Enhanced performance of amorphous solid and solubilized formulations for achieving therapeutic plasma concentrations

Abstract

To provide solid amorphous dispersions that exhibit excellent oral bioavailability and are chemically and physically stable in the solid state.SOLUTION: Solid amorphous dispersions comprising compound (I) having the formula below, and one or more polymers, or solution formulations comprising compound (I) and one or more co-solvents and surfactants, are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical formulations comprising inhibitors of factor XIa (FXIa) and, optionally, one or more polymers or one or more cosolvents as solid dispersants, a complexing agent, and a surfactant as a liquid dispersant. More specifically, the present invention relates to bioavailable amorphous solid dispersion or dissolved solution dosage forms (e.g., liquid-filled capsules) of inhibitors of FXIa that are stable in the solid or liquid state for extended periods of time. [Background technology]

[0002] BACKGROUND OF THE INVENTION Thromboembolic diseases remain a leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low-molecular-weight heparins (LMWHs), and synthetic pentasaccharides, as well as antiplatelet agents such as aspirin and clopidogrel (PLAVIX®). The oral anticoagulant warfarin inhibits the post-translational maturation of blood coagulation factors VII, IX, and X and prothrombin and has proven effective in treating both venous and arterial thrombosis. However, its narrow therapeutic index, slow therapeutic onset, interactions with numerous foods and medications, and the need for monitoring and dose adjustment limit its use. Therefore, it is increasingly important to discover and develop safe and effective oral anticoagulants to prevent and treat a wide range of thromboembolic disorders.

[0003] One solution is to inhibit thrombin generation by targeting factor XIa (FXIa). Factor XIa is a plasma serine protease involved in regulating blood coagulation, which begins in vivo when tissue factor (TF) binds to factor VII (FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complex activates factor IX (FIX) and factor X (FX), resulting in the production of factor Xa (FXa). The generated FXa catalyzes the conversion of prothrombin to small amounts of thrombin, after which this pathway is terminated by tissue factor pathway inhibitor (TFPI). The blood coagulation process then propagates further via feedback activation of factors V, VIII, and XI by catalytic amounts of thrombin (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007)). The resulting burst of thrombin converts fibrinogen to fibrin, which polymerizes to form the structural framework of the clot and activates platelets, a key cellular component of blood coagulation (Hoffman, M., Blood Reviews, 17:S1-S5(2003)). Factor XIa therefore plays a key role in propagating this amplification loop and is therefore an attractive target for antithrombotic therapy.

[0004] Recently, a novel inhibitor of FXIa, which may be useful in the treatment of thromboembolism, has been discovered: (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0]. 2,6 ]Octadeca-1(18),2(6),4,14,16-penten-8-one is represented by the formula (I): [ka] and is referred to herein as "Compound (I)." Compound (I), methods for making Compound (I), and methods of treatment using Compound (I) are disclosed in U.S. Patent Application Publication No. 2016 / 0096839 (assigned to the present applicant and incorporated herein by reference in its entirety). This compound is non-ionic in physiologically relevant ranges and exhibits low aqueous solubility at room temperature. These properties of Compound (I) make it difficult to formulate for oral administration to achieve therapeutically effective blood levels.

[0005] Solid dispersions of amorphous drug substances have been investigated with the aim of suppressing crystal growth and increasing the solubility of poorly water-soluble drug substances (see, e.g., European Journal of Pharmaceutics and Biopharmaceutics, 63:103-114 (2006)). Generally, it has been found that effective solid amorphous dispersions require the incorporation of at least 20% w / w polymer (see, e.g., WO 10 / 102245 and US 2003 / 0219489). In one example, 5% w / w providone (PVP) was reported to suppress crystal growth of indomethacin in a molecular dispersion, reportedly due to hydrogen bonding between the active ingredient and the PVP polymer (see, Pharmaceutical Research, 16:1722-1728 (1999)). Polymeric formulations of anthelmintics have also been disclosed which exhibit improved solubility and anthelmintic activity (see EP 0 224 249).

[0006] Therefore, what is currently needed in the art are bioavailable formulations of one or more Compounds (I) that are stable, have a desirable pharmaceutical profile, and are amenable to manufacturing conditions.

[0007] Surprisingly, according to the present invention, it has been found that Compound (I) can be formulated as an amorphous solid dispersion in a pharmaceutically suitable polymer, such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), by spray drying. The resulting spray-dried solid dispersion (SDD) has excellent physical and chemical stability and contains a high content of the active pharmaceutical ingredient (API), e.g., 100% amorphous API. Furthermore, the SDD exhibited unexpectedly excellent stability even in humid environments. No crystallization was observed in samples of this formulation, even when directly exposed to high RH (e.g., 75%) for 3 to 6 months. Furthermore, the dissolution behavior of the formulation was stable across all SDD compositions and did not change even when exposed to stress. Therefore, this drug substance formulation maintains its performance characteristics under all common storage conditions and does not require packaging management, such as desiccants and moisture-proofing agents. Surprisingly, according to the present invention, Compound (I) can be dissolved in solution, which can exhibit therapeutic efficacy equivalent to that of SDD formulations.

[0008] (Summary of the Invention) In one aspect, the present invention provides a compound of formula (I) below in amorphous form / amorphous form: [ka] The present invention provides a compound of the formula:

[0009] In another aspect, the present invention provides amorphous Compound (I) exhibiting a powder X-ray diffraction pattern (PXRD) substantially as shown in FIG.

[0010] In another aspect, the present invention provides amorphous Compound (I) exhibiting a powder X-ray diffraction pattern (PXRD) substantially as shown in FIG.

[0011] In another aspect, the present invention provides a method for preparing an amorphous form of Compound (I) by freeze-drying, spray-drying, evaporative freeze-drying, melt-quenching, or extrusion, or any combination thereof. For example, the amorphous form can be prepared by freeze-drying. In another example, the amorphous form can be prepared by spray-drying.

[0012] In another aspect, the present invention provides a compound of formula (I): [ka] and a pharmaceutically suitable polymer, wherein the polymer is selected from the group consisting of, but not limited to, PVP, HPMCAS, and HPMC.

[0013] In another aspect, the present invention provides a method for preparing an amorphous solid dispersion of Compound (I), the method comprising the steps of: (a) preparing a solution comprising compound (I), at least one polymer, and a solvent; and (b) spray drying the solution to produce an amorphous solid dispersion; Includes.

[0014] The solution can comprise at least one solvent selected from the group consisting of acetic acid, acetone, dichloromethane, tetrahydrofuran, alcohol (e.g., methanol or ethanol), ethyl acetate, methyl ether ketone, dichloromethane, and water. In some embodiments, the solution can comprise at least one solvent selected from the group consisting of acetone, tetrahydrofuran, alcohol, ethyl acetate, methyl ether ketone, dichloromethane, and water. In some embodiments, the solvent is dichloromethane and methanol. In some embodiments, the solvent is acetone, dichloromethane, and methanol. For example, the solvent can be acetone. The polymer can be selected from the group consisting of PVP, PVP-vinyl acetate copolymer, HPMCAS, and HPMC. For example, the polymer can be HPMCAS.

[0015] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an amorphous solid dispersion of the present invention.

[0016] In another aspect, the present invention provides pharmaceutical compositions for oral administration.

[0017] In another embodiment, the pharmaceutical composition formulated for oral administration is in the form of a capsule, tablet, pill, powder, granules, or suspension.

[0018] In another aspect, the present invention provides a solution formulation comprising Compound (I) and a co-solvent (e.g., an organic solvent), and optionally a complexing agent, polymer, surfactant, or water.

[0019] In another aspect, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of active Compound (I), together with up to about 85% (v / v) co-solvent, optionally up to about 20% (v / v) polymer, optionally up to about 20% (v / v) complexing agent, optionally up to about 60% (v / v) surfactant, and optionally up to about 10% (v / v) water.

[0020] In another aspect, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of active Compound (I), together with up to about 85% (v / v) polyethylene glycol (PEG) as a co-solvent, optionally up to about 20% (v / v) PVP K30 as a polymer and up to about 50% (v / v) Tween 80 or Vitamin E polyethylene glycol succinate (TPGS) as a surfactant.

[0021] In another aspect, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of active Compound (I), together with about 35-80% (v / v) PEG, about 0-20% PVP K30, and about 2-50% (v / v) Tween 80.

[0022] In another aspect, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of an active compound, together with about 50-85% (v / v) PEG and about 5-40% (v / v) Tween 80.

[0023] In another embodiment, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of an active compound, together with about 80% (v / v) PEG and about 20% (v / v) Tween 80.

[0024] In another aspect, the present invention provides a pharmaceutical capsule or semi-solid formulation comprising the solution, the pharmaceutical capsule preferably being a gel capsule.

[0025] In another aspect, the present invention provides a method for preparing a pharmaceutical composition, comprising dissolving Compound (I) in a solution of PEG, TPGS, PVP K30, Tween 80, ethanol, or water, or any combination thereof. In some embodiments, the method further comprises adding the composition to a pharmaceutical capsule.

[0026] In another aspect, the present invention provides a method for treating and preventing thromboembolic disorders (e.g., including, but not limited to, arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, and venous cerebrovascular thromboembolism), comprising administering to a patient a therapeutically effective amount of a pharmaceutical capsule composition according to one or more embodiments described herein.

[0027] In addition to the above objects, the present invention also relates to other important objects as described below. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 is a powder X-ray diffraction pattern of the lyophilized amorphous form of Compound (I). [Figure 2] FIG. 2 is a modulated differential scanning calorimetry (DSC) thermogram of the amorphous form of Compound (I). [Figure 3] FIG. 3 is a powder X-ray diffraction pattern of the spray-dried amorphous form of Compound (I). [Figure 4] FIG. 4 is a modulated differential scanning calorimetry (DSC) thermogram of the spray-dried amorphous form of Compound (I). [Figure 5] FIG. 5 is a solid-state nuclear magnetic resonance spectrum (ssNMR) of the spray-dried amorphous form of Compound (I). [Figure 6] FIG. 6 shows the powder X-ray diffraction pattern of an amorphous solid dispersion composition of Compound (I) and HPMCAS. DETAILED DESCRIPTION OF THE INVENTION

[0029] (definition) As used herein, the article "a" or "an" means one or more, unless otherwise specified.

[0030] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit a definitive X-ray diffraction pattern showing distinct maxima.

[0031] As used herein, "area under the drug blood concentration time curve" ("AUC") means the area under the curve defined by the change in blood concentration of an active pharmaceutical ingredient or a metabolite of the active pharmaceutical ingredient over time after administration of a dose of the active pharmaceutical ingredient. 0-inf " is the area under the concentration-time curve extrapolated to infinity after administration. "AUC 0-t " is the area under the concentration-time curve from time zero to time t after administration, where t is the last time point of measurable concentration.

[0032] As used herein, "C max " refers to the maximum blood concentration shown on a curve that shows the change over time in the blood concentration of a pharmaceutically active ingredient or a metabolite of the pharmaceutically active ingredient.

[0033] As used herein, "t max " refers to the earliest time at which the blood concentration of an active pharmaceutical ingredient or a metabolite of the active pharmaceutical ingredient reaches its maximum value.

[0034] As used herein, "bioavailability" refers to the rate and extent to which an active ingredient or active moiety is absorbed from a pharmaceutical product and becomes available at the site of action. For pharmaceutical products that are not intended to be absorbed into the bloodstream, bioavailability can be assessed by measurements intended to represent the rate and extent to which the active ingredient or active moiety becomes available at the site of action. For example, bioavailability can be measured by measuring the amount of active ingredient in blood (serum or plasma) as a function of time. Measurements and assessments of bioavailability include AUC, C max , t max Pharmacokinetic (PK) parameters such as:

[0035] As used herein, "dosage" or "dose" refers to any form of formulation containing a sufficient amount of active ingredient to produce a therapeutic effect upon single administration.

[0036] As used herein, "food effect" means that there is a significant difference in the bioavailability of a drug substance when administered to a patient in the fasted state compared to the fed state, and "no food effect" means that there is no significant difference in the bioavailability of a drug substance when administered to a patient in the fasted state compared to the fed state.

[0037] As used herein, "formulation" and "composition" are used interchangeably and refer to a combination of elements present together for a given purpose. Such terms are well known to those skilled in the art.

[0038] As used herein, "solid dispersion" refers to a solid-state system comprising at least two components, one component dispersed throughout the other component(s). As used herein, the term "amorphous solid dispersion" refers to a stable solid dispersion comprising an amorphous drug substance and a carrier matrix. As used herein, an "amorphous drug substance" refers to an amorphous solid dispersion comprising a drug substance in a substantially amorphous solid form. A substantially amorphous state can include at least about 80%, at least about 90%, or at least 95% of the drug substance in the dispersion being in amorphous form.

[0039] As used herein, "pharmaceutically acceptable" means those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0040] As used herein, the terms "stable compound" and "stable structure" refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is directed to stable compounds.

[0041] As used herein, "treating" or "treatment" refers to the treatment of a disease state in a mammal, particularly a human, and includes (a) preventing the disease state from occurring in the mammal, particularly when the mammal is predisposed to the disease state but has not yet been diagnosed with the disease; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) alleviating the disease state, i.e., causing regression of the disease state.

[0042] As used herein, "comprises," "including," "contains," "has," or "having," etc., mean "including."

[0043] All numerical values ​​preceded by the term "about" expressing ingredients, weight percents, temperatures, and the like should be understood as approximations only, with small variations above and below the stated value being sufficient to obtain substantially the same results as the stated value. Accordingly, unless indicated to the contrary, numerical parameters preceded by the word "about" are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and without intending to limit the scope of the claims to the application of the doctrine of equivalents, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0044] All measurements are subject to experimental error and are within the scope of the present invention.

[0045] Abbreviations used herein are defined as follows: "1x" is one time, "2x" is two times, "3x" is three times, "°C" is degrees Celsius, "eq" is equivalent, "g" is gram, "mg" is milligram, "kg" is kilogram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normality, "M" is mole, "mmol" is millimole, "min" is minute, "h" is hour, "rt" is room temperature, "RT" is retention time, "RBF" is round bottom flask, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentrate, "sat" or "sat'd" is saturated, "SFC" is supercritical fluid chromatography, "MW" is molecular weight, "mp" is melting point, "ee" is enantiomeric excess, "MS" or "Mass "Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high performance liquid chromatography, "RPHPLC" is reverse phase HPLC, "NMR" is nuclear magnetic resonance spectroscopy, "Hz" is defined as hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical symbols well known to those skilled in the art.

[0046] Amorphous Solid Dispersions In one aspect, the present invention provides an amorphous form of Compound (I). This novel amorphous form can be characterized, for example, by powder X-ray diffraction.

[0047] For example, as shown in Figure 1, the amorphous form has a powder X-ray diffraction pattern that does not exhibit crystalline peaks, indicating an amorphous solid. The amorphous compound defined above is further characterized by at least one of the following properties: a modulated DSC profile characterized by a glass transition temperature at about 163°C, as shown in Figure 2.

[0048] In one embodiment, the present invention provides a method for preparing a novel amorphous Compound (I). In one embodiment, amorphous Compound (I) was prepared by dissolving Compound (I) in a mixed solution of acetonitrile and water. The resulting solution was frozen with dry ice and lyophilized under vacuum. The starting material used to prepare amorphous Compound (I) is preferably in a crystalline form.

[0049] The amorphous compound (I) as defined above is chemically and physically stable. These properties allow the preparation of solid forms containing the compound of the present invention.

[0050] In another aspect, the present invention provides a compound of formula: [ka] The present invention relates to an amorphous solid dispersion composition comprising Compound (I) of formula (I) and a pharmaceutically suitable polymer, wherein the polymer is selected from the group consisting of PVP, HPMCAS, and HPMC, with HPMCAS being particularly preferred. The amorphous solid dispersion of Compound (I) of the present invention exhibits an unexpectedly advantageous pharmaceutical profile. The dispersion exhibits excellent oral bioavailability and is surprisingly chemically and physically stable in the solid state.

[0051] In one embodiment, an amorphous solid dispersion is provided in which the ratio of Compound (I) to polymer is present in the range of about 99 to about 75% (w / w) Compound (I) and about 1 to about 25% (w / w) polymer. Unless otherwise specified, percentages of components are given on a weight / weight or "w / w" basis.

[0052] In another embodiment, there is provided an amorphous solid dispersion in which the ratio of Compound (I) to polymer is in the range of about 74 to about 50% (w / w) Compound (I) and about 26 to about 50% (w / w) polymer.

[0053] In another embodiment, there is provided an amorphous solid dispersion in which the ratio of Compound (I) to polymer is in the range of about 49 to about 25% (w / w) Compound (I) and about 51 to about 75% (w / w) polymer.

[0054] In another embodiment, there is provided an amorphous solid dispersion prepared by freeze-drying or spray-drying, particularly spray-drying.

[0055] In another embodiment, an amorphous solid dispersion is provided that is stable in the solid state for at least about 12 months.

[0056] In another embodiment, an amorphous solid dispersion is provided that is stable in the solid state for at least about 24 months.

[0057] In another embodiment, a pharmaceutical composition is provided that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of the dispersion.

[0058] In another embodiment, an orally bioavailable composition comprising the dispersion is provided.

[0059] Various manufacturing procedures available to those skilled in the art can be used to prepare the compositions described herein. The amorphous dispersions of the present invention may be produced by freeze-drying or spray-drying. In some embodiments, dispersions produced by the methods described herein show no signs of crystallization. Spray-drying is a preferred method for producing the compositions described herein. Spray-drying reaction conditions can include the use of a solution of acetic acid, acetone, dichloromethane, methanol, ethanol, or other organic solvent, optionally containing 0-40% (v / v) water. Preferred spray-drying reaction conditions include the use of a solution of acetone, methanol, or ethanol (optionally containing 0-40% (v / v) water) and an inlet temperature of the spray dryer typically between about 70 and 175°C. Temperatures above 175°C are possible when using solvents with higher water contents, such as ethanol. Spray-dried materials can have particle sizes of 90% or less of 100 μm. Typically, spray-dried materials have particle sizes of 90% or less of 50 μm. Figure 6 confirms the non-crystalline, amorphous nature of the present invention. Surprisingly, the dispersions of the present invention are chemically and physically stable, as shown in Example 3. For example, based on the data presented in Example 3, it is believed that Compound (I) contained in the dispersion will degrade by less than 10% when stored at 25°C / 60% RH for at least 12 months.

[0060] The compositions of the present invention described herein in various embodiments can then be formed into tablets using equipment and techniques available in the art. If desired or necessary, suitable additional binders, lubricants, disintegrants, and coloring agents can be incorporated into the tableting mixture. Suitable binders include starch, gelatin, or natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, magnesium stearate, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

[0061] Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and compressing into tablets. The powder mixture is produced by mixing the appropriately comminuted compound with a diluent or base, as described above, and optionally with a binder (e.g., carboxymethylcellulose, alginate, gelling agent, or providone), a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and / or an absorbent (e.g., bentonite, kaolin, or dicalcium phosphate). Tablets may be coated or uncoated. In some embodiments, tablets are optimized for continuous production without significantly changing quality characteristics such as dissolution.

[0062] The powder mixture can be granulated by wetting it with a binder (e.g., syrup, starch paste, acacia mucilage, solutions of cellulosic or polymeric materials) and forcing it through a screen. Alternatively, the powder mixture can be run through a tablet press and the resulting imperfect rejects broken up into granules. The granules can be lubricated by the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent sticking to the tablet-forming dies. The lubricated mixture is then compressed into tablets.

[0063] The compounds of the present invention can also be combined with a free-flowing inert carrier and compressed directly into tablets without granulating or slugging.A clear or opaque protective coating consisting of a shellac sealing coat, a sugar or polymeric material coating, and a wax polish coating can be provided.Dyes can be added to these coatings to distinguish different unit doses.

[0064] As a non-limiting example, tablets containing about 1 to about 1000 mg, preferably about 10 to about 500 mg, and preferably about 25 to about 200 mg of Compound (I) can be prepared using the compositions described herein. Other dosage units are within the scope of the present invention. In particular, tablets containing compositions containing spray-dried Compound (I) and a polymer (e.g., HPMCAS) exhibit improved in vitro dissolution rates, good in vivo oral bioavailability in dogs and human subjects, and good chemical and physical stability.

[0065] The compositions of the present invention described herein according to various embodiments can be filled into capsules using equipment and procedures available in the art. The capsules are then produced by encasing them in a formed gelatin sheath or shell. In addition to gelatin, other materials for the capsule sheath or shell include hydroxypropyl methylcellulose (HPMC), cellulose, methylcellulose, starch, other materials, and combinations of any of the foregoing.

[0066] Other methods for producing capsules (both hard and soft) available to those skilled in the art may also be utilized, as described above. Flavoring agents, preservatives, dispersing agents, and coloring agents may be present as desired. Lubricants and glidants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol may be added to the mixture before the filling operation. Disintegrating or solubilizing agents such as agar-agar, calcium carbonate, or sodium carbonate may also be added to improve the availability of the pharmaceutical when the capsule is ingested. Furthermore, if necessary, suitable additional binders, lubricants, disintegrants, and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., gum acacia, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, betonite, xanthan gum and the like.

[0067] The two-piece capsule may be fitted together, for example, using a gelatin-based solution in the case of a hard gelatin capsule, or an HPMC-based solution in the case of an HPMC capsule.

[0068] As a non-limiting example, capsules containing about 1 to about 1000 mg, preferably about 50 to about 600 mg, and preferably about 100 to about 500 mg of Compound (I) can be prepared using the compositions described herein. Other dosage units are within the scope of the present invention.

[0069] In particular, capsules containing Compound (I) demonstrated favorable in vitro dissolution rates and good oral bioavailability in dogs. More importantly, compositions according to various embodiments of the present invention demonstrated consistently good bioavailability in humans when administered orally using a capsule formulation. This enhanced bioavailability was unexpected given the presence of significant drug substance precipitate observed in in vitro studies and the lack of in vitro / in vivo correlation.

[0070] The capsule compositions of the present invention containing Compound (I) have demonstrated excellent storage stability and good long-term chemical and physical stability, i.e., they exhibit little decomposition (less than about 5% decomposition) for at least about 12 months, preferably at least about 24 months, when stored in a sealed container at either about 25°C / 60% relative humidity or about 30°C / 65% relative humidity.

[0071] Thus, the present invention provides a method for inhibiting FXIa activity in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical tablet or capsule according to one or more of the embodiments described herein.

[0072] Pharmaceutical compositions of Compound (I) in the form of tablets or capsules are expected to be shelf-stable for extended periods of time. In some embodiments, tablets and capsules are shelf-stable for at least about 3 months. In some embodiments, tablets and capsules are shelf-stable for at least about 6 months. In some embodiments, tablets and capsules are shelf-stable for at least about 12 months. In some embodiments, tablets and capsules are shelf-stable for at least about 24 months.

[0073] The pharmaceutical composition of Compound (I) can be in the form of a suspension. In some embodiments, the suspension provides a peak blood drug concentration (C) that is at least 70-fold higher in vivo than a control composition containing the same amount of undispersed drug substance. max) in vivo. In some embodiments, the suspension provides a maximum blood drug concentration (Cmax) that is at least 80-fold higher compared to a control composition comprising the same amount of non-dispersed drug substance. In some embodiments, the suspension provides a maximum blood drug concentration (Cmax) that is at least 110-fold higher in vivo compared to a control composition comprising the same amount of non-dispersed drug substance. In some embodiments, the suspension provides an AUC that is at least 85-fold higher in vivo compared to a control composition comprising the same amount of non-dispersed drug substance. In some embodiments, the suspension exhibits an AUC that is at least 140-fold higher in vivo compared to a control composition comprising the same amount of non-dispersed drug substance. The non-dispersed drug substance may be Compound (I) in crystalline form.

[0074] Solution preparation In another aspect, the present invention provides a solution formulation comprising Compound (I) and a co-solvent (e.g., an organic solvent), and optionally a complexing agent, polymer, surfactant, or water.

[0075] Co-solvents include, but are not limited to, polar compounds containing one or more hydroxyl groups or other polar groups. For example, the solvents include alcohols, such as ethanol, preferably absolute ethanol, isopropanol, etc.; glycols, such as propylene glycol, polyethylene glycol (PEG400), polypropylene glycol, or glycerol; glycol ethers; and polyoxyethylene alcohols; tocopherol compounds, particularly tocopherol-polyethylene glycol, more specifically tocopherol polyethylene glycol diacid (e.g., succinate, maleate, etc.) esters, particularly tocopherol polyethylene glycol succinate, most preferably tocopherol polyethylene glycol 1000 succinate (TPGS1000).

[0076] Complexing agents include, but are not limited to, water-soluble unsubstituted or substituted α-cyclodextrin (αCD), β-cyclodextrin (βCD), and γ-cyclodextrin (γCD). Examples of substituted β-cyclodextrins that can be used herein include methyl β-cyclodextrin (MβCD), hydroxypropyl β-cyclodextrin (HPβCD), and sulfobutylether-β-cyclodextrin (SBEβCD). Examples of substituted γ-cyclodextrins include hydroxypropyl γ-cyclodextrin (HPGCD). Mixtures of cyclodextrins may also be used. In a preferred embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HPβCD).

[0077] The polymer component of the formulation is one selected from the group consisting of polyvinyl alcohol, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone (PVP), particularly PVP K30 and copovidone (PVP-polyvinyl acetate), Pluronic F108, Pluronic F127, Pluronic F68, and combinations thereof.

[0078] Preferably, for active compounds, Tween 80 is the preferred surfactant. Other surfactants that can be used in the present invention include, but are not limited to, Cremophor EL, Cremophor RH40, Etocas 40, Croduret 60, and Solutol HS 15.

[0079] In another embodiment, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of active Compound (I), together with up to about 85% (v / v) of a cosolvent, optionally up to about 20% (v / v) of a polymer, optionally up to about 20% (v / v) of a complexing agent, up to about 60% (v / v) of a surfactant, and optionally up to about 10% (v / v) of water. For example, the cosolvent can be selected from alcohol, PEG, PG, and TPGS. In certain instances, the cosolvent is PEG 400. The complexing agent can be α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. For example, the complexing agent can be hydroxypropyl β-cyclodextrin (HPβCD) or sulfobutylether-β-cyclodextrin (SBEβCD). The surfactant may be selected from Tween 20, Tween 80, Solutol HS 15, Cremophor EL, Cremophor RH40, Etocas 40, and Croduret 60. For example, the surfactant may be Tween 80. The polymer may be selected from PVP K30, Pluronic F108, Pluronic F127, and Pluronic F68.

[0080] In another embodiment, the solution formulation comprises about 1 mg / ml to 10 mg / ml of active Compound (I), up to about 85% (v / v) PEG, optionally up to about 20% (v / v) PVP K30, and up to about 50% (v / v) Tween 80 or TPGS. For example, the solution formulation may comprise about 1 mg / ml to 10 mg / ml of active Compound (I), about 35-85% (v / v) PEG, about 0-20% PVP K30, and about 2-50% (v / v) Tween 80. In another embodiment, the solution formulation comprises about 1 mg / ml to 10 mg / ml of Compound (I), about 50-85% (v / v) PEG, and about 5-40% (v / v) Tween 80. For example, a solution formulation may contain about 1 mg / ml to 10 mg / ml of active compound (I), about 80% (v / v) PEG 400, and 20% (v / v) Tween 80. In such a case, active compound (I) may be dissolved in the PEG 400 and the Tween 80.

[0081] In another embodiment, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of active Compound (I), together with up to about 80% (v / v) polyethylene glycol (PEG) as a co-solvent, optionally up to about 20% (v / v) PVPK30 as a polymer, and up to about 20% (v / v) Tween 80 or vitamin E polyethylene glycol succinate (TPGS) as a surfactant.

[0082] In another embodiment, the present invention provides a solution formulation comprising about 1 mg / ml to 10 mg / ml of active Compound (I), together with about 35-80% (v / v) PEG, about 0-20% PVP K30, and about 2-50% (v / v) Tween 80.

[0083] Preferably, a formulation is provided that contains about 1 mg / ml to 10 mg / ml of the active compound (I) together with about 35 to 80% (v / v) PEG, about 0 to 20% PVPK30, and about 2 to 60% (v / v) Tween 80. More preferably, a formulation is provided that contains about 1 mg / ml to 10 mg / ml of the active compound together with about 50 to 85% (v / v) PEG and about 5 to 40% Tween 80. Even more preferably, a formulation is provided that contains about 1 mg / ml to 10 mg / ml of the active compound together with about 80% PEG and about 20% Tween 80.

[0084] Other excipients such as pharmaceutical grade bulking agents and binders available in the art may also be incorporated into the composition, but this is optional.For the stability of the dosage form, the formulation may optionally contain pharmaceutically acceptable antioxidants.Examples include ascorbic acid, BHA, BHT, propyl gallate, vitamin E, etc.

[0085] Various manufacturing procedures available to those skilled in the art can be used to prepare the compositions described herein. Preferably, Compound (I) is dissolved in a mixed solution of polyethylene glycol (PEG) and Tween 80 at elevated temperatures using equipment and procedures available to those skilled in the art.

[0086] The liquid formulations of the present invention described in various embodiments can then be further modified for oral administration in individual units such as capsules. These capsules may be hard or soft capsules. For example, for oral administration in capsule form, the compositions described herein containing the active pharmaceutical ingredients may be used as is, or may be further combined with an oral, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, glycerin, water, etc.). The compositions of the present invention may be encapsulated as a liquid or semisolid.

[0087] The present invention provides methods for inhibiting FXIa activity in a patient, comprising administering to the patient a therapeutically effective amount of a solid or liquid formulation according to one or more embodiments described herein. The term "therapeutically effective amount" refers to the total amount of active ingredients sufficient to provide a patient benefit, i.e., a treatment that ameliorates symptoms or a disease. When used in reference to an individual active ingredient administered alone, the term refers to that ingredient alone. When used in combination, the term refers to the total amount of active ingredients that results in a therapeutic effect, whether administered in combination, sequentially, or simultaneously.

[0088] In another aspect, the present invention relates to a method for treating and / or preventing thromboembolic disorders, comprising administering to a patient in need thereof a therapeutically effective amount of an amorphous solid dispersion of Compound (I) as described herein.

[0089] In another aspect, the present invention relates to a method for treating and / or preventing thromboembolic disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a solution formulation of Compound (I) as described herein.

[0090] In some embodiments, the thromboembolic condition includes unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by a medical implant, device, or procedure in which thrombosis is promoted by exposure of blood to an artificial surface.

[0091] In another embodiment, the present invention relates to i) a method for treating a disorder, comprising administering a therapeutically effective amount of an amorphous solid dispersion formulation comprising Compound (I) to a patient in need of treatment; ii) use of an amorphous solid dispersion of Compound (I) for use in treating a disorder; iii) use of an amorphous solid dispersion of Compound (I) in the manufacture of a medicament for treating a disorder; or iv) use of a dissolved solution dosage form of Compound (I) in the manufacture of a medicament for treating a disorder, wherein said disorder is selected from unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis resulting from a medical implant, device or procedure in which thrombosis is promoted by exposure of blood to an artificial surface.

[0092] The present invention also encompasses all combinations of the different aspects of the invention mentioned herein. It is understood that any and all embodiments of the present invention may be combined with any other embodiment to describe additional embodiments of the present invention. Furthermore, any element of an embodiment may be combined with any and all other elements from any embodiment to describe additional embodiments.

[0093] The foregoing description is illustrative only and should not be construed as limiting in any way the scope or underlying principles of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0094] General method Powder X-ray diffraction (PXRD)

[0095] PXRD data were collected using a Bruker D8 Advance powder X-ray diffractometer equipped with a LynxEye™ detector in the theta / theta configuration in PSD mode with a detector aperture of 3°. The synchrotron radiation was CuKα (40 kV, 40 mA). The X-ray optics was equipped with a 0.3° motor-controlled divergence slit. The sample was placed in a top-loading, zero-background holder and rotated at 15 rpm during data collection. Diffraction data were collected over the 2-32° 2θ range in locked-coupled scan mode with a step size of 0.03° and a count time of 1 s per step.

[0096] PXRD data is available from LynxEye TM The data were collected using a Bruker D4 Endeavor powder X-ray diffractometer equipped with a CuKα detector (40 kV, 40 mA) in PSD mode with a detector aperture of 3°. The X-ray optics were equipped with a 0.6° divergence slit and a Ni-Kβ filter. Data were collected in continuous mode with a 0.03° step size and 1 s count time per step in the 2θ range of 4–32° by rotating the sample.

[0097] Modulated Differential Scanning Calorimetry (mDSC) mDSC data were generated using a TA INSTRUMENT® model Q2000, Q1000, or 2920. Sample sizes of approximately 2 to 10 mg were measured in a crimped aluminum pan. Measurements were performed in a nitrogen atmosphere from room temperature to 300°C at a heating rate of 2 or 2.5°C / min, with a modulation amplitude of 0.32 or 1.5°C applied every 60 seconds. DSC plots were generated with the endothermic peak pointing downward.

[0098] Solid state nuclear magnetic resonance (SSNMR) Carbon cross-polarization magic-angle spinning (CPMAS) solid-state NMR experiments were performed on a Bruker AV III instrument operating at a proton frequency of 400.13 MHz. Solid samples were spun at 13 kHz in a 4 mm ZrO2 rotor. Contact times ranged from 1.5 to 3 ms, with ramps from 50 to 100% in the proton channel (AE Bennett et al., J. Chem. Phys., 1995, 103, 6951) (G. Metz, X. Wu and SO Smith, J. Magn. Reson. A., 1994, 110, 219-227). Relaxation delays were five times slower than those observed in the API. 1 The H T1 was maintained at 100 ppm (typically 30 seconds). Proton decoupling was performed using a TPPM sequence with a 2.8-microsecond pulse (nominal bandwidth 90 kHz). The spectral sweep width was 300 ppm centered at 100 ppm. 2972 ​​data points were acquired (digital resolution 20 Hz), zero-filled to 8192 points, apodized, and line-broadened at 20 Hz. Free induction decays were typically applied from 1024 to 4096. Spectra were indirectly compared with TMS using 3-methylglutaric acid (D. Barich, E. Gorman, M. Zell, and E. Munson, Solid State Nuc. Mag. Mag. Res., 2006, 30, 125-129). Approximately 70 mg of sample was used for each experiment. The temperature was set at 280 K. [Example]

[0099] Example 1 Preparation of amorphous compound (I) by freeze-drying The free form of Compound (I) (30 mg) was dissolved in 2 ml of a 9:1 v / v acetonitrile-water mixture. The resulting solution was frozen using dry ice and lyophilized for 16 hours at -40 °C under a vacuum of 2 to 6 mBar using a Thermo Scientific ModulyoD 5L freeze dryer. The powder X-ray diffraction pattern (Figure 1) showed no observable crystalline peaks, indicating that it was an amorphous solid. The lyophilized amorphous Compound (I) was also characterized by modulated differential scanning calorimetry (mDSC), as shown in Figure 2.

[0100] Example 2 Preparation of amorphous compound (I) by spray drying A solution of Compound (I) in free form in acetone-water (9:1 w / w) containing 1.6% (w / w) solids was spray-dried using a Bend Lab Spray Dryer (Bend Research Inc.) under the following operating parameters and conditions: [Table 1]

[0101] The powder X-ray diffraction pattern (Figure 3) showed no observable crystalline peaks, indicating that it was an amorphous solid. The spray-dried amorphous compound (I) was also characterized by modulated differential scanning calorimetry (mDSC), which is shown in Figure 4. Furthermore, the spray-dried amorphous form was characterized by modulated differential scanning calorimetry (mDSC), which is shown in Figure 5. 13 The C solid state spectrum was collected according to the procedure described in "General Methods." The CPMAS chemical shift values ​​for this form are shown below: [Table 2]

[0102] Example 3 Preparation of spray-dried dispersions (SDD) of amorphous Compound (I) using HPMCAS (75:25% (w / w) ratio) Approximately 6% (w / w) Compound (I) and 2% (w / w) HPMCAS were dissolved in approximately 92% (w / w) of a 9:1 acetone:water (w / w) mixture. The solution was warmed to 50°C and then spray-dried using a laboratory-scale spray dryer with a drying gas capacity of 150 kg / hr, using the following parameters: gas flow rate: 1850 g / min; feed rate: 170 g / min; feed pressure: 400 psi; inlet temperature: 115°C. The product was a white powder that showed 97% purity by HPLC. The PXRD diffraction pattern showed a halo pattern with no crystalline peaks (Figure 6), indicating that the product was amorphous.

[0103] This formulation exhibited good stability under high humidity conditions. No crystallization was observed, even when samples of the spray-dried dispersion were exposed to high relative humidity; for example, an SDD containing 75% drug substance stressed for up to 12 months under different stability conditions showed no signs of crystallinity by PXRD (Table 1). [Table 3]

[0104] To demonstrate that the solid amorphous dispersion of Example 3 represents a solubility-improved form of Compound (I), an in vitro dissolution test was performed. Microcentrifuge dissolution tests were performed in a temperature-controlled box at 37°C. 1 mg of sample was weighed into two 2.0 mL Sorenson microcentrifuge tubes. 1.8 mL of 0.5% SIF / phosphate-buffered saline (PBS) (pH 6.5) was added to each tube, and a timer was started. The samples were vortexed for 1 minute at setting 8 on a Fisher Vortex Genie 2. The samples were then centrifuged at 13,000 rpm for 1 minute using an IEC Micromax microcentrifuge. At the 4-minute mark on the timer, 50 μL of supernatant from each microcentrifuge tube was dispensed into an HPLC vial containing 250 μL of diluent (HPLC-grade, 95:5 THF:water). The mixtures were vortexed for 25 seconds. This step was repeated at the following measurement time points: 10, 20, 40 and 90 minutes, and again after 20 hours.

[0105] [Table 4]

[0106] As a control, crystalline Compound (I) alone was evaluated using the same procedure, with enough compound added so that the concentration of Compound (I) would be 1000 μg / mL if all of the compound dissolved.

[0107] Using the concentrations of compound (I) obtained in these samples, the maximum dissolution concentration (MDC) of compound (I) in the solution within 90 minutes of the start of the test was calculated. 90 ), the area under the concentration-versus-time curve (AUC 90 The results are shown in Table 2.

[0108] Table 2: Microcentrifuge Dissolution Test [Table 5]

[0109] The dissolution behavior of the SDD was stable for all formulations and did not change when exposed to stress conditions. For example, an SDD containing 75% of the drug substance was stressed under different stability conditions for 3 months without significant changes in dissolution measurements.

[0110] Example 4 Bioavailability of SDD formulations For the formulation comparison study, three formulations were prepared: 1) a 75% SDD suspension, i.e., Compound (I):HPMCAS 75:25 (w / w%); 2) a 50% SDD suspension, i.e., Compound (I):HPMCAS 50:50 (w / w%); and 3) a crystalline suspension of Compound (I). Four fasted or fed male dogs (~10 kg) were administered 100 mg / dog. Dogs were given 50 mL of water (fasted) or 50 mL of a high-fat diet supplement (Boost + Coffeemate), and blood samples were drawn eight times post-dose.

[0111] Pharmacokinetic data are shown in Table 3. max is the maximum observed blood concentration of Compound (I), averaged over the number of dogs administered each formulation. AUC 0-24 is the mean area under the blood Compound (I) concentration versus time curve.

[0112] These data demonstrate that oral administration of spray-dried Compound (I) / HPMCAS dispersions to beagle dogs provides higher systemic exposure of Compound (I) than following administration of an aqueous suspension of crystalline Compound (I). [Table 6]

[0113] Example 5 tablet manufacturing Tablets were manufactured by compressing the ingredients listed in Table 4. The spray-dried 75% Compound (I):HPMCAS ingredient and all intragranular excipients were passed through a screen and then mixed in a mixer. This pre-blend was compressed in a slug, milled, and passed through a screen. All extragranular excipients were passed through a screen and added to the milled granules, which were then mixed in a mixer. The final blend was compressed into tablets of 25 mg and 100 mg strength. [Table 7]

[0114] Example 6 Compound (I) SDD Tablets - Stability Results for 100mg Dose Furthermore, this tablet formulation was physically and chemically stable under different storage conditions. Exposure of the samples to high humidity (40°C / 75% RH) resulted in a significant moisture gain (approximately 3-4% w / w), which was confirmed by loss-on-drying experiments (Table 5). This moisture gain was mostly due to the excipients in the formulation.

[0115] For the starting sample, dissolution data (Table 6) showed 90% release of drug substance in approximately 30 minutes relative to the starting label claim. Furthermore, there was no effect of storage conditions on the dissolution of the tablet formulation as a function of time.

[0116] The physical stability of the tablets was evaluated under various storage conditions. The 100 mg tablets were stable under all tested stability conditions as a function of time, exhibiting potency ranging from 99.6% to 100.9% under the storage conditions for up to 4 weeks (Table 5). [Table 8]

[0117] Example 7 Preparation of capsules Capsules were manufactured by filling hard-shell capsules with the ingredients listed in Table 4. The spray-dried 75% Compound (I):HPMCAS component and all intragranular and extragranular excipients were passed through a screen and then mixed in a mixer. The final mixture was filled into hard-shell capsules using a capsule filling machine.

[0118] Example 8 Compound (I) SDD Capsules - Characterization Results at the Starting 100mg Dose In the starting sample, the 100 mg dose capsules demonstrated 98.9% potency, and dissolution data indicated greater than 90% drug release in approximately 30 minutes relative to the initial label claim (Table 6). The initial moisture content was 2.6% w / w as determined from loss on drying experiments. [Table 9]

[0119] Example 9 Bioavailability of dissolved formulations in dogs Suitable solution formulations for direct administration or as a solution filled into capsules have been shown to provide desired exposures closely related to the SDD formulations described above (e.g., as suspension / tablet / capsule SDD dosage forms). Based on solubility data, fully aqueous formulations cannot achieve the target concentrations necessary to support clinical doses. Cosolvent-based API formulations in organic vehicles (e.g., polyethylene glycol 400 or ethanol) have been combined with complexing agents (e.g., cyclodextrins) or polymers (e.g., PVP, PVP-vinyl acetate copolymer, Poloxamer 188) or surfactants (e.g., TPGS, Tween 80). A specific embodiment of a dissolved solution formulation was prepared as Compound (I) at a concentration of 5 mg / ml in a PEG 400 / TPGS / water vehicle. A preclinical crossover study in dogs (n=4) demonstrated high exposures comparable to the SDD formulation and significantly exceeding those of the crystalline formulation (Example 4, Table 3). The favorable pharmacokinetic results of these solution formulations and the SDD formulation (described below) at a dose of 25 mg (approximately 75 mg human equivalent) are shown in Tables 7 and 8.

[0120] Therapeutic formulations are as follows: SDD suspension (25 mg dose) - fasted dogs pretreated with pentagastrin (n=4) Fasted dogs (n=4) pretreated with SDD tablets (25 mg dose)-pentagastrin Dissolved solution (25 mg dose) for administration as a solution or in capsules - fasted dogs pretreated with pentagastrin (n=4) SDD capsules (25 mg dose) - fasted dogs pretreated with pentagastrin (n=4) Table 7: Therapeutic Formulations

[0121] [Table 10]

[0122] Table 8: Summary of preclinical pharmacokinetics observed in dogs [Table 11]

[0123] Although the present invention has been described in detail and with reference to specific embodiments thereof, those skilled in the art will recognize that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

1. formula: 【Chemistry 1】 1. An amorphous solid dispersion comprising Compound (I) of formula (I) and a polymer selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose (HPMC).

2. The amorphous solid dispersion of claim 1, wherein at least 80%, at least 90% or at least 95% of Compound (I) is in amorphous form.

3. The amorphous solid dispersion of claim 1, which is freeze-dried amorphous.

4. An amorphous solid dispersion as described in claim 1, which shows no signs of crystallization.

5. The amorphous solid dispersion of claim 1, wherein the ratio of compound (I) to polymer is 99 to 75% (w / w) of compound (I) and 1 to 25% (w / w) of polymer.

6. The amorphous solid dispersion of claim 1, wherein the ratio of compound (I) to polymer is 74 to 50% (w / w) of compound (I) and 26 to 50% (w / w) of polymer.

7. The amorphous solid dispersion of claim 1, wherein the ratio of compound (I) to polymer is 49 to 25% (w / w) of compound (I) and 51 to 75% (w / w) of polymer.

8. The amorphous solid dispersion of claim 1, wherein the ratio of compound (I) and polymer is 75% (w / w) compound (I) and 25% (w / w) polymer.

9. Formula: 【Chemistry 2】 An amorphous solid dispersion comprising Compound (I) of the formula (I) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).

10. The amorphous solid dispersion of claim 9, wherein at least 80%, at least 90%, or at least 95% of Compound (I) is in amorphous form.

11. The amorphous solid dispersion of claim 9, which is freeze-dried amorphous.

12. The amorphous solid dispersion of claim 9, which shows no signs of crystallization.

13. The amorphous solid dispersion of claim 9, wherein the ratio of compound (I) to polymer is 99 to 75% (w / w) of compound (I) and 1 to 25% (w / w) of polymer.

14. The amorphous solid dispersion of claim 9, wherein the ratio of compound (I) to polymer is 74 to 50% (w / w) of compound (I) and 26 to 50% (w / w) of polymer.

15. The amorphous solid dispersion of claim 9, wherein the ratio of compound (I) to polymer is 49 to 25% (w / w) of compound (I) and 51 to 75% (w / w) of polymer.

16. The amorphous solid dispersion of claim 9, wherein the ratio of Compound (I) to polymer is 75% (w / w) Compound (I) and 25% (w / w) polymer.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the amorphous solid dispersion of any one of claims 1 to 16.

18. The pharmaceutical composition of claim 17, wherein the composition is in the form of a tablet.

19. The pharmaceutical composition of claim 18, wherein the tablet is storage stable for at least three months.

20. The pharmaceutical composition of claim 18, wherein the tablet is storage stable for at least 12 months.

21. The pharmaceutical composition of claim 17, wherein the composition is in the form of a capsule.

22. The pharmaceutical composition of claim 21, wherein the capsule is storage stable for at least three months.

23. The pharmaceutical composition of claim 21, wherein the capsule is storage stable for at least 12 months.

24. The pharmaceutical composition of claim 17, wherein the composition is in the form of a suspension.

25. The pharmaceutical composition of claim 17 for use in treating or preventing thromboembolism in a patient in need thereof.

26. The pharmaceutical composition of claim 25, wherein the thromboembolism is selected from the group consisting of arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism and venous cerebrovascular thromboembolism.

27. The pharmaceutical composition of claim 25, wherein the thromboembolism is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by a medical implant, device, or procedure in which thrombosis is promoted by exposure of blood to an artificial surface.

28. The pharmaceutical composition described in claim 25, wherein the thromboembolism is acute coronary syndrome.

29. The pharmaceutical composition described in claim 25, wherein the thromboembolism is atrial fibrillation.

30. The pharmaceutical composition of claim 25, wherein the thromboembolism is stroke.

Images