184] Some embodiments provide compositions comprising a solid dispersion as described herein and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0185] In some embodiments, the composition comprises about 40% to about 60% (w / w) solid dispersion. In some embodiments, the composition comprises about 45% to about 50% (w / w) solid dispersion.

[0186] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 43% to about 47% (w / w) one or more fillers, about 4% to about 6% (w / w) one or more disintegrants, about 0.5% to about 1% (w / w) one or more glidants, and less than 1% (w / w) one or more lubricants.

[0187] In some embodiments, the composition comprises about 47.3% (w / w) solid dispersion, about 47.3% (w / w) one or more fillers, about 4.1% (w / w) one or more disintegrants, about 0.6% (w / w) one or more glidants, and about 0.6% (w / w) one or more lubricants.

[0188] In some embodiments, the composition comprises about 50% (w / w) solid dispersion, about 17.5% (w / w) one or more fillers, about 31.8% (w / w) one or more disintegrants, and about 0.6% (w / w) one or more lubricants.

[0189] In some embodiments, the composition comprises about 35% to about 45% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0190] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0191] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 44% (w / w) one or more fillers, about 5% (w / w) one or more disintegrants, and about 0.5% (w / w) one or more lubricants.

[0192] In some embodiments, the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica;

[0193] The one or more disintegrants is croscarmellose sodium;

[0194] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0195] If present, the one or more glidants is colloidal silicon dioxide.

[0196] In some embodiments, the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; or

[0197] The one or more disintegrants is croscarmellose sodium; or

[0198] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; or

[0199] If present, the one or more glidants is colloidal silicon dioxide.

[0200] In some embodiments, the co-processed MCC includes MCC co-processed with alginate, chitosan, DCP, guar gum, mannitol, silicon dioxide, sorbitol, and the like.

[0201] In some embodiments, the one or more fillers are selected from MCC, mannitol, siliconized MCC, and mesoporous silica;

[0202] The one or more disintegrants is croscarmellose sodium;

[0203] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0204] If present, the one or more glidants is colloidal silicon dioxide.

[0205] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; or

[0206] The one or more disintegrants is croscarmellose sodium; or

[0207] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; or

[0208] If present, the one or more glidants is colloidal silicon dioxide.

[0209] In some embodiments, the one or more fillers are selected from MCC, mannitol, siliconized MCC, and mesoporous silica;

[0210] The one or more disintegrants is croscarmellose sodium; and

[0211] The lubricant(s) is magnesium stearate.

[0212] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; or

[0213] The one or more disintegrants is croscarmellose sodium; or

[0214] The lubricant(s) is magnesium stearate.

[0215] In some embodiments, the composition as described herein comprises a first filler and a second filler, and wherein the solid dispersion, the first filler and the second filler have a weight ratio of 2: 1: 1. In some embodiments, the composition as described herein comprises a first filler and a second filler, and wherein the solid dispersion, the first filler and the second filler have a weight ratio of about 2.2: 1.4: 1.

[0216] In some embodiments, the first filler and the second filler are independently selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0217] In some embodiments, the first filler and the second filler are each independently selected from the group consisting of MCC, mannitol, siliconized MCC, and mesoporous silica.

[0218] In some embodiments, the first bulking agent is MCC and the second bulking agent is mannitol.

[0219] In some embodiments, the one or more disintegrants is croscarmellose sodium; the one or more lubricants is sodium stearyl fumarate; and the one or more glidants is colloidal silicon dioxide.

[0220] In some embodiments, the one or more disintegrants is croscarmellose sodium; or the one or more lubricants is sodium stearyl fumarate; or the one or more glidants is colloidal silicon dioxide.

[0221] In some embodiments, the one or more disintegrants is croscarmellose sodium; or the one or more lubricants is magnesium stearate.

[0222] In some embodiments, the composition comprises about 40% to about 60% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein:

[0223] one or more fillers selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica;

[0224] The one or more disintegrants is croscarmellose sodium;

[0225] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0226] If present, the one or more glidants is colloidal silicon dioxide.

[0227] In some embodiments, the composition comprises about 40% to about 50% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein:

[0228] The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica;

[0229] The one or more disintegrants is croscarmellose sodium;

[0230] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0231] If present, the one or more glidants is colloidal silicon dioxide.

[0232] In some embodiments, the composition comprises about 40% to about 60% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein:

[0233] The solid dispersion comprises about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of HPMCAS;

[0234] one or more fillers selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica;

[0235] The one or more disintegrants is croscarmellose sodium;

[0236] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0237] If present, the one or more glidants is colloidal silicon dioxide.

[0238] In some embodiments, the composition comprises about 40% to about 50% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein:

[0239] The solid dispersion comprises about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of HPMCAS;

[0240] one or more fillers selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica;

[0241] The one or more disintegrants is croscarmellose sodium;

[0242] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0243] If present, the one or more glidants is colloidal silicon dioxide.

[0244] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; wherein:

[0245] The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica.

[0246] In some embodiments, the composition comprises about 47.3% (w / w) of a solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of croscarmellose sodium, about 0.6% (w / w) of colloidal silicon dioxide, and about 0.6% (w / w) of sodium stearyl fumarate; wherein:

[0247] The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica.

[0248] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25% to about 0.75% (w / w) of magnesium stearate; wherein:

[0249] The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica.

[0250] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 44% (w / w) of one or more fillers, about 5% (w / w) of croscarmellose sodium, and about 0.5% (w / w) of magnesium stearate; wherein:

[0251] The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica.

[0252] In some embodiments, the composition comprises about 45% to about 50% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; wherein:

[0253] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0254] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; wherein:

[0255] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0256] In some embodiments, the composition comprises about 47.3% (w / w) of a solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of croscarmellose sodium, about 0.6% (w / w) of colloidal silicon dioxide, and about 0.6% (w / w) of sodium stearyl fumarate; wherein:

[0257] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0258] In some embodiments, the composition comprises about 35% to about 45% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25% to about 0.75% (w / w) of magnesium stearate; wherein:

[0259] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0260] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25 to about 0.75% (w / w) of magnesium stearate; wherein:

[0261] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0262] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion; about 44% (w / w) of one or more fillers, about 5% (w / w) of croscarmellose sodium, and about 0.5% (w / w) of magnesium stearate; wherein:

[0263] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0264] In some embodiments, the composition comprises about 45% to about 50% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; wherein:

[0265] The solid dispersion comprises about 25% to about 40% (w / w) eltrodinam and about 60% to about 75% (w / w) HPMCAS; and

[0266] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0267] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; wherein:

[0268] The solid dispersion comprises about 25% to about 40% (w / w) eltrodinam and about 60% to about 75% (w / w) HPMCAS; and

[0269] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0270] In some embodiments, the composition comprises about 47.3% (w / w) of a solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of croscarmellose sodium, about 0.6% (w / w) of colloidal silicon dioxide, and about 0.6% (w / w) of sodium stearyl fumarate; wherein:

[0271] The solid dispersion comprises about 25% to about 40% (w / w) eltrodinam and about 60% to about 75% (w / w) HPMCAS; and

[0272] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0273] In some embodiments, the composition comprises about 35% to about 45% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25% to about 0.75% (w / w) of magnesium stearate; wherein:

[0274] The solid dispersion comprises about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of HPMCAS; and

[0275] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0276] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25 to about 0.75% (w / w) of magnesium stearate; wherein:

[0277] The solid dispersion comprises about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of HPMCAS; and

[0278] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0279] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion; about 44% (w / w) of one or more fillers, about 5% (w / w) of croscarmellose sodium, and about 0.5% (w / w) of magnesium stearate; wherein:

[0280] The solid dispersion comprises about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of HPMCAS; and

[0281] The one or more fillers are selected from MCC, mannitol, siliconized MCC and mesoporous silica.

[0282] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5% to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; and wherein the solid dispersion, the first filler, and the second filler have a 2:1:1 weight ratio.

[0283] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; and wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1.

[0284] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5% to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; and

[0285] And wherein the solid dispersion, the first filler and the second filler have a weight ratio of 2:1:1; and wherein the first filler and the second filler are independently selected from: selected from: anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica.

[0286] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; and wherein the solid dispersion, the first filler and the second filler have a weight ratio of about 2.2:1.4:1; and wherein the first filler and the second filler are independently selected from: selected from: anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica.

[0287] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5% to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; and

[0288] and wherein the solid dispersion, the first filler, and the second filler have a 2:1:1 weight ratio; and wherein the first filler and the second filler are each independently selected from the group consisting of MCC, mannitol, silicified MCC, and mesoporous silica.

[0289] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; and wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; and wherein the first filler and the second filler are each independently selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0290] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5% to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; and

[0291] and wherein the solid dispersion, the first filler, and the second filler have a 2:1:1 weight ratio; and wherein the first filler is MCC, and the second filler is mannitol.

[0292] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; and wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; and wherein the first filler is MCC and the second filler is mannitol.

[0293] In some embodiments, the composition comprises about 47% (w / w) of a solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; and

[0294] and wherein the solid dispersion, the first filler, and the second filler have a 2:1:1 weight ratio; and wherein the first filler is MCC, and the second filler is mannitol.

[0295] In some embodiments, the composition comprises about 40% (w / w) of a solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25% to about 0.75% (w / w) of magnesium stearate; and wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; and wherein the first filler is MCC and the second filler is mannitol.

[0296] Some embodiments provide intragranular components comprising a composition as described herein.

[0297] In some embodiments, the intragranular component comprises a solid dispersion as described herein and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0298] Particles

[0299] Some embodiments provide compositions comprising a solid dispersion as described herein and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0300] Some embodiments provide a granule comprising a spray-dried granule as described herein and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0301] In some embodiments, the particle comprises about 40% to about 60% (w / w) solid dispersion or spray-dried particle. In some embodiments, the particle comprises about 45% to about 50% (w / w) solid dispersion or spray-dried particle.

[0302] In some embodiments, the granules comprise: about 47% (w / w) solid dispersion or spray-dried granules, about 43% to about 47% (w / w) one or more fillers, about 4% to about 6% (w / w) one or more disintegrants, about 0.5% to about 1% (w / w) one or more glidants, and less than 1% (w / w) one or more lubricants.

[0303] In some embodiments, the granules comprise: about 47.3% (w / w) solid dispersion or spray-dried granules, about 47.3% (w / w) one or more fillers, about 4.1% (w / w) one or more disintegrants, about 0.6% (w / w) one or more glidants, and about 0.6% (w / w) one or more lubricants.

[0304] In some embodiments, the granules comprise: about 35% to about 45% (w / w) of the solid dispersion or spray-dried granules, about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0305] In some embodiments, the granules comprise about 40% (w / w) solid dispersion or spray-dried granules, about 44% (w / w) one or more fillers, about 5% (w / w) one or more disintegrants, and about 0.5% (w / w) one or more lubricants.

[0306] In some embodiments, the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; and / or

[0307] The one or more disintegrants is croscarmellose sodium; and / or

[0308] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and / or

[0309] If present, the one or more glidants is colloidal silicon dioxide.

[0310] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; and / or

[0311] The one or more disintegrants is croscarmellose sodium; and / or

[0312] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and / or

[0313] If present, the one or more glidants is colloidal silicon dioxide.

[0314] In some embodiments, the particles described herein comprise a first filler and a second filler, and wherein the solid dispersion, the first filler, and the second filler have a weight ratio of 2: 1: 1. In some embodiments, the particles as described herein comprise a first filler and a second filler, and wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2: 1.4: 1.

[0315] In some embodiments, the first bulking agent is MCC and the second bulking agent is mannitol.

[0316] In some embodiments, the one or more disintegrants is croscarmellose sodium; and / or

[0317] The one or more lubricants are sodium stearyl fumarate or magnesium stearate; and / or

[0318] If present, the one or more glidants is colloidal silicon dioxide.

[0319] In some embodiments, the one or more disintegrants is croscarmellose sodium; and / or

[0320] The one or more lubricants are sodium stearyl fumarate or magnesium stearate; and / or

[0321] If present, the one or more glidants are selected from colloidal silicon dioxide.

[0322] Exemplary Pharmaceutical Compositions

[0323] Some embodiments provide a pharmaceutical composition comprising an intragranular component comprising a composition as described herein and an extragranular component, the intragranular component comprising one or more fillers, optionally one or more disintegrants, optionally one or more glidants, and one or more lubricants.

[0324] Some embodiments provide a pharmaceutical composition comprising an intragranular component as described herein and an extragranular component comprising one or more fillers, optionally one or more disintegrants, optionally one or more glidants, and one or more lubricants.

[0325] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular components, or about 85% (w / w) intragranular components. In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular components. In some embodiments, the pharmaceutical composition comprises about 87% to about 93% (w / w) intragranular components. In some embodiments, the pharmaceutical composition comprises about 85% (w / w) intragranular components. In some embodiments, the pharmaceutical composition comprises about 90% (w / w) intragranular components.

[0326] In some embodiments, the intragranular component comprises: about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of one or more disintegrants, about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.5% to about 1.0% (w / w) of one or more lubricants. In some embodiments, the extragranular component comprises: about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0327] In some embodiments, the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, co-treated microcrystalline cellulose, silicified microcrystalline cellulose, and mesoporous silica;

[0328] If present, the one or more disintegrants is croscarmellose sodium;

[0329] The one or more lubricants is sodium stearyl fumarate or magnesium stearate; and

[0330] If present, the one or more glidants is colloidal silicon dioxide.

[0331] In some embodiments, the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, co-treated microcrystalline cellulose, silicified microcrystalline cellulose, and mesoporous silica; or

[0332] If present, the one or more disintegrants is croscarmellose sodium; or

[0333] The one or more lubricants is sodium stearyl fumarate or magnesium stearate; or

[0334] If present, the one or more glidants is colloidal silicon dioxide.

[0335] In some embodiments, the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica;

[0336] The one or more disintegrants is croscarmellose sodium;

[0337] The one or more lubricants is sodium stearyl fumarate; and

[0338] The one or more glidants is colloidal silicon dioxide.

[0339] In some embodiments, the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica; or

[0340] The one or more disintegrants is croscarmellose sodium; or

[0341] The one or more lubricants is sodium stearyl fumarate; or

[0342] The one or more glidants is colloidal silicon dioxide.

[0343] In some embodiments, the one or more fillers are selected from microcrystalline cellulose and mannitol, and the one or more lubricants is magnesium stearate.

[0344] In some embodiments, the pharmaceutical composition comprises two fillers, optionally in a 1:1 to 2:1 ratio.

[0345] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0346] The components in the granules include:

[0347] about 35% to about 50% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; and

[0348] The extragranular components include:

[0349] about 5% to about 15% (w / w) of one or more fillers, optionally about 1% to about 2% (w / w) of one or more disintegrants, optionally about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.25% to about 1.0% (w / w) of one or more lubricants;

[0350] in:

[0351] one or more fillers selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica;

[0352] The one or more disintegrants is croscarmellose sodium;

[0353] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0354] If present, the one or more glidants is colloidal silicon dioxide.

[0355] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0356] The components in the granules include:

[0357] about 35% to about 50% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; and

[0358] The extragranular components include:

[0359] about 5% to about 15% (w / w) of one or more fillers, optionally about 1% to about 2% (w / w) of one or more disintegrants, optionally about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.25% to about 1.0% (w / w) of one or more lubricants;

[0360] in:

[0361] one or more fillers selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose and mesoporous silica;

[0362] The one or more disintegrants is croscarmellose sodium;

[0363] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0364] If present, the one or more glidants is colloidal silicon dioxide.

[0365] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0366] The components in the granules include:

[0367] about 35% to about 50% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants and optionally one or more lubricants,

[0368] wherein the solid dispersion comprises about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of HPMCAS; and

[0369] The extragranular components include:

[0370] about 5% to about 15% (w / w) of one or more fillers, optionally about 1% to about 2% (w / w) of one or more disintegrants, optionally about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.25% to about 1.0% (w / w) of one or more lubricants;

[0371] in:

[0372] one or more fillers selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica;

[0373] The one or more disintegrants is croscarmellose sodium;

[0374] If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and

[0375] If present, the one or more glidants is colloidal silicon dioxide.

[0376] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0377] The components in the granules include:

[0378] about 45% to about 50% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants and optionally one or more lubricants,

[0379] wherein the solid dispersion comprises about 25% to about 40% (w / w) of edradinam and about 60% to about 75% (w / w) of HPMCAS; and

[0380] The extragranular components include:

[0381] about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of one or more disintegrants, about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.5% to about 1.0% (w / w) of one or more lubricants;

[0382] in:

[0383] one or more fillers selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose and mesoporous silica;

[0384] The one or more disintegrants is croscarmellose sodium;

[0385] If present, the one or more lubricants is sodium stearyl fumarate; and

[0386] If present, the one or more glidants is colloidal silicon dioxide.

[0387] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0388] The components in the granules include:

[0389] about 35% to about 45% (w / w) of a solid dispersion and one or more fillers, one or more disintegrants, optionally one or more glidants and optionally one or more lubricants,

[0390] wherein the solid dispersion comprises about 20% to about 40% (w / w) of edradinam and about 60% to about 80% (w / w) of HPMCAS; and

[0391] The extragranular components include:

[0392] about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of one or more lubricants;

[0393] wherein the one or more fillers are selected from microcrystalline cellulose and mannitol; the one or more disintegrants are croscarmellose sodium; and the one or more lubricants are magnesium stearate.

[0394] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0395] The intragranular component comprises about 47% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; and

[0396] The extragranular component comprises: about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silicon dioxide, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate;

[0397] wherein the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica;

[0398] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0399] The intragranular component comprises about 35% to about 45% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium and about 0.25% to about 0.75% (w / w) of magnesium stearate; and

[0400] The extragranular component comprises: about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of one or more lubricants;

[0401] wherein the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica;

[0402] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0403] The intragranular component comprises about 47.3% (w / w) of a solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of croscarmellose sodium, about 0.6% (w / w) of colloidal silicon dioxide, and about 0.6% (w / w) of sodium stearyl fumarate; and

[0404] The extragranular component comprises: about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silicon dioxide, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate;

[0405] wherein the one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica;

[0406] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0407] The intragranular component comprises about 47% (w / w) of a solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silicon dioxide, and less than 1% (w / w) of sodium stearyl fumarate; and

[0408] The extragranular component comprises: about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silicon dioxide, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate;

[0409] The one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose and mesoporous silicon dioxide.

[0410] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0411] The intragranular component comprises about 47.3% (w / w) of a solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of croscarmellose sodium, about 0.6% (w / w) of colloidal silicon dioxide, and about 0.6% (w / w) of sodium stearyl fumarate; and

[0412] The extragranular component comprises: about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silicon dioxide, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate;

[0413] The one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose and mesoporous silicon dioxide.

[0414] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component and the extragranular component; wherein:

[0415] The intragranular component comprises about 35% to about 45% (w / w) of a solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium and about 0.25% to about 0.75% (w / w) of magnesium stearate; and

[0416] The extragranular component comprises: about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of magnesium stearate;

[0417] The one or more fillers are selected from microcrystalline cellulose and mannitol.

[0418] In some embodiments, the one or more fillers of the intragranular component and the one or more fillers of the extragranular component are each independently selected from the above fillers. In some embodiments, the one or more fillers of the intragranular component are the same as the one or more fillers of the extragranular component. In some embodiments, the one or more fillers of the intragranular component are different from the one or more fillers of the extragranular component.

[0419] In some embodiments, the pharmaceutical composition or composition is a formulation of Table 16, Table 19, Table 20, or Table 24.

[0420] Exemplary Tablets

[0421] Some embodiments provide a pharmaceutical composition or a composition as described herein formulated as a tablet. In some embodiments, a tablet as described herein can be prepared according to methods known in the art.

[0422] Some embodiments provide tablets that are physically stable, chemically stable, have a stable in vitro dissolution profile, and / or have stable in vivo properties when stored in a sealed or open package for 3 months or more (e.g., 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months) at 25°C and 60% relative humidity (long-term stability test) or 40°C and 75% relative humidity (accelerated stability test). Stability can be assessed by a variety of analytical methods, including determination of edredinan and impurities by high performance liquid chromatography (HPLC), non-sinking dissolution test, sinking dissolution test, and pharmacokinetic analysis under fed and / or fasting conditions. Some embodiments provide tablets that are physically stable, chemically stable, have a stable in vitro dissolution profile, and / or have stable in vivo properties when stored in a sealed or open package for 6 months, 9 months, or 12 months at 25°C and 60% relative humidity (long-term stability test) or 40°C and 75% relative humidity (accelerated stability test).

[0423] Some embodiments provide tablets comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate, and a solid dispersion as described herein. Some embodiments provide tablets comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, magnesium stearate, and a solid dispersion as described herein.

[0424] In some embodiments, the tablet comprises about 25% to about 60% (w / w) of the solid dispersion. In some embodiments, the tablet comprises about 35% to about 55% (w / w) of the solid dispersion. In some embodiments, the tablet comprises about 30% to about 55% (w / w) of the solid dispersion. In some embodiments, the tablet comprises about 35% to about 45% (w / w) of the solid dispersion. In some embodiments, the tablet comprises about 40% to about 50% (w / w) of the solid dispersion.

[0425] In some embodiments, the tablet comprises about 40% to about 50% (w / w) of a solid dispersion as described herein, about 10% to 25% (w / w) of MCC, about 20% to about 25% (w / w) of mannitol, about 5% to about 6% (w / w) of croscarmellose sodium, about 1% (w / w) of colloidal silicon dioxide, and about 1% (w / w) of sodium stearyl fumarate. In some embodiments, the tablet comprises about 35% to about 45% (w / w) of a solid dispersion as described herein, about 30% to about 42% (w / w) of MCC, about 13% to about 23% (w / w) of mannitol, about 2% to about 8% (w / w) of croscarmellose sodium, and about 0.5% to about 1.5% (w / w) of magnesium stearate.

[0426] In some embodiments, the tablet is a tablet of Table 16, Table 19, Table 20, or Table 24.

[0427] In some embodiments, the tablet has a weight of about 100 mg to about 1 g. In some embodiments, the tablet has a weight of about 100 mg, about 250 mg, about 500 mg, or about 750 mg. In some embodiments, the tablet has a weight of 750 mg to 800 mg, 760 mg to 790 mg, 770 mg to 780 mg, 775 mg to 785 mg, or 780 mg to 790 mg.

[0428] In some embodiments, the tablet has a weight of 1 g. In some embodiments, the tablet has a weight of about 100 mg. In some embodiments, the tablet has a weight of about 250 mg. In some embodiments, the tablet has a weight of about 500 mg. In some embodiments, the tablet has a weight of about 750 mg.

[0429] In some embodiments, the tablets described herein further comprise a coating. In some embodiments, the coating is a non-functional coating.

[0430] Some embodiments provide a tablet as described herein, wherein the tablet is an immediate release tablet. Some embodiments provide a tablet as described herein, wherein the percentage of edradinam released at 45 minutes is not less than 85% as measured by the dissolution method of Table 21.

[0431] Some embodiments provide a tablet as described herein, wherein the tablet has a total impurity amount (% area) of less than 2% as measured by HPLC. The impurity analysis performed by HPLC can be performed as described herein. In some embodiments, the tablet has a total impurity amount (% area) of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% as measured by HPLC. In some embodiments, the tablet has a total impurity amount (% area) of less than 1% as measured by HPLC. In some embodiments, the tablet has a total impurity amount (% area) of less than 0.5% as measured by HPLC.

[0432] Some embodiments provide a tablet as described herein, wherein when stored in a sealed package at 25°C and 60% relative humidity for 6 months, 12 months, 18 months, 24 months or 36 months:

[0433] (i) the amount of etradinam in the tablet is from about 90% to about 110% of the value measured at 0 months;

[0434] (ii) less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5% total impurity amount (% area) as measured by HPLC;

[0435] (iii) passed the non-sinking dissolution test at 210 minutes (C 210 (µgA / mL) or AUC 35-210 FaSSIF The amount of edredinam measured at the end of the study period (minutes*µgA / mL) does not differ by more than 15% from the value measured at 0 months; or

[0436] (iv) Any combination of (i) to (ii).

[0437] In some embodiments, when stored in a sealed package at 25°C and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months:

[0438] (i) the amount of etradinam in the tablet is from about 90% to about 110% of the value measured at 0 months;

[0439] (ii) less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5% total impurity amount (% area) as measured by HPLC; or

[0440] (iii) Any combination of (i) to (ii).

[0441] In some embodiments, the amount of total impurities and the amount of edradinam by non-sinking dissolution at 210 minutes are as described herein.

[0442] The tablets described herein can be administered to a human in a fed or fasted state. In some embodiments, after administration of the tablet to a human in a fed or fasted state, the total exposure of the human to eltrodinam is equal. The total exposure can be measured by AUC last (Fasting) and AUC last (fed) ratio or by AUC inf In some embodiments, equivalence refers to the ratio of AUC (fasting) to AUC (fed). 0-inf Reaching an equivalence limit of 80%-125%.

[0443] The tablets described herein are contemplated to exhibit desirable properties including, but not limited to, favorable levels of weight, thickness, breaking force, flowability, tabletability, and / or compactability, and a robust disintegration profile as further described herein.

[0444] Some embodiments provide methods for preparing tablets as described herein. In some embodiments, tablets as described herein can be prepared according to the methods described in the examples provided herein. In some embodiments, certain components of tablets can be blended, lubricated, de-agglomerated, rolled, ground and / or compacted. The order of such steps can be modified as needed. In some embodiments, film coating can be applied. In some embodiments, the resulting tablets and / or film-coated tablets can be packaged accordingly, for example, to form a test kit as described herein.

[0445] Some embodiments provide a method for preparing a tablet as described herein, comprising: (i) blending a dispersion as described herein with one or more excipients as described herein, wherein blending can optionally be performed in one or more steps to provide a mixture; (ii) adding a lubricant; (iii) de-agglomeration; (iv) rolling and grinding to form granules; (v) adding one or more additional excipients to the granules to form a second mixture; (vi) compacting the second mixture to form a tablet; and optionally (vii) adding a film coating to form a film-coated tablet. In some embodiments, the order of step (ii) (adding a lubricant) and step (iii) can be reversed so that de-agglomeration occurs before adding a lubricant.

[0446] Some embodiments provide a method of preparing a tablet described herein, comprising: (i) blending a dispersion as described herein with one or more excipients as described herein to provide a mixture; (ii) grinding / dispersing the mixture; (iii) adding a lubricant and blending to form a second mixture; (iv) compacting; (v) grinding; (vi) adding one or more additional excipients and blending to form a third mixture; (vi) compacting the third mixture to form a tablet; and optionally (vii) adding a film coating to form a film-coated tablet.

[0447] V. Therapeutic and preventive uses

[0448] The present disclosure provides a method for inhibiting adenosine A 2A Receptor (A 2A R), adenosine A 2B Receptor (A 2B R) or adenosine A 2A Receptor (A 2B R) and adenosine A 2B Receptor (A 2B R) method.

[0449] As used herein, the term "inhibit" or the like refers to an antagonist that reduces the activity of a particular target (e.g., A 2A R.A. 2B R or A 2A R and A 2B The reduction is preferably at least 50%, and can be, for example, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0450] The present disclosure contemplates administration of the dispersions, compositions or pharmaceutical compositions described herein in any appropriate manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (interstitial) and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. Depot injections, which are typically administered subcutaneously or intramuscularly, can also be used to release the solid form of the edredinam dispersion disclosed herein within a defined time period. Some embodiments of the present disclosure contemplate oral administration.

[0451] The present disclosure also encompasses the use of the dispersions described herein, the compositions described herein, and the pharmaceutical compositions described herein for treating or preventing an organism that would benefit from inhibition of A 2A R.A. 2B R or A2A R and A 2B R both the use of diseases, disorders and / or conditions. Although the following details the specific use, it should be understood that the present disclosure is not limited thereto. In addition, although the following set forth general categories of specific diseases, disorders and conditions, some diseases, disorders and conditions may be members of more than one category, and other diseases, disorders and conditions may not be members of any of the disclosed categories.

[0452] Some embodiments provide for treating a condition at least in part caused by adenosine A 2A Receptor (A 2A R) and / or adenosine A 2B Receptor (A 2B R)-mediated disease, disorder or condition, comprising administering to a subject in need thereof a dosage form as described herein, a pharmaceutical composition as described herein, or a tablet as described herein.

[0453] In some embodiments, the diseases, disorders, and / or conditions described herein are caused, at least in part, by A 2A In some embodiments, the diseases, disorders, and / or conditions described herein are mediated, at least in part, by A 2B In some embodiments, the diseases, disorders, and / or conditions described herein are mediated, at least in part, by A 2A R and A 2B R both mediate. In some embodiments, the dispersions, compositions or pharmaceutical compositions described herein can be administered in an amount effective to treat or prevent cardiovascular disease, CNS-related and neurological disorders, immune-related disorders, metabolic diseases, microbial-related disorders or oncology and oncology-related diseases. Cardiovascular disease, CNS-related and neurological disorders, immune-related disorders, metabolic diseases, microbial-related disorders or oncology and oncology-related diseases are described in WO2018136700 and WO2020018680A1. For these diseases, A 2A R.A. 2B R or A 2A R and A 2B Treatment with inhibitors of both R, whose disclosures are incorporated herein by reference, may be beneficial.

[0454] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are effective to reduce or reverse the 2A R or A 2B R or A 2A R and A 2B R is administered in an amount that induces immunosuppression.

[0455] In some embodiments, the dispersion, composition, or pharmaceutical composition described herein is administered in an amount that increases or enhances an immune response, improves immunity (including increasing vaccine efficacy), or increases inflammation.

[0456] In some embodiments of the above methods, the dispersion described herein, the composition described herein, or the pharmaceutical composition described herein is used in combination with at least one additional therapy. Each additional therapy may be a therapeutic agent or another treatment modality. The additional therapies considered include those described in WO2018136700 and WO2020018680A1, and those described below. In embodiments including one or more additional therapeutic agents, each agent may target different but complementary mechanisms of action. The additional therapeutic agent may be a small chemical molecule; a macromolecule, such as a protein, antibody, peptibody, peptide, DNA, RNA, or a fragment of such a macromolecule; or cell therapy or gene therapy. Non-limiting examples of additional treatment modalities include surgical removal of tumors, bone marrow transplantation, radiotherapy, and photodynamic therapy. The use of a dispersion, composition, or pharmaceutical composition described herein in combination with one or more additional therapies may have a synergistic therapeutic or preventive effect on the underlying disease, disorder, or condition. Additionally or alternatively, the combination therapy may allow a dose reduction of one or more therapies, thereby improving, reducing, or eliminating side effects associated with one or more agents.

[0457] In embodiments comprising one or more additional treatment modalities, the dispersion, composition or pharmaceutical composition described herein may be administered before, after or during treatment with the additional treatment modality. In embodiments comprising one or more additional therapeutic agents, the therapeutic agents used in such combination therapy may be formulated as a single composition or a separate composition. If administered alone, each therapeutic agent in the combination may be administered simultaneously or approximately simultaneously, or at different times. In addition, even if the therapeutic agents have different administration forms (e.g., oral capsules and intravenous administration), they may be administered in "combination," with different dosing intervals, one therapeutic agent administered with a constant dosing regimen and another therapeutic agent titrated up, down or discontinued, or each therapeutic agent in the combination titrated up, down, increased or decreased dosage independently during the course of treatment of the patient, or discontinued and / or resumed administration. If the combination is formulated as a separate composition, in some embodiments, the separate compositions are provided together in a kit.

[0458] Oncology and tumor-related conditions

[0459] According to the present disclosure, the dispersions, compositions or pharmaceutical compositions described herein can be used to treat or prevent cancer (eg, carcinoma, sarcoma, leukemia, lymphoma, myeloma, etc.).

[0460] Provided herein are methods of treating cancer, comprising administering to a subject in need thereof a dosage form as described herein, a pharmaceutical composition as described herein, or a tablet as described herein.

[0461] In certain embodiments, the cancer may be locally advanced and / or unresectable, metastatic or at risk of becoming metastatic. Alternatively or in addition thereto, the cancer may be recurrent or no longer responding to treatment, such as standard care treatments known to those skilled in the art. In various embodiments, the dispersion, composition or pharmaceutical composition described herein may be used in an adjuvant environment or a new adjuvant environment. Alternatively or in addition thereto, the dispersion, composition or pharmaceutical composition described herein may be used as a first-line treatment, optionally for the treatment of locally advanced, unresectable or metastatic cancer. In some embodiments, the dispersion, composition or pharmaceutical composition described herein may be used for the treatment or prevention of cancer, and may be used as a second-line, third-line or greater treatment line, optionally for the treatment of locally advanced, unresectable or metastatic cancer. When indicated as a second-line or greater treatment, in some embodiments, an earlier therapy line includes a checkpoint inhibitor.

[0462] In some embodiments, the dispersions, compositions or pharmaceutical compositions described herein can be used to treat or prevent hematological malignancies. Exemplary types of cancers affecting the hematopoietic system include leukemias, lymphomas and myelomas, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute monocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and multiple myeloma.

[0463] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent solid tumors. Solid tumors can be, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell lung cancer), colon cancer, prostate cancer, cervical cancer, biliary tract cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (hepatocellular carcinoma), kidney cancer (renal cell carcinoma), head and neck tumors, mesothelioma, melanoma, sarcoma, central nervous system (CNS) hemangioblastoma, and brain tumors (e.g., gliomas, such as astrocytomas, oligodendrogliomas, and glioblastomas). In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent lung cancer, genitourinary cancer, gastrointestinal cancer, or a combination thereof.

[0464] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer. In some embodiments, the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is castration-resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial carcinoma.

[0465] In some embodiments, the dispersion, composition or pharmaceutical composition described herein can be used to treat or prevent breast cancer. In other embodiments, the breast cancer is hormone receptor positive (e.g., ERα positive breast cancer, PR positive breast cancer, ERα positive and PR positive breast cancer), HER2 positive breast cancer, HER2 overexpressing breast cancer or any combination thereof. In further embodiments, the breast cancer is triple negative breast cancer. In further embodiments, the breast cancer is locally advanced or metastatic triple negative breast cancer, optionally with disease progression in previous treatment.

[0466] In some embodiments, the compounds according to the present disclosure may be used to treat urogenital cancer. In further embodiments, the urogenital cancer is a gynecological cancer. In further embodiments, the gynecological cancer is endometrial cancer, cervical cancer, ovarian cancer or fallopian tube cancer. In further embodiments, the gynecological cancer is locally advanced or metastatic ovarian cancer, optionally with disease progression in previous treatment. In further embodiments, the urogenital cancer is urothelial carcinoma, optionally advanced or metastatic urothelial carcinoma. In some embodiments, the urogenital cancer is advanced or metastatic MTAP-deficient urothelial carcinoma. In further embodiments, the urogenital cancer is prostate cancer. In further embodiments, the urogenital cancer is prostate adenocarcinoma, optionally, it is suitable for radical prostatectomy. In further embodiments, the urogenital cancer is castration-resistant prostate cancer, optionally metastatic castration-resistant prostate cancer. In some embodiments, the dispersion, composition or pharmaceutical composition described herein may be used to treat or prevent renal cancer. In a further embodiment, the renal cancer is renal cell carcinoma.In an even further embodiment, the renal cell carcinoma is clear cell renal carcinoma.

[0467] In some embodiments, the compounds according to the present disclosure may be used to treat renal cancer. In further embodiments, the renal cancer is renal cell carcinoma. In still further embodiments, the renal cell carcinoma is clear cell renal carcinoma.

[0468] In some embodiments, compounds according to the present disclosure may be used to treat liver cancer. In further embodiments, the liver cancer is hepatocellular carcinoma.

[0469] In some embodiments, compounds according to the present disclosure may be used to treat head and neck cancer. In further embodiments, the head and neck cancer is head and neck squamous cell carcinoma, optionally wherein the cancer has not been previously treated.

[0470] In some embodiments, compounds according to the present disclosure may be used to treat skin cancer. In further embodiments, the skin cancer is melanoma.

[0471] In some embodiments, the compounds according to the present disclosure can be used to treat lung cancer. In further embodiments, the lung cancer is mesothelioma, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In further embodiments, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma. In further embodiments, the NSCLC is non-squamous NSCLC that is metastatic, locally advanced or recurrent with progression.

[0472] In some embodiments, the dispersion, composition or pharmaceutical composition described herein can be used to treat or prevent pancreatic cancer. In further embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor or a pancreatic adenocarcinoma.

[0473] In some embodiments, the dispersion, composition or pharmaceutical composition described herein can be used to treat or prevent a neuroendocrine tumor. In further embodiments, the neuroendocrine tumor is a pancreatic neuroendocrine tumor, a pheochromocytoma, a paraganglioma or an adrenal tumor.

[0474] In some embodiments, the dispersion, composition or pharmaceutical composition described herein can be used to treat or prevent brain cancer. In further embodiments, the brain cancer is a glioma. In further embodiments, the glioma is an astrocytoma, an oligodendroglioma or a glioblastoma.

[0475] In some embodiments, the dispersion, composition, or pharmaceutical composition described herein can be used to treat or prevent gastrointestinal (GI) cancer. In some embodiments, the gastrointestinal cancer is a lower GI cancer, such as colon or rectal cancer. In some embodiments, the lower GI cancer is a rectal adenocarcinoma, optionally a non-metastatic rectal adenocarcinoma. In some embodiments, the lower GI cancer is a metastatic, advanced, or progressive recurrent colorectal adenocarcinoma. In some embodiments, the GI cancer is an upper GI cancer, such as esophageal cancer or gastric cancer. In further embodiments, the upper GI cancer is adenocarcinoma, squamous cell carcinoma, or any combination thereof. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as "gastric cancer"), or any combination thereof, optionally wherein the upper GI cancer is metastatic, advanced, or recurrent with progression.

[0476] The present disclosure also provides methods for treating or preventing other cancer-related diseases, disorders and conditions. The use of the term cancer-related diseases, disorders and conditions is intended to broadly refer to conditions directly or indirectly related to cancer non-cancerous proliferative diseases, and includes, for example, angiogenesis, precancerous conditions (such as dysplasia) and non-cancerous proliferative diseases, disorders or conditions (such as benign proliferative breast diseases and papilloma). For clarity, the term cancer-related diseases, disorders and conditions do not include cancer itself.

[0477] In general, the disclosed methods for treating or preventing cancer or a cancer-related disease, disorder or condition in a subject in need thereof comprise administering to the subject a dispersion, composition or pharmaceutical composition as described herein. In some embodiments, the disclosure provides methods for treating or preventing cancer or a cancer-related disease, disorder or condition with a dispersion, composition or pharmaceutical composition as described herein and at least one additional therapy, examples of which are described elsewhere herein.

[0478] Patient selection

[0479] In some cases, methods according to the present disclosure can be provided to selected patients, such as subjects identified as having, for example, detectable PD-L1 expression, microsatellite instability (MSI), defective mismatch repair (dMMR), high tumor mutation load, or any combination thereof in relevant tissues or samples. In some cases, the subject is identified as having an oncogene-driven cancer having a mutation in at least one gene associated with the cancer.

[0480] In some embodiments, patients are selected by evaluating the expression of relevant biomarkers, e.g., PD-L1 expression, microsatellite instability markers, in relevant samples (such as peripheral blood samples or tumor biopsies) using immunohistochemistry, immunophenotyping, PCR-based amplification, RNA sequencing or other clinically validated assays. In one embodiment, the present disclosure provides a method of treating cancer in a patient with (i) detectable PD-L1 expression, (ii) elevated PD-L1 expression, (iii) MSI low, (iv) MSI high, or (v) any combination of (i) to (iv) by administering a compound, dispersion, composition, or pharmaceutical composition as described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with (i) detectable PD-L1 expression, (ii) elevated PD-L1 expression, (iii) MSI low, (iv) MSI high, or (v) any combination of (i) to (iv) by administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition as described herein. In still another embodiment, the present disclosure provides a method of administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition as described herein to an individual for treating cancer based on the determination of the relative amount of PD-L1 expression. In another embodiment, the present disclosure provides a method of administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition as described herein to an individual for treating cancer, the method comprising measuring PD-L1 expression and / or microsatellite instability (e.g., MSI-low or MSI-high) in a sample obtained from the individual, such as by immunohistochemistry, immunophenotyping, PCR-based amplification, or other clinically validated assay, and administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition to an individual whose sample contains detectable PD-L1 expression and / or microsatellite instability. In various embodiments of the present disclosure, detectable PD-L1 expression can be a tumor proportion (TPS) score of ≥50%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved assay. In various embodiments of the present disclosure, detectable PD-L1 expression may be a TPS score of <50% as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0481] Combination therapy

[0482] The present disclosure contemplates the use of a dispersion described herein, a composition described herein, a particle described herein, a pharmaceutical composition described herein, a dosage form described herein, or a tablet described herein in combination with one or more additional therapies for treating cancer. Some embodiments provide a method of treating cancer in a subject, the method comprising administering to the subject, to a subject in need thereof, a dosage form as described herein, a pharmaceutical composition as described herein, or a tablet as described herein; and at least one additional therapeutic agent; exemplary therapies are further described below, as well as in WO 2018 / 136700 (PCT Application No. PCT / US2018 / 014352) and WO 2020 / 018680 (PCT Application No. PCT / US2019 / 042226), the disclosures of which are incorporated herein by reference.

[0483] In some embodiments, the one or more additional therapies are additional treatment modalities.Exemplary treatment modalities include, but are not limited to, surgical removal of the tumor, bone marrow transplantation, radiation therapy, and photodynamic therapy.

[0484] In some embodiments, one or more additional therapies are therapeutic agents. Exemplary therapeutic agents include chemotherapeutic agents, radiopharmaceuticals, hormone therapy, epigenetic modulators, ATP-adenosine axis targeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, AXL inhibitors, PAK4 inhibitors, immunotherapeutic agents, cell therapy, gene therapy, immune checkpoint inhibitors, and agonists of stimulatory or costimulatory immune checkpoints.

[0485] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzotepa, carboquinone, metodepa, and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamime; nitrogen mustards, such as chlorambucil, naphthyl mustard, cholophosphamide, estramustine, ifosfamide, mechlorethamine, methoxychloramine hydrochloride, melphalan, novembic acid, and chlorambucil. hin), phenylephrine, prednimustine, trofosfamide and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as aclarubicin, dactinomycin, anthramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carrubicin, carmomycin, chromomycin, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, mexicomycin, mitomycin, mycophenolic acid, noramycin, olive mycin, pomalidomide, peplomycin, porfibrinocin, puromycin, triferro therapies such as methotrexate, 5-fluorouracil (5-FU), oxadiazine, cytoxan, dapoxetine, oxadiaz ... Acid supplements, such as folinic acid; acetoglucuronide; aldophosphamide glycoside; aminolevulinic acid; amsacrine; busamustine; bisantrene; edatrexate; defosfamide; colcemid; diazocrine; elformithine; elliptonium acetate; etoglucum; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguanidine; mitoxantrone; mopidarol; diamine nitracrine; pentostatin; methamine nitrogen mustard; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; sizoran; spirogermanium; tenuisporic acid; triazoline quinone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; piperobroman;gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxanes, such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; Navelbine; Noxol; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT11 proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; Topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone and teniposide; Difluoromethylornithine (DMFO); Retinoic acid; Esperamicin; Capecitabine; Anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above substances. In certain embodiments, the combination therapy includes a chemotherapy regimen containing one or more chemotherapeutic agents. In one embodiment, the combination therapy includes a chemotherapy regimen that includes one or more of FOLFOX (folinic acid, fluorouracil and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil and irinotecan), platinum and platinum coordination complexes (e.g., cisplatin, carboplatin, oxaliplatin, etc.), taxanes (e.g., docetaxel, paclitaxel, nanopaclitaxel, etc.), and / or gemcitabine. ;

[0486] In some embodiments, one or more of the additional therapeutic agents is a radiopharmaceutical. A radiopharmaceutical is a form of internal radiation therapy in which a radioactive source (i.e., one or more radionuclides) is placed into the subject's body. The radioactive source can be in solid form or in liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, iodobenzylguanidine-131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides associated (e.g., by covalent or ionic interactions) with a molecule ("targeting agent") that specifically binds to a target on a cell (usually a cancer cell or an immune cell). The targeting agent can be a small molecule, a carbohydrate (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein or a peptide, and the target is a tumor-associated antigen (enriched but not unique to cancer cells), a tumor-specific antigen (minimal to no expression in normal tissues), or a neoantigen (an antigen unique to the cancer cell genome resulting from a non-synonymous mutation in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (i.e., an antigen enriched but not unique to cancer cells), a tumor-specific antigen (i.e., an antigen minimally expressed to no expression in normal tissues), or a neoantigen (i.e., an antigen unique to the cancer cell genome resulting from a non-synonymous mutation in the tumor cell genome). Non-limiting examples of targeting radionuclides include radionuclides attached to: somatostatin or its peptide analogs (e.g., 177Lu-Dotatate, etc.); prostate specific membrane antigen or its peptide analogs (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); a cognate ligand of a receptor, a peptide derived from the ligand, or a variant thereof (e.g., 188Re-labeled VEGF 125-136 or its variants with higher affinity for VEGF receptors, etc.); antibodies targeting tumor antigens (e.g. 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-obotuzumab, etc.).

[0487] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormone therapy is used to regulate or inhibit the effects of hormones on tumors. Examples of hormone therapy include, but are not limited to, selective estrogen receptor degraders such as fulvestrant, Gilead, SAR439859, RG6171, AZD9833, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene; aromatase inhibitors such as anastrozole, ole), exemestane, letrozole and other aromatase inhibiting 4(5)-imidazoles; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin and goserelin (and goserelin); gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide and leuprolide; 5α-reductase inhibitors such as finasteride and dutasteride (and dutasteride); etc. In certain embodiments, the combination therapy comprises administration of a hormone or related hormonal agent. In one embodiment, the combination therapy comprises administration of enzalutamide.

[0488] In some embodiments, one or more of the additional therapeutic agents are epigenetic regulators. Epigenetic regulators change the epigenetic mechanisms that control gene expression, and can be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic regulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine. In one or more embodiments, the combination of dispersions, compositions, or pharmaceutical compositions described herein with histone deacetylase (HDAC) inhibitors is also contemplated. Exemplary HDAC inhibitors include vorinostat, givinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

[0489] In some embodiments, one or more of the additional therapeutic agents is an ATP-adenosine axis targeting agent. The ATP-adenosine axis targeting agent alters signaling mediated by adenosine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example by modulating the level of adenosine or targeting adenosine receptors. In certain embodiments, the ATP-adenosine axis targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of an adenosine receptor. Ecto-nucleotidases involved in the conversion of ATP to adenosine include ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39) and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or cluster of differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070, and quiliclostat (AB680). Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, uliledlimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates a dispersion, composition, or pharmaceutical composition described herein in combination with a CD73 inhibitor, such as those described in WO 2017 / 120508, WO 2018 / 067424, WO 2018 / 094148, and WO 2020 / 046813. In a further embodiment, the CD73 inhibitor is quilibrium.

[0490] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, targeted therapy may include a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug attached to a targeting agent. The targeting agent may be a small molecule, a carbohydrate (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not cancer cell-specific), a tumor-specific antigen (minimally expressed to no expression in normal tissues), or a new antigen (antigens specific to the cancer cell genome generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (enriched but not cancer cell-specific), a tumor-specific antigen (minimally expressed to no expression in normal tissues), or a new antigen (antigens specific to the cancer cell genome generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody-drug conjugate comprising an antibody and a drug, wherein the antibody specifically binds to Trop-2, HER2, HER3, nectin-4 or Trop-2. Specific examples of targeted therapies comprising antibodies and small molecule drugs include, but are not limited to, patritumab deruxtecan, sacituzumab govitecan-hziy, telisotuzumab vedotin and trastuzumab deruxtecan. Other targeted therapies can inhibit or interfere with specific proteins that help tumors grow and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, oncogenic transcription factor inhibitors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutics, ATP-adenosine axis targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF-2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis targeting agents are described above, while other agents are described in further detail below.

[0491] In some embodiments, one or more of the additional therapeutic agents is a signal transduction inhibitor. A signal transduction inhibitor is an agent that selectively inhibits one or more steps in a signaling pathway. The signal transduction inhibitors (STIs) contemplated by the present disclosure include, but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, and osimertinib) and anti-EGFR antibodies; (iii) inhibitors of transmembrane tyrosine kinases of the human epidermal growth factor (HER) family, such as HER-2 / neu receptor inhibitors (e.g., trastuzumab and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor (VEGFR ) inhibitors, including small molecule inhibitors (e.g., axitinib, regorafenib, sunitinib, and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.), and anti-VEGF antibodies (e.g., bevacizumab); (v) AKT family kinases or AKT pathway inhibitors (e.g., rapamycin); (vi) inhibitors of the serine / threonine-protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib, and encorafenib; (vii) rearrangement during transfection (RET) inhibitors, including, for example, selpercatinib and pralsetinib; (viii) tyrosine-protein kinase Met (MET) inhibitors (e.g., tepotinib, epotinib), tivantinib, cabozantinib, and crizotinib); (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (x) inhibitors of the RAS signaling pathway as described elsewhere herein (e.g., KRAS, HRAS, RAF, MEK, ERK inhibitors);(xi) FLT-3 inhibitors (e.g., gilteritinib); (xii) Trop-2 inhibitors; (xiii) JAK / STAT pathway inhibitors, e.g., JAK inhibitors, including tofacitinib and ruxolitinib, or STAT inhibitors, such as napabucasin; (xiv) NF-kB inhibitors; (xv) cell cycle kinase inhibitors (e.g., flavonoids); (xvi) phosphatidylinositol 3-kinase (PI3K) inhibitors; (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib); (xx) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, repretinib, etc.); and (xxi) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib, dacomitinib). In some embodiments, the additional therapeutic agent includes an inhibitor of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combination thereof. In some embodiments, the additional therapeutic agent comprises an EGFR and / or VEGFR inhibitor. ;

[0492] In some embodiments, one or more of the additional therapeutic agents is a RAS signaling inhibitor. Oncogenic mutations in the RAS gene family (e.g., HRAS, KRAS, and NRAS) are associated with a variety of cancers. For example, mutations of G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S, etc., in the KRAS gene family have been observed in multiple tumor types. Direct and indirect inhibition strategies have been studied for inhibiting mutant RAS signaling. Splicing inhibitors target effectors other than RAS in the RAS signaling pathway, and include, but are not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, and BI1701963. Direct inhibitors of RAS mutants have also been explored, and generally target KRAS-GTP complexes or KRAS-GDP complexes. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib, adagrasib, mRNA-5671, and ARS1620. In some embodiments, one or more RAS signaling inhibitors are selected from: RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, SOS1 inhibitors, mTORC1 inhibitors, SHP2 inhibitors, and AKT inhibitors. In other embodiments, one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0493] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of phosphatidylinositol 3-kinase (PI3K), particularly an inhibitor of the PI3Kγ isoform. PI3Kγ inhibitors can stimulate anti-cancer immune responses by regulating myeloid cells, for example, by inhibiting suppressive myeloid cells, inhibiting immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to prepare cytokines that contribute to effective T cell responses, thereby reducing cancer development and spread. Exemplary PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more PI3Kγ inhibitors described in WO 2020 / 0247496A1.

[0494] In some embodiments, one or more of the additional therapeutic agents is an arginase inhibitor. It has been shown that arginase is responsible for or participates in immune dysfunction triggered by inflammation, tumor immune escape, immunosuppression, and immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more arginase inhibitors described in WO WO 2019 / 173188 and WO 2020 / 102646.

[0495] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents can act at the expression level (e.g., RNAi, siRNA, etc.), by physical degradation, at the protein / protein level, at the protein / DNA level, or by binding in the activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, Menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factors, etc.

[0496] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. Exemplary HIF-2α inhibitors include belzutifan, ARO-HIF2, PT-2385, and those described in WO 2021113436 and WO 2021188769. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more HIF-2α inhibitors described in WO 2021188769.

[0497] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of anexelekto (AXL). The AXL signaling pathway is associated with tumor growth and metastasis and is thought to mediate resistance to a variety of cancer therapies. A variety of AXL inhibitors are being developed that also inhibit other kinases in the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases, including MET, FLT3, RON, and AURORA, among others. Exemplary multi-kinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, and RXDX-106. AXL-specific inhibitors have also been developed, for example, small molecule inhibitors, including DS-1205, SGI-7079, SLC-391, dubermatinib, bemcentinib, and DP3975; anti-AXL antibodies such as ADCT-601; and antibody drug conjugates (ADCs) such as BA3011. Another strategy to inhibit AXL signaling involves targeting AXL's ligand GAS6. For example, batiraxcept is under development, as is an Fc fusion protein that binds to the GAS6 ligand to inhibit AXL signaling. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more AXL inhibitors described in WO 2022 / 246177 (PCT / US2022 / 030227) or WO2022 / 246179 (PCT / US2022 / 030230).

[0498] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of p21-activated kinase 4 (PAK4). PAK4 overexpression has been demonstrated in a variety of cancer types, particularly those that are resistant to PD-1 therapy. Although PAK4 inhibitors have not yet been approved, some are under development and exhibit dual PAK4 / NAMPT inhibitor activity, such as ATG-019 and KPT-9274. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with PAK4 selective inhibitors. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with PAK4 / NAMPT dual inhibitors, such as ATG-019 or KPT-9274.

[0499] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits poly (ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib, etc.); (ii) an inhibitor of the Bcl-2 protein family (e.g., venetoclax, navitoclax, etc.); (iii) an MCL-1 inhibitor; (iv) an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody); or (v) an isocitrate dehydrogenase (IDH) inhibitor, such as an IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enasidenib, etc.).

[0500] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutics treat diseases by stimulating or suppressing the immune system. Immunotherapeutics that can be used to treat cancer generally trigger or amplify immune responses to cancer cells. Non-limiting examples of suitable immunotherapeutics include: immunomodulators; cellular immunotherapy; vaccines; gene therapy; ATP-adenosine axis targeting agents; immune checkpoint regulators; and certain signal transduction inhibitors. ATP-adenosine axis targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapy, vaccines, gene therapy, and immune checkpoint regulators are further described below.

[0501] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cytokine or chemokine, such as IL-1, IL-2, IL-12, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13 and anti-IL-10; bacterial lipopolysaccharide (LPS); organic or inorganic adjuvants that activate antigen-presenting cells and promote presentation of antigenic epitopes on major histocompatibility complex molecule agonists, including but not limited to Toll-like receptor (TLR) agonists, mevalonate pathway antagonists, STING agonists; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides, as well as other T-cell adjuvants.

[0502] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutics, more specifically cell therapy. Cell therapy is a form of treatment in which living cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents are cell immunotherapies that activate or suppress the immune system. Cell immunotherapies that can be used to treat cancer generally trigger or amplify immune responses. These cells can be autologous or allogeneic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subjects. Alternatively, these cells can be "(re)programmed" allogeneic immune cells produced from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells can be expanded cell subpopulations with different effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), can be genetically modified to target cells to specific antigens and / or enhance the anti-tumor effect of cells (e.g., engineered T cell receptor (TCR) cell therapy, chimeric antigen receptor (CAR) cell therapy, lymph node homing of antigen-loaded dendritic cells, etc.), can be engineered to express tumor-associated antigens or have increased expression of tumor-associated antigens, or can be any combination thereof. Non-limiting types of cell therapy include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, idecabtagene vicleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.z.

[0503] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a gene therapy. Gene therapy includes administering a recombinant nucleic acid to a subject or to a subject's cells ex vivo to modify the expression of an endogenous gene or cause heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not include nucleic acid components (e.g., large-range nucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies that can be used for cancer treatment include Gendicine ® (rAd-p53)、Oncorine ® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immune Gene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0504] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutics, more specifically agents that regulate immune checkpoints. Immune checkpoints are a group of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). When proteins on the surface of immune cells recognize and bind to their cognate ligands, immune checkpoints engage. The present disclosure contemplates the use of a combination of dispersions, compositions, or pharmaceutical compositions described herein with agonists of stimulatory or costimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways may have utility as agents that overcome different immunosuppressive pathways in the tumor microenvironment, inhibit T regulatory cells, reverse / prevent T cell anergy or exhaustion, trigger innate immune activation and / or inflammation at the tumor site, or a combination thereof.

[0505] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist that inhibits or co-inhibits immune checkpoints. The terms "immune checkpoint inhibitor," "checkpoint inhibitor," and "CPI" are used interchangeably herein. Immune checkpoint inhibitors can antagonize, inhibit, or co-inhibit immune checkpoints by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of some of these immune checkpoints (ligands and receptors) that are selectively upregulated in various types of cancer cells that can be antagonized include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, galectin-9, CEACAM-1, CD69, galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, as well as killer inhibitory receptors, which can be divided into two categories based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints that have been described in the literature are also considered, including receptors (e.g., 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)).

[0506] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In a further embodiment, the CTLA-4 antagonist can be an antagonist CTLA-4 antibody. Suitable antagonist CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

[0507] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonist PD-1 antibody small molecule or peptide. Suitable antagonist PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO2012 / 145493), nivolumab, pepstatin, and sirolimab. In some embodiments, the immune checkpoint inhibitor is sepaliimab.

[0508] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonist PD-L1 antibody. Suitable antagonist PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0509] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In a further embodiment, the TIGIT antagonist may be an antagonist TIGIT antibody. Suitable antagonist anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, vibostolimab. And bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonist anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, the immune checkpoint inhibitor is dunalimab or AB308.

[0510] In some embodiments, the immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonist LAG-3 antibody. Suitable antagonist LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0511] In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonist B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblituzumab, omburtumab, enoblituzumab, DS-7300a, ABBV-155, and SHR-A1811.

[0512] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or co-stimulatory immune checkpoint. Examples of stimulatory or co-stimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2.

[0513] In some embodiments, the agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist may be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab. In some embodiments, the agent that activates a stimulatory or co-stimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist may be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683). In some embodiments, the agent that activates a stimulatory or co-stimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist may be an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates, stimulates, or co-stimulates immune checkpoints is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, the agent that activates, stimulates, or co-stimulates immune checkpoints is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varilutuzumab.

[0514] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immunosuppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including emactuzumab or cabiralizumab.

[0515] In some embodiments, each additional therapeutic agent can be independently a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic regulator, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition as described herein in combination with one or more chemotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition as described herein in combination with one or more chemotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeting agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition as described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, a chemotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition as described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition as described herein in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeting agent, an immunotherapeutic agent, or a cell therapy. In further embodiments of the above, (a) the targeting agent is a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an AXL inhibitor, a PAK4 inhibitor, a VEGFR inhibitor, a VEGF kinase inhibitor, an anti-VEGF antibody or an antibody-drug conjugate; (b) the immunotherapeutic agent is an ATP-adenosine axis targeting agent or an immune checkpoint inhibitor; (c) the ATP-adenosine axis targeting agent is a CD73 inhibitor or a CD39 inhibitor; (d) the ATP-adenosine axis targeting agent is quetiapine or AB598; (e) the immunotherapeutic agent is an anti-PD-1 antagonist antibody, an anti-PD-L1 antagonist antibody or an anti-TIGIT antagonist antibody; (f) the immunotherapeutic agent is sepalizumab, dunalimumab or AB308 or (g) any combination thereof. In further embodiments of the foregoing, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with dunalimab, edrinam, quetiapine, sepalizumab, AB308, AB521, AB598, AB610, or any combination thereof.

[0516] The choice of the additional therapeutic agent can be informed by the current standard of care for a particular cancer and / or the mutational status and / or disease stage of the subject's cancer. For example, the National Comprehensive Cancer Network (NCCN) publishes detailed standards of care guidelines. See, for example, NCCN Colon Cancer v3.2021, NCCN Hepatobiliary Cancer v5.2021, NCCN Renal Cancer v3.2022, NCCN NSCLC v7.2021, NCCN Pancreatic Adenocarcinoma v2.2021, NCCN Esophageal and Esophagogastric Junction Cancer v4.2021, NCCN Gastric Cancer v5.2021, Cervical Cancer v1.2022, Ovarian / Fallopian Tube / Primary Peritoneal Cancer v3.2021.

[0517] VI. Administration

[0518] The dispersions, compositions or pharmaceutical compositions described herein can be administered to a subject in an amount that depends, for example, on the goal of administration (e.g., the desired degree of regression); the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen can also take into account the presence, nature and extent of any adverse effects associated with the administered agent. Effective doses and dosage regimens can be readily determined by, for example, safety and dose escalation trials, in vivo studies (e.g., animal models) and other methods known to the skilled artisan.

[0519] In general, dosing parameters indicate that the dose is less than the amount that is reversibly toxic to the subject (maximum tolerated dose (MTD)) but not less than the amount required to produce a measurable effect on the subject. This amount is determined by, for example, ADME-related pharmacokinetic and pharmacodynamic parameters, taking into account the route of administration and other factors.

[0520] The effective dose (ED) or therapeutically effective amount is the dose or amount of a drug that produces a therapeutic response or desired effect in a portion of the subjects taking it. The "half effective dose" or ED50 of a drug is the dose or amount of the drug that produces a therapeutic response or desired effect in 50% of the population to which the drug is administered. Although ED50 is generally used as a measure of reasonable expectation of the effect of a drug, it may not necessarily be considered appropriate by a clinician taking into account all relevant factors. Therefore, in some cases, the effective amount is greater than the calculated ED50, in other cases, the effective amount is less than the calculated ED50, and in other cases, the effective amount is the same as the calculated ED50.

[0521] In addition, an effective dose of edredinam of a dispersion, composition, or pharmaceutical composition described herein can be an amount that produces a desired result relative to a healthy subject when administered to a subject in one or more doses. For example, for a subject experiencing a particular condition, an effective dose can be an effective dose that improves a diagnostic parameter, measurement, marker, etc. of the condition by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as a diagnostic parameter, measurement, marker, etc. exhibited by a normal subject.

[0522] In some embodiments, the dispersions, compositions, and pharmaceutical compositions of eltrodinam contemplated by the present disclosure can be administered (e.g., orally) at a dosage level of about 0.01 mg / kg to about 50 mg / kg or about 1 mg / kg to about 25 mg / kg per day, one or more times per day, to obtain the desired therapeutic effect. In some embodiments, the dispersions, compositions, and pharmaceutical compositions of eltrodinam contemplated by the present disclosure can be administered (e.g., orally) at a dosage level of about 50 mg to about 250 mg, one or more times per day, to obtain the desired therapeutic effect.

[0523] As used herein, "total daily dose" refers to the total amount of active agent (e.g., edrolidine) administered within 24 hours. The total daily dose can be administered by any method (e.g., oral) or frequency. For example, a total daily dose of 100 mg of active agent can be administered as 50 mg twice a day or 100 mg once a day.

[0524] In some embodiments, the dispersions, compositions and pharmaceutical compositions of eltrodinam contemplated by the present disclosure can be orally administered to a subject in need thereof to provide a total daily dose of about 50 mg eltrodinam to about 250 mg eltrodinam, or about 50 mg eltrodinam to about 150 mg eltrodinam. In some embodiments, a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg or about 250 mg is administered to a subject.

[0525] In some embodiments, the dispersions, compositions and pharmaceutical compositions of edredinam contemplated by the present disclosure can be administered (e.g., orally) at the above-mentioned dosage levels without the need for dose adjustment or discontinuation due to the concurrent use of inhibitors or inducers of cytochrome P450 (CYP) enzymes, inhibitors or inducers of P-glycoprotein (P-gp), or inhibitors or inducers of breast cancer resistance protein (BCRP). P-gp and BCRP are efflux transporters expressed in the gastrointestinal tract and can affect the oral bioavailability of drugs. CYP enzymes are catalytic enzymes, and their inhibition or induction can affect the bioavailability of drugs by changing the rate of drug metabolism. The most common CYP enzymes involved in drug metabolism include enzyme isoforms of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 256 CYP2D6 and CYP3A. CYP inhibitors can be classified as strong, moderate or weak according to the effect of the inhibitor on the indicator substrate. Indicator CYP substrates are known in the art. See, for example, the International Committee for Harmonization (ICH) M12 guidance for drug interaction studies, published on July 21, 2022. The subject's genotype can also affect CYP activity. According to the U.S. Food and Drug Administration, normal metabolizers are subjects who do not have genetic variants that are expected to affect metabolism, ultra-rapid metabolizers are subjects who typically have two or more copies of genetic variants that increase metabolic function, intermediate metabolizers are subjects who typically have one or two copies of genetic variants that decrease the ability to metabolize a drug, and poor metabolizers are subjects who typically have two copies of genetic variants that result in little or no ability to metabolize a drug (www.fda.gov / medical-devices / precision-medicine / table-pharmacogenetic-associations).

[0526] In vitro data indicate that the metabolism of eltrodinam is mediated by CYP3A4, CYP2C8, and uridine 5'-diphosphoglucuronosyltransferase (UGT) isoforms, and that eltrodinam is a substrate for P-gp and breast cancer resistance protein (BCRP). However, as further described herein, in humans, co-administration of strong CYP3A4 inhibitors with eltrodinam has limited effects on the pharmacokinetics of eltrodinam, and co-administration of P-gp inhibitors with eltrodinam may not affect the oral absorption of eltrodinam. Thus, in some embodiments, the dispersions, compositions, and pharmaceutical compositions of eltrodinam contemplated by the present disclosure may be administered (e.g., orally) at the above-mentioned dose levels without the need for dose adjustment or discontinuation due to concomitant use of a CYP3A4 inhibitor or a P-gp inhibitor, or without the need for dose adjustment or discontinuation due to the subject being a poor CYP3A4 metabolizer.

[0527] Some embodiments provide a method of treating cancer in a subject who is concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor or in a subject who is a poor metabolizer of CYP3A4, the method comprising administering to a subject in need thereof a dosage form as described herein, a pharmaceutical composition as described herein, or a tablet as described herein. Some embodiments provide a method of treating a patient who has a tumor that is at least partially caused by adenosine A 2A Receptor (A 2A R) or adenosine A 2B Receptor (A 2B R)-mediated disease, disease, disorder or condition, wherein the patient is concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor, or the subject is a CYP3A4 poor metabolizer, the method comprising administering a therapeutically effective amount of edredinam. In some embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In some embodiments, the CYP3A4 inhibitor is a moderate CYP3A4 inhibitor. In some embodiments, the CYP3A4 inhibitor is a weak CYP3A4 inhibitor.

[0528] For oral administration, the composition can be provided in the form of tablets, capsules, etc. containing 1.0 mg to 1000.0 mg of active ingredient, particularly 1.0 mg, 3.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 150.0 mg, 200.0 mg, 250.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, 600.0 mg, 750.0 mg, 800.0 mg, 900.0 mg and 1000.0 mg of active ingredient. In some embodiments, the tablets or capsules described herein contain 10 mg to 100 mg of edredinam or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets or capsules described herein contain 50 mg to 100 mg of edredinam or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets or capsules described herein contain 75 mg of edradinam or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets or capsules described herein are administered once a day to obtain the desired therapeutic effect.

[0529] In some embodiments, a tablet as described herein comprises 50 mg of eltrodinam. In some embodiments, a tablet as described herein comprises 75 mg of eltrodinam. In some embodiments, a tablet as described herein comprises 100 mg of eltrodinam. In some embodiments, a tablet as described herein comprises 150 mg of eltrodinam.

[0530] In some embodiments, the dosage of the dispersion or composition of edrolidine or a pharmaceutically acceptable salt thereof is contained in a "unit dosage form". The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined amount of edrolidine, alone or in combination with one or more additional agents, sufficient to produce the desired effect. It should be understood that the parameters of the unit dosage form will depend on the specific agent and the effect to be achieved.

[0531] Exemplary Dosages

[0532] Some embodiments provide for treating a condition at least in part caused by adenosine A 2A Receptor (A 2A R), at least in part by adenosine A 2B Receptor (A 2B R), or at least in part by A 2A R receptors and A 2A The invention relates to a method for treating diseases, disorders and conditions mediated by both R and R receptors, the method comprising administering to a subject in need thereof a dosage form, pharmaceutical composition or tablet of the present disclosure.

[0533] Some embodiments provide methods for treating cancer, which methods include administering a dosage form, pharmaceutical composition or tablet of the present disclosure to a subject in need thereof. In some embodiments, cancer is a solid tumor. In some embodiments, cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer or gynecological cancer. In some embodiments, cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer or prostate cancer. In some embodiments, cancer is castration-resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prostate adenocarcinoma or urothelial carcinoma. In some embodiments, cancer is locally advanced, unresectable or metastatic cancer.

[0534] In some embodiments, the pharmaceutical composition is a formulation of Table 16, Table 19, Table 20, or Table 24. In some embodiments, the tablet is a tablet of Table 16, Table 19, Table 20, or Table 24.

[0535] In some embodiments, the subject is administered a total daily dose of about 50 mg to about 250 mg of eltrodinam, or about 50 mg eltrodinam to about 150 mg eltrodinam, optionally wherein the total daily dose is administered once a day.

[0536] In some embodiments, a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg is administered to the subject.

[0537] In some embodiments, the total daily dose of edredinam is not adjusted for subjects who are poor CYP3A4 metabolizers or subjects who are concomitantly taking a CYP3A4 inhibitor (eg, a weak, moderate, or strong CYP3A4 inhibitor) or a P-gp inhibitor.

[0538] In some embodiments, the subject is also administered one or more than one additional therapy (e.g., 1, 2, 3, etc.), optionally selected from radiation therapy, chemotherapeutic agents, checkpoint inhibitors, ATP-adenosine axis targeting agents, PI3K inhibitors, arginase inhibitors, HIF2α inhibitors, AXL inhibitors, PAK4 inhibitors, VEGFR inhibitors, VEGF kinase inhibitors, anti-VEGF antibodies, and antibody-drug conjugates.

[0539] In some embodiments, the subject is also administered one or more than one additional therapy (e.g., 1, 2, 3, etc.), optionally selected from radiation therapy, chemotherapeutic agents, AB308, AB521, AB598, AB801, dunalimab, quetiapine, and saccharomyces cerevisiae govenotecan.

[0540] In embodiments where one or more chemotherapeutic agents are administered to a subject, the one or more chemotherapeutic agents may be FOLFOX, FOLFIRI, CAPOX, platinum or platinum coordination complexes (e.g., cisplatin, carboplatin, oxaliplatin, etc.), taxanes (e.g., docetaxel, paclitaxel, nanopaclitaxel, etc.), gemcitabine, folic acid analogs (e.g., pemetrexed, etc.), or anti-androgens (e.g., enzalutamide, etc.).

[0541] VII. Kit

[0542] The present disclosure also contemplates kits comprising the dispersions, compositions, or pharmaceutical compositions described herein.The kits are generally in the form of a physical structure housing the various components, as described below, and can be used, for example, to practice the methods described above.

[0543] The kit may include one or more of the dispersions, compositions or pharmaceutical compositions described herein (e.g., provided in a sterile container). The dispersions, compositions or pharmaceutical compositions described herein may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form (e.g., powder) that requires, for example, reconstruction or dilution prior to administration. When the dispersions, compositions or pharmaceutical compositions described herein are in a form that requires user reconstruction or dilution, the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc., packaged together with the dispersions, compositions or pharmaceutical compositions described herein or separately. When contemplating combined therapy, the kit may contain several medicaments alone, or they may have been combined in the kit. Each component of the kit may be enclosed in a separate container, and all individual containers may be in a single package. The kit of the present disclosure may be designed to appropriately maintain the conditions (e.g., refrigeration or freezing) required for the components contained therein.

[0544] The kit may contain a label or package insert including identification information of the components therein and instructions for use of the components (e.g., dosing parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information, such as a batch number and an expiration date. The label or package insert may, for example, be integrated into a physical structure that houses the components, be contained separately within a physical structure, or be attached to a component of the kit (e.g., an ampoule, tube, or vial).

[0545] The label or insert may additionally include or be incorporated into a computer-readable medium, such as a disk (e.g., hard disk, card, memory disk), an optical disk such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage medium such as RAM and ROM or a mixture of these media, such as magnetic / optical storage media, flash memory media, or a storage-type card. In some embodiments, actual instructions are not present in the test kit, but means for obtaining instructions from a remote source, such as via the Internet, are provided.

[0546] Example

[0547] The following examples are put forward to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure. Although efforts have been made to ensure accuracy with respect to the values ​​used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be accounted for.

[0548] Unless otherwise indicated, temperatures are in degrees Celsius (°C) and pressures are at or near atmospheric. Standard abbreviations are used, including the following: rt or rt = room temperature; min = minute; h or hr = hour; ng = nanogram; µg = microgram; mg = milligram; g = gram; kg = kilogram; µl or µL = microliter; ml or mL = milliliter; l or L = liter; µM = micromole; mM = millimole; M = mole; mol = mole; mmol = millimole; nM = nanomole; gA = grams of active substance; mgA = milligrams of active substance; µgA = micrograms of active substance; HPMCAS = hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose acetate succinate; CAP = cellulose acetate phthalate; PVP-VA = polyvinylpyrrolidone / vinyl acetate copolymer (copovidone); FaSSIF = fasted state simulated intestinal fluid.

[0549] Example 1

[0550] The thermal properties and x-ray diffraction patterns of the starting drug substances used in the following examples were characterized by differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD).

[0551] Thermal properties. Thermal properties were measured using a TAInstruments Discovery DSC 2500 DSC equipped with a TA Instruments Refrigerated Cooling System 90 operating in modulated mode. Briefly, the raw drug substance was analyzed by standard DSC with a heating rate of 10 °C / min to 220 °C. Amorphous edredinam was prepared from the starting drug substance by rapid melt quenching using liquid N2 and then analyzed by modulated DSC (MDSC). Events monitored included the glass transition temperature (T g )、Cold crystallization(T c ) (defined as a crystallization event at a temperature below the melting temperature) and the melting temperature (T m ). In one experiment, the thermal characteristics are as follows: T g =69℃; T C = No crystallization below 220℃; T M = 192°C. There may be slight differences between batches.

[0552] XRPD. The diffraction pattern of the starting drug substance was obtained by XRPD. XRPD was performed using a Rigaku Miniflex 6G X-ray diffractometer. The samples were irradiated with monochromatic Cu Kα radiation and analyzed in continuous scan mode between 5° and 40°. The samples were rotated during the analysis to minimize the effects of preferential orientation. Table 1 summarizes the XRPD analysis parameters. The diffraction pattern of the starting drug substance indicated that the starting drug substance was a crystalline material ( Figure 1), which is consistent with the thermal analysis.

[0553] Table 1. XRPD analysis parameters

[0554]

[0555] Example 2: Comparative levodinam tablets containing crystalline API

[0556] The manufactured edrolidine tablets contain 50 mg of edrolidine crystalline free base. The tablets are prepared as follows. The API is blended with the intragranular components in a suitable blender. The blend is de-agglomerated and then compacted and ground into granules. The extragranular components are then blended with the granules and the mixture is tableted. Table 2 provides the tablet composition.

[0557] Table 2: Composition of edredinam tablets

[0558]

[0559] Example 3: Yitradinam Capsules

[0560] In many semi-solid filling preparations, the chemical stability of eltrodinam was detected under 5% drug loading. In short, the vehicle composition was prepared by mixing the selected excipients of melting. Then the starting drug substance was added, and the mixed preparation was heated until a clear solution was formed. The solution was then filled into the capsule and sealed with gelatin tape subsequently. By mixing gelatin into a solution of polysorbate 80 and water until the mixture was uniform, a gelatin tape solution was prepared.

[0561] The vehicle composition included PEG 400, PEG 1500 or PEG 4000 with Solutol HS 15, KolliphorRH40 or Gelucire 44 / 14 in a ratio ranging from 1:1 to 3:1. All tested semisolid fill formulations had improved solubility in water as compared to the starting drug substance and were chemically stable when stored for different lengths of time (e.g., 1 day, 7 days, 1 month, 2 months) at 2°C-8°C, 25°C and 40°C / 75% relative humidity (RH). Based on in vitro dissolution studies and nonclinical pharmacokinetic (PK) studies, a capsule containing 25 mg of edredinam and PEG 1500:KolliphorRH40 (3:1) was selected as the clinical formulation. Table 3 provides an exemplary formulation.

[0562] Table 3: Etrodinam capsules, 25 mg

[0563]

[0564] Example 4: Exemplary solid dispersion of edredinam

[0565] The kinetic solubility and supersaturation maintenance of edredinam were first measured in the presence of selected cellulose-based and vinylpyrrolidone-based polymer excipients. Solvent shift dissolution experiments were performed as follows. The starting drug substance was dissolved in dimethyl sulfoxide (DMSO) at 200 mg / mL to produce drug stock solutions. Each polymer was dissolved at 1 mg / mL and 3 mg / mL in FaSSIF (2 mg / mL simulated intestinal fluid (SIF) in 100 mM phosphate buffer solution (PBS), pH 6.8), prepared according to the manufacturer's instructions. The polymers tested included cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose E3 (HPMC E3LV), hydroxypropyl methylcellulose acetate succinate, H grade (HPMCAS-H), HPMCAS, L grade (HPMCAS-L), HPMCAS, M grade (HPMCAS-M), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone / vinyl acetate copolymer (copovidone) (PVP-VA), and Soluplus ® . 25 µL of drug stock solution was then introduced into 10 mL of polymer-based FaSSIF solution or into 10 mL of FaSSIF without polymer as a control, while stirring at 300 rpm with a magnetic stir bar (diluted to 1 mg / mL with edredinam). 0.5 mL aliquots were taken at the following time points: 5 min, 15 min, 30 min, 45 min, and 60 min without changing the medium. Aliquots were transferred to 1.5 mL centrifuge tubes and centrifuged at 13,000 rpm for 3 min. 100 µL of supernatant was taken, diluted with 900 µL of 3:1 ACN:H2O, and analyzed by HPLC using the parameters listed in Table 4.

[0566] Table 4: HPLC parameters for the assay and related substance analysis

[0567]

[0568] The concentrations of etradinam measured in the presence of polymers were compared to those measured in the absence of any polymer in FaSSIF. At 25% drug loading, i.e., a drug to polymer ratio of 1:3 (w / w), all polymers resulted in prolonged supersaturation of etradinam throughout 60 minutes compared to the control, which began to precipitate out after 45 minutes. At 50% drug loading, i.e., a drug to polymer ratio of 1:1 (w / w), all polymers improved the maintenance of supersaturation except for PVP and HPMCP. The 25% drug loading showed a higher degree of supersaturation than amorphous etradinam when compared to the 50% drug loading. The data are shown in Figure 2B and Figure 2Cmiddle.

[0569] Eight solid dispersions prepared with different ratios of starting drug substance to polymer (25:75 w / w or 40:60 w / w) and different polymers (HPMCAS-L, HPMCAS-M, CAP or PVP-VA) were then characterized. In this example, and throughout the following examples, solid dispersions (also referred to as SDIs) are identified using a nomenclature in which the weight ratio of drug to polymer is identified, followed by the identification of the drug and polymer. For example, "25:75 AB928:HPMCAS-M SDI" refers to a solid dispersion prepared using 25 wt % AB928 (Etradinam) and 75 wt % HPMCAS-M. In other words, 100 wt % of the solids used to prepare the dispersion can be attributed to Etradinam and HMPCAS-M, and the weight ratio of Etradinam to HMPCAS-M is 1:3. The resulting dispersion does not exactly contain 25 wt % Etradinam and 75 wt % HPMCAS-M, however, some weight of the dispersion may be accounted for by residual solvent, water and impurities.

[0570] Each of the eight formulations was spray dried from pure acetone. Briefly, the starting drug substance and one of the four polymers in the preceding paragraph were added to the spray solvent (acetone) at a solid loading of 10% (w / w) and mixed at 20°C-25°C until complete dissolution to obtain a spray solution. The spray solution was then spray dried by atomizing the spray solution into a drying chamber, where the solvent in the vehicle was removed and an SDI powder was produced. The spray drying parameters are provided in Table 5. The SDI powder was then subjected to secondary drying to remove residual solvent.

[0571] Table 5: Summary of spray drying parameters

[0572]

[0573] The obtained SDI powders were characterized by various analytical methods, including powder X-ray diffraction (XRPD), scanning electron microscopy (SEM), modulated differential scanning calorimetry (MDSC), residual solvents by gas chromatography headspace sampling (GC-HS), determination of related substances by high performance liquid chromatography (HPLC), water content by Karl Fischer titration (KF), and non-sinking dissolution.

[0574] GC-HS was used to measure the residual acetone remaining after secondary drying. Measurements were made using an HP 6890 Series GC equipped with an Agilent 7697A headspace sampler. A 30m×0.32mm×1.8µ capillary column and a 6% cyanopropylphenyl 94% dimethylpolysiloxane GC column were used for testing. GC samples were prepared by dissolving ~100mg of sample in 4mL of dimethyl sulfoxide (DMSO). The residual solvents in all preparations were well below the acetone limit (5000ppm) set forth by the International Conference on Harmonization (ICH).

[0575] MDSC thermal analysis performed as described in Example 1 showed that all dispersions (see legend for dispersions in FIG. 3 ) had a single, relatively high glass transition temperature (T g ) (Figure 3), ranging from about 76°C to about 123°C. A single T g The presence of indicates that the intimately mixed amorphous solid dispersion has good homogeneity, while the high T g The dispersion was indicated to have good physical stability, for example, eltrodinam had a low tendency to recrystallize during long-term storage.

[0576] To further evaluate the crystallinity of the spray-dried particles, SDI powder samples were analyzed by XRPD as described in Example 1. Amorphous materials give an "amorphous halo" diffraction pattern and will not have the discrete peaks found in crystalline materials. XRPD characterization indicated that the eight dispersions were amorphous and no crystalline peaks were observed in the diffraction pattern ( Figure 4 ).

[0577] The surface morphology of the spray-dried particles was characterized using SEM. The SEM samples were prepared by dispersing the SDI powder onto a sticky carbon-coated sample stub and coating a thin gold conductive layer using a Cressington 108 Auto. The samples were analyzed using a FEI Quanta200 SEM equipped with an Everhart-Thornley (secondary electron) detector operated in high vacuum mode. Micrographs of different magnifications were captured for qualitative particle morphology analysis. The experimental parameters including spot size, working distance, and accelerating voltage varied from sample to sample to obtain optimal imaging conditions. For each dispersion, the observed morphology consisted of intact and collapsed spheres with smooth surfaces. No crystalline material was observed in any sample.

[0578] The water content of the SDI powder collected after secondary drying was analyzed with a Metrohm 831 Karl Fischer coulometric titrator with a Metrohm 874 oven processor. About 100 mg of the sample was sealed in a 6 mL crimp vial and the water content was subsequently measured with the following parameters: Reagent Hydranal Coulomat AG-oven, oven temperature 130°C, and sample extraction time 300 seconds. The water content was typically less than 1% by weight.

[0579] The in vitro drug dissolution performance of each dispersion was evaluated under non-sinking conditions in a two-stage process of pH and bile salt concentrations simulating both gastric and intestinal exposures. In vitro solubility testing under non-sinking conditions allows for direct assessment of each dispersion's ability to generate and maintain supersaturation above the dissolution rate of crystalline edredinam; is used as a predictive surrogate to ensure product quality and in vivo performance; and is an effective test to differentiate between formulations under given stability conditions.

[0580] To initiate dissolution (t=0), SDI powder samples were briefly suspended in 4 mL of FaSSIF (2 mg / mL SIF in 100 mM PBS) and then transferred to 50 mL of SGF (0.1 N HCl (aq)) preheated to 37°C in a USP Type 2 mini-vessel (total vessel volume of 100 mL) while stirring (paddle) at 100 rpm. At 30 minutes, a gastric transfer step was performed in which the volume in each dissolution vessel was approximately doubled using 2x FaSSIF (4.48 mg / mL SIF powder (biorelevant)), resulting in a final pH of 6.8 in a total volume of 100 mL. Samples collected before and after the indicated time transfer were evaluated for drug concentration by HPLC. The drug concentrations measured in this test were a complex of drug without SDI, drug in micelles, and drug suspended in solution. Table 6 and Table 7 show a summary of the dissolution and HPLC parameters, respectively.

[0581] Table 6: Summary of non-sinking dissolution parameters

[0582]

[0583] Table 7. HPLC parameters for non-sinking dissolution testing

[0584]

[0585] All dispersions showed improved in vitro non-sinking dissolution performance relative to crystalline edrolidine ( Figure 5and Table 8). In this model, the predicted gastric solubility varied across formulations, with low correlation between gastric dissolution levels and subsequent predicted intestinal dissolution levels. All formulations maintained their intestinal dissolution levels throughout the experiment, with no precipitation observed. Overall, the non-settling dissolution testing suggests that the dispersions should improve the bioavailability of edredinam relative to the starting drug substance.

[0586] Table 8: Non-sinking dissolution data of edredinam dispersion

[0587]

[0588] To screen the physical and chemical stability of eltrodinam dispersions, SDI powders were subjected to stress for 4 and 12 weeks at 25°C and 60% relative humidity (RH) (25°C / 60% RH) in open high-density polyethylene (HDPE) bottles without caps and with cotton wool around the neck ("open packaging"), open packaging at 40°C / 75% RH, and sealed packaging at 40°C / 75% RH (i.e., dual low-density polyethylene (LDPE) bags, each sealed with a cable tie; 0.5 g of silica gel desiccant added between LDPE bags; and bags placed in HDPE bottles). The physical and chemical stability of SDI powders was evaluated (12 weeks only) by appearance, amorphous features by XRPD, presence of related substances by HPLC, particle morphology by SEM, and crystallinity by polarized light microscopy (PLM).

[0589] The appearance of the stability changes is summarized in Table 9. Notably, all SDIs showed stability up to 12 weeks under open dish accelerated stability conditions. The PVP-VA formulation showed greater particle fusion under high humidity conditions.

[0590] Table 9: Evaluation of the appearance stability of eltrodinam SDI

[0591]

[0592] XRPD analysis of the SDI stability samples showed that after 12 weeks, all SDI remained amorphous with no detectable crystalline material ( Figure 6 and Figure 7 ). The 4-week diffraction pattern also shows an amorphous halo.

[0593] The surface morphology of the SDI particles was characterized using SEM. A small amount of particle fusion was observed for the 40:60 AB928:HPMCAS-M SDI at 4 weeks under both open and closed conditions at 40°C / 75% RH. This fusion occurred to a greater extent by 12 weeks. For the remaining AB928:HPMCAS-M SDI samples, the typical SDI morphology observed at t=0 consisted of intact and collapsed spheres with smooth surfaces. No crystalline material was observed in any of the samples.

[0594] Fusion was also observed in AB928:PVP-VA SDI samples analyzed by SEM at 12 weeks. SDI particles fused into large clumps in the 25:75 AB928:PVP-VA SDI samples in both the open and closed 40°C / 75% RH, and in the 40:60 AB928:PVP-VA SDI samples in the open 40°C / 75% RH. Individual SDI particles in the 40:60 AB928:PVP-VA SDI samples appeared slightly fused at both the open 25°C / 60% RH and the closed 40°C / 75% RH. The 25:75 AB928:PVP-VA SDI samples exhibited typical SDI morphology at t=0 at 25°C / 60% RH relative humidity. No crystalline material was observed in any of the samples.

[0595] Purity analysis of SDI stability samples showed no change in impurities of interest relative to the crystalline API in all SDI samples when stored at 2°C-8°C for 4 weeks, 25°C / 60% RH, 40°C / 75% RH for 4 weeks and 12 weeks on and off.

[0596] Example 5: Exemplary solid dispersion of edredinam

[0597] Four dispersions prepared with different ratios of starting drug substance to HPMCAS-M (25:75, 30:70, 35:65, 40:60) were used for stability testing. Each formulation was spray dried from acetone: water (95:05) as generally described in Table 10. Samples of the dispersions were obtained at the time of manufacture (t=0) and after storage (t=1 month, 3 months, 6 months) in open and sealed packaging at 25±2°C / 60±5% RH and in open and sealed packaging at 40±2°C / 75±5% RH. The samples were characterized by various analytical methods, including powder X-ray diffraction (XRPD), modulated differential scanning calorimetry (MDSC), high performance liquid chromatography (HPLC) content and impurities / related substances and non-sinking dissolution. Samples obtained after 6 months of storage in open packaging were only analyzed for appearance and MDSC. A description of the analytical methods is provided in Example 4.

[0598] Table 10: Summary of spray drying parameters

[0599]

[0600] All samples were still off-white powder after 6 months of stability and were amorphous as shown by XRPD ( Figure 8 HPLC assay and impurity analysis showed that after 6 months of stability testing, the values ​​for eltrodinam were close to the target values ​​(±10%), the impurity profile matched the starting drug substance, and there was no significant impurity growth after 6 months.

[0601] The samples analyzed for MDSC showed a single T g (at approximately all time points, including after 6 months of stability). MDSC Irreversible In the stability of the 40:60 AB928:HPMCAS-M SDI, additional thermal events of ~180°C were detected after 3 weeks (open packaging) or 1 month (closed packaging). The severity of the events appeared to increase during storage. No changes in appearance were observed between 3 and 6 months. In the 35:75 AB928:HPMCAS-M SDI, additional thermal events of ~180°C were observed with MDSC Irreversible after 6 months of open and closed packaging stability testing. The additional endothermic event observed at ~180°C indicates a low level of crystallization. T g The values ​​are summarized in Tables 11 and 12 (+ indicates temperatures from about 70°C to about 90°C; ND = not determined); a representative MDSC curve is shown in FIG. 9 .

[0602] Table 11: T measured by MDSC g value

[0603]

[0604] Table 12: T measured by MDSC g value

[0605]

[0606] The non-sinking dissolution test at t = 0 confirmed that the formulation of edrolidine with HMPCAS-M as a solid dispersion improved the solubility of edrolidine in FaSSIF. 35-210 FaSSIF The stability of the samples was tested in closed or open containers at 25°C / 60% RH and 40°C / 75% RH and the non-sinking dissolution test was evaluated again. Tables 13 and 14 summarize the non-sinking dissolution data; representative dissolution curves are shown in Fig.10 and Fig.11 middle.

[0607] Table 13: Non-sinking dissolution data

[0608]

[0609] Table 14: Non-sinking dissolution data

[0610]

[0611]

[0612] Example 6: Exemplary Tablets Containing a Solid Dispersion of Etradinam

[0613] Four dispersions prepared with different ratios of starting drug substance to polymer were prepared for tableting: 25:75 AB928:HPMCAS-M, 40:60 AB928:HPMCAS-M, 25:7.5:67.5 AB928:TPGS:PVP-VA, and 40:7.5:52.5 AB928:TPGS:PVP-VA. TPGS (tocofersolan) was incorporated into both PVP-VA SDIs at 7.5% (w / w) to evaluate the effect of surfactant on dissolution performance. Each formulation was spray dried from neat acetone according to the parameters summarized in Table 15. The resulting SDI powders were then characterized by various methods, including XRPD, SEM, MDSC, and in vitro non-sinking dissolution. A description of the analytical methods is provided in Example 4.

[0614] Table 15. Summary of spray drying parameters

[0615]

[0616] Thermal analysis by MDSC showed that all four dispersions had a single T g , indicating an intimately mixed amorphous solid dispersion with good homogeneity. g The values ​​were from about 72°C to about 83°C. XRPD characterization indicated that the SDI was an amorphous dispersion, and no crystalline peaks were observed in the SDI diffraction pattern. The surface morphology of the SDI particles characterized by SEM showed a typical SDI morphology consisting of complete and collapsed spheres with smooth surfaces. Crystalline material was not observed in any sample. The dissolution performance of SDI was tested in a non-sinking dissolution test. Compared with the SDI described in Example 4, all SDIs showed similar dissolution performance, with the 25% AB928:HPMCAS-M formulation performing best. The introduction of 7.5% by weight of TPGS in PVP-VA SDI did not produce a significant increase in dissolution in vitro.

[0617] Immediate release tablets containing the four dispersions were then developed.Due to the poor flow properties of the dispersions, efforts were made to develop dry granules containing SDI.

[0618] For HPMCAS SDI, a 1:1 ratio of microcrystalline cellulose (MCC):mannitol was used because it was considered that the mixture of brittle and plastic fillers might help improve the mechanical properties of the tablet. Croscarmellose sodium (Ac-Di-Sol) was selected as a superdisintegrant because it was considered that acceptable disintegration times could be achieved with it. Colloidal silicon dioxide (Cab-O-Sil) was used as a glidant because it was considered to improve flow properties, which would be useful for scale-up work. Sodium stearyl fumarate (SSF) was selected as a lubricant because it was considered to help reduce sticking of the formulation on process equipment.

[0619] For PVP-VA SDI, crospovidone (Kollidon CL) was added as a superdisintegrant, and mesoporous silica (Parteck SLC and Syloid XDP 3150) was added as a disintegration aid; these components were considered to reduce the disintegration time. In addition, microcrystalline cellulose and colloidal silicon dioxide were replaced with silicified microcrystalline cellulose (Prosolv SMCC 90). After dry granulation, additional excipients were added before tableting. Extragranular excipients were selected because they were considered to reduce the risk of over-compaction of the formulation during tableting.

[0620] Table 16: 50 mg A and 100 mg A tablet formulations

[0621]

[0622]

[0623] Tablets are prepared as follows. SDI is blended with the intragranular components in a suitable blender. The blend is deagglomerated using a suitable conical grinder, followed by roller compaction and grinding. Using a roller compactor equipped with an oscillating grinder with a suitable screen (25 mesh), the blend is first compacted into ribbons (target solid fraction of about 0.7), which are then ground into granules. The extragranular components are then blended with the granules, and the mixture is tableted. The tablets are compacted into target mass using a rotary tablet press. Throughout the compaction operation, the single tablet weight, the average weight of 10 tablets, the tablet hardness and thickness are monitored at predetermined manufacturing process intervals.

[0624] Tabletability, compactability, compactability, and disintegration curves were generated for all formulations using 0.4062” and 0.5000” standard round convex (SRC) tools for 50 mgA and 100 mgA tablets, respectively. Compaction curves were generated in the range of 100 MPa-200 MPa.

[0625] Using Varian VK-100 disintegration apparatus, according to USP <701> "Disintegration" evaluates disintegration. The apparatus consists of a 1000 mL low-profile beaker and a basket assembly with six open-ended transparent tubes. The beaker contains 750 mL of RO1 water and the temperature is maintained at 37°C (±2°C). The basket is fully immersed at a frequency of 29 cycles to 32 cycles per minute, and the tablet disintegration time is recorded when the last visible tablet material passes through the basket.

[0626] Tablet tensile strength was calculated based on the following formula, which is applicable to standard round concave (SRC) tablets: where P = breaking load, D = tablet width, t = tablet thickness, and W = tape thickness.

[0627]

[0628] According to USP <1217> Tablet Breaking Force measures tablet hardness using a Natoli Hardness Tester (S / N 1403029). The tablet thickness and weight are measured prior to evaluating the tablet breaking force, as this is a destructive process. The tablet is placed in an automated breaking device and tablet hardness is measured in kilopounds (kP) or kilograms of force.

[0629] HPMCAS-M SDI tablets showed increased compressibility and achieved higher tensile strength at a given compaction pressure compared to PVP-VA SDI tablets. PVP-VA SDI tablets showed longer disintegration times than HPMCAS-M SDI tablets. See Figures 12 and 13.

[0630] As described in Example 4, the four tablet formulations were also characterized for assay and related substances / impurities by HPLC and non-sinking dissolution, and for water content by Karl Fischer coulometric titration using an oven drying method. For each polymer formulation, the moisture content values ​​of the tablets were consistent at both drug loadings. It is believed that the PVP-VA SDI tablets contain higher moisture content due to the increased hygroscopicity of the PVP-VA polymer compared to HPMCAS-M. Assay and related substance / impurity analysis of the tablets by HPLC showed similar total related substances compared to the parent SDI or intact crystalline edredinam, indicating that no chemical degradation occurred during spray drying or tablet manufacturing.

[0631] The dissolution performance of the tablets was tested in a non-sinking dissolution test. The dissolution performance of the tablets was also evaluated under accelerated stability conditions at 25°C / 60% RH and 40°C / 75% RH after 1 and 3 months of storage in sealed packaging. The release test results (described above) were used at the t=0 time point. Representative data are shown in Fig.14 and Fig.15 Non-sinking dissolution testing of AB928:HPMCAS-M SDI tablets was also conducted after the tablets were stable for 6, 9, and 12 months. Fig.16 .

[0632] As compared with the capsule control, the pharmacokinetics (PK) of SDI tablets were evaluated in male beagles fasted overnight before the study drug was administered. Whole blood samples were collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration of a single dose of the study drug (PO). As described in Table 2, the PK of crystallized AB928 tablets was also evaluated under similar conditions. Tables 17 and 18 summarize the test formulations and PK data (=Terminal_T1 / 2=terminal elimination half-life; MRTINF=average retention time from time 0 to infinity; other parameters as described herein). Representative data are shown in Figure 17.

[0633] Table 17

[0634]

[0635] Table 18

[0636]

[0637] Example 7: Exemplary Tablets Containing a Solid Dispersion of Etradinam

[0638] 25:75 AB928:HPMCAS-M SDI tablets were prepared as described in Example 6 using different intragranular excipients (Avicel PH-105, Partek M 100, FlowLac 90, Emcompress, AvicelDG, Nisso HPC SSL SFP) according to Table 19. During dry granulation, the target solid band fraction was 0.6 to 0.7. For tableting, the generated compaction curve was in the range of 50 MPa-200 MPa. The weight, thickness, hardness and disintegration of the resulting tablets were evaluated as described in Example 6.

[0639] Table 19: Exemplary 25:75 AB928:HPMCAS-M SDI tablets.

[0640]

[0641]

[0642] Initially, a first round of tablets F1-F5 were developed. All formulations showed good weight, thickness, rupture force, tabletability and compactability. The disintegration time of F1-F5 increased sharply at >150 MPa, indicating that achieving a robust disintegration profile was a significant technical hurdle.

[0643] A second round of tablets F1.1, F1.2 and F4.1 were then developed to implement various methods to shorten the disintegration time (e.g., reducing SDI content, increasing disintegrants, increasing extragranular fillers (e.g., Avicel PH-200, Partek M 200)). All formulations again showed good weight, thickness, rupture force, compressibility and compactability. It is worth noting that all formulations also achieved a robust disintegration profile.

[0644] Example 8: Exemplary Tablets Containing a Solid Dispersion of Etradinam

[0645] The manufactured edrolidine film-coated tablets contain 75 mg edrolidine. The tablets are prepared as follows. SDI is blended with the intragranular components in a suitable blender. The blend is depolymerized using a suitable conical grinder, and then roller compacted and ground. Using a roller compactor equipped with an oscillating grinder with a suitable screen, the blend is first compacted into a ribbon, which is then ground into granules. The extragranular components are then blended with the granules, and the mixture is tableted. The tablets are compacted into a target mass using a rotary tablet press, and then film coated. Throughout the compacting operation, the single tablet weight, the average weight of 10 tablets, the tablet hardness and thickness are monitored at predetermined manufacturing process intervals. Table 20 provides the tablet composition.

[0646] Table 20: Composition of edredinam tablets

[0647]

[0648] The tablets are packaged in high-density polyethylene (HDPE) bottles containing desiccant and sealed with foil heat induction seals and polypropylene (PP) child-resistant closures, and then stabilized at 25°C / 60% relative humidity and 40°C / 75% relative humidity.

[0649] Tablets were sampled over time and tested by HPLC for appearance, assay and impurities, water content, and dissolution. Assay was determined by reversed-phase gradient HPLC. Impurities (and degradation products of edredinam) were determined by reversed-phase gradient HPLC. Impurities were identified only by HPLC relative retention times (RRTs); these RRTs are approximate due to variability in HPLC analysis. According to USP <921> The water content in edradinam was determined by Ernst & Young Fischer coulometric titration using the oven dried method. The same HPLC method was used to identify the content and related substances and the parameters are summarized in Table 21 and the dissolution method is in Table 22.

[0650] Table 21

[0651]

[0652] Table 22: Dissolution method of edredinam film-coated tablets

[0653]

[0654] After 12 months of storage at long-term storage conditions of 25°C ± 2°C / 60% ± 5% RH and after 6 months of storage at accelerated storage conditions of 40°C ± 2°C / 75% ± 5% RH, there were no significant changes in appearance, assay, impurities, and dissolution. Under both conditions, the water content gradually increased over time.

[0655] The T=0 data correspond to the batch release results.

[0656] Table 23

[0657]

[0658] Example 9: Exemplary Tablets Containing a Solid Dispersion of Etradinam

[0659] The manufactured edrolidine tablets contain 50 mg or 75 mg edrolidine. The tablets are prepared as follows. SDI is blended with the intragranular components in a suitable blender. The blend is deagglomerated using a suitable conical grinder and then roller compacted and ground. Using a roller compactor equipped with an oscillating grinder with a suitable screen, the blend is first compacted into a ribbon and then ground into granules. The extragranular components are then blended with the granules and the mixture is tableted. The tablets are compacted into a target mass using a manual or rotary tablet press. Table 24 provides the tablet composition.

[0660] Table 24: Composition of edredinam tablets

[0661]

[0662] Example 10: Comparison of edrolidine tablets

[0663] Tablets comprising the edradinam salt were also prepared.

[0664] The crystalline form of eltrodinam phosphate ("phosphate Form I") was prepared as follows. About 176 mg of eltrodinam was suspended in about 4 mL of water:acetone. Then, about 140 µL of 85% H3PO4 was added and the sample was placed at room temperature.

[0665] A crystalline form of eltrodinam phosphate ("phosphate Form I") can also be prepared as follows. About 5 g of eltrodinam is suspended in about 20 mL of tetrahydrofuran. Next, about 1.5 mL of 85% H3PO4 diluted in about 2 mL of water is added to the suspension. A solution is formed, and the sample is seeded with seed crystals of phosphate Form I (prepared as described above). A suspension is formed and stirred overnight. The sample is filtered and washed with about 10 mL of water, and the solid is dried under vacuum with a nitrogen purge at room temperature to obtain Form I phosphate.

[0666] The crystalline form of eltrodinam phosphate ("phosphate Form I") is characterized by XRPD, such as Fig.19 shown.

[0667] Another sample of the crystalline form of eltrodinam phosphate ("Phosphate Form II") was prepared as follows. About 120 mL of ethanol: water (9: 1 volume) was added to a 250 mL container. About 2 molar equivalents of phosphoric acid were added thereto under the action of a magnetic stirrer. Next, about 6 grams of crystalline eltrodinam (Type I described in WO 2020 / 018680) was added, and the mixture was stirred at room temperature. An additional about 2 equivalents of phosphoric acid were added to the mixture and further stirred at room temperature. The resulting solid was filtered and washed twice with about 15 mL of ethanol: water (9: 1 volume) containing excess phosphoric acid. The sample was dried overnight in a funnel filter to give crystalline eltrodinam phosphate ("Phosphate Form II"), characterized by XRPD, such as Fig. 20 shown.

[0668] When a solution is formed by charging about 213 mg of crystalline eltrodinam (Form I prepared as described in WO 2020 / 018680), about 70 mg of fumaric acid and a few mL of tetrahydrofuran into a 4 mL glass vial, eltrodinam fumarate is isolated. The solution evaporates at ambient temperature and turns into a brown oil the next day. About 1 mL of methanol is added to the oil to obtain a suspension. After about a week, the solid is isolated and analyzed. Fig.21 The XRPD pattern of edradinan fumarate is shown.

[0669] The tablets of edrolidine are prepared manually to contain 50 mg edrolidine equivalents, incorporated as phosphate as described above or as fumarate as described above. The tablets are prepared as follows. The API is blended with the intragranular components in a suitable blender. The blend is de-agglomerated, then compacted and ground into granules. The extragranular components are then blended with the granules, and the mixture is tableted. The tablet composition of the phosphate is provided in Table 25, and the tablet composition of the fumarate is provided in Table 26.

[0670] Table 25: Composition of edredinam phosphate tablets

[0671]

[0672] a Equivalent to 10.0% w / w edradine, theoretical salt correction factor is 0.813

[0673] Table 26: Composition of edrolidine fumarate tablets

[0674]

[0675] a Equivalent to 10.0% w / w edradine, theoretical salt correction factor is 0.787

[0676] Fasting, pentagastrin pretreated beagle dog study: The pharmacokinetics (PK) of eltrodinam tablets were evaluated in male beagles fasted overnight prior to study drug administration. Each animal received a single intramuscular injection of 6µg / kg pentagastrin approximately 30 minutes prior to administration. Whole blood samples were collected prior to dosing and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after a single dose of study drug administration (PO). The data are shown in Table 27. The crystalline form of eltrodinam phosphate ("phosphate form I") cannot be reproduced and is therefore undesirable. The eltrodinam tablets with solid dispersion provide the highest oral bioavailability.

[0677] Table 27. PK data of fasted, pentagastrin-pretreated beagle dogs

[0678]

[0679] a When dosed IV at 5 mg / kg in beagle dogs, the % bioavailability was estimated based on an AUClast of 25100 hr*ng / mL.

[0680] Fasting, Famotidine pre-treated beagle dog study (understanding potential drug-drug-and acid inhibitor interactions): The pharmacokinetics (PK) of eltrodinam tablets were evaluated in male beagles fasted overnight before the study drug was administered. Each animal took a single 20 mg tablet of famotidine approximately 1 hour before the test article was administered. Whole blood samples were collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours before administration and after a single dose of study drug administration (PO). The data are shown in Table 28. The crystalline form of eltrodinam phosphate ("phosphate form I") cannot be reproduced and is therefore undesirable, while the crystalline fumarate exhibits the lowest oral bioavailability. The eltrodinam tablets with solid dispersions provide the highest oral bioavailability.

[0681] Table 28. PK data for fasted, famotidine-pretreated beagle dogs

[0682]

[0683] a When dosed IV at 5 mg / kg in beagle dogs, the % bioavailability was estimated based on an AUClast of 25100 hr*ng / mL.

[0684] Example 11: Pharmacokinetic studies

[0685] This example describes a Phase 1 study comparing the PK of a single dose of eltrodinam tablets with that of eltrodinam capsules in healthy adult participants (19-55 years old) and evaluating the effect of food on the PK of a single dose of eltrodinam tablets in healthy adult participants.

[0686] This study was an open-label, randomized, 3-treatment, 3-period crossover study designed to evaluate the relative bioavailability (BA) of tablet and capsule formulations of eltrodinam and the effect of food on tablet administration. A single dose of eltrodinam was administered on day 1 of each cycle in a 3-cycle crossover manner. Participants (n=24) received eltrodinam capsules under fasting (treatment A) conditions and eltrodinam tablets under fasting (treatment B) conditions and fed (high-fat meal; treatment C) conditions. PK samples of eltrodinam and its metabolites were collected before and up to 120 hours after dosing. There was a washout period of at least 7 days between doses of eltrodinam. All subjects who received at least one dose of eltrodinam (including those who terminated the study prematurely) were asked to return to the Clinical Research Unit (CRU) for a follow-up visit 14 (± 2) days after the last dose and to determine if any adverse events (AEs) had occurred since the last study visit.

[0687] Study treatments are described as follows. Treatment A = 150 mg of eltrodinam (6 × 25 mg capsules) taken at 0 hours on day 1; subjects fasted for at least 10 hours before eltrodinam administration and at least 4 hours after administration. Treatment B = 150 mg of eltrodinam (2 × 75 mg tablets) taken at 0 hours on day 1; subjects fasted for at least 10 hours before eltrodinam administration and at least 4 hours after administration. Treatment C = 150 mg of eltrodinam (2 × 75 mg tablets) taken at 0 hours on day 1, 30 minutes after the start of a high-fat meal; participants fasted for at least 10 hours until 30 minutes before eltrodinam administration, when they were given a high-fat breakfast that was completely consumed within 30 minutes; participants fasted for at least 4 hours after administration. Table 3 and Table 20 provide the compositions of eltrodinam capsules and eltrodinam tablets, respectively.

[0688] All edrolidine capsules or tablets were administered orally with approximately 240 mL of water. If all capsules and tablets could not be swallowed at the same time, up to 50 mL of additional water was given upon request by the subject. Administration was completed within 10 minutes.

[0689] Study objectives included pharmacokinetics (PK) and safety. The following plasma PK parameters of edredinam and its metabolites were calculated, as appropriate:

[0690]

[0691] Additional PK parameters were calculated if deemed appropriate. The least squares mean (LS) ratios of the ln-transformed PK parameters (AUClast, AUCinf, and Cmax) were calculated with 2-sided 90% confidence intervals (CI). Comparisons of interest included the following:

[0692] - Relative BA of tablets versus capsules: LSM ratio of the fasting tablet formulation (Treatment B - Test) versus the fasting capsule formulation (Treatment A - Reference).

[0693] - Effect of food: LSM ratio of the fed tablet formulation (Treatment C - Test) to the fasted tablet formulation (Treatment B - Reference).

[0694] A nonparametric Wilcoxon signed rank test can be performed on the variable Tmax to determine the test-reference difference and the results can be tabulated.

[0695] Table 29 shows the relative bioavailability of capsules and tablets. The Cmax, AUC and Tmax of edrolidine in capsules and tablets were statistically equivalent. Taking edrolidine in the fed state had no effect on its total exposure (AUClast and AUCINF) compared with the fasted state (Table 30).

[0696] Table 29: Relative bioavailability of capsules and tablets

[0697]

[0698] Table 30: Effect of Food on Tablets

[0699]

[0700] Example 12: Drug-drug interaction studies

[0701] An open-label, fixed-sequence, phase 2 drug-drug interaction (DDI) study was designed to evaluate the effects of multiple doses of strong inhibitors of CYP3A4 and P-gp on the PK of a single dose of edredinam in humans. edredinam is supplied as 25 mg capsules. The composition of edredinam capsules is provided in Table 3. Itraconazole is a representative strong inhibitor of CYP3A4 and P-gp. It is supplied by Janssen Pharmaceuticals as a 10 mg / mL oral solution, Sporanox ® (or generic equivalent) were supplied. Twenty (20) healthy adult male and female (non-fertile potential) participants were recruited. Subjects were screened within 28 days prior to the first dose.

[0702] On Day 1 of Phase 1, a single 150-mg oral dose of etraconazole was administered under fasting conditions (i.e., at least 10 hours before and 4 hours after dosing). PK sampling of etraconazole and its metabolites was performed before and until 120 hours after dosing. There was a 5-day washout period between the etraconazole dose in Phase 1 and the first itraconazole dose in Phase 2.

[0703] In Phase 2, 200 mg itraconazole was administered orally on Day 1 twice a day (BID) and once a day (QD) for 9 consecutive days (Days 2 to 10), and a single dose of 150 mg of etraconazole was administered orally 1 hour after itraconazole administration on Day 6. Itraconazole was administered under fasting conditions. On Day 6, subjects fasted for at least 10 hours before dosing and for at least 4 hours after etraconazole administration. PK sampling of etraconazole and its metabolites was performed before dosing and until 120 hours after etraconazole administration. PK samples of itraconazole and 1-hydroxyitraconazole were collected on Days 5, 6, 7, 9, and 11.

[0704] Two loading doses of itraconazole were administered on the first day of phase 2 to accelerate CYP3A inhibition, and then inhibition was maintained by administering itraconazole 200 mg QD for 9 consecutive days. The 200 mg BID dose level is expected to provide similar inhibition to the 400 mg QD dose. Although itraconazole reaches steady state in approximately 15 days, it has been determined that QD administration of 200 mg itraconazole for 3-5 days can maximally inhibit CYP3A, which is sufficient to detect DDI. Itraconazole is also a P-gp inhibitor, and it has been reported in the literature that 200 mg itraconazole QD for 5 days can increase the AUC of oral digoxin by approximately 1.7-fold. Therefore, in DDI studies, itraconazole administration for at least 4 days is sufficient as an inhibitor of CYP3A4 and P-gp. To maintain inhibition levels, itraconazole was administered throughout the PK sampling period of itraconazole (i.e., day 10 of phase 2). In addition, itraconazole oral solution was administered under fasting conditions to maximize bioavailability.

[0705] Participants were admitted to the Clinical Research Unit (CRU) at designated times on Day 1 of Period 1 until the 120-hour blood draw and completion of study procedures for Period 2. Safety was monitored throughout the study by repeated clinical and laboratory assessments. No participants were discontinued during this study. All subjects who received at least one dose of study drug (including those who terminated the study early) were asked to return to the CRU for a follow-up visit approximately 14 days after the last dose and to determine if any adverse events (AEs) had occurred since the last study visit. All AEs reported in the study were mild and resolved without treatment.

[0706] Table 27 and Fig.18 The plasma PK parameters of itraconazole and C max , AUC last and AUC inf Box and whisker plot. Compared with the use of etraconazole alone, multiple doses of itraconazole can increase the AUClast, AUCinf, and Cmax of etraconazole by approximately 63%, 62%, and 18%, respectively. After taking etraconazole and itraconazole at the same time, the AUC of etraconazole increased, indicating that the metabolism of etraconazole in humans is inhibited by itraconazole through CYP3A4. The magnitude of the increase (62%-63%) indicates that according to the U.S. Food and Drug Administration (FDA) Drug Interaction Guide (2020), etraconazole is neither a moderately sensitive nor a sensitive CYP3A4 substrate. Etraconazole C max The minimal increase in daptomycin (18%) suggests that co-administration of a P-gp inhibitor (itraconazole) with edradinan does not result in a meaningful exposure change in edradinan peak concentrations.

[0707] Multiple doses of a strong CYP3A4 and P-gp inhibitor (itraconazole) resulted in an increase in the metabolite-to-parent ratios of MP AUC0-24 and MP Cmax of the glucuronide metabolite of etrodinam compared to etrodinam alone. When coadministered with itraconazole, the MPAUC0-24 and MP Cmax values ​​increased by approximately 8% and 6%, respectively. The limited changes in the metabolite-to-parent ratios are consistent with etrodinam glucuronide being the major metabolite formed by direct glucuronidation of etrodinam. Therefore, coadministration of a CYP3A4 or P-gp inhibitor has little effect on the component of etrodinam eliminated via the glucuronidation pathway.

[0708] Multiple doses of a strong CYP3A4 and P-gp inhibitor (itraconazole) resulted in decreased metabolite-to-parent ratios of MP AUC0-24 and MP Cmax of N-dealkylated etraconazole compared to etraconazole alone. When co-administered with itraconazole, MP AUC0-24 and MP Cmax values ​​decreased by approximately 87% and 90%, respectively. The reduction in the formation of N-dealkylated etraconazole is consistent with the inhibition of the CYP3A4 elimination pathway by itraconazole, suggesting that etraconazole is eliminated by the CYP3A4 pathway via the formation of N-dealkylated etraconazole.

[0709] The total percentage changes in plasma drug-related substance exposure in the presence and absence of itraconazole were less than 26% and 7% for AUC0-24 and Cmax, respectively. This change is not clinically significant. Therefore, co-administration of P-gp inhibitors (itraconazole) with etraconazole does not affect the absorption of etraconazole.

[0710] In conclusion, the effects of strong CYP3A4 inhibitors on the PK of eltrodinam are limited; P-gp may not affect the oral absorption of eltrodinam. Physiologically based pharmacokinetic modeling suggests that the fraction of eltrodinam metabolized by CYP3A4 is approximately 0.4.

[0711] Table 31.

[0712]

Claims

1. A solid dispersion comprising about 20% to about 40% (w / w) of edredinam and about 60% to about 80% (w / w) of a polymer selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS), copolyvidone (PVP-VA), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose E3 (HPMC E3), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ® ).

2. A solid dispersion comprising about 20% to about 40% (w / w) of edredinam and about 60% to about 80% (w / w) of a polymer (w / w) selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS) and copolyvidone (PVP-VA).

3. The solid dispersion according to claim 1 or 2, wherein the solid dispersion comprises about 25% to about 35% (w / w) of edredinam; or About 25% to about 30% (w / w) eltrodinam.

4. The solid dispersion according to claim 1 or 2, wherein the solid dispersion comprises about 25% to about 35% (w / w) of edradinam and about 65% to about 75% of the polymer; or From about 25% to about 30% (w / w) of edradinam and from about 70% to about 75% (w / w) of the polymer.

5. The solid dispersion according to claim 1 or claim 2, wherein the solid dispersion comprises about 22.5% to about 27.5% (w / w) eltrodinam; or about 27% to about 33% (w / w) of edredinam; or About 31.5% to about 38.5% (w / w) eltrodinam.

6. The solid dispersion of claim 5, wherein the solid dispersion is characterized by a single glass transition temperature (T g ).

7. The solid dispersion according to claim 6, wherein the solid dispersion is characterized by The glass transition temperature (T) is about 75°C to about 100°C. g );or Not more than 5% crystallinity.

8. The solid dispersion according to claim 6, wherein the solid dispersion is characterized by The glass transition temperature (T) is about 75°C to about 100°C. g );or Not more than 1% crystallinity.

9. The solid dispersion according to claim 6, wherein the solid dispersion is characterized by Single melting temperature (T m );or The diffraction pattern of x-ray powder diffraction (XRPD) lacks discrete peaks.

10. The solid dispersion according to any one of claims 1 to 2, wherein the polymer is HPMCAS.

11. The solid dispersion of claim 10, wherein the HPMCAS comprises an acetyl content of about 5% to about 14%, a succinyl content of about 4% to about 18%, a methoxy content of about 20% to about 26%, and a hydroxypropoxy content of about 5% to about 10%.

12. The solid dispersion of claim 10, wherein the HPMCAS comprises an acetyl content of about 7% to about 11%, a succinyl content of about 10% to about 14%, a methoxy content of about 21% to about 25%, and a hydroxypropoxy content of about 5% to about 9%.

13. A solid dispersion according to any one of claims 10 to 12, wherein the solid dispersion comprises about 22.5% to about 27.5% (w / w) eltrodinam; or about 27% to about 33% (w / w) of edredinam; or About 31.5% to about 38.5% (w / w) eltrodinam.

14. The solid dispersion according to any one of claims 10 to 13, wherein the solid dispersion is characterized by a single T g .

15. The solid dispersion according to claim 14, wherein the solid dispersion is characterized by A single glass transition temperature (T) of about 75°C to about 85°C g );or Not more than 5% crystallinity.

16. The solid dispersion according to claim 14, wherein the solid dispersion is characterized by There are no other melting or crystallization events; or The XRPD diffraction pattern lacks discrete peaks.

17. The solid dispersion according to any one of claims 10 to 16, wherein the solid dispersion is formed by spray drying.

18. A solid dispersion according to any one of the preceding claims, wherein the solid dispersion has a non-sinking dissolution test in AUC 35-210 There was at least a 3-fold increase in FaSSIF (minutes*µgA / mL) compared to crystalline edredinam.

19. The solid dispersion according to claim 18, wherein the solid dispersion has a relative low molecular weight (AUC) of 35-210 There is approximately a 4-fold, 5-fold, 6-fold or 7-fold increase in FaSSIF (minutes*µgA / mL) compared to crystalline edredinam.

20. The solid dispersion according to any one of the preceding claims, wherein the solid dispersion has less than 1% total impurities (% area) as measured by HPLC.

21. A solid dispersion according to any one of the preceding claims, wherein the solid dispersion, when stored in a sealed package at 25°C and 60% relative humidity for 6 months, 12 months, 18 months, 24 months or 36 months: (i) the amount of etradinam in the solid dispersion is from about 90% to about 110% of the value measured at 0 months; (ii) the solid dispersion has a total impurity amount (% area) of less than or equal to 2%, or less than or equal to 1%, as measured by high performance liquid chromatography (HPLC); (iii) the solid dispersion is characterized by a single T by modulated differential scanning calorimetry (MDSC). g and optionally a single melting temperature (T m ); (iv) the solid dispersion is characterized by an XRPD diffraction pattern lacking discrete peaks; or (v) Any combination of (i) to (iv).

22. A spray-dried particle comprising a solid dispersion according to any one of claims 1 to 21, wherein the spray-dried particle is characterized by a Dv90 of less than 150 μm or a Dv50 of less than 50 μm.

23. The spray-dried particle of claim 22, wherein the spray-dried particle is characterized by Dv90 of about 80µm to about 130µm; or Dv50 of about 25µm to about 40µm.

24. A dosage form comprising the solid dispersion according to any one of claims 1 to 21 or the spray-dried particles according to claims 22 to 23.

25. The dosage form of claim 24, wherein the dosage form is a tablet or a capsule.

26. A granule comprising a solid dispersion according to any one of claims 1 to 21 and one or more fillers, one or more disintegrants, optionally one or more glidants and optionally one or more lubricants.

27. A composition comprising a solid dispersion according to any one of claims 1 to 21 and one or more fillers, one or more disintegrants, optionally one or more glidants and optionally one or more lubricants.

28. The composition of claim 27, wherein the composition comprises about 40% to about 60% (w / w) of the solid dispersion.

29. The composition of claim 27, wherein the composition comprises about 45% to about 50% (w / w) of the solid dispersion.

30. The composition of claim 27, wherein the composition comprises about 35% to about 45% (w / w) of the solid dispersion, about 40% to about 50% (w / w) of the one or more fillers, about 2% to about 7% (w / w) of the one or more disintegrants, and about 0.25% to about 0.75% (w / w) of the one or more lubricants.

31. The composition of claim 27, wherein the composition comprises about 47% (w / w) of the solid dispersion, about 43% to about 47% (w / w) of the one or more fillers, about 4% to about 6% (w / w) of the one or more disintegrants, about 0.5% to about 1% (w / w) of the one or more glidants, and less than 1% (w / w) of the one or more lubricants.

32. The composition of claim 27, wherein the composition comprises about 47.3% (w / w) of the solid dispersion, about 47.3% (w / w) of the one or more fillers, about 4.1% (w / w) of the one or more disintegrants, about 0.6% (w / w) of the one or more glidants, and about 0.6% (w / w) of the one or more lubricants.

33. The composition of claim 27, wherein the composition comprises about 50% (w / w) of the solid dispersion, about 17.5% (w / w) of the one or more fillers, about 31.8% (w / w) of the one or more disintegrants, and about 0.6% (w / w) of the one or more lubricants.

34. A composition according to any one of claims 27 to 33, wherein The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose and mesoporous silica; or The one or more disintegrants is croscarmellose sodium; or If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; or If present, the one or more glidants is colloidal silicon dioxide.

35. The composition according to claim 34, wherein The one or more fillers are selected from MCC, mannitol, silicified MCC and mesoporous silica; or The one or more disintegrants is croscarmellose sodium; or If present, the one or more lubricants are sodium stearyl fumarate or magnesium stearate; or If present, the one or more glidants is colloidal silicon dioxide.

36. The composition of claim 32, comprising a first filler and a second filler, and wherein the solid dispersion, the first filler, and the second filler have a 2:1:1 weight ratio.

37. The composition of claim 30 or claim 35, wherein the first filler is MCC and the second filler is mannitol.

38. The composition according to claim 36 or 37, wherein The one or more disintegrants is croscarmellose sodium; or The one or more lubricants is sodium stearyl fumarate; or The one or more glidants is colloidal silicon dioxide.

39. The composition according to claim 36 or 37, wherein The one or more disintegrants is croscarmellose sodium; The one or more lubricants is sodium stearyl fumarate; and The one or more glidants is colloidal silicon dioxide.

40. The composition of claim 37, wherein the one or more disintegrants is croscarmellose sodium; or the one or more lubricants is magnesium stearate.

41. A pharmaceutical composition comprising an intragranular component comprising a composition according to any one of claims 27 to 40 and an extragranular component comprising one or more fillers, optionally one or more disintegrants, optionally one or more glidants and one or more lubricants.

42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component, or about 85% (w / w) of the intragranular component.

43. The pharmaceutical composition of claim 41 or 42, wherein the extragranular component comprises: about 10% to about 15% (w / w) of the one or more fillers, about 1% to about 2% (w / w) of the one or more disintegrants, about 0.5% to about 1.0% (w / w) of the one or more glidants, and about 0.5% to about 1.0% (w / w) of the one or more lubricants.

44. The pharmaceutical composition of claim 41 or 42, wherein the extragranular component comprises: about 5% to about 15% (w / w) of the one or more fillers and about 0.25% to about 0.75% (w / w) of the one or more lubricants.

45. The pharmaceutical composition according to claim 42, wherein The one or more fillers are selected from anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, co-treated microcrystalline cellulose, silicified microcrystalline cellulose and mesoporous silica; or If present, the one or more disintegrants is croscarmellose sodium; or The one or more lubricants are sodium stearyl fumarate or magnesium stearate; or If present, the one or more glidants is colloidal silicon dioxide.

46. ​​The pharmaceutical composition according to claim 43, wherein The one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose and mesoporous silicon dioxide; or The one or more disintegrants is croscarmellose sodium; or The one or more lubricants is sodium stearyl fumarate; or The one or more glidants is colloidal silicon dioxide.

47. The pharmaceutical composition of claim 44, wherein the one or more fillers are selected from microcrystalline cellulose and mannitol, and the one or more lubricants is magnesium stearate.

48. A pharmaceutical composition according to any one of claims 41 to 47, wherein the pharmaceutical composition comprises two fillers, optionally in a 1:1 to 2:1 ratio.

49. The pharmaceutical composition of claim 41, wherein the composition is a formulation of Table 16, Table 19, Table 20 or Table 24.

50. A tablet comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate and the solid dispersion according to any one of claims 1 to 21.

51. The tablet of claim 50, wherein the tablet comprises about 25% to about 60% (w / w) of the solid dispersion.

52. The tablet of claim 50, wherein the tablet comprises about 35% to about 55% (w / w) of the solid dispersion.

53. A tablet according to any one of claims 50 to 52, wherein the solid dispersion is according to any one of claims 10 to 21.

54. The tablet of claim 53, wherein the solid dispersion is according to claim 17.

55. A tablet according to any one of claims 50 to 54, wherein the tablet comprises about 40% to about 50% (w / w) of the solid dispersion, about 10% to 25% (w / w) MCC, about 20% to about 25% (w / w) mannitol, about 5% to about 6% (w / w) croscarmellose sodium, about 1% (w / w) colloidal silicon dioxide, and about 1% (w / w) sodium stearyl fumarate.

56. A tablet comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, magnesium stearate and the solid dispersion according to any one of claims 1 to 21.

57. The tablet of claim 56, wherein the tablet comprises about 35% to about 45% (w / w) of the solid dispersion, about 30% to about 42% (w / w) of MCC, about 13% to about 23% (w / w) of mannitol, about 2% to about 8% (w / w) of croscarmellose sodium, and about 0.5% to about 1.5% (w / w) of magnesium stearate.

58. The tablet of claim 50, wherein the tablet is a tablet of Table 16, Table 19, Table 20 or Table 24.

59. The tablet of any one of claims 50 to 58, wherein the tablet has a weight of about 100 mg to about 1 g.

60. The tablet of claim 59, wherein the tablet has a weight of about 100 mg, about 250 mg, about 500 mg, or about 750 mg.

61. The tablet of claim 59, wherein the tablet has a weight of 750 mg to 800 mg, 760 mg to 790 mg, 770 mg to 780 mg, 775 mg to 785 mg, or 780 mg to 790 mg.

62. A tablet according to any one of claims 50 to 61 further comprising a coating.

63. The tablet of claim 62, wherein the coating is a non-functional coating.

64. A tablet according to any one of claims 50 to 63, wherein the percentage of edradinam released at 45 minutes as measured by the dissolution method of Table 21 is not less than 85%.

65. A tablet according to any one of claims 50 to 64, wherein when stored in a sealed package at 25°C and 60% relative humidity for 6 months, 12 months, 18 months, 24 months or 36 months: (i) the amount of etradinam in the tablet is from about 90% to about 110% of the value measured at 0 months; (ii) less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5% total impurity amount (% area) as measured by HPLC; or (iii) Any combination of (i) to (ii).

66. The tablet according to any one of claims 50 to 65, wherein when the tablet is administered to a human in a fed or fasted state, the total exposure of the human to eltridinam is equivalent.

67. A method for preparing a solid dispersion comprising edradinam, the method comprising mixing edradinam, a polymer selected from HPMCAS and copovidone, and a solvent to produce a spray solution; and The spray solution is spray dried to produce the solid dispersion.

68. The method of claim 67, wherein the weight ratio of etradinam to polymer is from 25:75 to 40:

60.

69. The method of claim 67 or 68, wherein the spray solution is prepared at a solids loading of 8% to 13%.

70. The method of any one of claims 67 to 69, wherein the spray drying step comprises atomizing the spray solution into a drying chamber having an outlet temperature of about 38°C to about 46°C, a gas-to-liquid ratio of about 0.5 to about 0.7, and a relative saturation (total) of about 15% to about 23%.

71. The method of any one of claims 67 to 70, wherein the solid dispersion undergoes further drying to produce a dry powder having a moisture content of less than about 1% (w / w).

72. A method for treating a disease at least in part by adenosine A 2A Receptor (A 2A R) and / or adenosine A 2B Receptor (A 2B R)-mediated disease, disorder or condition comprising administering to a subject in need thereof the dosage form of claim 24 or claim 25, the pharmaceutical composition of any one of claims 41 to 49, or the tablet of any one of claims 50 to 66.

73. The method of claim 72, wherein the disease, disorder or condition is caused at least in part by A 2A R mediated.

74. The method of claim 72, wherein the disease, disorder or condition is caused at least in part by A 2B R mediated.

75. The method of claim 72, wherein the disease, disorder or condition is caused at least in part by the A 2A R receptor and the A 2B R receptors mediate both.

76. A method of treating cancer, the method comprising administering to a subject in need thereof the dosage form of claim 24 or claim 25, the pharmaceutical composition of any one of claims 41 to 49, or the tablet of any one of claims 50 to 66.

77. A method of treating cancer in a subject, the method comprising administering to the subject; to a subject in need thereof a dosage form according to claim 24 or claim 25, a pharmaceutical composition according to any one of claims 41 to 49, or a tablet according to any one of claims 50 to 66 and at least one additional therapeutic agent.

78. The method of claim 77, wherein the cancer is a solid tumor.

79. The method of claim 77, wherein the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer.

80. The method of claim 77, wherein the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

81. The method of claim 77, wherein the cancer is castration-resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial carcinoma.

82. The method of any one of claims 72 to 81, wherein the subject is administered a total daily dose of about 50 mg etrodinam to about 250 mg etrodinam, or about 50 mg etrodinam to about 150 mg etrodinam.

83. The method of claim 82, wherein a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg is administered to the subject.

84. A method of treating cancer in a subject concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor or in a subject who is a poor CYP3A4 metabolizer, the method comprising administering to a subject in need thereof a dosage form according to claim 24 or claim 25, a pharmaceutical composition according to any one of claims 41 to 49, or a tablet according to any one of claims 50 to 66.

85. A method for treating a patient with a cellulitis caused at least in part by adenosine A 2A Receptor (A 2A R) or adenosine A 2B Receptor (A 2B A method for treating a disease, disorder or condition mediated by CYP3A4 or P-gp, wherein the patient is concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor, or the subject is a CYP3A4 poor metabolizer, the method comprising administering a therapeutically effective amount of edradinam.

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