Milvexian Pharmaceutical Composition

Abstract

Solid pharmaceutical compositions of FXIa inhibitors for oral administration are provided.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 483,486, filed February 6, 2023, which is incorporated herein by reference in its entirety.

[0002] The technical field of this invention is pharmaceuticals, and in particular the formulation of FXIa inhibitors in oral solid dosage forms prepared by direct compression. [Background technology]

[0003] Oral anticoagulants are the primary means of preventing and treating venous and arterial thromboembolism. Direct oral anticoagulants have replaced vitamin K antagonists in many indications, but bleeding remains a major side effect. Fear of bleeding has led to withholding anticoagulants in eligible patients with atrial fibrillation and inappropriate use of low-dose direct oral anticoagulant therapy. (Steinberg et al., International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. Am Heart J 2017;194:132-40; Sanghai et al., Rates of potentially inappropriate dosing of direct-acting oral anticoagulants and associations with geriatric conditions among older patients with atrial fibrillation: The SAGE-AF study. J Am Heart Assoc 2020;9:e014108) Therefore, there is a need for safer oral anticoagulants.

[0004] Factor XI is a promising target for the development of new anticoagulants because it is a key promoter of thrombus growth but plays a supporting role in homeostasis (Weitz et al., Factor XI inhibition to uncouple thrombosis from hemostasis: JACC review topic of the week. J Am Coll Cardiol 2021;78:625-31).

[0005] Milvexian is a direct-acting, reversible, small molecule therapeutic agent that binds to and inhibits the active form of human coagulation factor XI (FXIa) with high affinity and selectivity. Milvexian has the formula (I): [ka] It is a macrocyclic compound having the structure shown below.

[0006] Milvexian has the chemical name (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one. Milvexian and methods for making milvexian are described in U.S. Pat. No. 9,453,018, the entire contents of which are incorporated herein by reference.

[0007] Amorphous solid dispersion (ASD) compositions of milvexian in one or more polymers prepared by solvent-based spray drying, capsules thereof, and roller-compressed tablets thereof prepared by dry granulation are described in WO 2020 / 210629, the entire contents of which are incorporated herein by reference.

[0008] Tablets are composed of one or more active compounds and tablet excipients (e.g., diluents, binders, lubricants, and disintegrants). The active compounds and excipients are generally provided in the form of powders that are easy to tablet, with or without pre-processing. Currently, there are three common methods for tablet preparation: (1) wet granulation, (2) dry granulation (slugging or roller compaction), and (3) direct compression (Williams et al., "Strategies to Address Low Drug Solubility in Discovery and Development", 2013, Pharmacol. Rev., V65, pp.215-499). All three methods have drawbacks.

[0009] Wet granulation is the most widely used method. Its popularity is due to the high probability that the resulting granules will meet all the physical requirements for producing a quality tablet. The main drawback is the large number of individual steps, time, and labor required to carry out the procedure. The steps required in wet granulation are: (1) weighing, (2) mixing, (3) granulation, (4) screening of the wet weight after granulation, (5) drying, (6) dry screening, (7) lubrication, and (8) compression.

[0010] Dry granulation is a commonly used method when tablet ingredients are moisture-sensitive or cannot withstand high temperatures during drying. Although this method eliminates many steps, it still involves (1) weighing, (2) blending, (3) dry granulation, (4) dry screening, (5) lubrication, and (6) compression. However, this method requires that the tablet ingredients inherently have sufficient binding or cohesive properties for dry granulation. Dry granulation is typically used to produce tablets containing active compounds that are water-soluble, heat- and moisture-sensitive, or lack sufficient cohesion. This technique is not suitable for low-dose active compounds because it is difficult to create a uniform blend of dry powders.

[0011] Direct compression (DC) involves directly compressing tablet ingredients into tablets without wet or dry granulation. The advantages of direct compression are uniformity of the blend and the minimal manufacturing steps required; the entire process requires only three steps: (1) weighing, (2) mixing, and (3) compression. This significantly reduces time, eliminating heat and moisture, dispersing primary particles, and ensuring physical stability. However, direct compression is typically limited to cases where the drug or active ingredient possesses the physicochemical properties (e.g., moldability and low adhesion) required to form a pharmaceutically acceptable tablet. For example, if most of the active compound has poor compressibility and / or is used in a small amount per unit dose, the active compound must be mixed with directly compressible excipients to be directly compressible.

[0012] Segregation is another potential issue with direct compression technology, arising from the risk of powder separation, or "demixing." This demixing can result in tablets with non-uniform composition. Therefore, when using direct compression technology, poor distribution of the active compound in the excipients can occur, and segregation of the active compound and excipients can be observed during the blending operation, and especially during all transfer operations, resulting in variations in the weight and active compound content of the tablets. Poor flowability of the powder mixture is generally an exacerbating factor. Segregation of the active compound and excipients in the powder mixture before tableting can be observed, especially when the particle sizes of the active compound and excipients differ significantly.

[0013] A further potential problem with direct compression technology is the possible size of the compressed tablets. When the amount of active ingredient is high, pharmaceutical formulators may choose to wet granulate the active ingredient with other excipients to form tablets of an acceptable size containing the desired amount of active ingredient. Because the wet granulation process imparts the desired physical properties to the tablet, the amount of filler, binder, or other excipients required for wet granulation is less than that required for direct granulation.

[0014] Furthermore, for manufacturability reasons, high-speed rotary machines are used. In direct compression processes, gravity-operated feeders are generally very sensitive to powder agglomerates or their aggregated solids. Therefore, the rheology of the powder mixture to be tableted is a determining factor in ensuring tablet weight uniformity and content uniformity. When large quantities of product are required, producing tablets using continuous manufacturing techniques offers significant advantages. In this situation, direct compression offers clear advantages over wet and dry granulation methods, as it involves fewer and simpler steps. However, there are obvious challenges with the properties of the active compound and tablet ingredients, which must be optimized and selected for continuous, high-speed production.

[0015] Therefore, there is a need for industrial techniques and pharmaceutical excipients that allow manufacturers to prepare tablets of FXIa inhibitors by direct compression, either by batch or continuous production. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] U.S. Patent No. 9,453,018 [Patent Document 2] International Publication No. 2020 / 210629 [Non-patent literature]

[0017] [Non-Patent Document 1] Steinberg et al., International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. Am Heart J 2017;194:132-40 [Non-patent document 2] Sanghai et al., Rates of potentially inappropriate dosing of direct-acting oral anticoagulants and associations with geriatric conditions among older patients with atrial fibrillation: The SAGE-AF study. J Am Heart Assoc 2020; 9:e014108 [Non-patent document 3] Weitz et al., Factor XI inhibition to uncouple thrombosis from hemostasis: JACC review topic of the week. J Am Coll Cardiol 2021;78:625-31 [Non-patent document 4] Williams et al., “Strategies to Address Low Drug Solubility in Discovery and Development”, 2013, Pharmacol. Rev., V65, pp.215-499 Summary of the Invention

[0018] the purpose There is a need for improved pharmaceutical formulations of active pharmaceutical ingredients (APIs) (e.g., the FXIa inhibitors described in U.S. Pat. No. 9,453,018). There is a particular need for pharmaceutical formulations with acceptable bioavailability, particularly in solid dosage forms prepared by direct compression processes. There is a further need for pharmaceutical formulations with acceptable bioavailability, particularly in solid dosage forms prepared by direct compression processes that are amenable to continuous manufacturing.

[0019] WO 2020 / 210629 describes a spray-dried amorphous solid dispersion ("spray-dried powder" ("SDP"))-based capsule formulation and roller-compacted (RC) tablets formed by dry granulation of the SDP containing Milvexin and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in a 3:1 weight ratio (Milvexin:HPMC-AS). In this application, the RC tablets exhibited a substantially reduced dissolution profile compared to the RC mixture in the capsule.

[0020] An object of the present invention is to provide a solid form of Milvexian, or a pharmaceutically acceptable salt form thereof, that exhibits significantly improved solubility and bioavailability relative to the amorphous form while maintaining acceptable physical and chemical stability.

[0021] It is an object of the present invention to provide an amorphous solid dispersion of Milvexian or a pharmaceutically acceptable salt form thereof that is kinetically stable in accordance with regulatory requirements.

[0022] It is an object of the present invention to provide particles of a spray-dried amorphous dispersion of milvexian in an HPMC-AS-MG grade polymer to improve physical stability (e.g., improvement in terms of particle brittleness compared to the spray-dried solid dispersion particles described in WO 2020 / 210629).

[0023] It is an object of the present invention to provide a pharmaceutical powder blend that has physical properties (e.g., free flow, compressibility, tapped and bulk densities, and particle size distribution) suitable for direct compression tableting manufacture.

[0024] An object of the present invention is to provide a tablet prepared by direct compression comprising a spray-dried amorphous solid dispersion of Milvexian in HPMC-AS-MG grade polymer in a 3:1 weight ratio (Milbexian:HPMC-AS-MG).

[0025] The object of the present invention is to provide a direct compression tablet comprising a spray-dried amorphous solid dispersion of Milvexian in HPMC-AS-MG grade polymer in a 3:1 weight ratio (Milbexian:HPMC-AS-MG), wherein the drug exposure of Milvexian more closely matches the drug exposure of the capsule formulation described in WO 2020 / 210629.

[0026] An object of the present invention is to reduce the amount of excipients in solid dosage forms (e.g., tablets) of Milvexian or a pharmaceutically acceptable salt form thereof.

[0027] It is an object of the present invention to provide an SDP formulation of HPMC-AS and Milvexian, or a pharmaceutically acceptable salt form thereof, which is highly soluble in an organic solvent or solvent mixture.

[0028] It is an object of the present invention to provide an SDP formulation of HPMC-AS and Milvexian, or a pharmaceutically acceptable salt form thereof, that is suitable for processing by solvent evaporation to provide a powder suitable for tableting by direct compression.

[0029] An object of the present invention is to provide an SDP formulation of HPMC-AS and Milvexian, or a pharmaceutically acceptable salt form thereof, which, by selection of an appropriate solvent or solvent mixture, can give a solution having suitable properties for solvent removal and solid formation.

[0030] It is an object of the present invention to provide an SDP formulation of HPMC-AS and Milvexian, or a pharmaceutically acceptable salt form thereof, which can be spray-dried from a feed solution to yield SDP particles with improved physical stability.

[0031] It is an object of the present invention to provide an SDP formulation of HPMC-AS and Milvexian, or a pharmaceutically acceptable salt form thereof, which can be spray-dried from a donor solution to yield SDP particles with improved downstream manufacturability as evidenced by improved compressibility (particle friability) and flowability.

[0032] It is an object of the present invention to provide an SDP formulation of HPMC-AS and Milvexian, or a pharmaceutically acceptable salt form thereof, in which the spray-dried particles have an improved rate or degradability.

[0033] The object of the present invention is to provide an SDP formulation of Milvexian with a high content of Milvexian in order to reduce the number of drug tablets.

[0034] An object of the present invention is to reduce the number of medication tablets for patients treated with Milvexian or a pharmaceutically acceptable salt form thereof.

[0035] An object of the present invention is to provide an SDP formulation of Milvexian or a pharmaceutically acceptable salt thereof, which can be spray-dried from a feed solution to obtain SDP particles suitable for tableting by a continuous manufacturing process.

[0036] An object of the present invention is to provide a tablet formulation of Milvexian as an SDP formulation of Milvexian or a pharmaceutically acceptable salt form thereof, which has equivalent or improved drug exposure compared to a capsule formulation.

[0037] An object of the present invention is to provide a tablet formulation of Milvexian as an SDP formulation of Milvexian or a pharmaceutically acceptable salt thereof, which is suitable for continuous production.

[0038] An object of the present invention is to provide a tablet formulation of Milvexian as an SDP formulation of Milvexian or a pharmaceutically acceptable salt form thereof, which is suitable for film coating.

[0039] An object of the present invention is to provide a tablet formulation of Milvexian as an SDP formulation of Milvexian or a pharmaceutically acceptable salt form thereof that is chemically and physically compatible with coating.

[0040] An object of the present invention is to provide a tablet formulation of Milvexian as an SDP formulation of Milvexian or a pharmaceutically acceptable salt form thereof, which has low inter-patient variability within the clinical dose range (FIGS. 11A-B).

[0041] The objective of the present invention is to reduce the effect of food on the bioavailability of Milvexian or its pharmaceutically acceptable salt form in tablets. See Example 5.

[0042] overview The present disclosure provides a solid pharmaceutical composition for oral administration comprising: (a) a spray-dried amorphous solid dispersion (SDP) consisting essentially of milbexian-free bodies and a pH-dependent enteric polymer; (b) a binder that is microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof; (c) an excipient that is lactose monohydrate; (d) a disintegrant; and (e) a lubricant; the milbexian-free bodies are present in an amount ranging from about 10.0% to about 40.0% by weight of the total weight of the solid pharmaceutical composition; and the binder and lactose monohydrate are present in a weight ratio (binder:lactose monohydrate) ranging from about 3:2 to about 3:1.

[0043] The present disclosure further provides a pharmaceutical tablet comprising: (1) a core comprising: (a) a spray-dried amorphous solid dispersion (SDP) consisting essentially of milvexian free form and a pH-dependent enteric polymer; (b) a binder selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof; (c) lactose monohydrate; (d) a disintegrant; and (e) a lubricant; and (2) a film coating surrounding the core; wherein the milvexian is present in an amount ranging from about 10% to about 40% by weight of the total weight of the core; and the binder and lactose monohydrate are present in the core at a weight ratio (binder:lactose monohydrate) ranging from about 3:2 to about 3:1.

[0044] The present disclosure further provides a spray-dried amorphous solid dispersion (SDP) consisting essentially of 75% by weight of milvexian and 25.0% by weight of a pH-dependent enteric polymer, the SDP having a particle size distribution median diameter D of 60 μm or less over a span of about 1.9. V,50 In another embodiment, the SDP has a particle size distribution median diameter D of 50 μm or less over a span of about 1.9. V,50 In some embodiments, the SDP has a particle size distribution median diameter D of 45 μm or less over a span of about 1.9. V,50 It has. [Brief explanation of the drawings]

[0045] [Figure 1] FIG. 1 shows a flow chart of the spray-drying manufacturing process for a spray-dried amorphous solid dispersion (SDP) containing Milvexian and HPMC-AS-MG in a weight ratio of 3:1. [Figure 2] FIG. 2 illustrates the dissolution profiles of Examples 7 and 8 from dissolution tests conducted in 900 mL dissolution medium at 37.0° C. using a paddle apparatus (USP Type 2, Ph.Eur., JP.) at a rotation speed of 75 rpm. [Figure 3] FIG. 3 shows the particle size distribution of Example 8 (Tablettose®) in Example 2C. [Figure 4]FIG. 4 shows the particle size distribution of Example 7 (Supertab 11SD) in Example 2C. [Figure 5] FIG. 5 shows the dissolution profiles of Examples 9 (blue), 7 (red), and 10 (green) in Example 2D from quality control dissolution tests conducted in 900 mL dissolution medium at 37.0° C. using a paddle apparatus (USP Type 2, Ph.Eur., JP.) at a rotation speed of 75 rpm. [Figure 6] FIG. 6 shows the dissolution profiles of Examples 9 (blue), 7 (red), and 10 (green) in Example 2D from dissolution tests SGF FaSSIF conducted in 900 mL dissolution medium at 37.0° C. using a paddle apparatus (USP Type 2, Ph.Eur., JP.) at a rotation speed of 75 rpm. [Figure 7] FIG. 7 shows a manufacturing process flow chart for Milvexian 25 mg oral tablet core and 100 mg oral tablet core. [Figure 8] FIG. 8 shows a manufacturing process flowchart for Milvexian 25 mg oral film-coated tablets and 100 mg oral film-coated tablets. [Figure 9] 9 shows the PXRD pattern of the SDP prepared in Example 1e. The PXRD pattern demonstrated that milvexian exists in amorphous form in the SDP. [Figure 10] Figure 10 shows the dissolution profiles of 25 mg and 100 mg film-coated tablets after 3 months of storage at 40°C / 75% RH from quality control dissolution tests conducted in 900 mL dissolution medium at 37.0°C using a paddle apparatus (USP Type 2, Ph.Eur., JP.) at a rotation speed of 75 rpm. [Figure 11A] 11A shows the plasma concentration of milvexin as a function of time after administration of a film-coated direct compression tablet of the present disclosure compared to the plasma concentration of milvexin as a function of time after administration of a capsule containing milvexin. See the bioavailability study described in Example 5. [Figure 11B]11B shows the plasma concentration of milvexin as a function of time after administration of a film-coated roller-compressed tablet compared to the plasma concentration of milvexin as a function of time after administration of a capsule containing milvexin. See the bioavailability study described in Example 5. [Figure 12A] 12A shows the plasma concentration of milvexin as a function of time after administration of a film-coated direct compression tablet of the present disclosure to fasting patients compared to the plasma concentration of milvexin as a function of time after administration of a film-coated direct compression tablet of the present disclosure to fed patients. See the food effect study described in Example 5. [Figure 12B] 12B shows the plasma concentration of milvexin as a function of time after administration of a film-coated roller-compressed tablet of the present disclosure to fasting patients, compared to the plasma concentration of milvexin as a function of time after administration of a film-coated roller-compressed tablet of the present disclosure to fed patients. See the food effect study described in Example 5. [Figure 13A] 13A shows the plasma concentration of milvexin as a function of time on day 1 after BID administration of film-coated direct compression tablets (2 x 100 mg) of the present disclosure compared to the plasma concentration of milvexin as a function of time on day 1 after BID administration of milvexin-containing capsules (2 x 100 mg). See Example 5. [Figure 13B] 13B shows the plasma concentration of milvexin as a function of time on day 5 after BID administration of film-coated direct compression tablets (2 x 100 mg) of the present disclosure compared to the plasma concentration of milvexin as a function of time on day 5 after BID administration of milvexin-containing capsules (2 x 100 mg). See Example 5. [Figure 13C] 13C shows the day 1 plasma concentration of milvexin as a function of time after BID administration of a film-coated direct compression tablet (1 x 25 mg) of the present disclosure compared to the day 1 plasma concentration of milvexin as a function of time after BID administration of a capsule (1 x 25 mg) containing milvexin. See Example 5. [Figure 13D] 13D shows the plasma concentration of milvexin as a function of time on day 5 after BID administration of a film-coated direct compression tablet (1 x 25 mg) of the present disclosure compared to the plasma concentration of milvexin as a function of time on day 5 after BID administration of a capsule (1 x 25 mg) containing milvexin. See Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0046] definition As used herein, the term "about" refers to an actual given value and is intended to refer to an approximation of such given value that can be reasonably estimated based on ordinary skill in the art (including approximations based on experimental and / or measurement conditions and tolerances for such given value). As used herein, the term "about" refers to 0%, ±5.0%, ±10.0%, ±15.0%, ±20.0%, and ±25.0% (inclusive) of the stated numerical value. In a preferred embodiment, the term "about" used herein refers to ±10.0% of the stated numerical value. For example, the phrase "about 8" refers to a value of 7.2 to 8.8 (inclusive); as another example, the phrase "about 8%" refers to a value of 7.2 to 8.8 (inclusive).

[0047] All ranges, where present, are inclusive and combinable. For example, if a range of "1 to 5" is recited, the recited range should be interpreted as including the ranges "1 to 5," "1 to 4," "1 to 3," "1 to 2 and 4 to 5," "1 to 3 and 5," etc. Furthermore, where a list of alternatives is expressly provided, such list may also encompass embodiments in which any of the alternatives is excluded. For example, if a range of "1 to 5" is recited, such a recitation may encompass situations in which any of 1, 2, 3, 4, or 5 is excluded; thus, a recitation of "1 to 5" may encompass "1 and 3 to 5, but not 2," or simply "not including 2."

[0048] The term "amorphous" refers to a solid that lacks any long-range molecular order. The term "amorphous" also refers to a solid that contains crystalline and amorphous portions. The term "amorphous" also encompasses semi-crystalline solids.

[0049] In the context of the present invention, the term "amorphous solid dispersion" or "ASD" is used, although some authors in the literature use the term "solid solution", which has the same meaning as solid dispersion in the context of the present invention. In the following, the various types of solid dispersions (solid solutions, glass solutions, glass suspensions, amorphous precipitates in crystalline carriers, eutectics or monotectics, compound or complex formations, and combinations thereof) will be collectively referred to as solid dispersions.

[0050] In the context of the present invention, the term "crystallization" refers to crystallization when the active ingredient is not crystalline, and / or recrystallization when the active ingredient is crystalline, then transitions to an amorphous form, stabilizes in the amorphous form, and then crystallizes again.

[0051] The term "solid dispersion" defines a solid-state (as opposed to liquid or gaseous) system containing components of the present composition, in which one of the components is more or less uniformly dispersed in one or more other components (which may include additional pharmaceutically acceptable additives, e.g., plasticizers, preservatives, etc., as commonly known in the art). When the dispersion of the components is described as such that the system is chemically and physically uniform or homogeneous, or thermodynamically composed of a single phase, such a solid dispersion is called a "solid solution." Solid solutions are preferred physical systems because the components are typically rapidly bioavailable in the adult recipient. This advantage is perhaps easily explained by the ability of such solid solutions to form a liquid solution upon contact with a liquid solvent (e.g., gastrointestinal fluids). The ease of dissolution may be explained, at least in part, by the fact that less energy is required for a component to dissolve from a solid solution than for a component to dissolve from a crystalline or microcrystalline solid phase.

[0052] The solid solution may be a continuous solid solution in which Milvexian or a pharmaceutically acceptable salt form thereof is molecularly dispersed within a matrix formed by an orally pharmaceutically acceptable polymer.

[0053] The solid solution may be a discontinuous solid solution in which milvexian or a pharmaceutically acceptable salt form thereof is molecularly dispersed within a matrix formed by an oral pharmaceutically acceptable polymer, the discontinuous solid solution being partially miscible and comprising two phases despite the milvexian being molecularly dispersed.

[0054] The solid solution may be a substituted solid solution in which milvexian or a pharmaceutically acceptable salt form thereof is molecularly dispersed within a matrix formed by an oral pharmaceutically acceptable polymer. In this substituted solid solution, the difference between the diameter of the milvexian molecule and the diameter of the matrix (oral pharmaceutically acceptable polymer) is less than 15%. In this case, the milvexian and the matrix are substituted. This substituted solid solution may be continuous or discontinuous. When it is discontinuous, two phases exist, even though the milvexian is molecularly dispersed.

[0055] The solid solution may be an interstitial solid solution in which milvexian or a pharmaceutically acceptable salt form thereof is molecularly dispersed within a matrix formed by an oral pharmaceutically acceptable polymer, in which the diameter of the milvexian molecule is less than 59% of the diameter of the matrix (oral pharmaceutically acceptable polymer).

[0056] The term "solid dispersion" also includes dispersions that are less uniform throughout than solid solutions. Such dispersions are not chemically and physically uniform or contain two or more phases. For example, the term "solid dispersion" also refers to systems in which an amorphous, microcrystalline, or crystalline drug compound and / or an amorphous, microcrystalline, or crystalline oral pharmaceutically acceptable polymer, and optionally an amorphous, microcrystalline, or crystalline surfactant, have domains or small regions that are more or less uniformly dispersed within another phase that includes the solid solution containing the drug compound, polymer, and optionally the surfactant. The domains are regions within the solid dispersion that are distinct by some physical characteristic, small size, and are uniformly and randomly distributed within the solid dispersion.

[0057] The term "flow" refers to the plastic deformation of a bulk solid under an applied load (e.g., the fracture of a pre-compressed bulk solid sample). The amount of load required to flow is a measure of the flowability.

[0058] As used herein, the term "Flow Function Coefficient (FFC)" is frequently used to classify and compare powders according to their flowability (Svarovsky, 1987). A high FFC value indicates good flowability (see table below). The phrase "high flow behavior" usually means that the bulk solid flows easily, i.e., is not very stiff and does not require any flow-promoting devices. A product that experiences flow restrictions or that stiffens during storage or transportation is "poorly flowable." [Table 1]

[0059] The term "bulk density" is defined as the weight of a number of particles of a substance divided by the total volume occupied by the particles. The total volume includes particle volume, intermolecular void volume, and internal pore volume. (Powder Bulk Density - Bulk Solids density - Bulk Powder Properties - Powder Loose Density - Powder tapped density - PowderProcess.net." www.powderprocess.net. Retrieved 2018-02-22.)

[0060] As used herein, the "tap density" of a powder is the ratio of the weight of the powder to the volume it occupies after being tapped a predetermined number of times in various ways. Tap density is calculated using the formula: Tap density (g / mL) = M / V f " (where M = weight (g), and V f = tapped volume (mL). The tapped density of a powder represents the closest packing of the powder - United States Pharmacopoeia <616> According to [theoretically], tapping continues until the volume no longer changes. Tapped and untapped (bulk) densities are determined by calibrating a small cuvette of known volume, then filling the cuvette with a small amount of powder (bulk density) and tapping it vertically 50 times on a padded tabletop (tapped density). See Ferreira et al., Multivariate Analysis in the Pharmaceutical Industry, Academic Press, 2018, Chapter 10, pp. 235-267.

[0061] The term "Hausner ratio" refers to the ratio of tapped density to bulk density. The Hausner ratio is suggested to provide a numerical value related to the flowability of a powder. [Table 2]

[0062] The term "pH-dependent enteric polymer" refers to a polymer that is stable and insoluble in the stomach and upper intestine, but dissolves immediately upon reaching the target site in the intestine, releasing the contained active pharmaceutical ingredient (API). The solubility of the pH-dependent enteric polymer depends on the acidic or basic conditions in the intestine. In some embodiments, the SDP particles consist essentially of milvexian and a pH-dependent enteric polymer in a 3:1 weight ratio as described herein, and dissolve primarily in the small intestine. In other embodiments, the SDP particles consist essentially of milvexian and a pH-dependent enteric polymer in a 3:1 weight ratio as described herein, and begin to dissolve in the small intestine. The solubility of pH-dependent enteric polymers is measured in USP phosphate buffer according to the manufacturer's product catalog (https: / / www.setylose.com / fileadmin / download_pfmd / 49.pdf) or by the solubility test described by Sarabu et al. in Hypromellose Acetate Succinate based Amorphous Solid Dispersions via Hot Melt Extrusion: Effect of Drug Physicochemical Properties, Carbohydr Polym. 2020 April 01;233:115828.

[0063] The term "solid pharmaceutical composition for oral administration" as used herein includes pharmaceutical powder mixtures (e.g., suitable for tableting or encapsulation), pharmaceutical powder mixtures for direct oral administration, as well as pharmaceutical dosage forms (e.g., tablets, capsules) formed from such powder mixtures.

[0064] As used herein, the term "milvexian-free form" refers to milvexian that is not in a salt form or a solvated form (i.e., unsolvated milvexian-free form).

[0065] As used herein, the term "aqueous medium" refers to a liquid solvent containing water. Aqueous media include water, fruit juice (e.g., apple juice), vegetable juice, saline, buffer solutions, and the like.

[0066] As used herein, the terms "wt. %," "% by weight," and "% (wt. / wt.)" refer to the weight of a specified component as a percentage of the weight of the specified composition. For example, if a composition is described as containing 10.0% by weight (10.0 wt. %) (or 10.0% by weight) of a bulking agent, 10.0% of the weight of the composition is attributable to the bulking agent. That is, for every 100 g of the composition, 10 g is the bulking agent.

[0067] Spray-dried amorphous solid dispersions (SDP) The pharmaceutical compositions described herein comprise an amorphous solid dispersion of free milbexian.

[0068] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a spray-dried amorphous solid dispersion of milbexian free form.

[0069] In pharmaceutical development, the most frequent challenges in preparing amorphous solid dispersions (ASDs) include, but are not limited to, (1) selecting an appropriate manufacturing technology; (2) physical stability of the drug and amorphous solid dispersion; (3) the type and amount of polymer matrix; (4) the ratio of API to polymer matrix that provides stability and a sufficient API release rate; and (5) the physical and chemical stability of the amorphous solid dispersion and the incorporated API. (Williams et al., supra; Anane-Adjei et al., “Amorphous solid dispersions: Utilization and challenges in preclinical drug development within AstraZeneca,” 2022, Int. J. Pharm., V614 + He and Ho, “Amorphous Solid Dispersions - Utilization and Challenges in Drug Discovery and Development,” 2015, J. Pharm Sci., V104, pp. 3237-3258)

[0070] A further obstacle in the development of amorphous solid dispersions is that the stated challenges must be addressed simultaneously and based on limited information due to the interplay of challenges / options (i.e., the choice of polymer matrix can influence the manufacturing technique and stability choices, and vice versa).

[0071] The physical properties of SDP particles prepared by the spray-drying process depend on a) the API polymorph selection, b) the solvent system used in the manufacturing process, c) the polymer matrix used, and d) the manufacturing process. The methods and excipients selected for the present invention are known to those skilled in the art and in some respects contrast with commonly known methods and excipients for preparing amorphous solid dispersions (ASDs).

[0072] During the development of the SDP for milvexian and HPMC-AS, various polymorphs of milvexian and various solvent systems for the spray-dried solution were evaluated. Ultimately, the crystalline P1.acetone form of milvexian (acetone solvate) was selected along with an 80 / 20 wt / wt% dichloromethane (DCM) / MeOH solution as the spray-drying solvent system, resulting in an amorphous solid dispersion of amorphous milvexian free form in an HPMC-AS matrix.

[0073] a) Milvexian polymorphic selection Milbexian compound (API) can exist in several polymorphs with different solubilities and stabilities in organic solvents, such as amorphous forms; crystalline forms of free milbexian (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form H, Form I, and Form J); and crystalline forms of acetone solvates (P1.acetone). In principle, any of these polymorphs or solvates can be used to prepare SDPs. Preferred polymorphs or solvates are those that are most soluble in solvents useful for spray drying.

[0074] The crystalline acetone solvate of milbexian (P1. acetone) can be prepared, for example, according to the process described in WO 2022 / 081473.

[0075] Amorphous milbexian can be prepared, for example, according to the spray-drying procedure of Example 1, as described in International Publication No. 2020 / 210629 (incorporated herein by reference in its entirety). Amorphous milbexian is characterized by the absence of any crystalline peaks in powder X-ray diffraction. Amorphous milbexian is also characterized by a temperature-modulated differential scanning calorimetry (mDSC) endotherm with an onset temperature of 160°C and a glass transition peak temperature of approximately 163°C.

[0076] Milbexian-free crystalline forms (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form H, Form I, and Form J) can be prepared, for example, as described in International Publication No. 2021 / 207659 (the entire contents of which are incorporated herein by reference) according to the procedure of Example 1. For example, Milbexian-free crystalline Form A has at least one peak selected from 5.0, 5.3, 8.2, 10.0, 10.7, 10.9, 13.0, 14.6, 15.1, 161.1, 17.2, 190.0, 19.5, 20.5, 21.5, 22.9, and 24.5 (2θ degrees) ± 0.2 (2θ degrees) in a powder X-ray diffraction pattern (CuKα λ = 1.541874 A at room temperature), and the PXRD pattern of Form J is measured at room temperature. The milbeczian-free crystalline Form J has at least one peak selected from the following in a powder X-ray diffraction pattern (CuKα λ=1.541874 A at room temperature): 7.4±0.2, 9.0±0.2, 11.3±0.2, 11.7±0.2, 12.5±0.2, 14.8±0.2, 15.1±0.2, 15.5±0.2, 16.1±0.2, 17.6±0.2, 18.4±0.2, 18.8±0.2, 19.3±0.2, 23.3±0.2, 24.4±0.2, 26.2±0.2, 26.6±0.2, 27.7±0.2, 28.2±0.2, and 28.8±0.2 (2θ degrees), the PXRD pattern of Form J measured at room temperature. Crystalline Forms A-J were also characterized by solid-state nuclear magnetic resonance spectroscopy (ssNMR), infrared spectroscopy (IR), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and thermogravimetric analysis (TGA).

[0077] Another crystalline form of milbexian acetone solvate (1:1 molar ratio of milbexian:acetone, P1.acetone) can be prepared according to the procedure of Example 1 described in WO 2022 / 081473, the entire contents of which are incorporated herein by reference. P1. Acetone form is 8.2321, 10.0872, 14.3163, 16.1898, 16.5524, 17.5729, 18.6786, 19.1386, 19.4389, 19.5888, 20.0236, 21.2896, 21.5821, 22.0945; 22.4947, 23.5085, 23.8930, 24.9851, 25.0767, 25.4275, 25.7772, 26.4620, 26.6794, 27.1315, 27.3484, 36.4135, 36.7245, 38.9401, 40.1133, 43.2735, 43.4015, 43.7011, 44.9886, 46.1717, 48.4294, 49.2681 (2θ degrees) ±0.2 (2θ degrees). The crystalline P1.acetone form was also characterized by infrared spectroscopy (IR).

[0078] The P1.acetone form has been found to be one of the most stable polymorphs. Typically, the free form of milbexian is preferred for spray-drying because it lacks a solvent. In some embodiments, the crystalline acetone solvate of milbexian (P1.acetone) prepared according to WO 2022 / 081473 or crystalline Form J prepared according to WO 2021 / 207659 are preferred as starting materials for the production of spray-dried amorphous solid dispersions, instead of the amorphous form of milbexian or other known crystalline forms, due to their excellent morphology and robust crystallization process. Other polymorphs with sufficient solubility in organic solvent systems (e.g., crystalline Form J of the free form of milbexian, which has a solubility of 230 mg / mL in 80 / 20% w / w DCM / MeOH, and crystalline Form A of the free form of milbexian, which has a solubility of 255 mg / mL in 80 / 20% w / w DCM / MeOH) can also be used as starting materials for SDP production.

[0079] b) Solvent system selection for feed solution preparation In early efforts to screen solvent systems, aqueous media such as a mixture of acetone and water (acetone / water), in various ratios (wt / wt%), were found to be useful for preparing feed solutions of milvexian and HPMC-AS polymer for the spray-drying process. In the acetone / water (90 / 10 wt / wt%) solvent system, the solubility of milvexian was found to be 36 mg / mL at room temperature and 70 mg / mL at 49°C. The above milvexian feed solution exhibited chemical and physical stability at 50°C for at least two weeks.

[0080] Surprisingly, an organic solvent system containing a mixture of dichloromethane (DCM) and methanol in a ratio of 80% wt.:20% wt., respectively, increased the stability of Milvexian at room temperature by more than fivefold, i.e., to >200 mg / mL, for various Milvexian polymorphs. This increased stability, combined with the selected 3:1 weight ratio (Milvexian:HPMC-AS), allowed the soluble weight (dry weight of HPMC-AS and Milvexian relative to the total weight of the feed solution) in the feed solution to be at least 15.0 wt.% at room temperature. This concentration is substantially higher than that typically used in ASD spray-drying feed solutions. Milvexian and HPMC-AS feed solutions dissolved in an organic solvent system of DCM / MeOH (80 / 20 wt. / wt.) were stable at room temperature for up to 14 days, and the viscosity was high enough to form large particles suitable for direct compression. The increased stability of milvexian allows for a high melt weight, resulting in a directly compressible SDP powder with suitable flowability and bulk / tap density during spray drying. (See "Spray drying formulation of amorphous solid dispersions," Singh and Van den Mooter, 2016, Advanced Drug Delivery Reviews, V100, pp. 27-50; "Pharmaceutical amorphous solid dispersions: A review of manufacturing strategies," Bhujbal et al., 2021, Acta Pharmaceutica Sinica B, V11(8), pp. 2506-2536; and "Efficient production of solid dispersions by spray drying solutions of high solid content using a 3-fluid nozzle," Kauppinen et al., 2018, European Journal of Pharm and Biopharm, V123, pp. 50-58.) See Example 1.

[0081] In one embodiment, a feed solution having a 15 wt% solution weight (dry weight of Milvexian and HPMC-AS relative to the total weight of the feed solution) in an 80 / 20 wt / wt% DCM / methanol mixture is spray-dried to provide a powder containing micron particles with a median size of 38 μm, a span of 1.67, a bulk / tap density of 0.31 / 0.38 g / mL, and a flow function coefficient of 9.3, indicating that the powder flows easily and is nearly free-flowing (flow function coefficient (FFC) >10). This is a significant improvement over previous powders, which had FFCs in the range of 4-5. The increased particle size, bulk / tap density, and greatly improved flowability mean that the Milvexian / HPMC-AS (3:1 wt) SDP powder can be directly blended with tablet excipients, directly compressed, and fed directly to blending equipment in continuous production without pre-treatment or pre-blending with glidants.

[0082] DCM / methanol mixed solvent is superior to acetone / water mixed solvent due to its higher API solubility at room temperature.

[0083] The methods described herein for preparing SDP do not result in detectable amounts of impurities (eg, 2-methoxy-1-propane and 2,2-dimethoxypropane).

[0084] c) pH-dependent enteric polymer selection In some embodiments, the present disclosure is directed to an amorphous solid dispersion (ASD) consisting essentially of milvexian and a pH-dependent enteric polymer. In some embodiments, the present disclosure is directed to an SDP comprising milvexian and a pH-dependent enteric polymer.

[0085] In certain embodiments, the present disclosure provides SDP particles of milvexian in HPMC-AS polymer that are suitable for direct compression tableting processes and have improved physical properties (e.g., free flow as measured by large particle size, bulk and tapped densities, and flow function coefficients, and improved particle friability / compressibility).

[0086] In some embodiments, the present disclosure provides SDP particles of pH-dependent enteric polymers and Milvexian. In some embodiments, the SDP particles can be further combined with pharmaceutically acceptable excipients (e.g., binders, fillers, diluents, flavorings, colorings, lubricants, glidants, flavoring agents, preservatives, adsorbents, or sweeteners).

[0087] In some embodiments of the SDP particles of the present disclosure, the pH-dependent enteric polymer is selected from cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS) LF, LG, MF, MG, or HF grades (e.g., Aqoat®), polyvinyl acetate phthalate (PVAP) (e.g., Sureteric® and Opadry®, and shellac resins (e.g., SSB® Aquagold)), or polyvinylpyrrolidone (PVP).

[0088] In some embodiments, the pH-dependent enteric polymer dissolves in aqueous media at a pH of about 5.5 to about 6.8, e.g., about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8.

[0089] In preferred embodiments of the SDPs described herein, the pH dependent enteric polymer dissolves in aqueous media at a pH of 6.0 or greater, such as a pH of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, and the like.

[0090] In a preferred embodiment of the SDP described herein, the pH-dependent enteric polymer that dissolves in aqueous media at a pH of 6.0 or greater is selected from HPMC-AS, PVP, or any combination thereof.

[0091] In a preferred embodiment of the SDP described herein, the enteric polymer that dissolves in aqueous media at a pH of 6.0 or greater is selected from HPMC-AS-MG, HPMC-AS-LG.

[0092] In a more preferred embodiment of the SDP described herein, the pH-dependent enteric polymer that dissolves in aqueous media at a pH of 6.0 or greater is HPMC-AS.

[0093] In a further preferred embodiment, the HPMC-AS is selected from the group consisting of HPMC-AS-LG, HPMC-AS-MG, HPMC-AS-HG, HPMC-AS-LF, HPMC-AS-MF, HPMC-AS-HF, HPMC-AS-LMP, HPMC-AS-MMP, HPMC-AS-HMP, Affinisol (登録商標) HPMC-AS 716, Affinisol (登録商標) HPMC-AS 912, or Affinisol (登録商標) HPMC-AS 126.

[0094] In a further preferred embodiment, the HPMC-AS is selected from HPMC-AS-LG, HPMC-AS-MG, or HPMC-AS-HG.

[0095] In a most preferred embodiment, the HPMC-AS is HPMC-AS-MG.

[0096] In some embodiments of the SDPs described herein, the milbexian-free form and the pH-dependent enteric polymer are included in any weight ratio (weight / weight; milbexian-free form:pH-dependent enteric polymer).

[0097] In some embodiments of the SDPs described herein, the milvexian free form and the pH-dependent enteric polymer are included in a weight ratio (weight / weight; milvexian:pH-dependent enteric polymer) selected from about 1:1, about 1:3, or about 3:1.

[0098] In some embodiments of the SDPs described herein, the milvexian free form and the pH-dependent enteric polymer are included in a weight ratio (weight / weight; milvexian:pH-dependent enteric polymer) selected from 1:1, 1:3, or 3:1.

[0099] In a preferred embodiment of the SDP described herein, the milbexian free form and the pH-dependent enteric polymer are included in a weight ratio of about 3:1.

[0100] In another preferred embodiment of the SDP described herein, the milbexian free form and the pH-dependent enteric polymer are included in a weight ratio of 3:1.

[0101] In a preferred embodiment of the SDP described herein, the free milbexian and the pH-dependent enteric polymer that dissolves in an aqueous medium at a pH of 6.0 or greater are contained in a weight ratio (weight / weight; milbexian:pH-dependent enteric polymer) selected from about 1:1, about 1:3, or about 3:1.

[0102] In other preferred embodiments of the SDP described herein, the free milbexian and the pH-dependent enteric polymer that dissolves in an aqueous medium at a pH of 6.0 or greater are contained in a weight ratio (weight / weight; milbexian:pH-dependent enteric polymer) selected from 1:1, 1:3, or 3:1.

[0103] In another preferred implementation of the SDP described herein, the free milvexin and the pH-dependent enteric polymer that dissolves in aqueous media at a pH of 6.0 or greater are included in a weight ratio of about 3:1 (weight / weight; milvexin:pH-dependent enteric polymer).

[0104] In another preferred implementation of the SDP described herein, the free milbexian and the pH-dependent enteric polymer that dissolves in aqueous media at a pH of 6.0 or greater are included in a weight ratio of 3:1 (weight / weight; milbexian:pH-dependent enteric polymer).

[0105] In a more preferred implementation of the SDP described herein, the milvexian free form and HPMC-AS MG are included in a weight ratio (wt / wt; milvexian:polymer) selected from about 1:1, about 1:3, or about 3:1.

[0106] In a more preferred implementation of the SDP described herein, the milvexian free form and HPMC-AS MG are included in a weight ratio (wt / wt; milvexian:polymer) selected from 1:1, 1:3, or 3:1.

[0107] In a more preferred implementation of the SDP described herein, the milvexian free form and HPMC-AS MG are included in a weight ratio (wt / wt; milvexian:polymer) of about 3:1.

[0108] In a more preferred implementation of the SDP described herein, the milvexin free form and HPMC-AS MG are included in a weight ratio (wt / wt; milvexin:polymer) of 3:1.

[0109] In some embodiments, the present disclosure provides an SDP prepared by the methods described herein, the SDP having the components set forth in Table 1 below. [Table 3]

[0110] HPMC-AS, or hydroxypropyl methylcellulose acetate succinate, or hypromellose acetate succinate, is a mixture of acetic acid and the monosuccinic acid ester of hydroxypropyl methylcellulose (IUPAC name: cellulose, 2-hydroxypropyl methyl ester, acetate, hydrogen butanedioate). HPMC AS is an enteric polymer commercially available in three grades: LG, MG, and HG. Important properties of HPMC AS include a high Tg (119°C-122°C), amphiphilicity, and insolubility in water and simulated gastric fluid, with melt viscosities of approximately 2.4-3.6 mPa.S. Different grades are available, distinguished by the degree / percentage of substituents (acetyl groups, succinoyl groups) and particle size (micronized or fine (F), and granular (G)). Because HPMC-AS dissolves during preparation of the amorphous solid dispersions of the present invention, particle size (F or G) is not a significant factor. HPMC-AS grades are individually named by the manufacturer. HPMC-AS (AQOAT) was purchased from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Multiple grades of HPMC-AS are available. According to the manufacturer's report, each grade dissolves in McIlvaine buffer at the following pH values: -LF and -LG, 5.5 g; -MF and -MG, 6.0 g; and -HF and -HG, 6.8 g. However, the -LF and -LG grades dissolve sparingly in aqueous solutions at pH > about 4.8, the -MF and -MG grades at pH > about 5.2, and the -HF and -HG grades at pH > about 5.7, forming colloidal solutions (see Sarabu et al., cited above).

[0111] For example, the AQOAT® brand of AHPMC-AS by Shin-Etsu Chemical Co., Ltd. defines these grades as set forth in Table 2 below. [Table 4]

[0112] MW of AQOAT® Brand HPMC-AS Polymer * Molecular weight data was obtained from Fukasawa et al., Chem. Phar. Bull., 2004, vol. 52, pp. 1391-1393. Mn ** :Number average molecular weight

[0113] Additional grades from Shin-Etsu Chemical Co., Ltd. include AQOAT® HPMC-AS:HPMC-AS-LMP, HPMC-AS-MMP, and HPMC-AS-HMP, which have median particle sizes of about 70 to about 300 pm.

[0114] Dow® is a registered trademark of Dow Corporation under the brand name Affinisol®, as shown in Table 3. (登録商標) and define the grades of HPMC-AS with numerical codes. [Table 5]

[0115] Thus, the HPMC-AS in the amorphous solid dispersion with Milvexian may be, but is not limited to, HPMC-AS-LG, HPMC-AS-MG, HPMC-AS-HG, HPMC-AS-LF, HPMC-AS-MF, HPMC-AS-HF, HPMC-AS-LMP, HPMC-AS-MMP, HPMC-AS-HMP grades listed in Table 2 above; Affinisol® listed in Table 3 above. (登録商標) HPMC-AS 716, Affinisol (登録商標) HPMC-AS 912, and Affinisol (登録商標) HPMC-AS 126 grade may be selected.

[0116] d) Manufacturing process selection The selection of manufacturing techniques for amorphous solid dispersions is as follows: API melting point Polymer glass transition temperature (Tg) Decomposition temperature of API and polymer Solubility of APIs in organic / aqueous media for solvent-based manufacturing processes API crystallization mechanism Solubility of polymers in organic / aqueous media for solvent-based manufacturing processes It depends on several factors and considerations, including:

[0117] The SDP of the present disclosure can be manufactured using any suitable method. In some embodiments, the SDP of the present disclosure is prepared by spray drying (a "spray-dried SDP").

[0118] Here, the API melting point of Milvexin is generally above 248°C (depending on the specific polymorph), and when it exists as an API-solvate, the desolvation temperature is approximately 180°C. Because most polymers decompose in the range of 175-250°C, melt-based manufacturing techniques were not feasible due to the high manufacturing temperatures. Therefore, manufacturing techniques were limited to solvent-based techniques.

[0119] In some embodiments, the SDPs disclosed herein are prepared by spray drying a solution comprising milvexian, a pH-dependent enteric polymer, and an organic solvent.

[0120] In some embodiments, the SDPs disclosed herein are prepared by spray drying a solution formed by dissolving milvexian and a pH-dependent enteric polymer in a mixture of dichloromethane / methanol.

[0121] In some embodiments, the SDP disclosed herein is prepared by spray drying a solution formed by dissolving Milvexian P1. acetone crystals and a pH-dependent enteric polymer in a mixture of dichloromethane / methanol.

[0122] In some embodiments, the SDP disclosed herein is prepared by spray drying a solution formed by dissolving Milvexian P1. acetone crystalline and hypromellose acetate succinate (HPMC-AS) in a mixture of dichloromethane / methanol.

[0123] In some embodiments, the SDP disclosed herein is prepared by spray drying a solution formed by dissolving Milvexian P1. acetone crystalline and hypromellose acetate succinate (HPMC-AS) in a mixture of dichloromethane / methanol (80 / 20% w / w).

[0124] In some embodiments, the SDP disclosed herein is prepared by spray drying a solution formed by dissolving Milvexian P1. acetone crystalline form and hypromellose acetate succinate (HPMC-AS) in a 3:1 weight / weight ratio (based on Milvexian free form) in a mixture of dichloromethane / methanol (80 / 20% w / w).

[0125] In embodiments where a solvate of milbexian is used as the API source (e.g., acetone in P1. acetone crystalline), the solvate is removed during the spray drying process, so that milbexian in the ASD is in free form.

[0126] In some embodiments, the process for preparing the amorphous solid dispersion comprises (i) dissolving milbexian acetone solvate and HPMC-AS MG in a mixture of 80 / 20 (wt / wt) DCM / MeOH at a dissolved solids concentration of 15 wt%, and (ii) feeding the solution at 20°C and spray-drying the solution to create a large droplet size.

[0127] Properties of SDP Milvexian SDP must have properties (e.g., suitable flowability) that are suitable for continuous supply and continuous production. The flowability of a powder can be affected by its cohesion, moisture absorption, specific surface area, and particle size.

[0128] The SDP prepared by the method described herein has good flowability, good compressibility, and low sticking property; properties that are important for solid processing and tableting. Moreover, the ASD prepared herein is compatible with direct compression for tablet preparation. The spray-drying method disclosed herein also produces ASD with particle sizes that contribute to these properties.

[0129] In some embodiments, the SDP is a solid solution of the polymer in the milvexian.

[0130] In some embodiments, the SDP has a particle size distribution median diameter D of 60 mm or less, over a span of about 1.9. V,50 In some embodiments, the SDP has a particle size distribution median diameter D of 50 mm or less, with a span of about 1.9. V,50 In some embodiments, the SDP has a particle size distribution median diameter D of 45 mm or less, with a span of about 1.9. V,50 In some embodiments, the SDP has a particle size distribution median diameter D of 15 mm or less. V,10 , 45mm or less D V,50 ; and D below 95mm V,90 In a preferred embodiment, the SDP has a particle size distribution median diameter D of 20 mm or less. V,10 , 50mm or less D V,50 ; and D below 110mm V,90 In a further preferred embodiment, the SDP has a particle size distribution median diameter D of 25 mm or less. V,10 , 60mm or less D V,50 and D below 140mm V,90 In a further preferred embodiment, the SDP has a particle size distribution median diameter D of 45 μm or less. V,50 In a most preferred embodiment, the SDP has a particle size distribution median diameter D of about 40 μm. V,50 It has.

[0131] In some embodiments, the SDP is about 0.27 g / cm 3~Approx. 0.36g / cm 3 It has a bulk density of

[0132] In other embodiments, the SDP is about 0.34 g / cm 3 ~Approx. 0.45g / cm 3 The tap density is

[0133] In some embodiments, the SDP has an XRD that indicates that the milvexian in the amorphous solid is amorphous (e.g., 100% amorphous, 99% amorphous, 98% amorphous, 97% amorphous, 96% amorphous, 95% amorphous, 94% amorphous, 93% amorphous, 92% amorphous, 91% amorphous, or 90% amorphous).

[0134] In some embodiments, the SDP is stable with respect to amorphous milvexian content, i.e., the milvexian in the amorphous solid dispersion remains amorphous over time and under a variety of conditions.

[0135] Solid pharmaceutical compositions for oral administration Solid pharmaceutical compositions for oral administration of the present disclosure include pharmaceutical powder blends (e.g., suitable for tableting or encapsulation), pharmaceutical powder blends for direct oral administration, and unit pharmaceutical dosage forms (e.g., tablets, capsules) formed from such pharmaceutical powder blends.

[0136] a) Excipients used in the pharmaceutical compositions of the present disclosure In some embodiments, the present disclosure is directed to a solid pharmaceutical composition for oral administration comprising a spray-dried amorphous solid dispersion (SDP) consisting of a milbexian free form and a pH-dependent enteric polymer, and one or more pharmaceutically acceptable excipients selected from binders, fillers, diluents, disintegrants, colorants, lubricants, glidants, and coatings.

[0137] In some embodiments, the present disclosure is directed to a solid pharmaceutical composition for oral administration comprising a spray-dried amorphous solid dispersion (SDP) consisting essentially of milbexian-free bodies and a pH-dependent enteric polymer, a binder selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof, in a weight ratio of about 3:1 (milbexian-free bodies:pH-dependent enteric polymer); a filler that is lactose monohydrate; a disintegrant; and a lubricant, wherein the milbexian-free bodies are present in an amount ranging from about 10.0% to about 40.0% by weight of the total weight of the solid pharmaceutical composition; and the binder and lactose monohydrate are present in a weight ratio (binder:lactose monohydrate) ranging from about 3:2 to about 3:1.

[0138] In some embodiments, the present disclosure provides a solid pharmaceutical composition for oral administration comprising SDP particles consisting essentially of milvexian and HPMC-AS-MG in a 3:1 weight ratio (milvexian-free:HPMC-AS-MG) and one or more pharmaceutically acceptable excipients selected from binders, fillers, diluents, disintegrants, colorants, lubricants, glidants, and coatings.

[0139] In some embodiments, the solid pharmaceutical composition for oral administration is a tablet core formed by direct compression of pharmaceutical powder.

[0140] In some embodiments, a solid pharmaceutical composition for oral administration is a pharmaceutical powder blend (eg, a powder blend suitable for tableting by direct compression).

[0141] In some embodiments, the pharmaceutical powders of the present disclosure have properties suitable for direct compression tablet manufacture.

[0142] In some embodiments, the pharmaceutical powder of the present disclosure has a tap density of about 0.56 g / mL.

[0143] In some embodiments, the pharmaceutical powder of the present disclosure has a bulk density of about 0.47 g / mL.

[0144] In some embodiments, the pharmaceutical powder of the present disclosure has a flow function coefficient (ring shear) of 10.28.

[0145] In some embodiments, the pharmaceutical powder of the present disclosure has a flow function coefficient (ring shear) of about 10.28.

[0146] In some embodiments, the pharmaceutical powder blend has the composition set forth in Table 4 below. [Table 6]

[0147] The pharmaceutical powder blends set forth in the table above are for the preparation of direct compression immediate release oral tablet cores containing silicified microcrystalline cellulose and lactose monohydrate as binders / fillers, croscarmellose sodium as a disintegrant, and magnesium stearate as a lubricant. The powder blends of spray-dried ASD containing tablet excipients have been modified to optimize tablet manufacturability.

[0148] In some embodiments, the present disclosure provides a solid pharmaceutical composition that is a tablet having the composition set forth in Table 5 below. [Table 7]

[0149] In some embodiments, the present disclosure is directed to a solid pharmaceutical composition that is an immediate release tablet core having the composition set forth in Table 6 below. [Table 8]

[0150] It has been found that drug load affects the flowability of the powder blend and the friability of direct compression tablets (e.g., less than 1%). An effective range of drug load is about 10.0% to about 40.0% by weight, based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet). A preferred range of drug load is about 11.0% to about 21.0% by weight, based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet). The most preferred drug load is 16.67% by weight, based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet).

[0151] In some embodiments, the solid pharmaceutical composition (powder mixture or uncoated tablet) of the present disclosure contains about 10.0% to about 40.0% by weight of the milbexian free form, based on the total weight of the solid pharmaceutical composition (powder mixture or uncoated tablet), for example, about 10.0% by weight, about 11.0% by weight, about 12.0% by weight, about 13.0% by weight, about 14.0% by weight, about 15.0% by weight, about 16.0% by weight, about 17.0% by weight, about 18.0% by weight, about 19.0% by weight, about 20.0% by weight, or , about 21.0 wt%, about 22.0 wt%, about 23.0 wt%, about 24.0 wt%, about 25.0 wt%, about 26.0 wt%, about 27.0 wt%, about 28.0 wt%, about 29.0 wt%, about 30.0 wt%, about 31.0 wt%, about 32.0 wt%, about 33.0 wt%, about 34.0 wt%, about 35.0 wt%, about 36.0 wt%, about 37.0 wt%, about 38.0 wt%, about 39.0 wt%, or about 40.0 wt% milbexian free body.

[0152] In some embodiments, the solid pharmaceutical composition (powder blend or uncoated tablet) of the present disclosure comprises about 15.0% to about 28.0% by weight of milbexian-free body, for example, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, or about 28.0% by weight of milbexian-free body, based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet).

[0153] In other embodiments, the solid pharmaceutical composition (powder blend or uncoated tablet) of the present disclosure contains about 11.0% to about 21.0% by weight of milbexian-free body, based on the total weight of the uncoated tablet, e.g., about 11.0%, about 12.0%, about 13.0%, about 14.0%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, or about 21.0% by weight of milbexian-free body.

[0154] In some embodiments, the solid pharmaceutical composition (powder blend or uncoated tablet) of the present disclosure comprises about 16.67% by weight of free milbexian, based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet).

[0155] In some embodiments, the solid pharmaceutical composition (powder blend or uncoated tablet) of the present disclosure contains an SPD consisting essentially of milbexian-free form and pH-dependent enteric polymer in a weight ratio of about 3:1 (milbexian-free form:pH-dependent enteric polymer) in an amount of about 13.3% to about 53.3% by weight, e.g., about 13.3%, about 14.3%, about 15.3%, about 16.3%, about 17.3%, about 18.3%, about 19.3%, about 20.3%, about 21.3%, about 22.3%, about 23.3%, about 24.3%, about 25.3%, about 26.3%, about 27.3%, about 28. 3% by weight, about 29.3% by weight, about 30.3% by weight, about 31.3% by weight, about 32.3% by weight, about 33.3% by weight, about 34.3% by weight, about 35.3% by weight, about 36.3% by weight, about 37.3% by weight, about 38.3% by weight, about 39.3% by weight, about 40.3% by weight, about 41.3% by weight, about 42.3% by weight, about 43.3% by weight, about 44.3% by weight, about 45.3% by weight, about 46.3% by weight, about 47.3% by weight, about 48.3% by weight, about 49.3% by weight, about 50.3% by weight, about 51.3% by weight, about 52.3% by weight, or about 53.3% by weight; said weight percentages are based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet).

[0156] In some embodiments, the solid pharmaceutical composition (powder blend or uncoated tablet) of the present disclosure comprises about 14.67% to about 28.0% by weight, e.g., about 14.67%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, or about 28.0% by weight, of an SPD consisting essentially of milbexian-free form and pH-dependent enteric polymer in a weight ratio of about 3:1 (milbexian-free form:pH-dependent enteric polymer); said weight percentages are based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet).

[0157] In some embodiments, the solid pharmaceutical composition (powder blend or uncoated tablet) of the present disclosure comprises about 22.22 wt.% of an SPD consisting essentially of milbexian-free form and pH-dependent enteric polymer in a weight ratio of about 3:1 (milbexian-free form:pH-dependent enteric polymer); said wt.% is based on the total weight of the solid pharmaceutical composition (powder blend or uncoated tablet).

[0158] In other embodiments, the present disclosure provides an immediate release tablet core comprising 25 mg or 100 mg of milbexian-free form, having the composition shown in Table 7 below. [Table 9]

[0159] It has been unexpectedly found that a mixture of a binder (e.g., SMCC90) and lactose monohydrate in a weight / weight ratio of 3:2 has the following desirable physical properties:

[0160] (i) free flowing, allowing for bulk transport during batch or continuous direct compression tableting processes;

[0161] (ii) excellent compressibility, enabling a direct compression manufacturing process to prepare tablet cores with excellent physical stability (e.g., less than 0.5% friability);

[0162] (iii) self-lubricating, without sticking to the walls of the tablet press; and

[0163] (iv) rigid enough to maintain the shape of the SDP particles;

[0164] None of these advantageous properties have been reported in the prior art.

[0165] The specific excipients and their respective amounts used in the solid pharmaceutical compositions for oral administration described herein were determined by screening the excipients for manufacturability in direct compression tablet manufacturing processes and impact on the quality of the formulated drug (e.g., measuring free flow, compressibility in the direct compression tablet manufacturing process, compatibility with Milvexian, 2-year stability (including physical, amorphous, and chemical stability with Milvexian), low friability (e.g., less than 1%), hardness in the range of 60N to 220N, and disintegration time of less than 5 minutes). See Examples 1-4.

[0166] Binder In some aspects, the present disclosure is directed to a solid pharmaceutical composition for oral administration that includes a binder.

[0167] In some embodiments of the solid pharmaceutical composition for oral administration, the binder is selected from hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), polyvinylpyrrolidone (PVP), lactose, starch, or combinations thereof.

[0168] In some embodiments of the solid pharmaceutical composition for oral administration, the binder is selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof.

[0169] In some embodiments of the solid pharmaceutical composition for oral administration, the binder consists of microcrystalline cellulose and silicified microcrystalline cellulose.

[0170] In some embodiments of the solid pharmaceutical composition for oral administration, the binder is silicified microcrystalline cellulose (SMCC).

[0171] In some embodiments, the solid pharmaceutical composition comprises about 21.0% to about 71.0% by weight of binder, e.g., about 21.0% by weight, about 22.0% by weight, about 23.0% by weight, about 24.0% by weight, about 25.0% by weight, about 26.0% by weight, about 27.0% by weight, about 28.0% by weight, about 29.0% by weight, about 30.0% by weight, about 31.0% by weight, about 32.0% by weight, about 33.0% by weight, about 34.0% by weight, about 35.0% by weight, about 36.0% by weight, about 37.0% by weight, about 38.0% by weight, about 39.0% by weight, about 40.0% by weight, about 41.0% by weight, about 42.0% by weight, about 43.0% by weight, about 44.0% by weight, about 45.0% by weight, about 46.0% by weight, about 47.0% by weight, about 48.0% by weight, about 49.0% by weight, about 50.0% by weight, about 51.0% by weight, about 52.0% by weight, about 53.0% by weight, about 54.0% by weight, about 55.0% by weight, about 56.0% by weight, about 57.0% by weight, about 58.0% by weight, about 59.0% by weight, about 60.0% by weight, about 61.0% by weight, about 62.0% by weight, about 63.0% by weight, about 64.0% by weight, about 65.0% by weight, about 66.0% by weight, about 67.0% by weight, about 68.0% %, about 45.0%, about 46.0%, about 47.0%, about 48.0%, about 49.0%, about 51.0%, about 52.0%, about 53.0%, about 54.0%, about 56.0%, about 57.0%, about 58.0%, about 59.0%, about 60.0%, about 61.0%, about 62.0%, about 63.0%, about 64.0%, about 65.0%, about 66.0%, about 67.0%, about 68.0%, about 69.0%, about 70.0%, or about 71.0% by weight of binder; said weight percentages are based on the total weight of the solid pharmaceutical composition.

[0172] In some embodiments, the solid pharmaceutical composition comprises about 21.0 wt% to about 71.0 wt% silicified microcrystalline cellulose (SMCC), for example, about 21.0 wt%, about 22.0 wt%, about 23.0 wt%, about 24.0 wt%, about 25.0 wt%, about 26.0 wt%, about 27.0 wt%, about 28.0 wt%, about 29.0 wt%, about 30.0 wt%, about 31.0 wt%, about 32.0 wt%, about 33.0 wt%, about 34.0 wt%, about 35.0 wt%, about 36.0 wt%, about 37.0 wt%, about 38.0 wt%, about 39.0 wt%, about 40.0 wt%, about 41.0 wt%, about 42.0 wt%, about 43.0 wt%, about 44.0 wt%, about 45.0 wt%, about 46.0 wt%, about 47.0 wt%, about 48.0 wt%, about 49.0 wt%, about 50.0 wt%, about 51.0 wt%, about 52.0 wt%, about 53.0 wt%, about 54.0 wt%, about 55.0 wt%, about 56.0 wt%, about 57.0 wt%, about 58.0 wt%, about 59.0 wt%, about 60.0 wt%, about 61.0 wt%, about 62.0 wt%, about 63.0 wt%, about 64.0 wt%, about 65.0 wt%, about 66.0 wt%, about 67.0 wt%, about 68.0 wt%, about 69.0 wt%, about 70.0 wt%, about 71.0 wt% silicified microcrystalline cellulose ( %, about 45.0 wt%, about 46.0 wt%, about 47.0 wt%, about 48.0 wt%, about 49.0 wt%, about 51.0 wt%, about 52.0 wt%, about 53.0 wt%, about 54.0 wt%, about 56.0 wt%, about 57.0 wt%, about 58.0 wt%, about 59.0 wt%, about 60.0 wt%, about 61.0 wt%, about 62.0 wt%, about 63.0 wt%, about 64.0 wt%, about 65.0 wt%, about 66.0 wt%, about 67.0 wt%, about 68.0 wt%, about 69.0 wt%, about 70.0 wt%, or about 71.0 wt% silicified microcrystalline cellulose (SMCC); said weight percentages are based on the total weight of the solid pharmaceutical composition.

[0173] In some embodiments, the solid pharmaceutical composition comprises about 31.0% to about 61.0% by weight of binder, e.g., about 31.0% by weight, about 32.0% by weight, about 33.0% by weight, about 34.0% by weight, about 35.0% by weight, about 36.0% by weight, about 37.0% by weight, about 38.0% by weight, about 39.0% by weight, about 40.0% by weight, about 41.0% by weight, about 42.0% by weight, about 43.0% by weight, about 44.0% by weight, about 45.0% by weight, about 46.0% by weight, about 47.0% by weight, about 48.0% by weight, about 49.0% by weight, about 50.0% by weight, about 51.0% by weight, about 52.0% by weight, about 53.0% by weight, about 54.0% by weight, about 55.0% by weight, about 56.0% by weight, about 57.0% by weight, about 58.0% by weight, about 59.0% by weight, about 60.0% by weight, about 61.0% by weight, about 62.0% by weight, about 63.0% by weight, about 64.0% by weight, about 65.0% by weight, about 66.0% by weight, about 67.0% by weight, about 68.0% by weight, about 69.0% by weight, about 70.0% by weight, about 71.0% by weight, about 72.0% by weight, about 73.0% by weight, about 74.0% by weight, about 75.0% by weight, about 76.0% by weight, about 77.0% by weight, about 78.0% about 45.0 wt%, about 46.0 wt%, about 47.0 wt%, about 48.0 wt%, about 49.0 wt%, about 51.0 wt%, about 52.0 wt%, about 53.0 wt%, about 54.0 wt%, about 56.0 wt%, about 57.0 wt%, about 58.0 wt%, about 59.0 wt%, about 60.0 wt%, or about 61.0 wt% of binder; said weight percentages are based on the total weight of the solid pharmaceutical composition.

[0174] In some embodiments, the solid pharmaceutical composition comprises about 31.0% to about 61.0% by weight of silicified microcrystalline cellulose (SMCC), for example, about 31.0% by weight, about 32.0% by weight, about 33.0% by weight, about 34.0% by weight, about 35.0% by weight, about 36.0% by weight, about 37.0% by weight, about 38.0% by weight, about 39.0% by weight, about 40.0% by weight, about 41.0% by weight, about 42.0% by weight, about 43.0% by weight, about 44.0% by weight, about 45.0% by weight, about 46.0% by weight, about 47.0% by weight, about 48.0% by weight, about 49.0% by weight, about 50.0% by weight, about 51.0% by weight, about 52.0% by weight, about 53.0% by weight, about 54.0% by weight, about 55.0% by weight, about 56.0% by weight, about 57.0% by weight, about 58.0% by weight, about 59.0% by weight, about 60.0% by weight, about 61.0% by weight, about 62.0% by weight, about 63.0% by weight, about 64.0% by weight, about 65.0% by weight, about 66.0% by weight, about 67.0% by weight, about 68.0% by weight, about 69.0% by weight, about 70.0% by weight, about 71.0% by weight, about 72.0% by weight, about 73.0% by weight, about 74.0% by weight, about 75.0% by weight, about 76.0% by weight, about 77.0% by weight %, about 45.0 wt%, about 46.0 wt%, about 47.0 wt%, about 48.0 wt%, about 49.0 wt%, about 51.0 wt%, about 52.0 wt%, about 53.0 wt%, about 54.0 wt%, about 56.0 wt%, about 57.0 wt%, about 58.0 wt%, about 59.0 wt%, about 60.0 wt%, or about 61.0 wt% of silicified microcrystalline cellulose (SMCC); said weight percentages are based on the total weight of the solid pharmaceutical composition.

[0175] In some embodiments, the solid pharmaceutical composition comprises about 38.0% to about 48.0% by weight of the binder, e.g., about 38.0%, about 39.0%, about 40.0%, about 41.0%, about 42.0%, about 43.0%, about 44.0%, about 45.0%, about 46.0%, about 47.0%, or about 48.0% by weight; the weight percentages are based on the total weight of the solid pharmaceutical composition.

[0176] In some embodiments, the solid pharmaceutical composition comprises about 38.0% to about 48.0% by weight of silicified microcrystalline cellulose (SMCC), e.g., about 38.0%, about 39.0%, about 40.0%, about 41.0%, about 42.0%, about 43.0%, about 44.0%, about 45.0%, about 46.0%, about 47.0%, or about 48.0% by weight of silicified microcrystalline cellulose (SMCC); the weight percentages are based on the total weight of the solid pharmaceutical composition.

[0177] In some embodiments, the solid pharmaceutical composition comprises about 25.0% to about 50.0% by weight of silicified microcrystalline cellulose, such as about 25.0% by weight, about 26.0% by weight, about 27.0% by weight, about 28.0% by weight, about 29.0% by weight, about 30.0% by weight, about 31.0% by weight, about 32.0% by weight, about 33.0% by weight, about 34.0% by weight, about 35.0% by weight, about 36.0% by weight, about 37.0% by weight, about 38.0% by weight, about 39.0% by weight, about 40.0% by weight, about 41.0% by weight, about 42.0% by weight, about 43.0% by weight, about 44.0% by weight, about 45.0% by weight, about 46.0% by weight, about 47.0% by weight, about 48.0% by weight, about 49.0% by weight, about 50.0% by weight, about 51.0% by weight, about 52.0% by weight, about 53.0% by weight, about 54.0% by weight, about 55.0% by weight, about 56.0% by weight, about 57.0% by weight, about 58.0% by weight, about 59.0% by weight, about 60.0% by weight, about 61.0% by weight, about 62.0% by weight, about 63.0% by weight, about 64.0% by weight, about 65.0% by weight, about 66.0% by weight, about 67.0% by weight, about 68.0% by weight, about 69.0% by weight, about 70.0% by weight, about 71.0% by weight, about 7 7.0%, about 38.0%, about 39.0%, about 40.0%, about 41.0%, about 42.0%, about 43.0%, about 44.0%, about 45.0%, about 46.0%, about 47.0%, about 48.0%, about 49.0%, or about 50.0% by weight of silicified microcrystalline cellulose; said weight percentages are based on the total weight of the solid pharmaceutical composition.

[0178] In some embodiments, the solid pharmaceutical composition comprises about 35.0% to about 50% by weight of silicified microcrystalline cellulose, e.g., about 35.0%, about 36.0%, about 37.0%, about 38.0%, about 39.0%, about 40.0%, about 41.0%, about 42.0%, about 43.0%, about 44.0%, about 45.0%, about 46.0%, about 47.0%, about 48.0%, about 49.0%, or about 50.0% by weight of silicified microcrystalline cellulose; said weight percentages are based on the total weight of the solid pharmaceutical composition.

[0179] In some embodiments, the solid pharmaceutical composition comprises about 40.0 to about 45.0 wt.% silicified microcrystalline cellulose, e.g., about 40.0 wt.%, about 41.0 wt.%, about 42.0 wt.%, about 43.0 wt.%, about 44.0 wt.%, or about 45.0 wt.% (wt / wt) silicified microcrystalline cellulose; said wt.% being based on the total weight of the solid pharmaceutical composition.

[0180] In some embodiments, the solid pharmaceutical composition comprises about 40.0% to about 45.0% by weight of silicified microcrystalline cellulose, based on the total weight of the solid pharmaceutical composition.

[0181] In some embodiments, the solid pharmaceutical composition comprises about 43.0% by weight of silicified microcrystalline cellulose, based on the total weight of the solid pharmaceutical composition.

[0182] In some embodiments, the solid pharmaceutical composition comprises about 43.07% by weight of silicified microcrystalline cellulose, based on the total weight of the solid pharmaceutical composition.

[0183] Microcrystalline cellulose is refined wood pulp. Microcrystalline cellulose is a white, free-flowing powder. Chemically, it is an inactive substance, not broken down during digestion, and is hardly absorbed. When taken in large amounts, it can add bulk to meals and have a laxative effect. Tablets can be formed to be hard but quickly dissolving. Microcrystalline cellulose is the same as cellulose, except that it meets USP standards. In some embodiments, the commercially available microcrystalline cellulose used in the solid oral dosage formulations described herein may include MCC, sold under the trade name Avicel PH102 (registered trademark) (Dupont Pharma).

[0184] Silicified microcrystalline cellulose serves as an excipient for the solid oral dosage formulations described herein. Silicified microcrystalline cellulose is commercially available and is an intimate physical mixture of two components: microcrystalline cellulose (98% w / w) and colloidal silicon dioxide (2% w / w). At low magnification, conventional MCC and silicified MCC appear very similar in terms of particle size and shape. However, at high magnification, electron microscopy reveals differences in the microstructure of silicified MCC and conventional MCC. A wide variety of PROSOLV SMCC® grades exist with different physical properties (see Table 8 below). [Table 10]

[0185] In some embodiments of the solid pharmaceutical compositions described herein, the SMCC has the trademark PROSOLV SMCC® and is a grade selected from PROSOLV SMCC® 50, PROSOLV SMCC® 50 LD, PROSOLV SMCC® 90, PROSOLV SMCC® HD 90, or PROSOLV SMCC® 90 LM grades described in Table 8 above.

[0186] In the most preferred embodiment of the solid pharmaceutical compositions described herein, SMCC is included in an amount of about 43.0% by weight, based on the total weight of the solid pharmaceutical formulation. This amount of binder has been found to allow for the production of directly compressed tablets with favorable properties (e.g., friability of less than 0.5%, and disintegration times of less than 2 minutes, and in many cases less than 30 seconds).

[0187] bulking agent In some embodiments, the solid pharmaceutical compositions of the present disclosure comprise a filler.

[0188] In some embodiments of the solid pharmaceutical composition of the present disclosure, the filler is selected from lactose, mannitol, or a combination thereof.

[0189] In some embodiments of the solid pharmaceutical composition of the present disclosure, the filler is lactose.

[0190] In some embodiments, the lactose is lactose anhydrous or lactose monohydrate.

[0191] In some embodiments, the lactose is lactose monohydrate.

[0192] In some embodiments, the bulking agent consists of lactose monohydrate.

[0193] In some embodiments, the lactose monohydrate is that sold under the trade name Supertab 11SD® (DFE Pharma.).

[0194] In some embodiments of the solid pharmaceutical compositions described herein, the filler is included in the composition in an amount of about 25.0% to 33.0% by weight, e.g., about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%, about 32.0%, or about 33.0% by weight; said weight percentages being based on the total weight of the solid pharmaceutical composition.

[0195] In some embodiments of the solid pharmaceutical compositions described herein, lactose monohydrate is included in the composition in an amount of about 25.0% to 33.0% by weight, e.g., about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%, about 32.0%, or about 33.0% by weight; said weight percentages being based on the total weight of the solid pharmaceutical composition.

[0196] In some embodiments of the solid pharmaceutical compositions described herein, the filler is present in the composition in an amount of about 28.0% to 30.0% by weight, e.g., about 28.0% by weight, about 29.0% by weight, or about 30.0% by weight; said weight percentages being based on the total weight of the solid pharmaceutical composition.

[0197] In some embodiments of the solid pharmaceutical compositions described herein, lactose monohydrate is present in the composition in an amount of about 28.0% to 30.0% by weight, e.g., about 28.0% by weight, about 29.0% by weight, or about 30.0% by weight; said weight percentages being based on the total weight of the solid pharmaceutical composition.

[0198] In some embodiments of the solid pharmaceutical compositions described herein, the filler is present in the composition in an amount of about 29.0% by weight, based on the total weight of the solid pharmaceutical composition.

[0199] In some embodiments of the solid pharmaceutical compositions described herein, lactose monohydrate is included in the composition in an amount of about 29.0% by weight, based on the total weight of the solid pharmaceutical composition.

[0200] In some embodiments of the solid pharmaceutical compositions described herein, the filler is present in the composition in an amount of about 28.0% by weight, based on the total weight of the solid pharmaceutical composition.

[0201] In some embodiments of the solid pharmaceutical compositions described herein, lactose monohydrate is included in the composition in an amount of about 28.0% by weight, based on the total weight of the solid pharmaceutical composition.

[0202] In some embodiments of the solid pharmaceutical compositions described herein, the filler is present in the composition in an amount of 28.71% by weight, based on the total weight of the solid pharmaceutical composition.

[0203] In some embodiments of the solid pharmaceutical compositions described herein, lactose monohydrate is included in the composition in an amount of 28.71% by weight, based on the total weight of the solid pharmaceutical composition.

[0204] Binder:filler weight ratio The weight ratio of binder:filler has been found to be important in imparting certain desirable properties to a solid pharmaceutical composition for oral administration (e.g., friability and cohesion of the direct compression tablets of the present disclosure).

[0205] In some embodiments, the weight ratio of binder:filler ranges from about 100:0 to 0:100.

[0206] In some embodiments, the weight ratio of binder:filler ranges from about 99:1 to 0.5:1.

[0207] In preferred embodiments, the weight ratio of binder:filler is in the range of about 3:2 to about 3:1, e.g., about 3:2, about 3:1.9, about 3:1.8, about 3:1.7, about 3:1.6, about 3:1.5, about 3:1.4, about 3:1.3, about 3:1.2, about 3:1.1, or about 3:1.

[0208] In preferred embodiments, the weight ratio of silicified microcrystalline cellulose (SMCC):lactose monohydrate is in the range of about 3:2 to about 3:1, e.g., about 3:2, about 3:1.9, about 3:1.8, about 3:1.7, about 3:1.6, about 3:1.5, about 3:1.4, about 3:1.3, about 3:1.2, about 3:1.1, or about 3:1.

[0209] In another preferred embodiment, the weight ratio of silicified microcrystalline cellulose (SMCC):lactose monohydrate is about 3:2.

[0210] In preferred embodiments, the weight ratio of microcrystalline cellulose (MCC):lactose monohydrate is in the range of about 3:2 to about 3:1, e.g., about 3:2, about 3:1.9, about 3:1.8, about 3:1.7, about 3:1.6, about 3:1.5, about 3:1.4, about 3:1.3, about 3:1.2, about 3:1.1, or about 3:1.

[0211] In another preferred embodiment, the weight ratio of microcrystalline cellulose (MCC):lactose monohydrate is about 3:2.

[0212] This ratio of about 3:2 to about 3:1 binder:lactose monohydrate has been found to impart desirable non-stick properties to the composition, preventing it from sticking to the walls of tableting machinery. This property allows for continuous production of tablets, which in turn allows for cost-effective commercial manufacturing. See Example 2A.

[0213] Disintegrant In some embodiments, the solid pharmaceutical composition of the present disclosure comprises a disintegrant.

[0214] In some embodiments of the solid pharmaceutical compositions described herein, the disintegrant is selected from sodium carboxymethylcellulose crosslinked (croscarmellose sodium, CCS), polyvinylpyrrolidone crosslinked (crospovidone, CPV), or a combination thereof.

[0215] In a preferred embodiment of the solid pharmaceutical composition described herein, the disintegrant is croscarmellose sodium. Croscarmellose sodium is a cross-linked polymer of carboxymethylcellulose. In a preferred embodiment, the disintegrant is croscarmellose sodium sold under the brand name Ac-di-sol SD-711 (Dupont Pharma, Delaware, US).

[0216] In some embodiments, the solid pharmaceutical composition comprises a disintegrant in an amount of up to 10.0% by weight, for example, up to 1.0% by weight, up to 2.0% by weight, up to 3.0% by weight, up to 4.0% by weight, up to 5.0% by weight, up to 6.0% by weight, up to 7.0% by weight, up to 8.0% by weight, up to 9.0% by weight, or up to 10.0% by weight, based on the total weight of the solid pharmaceutical composition.

[0217] In some embodiments, the solid pharmaceutical composition comprises up to 10.0% by weight of croscarmellose sodium, e.g., up to 1.0%, up to 2.0%, up to 3.0%, up to 4.0%, up to 5.0%, up to 6.0%, up to 7.0%, up to 8.0%, up to 9.0%, or up to 10.0% by weight of croscarmellose sodium, based on the total weight of the solid pharmaceutical composition.

[0218] In some embodiments, the solid pharmaceutical composition comprises about 2.0% to about 8.0% by weight of disintegrant, for example, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, or about 8.0% by weight of disintegrant, based on the total weight of the solid pharmaceutical composition.

[0219] In some embodiments, the solid pharmaceutical composition comprises about 2.0% to about 8.0% by weight of croscarmellose sodium, e.g., about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, or about 8.0% by weight of croscarmellose sodium, based on the total weight of the solid pharmaceutical composition.

[0220] In some embodiments, the solid pharmaceutical composition comprises about 3.0% to about 7.0% by weight of disintegrant, for example, about 3.0%, about 4.0%, about 5.0%, about 6.0%, or about 7.0% by weight of disintegrant, based on the total weight of the solid pharmaceutical composition.

[0221] In some embodiments, the solid pharmaceutical composition comprises about 3.0% to about 7.0% by weight of croscarmellose sodium, e.g., about 3.0%, about 4.0%, about 5.0%, about 6.0%, or about 7.0% by weight of croscarmellose sodium, based on the total weight of the solid pharmaceutical composition.

[0222] In some embodiments, the solid pharmaceutical composition comprises about 4.0% to about 6.0% by weight of disintegrant, for example, about 4.0%, about 5.0%, or about 6.0% by weight of disintegrant, based on the total weight of the solid pharmaceutical composition.

[0223] In some embodiments, the solid pharmaceutical composition comprises about 4.0% to about 6.0% by weight of croscarmellose sodium, e.g., about 4.0%, about 5.0%, or about 6.0% by weight of croscarmellose sodium, based on the total weight of the solid pharmaceutical composition.

[0224] In some embodiments, the solid pharmaceutical composition comprises about 5.0% by weight of a disintegrant, based on the total weight of the solid pharmaceutical composition.

[0225] In some embodiments, the solid pharmaceutical composition comprises about 5.0% by weight of croscarmellose sodium, based on the total weight of the solid pharmaceutical composition.

[0226] It was found that this amount of croscarmellose sodium resulted in a pharmaceutical composition that could be formed into a directly compressed tablet with a friability of less than 0.5% and a disintegration time of less than 2 minutes. See Examples 2D and 3A-C.

[0227] lubricant In some embodiments, the solid pharmaceutical compositions of the present disclosure comprise a lubricant.

[0228] In some embodiments of the solid pharmaceutical composition of the present disclosure, the lubricant is selected from vegetable stearin, magnesium stearate, stearic acid, or a combination thereof.

[0229] In some embodiments of the solid pharmaceutical composition of the present disclosure, the lubricant is magnesium stearate.

[0230] In some embodiments of the solid pharmaceutical composition of the present disclosure, the lubricant is vegetable-derived magnesium stearate.

[0231] In some embodiments, the solid pharmaceutical composition of the present disclosure comprises a lubricant in an amount of up to 3.0% by weight, e.g., up to 1.0% by weight, up to 2.0% by weight, or up to 3.0% by weight, based on the total weight of the solid pharmaceutical composition.

[0232] In some embodiments, the solid pharmaceutical composition of the present disclosure comprises up to 3.0% by weight of magnesium stearate, e.g., up to 1.0% by weight, up to 2.0% by weight, or up to 3.0% by weight of magnesium stearate, based on the total weight of the solid pharmaceutical composition.

[0233] In a preferred embodiment, the solid pharmaceutical composition of the present disclosure comprises about 0.5% to about 2.0% by weight of a lubricant, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% by weight of a lubricant, based on the total weight of the solid pharmaceutical composition.

[0234] In a preferred embodiment, the solid pharmaceutical composition of the present disclosure comprises about 0.5% to about 2.0% by weight of magnesium stearate, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% by weight of magnesium stearate, based on the total weight of the solid pharmaceutical composition.

[0235] In a most preferred embodiment, the solid pharmaceutical composition of the present disclosure comprises about 0.5% to about 1.5% by weight of a lubricant, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight of a lubricant, based on the total weight of the solid pharmaceutical composition.

[0236] In a most preferred embodiment, the solid pharmaceutical composition of the present disclosure comprises about 0.5% to about 1.5% by weight of magnesium stearate, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight of magnesium stearate, based on the total weight of the solid pharmaceutical composition.

[0237] In a most preferred embodiment, the solid pharmaceutical composition of the present disclosure comprises about 1.0% by weight of a lubricant, based on the total weight of the solid pharmaceutical composition.

[0238] In a most preferred embodiment, the solid pharmaceutical composition of the present disclosure comprises about 1.0% by weight of magnesium stearate, based on the total weight of the solid pharmaceutical composition. Film-coated pharmaceutical tablets Film Coating

[0239] In some embodiments of the present disclosure, a film-coated tablet is prepared by directly compressing the solid pharmaceutical composition of the present disclosure onto a tablet core, which is then film-coated.

[0240] In some embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc.

[0241] In another embodiment, the film coating comprises a polyethylene glycol-polyvinyl alcohol graft copolymer.

[0242] In some embodiments, the film coating is selected from the group consisting of a film coating comprising polyvinyl alcohol (PVA) and 20% polyethylene glycol (PEG); hydroxypropyl methylcellulose (HPMC); polyvinyl alcohol and polyethylene glycol graft copolymer (e.g., the film coating sold under the trade name Opadry® QX by Colorcon); and PEG-free polyvinyl alcohol (e.g., the film coating sold under the trade name Opadry® AMB II by Colorcon).

[0243] In some embodiments, the film coating is selected from the group consisting of PVA+PEG (Opadry II 85F220241), HPMC (Opadry II 32F220042), PVA (Opadry amb II 88A520052), and PVA / PEG (Opadry QX 321A220057).

[0244] In some such embodiments, the Opadry® QX film coating comprises polyvinyl alcohol, titanium dioxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc. An example of such a coating is an Opadry® QX grade film coating material having the composition shown in Table 9 below. In some embodiments, the film coating is titanium dioxide-free. [Table 11]

[0245] In some embodiments of the film-coated tablets of the present disclosure, the film coating comprises a weight gain of about 2.0% to about 4.0% relative to the uncoated tablet, for example, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, or about 4.0%.

[0246] The phrase "weight increase (%) relative to the uncoated tablet" used to describe the weight of the coating of the film-coated tablets of the present disclosure refers to the percentage of the weight of the coating relative to the weight of the uncoated tablet. This percentage is calculated by: ([(weight of coated tablet) - (weight of uncoated tablet)] ÷ (weight of uncoated tablet)) * For example, if the weight of the coated tablet is 154.5 mg and the weight of the uncoated tablet is 150 mg, the "weight gain (%) relative to the uncoated tablet" is [(154.5 mg - 150 mg) ÷ 150 mg] * 100=equals 3.0%.

[0247] In some embodiments of the film-coated tablets of the present disclosure, the film-coated tablet comprises a weight gain of about 2.5% to about 3.3% relative to the uncoated tablet, for example, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, or about 3.3%.

[0248] In some embodiments of the film-coated tablets of the present disclosure, the film-coated tablets comprise a weight gain of about 3.0% relative to the uncoated tablets.

[0249] Film coating may be performed by any coating method known to those skilled in the art.

[0250] In some embodiments, the present disclosure is directed to an immediate-release film-coated tablet having the composition shown in Table 10 below and containing 25 mg or 100 mg of Milvexian. [Table 12]

[0251] In embodiments, the present disclosure also provides tablets that disperse quickly in aqueous media.

[0252] In some embodiments, the tablets that disperse quickly in aqueous media are characterized by having a disintegration time of less than 1 minute, a hardness in the range of 60 to 200 N, and containing 25 mg or 100 mg of free milbexian.

[0253] In some embodiments, the tablet that disperses quickly in an aqueous medium is characterized by having a disintegration time of less than 1 minute, a hardness in the range of 60 to 120 N, and containing 25 mg of free milbexian.

[0254] In some embodiments, the tablet that disperses quickly in aqueous media is characterized by having a disintegration time of less than 1 minute, a hardness of 90 N, and containing 25 mg of free milbexian.

[0255] In some embodiments, the tablet that disperses quickly in an aqueous medium is characterized by having a disintegration time of less than 1 minute, a hardness in the range of 140 to 220 N, and containing 100 mg of free milbexian.

[0256] In some embodiments, the tablet that disperses quickly in aqueous media is characterized by having a disintegration time of less than 1 minute, a hardness of 180 N, and containing 100 mg of free milbexian.

[0257] In some embodiments, the tablets that disperse quickly in aqueous media have the compositions set forth in Tables 5-7 and 10 above.

[0258] In some embodiments, the tablet that disperses quickly in an aqueous medium has the composition set forth above in Table 7. In some embodiments, the tablet that disperses quickly in an aqueous medium has the composition set forth above in Table 10.

[0259] In some embodiments, the present disclosure provides a dispersion of an amorphous solid dispersion (ASD) in an aqueous medium selected from water, deionized water, saline, phosphate buffer, or fruit juice (e.g., apple juice, cranberry juice, orange juice, vegetable juice). In some embodiments, the aqueous dispersion of an ASD can be administered to patients who are unable to take medication via a feeding tube (e.g., NG tube) or spoon.

[0260] In some aspects, the present disclosure is directed to a pharmaceutical tablet formed by a process comprising direct compression of a solid pharmaceutical composition of the present disclosure.

[0261] In some embodiments, the present disclosure is directed to a pharmaceutical tablet formed by a process comprising direct compression of a solid pharmaceutical composition of the present disclosure, the process further comprising covering the tablet core formed by the direct compression process with a film coating.

[0262] In some embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc; (eg, Opadry® QX grade sold by Colorcon).

[0263] In another embodiment, the film coating comprises a polyethylene glycol-polyvinyl alcohol graft copolymer.

[0264] In some embodiments, the present disclosure provides: a) i) a spray-dried amorphous solid dispersion (SDP) consisting essentially of milbectic free bodies and a pH-dependent enteric polymer; ii) a binder selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof; iv) Lactose monohydrate v) Lubricants a nucleus containing b) A film coating covering the nucleus A pharmaceutical tablet comprising: The milvexian is contained in an amount ranging from about 10.0 wt. % to about 40.0 wt. % of the total weight of the core; and The binder and lactose monohydrate are contained in the core in a weight ratio (binder:lactose monohydrate) ranging from about 3:2 to about 3:1. For pharmaceutical tablets.

[0265] In these embodiments, the tablet core is a pharmaceutical composition of the present disclosure, wherein the spray-dried amorphous solid dispersion (SDP); the binder selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof; the lactose monohydrate, the disintegrant, and the lubricant are as disclosed above for the pharmaceutical composition of the present disclosure.

[0266] In some embodiments, the pharmaceutical tablet of the present disclosure comprises about 25 mg of free milbexian.

[0267] In other embodiments, the pharmaceutical tablet of the present disclosure contains about 100 mg of free milbexian.

[0268] In some embodiments, the pharmaceutical tablets of the present disclosure have a friability of less than 0.5%.

[0269] In some embodiments, the pharmaceutical tablets of the present disclosure have a disintegration time of less than 2 minutes.

[0270] In some embodiments, the pharmaceutical tablets of the present disclosure have a disintegration time of less than 20 minutes.

[0271] In some embodiments, the pharmaceutical tablets of the present disclosure have a disintegration time of less than 20 seconds.

[0272] In some embodiments, the tablet cores of the present disclosure are formed by direct compression of the solid pharmaceutical composition of the present disclosure.

[0273] Thus, in some embodiments, the tablet cores of the present disclosure have the same weight ratio amounts of milvexin, silicified microcrystalline cellulose, lactose monohydrate, disintegrant, and lubricant as described above for the pharmaceutical powder blend.

[0274] In some embodiments, the tablets of the present disclosure contain about 25 mg of free milbexian.

[0275] In some embodiments, the tablets of the present disclosure contain about 100 mg of free milbexian.

[0276] In some embodiments, the tablet of the present disclosure has a hardness of about 50N to about 140N, about 60N to about 120N. In some embodiments, the tablet of the present disclosure has a hardness in the range of about 50N to about 140N. In some embodiments, the tablet of the present disclosure has a hardness in the range of about 60N to about 120N, for example, about 60N, about 65N, about 70N, about 75N, about 80N, about 85N, about 90N, about 95N, about 100N, about 105N, about 110N, about 115N, or about 120N.

[0277] In other embodiments, the tablet of the present disclosure has a hardness of about 140N to about 220N, or about 100N to about 260N. In some embodiments, the tablet of the present disclosure has a hardness in the range of about 100N to about 260N. In a preferred embodiment, the tablet of the present disclosure has a hardness in the range of about 140N to about 220N, for example, about 140N, about 145N, about 150N, about 155N, about 160N, about 165N, about 170N, about 175N, about 180N, about 185N, about 190N, about 195N, about 200N, about 205N, about 210N, about 215N, or about 220N.

[0278] In other embodiments, tablets of the present disclosure have a friability of less than 1%, e.g., less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1%.

[0279] In some embodiments, tablets of the present disclosure have a disintegration time of 5 minutes or less, e.g., 5 minutes or less, 4.5 minutes or less, 4.0 minutes or less, 3.5 minutes or less, 3.0 minutes or less, 2.5 minutes or less, 2.0 minutes or less, 2.0 minutes or less, 1.5 minutes or less, 1.0 minute or less, or 0.5 minutes or less.

[0280] In some embodiments, the tablets of the present disclosure have specific profiles of action.

[0281] Medicines and Use In some aspects, the present disclosure is directed to a method of administering Milvexian to a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition of the present disclosure.

[0282] In some aspects, the present disclosure is directed to a method of administering Milvexian to a patient in need thereof, comprising orally administering to the patient a tablet of the present disclosure.

[0283] In some aspects, the present disclosure is directed to a method of administering Milvexian to a patient in need thereof, comprising dispersing a tablet of the present disclosure in an aqueous medium and then administering the resulting dispersion to the patient through a feeding tube.

[0284] In some embodiments, the present disclosure is directed to a method of administering Milvexian to a patient in need thereof, comprising dispersing a tablet of the present disclosure in an aqueous medium, adding applesauce to the dispersion and mixing, and then orally administering the resulting mixture to the patient.

[0285] In some embodiments, the aqueous medium is water.

[0286] In some embodiments, the aqueous medium comprises a fruit or vegetable juice, such as apple juice, orange juice, or cranberry juice.

[0287] In some embodiments, the present disclosure is directed to a method of treating and / or preventing a thromboembolic disorder in a patient in need thereof, comprising administering to the patient a tablet of the present disclosure.

[0288] In another aspect, the present disclosure is directed to a method of treating and / or preventing a thromboembolic disorder in a patient in need thereof, comprising dispersing a tablet of the present disclosure in an aqueous medium and then administering the resulting dispersion to the patient through a feeding tube.

[0289] In another aspect, the present disclosure is directed to a method of treating and / or preventing a thromboembolic disorder in a patient in need thereof, comprising dispersing a tablet of the present disclosure in an aqueous medium, adding applesauce to the dispersion and mixing, and then orally administering the resulting mixture to the patient.

[0290] In some embodiments, the thromboembolic disorder is unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic cerebrovascular accident, transient ischemic attack, stroke, atherosclerosis, peripheral arterial occlusive disease, venous thrombosis, deep vein thrombosis, venous thrombosis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal infarction, pulmonary infarction, or thrombosis resulting from a medical implant, device, or procedure that exposes a blood vessel to an artificial surface that promotes thrombosis. [Example]

[0291] A feature of the present invention is the spray-dried SDP particles having a particle size compatible with direct compression tableting processes (e.g., spray-dried SDP having a particle size distribution median diameter D in the range of 30 μm to 60 μm). 50 and an improved solvent-based spray drying process for producing film-coated direct compression tablets thereof. The present invention is further illustrated and described in the following non-limiting examples. Abbreviation API: Active Pharmaceutical Ingredient ASD: amorphous solid dispersion DCM: dichloromethane DC tablets: Directly compressed tablets RC tablets: roller compressed tablets FFC: Flow function coefficient LOD: Loss on drying HPMC-AS MG: Hydroxypropyl methylcellulose acetate succinate sold under the trademark AQOAT® AS-MG (Shin-Etsu Chemical Co., Ltd., Niigata, Japan) Macrogol: Polyethylene glycol MeOH: Methanol PXRD: Powder X-ray diffraction SDP: spray-dried amorphous solid dispersion rBA: Relative Bioavailability rh: relative humidity UHPLC: Ultra High Performance Liquid Chromatography UV: Ultraviolet light

[0292] Analysis method 1.Particle size analysis The average particle size can be determined by multi-angle dynamic light scattering and laser scattering techniques. In the examples below, the particle size of a 3:1 (wt / wt) Milvexian / HPMC-AS-MG spray-dried ASD was measured using a multi-angle particle size analyzer. Immediately after the measurement was completed, the sample cells were removed, cleaned, and the suspension medium was refilled. The sampling procedure was repeated three times for a total of three measurements.

[0293] 2. Bulk and Tapped Density Measurement Bulk density is determined by weighing a specified sample amount (50 g) to the nearest 0.1 g. The sample is poured into a 250 mL measuring cylinder and the volume is read after carefully leveling the surface of the powder bed. The bulk density is then calculated by dividing the sample weight by the volume of the powder bed.

[0294] Tap density is measured by placing the bulk density sample, still in the 250 mL measuring cylinder, on a stirrer and securing it. The stirrer is then set to 500 oscillations and started. After 500 oscillations, the stirring is stopped and the volume of the powder bed is read. The tap density is then calculated by dividing the sample weight by the read volume of the powder bed.

[0295] 3. Tablet friability measurement Friability is the tendency of a tablet to powder, chip, or break into pieces.

[0296] Tablet core friability is determined according to USP <1216> Friability was determined according to the guidelines described in. Friability was measured on a sample of whole tablets equivalent to 6.5 g. Tablets were carefully de-dusted before testing. Tablets were accurately weighed and placed in a drum that rotated 100 times. Tablets were removed from the drum, cleared of all dust, and then accurately weighed. A maximum average weight loss of 1.0% or less from a sample was considered acceptable. If the tablets were visibly cracked, split, or disintegrated, the test was considered to have failed. 4. Tablet hardness measurement

[0297] Tablet hardness (or crushing strength) is the force required to crush a tablet when force is applied to the edge of the tablet (see USP <1217> Tablet Breaking Force).

[0298] The thickness, hardness, and diameter of the tablets were determined using a diametral hardness tester (Kraemer Universal Test System UTS4.1).

[0299] 5.XRPD method Powder X-ray diffraction (PXRD) data were recorded on a PANalytical XPertPRO or Empyrean diffractometer using monochromated Cu-Kα radiation, a position-sensitive detector, and generator settings of 45 kV and 40 mA. Samples were collected in transmission or reflection mode. The scan range was from 3° to 50° 2θ, with a step size of 0.1° or 0.2°, and each step took a minimum of 60 seconds.

[0300] 6. Disintegration Time Method Disintegration time is the time required for a tablet to break into particles under given conditions.

[0301] The disintegration time was determined (n=6) using the apparatus described in Eur.Ph. (PTZ-E Pharmaceutical Testing, Hainburg, Germany). The test was carried out with discs in distilled water at 37°C.

[0302] 7. Powder fluidity test Powder flowability can be measured by several methods and using various devices. For pharmaceutical powders, one commonly used method is the "shear test", which measures the movement of a powder from non-flowing to flowing. The test can be described as follows (see https: / / www.freemantech.co.uk / powder-testing / ft4-powder-rheometer-powder-flow-tester / shear-testing):

[0303] At a very slow speed, a shear (or horizontal) force is applied to an upper layer of powder while keeping the adjacent lower layer motionless (or vice versa). The force continues to increase, but no relative motion occurs at the shear plane until the shear force becomes high enough to overcome the shear strength of the powder (when the powder bed "yields" and the upper layer of powder slides relative to the lower layer).

[0304] In a series of conventional shear cell tests, shear tests are carried out at various levels of normal stress. The data obtained show the relationship between shear stress and normal stress, which can be plotted to determine the failure envelope of the powder.

[0305] A number of mathematical models can be applied to this data, but in doing so it is important to consider the possibility that trends may be exaggerated or minimized. Fitting Mohr's stress circle to the failure envelope yields the maximum principal stress (σ1) and uniaxial collapse stress (σc), and the ratio of the former to the latter defines the flow function, FF. The flow function is a parameter commonly used to rank flow properties, with values ​​below 4 indicating poor flow and values ​​above 10 indicating good flow.

[0306] Example 1. Preparation of an amorphous solid dispersion of Milvexian in HPMC-AS-MG For all spray-drying processes described in Examples 1b-1g below, optimization of the spray-drying process was first performed in a medium-scale spray dryer, with post-drying performed in a vacuum drying oven. This was then transferred to an industrial-scale spray dryer, with post-drying performed using a dynamic post-dryer. Production of an ASD containing 750 mg of milvexin and 250 mg of HPMC-AS-MG in both medium- and industrial-scale spray dryers was found to produce powders with similar physical properties, i.e., large particle size, high bulk / tap density, and extremely high flowability. The powders produced at medium and industrial scales exhibited similar physical properties immediately after spray-drying (wetting the spray-dried powder). However, post-drying at the industrial scale, using a dynamic dryer instead of a tray dryer to take advantage of the fragility of the spray-dried powder due to the high amount of milvexin in the amorphous solid dispersion, resulted in a surprising increase in bulk / tap density compared to the powder produced at medium scale.

[0307] Example 1a. Solubility of Milvexian in Various Organic Solvents The main challenge in preparing spray-dried powders for direct compression is obtaining spray-dried powders with adequate flowability, large particle size, and high density. The key here is to obtain the highest possible dissolved solids concentration in a given organic solvent mixture. Additionally, solvent mixtures with low boiling points are preferred to promote rapid evaporation, keep drying temperatures low (to avoid issues related to low glass transition temperatures), and shorten drying times for large droplets / particles. The dissolved solids content and formulation must be designed to ensure a viscosity high enough to form large droplets while still being pumpable. A high dissolved solids content in the spray-dried droplets generally produces dense particles and allows for the design of particles that are more suitable for downstream processing.

[0308] Previous spray-drying solvent mixtures for milvexin are acetone / water mixtures, as disclosed in WO 2020 / 212629. Preferably, the acetone / water mixture has a 90:10 wt / w ratio, resulting in milvexin solubility of 36 mg / mL at 20°C and 70 mg / mL at 50°C, resulting in spray-dried solids contents of 5 wt% and 8 wt%, respectively. Heating the feed solution is a viable solution for production, but it introduces more complex setup, the risk of dissolved components crashing out if cold spots occur, and plant safety issues. Various solvent systems (see Table 11 below) were investigated, with a focus on solvent systems containing DCM due to its low boiling point and excellent solubility properties. [Table 13]

[0309] The results shown in the table indicate that very high solubilities of over 200 mg / mL were obtained using the DCM / MeOH system at 20° C., thus eliminating the need to heat the solution to increase solubility. Based on the data, 70 / 30% w / w DCM / MeOH and 80 / 20% w / w DCM / MeOH were determined to be promising solvent mixtures, and more accurate solubility determinations were performed for both Form A and P1, acetone solvate, in 80 / 20% w / w DCM / MeOH at 20° C., yielding the results shown in Table 12 below. [Table 14]

[0310] The present results indicate that solubilities of >220 mg / mL are achievable for both milvexian Form A and the P1.acetone milvexian form. P1.acetone is the more preferred crystalline form of milvexian for reasons of physical stability and manufacturability. Based on the above, the 80 / 20 wt / wt% DCM / MeOH solvent system was selected for development because its solubility significantly exceeded that of the 90 / 10 wt / wt% acetone / water solvent system.

[0311] Example 1b. SDP prepared using 70 / 30 wt / wt% DCM / MeOH In an initial study, 3.75 wt% HPMC-AS MG and approximately 11.25 wt% Milbexian Form A were spray-dried in a solvent mixture containing 70 / 30 wt% DCM / MeOH. Milbexian Form A began to dissolve immediately, yielding a clear yellow solution. After stirring for 10 minutes at 21°C, approximately 3.75 wt% HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd., Niigata, Japan) was added to the Milbexian solution. Stirring was continued for 5 minutes, yielding a slightly hazy yellow solution of Milbexian and HPMC-AS-MG. The viscosity of this hazy yellow solution was 21 mPa.s at 20°C. The cloudy yellow solution was spray-dried using a Buchi B-290 spray dryer equipped with a two-fluid nozzle at a maximum drying gas flow rate of approximately 35 kg / hr with the following parameters: atomization gas flow rate setting of 25 mm (301 L / hr); feed rate of 7.7 g / min; inlet / exhaust temperature of 70 / 43°C; liquefier temperature of -20°C; spray nozzle orifice diameter of 0.7 mm; and spray nozzle cap diameter of 1.4 mm. The spray-drying process lasted for 11 minutes, yielding 15.30 g of wet ASD (98% yield). The wet ASD was then dried in a vacuum oven (Heraeus, Model VT6130 M) at 40°C with nitrogen flow and a vacuum of approximately 250 mbar for 24 hours, yielding 14.40 g (92% yield) of the desired SDP product. The SDP product was a white powder with an assay of 99.5% and a purity of 100% by HPLC. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks present, indicating that the product was amorphous.

[0312] Example 1c. SDP prepared using 70 / 30 wt / wt% DCM / MeOH A solution containing approximately 12.3 wt% Milvexian P1 in acetone (corresponding to approximately 11.25 wt% free Milvexian) and 3.75 wt% HPMC-AS MG was prepared in a 70 / 30 wt% DCM / MeOH solvent mixture. Milvexian P1 in acetone immediately began to dissolve, but the solution remained slightly cloudy. After stirring for 10 minutes at room temperature (i.e., 25°C), approximately 250 mg (3.75 wt%) of HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd., Niigata, Japan) was added to the Milvexian solution. Stirring was continued for 5 minutes, resulting in a yellow, cloudy solution of Milvexian and HPMC-AS-MG. The viscosity of this yellow, cloudy solution was 17 mPa.s at 20°C. The cloudy yellow solution was spray-dried using a Buchi B-290 spray dryer equipped with a two-fluid nozzle at a maximum drying gas flow rate of approximately 35 kg / hr with the following parameters: atomization gas flow rate setting of 25 mm (301 L / hr); feed rate of 7.8 g / min; inlet / exhaust temperature of 67 / 46°C; liquefier temperature of -20°C; spray nozzle orifice diameter of 0.7 mm; and spray nozzle cap diameter of 1.4 mm. The spray-drying process lasted for 11 minutes, yielding 12.08 g of wet ASD (93% yield). The wet ASD was then dried in a vacuum oven (Heraeus, Model VT6130 M) at 40°C with nitrogen flow and a vacuum of approximately 250 mbar for 24 hours, yielding 11.33 g (87% yield) of the desired SDP product. The SDP product was a white powder with an assay of 101.4% and a purity of 99.8% by HPLC. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks present, indicating that the product was amorphous.

[0313] When dissolving Milvexian (P1, acetone) in 70 / 30 wt / wt% DCM / MeOH, due to the cloudy appearance of the solution, a solubility test was performed by adding 3.75 g of Milvexian (P1, acetone) to a mixture of 19.83 g of DCM and 8.5 g of MeOH (70 / 30 wt / wt%) while stirring with a magnetic stirrer. The appearance of the solution was evaluated at different time points over a 20-hour period. After mixing for approximately 20 hours, the solution remained cloudy, leading to the conclusion that Milvexian was not fully soluble. However, no crystalline material was present, suggesting only a small amount of insoluble material.

[0314] The SDPs of Examples 1b and 1c were stored under different storage conditions and evaluated for physical and chemical stability, as shown in the table below. SEM analysis showed spherical and "imploded" spherical particles in both SDPs at all storage conditions, indicating the amorphous solid state of the SDPs. This was also supported by synchrotron-XRD analysis, which showed no trace of crystalline drug substance in the SDP of Example 1a. PXRD analysis indicated that both ASDs were amorphous at all tested storage conditions (see Table 13 below). Modulated DSC analysis of both ASDs showed a stable time-dependent glass transition temperature (Tg) in the range of 144-147°C. [Table 15]

[0315] Example 1d. Preparation of SDP using 80 / 20 wt / wt% DCM / MeOH A solution containing approximately 12.3 wt% milvexian P1.acetone (corresponding to approximately 11.25% free milvexian) and approximately 3.75% HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd., Niigata, Japan) in an 80 / 20 wt% DCM / MeOH solvent mixture was prepared. The P1.acetone and HPMC-AS MG dissolved immediately, resulting in a pale yellow, clear solution. The clear solution was then spray-dried at room temperature (i.e., 21°C) using a Buchi B-290 spray dryer with a maximum drying gas flow rate of approximately 35 kg / hr and the following parameters: atomization gas flow rate set at 25 mm (301 L / hr); feed rate of 7.7 g / min; inlet / exhaust temperatures of 64 / 45°C; liquefier temperature of -20°C; spray nozzle orifice diameter of 0.7 mm; and spray nozzle cap diameter of 1.4 mm. The spray-drying process was carried out for 11 minutes to give 9.9 g of wet SDP (76% yield), which was then dried in a vacuum oven (Heraeus, Model VT6130 M) at 40°C with nitrogen flow and a vacuum of approximately 250 mbar for 24 hours to give 9.3 g (72% yield) of the desired dry SDP.

[0316] The SDP product was a white powder with an assay of 97.7% and a purity of 99.9% by HPLC. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks present, indicating that the product was amorphous.

[0317] The resulting spray-dried SDP was evaluated for manufacturability and assayed for impurities, residual solvents, and solid-state analysis. The assay was 97.7% and the purity was 99.9%. Residual solvent concentrations after spray drying were: methanol <50 ppm, acetone 278 ppm, and methylene chloride 118 ppm. All concentrations were well below the required solvent concentrations specified in the ICH Q3C guidelines. Overall, the results demonstrated that the formulation was suitable for manufacturing. Solid-state NMR analysis indicated that the powder was amorphous and had a glass transition temperature of approximately 145°C.

[0318] Example 1e. Preparation of SDP using 80 / 20% w / w DCM / MeOH A solution containing approximately 12.3 wt% milvexian P1.acetone (approximately 11.25% free milvexian) and approximately 3.75% HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd., Niigata, Japan) in an 80 / 20 wt% DCM / MeOH solvent mixture was prepared. The P1.acetone and HPMC-AS MG dissolved immediately, resulting in a pale yellow, clear solution. The clear solution was then spray-dried at room temperature (i.e., 21°C) using a Buchi B-290 spray dryer with a maximum drying gas flow rate of approximately 35 kg / hr and the following parameters: atomization gas flow rate set at 25 mm (301 L / hr); feed rate of 7.5 g / min; inlet / exhaust temperatures of 65 / 43°C; liquefier temperature of -20°C; spray nozzle orifice diameter of 0.7 mm; and spray nozzle cap diameter of 1.4 mm. The spray-drying process was carried out for 11 minutes to give 10.4 g of wet SDP (82% yield), which was then dried in a vacuum oven (Heraeus, Model VT6130 M) at 40°C with nitrogen flow and a vacuum of approximately 200 mbar for 24 hours to give 9.6 g (76% yield) of the desired dry SDP.

[0319] The SDP product was a white powder with an assay of 96.7% and a purity of 99.9% by HPLC. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks, indicating that the product was amorphous.

[0320] The resulting spray-dried SDP was evaluated for manufacturability and assayed for impurities, residual solvents, and solid-state analysis. The assay was 96.7% and the purity was 99.9%. Residual solvent concentrations after spray drying were: methanol <50 ppm, acetone 310 ppm, and methylene chloride 117 ppm. All concentrations were well below the required solvent concentrations specified in the ICH Q3C guidelines. Overall, the results demonstrated that the formulation was suitable for manufacturing. Solid-state NMR analysis indicated that the powder was amorphous, and mDSC analysis indicated a glass transition temperature of approximately 144°C.

[0321] Example 1f. Preparation of SDP using 80 / 20% w / w DCM / MeOH A solution containing approximately 12.3 wt% milvexian P1.acetone (corresponding to approximately 11.25% free milvexian) and approximately 3.75% HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd., Niigata, Japan) in an 80 / 20 wt% DCM / MeOH solvent mixture was prepared. The P1.acetone and HPMC-AS MG dissolved fairly quickly, resulting in a clear, pale yellow solution. The clear solution was then spray-dried at 21°C using a Buchi B-290 spray dryer with a maximum drying gas flow rate of approximately 35 kg / hr and the following parameters: atomization gas flow rate set to 25 mm (301 L / hr); feed rate of 7.7 g / min; inlet / exhaust temperatures of 67 / 44°C; liquefier temperature of -19°C; spray nozzle orifice diameter of 0.7 mm; and spray nozzle cap diameter of 1.4 mm. The spray-drying process was carried out for 11 minutes, yielding 11.5 g of wet SDP (89% yield). The wet SDP was then dried in a vacuum oven (Heraeus, Model VT6130 M) at 40°C, nitrogen flow, and approximately 200 mbar vacuum for 24 hours, yielding 10.7 g (83%) of the desired dry SDP.

[0322] The SDP product was a white powder with an assay of 98.8% and a purity of 99.9% by HPLC. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks, indicating that the product was amorphous.

[0323] The resulting spray-dried SDP was evaluated for manufacturability and assayed for impurities, residual solvents, and solid-state analysis. The assay was 98.8% and the purity was 99.9%. Residual solvent concentrations after spray drying were: methanol <50 ppm, acetone 225 ppm, and methylene chloride <52 ppm. All concentrations were well below the required solvent concentrations specified in the ICH Q3C guidelines. Overall, the results demonstrated that the formulation was suitable for manufacturing. Solid-state NMR analysis indicated that the powder was amorphous, and mDSC analysis indicated a glass transition temperature of approximately 144°C. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks, indicating the product was amorphous (Figure 9).

[0324] As a result of the poor solubility of Milvexian in a solvent system containing 70 / 30% w / w DCM / MeOH (remaining cloudy after 20 hours), as seen in Example 1c, and based on the comparable stability of the spray-dried powder produced from Milvexian P1.acetone Form A to Milvexian crystalline Form A, as seen in Examples 1d-1f above, and Example 1b, the volume ratio of DCM / MeOH was increased from 70 / 30 to 80 / 20% w / w, and crystalline Milvexian acetone solvate Form P1.acetone was used in place of Milvexian crystalline Form A.

[0325] Based on the above experimental results, a 3 / 1 milbexian / HPMC-AS MG formulation was selected for spray-drying ASDP tablet production. This formulation contains approximately 750 mg of free milbexian (equivalent to 819.67 mg of crystalline P1 acetone solvate form) per gram, i.e., approximately 750 mg of free milbexian (acetone solvate, equivalent to 750 mg of free milbexian) per 250 mg of HPMC-AS MG. The flow chart in Figure 1 illustrates the entire spray-drying process.

[0326] Example 1g. Scale-up of the spray-drying process Approximately 12.3 wt.% Milvexian P1.acetone (corresponding to approximately 11.25 wt.% free Milvexian) and approximately 3.75 wt.% HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd., Niigata, Japan) were mixed with a solvent mixture containing 80 / 20 wt.% DCM / MeOH. The Milvexian P1.acetone and HPMC-AS MG dissolved fairly quickly, yielding 400 kg of a pale yellow, clear solution. The clear solution at 21°C was spray-dried using a GEA PSD-3 spray dryer with the following parameters: drying gas flow rate of 750 kg / hr, pressure atomization at 28 Bar, feed rate of approximately 75 kg / h; inlet / outlet temperatures of approximately 98 / 45°C; and liquefier temperature of approximately -10°C. The spray-drying process continued for approximately 1.5 hours, yielding 12.4 kg of wet SDP. The wet SDP was dried in a vacuum oven (Pink, Model VSD-650-650-140-7) at 40° C. for 22 hours under nitrogen flow and a vacuum of approximately 200 mbar.

[0327] The powder product has a particle size distribution median diameter D of about 49 μm with a span of about 1.7 V,50 and 0.20 / 0.28 g / cm 3 The bulk / tap density was

[0328] Example 1h. Solubility of SDP prepared in Example 1c During this spray-drying process, the crystalline acetone solvate (P1.acetone) form was dissolved in an 80 / 20% w / w DCM / MeOH solvent mixture and then converted to the amorphous free form as all solvent was evaporated to below ICH Q3C concentration. The crystalline Milvexian P1.acetone form is preferred instead of the free form of Milvexian as the starting material for the production of SDP due to its superior morphology and robust crystallization process.

[0329] As shown in Table 14, the aqueous solubility of the amorphous form (SDP) was found to be higher compared to the crystalline Milbexian Acetone P1.acetone. The dissolution rate of the amorphous form of the drug substance (amorphous solid dispersion-based spray-dried powder) is also significantly higher than the crystalline free form of the drug substance in aqueous media based on human physiology. [Table 16]

[0330] Example 2. Film-coated tablets manufactured by direct compression Example 2A. Optimization of Binder / Bulking Agent Weight Ratio Initially, microcrystalline cellulose (MCC) and lactose were selected as excipients due to their manufacturability, compressibility, and flowability. Various MCC / lactose ratios were tried in this initial screening study.

[0331] A 25 mg dose of milbexian-free solids with 33 wt % solid amorphous dispersion particles was used in Examples 1, 2, 3, and 4. See Table 15. Croscarmellose sodium was selected as a disintegrant at 5 wt % based on the total weight of the powder mixture, enabling a short tablet disintegration time (e.g., less than 2 minutes). Magnesium stearate was selected as a lubricant at 1 wt % based on the total weight of the powder mixture, taking into account continuous manufacturing (CM) requirements (e.g., the ability to provide low-density materials at high throughput). The compositions of Examples 1, 2, 3, and 4 are provided in Table 19 below. The ingredients of the powder blends of Examples 1, 2, 3, and 4 were mixed using a Turbula blender and compressed on a Courtoy Excentre single punch press (KC01) equipped with punch set AC27 / 4 (6 mm round) at a compression force of 300 kg (2.9 kN) for Examples 1 and 4, 550 kg (5.4 kN) for Example 2, and 400 kg (3.9 kN) for Example 3. Manufacturability (adhesion and tablet stability) was assessed based on powder blend properties (visual observation) and tablet properties (weight (variability), hardness, disintegration time). In-process control (IPC) results for tablet properties and powder blend manufacturability are summarized in Table 15 below. [Table 17]

[0332] According to the results in Table 15 above, the powder mixture of Example 4 exhibited extremely high manufacturability (e.g., no wall sticking was observed), and the resulting tablets exhibited extremely high stability (e.g., little variation in tablet weight and quality). Therefore, for the tablet composition of Example 4, a 3:2 weight ratio (60 / 40 wt / wt%) of binder (microcrystalline cellulose):lactose monohydrate (excipient) was selected for further investigation. In addition, 5.0 wt% croscarmellose sodium and 1 wt% magnesium stearate were deemed suitable for achieving the desired tablet quality.

[0333] Example 2B. Binder Optimization The binder composition shown in Example 4 (see Table 15 above), in which the weight ratio of MCC PH102 (binder) / lactose monohydrate (excipient) is 60 / 40, was further optimized. As illustrated in Examples 5, 6, and 7, the microcrystalline cellulose PH102 in Example 4 was replaced with silicified microcrystalline cellulose SMCC 90 and SMCC HD90.

[0334] A dose of 25 mg of free milbexian per 100 mg tablet weight (33 wt % spray-dried SDP load) was used in Examples 4, 5, and 6. See Table 16. A dose of 25 mg of free milbexian per 150 mg tablet weight (22 wt % spray-dried SDP load) was used in Example 7. Croscarmellose sodium and magnesium stearate were used as disintegrants and lubricants, respectively.

[0335] The compositions of Examples 4, 5, 6, and 7 are provided in Table 16 below. The ingredients for the compositions of Examples 4, 5, and 6 (100 mg total tablet weight) were blended using a Turbula blender and compressed on a Courtoy Excentre single punch press equipped with punch set AC27 / 4 (6 mm round) at 300 kg (2.9 kN) compression force. The ingredients for the composition of Example 7 (150 mg total tablet weight) were blended and compressed on a Courtoy Excentre single punch press (KC01) equipped with punch set AC27 / 7 (7 mm round) at 350 kg (3.4 kN) compression force. Manufacturability was assessed based on blend characteristics (visual inspection) and tablet characteristics (weight (variability), hardness, thickness, disintegration time). In-process control (IPC) results are shown in Table 16 below.

[0336] In Examples 4, 5, and 6, each having a total tablet weight of 100 mg, only Example 4 exhibited acceptable blend properties, as blend sticking to the wall was observed in Examples 5 and 6. The powder blend of Example 7, having a total weight of 150 mg, did not exhibit wall sticking. Furthermore, the 150 mg tablets obtained in Example 7 exhibited a short disintegration time (13 seconds) compared to the disintegration time of the 100 mg tablets obtained in Example 4 (48 seconds).

[0337] Considering the results of Examples 4, 5, 6, and 7 shown in Table 16, the composition of Example 7 (22 wt% SDP loading) for preparing 150 mg tablets (Example 7 including a 3:2 (60 / 40) ratio of SMCC 90 / lactose monohydrate) was selected as the lead composition for further optimization to improve tablet robustness. Additionally, SMCC 90 grade as a binder and a 3:2 (60 / 40) weight ratio of SMCC 90:lactose monohydrate were selected for the solid pharmaceutical compositions of Milvexian described herein. [Table 18]

[0338] Example 2C. Optimization of lactose grade Previous experience has shown that the use of lactose monohydrate (lactose Supertab) can cause problems in physiologically based dissolution tests (PBDTs). Lactose Supertab has been observed to trap solid dosage forms in the PBDT dissolution tank. To evaluate this possible effect of lactose grade, a new formulation (Example 8) containing lactose tablettose was prepared. The compositions of Examples 7 and 8 are provided in Table 17 below, and various grades of lactose were used. [Table 19]

[0339] Both Example 7 and Example 8 were evaluated for PBDT and blend properties. Both Example 7 and Example 8 had similar PBDT profiles, suggesting that lactose grade does not have a significant effect on the PBDT dissolution profile. See Figure 2.

[0340] However, the properties of the blend of Example 8 are less favorable compared to those of the blend of Example 7 (see Table 17 and Figures 3-4). The bulk and tapped densities of Example 8 are lower than those of Example 7, which may make it less manufacturable when using a continuous production mode for tableting, as the density is too low to be fed through a feeder at high throughput. Taking into account the similar PBDT profile and the more favorable blend properties of Example 7, lactose grade Supertab 11SD is selected for the solid pharmaceutical composition of Milvexian described herein.

[0341] Example 2D. Optimization of Disintegrants To explore different types of disintegrants, the lead formulation using croscarmellose sodium (Example 7) was compared to Examples 9 and 10, which contained L-hydroxypropyl cellulose (L-HPC) and crospovidone as disintegrants, respectively. The compositions of Examples 7, 9, and 10, as well as the powder mixing and compression equipment and parameters, are provided in Table 18 below.

[0342] Three different powder blends, each with a different disintegrant (Example 7: croscarmellose sodium, Example 9: L-HPC, and Example 10: crospovidone), were prepared according to the compositions provided in Table 18 below. Based on previous formulation screening studies shown in Tables 15-17 above, SMCC 90 was selected as the binder, and lactose monohydrate Supertab 11SD was used as the filler (a weight ratio of 3:2 (60 / 40) SMCC 90 / Lactose Monohydrate® 11SD), applying a dose of 25 mg of milbexian-free form per 150 mg of total weight (resulting in a 22% SDP load).

[0343] Manufacturability was evaluated based on blend characteristics (visual inspection) and tablet characteristics (weight (variability), hardness, thickness, disintegration time) (Table 18 below). The dissolution profiles of Examples 7, 9, and 10 were compared per dose strength (Figures 5 and 6). [Table 20]

[0344] Slightly longer disintegration time results and a slower dissolution profile were observed in Example 9 (containing L-HPC) compared to Example 7 (containing croscarmellose sodium). Similar dissolution profiles, blend and tablet properties were observed in Example 10 (containing crospovidone) compared to Example 7 (containing croscarmellose sodium). Based on these results shown in Table 18 above, croscarmellose sodium was used as the disintegrant.

[0345] From the screening study so far, it can be concluded that Example 7 is selected as the lead composition for the 25 mg tablet of Milvexian-free. The composition for scale-up production is shown in Table 19. [Table 21]

[0346] Example 3. Scaled-up direct compression manufacturing process for Milvexian 25 mg and 100 mg film-coated tablets Example 3A The manufacturing process flow chart for Milvexian 25 mg oral tablet cores and 100 mg oral tablet cores is shown in Figure 7. The manufacturing process flow chart for Milvexian 25 mg oral film-coated tablets and 100 mg oral film-coated tablets is shown in Figure 8. Therefore, Figures 7 and 8 together describe the manufacturing process for Milvexian tablets.

[0347] In this study, the dose proportionality of the lead composition (see Table 19) was evaluated. A mixture (having a 22% SDP loading) was prepared according to the composition shown in Table 19. This mixture was then used to make four dose proportional tablet compositions with 25, 50, 75, and 100 mg doses of milbexian-free agent per 150, 300, 450, and 600 mg total tablet weight, respectively. A summary of the test compositions is provided in Table 20. [Table 22]

[0348] Four compositions were prepared from the same mixture (Table 19 above) using the manufacturing equipment and compression forces indicated in Table 21. [Table 23]

[0349] The manufacturability was evaluated based on the blend properties (sticking / static tendency, flowability, segregation tendency) and tablet properties (weight (variability), hardness, thickness, disintegration time). The blend IPC results and tablet IPC results are shown in Table 22 and Table 23. Figure 4 shows the particle size distribution of the blends. [Table 24] [Table 25]

[0350] Based on the blend IPC and tablet IPC results, it can be concluded that the composition of the lead composition of Milvexian Free 25 mg tablets (see Table 19 above) is suitable for the manufacture of dose proportional tablets.

[0351] In this study, round punches were used for all tablet strengths. For the 100 mg tablets, round punches were not preferred for patient compliance (swallowability issues in the elderly), so 11 mm round tablets were prepared. Therefore, oval tablets were evaluated for the 100 mg dose tablets.

[0352] The tablets were compressed on an Excentre single punch tablet press with punch set AC27 / 67 (16.6 mm x 8 mm oval) at 650 kg (6.4 kN) compression force. Manufacturability was assessed based on blend properties (visual inspection) and tablet properties (weight (variability), hardness, thickness, disintegration time). IPC results are shown in Table 24. [Table 26]

[0353] Based on these results, it is believed that a change in dosage form from round to oval is appropriate for the 100 mg Milvexian-free tablet formulation.

[0354] The same disintegrant screening performed on the 25 mg Milvexian-free tablets was also performed on the 100 mg Milvexian-free tablets. Croscarmellose sodium was similarly selected as the disintegrant, and the 100 mg Milvexian-free tablets, which have the same formulation as the lead 25 mg tablets, were selected as the lead composition. Both lead compositions are shown in Table 25 below. [Table 27]

[0355] Example 3B. Scale-up of direct compression film-coated tablet manufacturing process The manufacturing process flow charts for Milvexian 25 mg oral tablet core (Example 11) and 100 mg oral tablet core (Example 12) are shown in Table 25 and Figure 7.

[0356] The manufacturing process flow charts for Milvexian 25 mg film-coated tablets (Example 17) and 100 mg film-coated tablets (Example 18) are shown in Table 26 and Figure 8.

[0357] Various continuous manufacturing runs using the optimized process described in Example 3B demonstrated a robust continuous manufacturing process for flowability, CU, hardness, and weight (see backup slide). Robust content uniformity achieved during development: 11 CM runs for both 25 mg and 100 mg with RSDs of 0.8% to 2.2%. Robust weight achieved during development for both strengths: 11 CM runs for both 25 mg and 100 mg with RSDs of 0.5% to 2%. Robust tablet hardness: Within IPC limits regardless of spray drying scale, spray drying conditions, and CM conditions (mixing and lubrication speed, and line throughput). [Table 28]

[0358] Example 3C. Film-coated tablets of Milvexian, 100 mg per dose, prepared by roller compaction The SDP prepared according to Example 1e above was used to prepare a 100 mg per dose film-coated tablet of Milvexian by dry granulation and roller compaction (RC tablet, Example 19). The composition of the RC tablet of Example 19 is shown in Table 27 below. [Table 29]

[0359] Example 4. Dissolution and stability tests of Examples 17 and 18 Stability Testing and Results The shelf-life stability of the formulations of Examples 17 and 18 in all climate zones was determined at 25°C / 60% RH and 30°C / 75% RH in high-density polyethylene (HDPE) bottles containing 2g silica. No changes in appearance were observed. HPLC assays showed no degradation impurities. XPRD showed no signs of crystalline API formation in the formulations. Film-coated tablets of 25mg and 100mg Milvexian are stable at 25°C / 60% RH and 30°C / 75% RH for at least 24 months.

[0360] In a given dissolution test using a paddle apparatus (USP Type 2), the plateaus show no signs of crystalline API formation in the formulation. Additionally, solid-state NMR showed no evidence of crystalline API formation upon storage of the formulation in HDPE bottles for 22 months.

[0361] Dissolution Test and Results Dissolution tests were conducted in 900 mL dissolution medium at 37°C using a paddle apparatus (USP Type 2, Ph.Eur., JP) at a rotation speed of 75 rpm. Samples were removed at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes and analyzed for Milvexian by UHPLC with UV at 220 nm. 0.05 M acetate buffer, pH 4.5, containing 0.2% (w / v) sodium lauryl sulfate (SLS) solution was used as the dissolution medium during formulation development. The role of SLS (a surfactant) in the dissolution medium is not to enhance the solubility of Milvexian, but rather to act as a wetting aid to promote complete dissolution of Milvexian from the tablets. Unless otherwise specified, dissolution data from both tests are included in this disclosure, and reported results are the average of six tablets.

[0362] Dissolution testing using the standard USP method described above was performed on the 25 mg and 100 mg tablets of Examples 17 and 18 and is summarized below in Table 28. The results are also illustrated in Figure 10. [Table 30]

[0363] Example 5. Bioavailability testing and results of Examples 17 and 18 compared to Comparative Examples 1 and 2 in healthy subjects The Phase 1 study is an open-label, randomized, crossover study to evaluate the relative oral bioavailability, pharmacokinetics, and food effect after single (Parts 1, 3, and 4) or multiple (Part 2) doses. The objective of Part 1 of this initial Phase 1 study is to evaluate the relative bioavailability and food effect of a single 200 mg dose of Milvexian administered as a film-coated DC tablet of Example 18 and a film-coated RC tablet of Example 19 compared to SDP oral capsules of Comparative Example 1 under fasted and fed conditions. The objective of Part 2 of this initial Phase 1 study is to characterize the pharmacokinetics (PK) of repeated twice-daily, 5-day doses of Milvexian administered as Example 18 and 25 mg or 200 mg of Comparative Example 1 or Comparative Example 2 (SDP oral capsules). Comparative Example 1 and Comparative Example 2 capsule formulations (see Table 29 below) are described in WO 2020 / 210629, and the capsules contain MCC and lactose anhydrous DC in a 1:1 weight ratio (binder (MCC): filler (lactose anhydrous)).

[0364] As specified in the clinical study protocol, blood samples were collected at predetermined time points after drug administration. Sample concentrations were measured using a validated analytical method (liquid chromatography / tandem gravimetric analysis). Pharmacokinetic parameters of interest (e.g., Cmax, AUC last , and AUC ∞ ) is calculated from the time-concentration profile by Phoenix (登録商標) WinNonlin (登録商標) (Version 8.1, Pharsight, A Certara (登録商標) The non-compartmental method is derived using software from the University of Pennsylvania (University of Pennsylvania, Princeton, NJ, USA). [Table 31]

[0365] The treatment regimens for Parts 1 and 2 are summarized in Table 30 below. [Table 32]

[0366] The results of the Part 1 study are summarized in Tables 31-32 and Figures 11A-B and 12A-B.

[0367] In Part 1, a single-dose regimen, at a 200 mg dose, compared to Comparative Example 1 (SDP capsule), Example 18 (DC tablet) exhibited approximately 9.0% to approximately 11% lower bioavailability, and Example 19 (RC tablet) exhibited approximately 15% to approximately 20% lower bioavailability. At a 200 mg dose, Example 18 (DC tablet) exhibited approximately 20% to 40% higher drug exposure under fed conditions, and Example 19 (RC tablet) exhibited approximately 60% to 80% higher drug exposure under fed conditions. At a 200 mg dose, Example 18 (DC tablet) exhibited approximately 42% higher drug exposure under fed conditions [AUCinf], and Example 19 (RC tablet) exhibited approximately 76% higher drug exposure under fed conditions [AUCinf]. Example 18 (DC tablet) exhibited minimal food effects. To achieve better patient compliance, Milvexian is preferably administered with or without food. A formulation with reduced food effect provides better patient compliance. The results in Figures 12A and 12B show that Example 18DC tablets performed better than Example 19RC tablets due to reduced food effect.

[0368] Table 31 summarizes the statistical results for the mean estimated proportion and 90% confidence interval (90% CI) of milbexian: Treatment A / Treatment C; pharmacokinetic data analysis set (Figures 11A-11B). [Table 33]

[0369] Table 32 summarizes the statistical results for the mean estimated proportions and 90% confidence intervals (90% CI) of the Milvexian sensitivity analysis: Treatment D / Treatment A; pharmacokinetic data analysis set (Figures 12A and 12B below). [Table 34]

[0370] In Part 2 of the multiple-dose BID regimen, Example 18 (DC tablets) exhibits approximately 5-7% lower bioavailability at 200 mg compared to Comparative Example 1 (SDP capsules). At 25 mg, Example 17 (DC tablets) exhibits approximately 11-13% lower bioavailability compared to Comparative Example 2 (SDP capsules).

[0371] The results are summarized in Tables 33-34 and Figures 13A-13D. Table 33 summarizes the mean estimated proportions and 90% confidence intervals for Milvexians: Treatment G / Treatment H; Pharmacokinetic Data Analysis Set. [Table 35]

[0372] Table 34 summarizes the mean estimated proportions and 90% confidence intervals (90% CI) of Milvexians: Treatment I / Treatment J; Pharmacokinetic Data Analysis Set. [Table 36]

[0373] In the second Phase 1 study, Part 1 was an open-label, randomized, three-way crossover study in healthy subjects to evaluate the relative oral bioavailability, pharmacokinetics, and food effect of a single oral dose of 200 mg Milvexian as 2 x 100 mg DC tablets of Example 18 compared to a 200 mg capsule of Comparative Example 1 under fasting conditions. It also evaluated the effect of food on the bioavailability of Milvexian after a single dose of 200 mg Milvexian as 2 x 100 mg DC tablets of Example 18. Part 2 was an open-label, randomized, two-way crossover study in healthy subjects to evaluate the PK and relative bioavailability of a single oral dose of 50 mg Milvexian as 2 x 25 mg DC tablets of Example 17 compared to 50 mg Milvexian as 2 x 25 mg granule capsules of Comparative Example 2 under fasting conditions in healthy subjects.

Claims

1. a. A spray-dried amorphous solid dispersion (SDP) consisting essentially of milbecian free form and a pH-dependent enteric polymer; b. a binder that is microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof; c. a bulking agent that is lactose monohydrate; d. disintegrants; and e. Lubricant 1. A solid pharmaceutical composition for oral administration comprising: The free milbexian is present in an amount ranging from about 10% to about 40% by weight of the total weight of the solid pharmaceutical composition; and the binder and lactose monohydrate are present in a weight ratio (binder:lactose monohydrate) ranging from about 3:2 to about 3:1; Solid pharmaceutical compositions.

2. The pH-dependent enteric polymer dissolves in an aqueous medium at a pH of about 5.5 to about 6.

8. The solid pharmaceutical composition of claim 1.

3. The solid pharmaceutical composition comprises about 11.0% to about 21.0% by weight of milbexian free form. A solid pharmaceutical composition according to any one of the preceding claims.

4. The solid pharmaceutical composition comprises about 16.67% by weight of free milbexian. A solid pharmaceutical composition according to any one of the preceding claims.

5. The pH-dependent enteric polymer is hydroxypropyl methylcellulose-AS MG; A solid pharmaceutical composition according to any one of the preceding claims.

6. The spray-dried amorphous solid dispersion has a particle size distribution median diameter D of 45 μm or less. Ｖ，５０ having A solid pharmaceutical composition according to any one of the preceding claims.

7. the solid pharmaceutical composition comprising from about 13.3% to about 53.3% by weight of the spray-dried amorphous solid dispersion; A solid pharmaceutical composition according to any one of the preceding claims.

8. the solid pharmaceutical composition comprising from about 14.67% to about 28.0% by weight of the spray-dried amorphous solid dispersion; A solid pharmaceutical composition according to any one of the preceding claims.

9. the solid pharmaceutical composition comprising about 22.22% by weight of the spray-dried amorphous solid dispersion; A solid pharmaceutical composition according to any one of the preceding claims.

10. the binder is silicified microcrystalline cellulose; A solid pharmaceutical composition according to any one of the preceding claims.

11. the solid pharmaceutical composition comprising about 21.0% to about 71.0% by weight of silicified microcrystalline cellulose; A solid pharmaceutical composition according to any one of the preceding claims.

12. the solid pharmaceutical composition comprising about 31.0% to about 61.0% by weight of silicified microcrystalline cellulose; A solid pharmaceutical composition according to any one of the preceding claims.

13. the solid pharmaceutical composition comprising about 38.0% to about 48.0% by weight of silicified microcrystalline cellulose; A solid pharmaceutical composition according to any one of the preceding claims.

14. The solid pharmaceutical composition comprises about 43.07% by weight of silicified microcrystalline cellulose. A solid pharmaceutical composition according to any one of the preceding claims.

15. the solid pharmaceutical composition comprising about 25.0% to about 33.0% by weight of lactose monohydrate; A solid pharmaceutical composition according to any one of the preceding claims.

16. The solid pharmaceutical composition comprises about 28.71% by weight of lactose monohydrate. A solid pharmaceutical composition according to any one of the preceding claims.

17. The disintegrant is croscarmellose sodium. A solid pharmaceutical composition according to any one of the preceding claims.

18. the solid pharmaceutical composition comprising about 3.0% to about 7.0% by weight of croscarmellose sodium; A solid pharmaceutical composition according to any one of the preceding claims.

19. The solid pharmaceutical composition comprises about 5.0% by weight of croscarmellose sodium. A solid pharmaceutical composition according to any one of the preceding claims.

20. The lubricant is magnesium stearate, A solid pharmaceutical composition according to any one of the preceding claims.

21. the composition comprising about 0.5% to about 2.0% by weight of magnesium stearate; A solid pharmaceutical composition according to any one of the preceding claims.

22. the composition comprising about 1.0% (wt / wt) magnesium stearate; A solid pharmaceutical composition according to any one of the preceding claims.

23. a) about 11.0% to about 21.0% by weight of free milbexian; b) about 14.67% to about 28.0% by weight of a spray-dried amorphous solid dispersion (SDP); c) about 38.0% to about 48.0% by weight of silicified microcrystalline cellulose (SMCC90); d) about 25.0% to about 33.0% by weight of lactose monohydrate; e) about 3.0% to about 7.0% by weight of croscarmellose sodium; and f) about 0.5% to about 1.5% by weight of magnesium stearate consisting essentially of The solid pharmaceutical composition of claim 1.

24. a) about 16.67% by weight of free milbexian; b) about 22.22% by weight of a spray-dried amorphous solid dispersion (SDP); c) about 43.07% by weight of silicified microcrystalline cellulose (SMCC90); d) about 28.71% by weight of lactose monohydrate; e) about 5.0% by weight of croscarmellose sodium; and f) about 1.0% by weight of magnesium stearate consisting essentially of The solid pharmaceutical composition of claim 1.

25. The solid pharmaceutical composition is a free-flowing powder mixture. A solid pharmaceutical composition according to any one of the preceding claims.

26. the free-flowing powder mixture having a tap density of about 0.56 g / mL; 26. The solid pharmaceutical composition of claim 25.

27. the free-flowing powder mixture having a bulk density of about 0.47 g / mL; 27. A solid pharmaceutical composition according to claim 25 or 26.

28. The free flowing powder mixture has a flow function coefficient (ring shear) of 10.

28. The solid pharmaceutical composition according to any one of claims 25 to 27.

29. The free flowing powder mixture has an angle of repose of 50.

17. The solid pharmaceutical composition according to any one of claims 25 to 28.

30. A unit dosage form for oral administration comprising the solid pharmaceutical composition of any one of claims 1 to 29.

31. A pharmaceutical capsule comprising the solid pharmaceutical composition of any one of claims 1 to 29.

32. A pharmaceutical tablet core comprising the solid pharmaceutical composition of any one of claims 1 to 29.

33. A pharmaceutical tablet core formed by direct compression of the pharmaceutical composition of any one of claims 1 to 29.

34. 34. A film-coated pharmaceutical tablet comprising the pharmaceutical tablet core of claim 32 or 33 and a film coating covering the outer surface of the pharmaceutical tablet core.

35. the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc; or the film coating comprises a polyethylene glycol-polyvinyl alcohol graft copolymer; 35. The film-coated pharmaceutical tablet of claim 34.

36. the film coating is polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc; 36. A film-coated pharmaceutical tablet according to claim 34 or 35.

37. The film coating has a weight increase of about 2.0% to about 4.0% relative to the uncoated tablet. The film-coated pharmaceutical tablet according to any one of claims 34 to 36.

38. The film coating accounts for a weight increase of about 3.0% compared to the uncoated tablet. The film-coated pharmaceutical tablet according to any one of claims 34 to 37.

39. a. i. A spray-dried amorphous solid dispersion (SDP) consisting essentially of a milbectic free form and a pH-dependent enteric polymer ii. a binder selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof; iii. lactose monohydrate; iv. disintegrants; v. Lubricant a nucleus comprising: b. A film coating covering the core, comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc; or a film coating comprising polyethylene glycol-polyvinyl alcohol graft copolymer. A pharmaceutical tablet comprising: The milvexian is present in an amount ranging from about 10% to about 40% by weight of the total weight of the core; and the binder and lactose monohydrate are contained in the core in a weight ratio (binder:lactose monohydrate) ranging from about 3:2 to about 3:1; Pharmaceutical tablets.

40. The tablet contains about 25 mg of Milvexian. The tablet according to any one of claims 32 to 39.

41. The tablet contains about 100 mg of Milvexian. The tablet according to any one of claims 32 to 39.

42. The tablets have a friability of less than 0.5%. The tablet according to any one of claims 32 to 41.

43. The tablet has a disintegration time of less than 2 minutes. The tablet according to any one of claims 32 to 42.

44. The tablet has a disintegration time of less than 20 seconds. The tablet according to any one of claims 32 to 42.

45. An amorphous solid dispersion comprising 75% by weight of Milvexian and 25% by weight of a pH-dependent enteric polymer, wherein the amorphous solid dispersion has a particle size distribution median diameter D of 45 μm or less. Ｖ，５０ 1. An amorphous solid dispersion comprising:

46. The polymer is hydroxypropylmethylcellulose-AS-MG; 46. ​​The amorphous solid dispersion of claim 45.

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