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 pharmaceuticals, in particular to a method for the preparation of a compound comprising: (a) an inert substrate; and (b) an N-(3-(6-amino-5 -(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro 2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its drug and a mixture comprising a biologically acceptable salt or a free form thereof and at least one binder. The present invention relates to a pharmaceutical composition for oral administration, comprising: and the use of said pharmaceutical composition in the manufacture of a medicament. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that mediates the expression of TEC kinases. It is a member of the α-amyloidase family (Smith et al, BioEssays, 2 001,23,436-446). BTK is expressed in B cells, macrophages, mast cells, and halophils. It is expressed in selected cells of the adaptive and innate immune systems, including basal cells and platelets.

[0003] The important role of BTK in autoimmune diseases has been demonstrated in BTK-deficient mice with rheumatoid arthritis (J ansson and Holmdahl,Clin.Exp.Immunol.199 3,94,459-465), systemic lupus erythematosus and allergic diseases and ana This is highlighted by the observation that the drug is protective in standard preclinical models of phylaxis. Furthermore, many cancers and lymphomas that express BTK are dependent on BTK function. (Davis et al. Nature, 2010, 463, 88-92) The role of BTK in diseases including autoimmunity, inflammation, and cancer has been recently reviewed (Tan et al. 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-methylacrylamide ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclohexyl Chloropropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a prodrug thereof The released form is referred to as compound (A) of the formula below. [ka]

[0005] Compound (A) is a selective, potent, irreversible covalent BTK inhibitor and represents a new generation of Compound (A) is one of the covalent enzyme inhibitors that have been proposed. Compound (A) is incorporated herein by reference in its entirety. The present invention is incorporated in International Publication No. 2015 / 079417, filed on November 28, 2014. First published in Example 6 of the pamphlet (Attorney Docket No. PAT056021-WO-PCT) Compound A is marketed as LOU064, which has the international nonproprietary name remibrutinib. The compounds are known to be effective in treating conditions mediated by BTK or improved by the inhibition of BTK. The compound can be used to treat or prevent diseases or disorders that are 5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro (4-cyclopropyl-2-fluorobenzamide) or its derivatives To provide a commercially viable pharmaceutical composition comprising a pharma- ceutically acceptable salt or a free form thereof. It is necessary to provide

[0006] N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidinyl) 4-cyclopropyl-2-phenyl-5-fluoro-2-methylphenyl Fluorobenzamide or a pharma- ceutical acceptable salt thereof or its free form (referred to herein as "fluorenyl benzamide"). The present invention provides pharmaceutical compositions, pharmaceutical dosage forms, and pharmaceutical compositions of BTK inhibitors such as It has been difficult to design a commercially viable process for the production of this BTK inhibitor. The compounds are difficult to formulate due to their physicochemical properties, e.g., low solubility, low exposure, and has some tendency to gel under certain pH conditions and when exposed to certain temperatures and / or UV light Ultimately, these problems affected the manufacturing process. This also affected the bioavailability and dispersibility of the BTK inhibitors of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a need to develop a suitable robust solid pharmaceutical composition that overcomes the above problems. The present invention provides enhanced drug dissolution rate, increased absorption, increased bioavailability and Further, the present invention provides a pharmaceutical composition having a reduced inter-patient variability. A process for producing Provide a process. [Means for solving the problem]

[0008] In view of the above difficulties and considerations, (a) an inactive substrate and (b) an N-(3-(6-amino) -5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-furan fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or or a mixture comprising a pharma- ceutically acceptable salt thereof or its free form and at least one binder. and (b) finding a method for preparing a stable pharmaceutical composition, which enables the preparation of a pharmaceutical composition comprising was surprising.

[0009] Aspects and advantageous features of the invention summarized in the following items, taken alone or in combination: and the preferred embodiments contribute to solving the object of the present invention.

[0010] Embodiments: 1. A pharmaceutical composition for oral administration comprising granule particles, the granule particles comprising: (a) an inert substrate; (b) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form and at least A mixture containing one binder 13. A pharmaceutical composition comprising:

[0011] 2. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 The pharmaceutical composition of embodiment 1, wherein the fluorobenzamide is in free form.

[0012] 3. (b) The mixture according to embodiment 1 or 2, optionally further comprising a surfactant. Pharmaceutical compositions.

[0013] 4. (b) The mixture and optional surfactant are (a) layered onto an inert substrate; A pharmaceutical composition according to any one of embodiments 1 to 3.

[0014] 5.(b) The mixture and optional surfactants are spray granulated using the spray granulation method to form (a) an inert The pharmaceutical composition of embodiment 4, wherein the pharmaceutical composition is layered on a substrate.

[0015] 6. (a) Inert substrates are lactose, microcrystalline cellulose, mannitol, and sucrose. from the group consisting of sappan, starch, granulated hydrophilic fumed silica or mixtures thereof The selected material is preferably from the group consisting of lactose, mannitol or mixtures thereof. and most preferably, the material is mannitol. 5. A pharmaceutical composition according to any one of claims 1 to 4.

[0016] 7. Binders include polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone , Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Hypromello cellulose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene Polyethylene-Propylene Glycol Copolymer, Vitamin E polyethylene glycol succinate or a mixture thereof. Preferably, the binder is a polyvinylpyrrolidone-vinyl acetate copolymer. The pharmaceutical composition according to any one of aspects 1 to 6.

[0017] 8. Surfactants include sodium lauryl sulfate, potassium lauryl sulfate, and alumina lauryl sulfate. Ammonium, sodium lauryl ether sulfate, polysorbate, perfluorobutane dioctyl sulfonate, dioctyl sulfosuccinate or a mixture thereof. Preferably, the surfactant is sodium lauryl sulfate. The pharmaceutical composition described above.

[0018] 9.(b) The mixture is N-(3-(6-amino-5-(2-(N-methylacrylamide) ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclohexyl Chloropropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a prodrug thereof Forming, polyvinylpyrrolidone-vinyl acetate copolymer as a binder and optionally a boundary layer As described in any one of embodiments 1 to 8, comprising sodium lauryl sulfate as a surfactant. A pharmaceutical composition comprising:

[0019] 10. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form and a binder and the weight ratio between is about [3:1], about [2:1], about [1:1], about [1:2] or about [ 1:3], preferably about [1:1], and more preferably about [2:1]. 9. A pharmaceutical composition according to any one of claims 1 to 9.

[0020] 11. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, and The weight ratio of the agent to the surfactant is [3:1:1], or about [3:1:0.5], or about [ 3:1:0.1], or about [2:1:1], or about [2:1:0.5], or about [2:1 :0.1], or about [2:1:0.08], or about [2:1:0.05], or about [2: 1:0.04], or about [2:1:0.03], or about [2:1:0.02], or about [ 1:1:0.5], or about [1:1:0.1], or about [1:1:0.07], or about [ 1:1:0.05], or about [1:1:0.04], or about [1:1:0.02], or Approximately [1:3:0.1], or approximately [1:3:0.2], or approximately [1:1.5:0.25] Preferably, the ratio is about [2:1:1], or about [2:1:0.5], or about [2: 1:0.1], or about [2:1:0.08], or about [2:1:0.05], or about [2 :1:0.04], or about [2:1:0.03], or about [2:1:0.02], or about [1:1:0.5], or about [1:1:0.1], or about [1:1:0.07], or about [1:1:0.05], or about [1:1:0.04], or about [1:1:0.02] More preferably, the ratio is about [2:1:1], or about [2:1:0.08], or about [ 2:1:0.5], or about [2:1:0.1], or about [2:1:0.05], or about [ 2:1:0.04], or about [2:1:0.03], or about [2:1:0.02] 10. 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- 5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorophenyl 25% w / w based on azuramide or its pharma- ceutically acceptable salt or its free form ~ about 100% w / w, preferably N-(3-(6-amino-5-(2-(N-methylacrylamide arylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl) -4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof, (b) in an amount of about 50% w / w or about 100% w / w based on the weight of its free form; 12. The pharmaceutical composition according to any one of embodiments 1 to 11, wherein the compound is present in a mixture.

[0022] 13.(b) The mixture is N-(3-(6-amino-5-(2-(N-methylacrylamide 5-fluoro-2-methylphenyl)-4-(2-methylphenyl)-5-fluoro-2-methylphenyl Cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or Based on the weight of the free form, 1% w / w to about 10% w / w, preferably N-(3-(6- Amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)- 5-Fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or about 4% w / w or less based on the weight of its pharma- ceutically acceptable salt or its free form. The preparation further comprises a surfactant (e.g., sodium lauryl sulfate) in an amount of about 5% w / w. A pharmaceutical composition according to any one of embodiments 1 to 12.

[0023] 14. The N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropane Particles of 2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof The pharmaceutical composition according to any one of embodiments 1 to 13, wherein the diameter is less than 1000 nm.

[0024] 15. The N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropane Particles of 2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof The pharmaceutical composition of embodiment 14, wherein the diameter is less than 500 nm.

[0025] 16. The N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropane Particles of 2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof The pharmaceutical composition according to embodiment 15, wherein the diameter is less than 350 nm, preferably less than 250 nm. Composition.

[0026] 17. The N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropane 1, wherein the compound is 2-fluoro-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof. The particle size as measured by PCS is about 100 nm to about 350 nm; preferably about 110 nm The pharmaceutical composition of embodiment 14, wherein the molecular weight of the pharmaceutical composition is about 100 nm to about 180 nm.

[0027] 18. The method further comprising the steps of: A pharmaceutical composition according to any one of Forms 1 to 17.

[0028] 19. One or more pharma- ceutically acceptable excipients may be selected from the group consisting of fillers, disintegrants, lubricants and glidants. 19. The pharmaceutical composition according to embodiment 18, wherein said compound is selected from the group consisting of

[0029] 20. The external phase may be 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 calcium sodium phosphate or a mixture thereof, preferably mannitol or cellulose or The pharmaceutical composition according to embodiment 18 or 19, further comprising one or more fillers selected from the mixture of Pharmaceutical composition.

[0030] 21. The external phase is croscarmellose sodium, crospovidone, and starch glycol. sodium acetate, corn starch or alginic acid or a mixture thereof. 21. The pharmaceutical composition according to any one of embodiments 18 to 20, comprising one or more disintegrants.

[0031] 22. The external phase is magnesium stearate, sodium stearyl fumarate, stearyl and one or more lubricants selected from the group consisting of phosphate, talc, and mixtures thereof. 22. The pharmaceutical composition according to any one of aspects 18 to 21.

[0032] 23. The external phase contains mannitol and cellulose as bulking agents and fumaric acid as a lubricant. Sodium stearyl acid or magnesium stearate, and croscamel as a disintegrant 23. The method according to any one of claims 18 to 22, comprising the steps of: A pharmaceutical composition comprising:

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

[0034] 25. Optionally, the composition may be formulated into a final dosage form in the presence of at least one pharma- ceutically acceptable excipient. and the final dosage form is a capsule, tablet, sachet or stick pack. A pharmaceutical composition according to any one of embodiments 1 to 24.

[0035] 26. The pharmaceutical composition according to embodiment 25, wherein the final dosage form is a capsule or preferably a tablet. Composition.

[0036] 27. Capsules are classified into hard shell capsules, hard gelatin capsules, and soft shell capsules. capsule, soft gelatin capsule, vegetable shell capsule or mixtures thereof. 27. The pharmaceutical composition according to embodiment 25 or 26, wherein the tablet is preferably a film-coated tablet. composition.

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

[0038] 29. A final tablet formulation comprising the pharmaceutical composition according to any one of embodiments 1 to 25. Dosage form.

[0039] 30. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form is In an amount of about 0.4% w / w to about 35% w / w, preferably about 10%, based on the total weight of the dosage form. The active ingredient is present in an amount of about 19% to about 20% w / w, more preferably in an amount of about 25% w / w. 30. The final dosage form according to embodiment 29.

[0040] 31. The filler is present in an amount of about 20 to about 40% w / w, based on the total weight of the final dosage form. The final dosage form of embodiment 29 or 30.

[0041] 32. The disintegrant is preferably present in an amount of about 5% w / w to about 10% w / w based on the total weight of the final dosage form. or about 5 or about 6%.

[0042] 33. The inert substrate comprises about 20% w / w to about 40% w / w based on the total weight of the final dosage form. 33. The final composition according to any one of embodiments 29 to 32, which is preferably present in an amount of about 30%. Dosage form.

[0043] 34. The binder is preferably present in an amount of about 5% w / w to about 25% w / w based on the total weight of the final dosage form. or in an amount of about 8 to about 12% w / w. The final dosage form.

[0044] 35. The lubricant is present in an amount of about 0.1 to about 2% w / w, preferably about 0.1 to about 2% w / w, based on the total weight of the final dosage form. Any one of embodiments 29 to 34, wherein the compound is present in an amount of about 0.5% w / w to about 1.5% w / w. The final dosage form described in .

[0045] 36. The surfactant is about 0.1% w / w to about 2.5% w / w based on the total weight of the final dosage form. In embodiments 29 to 30, the amount of 35. The final dosage form according to any one of claims 1 to 35.

[0046] 37. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form is added to about 0. 5 mg to about 600 mg, for example, about 5 mg to about 400 mg, for example, about 10 mg to about 150 mg The final dosage form according to any one of embodiments 29 to 36, comprising 0.1 g of ...

[0047] 38. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form is added to about 0. 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 , about 400 mg, about 450 mg, about 500 mg, or about 600 mg, preferably about 10 Any of embodiments 29 to 37, comprising an amount of about 100 mg, about 25 mg, about 50 mg, and about 100 mg. The final dosage form described in any 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)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least (b) mixing the mixture containing at least one binder and optionally a surfactant in a liquid medium. Process, and (ii) adding said mixture (i) to an (a) inert matrix of granular particles; A process including.

[0049] 40. The process according to embodiment 39, wherein step (i) is carried out in a wet grinding chamber. Seth.

[0050] 41. The liquid medium is preferably an aqueous solution having a pH value of 5 to 8, e.g., purified water. , The process according to embodiment 39 or 40.

[0051] 42. The mixture of step (i) is (a) dispersed on an inert substrate, according to any of embodiments 39 to 41. 2. The process according to claim 1 ,

[0052] 43. The mixture resulting from step (ii) is mixed with at least one pharma- ceutically acceptable excipient. The method of any one of embodiments 39 to 42, further comprising blending to prepare the final dosage form. 2. The process according to claim 1 .

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

[0054] 45. The final dosage form is tableted, and the resulting tablets are further film-coated. The process of embodiment 44.

[0055] 46. ​​A process for preparing a suspension, comprising: -Methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methyl 4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least one binder and optionally a surfactant. (b) A process which involves mixing the mixture with a liquid medium.

[0056] 47.N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least A suspension comprising a 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 or 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. 49. The suspension according to embodiment 47 or 48, wherein the suspension is, for example, purified water.

[0059] 49. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form is a suspension. About 10% to about 40% of the total weight of the liquid, preferably about 20% or about 25% of the total weight of the suspension 50. The suspension according to any one of embodiments 47 to 49, wherein the suspension is present in an amount of

[0060] 50. The at least one binder is present in an amount of about 3% to about 15% of the total weight of the suspension. , A suspension according to embodiments 47 to 50.

[0061] 51. The surfactant is present in an amount of about 0.05% to about 1% of the total weight of the suspension. 52. The suspension according to any one of aspects 47 to 51.

[0062] 52. A pharmaceutical composition according to any one of embodiments 1 to 27 for use as a medicament. The final dosage form according to any one of embodiments 29 to 37 for use as a pharmaceutical or medicament. .

[0063] 53. Diseases mediated by BTK or ameliorated by inhibition of BTK The method according to any one of embodiments 1 to 27 for use in the treatment or prevention of a disorder. or a pharmaceutical composition of the present invention, Any of embodiments 29 to 37 for use in the treatment or prevention of a disease or disorder. The final dosage form described in 1.

[0064] 54. Diseases or disorders mediated by BTK or ameliorated by inhibition of BTK is a treatment for autoimmune diseases, inflammatory diseases, allergic diseases, asthma and chronic obstructive pulmonary disease (COP). D) and other airway diseases, transplant rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJI) A), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple myelopathy Sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasm Antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic hepatitis Measles (chronic idiopathic urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory Intestinal diseases, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's Thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell Antibody production, antigen presentation, and cell proliferation, including subacute, acute, and chronic graft rejection mediated by Disorders in which kinetin production or lymphoid tissue formation is abnormal or undesirable; thromboembolic disorders, Myocardial infarction, angina, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute bone marrow disease Myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma ;lymphoma;polycythemia vera;essential thrombocytosis;myelofibrosis with myeloid metaplasia;and Waldens disease In an embodiment, the present invention is selected from cancers of hematopoietic origin, including, but not limited to, Strehle's disease. A pharmaceutical composition for use as defined in embodiment 53 or 54 or as defined in embodiment 53 or 54. Preferably, the final dosage form is a therapeutic agent that is mediated by BTK or improved by inhibition of BTK. The diseases or disorders that may be treated include rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; The condition 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 OPD) and other airway diseases, transplant rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SO JIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, Multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cells Anticytic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic Urticaria (chronic idiopathic urticaria, induced urticaria), chronic allergy (atopic dermatitis, contact dermatitis), Contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammation Inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell Antibody production, antigen presentation, and suppression of graft rejection, including subacute, acute, and chronic graft rejection mediated by cytoplasmic vesicles. Disorders in which cytokine production or lymphoid tissue formation is abnormal or undesirable; thromboembolic diseases Myocardial infarction, angina, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute Myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; polycythemia vera; essential thrombocytosis; myelofibrosis with myeloid metaplasia; and Waldenstrom cancers of hematopoietic origin, including, but not limited to, B.T. Medicaments for diseases or disorders mediated by BTK or ameliorated by inhibition of BTK Use of a pharmaceutical composition according to any one of embodiments 1 to 27 for the manufacture of a product. In particular, diseases or disorders that are mediated by BTK or that are ameliorated by inhibition of BTK are , rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjogren's syndrome, multiple The disease is selected from chronic sclerosis or asthma.

[0066] 56. Diseases or disorders mediated by BTK or ameliorated by inhibition of BTK The present invention relates to a method for treating or preventing an The pharmaceutical composition according to 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 BTK or ameliorated by inhibition of BTK is a treatment for autoimmune diseases, inflammatory diseases, allergic diseases, asthma and chronic obstructive pulmonary disease (COP). D) and other airway diseases, transplant rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJI) A), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple myelopathy Sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasm Antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic hepatitis Measles (chronic idiopathic urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory Intestinal diseases, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's Thyroiditis, Graves' disease, antibody-mediated graft rejection (AMR), graft-versus-host disease, B-cell Antibody production, antigen presentation, and cell proliferation, including subacute, acute, and chronic graft rejection mediated by Disorders in which kinetin production or lymphoid tissue formation is abnormal or undesirable; thromboembolic disorders, Myocardial infarction, angina, stroke, ischemic disease, pulmonary embolism; multiple myeloma; leukemia; acute bone marrow disease Myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma ;lymphoma;polycythemia vera;essential thrombocytosis;myelofibrosis with myeloid metaplasia;and Waldens disease In an embodiment, the present invention is selected from cancers of hematopoietic origin, including, but not limited to, Strehle's disease. 57. The method of claim 57, wherein the disorder is mediated by BTK or is improved by inhibition of BTK. The diseases or disorders that may be treated include rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; The condition is selected from Glenn's syndrome, multiple sclerosis or asthma. [Brief description of the drawings]

[0068] [Figure 1] 1 shows the dissolution rate profile of granule particles containing compound (A) at pH 2 (paddle 50 rpm). [Diagram 2] 1 shows the dissolution rate profile of granule particles containing compound (A) at pH 3 (paddle 50 rpm). [Diagram 3] 1 shows the pharmacokinetic (PK) profile of granule particles containing Compound (A) at pH 2 (HCl 0.01N) in dogs. [Figure 4] 1 shows the pharmacokinetic (PK) profile of granule particles containing Compound (A) at pH 3 (HCl 0.01N) in dogs. [Diagram 5] 1 shows the pharmacokinetic (PK) profile of granule particles containing Compound (A) in dogs at pH 4.5 (acetate buffer), paddle 50 rpm. [Figure 6] 1 shows the pharmacokinetic (PK) profile of granule particles containing compound (A) in dogs at pH 6.8 (phosphate buffer) and paddle 50 rpm. [Figure 7] 1 shows the effect of particle size of compound (A) on the dissolution rate at pH 2 (paddle 50 rpm). [Figure 8] 1 shows the effect of particle size of compound (A) on the dissolution rate at pH 3 (paddle 50 rpm). [Figure 9] FIG. 1 shows pharmacokinetic (PK) profiles in dogs using granule particles containing micron-sized Compound (A) or nano-sized Compound (A). [Figure 10] FIG. 1 shows semi-logarithmic pharmacokinetic (PK) profiles in dogs using granule particles containing micron-sized compound (A) or nano-sized compound (A). [Figure 11] 1 shows a scanning electron micrograph (SEM) of a wet-milled suspension containing compound (A). [Figure 12] 1 represents the dynamic viscosity of a wet media milled suspension containing compound (A). [Figure 13] 1 shows scanning electron micrographs (SEM) of wet media milled suspensions containing compound (A) used in formulations F2, F5 and F6. [Figure 14] 1 shows scanning electron micrographs (SEM) of wet media milled suspensions containing compound (A) used in F7, F8 and F9 formulations. [Figure 15-1]Figure 15: Dynamic viscosity of different wet media milled 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] FIG. 16: Pareto chart showing the six factors that most affect blend particle size (FIG. 16A and FIG. 16B). [Figure 16-2] (As stated above.) [Figure 17] FIG. 1 depicts a Pareto chart showing the three factors that most affect blend bulk and density. [Figure 18] 1 depicts the flowability of various external phase compositions according to the Pharmacopoeia flowability scale (Carr's index less than 25% and Hausner ratio less than 1.31). [Figure 19] FIG. 1 depicts a Pareto chart showing the two factors that most affect tablet tensile strength. [Figure 20] FIG. 1 depicts a Pareto chart showing the main influencing factors of tablet ejection force. [Figure 21] Figure 2 represents the disintegration time of tablet cores in HCl, 0.01N pH 2 of different formulations. [Figure 22] FIG. 1 depicts a Pareto chart showing the main influencing factors of dissolution rate. [Figure 23-1] FIG. 23: Pareto diagram showing the main influencing factors on the particle size distribution of granules (FIG. 23A and FIG. 23B). [Figure 23-2] (As stated above.) [Figure 24] FIG. 1 depicts a Pareto chart showing the main influencing factors on granule bulk density and tapped density. [Diagram 25] Figure 1 shows the flowability of different granulation compositions according to the Pharmacopoeia flowability scale (Carr's index less than 15% and Hausner ratio less than 1.18). [Figure 26] FIG. 1 depicts a Pareto chart showing the main influencing factors on granule flowability. [Figure 27] 1 depicts a Pareto diagram showing the main influencing factors on tensile strength at 30 kN compressive force. [Figure 28] FIG. 1 depicts a Pareto diagram showing the main influencing factors on granule pushing force at 30 kN. [Figure 29-1] FIG. 29: Pareto chart showing the main influencers on the final blend PSD (FIGS. 29A and 29B). [Figure 29-2] (As stated above.) [Diagram 30] Express the flowability of the final blend according to the Pharmacopoeia flowability scale (Carr's index less than 15% and Hausner ratio less than 1.18). [Diagram 31] FIG. 1 depicts a Pareto chart showing the main influencers on final blend flowability. [Diagram 32] 3 depicts granule and final blend sieve segregation profiles. [Diagram 33] FIG. 1 depicts a Pareto chart showing the main influencing factors on tablet tensile strength at 20 kN compression force. [Diagram 34] FIG. 1 depicts a Pareto diagram showing the main influencing factors on tablet push force at 20 kN. [Diagram 35] FIG. 1 depicts a Pareto chart showing the major influencing factors on tablet core disintegration time at pH 2. [Diagram 36] 1 depicts a binary interaction graph of disintegration time for 90N tablet cores. [Figure 37-1] FIG. 37: Pareto chart showing the main influencing factors on the average dissolution (90N and 120N) (FIG. 37A and FIG. 37B). [Figure 37-2] (As stated above.) [Figure 38] 1 depicts a binary interaction graph of dissolution rate with various drug and copovidone loadings. [Figure 39] Figure 1 shows the evolution of average particle size of compound (A) versus specific energy for several batches processed at process conditions with product temperatures of about 34 to about 40°C, air to liquid ratios of about 2.0 to about 3.2, batch sizes (M) of about 62 to 175 kg, and process parameters rotor tip speed (v) of 10 to 14 m / sec and suspension flow rate (V) of 5 to 20 L / min. The average particle size of compound (A) was measured by photon correlation spectroscopy (PCS) analysis. [Diagram 40] Figure 1 depicts loss on drying (LOD) trajectories of in-process granules for batches processed at process conditions with different product temperatures (T) from 34 to 40 °C, spray speeds (m), atomization air pressures (p) and air to liquid flow rates, air to liquid ratios (A / L) ranging from about 2.0 to about 3.2, respectively; LOD was measured offline using a halogen moisture meter from granule samples taken during processing (offline LOD) and online from fluidized granules during processing using a near-infrared (NIR) spectroscopy probe installed inside the fluidized bed spray granulator (online LOD). [Diagram 41] FIG. 40 shows the particle size distribution of granules produced from process conditions with different product temperatures (T) from 34 to 40° C., spray speeds (m), atomization air pressures (p) and air flow rate to liquid flow rate ratios, respectively, with air to liquid ratios (A / L) ranging from about 2.0 to about 3.2, corresponding to the experimental results shown in FIG. 40; granule particle size distribution was measured by sieve analysis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] BTK inhibitor N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) 5-fluoro-2-methylphenyl)-4-cyclopropyloxypyrimidin-4-yl Pyr-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form ( Effective formulation of compound (A), herein referred to as compound (A), has proven difficult. For example, there are problems with its strong pH-dependent solubility, e.g., gelation under certain pH conditions. Difficult to formulate due to tendency to form granules when exposed to some temperature and / or UV light Instability, poor dissolution rate (e.g., dispersibility), low solubility, low exposure and bioavailability Ultimately, these problems were observed in the manufacturing process of the pharmaceutical composition. had an impact on.

[0070] Surprisingly, the present invention relates to a method for treating a BTK-related disease comprising administering to a patient a therapeutically effective amount of at least one of: (a) an inactive substrate; and (b) a BTK inhibitor and at least one binding agent. and a mixture containing the agent, According to the present disclosure, the BTK inhibitor is an N-(3-(6 -Amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl -5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof (referred to herein as compound (A) (also called the "

[0071] In one aspect, the present invention provides a pharmaceutical composition for oral administration comprising granule particles, The granule particles comprise: (a) an inert substrate; and (b) N-(3-(6-amino-5-(2-(N -Methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methyl 4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof and a mixture comprising a compound which can be used as a pharmaceutical composition or a salt thereof in its free form and at least one binder. The composition is provided.

[0072] In another embodiment of the present invention, compound (A) is present in a pharma- ceutically acceptable salt form. In a preferred embodiment of the present invention, compound (A) is present in its free form, e.g. Compound (A) is present in its anhydrous form. In particular, compound (A) is International Publication No. 2020 / 234779 filed on the 20th (Attorney Reference Number In yet another embodiment, the compound is present in the form (A) as described in US Pat. In the present invention, the crystalline form of compound (A) is substantially phase pure.

[0073] According to the present invention, the pharmaceutical composition comprises (a) an inert substrate, on which compound (A) and A mixture (b) containing at least one binder is added. The inert substrate is a compound (A). and (b) containing a material that is chemically unreactive with the mixture. (a) An inert substance is, for example, one that does not chemically or physically interact with an active substance. Optionally, (a) an inert excipient is a pharma- ceutically acceptable excipient known in the art. A substance must be (a) free from undesirable chemical or physical interactions that may occur during the formulation process; The active substance may also be coated with a layer that protects it. In such a case, the term "inert substrate" refers to The term "carrier particles" is used interchangeably. (a) The inert substances are lactose, microcrystalline cellulose, etc. Lubricant, 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) or mixtures thereof. Preferably, the material is selected from the group consisting of lactose, mannitol or a mixture thereof. Alternatively, the material may be mannitol SD, mannitol SD100 or mannitol SD20. 0 and other mannitols.

[0074] Granule size can be determined by one of skill in the art, for example, by laser diffraction methods (e.g., particle size distribution (PSD)). It is measured using known methods and equipment.

[0075] Suitable binders are, for example, polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl Pyrrolidone, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Promellose, carboxymethylcellulose (e.g., sodium cellulose gum, cell Rose gum), methylcellulose (e.g., cellulose methyl ether, Tylose) , Hydroxyethyl cellulose, Carboxyethyl cellulose, Carboxymethyl hydro hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, Polyvinyl alcohol-polyethylene glycol copolymer, polyethylene-propylene Glycol copolymer, Vitamin E polyethylene glycol succinate or a mixture of these Preferably, the binder is selected from the group consisting of polyvinylpyrrolidone-vinyl acetate. It is a copolymer (also known as copovidone).

[0076] (b) the at least one binder present in the mixture is The ranges listed above may be present in an amount of about 25% w / w to about 100% w / w. The present invention relates to all of the above-mentioned binders. Preferably, the binder is polyvinylpyrrolidone-vinyl acetate. copolymer, and is about 25% w / w to about 100% w / w based on the weight of compound (A). In a preferred embodiment, the binder, preferably copovidone, is present in the compound. present in the mixture (b) in an amount of about 50% or about 100% w / w based on the weight of the substance (A); In yet another preferred embodiment, (b) the ratio of compound (A) and binder in the mixture is The weight ratio is in the range of about [3:1] to about [1:3]; for example, about [3:1], about [2:1], It is about [1:1], about [1:2] or about [1:3], preferably [2:1]. Or, (b) the weight ratio of compound (A) to binder in the mixture is about [1:1]. In another embodiment, the weight ratio of compound (A) to binder in the pharmaceutical composition is about [3:1] It is about [2:1] or about [1:1], most preferably [2:1].

[0077] In another aspect, the present invention relates to a pharmaceutical composition comprising: (b) a mixture optionally further comprising a surfactant; Compositions (e.g., for oral administration) are also provided. According to the present invention, pharmaceutical compositions (e.g., for oral administration) are The method for preparing the composition for use in the present invention comprises (a) an inert substrate, on which is disposed compound (A), at least one binder, and Optionally, a (b) mixture containing a surfactant is added. Suitable surfactants include, for example: Sodium lauryl sulfate (SLS), potassium lauryl sulfate, ammonium lauryl sulfate , sodium lauryl ether sulfate, polysorbate, perfluorobutane sulfonate , dioctyl sulfosuccinate or a mixture thereof. The surfactant is sodium lauryl sulfate (SLS).

[0078] The surfactant, when present in the mixture (b), is present in an amount of about 1% by weight based on the weight of compound (A). % w / w to about 10% w / w. The above ranges are inclusive of the surfactants listed above. Preferably, the surfactant is sodium lauryl sulfate (SLS). and in an amount of about 1% w / w to about 10% w / w based on the weight of compound (A), preferably The amount of the compound (A) is 2 to 6% w / w based on the weight of the compound (A), and more preferably 2 to 6% w / w based on the weight of the compound (A). In accordance with an embodiment of the present invention, (b) the compound (A) in the mixture with at least one binder, if a surfactant is present; and the surfactant by weight ratio is about [3:1:1], or about [3:1:0.5], or about [ 3:1:0.1], or about [2:1:1], or about [2:1:0.5], or about [2:1 :0.1], or about [2:1:0.08], or about [2:1:0.05], or about [2: 1:0.04], or about [2:1:0.03], or about [2:1:0.02], or about [ 1:1:0.5], or about [1:1:0.1], or about [1:1:0.07], or about [ 1:1:0.05], or about [1:1:0.04], or about [1:1:0.02] Preferably, the ratio is about [2:1:1], or about [2:1:0.5], or about [2:1: 0.1], or about [2:1:0.08], or about [2:1:0.05], or about [2:1 :0.04], or about [2:1:0.03], or about [2:1:0.02], or about [1 :1:0.5], or about [1:1:0.1], or about [1:1:0.07], or about [1 :1:0.05], or about [1:1:0.04], or about [1:1:0.02], or about [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 about [2:1:0.1], or about [2:1:0.05], or about [2 :1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02]. In one embodiment, if a surfactant is present, (b) the surfactant is present in the mixture in a proportion of compound (A) and at least The weight ratio of the at least one binder to the surfactant is about [2:1:0.08]. In certain embodiments, the surfactant is SLS and the binder is copovidone; and (b) The weight ratio of compound (A), copovidone, and SLS in the mixture is about [2:1:1], is approximately [2:1:0.08], or approximately [2:1:0.5], or approximately [2:1:0.1], or is approximately [2:1:0.05], or approximately [2:1:0.04], or approximately [2:1:0.03] or about [2:1:0.02]; more preferably about [2:1:0.08].

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

[0080] According to an embodiment of the present invention, a compound (A), at least one binder and optionally a surfactant are included. The (b) mixture containing the dispersing agent is premixed together. The (b) mixture is premixed together so that it is essentially insoluble. The liquid medium may be, for example, It can be aqueous or non-aqueous. Preferably, the liquid medium is an aqueous solution, such as water. According to a particular 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 about 5% w / w based on the combined total weight of the premix. in an amount of about 10% w / w to about 40% w / w, preferably in an amount of about 10% w / w, or in an amount of about 15% w / w, or or in an amount of about 20% w / w, or in an amount of about 25% w / w, or in an amount of about 30% w / w, more preferably or may be present in an amount of about 20% w / w based on the weight of the premix.

[0082] The at least one binder is in a liquid medium at about 3% by weight based on the weight of the premix. % w / w to about 15% w / w; preferably about 4% w / w based on the weight of the premix. , or about 6% w / w, or about 8% w / w or about 10% w / w, more preferably about 4% w / It may be present in an amount of w.

[0083] The surfactant, if present, is present in the liquid medium in an amount of about 0.0 based on the weight of the premix. In an amount of 5% to about 1%, preferably about 0.1%, or about 0.5%, based on the weight of the premix. %, or about 0.75%, more preferably about 0.1% w / w.

[0084] According to the present invention, the premix can be used directly or can be subjected to mechanical means to reduce the average particle size to 1. The particle size can be measured, for example, by laser diffraction (e.g., particle size determination). The particle size distribution (PSD) is measured using methods and equipment known to those skilled in the art. Alternatively, the particle size as measured by PCS is less than 500 nm, more preferably less than 350 nm. In one embodiment, the optical density is measured by PCS. The particle size of the suspension is about 50 nm to about 1000 nm, or about 50 nm to 500 nm, or is about 50 nm to about 350 nm, or about 100 nm to 170 nm, for example, the particle size is About 50 nm, or about 70 nm, or about 90 nm, or about 100 nm, or about 110 nm, or about 120 nm, or about 130 nm, or about 140 nm, or about 150 nm, or about 1 60 nm, or about 170 nm, or about 180 nm, or about 190 nm, or about 200 nm , or about 230 nm, or about 250 nm, or about 280 nm, or about 300 nm, or about 3 20 nm, or about 350 nm, or about 370 nm, or about 400 nm, or about 450 nm More preferably, the particle size is about 100 nm to about 350 nm, or about 500 nm. The diameter of the particles formed is about 110 nm to about 180 nm, or about 250 nm to about 350 nm. The particles can be stably maintained at a desired size, as defined herein. The mixture is stabilized by the presence of a binder in the premix.

[0085] According to the invention, a compound (A), at least one binder and optionally a surfactant are The (b) mixture as defined herein may comprise any of the compounds known in the art as described herein. (a) can be added onto an inert substrate using a variety of techniques, preferably: A composition as defined herein comprising compound (A), at least one binder and optionally a surfactant. The (b) mixture is dispersed on an (a) inert substrate. (a) The inert matrix comprises compound (A), at least one binder and a surfactant (b In another preferred embodiment, the coating is a mixture of The mixture (A), at least one binder and optionally a surfactant (b) is a suspension. (a) a suspension, preferably as separate particles, dispersed or coated on an inert core; As such, it provides a large surface area for immediate dissolution of the drug despite its poor solubility. do.

[0086] Another aspect of the present invention is N-(3-(6-amino-5-(2-(N-methylacrylamide) ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclohexyl Chloropropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a prodrug thereof A release agent, (herein referred to as compound (A)), at least one binder and any The surfactant may be optionally added to an aqueous solution (e.g., preferably 5 to 8, more preferably 5 to 6 p According to the present invention, a suspension containing PC The particle size of the suspension, as measured by S, as defined herein, is less than 1000 nm. less than 500 nm, preferably less than 350 nm, and most preferably less than 250 Specifically, the average particle size of the suspension as measured by PCS is less than about 50 nm. nm to about 1000 nm, or about 50 nm to 500 nm, or about 50 nm to about 350 nm, or about 100 nm to 170 nm, for example, the particle size is about 50 nm, or about 70 nm, Or about 90 nm, or about 100 nm, or about 110 nm, or about 120 nm, or about 13 0 nm, or about 140 nm, or about 150 nm, or about 160 nm, or about 170 nm, or about 180 nm, or about 190 nm, or about 200 nm, or about 230 nm, or about 2 50 nm, or about 280 nm, or about 300 nm, or about 320 nm, or about 350 nm , or about 370 nm, or about 400 nm, or about 450 nm, or about 500 nm. More preferably, the particle size is from about 100 nm to about 350 nm, or from about 110 nm to about 180 nm. m, or from about 250 nm to about 350 nm.

[0087] Another aspect of the present invention is N-(3-(6-amino-5-(2-(N-methylacrylamide) ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclohexyl Chloropropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a prodrug thereof A release agent, (herein referred to as compound (A)), at least one binder and any The surfactant may be optionally added to an aqueous solution (e.g., preferably 5 to 8, more preferably 5 to 6 p The present invention provides a dispersible solution of the composition comprising the composition in a liquid medium, such as purified water having a H value.

[0088] According to the present invention, the pharmaceutical composition contains about 0.5 mg to about 600 mg of compound (A) in a small amount. The composition is prepared by mixing the composition with at least one binder and, optionally, a surfactant. The pharmaceutical composition preferably contains about 5 mg to about 400 mg of compound (A) and at least one binding agent. More preferably, the pharmaceutical composition is prepared by mixing the pharmaceutical composition with an agent and optionally a surfactant. The composition comprises about 10 mg to about 150 mg of compound (A), at least one binder, and optionally The pharmaceutical compositions disclosed herein are prepared by optionally mixing with a surfactant. For example, for oral administration, a 10 mg dose of Compound (A) containing at least one binder and optionally The pharmaceutical composition may contain 15 mg of compound (A) and at least one surfactant. It may also include a mixture of a binder and, optionally, a surfactant. The composition (e.g., for oral administration) contains 20 mg of Compound (A) and at least one binder and any Optionally, the composition may be formulated with a surfactant. For administration, the composition may contain, for example, 25 mg of compound (A), at least one binder and optionally A surfactant may also be included. In another example, the pharmaceutical composition contains 50 mg of compound (A) in a small amount. It is prepared by mixing at least one binder and optionally a surfactant. In an example, the pharmaceutical composition comprises 100 mg of compound (A), at least one binder and In another example, the pharmaceutical composition ( For example, for oral administration, 150 mg of compound (A) is mixed with at least one binder and optionally Alternatively, the pharmaceutical composition may be prepared by mixing with a surfactant. The method comprises mixing 200 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition (e.g., for oral administration) is prepared by mixing: 250 mg of compound (A) is mixed with at least one binder and optionally a surfactant. In another example, the pharmaceutical composition may be prepared by adding 300 mg of the compound ( A) with at least one binder and optionally a surfactant. In another example, the pharmaceutical composition (e.g., for oral administration) contains 350 mg of Compound (A). with at least one binder and optionally a surfactant. In another example, the pharmaceutical composition may contain 400 mg of compound (A) and at least one In another example, the composition is prepared by mixing the composition with a binder and optionally a surfactant. The pharmaceutical composition (e.g., for oral administration) contains 450 mg of compound (A) and at least one binding agent. It can also be prepared by mixing the composition with a combination of ingredients and, optionally, a surfactant. The pharmaceutical composition comprises 500 mg of compound (A), at least one binder and optionally In another example, the pharmaceutical composition (e.g., oral The dosage form for administration contains 600 mg of compound (A), at least one binder and optionally an interfacial agent. It may also be prepared by mixing with an active agent.

[0089] According to an embodiment of the present invention, the granule particles as defined herein may optionally include an outer seal coat layer. The outer seal coat layer may optionally include a (b) mixture as defined herein. It does not react with, and may occur during the formulation process, e.g. additives, pharma- ceutically acceptable excipients or (b) from undesirable chemical or physical interactions with any further active pharmaceutical ingredients; The outer seal coat layer contains a material that protects the compound. c) or gastric while allowing intestinal release. If present, the outer layer may also provide an additional barrier for stomach release. The seal coat layer may be, for example, hydroxypropyl methylcellulose, magnesium stearate, Cium, polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose Roth, methylcellulose, hydroxyethylcellulose, carboxyethylcellulose , carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl Alcohol, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT ), Hydroxypropyl methylcellulose phthalate (HPMCP), Hydroxypropyl Polymethylcellulose acetate succinate (HPMCAS), polyvinyl acetate Poly(vinyl acetate) methacrylate, methyl methacrylate-co-methacrylic acid, succinic acid acetate Selected from cellulose, fatty acids, waxes, shellac, sodium alginate, or mixtures thereof. can be selected, but is not limited to these.

[0090] In one embodiment, the present invention provides a pharmaceutical composition comprising a drug substance (i.e., compound (A)) having a particle size of 1000 nm Preferably, the pharmaceutical composition as defined above has a PCS value of less than 100 mg / kg. The particle size of the compound (A) to be used is preferably less than 500 nm, more preferably less than 350 nm, and most preferably less than 500 nm. Preferably, the compound is less than 250 nm. The particle size of (A) is about 50 nm to about 1000 nm, or about 50 nm to 500 nm, or about 5 For example, the particle size is about 500 nm to about 350 nm, or about 100 nm to 170 nm. nm, or about 70 nm, or about 90 nm, or about 100 nm, or about 110 nm, or about 120 nm, or about 130 nm, or about 140 nm, or about 150 nm, or about 160 nm m, or about 170 nm, or about 180 nm, or about 190 nm, or about 200 nm, or About 230 nm or about 250 nm, or about 280 nm, or about 300 nm, or about 320 nm m, or about 350 nm, or about 370 nm, or about 400 nm, or about 450 nm, or More preferably, the particle size of the compound (A) is about 100 nm to about 350 nm. nm, or from about 110 nm to about 180 nm, or from about 250 nm to about 350 nm.

[0091] A further aspect of the invention is the preparation of a pharmaceutical composition as defined herein (e.g. for oral administration). A process for producing (i) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least (b) mixing the mixture containing at least one binder and optionally a surfactant in a liquid medium. Process, and (ii) adding said mixture (i) to (a) carrier particles of an inert matrix; The present invention provides a process including:

[0092] Another aspect of the invention is the preparation of a pharmaceutical composition (e.g. for oral administration) as defined herein. A process comprising: (iii) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) )pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl -2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, (b) a mixture containing at least one binder and optionally a surfactant, in an aqueous or non-aqueous mixing in a liquid medium; (iv) adding said mixture (i) to (a) carrier particles of an inert matrix. The present invention provides a process including:

[0093] Another aspect of the invention is the preparation of a pharmaceutical composition (e.g. for oral administration) as defined herein. A process comprising: (i) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least (b) a mixture containing at least one binder and optionally a surfactant in an aqueous solution of water; combining the (ii) adding said mixture (i) to (a) carrier particles of an inert matrix; Including, The BTK inhibitor, such as Compound (A), as defined herein, is administered in an amount of about 0.5 mg to about 60 mg. 0 mg, or from about 5 mg to about 400 mg, or from about 10 mg to about 150 mg; Regarding the process.

[0094] As described herein above, (b) the mixture is dissolved in a liquid medium in which it is essentially insoluble ( For example, an aqueous solution) to form a premix. The liquid is stirred using suitable agitation until a homogenous dispersion or suspension without large agglomerates is observed. It can be dispersed or suspended in a medium. Mechanical means that can be used to reduce the particle size of compound (A) The means may be any mechanical means known to those skilled in the art. Preferably, the means comprises a compound (A). (b) The mechanical means used to reduce the particle size of a mixture (or premix) shall The grinding means is implemented in a grinding chamber. Suitable grinding techniques include, for example, ball milling. Mill grinding, wet grinding, media grinding, wet media grinding, agitation grinding, agitation media grinding, wet agitation media Grinding, agitator grinding, agitator media grinding, wet agitator media grinding, bead grinding, agitator bead powder These include grinding, wet mixer bead milling and high pressure homogenization. Preferably, the nano-sized particles are produced by wet mixer bead milling. The composition is prepared using a milling technique selected from grinding, media milling, wet media milling, or high pressure homogenization. More preferably, the milling techniques are wet milling, media milling and wet media milling. Typically, nano-sized particles are prepared using wet media milling techniques. According to this, step (i) of the process defined herein comprises the steps of: The pH of the premix in the grinding chamber is approximately pH=5. and pH=8, preferably the pH in the grinding chamber is about 6. The process is Minimum specific energy introduced into the suspension of 0.00 kJ / kg and grinding chal- temperature up to 35°C This is achieved by the process parameters that result in the suspension temperature at the outlet of the reactor. Preferably, the process has a higher specific energy of more than 200 kJ / kg and a temperature of less than 35° C. This is achieved by a lower suspension temperature at the exit of the grinding chamber, i.e. a temperature of 0.25° C. Kwade(Kwade,Powder Technology 1999,105 ,14-20 and Kwade,Chemical Engineering and T This relationship is calculated according to the can be adjusted for different batch sizes, e.g., about 62-175 kg, rotor tip speeds, e.g., 1 A range of 0-14 m / sec and liquid flow rates, e.g., 5-20 L / min, were considered. Various batch sizes and process parameter settings for rotor tip speed and suspension flow rate The established relationship between the average particle size and the specific energy of differently produced batches, taking into account The particle size of compound (A) varies with the batch size, rotor tip speed and suspension temperature investigated. Despite the difference in flow rate, the process was reasonably controlled by the parameter specific energy. The minimum specific energy introduced into the suspension is about 200 kJ / kg and the grinding temperature is 35°C. The process parameters were determined by the temperature of the suspension at the outlet of the chamber. Alternatively, the process may have a higher specific energy of more than 300 kJ / kg and a maximum operating temperature of up to 32°C. The suspension temperature at the outlet of the grinding chamber is controlled by the following steps: With specific energy exceeding 600 kJ / kg and temperatures between 16 and 32°C at the exit of the grinding chamber This was carried out by the suspension temperature.

[0095] Thus, one aspect of the present invention is to provide a compound comprising N-(3-(6-amino-5-(2-(N-methylamino) Acrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-4-Cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof, or its free form, at least one binder and optionally a surfactant in a liquid medium. In one embodiment, 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 nm In another embodiment, the liquid medium of the suspension is preferably 5 to 8, more preferably 10 to 20 μm. Preferably, the aqueous solution has a pH value of 5 to 6, such as purified water.

[0096] In another embodiment, the above suspension contains compound (A) or a pharma- ceutically acceptable salt thereof or Compound (A) or a pharma- ceutically acceptable salt thereof or a free form thereof The form is about 10% to about 40% of the total weight of the suspension, preferably about 20% or is present in an amount of about 25%.

[0097] In yet a further embodiment, the present invention relates to a method for the preparation of a composition comprising at least one binder, preferably copovidone. The suspension as described above is provided, wherein the hydroxypropyl amine is present in an amount of about 3% to about 15% by total weight of the suspension.

[0098] In yet a further aspect, the present invention relates to a method for preparing a suspension comprising the steps of: The suspension as defined above is provided, present in an amount of about 0.05% to about 1% by total weight.

[0099] According to the present invention, a process for preparing a pharmaceutical composition (e.g. for oral administration) as defined herein is provided. The process further comprises mixing the mixture of step (i)(b) with (a) an inert matrix carrier, as defined herein. (b) The mixture may be added to particles by, for example, spray drying, spray granulation, spray layering, spray spraying, spray spraying, spray drying, spray granulation, spray spraying ... Mist dispersion, spray coating, fluid bed drying, fluid bed coating, fluid bed spray granulation, with spray nozzle Various techniques known in the art, such as granulators or combinations of these spraying techniques. According to the present invention, coating or spraying can be carried out, for example, by applying a coating agent to the 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 upper and lower coatings can be carried out simultaneously or successively from both directions. Spraying or top coating is preferred. Preferably, (a) an inert substrate is coated with (b) the mixture. More preferably, the mixture of process step (i) is The mixture is (a) dispersed on an inert substrate. Specifically, (b) the mixture is dispersed on an inert substrate, e.g., by spraying. The mixture may be added using drying, spray granulation, fluid bed spray granulation or a combination thereof of these spraying techniques. The liquid medium, for example, purified water, is used to keep the product (compound (A)) at a temperature of about 30°C to about 45°C. Preferably, the product temperature is about 36° C. to about 44° C. More preferably, Preferably, the temperature is about 36° C. to about 40° C. During the spray granulation process, the spray rate and the atomization space are Air pressure is a parameter that determines the droplet size of the spray liquid when it is sprayed. The parameters depend on the nozzle geometry. Each nozzle has a specific air consumption at a particular atomizing air pressure. This factor is typically provided by the nozzle manufacturer as an air consumption char. This value and the spray rate used are used to determine the amount of The ratio of air mass to liquid mass was calculated. The granulation process was carried out at a ratio of about 1.1 to about 3.2, e.g. Spray velocity and atomization resulting in a range of "air mass to liquid mass flow ratios" from about 1.1 to about 2.3 This is done using air pressure. The ratio of the air mass to the liquid mass flow rate is about 1.1 to about 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 important during later tablet compression and breakthroughs. This results in less optimal granulation due to the uniformity of the blend and the risk of segregation. Loss on Drying of Granules (LOD) is, for example, the spray liquid of the material parameter and the process parameter Spray velocity, air flow rate and inlet air temperature are considered to determine the material and process characteristics during spray granulation processing. It is a widely accepted surrogate that quantitatively describes the complex relationships between 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 loss on drying (LOD) trajectory is the most The preferred process conditions (i.e., product temperature is about 34 to about 40° C. and air-to-liquid ratio is about 2.0 to about 3.2) FIG. 40 shows the LOD trajectory for the most favorable process conditions defined above. The lower LOD trajectory corresponds to slightly wetter process conditions (higher LOD trajectory) and slightly dry The range of most preferred process conditions for dry process conditions (lower LOD locus) is shown. The corresponding product granule size distribution is shown in Figure 41. OD trajectory) results in a coarser granule size distribution, while the slightly drier process conditions (lower L The LOD trajectory results in a finer granule size distribution. The LOD trajectory As shown, the process was reasonably controlled under the most favorable process conditions defined above. Process conditions beyond the high and low LOD locus have an impact on tablet compression and blend uniformity. This resulted in granules with less than optimal properties.

[0100] In a further aspect, the present invention relates to a process for preparing a suspension comprising the steps of: (b) a process comprising mixing the mixture in a liquid medium as defined herein. Thus, another aspect of the present invention provides a pharmaceutical composition as defined herein (e.g. 2. A process for preparing a pharmaceutical composition for oral administration, comprising: (i) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least (b) a mixture containing at least one binder and optionally a surfactant is mixed in a liquid medium. The liquid medium is preferably 5 to 8, more preferably the aqueous solution having a pH value of 5 to 6, e.g., purified water; and (ii) adding the suspension of step (i) to (a) carrier particles of an inert matrix. The present invention relates to a process comprising:

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

[0102] In another aspect, the present invention is a process for preparing a dispersion comprising the steps of: (b) mixing the mixture with a liquid medium as defined herein. Therefore, another aspect of the present invention provides a pharmaceutical composition as defined herein (e.g., 2. A process for preparing a pharmaceutical composition for administration, comprising: (i) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least (b) a mixture containing at least one binder and optionally a surfactant is mixed in a liquid medium. The liquid medium is preferably 5 to 8, more preferably an aqueous solution having a pH value of 5 to 6, for example purified water, (ii) adding said dispersion of step (i) to (a) carrier particles of an inert matrix. The present invention relates to a process comprising:

[0103] In one embodiment of the above process, the suspension is provided with a crystalline solid, as measured by PCS, of less than 1000 nm. Preferably, the particle size is about 50 nm to about 1000 nm, or about 50 nm to 500 nm, or about 50 nm to about 350 nm, or about 100 nm to 170 nm For example, the particle size is about 50 nm, or about 70 nm, or about 90 nm, or about 100 nm, or about 110 nm, or about 120 nm, or about 130 nm, or about 140 nm, or is about 150 nm, or about 160 nm, or about 170 nm, or about 180 nm, or about 19 0 nm, or about 200 nm, or about 230 nm, or about 250 nm, or about 280 nm, or is about 300 nm, or about 320 nm, or about 350 nm, or about 370 nm, or about 40 More preferably, the particle size is about 110 nm, or about 450 nm, or about 500 nm. 0 nm to about 350 nm, or about 110 nm to about 160 nm, or about 250 nm to about 350 nm.

[0104] In a further aspect, the present invention relates to a pharmaceutical composition as defined herein (e.g. for oral administration). The process for preparing a soluble ... The final dosage form is prepared by blending the compound with an external phase containing a pharma- ceutically acceptable salt thereof. For example, the external phase as defined herein may be a mixture of particles and a final Chemical-physical interactions with other active or inactive substances that may be used in the preparation of the dosage form. The added benefits of an external phase include acceptable dissolution rate, acceptable disintegration rate, and The objective of the present invention is to provide tablet formability such as break time, better processability and tablet tensile strength.

[0105] Another aspect of the invention is a process for preparing a unit dosage form (e.g., for oral administration), comprising: (i) N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form, at least Another binder (e.g., polyvinylpyrrolidone-vinyl acetate copolymer) and optionally (b) a mixture containing a surfactant (e.g., sodium lauryl sulfate (SLS)) in water A solution (e.g., purified water having a pH value of preferably 5 to 8, more preferably 5 to 6), etc. (b) mixing the compounds in the mixture in a liquid medium of The average particle size of the substance (A) is less than 1000 nm, preferably less than 500 nm, more preferably less than 3 The particle size is less than 50 nm, and most preferably less than 250 nm (particle size is as disclosed herein). As described above, the diameter is, for example, about 100 nm to about 350 nm or about 110 nm to 180 nm. (ii) adding said mixture (i) to (a) carrier particles of an inert matrix; and (iii) mixing the mixture resulting from step (ii) with at least one pharma- ceutically acceptable excipient; In a blend with an agent, a BTK inhibitor, such as compound (A), is About 0.5 mg to about 600 mg, or about 5 mg to about 400 mg, or about 10 mg to about 150 and obtaining a final dosage form present in an amount of 100 mg. Also provided is a process comprising:

[0106] Another aspect of the present invention is a process for preparing a pharmaceutical composition, for example, the process Provide a process that follows a flow chart.

[0107] [Table 1]

[0108] Another aspect of the present invention is the process as defined herein, wherein the final dosage form is an encapsulated If the final dose is a tablet, the tablet is film-coated. It can be.

[0109] Another aspect of the present invention is to provide a method for preparing a carrier particle comprising the steps of: ) to prepare the final dosage form. The matrix particles may contain at least one pharma- ceutically acceptable excipient and / or matrix forming agent. The final dosage form (e.g., tablet, capsule) can be produced, for example, by granulation, freeze drying, or spray drying. Suitable pharma- ceutically acceptable excipients include, for example, lactose. , mannitol (e.g., Mannitol DC), microcrystalline cellulose (e.g., Avicel PH101 (registered trademark), Avicel PH102 (registered trademark), dicalcium phosphate um, polyvinylpyrrolidone, hydroxypropyl methylcellulose, croscarmellose sodium, polyvinylpyrrolidone-vinyl acetate copolymers (e.g., crospovidone ), sodium starch glycolate, colloidal silicon dioxide, magnesium stearate sodium hydrogen carbonate, sodium stearyl fumarate or a mixture thereof Preferably, the excipient is selected from the group consisting of mannitol (such as mannitol DC), Croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, At least one of the at least one carboxylic acid salts may be selected from the group consisting of sodium bicarbonate, sodium phosphate, sodium phosphate dihydrate, sodium phosphate ester, sodium phosphate ester, sodium phosphate dihydrate ... The pharma- ceutically acceptable excipient provides a formulation with good disintegration and dispersibility of compound (A); It is therefore selected to reduce its gelling behavior.

[0110] The pharmaceutical compositions disclosed herein can be administered to humans and animals, e.g., as capsules, caplets, , powder, pellets, granules, tablets, mini tablets (up to 3mm or 5mm), sachets, Intended to be administered orally in unit or multi-dosage form such as a pouch or stick pack. Preferably, the unit dosage form or multiple dosage form is, for example, a capsule, tablet, sachet, pouch or More preferably, the pharmaceutical composition is in the form of a capsule or tablet. This means that the pharmaceutical composition as defined herein can be formulated without the addition of fillers (also called diluents). , lubricants, glidants, disintegrants and / or absorbents, colorants, flavors and sweeteners. This can be achieved by:

[0111] Capsules containing the pharmaceutical compositions of the present invention as defined herein are known in the art. Suitable capsules include hard shell capsules, hard gelatin capsules, and the like. Capsules, soft gelatin capsules, soft shell capsules, vegetable shell capsules, The capsules may be selected from promellose (HPMC)-based capsules or mixtures thereof. The pharmaceutical composition may be a hard gelatin capsule, a hard shell capsule or a vegetable hard capsule. The pharmaceutical composition may be presented in a dossier capsule, a hypromellose (HPMC) capsule, , inert solid diluents, such as calcium carbonate, calcium phosphate, magnesium stearate sodium bicarbonate or cellulosic excipients (e.g. microcrystalline cellulose) The hard gelatin capsule is made up of two parts called the body and the cap. The shell is made of vegetable or animal gelatin (e.g. , pork, beef or fish gelatin), water, one or more plasticizers and optionally some preservatives. The capsule may contain a BTK inhibitor, such as Compound (A), at least one binding agent, and optionally containing surfactants and / or other excipients, The dry mixture may be in the form of particles. The shell may be transparent, opaque, colored or The capsules containing the particles may be prepared using techniques well known in the art. and coated with an enteric and / or gastro-resistant or delayed release coating material, e.g. It is possible to achieve greater stability in the gastrointestinal tract or to achieve a desired release rate. Hard gelatin capsules of any size (e.g., sizes 000 to 5) can be prepared.

[0112] Tablets containing the pharmaceutical composition of the present invention as defined herein can be prepared by any method known in the art. A suitable tablet can be prepared by mixing the particles with a non-toxic pharmaceutical agent suitable for tablet manufacture. These excipients may be, 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 phosphate), inert such as calcium phosphate or sodium phosphate or mixtures thereof Diluents (or sometimes called fillers); disintegrants Disintegrants (also called disintegrants), e.g. Roscarmellose sodium, crospovidone, sodium starch glycolate, tow Sorghum starch or alginic acid or mixtures thereof; gliding agents gent) (also called glidant), such as fumed silica (e.g., Aerosil®, Aeroperl®); binders (b Inding agents (also called binders) (e.g., As methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, starch and lubricants (gum arabic, gelatin or gum arabic) or mixtures thereof; lubricant (also called steering agent), e.g. Magnesium phosphate, sodium stearyl fumarate, stearic acid or talc, or These mixtures. Mixtures of particles mixed with non-toxic pharmaceuticals, e.g. -Mix using many known methods, such as mixing in a bowl or tumble blending. The mixture of particles mixed with a non-toxic pharmaceutical agent can be, for example, Compression on a press, double punch press, rotary tablet press or roller compactor. The tablets can be compressed into tablets using tabletting techniques well known in the art. The compression force can be any suitable compression force that allows a tablet to be obtained, for example, the applied pressure The compression may be from 0.5 to 60 kN, or from 1 to 50 kN, or from 5 to 45 kN. The compression force is 5 to 25 kN. The tablets or granules may be uncoated or may be coated by known techniques. It is coated with a syrup to delay disintegration and absorption in the digestive tract, thereby maintaining its action for a long period of time. For example, tablets may be coated with a suitable polymer or conventional coating material. For example, to achieve greater stability in the gastrointestinal tract or to achieve a desired release rate, For example, tablets contain hypromellose (HPMC), magnesium stearate, polyethylene Polyethylene glycol (PEG), polyvinyl alcohol (PVA), Opadry® , Opadry II®, or mixtures thereof. A time delay material such as glyceryl allyl ester or glyceryl distearate can be utilized. Tablets of any shape or size can be prepared and they can be opaque, colored, or In particular, the pharmaceutical compositions disclosed herein may be film coated. It is in the form of a tablet.

[0113] N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidinyl) 4-cyclopropyl-2-phenyl-5-fluoro-2-methylphenyl Fluorobenzamide or a pharma- ceutical acceptable salt thereof or its free form (referred to herein as "fluorenyl benzamide"). BTK inhibitors, such as those described herein as Compound (A), have been shown to cause undesirable side effects in treated patients. It will be present in the pharmaceutical composition in an amount sufficient to exert a therapeutically useful effect in the absence of any activity. Each unit dose contains a predetermined amount of compound (A) sufficient to produce the desired therapeutic effect. Each unit dose disclosed herein is suitable for human and animal subjects and is individually packaged. A multiple dose form may be a divided unit dose form. A multiple dose form is a plurality of identical unit dosage forms packaged in one container, each of which is administered in a single dose. Examples of such include a vial, blister or bottle.

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

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

[0116] A further aspect of the invention is a method for the preparation of a pharmaceutical composition comprising the steps of: The present invention relates to a pharmaceutical composition (eg for oral administration) as defined above.

[0117] Another aspect of the invention is a method for administering a BTK inhibitor, such as Compound (A), in an amount of about 0.5 mg to about 600 mg. an inhibitor, at least one binder, optionally a surfactant and at least one pharma- ceutically acceptable A capsule for oral administration is provided comprising an acceptable excipient.

[0118] Another embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutical composition comprising at least one compound (A) in an amount of about 0.5 mg to about 600 mg. A binder, optionally a surfactant, and at least one pharma- ceutically acceptable excipient. The present invention provides tablets, preferably film-coated tablets, for oral administration.

[0119] The pharmaceutical compositions disclosed herein (e.g., for oral administration) are useful as medicines, e.g. In particular, the pharmaceutical composition (e.g., for oral administration) is useful for treating, for example, autoimmune diseases, inflammatory diseases, Allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; Rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic Thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjoegren's disease Renn's syndrome, autoimmune hemolytic anemia, antineutrophil 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), Rohm's arteriosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease , pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-related Anti-allergic graft rejection (AMR), graft-versus-host disease, B cell-mediated subacute, acute and Abnormalities in 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 Disease, pulmonary embolism; multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; Myeloid leukemia; Non-Hodgkin's lymphoma; Lymphoma; Polycythemia vera; Essential hematopoietic leukemia Myelofibrosis with myeloid metaplasia; and Waldenstrom's disease. Cancers of unspecified hematopoietic origin, such as those mediated by BTK or those that are inhibited by BTK The present invention is useful as a medicament for treating or preventing the disease or disorder to be improved. The disclosure relates to a method for treating rheumatoid arthritis; chronic urticaria (preferably chronic idiopathic urticaria); Sjogren's syndrome. a BTK-mediated or BTK-inhibiting disease selected from the group consisting of multiple sclerosis and asthma; Use of said pharmaceutical composition in the treatment or prevention of a disease or disorder ameliorated by injury or disease. do.

[0120] Another aspect of the invention is a method for treating a disease mediated by BTK or improved by inhibition of BTK. The pharmaceutical compositions disclosed herein (e.g., The use of a medicament for oral administration, wherein the disease or disorder is an autoimmune disease, an inflammatory disease, an allergy, respiratory tract diseases such as asthma and chronic obstructive pulmonary disease (COPD); transplant rejection; Urine, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenia Diabetic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's disease syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cold globulopathy Phosphatemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria) , chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atheroma Atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis , glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-related transplantation Anti-inflammatory cytokines (AMR), graft-versus-host disease, subacute, acute and chronic myeloid leukemia mediated by B cells Abnormalities in antibody production, antigen presentation, cytokine production, or lymphoid tissue formation, including graft rejection thromboembolic disease, myocardial infarction, angina pectoris, stroke, ischemic disease, Pulmonary embolism;Multiple myeloma;Leukemia;Acute myeloid leukemia;Chronic myeloid leukemia;Lymphocyte myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocytopenia myelofibrosis with myeloid metaplasia; and Waldenstrom's disease Specifically, the present disclosure provides a method for treating cancer of hematopoietic origin in which BTK is not involved. and (b) a pharmaceutical agent for a disease or disorder mediated by BTK or ameliorated by inhibition of BTK. Use of a pharmaceutical composition disclosed herein (e.g., for oral administration) for the manufacture of a The disease or disorder is rheumatoid arthritis; chronic urticaria (preferably chronic idiopathic urticaria); Shag The present invention provides a method for treating a disease comprising administering to a patient suffering from a pulmonary circulation, in a patient suffering from a pulmonary artery disease ...

[0121] Another aspect of the invention is a method for treating a disease mediated by BTK or improved by inhibition of BTK. The present invention relates to a method for treating or preventing a disease or disorder in need of such treatment or prevention. Also provided are methods comprising administering to a subject a pharmaceutical composition or final dosage form disclosed herein. do.

[0122] definition The term "pharmaceutically acceptable salt" refers to, for example, an acid addition salt, preferably with an organic or inorganic acid. For isolation or purification purposes, pharma- ceutically unacceptable salts, e.g. It is also possible to use phosphate or perchlorate salts. For therapeutic use, pharma- ceuticals approved for use are Only acceptable salts or free compounds are utilized (in the form of pharmaceutical preparations, if applicable), but Therefore, these are preferred. The term "pharmaceutical acceptable" means a compound that does not cause excessive toxicity, irritation, or allergies. - Suitable for use in contact with human and animal tissues without reactions, other problems or complications and which are commensurate with a reasonable benefit / risk ratio. Refers to...

[0123] The terms "treat," "treating," or "treatment" of a disease or disorder refer to the Ameliorating the disorder (e.g., slowing the onset of a disease or at least one of its clinical symptoms). Furthermore, these terms are used interchangeably by the patient. Alleviating or improving at least one physical parameter, including one that may not be recognizable and physical (e.g., stabilization of discernible symptoms) and physiological (e.g., physical parameters) This refers to modulating the disease or disorder through the regulation of the immune system, regulating the immune system, or both.

[0124] The terms "prevent," "preventing," or "prevention" of a disease or disorder refer to the It refers to delaying the onset, development, or progression of a disorder.

[0125] As used herein, the term "about" refers to measurements taken across different instruments, samples, and sample preparations. Describes the variation that may be seen in the values ​​and indicates whether a given value is "a little above" or "a little below" the endpoints. The terminology generally provides flexibility in the numerical range endpoints, assuming that a given It means within 10% of a value or range, preferably within 5%, and more preferably within 1%.

[0126] The terms "pharmaceutical composition" and "formulation" can be used interchangeably herein and refer to a pharmaceutical composition for use in treating a mammal. The compound is to be administered to a mammal, e.g., a human, to prevent, treat, or control a particular disease or condition. The term refers to a physical mixture that contains a therapeutic compound, for example, formed at high temperature and pressure. The term also includes homogeneous physical mixtures in which the components are mixed.

[0127] The term "oral administration" refers to administration of a therapeutic compound by swallowing, chewing, or inhaling an oral dosage form. By this, it refers to any method of administration that can be administered by the oral route. Conventionally, active agents are substantially released and administered in the digestive tract beyond the mouth and / or buccal cavity. and / or is intended to deliver

[0128] As used herein, the term "therapeutically effective amount" of a compound refers to a therapeutically effective amount of a compound that is effective in treating a subject's biological or elicits a medical response, e.g., improves symptoms, alleviates pathology, slows disease progression, or The term "therapeutically effective amount" refers to an amount that, when administered to a subject, reduces or delays the progression of a disease, disorder, or the like. It also refers to the amount of a compound that is effective to at least partially alleviate and / or ameliorate a disease or injury. The term "effective amount" refers to the amount of a substance that is being sought by a researcher, physician, or other clinician in a cell, tissue, The amount of a compound of interest that produces a biological or medical response in an organ, system, animal, or human means...

[0129] The term "including" is used herein in its open-ended, non-limiting sense unless otherwise specified. In a more restrictive embodiment, "including" is used in the sense of the non-exclusive "including In its most restrictive form, it can be replaced with "which is The method may include only those steps or values ​​listed below.

[0130] As used herein, the term "inert substrate" refers to a substance that is neither chemically active nor biologically active. For example, an inert matrix is ​​a substance or material that does not react with or decompose in a suspension. (b) a mixture that is chemically unreactive (i.e., a compound (A) and at least one binder); This refers to a substance or material that does not chemically react with the mixture.

[0131] As used herein, the term "glidant" or "glidin "Flow agent" refers to a substance or material that improves the flowability of the final blend.

[0132] As used herein, the term "disintegrant" or "disintegrant" refers to a "Integrating agents" are agents added to oral solid dosage forms, e.g. tablets. and aids in the disintegration of solid dosage forms by causing rapid disintegration when in contact with moisture. Refers to quality or material.

[0133] The term "binder" or "binding agent" refers to They are used interchangeably in the specification and are their established meaning in the medical field. The compound (A) may be added together with the active pharmaceutical ingredient (herein referred to as compound (A)). (A) allowing for adhesion to inert substrate particles in the case of deposition or for the formation of granules in the case of tableting; A promoter of cohesive compaction that ensures the formation of granules with the required mechanical strength All of the binding agents referred to herein are suitable for pharmaceutical use. and is commercially available under various trademarks as shown in the following examples: -Polyvinylpyrrolidone-vinyl acetate copolymer is sold under the trade name Copovidone (approximate molecular weight Copovidone (Ph.Eur.) is available in 1 It is a copolymer of -ethenylpyrrolidin-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 It may be commercialized under the name Kollidon® VA 64. -Polyvinylpyrrolidone (INN Ph.Eur.) is available under the trade name Povidone K30 or PV It is commercially available as P K30 (approximate molecular weight 50,000). -Carboxymethylcellulose (USP / NF) is a polycarboxymethyl cellulose It is also known as the calcium salt of ether. It is sold under the trade name Calcium Carmellose. It is commercially available at. -Shellac (INN Ph.Eur.) is an insecticide that is used to kill Laccifer lacca-carr (Lac cifer lacca Kerr, Kerria Lacca Kerr a Kerr), Tachardia lacca, Cocca Coccus lacca and Carteria lacca Shellac is a commercially available resin secreted by females of various trees. As follows: 46% Aryl acid (HOCH2(CH2)5CHOHCHOH(C H2)7COOH), 27% sherolic acid (cyclic dihydroxydicarboxylic acids and their homologues) body), 5% kerolinic acid (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. colouring substances) and 12% unspecified polybasic acid esters. - Polyvinyl alcohol (INN Ph.Eur.) is sold under the trade name 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 of 200 00). -Polyvinyl alcohol-PEG copolymer, also known as PEG-PVA Polyvinyl alcohol-polyethylene glycol copolymer. -α-hydro-ω-hydroxypoly(oxyethylene) poly(oxypropylene) poly( Also known as ethylenedioxyethylene block copolymer (CAS 9003-11-6) The polyethylene-propylene glycol copolymer used is called poloxamer (INN P h.Eur.) Poloxamer polyols have the general formula HO(CHO ) a (C3H6O) b (C2H4O) a Ethylene oxide and propylene oxide according to H are a series of closely related block copolymers.

[0134] The term "surfactant" or "surface active agent" "Amphiphilic agents" refer to organic compounds that are amphiphilic and can be used to This means that the surfactant has both a hydrophilic head and a hydrophilic tail. It contains both insoluble (or oil-soluble) and water-soluble components. Surfactants have properties that change when ionized. They are therefore classified as ionic (eg, anionic or cationic) or nonionic. - Polysorbate is commercially available under the name Tween 80. It is used in the literature under the name Name: Polysorbate 80, PEO(20) Sorbitan Monooleate (INCI, formerly known as It is known by the nickname Crillet 4 Super.

[0135] The term "nano-sized" or "nanoparticle-like" refers to particles ranging from about 100 nm to about 1000 nm. It refers to a particle having a particle size.

[0136] Abbreviation %w / w Percent by weight ℃ Celsius degree API Active Pharmaceutical Ingredients Area under the AUC curve AUCinf 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 of Cosmetic Ingredients INN International Generic Name Kg / g / mg / ng / μg Kilogram / Gram / Milligram / Nanogram / Microgram Grams kN kilonewton LCMS Liquid Chromatography-Mass Spectrometry mL / L Milliliters per 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 peak maximum concentration (Cmax) US Ultrasonic Treatment USP United States Pharmacopeia USP / NF United States Pharmacopeia / National Formulary w / v weight to volume ratio w / w weight ratio XRPD X-ray powder diffraction EXAMPLES

[0137] The following examples are illustrative of the present invention and are intended to support the present disclosure without limiting the scope of the present invention. give.

[0138] Analytical centrifugation (AC), e.g. LUMiSizer, LUM GmbH Germ any, SEPView 6.1.2570.2022. Approximately 1 Use purified aqueous solutions for dilution of the suspension to an appropriate attenuation level with 0-70% transmission Results reported for X10, X50, and X90 are weighted by intensity. It is being done.

[0139] Photon correlation spectroscopy (PCS), e.g., Zetasizer Nano ZS, Malv er Panalytical Ltd., UK, version 7.3. Attenuation index of approximately 2 to 9 0.1 mM NaCl solution (purified) for dilution of the suspension to the appropriate attenuation level with The results reported for Xmean are weighted by intensity. Specifically, the decay exponent is 5. Preferably, the measurements are carried out at 25°C. Further preferred settings of the measurement system are as follows: Cell: Disposable sizing cuvette Count rate (KcPs): 315 Duration: 60 seconds Measurement position (mm): 4.65 Zeta potential, e.g. Zetasizer Nano, Malvern Panalyt ical Ltd., UK Scanning Electron Micrograph (SEM), e.g., Supra 40, Carl Zeiss SMT AG, Germany Dynamic viscosity, e.g., Haake Mars, ThermoFisher Scienti fic GmbH, Germany Sinker method, e.g., a ceiling with a weight for liquid density Scales, Mettler Toledo GmbH, Switzerland Viable count test (MET).

[0140] Example 1: Preparation of Granule Particles The role of the inert substrate is to separate the different (b) mixtures, as defined herein, into different types of (a ) Evaluated by formulating on inert substrates such as mannitol and lactose The different granule particle compositions were prepared using the binder polyvinylpyrrolidone-vinyl acetate copolymer ( copovidone), Compound (A) as defined herein and the surfactant sodium lauryl sulfate The different variants were prepared by suspending them in a liquid medium such as purified water. Please write down.

[0141] [Table 2]

[0142] Variants containing higher ratios of polyvinylpyrrolidone-vinyl acetate copolymer (copovidone) It was observed that bodies P1, P4, P5 and P7 showed the best resuspension properties compared to the starting suspension. Variants P1 and P7, which contain higher ratios of SLS, also show superior resuspension properties. Variant P7 was selected as the optimized granule composition in terms of copovidone and SLS ratio. However, the amount sprayed onto the inert substrate (carrier particles) is therefore limited to a reasonable amount of granules in a reasonable treatment time. The composition of the granules allows for a drug loading of 20% based on the total weight of the capsule. The dissolution performance of the drug was evaluated to ensure that the dissolution profile was in a good range. As can be seen in FIG. 2, the granule particles prepared as mentioned in Table 1 were placed in a capsule (e.g., By adding it to a gelatin capsule, the dissolution rate was controlled according to the conventional method (European Pharmacopoeia 2. 9.3 Dissolution Test for Solid Dosage Forms "United States Pharmacopoeia Dosage Forms" <711> "Dissolution Dissolution test) or the paddle method according to Japanese Pharmacopoeia <6.10> "Dissolution test". Figure 1 shows the dissolution rate at pH 2, independent of the particle size of the drug substance, for a tested dose of 50 mg. The above-mentioned granule particles were used in the test. In some capsules, the disintegration and dispersion of the contents was delayed, and the dissolution was delayed at 50 rpm. The disintegration and dispersion of the formulation contents at pH 2 were measured. To improve the composition, the addition of at least one pharma- ceutically acceptable excipient (e.g., as an external phase) is Figure 2 shows that the maximum solubility of compound (A) at pH 3 is 50 As can be seen in Figure 2, the high levels of polyvinyl chloride reach 90% at 1 mg dose. P1 granules containing pyrrolidone-vinyl acetate copolymer and SLS have good resuspension properties. However, it has low levels of polyvinylpyrrolidone-vinyl acetate copolymer and SLS. P2 granule particles did not achieve a good level of resuspension. No significant difference in separation behavior was observed between the 22 μm filter and the 22 μm filter. The dissolution profiles of the P2 granule particles overlap completely (as depicted in Figure 2).

[0143] Granule particles P1, P2, P3, P7 (prepared according to Table 1) and additional excipients were then added. One type of granule (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 intersubject variability of Cmax and AUClast, as assessed by CV (%), was The results showed that the efficacy rates among the agents ranged from 40.7% to 90.1% and 49.6% to 69.7%, respectively. The maximum concentration (Cmax) was reached in 0.5 to 2 hours (median) across formulations. Based on the results, resuspension supports higher in vivo exposure in dogs, and different variables Used as a selection criterion to rank among forms (e.g., P1, P2, P3, P7 and P7''). It was concluded that it could be used.

[0147] To better understand the formulation / pH profile, the dissolution profiles of the formulations in Tables 2 and 3 were The exit velocity profiles were measured at pH 2, pH 3, pH 4.5 and pH 6.8. The results are summarized in Figures 3, 4, 5, and 6. The formulation behavior changed between pH 2 and pH 3. It was shown that the smaller amount of binder (polyvinylpyrrolidone-vinyl acetate copolymer ) and surfactant (sodium lauryl sulfate) compared with formulations containing higher amounts. The slow dissolution rate of the formulation is related to the observed gelation behavior. It is observed that the small amount of binder and surfactant is not seen. At low pH, none of the formulations exhibited gelling activity and the entire capsule contents were dispersed within the first 10 minutes. It is scattered.

[0148] Example 2: Role of particle size Have a good understanding of particle size distribution, dissolution profiles of different formulations and the effect of particle size on formulation The role of particle size of compound (A) as defined herein was also investigated to understand the effect of the granules on the composition. The particles were prepared according to the procedure in Example 1. Several particle sizes of the drug substance (i.e., compound (A)) were The results were obtained as shown in Figures 7 and 8. Depict in 8: V1 = 120 nm particle size - nanoparticulate formulation (wet milled suspension). V2 = 1.2 μm particle size - as a non-wet milled suspension. V3 = 1.2 μm particle size - as powder blend. V4 = 2.4 μm particle size - as powder blend. V5 = 13.9 μm particle size - as powder blend.

[0149] Already at pH 2, a strong particle size effect was observed on the dissolution rate profile, as observed in Figure 7. Formulation V5 (13.9 μm) showed an infinitely large deviation of about 40% from complete release. The particle size of 2.4 μm (V2 and V3) is delayed. The 120 μm (V4) shows a clear decrease in the dissolution rate and also a retarded profile. Comparison of V1 formulation with a particle size of 1.2 nm and formulations with a particle size of 1.2 μm (V2 and V3) The 1.2 μm particle size formulation showed a faster rate of dissolution at the beginning of the profile, but The dissolution rate (DR) profile at pH 2 showed that the two compounds reached the same end point (Figure 7). The effect of particle size is even more evident at pH 3 as depicted in FIG. As shown, the gap between the 13.9 μm particle size (V5) and the 120 nm particle size (V1) is about 6 0%. The fastest micron-sized drug substance (V2) is about 20% faster than V1. Shows.

[0150] The role of particle size (e.g., micron or nano size) and its effect on formulation PK The effects were evaluated in 13 male beagle dogs following administration of a 50 mg dose of Compound (A). Arithmetic mean (SD) blood concentration-time plots per dose are presented in Figures 9 and 10. PK parameters The parameters are summarized in Table 4 below.

[0151] [Table 5]

[0152] A slightly earlier median Tmax was observed for the compound ( A) was administered the formulation containing nano-sized particles (0.75 hours). Cmax The geometric mean CV% of the nano-sized formulation was 117.3%, whereas the micron-sized formulation Similarly, the geometric mean CV% of AUClast was 178.1% for the nano-sized The PK response was 94.7% for the drug and 212.5% ​​for the micron-sized formulation. Statistical analysis of the effect of particle size showed that the micron-sized formulations were significantly greater than the nano-sized formulations in AUC (geometric mean ratio). : 0.405, 90% confidence interval (CI): 0.215, 0.763) and Cmax (geometric mean ratio: 0.409, 90% CI: 0.233, 0.717) Furthermore, significantly lower variability was achieved with the micron-sized formulation. was seen in comparison.

[0153] Example 3: Composition of the Suspension The formulation composition of the wet media milled suspension of compound (A) was prepared by mixing the polyvinylpyrrolidone-acetic acid Vinyl copolymer (copovidone) and sodium lauryl sulfate (SLS) are considered as excipients. The increase in the concentration of the drug in suspension was investigated by using several formulation compositions as shown in Table 5 and Table The results were evaluated as shown in FIG. 6.

[0154] [Table 6]

[0155] The experimental results obtained were analyzed by analytical centrifugation (AC), photon correlation spectroscopy (PCS) and Zeta The particle size according to the potential is summarized in Table 6. Scanning electron microscope image of the obtained drug particles Identified by photography and rotational ramp-up rheology testing at 25°C The dynamic viscosity is depicted in FIGS.

[0156] [Table 7]

[0157] Formulation of wet media milled suspension containing Compound (A) based on 25% w / w drug concentration The composition was subjected to screening experiments using a steric stabilizer, a binder (e.g., polyvinyl chloride), and a tertiary stabilizer. pyrrolidone-vinyl acetate copolymer) and surfactants (e.g., sodium lauryl sulfate Based on the suitable particle size and viscosity obtained for different compositions of excipients such as cellulose acetate, Experiments were performed with standardized equipment and process parameter settings for proper comparison. The formulation compositions investigated are shown in Table 7 below.

[0158] [Table 8]

[0159] The experimental results obtained were 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 micrographs of the drug particles are shown in Figures 13 and 14. The dynamic viscosity is shown in Figure 15. As shown in Fig. 1, the rotational ramp-up rheology test was performed at 10°C, 25°C and 40°C. The assay and density of the wet media milled suspension containing compound (A) were then characterized. Each was characterized by HPLC and gravimetrically using a weight method. The results are summarized in Table 9 below. Can.

[0162] [Table 10]

[0163] Formulation Composition F2 (25% w / w Compound (A), 4% w / w Copovidone) in a wet medium suspension binder and 0.1% w / w SLS surfactant) with appropriate particle size data, Low dynamic viscosity over the shear rates tested by rheology, both at rest and at low Photon correlation spectroscopy to compare low complex viscosity at frequencies and particle size with and without ultrasound No or low signs of particle agglomeration identified and further identified by frequency sweep testing The formulations were selected based on their linear behavior at low frequencies as determined by the formula. Other formulations had higher viscosities (F 5, F6, F7 and F8) were not considered suitable for development. Particle growth by tow ripening occurs at high sodium lauryl sulfate (SLS) concentrations (F9). was observed.

[0164] Composition F2 has the following characteristics: (a) Quality: homogeneity; and (b) Operation: handling of the suspension and the spraying process. The suspensions used have a low viscosity which is advantageous with regard to downstream processing into a dry product (granules).

[0165] Grinding process: Formulation composition Compound (A): 25% w / w, Copovidone: 4% w / w and SLS: 0.1% w / w to a 6 liter batch size using the following equipment and process parameters: Scaled up: 600ml grinding chamber volume, zirconia grinding media, 100μm grinding media diameter, grinding media filling level in the grinding chamber of 80% v / v, speed of 9 m / s tip speed of the thaller, suspension inlet temperature of about 19°C, suspension outlet temperature of about 23°C, process Suspension flow rate of 7 l / h during ramp-up and increased to 33 l / h after 1 h of treatment, 8 Grinding period of time.

[0166] The particle size of compound (A) was measured by PCS, and such a process reduced the particle size by approximately It could be reduced from 110nm to about 130nm.

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

[0168] To evaluate the role of excipients, the granules were administered at doses of 10 mg, 20 mg, and 50 mg. The amount of compound (A) was prepared as mentioned in the above examples using micron-sized particle size. The granulated particles are then mixed with at least one pharma- ceutically acceptable excipient and cytosine. The drug was encapsulated in a size 0 hard gelatin capsule.

[0169] [Table 11]

[0170] Assay Stability Data for Capsules A suspension containing compound (A) as defined herein was subjected to technical stability. Appearance, PC No significant changes in particle size, microscopy, or assay due to S were observed under storage conditions of 40°C and 75 relative humidity (RH). Storage for up to 10 weeks at 5°C / ambient RH and 25°C_60RH Not observed for up to 9 months storage. Relative retention time (RRT) of 0.81, 25℃_60% Decomposition products were observed to form in samples stored at 40°C_75%RH and 40°C_75%RH. It increased with increasing storage temperature and time (25℃_60%RH: 0 after 9 months 0.23% after 10 weeks at 40℃_75%RH, and 0.34% after 10 weeks at 40℃_75%RH). To avoid this, the suspension is stored in a refrigerator and the stability results are showed that after storage for up to 9 months at room temperature, the degradation products remained unchanged at less than 0.05%. Besides the degradation product with an RRT of 0.81, no other significant changes or increases in impurities were observed in the samples tested. No changes were observed under different storage conditions and storage periods. 5℃ / ambient and 25℃_60%RH After 8 weeks of storage at room temperature, no microbial contamination was detected by plate count (MET). Ta.

[0171] Example 5: Testing of External Phase Composition The effect of formulation factors on the quality attributes of Compound (A) 50 mg tablet cores was investigated. The children were evaluated by filler ratio, disintegrant level and type, lubricant level, and lubricant level and type. there were.

[0172] For this study, a fluid bed granulator with a top spray configuration was selected for development. For this study, 40% w / w drug loading, 20% w / w copovidone and One granule composition containing 0.2% w / w sodium lauryl sulfate was selected. A DOE was performed to determine the blending efficiency at laboratory scale (i.e., 250 g tablet batch size). The blend and tablet core properties were evaluated and improved. The experiments involved the evaluation of several variables (i.e., filler ratio, disintegrant type, amount of disintegrant, amount of lubricant, type of lubricant and amount of lubricant) The formulation flowability and compactibility were screened and evaluated.

[0173] The purpose of this study was primarily to determine the composition of selected granules (see granule composition in Table 11). The objective of the present invention is to evaluate the release of compound (A) for different 50% w / w external phase compositions on the The study focuses only on the granulation and tableting process steps.

[0174] [Table 12]

[0175] The design used was a six-factor (Table 12) score in 12 design runs (Table 13). It was a leaning design.

[0176] [Table 13]

[0177] [Table 14]

[0178] Physical properties were evaluated and compared to assess the effect of factors on the final blends obtained. (i.e. flowability, bulk density, Carr's index, Hausner ratio). Finally, the final blend is compressed. To understand the effect of related factors on tablet core tensile strength, disintegration time and dissolution rate. Ta.

[0179] Table 14 lists the response variables 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 of compound (A) by wet media milling and fluid bed spray granulation 1. Dissolve copovidone in water with 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 with stirring. 4. Carry out wet media milling using the suspension from step 3 5. Add the required amount of sodium lauryl sulfate and copovidone to additional purified water with stirring. Dissolve 6. Weigh out the required amount of wet media milled suspension from step 4 and mix with the copovidone and laurocin from step 5. Add to the purified aqueous solution of sodium uryl sulfate to complete the suspension for spray granulation. 7. Load the Mannitol SD200 Carrier into the Fluid Bed Dryer 8. The entire amount of the suspension for spray granulation in step 5 is sprayed onto the mannitol SD200 carrier in step 7. Spray granulation is carried out by spraying the nanosuspension onto the Note that this should not be the case.

[0186] Compound (A) Final Blend Preparation and Compression Manufacturing Process 9. Sift the granules through a 0.8mm screen size. 10. Avicel PH102, Mannitol DS, Super Disintegrant (i.e. Starch Glycol Sodium cholate, crospovidone, croscarmellose sodium) at 0.5 mm Sift through a 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 and mix with the mixture from step 11. Add to 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 final blend properties Final Blend Particle Size Distribution: The percentage of particles on each mesh size of the CAMSIZER device was measured. It was observed that the addition of the agent to the final blend caused a reduction in the amount of coarse particles.

[0189] The Pareto charts depicted in Figures 16A and 16B show the relative importance of the effects relative to one another. Showing the six main effects from the study design plotted from highest to lowest effect for It is a positive effect (high levels of a factor give a higher response than low levels of a factor) We use - for negative effects (opposite direction) and - for negative effects (opposite direction). The significance lines indicate which effects are statistically different from zero. In this case, for the final blend d10, d50 and d90, The most influential factor is the filler ratio cellulose / mannitol, which is significant. The use of mannitol (low filler ratio: 0.25) resulted in a coarser granule in the final blend. This graph shows that several factors affect the final blend span. It is also shown that the effect of SD levels and type, and filler ratio on the

[0190] Final Blend Bulk and Tap Density Bulk and tapped densities were obtained from 16 batches of the final blend. Batches containing high amounts of mannitol (i.e. batches F3-06, F3-11, F3-1 2, F3-14 and F3-16), batches containing a large amount of MCC (filler ratio: 0.75, From batches F3-02, F3-03, F3-07, F3-08 and F3-15, Lower hardness and tap density were observed.

[0191] The Pareto chart depicted in FIG. 17 shows that the final blend bulk and tapped densities are significantly affected by the The three most influential factors that influence the composition of the formulation are: lubricant level, filler ratio and disintegration rate. It is a type of destructive agent.

[0192] Final Blend Flowability: Carr's index and Hausner ratio data suggest a theoretical flowability of 16 batches. The final blend behavior was characterized by a rotary powder analysis tester. This instrument consists of a rotating drum (100mm diameter at 0.6rpm) to measure changes in force, time and energy It measures the ability of a powder to flow.

[0193] FIG. 18 shows that all batches were similar and had a pharmacopoeial flowability scale (Carr's index less than 25% and It has average theoretical fluidity according to the Hausner ratio of 1.31.

[0194] The most influential factor on the final blend Carr's index and Hausner ratio is the filler ratio cellulose / Mannitol. Using a large amount of mannitol provides better flowability. This means that...

[0195] Bulk density and flow properties are seen to be final blend properties that vary between batches. These differences are believed to be the result of changes in the external phase composition (qualitative and quantitative). The flow results show a higher filler ratio (PSD) corresponding to 0.25. The batches containing the highest amount of mannitol (e.g., F4-6, 11, 12 and 16) showed better Represents liquidity.

[0196] Evaluation of tablet core properties 16 final blends are punched with a 9mm round flat punch tool with power assist. They were compressed using a single punch tablet press (KORSCH XP1). The shrinkage behavior was tested and compared.

[0197] Compression Profile To select the ideal compression force and hardness, a compression force-hardness profile was prepared before the start of the compression experiment. Seven compression forces ranging from 6 kN to 15 kN were evaluated for each batch. The tablet crushing force (or hardness) was evaluated using a testing machine. The tensile strength was also evaluated based on the adhesion of the compact. The hardness and tensile strength variations under pressure are then used to describe the degree of hardness. Plotted as a function of compression force.

[0198] Compression force-hardness profiles were measured for 16 batches. Tablet hardness increased with increasing compression force. It was observed that the different compression force-hardness profiles depended on the external phase composition of the final blend. This is likely due to the difference in the quantity and quality of the batch F3-15. shows the best compression force-hardness profile, while batch F3-14 shows the worst compression force-hardness profile. The height profile is shown.

[0199] To assess the significance of these results, the tensile strength was calculated using the formula (see below). Tensile strength profiles are plotted to normalize values ​​and compare batch to batch. The compression ratio is determined as shown in the following formula to show the compressibility comparison. The results show the same trend as those reported above.

number

[0200] The tensile strength values ​​taken in the Pareto chart come from tablet hardness of 90N and are compared across all batches. The 90N tablet hardness was chosen to provide a good balance between low friability results and acceptable disintegration time. The Pareto chart (see FIG. 19) shows the superdisintegrant (SD) type and The lubricant type is one of the two factors that significantly affect the tensile strength. The use of croscarmellose sodium as a disintegrant and croscarmellose sodium as a disintegrant resulted in higher compression. Brings sex.

[0201] Extrusion Profile The force required to eject a finished tablet is known as the ejection force and is determined by powder sticking. This force can be used to quantify the effect of breaking the tablet / die wall seal. Inadequate lubrication can cause fluctuations in the ejection force and tablet thickness. It is preferable that it is 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 exhibited the highest pushing force profile (>800N) close to or far from the recommended value of 500N. It was observed that the other profiles were lower (>200N). The specific extrusion is calculated by dividing the output by the tablet weight and expressed in N / g. The results are shown in the extrusion profile. The results showed the same trends as the previous files, but could be divided into three groups: A high specific extrusion profile was recorded for batch 0033-14, which was 4000N / g It exhibited higher specific extrusion. Medium profile, 700N / g to 2500N / g, 3 batches of 0033-0 4, 0033-08 and 0033-16. Lower profiles were recorded in other batches that were below 600N / g.

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

[0204] The two Pareto charts (Figure 20) show that the four main contributors to the pushing force and specific pushing force are: The amount and type of lubricant, the filler ratio and the amount of lubricant were indicated.

[0205] The amount and type of disintegrant was considered negligible. The results showed that the formulations with good performance were Use a minimum of 1% sodium stearyl fumarate · Small amount of lubricant (less than 1.25%) A small amount of mannitol (up to 0.5 filler ratio) It was shown that.

[0206] Disintegration time (DT) of tablet core The disintegration of the tablet core is associated with the unique gelling properties described above, The experiments were carried out in HCl, 0.01N pH 2, which represents the worst case medium for tablet disintegration. The disintegration time is expressed as the maximum value of the three tablet cores (see Figure 21: Maximum disintegration time value (9 0N).

[0207] Only batch F3-02 shows a higher disintegration time, exceeding 900 sec / 15 min. All batches did not exceed 600 sec / 10 min, but the batches were slightly shorter than 600 sec / 10 min, possibly due to differences in the external phase composition. High variability between the DT and DT-max was observed. All six factors were found to have a significant effect on the DT-max. However, considering the magnitude of the values, the ratio of fillers and the amount of lubricant type are negligible. Four other factors are considered to be the major contributing factors. Sodium fumarate (up to 6%) and high amounts of sodium stearyl fumarate (up to 1%) Contributes to faster tablet core disintegration time.

[0208] Table 15 below summarizes the tablet core DT values ​​based on the six factors and levels. It includes the average of the low and high DTs as well as the average of the median DTs (all 6 batches). The recommendation for tablet core DT value is -Filler ratio: less than 0.5% - Super disintegrant (SD) type: sodium starch glycolate (DT: 159 seconds) or clo Sodium scalmellose (DT: 255 seconds) -Disintegrant level: >6% - Lubricant level: approx. 1.25 (minimum DT with 1.25% lubricant) -Lubricant type: Sodium stearyl fumarate - Lubricant level: less than 1% It can be concluded that.

[0209] [Table 20]

[0210] Dissolution profile of tablet core The dissolution rate (DR) of tablet cores containing compound (A) was measured by UV spectroscopy in an automated setup. The measurement was performed in 0.01M HCl (pH 2) at 100 rpm in a basket. This will be carried out.

[0211] Batch F3-02 had the worst dissolution profile, i.e., the highest disintegration rate for this batch. In all other batches, more than 50% of compound (A) was dissolved in 30 minutes. It is served.

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

[0213] Based on tablet core dissolution rates at 15 and 30 minutes, fast tablet core DR value recommendation -Filler ratio: less than 0.5% -Disintegrant type: Sodium starch glycolate or croscarmellose sodium -Disintegrant level: >6% -Lubricant level: No effect on DR -Lubricant type: Sodium stearyl fumarate - Lubricant level: less than 1% It was concluded that.

[0214] [Table 21]

[0215] Conclusions of external phase composition testing Based on this statistical analysis, the study demonstrated that the filler ratio had an effect on the final blend and tablet core properties. The results reveal that high levels and types of superdisintegrants are the major factors affecting the disintegration process. The lubricant level had the least effect on the response. The level and type of lubricant significantly affects tablet core properties. The use of hydrophilic lubricants (i.e. sodium stearyl fumarate) is tends to reduce extrusion force and increase / improve disintegration time and dissolution rate compared to sodium Based on the experiments tested, Table 17 shows that the glycerin is used in an amount of 50% w / w of the total composition weight. If so, the composition of the external phase is most likely to be the optimal external phase for the formulation of compound (A). vinegar. -Bulking ratio: 0.5 based on a good balance between high dissolution rate and low disintegration time Select -Type and level of super disintegrant: sodium starch glycolate and croscarmellose sodium thorium -A minimum of 6% disintegrant is required - Lubricant levels show minimal impact on tablet properties and can be used optionally, e.g., in amounts of 1%. Cut. -Lubricant type: Sodium stearyl fumarate shows good DT and DR -A minimum lubricant 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 testing in Example 5 was limited to compositions containing an 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 was varied from 24% to 5%. 0% and several more trials were carried out with different disintegrant types as well as microcrystalline cellulose and malic acid. The experiment was carried out with a variation of the filler with ethanol. Since lubricant was found to be optional, No lubricant was used in these trials.

[0218] Tablet dosage forms were prepared using formulations T1 and 25 containing 20% ​​w / w of Compound (A) as shown in Table 18. The formulation was developed using formulation T2 containing compound (A) at 100% w / w. Granules containing compound (A) The capsule formulation is prepared by mixing the capsule with at least one pharma- ceutically acceptable excipient in the same manner as in the capsule formulation. The tablet formulation shown in Table 18 was prepared in accordance with the following procedure.

[0219] [Table 23]

[0220] As mentioned in the present application, the problem with formulations containing compound (A) is that compound (A) is easily dissolved at pH 2 or less. This gelation behavior occurs when the formulation (e.g., tablet) disintegrates. Therefore, the disintegration time was measured in water and at pH = 2, which is the standard test. The measurements were performed in hydrochloric acid containing

[0221] All the tested formulations in Table 18 had good disintegration behavior in water, but no differences were observed at pH=2. The fastest disintegration time in both media was observed for the 50% amount of pharma- ceutically acceptable excipients in the external phase. Another factor for the rapid decay is (a) the amount of compound (A) added onto the inert substrate. In this first screening trial, it was found that the key to success was the selection of the amount and type of disintegrant. , 1-ethenyl-2-pyrrolidinone homopolymer (commercially available under the name Crospovidone - CAS 9003-39-8) and croscarmellose sodium have the fastest disintegration at pH=2. The amount of 40% w / w of pharma- ceutically acceptable excipients in the outer phase and 20% w / w of the granules were The combination of %w / w of compound (A) was dissolved in water at pH 2 in less than 15 minutes by the best performing disintegrant. It was time for a complete collapse.

[0222] It was concluded that a minimum external phase of 40% w / w is preferred.

[0223] Finally, to gain knowledge of their chemical and physical stability, the two variants were subjected to short stability tests. 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] The formulations containing the above-mentioned compound (A) in Table 19 can be described as very stable, and No incompatibility was observed between the formulation and the water uptake during storage (hygroscopic excipients present) Even the smallest particle size distribution (as would be expected) did not result in any observations during visual examination.

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

[0227] [Table 25]

[0228] The excipient is based on the amount of solids to be sprayed onto the carrier surface to form the matrix. The ratio defines the granule composition. The excipient levels are then defined by the following formula: Excipient level = drug loading x excipient ratio.

[0229] As shown in Table 21, a second-order polynomial model (2 4-1 Fractional Factorial ) will be used to conduct experiments, totalling 12 experiments.

[0230] [Table 26]

[0231] Four replicates were tested with center points, all four main effects, and three confounded pairs of two-way interactions. The effect of the factors on the resulting granules and final blends was measured using the experimental error. To evaluate the effectiveness of the cellulose, the physical properties of each cellulose were evaluated and compared (i.e., flowability, bulk density, viscosity, Finally, the final blend was compressed to determine tablet core tensile strength, disintegration index, and Hausner ratio. The effect of each factor on the disintegration time and dissolution rate was understood.

[0232] Response variables are the observed responses of an experiment that result from induced changes in process / formulation variables. Table 22 lists the response variables tested.

[0233] [Table 27]

[0234] Twelve tablet core batches were manufactured according to the proposed experimental design. Tables 23-2 and 23-3 show 12 batch combinations with a granule batch size of approximately 250 g. 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 with respect to their shape, surface morphology and roughness.

[0239] Batches containing copovidone ratios up to 0.5 (F6-01-04-05-08 and 4 Center point F6-09-10-11-12) consists of coarser particles with d50 > 250 μm It was observed that agglomerations between granules can be observed from the SEM images. The rate diagram summarizes the various effects. The level of copovidone is It has been shown that high amounts of copovidone significantly affect the distribution of coarser granules. Drop.

[0240] Granule bulk density and tap density Bulk density and tapped density data were obtained for the 12 batches of sieved granules measured in Example 6. Obtained from grains.

[0241] The bulk and tapped densities of the batches containing a small amount of copovidone (i.e., F6-02-0 The Pareto diagram shown in Figure 24 shows that the granules The most influential factor that significantly affected the capsule density was copovidone (0.50g / ml to 0. 57 g / ml).

[0242] Granular flow characteristics (granular Carr's index and Hausner ratio) Granule Carr's Index and Hausner Ratio data suggest theoretical flowability for 12 batches Figure 25 shows that all batches were similar and had a flowability scale of pharmacopoeia (Carr's index below 15%). It has good / excellent theoretical flowability according to the 1.00% Cr content (1.00 or less and Hausner ratio less than 1.18). vinegar.

[0243] Granule fluidity The granulation behavior was characterized by a rotary powder analysis tester. This equipment consists of a rotating drum (0. By measuring the changes in force, time and energy within a 100mm diameter at 6 rpm The ability of the powder to flow can be measured. The angle results (37° to 42°) show fair / good flowability for all 12 granule batches. The results of collapsing force (<18cch) and surface linearity (≧0.99%) indicate good flowability. show.

[0244] The Pareto chart in FIG. 26 showed that copovidone had a significant effect on granule flowability. In tests, higher levels of copovidone also resulted in better flow behavior for coarser particles and granules. Drop.

[0245] Granule assay and resuspension Granule assay and granule resuspension properties of 12 batches are listed in Table 24. Measured on whole granules. No correction was applied during spray granulation.

[0246] The granules were subjected to reconstitution / resuspension by PSD using Photon Correlation Spectroscopy (PCS). Photon correlation spectroscopy (PCS) is used to differentiate particles from less than 5 nm to several microns in size. This technique works on the principle that particles move randomly in a gas or liquid. The particle size of the drug substance during wet media milling before dilution for mist granulation is 123 nm.

[0247] [Table 31]

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

[0249] Granule compression behavior The compression behavior of 12 granule batches was characterized to gain knowledge about the products. Therefore, the granules were pressed into a single punch tablet press (Styl'One) with auxiliary power. Compression was performed using a 1.28 mm round flat punch tool.

[0250] Granule Compressibility: Compressibility is the ability of a powder to deform under pressure. During powder densification, the powder bed The porosity of the material decreases. Densification can be tested by monitoring the porosity under load. Tablet porosity can be determined by measuring tablet dimensions (i.e. thickness, diameter), weight and density. It was observed that the porosity decreased with higher compression force. All batches show less than 8% porosity at 25 MPa compression force. The four center points are It exhibited the best porosity profile compared to the batch.

[0251] Granule Compressibility: Compressibility is the ability to form mechanically strong compacts. Compression Force-Hardness Pro Perform different tests such as file and tensile strength profiles. Compressive force-hardness profile. The test was carried out on each batch. Five types of compression force from 5kN to 45kN were evaluated. The tablet crushing force (or hardness) was evaluated using the following method. Tensile strength is usually measured using a compacted tablet. The variation of hardness and tensile strength under pressure is then used to describe the degree of adhesion. It is expressed as a function of the main compression force.

[0252] Tablet hardness was observed to increase with increasing compression force. Different compression behavior was observed between batches. Batch F6-01 showed low variability at each compression force. The three granules F6-05, 07 and 09 showed a plateau above 25 kN. The four center points exhibited similar compression force-hardness profiles at the lowest. The force-hardness profiles are likely related to differences in granule phase composition, as expected. To assess the significance of these results, tensile strength profiles were plotted and the values ​​were normalized. All granules exhibited high tabletability and similar compression force-hardness profiles. showed a tendency.

[0253] The tensile strength values ​​taken from the Pareto diagram below are from tablets compressed at 25-30kN. The Pareto chart (Figure 27) shows that the levels of copovidone, SLS and mannitol are It is shown that the three factors significantly affect the tensile strength. The absence of glycerol, small amounts of SLS and mannitol results in better tabletability.

[0254] Granule compressibility: The tensile strength of compacted granules was observed to decrease with higher porosity. The compacted material had a 20% porosity and a tensile strength of about 2 MPa, so it had a similar compaction profile. Illness was observed in all granule batches.

[0255] Granule extrusion profile: The extrusion force profile was recorded for every batch during the compression cycle. For greater accuracy, the specific extrusion force was calculated by dividing the extrusion force by the tablet weight, expressed in N / g. Figure 28 shows the influence of various granule composition factors on the specific extrusion profile.

[0256] Evaluation of final blend properties Characterization of the 12 final blends was performed and the results are summarized in Tables 25-1 and 25-2. Further details are provided in the subsections below.

[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 phase excipients in the granules reduces the amount of coarse particles. Woke him up.

[0260] The Pareto plots shown in Figures 29A and 29B show that the copovidone levels in the final blend d5 This indicates that it is the factor that has the greatest effect on fine powder particles of less than 0, d90 and 125 μm. A trend is observed for the granules: higher amounts of copovidone result in coarser particles. Povidone produces a significant amount of fines.

[0261] Final Blend Bulk and Tap Density According to the summary table above, the bulk and tapped densities are similar between batches.

[0262] Carr's index and Hausner ratio: Carr's index and Hausner ratio data are from 12 batches of Figure 30 shows that all batches were similar and conformed to the pharmacopoeial flowability scale. The results show that the batch F7-08 has excellent flowability according to the theoretical flow rule.

[0263] Final Blend Fluidity The final blend behavior was characterized by a rotary powder analysis tester. The force, time and energy changes were measured in a gyro (100 mm diameter at 0.6 rpm). This allows the powder's ability to flow to be measured. Median avalanche results (1.7 seconds to 3.1 seconds) The results of the avalanche angle (38°~48°) indicate that the FB has fair / good flowability. The collapsing force results (<18cch) and surface linearity results (>0.99%) indicate good flowability.

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

[0265] Final blend flow segregation prediction Segregation or separation occurs when particles separate from a mixture of particles due to differences in physical properties (size, shape, density, etc.). There are several driving forces or mechanisms that can cause segregation. The most common mechanisms for this are sieving, fluidization and sparging. In addition, the particle size distribution (PSD) of the materials must have the same distribution. For example, the granules and excipients A large difference in PSD between the coarser particles can physically separate the mixture and cause segregation. The coarse particles are dragged along by gravity at the bottom and the finer particles sit at the top of the blend. Depending on the powder behavior, the opposite may occur with coarser particles on top and fine powder on the bottom. The mixture may be clearly divided. The outer phase composition is approximately 50% w / w of the tablet weight. (The majority of the two fillers are Avicel PH102 and Mannitol DC). A large amount of external phase can potentially lead to separation between the components due to particle size differences.

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

[0267] Particle size distribution comparison method: This study was carried out on each final blend, granule and external phase excipient (i.e., Avicel PH10 2. To compare the particle size distribution of mannitol DC and croscarmellose sodium The difference in particle size between the internal phase (i.e., granules) and the external phase can cause segregation. Upon this, the granule PSD shifts to the right corresponding to the coarse particles, while the external phase excipients (i.e. MCC and mannitol) are observed to shift to the left, which corresponds to finer particles. An ideal blend that can limit the segregation phenomenon should have similar PSD curves. From the point of view, batch F7-06 has the best PSD. It shows a tendency to separate.

[0268] Sieving Segregation Method: For the sieving segregation method, the powder was subjected to stress by vibration (amplitude 1.0 mm, 5 min). To segregate, the powder mixture is added to a column of screen sieves. The fine particles are at the bottom and the coarse particles are at the top. The mixture was then split into four fractions corresponding to the relevant screen sieves with the white particles at the top of the device. Force separation. Then evaluate how the API is distributed across particle size fractions. To determine the API content, the API content is measured for each fraction. Finally, the standard deviation is calculated to determine the Determine the potential segregation of objects. High standard deviation results in high potential segregation. F6-01 , F6-08 and F6-11 and their corresponding final blends F7 Only F7-01, F7-08 and F7-11 were evaluated.

[0269] Table 26 summarizes the API content determined for each fraction. RSD values ​​are shown for batch-to-batch The API is part of the granules and is therefore not present in the external phase. The highest API content measured in the fraction from the top of the can represents the coarser fraction. The drug substance may be homogeneously distributed in the granules for each fraction, whereas the final The blends had higher RSD values ​​(i.e., 63% to 82% RSD), indicating higher segregation. It was observed that batch F6-01 shows the highest RSD. This batch However, there is a tendency for high segregation as evidenced by the large difference in PSD between the granules and the external phase. Therefore, it was found that the external phase level has a significant effect on the drug content uniformity. It can be concluded that a good balance between the level of external phase and appropriate granule size distribution is , it will be less likely to cause segregation.

[0270] [Table 34]

[0271] Final blend compression behavior The twelve final blends were then subjected to compression characterization using standard 11.28 mm round flasks. Single punch tablet press with auxiliary power (Compact Simulator S They were compressed using the typ'One Evolution. were tested and the results were compared.

[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. Densification is measured by monitoring the porosity under load. Tablet porosity can be measured by measuring the tablet dimensions (i.e. thickness, diameter), weight and density. The porosity is calculated after extrusion by measuring the porosity. was observed. All final blend batches exhibited similar porosity profiles.

[0273] Final blend tabletability Tabletability is the ability to form mechanically strong compacts. Tabletability (i.e. compression force - hardness) Various tests were carried out to test the mechanical properties (strength, strength and tensile strength).

[0274] Compressive force-hardness profiles were performed on each batch. Five different compressive forces were applied, ranging from 5 kN to 45 kN. The tablet crushing strength (or hardness) was evaluated using a hardness tester. The tensile strength was It is commonly used to describe the degree of compaction. Then there is the hardness and tensile strength under pressure. The variation of the main compression force is depicted as a function of the main compression force. Increasing the compression force results in higher tablet hardness. Different compaction behavior was observed between batches with low variability. Batch F Granules F7-01 show a hardness that decreases with a compressive force of 25 kN or more. Granules F7-06 show the best compressive strength. The tabletability profiles of the batches F7-01 and F7-04 were the worst. Compared with the granule compression profile, the hardness decline or plateau tendency is not observed in the final break. It was concluded that the external phase excipients had a positive effect on this property. Tensile strength profiles were recorded to allow for tableting comparisons. All tensile strength profiles are now calculated using the tensile strength vs. compressive strength curve for more accurate values. It was shown that the profiles showed similar trends.

[0275] The tensile strength values ​​taken in the Pareto chart below come from tablets compressed at 20 kN. The Pareto plot (Figure 33) shows that no factors have a significant effect on the final blend tensile strength. This indicates that.

[0276] Final Blend Extrusion Profile: The extrusion force profile is determined by the amount of extrusion of all batches during the compression cycle. For greater accuracy, the specific extrusion force was calculated by dividing the extrusion force by the tablet weight. The Pareto chart (Figure 34) shows that the main contributors to the specific thrust are The levels of copovidone are shown. Higher amounts of copovidone result in lower specific force.

[0277] Evaluation of tablet core properties at tablet hardnesses of 90N and 120N with suitable punches. Punching tool Table 27 shows the results of the different tablet weights (i.e., 25%, 35%, 40% combined with 50% external phase). A 50 mg dose strength with three different drug loadings resulting in a granule drug loading of 100% was used. Summary of tablet punch tools.

[0278] [Table 35]

[0279] Tablet core extrusion force Table 28 presents the extrusion force values ​​recorded for tablet cores produced at 90N and 120N. It was found that for all batches of both hardness levels, the extrusion force was compared to the recommended value of 500N. The results show that the

[0280] [Table 36]

[0281] Tablet core disintegration time Disintegration of the tablet cores was evaluated for both tablet core hardness levels (90N and 120N) using HCl, 0 The disintegration time in water was also measured for the 120N tablet cores. Disintegration time values ​​were expressed as the maximum of three tablet cores (see Table 29). Only F7-07 exhibited a higher disintegration time (DT), exceeding 900 sec / 15 min. All other batches did not exceed 480 sec / 8 min. In batch F7-07, the DT was The tablet hardness was four times lower than that of tablets with a higher tablet hardness.

[0282] [Table 37]

[0283] As shown in the Pareto chart in Figure 35, all factors were significantly higher in the tablet core DT manufactured at 90N. Significantly affected tablet core DT with higher tablet hardness at 120N There are no factors that influence the results. The two main influencing factors are the amount of copovidone and the drug load. A higher amount of copovidone and a higher drug loading result in a higher DT at 90N tablet core hardness. Tablet hardness appears to have a significant effect on DT. It is believed that the use of high copovidone and mannitol in the spray suspension is more It has been shown to result in long disintegration times.

[0284] Dissolution profile of tablet core Dissolution rates of tablet cores containing compound (A) with tablet hardness of 90N and 120N, respectively was measured by UV spectroscopy in an automated device, with a paddle at 50 rpm and pH 3 and 0.0 The dissolution test is carried out in 1M HCl pH 2 with a basket speed of 100 rpm (conventional method for dissolution testing). Method: European Pharmacopoeia 2.9.3 "Dissolution test of solid dosage forms" or United States Pharmacopoeia <711> "Elution " or the basket method according to the Japanese Pharmacopoeia <6.10> "Dissolution test".

[0285] Dissolution profiles of 90N and 120N tablet cores in baskets at a speed of 100 rpm ( pH2) Low variability was observed in all batches except batch F7-07, which had a higher RSD value of up to 5%. The results were consistent across the four focal batches (i.e., F7-09-10-1). 1-12) were reproducible and showed similar dissolution profiles.

[0286] Three batches of 90N hardness: F7-01, F7-05 and F7-07, 0.01M The lowest dissolution profile was observed with the basket at 100 rpm in HCl pH 2. This finding is supported by the highest disintegration times observed for these batches. In all batches, over 80% of compound (A) was dissolved in 30 minutes, but 100% was dissolved in 60 minutes. Between 60 and 75 minutes, the basket speed was increased from 100 to 200 rpm. increased to.

[0287] Tablet core dissolution rates at 15 and 30 minutes standardized for the tablet core assay Charts (Fig. 37A, 37B): Chart 37A at 90N, Chart 37B at 120N) , indicating that the main significant contributing factors are drug loading and amount of SLS. To achieve this, low drug loading and high amounts of sodium lauryl sulfate are recommended. FIG. 38 shows that low drug loading and low copovidone are combined in basket 100. Binary interactions shown to result in high dissolution rates of 90N tablet cores measured by the rpm method A Pareto chart is shown.

[0288] Dissolution profile of 120N tablet cores in paddles at a speed of 50 rpm (pH 3) As mentioned above, the drug substance (compound (A)) is a Class 2 compound in the Biopharmaceutical Classification System. It is a weak base and exhibits a strong pH-dependent solubility (3 mg / mL at pH 1.2 and p H3 at 0.003 mg / mL). The dissolution rate of 120N tablet cores was measured at pH 3, 50 rpm The results were evaluated in 900 mL of 0.001 M HCl pH 3 with a paddle speed of 1.0. Low variability was observed among all batches (RSD < 5%).

[0289] The Pareto plot (Figure 37) represents the 120N tablet core dissolution rates at 15 and 30 minutes. Only slight differences between the paddles are observed, but the Pareto plot shows that the paddle m indicates that all four factors have a significant effect on the dissolution rate at 15 minutes. At 30 minutes, the primary influencing factor is the amount of SLS.

[0290] Conclusion of all experiments on granule qualitative and quantitative composition The excipient ratio from the granular composition is determined based on the solid to be sprayed onto the carrier to form the matrix. The amounts of copovidone, sodium lauryl sulfate, mannitol, and The external composition is added in an amount that is considered favorable for tablet disintegration, dispersion, and associated dissolution rates. As expected, this is fixed at 50% in these experiments.

[0291] Granulation, final blend (i.e. flowability, density, particle size distribution) and tablet cores (i.e. compaction The properties of the granules, final product (disintegration time, dissolution rate) were evaluated. Summary of major statistically significant influencers on blend and tablet core response. be.

[0292] [Table 38]

[0293] [Table 39]

[0294] [Table 40]

[0295] Based on the statistical analysis, this study showed that the ratio of copovidone, sodium lauryl sulfate and drug Loading was found to be the major factor affecting granule, final blend and tablet core properties. Mannitol has little effect on the response. High levels of copovidone are High levels of sodium lauryl sulfate and low drug loading result in better This contributes to a faster dissolution rate. In all batches, the final blend flowability was acceptable. As a result, the final blend exhibited good tabletability in terms of tensile strength and low extrusion force.

[0296] Based on the above experiments, the following granule composition (Table 31) is selected: Crospovidone ratio: Medium ratio of 0.5, low fine powder, low extrusion force and fast tablet compression. It shows a good compromise regarding granule size with ADT and DR Sodium Lauryl Sulfate: A higher ratio level of 0.04 is required for a higher dissolution rate. Can Mannitol SD200 ratio (from spray suspension): The presence of mannitol is essential for the granules, final batch The effect on the physical properties of the blend and tablets is low. The decision was made to remove the Drug loading: Lower specific levels (<35%) contribute to faster dissolution rates

[0297] [Table 41]

[0298] Example 8: Film-coated tablets Using all the optimized parameters obtained from the experiments in the previous examples, the following A 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 recipe

[0303] [Table 44]

[0304] Final product composition

[0305] [Table 45]

[0306] Example 9: Preparation The capsule and tablet final blends were prepared following a procedure similar to that described in the flow chart above. It was prepared accordingly. a. Add a binder, such as polyvinylpyrrolidone-vinyl acetate copolymer, to the water with stirring. Allow to dissolve. b. Add a surfactant, such as sodium lauryl sulfate (SLS), to the solution from step a and stir. Dissolve while stirring. c. Add compound (A) to the solution of step b and suspend with stirring. d. Milling, for example wet media milling, is carried out with the suspension of step c. e. Add the required amount of SLS and polyvinylpyrrolidone-vinyl acetate copolymer with stirring. Then dissolve in additional purified water. f. Weigh out the required amount of the suspension from step d and add it to the solution from step e and spray, e.g. spray granulation. The suspension is then completed. g. Load the inert substrate (carrier particles), e.g., mannitol SD. h. The suspension of step e is sprayed onto the inert substrate of step g, e.g., mannitol SD200. Thereby, spraying, for example spray granulation, is carried out. i. The granule particles of step h are mixed with any pharma- ceutically acceptable excipient, e.g., mannitol. DS, sodium starch glycolate, polyvinylpyrrolidone-vinyl acetate copolymer , and further mixed with croscarmellose sodium. j. The blended mixture of step i is introduced into capsules or compressed to form tablets.

[0307] Process Flow Diagram

[0308] [Table 46]

[0309] Example 10: Stability Studies Stability Data of Capsules of Example 4 Stability data for Example 4 (10 mg, 25 mg and 50 mg) up to 24 months Stability Program: Stability program includes aluminum induction seals and child-resistant screws - Square high density polyethylene bottle with cap fastener (175ml, 30 capsules) The hard gelatin capsules (10 mg, 25 mg and 50 mg) of Example 4 were packaged in 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] Photostability test: Photostability testing is defined as "Photostability testing of new drug substances and new preparations." y testing of new active substances and m In accordance with the ICH guidelines for "edicinal products" [ICH Q1B] Therefore, the hard gelatin capsules of Example 4 were used with ICH Q1B Option 2 as the light source. The capsules (10 mg, 25 mg and 50 mg) were tested together with the unpackaged product. Alongside the illuminated samples, samples protected from light were run to serve as controls.

[0311] The light-stable sample load must be at least 200 watts at a total illumination of at least 1.2 million lux. The near ultraviolet energy was measured in milliseconds per square meter.

[0312] Open Bottle: This test was performed on the hard gelatin capsules of Example 4 stored in an open glass dish. The samples were stored at 25°C / 60% RH for up to one month. The mechanical and physical properties were analyzed.

[0313] Freeze-thaw cycles: This test is performed on aluminum induction seals and child-resistant screw caps. Square high density polyethylene bottle (HDPE) with a cap (175 ml, 30 caps) The hard gelatin capsules (10 mg, 25 mg and 5 mg) of Example 4 were packaged in a capsule. Stability samples were subjected to four complete freeze-thaw cycles (-20°C / week). The samples were stored at room temperature for 6 days followed by 25°C / 60% RH for 1 day. After 28 days, samples were harvested and analyzed for chemical and physical properties.

[0314] Test Method: The following tests are performed as described in the table below.

[0315] [Table 47]

[0316] Stability results for hard gelatin capsules Hard gelatin capsules (10 mg, 25 mg and 50 mg) in HDPE bottles Store at 5°C / ambient RH, 25°C / 60% RH or 30°C / 75% RH for up to 24 months When the material was heated, it showed good physical and chemical stability. No significant changes in chemical and physical properties were observed. No polymerization was observed.

[0317] Hard gelatin capsules (10 mg, 25 mg and 50 mg) in HDPE bottles It exhibits good physical and chemical stability when stored at 40℃ / 75%RH for up to 6 months. No significant changes in chemical and physical properties were observed.

[0318] Hard gelatin capsules (10 mg, 25 mg and 50 mg) in HDPE bottles It exhibits good physical and chemical stability when stored at 50℃ / 75%RH for up to one month. No significant changes in chemical and physical properties were observed.

[0319] Light of hard gelatin capsules (10mg, 25mg and 50mg) in HDPE bottles Stability The samples demonstrated good physical and chemical stability.

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

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

[0322] Stability Data of Film-Coated Tablets (50 mg) of Example 8 Stability Program: The stability program covers up to 18 months of aluminum induction sealed and Rectangular high density polyethylene with cold resistance screw cap closure container Film-coated tablets (10) of Example 8 packaged in a bottle (175 ml, 30 capsules) , 25, 50 and 100 mg) were tested: 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 testing as well as freeze-thaw cycle testing were performed according to the tests described above for the capsules. This was carried out.

[0324] The test method is carried out as described above for the capsules.

[0325] Stability test results: Film-coated tablets of Example 8 (10, 25, 50 and 100 mg) were stored at 5° C. / ambient RH When stored at 25℃ / 60%RH and 30℃ / 75%RH, good aging was observed for up to 18 months. The chemical and physical stability was demonstrated.

[0326] Chemical (assay and degradation products) and physical (appearance, thickness, diameter, dissolution 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 40°C / 75% Good chemical and physical stability for up to 6 months when stored in HDPE bottles at RH After storage in an HDPE bottle at 40℃ / 75%RH, the initial value (150.1 nm) and A slight increase in particle size was observed in the 10 mg and 25 mg tablets compared to the 177.6 nm particle size. This small increase is not expected to have any impact.

[0328] The film-coated tablets of Example 8 (10, 25, 50 and 100 mg) were 50°C / 75% Good chemical and physical stability for up to 1.5 months when stored in HDME bottles at 4°C. Other than the particle size of the 10 mg clinical batch, the chemical (assay and degradation products) and physical No significant changes in properties (appearance, thickness, diameter, dissolution rate, water content) were observed. 5 After 1.5 months of storage in HDPE bottles at 0°C / 75% RH, the particle size of the 10 mg tablet was slightly A significant increase was observed (from 150.5 nm at the initial time point to 196.0 nm). The small increase is not expected to have any impact.

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

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

[0331] Freezing and thawing of film-coated tablets (10, 25, 50 and 100 mg) in HDPE bottles The cycled samples showed good physical and chemical stability.

[0332] The stability of the crystalline form was assessed by XRPD: Test specimens stored for 9 months at 5°C / ambient RH, 25°C / 60% RH and 30°C / 75% RH The film-coated tablets of Example 8 (10 mg, 25 mg, 50 mg and 100 mg) There was no change in the XRPD pattern. The crystalline form (A) described in this article remains stable under these conditions. No conversion was observed.

Claims

1. 1. A pharmaceutical composition for oral administration comprising granule particles, the granule particles comprising: (a) an inert substrate; (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or its free form and at least one binder; 13. A pharmaceutical composition comprising:

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

3. The pharmaceutical composition of claim 1 or 2, wherein the mixture (b) optionally further comprises a surfactant.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the (b) mixture and optional surfactant are layered onto the (a) inert substrate.

5. 5. The pharmaceutical composition of claim 4, wherein the (b) mixture and optional surfactant are layered onto the (a) inert substrate using a spray granulation process.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the (a) inert substrate comprises a material selected from the group consisting of lactose, microcrystalline cellulose, mannitol, sucrose, starch, granulated hydrophilic fumed silica or mixtures thereof, preferably a material selected from the group consisting of lactose, mannitol or mixtures thereof, and most preferably the material is mannitol.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the binder is independently selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene glycol copolymer, polyethylene-propylene glycol copolymer or mixtures thereof, preferably the binder is polyvinylpyrrolidone-vinyl acetate copolymer.

8. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, potassium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, polysorbate, perfluorobutanesulfonate, dioctyl sulfosuccinate or mixtures thereof, preferably, the surfactant is sodium lauryl sulfate.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the mixture (b) comprises N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt or a free form thereof, polyvinylpyrrolidone-vinyl acetate copolymer as a binder, and optionally sodium lauryl sulfate as a surfactant.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the weight ratio between N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form and said binder is about [3:1], about [2:1] or about [1:1] or about [1:2] or about [1:3], preferably about [1:1], more preferably about [2:1].

11. The weight ratio of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof, the binder, and the surfactant is [3:1:1], or about [3:1:0.5], or about [3:1:0.1], or about [2:1:1], or about [2:1 :0.5], or about [2:1:0.1], or about [2:1:0.08], or about [2:1:0.05], or about [2:1:0.04], or about [2:1:0.03], or about [2:1:0.02], or about [1:1:0.5], or about [1:1:0.1], or about [1:1:0.07], or about [1:1:0.05], or about [1:1:0.04], or about [1:1:0.02], preferably said ratio is about [ 2:1:1], or about [2:1:0.5], or about [2:1:0.1], or about [2:1:0.08], or about [2:1:0.05], or about [2:1:0.04], or about [2:1:0.03], or about [2:1:0.02], or about [1:1:0.5], or about [1:1:0.1], or about [1:1:0.07], or about [1:1:0.05], or about [1:1:0.04], or about [1:1:0.02], or 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the ratio is about [1:3:0.1], or about [1:3:0.2], or about [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 about [2:1:0.1], or about [2:1:0.05], or about [2:1:0.04], or about [2:1:0.03], or about [2:1:0.02].

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the binder (e.g. polyvinylpyrrolidone-vinyl acetate copolymer) is present in the (b) mixture in an amount of 25% w / w to about 100% w / w based on the weight of the N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form, preferably about 50% w / w or about 100% w / w based on the weight of the N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the mixture (b) further comprises a surfactant (e.g., sodium lauryl sulfate) in an amount of 1% w / w to about 10% w / w based on the weight of the N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form, preferably about 4% w / w or about 5% w / w based on the weight of the N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form is less than 1000 nm.

15. 15. The pharmaceutical composition of claim 14, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form is less than 500 nm.

16. 16. The pharmaceutical composition according to claim 15, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form is less than 350 nm, preferably less than 250 nm.

17. 15. The pharmaceutical composition of claim 14, wherein the particle size of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharma- ceutically acceptable salt or its free form is from about 100 nm to about 350 nm, preferably from about 110 nm to about 180 nm, as measured by PCS.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, further comprising an external phase, said external phase comprising one or more pharma- ceutically acceptable excipients.

19. 19. The pharmaceutical composition of claim 18, wherein the one or more pharma- ceutically acceptable excipients are selected from fillers, disintegrants, lubricants and glidants.

20. 20. A pharmaceutical composition according to claim 18 or 19, wherein the external phase comprises one or more fillers selected from calcium carbonate, sodium carbonate, lactose (e.g. lactose SD), mannitol (e.g. mannitol DC), magnesium carbonate, kaolin, cellulose (e.g. microcrystalline cellulose, powdered cellulose), calcium or sodium phosphate or mixtures thereof, preferably mannitol or cellulose or mixtures thereof.

21. 21. The pharmaceutical composition according to any one of claims 18 to 20, wherein the external phase comprises one or more disintegrants selected from croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch or alginic acid or mixtures thereof.

22. 22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the external phase comprises one or more lubricants selected from magnesium stearate, sodium stearyl fumarate, stearic acid or talc, or mixtures thereof.

23. 23. The pharmaceutical composition according to any one of claims 18 to 22, wherein the external phase comprises mannitol and cellulose as fillers, sodium stearyl fumarate or magnesium stearate as lubricants, and croscarmellose sodium or sodium carbonate as disintegrants.

24. 24. The pharmaceutical composition according to any one of claims 18 to 23, wherein the external phase is present in an amount of 20-50% w / w of the total weight of the composition, preferably in an amount of 40% w / w of the total weight of the composition.

25. 25. The pharmaceutical composition according to any one of claims 1 to 24, further formulated into a final dosage form, optionally in the presence of at least one pharma- ceutically acceptable excipient, said final dosage form being a capsule, tablet, sachet or stick pack.

26. 26. The pharmaceutical composition according to claim 25, wherein the final dosage form is a capsule or preferably a tablet.

27. 27. The pharmaceutical composition according to claim 25 or 26, wherein the capsule is selected from a hard shell capsule, a hard gelatin capsule, a soft shell capsule, a soft gelatin capsule, a vegetable shell capsule or a mixture thereof and the tablet is preferably a film coated tablet.

28. A final dosage form which is a capsule formulation comprising the pharmaceutical composition according to any one of claims 1 to 25.

29. A final dosage form which is a tablet formulation comprising the pharmaceutical composition according to any one of claims 1 to 25.

30. 30. The final dosage form of claim 29, wherein N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt or a free form thereof is present in an amount of about 10% w / w to about 25% w / w, preferably about 19% or about 20%, based on the total weight of the final dosage form.

31. 31. The final dosage form of claim 29 or 30, wherein the filler is present in an amount of about 20 to about 40% w / w, based on the total weight of the final dosage form.

32. 32. The final dosage form according to any one of claims 29 to 31, wherein the disintegrant is present in an amount of about 5% w / w to about 10% w / w, preferably about 5 or about 6%, based on the total weight of the final dosage form.

33. 33. The final dosage form according to any one of claims 29 to 32, wherein the inert substrate is present in an amount of about 20% w / w to about 40% w / w, preferably about 30%, based on the total weight of the final dosage form.

34. 34. The final dosage form according to any one of claims 29 to 33, wherein the binder is present in an amount of about 5% w / w to about 25% w / w, preferably about 8 to about 12% w / w, based on the total weight of the final dosage form.

35. 35. The final dosage form according to any one of claims 29 to 34, wherein the lubricant is present in an amount of about 0.1 to about 2% w / w, preferably about 0.5% w / w to about 1.5% w / w, based on the total weight of the final dosage form.

36. 36. The final dosage form according to any one of claims 29 to 35, wherein the surfactant is present in an amount of about 0.1% w / w to about 2.5% w / w, preferably about 0.2% w / w to about 0.8% w / w, based on the total weight of the final dosage form.

37. 37. The final dosage form of any one of claims 29 to 36, comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof in an amount of from about 0.5 mg to about 600 mg, such as from about 5 mg to about 400 mg, for example from about 10 mg to about 150 mg.

38. 38. The final dosage form of any one of claims 29 to 37, comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof in an amount of about 0.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg or about 600 mg, preferably in an amount of about 10 mg, about 25 mg, about 35 mg, about 50 mg, about 75 mg and about 100 mg.

39. A process for preparing a pharmaceutical composition according to any one of claims 1 to 27, comprising the steps of: i) mixing said (b) mixture in a liquid medium comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof, at least one binder and optionally a surfactant; and ii) adding said mixture (i) to said (a) inert matrix of said granule particles. A process including.

40. 40. The process of claim 39, wherein step (i) is carried out in a wet-grinding chamber.

41. The process according to claim 39 or 40, wherein the liquid medium is preferably an aqueous solution having a pH value of from 5 to 8, more preferably from 5 to 6, such as purified water.

42. 42. The process of any one of claims 39 to 41, wherein the mixture of step (i) is dispersed on the (a) inert substrate.

43. 43. The process according to any one of claims 39 to 42, further comprising preparing the final dosage form by blending the mixture resulting from step (ii) with at least one pharma- ceutically acceptable excipient.

44. 44. The process of claim 43, wherein the final dosage form is encapsulated or tableted.

45. 45. The process of claim 44, wherein the final dosage form is tableted and the resulting tablets are further film coated.

46. 1. A process for preparing a suspension comprising mixing (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof, at least one binder, and optionally a surfactant, with a liquid medium.

47. A suspension comprising N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof or a free form thereof, at least one binder and optionally a surfactant in a liquid medium.

48. 48. A suspension according to claim 47, wherein the particle size of the suspension is less than 1000 nm, preferably less than 500 nm, more preferably less than 350 nm, most preferably less than 250 nm.

49. A suspension according to claim 47 or 48, wherein the liquid medium is preferably an aqueous solution having a pH value of from 5 to 8, more preferably from 5 to 6, such as purified water.

50. 50. The suspension of any one of claims 47 to 49, wherein N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt or a free form thereof is present in an amount of about 10% to about 40% of the total weight of the suspension, preferably about 20% or about 25% of the total weight of the suspension.

51. 51. The suspension according to any one of claims 47 to 50, wherein the at least one binder is present in an amount of from about 3% to about 15% by total weight of the suspension.

52. 52. A suspension according to any one of claims 47 to 51, wherein the surfactant is present in an amount of from about 0.05% to about 1% of the total weight of the suspension.

53. A pharmaceutical composition according to any one of claims 1 to 27 or a final dosage form according to any one of claims 29 to 37 for use as a medicament.

54. A pharmaceutical composition according to any one of claims 1 to 27 or a final dosage form according to any one of claims 27 to 39 for use in the treatment or prevention of a disease or disorder mediated by BTK or ameliorated by inhibition of BTK.

55. The diseases or disorders mediated by BTK or ameliorated by inhibition of BTK include autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, cryoglobulinemia, 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, Crohn's disease, 55. The pharmaceutical composition for use or the final dosage form for use according to claim 53 or 54, selected from diseases in which antibody production, antigen presentation, cytokine production or lymphoid tissue formation is abnormal or undesirable, including pancreatitis, glomerulonephritis, Goodpasture's 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; 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's lymphoma; lymphoma; polycythemia vera; essential thrombocytosis; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease, cancers of hematopoietic origin, including, but not limited to: Preferably, said disease or disorder mediated by BTK or ameliorated by inhibition of BTK is selected from rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjogren's syndrome, multiple sclerosis or asthma.

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