Oral formulations containing abatrombopag and related uses

Abstract

This disclosure provides a pharmaceutical formulation comprising avathrombopag or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Description

Technical Field

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 509,862, filed on June 23, 2023, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Thrombocytopenia is a potentially serious disorder characterized by a deficiency of platelets in the circulatory system. This disorder is particularly associated with an increased risk of bleeding from small capillaries, leading to thrombocytopenic purpura. Causes of thrombocytopenia include decreased platelet production in the bone marrow and decreased platelet survival in the blood. There are specific thrombocytopenia disorders associated with diseases, such as immune (idiopathic) thrombocytopenic purpura (ITP) and thrombocytopenia caused by other diseases, such as infections including malignancies and hepatitis, that indirectly affect the bone marrow. Currently, the management of thrombocytopenia is mainly based on platelet transfusion. Although transfusion is effective, approximately 30% of transfusions are associated with serious complications including alloimmunization, febrile reactions and allergic reactions, circulatory overload, acute lung injury, and bacterial or viral infections. 15% - 25% of patients who require repeated platelet transfusions have insufficient platelet response due to alloimmunization against human leukocyte antigen (HLA). Therefore, a safe platelet production promoter that can reduce or eliminate the need for platelet transfusion can contribute to the health of patients and may significantly reduce medical costs. Thus, there is a need for a novel formulation of a platelet production promoter.

Summary of the Invention

[0003] The present disclosure provides avatrombopag or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, in a solid particle formulation.

[0004] In a particular embodiment, the Disclosure provides a method for preparing a dispersed particle formulation, comprising dispersing the particle formulation disclosed herein in a culture medium.

[0005] In a particular embodiment, this disclosure provides a dispersed particle formulation prepared by the method disclosed herein.

[0006] In certain embodiments, the Disclosure provides a method for treating or preventing a disease in question, the method comprising administering a dispersed particle formulation disclosed herein to the subject.

[0007] In certain embodiments, the disclosure provides the use of dispersed particle formulations disclosed herein in the manufacture of a pharmacopoeia for treating or preventing a disease of interest.

[0008] In a particular embodiment, the Disclosure provides dispersed particle formulations disclosed herein for use in the treatment or prevention of a disease in a subject.

[0009] In a particular embodiment, the Disclosure provides a method for treating a disease of interest, the method comprising administering a dispersed particle formulation disclosed herein to the subject.

[0010] In a particular embodiment, the disclosure provides the use of dispersed particle formulations disclosed herein in the manufacture of a pharmacopoeia for treating a disease of interest.

[0011] In a particular embodiment, the disclosure provides dispersed particle formulations disclosed herein for use in treating a disease of interest.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this disclosure pertains. In this specification, singular nouns also include plural nouns unless the context explicitly indicates otherwise. When performing or testing the disclosures, methods and materials similar to or equivalent to those described herein may be used, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein are not considered prior art to the claimed inventions. In case of any conflict, this specification shall prevail, including definitions. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0013] Other features and advantages of this disclosure will become apparent from the embodiments and claims for carrying out the invention described below. [Brief explanation of the drawing]

[0014] [Figure 1] This graph shows the dissolution profile of 10 mg of avathrombopag powder for oral suspension in capsules. [Figure 2] This graph shows the dissolution profile of avathrombopag capsules 10 mg for oral suspension in development and clinical batches. [Figure 3] This is a flowchart of the manufacturing process. [Figure 4] This is a bar graph showing the particle size distribution of Avathrombopag granules. [Modes for carrying out the invention]

[0015] As used herein, "avatrombopag" refers to a compound having the following structure: [ka] This compound can be identified by the CAS number 570406-98-3 and / or the IUPAC name 1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid.

[0016] Although not intended to be bound by theory, the tablet formulation of avatrombopag may not be suitable for subjects who cannot swallow the tablet or have difficulty swallowing it. Furthermore, the intravenous administration route of avatrombopag may not be a preferred route for outpatient use and may also be difficult to develop due to its solubility. Therefore, the formulations of the present disclosure can be age-appropriate avatrombopag formulations that enable the administration of avatrombopag to subjects 1 month of age or older and less than 18 years of age who cannot swallow the tablet, or to subjects of any age who cannot swallow the tablet or have difficulty swallowing it.

[0017] In certain embodiments, the present disclosure provides a solid particle formulation comprising avatrombopag or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0018] In certain embodiments, the formulation is substantially lactose-free. Solid particles

[0019] In certain embodiments, the solid particles are powders or granules.

[0020] In certain embodiments, the solid particles are granules.

[0021] In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 700 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 600 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 500 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 400 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 300 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 100 μm to approximately 200 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 700 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 600 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 500 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 400 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 200 μm to approximately 300 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 700 μm.In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 600 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 500 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 300 μm to approximately 400 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 400 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 400 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 400 μm to approximately 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 400 μm to approximately 700 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 400 μm to approximately 600 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 400 μm to approximately 500 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 500 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 500 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 500 μm to approximately 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 500 μm to approximately 700 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 500 μm to approximately 600 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 600 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 600 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 600 μm to approximately 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 600 μm to approximately 700 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 700 μm to approximately 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 700 μm to approximately 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of approximately 700 μm to approximately 800 μm.In certain embodiments, the aggregate of solid particles has an average diameter of from about 800 μm to about 1000 μm. In certain embodiments, the aggregate of solid particles has an average diameter of from about 800 μm to about 900 μm. In certain embodiments, the aggregate of solid particles has an average diameter of from about 900 μm to about 1000 μm.

[0022] In certain embodiments, the aggregate of solid particles has an average diameter of about 300 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 350 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 400 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 450 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 500 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 550 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 600 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 650 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 700 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 750 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 800 μm. In certain embodiments, the aggregate of solid particles has an average diameter of about 850 μm.

[0023] In certain embodiments, the aggregate of solid particles has a bulk density of about 0.54 g / mL to about 0.78 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.54 g / mL to about 0.74 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.54 g / mL to about 0.70 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.54 g / mL to about 0.66 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.54 g / mL to about 0.62 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.54 g / mL to about 0.58 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.58 g / mL to about 0.78 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.58 g / mL to about 0.74 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.58 g / mL to about 0.70 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.58 g / mL to about 0.66 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.58 g / mL to about 0.62 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.62 g / mL to about 0.78 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.62 g / mL to about 0.74 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.62 g / mL to about 0.70 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.62 g / mL to about 0.66 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.66 g / mL to about 0.78 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.66 g / mL to about 0.74 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.66 g / mL to about 0.70 g / mL.In certain embodiments, the aggregate of solid particles has a bulk density of about 0.70 g / mL to about 0.78 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.70 g / mL to about 0.74 g / mL. In certain embodiments, the aggregate of solid particles has a bulk density of about 0.74 g / mL to about 0.78 g / mL.

[0024] In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.58 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.60 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.61 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.62 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.63 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.64 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.65 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.66 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.68 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of about 0.70 g / mL. In a particular embodiment, the aggregate of solid particles has a bulk density of approximately 0.72 g / mL.

[0025] Abatrombo Pug In a particular embodiment, the formulation comprises avathrombopag.

[0026] In certain embodiments, the formulation comprises a pharmaceutically acceptable salt of avathrombopag.

[0027] In certain embodiments, the pharmaceutically acceptable salt of avathrombopag is avathrombopag maleate.

[0028] In certain embodiments, the pharmaceutically acceptable salt of avathrombopag is avathrombopag monomaleate.

[0029] In a particular embodiment, the formulation contains avathrombopag maleate.

[0030] In a particular embodiment, the formulation comprises avathrombopag monomaleate.

[0031] In certain embodiments, the formulation comprises an aggregate of solid particles composed of avathrombopag or a pharmaceutically acceptable salt thereof.

[0032] In a particular embodiment, the formulation comprises an aggregate of solid particles composed of avathrombopag.

[0033] In certain embodiments, the formulation comprises an aggregate of solid particles composed of a pharmaceutically acceptable salt of avathrombopag.

[0034] In a particular embodiment, the formulation comprises an aggregate of solid particles composed of avathrombopagmaleate.

[0035] In a particular embodiment, the formulation comprises an aggregate of solid particles composed of a monomaleate.

[0036] In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 18.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 16.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 14.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 12.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 10.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 8.0% w / w.

[0037] In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 7.0% w / w to about 18.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 7.0% w / w to about 16.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 7.0% w / w to about 14.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 7.0% w / w to about 12.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 7.0% w / w to about 10.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 7.0% w / w to about 8.0% w / w.

[0038] In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 9.0% w / w to about 18.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 9.0% w / w to about 16.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 9.0% w / w to about 14.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 9.0% w / w to about 12.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 9.0% w / w to about 10.0% w / w.

[0039] In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 11.0% w / w to about 18.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 11.0% w / w to about 16.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 11.0% w / w to about 14.0% w / w. In certain embodiments, avathrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 11.0% w / w to about 12.0% w / w.

[0040] In a particular embodiment, avathrombopag is present in an amount of about 10.0% w / w, or avathrombopag monomaleate is present in an amount of about 11.8% w / w.

[0041] Pharmaceutically acceptable excipients In certain embodiments, the solid particle formulation comprises one or more pharmaceutically acceptable excipients.

[0042] Diluent In certain embodiments, the formulation includes a diluent.

[0043] In some embodiments, the diluent is selected from lactose, sucrose (e.g., Dipac®), dextrose, dextrate, maltodextrin, mannitol, xylitol (e.g., Xylitab®), sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose (e.g., Avicel®), microcellulose, and talc.

[0044] In certain embodiments, the diluent comprises microcrystalline cellulose. In certain embodiments, the diluent comprises mannitol. In certain embodiments, the diluent comprises microcrystalline cellulose and mannitol.

[0045] In certain embodiments, the diluent is present in an amount ranging from approximately 66.0% w / w to approximately 86.0% w / w. In certain embodiments, the diluent is present in an amount ranging from approximately 66.0% w / w to approximately 82.0% w / w. In certain embodiments, the diluent is present in an amount ranging from approximately 66.0% w / w to approximately 78.0% w / w. In certain embodiments, the diluent is present in an amount ranging from approximately 66.0% w / w to approximately 74.0% w / w. In certain embodiments, the diluent is present in an amount ranging from approximately 66.0% w / w to approximately 70.0% w / w. In certain embodiments, the diluent is present in an amount ranging from approximately 70.0% w / w to approximately 86.0% w / w. In certain embodiments, the diluent is present in an amount ranging from approximately 70.0% w / w to approximately 82.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 70.0% w / w to about 78.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 70.0% w / w to about 74.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 74.0% w / w to about 86.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 74.0% w / w to about 82.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 74.0% w / w to about 78.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 78.0% w / w to about 86.0% w / w. In certain embodiments, the diluent is present in an amount ranging from about 78.0% w / w to about 82.0% w / w.

[0046] In certain embodiments, the diluent is present in an amount of about 66.0% w / w. In certain embodiments, the diluent is present in an amount of about 68.0% w / w. In certain embodiments, the diluent is present in an amount of about 70.0% w / w. In certain embodiments, the diluent is present in an amount of about 72.0% w / w. In certain embodiments, the diluent is present in an amount of about 74.0% w / w. In certain embodiments, the diluent is present in an amount of about 76.0% w / w. In certain embodiments, the diluent is present in an amount of about 78.0% w / w. In certain embodiments, the diluent is present in an amount of about 80.0% w / w. In certain embodiments, the diluent is present in an amount of about 82.0% w / w. In certain embodiments, the diluent is present in an amount of about 84.0% w / w. In certain embodiments, the diluent is present in an amount of about 86.0% w / w.

[0047] In a particular embodiment, the diluent is present in an amount of about 77.2±20.0% w / w, about 77.2±15.0% w / w, about 77.2±10.0% w / w, about 77.2±9.0% w / w, about 77.2±8.0% w / w, about 77.2±7.0% w / w, about 77.2±6.0% w / w, about 77.2±5.0% w / w, about 77.2±4.0% w / w, about 77.2±3.0% w / w, about 77.2±2.0% w / w, or about 77.2±1.0% w / w (e.g., about 77.2% w / w).

[0048] In a particular embodiment, the diluent contains microcrystalline cellulose, which is present in an amount of approximately 28.0% w / w.

[0049] In a particular embodiment, the diluent contains mannitol, which is present in an amount of approximately 49% w / w.

[0050] In a particular embodiment, the diluent comprises microcrystalline cellulose and mannitol, wherein the microcrystalline cellulose is present in an amount of about 28.0% w / w and the mannitol is present in an amount of about 49% w / w.

[0051] Binder In a particular embodiment, the formulation includes a binder.

[0052] In certain embodiments, the binder is selected from polyvinylpyrrolidone (PVP) (e.g., PVP K15, PVP K19, PVP K25, PVP K30, Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), cross-linked polyvinyl N-pyrrolidone (crospovidone), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), sodium carboxymethylcellulose, methylcellulose, lactose, sucrose, sorbitol, xylitol, mannitol, starch, sodium alginate, gelatin, and polyethylene glycol (PEG).

[0053] In a particular embodiment, the binder includes crospovidone.

[0054] In certain embodiments, the binder is present in an amount ranging from about 2.0% w / w to about 8.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 2.0% w / w to about 7.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 2.0% w / w to about 6.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 2.0% w / w to about 5.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 2.0% w / w to about 4.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 2.0% w / w to about 3.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 3.0% w / w to about 8.0% w / w. In certain embodiments, the binder is present in an amount ranging from about 3.0% w / w to about 7.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 3.0% w / w to approximately 6.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 3.0% w / w to approximately 5.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 3.0% w / w to approximately 4.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 4.0% w / w to approximately 8.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 4.0% w / w to approximately 7.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 4.0% w / w to approximately 6.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 4.0% w / w to approximately 5.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 5.0% w / w to approximately 8.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 5.0% w / w to approximately 7.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 5.0% w / w to approximately 6.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 6.0% w / w to approximately 8.0% w / w. In certain embodiments, the binder is present in an amount ranging from approximately 6.0% w / w to approximately 7.0% w / w.

[0055] In certain embodiments, the binder is present in an amount of about 2.0% w / w. In certain embodiments, the binder is present in an amount of about 2.5% w / w. In certain embodiments, the binder is present in an amount of about 3.0% w / w. In certain embodiments, the binder is present in an amount of about 3.5% w / w. In certain embodiments, the binder is present in an amount of about 4.0% w / w. In certain embodiments, the binder is present in an amount of about 4.5% w / w. In certain embodiments, the binder is present in an amount of about 5.0% w / w. In certain embodiments, the binder is present in an amount of about 5.5% w / w. In certain embodiments, the binder is present in an amount of about 6.0% w / w. In certain embodiments, the binder is present in an amount of about 6.5% w / w. In certain embodiments, the binder is present in an amount of about 7.0% w / w. In certain embodiments, the binder is present in an amount of about 7.5% w / w. In a particular embodiment, the binder is present in an amount of approximately 8.0% w / w.

[0056] In certain embodiments, the binder is present in an amount of about 5.0 ± 3.0% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 2.8% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 2.6% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 2.4% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 2.2% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 2.0% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 1.8% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 1.6% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 1.4% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 1.2% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 1.0% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 0.8% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 0.6% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 0.4% w / w. In certain embodiments, the binder is present in an amount of about 5.0 ± 0.2% w / w (e.g., 5.0% w / w).

[0057] In a particular embodiment, the binder comprises crospovidone, which is present in an amount of about 5.0% w / w.

[0058] Disintegrant In certain embodiments, the formulation includes a disintegrant.

[0059] In certain embodiments, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose (e.g., Methocel®), cross-linked starches such as croscarmellose, croscarmellose sodium, cross-linked carboxymethylcellulose sodium, cross-linked carboxymethylcellulose, cross-linked croscarmellose, and sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, and sodium alginate, clay, and gum.

[0060] surfactants In a particular embodiment, the formulation includes a surfactant.

[0061] In certain embodiments, the surfactant includes sodium lauryl sulfate.

[0062] In certain embodiments, the surfactant is present in an amount ranging from about 2.0% w / w to about 8.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 2.0% w / w to about 7.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 2.0% w / w to about 6.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 2.0% w / w to about 5.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 2.0% w / w to about 4.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 2.0% w / w to about 3.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 3.0% w / w to about 8.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 3.0% w / w to about 7.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 3.0% w / w to about 6.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 3.0% w / w to about 5.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 3.0% w / w to about 4.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 4.0% w / w to about 8.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 4.0% w / w to about 7.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 4.0% w / w to about 6.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 4.0% w / w to about 5.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 5.0% w / w to about 8.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 5.0% w / w to about 7.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 5.0% w / w to about 6.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 6.0% w / w to about 8.0% w / w. In certain embodiments, the surfactant is present in an amount ranging from about 6.0% w / w to about 7.0% w / w.

[0063] In certain embodiments, the surfactant is present in an amount of about 2.0% w / w. In certain embodiments, the surfactant is present in an amount of about 2.5% w / w. In certain embodiments, the surfactant is present in an amount of about 3.0% w / w. In certain embodiments, the surfactant is present in an amount of about 3.5% w / w. In certain embodiments, the surfactant is present in an amount of about 4.0% w / w. In certain embodiments, the surfactant is present in an amount of about 4.5% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0% w / w. In certain embodiments, the surfactant is present in an amount of about 5.5% w / w. In certain embodiments, the surfactant is present in an amount of about 6.0% w / w. In certain embodiments, the surfactant is present in an amount of about 6.5% w / w. In certain embodiments, the surfactant is present in an amount of about 7.0% w / w. In certain embodiments, the surfactant is present in an amount of about 7.5% w / w. In a particular embodiment, the surfactant is present in an amount of about 8.0% w / w.

[0064] In certain embodiments, the surfactant is present in an amount of about 5.0 ± 3.0% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 2.8% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 2.6% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 2.4% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 2.2% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 2.0% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 1.8% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 1.6% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 1.4% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 1.2% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 1.0% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 0.8% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 0.6% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 0.4% w / w. In certain embodiments, the surfactant is present in an amount of about 5.0 ± 0.2% w / w (e.g., 5.0% w / w).

[0065] In a particular embodiment, the surfactant comprises sodium lauryl sulfate and is present in an amount of about 5.0% w / w.

[0066] lubricant In certain embodiments, the formulation includes a lubricant.

[0067] In a particular embodiment, the lubricant comprises magnesium stearate.

[0068] In certain embodiments, the lubricant is present in an amount ranging from about 0.1% w / w to about 3.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.1% w / w to about 2.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.1% w / w to about 2.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.1% w / w to about 1.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.1% w / w to about 1.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.1% w / w to about 0.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.5% w / w to about 3.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.5% w / w to about 2.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.5% w / w to about 2.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.5% w / w to about 1.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.5% w / w to about 1.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.8% w / w to about 3.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.8% w / w to about 2.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.8% w / w to about 2.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.8% w / w to about 1.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 0.8% w / w to about 1.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 1.2% w / w to about 3.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 1.2% w / w to about 2.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 1.2% w / w to about 2.0% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 1.2% w / w to about 1.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 1.5% w / w to about 3.0% w / w.In certain embodiments, the lubricant is present in an amount ranging from about 1.5% w / w to about 2.5% w / w. In certain embodiments, the lubricant is present in an amount ranging from about 1.5% w / w to about 2.0% w / w.

[0069] In certain embodiments, the lubricant is present in an amount of about 0.1% w / w. In certain embodiments, the lubricant is present in an amount of about 0.2% w / w. In certain embodiments, the lubricant is present in an amount of about 0.3% w / w. In certain embodiments, the lubricant is present in an amount of about 0.4% w / w. In certain embodiments, the lubricant is present in an amount of about 0.5% w / w. In certain embodiments, the lubricant is present in an amount of about 0.6% w / w. In certain embodiments, the lubricant is present in an amount of about 0.7% w / w. In certain embodiments, the lubricant is present in an amount of about 0.8% w / w. In certain embodiments, the lubricant is present in an amount of about 0.9% w / w. In certain embodiments, the lubricant is present in an amount of about 1.0% w / w. In certain embodiments, the lubricant is present in an amount of about 1.1% w / w. In certain embodiments, the lubricant is present in an amount of about 1.2% w / w. In certain embodiments, the lubricant is present in an amount of about 1.3% w / w. In certain embodiments, the lubricant is present in an amount of about 1.4% w / w. In certain embodiments, the lubricant is present in an amount of about 1.5% w / w. In certain embodiments, the lubricant is present in an amount of about 1.6% w / w. In certain embodiments, the lubricant is present in an amount of about 1.8% w / w. In certain embodiments, the lubricant is present in an amount of about 2.0% w / w. In certain embodiments, the lubricant is present in an amount of about 2.2% w / w. In certain embodiments, the lubricant is present in an amount of about 2.4% w / w. In certain embodiments, the lubricant is present in an amount of about 2.6% w / w. In certain embodiments, the lubricant is present in an amount of about 2.8% w / w. In certain embodiments, the lubricant is present in an amount of about 3.0% w / w.

[0070] In certain embodiments, the surfactant is present in an amount of about 1.0 ± 0.5% w / w. In certain embodiments, the surfactant is present in an amount of about 1.0 ± 0.4% w / w. In certain embodiments, the surfactant is present in an amount of about 1.0 ± 0.3% w / w. In certain embodiments, the surfactant is present in an amount of about 1.0 ± 0.2% w / w. In certain embodiments, the surfactant is present in an amount of about 1.0 ± 0.1% w / w (e.g., 1.0% w / w).

[0071] In a particular embodiment, the lubricant comprises magnesium stearate, which is present in the particulate formulation in an amount of about 1.0% w / w.

[0072] In certain embodiments, one or more pharmaceutically acceptable excipients include diluents, binders, surfactants, and lubricants.

[0073] Exemplary Embodiments of the Formulation In certain embodiments, the formulation comprises a diluent, a binder, a surfactant, and a lubricant.

[0074] In a particular embodiment, avathrombopag and the diluent are present in the formulation in a ratio of approximately 12:77.

[0075] In a particular embodiment, the diluent and the binder are present in the formulation in a ratio of approximately 77:5.

[0076] In a particular embodiment, the diluent and the surfactant are present in the formulation in a ratio of approximately 77:5.

[0077] In a particular embodiment, the diluent and the lubricant are present in the formulation in a ratio of approximately 77:1.

[0078] In a particular embodiment, the diluent, binder, surfactant, and lubricant are present in the formulation in a ratio of approximately 12:77:5:5:1.

[0079] In a particular embodiment, the formulation is Approximately 11.8 ± 3.0% w / w of avathrombopag monomaleate, A diluent of approximately 77.2 ± 20.0% w / w, Approximately 5.0 ± 3.0% w / w of binder, Approximately 5.0 ± 3.0% w / w of surfactant, It contains approximately 1.0 ± 0.5% w / w of lubricant.

[0080] In a particular embodiment, the formulation is Approximately 11.8 ± 3.0 mg of avathrombopag monomaleate, Approximately 49.2 ± 10.0 mg of mannitol, Approximately 28.0 ± 10.0 mg of microcrystalline cellulose, Approximately 5.0 ± 3.0 mg of crospovidone type A, Approximately 5.0 ± 3.0 mg of sodium lauryl sulfate, Contains approximately 1.0 ± 0.5 mg of magnesium stearate.

[0081] In a particular embodiment, the formulation is Approximately 11.8 mg of avathrombopag monomaleate, Approximately 49.2 mg of mannitol, Approximately 28.0 mg of microcrystalline cellulose, Approximately 5.0 mg of crospovidone type A, Approximately 5.0 mg of sodium lauryl sulfate, Contains approximately 1.0 mg of magnesium stearate. Dosage form

[0082] In certain embodiments, the present disclosure provides oral dosage forms comprising solid particle formulations disclosed herein.

[0083] In a particular embodiment, the oral dosage form is a capsule.

[0084] In a particular embodiment, the capsule is configured to be easily opened.

[0085] How to use In a particular embodiment, the Disclosure provides a method for preparing a dispersed particle formulation, comprising dispersing the particle formulation disclosed herein in a culture medium.

[0086] In certain embodiments, the culture medium is either a solid medium or a liquid medium.

[0087] In a particular embodiment, the culture medium is an aqueous medium.

[0088] In a particular embodiment, this disclosure provides a dispersed particle formulation prepared by the method disclosed herein.

[0089] In certain embodiments, the Disclosure provides a method for treating or preventing a disease in question, the method comprising administering a dispersed particle formulation disclosed herein to the subject.

[0090] In certain embodiments, the disclosure provides the use of dispersed particle formulations disclosed herein in the manufacture of a pharmacopoeia for treating or preventing a disease of interest.

[0091] In a particular embodiment, the Disclosure provides dispersed particle formulations disclosed herein for use in the treatment or prevention of a disease in a subject.

[0092] In a particular embodiment, the Disclosure provides a method for treating a disease of interest, the method comprising administering a dispersed particle formulation disclosed herein to the subject.

[0093] In a particular embodiment, the disclosure provides the use of dispersed particle formulations disclosed herein in the manufacture of a pharmacopoeia for treating a disease of interest.

[0094] In a particular embodiment, the disclosure provides dispersed particle formulations disclosed herein for use in treating a disease of interest.

[0095] In a particular embodiment, the disease or disorder is thrombocytopenia.

[0096] In certain embodiments, thrombocytopenia is idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria (PNH), antiphospholipid syndrome, systemic lupus erythematosus (SLE), post-transfusion purpura, neonatal alloimmune thrombocytopenia (NAITP), platelet sequestration by the spleen due to hypersplenism, dengue fever, thrombocytopenia associated with myelodysplastic syndrome (MDS), or chemotherapy-induced thrombocytopenia, severe aplastic anemia (SAA), Evans syndrome after hematopoietic stem cell transplantation (HSCT), or hereditary thrombocytopenia.

[0097] In a particular embodiment, the disease or disorder is immune thrombocytopenia (ITP).

[0098] In a particular embodiment, the patient is a pediatric patient.

[0099] In certain embodiments, the patient is under 18 years of age. In certain embodiments, the patient is under 5 years of age. In certain embodiments, the patient is unable to swallow tablets or pills.

[0100] In a particular embodiment, the patient has had primary ITP for ≥6 months or has had an inadequate response to previous treatments.

[0101] In a particular embodiment, the patient had an average platelet count of 30 × 10⁶ measured over two measurements. 9 It is less than / L, and in all measurements, >35×10 9 The value of / L is not shown.

[0102] definition As used herein and in the appended claims, unless otherwise intended, the following terms have the meanings set forth below.

[0103] When used before a number, the term "approximately" may indicate that the value may vary within a reasonable range, such as ±10%, ±5%, ±3%, or ±1% of the stated value.

[0104] The “subjects” to which the drug is intended to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (young adults, middle-aged adults, or elderly adults)) and / or non-human mammals, e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a patient. In certain embodiments, the subject is a non-human mammal.

[0105] "Effective dose" refers to the amount of a compound sufficient to produce an effect on treatment or prevention of a disease when administered to a subject. The "effective dose" can vary depending on the compound, the disease and its severity, and the age and weight of the patient receiving treatment. "Therapeutic effective dose" refers to the amount effective for a therapeutic treatment. "Prophylactic effective dose" refers to the amount effective for a prophylactic treatment.

[0106] "Prevention," "prevention," or "preventive measures" means reducing the risk of contracting or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a person who has not yet been exposed to the pathogen or who has a predisposition to contract the disease before the onset of the disease).

[0107] The term "prophylaxis" is related to "prevention" and refers to means or measures aimed at preventing a disease rather than treating or curing it. Examples of non-limiting preventive measures include the administration of vaccines, for example, the administration of low molecular weight heparin to hospitalized patients at risk of thrombosis due to immobilization, and the administration of antimalarial drugs such as chloroquine before visiting areas where malaria is endemic or at high risk of infection.

[0108] In one embodiment, “treating,” “treatment,” or “therapeutic treatment” of any disease or disorder means improving the disease or disorder (i.e., preventing the disease or reducing the manifestation, degree, or severity of at least one clinical symptom of the disease). In another embodiment, “treating” or “treatment” means improving at least one physical parameter, even if the subject is not perceptible. In yet another embodiment, “treating” or “treatment” means modulating the disease or disorder physically (e.g., stabilizing perceptible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0109] As used herein, the term “Subjects in need” means subjects who have or are at high risk of developing any of the diseases or disorders disclosed herein. Subjects in need may be subjects who have been previously diagnosed or identified as having any of the diseases or disorders disclosed herein. Subjects in need may also be subjects currently suffering from any of the diseases or disorders disclosed herein. Alternatively, subjects in need may be subjects who are at high risk of developing such a disease or disorder compared to the general population (i.e., subjects who are more likely to develop such a disease or disorder compared to the general population). Subjects in need may have refractory or resistant diseases or disorders disclosed herein (i.e., diseases or disorders disclosed herein that do not respond to or have not yet responded to treatment). Subjects may exhibit resistance at the start of treatment or may develop resistance during treatment. In some embodiments, subjects in need have failed to receive all known effective treatments for any of the diseases or disorders disclosed herein. In some embodiments, subjects in need have received at least one prior treatment.

[0110] As used herein, the terms “treating” or “treat” mean managing and caring for a patient with the aim of combating a disease or disorder, and include administering the compounds of this disclosure, or their pharmaceutically acceptable salts, polymorphs, or solvates, to alleviate the symptoms or complications of the disease or disorder, or to eliminate the disease or disorder. The term “treat” may also include the treatment of in vitro cell or animal models. It should be understood that references to “treating” or “treatment” include the alleviation of established symptoms of a medical condition. Therefore, “treating” or “treatment” of a stage, disorder, or condition includes (1) preventing or delaying the onset of the clinical symptoms of the stage, disorder, or condition in a person who is susceptible to or prone to the condition but has not yet experienced or exhibited any clinical or paraclinical symptoms of the stage, disorder, or condition; (2) inhibiting the stage, disorder, or condition, i.e., preventing, reducing, or delaying the onset or recurrence of the disease, or at least one of its clinical or paraclinical symptoms (in the case of conservative treatment); or (3) alleviating or reducing the disease, i.e., regressing the stage, disorder, or condition, or at least one of its clinical or paraclinical symptoms.

[0111] As used herein, the term “pharmaceutical composition” refers to a formulation containing the compounds of this disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk form or in unit dose form. The unit dose form is any of various forms, including, for example, capsules, IV bags, tablets, single-use pumps for aerosol inhalers, or vials. In one embodiment, the active compound is mixed with a pharmaceutically acceptable carrier under sterile conditions and, if necessary, with any preservatives, buffers, or propellants.

[0112] As used herein, the term “pharmaceutically acceptable” means a compound, anion, cation, material, composition, carrier, and / or dosage form that is suitable for use in contact with human and animal tissues, within reasonable medical judgment, and commensurate with a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reaction, or other problems or complications.

[0113] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and useful in the preparation of a pharmaceutical composition that is not biologically or otherwise harmful, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and more such excipients.

[0114] Pharmaceutical compositions comprising the active compound of this disclosure may be manufactured in a manner generally known, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet manufacturing, polishing, emulsification, encapsulation, encapsulation, or lyophilization processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation.

[0115] "Pharmacologically acceptable salt" means a salt of the compound of this disclosure that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts may be non-toxic and may be inorganic or organic acid addition salts and base addition salts.

[0116] In salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0117] As used herein, the phrase "compounds of the disclosure" refers generally and specifically to the compounds disclosed herein.

[0118] It will be understood that the compounds disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers of the compounds, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0119] Even if a compound disclosed herein is shown having a particular structure, such particular structure should not be construed as limiting this disclosure to any isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. Where a compound described herein is shown having a particular structure, that particular structure is intended to encompass and refer to all available isomers, tautomers, positional isomers, and stereoisomers of the compound, or mixtures thereof, and is also intended to refer to the particular structure of the compound itself.

[0120] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the order of their atomic bonding or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are mirror images of each other but cannot be superimposed are sometimes called "enantiomers" or optical isomers. A mixture containing equal amounts of individual enantiomers with opposite chiralities is called a "racemic mixture."

[0121] As used herein, the term “geometric isomer” means a diastereomer that is hindered from rotating around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These arrangements are distinguished in their names by the prefixes cis and trans, or Z and E, indicating that the group is on the same side or opposite side of the double bond within the molecule, according to the Kahn-Ingold-Prelogue rule.

[0122] It should be understood that the compounds of this disclosure may be illustrated as different chiral or geometric isomers. Where a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and the name of the compound does not exclude any of the isomeric forms. It should be understood that not all isomers have the same level of activity.

[0123] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropisomers. It should also be understood that not all atropisomers have the same level of activity.

[0124] As used herein, the term “atropisomer” refers to a type of stereoisomer in which the atoms of two isomers are spatially distinct. The existence of atropisomers is due to rotational constraints resulting from the obstruction of rotation of the larger group around a central bond. Such atropisomers typically exist as a mixture, but recent advances in chromatography techniques have made it possible, in some cases, to separate a mixture of two atropisomers.

[0125] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and into which one isomeric form is readily convertible. This conversion results in a formal transfer of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of aggregates of tautomers. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to produce a cyclic (ring-shaped) form, as exemplified by glucose.

[0126] It should be understood that the compounds in this disclosure may be described as different tautomers. If a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the name of the compound does not exclude tautomer forms. It should also be understood that certain tautomers may have higher activity levels than others.

[0127] Compounds with the same molecular formula but different atomic bonding properties or order, or different spatial arrangements of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively) according to the Kahn-Prelogue RS order rule or by the way the molecule rotates its plane of polarization. Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0128] The compounds of this disclosure may have one or more chiral centers, and therefore such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in this specification and claims are intended to include both individual enantiomers and their racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by separation of racemic forms (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of this disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that this disclosure encompasses all optical, diastereoisomers, and geometric isomers, as well as mixtures thereof, that have inflammasome inhibitory activity.

[0129] This disclosure also includes compounds of the disclosure as defined herein, which involve one or more isotopic substitutions. Exemplary Embodiments Exemplary Embodiment 1 A solid particle formulation, A Avatronbo Pag having the following structure, [ka] or a pharmaceutically acceptable salt thereof, The solid particle formulation comprising one or more pharmaceutically acceptable excipients. Exemplary Embodiment 2 The pharmaceutically acceptable salt of avathrombopag is avathrombopag monomaleate, as described in any one of the preceding exemplary embodiments of the solid particle formulation. Exemplary Embodiment 3 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the solid particles are granules. Exemplary Embodiment 4 The aggregate of solid particles has an average particle diameter of about 400 μm to about 600 μm, as described in any one of the preceding exemplary embodiments of the solid particle formulation. Exemplary Embodiment 5 The aggregate of solid particles has a bulk density of approximately 0.58 g / mL to approximately 0.66 g / mL, as described in any one of the preceding exemplary embodiments of the solid particle formulation. Exemplary Embodiment 6 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the abatrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 18.0% w / w. Exemplary Embodiment 7 A solid particle formulation according to any one of the preceding exemplary embodiments, wherein the abatrombopag is present in an amount of about 10.0 ± 5% w / w, or a pharmaceutically acceptable salt of the abatrombopag is present in an amount of about 11.8 ± 5% w / w. Exemplary Embodiment 8 A solid particle formulation according to any one of the preceding exemplary embodiments, comprising one or more pharmaceutically acceptable excipients, a diluent, a binder, a surfactant, or a lubricant. Exemplary Embodiment 9 The diluent is selected from lactose, sucrose (e.g., Dipac®), dextrose, dextrate, maltodextrin, mannitol, xylitol (e.g., Xylitab®), sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose (e.g., Avicel®), microcellulose, and talc, and is a solid particle formulation according to any one of the preceding exemplary embodiments. Exemplary Embodiment 10 The diluent is present in an amount ranging from approximately 70.0% w / w to approximately 85.0% w / w, in the solid particle formulation according to any one of the preceding exemplary embodiments. Exemplary Embodiment 11 The diluent comprises microcrystalline cellulose and mannitol, the solid particle formulation according to any one of the preceding exemplary embodiments. Exemplary Embodiment 12 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the diluent comprises microcrystalline cellulose and mannitol, the microcrystalline cellulose being present in an amount of about 30.0 ± 5.0% w / w and the mannitol being present in an amount of about 49.0 ± 5.0% w / w. Exemplary Embodiment 13 The binder is selected from polyvinylpyrrolidone (PVP) (e.g., PVP K15, PVP K19, PVP K25, PVP K30, Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), cross-linked polyvinyl N-pyrrolidone (crospovidone), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), sodium carboxymethylcellulose, methylcellulose, lactose, sucrose, sorbitol, xylitol, mannitol, starch, sodium alginate, gelatin, and polyethylene glycol (PEG), as described in any one of the preceding exemplary embodiments of the solid particle formulation. Exemplary Embodiment 14 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the binder is present in an amount of about 2.0% w / w to about 8.0% w / w. Exemplary Embodiment 15 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the binder comprises crospovidone, the crospovidone present in an amount of about 5.0% w / w. Exemplary Embodiment 16 The surfactant comprises sodium lauryl sulfate, as described in any one of the preceding exemplary embodiments of the solid particle formulation. Exemplary Embodiment 17 The solid particle formulation according to exemplary embodiment 16, wherein the surfactant is present in an amount of about 2.0% w / w to about 8.0% w / w. Exemplary Embodiment 18 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the surfactant comprises sodium lauryl sulfate, and the sodium lauryl sulfate is present in an amount of about 5.0% w / w. Exemplary Embodiment 19 The lubricant comprises magnesium stearate, as described in any one of the preceding exemplary embodiments of the solid particle formulation. Exemplary Embodiment 20 The lubricant is present in an amount of about 0.1% w / w to about 3.0% w / w, in the solid particle formulation according to any one of the preceding exemplary embodiments. Exemplary Embodiment 21 The solid particle formulation according to any one of the preceding exemplary embodiments, wherein the lubricant comprises magnesium stearate, and the magnesium stearate is present in the particle formulation in an amount of about 1.0 w / w%. Exemplary Embodiment 22 The aforementioned solid particle formulation is Approximately 11.8 ± 3.0% w / w of the aforementioned abatrombopag monomaleate, The aforementioned diluent is approximately 77.0 ± 20.0% w / w, The aforementioned binder is present in an amount of approximately 5.0 ± 3.0% w / w, The aforementioned surfactant in an amount of approximately 5.0 ± 3.0% w / w, A solid particle formulation according to any one of the preceding exemplary embodiments, comprising approximately 1.0 ± 0.9% w / w of the lubricant. Exemplary Embodiment 23 The aforementioned solid particle formulation is Approximately 11.8 ± 3.0 mg of the aforementioned abatrombopag monomaleate, Approximately 49.2 ± 10.0 mg of mannitol, Approximately 28.0 ± 10.0 mg of microcrystalline cellulose, Approximately 5.0 ± 3.0 mg of crospovidone type A, Approximately 5.0 ± 3.0 mg of sodium lauryl sulfate, A solid particle formulation according to any one of the preceding exemplary embodiments, comprising approximately 1.0 ± 0.9 mg of magnesium stearate. Exemplary Embodiment 24 The aforementioned solid particle formulation is Approximately 11.8 mg of the aforementioned abatrombopag monomaleate, Approximately 49.2 mg of mannitol, Approximately 28.0 mg of microcrystalline cellulose, Approximately 5.0 mg of crospovidone type A, Approximately 5.0 mg of sodium lauryl sulfate, A solid particle formulation according to any one of the prior exemplary embodiments, comprising approximately 1.0 mg of magnesium stearate. Exemplary Embodiment 25 The formulation is a solid particle formulation according to any one of the prior exemplary embodiments, which is substantially lactose-free. Exemplary Embodiment 26 An oral dosage form comprising a solid particle formulation described in any one of the preceding exemplary embodiments. Exemplary Embodiment 27 The oral dosage form is a capsule, as described in any one of the preceding exemplary embodiments. Exemplary Embodiment 28 The capsule is configured to be easily opened, in an oral dosage form according to any one of the preceding exemplary embodiments. Exemplary Embodiment 29 A method for preparing a dispersed particle formulation, comprising dispersing a particle formulation described in any one of the preceding exemplary embodiments in a culture medium. Exemplary Embodiment 30 The method according to any one of the preceding exemplary embodiments, wherein the culture medium is a solid medium or a liquid medium. Exemplary Embodiment 31 The method according to any one of the preceding exemplary embodiments, wherein the culture medium is an aqueous culture medium. Exemplary Embodiment 32 A dispersed particle formulation prepared by the method described in any one of the preceding exemplary embodiments. Exemplary Embodiment 33 A method for treating or preventing a target disease, comprising administering to the target a dispersed particle formulation described in any one of the preceding exemplary embodiments. Exemplary Embodiment 34 Use of a dispersed particle formulation described in any one of the prior exemplary embodiments in the manufacture of a drug for treating or preventing a target disease. Exemplary Embodiment 35 A dispersed particle formulation according to any one of the prior exemplary embodiments, used for treating or preventing a target disease. Exemplary Embodiment 36 The disease or disorder is idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria (PNH), antiphospholipid syndrome, systemic lupus erythematosus (SLE), post-transfusion purpura, neonatal alloimmune thrombocytopenia (NAITP), platelet sequestration by the spleen due to hypersplenism, dengue fever, thrombocytopenia associated with myelodysplastic syndrome (MDS), or chemotherapy-induced thrombocytopenia, the method, use, or particle formulation used in any one of the preceding exemplary embodiments. Exemplary Embodiment 37 The disease or disorder is immune thrombocytopenia (ITP), the method, use, or particle formulation used in any one of the preceding exemplary embodiments. [Examples]

[0130] Examples are provided below to allow for a more complete understanding of the inventions described herein. The examples described herein are provided to illustrate the formulations and methods provided herein and should not be construed as limiting their scope.

[0131] Example 1. Exemplary Capsule Formulation A 10 mg oral suspension of avathrombopag powder capsules was prepared, consisting of white / bright blue capsules containing white or off-white granules. The appearance and physical dimensions of the capsules are detailed in Table E1. [Table 1]

[0132] The qualitative and quantitative composition of Avathrombopag Powder Capsules 10 mg for Oral Suspension is shown in Table E2. [Table 2]

[0133] Example 2. Development of an exemplary formulation The exemplary formulation was developed to enable the administration of avathrombopag to patients who are unable to swallow tablets or have difficulty swallowing them.

[0134] This pharmaceutical product consists of drug granules contained in a two-part rigid gelatin capsule specifically designed to be easily opened by the patient and to allow the user to take the contents of the capsule in a consistent manner. Compared to standard capsules, which require sufficient dexterity to open the capsule locking mechanism, this capsule offers a more convenient and simpler method of dispensing the drug onto food or into beverages.

[0135] component A dry granulation process for this formulation was developed using conventional excipients suitable for dry granulation. The excipients for 10 mg of avathrombopag powder capsules for oral suspension were selected to optimize drug dissolution and are shown in Table E3. [Table 3]

[0136] The components of avathrombopag powder capsules 10 mg for oral suspension, as proposed for clinical trials and intended for commercial production, are as follows:

[0137] drug substance Abatrombopag maleate was used.

[0138] Excipients Focusing on the stability of the formulation, the compatibility of the active pharmaceutical ingredient (API), avathrombopag maleate, with potential excipients was evaluated. A two-component mixture of the API and excipients was prepared in an API / excipient ratio of 1:10 and exposed to high temperature and humidity conditions for 4 weeks. The samples were analyzed to check for degradation of avathrombopag. After 4 weeks, no degradation of the API was observed in any mixture with any of the excipients used in the formulation of 10 mg oral suspension avathrombopag powder capsules. Furthermore, capsule stability tests confirmed that avathrombopag maleate is compatible with all of the excipients used in the formulation.

[0139] All excipients used are subject to monographs in the European Pharmacopoeia (Ph Eur) and the United States Pharmacopeia (USP). Furthermore, all excipients are listed in the U.S. Food and Drug Administration's Inactive Ingredients Database (IID), and the proposed excipient content does not exceed the maximum content per unit dose listed in that database for FDA-approved medicinal products. In addition, no particular concerns are known regarding the use of any of the proposed excipients in the formulation. All proposed excipients are TSE / BSE-free, synthetic, and contain no animal-derived raw materials.

[0140] Abatrombopag Powder Capsules 10mg for Oral Suspension We developed a 10 mg avathrombopag powder for suspension, filled in a capsule. Because the original capsule of this formulation was difficult to open, we transferred the formulation to a sprinkle capsule to facilitate opening of the dosage unit.

[0141] The manufacturing formula for 10 mg of avathrombopag powder capsules for suspension is shown in the table. [Table 4]

[0142] For administration, the caregiver is expected to remove the top of the capsule immediately before administration and suspend the capsule contents in an appropriate vehicle. Therefore, a sprinkle capsule was selected as the appropriate capsule shell.

[0143] Sprinkle capsules are two-part rigid hypromellose capsules specially designed for easy opening by patients, allowing users to take the capsule contents in a consistent manner. Compared to standard capsules, which require sufficient dexterity and force to reopen their strong capsule locking mechanism, these capsules offer a more convenient and simpler method of dispensing medication onto food or into beverages. Vcaps® Plus two-part hypromellose capsules supplied by Capsugel® are manufactured from non-animal-derived materials and feature an innovative closure structure that requires less force to open, making them easier and safer to open.

[0144] Development of dissolution tests for 10 mg avathrombopag powder capsules for oral suspension. The development of dissolution conditions for 10 mg avathrombopag powder capsules for suspension began with an initial evaluation of the suitability of dissolution parameters established for avathrombopag film-coated tablets. The dissolution method parameters developed for avathrombopag film-coated tablets were not suitable for granules due to the difference in physical properties between granules in capsules and tablets. Upon sample introduction, the suspension granules immediately settled to the bottom of the container, forming a cone and hindering complete dissolution. Therefore, the dissolution container was upgraded to a peak-type dissolution container with a "recess" at the bottom to minimize cone formation of the drug. In addition, because granules have a larger surface area than tablets, the paddle speed and surfactant concentration were adjusted to make the dissolution profile of the granules more discernible.

[0145] The dissolution profile of 10 mg avathrombopag powder capsules for suspension is shown in 1. Error! Reference not found.

[0146] Food suitability testing To evaluate the integrity, efficacy, stability, and uniformity of avathrombopag in various liquids and foods of varying concentrations, in vitro food and vehicle compatibility tests were conducted, and vehicles suitable for administration were selected.

[0147] Prior to food compatibility testing, basic screening was performed in accordance with the FDA guidance "Use of Liquids and / or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments." The results showed that the avathrombopag active pharmaceutical ingredient (API) was stable in ingested artificial gastric juice (FeSSGF). The API was exposed to FeSSGF for 10 minutes and 1 hour. No significant degradation was observed in the initial (control) sample preparation, the 10-minute preparation, or the 1-hour preparation (99.7% and 100.2% of the control, respectively), indicating that the avathrombopag API is stable in FeSSGF.

[0148] For food compatibility testing, 10 mg avathrombopag powder capsules for oral suspension were opened, and the granules were transferred to a culture medium bottle. For each food / liquid vehicle, the contents of the capsules were mixed with the food vehicle at a ratio of 3 capsules per 5 mL of vehicle. This test evaluated the compatibility of the drug at the time of administration after exposure to apple sauce, strawberry jelly, Pedialyte®, and orange juice. After exposure to food substances, efficacy, stability, uniformity, and dissolution tests were performed on the drug / food mixture and drug control samples. A simplified food test using bottled water was also conducted to evaluate the compatibility of the drug at the time of administration after exposure to bottled water for 30 minutes. After exposure to bottled water for 30 minutes, efficacy and stability were evaluated, and the results were compared with the drug control sample.

[0149] The results showed that applesauce, Pedialyte®, orange juice, strawberry jelly, and water are safe and effective vehicles for administering avathrombopag to patients.

[0150] Closing the container The 10 mg avathrombopag powder capsules for suspension are packaged in a 60 cc white HDPE bottle with a child-resistant polypropylene cap with an induction seal.

[0151] Microbiological properties All excipients used in the manufacture of 10 mg avathrombopag powder capsules for suspension are pharmacopoeia grade. In accordance with Good Manufacturing Practices (OK) requirements, and to ensure a high level of quality control, the specifications of the final product include microbiological testing suitable for oral formulations based on the official methods described below.

[0152] USP <61> / Ph. Eur.2.6.12. / JP4.05 Microbiological testing of non-sterile preparations: Viable cell count test

[0153] USP <62> / Ph. Eur.2.6.13. / JP4.05 Microbiological testing of non-sterile preparations: Specific bacterial testing

[0154] The limits for viable cell count testing are as follows: Total number of aerobic microorganisms: 10 3 CFU / g or less Total yeast / mold count: 10 2 CFU / g or less The limit values ​​for the specific bacterial test are as follows: Escherichia coli absent Pseudomonas aeruginosa absent Staphylococcus aureus absent

[0155] Example 3. Manufacturing of an exemplary formulation Manufacturing formula The batch manufacturing formulation for 10 mg avathrombopag powder capsules for oral suspension at the intended commercial production scale (120,000 capsules) is shown in the table. [Table 5]

[0156] Overview of Manufacturing Processes and Process Controls The manufacturing process for Avathrombopag Powder Capsules 10 mg for Oral Suspension consists of sieving, compounding, smoothing, roller compression, capsule filling, bulk packaging, and subsequent primary packaging into HDPE bottles. A flowchart of the manufacturing process for Avathrombopag Powder Capsules 10 mg for Oral Suspension is shown in 3. Error! Reference not found.

[0157] The following is an overview of the manufacturing process for Avathrombopag Powder Capsules 10 mg for Oral Suspension. 1. Blend mannitol in a slant cone blender to coat the inside of the blender. Add Abatrombopag API, Kollidon-CL crospovidone, and Kollidon SLS to the blender and blend. 2. Discard the mixture from the blender and pass it through the combill. Pass the microcrystalline cellulose through the combill and combine it with the other ingredients. 3. Put the ground ingredients into a slant cone blender and blend them. 4. Sift the magnesium stearate through a hand screen. Fill a 1-liter amber glass bottle with the de-aggregated magnesium stearate, then fill the bottle about halfway with the blend from step 3. Mix at medium speed. Sift the mixture from the Turbula and transfer it to a slant cone blender. 5. Discharge the mixture and store it in a sealed container double-lined with polyethylene bags, with a desiccant placed between the liners and between the outer liner and the drum, until roller compression is performed. 6. Perform roller compression. Make adjustments as needed to obtain a ribbon of the target thickness and density. 7. The ribbon obtained by roller compression is passed through a combill. The crushed ribbon is classified using a 50-mesh sieve. The crushed granules held in the 50-mesh screen are collected as acceptable granules. The crushed granules that pass through the 50-mesh screen are collected for additional roller compression. 8. Repeat steps 6 and 7 a total of four times, collecting the ground granules held on a 50-mesh screen as the acceptable granules. Place all the retained acceptable granules into a slant cone blender and blend. 9. The formulated granules are placed in a container and encapsulated using an automated encapsulation device. During encapsulation, the filling weight of the granules is 100 mg ± 5 mg. In-process weight testing is performed. 10. The filled capsules, after weight sorting, are double-lined with polyethylene bags and collected in a lidded plastic drum with one desiccant placed between the polyethylene bags and between the polyethylene bags and the drum. 11. The bulk capsules are packaged in HDPE bottles with child-resistant caps.

[0158] Management of key steps and intermediates The key process steps, tests, and current acceptance criteria for the in-process control of 10 mg avathrombopag powder capsules for oral suspension are currently under development. The currently proposed in-process tests are shown in the table below. [Table 6] [Table 7]

[0159] In the manufacture of 10 mg avathrombopag powder capsules for oral suspension, the granulation process is identified as a critical manufacturing step. Control of the critical manufacturing step is achieved by setting critical operating parameters that are essential for the pharmaceutical product to meet the final product specifications. The steps of the critical process, along with their respective parameter settings and acceptance ranges, are listed in the table. [Table 8]

[0160] Ribbon thickness, roll pressure, roll speed, and auger speed are all potentially related to dissolution, and this dissolution is a critical quality characteristic (CQA) of Avathrombopag Powder Capsules 10 mg for Oral Suspension.

[0161] Equal portions Details of one or more embodiments of this disclosure are specified in the accompanying description above. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but preferred methods and materials are described herein. Other features, purposes, and advantages of this disclosure will become apparent from the description and the claims. In the specification and the accompanying claims, singular nouns refer to plural subjects unless the context explicitly states otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0162] The foregoing description is provided for illustrative purposes only and is not intended to limit this disclosure to the exact form disclosed, but is intended to be limited by the claims appended herein.

Claims

1. A solid particle formulation, A Avatronbo Pag having the following structure, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, The solid particle formulation comprising one or more pharmaceutically acceptable excipients.

2. The pharmaceutically acceptable salt of avathrombopag is avathrombopag monomaleate, according to claim 1.

3. The solid particle formulation according to claim 1 or 2, wherein the solid particles are granules.

4. The solid particle formulation according to any one of claims 1 to 3, wherein the aggregate of solid particles has an average particle diameter of about 400 μm to about 600 μm.

5. The solid particle formulation according to any one of claims 1 to 4, wherein the aggregate of solid particles has a bulk density of about 0.58 g / mL to about 0.66 g / mL.

6. The solid particle formulation according to any one of claims 1 to 5, wherein the abatrombopag or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 5.0% w / w to about 18.0% w / w.

7. The solid particle formulation according to any one of claims 1 to 5, wherein the abatrombopag is present in an amount of about 10.0 ± 5% w / w, or the pharmaceutically acceptable salt of the abatrombopag is present in an amount of about 11.8 ± 5% w / w.

8. The solid particle formulation according to any one of claims 1 to 7, wherein one or more pharmaceutically acceptable excipients include a diluent, a binder, a surfactant, or a lubricant.

9. The solid particle formulation according to claim 8, wherein the diluent is selected from lactose, sucrose (e.g., Dipac®), dextrose, dextrate, maltodextrin, mannitol, xylitol (e.g., Xylitab®), sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose (e.g., Avicel®), microcellulose, and talc.

10. The solid particle formulation according to claim 9, wherein the diluent is present in an amount in the range of about 70.0% w / w to about 85.0% w / w.

11. The solid particle formulation according to claim 9 or 10, wherein the diluent comprises microcrystalline cellulose and mannitol.

12. The solid particle formulation according to claim 11, wherein the diluent comprises microcrystalline cellulose and mannitol, the microcrystalline cellulose being present in an amount of about 30.0 ± 5.0% w / w, and the mannitol being present in an amount of about 49.0 ± 5.0% w / w.

13. The solid particle formulation according to claim 8, wherein the binder is selected from polyvinylpyrrolidone (PVP) (e.g., PVP K15, PVP K19, PVP K25, PVP K30, Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), cross-linked polyvinyl N-pyrrolidone (crospovidone), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), sodium carboxymethylcellulose, methylcellulose, lactose, sucrose, sorbitol, xylitol, mannitol, starch, sodium alginate, gelatin, and polyethylene glycol (PEG).

14. The solid particle formulation according to claim 13, wherein the binder is present in an amount of about 2.0% w / w to about 8.0% w / w.

15. The solid particle formulation according to claim 13 or 14, wherein the binder comprises crospovidone, and the crospovidone is present in an amount of about 5.0% w / w.

16. The solid particle formulation according to claim 8, wherein the surfactant comprises sodium lauryl sulfate.

17. The solid particle formulation according to claim 16, wherein the surfactant is present in an amount of about 2.0% w / w to about 8.0% w / w.

18. The solid particle formulation according to claim 17, wherein the surfactant comprises sodium lauryl sulfate, and the sodium lauryl sulfate is present in an amount of about 5.0% w / w.

19. The solid particle formulation according to claim 8, wherein the lubricant comprises magnesium stearate.

20. The solid particle formulation according to claim 19, wherein the lubricant is present in an amount of about 0.1% w / w to about 3.0% w / w.

21. The solid particle formulation according to claim 20, wherein the lubricant comprises magnesium stearate, and the magnesium stearate is present in the particle formulation in an amount of about 1.0 w / w%.

22. The aforementioned solid particle formulation is Approximately 11.8 ± 3.0% w / w of the aforementioned abatrombopag monomaleate, The aforementioned diluent in an amount of approximately 77.0 ± 20.0% w / w, The binder is present in an amount of approximately 5.0 ± 3.0% w / w, The surfactant is present in an amount of approximately 5.0 ± 3.0% w / w, The solid particle formulation according to claim 8, comprising approximately 1.0 ± 0.9% w / w of the lubricant.

23. The aforementioned solid particle formulation is Approximately 11.8 ± 3.0 mg of the aforementioned abatrombopag monomaleate, Approximately 49.2 ± 10.0 mg of mannitol, Approximately 28.0 ± 10.0 mg of microcrystalline cellulose, Approximately 5.0 ± 3.0 mg of crospovidone type A, Approximately 5.0 ± 3.0 mg of sodium lauryl sulfate, The solid particle formulation according to claim 8, comprising approximately 1.0 ± 0.9 mg of magnesium stearate.

24. The aforementioned solid particle formulation is Approximately 11.8 mg of the aforementioned abatrombopag monomaleate, Approximately 49.2 mg of mannitol and Approximately 28.0 mg of microcrystalline cellulose, Approximately 5.0 mg of crospovidone type A, Approximately 5.0 mg of sodium lauryl sulfate, The solid particle formulation according to claim 8, comprising approximately 1.0 mg of magnesium stearate.

25. The formulation is a solid particle formulation according to any one of claims 1 to 24, wherein the formulation is substantially lactose-free.

26. An oral dosage form comprising a solid particle formulation according to any one of claims 1 to 25.

27. The oral dosage form according to claim 26, wherein the oral dosage form is a capsule.

28. The oral dosage form according to claim 26, wherein the capsule is configured to be easily opened.

29. A method for preparing a dispersed particle formulation, comprising dispersing the particle formulation according to any one of claims 1 to 28 in a culture medium.

30. The method according to claim 29, wherein the culture medium is a solid culture medium or a liquid culture medium.

31. The method according to claim 29, wherein the culture medium is an aqueous culture medium.

32. A dispersed particle formulation prepared by the method described in any one of claims 29 to 31.

33. A method for treating or preventing a target disease, comprising administering the dispersed particle formulation described in claim 32 to the target.

34. Use of the dispersed particle formulation according to claim 32 in the manufacture of a drug for treating or preventing a target disease.

35. A dispersed particle formulation according to claim 32, used for treating or preventing a target disease.

36. The disease or disorder is idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria (PNH), antiphospholipid syndrome, systemic lupus erythematosus (SLE), post-transfusion purpura, neonatal alloimmune thrombocytopenia (NAITP), platelet sequestration by the spleen due to hypersplenism, dengue fever, thrombocytopenia associated with myelodysplastic syndrome (MDS), or chemotherapy-induced thrombocytopenia, the method, use, or particle formulation used according to any one of claims 33 to 35.

37. The method, use, or particle formulation used according to claim 36, wherein the disease or disorder is immune thrombocytopenia (ITP).

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