Pharmaceutical composition

Abstract

To provide: a pharmaceutical composition with enhanced drug dissolution rate, increased absorption, the increase of bioavailability, and the decrease of patient-to-patient variability; and furthermore, a process for manufacturing pharmaceutical compositions that provides ease of scalability, robust processing, and economic advantages.SOLUTION: A pharmaceutical composition for oral administration comprises granule particles, the granule particles containing: (a) an inert substrate; and (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, or a free form thereof, and at least one binder.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the field of pharmacy, particularly to a mixture comprising (a) an inert substrate, (b) N-(3-(6-amino-5 -(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro ro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt or its free form thereof and at least one binder, and to a pharmaceutical composition for oral administration. The present invention also relates to a process for preparing the pharmaceutical composition for oral administration; and the use of the pharmaceutical composition in the manufacture of pharmaceuticals.

Background Art

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a member of the TEC kinase family (Smith et al, BioEssays, 2 001, 23, 436-446). BTK is expressed in selected cells of the acquired and innate immune systems, including B cells, macrophages, mast cells, eosinophils and platelets.

[0003] The important role of BTK in autoimmune diseases is highlighted by the observation that BTK-deficient mice are protected in standard preclinical models of rheumatoid arthritis (J ansson and Holmdahl, Clin. Exp. Immunol. 199 3, 94, 459-465), systemic lupus erythematosus and allergic diseases and anaphylaxis Furthermore, many cancers and lymphomas expressing BTK appear to be dependent on BTK function (Davis et al. Nature, 2010, 463, 88-92). The role of BTK in diseases including autoimmune, inflammatory, and cancer has recently been outlined. t al,Pharmacol.Ther.,2013,294-309;Whang et al, Drug Discov. Today, 2014, 1200-4).

[0004] Specific BTK inhibitors N-(3-(6-amino-5-(2-(N-methylacrylamine Ethoxypyrimidine-4-yl-5-fluoro-2-methylphenyl-4-syl Clopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free agent The separated form is referred to as compound (A) of the following formula. [ka]

[0005] Compound (A) is a selective, potent, and irreversible covalent BTK inhibitor, and is a new generation of technology. It is one of the covalent enzyme inhibitors that have been identified. Compound (A) is combined as a whole by reference. This is included in International Publication No. 2015 / 079417, filed on November 28, 2014. In example 6 of the pamphlet (agent reference number PAT056021-WO-PCT), first It was disclosed that compound A, with the international generic name remibrutinib, is known as LOU064. It is known that the compound is improved by BTK-mediated or BTK-inhibited. It may be used in the treatment or prevention of diseases or disorders. Therefore, N-(3-(6-amino- 5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-flu Oro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or the We propose a commercially viable pharmaceutical composition containing a pharmaceutically acceptable salt or its free form. It needs to be provided.

[0006] N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrim Zin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-f Luolobenzamide or its pharmaceutically acceptable salt or its free form (as specified herein) Pharmaceutical compositions, dosage forms, and formulations of BTK inhibitors such as compound (A) Designing a commercially viable process for manufacturing this BTK inhibitor is difficult. Due to their physicochemical properties, such as low solubility and low exposure, formulations are difficult, and the compounds are specific. It has some gelling tendency under certain pH conditions and is exposed to some temperature and / or UV light. It was unstable when this happened. Ultimately, these problems affected the manufacturing process. This also affected the bioavailability and variability of the BTK inhibitor of the present invention. [Overview of the project] [Problems that the invention aims to solve]

[0007] Therefore, there is a need to develop suitable and robust solid pharmaceutical compositions that overcome the above problems. The present invention provides increased drug dissolution rate, increased absorption, increased bioavailability, and Furthermore, the present invention provides a pharmaceutical composition that reduces variability among patients. A manufacturing process that provides ease of scaling, robust processing, and economic advantages. Provide the process. [Means for solving the problem]

[0008] Considering the above difficulties and considerations, (a) an inactive substrate and (b) N-(3-(6-amino -5-(2-(N-Methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro oro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt or free form thereof and at least one binder, A method for preparing a stable pharmaceutical composition that enables the preparation of a pharmaceutical composition containing the same. was surprisingly found.

[0009] Aspects, advantageous features and preferred embodiments of the present invention summarized in the following items, either alone or in combination, contribute to solving the object of the present invention. [[ID=!5]]

[0010] Embodiment: 1. A pharmaceutical composition for oral administration comprising particulate particles, said particulate particles comprising (a) an inert matrix, and <! (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)py rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharmaceutically acceptable salt or free form thereof and at least one binder. A pharmaceutical composition comprising

[0011] 2. The pharmaceutical composition according to embodiment 1, wherein N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)py [[ID=!7]] rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide is in free form.

[0012] 3. The pharmaceutical composition according to embodiment 1 or 2, wherein the mixture (b) further optionally comprises a surfactant. A pharmaceutical composition.

[0013] | 4. (b) The mixture and the optionally selected surfactant are (a) layered on an inert substrate. A pharmaceutical composition according to any one of Embodiments 1 to 3.

[0014] 5. (b) The mixture and any selected surfactant are (a) inert by spray granulation. A pharmaceutical composition according to Embodiment 4, which is layered on a substrate.

[0015] 6. (a) Inactive substrates include lactose, microcrystalline cellulose, mannitol, and sucrose. From the group consisting of sucrose, starch, granulated hydrophilic fumed silica, or mixtures thereof. The selected material, preferably consisting of lactose, mannitol, or a mixture thereof. The material includes a selected material, most preferably mannitol, Embodiment 1~ A pharmaceutical composition as described in any one of the five items.

[0016] 7. The binder is polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone Hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellol S, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethyl Boxyethylcellulose, carboxymethylhydroxyethylcellulose, polyethylene Polyglycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene Polyethylene glycol copolymer, polyethylene-propylene glycol copolymer, vitamin E A substance independently selected from the group consisting of polyethylene glycol succinate or mixtures thereof. Preferably, the binder is polyvinylpyrrolidone-vinyl acetate copolymer, A pharmaceutical composition as described in any one of states 1 to 6.

[0017] 8. Surfactants include sodium lauryl sulfate, potassium lauryl sulfate, and sodium lauryl sulfate. Monium, sodium lauryl ether sulfate, polysorbate, perfluorobutance Selected from the group consisting of ruhonate, dioctyl sulfosuccinate, or mixtures thereof, In any one of embodiments 1 to 7, the surfactant is sodium lauryl sulfate. The pharmaceutical composition described above.

[0018] 9. (b) The mixture is N-(3-(6-amino-5-(2-(N-methylacrylamine Ethoxypyrimidine-4-yl-5-fluoro-2-methylphenyl-4-syl Clopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free agent Polyvinylpyrrolidone-vinyl acetate copolymer and optionally a binder are used for release. The description of any one of Embodiments 1 to 8 includes sodium lauryl sulfate as a surfactant. A pharmaceutical composition.

[0019] 10. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form and a binder The weight ratio between them is approximately [3:1], approximately [2:1], approximately [1:1], approximately [1:2], or approximately [ Embodiments 1 to 1:3, preferably about [1:1], more preferably about [2:1] A pharmaceutical composition as described in any one of the nine items.

[0020] 11. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, and The weight ratio of the agent to the surfactant is [3:1:1], or approximately [3:1:0.5], or approximately [ 3:1:0.1], or approximately [2:1:1], or approximately [2:1:0.5], or approximately [2:1 :0.1], or approximately [2:1:0.08], or approximately [2:1:0.05], or approximately [2: 1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02], or approximately [ 1:1:0.5], or approximately [1:1:0.1], or approximately [1:1:0.07], or approximately [ 1:1:0.05], or approximately [1:1:0.04], or approximately [1:1:0.02], or Approximately [1:3:0.1], or approximately [1:3:0.2], or approximately [1:1.5:0.25] Yes, preferably the ratio is about [2:1:1], or about [2:1:0.5], or about [2: [1:0.1], or approximately [2:1:0.08], or approximately [2:1:0.05], or approximately [2 :1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02], or approximately [1:1:0.5], or approximately [1:1:0.1], or approximately [1:1:0.07], or approximately [1:1:0.05], or approximately [1:1:0.04], or approximately [1:1:0.02] More preferably, the ratio is approximately [2:1:1], or approximately [2:1:0.08], or approximately [ 2:1:0.5], or approximately [2:1:0.1], or approximately [2:1:0.05], or approximately [ It is approximately [2:1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02]. or the pharmaceutical composition according to any one of Embodiments 1 to 9.

[0021] 12. The binder (e.g., polyvinylpyrrolidone-vinyl acetate copolymer) is N-(3 -(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4- Iyl-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluoroben Based on 25% w / w of zuamide or its pharmaceutically acceptable salt or its free form. ~Approximately 100% w / w, preferably N-(3-(6-amino-5-(2-(N-methyl ammonium compound). (Lylamide) Ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl) -4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof (b) mixed in an amount of approximately 50% w / w or approximately 100% w / w based on the weight of its free form. A pharmaceutical composition according to any one of Embodiments 1 to 11, which is present in the compound.

[0022] 13. (b) The mixture is N-(3-(6-amino-5-(2-(N-methylacrylamine Mid(ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4- Cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or Based on the weight of the free form, 1% w / w to approximately 10% w / w, preferably N-(3-(6- Amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)- 5-Fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide Or, based on the weight of the pharmaceutically acceptable salt or its free form, approximately 4% w / w. It also contains a surfactant (e.g., sodium lauryl sulfate) in an amount of approximately 5% w / w. A pharmaceutical composition as described in any one of the application forms 1 to 12.

[0023] 14. The aforementioned N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy (C)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl 2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form granules A pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the diameter is less than 1000 nm.

[0024] 15. The aforementioned N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy (C)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl 2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form granules The pharmaceutical composition according to Embodiment 14, wherein the diameter is less than 500 nm.

[0025] 16. The aforementioned N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy (C)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl 2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form granules The diameter is less than 350 nm, preferably less than 250 nm, as described in Embodiment 15 of the pharmaceutical combination A finished product.

[0026] 17. The aforementioned N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy (C)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl 2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, The particle size measured by PCS is approximately 100 nm to approximately 350 nm; preferably approximately 110 nm. The pharmaceutical composition according to Embodiment 14, wherein the wavelength is approximately m to 180 nm.

[0027] 18. The Minister of Foreign Affairs further includes, the Minister of Foreign Affairs, which includes one or more pharmaceutically acceptable excipients, A pharmaceutical composition as described in any one of Forms 1 to 17.

[0028] 19.1 More than pharmaceutically acceptable excipients are fillers, disintegrants, lubricants and lubricants. A pharmaceutical composition according to Embodiment 18, selected from the above.

[0029] 20. The external agent is calcium carbonate, sodium carbonate, lactose (e.g., lactose S D), mannitol (e.g., mannitol DC), magnesium carbonate, kaolin, cell Cellulose (e.g., microcrystalline cellulose, powdered cellulose), calcium phosphate, or cellulose Sodium phosphate or mixtures thereof, preferably mannitol or cellulose or The medical device according to Embodiment 18 or 19, comprising one or more fillers selected from these mixtures. A pharmaceutical composition.

[0030] 21. The Foreign Minister stated that croscarmellose sodium, crospovidone, and starch glycol were used. Selected from sodium phosphate, corn starch, or alginic acid, or a mixture thereof. A pharmaceutical composition according to any one of embodiments 18 to 20, comprising one or more disintegrants.

[0031] 22. The Foreign Minister said, magnesium stearate, sodium stearyl fumarate, stearyl Implementation comprising one or more lubricants selected from nic acid, talc, or mixtures thereof, A pharmaceutical composition as described in any one of the statements 18 to 21.

[0032] 23. The foreign substance consists of mannitol and cellulose as fillers, and fumellum as a lubricant. Sodium stearyl acid or magnesium stearate, and crocamel as a disintegrant. One of Embodiments 18 to 22, comprising sodium or sodium carbonate. A pharmaceutical composition.

[0033] 24. The external phase shall be in an amount of 20-50% w / w of the total weight of the composition, preferably the total weight of the composition A pharmaceutical composition according to any one of embodiments 18 to 23, present in an amount of 40% w / w. .

[0034] 25. The final dosage form is obtained in the presence of at least one pharmaceutically acceptable excipient of optional choice. The product is further formulated, and the final dosage form is a capsule, tablet, sachet, or stick pack. A pharmaceutical composition as described in any one of the application forms 1 to 24.

[0035] 26. The final dosage form is a capsule or preferably a tablet, according to Embodiment 25. A finished product.

[0036] 27. Capsules include hard shell capsules, hard gelatin capsules, and soft shell capsules. Capsules, soft gelatin capsules, vegetable shell capsules, or a mixture thereof, as selected. The pharmaceutical invention according to Embodiment 25 or 26 is preferably a film-coated tablet. composition.

[0037] 28. A capsule formulation comprising the pharmaceutical composition described in any one of Embodiments 1 to 25. Final dosage form.

[0038] 29. Final tablet formulation comprising the pharmaceutical composition described in any one of Embodiments 1 to 25. Dosage form.

[0039] 30. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or its pharmaceutically acceptable salt or its free form is the final An amount of approximately 0.4% w / w to approximately 35% w / w based on the total weight of the dosage form, preferably about 10% It is present in an amount of w / w ~ approximately 25% w / w, more preferably approximately 19% or approximately 20%. The final dosage form as described in application method 29.

[0040] 31. The filler is present in an amount of approximately 20-40% w / w of the total weight of the final product. or the final dosage form described in Embodiment 29 or 30.

[0041] 32. The disintegrant is preferably approximately 5% w / w to 10% w / w based on the total weight of the final dosage form. The final dosage form according to Embodiments 29, 30, or 31, which is present in an amount of approximately 5 or approximately 6%.

[0042] 33. The inactive substrate should be approximately 20% w / w to 40% w / w of the total weight of the final dosage form. , preferably present in an amount of about 30%, the final Dosage form.

[0043] 34. The binder is preferably approximately 5% w / w to approximately 25% w / w based on the total weight of the final dosage form. Or, present in an amount of approximately 8 to approximately 12% w / w, as described in any one of embodiments 29 to 33. The final dosage form.

[0044] 35. The lubricant should be approximately 0.1 to approximately 2% w / w based on the total weight of the final formulation, preferably. It is present in an amount of approximately 0.5% w / w to approximately 1.5% w / w, one of any one of embodiments 29 to 34. The final dosage form as described above.

[0045] 36. The surfactant content is approximately 0.1% w / w to approximately 2.5% w / w based on the total weight of the final formulation. / w, preferably present in an amount of about 0.2% w / w to about 0.8% w / w, Embodiment 29~ The final dosage form listed in any one of the 35 items.

[0046] 37. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- Approximately 0.2-Fluorobenzamide or its pharmaceutically acceptable salt or its free form. 5mg to approximately 600mg, for example, approximately 5mg to approximately 400mg, for example, approximately 10mg to approximately 150mg The final dosage form according to any one of embodiments 29 to 36, containing an amount of g.

[0047] 38. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- Approximately 0.2-Fluorobenzamide or its pharmaceutically acceptable salt or its free form. 5mg, about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg an amount of approximately 400 mg, approximately 450 mg, approximately 500 mg, or approximately 600 mg, preferably approximately 10 The embodiments 29 to 37 contain the amounts of mg, approximately 25 mg, approximately 50 mg, and approximately 100 mg. The final dosage form listed in one of the following.

[0048] 39. A process for preparing a pharmaceutical composition according to any one of Embodiments 1 to 27 hand, (i)N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Limidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least (b) A mixture containing one type of binder and optionally a surfactant is mixed in a liquid medium. The course, and (ii) Adding the mixture (i) to the (a) inert substrate of the granular particles. A process that includes this.

[0049] 40. Step (i) is carried out in a wet grinding chamber, as described in Embodiment 39. Seth.

[0050] 41. The liquid medium is preferably an aqueous solution having a pH value of 5 to 8, such as purified water. or the process described in Embodiment 39 or 40.

[0051] 42. The mixture from step (i) is dispersed on an inert substrate, as in Embodiments 39-41. The process described in one of the following.

[0052] 43. The mixture obtained from step (ii) and at least one pharmaceutically acceptable excipient Embodiments 39-42 further include preparing the final dosage form by blending. The process described in any one of the following.

[0053] 44. The process according to Embodiment 43, wherein the final dosage form is encapsulated or tableted.

[0054] 45. The final dosage form is formed into tablets, and the resulting tablets are further film-coated. The process described in the application method 44.

[0055] 46. ​​A process for preparing a suspension, wherein N-(3-(6-amino-5-(2-(N -Methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methyl (Phenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable thereof A syrup or its free form, at least one binder, and optionally a surfactant. (b) A process comprising mixing a mixture with a liquid medium.

[0056] 47. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or its pharmaceutically acceptable salt or its free form, at least A suspension containing one type of binder and optionally a surfactant in a liquid medium.

[0057] 48. The particle size of the suspension is less than 1000 nm, preferably less than 500 nm, more preferably The coefficient of flux according to Embodiment 47 is less than 350 nm, most preferably less than 250 nm. Turbid liquid.

[0058] The liquid medium is preferably an aqueous solution having a pH value of 5 to 8, more preferably 5 to 6, e.g. For example, the suspension according to embodiment 47 or 48, which is purified water.

[0059] 49. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form is suspended Approximately 10% to 40% of the total weight of the liquid, preferably about 20% or 25% of the total weight of the suspension. A suspension according to any one of embodiments 47 to 49, present in an amount.

[0060] 50. At least one binder is present in an amount of approximately 3% to 15% of the total weight of the suspension. , the suspensions described in embodiments 47 to 50.

[0061] 51. Surfactants are present in amounts of approximately 0.05% to 1% of the total weight of the suspension. The suspension described in sections 47-51.

[0062] 52. A pharmaceutical composition according to any one of Embodiments 1 to 27 for use as a pharmaceutical. Final dosage form according to any one of Embodiments 29 to 37 for use as a substance or pharmaceutical .

[0063] 53. Diseases mediated by BTK or improved by inhibition of BTK Or, as described in any one of Embodiments 1 to 27, for use in the treatment or prevention of a disorder. The pharmaceutical composition or is mediated by or improved by BTK inhibition. Any of Embodiments 29 to 37 for use in the treatment or prevention of a disease or disorder The final dosage form listed in one document.

[0064] 54. Diseases or disorders mediated by or improved by inhibition of BTK This includes autoimmune diseases, inflammatory diseases, allergic diseases, asthma, and chronic obstructive pulmonary disease (COPD). D) Respiratory tract diseases such as, graft rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJI) A) Gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple Hemolytic sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasm Antibody (ANCA)-associated vasculitis, cold globulinemia, thrombotic thrombocytopenic purpura, chronic urticaria Measles (chronic idiopathic urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis) Dermatitis, allergic rhinitis, atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory Intestinal diseases, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture syndrome, Hashimoto Thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B cells This includes subacute, acute, and chronic graft rejection, which is mediated by antibody production, antigen presentation, and site Diseases in which cayne production or lymphoid tissue formation is abnormal or undesirable; thromboembolic diseases, Myocardial infarction, angina pectoris, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute bone Myelin leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma Lymphoma; polycythemia vera; essential thrombocythopathy; myelofibrosis with myelogenesis; and Waldens Embodiments selected from cancers of hematopoietic origin, including but not limited to Thurröm's disease. Pharmaceutical compositions for use as described in 53 or 54, or the embodiments described in 53 or 54. The final dosage form. Preferably, mediated by BTK or improved by inhibition of BTK. The diseases or disorders that are treated include rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; and sedge. The diagnosis is selected from Glenn's syndrome, multiple sclerosis, or asthma.

[0065] 55. Autoimmune diseases, inflammatory diseases, allergic diseases, asthma and chronic obstructive pulmonary disease (C) Airway diseases such as OPD, graft rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SO2). JIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, Multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophils Anticytic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic Urticaria (chronic idiopathic urticaria, induced urticaria), chronic allergies (atopic dermatitis, inflammatory bowel disease) Touch dermatitis, allergic rhinitis, atherosclerosis, type 1 diabetes, type 2 diabetes, inflammation Symptomatic bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B cell This includes subacute, acute, and chronic graft rejection mediated by cells, including antibody production, antigen presentation, and Diseases in which itokine production or lymphoid tissue formation is abnormal or undesirable; thromboembolic diseases Diseases such as myocardial infarction, angina pectoris, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute Myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphocyte Parkinson's disease; lymphoma; polycythemia vera; essential thrombocythopathy; myelofibrosis with myelogenesis; and Walde Selected from cancers of hematopoietic origin, including but not limited to Ström's disease, BT Medicines for diseases or disorders mediated by K or improved by inhibition of BTK Use of the pharmaceutical composition described in any one of Embodiments 1 to 27 for the manufacture of the product. Diseases or disorders that are mediated by BTK or improved by BTK inhibition are Rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjögren's syndrome, multiple The diagnosis is selected from either esophageal sclerosis or asthma.

[0066] 56. Diseases or disorders mediated by or improved by inhibition of BTK A method for treating or preventing a disease, which is implemented in a manner suitable for a person in need of such treatment or prevention. A pharmaceutical composition described in any one of embodiments 1 to 27 or any one of embodiments 29 to 37 A method comprising administering the final dosage form described.

[0067] 57. Diseases or disorders mediated by or improved by inhibition of BTK This includes autoimmune diseases, inflammatory diseases, allergic diseases, asthma, and chronic obstructive pulmonary disease (COPD). D) Respiratory tract diseases such as, graft rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJI) A) Gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple Hemolytic sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasm Antibody (ANCA)-associated vasculitis, cold globulinemia, thrombotic thrombocytopenic purpura, chronic urticaria Measles (chronic idiopathic urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis) Dermatitis, allergic rhinitis, atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory Intestinal diseases, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture syndrome, Hashimoto Thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B cells This includes subacute, acute, and chronic graft rejection, which is mediated by antibody production, antigen presentation, and site Diseases in which cayne production or lymphoid tissue formation is abnormal or undesirable; thromboembolic diseases, Myocardial infarction, angina pectoris, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute bone Myelin leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma Lymphoma; polycythemia vera; essential thrombocythopathy; myelofibrosis with myelogenesis; and Waldens Embodiments selected from cancers of hematopoietic origin, including but not limited to Thurröm's disease. 57 methods. Preferably, mediated by BTK or improved by inhibition of BTK. The diseases or disorders that are treated include rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; and sedge. The diagnosis is selected from Glenn's syndrome, multiple sclerosis, or asthma. [Brief explanation of the drawing]

[0068] [Figure 1] The elution rate profile of granular particles containing compound (A) at pH 2 (paddle 50 rpm) is shown. [Figure 2] The elution rate profile of granular particles containing compound (A) at pH 3 (paddle 50 rpm) is shown. [Figure 3] This shows the pharmacokinetic (PK) profile of granular particles containing compound (A) in dogs at pH 2 (HCl 0.01N). [Figure 4] This shows the pharmacokinetic (PK) profile of granular particles containing compound (A) in dogs at pH 3 (HCl 0.01N). [Figure 5] This shows the pharmacokinetic (PK) profile of granular particles containing compound (A) in dogs at pH 4.5 (acetic acid buffer) and a paddle speed of 50 rpm. [Figure 6] This shows the pharmacokinetic (PK) profile of granular particles containing compound (A) in dogs at pH 6.8 (phosphate buffer) and a paddle speed of 50 rpm. [Figure 7] This shows the effect of compound (A) particle size on the elution rate at pH 2 (paddle 50 rpm). [Figure 8] This shows the effect of compound (A) particle size on the elution rate at pH 3 (paddle 50 rpm). [Figure 9] This represents the pharmacokinetic (PK) profile in dogs using granular particles containing micron-sized compound (A) or nano-sized compound (A). [Figure 10] Pharmacokinetic (PK) profiles in dogs using granular particles containing micron-sized compound (A) or nano-sized compound (A) - semi-logarithmic graph. [Figure 11] This image shows a scanning electron microscope (SEM) photograph of a wet-ground suspension containing compound (A). [Figure 12] This represents the dynamic viscosity of a suspension of compound (A) that has been pulverized in a wet medium. [Figure 13] This image shows a scanning electron microscope (SEM) photograph of a wet-media-ground suspension containing compound (A), used in formulations F2, F5, and F6. [Figure 14] This image shows a scanning electron microscope (SEM) photograph of a wet-media-ground suspension containing compound (A), used in formulations F7, F8, and F9. [Figure 15-1]Figure 15: Shows the dynamic viscosity of different wet-media ground suspensions containing 25% w / w compound (A) used in optimization trials at 40°C (Figure 15a), 25°C (Figure 15b), and 10°C (Figure 15c). [Figure 15-2] (As stated above.) [Figure 15-3] (As stated above.) [Figure 16-1] Figure 16: Pareto charts showing the six factors that have the greatest impact on blend particle size (Figures 16A and 16B). [Figure 16-2] (As stated above.) [Figure 17] This Pareto chart shows the three factors that have the greatest impact on blend volume and density. [Figure 18] This represents the fluidity of various external phase compositions according to the pharmacopoeia fluidity scale (Carr index less than 25% and Hausner ratio 1.31). [Figure 19] This Pareto chart shows the two factors that have the greatest influence on the tensile strength of a tablet. [Figure 20] This represents a Pareto chart showing the main factors influencing the extrusion force of a tablet. [Figure 21] This shows the disintegration time of tablet cores in HCl, 0.01N pH2 for different formulations. [Figure 22] This represents a Pareto chart showing the main factors influencing the dissolution rate. [Figure 23-1] Figure 23: Pareto charts showing the main factors influencing the particle size distribution of granules (Figures 23A and 23B). [Figure 23-2] (As stated above.) [Figure 24] This Pareto chart shows the main influencing factors for granule bulk density and tap density. [Figure 25] This represents the fluidity of different granular compositions according to the pharmacopoeia fluidity scale (Carr index less than 15% and Hausner ratio less than 1.18). [Figure 26] This represents a Pareto chart showing the main factors influencing granule flowability. [Figure 27] This Pareto chart shows the main influencing factors for tensile strength under a 30kN compressive force. [Figure 28] This Pareto chart shows the main influencing factors for granular pressing force at 30 kN. [Figure 29-1] Figure 29: Pareto charts showing the major influencing factors for the final blend PSD (Figures 29A and 29B). [Figure 29-2] (As stated above.) [Figure 30] This represents the liquidity of the final blend according to the pharmacopoeia liquidity scale (Carr index less than 15% and Hausner ratio less than 1.18). [Figure 31] This represents a Pareto chart showing the main factors influencing the final blend fluidity. [Figure 32] This shows the granule and final blend sieving and coagulation profiles. [Figure 33] This Pareto chart shows the main factors influencing the tensile strength of tablets under a 20kN compressive force. [Figure 34] This Pareto chart shows the main factors influencing the tablet extrusion force at 20 kN. [Figure 35] This Pareto chart shows the main factors influencing tablet core disintegration time at pH 2. [Figure 36] This graph shows the binary interaction graph of the disintegration time of a 90N tablet core. [Figure 37-1] Figure 37: Pareto charts showing the main factors influencing average elution (90N and 120N) (Figures 37A and 37B). [Figure 37-2] (As stated above.) [Figure 38] This graph shows the binary interaction of dissolution rates under various drug loads and copovidone loads. [Figure 39] This represents the development of the average particle size of compound (A) against the specific energy of several batches processed under process conditions where the product temperature was approximately 34–40°C, the air-to-liquid ratio was approximately 2.0–3.2, the batch size (M) was approximately 62–175 kg, and the process parameters were rotor tip speed (v) 10–14 m / sec and suspension flow rate (V) 5–20 L / min. The average particle size of compound (A) was measured by photon correlation spectroscopy (PCS) analysis. [Figure 40] This represents the drying loss (LOD) trajectory of granules during processing for batches processed under process conditions with different product temperatures (T) of 34–40°C, spray velocity (m), atomizing air pressure (p), and air-to-liquid flow rate ratio (A / L), where the air-to-liquid ratio (A / L) was approximately 2.0–3.2; LOD was measured offline (offline LOD) from granule samples taken during processing using a halogen moisture meter, and online (online LOD) from fluidized granules during processing using a near-infrared (NIR) spectroscopic probe installed in a fluidized bed spray granulator. [Figure 41] Figure 40 shows the particle size distribution of granules produced under process conditions corresponding to the experimental results shown, with different product temperatures (T) of 34-40°C, spray velocity (m), atomizing air pressure (p), and air-to-liquid flow rate ratios, and air-to-liquid ratios (A / L) of approximately 2.0-3.2. The granule particle size distribution was measured by sieve analysis. [Modes for carrying out the invention]

[0069] BTK inhibitor N-(3-(6-amino-5-(2-(N-methylacrylamide)eth Xy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopro Pyr-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form ( In this specification, it has been found that it is difficult to formulate an effective compound (referred to as compound (A)). Yes, for example, the problem of solubility that is highly pH-dependent, for example, gelation under specific pH conditions. Formulation is difficult due to the tendency, and when exposed to some temperature and / or UV light. Instability, poor elution rate (e.g., dispersibility), low solubility, low exposure, and bioavailability. Irritability issues were observed. Ultimately, these problems were related to the manufacturing process of the pharmaceutical composition. It had an impact.

[0070] Surprisingly, (a) an inactive substrate and (b) a BTK inhibitor and at least one binding By preparing a pharmaceutical composition for oral administration that includes a mixture containing the agent, It has been found that the challenge can be overcome. According to this disclosure, the BTK inhibitor is N-(3-(6 -amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl) -5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide D or a pharmaceutically acceptable salt thereof or its free form (compound (A) as specified herein) It is called ( ).

[0071] In one embodiment, the present invention provides a pharmaceutical composition for oral administration comprising granular particles, The granular particles consist of (a) an inert substrate and (b) N-(3-(6-amino-5-(2-(N -Methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methyl (Phenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable thereof A pharmaceutical compound comprising a salt or its free form and a mixture containing at least one binder. To provide finished products.

[0072] In another aspect of the present invention, compound (A) exists in a pharmaceutically acceptable salt form. In a preferred embodiment of the present invention, compound (A) exists in its free form, for example, Compound (A) exists in its anhydrous form. More specifically, compound (A) was found in May 2020. International Publication No. 2020 / 234779 brochure filed on the 20th (agent reference number) It exists as the crystal form (A) described in PAT058512). In this case, the crystalline form of compound (A) is substantially phase-pure.

[0073] According to the present invention, a pharmaceutical composition comprises (a) an inert substrate, and compound (A) and (b) A mixture containing at least one binder is added. The inert substrate is compound (A) (b) A mixture containing at least one binder, and a material that does not chemically react with the mixture. (a) Inert substances, for example, do not interact chemically or physically with active substances. These are pharmaceutically acceptable excipients known in the art. Optionally, (a) inactive. The substance is (a) undesirable from undesirable chemical or physical interactions that may occur during the formulation process. The active substance may also be coated with a protective layer. In such cases, the term "inactive substrate" is used. The term is used interchangeably with "carrier particles." (a) The inert substance is lactose, microcrystalline sediment Lurose, mannitol, sucrose, starch, granulated hydrophilic fumed silica Sugar beads (Kayaert et al., J. Pharm. Pharmaco) l.2011,63,1446-1453), polymer film (Sievens-Fi gueroa et al.,Int.J.Pharm.2012,423,496-5 08) may include a material selected from the group consisting of mixtures thereof. Preferably, the material It is selected from the group consisting of lactose, mannitol, or mixtures thereof. Alternatively, the materials are mannitol SD, mannitol SD100, or mannitol SD20. This is mannitol, such as 0.

[0074] The granule size can be determined by, for example, laser diffraction (e.g., particle size distribution (PSD)) to those skilled in the art. Measurements are taken using publicly known methods and apparatus.

[0075] Suitable binders include, for example, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl Pyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hi Promellose, carboxymethylcellulose (e.g., sodium cellulose gum, cellulose) Rose gum, methylcellulose (e.g., cellulose methyl ether, tyrose) hydroxyethylcellulose, carboxyethylcellulose, carboxymethyl hydroxy Xyethylcellulose, polyethylene glycol, polyvinyl alcohol, shellac, Polyvinyl alcohol-polyethylene glycol copolymer, polyethylene-propylene Glycol copolymer, vitamin E polyethylene glycol succinate, or mixtures thereof It can be selected from the group consisting of compounds. Preferably, the binder is polyvinylpyrrolidone-vinyl acetate. It is a nilic copolymer (also known as copovidone).

[0076] (b) At least one binder present in the mixture is determined based on the weight of compound (A) It can be present in amounts ranging from approximately 25% w / w to approximately 100% w / w. The above range is as listed above. This applies to all binders. Preferably, the binder is polyvinylpyrrolidone-vinyl acetate. It is a copolymer, with a viscosity of approximately 25% w / w to 100% w / w based on the weight of compound (A). It is present in an amount. In a preferred embodiment, the binder (preferably copovidone) is a compound (b) is present in the mixture at an amount of approximately 50% or approximately 100% w / w of the weight of substance (A). In yet another preferred embodiment, (b) the compound in the mixture is (A) and the binder The weight ratio ranges from approximately [3:1] to approximately [1:3]; for example, approximately [3:1], approximately [2:1], The ratio is approximately [1:1], approximately [1:2], or approximately [1:3], preferably [2:1]. Furthermore, (b) the weight ratio of compound (A) to the binder in the mixture is approximately [1:1]. In another embodiment, the weight ratio of compound (A) to binder in the pharmaceutical composition is approximately [3:1] The ratio is approximately [2:1] or approximately [1:1], most preferably [2:1].

[0077] In another embodiment, the present invention relates to a pharmaceutical invention in which (b) a mixture optionally further comprises a surfactant. Compositions (for example, for oral administration) are also provided. According to the present invention, pharmaceutical compositions (for example, for oral administration) are also provided. (a) comprises an inert substrate, compound (A), at least one binder and A mixture (b) containing a surfactant is optionally added. Suitable surfactants include, for example, Sodium lauryl sulfate (SLS), potassium lauryl sulfate, ammonium lauryl sulfate , sodium lauryl ether sulfate, polysorbate, perfluorobutanesulfonate It may be selected from the group consisting of dioctyl sulfosuccinate or mixtures thereof. Preferably The surfactant is sodium lauryl sulfate (SLS).

[0078] (b) When the surfactant is present in the mixture, it is approximately 1 based on the weight of compound (A) It can be present in amounts of approximately 10% w / w. The above range refers to the surfactants listed above. This applies to all agents. Preferably, the surfactant is sodium lauryl sulfate (SLS). Yes, in an amount of about 1% w / w to about 10% w / w based on the weight of compound (A), preferably. Based on the weight of compound (A), an amount of 2-6% w / w, more preferably the weight of compound (A) It is present in an amount of approximately 4% w / w or approximately 5% w / w based on the quantity. According to an aspect of the present invention, If a surfactant is present, (b) compound (A) in the mixture and at least one binder The weight ratio of the surfactant is approximately [3:1:1], or approximately [3:1:0.5], or approximately [ 3:1:0.1], or approximately [2:1:1], or approximately [2:1:0.5], or approximately [2:1 :0.1], or approximately [2:1:0.08], or approximately [2:1:0.05], or approximately [2: 1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02], or approximately [ 1:1:0.5], or approximately [1:1:0.1], or approximately [1:1:0.07], or approximately [ It is approximately [1:1:0.05], or approximately [1:1:0.04], or approximately [1:1:0.02]. Preferably, the ratio is approximately [2:1:1], or approximately [2:1:0.5], or approximately [2:1: 0.1], or approximately [2:1:0.08], or approximately [2:1:0.05], or approximately [2:1 :0.04], or approximately [2:1:0.03], or approximately [2:1:0.02], or approximately [1 :1:0.5], or approximately [1:1:0.1], or approximately [1:1:0.07], or approximately [1 :1:0.05], or approximately [1:1:0.04], or approximately [1:1:0.02], or approximately The ratio is [1:3:0.1], or approximately [1:3:0.2], or approximately 1:1.5:0.25]. More preferably, the ratio is about [2:1:1], or about [2:1:0.08], or about [2 :1:0.5], or approximately [2:1:0.1], or approximately [2:1:0.05], or approximately [2 It is approximately [1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02]. In one embodiment, when a surfactant is present, (b) compound (A) in the mixture and a small amount At the very least, the weight ratio of one type of binder to the surfactant is approximately [2:1:0.08]. In a certain embodiment, the surfactant is SLS, the binder is copovidone, and (b) The weight ratio of compound (A) in the mixture to copovidone and SLS is approximately [2:1:1], and It is approximately [2:1:0.08], or approximately [2:1:0.5], or approximately [2:1:0.1], or This is approximately [2:1:0.05], or approximately [2:1:0.04], or approximately [2:1:0.03] , or approximately [2:1:0.02]; more preferably approximately [2:1:0.08].

[0079] In another embodiment, when a surfactant is present, compound (A) in the pharmaceutical composition and The weight ratio of at least one binder to the surfactant is approximately [2:1:1], or approximately [2: 1:0.08], or approximately [2:1:0.5], or approximately [2:1:0.1], or approximately [2: 1:0.05], or approximately [2:1:0.04], or approximately [2:1:0.03], or approximately [ [2:1:0.02]. In a further embodiment, if a surfactant is present, the pharmaceutical compound The weight ratio of compound (A) in the product, at least one binder, and the surfactant is approximately [2: [1:0.08]. In a particular embodiment of this embodiment, the surfactant is SLS Yes, the binder is copovidone, and compound (A) in the pharmaceutical composition, copovidone, and SL The weight ratio with S is approximately [2:1:1], or approximately [2:1:0.08], or approximately [2:1:0 .5], or approximately [2:1:0.1], or approximately [2:1:0.08], or approximately [2:1:0 .05], or approximately [2:1:0.04], or approximately [2:1:0.03], or approximately [2:1 [0.02], more preferably about [2:1:0.08].

[0080] According to aspects of the present invention, a compound (A), at least one binder, and optionally a surfactant (b) The mixture containing the stimulant is premixed together. (b) The mixture is basically insoluble It can be added to a liquid medium to form a premix. The liquid medium has properties such as It can be aqueous or non-aqueous. Preferably, the liquid medium is an aqueous solution, such as water. According to the present embodiment, (b) the mixture is in the form of a suspension or dispersion, more preferably a suspension. be.

[0081] Compound (A) is present in the liquid medium at approximately 5% w / based on the combined total weight of the premixture. w~ an amount of about 40% w / w, preferably an amount of about 10% w / w, or an amount of about 15% w / w, The amount is approximately 20% w / w, or approximately 25% w / w, or approximately 30% w / w, more preferably It may be present in an amount of approximately 20% w / w based on the weight of the premixture.

[0082] At least one binder, in a liquid medium, is present in a quantity of about 3 based on the weight of the premixture. A quantity of approximately 15% w / w; preferably about 4% w / w based on the weight of the premixture. , or about 6% w / w, or about 8% w / w or about 10% w / w, more preferably about 4% w / It can exist in quantities of w.

[0083] If present, surfactants are present in the liquid medium at a concentration of approximately 0.0 based on the weight of the premixture. An amount of 5% to about 1%, preferably about 0.1% or about 0.5% based on the weight of the premixture. It is present in an amount of %, or about 0.75%, more preferably about 0.1% w / w.

[0084] According to the present invention, the premixture can be used directly or subjected to mechanical means to reduce the average particle size to 1 It can also be reduced to less than 000 nm. Particle size can be determined, for example, by laser diffraction (e.g., particle size The distribution (PSD) is measured using methods and apparatus known to those skilled in the art. Alternatively, the particle size measured by PCS is less than 500 nm, more preferably 350 nm. Less than 250 nm, most preferably less than 250 nm. In one embodiment, measured by PCS. The particle size of the suspension is approximately 50 nm to 1000 nm, or approximately 50 nm to 500 nm. The wavelength range is approximately 50 nm to 350 nm, or approximately 100 nm to 170 nm. For example, the particle size is Approximately 50nm, or approximately 70nm, or approximately 90nm, or approximately 100nm, or approximately 110nm, Or approximately 120 nm, or approximately 130 nm, or approximately 140 nm, or approximately 150 nm, or approximately 1 60nm, or approximately 170nm, or approximately 180nm, or approximately 190nm, or approximately 200nm , or approximately 230nm or approximately 250nm or approximately 280nm or approximately 300nm or approximately 3 20nm, or approximately 350nm, or approximately 370nm, or approximately 400nm, or approximately 450nm , or about 500 nm. More preferably, the particle size is about 100 nm to about 350 nm, The size is approximately 110 nm to 180 nm, or approximately 250 nm to 350 nm. The child is capable of maintaining the particles in a stable state at a desired size, as defined herein. It is stabilized by the presence of a binder in the premixture.

[0085] According to the present invention, compound (A), at least one binder and optionally a surfactant The mixtures (b) as defined herein are known in the art as described herein. (a) It can be added to an inert substrate using various techniques. Preferably, Compound (A), defined herein, comprising at least one binder and optionally a surfactant. The mixture (b) is dispersed on the inert substrate (a). In another preferred embodiment, (a) The inert substrate comprises compound (A), at least one binder and a surfactant (b ) is coated with a mixture. In another preferred embodiment, as defined herein, A mixture (A), comprising at least one binder and optionally a surfactant (b), is suspended. A turbid liquid, preferably dispersed or coated on (a) an inert core as separate particles, In this way, despite the poor solubility of the drug, it provides a large surface area for immediate dissolution. ru.

[0086] Another aspect of the present invention is N-(3-(6-amino-5-(2-(N-methylacrylamine Ethoxypyrimidine-4-yl-5-fluoro-2-methylphenyl-4-syl Clopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free agent Release form, (referred to as compound (A) herein), at least one binder and A surfactant is selectively added to an aqueous solution (for example, preferably 5-8 p, more preferably 5-6 p). The present invention provides a suspension contained in a liquid medium such as purified water having an H value. The particle size of the suspension measured by S is less than 1000 nm, as defined herein. Full, preferably less than 500 nm, more preferably less than 350 nm, most preferably 250 It is less than nm. More specifically, the average particle size of the suspension measured by PCS is about 50 nm to approximately 1000 nm, or approximately 50 nm to 500 nm, or approximately 50 nm to approximately 350 nm, Or it is about 100 nm to 170 nm, for example, the particle size is about 50 nm or about 70 nm. Or approximately 90 nm, or approximately 100 nm, or approximately 110 nm, or approximately 120 nm, or approximately 13 0nm, or approximately 140nm, or approximately 150nm, or approximately 160nm, or approximately 170nm, Or approximately 180 nm, or approximately 190 nm, or approximately 200 nm, or approximately 230 nm, or approximately 2 50nm, or approximately 280nm, or approximately 300nm, or approximately 320nm, or approximately 350nm , or approximately 370 nm, or approximately 400 nm, or approximately 450 nm, or approximately 500 nm. More preferably, the particle size is approximately 100 nm to approximately 350 nm, or approximately 110 nm to approximately 180 nm. m, or approximately 250 nm to approximately 350 nm.

[0087] Another aspect of the present invention is N-(3-(6-amino-5-(2-(N-methylacrylamine Ethoxypyrimidine-4-yl-5-fluoro-2-methylphenyl-4-syl Clopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free agent Release form, (referred to as compound (A) herein), at least one binder and A surfactant is selectively added to an aqueous solution (for example, preferably 5-8 p, more preferably 5-6 p). The present invention provides a dispersible solution contained in a liquid medium such as purified water having an H value.

[0088] According to the present invention, the pharmaceutical composition contains approximately 0.5 mg to approximately 600 mg of compound (A) It is prepared by mixing at least one type of binder and optionally a surfactant. The pharmaceutical composition contains approximately 5 mg to approximately 400 mg of compound (A) bonded to at least one other compound. It is prepared by mixing it with an agent and optionally with a surfactant. More preferably, a pharmaceutical compound The product consists of approximately 10 mg to 150 mg of compound (A), at least one binder and optional Prepared by mixing with a surfactant of choice. Pharmaceutical compositions disclosed herein ( For example, for oral administration, the formulation consists of 10 mg of compound (A), at least one binder, and an optional agent. The compound may contain a mixture of surfactants. The pharmaceutical composition contains 15 mg of compound (A) and at least It may also include a mixture of one type of binder and optionally a surfactant. In another example, the pharmaceutical composition The substance (for example, for oral administration) contains 20 mg of compound (A) and at least one binder and It can also be prepared by surfactants of choice. In another example, pharmaceutical compositions (e.g., orally) For administration, for example, 25 mg of compound (A), at least one binder and optionally It may also include surfactants. In another example, the pharmaceutical composition contains 50 mg of compound (A) in small amounts. It can be prepared by mixing at least one type of binder and optionally a surfactant. In the example, the pharmaceutical composition contains 100 mg of compound (A) as at least one binder and It is prepared by mixing with a surfactant of optional choice. In another example, the pharmaceutical composition ( For example, for oral administration, 150 mg of compound (A) is used, along with at least one binder and an optional It can also be prepared by mixing with a surfactant of choice. In another example, a pharmaceutical composition This involves 200 mg of compound (A) with at least one binder and optionally a surfactant. It is prepared by mixing. In another example, a pharmaceutical composition (e.g., for oral administration) is Mix 250 mg of compound (A) with at least one binder and optionally a surfactant. It can also be prepared by the following: In another example, the pharmaceutical composition is 300 mg of compound ( A) is prepared by mixing it with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition (e.g., for oral administration) contains 350 mg of compound (A) It can also be prepared by mixing it with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition may contain 400 mg of compound (A), at least one of the following: It is prepared by mixing it with a binder and optionally a surfactant. In another example, A pharmaceutical composition (for example, for oral administration) comprises 450 mg of compound (A), and at least one compound It can also be prepared by mixing with a surfactant as a combination agent or, optionally, with a surfactant. In another example... The pharmaceutical composition contains 500 mg of compound (A) as at least one binder and optionally It is prepared by mixing with a surfactant. In another example, a pharmaceutical composition (e.g., orally) For administration, 600 mg of compound (A) is used, with at least one binder and optionally an interface. It can also be prepared by mixing it with an activator.

[0089] According to aspects of the present invention, the granular particles as defined herein optionally coat the outer seal coat layer. The outer seal coat layer may be chemically mixed with the mixture (b) as defined herein. Non-reactive substances that may occur during the formulation process, such as additives, pharmaceutically acceptable excipients, or (b) Unwanted chemical or physical interactions with any further active pharmaceutical ingredients Includes materials to protect the contents. The outer seal coat layer is for flavoring and enteri c) or gastric Alternatively, it can also provide an additional barrier for stomach release. If present, outside The seal coat layer is, for example, hydroxypropyl methylcellulose, magnesium stearate. Cium, polyvinylpyrrolidone, hydroxypropylcellulose, carboxymethylcellulose Rose, methylcellulose, hydroxyethylcellulose, carboxyethylcellulose carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl Alcohol, cellulose phthalate acetate (CAP), cellulose trimellitic acetate (CAT) ), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl Methylcellulose acetate succinate (HPMCAS), polyvinyl acetate Talate (PVAP), methyl methacrylate-methacrylate copolymer, succinic acid acetate Selected from cellulose, fatty acids, waxes, shellac, sodium alginate, or mixtures thereof. These are some possible options, but are not limited to them.

[0090] In one embodiment, the present invention relates to a drug substance (i.e., compound (A)) with a particle size of 1000 nm The present invention provides a pharmaceutical composition defined above, which is less than [amount missing]. Preferably measured by PCS. The particle size of compound (A) is less than 500 nm, more preferably less than 350 nm, and most preferably less than 500 nm. The wavelength is less than 250 nm. In one embodiment, the compound measured by PCS The particle size of (A) is approximately 50 nm to approximately 1000 nm, or approximately 50 nm to 500 nm, or approximately 5 The range is 0 nm to approximately 350 nm, or approximately 100 nm to 170 nm. For example, the particle size is approximately 50 nm, or approximately 70 nm, or approximately 90 nm, or approximately 100 nm, or approximately 110 nm, or approximately 120nm, or approximately 130nm, or approximately 140nm, or approximately 150nm, or approximately 160nm m, or approximately 170 nm, or approximately 180 nm, or approximately 190 nm, or approximately 200 nm, Approximately 230nm, or approximately 250nm, or approximately 280nm, or approximately 300nm, or approximately 320nm m, or approximately 350 nm, or approximately 370 nm, or approximately 400 nm, or approximately 450 nm, It is approximately 500 nm. More preferably, the particle size of compound (A) is approximately 100 nm to approximately 350 nm. This range is nm, or approximately 110 nm to 180 nm, or approximately 250 nm to 350 nm.

[0091] A further aspect of the present invention is a process for preparing a pharmaceutical composition (e.g., for oral administration) as defined herein, comprising: (i) mixing a (b) mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt or free form thereof, at least one binder and optionally a surfactant in a liquid medium, and and (ii) adding the mixture (i) to (a) carrier particles of an inert substrate. There is provided a process comprising these steps. (ii) adding the mixture (i) to (a) carrier particles of an inert substrate. There is provided a process comprising these steps.

[0092] Another aspect of the present invention is a process for preparing a pharmaceutical composition (e.g., for oral administration) as defined herein, comprising: (iii) mixing a (b) mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt or free form thereof, at least one binder and optionally a surfactant in a liquid medium which is an aqueous or non-aqueous solution, and and (iv) adding the mixture (i) to (a) carrier particles of an inert substrate. (iv) adding the mixture (i) to (a) carrier particles of an inert substrate. There is provided a process comprising these steps.

[0093] Another aspect of the present invention is a process for preparing a pharmaceutical composition (e.g., for oral administration) as defined herein, comprising: (i) N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt or free form thereof, at least one binder and optionally a surfactant in a liquid medium, and -Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least (b) A mixture containing one type of binder and optionally a surfactant is mixed in an aqueous solution of water. The process of combining, and (ii) Adding the mixture (i) to the carrier particles of the inert substrate (a) Includes, BTK inhibitors such as compound (A) are administered in doses of approximately 0.5 mg to approximately 60 mg as defined herein. It is present in amounts of 0 mg, or approximately 5 mg to approximately 400 mg, or approximately 10 mg to approximately 150 mg. Regarding the process.

[0094] As stated above in this specification, (b) the mixture is a liquid medium in which it is essentially insoluble. For example, it can be added to an aqueous solution to form a premixture. The premixture is visible to the naked eye. Using appropriate stirring, the liquid is stirred until a homogeneous dispersion or suspension without large clumps is observed. It can be dispersed or suspended in a medium. A mechanical device can be used to reduce the particle size of compound (A). The means are any mechanical means known to those skilled in the art. Preferably, the means include compound (A). (b) Mechanical means used to reduce the particle size of a mixture (or premixture) are powder This is a grinding method carried out in a grinding chamber. A suitable grinding technique is, for example, ball Mill grinding, wet grinding, media grinding, wet media grinding, agitated grinding, agitated media grinding, wet agitated media Grinding, agitator grinding, agitator media grinding, wet agitator media grinding, bead grinding, agitator bead powder The processes include crushing, wet agitator bead grinding, and high-pressure homogenization. Preferably, nano-sized particles are processed wet. Prepared using a grinding technique selected from grinding, media grinding, wet media grinding, or high-pressure homogenization. The further methods and grinding techniques are wet grinding, media grinding, and wet media grinding. Specifically, nano-sized particles are prepared using a wet media grinding technique. Therefore, the present invention According to this specification, step (i) of the process is performed in a grinding chamber, particularly in a humid environment. This is carried out in a grinding chamber. The pH of the preliminary mixture in the grinding chamber is approximately pH=5 The pH is 8, and preferably the pH inside the grinding chamber is about 6. The process is 2 The minimum specific energy and temperature up to 35°C are introduced into a suspension of 00kJ / kg. This is achieved by process parameters that result in the suspension temperature at the outlet of the tube. Furthermore, the process involves a higher specific energy than 200 kJ / kg and a temperature below 35°C. This is carried out by a lower suspension temperature at the outlet of the grinding chamber. Specific energy Kwade(Kwade,Powder Technology 1999,105 ,14-20 and Kwade, Chemical Engineering and T This is calculated according to ecology 2003, 26, 199-205). This includes different batch sizes, for example, approximately 62-175 kg, and rotor tip speed, for example, 1 The study considered the range of 0-14 m / s and the liquid flow rate, for example, 5-20 L / min. Figure 39 shows: Various batch sizes and process parameter settings for rotor tip speed and suspension flow rate. An established relationship between the average particle size and specific energy of differently manufactured batches, taking into consideration. The particle size of compound (A) is shown below. The batch size investigated, rotor tip speed, and suspension Despite differences in flow rates, the process was reasonably controlled by the parameterized specific energy. This involves introducing the minimum specific energy into a suspension of approximately 200 kJ / kg and grinding up to 35°C. This was carried out by process parameters that resulted in the suspension temperature at the chamber outlet. Alternatively, the process was carried out with a higher specific energy exceeding 300 kJ / kg and up to 32 °C by the suspension temperature at the outlet of the grinding chamber. Most preferably, the process was carried out with a specific energy exceeding 600 kJ / kg and a suspension temperature at the outlet of the grinding chamber of 16 - 32 °C.

[0095] Thus, one aspect of the present invention is to provide a suspension containing N-(3-(6-amino-5-(2-(N-methyl acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least one binder, and optionally a surfactant in a liquid medium. In one aspect, the particle size of the suspension is less than 1000 nm , preferably less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 n m. In another aspect, the liquid medium of the suspension is preferably an aqueous solution having a pH value of 5 - 8, more preferably 5 - 6, such as purified water.

[0096] In another aspect, the above-mentioned suspension contains compound (A) or a pharmaceutically acceptable salt thereof or its free form, and compound (A) or a pharmaceutically acceptable salt thereof or its free form is present in an amount of about 10% - about 40% of the total weight of the suspension, preferably about 20% or about 25% of the total weight of the suspension.

[0097] In yet a further aspect, the present invention provides the above-mentioned suspension in which at least one binder (preferably copovidone ) is present in an amount of about 3% - about 15% of the total weight of the suspension.

[0098]

[0098] In a further embodiment, the present invention relates to a surfactant (preferably SLS) in a suspension The suspension as defined above is provided, present in an amount of approximately 0.05% to 1% of the total weight.

[0099] According to the present invention, a pharmaceutical composition (for example, for oral administration) as defined herein is prepared. The process involves (i) (b) the mixture, which is a support for an inert substrate as defined herein. (b) The mixture is subjected to, for example, spray drying, spray granulation, spray lamination, spray Features include mist dispersion, spray coating, fluidized bed drying, fluidized bed coating, fluidized bed spray granulation, and spray nozzles. Various techniques known in the art, such as granulators or combinations thereof of these spraying techniques. It can be added using the following. According to the present invention, coating or spraying is, for example, of carrier particles From the top (e.g., top spray or top coating), to the bottom of the carrier particles (e.g., bottom spray or The lower covering can be carried out simultaneously or subsequently from both directions. According to the present invention, the upper Spraying or top coating is preferred. Preferably, (a) an inert substrate is coated with (b) a mixture. The mixture (b) as defined herein, which is made in step (i). The mixture is (a) dispersed on an inert substrate. Specifically, (b) the mixture is sprayed, for example. Add using drying, spray granulation, fluid bed spray granulation, or a combination of these spraying techniques. It can be done. In a liquid medium, such as purified water, the temperature of the product (compound (A)) is approximately 30°C to approximately 45°C. It is evaporated while maintaining a certain temperature. Preferably, the product temperature is about 36°C to about 44°C. The temperature is approximately 36°C to 40°C. During the spray granulation process, the spray rate and atomization air are important. Atmospheric pressure is a parameter that determines the droplet size of the sprayed liquid when it is atomized. The parameters depend on the nozzle shape. Each nozzle has a specific atomizing air pressure and air consumption. It is characterized by a factor that is typically air consumption charge from nozzle manufacturers. This value and the spray rate used are applied during the spraying process. The ratio of air mass to liquid mass was calculated. The granulation process is approximately 1.1 to 3.2, for example. Spray velocity and atomization that result in an air-to-liquid mass flow rate range of approximately 1.1 to 2.3. It is carried out using air pressure. The ratio of the flow rate of air mass to liquid mass is approximately 1.1 to 3.2. This is important because it controls the droplet size distribution of the liquid after atomization. The droplet size increases as the air-to-liquid ratio decreases, which is due to subsequent tablet compression and shaking. This results in less-than-optimal granules due to uneven uniformity and the risk of coagulation. Loss of weight due to drying of granules. (LOD) is, for example, a material parameter for spray liquid and a process parameter for The spray rate, airflow rate, and intake air temperature were examined to determine the materials and processes during spray granulation processing. It is a widely accepted surrogate that quantitatively describes complex relationships with parameters. Ochsenbein DRet al.,Int.J.Pharm.X1(201 9)100028,Lyngberg O.et al.,Applications of Modeling in Oral Solid Dosage Form De velopment and Manufacturing,In:Process S imulation and Data Modeling in Solid Ora l Drug Development and Manufacturing,Ierap etritou MGand Ramachandran R.(Editors) Humana Press (2016) 1-42). The dry weight loss (LOD) trajectory is the most Preferred process conditions (i.e., product temperature is approximately 34 to approximately 40°C, and air-liquid ratio is approximately It was experimentally established as a characteristic surrogate for process conditions (2.0 to approximately 3.2). Figure 40 shows the LOD trajectory for the most preferred process conditions defined above. And lower LOD trajectories are associated with slightly wet process conditions (higher LOD trajectories) and slightly dry conditions. This represents the range of most preferred process conditions for dry process conditions (lower LOD trajectory). The corresponding product granule particle size distribution is shown in Figure 41. Slightly humid process conditions (higher L OD trajectory results in a coarser granule size distribution, and slightly drier process conditions (lower L) The LOD (Line of Direction) locus results in a finer granule size distribution. The granule size distribution is expressed by the LOD locus. As described above, the process was reasonably controlled by the most preferred process conditions defined above. Process conditions exceeding high and lower LOD trajectories affect the uniformity of tablet compression and blending. This resulted in granules with less-than-optimal properties.

[0100] In a further embodiment, the present invention relates to a process for preparing a suspension, as specified herein The process includes mixing the (b) mixture in a liquid medium as defined herein. To provide a solution. Therefore, another aspect of the present invention is a pharmaceutical composition as defined herein (for example) A process for preparing (for oral administration), (i)N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Limidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least (b) A mixture containing one type of binder and optionally a surfactant is mixed in a liquid medium. The process involves preparing a suspension, wherein the liquid medium is preferably 5 to 8, more preferably The process involves using an aqueous solution having a pH value of 5-6, such as purified water, and (ii) Adding the suspension from step (i) to the carrier particles of the inert substrate (a) Regarding processes that include this.

[0101] In one embodiment of the above process, the suspension is measured by PCS at a wavelength of less than 1000 nm. It has a defined average particle size. Preferably, the particle size of the suspension measured by PCS is 5 The wavelength is less than 00 nm, more preferably less than 350 nm, and most preferably less than 250 nm. In one embodiment, the particle size of the suspension measured by PCS is approximately 50 nm to approximately 100 nm. 0nm, or approximately 50nm to 500nm, or approximately 50nm to 350nm, or approximately 100nm The wavelength ranges from m to 170 nm, for example, the particle size is approximately 50 nm, 70 nm, or 90 nm. , or approximately 100 nm, or approximately 110 nm, or approximately 120 nm, or approximately 130 nm, or approximately 140nm, or approximately 150nm, or approximately 160nm, or approximately 170nm, or approximately 180nm m, or approximately 190 nm, or approximately 200 nm, or approximately 230 nm, or approximately 250 nm, or approximately 280nm, or approximately 300nm, or approximately 320nm, or approximately 350nm, or approximately 370nm m, or about 400 nm, or about 450 nm, or about 500 nm. More preferably, The particle size is approximately 100 nm to 350 nm, or approximately 110 nm to 180 nm, or approximately 250 The range is approximately 350 nm.

[0102] In another embodiment, the present invention relates to a process for preparing a dispersion, as defined herein. (b) A process comprising mixing the mixture with a liquid medium as defined herein. To provide. Therefore, another aspect of the present invention is a pharmaceutical composition as defined herein (e.g., orally). A process for preparing (for administration), (i)N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Limidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least (b) A mixture containing one type of binder and optionally a surfactant is mixed in a liquid medium. The process involves preparing a dispersion, wherein the liquid medium is preferably 5 to 8, more preferably The process involves using an aqueous solution having a pH value of 5-6, for example, purified water, and (ii) Adding the dispersion from step (i) to the carrier particles of the inert substrate. Regarding processes that include this.

[0103] In one embodiment of the above process, the suspension is measured by PCS at a wavelength of less than 1000 nm. It has a defined average particle size. Preferably, the particle size is about 50 nm to about 1000 nm, or about 50nm to 500nm, or approximately 50nm to approximately 350nm, or approximately 100nm to 170nm For example, the particle size is approximately 50 nm, or approximately 70 nm, or approximately 90 nm, or approximately 100 nm. nm, or approximately 110 nm, or approximately 120 nm, or approximately 130 nm, or approximately 140 nm, or This is approximately 150nm, or approximately 160nm, or approximately 170nm, or approximately 180nm, or approximately 19 0 nm, or approximately 200 nm, or approximately 230 nm, or approximately 250 nm, or approximately 280 nm, or This is approximately 300nm, or approximately 320nm, or approximately 350nm, or approximately 370nm, or approximately 40 The particle size is 0 nm, or about 450 nm, or about 500 nm. More preferably, the particle size is about 11 0nm to approximately 350nm, or approximately 110nm to approximately 160nm, or approximately 250nm to approximately 350 It is in nm.

[0104] In a further embodiment, the present invention relates to pharmaceutical compositions as defined herein (e.g., oral administration). A process for preparing a product (for use), wherein the mixture obtained from step (ii) is divided into at least one type The final dosage form is prepared by blending it with an external phase containing a pharmaceutically acceptable salt. The process further includes the following. For example, the external phase as defined herein includes particles and the final Chemical-physical interactions between other active or inactive substances that may be used in the preparation of dosage forms It can be added to prevent use. The additional benefits of the external phase are an acceptable elution rate and an acceptable breakdown rate. The objective is to provide tablet moldability, including reduced breakage time, improved processability, and increased tablet tensile strength.

[0105] Another aspect of the present invention is a process for preparing a unit dosage form (for example, for oral administration), (i)N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Limidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -Fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least Also one type of binder (e.g., polyvinylpyrrolidone-vinyl acetate copolymer) and optional (b) a mixture containing a surfactant (e.g., sodium lauryl sulfate (SLS)), water A solution (for example, purified water having a pH value of preferably 5-8, more preferably 5-6), etc. A step of mixing in a liquid medium in a wet grinding chamber, wherein (b) the chemicals in the mixture The average particle size of material (A) is less than 1000 nm, preferably less than 500 nm, more preferably 3 The particle size is less than 50 nm, most preferably less than 250 nm, as disclosed herein. As mentioned, for example, it is approximately 100nm to 350nm or approximately 110nm to 180nm. (ii) the step of adding the mixture (i) to the carrier particles of the inert substrate (a), and (iii) The mixture obtained from step (ii) in at least one pharmaceutically acceptable excipient When blended with the agent, BTK inhibitors such as compound (A) (as defined herein) Approximately 0.5 mg to approximately 600 mg, or approximately 5 mg to approximately 400 mg, or approximately 10 mg to approximately 150 mg The process of obtaining the final dosage form in mg quantities. We also provide processes that include this.

[0106] Another aspect of the present invention is a process for preparing a pharmaceutical composition, for example, the following process Provides a process that follows a flowchart.

[0107] [Table 1]

[0108] Another aspect of the present invention is a process as defined herein, wherein the final dosage form is encapsulated. Alternatively, it provides a process for tableting. If the final dose is a tablet, the tablet is film coated. It may be possible.

[0109] Another aspect of the present invention relates to a carrier particle that is coated with at least one pharmaceutically acceptable excipient (external phase). The process further includes preparing the final dosage form by mixing with ). Body particles contain at least one pharmaceutically acceptable excipient and / or matrix-forming agent. It can be used to form the final dosage form (e.g., tablets, capsules) by, for example, granulation, freeze-drying, or spray-drying. It can be converted to (L). Suitable pharmaceutically acceptable excipients include, for example, lactose. , mannitol (such as mannitol DC), microcrystalline cellulose (for example, Avicel PH101 (registered trademark), Avicel PH102 (registered trademark), dicalcium phosphate Um, polyvinylpyrrolidone, hydroxypropyl methylcellulose, croscarmellol Sodium, polyvinylpyrrolidone-vinyl acetate copolymer (e.g., crospovidone) ), sodium starch glycolate, colloidal silicon dioxide, magnesium stearate It consists of um, sodium bicarbonate, sodium stearyl fumarate, or a mixture thereof. It can be selected from the group. Preferably, the excipient is mannitol (such as mannitol DC), Croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, The group may consist of sodium bicarbonate or mixtures thereof. At least one Pharmacopoecially acceptable excipients provide a formulation that exhibits good disintegration and dispersion of compound (A). Therefore, it is selected to reduce its gelation behavior.

[0110] The pharmaceutical compositions disclosed herein are for use in humans and animals, for example, in capsules, caplets. Powder, pellets, granules, tablets, mini-tablets (up to 3mm or 5mm), individual packets, Intended to be administered orally in single or multiple dosage forms, such as pouches or stick packs. Preferably, the single dosage form or multiple dosage forms may be, for example, capsules, tablets, individual packets, pouches, or It is a stick pack. More preferably, the pharmaceutical composition is in the form of a capsule or tablet. Yes. This refers to the pharmaceutical composition as defined herein, which is a filler (also referred to as a diluent). Mix with lubricants, slicks, disintegrants and / or absorbents, colorants, fragrances and sweeteners. This can be achieved.

[0111] Capsules containing the pharmaceutical composition of the present invention as defined herein are known in the art. It can be prepared using the technique. Suitable capsules are hard shell capsules and hard gelatin capsules. Capsules, soft gelatin capsules, soft shell capsules, vegetable shell capsules, Promellose (HPMC) capsules or mixtures thereof can be selected. The listed pharmaceutical compositions are hard gelatin capsules, hard shell capsules, or vegetable hard capsules. The pharmaceutical composition may be expressed in Dossel capsules and hypromellose (HPMC) capsules. inert solid diluents, such as calcium carbonate, calcium phosphate, magnesium stearate. Nesium, sodium bicarbonate, or cellulosic excipients (e.g., microcrystalline cellulose) Further mixed. Hard gelatin capsules consist of two parts: body and cap. It is made of a gelatin shell on the outside. The shell is made of vegetable or animal gelatin (for example) (Pork, beef, or fish-based gelatin), water, one or more plasticizers, and optionally some preservatives. The capsule may contain a BTK inhibitor such as compound (A), at least one binder, and A powder, very small pellet or optionally containing surfactants and / or other excipients. It can contain dry mixtures in the form of particles. The shell can be transparent, opaque, colored, or They may also be flavored. Capsules containing particles are a technique well known in the art. Therefore, it is coated with an enteric-coated and / or gastric-resistant or delayed-release coating material, for example, Higher stability in the gastrointestinal tract can be achieved, or the desired release rate can be achieved. Hard gelatin capsules of various sizes (for example, sizes 000 to 5) can be prepared.

[0112] Tablets comprising the pharmaceutical composition of the present invention as defined herein are based on techniques known in the art. It can be prepared using [a specific method]. Suitable tablets are made from particles of a non-toxic pharmaceutical suitable for tablet manufacture. These excipients may be included in a mixed state. These excipients include, for example, calcium carbonate, sodium carbonate. Lactose (e.g., lactose SD), mannitol (e.g., mannitol DC) ), magnesium carbonate, kaolin, cellulose (e.g., microcrystalline cellulose, powdered cellulose) Inert substances such as phosphate, calcium phosphate, sodium phosphate, or mixtures thereof. Diluent (or filler in other cases); disintegrating agent agent) (also called disintegrant), for example, Roscarmellose sodium, crospovidone, sodium starch glycolate, tou Sorghum starch or alginic acid or mixtures thereof; lubricants (gliding a A gent (also called a glidant), for example, fumed silica (For example, Aerosil®, Aeroperl®); binder (b (Also called binding agent) (For example, Methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, starch (Gum, gelatin, or gum arabic) or mixtures thereof; and lubricants (lubricants) ng agent) (also called lubricant), for example, steer Magnesium phosphate, sodium stearyl fumarate, stearic acid, or talc or These are mixtures. A mixture of particles mixed with non-toxic pharmaceuticals is, for example, frightening. Mix using many known methods, such as mixing with a ball or tumble blending. Yes, it is possible. A mixture of particles mixed with non-toxic pharmaceuticals can be used, for example, in a single punch press. Compression on a double punch press, rotary tablet press, or roller compression device, etc. It can be compressed into tablets using the commonly known tableting technique. The compressive force can be any suitable compressive force from which a tablet can be obtained, for example, the pressure applied. The compression can be 0.5 to 60 kN, or 1 to 50 kN, or 5 to 45 kN. Preferably The compressive force is 5-25kN. The tablets or granules may not be coated, or they may be coated by known techniques. The coating delays disintegration and absorption within the digestive tract, thereby providing a sustained effect over a long period. It may also give. For example, tablets may be coated with a suitable polymer or conventional coating material. For example, this can achieve higher stability within the gastrointestinal tract or achieve a desired release rate. For example, the tablets contain hypromellose (HPMC), magnesium stearate, and polyethylene. Glycol (PEG), polyvinyl alcohol (PVA), Opadry® It can be coated with Opadry II® or a mixture thereof. For example, Time-delaying materials such as glyceryl phosphate or glyceryl distearate may be used. Tablets of any shape or size can be prepared, and they may be opaque, colored, or It can be flavored. Specifically, the pharmaceutical compositions disclosed herein are film coatings. It is in the form of a lock.

[0113] N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrim Zin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-f Luolobenzamide or its pharmaceutically acceptable salt or its free form (as specified herein) BTK inhibitors, such as those referred to as compound (A), have undesirable side effects on the patients being treated. It is present in the pharmaceutical composition in an amount sufficient to exert a therapeutically useful effect even when it is not in action. Each unit dose contains a predetermined amount of compound (A) sufficient to produce the desired therapeutic effect. Each unit dose disclosed in the specification is suitable for human and animal subjects and is individually packaged. It may be administered in a fraction of that amount or several times that amount. Multiple dosage forms are divided unit dosage forms. It is administered as multiple identical unit dosage forms packaged in a single container. Examples include vials, blisters, or bottles.

[0114] According to the present invention, compound (A) is used in a pharmaceutical composition (e.g., in an amount of about 0.5 mg to about 600 mg). For example, it may be present in (for oral administration). In one embodiment, the present invention relates to a final dosage form in which the compound (A ) in approximately 0.5 mg to 600 mg, or approximately 5 mg to 400 mg, or approximately 10 mg to 600 mg. This relates to a pharmaceutical composition for oral administration containing 150 mg of the substance. Preferably, in the final dosage form. The amount of compound (A) is approximately 0.5 mg, or approximately 5 mg, or approximately 10 mg, or approximately 15 mg , or approximately 20 mg, or approximately 25 mg, or approximately 30 mg, or approximately 35 mg, or approximately 40 mg , or approximately 45 mg, or approximately 50 mg, or approximately 60 mg, or approximately 70 mg, or approximately 80 mg , or about 90 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 1 50 mg, or approximately 180 mg, or approximately 200 mg, or approximately 220 mg, or approximately 240 mg , or approximately 250 mg, or approximately 270 mg, or approximately 300 mg, or approximately 320 mg, or approximately 350 mg, or approximately 370 mg, or approximately 400 mg, or approximately 430 mg, or approximately 450 mg g, or approximately 480 mg, or approximately 500 mg, or approximately 550 mg, or approximately 600 mg. More preferably, the amount is about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg. g, or approximately 50 mg, or approximately 100 mg, or approximately 150 mg, or approximately 200 mg, or approximately 250 mg, or approximately 300 mg, or approximately 350 mg, or approximately 400 mg, or approximately 450 mg g, or about 500 mg, or about 600 mg. Preferably, the compound (A) in the final dosage form. The amount is approximately 10 mg, approximately 25 mg, approximately 35 mg, approximately 50 mg, approximately 75 mg, or approximately 100 mg The amount is mg. More preferably, the amount of compound (A) in the final dosage form is about 10 mg, about 25 mg. g is approximately 50 mg or approximately 100 mg.

[0115] According to the present invention, the final dosage form contains compound (A) in an amount of approximately 10 mg. Another form of the present invention In this embodiment, the final dosage form contains compound (A) in an amount of approximately 20 mg. The final dosage form contains compound (A) in an amount of approximately 25 mg. In another embodiment of the present invention, The final dosage form contains compound (A) in an amount of approximately 35 mg. In another embodiment of the present invention, the final form The form contains compound (A) in an amount of approximately 50 mg. In yet another embodiment of the present invention, the final agent The form contains approximately 100 mg of compound (A).

[0116] Further aspects of the present invention include at least one further pharmaceutically active ingredient, as specified herein. This relates to pharmaceutical compositions (e.g., for oral administration) as defined in [the relevant text].

[0117] Another aspect of the present invention involves a BTK inhibitor such as compound (A) in an amount of about 0.5 mg to about 600 mg. Harmful agents, at least one binder, optionally a surfactant, and at least one pharmaceutically acceptable agent. The present invention provides capsules for oral administration containing an acceptable excipient.

[0118] Another aspect of the present invention involves compound (A) in an amount of about 0.5 mg to about 600 mg, at least 1 It contains a type of binder, optionally a surfactant, and at least one pharmaceutically acceptable excipient. The present invention provides tablets for oral administration, preferably film-coated tablets.

[0119] The pharmaceutical compositions disclosed herein (e.g., for oral administration) are useful as pharmaceuticals, for example. In particular, pharmaceutical compositions (for example, for oral administration) are used for, for example, autoimmune diseases, inflammatory diseases, and Allergic diseases, respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), graft rejection; Rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic Thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's disease Lennill syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cold Globulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria) Measles, chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), uterine rhinitis Roaming arteriosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease Pancreatitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-related conditions Type A graft rejection (AMR), graft-versus-host disease, subacute, acute and B cell-mediated diseases. Disorders of antibody production, antigen presentation, cytokine production, or lymphoid tissue formation, including chronic graft rejection. Common or undesirable diseases; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic Diseases, pulmonary embolism; multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; Lymphocyte leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphoma; polycythemia vera; essential lymphoma This includes, but is not limited to, plaque; myelofibrosis with myelo-metaplasia; and Waldenström disease. Cancers of hematopoietic origin that are not defined are mediated by BTK or inhibited by BTK. It is useful as a medicine for the treatment or prevention of diseases or disorders that can be improved. Specifically, this Disclosures include: rheumatoid arthritis; chronic urticaria (preferably chronic idiopathic urticaria); Sjögren's syndrome. A condition selected from sclerosing, multiple sclerosis, or asthma, which is mediated by or inhibited by BTK. To provide the use of the pharmaceutical composition in the treatment or prevention of diseases or disorders that are improved by the harm. do.

[0120] Another aspect of the present invention relates to a condition mediated by or improved by BTK inhibition. Pharmaceutical compositions disclosed herein for the manufacture of pharmaceuticals for diseases or disorders (e.g.) (For oral administration) use, in cases where the disease or disorder is an autoimmune disease, inflammatory disease, allergy - Sexually transmitted diseases, respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), graft rejection; arthritis Rheumatism, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic platelet disease Hemiplegic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome Syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cold globus globulin Phosphateemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria) Chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atheroma Arteriosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis Glomerulonephritis, Goodpasture syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-associated transplantation Graft rejection (AMR), graft-versus-host disease, subacute, acute and chronic migration mediated by B cells Abnormalities in antibody production, antigen presentation, cytokine production, or lymphoid tissue formation, including graft rejection. Diseases that are either desirable or undesirable; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic diseases, Pulmonary embolism; multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytes Myeloid leukemia; non-Hodgkin lymphoma; lymphoma; polycythemia vera; essential thrombocytosis This includes, but is not limited to, myelofibrosis with myelometaplasia and Waldenström disease. It is selected from cancers of hematopoietic origin and also provides use. Specifically, this disclosure provides BTK Therefore, pharmaceuticals for diseases or disorders that are mediated or improved by BTK inhibition. Use of the pharmaceutical compositions disclosed herein (e.g., for oral administration) for the manufacture of, The disease or disorder is rheumatoid arthritis; chronic urticaria (preferably chronic idiopathic urticaria); sjögren's disease. It provides a use selected from Lennill syndrome, multiple sclerosis, or asthma.

[0121] Another aspect of the present invention relates to a condition mediated by or improved by BTK inhibition. A method for treating or preventing a disease or disorder that requires such treatment or prevention The invention also provides a method that includes administering the pharmaceutical composition or final dosage form disclosed herein to the subject. do.

[0122] definition The term "pharmaceutically acceptable salt" refers, for example, to an acid addition salt, preferably with an organic or inorganic acid. This refers to salts that can be formed as follows. For isolation or purification purposes, pharmaceutically unacceptable salts, such as pi It is also possible to use chlorates or perchlorates. For therapeutic use, pharmacy permits Only acceptable salts or free compounds are used (in the form of pharmaceutical preparations, where applicable), however These are preferable. The term "pharmaceutically acceptable" means that there is no excessive toxicity, irritation, or allergen. - Suitable for use in contact with human and animal tissues, without reactions, other problems, or complications. and a compound, material, composition and / or dosage form that is balanced by a reasonable benefit / risk ratio. It refers to.

[0123] The terms “to treat,” “to treat,” or “treatment” of a disease or disorder are used to describe a disease or disorder. To improve a disorder (for example, to slow the onset of a disease or at least one of its clinical symptoms) It refers to stopping or reducing something. Furthermore, these terms are used by patients. To alleviate or improve at least one physical parameter, including one that may not be recognizable. Also, physically (for example, stabilization of recognizable symptoms), physiologically (for example, physical paralysis) This refers to regulating a disease or disorder by stabilizing the meter (or both).

[0124] The terms “preventing,” “preventing,” or “prevention” of a disease or disorder are used to describe a disease or disorder. This refers to delaying the onset, occurrence, or progression of a disability.

[0125] As used herein, the term "about" refers to measurements taken between different instruments, samples, and sample preparations. Explain the possible variations in the value, and consider the case where a given value is "slightly above" or "slightly below" the endpoint. Assuming that we obtain this, we will give flexibility to the endpoint of the numerical range. The term is usually given This means within 10% of the value or range, preferably within 5%, and more preferably within 1%.

[0126] The terms “pharmaceutical composition” or “formulation” may be used interchangeably herein and may affect mammals. To prevent, treat, or control a specific disease or condition, administer to a mammal, such as a human. This relates to physical mixtures containing therapeutic compounds. The term refers, for example, to mixtures formed under high temperature and high pressure. It also includes homogeneous physical mixtures.

[0127] The term "oral administration" refers to the administration of a therapeutic compound by swallowing, chewing, or inhaling the oral dosage form. This represents any method of administration that can be administered orally. Such oral dosage forms Conventionally, in the gastrointestinal tract beyond the mouth and / or buccal oral cavity, the active agent is substantially released and / or intended to be delivered.

[0128] As used herein, the term “therapeutically effective amount” of a compound refers to the biological or It elicits a medical response, for example, improving symptoms, alleviating the condition, slowing disease progression, or This refers to an amount that causes delay or other adverse effects. The term "therapeutically effective amount" means that when administered to a target, it affects the disease state or impairment. The amount of a compound that is effective in at least partially alleviating and / or improving harm or disease is also indicated. The term "effective dose" refers to the amount of cells, tissues, etc., sought by researchers, physicians, or other clinicians. The amount of the target compound that causes a biological or medical reaction in an organ, system, animal, or human. It means...

[0129] The term "including" in this specification means, unless otherwise specified, an unrestricted and unlimited meaning. Used in terms of taste. In a more restrictive embodiment, "includes" is not non-restrictive. It can be replaced with "become". In its most restrictive form, it is in each embodiment It may only include the characteristic processes or values ​​listed below.

[0130] As used herein, the term "inactive substrate" refers to both chemically active and biologically active substances. This refers to a substance or material that does not react with or decompose other substances. For example, an inert substrate is a suspension and Chemically non-reactive (i.e., compound (A) and (b) containing at least one binder) This refers to a substance or material that does not chemically react with the compound.

[0131] The term "glidant" or "glidin" as used herein "g agent" refers to a substance or material that improves the fluidity of the final blend.

[0132] The term "disintegrant" or "disintegrant" as used herein refers to the same term as "d The "integrating agent" is added to oral solid dosage forms, such as tablets. And, when it comes into contact with moisture, it causes rapid fragmentation of the solid form, thereby aiding in its decomposition. It refers to quality or material.

[0133] The term "binder" or "binding agent" is used in this book. It is used interchangeably in specifications and has its established meaning in the field of medicine. A compound added together with the active pharmaceutical ingredient (referred to herein as compound (A)), for example, In the case of material (A) deposition, it allows for adhesion to inert substrate particles or, in the case of tableting, enables the formation of granules. A promoter of cohesive compaction that ensures the formation of granules with the required mechanical strength. This refers to an inactive substance as such. All binders referred to herein are suitable for pharmaceutically acceptable use. It is used in large quantities and marketed under various trademarks, as shown in the following examples: Polyvinylpyrrolidone-vinyl acetate copolymer is sold under the trade name Copovidone (approximate molecular weight) It is sold commercially in quantities of 45,000 to 70,000. Copovidone (Ph.Eur.) is 1 It is a copolymer of -ethenylpyrrolidine-2-one and ethenyl acetate in a mass ratio of 3:2. It contains 7.0-8.0% nitrogen and 35.3-42.0% ethenyl acetate (dry (Substance). It may be commercialized under the name Kollidon® VA 64. -Polyvinylpyrrolidone (INN Ph.Eur.) is traded as Povidone K30 or PV It is commercially available as PK30 (approximate molecular weight 50,000). -Carboxymethylcellulose (USP / NF) is a polycarboxymethyl cellulose. It is also known as the calcium salt of ether. Its trade name is Carmellose Calcium. It is available commercially. -Shellac (INN Ph.Eur.) is the insect Laccifer lacca kar (Lac cifer lacca Kerr), Kerria Lacc a Kerr), Tachardia lacca, Kokka Coccus lacca and Carteria lacca Shellac is a commercially available resin secreted by the female of the plant *Lacca* on various trees. The composition of shellac is as follows: As noted: 46% alloyl phosphate (HOCH2(CH2)5CHOHCHOH(C H2)7COOH), 27% sherolic acid (cyclic dihydroxydicarboxylic acid and its homologues) Body), 5% kerophosphate (CH3(CH2) 10(CHOH)4COOH), 1% Butol Acid (C 14 H 28 (OH)(COOH)), 2% wax alcohol and acid ester, 7 % unspecified neutral substances (e.g., colorants) and 12% unspecified polybasic acid esters. -Polyvinyl alcohol (INN Ph.Eur.) is traded as Polyviol or P It is commercially available as VA (approximate molecular weight 28,000-40,000). -Polyethylene glycol (Ph.Eur.) is commercially available under the trade name PEG-n. Here, "n" is the number of ethylene oxide units (EO units) (approximate molecular weight 200 (Up to 00). -Polyvinyl alcohol-PEG copolymer, also known as PEG-PVA Livinyl alcohol-polyethylene glycol copolymer. -α-Hydro-ω-hydroxypoly(oxyethylene)poly(oxypropylene)poly( Also known as oxyethylene block copolymer (CAS 9003-11-6) Polyethylene-propylene glycol copolymer is known as poloxamer (INN P It is commercially available in h.Eur. poloxamer polyol has the general formula HO(C2H4O ) a (C3H6O) b (C2H4O) a Ethylene oxide and propylene oxide, depending on H These are a series of closely related block copolymers.

[0134] The term "surfactant" or "surfactant (surface a "Active agent" refers to an amphiphilic organic compound, and these compounds are hydrophobic carbon This means that it has both a hydrogenated chain (tail) and a hydrophilic head. Surfactants are water It contains both insoluble (or oil-soluble) and water-soluble components. Surfactants have properties that change upon ionization. Therefore, they are classified as either ionic (e.g., anionic or cationic) or nonionic. - Polysorbate is marketed under the name Tween 80. It is listed in the literature as follows: Named Polysorbate 80, PEO(20) Sorbitan Monooleate (INCI, former name It is known as the Crillet 4 Super.

[0135] The terms "nano-sized" or "nanoparticle-like" refer to the range of approximately 100 nm to approximately 1000 nm. This refers to particles that have a specific particle size.

[0136] Abbreviation %w / w Percentage by weight °C (degrees Celsius) API (Active Ingredients in Pharmaceuticals) Area under the AUC curve AUCinf is the AUC curve up to infinite time. AUClast AUC to the final measurable concentration Cmax maximum concentration CV% Coefficient of Variation (%) DR elution rate DSC (Differential Scanning Calorimetry) g / min (grams per minute) HPLC (High-Performance Liquid Chromatography) HR-XRPD High-Resolution X-ray Powder Diffraction INCI International Nomenclature for Cosmetic Ingredients INN (International General Name) Kg / g / mg / ng / μg (kilogram / gram / milligram / nanogram / microgram) Grams kN (kilonewton) LC-MS (Liquid Chromatography-Mass Spectrometry) mL / L (milliliters / liter) MRT mean resistance time nm / μm (nanometer / micrometer) PCS Photon Correlation Spectroscopy Ph.Eur. European Pharmacopoeia (9th Edition) PK Pharmacokinetic RH (Relative Humidity) Rpm (revolutions per minute) RRT (Relative Retention Time) RT room temperature SD and RSD: Standard deviation and relative standard deviation. SEM (Scanning Electron Microscopy) SLS sodium lauryl sulfate TFA (Trifluoroacetic Acid) TGA thermogravimetric analysis Tmax: Time to reach peak concentration (Cmax) US ultrasonic treatment USP (United States Pharmacopeia) USP / NF United States Pharmacopeia / National Pharmaceutical Collection w / v: Ratio of weight to volume w / w weight ratio XRPD (X-ray Powder Diffraction) [Examples]

[0137] The following examples illustrate the present invention and support the present disclosure without limiting the scope of the invention. give.

[0138] Analytical centrifugation (AC), e.g., LUMiSizer, LUM GmbH Germ any, SEPView 6.1.2570.2022. Approximately 1 of the first measurement profile Use a purified aqueous solution to dilute the suspension to an appropriate decay level with 0-70% permeability. A wet dispersion method. The results reported for X10, X50, and X90 are weighted by intensity. It has been deleted.

[0139] Photon correlation spectroscopy (PCS), e.g., Zetasizer Nano ZS, Malv Panalytical Ltd., UK, version 7.3. Approximately 2-9 damping fingers. 0.1 mM NaCl solution (purified) for diluting the suspension to an appropriate decay level with a certain number of units. A wet dispersion method using water. The results reported for Xmean are weighted by intensity. It has been removed. Specifically, the attenuation index is 5. Preferably, the measurement is performed at 25°C. Further preferred settings for the measurement system are as follows: Cell: Disposable sizing cuvettes Count rate (KcPs): 315 Duration: 60 seconds Measurement position (mm): 4.65 Zeta potential, e.g., Zetasizer Nano, Malvern Panalyte ical Ltd., UK Scanning electron microscope (SEM), e.g., Supra 40, Carl Zeiss SMT AG, Germany Dynamic viscosity, e.g., Haake Mars, ThermoFisher Scientist fic GmbH, Germany The sinker method, for example, the sinker method for determining the density of a liquid. Scales, Mettler Toledo GmbH, Switzerland Viable cell count test (MET).

[0140] Example 1: Preparation of granular particles The role of the inert substrate is to provide a mixture of different (b) types as defined herein, and different kinds of (a) ) Evaluation by adding an inactive substrate, such as mannitol and lactose, to the preparation. The different granular particle compositions use polyvinylpyrrolidone-vinyl acetate copolymer as a binder. Copovidone, compound (A) as defined herein, and surfactant sodium lauryl sulfate The substance was prepared by suspending it in a liquid medium such as purified water. Different variants are shown in Table 1. To include.

[0141] [Table 2]

[0142] Modifications containing a higher ratio of polyvinylpyrrolidone-vinyl acetate copolymer (copovidone) It was observed that compounds P1, P4, P5, and P7 exhibited the best resuspendability compared to the starting suspension. It was found that the variants P1 and P7, which contain a higher ratio of SLS, also exhibit superior resuspension properties. Modifier P7 was selected as a granular composition optimized in terms of copovidone and SLS ratio. However, for this reason, the amount sprayed onto the inert substrate (carrier particles) is granular with a reasonable processing time. Allows for a 20% drug load based on the child's total weight. Different variants of granular particle composition. The dissolution performance was evaluated to ensure that the dissolution profile was within a good range. (Figure 1 and...) As can be seen in Figure 2, the granular particles prepared as described in Table 1 are encapsulated (for example, in a capsule). By adding it to gelatin capsules, the dissolution rate is increased compared to conventional methods (European Pharmacopoeia 2. 9.3 Dissolution Test for Solid Dosage Forms Dosage Forms) or United States Pharmacopeia <711> "Dissolution (Dissolution) Measurement is performed by the paddle method according to the Japanese Pharmacopoeia <6.10> "Dissolution Test Method". Figure 1 shows the dissolution rate at pH 2, independently of the particle size of the active pharmaceutical ingredient, for a 50 mg dose tested. This provides sink conditions (solubility of 0.3 mg / mL). The above-mentioned granular particles were tested. In some capsules, the disintegration and dispersion of the contents were delayed, and the dissolution was delayed at 50 rpm paddle speed. This resulted in a discharge rate (DR) profile, particularly regarding the disintegration and dispersion of the formulation contents at pH 2. To improve this, at least one pharmaceutically acceptable excipient (e.g., as an external phase) may be added. The solubility of compound (A) at pH 3 was 50 in 900 mL. Figure 2 shows that the maximum solubility of compound (A) at pH 3 was 50. This shows that 90% is reached with mg doses. As can be seen in Figure 2, high levels of polyvinyl P1 granular particles containing pyrrolidone-vinyl acetate copolymer and SLS exhibit good resuspendability. As shown, it has low levels of polyvinylpyrrolidone-vinyl acetate copolymer and SLS. P2 granular particles did not achieve a good level of resuspendability. (0.1 μm filter and 0.0.) No significant difference in separation behavior was observed between the 22μm filter and the 22μm filter. The elution profiles of P2 granule particles completely overlap (as depicted in Figure 2).

[0143] Next, the granular particles P1, P2, P3, and P7 (prepared according to Table 1) and additional excipients are included. One type of granular particle (P7'') was evaluated in male beagle dogs, as summarized in Tables 2 and 3. did.

[0144] [Table 3]

[0145] [Table 4]

[0146] The results showed that the variability between subjects in Cmax and AUClast, as evaluated by CV(%), was The results showed that the rates were 40.7–90.1% and 49.6–69.7% between the two formulations, respectively. The maximum concentration (Cmax) was reached between formulations in a median of 0.5 to 2 hours. Based on the results, resuspension supports higher in vivo exposure in dogs, and different mutations Used as a selection criterion for classifying between forms (e.g., P1, P2, P3, P7, and P7''). I concluded that it could be used.

[0147] To better understand the formulation / pH profile, the dissolution of the formulations listed in Tables 2 and 3 The output velocity profile was measured at pH 2, pH 3, pH 4.5, and pH 6.8. The results were obtained. This is summarized in Figures 3, 4, 5, and 6. The formulation behavior changes between pH 2 and pH 3. It was shown that a smaller amount of binder (polyvinylpyrrolidone-vinyl acetate copolymer) is present. Formulations containing ) and surfactants (sodium lauryl sulfate) are compared to formulations containing a larger amount The dissolution rate was fast. The slow dissolution rate of the formulation is related to the observed gelation behavior. This was observed, and it was not seen with small amounts of binder and surfactant. pH 3 and higher At this pH level, no formulations exhibited gelling activity, and the contents of all capsules dissolved within the first 10 minutes. They are scattered.

[0148] Example 2: Role of particle size We have a good understanding of particle size distribution and the dissolution profiles of different formulations, and the impact of particle size on the formulation. To understand the impact, the role of particle size in compound (A) as defined herein was also investigated. Particles were prepared according to the procedure of Example 1. Several particle sizes of the active pharmaceutical ingredient (i.e., compound (A)) were used. The following investigation was conducted (using compound (A) administered at a dose of 50 mg), and the results are shown in Figure 7 and Figure 7. Describe in 8: V1 = 120 nm particle size - nano-granular formulation (wet-ground suspension). V2 = 1.2 μm particle size - as a non-wet ground suspension. V3 = 1.2 μm particle size - as a powder blend. V4 = 2.4 μm particle size - as a powder blend. V5 = 13.9 μm particle size - as a powder blend.

[0149] At pH 2, a strong particle size effect is already observed in the elution rate profile, as shown in Figure 7. Formulation V5 (13.9 μm) showed an infinitely large gap of approximately 40% from complete release. And it shows a delayed profile. Particle size 2.4 μm compared to particle size 1.2 μm (V2 and V3) μm(V4) shows a clear decrease in elution rate and also exhibits a delayed profile. 120 Comparison of formulation V1 with a particle size of nm and formulations (V2 and V3) with a particle size of 1.2 μm. The formulation with a particle size of 1.2 μm is faster at the beginning of the profile, but ultimately It was shown that they reached the same endpoint (Figure 7). The elution rate (DR) profile at pH 2 was observed. The effect of particle size is even more evident at pH 3, as shown in Figure 8. As shown, the difference between a 13.9 μm particle size (V5) and a 120 nm particle size (V1) is approximately 6 It is 0%. The fastest micron-sized active pharmaceutical ingredient (V2) is about 20% faster than V1. This indicates.

[0150] The role of particle size (e.g., micron or nano size) and the effect of formulation on PK. The evaluation was conducted in 13 male beagle dogs after administration of a 50 mg dose of compound (A). Treatment The arithmetic mean (SD) blood concentration-time plots per unit area are shown in Figures 9 and 10. PK parameters The data is summarized in Table 4 below.

[0151] [Table 5]

[0152] The median Tmax was slightly earlier compared to the micron-sized formulation (1.0 hour) of the compound ( This was observed (after 0.75 hours) when the formulation containing nano-sized particles of A) was administered. Cmax The geometric mean CV% was 117.3% for nano-sized formulations, but for micron-sized formulations... The result was 178.1%. Similarly, the geometric mean CV% of AUClast is for nano-sized materials. The efficacy rate was 94.7% for the formulation and 212.5% ​​for the micron-sized formulation. Statistical analysis of the effect of particle size shows that micron-sized formulations have a greater AUC (geometric mean ratio) than nano-sized formulations. (0.405, 90% confidence interval (CI): 0.215, 0.763) only 40.5% and Cmax (geometric mean ratio: 0.409, 90% CI: 0.233, 0.717) It demonstrated that a 0.9% variability was achieved in micron-sized formulations. Furthermore, significantly lower variability was observed in micron-sized formulations. It was compared to this.

[0153] Example 3: Composition of the suspension A formulation composition of a suspension of compound (A) pulverized in a wet medium is prepared by polyvinylpyrrolidone-acetic acid. Vinyl copolymer (copovidone) and sodium lauryl sulfate (SLS) are considered excipients. The increase in the concentration of the suspended drug was investigated. Several formulation compositions were examined in Table 5 and Table The evaluation was conducted as shown in section 6.

[0154] [Table 6]

[0155] The obtained experimental results were analyzed using analytical centrifugation (AC), photon correlation spectroscopy (PCS), and zeta The particle size is summarized in Table 6 below based on the electrical potential. Scanning electron microscope images of the obtained drug particles. Identified by photographs and rotational ramp-up rheology tests at 25°C. Dynamic viscosity is depicted in Figures 11 and 12.

[0156] [Table 7]

[0157] Formulation of a wet-medium pulverized suspension containing compound (A) based on a 25% w / w drug concentration Regarding the finished product, for screening experiments, the steric stabilizer and the binder (e.g., polyvinyl chloride) were used. Lupyrolidone-vinyl acetate copolymer) and surfactants (e.g., sodium lauryl sulfate) Based on the appropriate particle size and viscosity obtained for different compositions of excipients such as (m), The experiment was conducted using standardized equipment and process parameter settings for appropriate comparison. The pharmaceutical compositions investigated are shown in Table 7 below.

[0158] [Table 8]

[0159] The obtained experimental results are analyzed using analytical centrifugation (AC) and photon correlation spectroscopy (PCS). The particle size, zeta potential, and pH are summarized in Table 8 below.

[0160] [Table 9]

[0161] Scanning electron microscope images of drug particles are shown in Figures 13 and 14. Dynamic viscosity is shown in Figure 15. As shown, rotational ramp-up rheology tests were performed at 10°C, 25°C, and 40°C. The assay and density of the wet-medium-ground suspension containing compound (A) were further characterized. Each sample was characterized by HPLC and the weight method, respectively. The results are summarized in Table 9 below. Mel.

[0162] [Table 10]

[0163] Wet media suspension formulation composition F2 (25% w / w compound (A), 4% w / w copovidone) A binder and 0.1% w / w SLS surfactant are used, along with appropriate particle size data and rotation. Low dynamic viscosity across shear rates tested by lureology, at rest and at low temperatures, respectively. By comparing the particle size with and without ultrasound and low complex viscosity at various frequencies using photon correlation spectroscopy No or low signs of specific particle agglomeration, and further identified by frequency sweep tests. It was selected based on its linear behavior at low frequencies. Other formulation compositions have a higher viscosity (F 5, F6, F7 and F8) were not considered suitable for development. Furthermore, male Particle growth due to Toilede aging occurs at high sodium lauryl sulfate (SLS) concentrations (F9). It was observed.

[0164] Composition F2 has (a) quality: homogeneity, and (b) operation: handling of suspensions, spraying process. It has a low viscosity, which is advantageous for downstream processing of the suspension used into a dried product (granules).

[0165] Grinding process: Formulation composition: Compound (A): 25% w / w, Copovidone: 4% w / w, and SLS: 0.1% w / w is converted to a 6-liter batch size using the following equipment and process parameters. Expanded scale: 600 ml grinding chamber volume, zirconia grinding medium, 100 μm The diameter of the grinding medium, the grinding medium filling level in the grinding chamber at 80% v / v, and the speed of the grinding medium at 9 m / s. Thaler tip speed, suspension inlet temperature of approximately 19°C, suspension outlet temperature of approximately 23°C, process The suspension flow rate was 7 l / h during ramp-up and increased to 33 l / h after 1 hour of processing. A period of time disruption.

[0166] When the particle size of compound (A) is measured by PCS, such a process reduces the particle size to approximately The wavelength was reduced from 110nm to approximately 130nm.

[0167] Example 4: Capsule Formulation Development of suspension compositions for spray granulation and several inert substrates (carrier granules) for spray granulation After the test, the granules were filled into capsules. During the dissolution rate, capsule disintegration and the separation of carrier particles were observed. It was observed that the dispersion was not good at pH 2 (as seen in Examples 1, 2 and 3). (i) It was not possible to directly fill the capsules with carrier particles without further formulation steps. Therefore, different pharmaceutically acceptable excipients (e.g., disintegrants, fillers) were tested. The presence of the external phase was investigated by improving the poor capsule disintegration and dispersion at pH 2.

[0168] To evaluate the role of the excipients, granular particles were administered in doses of 10 mg, 20 mg, and 50 mg. In terms of quantity, compound (A) with micron-sized particle size was used as described in the above examples. It was prepared. Next, the granular particles were mixed with at least one pharmaceutically acceptable excipient, and then sizing It was encapsulated in 0-cost hard gelatin capsules.

[0169] [Table 11]

[0170] Capsule assay stability data A suspension containing compound (A) as defined herein was subjected to technical stability testing. Appearance, PC Significant changes in particle size, microscopy, and assay due to S are due to storage conditions of 40°C and 75°C relative humidity. Storage for up to 10 weeks at RH, and under storage conditions of 5°C / ambient RH and 25°C-60RH. This does not occur with storage up to 9 months. At a relative retention time (RRT) of 0.81, at 25°C and 60% humidity. Decomposition products were observed to form in samples stored at RH and 40°C_75%RH. It increased with increasing storage temperature and time (25℃_60%RH: 0 after 9 months). Up to 0.23%, 40℃_75%RH: down to 0.34% after 10 weeks). This degradation product To avoid this, store the suspension in the refrigerator. Stability results are as follows: Refrigerator (5°C / ambient) The study showed that after storage for up to 9 months, the degradation products remained unchanged at less than 0.05%. In addition to the decomposition products of 0.81 RRT, no other significant changes or increases in impurities were observed during testing. It was not observed under different storage conditions and for different storage periods: 5°C / ambient and 25°C_60%RH. After 8 weeks of storage, no microbial contamination was detected by the methyl microbial count (MET) test. Ta.

[0171] Example 5: Testing of the external phase composition The influence of formulation factors on the quality attributes of compound (A) 50 mg tablet cores was investigated. The child is determined by the filler ratio, the level and type of disintegrant, the level of lubricant, and the level and type of lubricant. there were.

[0172] For this test, a fluidized bed granulator with an upper spray configuration was selected for development. This was the procedure. For this test, a 40% w / w drug load, 20% w / w copovidone and A granular composition containing 0.2% w / w sodium lauryl sulfate was selected. The Department of Exposure (DOE) method was implemented to measure the variation on a laboratory scale (i.e., a 250g tablet batch size). The properties of the lead and tablet core were evaluated and improved. The experiment involved several variable factors (i.e., filler). As a result of the ratio, type of disintegrant, amount of disintegrant, amount of lubricant, type of lubricant and amount of lubricant The fluidity and compactibility of the formulation were screened and evaluated.

[0173] The purpose of this test is primarily to evaluate the selected granules (see granule compositions in Table 11). ) The release of compound (A) is evaluated for the above different 50% w / w external phase compositions. The test focused only on the granulation and tableting processes.

[0174] [Table 12]

[0175] The design used was based on the 6 factors (Table 12) in 12 design runs (Table 13). It was a lean design.

[0176] [Table 13]

[0177] [Table 14]

[0178] To evaluate the influence of the factors on the final blend, we assessed and compared the physical properties. (i.e., fluidity, bulk density, Kerr index, Hausner ratio). Finally, the final blend is pressed. To understand the influence of relevant factors on tablet core tensile strength, disintegration time, and dissolution rate, Ta.

[0179] Table 14 lists the response variables that were tested.

[0180] [Table 15]

[0181] Tables 14-1 and 14-2 list the detailed batch compositions.

[0182] [Table 16]

[0183] [Table 17]

[0184] [Table 18]

[0185] Such formulations were manufactured according to the following process: Manufacturing process for compound (A) wet media grinding and fluidized bed spray granulation 1. Dissolve copovidone in water while stirring. 2. Add sodium lauryl sulfate to the solution from step 1 and dissolve while stirring. 3. Add compound (A) to the solution from step 2 and suspend while stirring. 4. Wet media grinding is performed using the suspension from step 3. 5. Add the required amounts of sodium lauryl sulfate and copovidone to the additional purified water while stirring. Dissolve 6. Weigh the required amount of the wet media-ground suspension from step 4, and add the copovidone and larvae from step 5. Add the purified aqueous solution of sodium uryl sulfate to complete the suspension for spray granulation. 7. Load the mannitol SD200 carrier into the fluidized bed dryer. 8. Transfer the entire amount of the suspension for spray granulation from step 5 onto the mannitol SD200 carrier from step 7. Spray granulation is performed by spraying. The nano suspension must be stirred for 5 minutes before spraying. It is important to note that this must be done.

[0186] Manufacturing process for final blend preparation and compression of compound (A) 9. Sift the granules through a screen with a size of 0.8 mm. 10. Avicel PH102, mannitol DS, super-disintegrant (i.e., starch gum) (Sodium cholate, crospovidone, croscarmellose sodium) 0.5 mm Sift through the screen size and add to the granules in step 9. 11. Blend the mixture from step 10. 12. Sift the magnesium stearate through a 0.5 mm screen to step 11. Add to the blend 13. Blend the mixture from step 12 in a diffusion mixer. 14. Compress the blend from step 13.

[0187] [Table 19]

[0188] Evaluation of the final blend properties Final blend particle size distribution: The particle ratio on each mesh size of the CAMSIZER instrument was measured. 50% external shaping It was observed that the addition of the agent to the final blend resulted in a reduction in the amount of coarse particles.

[0189] The Pareto charts shown in Figures 16A and 16B illustrate the relative importance of each other's effects. Therefore, the following shows six major effects from the test design, plotted from highest to lowest effect. This indicates a positive effect (higher levels of a factor give a greater response than lower levels of a factor). Use the minus sign (-) for negative effects (the opposite direction). The significance line indicates which effects are statistically zero. This indicates whether they are significantly different in nature. In this case, for the final blends d10, d50, and d90 The most influential factor, in terms of significance, is the filler ratio of cellulose to mannitol. Using mannitol (low filler ratio: 0.25) results in a coarser blend in the final mix. This means that it brings about fine particles. This graph shows that several factors affect the final blend span. It also shows that it had an impact (i.e., the level and type of SD, and the filler ratio).

[0190] Final blend bulk density and tap density Bulk density and tap density were obtained from the final blend of 16 batches. Corresponding to a ratio of 0.25. Batch containing a large amount of mannitol (i.e., batches F3-06, F3-11, F3-1 2. In batches containing a large amount of MCC (Filler ratio: 0.75, F3-14 and F3-16), Batch F3-02, F3-03, F3-07, F3-08 and F3-15) are bulkier. Lower degrees and tap densities were observed.

[0191] The Pareto chart shown in Figure 17 significantly affects the final blend bulk density and tap density. The three most influential factors are: the level of lubricant, the filler ratio, and the breakdown. It is a type of destructive agent.

[0192] Final blend fluidity: Carr's index and Hausner ratio data suggest theoretical liquidity for 16 batches. The final blend behavior was characterized using a rotary powder analysis tester. This device uses a rotating drum. (Measure the changes in force, time, and energy within a diameter of 100 mm at 0.6 rpm.) This allows for the measurement of the powder's ability to flow.

[0193] Figure 18 shows that all batches are similar and have a pharmacopoeia fluidity scale (Carr's index less than 25%). This demonstrates that it has average theoretical liquidity according to the Hausner ratio (1.31).

[0194] The most influential factors in the final blender index and Hausner ratio are the filler ratio cellulose / It is mannitol. Using a large amount of mannitol results in better fluidity. It means that.

[0195] The bulk density and flow characteristics indicate that the final blend properties differ between batches. These differences are thought to be the result of changes (qualitative and quantitative) in the composition of the outer phase. The fabric (PSD) shows equivalent values. The fluidity result corresponds to a filler ratio of 0.25, which is higher. Better results with batches containing a larger amount of mannitol (e.g., F4-6, 11, 12, and 16). It represents liquidity.

[0196] Evaluation of tablet core properties The final blend of 16 types is powered by a 9mm round flat punch tool. They were compressed using a single-punch tablet press (KORSCH XP1). We tested and compared the compression behavior.

[0197] Compression profile To select the ideal compressive force and stiffness, a compressive force-stiffness profile should be used before starting the compression experiment. The experiment was conducted. For each batch, seven types of compressive forces ranging from 6kN to 15kN were evaluated. Hardness The tablet crushing force (or hardness) was evaluated using a testing machine. Furthermore, the tensile strength was assessed to evaluate the adhesion of the compacted material. It is commonly used to describe the degree. Then, the variation in hardness and tensile strength under pressure is mainly Describe it as a function of compressive force.

[0198] The compressive force-hardness profile was measured in 16 batches. Tablet hardness increased with increasing compressive force. It was observed that different compressive force-stiffness profiles were due to the external phase composition of the final blend. It is highly likely that this is due to differences (quantitative and qualitative). In fact, batch F3-15 While batch F3-14 exhibits the best compression-stiffness profile, batch F3-14 has the lowest compression-stiffness profile. This shows the profile.

[0199] To assess the significance of these results, the tensile strength was measured using the formula (see below). Draw a tensile strength profile, standardize the values, and compare batches. The compressibility is determined as shown in the following formula, and a comparison of compressibility is shown. It is described in relation to compression. It shows the same trend as the previous one.

number

[0200] The tensile strength values ​​used in the Pareto chart are derived from a tablet hardness of 90N, and the comparison was made across all batches. The 90N tablet hardness strikes a good balance between low abrasion and an acceptable disintegration time. The selection was based on the following: Pareto chart (see Figure 19) shows the types of super-disintegrants (SD) and This study demonstrates that the type of lubricant is one of two factors that significantly influence tensile strength. SSF is used as the lubricant. Furthermore, using croscarmellose sodium as a disintegrant results in higher compression. It brings about sexuality.

[0201] Extrusion Profile The force required to extrude a finished tablet is known as the extrusion force, and the sticking of the powder. It can be used to quantify the effect. This force breaks the adhesion between the tablet / die wall, thus reducing the tablet's effectiveness. The agent can be extruded. If lubrication is inadequate, the extrusion force will fluctuate, and the tablet thickness will change. It depends on the following. It is preferable that it be as low as possible or less than 500N.

[0202] During the compression cycle, the extrusion force profile was recorded for all batches. Batch F3-14 It exhibits the best press force profile (>800N) which is close to or far from the recommended value of 500N. This was observed. Other profiles were low (>200N). To increase accuracy, press The specific extrusion is calculated by dividing the output by the tablet weight and expressed in N / g. The result is the extrusion profile. They showed the same trend as File, but can be divided into three groups: • A high specific extrusion profile was recorded in batch 0033-14, which was 4000 N / g. It exhibited a higher specific extrusion. • Medium profile, 3 batches 0033-0 ranging from 700 N / g to 2500 N / g Recorded in 4, 0033-08 and 0033-16. • Low profiles were recorded in other batches where the levels were less than 600 N / g.

[0203] These differences can be explained by differences in the composition of the external phase.

[0204] The two Pareto charts (Figure 20) show that there are four main contributing factors to the push force and relative push force. This indicates the amount and type of lubricant, the ratio of fillers, and the amount of lubricant.

[0205] The amount and type of disintegrant were considered negligible. The result was that a formulation with good performance was • Use of at least 1% stearyl sodium fumarate • A small amount of lubricant (less than 1.25%) • Small amounts of mannitol (filler ratio up to 0.5) This demonstrated that...

[0206] Tablet core disintegration time (DT) The disintegration of the tablet core is related to the intrinsic gelling properties described above, compound (A) The test was conducted in HCl, 0.01N pH2, representing the worst-case medium for tablet disintegration. The decay time is represented by the maximum value of the three tablet cores (see Figure 21: maximum decay time value (9 0N).

[0207] Only batch F3-02 shows a higher decay time, exceeding 900 seconds / 15 minutes. All batches did not exceed 600 seconds / 10 minutes, but this was probably due to differences in the composition of the external phases. High variability was observed between the six factors. All six factors had a significant effect on maximum DT. It was found. However, considering the magnitude of the values, the ratio of fillers and the amount of each type of lubricant can be ignored. It is thought to be possible. The other four factors are the main influencing factors. Large amounts of crosscarmelo Sodium stearyl (up to 6%) and large amounts of sodium stearyl fumarate (up to 1%) are, This contributes to a faster tablet core disintegration time.

[0208] Table 15 below summarizes the tablet core DT values ​​based on six factors and levels. This includes the average of low and high DT, as well as the average of the central DT (all 6 batches). Therefore, The recommendation for the tablet core DT value is, - Filler ratio: Less than 0.5% - Super-disintegrant (SD) type: Sodium starch glycolate (DT: 159 seconds) or chlorofluorocarbon Skarmellose sodium (DT: 255 seconds) - Disintegrant level: over 6% - Lubricant level: Approximately 1.25 (Minimum DT with 1.25% lubricant) - Lubricant type: Sodium stearyl fumarate - Lubrication level: Less than 1% We can conclude that this is the case.

[0209] [Table 20]

[0210] Tablet core dissolution profile The dissolution rate (DR) of the tablet core containing compound (A) was determined by UV spectroscopy using an automated device. Further measurement was performed in 0.01M HCl (pH 2) at a speed of 100 rpm in the basket. It will be implemented there.

[0211] Batch F3-02 has the lowest elution profile, meaning it has the best elution profile in this batch. Decomposition time was observed. In all other batches, more than 50% of compound (A) dissolved in 30 minutes. It will be released.

[0212] The Pareto charts of tablet core dissolution rates at 15 and 30 minutes (Figure 22) show all six factors. However, it had a statistically significant effect on the tablet dissolution rate in 15 minutes, and five out of six factors This shows that it has a statistically significant effect in 30 minutes.

[0213] Based on the tablet core dissolution rate at 15 minutes and 30 minutes, the fast tablet core The recommended DR value is - Filler ratio: Less than 0.5% - Disintegrant type: Sodium starch glycolate or croscarmellose sodium - Disintegrant level: over 6% - Lubricant level: No effect on DR - Lubricant type: Sodium stearyl fumarate - Lubrication level: Less than 1% I concluded that this was the case.

[0214] [Table 21]

[0215] Conclusions of the Foreign Agent Composition Test Based on this statistical analysis, this experiment shows that the filler ratio affects the final blend and tablet core properties. It is revealed that these are the major influencing factors. High levels and types of super-disintegrants are better. It contributes to favorable disintegration time and dissolution rate. The level of lubricant has the least effect on the response. This is a significant factor. The level and type of lubricant have a considerable impact on the properties of the tablet core. The use of hydrophilic lubricants (i.e., sodium stearyl fumarate) is due to magnesium stearate. Compared to citric acid, it tends to reduce extrusion force and increase / improve decay time and elution rate. Based on the experiments conducted, Table 17 shows the amount used at 50% w / w of the total composition weight. In this case, the most promising external phase composition, which is the optimal external phase for the formulation of compound (A), is indicated. vinegar. -Filler ratio: Based on a good balance between high dissolution rate and low decay time, 0.5 Select -Type and level of super-disintegrant: Sodium starch glycolate and croscarmellose thorium - A minimum of 6% disintegrant is required. - The lubricant level has the least effect on the tablet properties and can be used optionally, for example, in an amount of 1%. Cut. - Lubricant type: Sodium stearyl fumarate exhibits good DT and DR. - A minimum lubrication level of 1% is required for better compression performance.

[0216] [Table 22]

[0217] Example 6: Further testing of the external phase (amount) The external phase test in Example 5 was limited to compositions containing the external phase in an amount of 50% w / w. To further understand the amount of external phase needed to solve the gelation problem, the amount of external phase is 24%~5 Change to 0%, and then several more trials with different types of disintegrants and microcrystalline cellulose and ma This was done by observing the variation in the filler material due to nitrol. It was found that the lubricant was optional. No lubricant was used in these trials.

[0218] The tablet dosage forms are as shown in Table 18, formulations T1 and 25 containing 20% ​​w / w compound (A). Developed using formulation T2 containing compound (A) at %w / w concentration. Mix the child with at least one pharmaceutically acceptable excipient in the same manner as in a capsule formulation. Based on this, the tablet formulations shown in Table 18 were prepared.

[0219] [Table 23]

[0220] As mentioned in this application, the problem with formulations containing compound (A) is that compound (A) is present at a pH of 2 or lower. It has its own unique gelation behavior. This gelation behavior occurs when the formulation (e.g., a tablet) disintegrates. This has an influence, and therefore the decay time is affected by the standard test in water and also by pH=2. The measurement was performed in hydrochloric acid.

[0221] All tested formulations in Table 18 exhibited good disintegration behavior in water, but differences were not observed at pH=2. It was determined. The fastest decay time in both media was observed with 50% of the pharmaceutically acceptable excipient in the external phase. This was achieved. Another factor in rapid decay is (a) compound (A) added to the inert substrate It was found that the selection of quantity and type of disintegrant was crucial. , 1-ethenyl-2-pyrrolidine homopolymer (commercially known as crospovidone - CAS 9003-39-8) and croscarmellose sodium disintegrate most rapidly at pH=2. The interval was achieved. A pharmaceutically acceptable excipient in an amount of 40% w / w in the external phase and 20 in the granules The combination of compound (A) with %w / w yielded the best performance with the most effective disintegrant, and remained unchanged at pH 2 for 15 minutes. It was the moment of complete collapse.

[0222] They concluded that a foreign minister with a minimum of 40% w / w is preferable.

[0223] Finally, in order to gain knowledge of chemical and physical stability, the two variants were subjected to a short stability test. The program was selected. Both variants were delivered as film-coated tablets. Compound (A)-F12-01 has the same composition as compound (A)-F10-04. Compound (A)-F12-02 has the same composition as compound (A)-F10-07.

[0224] [Table 24]

[0225] Table 19 can be described as indicating that the formulation containing the above-mentioned compound (A) is very stable, and the active pharmaceutical ingredient No incompatibility was observed between the formulation composition and the water absorption during storage (existing hygroscopic excipients). Even the predicted results did not yield any observations during the visual inspection.

[0226] Example 7: Quantitative and qualitative testing of granules Experiments were conducted to investigate the quantitative and qualitative composition of granules. Four factors were selected for evaluation. These are then listed in Table 20.

[0227] [Table 25]

[0228] Excipients are based on the amount of solid to be sprayed onto the carrier surface to form a matrix. The granular composition is defined by the ratio. Then, the excipient level is defined by the following formula: Excipient level = drug load × excipient ratio.

[0229] As shown in Table 21, the quadratic polynomial model (2 4-1 Some implementation factors We will conduct experiments using ) and perform a total of 12 experiments.

[0230] [Table 26]

[0231] The four iterative center points were tested for all four major effects and three confounded pairs of binary interactions. Used as experimental error for testing. Influence of the factor on the resulting granules and final blend. To evaluate this, we evaluated and compared each physical property (i.e., fluidity, bulk density, etc.). - index, Hausner ratio). Finally, the final blend is compressed to determine the tablet core tensile strength and collapse. We understood the influence of each factor on decay time and dissolution rate.

[0232] The response variable is the observed response in the experiment that results from the induced changes in the process / formulation variable. Table 22 lists the response variables that were tested.

[0233] [Table 27]

[0234] Twelve tablet core batches were prepared according to the proposed experimental design. Table 23-1 and Tables 23-2 and 23-3 show 12 batch sets with a granule batch size of approximately 250g. This represents the summary of the finished product. The manufacturing process was as described in Example 6.

[0235] [Table 28]

[0236] [Table 29]

[0237] [Table 30]

[0238] Granule scanning electron microscopy (SEM) The granules were visualized and analyzed in terms of their shape, surface morphology, and roughness.

[0239] Batch containing copovidone ratios up to 0.5 (F6-01-04-05-08 and 4 of the four batches) The core point (F6-09-10-11-12) consists of coarser particles with a d50 of over 250 μm. This was observed. Clusters between granules can be seen in the SEM images. Figures 23A and 23B The rate chart summarizes various effects. The level of copovidone corresponds to the granular PSD (particle size). It has been shown to significantly affect the distribution. Large amounts of copovidone produce coarser granular particles. To drip.

[0240] Granule bulk density and tap density Bulk density and tap density data were obtained from sieved granules from 12 batches measured in Example 6. It was obtained from grains.

[0241] The bulk density and tap density of a batch containing a small amount of copovidone (i.e., F6-02-0 Higher levels were observed in 3-06-07). The Pareto diagram shown in Figure 24 is a granular structure. The most influential factor significantly affecting occlusion density is copovidone (0.50 g / ml~0. It was shown to be 57 g / ml.

[0242] Granule flow characteristics (granule Kerr index and Hausner ratio) The granular Kerr exponents and Hausner ratio data suggest theoretical liquidity for 12 batches. Figure 25 shows that all batches are similar and the pharmacopoeia fluidity scale (Carr's index 15%) is not met. It demonstrates good / excellent theoretical liquidity according to the full and Hausner ratio (less than 1.18). vinegar.

[0243] Granule fluidity The granular behavior was characterized using a rotary powder analysis tester. This device uses a rotating drum (0. By measuring the changes in force, time, and energy within a diameter of 100 mm at 6 rpm, The ability of the powder to flow can be measured. The results of the avalanche median (2.2 seconds to 3.0 seconds) and avalanche... The angle results (37°~42°) indicate average / good fluidity for all 12 granule batches. All snow The results for collapse force (<18cch) and surface linearity (≧0.99%) indicate good fluidity. show.

[0244] The Pareto chart in Figure 26 shows that copovidone has a significant effect on granule fluidity. In the test, high levels of copovidone resulted in better flow behavior of coarser particles and granules. To drip.

[0245] Granule assay and resuspension Table 24 lists the granule assay and granule resuspension properties for 12 batches. 95±2% of the active pharmaceutical ingredient Measurements were taken for all granules. No corrections were applied during spray granulation.

[0246] The granules were made reconstituted / resuspended using PSD with photon correlation spectroscopy (PCS). Photon correlation spectroscopy (PCS) is used to separate particles ranging from less than 5 nm to several microns in size. This technique operates on the principle that particles move randomly in a gas or liquid. The particle size of the active pharmaceutical ingredient during wet media grinding before dilution for atomization is 123 nm.

[0247] [Table 31]

[0248] The results indicate that copovidone and SLS have a significant effect on granule resuspension.

[0249] Granule compression behavior The compression behavior of 12 different granule batches was characterized to gain knowledge about the products. Therefore, the granules were processed using an auxiliary powered single punch tablet press (Styl'One) It was compressed using a 1.28mm round flat punch tool.

[0250] Granular compressibility: Compressibility is the ability of a powder to deform under pressure. During powder densification, the powder bed... The porosity decreases. Higher density is tested by monitoring porosity under load. To determine tablet porosity, measure the dimensions (i.e., thickness, diameter), weight, and density of the tablet. Therefore, calculations are performed after extrusion. It was observed that porosity decreases with higher compressive forces. All batches exhibit less than 8% porosity at a compression force of 25 MPa. The four central points are different from the others. It exhibited the best porosity profile compared to the batch.

[0251] Granular tablet properties: Tablet properties refer to the ability to form a mechanically strong compacted body. Compression force - hardness Perform different tests such as file and tensile strength profiles. Compressive force-hardness profile The test was performed on each batch. Five types of compressive forces ranging from 5kN to 45kN were evaluated. Hardness testing machine The tablet crushing force (or hardness) was evaluated using [a specific method]. Tensile strength is typically measured in the compacted material. It is used to describe the degree of adhesion. Then, the changes in hardness and tensile strength under pressure are described. Express it as a function of the principal compressive force.

[0252] It was observed that tablet hardness increased with increasing compressive force. Different compression behaviors were observed between batches. This was observed, and variability was low at each compression force. Batch F6-01 was observed at compression forces of 25kN or more. It exhibits decreasing hardness. The three types of granules F6-05, 07, and 09 plateau at 25kN or higher. This shows that the four center points exhibited the lowest and most similar compressive force-stiffness profiles. The force-hardness profile is likely, as predicted, related to differences in the granular phase composition. To assess the significance of these results, we plotted tensile strength profiles and standardized the values. Compare between batches. All granules have high tabletability and the same compressibility-hardness profile. It showed a tendency.

[0253] The tensile strength values ​​adopted from the following Pareto chart are derived from tablets compressed with 25-30 kN. It is coming. The Pareto chart (Figure 27) shows the levels of copovidone, SLS and mannitol, This shows that there are three factors that significantly affect tensile strength. A large amount of copovide in the granular composition. The absence of small amounts of SLS and mannitol results in better tablet compressibility.

[0254] Granule compressibility: It was observed that the tensile strength of compacted granules decreased with increasing porosity. The compacted material is 20% porous and exhibits a tensile strength of approximately 2 MPa, so a similar compaction profile... Ill was observed in the entire granule batch.

[0255] Granule extrusion profile: Extrusion force profile was recorded for all batches during the compression cycle. To increase accuracy, the specific force is calculated by dividing the extrusion force by the tablet weight, and the result is N / g This is represented by [this symbol]. Figure 28 shows the various influencing factors of the granular composition on the specific extrusion profile.

[0256] Evaluation of the final blend properties The characteristics of 12 final blends were identified, and the results are summarized in Tables 25-1 and 25-2. Further details are provided in the following subsections.

[0257] [Table 32]

[0258] [Table 33]

[0259] Final blend particle size Final blend particle size distribution As shown in the table above, the addition of 50% external excipients to the granules reduces the amount of coarse particles. I woke him up.

[0260] The Pareto charts shown in Figures 29A and 29B show that the copovidone level is in the final blend d5. This indicates that it is the most influential factor for fine powder particles smaller than 0, d90, and 125 μm. A tendency is observed in granules: large amounts of copovidone result in coarser particles. On the other hand, low copovidone Povidone significantly produces a large amount of fine powder.

[0261] Final blend bulk density and tap density According to the summary table above, bulk density and tap density are similar across batches.

[0262] Carr exponents and Hausner ratios: Carr exponents and Hausner ratio data are calculated in 12 batches. This suggests logical fluidity. Figure 30 shows that all batches are similar, and the pharmacopoeial fluidity scale... This demonstrates theoretical liquidity according to the rules. Batch F7-08 shows excellent liquidity.

[0263] Final blend fluidity The final blend behavior was characterized using a rotary powder analysis tester. This device uses a rotary drive Within a 100mm diameter area (at 0.6 rpm), we measure changes in force, time, and energy. This allows for the measurement of the powder's ability to flow. Avalanche median time (1.7 seconds to 3.1 seconds) results. The avalanche angle results (38°~48°) indicate average / good fluidity for FB. All snow The collapse force results (<18cch) and surface linearity results (>0.99%) indicate good fluidity.

[0264] The Pareto chart in Figure 31 shows that drug loading significantly affects the final blend fluidity.

[0265] Final blend flow-to-congeal separation prediction Coagulation or segregation occurs due to differences in physical properties (size, shape, density, etc.) of granular mixtures. This involves the separation of these components. There are several driving forces or mechanisms that can cause coagulation. Industrial odor The most common mechanisms are sieving, fluidization, and dispersal. Furthermore, the material particle size distribution (PSD) must have the same distribution. For example, granules and excipients. The big difference between PSD and other materials is that PSD can physically separate the mixture and cause coagulation. Larger particles are dragged down by gravity at the bottom, while finer particles are positioned at the top of the blend. Depending on the powder behavior, the opposite can happen: coarser particles may be at the top and finer particles at the bottom. The mixture may be clearly separated. The outer phase composition is approximately 50% w / w of the tablet weight. (The majority of the amount is filled with two types of fillers: Avicel PH102 and mannitol DC). The large amount of external phase, due to differences in particle size, can potentially lead to separation between components.

[0266] Two methods were used to predict potential coagulation phenomena: 1. Comparison of particle size distribution between materials (i.e., granules, final blend, and each excipient) 2. Sieving and coagulation using different screen sieves.

[0267] Particle size distribution comparison method: This test was conducted on each final blend, granules, and external excipient (i.e., Avicel PH10 2. Compare the particle size distribution of mannitol DC and croscarmellose sodium. The objective is to achieve this. Differences in particle size between the internal phase (i.e., granules) and the external phase can cause coagulation. At that time, the granular PSD shifts to the right, corresponding to the coarser particles, while the external phase excipient (i.e.) It is observed that MCC and mannitol shift to the left, corresponding to finer particles. An ideal blend that can limit the coagulation phenomenon should have a similar PSD curve. From this perspective, batch F7-06 has the optimal PSD. Batch F7-05 has high concentration. It shows a tendency to diverge.

[0268] Sieving and condensation method: For the sieving coagulation method, stress is applied to the powder and vibrated (amplitude 1.0 mm, 5 mins) To coagulate, the powder mixture is added to the column of the screen sieve. The fine particles settle at the bottom. The mixture is divided into four fractions corresponding to the relevant screen sieves at the top of the apparatus, where the particles are located. The particles are forcibly separated. Then, the distribution of the API across the entire particle size fraction is evaluated. To do this, the API content is measured for each fraction. Finally, the standard deviation is calculated for the mixture. Determines the potential condensation of an object. A high standard deviation results in high potential condensation. F6-01 , three granule batches F6-08 and F6-11 and their corresponding final blend F7 Only -01, F7-08, and F7-11 were evaluated.

[0269] Table 26 summarizes the active pharmaceutical ingredient content measured in each fraction. The RSD values ​​are compared between batches. It is used as a criterion for comparing the coagulation. Since API is part of the granules, it exists in the outer phase. Not present. The highest API content, measured from the top of the can, exhibits a coarser fractionation. This may relate to the granules. The active pharmaceutical ingredient is homogeneously distributed within the granules with respect to each fraction, while the final The blend has a high RSD value (i.e., 63% to 82% RSD) and higher coagulation. It was observed that this suggests potential. Batch F6-01 shows the best RSD. This batch As can be seen from the large difference in PSD between the granules and the outer phase, there is a tendency for high coagulation. (Figure 32). Therefore, the external phase level has a significant impact on the uniformity of the drug content. We can conclude that a good balance between the level of the external phase and an appropriate granule size distribution is Therefore, coagulation is unlikely to occur.

[0270] [Table 34]

[0271] Final blend compression behavior The 12 final blends were then compressed using a standard 11.28mm round flatbread. Single-punch tablet press with auxiliary power (Compaction Simulator S) They were compressed using 'One Evolution'. Their compression behavior is related to this. We conducted tests and compared the results.

[0272] Final blend compressibility: Compressibility is the ability of a powder to deform under pressure. (During powder densification) The porosity of the powder bed decreases. Higher density allows monitoring of porosity under load. Tablet porosity can be tested by the following: the dimensions (i.e., thickness, diameter), weight, and density of the tablet. The porosity decreases with increasing compressive force. This was observed. All final blend batches exhibited similar porosity profiles.

[0273] Final blend tablet properties Tabletability is the ability to form a mechanically strong compressed body. Tabletability (i.e., compressive force-hardness) Various tests were conducted to examine the profile and tensile strength profile.

[0274] Compression force-stiffness profiles were performed for each batch. Five types of compression forces were used, ranging from 5kN to 45kN. The tablets were evaluated. A hardness tester was used to assess the tablet crushing strength (or hardness). The tensile strength was: It is commonly used to describe the degree of adhesion of a compacted material. Subsequently, it describes the hardness and tensile strength under pressure. The variation is described as a function of the principal compressive force. An increase in compressive force results in a higher tablet hardness. This was observed. Different compression behaviors were observed between batches, and the variability was low. Batch F 7-01 exhibits a decrease in hardness under compressive forces of 25kN or more. The granules of F7-06 are the best hit The tablet profile is shown, with batches F7-01 and F7-04 having the lowest tablet profile. This indicates that, compared to the granular tableting profile, the decrease in hardness or the tendency towards a plateau is in the final variation. It was not observed at all in the band. It was concluded that the external excipients have a positive effect on this property. The tensile strength profile was recorded to enable tableting comparison. All tensile strength profiles use tensile strength to provide more accurate values ​​for compressive strength-stiffness. The results showed similar trends compared to the profile.

[0275] The tensile strength values ​​used in the following Pareto chart are derived from tablets compressed with 20 kN. The Pareto chart (Figure 33) shows no factors that have a significant effect on the final blend tensile strength. This indicates that.

[0276] Final blend extrusion profile: The extrusion force profile is used for all batches during the compression cycle. Records were made regarding the force. To increase accuracy, the specific force was calculated by dividing the extrusion force by the weight of the tablet. The value is calculated and expressed in N / g. The Pareto chart (Figure 34) shows the main contributing factors to the relative pressure output. This indicates the level of copovidone. Large amounts of copovidone result in low relative force.

[0277] Evaluation of tablet core properties at tablet hardnesses of 90N and 120N using appropriate punching. Punching tool Table 27 shows different tablet weights (i.e., 25%, 35%, and 40% combined with 50% external phase). Used with a 50 mg dose intensity, which has three different drug loads resulting in a 1% granular drug load. I compiled a list of tablet punching tools.

[0278] [Table 35]

[0279] Tablet core pressing force Table 28 shows the recorded extrusion force values ​​for tablet cores manufactured at 90N and 120N. For all batches of both hardness levels, the extrusion force is compared to the recommended value of 500N. This indicates a much lower level.

[0280] [Table 36]

[0281] Tablet core disintegration time The disintegration of the tablet core was controlled by HCl, 0 for both tablet core hardness levels (90N and 120N). The experiment was conducted in 0.01N pH2 water. For the 120N tablet core, the disintegration time in water was also measured. The decay time value was expressed as the maximum value of the three tablet cores (see Table 29). Only the Chi-F7-07 exhibited a higher decay time (DT) exceeding 900 seconds / 15 minutes. All other batches did not exceed 480 seconds / 8 minutes. In batch F7-07, DT was Compared to tablets with higher hardness, tablets with lower hardness had only a quarter of the hardness.

[0282] [Table 37]

[0283] As shown in Figure 35 of the Pareto chart, all factors are in the tablet core DT manufactured at 90N. This has a significant impact, and significantly affects tablet core DT with higher tablet hardness at 120N. There are no other contributing factors. The two main influencing factors are the amount of copovidone and the drug load. The high dose of copovidone and the high drug load result in a higher DT (Drug Degree) with a tablet core hardness of 90N. The hardness of the tablet appears to have a significant impact on the drug dose (DT). Figure 36 shows the binary representation for a 90N tablet core. It shows interaction. It is because the use of high copovidone and mannitol in spray suspension is This indicates that it will result in a long collapse time.

[0284] Tablet core dissolution profile Dissolution rate of tablet cores containing compound (A) having tablet hardness of 90N and 120N, respectively. The pH was measured using UV spectroscopy with an automated device, with a paddle at 50 rpm at pH 3 and 0.0. The procedure is performed in a basket at a speed of 100 rpm in 1M HCl pH2 (conventional dissolution test). Method: European Pharmacopoeia 2.9.3 "Dissolution Test for Solid Dosage Forms" or United States Pharmacopoeia <711> "Elution (or basket method according to the Japanese Pharmacopoeia <6.10> "Dissolution Test").

[0285] Dissolution profiles of 90N and 120N tablet cores in a basket at a speed of 100 rpm ( pH2) Except for batch F7-07, which has a higher RSD value of up to 5%, all batches have low variability. Observed in (RSD < 5%). Four center point batches (i.e., F7-09-10-1) Samples 1-12) were reproducible and exhibited similar elution profiles.

[0286] Three batches with a hardness of 90N: F7-01, F7-05, and F7-07 are 0.01M The lowest elution profile was observed using a basket at a speed of 100 rpm in HCl pH2. This finding is supported by the best decay times observed in these batches. In one batch, over 80% of compound (A) dissolved in 30 minutes, but 100% dissolved in 60 minutes. It did not reach that point. Between 60 and 75 minutes, the basket speed was increased from 100 rpm to 200 rpm. It was increased to [a certain value].

[0287] For tablet core assays, standardized tablet core dissolution rates at 15 and 30 minutes were obtained. Chart (Figures 37A and 37B): Figure 37A chart at 90N, Figure 37B chart at 120N This indicates that the main significant contributing factors are drug load and SLS amount. To achieve this goal, a low drug load and a large amount of sodium lauryl sulfate are recommended. This is a combination. Figure 38 shows that low drug load and low copovidone in a basket of 100. A binary interaction that demonstrates a high dissolution rate for 90N tablet cores, as measured by the rpm method. A Pareto chart is shown.

[0288] Dissolution profile of a 120N tablet core in a paddle at a speed of 50 rpm (pH3) As already mentioned, the active pharmaceutical ingredient (compound (A)) is a Class 2 compound in the biopharmaceutical classification system. It is present, a weak base, and exhibits a strongly pH-dependent solubility (3 mg / mL and p at pH 1.2). (0.003 mg / mL at H3). Dissolution rate of 120N tablet core at pH3, 50 rpm. The evaluation was performed using a paddle at a certain speed in 0.001 M HCl pH 3 (900 mL). High variability was observed in all batches (RSD < 5%).

[0289] The Pareto chart (Figure 37) shows the 120N tablet core dissolution rates at 15 and 30 minutes. Although only slight differences are observed between the taps, the Pareto diagram shows that at pH 3, the paddle is 50 rp. The results of the study (m) indicate that all four factors have a significant effect on the elution rate at 15 minutes. In 30 minutes, the primary influencing factor is the amount of SLS.

[0290] Conclusions from all experiments on the qualitative and quantitative composition of granules The ratio of excipients from the granular composition is the ratio of solids to be sprayed onto the carrier to form a matrix. It was based on the amount of (i.e., copovidone, sodium lauryl sulfate, mannitol and (Drug load). The external composition is considered to be in a good amount for tablet disintegration, dispersion, and associated dissolution rates. As such, these experiments will be fixed at 50%.

[0291] Granules, final blend (i.e., fluidity, density, particle size distribution) and tablet core (i.e., compaction) The properties (disintegration time, dissolution rate, etc.) were evaluated. Tables 30-1 and 30-2 show the granules and final form. This summarizes the major influencing factors that are statistically significant to the blend and tablet core responses. be.

[0292] [Table 38]

[0293] [Table 39]

[0294] [Table 40]

[0295] Based on statistical analysis, this experiment was found to be related to the ratio of copovidone, sodium lauryl sulfate, and the drug The study revealed that load is a major factor influencing the properties of granules, the final blend, and the tablet core. Mannitol has little effect on the response. High levels of copovidone cause coarse granules. It results in particles and low fine powder. High levels of sodium lauryl sulfate and low drug load are This contributes to a faster dissolution rate. In all batches, the final blend fluidity is acceptable. The final blend exhibited good tablet properties in terms of tensile strength and low compressibility.

[0296] Based on the above experiments, select the following granular composition (Table 31)). • Crospovidone ratio: A moderate ratio of 0.5, resulting in less fine powder, lower extrusion force, and faster tablet formation. A good compromise is found regarding granule size with DT and DR. • Sodium lauryl sulfate: Higher specific level of 0.04, required for high elution rate be • Mannitol SD200 ratio (from spray suspension): The presence of mannitol is in granules, final b It has little effect on the physical properties of the blend and tablets. From granular compositions for development, mannitol We decided to remove the 'ru'. • Drug load: Lower ratio levels (less than 35%) contribute to a faster dissolution rate.

[0297] [Table 41]

[0298] Example 8: Film-coated tablets Using all the optimized parameters obtained from the experiments in the previous example, the following F The film-coated formulation was prepared as the optimal variant and a good compromise between all variables. Ta.

[0299] Compound (A) spray suspension Process diagram

[0300] [Table 42]

[0301] [Table 43]

[0302] Manufacturing formula

[0303] [Table 44]

[0304] Composition of the final product

[0305] [Table 45]

[0306] Example 9: Manufacturing The final blend of capsules and tablets is prepared using a procedure similar to that described in the flowchart above. Therefore, it was prepared. a. Add a binder, such as polyvinylpyrrolidone-vinyl acetate copolymer, to water while stirring. Dissolve. b. Add a surfactant, such as sodium lauryl sulfate (SLS), to the solution from step a and stir. Dissolve while doing so. c. Add compound (A) to the solution from step b and suspend it while stirring. d. Using the suspension from step c, grinding is carried out, for example, wet media grinding. e. Add the required amount of SLS and polyvinylpyrrolidone-vinyl acetate copolymer while stirring. Then, dissolve it in additional purified water. f. Weigh the required amount of suspension from step d, add it to the solution from step e, and spray, for example, spray granulation. Complete the suspension for that purpose. g. Load an inert substrate (carrier particle), such as mannitol SD. h. Spray the suspension from step e onto the inert substrate from step g, for example, mannitol SD200. This allows for spraying, such as spray granulation. i. The granular particles of step h are given some pharmaceutically acceptable excipient, for example, mannitol. DS, sodium starch glycolate, polyvinylpyrrolidone-vinyl acetate copolymer It was then further mixed with croscarmellose sodium. j. The blend mixture from step i was introduced into a capsule or compressed to form a tablet.

[0307] Process flow diagram

[0308] [Table 46]

[0309] Example 10: Stability Experiment Stability data of the capsule in Example 4 Stability data up to 24 months for Example 4 (10 mg, 25 mg, and 50 mg) Stability Program: The stability program includes aluminum induction seals and child-resistant screws. - Rectangular high-density polyethylene bottle with cap fastener (175ml, 30 capsules) Hard gelatin capsules of Example 4 (10 mg, 25 mg, and 50 mg) packaged inside (L) g) was tested under the following storage conditions: 5℃ / ambient RH; 25℃ / 60%RH; 30℃ / 75%RH; 40℃ / 75%RH and 5 0℃ / 75%RH (RH relative humidity).

[0310] Lightstability test: The photostability test is called "Photostability Test of New Active Pharmaceutical Ingredients and New Formulations (Photostabilitation Test)" y testing of new active substances and m In accordance with the ICH guidelines [ICH Q1B] for "edicinal products" Therefore, using ICH Q1B option 2 as the light source, the hard gelatin of Example 4 The test was conducted on capsules (10 mg, 25 mg, and 50 mg) together with the unpackaged product. Samples exposed to light were tested in parallel with samples protected from light, to be used as a control.

[0311] The photostable sample load is at least 200 watts at a total illuminance of at least 1.2 million lux. The energy was near ultraviolet at 1 / hour / square meter.

[0312] Open bottle: This test was performed on the hard gelatin capsules of Example 4 stored in an open glass dish. The procedure was carried out as follows. The samples were stored at 25°C / 60%RH for up to one month. After that, the chemistry of the samples was... The target and physical properties were analyzed.

[0313] Freeze-thaw cycle: This test involves aluminum induction seals and child-resistant screw caps. Square high-density polyethylene (HDPE) bottle with fastener (175ml, 30 bottles) Hard gelatin capsules of Example 4 (10 mg, 25 mg and 5 mg) packaged inside the capsule The test was performed using 0 mg. Stability samples were subjected to four complete freeze-thaw cycles (-20°C / week). The samples were stored in ambient RH for 6 days, followed by 1 day at 25°C / 60%RH. Samples were collected 28 days later and their chemical and physical properties were analyzed.

[0314] Test method: The following tests will be conducted as described in the table below.

[0315] [Table 47]

[0316] Stability results of hard gelatin capsules The hard gelatin capsules (10mg, 25mg, and 50mg) in HDPE bottles are Store at 5°C / ambient RH, 25°C / 60% RH, or 30°C / 75% RH for up to 24 months. When subjected to this condition, it exhibited good physical and chemical stability. Significant changes in chemical and physical properties were not observed. No transformation was observed at all.

[0317] The hard gelatin capsules (10mg, 25mg, and 50mg) in HDPE bottles are When stored at 40°C / 75%RH for up to 6 months, it exhibits good physical and chemical stability. No significant changes in chemical or physical properties were observed.

[0318] The hard gelatin capsules (10mg, 25mg, and 50mg) in HDPE bottles are When stored at 50°C / 75%RH for up to one month, it exhibits good physical and chemical stability. No significant changes in chemical or physical properties were observed.

[0319] Hard gelatin capsules (10mg, 25mg, and 50mg) in HDPE bottles are exposed to light. The stable samples exhibited good physical and chemical stability.

[0320] Freezing of hard gelatin capsules (10mg, 25mg, and 50mg) in HDPE bottles The fusion-cycled samples showed good physical and chemical stability.

[0321] Opening of hard gelatin capsules (10mg, 25mg, and 50mg) in HDPE bottles The samples in the dispensing test showed good physical and chemical stability.

[0322] Stability data for the film-coated tablet (50 mg) of Example 8 Stability Program: The stability program covers up to 18 months under the following storage conditions, including aluminum induction seals and chips. Square high-density polyethylene container with gyrated-resistant screw cap fasteners. The film-coated tablets of Example 8 packaged in a bottle (175 ml, 30 capsules) (10 The following were tested: 25, 50, and 100 mg: 5℃ / ambient RH; 25℃ / 60%RH; 25℃ / 60%RH open; 30℃ / 75%RH; 30℃ / 75%RH (open); 40℃ / 75%RH and 50℃ / 75%RH (RH relative humidity) .

[0323] Photostability tests and freeze-thaw cycle tests were conducted on the capsules in accordance with the tests described above. It was implemented.

[0324] The testing method for the capsules shall be carried out as described above.

[0325] Stability test results: The film-coated tablets of Example 8 (10, 25, 50, and 100 mg) were prepared at 5°C / ambient RH. When stored at 25°C / 60%RH and 30°C / 75%RH, it will maintain its good condition for up to 18 months. It demonstrated scientific and physical stability.

[0326] Chemical (assay and degradation products) and physical (appearance, thickness, diameter, elution rate, water content) No significant changes in properties were observed.

[0327] The film-coated tablets of Example 8 (10, 25, 50, and 100 mg) were tested at 40°C / 75%. When stored in HDPE bottles under RH conditions, it maintains good chemical and physical stability for up to 6 months. The results were shown. After storage in an HDPE bottle at 40°C / 75%RH, the initial value (150.1nm) and In comparison, a slight increase in particle size was observed in the 10 mg and 25 mg tablets (177.6 nm). This slight increase is not expected to have any significant impact.

[0328] The film-coated tablets of Example 8 (10, 25, 50, and 100 mg) were tested at 50°C / 75%. When stored in an HDME bottle, it maintains good chemical and physical stability for up to 1.5 months. This was shown, in addition to the particle size of the 10 mg clinical batch, chemical (assay and degradation products) and physical No significant changes were observed in the properties (appearance, thickness, diameter, dissolution rate, water content). 5 After being stored in an HDPE bottle at 0℃ / 75%RH for 1.5 months, the 10mg tablet had a slightly different particle size. A significant increase is observed (from 150.5 nm at the initial point to 196.0 nm). However, this No impact is predicted due to the slight increase.

[0329] The film-coated tablets of Example 8 (10, 25, 50, and 100 mg) were stored at 25°C / 60%. And, when stored in an open HDME bottle at 30°C / 75%, it will remain in good condition for up to 3 months. Chemical and physical stability was demonstrated. Chemical (assay and degradation products) and physical (appearance) stability were observed. There are no significant changes in properties (thickness, diameter, dissolution rate, water content). For 100mg tablets, 30 After 3 months of storage in an open HDME bottle at 75% °C, a slight increase in the elution rate was observed. Observed (105%). A slight increase in particle size compared to the initial value at 30°C / 75%RH. Observed in tablets stored for 3 months in open HDPE bottles. In 10 mg tablets, The particle size increased from 150.5 nm to 201.1 nm, but in the 25 mg tablet, the particle size was 15 The particle size increased from 0.1 nm to 181.4 nm. Similarly, in a 50 mg tablet, the particle size was 148 It shows an increase from 0.9nm to 178.7nm, and in a 100mg tablet, the particle size is 140.7nm. The wavelength increased from m to 177.0 nm. This slight increase is not expected to have any significant impact.

[0330] Photostability of film-coated tablets (10, 25, 50, and 100 mg) in HDPE bottles The sample showed good physical and chemical stability. Chemical (assay and degradation products) and There are no significant changes in physical properties (appearance, thickness, diameter, dissolution rate, water content, particle size). Light has absolutely no effect on the stability of Lumcort tablets.

[0331] Freeze-thaw cycle of film-coated tablets (10, 25, 50, and 100 mg) in HDPE bottles The cyclic samples exhibited good physical and chemical stability.

[0332] The stability of the crystal morphology was evaluated using XRPD: The fruits were stored for 9 months at 5°C / ambient RH, 25°C / 60%RH, and 30°C / 75%RH. Observed in the film-coated tablets (10 mg, 25 mg, 50 mg, and 100 mg) of Example 8. There was no change in the XRPD pattern. International Publication No. 2020 / 234779 pamphlet The crystal form (A) described in the diagram remains stable under these conditions. No conversion was observed.

Claims

1. A pharmaceutical composition for oral administration comprising granular particles, wherein the granular particles are (a) an inert substrate selected from lactose, mannitol, or a mixture thereof, (b) A mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, a binder which is polyvinylpyrrolidone-vinyl acetate copolymer, and a surfactant which is sodium lauryl sulfate. Includes, A pharmaceutical composition in which the weight ratio between N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and polyvinylpyrrolidone-vinyl acetate copolymer is in the range of [3:1] to [1:3].

2. The pharmaceutical composition according to claim 1, wherein N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is in a free form.

3. The pharmaceutical composition according to claim 1 or 2, wherein the mixture (b) and an optional surfactant are layered on the inert substrate (a).

4. The pharmaceutical composition according to claim 3, wherein the mixture (b) and an optional surfactant are layered on the inert substrate (a) using a spray granulation method.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the weight ratio between N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form and polyvinylpyrrolidone-vinyl acetate copolymer is [3:1], [2:1], or [1:1], or [1:2], or [1:3].

6. The pharmaceutical composition according to claim 5, wherein the weight ratio of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form to polyvinylpyrrolidone-vinyl acetate copolymer is [1:1] or [2:1].

7. The weight ratio of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, polyvinylpyrrolidone-vinyl acetate copolymer, and sodium lauryl sulfate is [3:1:1], or [3:1:0.5], or [3:1:0.1], or [2:1: The pharmaceutical composition according to any one of claims 1 to 6, wherein the ratio is [1], or [2:1:0.5], or [2:1:0.1], or [2:1:0.08], or [2:1:0.05], or [2:1:0.04], or [2:1:0.03], or [2:1:0.02], or [1:1:0.5], or [1:1:0.1], or [1:1:0.07], or [1:1:0.05], or [1:1:0.04], or [1:1:0.02].

8. The pharmaceutical composition according to claim 7, wherein the weight ratio of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, polyvinylpyrrolidone-vinyl acetate copolymer, and sodium lauryl sulfate is [2:1:1], or [2:1:0.08], or [2:1:0.5], or [2:1:0.1], or [2:1:0.05], or [2:1:0.04], or [2:1:0.03], or [2:1:0.02].

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein polyvinylpyrrolidone-vinyl acetate copolymer is present in the mixture (b) in an amount of 25% w / w to 100% w / w based on the weight of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form.

10. The pharmaceutical composition according to claim 9, wherein polyvinylpyrrolidone-vinyl acetate copolymer is present in the mixture (b) in an amount of 50% w / w or 100% w / w based on the weight of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein sodium lauryl sulfate is present in the mixture of (b) in an amount of 1% w / w to 10% w / w based on the weight of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form.

12. The pharmaceutical composition according to claim 11, wherein sodium lauryl sulfate is present in the mixture of (b) in an amount of 4% w / w or 5% w / w based on the weight of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form is less than 500 nm.

14. The pharmaceutical composition according to claim 13, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form is less than 250 nm.

15. The pharmaceutical composition according to claim 13, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, as measured by photon correlation spectroscopy, is 100 nm to 350 nm.

16. A pharmaceutical composition according to any one of claims 1 to 15, further comprising an external phase, wherein the external phase comprises one or more pharmaceutically acceptable excipients.

17. The pharmaceutical composition according to claim 16, wherein the one or more pharmaceutically acceptable excipients are selected from fillers, disintegrants, lubricants, and slicks.

18. The pharmaceutical composition according to claim 16 or 17, wherein the outer phase comprises one or more fillers selected from calcium carbonate, sodium carbonate, lactose, mannitol, magnesium carbonate, kaolin, cellulose, calcium phosphate, or sodium phosphate, or mixtures thereof.

19. The pharmaceutical composition according to any one of claims 16 to 18, wherein the external phase comprises one or more disintegrants selected from croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, or alginic acid, or a mixture thereof.

20. The pharmaceutical composition according to any one of claims 16 to 19, wherein the external phase comprises one or more lubricants selected from magnesium stearate, sodium stearyl fumarate, stearic acid, talc, or mixtures thereof.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the external phase comprises mannitol and cellulose as fillers, sodium stearyl fumarate or magnesium stearate as a lubricant, and sodium crocamerose or sodium carbonate as a disintegrant.

22. The pharmaceutical composition according to any one of claims 16 to 21, wherein the external phase is present in an amount of 20 to 50% w / w of the total weight of the composition.

23. The pharmaceutical composition according to any one of claims 1 to 22, further formulated into a final dosage form in the presence of at least one pharmaceutically acceptable excipient of any choice, wherein the final dosage form is a capsule, tablet, sachet, or stick pack.

24. The pharmaceutical composition according to claim 23, wherein the final dosage form is a capsule or a tablet.

25. The pharmaceutical composition according to claim 23 or 24, wherein the capsule is selected from hard shell capsules, hard gelatin capsules, soft shell capsules, soft gelatin capsules, vegetable shell capsules, or a mixture thereof, and the tablet is a film-coated tablet.

26. The final dosage form is a capsule formulation comprising the pharmaceutical composition described in any one of claims 1 to 23.

27. The final dosage form is a tablet formulation containing the pharmaceutical composition described in any one of claims 1 to 23.

28. The final dosage form according to claim 27, wherein N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof is present in an amount of 10% w / w to 25% w / w based on the total weight of the final dosage form.

29. The final dosage form according to claim 27 or 28, wherein the filler is present in an amount of 20 to 40% w / w based on the total weight of the final dosage form.

30. The final dosage form according to any one of claims 27 to 29, wherein the disintegrant is present in an amount of 5% w / w to 10% w / w based on the total weight of the final dosage form.

31. The final dosage form according to any one of claims 27 to 30, wherein the inactive substrate is present in an amount of 20% w / w to 40% w / w based on the total weight of the final dosage form.

32. The final dosage form according to any one of claims 27 to 31, wherein the binder is present in an amount of 5% w / w to 25% w / w based on the total weight of the final dosage form.

33. The final dosage form according to any one of claims 27 to 32, wherein the lubricant is present in an amount of 0.1 to 2% w / w based on the total weight of the final dosage form.

34. The final dosage form according to any one of claims 27 to 33, wherein the surfactant is present in an amount of 0.1% w / w to 2.5% w / w based on the total weight of the final dosage form.

35. The final dosage form according to any one of claims 27 to 34, comprising 0.5 mg to 150 mg of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

36. The final dosage form according to any one of claims 27 to 35, comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide in an amount of 0.5 mg, 10 mg, 25 mg, 35 mg, 50 mg, 75 mg, or 100 mg.

37. A method for preparing a pharmaceutical composition according to any one of claims 1 to 25, i) a step of mixing the (b) mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, polyvinylpyrrolidone-vinyl acetate copolymer, and sodium lauryl sulfate in a liquid medium, and ii) Adding the mixture (i) to the inert substrate (a) of the granular particles. A method that includes this.

38. The method according to claim 37, wherein step (i) is carried out in a wet grinding chamber.

39. The method according to claim 37 or 38, wherein the liquid medium is an aqueous solution having a pH value of 5 to 8.

40. The method according to any one of claims 37 to 39, wherein the mixture of step (i) is dispersed on the inert substrate of (a).

41. The method according to any one of claims 37 to 40, further comprising preparing a final blended mixture by blending the mixture obtained from step (ii) with at least one pharmaceutically acceptable excipient.

42. The method according to claim 41, further comprising encapsulating or tabletizing the final blend mixture.

43. The method according to claim 42, further comprising forming the final blend mixture into tablets to produce tablets, and film-coating the resulting tablets.

44. A pharmaceutical composition according to any one of claims 1 to 25, or a final dosage form according to any one of claims 27 to 35, for use as a pharmaceutical.

45. A pharmaceutical composition according to any one of claims 1 to 25 or a final dosage form according to any one of claims 26 to 36, for use in the treatment or prevention of diseases or disorders mediated by or improved by inhibition of BTK.

46. The diseases or disorders mediated by or improved by BTK include autoimmune diseases, inflammatory diseases, allergic diseases, respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), graft rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cold globulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, and Crohn's disease. A pharmaceutical composition for use or final dosage form for use according to claim 45, selected from cancers of hematopoietic origin, including but not limited to: disease, pancreatitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, subacute, acute and chronic graft rejection mediated by B cells, and diseases in which antibody production, antigen presentation, cytokine production or lymphoid tissue formation is abnormal or undesirable; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphoma; polycythemia vera; essential thrombocythopathy; myelofibrosis with myelogenesis; and Waldenström disease.

Images