Pharmaceutical composition

Abstract

The present invention relates to the field of pharmacy, in particular to a pharmaceutical composition for oral administration comprising a pharmaceutical composition for oral administration comprising (a) an inert matrix, and (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof and at least one binding agent. The present invention further relates to a process for the preparation of said pharmaceutical composition for oral administration; and to the use of said pharmaceutical composition for the manufacture of a medicament.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and particularly to pharmaceutical compositions for oral administration, the pharmaceutical compositions comprising: (a) an inert matrix, and (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, and at least one binder. The invention also relates to methods for preparing said pharmaceutical compositions for oral administration; and to the use of said pharmaceutical compositions in the manufacture of pharmaceuticals. Background Technology

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a member of the TEC kinase family (Smith et al., BioEssays, 2001, 23, 436-446). BTK is expressed in selected cells of the adaptive and innate immune systems, including B cells, macrophages, mast cells, basophils, and platelets.

[0003] BTK-deficient mice were protected in standard preclinical models of rheumatoid arthritis (Jansson and Holmdahl, Clin. Exp. Immunol. [Clinical and Experimental Immunology] 1993, 94, 459-465), systemic lupus erythematosus, and allergic diseases and anaphylactic reactions, highlighting the important role of BTK in autoimmune diseases. Furthermore, many BTK-expressing cancers and lymphomas appear to depend on BTK function (Davis et al., Nature, 2010, 463, 88-92). The roles of BTK in diseases including autoimmune, inflammatory, and cancer have recently been reviewed (Tan et al., Pharmacol. Ther. [Pharmacology and Therapeutics], 2013, 294-309; Whang et al., Drug Discov. Today, 2014, 1200-4).

[0004] A specific BTK inhibitor, N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, or its free form, is referred to as a compound (A) of the following formula:

[0005]

[0006] Compound (A) is a selective, potent, irreversible covalent BTK inhibitor and is one of the next-generation covalent enzyme inhibitors. Compound (A) was first disclosed in Example 6 of WO 2015 / 079417 (Attorney's Case No. PAT056021-WO-PCT), filed November 28, 2014, which is incorporated herein by reference in its entirety. Compound A is referred to as LOU064, and its INN name is Remibrutinib. The compound is intended for the treatment or prevention of diseases or conditions mediated by or improved by BTK inhibition. Therefore, there is a need to provide commercially viable pharmaceutical compositions comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, or a free form thereof. Attached Figure Description

[0007] Figure 1 The dissolution rate curves of particles containing compound (A) at pH 2 (paddle speed 50 rpm) are shown.

[0008] Figure 2 The dissolution rate curves of particles containing compound (A) at pH 3 (paddle speed 50 rpm) are shown.

[0009] Figure 3 The pharmacokinetic (PK) curves of particulate matter containing compound (A) in dogs at pH 2 (HCl 0.01N) were plotted.

[0010] Figure 4 The pharmacokinetic (PK) curves of particulate matter containing compound (A) in dogs at pH 3 (HCl 0.01N) were plotted.

[0011] Figure 5 The pharmacokinetic (PK) curves of the particles containing compound (A) in dogs were plotted at pH 4.5 (acetate buffer) and a paddle speed of 50 rpm.

[0012] Figure 6 The pharmacokinetic (PK) curves of the particles containing compound (A) in dogs were plotted at pH 6.8 (phosphate buffer) and a paddle speed of 50 rpm.

[0013] Figure 7 The effect of particle size of compound (A) on the dissolution rate at pH 2 (paddle speed 50 rpm) is shown.

[0014] Figure 8 The effect of particle size of compound (A) on dissolution rate at pH 3 (paddle speed 50 rpm) is shown.

[0015] Figure 9 Pharmacokinetic (PK) curves were plotted in dogs using particles containing micron-sized compound (A) or nano-sized compound (A).

[0016] Figure 10 Pharmacokinetic (PK) curves in dogs were plotted using particles of compound (A) with micron-sized or nano-sized particles (A).

[0017] Figure 11 Scanning electron micrographs (SEM) depict the wet milling suspension containing compound (A).

[0018] Figure 12 The dynamic viscosity of a wet media grinding suspension containing compound (A) was described.

[0019] Figure 13 Scanning electron micrographs (SEMs) depict wet media milling suspensions containing compound (A) for formulations F2, F5, and F6.

[0020] Figure 14 Scanning electron micrographs (SEMs) depict wet media milling suspensions containing compound (A) for formulations F7, F8, and F9.

[0021] Figure 15 depicts the temperature at 40℃ ( Figure 15a ), 25℃ Figure 15b ) and 10℃ ( Figure 15c The dynamic viscosity of different wet media grinding suspensions containing 25% w / w compound (A) used for optimization experiments was determined.

[0022] Figure 16 depicts a Pareto chart, which shows the six factors that have the greatest impact on the particle size of the blend. Figure 16A and Figure 16B )

[0023] Figure 17 A Pareto diagram was drawn, showing the three factors that have the greatest impact on the volume and density of the blend.

[0024] Figure 18 The flow properties of various external phase compositions were described using a pharmacopoeia flow scale (Carr's index below 25% and Hausner ratio of 1.31).

[0025] Figure 19 Pareto plots were drawn, showing the two most influential factors on the tensile strength of the tablet.

[0026] Figure 20 Pareto plots were drawn, showing the main factors affecting tablet pushing force.

[0027] Figure 21 The disintegration time of tablet cores of different formulations in HCl (0.01N pH2) was described.

[0028] Figure 22 Pareto plots were plotted, showing the main factors influencing the dissolution rate.

[0029] Figure 23 depicts a Pareto diagram, which shows the main factors influencing particle size distribution. Figure 23A and Figure 23B )

[0030] Figure 24 Pareto plots were drawn, showing the main factors affecting particle bulk density and tap density.

[0031] Figure 25 The flow properties of different particulate compositions were described according to the pharmacopoeia flow scale (Karl index below 15% and Hausnerby below 1.18).

[0032] Figure 26 A Pareto plot was drawn, which shows the main factors affecting particle flowability.

[0033] Figure 27 Pareto plots were drawn, showing the main factors affecting tensile strength under a compressive force of 30 kN.

[0034] Figure 28 A Pareto plot was drawn, showing the main factors affecting the particle pushing force at 30 kN.

[0035] Figure 29 depicts a Pareto chart, showing the main factors influencing the final blend PSD. Figure 29A and Figure 29B )

[0036] Figure 30 The flow properties of the final blend were described according to the pharmacopoeia flow scale (Karst index below 15% and Hausnerby below 1.18).

[0037] Figure 31 A Pareto diagram was plotted, showing the main factors affecting the flowability of the final blend.

[0038] Figure 32 The sieving separation curves of the particles and the final blend were plotted.

[0039] Figure 33Pareto plots were drawn, showing the main factors affecting the tensile strength of tablets under a compressive force of 20 kN.

[0040] Figure 34 A Pareto plot was drawn, which shows the main factors affecting the tablet pushing force at 20 kN.

[0041] Figure 35 Pareto plots were plotted, showing the main factors affecting the core disintegration time at pH 2.

[0042] Figure 36 A two-way interaction diagram was drawn: the disintegration time of the 90N core.

[0043] Figure 37 depicts a Pareto chart, which shows the main factors influencing average dissolution (90 N and 120 N). Figure 37A and Figure 37B ).

[0044] Figure 38 A two-way interaction diagram was plotted: dissolution rates for various drug loadings and copovidone loadings.

[0045] Figure 39 The evolution of average particle size relative to specific energy for several batches of compound (A) processed under the following conditions was depicted: product temperature from about 34°C to about 40°C; air-to-liquid ratio from about 2.0 to about 3.2; batch size (M) from about 62 to 175 kg; and process parameters including rotor tip velocity (v) from 10 to 14 m / s and suspension flow rate (V) from 5 to 20 L / min. The average particle size of compound (A) was determined by photon correlation spectroscopy (PCS).

[0046] Figure 40 The loss on drying (LOD) trajectories of granules processed under the following process conditions were depicted during processing: product temperature (T) ranging from 34°C to 40°C, spray rate (m), atomizing air pressure (p), and air-to-liquid mass flow rate ratio (A / L) ranging from approximately 2.0 to approximately 3.2. LOD was determined offline (offline LOD) from granule samples collected during processing using a halogen moisture analyzer, and online (online LOD) from fluidized granules during processing was determined using a near-infrared (NIR) spectral probe installed in a fluidized bed spray granulation apparatus.

[0047] Figure 41 Depicting the corresponding Figure 40The experimental results shown are the particle size distribution of particles produced under the following process conditions, which have different product temperatures (T) between 34°C and 40°C, spray rates (m), atomizing air pressures (p), and air-to-liquid mass flow rates (A / L) between about 2.0 and about 3.2; the particle size distribution was determined by sieve analysis. Summary of the Invention

[0048] Designing pharmaceutical compositions, dosage forms, and commercially viable methods for preparing BTK inhibitors such as N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or its pharmaceutically acceptable salts or its free form (hereinafter referred to as compound (A)) is challenging. This BTK inhibitor is difficult to formulate due to its physicochemical properties (e.g., low solubility, low exposure), exhibits a tendency to gel under certain pH conditions, and is unstable when exposed to certain temperatures and / or UV light. Ultimately, these issues affect the manufacturing process and, consequently, the bioavailability and dispersibility of the BTK inhibitor of the present invention.

[0049] Therefore, there is a need to develop suitable and robust solid pharmaceutical compositions that overcome the aforementioned problems. This invention provides pharmaceutical compositions that exhibit improved drug dissolution rates, increased absorption, increased bioavailability, and reduced inter-patient variability. Furthermore, this invention provides a method for preparing the pharmaceutical composition, wherein this method offers advantages such as ease of scale-up, robust processing, and cost-effectiveness.

[0050] Given the aforementioned difficulties and considerations, it is surprising that a method for preparing stable pharmaceutical compositions has been discovered that allows for the preparation of pharmaceutical compositions comprising: (a) an inert matrix, and (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-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.

[0051] The various aspects, advantageous features, and preferred embodiments of the invention, summarized individually or in combination in the following items, contribute to achieving the objectives of the invention.

[0052] Example:

[0053] 1. A pharmaceutical composition for oral administration, the pharmaceutical composition comprising particulate particles, the particulate particles comprising:

[0054] (a) Inert matrix, and

[0055] (b) A mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form and at least one binder.

[0056] 2. The pharmaceutical composition according to Example 1, wherein N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is in free form.

[0057] 3. The pharmaceutical composition according to Example 1 or 2, wherein the mixture (b) optionally further comprises a surfactant.

[0058] 4. The pharmaceutical composition according to any one of Examples 1-3, wherein the mixture (b) and optionally a surfactant are laminated onto the inert matrix (a).

[0059] 5. The pharmaceutical composition according to Example 4, wherein the mixture (b) and optional surfactant are laminated onto the inert matrix (a) using a spray granulation method.

[0060] 6. The pharmaceutical composition according to any one of Examples 1-5, wherein the (a) inert matrix comprises a material selected from the group consisting of lactose, microcrystalline cellulose, mannitol, sucrose, starch, granular hydrophilic pyrolytic 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.

[0061] 7. The pharmaceutical composition according to any one of Examples 1-6, wherein the adhesive is independently selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene glycol copolymer, polyethylene glycol-propylene glycol copolymer, vitamin E polyethylene glycol succinate, or mixtures thereof, preferably the adhesive being polyvinylpyrrolidone-vinyl acetate copolymer.

[0062] 8. The pharmaceutical composition according to any one of Examples 1-7, wherein the surfactant is selected from the group consisting of sodium dodecyl sulfate, potassium dodecyl sulfate, ammonium dodecyl sulfate, sodium dodecyl ether sulfate, polysorbate, perfluorobutane sulfonate, dioctyl sulfosuccinate, or mixtures thereof, preferably sodium dodecyl sulfate.

[0063] 9. The pharmaceutical composition according to any one of Examples 1-8, wherein the mixture (b) comprises N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof, a polyvinylpyrrolidone-vinyl acetate copolymer as a binder, and optionally sodium dodecyl sulfate as a surfactant.

[0064] 10. The pharmaceutical composition according to any one of Examples 1-9, wherein the weight ratio between N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form and the binder 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].

[0065] 11. The pharmaceutical composition according to any one of Examples 1-9, wherein the weight ratio of N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, 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] [2:1:0.5], [2:1:0.1], [2:1:0.08], [2:1:0.05], [2:1:0.04], [2:1:0.03], [2:1:0.02], [1:1:0.5], [1:1:0.1], [1:1:0.07], [1:1:0.05], [1:1:0.04], or [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 approximately [2∶1∶1], or approximately [2∶1∶0.5], or approximately [2∶1∶0.1], or approximately [2∶1∶0.08], or approximately [2∶1∶0.05], or approximately [2∶1∶0.04], or approximately [2∶1∶0.03], or approximately [2∶1∶0.02], or approximately [1∶1∶0.5], or approximately [1∶1∶0.25]. 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], and 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].

[0066] 12. The pharmaceutical composition according to any one of Examples 1-11, wherein the binder (e.g., polyvinylpyrrolidone-vinyl acetate copolymer) is present in the mixture (b) in an amount of about 25% w / w to about 100% w / w based on N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, preferably based on about 50% w / w or about 100% w / w based on N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form.

[0067] 13. The pharmaceutical composition according to any one of Examples 1-12, wherein the mixture (b) further comprises a surfactant (e.g., sodium dodecyl sulfate) in an amount based on 1% w / w to about 10% w / w of N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, preferably based on about 4% w / w or about 5% w / w of N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form.

[0068] 14. The pharmaceutical composition according to any one of Examples 1-13, wherein the particle size of the N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or the free form thereof is less than 1000 nm.

[0069] 15. The pharmaceutical composition according to Example 14, wherein the particle size of the N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or the free form thereof is less than 500 nm.

[0070] 16. The pharmaceutical composition according to Example 15, wherein the particle size of the N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or the free form thereof is less than 350 nm, preferably less than 250 nm.

[0071] 17. The pharmaceutical composition according to Example 14, wherein the particle size of the N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, as measured by PCS, is between about 100 nm and about 350 nm; preferably between about 110 nm and about 180 nm.

[0072] 18. The pharmaceutical composition according to any one of Examples 1-17, wherein the pharmaceutical composition further comprises an external phase, wherein the external phase comprises one or more pharmaceutically acceptable excipients.

[0073] 19. The pharmaceutical composition according to Example 18, wherein the one or more pharmaceutically acceptable excipients are selected from fillers, disintegrants, lubricants and flow aids.

[0074] 20. The pharmaceutical composition according to Example 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 phosphate or sodium phosphate, or mixtures thereof, preferably mannitol or cellulose, or mixtures thereof.

[0075] 21. The pharmaceutical composition according to any one of Examples 18-20, wherein the external phase comprises one or more disintegrants selected from croscarmellose sodium, crosspovidone, sodium glycolate starch, corn starch, or alginate or mixtures thereof.

[0076] 22. The pharmaceutical composition according to any one of Examples 18-21, wherein the external phase comprises one or more lubricants selected from magnesium stearate, sodium stearate fumarate, stearic acid, or talc or mixtures thereof.

[0077] 23. The pharmaceutical composition according to any one of Examples 18-22, wherein the external phase comprises mannitol and cellulose as fillers, sodium stearate or magnesium stearate as lubricants, and croscarmellose sodium or sodium carbonate as disintegrants.

[0078] 24. The pharmaceutical composition according to any one of Examples 18-23, wherein the exogenous phase is present in an amount of 20-50% w / w / of the total weight of the composition, preferably 40% w / w / of the total weight of the composition.

[0079] 25. The pharmaceutical composition according to any one of Examples 1-24, wherein the pharmaceutical composition is optionally further formulated into a final dosage form in the presence of at least one pharmaceutically acceptable excipient, and wherein the final dosage form is a capsule, tablet, sac, or stickpack.

[0080] 26. The pharmaceutical composition according to Example 25, wherein the final dosage form is a capsule or preferably a tablet.

[0081] 27. The pharmaceutical composition according to Example 25 or 26, wherein the capsule is selected from hard-shell capsules, hard gelatin capsules, soft-shell capsules, soft gelatin capsules, plant-based shell capsules or mixtures thereof, and wherein the tablet is preferably a film-coated tablet.

[0082] 28. A final dosage form comprising a capsule formulation of a pharmaceutical composition according to any one of Examples 1-25.

[0083] 29. A final dosage form comprising a tablet formulation comprising the pharmaceutical composition according to any one of Examples 1-25.

[0084] 30. The final dosage form according to Example 29, wherein N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form is present in an amount of about 0.4% w / w to about 35% w / w based on the total weight of the final dosage form, preferably about 10% w / w to about 25% w / w, and more preferably about 19% or about 20%.

[0085] 31. The final dosage form according to Example 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.

[0086] 32. The final dosage form according to Examples 29, 30 or 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.

[0087] 33. The final dosage form according to any one of Examples 29-32, wherein the inert matrix is ​​present in an amount of about 20% w / w to about 40% w / w, preferably about 30% w / w, based on the total weight of the final dosage form.

[0088] 34. The final dosage form according to any one of Examples 29-33, wherein the adhesive 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.

[0089] 35. The final formulation according to any one of Examples 29-34, 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 formulation.

[0090] 36. The final dosage form according to any one of Examples 29-35, 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.

[0091] 37. The final dosage form according to any one of Examples 29-36, wherein the final dosage form comprises an amount of 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 of N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof.

[0092] 38. The final dosage form according to any one of Examples 29-37, wherein the final dosage form comprises 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 about 10 mg, about 25 mg, about 50 mg, and about 100 mg of N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof.

[0093] 39. A method for preparing a pharmaceutical composition according to any one of Examples 1-27, the method comprising the following steps:

[0094] (i) Mixing the mixture of (b) in a liquid medium, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, at least one binder, and optionally a surfactant, and

[0095] (ii) Add the mixture (i) to the inert matrix (a) of the particulate particles.

[0096] 40. The method according to Example 39, wherein step (i) is performed in a wet grinding chamber.

[0097] 41. The method according to Example 39 or 40, wherein the liquid medium is an aqueous solution, such as purified water, preferably having a pH value between 5 and 8.

[0098] 42. The method according to any one of Examples 39-41, wherein the mixture of step (i) is dispersed on the inert matrix (a).

[0099] 43. The method according to any one of Examples 39-42, wherein the method further comprises preparing the final dosage form by blending the mixture obtained from step (ii) with at least one pharmaceutically acceptable excipient.

[0100] 44. The method according to Example 43, wherein the final dosage form is filled into capsules or compressed into tablets.

[0101] 45. The method according to Example 44, wherein the final dosage form is compressed into tablets and the resulting tablets are further coated with a film.

[0102] 46. ​​A method for preparing a suspension, the method comprising mixing the mixture (b) with a liquid medium, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof, at least one binder and optionally a surfactant.

[0103] 47. A suspension comprising, in a liquid medium, N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof, at least one binder and optionally a surfactant.

[0104] 48. The suspension according to Example 47, wherein 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.

[0105] The suspension according to Example 47 or 48, wherein the liquid medium is an aqueous solution, such as purified water, preferably having a pH value between 5 and 8, and more preferably between 5 and 6.

[0106] 49. The suspension according to any one of Examples 47 to 49, wherein N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form 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.

[0107] 50. The suspension according to Examples 47 to 50, wherein the at least one binder is present in an amount of about 3% to about 15% of the total weight of the suspension.

[0108] 51. The suspension according to Examples 47 to 51, wherein the surfactant is present in an amount of about 0.05% to about 1% of the total weight of the suspension.

[0109] 52. The pharmaceutical composition according to any one of Examples 1-27, used as a medicine, or the final dosage form according to any one of Examples 29-37, used as a medicine.

[0110] 53. The pharmaceutical composition according to any one of Examples 1-27, used for the treatment or prevention of diseases or conditions mediated by or improved by BTK inhibition, or the final dosage form according to any one of Examples 29-37, used for the treatment or prevention of diseases or conditions mediated by or improved by BTK inhibition.

[0111] 54. The pharmaceutical composition used according to Example 53 or 54, or the final dosage form according to Example 53 or 54, wherein the disease or condition improved by BTK-mediated or by inhibiting BTK is selected from autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases with abnormalities or adverse events in antibody production, antigen presentation, cytokine production, or lymphatic organs; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, common carcinoma. Pemphigus, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), chronic allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease (Morbus syndrome) Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic diseases, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenstrom's disease. Preferably, the disease or condition that is improved by BTK-mediated or by inhibiting BTK is selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma.

[0112] 55. Use of the pharmaceutical composition according to any one of Examples 1-27 in the manufacture of a medicament for the improvement of a disease or condition mediated by or by inhibiting BTK, said disease or condition being selected from autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases with abnormalities or adverse effects on antibody production, antigen presentation, cytokine production, or lymphoid organs; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (Chronic Spontaneous 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, pancreatitis, glomerulonephritis, Goodpasser syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic diseases, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenström's disease. Preferably, the disease or condition that is improved by BTK-mediated or by inhibiting BTK is selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma.

[0113] 56. A method for treating or preventing a disease or condition mediated by or improved by inhibiting BTK, the method comprising administering to a subject in need of such treatment or prevention a pharmaceutical composition according to any one of Examples 1-27 or a final dosage form according to any one of Examples 29-37.

[0114] 57. The method according to Example 57, wherein the disease or condition improved by BTK-mediated or by inhibiting BTK is selected from autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases with abnormalities or adverse events in antibody production, antigen presentation, cytokine production, or lymphoid organs; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria) Herpes simplex virus (HSV), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasser syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic diseases, pulmonary embolism; cancers of hematopoietic origin, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenström's disease. Preferably, the disease or condition that is improved by BTK-mediated or by inhibiting BTK is selected from rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, or asthma. Detailed Implementation

[0115] Efficient formulation of the BTK inhibitor N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form (referred to herein as compound (A)) has proven difficult. For example, formulation difficulties have been observed due to its strongly pH-dependent solubility problems, such as a tendency to gel under certain pH conditions, instability upon exposure to certain temperatures and / or UV light, poor dissolution rates (e.g., dispersibility), low solubility, low exposure, and bioavailability issues. Ultimately, these problems affect the manufacturing process of pharmaceutical compositions.

[0116] Surprisingly, it was found that these challenges could be overcome by preparing a pharmaceutical composition for oral administration comprising: (a) an inert matrix, and (b) a mixture comprising a BTK inhibitor and at least one binder. According to this disclosure, the BTK inhibitor is N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form (referred herein to as compound (A)).

[0117] In one aspect, the present invention provides a pharmaceutical composition for oral administration, the pharmaceutical composition comprising particulate particles, the particulate particles comprising: (a) an inert matrix, and (b) a mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form and at least one binder.

[0118] In another aspect of the invention, compound (A) is present in the form of a pharmaceutically acceptable salt. In a preferred aspect of the invention, compound (A) is present in its free form, for example, in its anhydrous form. In particular, compound (A) is present in the crystal form (A) described in WO 2020 / 234779 (Attorney General's File No. PAT058512), filed May 20, 2020. In yet another embodiment, the crystal form of compound (A) is substantially homogeneous.

[0119] According to the present invention, a pharmaceutical composition comprises (a) an inert matrix, to which (b) a mixture comprising compound (A) and at least one binder is added. The inert matrix comprises a material that does not chemically react with the mixture comprising compound (A) and at least one binder. The inert substance (a), such as a pharmaceutically acceptable excipient known in the art, does not chemically or physically interact with the active substance. Optionally, the inert substance (a) may also be coated with a layer to protect it from any unwanted chemical or physical interactions that may occur during the formulation process. In this context, the term "inert matrix" may be used interchangeably with the term "carrier particle". (a) The inert matrix may comprise a material selected from the group consisting of lactose, microcrystalline cellulose, mannitol, sucrose, starch, granular hydrophilic pyrolytic silica, sugar beads (Kayaert et al., J. Pharm. Pharmacol. 2011, 63, 1446-1453), polymer films (Sievens-Figueroa et al., Int. J. Pharm. 2012, 423, 496-508), or mixtures thereof. Preferably, the material is selected from the group consisting of lactose, mannitol, or mixtures thereof. More preferably, the material is mannitol, such as mannitol SD, mannitol SD100, or mannitol SD200.

[0120] Particle size is measured, for example, by laser diffraction methods (e.g., particle size distribution (PSD)) using methods and instruments known to those skilled in the art.

[0121] Suitable adhesives may be selected from, for example, the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose (e.g., sodium cellulose gum, cellulose gum), methylcellulose (e.g., cellulose methyl ether, tylose), hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene glycol copolymer, polyethylene glycol-propylene glycol copolymer, vitamin E polyethylene glycol succinate, or mixtures thereof. Preferably, the adhesive is a polyvinylpyrrolidone-vinyl acetate copolymer (also known as copolyvinylpyrrolidone).

[0122] At least one adhesive present in mixture (b) may be present in an amount of about 25% w / w to about 100% w / w based on the weight of compound (A). The above range applies to all adhesives listed above. Preferably, the adhesive is a polyvinylpyrrolidone-vinyl acetate copolymer and is present in an amount of about 25% w / w to about 100% w / w based on the weight of compound (A). In a preferred embodiment, the adhesive (preferably copovidone) is present in mixture (b) in an amount of about 50% or about 100% w / w based on the weight of compound (A). In yet another preferred embodiment, the weight ratio of compound (A) to adhesive in mixture (b) is in the range of about [3:1] to about [1:3]; for example, about [3:1], about [2:1], about [1:1], about [1:2] or about [1:3], preferably [2:1]. More preferably, the weight ratio of compound (A) to adhesive in mixture (b) is about [1:1]. In yet another embodiment, the weight ratio of compound (A) to binder in the pharmaceutical composition is about [3:1], about [2:1], or about [1:1], most preferably [2:1].

[0123] In another aspect, the present invention also provides a pharmaceutical composition (e.g., for oral administration) wherein (b) the mixture optionally further comprises a surfactant. According to the invention, the pharmaceutical composition (e.g., for oral administration) comprises (a) an inert matrix, on which (b) the mixture comprising compound (A), at least one binder, and optionally a surfactant is added. Suitable surfactants may be selected, for example, from the group consisting of sodium lauryl sulfate (SLS), potassium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, polysorbate, perfluorobutane sulfonate, dioctyl sulfosuccinate, or mixtures thereof. Preferably, the surfactant is sodium lauryl sulfate (SLS).

[0124] When present in mixture (b), the surfactant may be present in an amount of about 1% w / w to about 10% w / w based on the weight of compound (A). The above range applies to all surfactants listed above. Preferably, the surfactant is sodium dodecyl sulfate (SLS) and is present in an amount of about 1% w / w to about 10% w / w based on the weight of compound (A), preferably in an amount of 2 to 6% w / w based on the weight of compound (A), and more preferably in an amount of about 4% w / w or about 5% w / w based on the weight of compound (A). According to an aspect of the invention, when a surfactant is present, (b) the weight ratio of compound (A), at least one adhesive and surfactant in the mixture 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 approximately [2:1:1], or approximately [2:1:0.5], or approximately [2:1:0.1], or approximately [2:1:0.08], or approximately [2:1:0.05], or approximately [2:1:0.04], or approximately [2:1:0.03], or approximately [2:1:0.02], or approximately [1:1:0.5], or approximately [1:1:0.1], or approximately [1:1:0.07], or approximately [1:1:0.05], or approximately [1:1:0.04], or approximately [1:1:0.02], or approximately [1:3:0.1], or approximately [1:3:0.2], or approximately 1:1.5:0.25. 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]. In one embodiment, when a surfactant is present, (b) the weight ratio of compound (A), at least one binder, and surfactant in the mixture is about [2:1:0.08].In a particular embodiment, 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], 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], more preferably about [2:1:0.08].

[0125] In another embodiment, when a surfactant is present, the weight ratio of compound (A), at least one binder, and surfactant in the pharmaceutical composition 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]. In yet another aspect, when a surfactant is present, the weight ratio of compound (A), at least one binder, and surfactant in the pharmaceutical composition is about [2:1:0.08]. In a particular aspect of this embodiment, the surfactant is SLS and the binder is copovidone, and the weight ratio of compound (A), copovidone and SLS in the pharmaceutical composition 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], more preferably about [2:1:0.08].

[0126] According to an aspect of the invention, mixture (b), comprising compound (A), at least one binder, and optionally a surfactant, is premixed together. Mixture (b) can be added to a liquid medium, which is substantially insoluble in the liquid medium, to form a premix. The liquid medium can be, for example, aqueous or non-aqueous. Preferably, the liquid medium is an aqueous solution, such as water. According to an aspect of the invention, mixture (b) is in the form of a suspension or dispersion, more preferably a suspension.

[0127] Compound (A) may be present in a liquid medium in an amount of about 5% w / w to about 40% w / w based on the total combined weight of the premix, preferably in an amount of about 10% w / w, or about 15% w / w, or about 20% w / w, or about 25% w / w, or about 30% w / w, more preferably in an amount of about 20% w / w based on the weight of the premix.

[0128] At least one adhesive may be present in the liquid medium in an amount of about 3% w / w to about 15% w / w based on the weight of the premix; preferably in an amount of about 4% w / w, or about 6% w / w, or about 8% w / w, or about 10% w / w, more preferably about 4% w / w based on the weight of the premix.

[0129] The surfactant, when present, is present in the liquid medium in an amount of about 0.05% to about 1% based on the weight of the premix, preferably about 0.1%, or about 0.5%, or about 0.75% based on the weight of the premix, and more preferably about 0.1% w / w.

[0130] According to the invention, the premix can be used directly or subjected to mechanical treatment to reduce the average particle size to less than 1000 nm. Particle size is measured, for example, by laser diffraction (e.g., particle size distribution (PSD)) using methods and instruments known to those skilled in the art. Preferably, the particle size measured by PCS is less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm. In one embodiment, the particle size of the suspension measured by PCS is 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, particle sizes of 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 160 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 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, or from about 250 nm to about 350 nm. The formed particles are stabilized by the presence of a binder as defined herein in the premix, which is capable of maintaining the particles in a stable state at the desired particle size.

[0131] According to the invention, a mixture (b) comprising compound (A), at least one binder, and optionally a surfactant, as defined herein, can be added to an inert matrix (a) using various techniques known in the art as described herein. Preferably, the mixture (b) comprising compound (A), at least one binder, and optionally a surfactant, as defined herein, is dispersed onto the inert matrix (a). In another preferred aspect, the inert matrix (a) is coated with the mixture (b) comprising compound (A), at least one binder, and surfactant. In yet another preferred aspect, the mixture (b) comprising compound (A), at least one binder, and optionally a surfactant, as defined herein, is a suspension and is preferably dispersed or coated as discrete particles on an inert core (a), thus providing a large surface area for immediate dissolution despite poor solubility of the drug.

[0132] Another aspect of the invention provides a suspension comprising, in a liquid medium such as an aqueous solution (e.g., purified water, preferably with a pH of 5 to 8, more preferably 5 to 6), N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof (hereinafter referred to as compound (A)), at least one binder, and optionally a surfactant. According to the invention, the particle size of said suspension, as measured by PCS, is less than 1000 nm, preferably less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm, as defined herein. Specifically, the average particle size of the suspension, as measured by PCS, 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, particle sizes of 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 160 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 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 about 100 nm to about 350 nm, or about 110 nm to about 180 nm, or about 250 nm to about 350 nm.

[0133] Another aspect of the invention provides a dispersible solution comprising, in a liquid medium such as an aqueous solution (e.g., purified water, preferably with a pH of 5 to 8, more preferably 5 to 6), N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof (referred to herein as compound (A)), at least one binder, and optionally a surfactant.

[0134] According to the present invention, a pharmaceutical composition is prepared by mixing about 0.5 mg to about 600 mg of compound (A) with at least one binder and optionally a surfactant. Preferably, the pharmaceutical composition is prepared by mixing about 5 mg to about 400 mg of compound (A) with at least one binder and optionally a surfactant. More preferably, the pharmaceutical composition is prepared by mixing about 10 mg to about 150 mg of compound (A) with at least one binder and optionally a surfactant. The pharmaceutical composition disclosed herein (e.g., for oral administration) may comprise a mixture of 10 mg of compound (A) with at least one binder and optionally a surfactant. The pharmaceutical composition may also comprise a mixture of 15 mg of compound (A) with at least one binder and optionally a surfactant. In another example, the pharmaceutical composition (e.g., for oral administration) may also be prepared with 20 mg of compound (A) and at least one binder and optionally a surfactant. In another example, the pharmaceutical composition (e.g., for oral administration) may also comprise, for example, 25 mg of compound (A), at least one binder, and optionally a surfactant. In another example, the pharmaceutical composition is prepared by mixing 50 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition is prepared by mixing 100 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition (e.g., for oral administration) may also be prepared by mixing 150 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition is prepared by 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) may also be prepared by mixing 250 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition is prepared by mixing 300 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition (e.g., for oral administration) may also be prepared by mixing 350 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition is prepared by mixing 400 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition (e.g., for oral administration) may also be prepared by mixing 450 mg of compound (A) with at least one binder and optionally a surfactant. In another example, a pharmaceutical composition may be prepared by mixing 500 mg of compound (A) with at least one binder and optionally a surfactant.In another example, a pharmaceutical composition (e.g. for oral administration) may also be prepared by mixing 600 mg of compound (A) with at least one binder and optionally a surfactant.

[0135] According to aspects of the invention, the particulate particles as defined herein may optionally include an external sealing coating layer. The material contained in the external sealing coating layer does not chemically react with the mixture as defined herein (b) and protects the mixture from any undesirable chemical or physical interactions that may occur during formulation, such as any undesirable chemical or physical interactions with additives, pharmaceutically acceptable excipients, or any other active pharmaceutical ingredient. The external sealing coating layer may also provide additional barriers for taste masking and gastric (gastric or stomach) release, while allowing intestinal (enteric or intestinal) release. If present, the outer sealing coating layer may be selected from, for example, but not limited to, hydroxypropyl methylcellulose, magnesium stearate, polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, cellulose acetate phthalate (CAP), cellulose trimellitate acetate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, cellulose acetate succinate, fatty acids, waxes, shellac, sodium alginate, or mixtures thereof.

[0136] In one embodiment, the present invention provides a pharmaceutical composition as defined above, wherein the particle size of the pharmaceutical substance (i.e., compound (A)) is less than 1000 nm. Preferably, the particle size of compound (A) as measured by PCS is less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm. In one embodiment, the particle size of compound (A) measured by PCS is from 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, a particle size of 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 160 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 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 of compound (A) is about 100 nm to about 350 nm, or about 110 nm to about 180 nm, or about 250 nm to about 350 nm.

[0137] Another aspect of the invention provides a method for preparing a pharmaceutical composition as defined herein (e.g., for oral administration), the method comprising the steps of:

[0138] (i) Mixing the mixture of (b) in a liquid medium, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, at least one binder, and optionally a surfactant, and

[0139] (ii) Add the mixture (i) to the inert matrix (a) of the carrier particles.

[0140] Another aspect of the invention provides a method for preparing a pharmaceutical composition as defined herein (e.g., for oral administration), the method comprising the steps of:

[0141] (iii) Mixing the mixture of (b) in a liquid medium, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, at least one binder, and optionally a surfactant, wherein the liquid medium is an aqueous or non-aqueous solution, and

[0142] (iv) Add the mixture (i) to the inert matrix (a) of the carrier particles.

[0143] Another aspect of the invention relates to a method for preparing a pharmaceutical composition as defined herein (e.g., for oral administration), the method comprising the steps of:

[0144] (i) Mixing the mixture described in (b) in an aqueous solution, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, at least one binder, and optionally a surfactant, wherein the aqueous solution is water, and

[0145] (ii) Add the mixture (i) to the inert matrix (a) of the carrier particles.

[0146] BTK inhibitors, such as compound (A), are present in amounts of about 0.5 mg to about 600 mg, or about 5 mg to about 400 mg, or about 10 mg to about 150 mg, as defined herein.

[0147] As described above, mixture (b) can be added to a liquid medium (e.g., an aqueous solution) that is substantially insoluble in the liquid medium to form a premix. The premix can be dispersed or suspended in the liquid medium using suitable agitation until a homogeneous dispersion or suspension is observed, in which large agglomerates are not visible to the naked eye. Mechanical means that can be used to reduce the particle size of compound (A) are any mechanical means known to those skilled in the art. Preferably, the mechanical means for reducing the particle size of mixture (b) (or premix) containing compound (A) is a grinding process performed in a grinding chamber. Suitable grinding techniques include, for example, ball milling, wet milling, media milling, wet media milling, stirred milling, stirred media milling, wet stirred media milling, stirrer milling, stirrer media milling, wet stirrer media milling, bead milling, stirrer bead milling, wet stirrer bead milling, and high-pressure homogenization. Preferably, nanoscale particles are prepared using a milling technique selected from wet milling, media milling, wet media milling, or high-pressure homogenization. More preferably, the milling technique is wet milling, media milling, and wet media milling. Specifically, nanoscale particles are prepared using a wet media milling technique. Therefore, according to the present invention, step (i) of the method as defined herein is carried out in a grinding chamber, particularly in a wet grinding chamber. The pH of the premix in the grinding chamber is from about pH 5 to pH 8, preferably about pH 6. The method is carried out with process parameters such that the minimum specific energy introduced into the suspension is 200 kJ / kg and the suspension temperature at the grinding chamber outlet is at most 35°C. More preferably, the method is carried out with a higher specific energy above 200 kJ / kg and a lower suspension temperature at the grinding chamber outlet below 35°C. The specific energy is calculated according to Kwade (Kwade, Powder Technology 1999, 105, 14-20; and Kwade, Chemical Engineering and Technology 2003, 26, 199-205). This relationship is studied for different batch sizes (e.g., from about 62 to 175 kg), rotor tip speeds (e.g., from 10 to 14 m / s), and liquid flow rates (e.g., from 5 to 20 L / min). Figure 39This demonstrates the relationship between average particle size and specific energy established for different manufacturing batches, taking into account various batch sizes, rotor tip speeds, and suspension flow rates. Although the studied batch sizes, rotor tip speeds, and suspension flow rates differed, the particle size of compound (A) was reasonably controlled by the specific energy parameter. The method was carried out with process parameters resulting in a minimum specific energy of approximately 200 kJ / kg introduced into the suspension and a maximum suspension temperature of 35°C at the grinding chamber outlet. Preferably, the method was carried out with a higher specific energy above 300 kJ / kg and a maximum suspension temperature of 32°C at the grinding chamber outlet. Most preferably, the method was carried out with a specific energy above 600 kJ / kg and a suspension temperature of 16°C to 32°C at the grinding chamber outlet.

[0148] Therefore, one aspect of the present invention is to provide a suspension comprising, in a liquid medium, N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof, at least one binder, and optionally a surfactant. In one aspect, the suspension has a particle size of less than 1000 nm, preferably less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm. In another aspect, the liquid medium of the suspension is an aqueous solution, such as purified water, preferably having a pH value between 5 and 8, and more preferably between 5 and 6.

[0149] In another aspect, the suspension described above contains compound (A) or a pharmaceutically acceptable salt thereof or a free form thereof, wherein compound (A) or a pharmaceutically acceptable salt thereof 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.

[0150] In another aspect, the present invention provides a suspension as described above, wherein at least one binder (preferably copovidone) is present in an amount of about 3% to about 15% of the total weight of the suspension.

[0151] In another aspect, the present invention provides a suspension as defined above, wherein a surfactant (preferably SLS) is present in an amount of about 0.05% to about 1% of the total weight of the suspension.

[0152] According to the present invention, a method for preparing a pharmaceutical composition as defined herein (e.g., for oral administration) comprises adding the mixture from step (i) to an inert matrix (a) of carrier particles, as defined herein. The mixture (b) can be added using various techniques known in the art, such as spray drying, spray granulation, spray layering, spray dispersion, spray coating, fluidized bed drying, fluidized bed coating, fluidized bed spray granulation, a granulator with nozzles, or combinations of these spraying techniques. According to the present invention, coating or spraying can be performed, for example, simultaneously or sequentially from above the carrier particles (e.g., top spraying or top coating) and below the carrier particles (e.g., bottom spraying or bottom coating). According to the present invention, top spraying or top coating is preferred. Preferably, the mixture (b) as defined herein, wherein the inert matrix (a) is coated with the mixture (b). More preferably, the mixture from process step (i) is dispersed onto the inert matrix (a). Specifically, mixture (b) is added using, for example, spray drying, spray granulation, fluidized bed spray granulation, or a combination of these spraying technologies. A liquid medium, such as purified water, is evaporated to maintain the product (compound (A)) temperature between about 30°C and about 45°C. Preferably, the product temperature is between about 36°C and about 44°C. More preferably, at a temperature between about 36°C and about 40°C. In the spray granulation process, the spray rate and atomizing air pressure are parameters that determine the droplet size of the sprayed liquid during spraying. These parameters depend on the geometry of the nozzle. Each nozzle is characterized by the air consumption at a specific atomizing air pressure. This factor is typically provided by the nozzle manufacturer in an air consumption chart. This value, along with the spray rate used, is used to calculate the air-to-liquid mass ratio applied during the spraying process. The granulation process is carried out using a spray rate and atomizing air pressure that results in an "air-to-liquid mass flow ratio" ranging from about 1.1 to about 3.2, for example, from about 1.1 to about 2.3. An air-to-liquid mass flow rate ratio between approximately 1.1 and approximately 3.2 is important because it controls the droplet size distribution of the liquid after atomization. Droplet size increases as the air-to-liquid ratio decreases, which results in particles that are less desirable for subsequent tablet compression, blend uniformity, and separation risk.Loss on drying (LOD) of particles is a widely accepted alternative metric for quantitatively describing the complex relationship between material and process parameters during spray granulation, such as material parameters (spray liquid) and process parameters (spray rate, air velocity, and inlet air temperature) (Ochsenbein DR et al., Int. J. Pharm. X1 (2019) 100028; Lyngberg O et al., Applications of Modeling in Oral Solid Dosage Form Development and Manufacturing, in: Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture, Ierapetritou M.G. and Ramachandran R. (eds.), Humana Press (2016) 1-42). Experimentally, a loss-of-drying (LOD) trajectory was established as a characteristic alternative to the optimal process conditions (i.e., process conditions in which the product temperature is from about 34°C to about 40°C and the air-to-liquid ratio is from about 2.0 to about 3.2). Figure 40 The LOD trajectories for the optimal process conditions as defined above are shown. Higher and lower LOD trajectories indicate the range of optimal process conditions for relatively wet process conditions (higher LOD trajectories) and relatively dry process conditions (lower LOD trajectories). The corresponding product particle size distribution is shown in... Figure 41 In general, relatively wet process conditions (higher LOD trajectory) result in a coarser particle size distribution, while relatively dry process conditions (lower LOD trajectory) result in a finer particle size distribution. Particle size distribution is rationally controlled by the optimal process conditions as defined above, represented by the LOD trajectory. Process conditions exceeding both higher and lower LOD trajectories result in particles with less desirable properties for tablet compression and blend uniformity.

[0153] In another aspect of the invention, a method for preparing a suspension is provided, the method comprising mixing a mixture as defined herein (b) in a liquid medium as defined herein. Therefore, another aspect of the invention relates to a method for preparing a pharmaceutical composition as defined herein (e.g., for oral administration), the method comprising the steps of:

[0154] (i) A suspension is prepared by mixing the mixture in (b) in a liquid medium, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, at least one binder, and optionally a surfactant, wherein the liquid medium is an aqueous solution, such as purified water, preferably having a pH value between 5 and 8, and more preferably between 5 and 6, and

[0155] (ii) The suspension from step (i) is added to the inert matrix of the carrier particles in step (a).

[0156] In one aspect of the above method, the suspension has an average particle size of less than 1000 nm as measured by PCS. Preferably, the particle size of the suspension measured by PCS is less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm. In one embodiment, the particle size of the suspension measured by PCS is 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, particle sizes of 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 160 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 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 about 100 nm to about 350 nm, or about 110 nm to about 180 nm, or about 250 nm to about 350 nm.

[0157] In another aspect, the present invention provides a method for preparing a dispersion, the method comprising mixing a mixture as defined herein (b) with a liquid medium as defined herein. Therefore, another aspect of the invention relates to a method for preparing a pharmaceutical composition as defined herein (e.g., for oral administration), the method comprising the steps of:

[0158] (i) A dispersion is prepared by mixing the mixture of (b) in a liquid medium, the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or in its free form, at least one binder, and optionally a surfactant, wherein the liquid medium is an aqueous solution, such as purified water, preferably having a pH value between 5 and 8, and more preferably between 5 and 6, and

[0159] (ii) The dispersion from step (i) is added to the inert matrix of the carrier particles in step (a).

[0160] In one aspect of the above method, the suspension has an average particle size of less than 1000 nm as measured by PCS. 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, particle sizes of 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 160 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 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 about 110 nm to about 350 nm, or about 110 nm to about 160 nm, or about 250 nm to about 350 nm.

[0161] Another aspect of the invention relates to a method for preparing a pharmaceutical composition (e.g., for oral administration) as defined herein, the method further comprising preparing a final dosage form by blending the mixture obtained from step (ii) with an external phase comprising at least one pharmaceutically acceptable salt thereof. For example, an external phase as defined herein may be added to prevent chemical-physical interactions between the particles and any other active or inactive substances that may be used to prepare the final dosage form. An additional advantage of the external phase is that it provides acceptable dissolution rates, acceptable disintegration times, better processability and compressibility, such as tablet tensile strength.

[0162] Another aspect of the invention provides a method for preparing unit dosage forms (e.g., for oral administration), the method comprising the steps of:

[0163] (i) The mixture (b) is mixed in a wet grinding chamber in a liquid medium such as an aqueous solution (e.g., purified water, preferably having a pH between 5 and 8, and more preferably between 5 and 6), the mixture comprising N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, at least one binder (e.g., polyvinylpyrrolidone-vinyl acetate copolymer), and optionally a surfactant (e.g., sodium dodecyl sulfate (SLS)), wherein the average particle size of compound (A) in the mixture (b) is less than 1000 nm, preferably less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm (particle size, for example, from about 100 nm to about 350 nm, or from about 110 nm to 180 nm, as disclosed herein).

[0164] (ii) adding the mixture (i) to the inert matrix (a) of the carrier particles, and

[0165] (iii) The mixture obtained from step (ii) is blended with at least one pharmaceutically acceptable excipient to obtain a final dosage form in which a BTK inhibitor, such as compound (A), is present 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 150 mg (as defined herein).

[0166] Another aspect of the present invention provides a method for preparing a pharmaceutical composition, wherein the method, for example, follows the following process flow diagram.

[0167]

[0168] Another aspect of the invention provides a method as defined herein, wherein the final dosage form is filled into capsules or compressed into tablets. When the final dosage form is a tablet, the tablet may be film-coated.

[0169] Another aspect of the invention provides a method for preparing a final dosage form by mixing carrier particles with at least one pharmaceutically acceptable excipient (external phase). The carrier particles can be converted into a final dosage form (e.g., tablets, capsules) using at least one pharmaceutically acceptable excipient and / or matrix forming agent via, for example, granulation, freeze-drying, or spray drying. Suitable pharmaceutically acceptable excipients may be selected from, for example, lactose, mannitol (e.g., mannitol DC), microcrystalline cellulose (e.g., Avicel). Avicel The excipients may be selected from the group consisting of dicalcium phosphate, polyvinylpyrrolidone, hydroxypropyl methylcellulose, croscarmellose sodium, polyvinylpyrrolidone-vinyl acetate copolymer (e.g., cross-linked polyvinylpyrrolidone), sodium glycolate starch, colloidal silica, magnesium stearate, sodium bicarbonate, sodium stearate fumarate, or mixtures thereof. Preferably, the excipients may be selected from the group consisting of mannitol (e.g., mannitol DC), croscarmellose sodium, colloidal silica, magnesium stearate, sodium bicarbonate, or mixtures thereof. Selection of the at least one pharmaceutically acceptable excipient provides a formulation with good disintegration and dispersion of compound (A), thereby reducing its gelling behavior.

[0170] As disclosed herein, the pharmaceutical composition is intended for oral administration to humans and animals in unit dosage forms or multiple dosage forms, such as capsules, microcapsules, powders, pellets, granules, tablets, microtablets (up to 3 mm or 5 mm), capsules, sachets, or strip pouches. Preferably, the unit dosage form or multiple dosage forms are, for example, capsules, tablets, capsules, sachets, or strip pouches. More preferably, the pharmaceutical composition is in the form of capsules or tablets. This can be achieved by mixing the pharmaceutical composition as defined herein with fillers (or also called diluents), lubricants, flow aids, disintegrants and / or absorbents, colorants, flavoring agents, and sweeteners.

[0171] Capsules containing pharmaceutical compositions of the present invention as defined herein can be prepared using techniques known in the art. Suitable capsules may be selected from hard-shell capsules, hard gelatin capsules, soft gelatin capsules, soft-shell capsules, plant-based shell capsules, hydroxypropyl methylcellulose (HPMC)-based capsules, or mixtures thereof. The pharmaceutical compositions described herein may be present in hard gelatin capsules, hard-shell capsules, or hard plant-shell capsules, hydroxypropyl methylcellulose (HPMC) capsules, wherein the pharmaceutical composition is further mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, magnesium stearate, sodium bicarbonate, or a cellulose-based excipient (e.g., microcrystalline cellulose). Hard gelatin capsules are made from a two-piece outer gelatin shell called the body and the cap. The shell may contain plant or animal gelatin (e.g., gelatin based on pork, beef, or fish), water, one or more plasticizers, and possibly some preservatives. The capsule may contain a dry mixture in powder, very small pellets, or particulate form containing a BTK inhibitor such as compound (A), at least one binder, and optionally a surfactant and / or other excipients. The shell may be transparent, opaque, colored, or flavored. Capsules containing particles can be coated with intestinal and / or gastric resistant or delayed-release coating materials using techniques well known in the art, thereby achieving, for example, greater stability in the gastrointestinal tract, or thus achieving a desired release rate. Hard gelatin capsules of any size (e.g., size 000 to 5) can be prepared.

[0172] Tablets comprising the pharmaceutical compositions of the present invention as defined herein can be prepared using techniques known in the art. Suitable tablets may contain particles mixed with a non-toxic pharmaceutical agent suitable for tablet manufacture. These excipients are, for example, inert diluents (or additionally called fillers), such as 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 phosphate or sodium phosphate, or mixtures thereof; disintegrating agents (or also called disintegrants), such as croscarmellose sodium, crospovidone, sodium glycolate starch, corn starch, or alginate, or mixtures thereof; gliding agents (or also called glidants), such as pyrolytic silica (e.g., croscarmellose sodium, crospovidone, sodium glycolate starch, corn starch, or alginate, or mixtures thereof. The mixture contains: a binding agent (or binder) (e.g., methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, starch, gelatin, or gum arabic) or mixtures thereof; and a lubricating agent (or lubricant), such as magnesium stearate, sodium stearate fumarate, stearic acid, or talc or mixtures thereof. The mixture of particles with the non-toxic drug can be mixed using various known methods, such as mixing in a free sphere or roller blending. The mixture of particles with the non-toxic drug can be compressed into tablets using tableting techniques known in the art (e.g., single-punch press, double-punch press, rotary tablet press, or compression on a roller press). The compressive force applied to form the tablet can be any suitable compressive force that allows for obtaining the tablet; for example, the applied compressive force can be 0.5 to 60 kN, or 1 to 50 kN, or 5 to 45 kN. Preferably, the compressive force is 5 to 25 kN. Tablets or granules may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect for a longer period of time. For example, tablets may be coated with suitable polymers or conventional coating materials to achieve, for example, greater stability in the gastrointestinal tract or a desired release rate; tablets may be coated with hydroxypropyl methylcellulose (HPMC), magnesium stearate, polyethylene glycol (PEG), or polyvinyl alcohol (PVA). Or a mixture thereof. For example, time-retarding materials such as glyceryl monostearate or glyceryl distearate may be used for coating. Tablets of any shape or size may be prepared, and they may be opaque, colored, or flavored. Specifically, the pharmaceutical compositions disclosed herein are in the form of film-coated tablets.

[0173] BTK inhibitors such as N-(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or a free form thereof (referred to herein as compound (A)) are present in the pharmaceutical composition in an amount sufficient to exert a therapeutically useful effect on the treated patient without undesirable side effects. Each unit dose contains a predetermined amount of compound (A) sufficient to produce the desired therapeutic effect. As disclosed herein, each unit dose is suitable for human and animal subjects, individually packaged, and may be administered in fractions or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, blister packs, or bottles.

[0174] According to the present invention, compound (A) may be present in a pharmaceutical composition (e.g., for oral administration) in an amount of about 0.5 mg to about 600 mg. In one aspect, the present invention relates to a pharmaceutical composition for oral administration, wherein the final dosage form comprises 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 150 mg. Preferably, the amount of compound (A) in the final dosage form 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. g, or about 150 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, 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, 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, or about 500 mg, or about 600 mg. Preferably, the amount of compound (A) in the final dosage form 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, about 50 mg, or about 100 mg.

[0175] According to the present invention, the final dosage form comprises about 10 mg of compound (A). In another aspect of the present invention, the final dosage form comprises about 20 mg of compound (A). In another aspect of the present invention, the final dosage form comprises about 25 mg of compound (A). In another aspect of the present invention, the final dosage form comprises about 35 mg of compound (A). In another aspect of the present invention, the final dosage form comprises about 50 mg of compound (A). In yet another aspect of the present invention, the final dosage form comprises about 100 mg of compound (A).

[0176] Another aspect of the invention relates to pharmaceutical compositions (e.g., for oral administration) as defined herein, which comprise at least one additional active pharmaceutical ingredient.

[0177] Another aspect of the invention provides a capsule for oral administration, the capsule comprising about 0.5 mg to about 600 mg of a BTK inhibitor such as compound (A), at least one binder, optionally a surfactant, and at least one pharmaceutically acceptable excipient.

[0178] Another aspect of the invention provides a tablet for oral administration, preferably a film-coated tablet, the tablet comprising about 0.5 mg to about 600 mg of compound (A), at least one binder, optionally a surfactant, and at least one pharmaceutically acceptable excipient.

[0179] The pharmaceutical compositions disclosed herein (e.g., for oral administration) can be used as, for example, medicines. In particular, the pharmaceutical compositions (e.g., for oral administration) can be used as medicines for the treatment or prevention of diseases or conditions mediated by or improved by BTK inhibition, such diseases or conditions include, for example, autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases involving abnormalities or dysfunctions in antibody production, antigen presentation, cytokine production, or lymphoid organs; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, and chronic urticaria (chronic spontaneous). 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, pancreatitis, glomerulonephritis, Goodpasser syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic diseases, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenström's disease. Specifically, this disclosure provides the use of the pharmaceutical composition in the treatment or prevention of diseases or conditions mediated by or improved by BTK inhibition, selected from rheumatoid arthritis; chronic urticaria (preferably chronic spontaneous urticaria); Sjögren's syndrome, multiple sclerosis, or asthma.

[0180] Another aspect of the invention provides the use of pharmaceutical compositions as disclosed herein (e.g., for oral administration) in the manufacture of medicaments for improving a disease or condition mediated by or by inhibiting BTK, wherein the disease or condition is selected from autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases with abnormalities or dysfunctions in antibody production, antigen presentation, cytokine production, or lymphoid organs; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic Urticaria (chronic spontaneous 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, pancreatitis, glomerulonephritis, Goodpasser syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic diseases, pulmonary embolism; hematopoietic cancers, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid metaplastic myelofibrosis; and Waldenström's disease. Specifically, this disclosure provides the use of pharmaceutical compositions as disclosed herein (e.g. for oral administration) in the manufacture of a medicament for a disease or condition that is improved by or through the inhibition of BTK, wherein the disease or condition is selected from rheumatoid arthritis; chronic urticaria (preferably chronic spontaneous urticaria); Sjögren's syndrome, multiple sclerosis, or asthma.

[0181] Another aspect of the invention provides a method for treating or preventing a disease or condition mediated by or improved by inhibiting BTK, the method comprising administering to a subject requiring such treatment or prevention a pharmaceutical composition or final dosage form as disclosed herein.

[0182] definition

[0183] The term "pharmaceutically acceptable salt" refers to salts that can be formed, for example, as acid addition salts, preferably with organic or inorganic acids. Pharmaceutically unacceptable salts, such as picrates or perchlorates, may also be used for separation or purification purposes. For therapeutic uses, only pharmaceutically acceptable salts or free compounds (where applicable to pharmaceutical formulations) are used, and therefore these are preferred. The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, other problems, or complications, commensurate with a reasonable benefit / risk ratio.

[0184] The term "treatment" for any disease or condition refers to improving the disease or condition (e.g., slowing, halting, or reducing the development of at least one of the disease or its clinical symptoms). Additionally, these terms refer to reducing or alleviating at least one bodily parameter, including those that are not identifiable by the patient, and also to regulating the disease or condition physically (e.g., stabilization of identifiable symptoms) or physiologically (e.g., stabilization of bodily parameters) or both.

[0185] The term “prevent” (“preventing” or “prevention”) for any disease or condition refers to delaying the onset, development, or progression of that disease or condition.

[0186] As used herein, the term “about” is intended to provide flexibility in the endpoints of a numerical range, provided that a given value can be “slightly above” or “slightly below” the endpoints to account for differences visible in measurements performed between different instruments, samples, and sample formulations. The term generally means within 10%, preferably within 5%, and more preferably within 1%, of a given value or range.

[0187] The terms "pharmaceutical composition" or "formulation" are used interchangeably herein and refer to physical mixtures containing therapeutic compounds intended to be administered to mammals, such as humans, to prevent, treat, or control specific diseases or symptoms affecting said mammals. The term also encompasses, for example, tightly packed physical mixtures formed under high temperature and pressure.

[0188] The term "oral administration" refers to any method of administration in which a therapeutic compound is administered via the oral route, by swallowing, chewing, or inhaling an oral dosage form. Such oral dosage forms are traditionally designed to substantially release and / or deliver the active pharmaceutical agent in the gastrointestinal tract below the oral cavity and / or buccal cavity.

[0189] As used herein, the term "therapeuticly effective amount" of a compound refers to an amount that will elicit a biological or medical response in a subject, such as improvement of symptoms, relief of symptom, slowing or delaying disease progression. The term "therapeuticly effective amount" also refers to an amount of a compound that, when administered to a subject, effectively at least partially relieves and / or improves symptoms, condition, or disease. The term "effective amount" means an amount of the subject compound that will produce a biological or medical response in cells, tissues, organs, systems, animals, or humans that is being sought by researchers, physicians, or other clinicians.

[0190] Unless otherwise stated, the term "comprising" is used herein in an open-ended and non-limiting sense. In a more limited embodiment, "comprising" may be replaced by the no longer open-ended "consisting of". In the most limited version, it may include only the characteristic steps or the values ​​listed in the various embodiments.

[0191] As used herein, the term "inert matrix" refers to a substance or material that does not react chemically or biologically with reactive substances and will not decompose. For example, an inert matrix refers to a substance or material that does not react chemically with a suspension (i.e., does not react chemically with a mixture (b) comprising compound (A) and at least one binder).

[0192] As used herein, the term "glidant" or "gliding agent" refers to a substance or material that improves the flowability of the final blend.

[0193] As used herein, the term "disintegrant" (or "disintegrating agent") refers to a substance or material added to an oral solid dosage form, such as a tablet, to facilitate its depolymerization by causing rapid breakage of the solid dosage form upon contact with moisture.

[0194] The term "binder" (or "binding agent") is used interchangeably herein and within its established meaning in the pharmaceutical field. It refers to, for example, an inactive substance that adheres to inert matrix particles, added together with the active pharmaceutical ingredient (referred to herein as compound (A)) in the case of compound (A) deposition, or in the case of tableting as a facilitating factor enabling the formation of granules and ensuring the formation of granules with the desired mechanical strength. All binders mentioned herein are used in accordance with the quality suitable for pharmaceutical use and are commercially available under various brand names as shown in the following examples:

[0195] Polyvinylpyrrolidone-vinyl acetate copolymers are commercially available under the trade name Copovidone (approximate molecular weight 45,000-70,000). Copovidone (Ph.Eur.) is a copolymer of 1-vinylpyrrolidone-2-one and vinyl acetate in a mass ratio of 3:2. It contains 7.0% to 8.0% nitrogen and 35.3% to 42.0% vinyl acetate (dry matter). It can be named... VA 64 commercialization.

[0196] Polyvinylpyrrolidone (INN Ph.Eur.) is commercially available under the trade names Povidone K30 or PVP K30 (approximate molecular weight 50,000).

[0197] Carboxymethyl cellulose (USP / NF), also known as the calcium salt of polycarboxymethyl ether cellulose, is commercially available under the trade name Carmellose Calcium.

[0198] Shellac (INN Ph.Eur.) is a commercially available resin excreted by female lac insects found on various trees, including the lac beetle (Laccifer lacca Kerr), the lac scale insect (Kerria lacca Kerr), the lac larva (Tachardia lacca), the small fruit borer (Coccus lacca), and the scale insect (Carteria lacca). The shellac composition is as follows: 46% lac acid (HOCH2(CH2)5CHOHCHOH(CH2)7COOH), 27% lac acid (cyclic dihydroxydicarboxylic acid and its homologues), and 5% kelic acid (CH3(CH2)... 10 (CHOH)4COOH), 1% Ziyu Alcoholic Acid (C 14 H 28 (OH)(COOH)), 2% wax alcohols and acid esters, 7% unidentified natural substances (e.g., coloring substances), and 12% unidentified polyesters.

[0199] Polyvinyl alcohol (INN Ph.Eur.) is commercially available under the trade names Polyviol or PVA (approximate molecular weight 28,000 to 40,000).

[0200] Polyethylene glycol (Ph.Eur.) is commercially available under the trade name PEG-n, where "n" is the number of ethylene oxide units (EO-units) (approximately up to 20,000 molecular weight).

[0201] Polyvinyl alcohol-polyethylene glycol copolymer is also known as polyvinyl alcohol-PEG copolymer or PEG-PVA.

[0202] Polyethylene glycol-propylene glycol copolymer, also known as α-hydrogen-ω-hydroxy poly(ethylene oxide)poly(propylene oxide)poly(ethylene oxide) block copolymer (CAS 9003-11-6), is commercially available under the name poloxamer (INN Ph.Eur.). Poloxamer polyols are a series of closely related block copolymers of ethylene oxide and propylene oxide, conforming to the general formula HO(C2H4O). a (C3H6O) b (C2H4O) a H.

[0203] The term "surfactant" (or "surface active agent") refers to amphiphilic organic compounds, meaning they have both a hydrophobic hydrocarbon chain (tail) and a hydrophilic head. Surfactants contain both water-insoluble (or oil-soluble) and water-soluble components. Based on their dissociation properties, surfactants are classified as ionic (e.g., anionic or cationic) or nonionic.

[0204] - Polysorbate is commercially available under the name Tween 80. In the literature, it is also referred to as polysorbate 80, PEO(20) dehydrated sorbitol monooleate (INCI, formerly known as Crillet4Super).

[0205] The term “nanosize” or “nanoparticle” refers to particles with a size ranging from about 100 nm to about 1000 nm.

[0206] abbreviation

[0207] % w / w (by weight)

[0208] ℃ Celsius

[0209] API active pharmaceutical ingredients

[0210] Area under the AUC curve

[0211] AUCinf refers to the AUC curve up to infinity.

[0212] AUClast is the AUC at which the final measurable concentration is reached.

[0213] Cmax (maximum concentration)

[0214] CV% (coefficient of variation)

[0215] DR dissolution rate

[0216] DSC Differential Scanning Calorimetry

[0217] g / min

[0218] HPLC (High Performance Liquid Chromatography)

[0219] HR-XRPD High-Resolution X-ray Powder Diffraction

[0220] INCI International Terminology for Cosmetic Ingredients

[0221] INN (International Nonproprietary Names of Medicines)

[0222] Kg / g / mg / ng / μg kg / g / mg / nanogram / microgram

[0223] kN kilonewton

[0224] LCMS (Liquid Chromatography-Mass Spectrometry)

[0225] mL / L (milliliters / liter)

[0226] MRT average stay time

[0227] nm / μm nanometer / micrometer

[0228] PCS photon correlation spectroscopy

[0229] European Pharmacopoeia (9th Edition)

[0230] PK Pharmacokinetics

[0231] RH (Relative Humidity)

[0232] RPM (revolutions per minute)

[0233] RRT Relative Retention Time

[0234] RT room temperature

[0235] Standard deviation and relative standard deviation of SD and RSD

[0236] SEM (Scanning Electron Microscopy)

[0237] SLS Sodium Lauryl Sulfate

[0238] TFA (trifluoroacetic acid)

[0239] TGA Thermogravimetric Analysis

[0240] Tmax is the time to reach the peak concentration (Cmax).

[0241] US ultrasonic treatment

[0242] USP (United States Pharmacopeia)

[0243] USP / NF (United States Pharmacopeia / National Formulary)

[0244] w / v (weight to volume)

[0245] w / w weight ratio

[0246] XRPD X-ray powder diffraction

[0247] Example

[0248] The following examples illustrate the present invention and provide support for the disclosure of the present invention, but the present invention does not limit the scope of the present invention.

[0249] Analytical centrifugation (AC), such as LUMiSizer, LUM GmbH Germany, SEPView 6.1.2570.2022. For wet dispersion, the suspension is diluted to an appropriate attenuation level using a purified aqueous solution; the transmittance of the first measurement curve is approximately 10% to 70%. Results reported for X10, X50, and X90 are intensity-weighted.

[0250] Photon correlation spectroscopy (PCS), such as Zetasizer Nano ZS, Malver Panalytical Ltd., UK, version 7.3. A wet dispersion method is used, where the suspension is diluted to a suitable attenuation level with an attenuation index of approximately 2 to 9 using a 0.1 mM NaCl solution (in purified water). The reported X-mean is intensity-weighted. Specifically, the attenuation index is 5. Preferably, the measurement is performed at 25°C. Further preferred settings for the measurement system are as follows:

[0251] Cuvettes: Disposable quantitative cuvettes

[0252] Counting rate (KcPs): 315

[0253] Duration: 60s

[0254] Measurement location (mm): 4.65

[0255] Zeta potential, for example, Zetasizer Nano, Malvern Panaco Ltd., UK

[0256] Scanning electron micrographs (SEM), such as the Supra 40, from Carl Zeiss SMT AG, Germany.

[0257] Dynamic viscosity, for example, that of Haake Mars (Thermo Fisher Scientific GmbH, Germany).

[0258] The sinker method, such as balances with liquid density sinkers, is employed by Mettler Toledo GmbH, Switzerland.

[0259] Microbial count test (MET).

[0260] Example 1: Preparation of particulate particles

[0261] The role of inert matrices was evaluated by adding different mixtures (b) as defined herein to different types of (a) inert matrices (e.g., mannitol and lactose). Different particulate compositions were prepared by suspending the binder polyvinylpyrrolidone-vinyl acetate copolymer (copolyvinyl acetate), compound (A) as defined herein, and surfactant sodium dodecyl sulfate in a liquid medium such as purified water. Different variants are described in Table 1.

[0262] Table 1. Studies on different particle variants and particle size distributions

[0263]

[0264]

[0265] Variants P1, P4, P5, and P7, containing a higher ratio of polyvinylpyrrolidone-vinyl acetate copolymer (copovidone), exhibited the best resuspension properties compared to the initial suspension. Variants P1 and P7, containing a higher ratio of SLS, also showed excellent resuspension properties. Variant P7 was selected as the optimized particulate composition based on the copovidone to SLS ratio, thus achieving a drug loading of 20% of the total weight of the particulate particles by spraying onto an inert matrix (carrier particles) within a reasonable processing time. The dissolution properties of different variants of the particulate particle composition were evaluated to ensure that the dissolution profiles were within a favorable range. The particulate particles prepared as described in Table 1 were added to capsules (e.g., hard gelatin capsules) using conventional methods (according to European Pharmacopoeia 2.9.3 "Dissolution Test for Solid Dosage Forms" or United States Pharmacopeia). <711> The dissolution rate is measured using the paddle method (as described in Japanese Pharmacopoeia <6.10> "Dissolution Test"). Figure 1 and Figure 2 As seen in the text. Figure 1Dissolution rates at pH 2 are shown, and drain conditions (solubility of 0.3 mg / mL) for a 50 mg test dose, independent of the particle size of the drug substance, are provided. For some test capsules containing the aforementioned particulate matter, delayed disintegration and dispersion of the contents resulted in delayed dissolution rate (DR) curves at a paddle speed of 50 rpm. To improve the disintegration and dispersion of the formulation contents, particularly at pH 2, the addition of at least one pharmaceutically acceptable excipient (e.g., as an external phase) was investigated. Figure 2 The results show that for a dose of 50 mg in 900 mL, compound (A) has a maximum solubility of 90% at pH 3. Figure 2 As observed, P1 particles with high levels of polyvinylpyrrolidone-vinyl acetate copolymer and SLS exhibited good resuspension, while P2 particles with low levels of polyvinylpyrrolidone-vinyl acetate copolymer and SLS did not achieve good resuspension. No significant difference in separation behavior was observed between the 0.1 and 0.22 μm filters. For both filters, the dissolution profiles of P2 particles completely overlapped (e.g., ...). Figure 2 (As depicted in the text).

[0266] Then, in male beagle dogs, particulate particles P1, P2, P3, P7 (prepared according to Table 1) and a particulate particle with an additional excipient (P7”) were evaluated, as summarized in Tables 2 and 3.

[0267] Table 2. Canine PK Studies - Formulations P1, P2, P3, P7 and P7

[0268]

[0269]

[0270] Table 3. Results of the dog-to-dog competition

[0271]

[0272] Provide the mean ± SD, *: median [time range]

[0273] The results showed that the inter-subject differences (%) in Cmax and AUClast, as assessed by CV, were 40.7%–90.1% and 49.6%–69.7%, respectively, within the formulation. The maximum concentration (Cmax) within the formulation was reached between 0.5 and 2 hours (median). Based on the results of this study, it is concluded that resuspension supports higher exposure levels in dogs and can be used as a selection criterion for rating different variants (e.g., P1, P2, P3, P7, and P7").

[0274] To better understand the formulation / pH profiles, dissolution rate profiles of the formulations described in Tables 2 and 3 were measured at pH 2, pH 3, pH 4.5, and pH 6.8. The results are summarized in... Figure 3 , Figure 4 , Figure 5 and Figure 6 The results showed that the formulation behavior varied between pH 2 and pH 3. Formulations containing small amounts of binder (polyvinylpyrrolidone-vinyl acetate copolymer) and surfactant (sodium dodecyl sulfate) had faster dissolution rates compared to formulations containing higher amounts. A slower dissolution rate was observed in relation to the observed gelling behavior, which was not observed at lower amounts of binder and surfactant. At pH 3 and higher, no formulations exhibited gelling, and the contents of all capsules dispersed within the first 10 minutes.

[0275] Example 2: The role of granularity

[0276] The role of particle size in compound (A) as defined herein was also investigated to better understand particle size distribution, dissolution profiles of different formulations, and the effect of particle size on formulations. Particulate particles were prepared according to the procedure in Example 1. Several particle sizes of the drug substance (i.e., compound (A)) were investigated as described below (using a 50 mg dose of compound (A)), and the results are plotted on... Figure 7 and Figure 8 middle:

[0277] Particle size V1 = 120 nm - nanoparticle formulation (wet-milled suspension).

[0278] Particle size V2 = 1.2 μm - as a suspension for non-wet milling.

[0279] Particle size V3 = 1.2 μm - as a powder blend.

[0280] Particle size V4 = 2.4 μm - as a powder blend.

[0281] Particle size V5 = 13.9 μm - as a powder blend.

[0282] At pH 2, a strong effect of particle size on the dissolution rate profile has already been observed, as in... Figure 7The following observations were made. Formulation V5 (13.9 μm) showed a significant gap from complete release at infinity, approximately 40%, and exhibited a delayed curve. Compared to 1.2 μm (V2 and V3), particle size 2.4 μm (V4) showed a significant decrease in dissolution rate and also exhibited a delayed curve. A comparison between formulation V1 (120 nm) and formulations with particle size 1.2 μm (V2 and V3) showed that the 1.2 μm formulation started faster on the curve but eventually reached the same endpoint. Figure 7 ).like Figure 8 The particle size effect, as depicted in the dissolution rate (DR) curve at pH 2, is even more pronounced at pH 3. Figure 8 As shown, the difference between the 13.9 μm particle size (V5) and the 120 nm particle size (V1) is approximately 60%. The fastest micron-sized drug substance (V2) shows a difference of approximately 20% compared to V1.

[0283] The effects of particle size (e.g., micrometer or nanometer size) and formulation on pharmacokinetic were evaluated in 13 male beagle dogs following administration of a 50 mg dose of compound (A). Arithmetic mean (SD) hematopoietic concentration-time plots for each treatment are shown below. Figure 9 and Figure 10 The PK parameters are summarized in Table 4 below.

[0284] Table 4. Summary Statistics of PK Parameter Values ​​- Influence of Granularity

[0285]

[0286] The statistic is the mean ± SD (CV%).

[0287] Median (Minimum - Maximum) [n]

[0288] CV% = Coefficient of Variation (%) = SD / Mean × 100

[0289] For Tmax and T1 / 2, only the median (minimum - maximum)[n] is given.

[0290] Compared to the micron-sized formulation (1.0 h), a slightly earlier median Tmax was observed when the formulation containing nano-sized particles of compound (A) was administered (0.75 h). The geometric mean CV% of Cmax for the nano-sized formulation was 117.3%, compared to 178.1% for the micron-sized formulation. Similarly, the geometric mean CV% of AUClast for the nano-sized formulation was 94.7%, compared to 212.5% ​​for the micron-sized formulation. Statistical analysis of the effect of particle size on PK showed that the micron-sized formulation achieved only 40.5% of the AUC (geometric mean ratio: 0.405, 90% confidence interval (CI): 0.215, 0.763) and 40.9% of the Cmax (geometric mean ratio: 0.409, 90% CI: 0.233, 0.717) of the nano-sized formulation. Furthermore, considerably low variability was observed when compared to the micron-sized formulation.

[0291] Example 3: Composition of a suspension

[0292] Considering polyvinylpyrrolidone-vinyl acetate copolymer (copolyvinylpyrrolidone) and sodium dodecyl sulfate (SLS) as excipients, formulation compositions of compound (A) suspensions milled in wet media were investigated to increase drug concentration in the suspension. Several formulation compositions were evaluated as shown in Tables 5 and 6.

[0293] Table 5: Formulation compositions containing compound (A)

[0294]

[0295] The experimental results obtained, based on particle size determination by analytical centrifugation (AC), photon correlation spectroscopy (PCS), and zeta potential, are summarized in Table 6 below. Scanning electron micrographs of the obtained drug particles and the dynamic viscosity determined by a rotating inclined rheological experiment at 25°C are depicted in... Figure 11 and Figure 12 middle.

[0296] Table 6: Particle size and zeta potential of suspensions containing compound (A)

[0297]

[0298] For different compositions of excipients such as steric stabilizers, corresponding binders (e.g., polyvinylpyrrolidone-vinyl acetate copolymer), and surfactants (e.g., sodium dodecyl sulfate), formulation compositions containing a wet media milling suspension of compound (A) at a 25% w / w drug concentration were selected based on suitable particle size and viscosity obtained from screening experiments. Experiments were conducted under standardized equipment and process parameter settings for thorough comparison. The formulation compositions studied are shown in Table 7 below.

[0299] Table 7. Formulation compositions used for suspension optimization experiments in wet media milling of compound (A)

[0300]

[0301] The experimental results obtained regarding particle size determination using analytical centrifugation (AC), photon correlation spectroscopy (PCS), zeta potential, and pH are summarized in Table 8 below.

[0302] Table 8: Particle size (AC and PCS), zeta potential, and pH of suspensions produced by wet media milling

[0303]

[0304] Scanning electron micrographs of drug particles, such as Figure 13 and Figure 14 As shown in Figure 15, the dynamic viscosity was characterized by rotating inclined rheological tests at 10°C, 25°C, and 40°C. The content and density of the wet media milling suspension containing compound (A) were determined by HPLC and by gravimetric analysis using a sinker method, respectively. The results are summarized in Table 9 below.

[0305] Table 9: Content and Density Determination of Suspensions from Wet Media Grinding

[0306]

[0307] The formulation composition (25% w / w compound (A), 4% w / w copovidone binder, and 0.1% w / w SLS surfactant) for wet medium suspension F2 was selected based on the following factors: appropriate particle size data; low dynamic viscosity at shear rate as determined by rotational rheology testing; low composite viscosity at rest (at low frequencies, respectively); and no or minimal signs of particle aggregation as determined by comparing particle size with and without sonication using photon correlation spectroscopy; furthermore, linear behavior at low frequencies as determined by frequency scanning testing. Other formulation compositions (F5, F6, F7, and F8) were deemed unsuitable for development due to their higher viscosity. Furthermore, particle growth via Ostwald ripening was observed at increased sodium dodecyl sulfate (SLS) concentrations (F9).

[0308] Composition F2 has low viscosity, which is advantageous in the following aspects: (a) quality: uniformity, and (b) operation: treatment of suspensions, using a spray process to downstream process the suspension into dried products (particles).

[0309] Grinding process:

[0310] The formulation composition compound (A): 25% w / w, copovidone: 4% w / w, and SLS: 0.1% w / w were scaled up to a 6-liter batch using the following equipment and process parameters: grinding chamber volume of 600 ml, grinding media made of zirconium oxide with a diameter of 100 μm, grinding media fill level in the grinding chamber of 80% v / v, agitator tip speed of 9 m / s, suspension inlet temperature of approximately 19 °C, suspension outlet temperature of approximately 23 °C, suspension flow rate of 7 l / h during the process ramp-up and increased to 33 l / h after 1 hour of processing, and grinding duration of 8 hours.

[0311] The particle size of compound (A) is measured by PCS, and this method allows for a particle size reduction from about 110 nm to about 130 nm.

[0312] Example 4: Capsule Formulation

[0313] After developing suspension compositions for spray granulation and testing several inert matrices (carrier particles) for spray granulation, the particles were filled into capsules. It was observed that capsule disintegration and carrier particle dispersion were poor at pH 2 during the dissolution rate (as seen in Examples 1, 2, and 3), making it impossible to directly fill the capsules with carrier particles without further formulation steps. Therefore, the presence of an external phase was investigated to improve the poor capsule disintegration and dispersion at pH 2 by testing different pharmaceutically acceptable excipients (e.g., disintegrants, fillers).

[0314] To evaluate the effect of the excipients, micron-sized compound (A) was used to prepare particulate particles as described in the examples above, at doses of 10 mg, 20 mg, and 50 mg. The particulate particles were then mixed with at least one pharmaceutically acceptable excipient and filled into No. 0 hard gelatin capsules.

[0315] Table 10. Capsule Formulations

[0316]

[0317]

[0318] 1 The theoretical quantity of the batch

[0319] 2 Water is removed during the spray granulation process.

[0320] 3 The compensating material for changes in particle content is microcrystalline cellulose (e.g., Avicel). )

[0321] Determining the stability data of capsules

[0322] Technical stability analysis was performed on suspensions containing compound (A) as defined herein. No significant changes in appearance or particle size were observed by PCS, microscopy, and content determination after storage for up to 10 weeks at 40°C / 75% RH and up to 9 months at 5°C / ambient RH and 25°C / 60% RH. Degradation products were observed in samples stored at 25°C / 60% RH and 40°C / 75% RH at a relative retention time (RRT) of 0.81. These degradation products increased with increasing storage temperature and time (up to 0.23% after 9 months at 25°C / 60% RH and up to 0.34% after 10 weeks at 40°C / 75% RH). To avoid these degradation products, the suspensions were stored in a refrigerator, and stability results showed that the degradation products remained unchanged (<0.05%) after storage in a refrigerator (5°C / ambient RH) for up to 9 months. Apart from the degradation products with an RRT of 0.81, no other significant changes or increases in impurities were observed under the different storage conditions and durations tested. Microbial contamination was not detected by the Microbial Count Test (MET) after 8 weeks of storage at 5°C / ambient and 25°C / 60% RH.

[0323] Example 5: Study of foreign phase compositions

[0324] The effects of formulation factors on the quality properties of 50mg tablet cores of compound (A) were investigated. The factors studied were filler ratio, disintegrant level and type, glidant level, and lubricant level and type.

[0325] For this study, a fluidized bed granulator with a top spray configuration was the technology chosen for development. A granular composition containing 40% w / w drug loading, 20% w / w copovidone, and 0.2% w / w sodium dodecyl sulfate was selected. A design of experiment (DOE) was performed to evaluate and improve the properties of the blend and tablet cores at a laboratory scale (i.e., 250g tablet batches). This experiment screened and evaluated several variables (i.e., filler ratio, disintegrant type, disintegrant amount, glidant amount, lubricant type, and lubricant amount) affecting the formulation's flowability and compressibility.

[0326] The primary objective of this study was to evaluate the release of compound (A) from different 50% w / w external phase compositions on selected particles (see particle compositions in Table 11). This study focused solely on the granulation and tableting process steps.

[0327] Table 11. Selected particulate compositions studied in the experiment

[0328]

[0329] The design used was a screening design with 6 factors in 12 design runs (Table 13) (Table 12).

[0330] Table 12. Selected variables and intervals studied in the DOE

[0331]

[0332] Table 13. List of Experimental Conditions

[0333]

[0334]

[0335] 1 Midpoint

[0336] To estimate the impact of these factors on the resulting final blend, physical properties (i.e., flowability, bulk density, Cartesian index, Hausner ratio) were evaluated and compared. Finally, the final blend was compressed to understand the effects of these factors on the core tensile strength, disintegration time, and dissolution rate.

[0337] Table 14 lists the response variables studied.

[0338]

[0339] Tables 14-1 and 14-2 list detailed batch compositions.

[0340] Table 14-1

[0341]

[0342]

[0343] Table 14-2

[0344]

[0345]

[0346] Such formulations are manufactured according to the following process:

[0347] Manufacturing process of compound (A) by wet media grinding and fluidized bed spray granulation

[0348] 1. Dissolve copovidone in water with stirring.

[0349] 2. Add sodium dodecyl sulfate to the solution from step 1 and dissolve it while stirring.

[0350] 3. Add compound (A) to the solution from step 2 and suspend it under stirring.

[0351] 4. Perform wet media grinding using the suspension from step 3.

[0352] 5. Dissolve the required amounts of sodium dodecyl sulfate and copovidone in a separate purified water with stirring.

[0353] 6. Weigh the required amount of the wet media milling suspension obtained in step 4 and add it to the solution of copovidone and sodium dodecyl sulfate in purified water obtained in step 5 to complete the suspension for spray granulation.

[0354] 7. Load mannitol SD200 carrier into the fluidized bed dryer.

[0355] 8. Spray granulation is performed by spraying the entire amount of the suspension obtained from step 5 onto the mannitol SD200 carrier obtained from step 7. Note that the nano suspension must be stirred for 5 minutes before spraying.

[0356] Manufacturing process for the final blend preparation and compression of compound (A)

[0357] 9. Use a sieve with a mesh size of 0.8 mm to sieve the particles.

[0358] 10. Sift Avicel PH102, mannitol DS, and superdisintegrants (i.e., sodium glycolate starch, crospovidone, and croscarmellose sodium) through a 0.5 mm sieve and add them to the granules from step 9.

[0359] 11. Blending to obtain the mixture from step 10

[0360] 12. Sieve magnesium stearate using a 0.5 mm sieve and add it to the blend from step 11.

[0361] 13. Blend the mixture from step 12 on a diffusion mixer.

[0362] 14. Compression of the blend obtained from step 13

[0363] flow chart

[0364]

[0365] Evaluation of the final properties of the blend

[0366] Final blend particle size distribution:

[0367] The particle fraction at each sieve size in the CAMSIZER apparatus was determined. It was observed that adding 50% external excipient to the final mixture resulted in a reduction in the amount of coarse particles.

[0368] Figure 16A and Figure 16BThe Pareto plot presented in the figure shows the six principal effects in the study design, plotted from highest to lowest effect to understand the relative importance of the effects to each other. It uses a + sign for positive effects (higher levels of the factor give a higher response than lower levels) and a - sign for negative effects (opposite direction). The significance line shows which effects are statistically significant from zero. In this case, the factor with the greatest impact on the final blend d10, d50, and d90 is the cellulose / mannitol filler ratio. This means that using a high amount of mannitol (low filler ratio: 0.25) results in coarser particles in the final blend. The figure also shows that several factors have an impact on the final blend span (i.e., the level and type of SD, and the filler ratio).

[0369] Final bulk density and tap density of the blend

[0370] Bulk density and tapped density were obtained from 16 batches of the final blends. It was observed that the batches containing high mannitol content corresponding to a ratio of 0.25 (i.e., batches F3-06, F3-11, F3-12, F3-14, and F3-16) had lower bulk density and tapped density than the batches containing high MCC content (filler ratio: 0.75, batches F3-02, F3-03, F3-07, F3-08, and F3-15).

[0371] Figure 17 The Pareto plot presented shows the three factors that have the greatest impact on the final bulk density and tapped density of the blend. These three factors are the level of the flow aid, the filler ratio, and the type of disintegrant.

[0372] Final blend flowability:

[0373] Karl Fischer index and Hausner-Nabi data provide indications of the theoretical flow properties for 16 batches. The final blend behavior was characterized using a rotary powder analyzer. This instrument measures the flowability of the powder by measuring changes in power, time, and energy within a 100 mm diameter drum at 0.6 rpm.

[0374] Figure 18 This indicates that, according to the pharmacopoeia flowability scale (Karst index below 25% and Hausnerby 1.31), all batches are similar and have acceptable theoretical flowability.

[0375] The most significant factor influencing the final blend's Karl Fischer index and Hausner ratio is the cellulose / mannitol filler ratio. This means that using a higher mannitol content results in better flowability.

[0376] As can be seen, bulk density and flow properties are the different final blend properties between batches. These differences are considered to be the result of variations in the external phase composition (qualitative and quantitative). Particle size distribution (PSD) shows comparable values. Flowability results demonstrate that batches containing a higher amount of mannitol corresponding to a filler ratio of 0.25 (e.g., batches F4-6, 11, 12, and 16) have better flowability.

[0377] Evaluation of chip core properties

[0378] Sixteen final blends were compressed using a power-assisted single-punch tablet press (KORSCH XP1) with a 9mm circular flat punch. Their compression behavior was studied and compared together.

[0379] Compression curve

[0380] To select the ideal compression force and hardness, a compression force-hardness profile was created before the start of compression runs. 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 hardness tester. Tensile strength is typically used to describe the cohesion of the compressed material. The changes in hardness and tensile strength under pressure were then plotted as a function of the principal compression force.

[0381] The compression force-hardness profiles were determined for 16 batches. It was observed that tablet hardness increased with increasing compression force. The different compression force-hardness profiles are most likely due to differences (quantitative and qualitative) in the external phase composition of the final blend. Specifically, batch F3-15 showed the highest compression force-hardness profile, while batch F3-14 showed the lowest.

[0382] To evaluate the significance of these results, tensile strength curves were plotted by normalizing the values ​​using an equation (see below) and comparing them between batches. The tensile strength curves were determined and show a comparison of compressibility, as illustrated in the following equation. It shows the same trend as described for compression.

[0383] Tensile strength,

[0384] Where: F is the crushing force (hardness); D is the diameter of the compacted object; and t is the thickness of the compacted object.

[0385] The tensile strength values ​​used for the Pareto chart were derived from a tablet hardness of 90 N for comparison across all batches. The 90 N tablet hardness was chosen based on a good balance between low friability and acceptable disintegration time. (See Pareto chart for details.) Figure 19The results show that the type of superdisintegrant (SD) and lubricant are two factors that significantly affect tensile strength. Using SSF as a lubricant and croscarmellose sodium as a disintegrant resulted in higher compressibility.

[0386] Launch Curve

[0387] The force required to eject a finished tablet is called the ejector force, and it can be used to quantify the adhesion effect of the powder. This force ejects the tablet by breaking the adhesion between the tablet and the die wall. The ejector force also changes when lubrication is insufficient and depends on the tablet thickness. Preferably, it is as low as possible or less than 500 N.

[0388] The ejection force curves for all batches were recorded during compression cycles. It was observed that batch F3-14 exhibited the highest ejection force curve (>800N), approaching or far from the recommended value of 500N. Other curves were lower (>200N). For greater precision, the specific ejection force was calculated by dividing the ejection force by the tablet weight and expressed in N / g. The results showed the same trend as the ejection curves and could be divided into three groups:

[0389] • For batch 0033-14, which exhibited a specific ejection ratio exceeding 4000 N / g, high specific ejection curves were recorded.

[0390] Intermediate curves were recorded for three batches (0033-04, 0033-08, and 0033-16) with N / g values ​​between 700 N / g and 2500 N / g.

[0391] • For other batches below 600 N / g, low curves were recorded.

[0392] These differences can be explained by differences in the external phase composition.

[0393] Two Pareto charts ( Figure 20 The results show that the four main factors affecting the pusher force and specific pusher force are the amount and type of lubricant, the filler ratio, and the amount of flow aid.

[0394] The amount and type of disintegrant were considered negligible. Results showed that the formulation with good performance was:

[0395] • Use at least 1% sodium stearate

[0396] • Small amount of glialant (less than 1.25%)

[0397] • Small amount of mannitol (maximum filler ratio 0.5).

[0398] Chip core disintegration time (DT)

[0399] The tablet cores disintegrated in HCl (0.01N pH2), which represents the worst-case medium for the disintegration of compound (A) tablets, and is related to the inherent gelling properties, as described above. Disintegration time is expressed as the maximum value for the three tablet cores (see [link to original text]). Figure 21 Maximum disintegration time (90N)

[0400] Only batch F3-02 showed a higher disintegration time of over 900 seconds / 15 minutes. All other batches did not exceed 600 seconds / 10 minutes, but high variability was observed between batches, likely due to differences in the external phase composition. All six factors were found to have a significant effect on the maximum disintegration time (DT). However, the filler ratio and the amount of flow aid type could be considered negligible in terms of magnitude. The other four factors were the major influencing factors. High contents of croscarmellose sodium (up to 6%) and high contents of stearyl fumarate sodium (up to 1%) contributed to a faster core disintegration time.

[0401] Table 15 below summarizes the core DT values ​​based on six factors and levels, including the average for low and high DT, as well as the average for intermediate DT (all 6 batches). Therefore, the recommended rapid core DT values ​​can be concluded as follows:

[0402] - Filler ratio: less than 0.5%

[0403] - Superdisintegrant (SD) type: Sodium glycolate starch (DT: 159 seconds) or croscarmellose sodium (DT: 255 seconds)

[0404] - Disintegrant level: above 6%

[0405] - Drainage agent level: Approximately 1.25 (DT is lowest when using 1.25% drainage agent)

[0406] - Lubricant type: Sodium stearate fumarate

[0407] - Lubricant level: less than 1%

[0408] Table 15. Core Disintegration Time Based on Factors and Levels

[0409]

[0410] Core Dissolution Curve

[0411] The dissolution rate (DR) of the core containing compound (A) was measured by UV spectroscopy in an automated apparatus and carried out in a basket at 100 rpm in 0.01 M HCl (pH 2).

[0412] Batch F3-02 had the lowest dissolution profile, i.e., the highest disintegration time observed for that batch. For all other batches, more than 50% of compound (A) dissolved within 30 minutes.

[0413] Pareto plots of dissolution rates of the tablet core at 15 min and 30 min ( Figure 22 The results showed that all six factors had a statistically significant effect on the core dissolution rate at 15 minutes, and five of the six factors had a statistically significant effect at 30 minutes.

[0414] Based on the core dissolution rates at 15 min and 30 min, the recommended fast core DR value is as follows:

[0415] - Filler ratio: less than 0.5%

[0416] - Disintegrant type: Sodium glycolic acid starch or sodium croscarmellose

[0417] - Disintegrant level: above 6%

[0418] - Drip aid level: No effect on DR

[0419] - Lubricant type: Sodium stearate fumarate

[0420] - Lubricant level: less than 1%

[0421] Table 16. Core Disintegration Time Based on Factors and Levels

[0422]

[0423] Conclusions of the study on external phase compositions

[0424] Based on this statistical analysis, the experiment revealed that the filler ratio is the main factor affecting the final blend and core properties. A high level and type of superdisintegrant contributes to better disintegration time and dissolution rate. The level of the gliding agent is the least influential factor on the response. The level and type of lubricant significantly affect core properties. Compared to magnesium stearate, the use of a hydrophilic lubricant (i.e., sodium stearate fumarate) tends to reduce the pushing force and increase / improve disintegration time and dissolution rate. Based on the experiments studied, Table 17 shows the most promising external phase composition, which is the most suitable external phase for the formulation of compound (A) when used at 50% w / w of the total composition weight.

[0425] - Filler ratio: 0.5 was chosen based on a good balance between high dissolution rate and low disintegration time.

[0426] - Superdisintegrant types and levels: Sodium glycolate starch and sodium croscarmellose

[0427] - Requires at least 6% disintegrant

[0428] - The level of gliding agent shows minimal effect on tablet properties, but may optionally be used, for example, at a dose of 1%.

[0429] - Lubricant type: Sodium stearate fumarate shows good performance in DT and DR.

[0430] - To achieve better compression performance, a minimum lubricant level of 1% is required.

[0431] Table 17. External Phase Compositions

[0432]

[0433] Example 6: Further research on the external phase (quantity)

[0434] The external phase study in Example 5 was limited to compositions containing 50% w / w of the external phase. To further understand the amount of external phase required to resolve the gelation problem, the amount of external phase was varied between 24% and 50%, and further experiments were conducted with different types of disintegrants and variations in fillers such as microcrystalline cellulose and mannitol. Gliders were not used in these experiments because they have been shown to be optional.

[0435] Tablet formulations were developed using formulation T1 containing 20% ​​w / w compound (A) and formulation T2 containing 25% w / w compound (A), as shown in Table 18. The tablet formulations depicted in Table 18 were prepared by mixing particulate particles containing compound (A) and at least one pharmaceutically acceptable excipient in a manner similar to that used for capsule formulations.

[0436] Table 18: Tablet formulations containing compound (A)

[0437]

[0438]

[0439] As mentioned in this application, a problem with formulations containing compound (A) is the inherent gelling behavior of compound (A) at pH ≤ 2. This gelling behavior affects the disintegration time of the formulation (e.g., tablets), which is therefore measured in water as a standard test and additionally in hydrochloric acid at pH = 2.

[0440] All tested formulations in Table 18 exhibited good disintegration behavior in water, with differences observed at pH 2. The fastest disintegration time in both media was achieved with 50% w / w of pharmaceutically acceptable excipients in the external phase. Another factor found to contribute to rapid disintegration was the amount of compound (A) added to (a) the inert matrix and the choice of disintegrant type. In this first screening test, 1-vinyl-2-pyrrolidone homopolymer (commercially available under the trade name crospovidone - CAS 9003-39-8) and croscarmellose sodium achieved the fastest disintegration time at pH 2. A combination of 40% w / w of pharmaceutically acceptable excipients in the external phase and 20% w / w of compound (A) in the particles resulted in a disintegration time of less than 15 min at pH 2 when using the best-performing disintegrant.

[0441] The conclusion drawn is that an external phase of at least 40% w / w is preferred.

[0442] Finally, to gain an understanding of chemical and physical stability, two variants were selected for the short-term stability procedure. Both variants were provided as film-coated sheets.

[0443] Compound (A)-F12-01 has the same composition as compound (A)-F10-04.

[0444] Compound (A)-F12-02 has the same composition as compound (A)-F10-07.

[0445] Table 19. Stability Samples

[0446]

[0447]

[0448] For coating, use standard Opadry1.

[0449] As described in Table 19 above, the formulation containing compound (A) is very stable, and no incompatibility between the drug substance and the formulation composition has been observed. Even water absorption during storage (as expected with the presence of hygroscopic excipients) did not lead to any abnormal observations during appearance testing.

[0450] Example 7: Quantitative and Qualitative Studies of Particles

[0451] Experiments were conducted to investigate the quantitative and qualitative composition of the particles. Four factors were selected for evaluation and are listed in Table 20.

[0452] Table 20. Variables and intervals selected for experimental design

[0453]

[0454] The particulate composition is defined by an excipient ratio based on the amount of solids to be sprayed onto a carrier surface to form a matrix. The excipient level is then defined by the following equation:

[0455] Excipient level = Drug loading × Excipient ratio

[0456] A second-order polynomial model including the four intermediate points as described in Table 21 will be used (2 4-1 The experiment will be conducted using partial analysis factors, resulting in a total of 12 experiments.

[0457] Table 21: Experiment List

[0458]

[0459] Four repeating midpoints were used as experimental errors to test all four main effects, resulting in three sets of mixed bidirectional interaction pairs. To estimate the impact of these factors on the resulting particles and the final blend, the corresponding physical properties (i.e., flowability, bulk density, Karl Fischer index, Hausner ratio) were evaluated and compared. Finally, the final blend was compressed to understand the effects of these factors on the core tensile strength, disintegration time, and dissolution rate.

[0460] The response variable is the experimental response observed due to induced changes in process / formulation variables. Table 22 lists the response variables studied.

[0461] Table 22: List of Response Variables

[0462]

[0463] Twelve batches of cores were manufactured according to the proposed experimental design. Tables 23-1, 23-2, and 23-3 provide an overview of the 12 batches of compositions with a particle size of approximately 250 g. The manufacturing process is as described in Example 6.

[0464] Table 23-1

[0465]

[0466] Table 23-2

[0467]

[0468] Table 23-3

[0469]

[0470]

[0471] 1 Midpoint

[0472] Scanning electron microscopy (SEM) of particles

[0473] Observe and analyze the shape, surface morphology, and roughness of the particles.

[0474] Batches containing a copolyvinylpyrrolidone ratio as high as 0.5 (F6-01-04-05-08 and four intermediate points F6-09-10-11-12) were observed to consist of coarser particles with d50 > 250 μm. Agglomeration between particles could be observed from SEM images. Figure 23A and Figure 23B The Pareto plot summarizes the various effects. The level of copovidone is shown to significantly affect the particle PSD (particle size distribution). High copovidone content results in coarser particle size.

[0475] Particle bulk density and tap density

[0476] As measured in Example 6, bulk density and tap density data were obtained from 12 batches of sieved particles.

[0477] It was observed that the batch containing a small amount of copovidone (i.e., F6-02-03-06-07) had a higher bulk density and tap density. Figure 24 The Pareto plot shown indicates that the most significant factor affecting particle tap density is copovidone (from 0.50 g / ml to 0.57 g / ml).

[0478] Particle flow characteristics (Carpito index and Hausner ratio)

[0479] The particle Carbide index and Hausner data provide an indication of the theoretical flow properties of 12 lots. Figure 25 This indicates that, according to the pharmacopoeia flowability scale (Karst index below 15% and Hausnerby below 1.18), all batches are similar and have good / excellent theoretical flowability.

[0480] Particle Flow

[0481] The particle behavior was characterized using a rotating powder analysis instrument. This instrument measures the flowability of the powder by measuring the power, time, and energy changes within a 100 mm diameter drum at 0.6 rpm. Median collapse time (between 2.2 and 3.0 seconds) and collapse angle (between 37° and 42°) results showed that all 12 particle batches exhibited acceptable / good flowability. All collapse power results (<18 cch) and surface linearity results (≥0.99%) indicated good flowability (R).

[0482] From Figure 26The Pareto plots showed that copovidone had a significant impact on particle flowability. In this study, high levels of copovidone led to coarser particles and better particle flow behavior.

[0483] Particle content determination and resuspension

[0484] The particle content determination and particle resuspension of 12 batches are listed in Table 24. For all particles, 95 ± 2% of the drug substance was measured. No compensation was performed during spray granulation.

[0485] Particle reconfiguration / resuspension was analyzed via PSD using photon correlation spectroscopy (PCS). Particle sizes ranging from below 5 nm to several micrometers were measured using PCS. The technique operates on the principle of random particle movement in a gas or liquid. In a wet medium diluted for spray granulation, the particle size of DS was 123 nm.

[0486] Table 24. Particle content determination and resuspension properties

[0487]

[0488]

[0489] The results showed that copovidone and SLS had a significant effect on particle resuspension.

[0490] Particle compression behavior

[0491] The compression behavior of 12 batches of granules was characterized to gain insight into the product. Therefore, a power-assisted single-punch tablet press (Styl'One) was used to compress the granules with an 11.28mm circular flat punch.

[0492] Particle compressibility: Compressibility is the ability of a powder to deform under pressure. During powder densification, the porosity of the powder bed decreases. Densification can be studied by monitoring porosity under load. Tablet porosity is calculated after extrusion by measuring tablet dimensions (i.e., thickness, diameter), weight, and density. It was observed that porosity decreases with increasing compressive force. All batches showed porosity below 8% at a compressive force of 25 MPa. The four intermediate points exhibited the highest porosity distribution compared to other batches.

[0493] Compressibility of Granules: Compressibility is the ability to form compressed objects with high mechanical strength. Various tests were performed, such as compression force-hardness curves and tensile strength curves. Compression force-hardness curve testing was conducted for each batch. Five compression forces ranging from 5 kN to 45 kN were evaluated. Tablet crushing force (or hardness) was evaluated using a hardness tester. Tensile strength is typically used to describe the cohesion of the compressed object. The changes in hardness and tensile strength under pressure are then shown as a function of the primary compression force.

[0494] Observations showed that tablet hardness increased with increasing compression force. Different compression behaviors were observed between batches, with low variability across compression forces. Batch F6-01 showed a continuous decrease in hardness at compression forces ≥25 kN. The three particle types F6-05, 07, and 09 showed plateaus at ≥25 kN. The four intermediate points exhibited the lowest and most similar compression force-hardness curves. As expected, the different compression force-hardness curves are most likely related to differences in particle phase composition. To evaluate the significance of these results, tensile strength curves were plotted, values ​​were normalized, and compared between batches. All particles exhibited high compressibility and followed the same trend as the compression force-hardness curves.

[0495] The tensile strength values ​​used for the following Pareto charts are derived from tablets compressed at 25-30 kN. Pareto Chart ( Figure 27 The results showed that the levels of copovidone, SLS, and mannitol were the three factors that significantly affected tensile strength. High levels of copovidone, low levels of SLS, and no mannitol in the granular composition resulted in higher compressibility.

[0496] Particle compressibility: It was observed that the tensile strength of compacted particles decreased with increasing porosity. Similar compressibility characteristics were observed for all particle batches, as the compacted material exhibited a tensile strength of approximately 2 MPa at 20% porosity.

[0497] Particle push force curve: Records the push force curve for all batches during compression cycles. For greater accuracy, the specific push force is calculated by dividing the push force by the tablet weight and expressed in N / g. Figure 28 The comparative ejection curves of the particulate composition are shown, illustrating various influencing factors.

[0498] Evaluation of the final properties of the blend

[0499] The twelve final blends were characterized, and the results are summarized in Tables 25-1 and 25-2, and further detailed in the following subsections.

[0500] Table 25-1. Summary of the properties of the final blend

[0501]

[0502]

[0503] 1 Pharmacopoeia Flow Scale

[0504] Table 25-2. Summary of the properties of the final blends

[0505]

[0506]

[0507] 1 Pharmacopoeia Flow Scale

[0508] Final blend particle size

[0509] Final blend particle size distribution

[0510] As shown in the table above, adding 50% of the external phase excipient to the particles resulted in a reduction in the amount of coarse particles.

[0511] Figure 29A and Figure 29B The Pareto plots presented show that the copovidone level is the most influential factor for the final blend's d50, d90, and fine particles below 125 μm. The same trend was observed for individual particles: higher copovidone content resulted in coarser particles. Conversely, lower copovidone content significantly led to a higher content of fine particles.

[0512] Final bulk density and tap density of the blend

[0513] Based on the summary table above, it was observed that the bulk density and tap density were similar across batches.

[0514] Karl Fischer Index and Hausnerby: Karl Fischer Index and Hausnerby data provide an indication of the theoretical liquidity properties of 12 lots. Figure 30 This indicates that, according to the pharmacopoeia flowability scale, all batches are similar and have good theoretical flowability. Batch F7-08 exhibits excellent flowability.

[0515] Final blend flow properties

[0516] The final blend behavior was characterized using a rotary powder analyzer. This instrument measures the flowability of the powder by measuring the power, time, and energy changes in a rotating drum (100 mm in diameter, 0.6 rpm). Median collapse time (between 1.7 and 3.1 seconds) and collapse angle (between 38° and 48°) indicate acceptable / good flowability for FB. All collapse power results (<18 cch) and surface linearity results (>0.99%) indicate good flowability.

[0517] From Figure 31 The Pareto plot shows that drug load significantly affects the flowability of the final blend.

[0518] Final Blend Separation Prediction

[0519] Separation or stratification occurs when components separate from a particulate mixture due to differences in physical properties (size, shape, density, etc.). Several driving forces or mechanisms can lead to separation. The most common mechanisms in industry are sieving, fluidization, and dust removal. To limit separation, the material particle size distribution (PSD) should be uniform. For example, a large difference in PSD between particles and excipients can physically separate the mixture and lead to separation. Coarser particles may be trapped at the bottom due to gravity, while finer particles are located at the top of the blend. Depending on the behavior of the powder, the opposite may occur, with coarser particles at the top and finer particles at the bottom. The mixture can be noticeably separated. The external phase composition is approximately 50% w / w of the tablet weight (the main amounts of the two fillers: Avicel PH102 and mannitol DC). This high content of the external phase can cause separation between components due to differences in particle size.

[0520] Two methods were used to predict potential separation phenomena:

[0521] 1. Comparison of particle size distribution among materials (i.e., particles, final blends, and each excipient).

[0522] 2. Separation using different screens

[0523] Particle size distribution comparison method:

[0524] This study aimed to compare the particle size distribution of each final blend, particle, and external phase excipient (i.e., Avicel PH102, mannitol DC, and croscarmellose sodium). The particle size difference between the internal phase (i.e., particles) and the external phase can lead to separation. Indeed, it was observed that the particle PSD shifted to the right, corresponding to coarser particles, while the external phase excipients (i.e., MCC and mannitol) shifted to the left, corresponding to finer particles. An ideal blend to limit separation should have similar PSD profiles. From this perspective, batch F7-06 exhibited the most suitable PSD. Batch F7-05 showed a high tendency to separate.

[0525] Sieving and separation method:

[0526] For the sieving separation method, the powder mixture is added to a series of sieves to apply stress to the powder through vibration (amplitude 1.0 mm, 5 min), causing it to separate. This forces the mixture into four fractions corresponding to the relevant sieves, with fine particles at the bottom of the apparatus and coarse particles at the top. The API content of each fraction is then determined to evaluate how the API is distributed in each particle size fraction. Finally, the standard deviation is calculated to determine the potential separation of the mixture. A high standard deviation results in high potential separation. Only three particle batches, F6-01, F6-08, and F6-11, and their corresponding final blends, F7-01, F7-08, and F7-11, were evaluated.

[0527] Table 26 summarizes the drug substance content measured in each fraction. RSD values ​​were used as the basis for comparing separation between batches. API is part of the particles and therefore not present in the external phase. The highest API content measured in the top fraction can be associated with particles exhibiting coarser fractions. It was observed that for each fraction, the drug substance was uniformly distributed in the particles, and the final blends showed a higher probability of separation with high RSD values ​​(i.e., 63% to 82% RSD). Batch F6-01 exhibited the highest RSD. The high difference in PSD between the particles and the external phase indicates that this batch tends to have high separation (…). Figure 32 Therefore, it can be concluded that the external phase level has a significant impact on the uniformity of drug content. A good balance between the external phase level and a suitable particle size distribution will not easily lead to separation.

[0528] Table 26. Prediction of particle and final blend separation by sieve analysis (% of compound (A) in each fraction)

[0529]

[0530]

[0531] Final blend compression behavior

[0532] Twelve final blends were compressed using a power-assisted single-punch tablet press (Styl'One Evolution compaction simulator) with a standard 11.28 mm round flat punch for compression characterization. Their compression behavior was studied, and the results were compared.

[0533] 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 can be studied by monitoring porosity under load. Tablet porosity is calculated after extrusion by measuring tablet dimensions (i.e., thickness, diameter), weight, and density. It has been observed that porosity decreases with increasing compressive force. All final blend batches showed a similar porosity distribution.

[0534] Final blend compressibility

[0535] Compressibility is the ability to form compressed objects with high mechanical strength. Various tests were conducted to study compressibility (i.e., compressive force-stiffness curves and tensile strength curves).

[0536] Compression force-hardness curves were performed on each batch. Five compression forces ranging from 5 kN to 45 kN were evaluated. The crushing strength (or hardness) of the tablets was evaluated using a hardness tester. Tensile strength is typically used to describe the cohesion of the compressed material. The changes in hardness and tensile strength under pressure were then plotted as a function of the principal compression force. It was observed that increasing the compression force resulted in higher tablet hardness. Different compression behaviors were observed between batches, with low variability. Batch F7-01 showed a continuous decrease in hardness at compression forces ≥25 kN. Particles from F7-06 showed the highest compressibility curve, while batches F7-01 and F7-04 showed the lowest. No trend of hardness loss or plateau was observed for the final blend compared to the particle compressibility curve. It was concluded that the external phase excipients have a positive influence on this property. Tensile strength curves were recorded to allow for comparison of compressibility. The results show that all the tensile strength curves of the final blends exhibit similar trends compared to the compressive strength-hardness curves, and using tensile strength values ​​is more accurate.

[0537] The tensile strength values ​​used for the following Pareto charts are derived from tablets compressed at 20 kN. Pareto Chart ( Figure 33 The results showed that no factors had a significant impact on the tensile strength of the final blend.

[0538] Final blend push force profile: Push force profiles for all batches were recorded during compression cycles. For greater accuracy, specific push force was calculated by dividing the push force by the tablet weight and expressed in N / g. Pareto chart ( Figure 34 The data shows that the main factor affecting specific tablet push force is the level of copovidone. High copovidone content results in low specific tablet push force.

[0539] Evaluation of tablet core properties using a sufficient punch at tablet hardnesses of 90N and 120N.

[0540] punch tools

[0541] Table 27 summarizes the tablet punches used for three different drug loadings at a dose intensity of 50 mg, resulting in different tablet weights (i.e., 25%, 35%, and 40% particle drug loading combined with 50% external phase).

[0542] Table 27. Punch Tools

[0543]

[0544] Core pushing force

[0545] Table 28 shows the push force values ​​recorded for cores manufactured at 90N and 120N. It indicates that for all batches at both hardness levels, the push force is significantly lower than the recommended value of 500N.

[0546] Table 28. Tablet pushing force values ​​at tablet hardness of 90N and 120N

[0547]

[0548] Core Disintegration Time

[0549] For both core hardness levels (90N and 120N), core disintegration was performed in HCl (0.01N, pH 2). For the 120N core, disintegration time in water was also measured. Disintegration time values ​​are expressed as the maximum of the three core values ​​(see Table 29). Only batch F7-07 showed a higher disintegration time (DT) exceeding 900 seconds / 15 minutes. All other batches did not exceed 480 seconds / 8 minutes. For batch F7-07, the DT for the lower tablet hardness was one-quarter that of the tablets with the higher tablet hardness.

[0550] Table 29: Core disintegration time at 90N and 120N (maximum value in seconds)

[0551]

[0552]

[0553] like Figure 35 As shown in the Pareto plot, all factors significantly affect the tablet core DT manufactured at 90 N, while none significantly affects the tablet core DT with a higher tablet hardness of 120 N. The two main influencing factors are the amount of copovidone and the drug loading. Higher copovidone content and higher drug loading result in higher DT with a 90 N tablet core hardness. Tablet hardness appears to have a significant impact on DT. Figure 36 The bidirectional interaction on the 90N core was shown. This indicates that the high copolyvinyl alcohol content in the spray suspension and the use of mannitol resulted in a longer disintegration time.

[0554] Core Dissolution Curve

[0555] Dissolution rates of tablet cores containing compound (A) with tablet hardness of 90N and 120N, respectively, were measured by UV spectroscopy in an automated apparatus and in 0.01M HCl at pH 3 at a paddle speed of 50 rpm and in a basket at pH 2 at a speed of 100 rpm. (Standard method for dissolution testing: according to European Pharmacopoeia 2.9.3 "Dissolution Test for Solid Dosage Forms" or United States Pharmacopeia) <711> (The basket method for "Dissolution" or "Dissolution Test" in Japanese Pharmacopoeia <6.10>)

[0556] Dissolution profiles of 90N and 120N tablets in a basket at 100 rpm (pH 2).

[0557] Except for batch F7-07, which had a relatively high RSD value of up to 5%, all batches showed low variability (RSD < 5%). The four intermediate batches (i.e., F7-09-10-11-12) were reproducible and exhibited similar dissolution profiles.

[0558] Three batches with a hardness of 90 N: F7-01, F7-05, and F7-07 showed the lowest dissolution profiles in a basket at 100 rpm in 0.01 M HCl at pH 2. This finding is supported by the highest disintegration time observed in these batches. For all other batches, over 80% of compound (A) dissolved within 30 min, but none reached 100% at 60 min. From 60 min to 75 min, the basket speed was increased from 100 rpm to 200 rpm.

[0559] Pareto plots of the dissolution rate of the tablet core at 15 min and 30 min after normalization of the core measurements. Figure 37A , Figure 37B : Figure 37A The chart is at 90N. Figure 37B The chart at 120N shows that the main significant influencing factors are drug loading and the amount of SLS. A combination of low drug loading and high sodium dodecyl sulfate (SLS) content is recommended for achieving a rapid dissolution rate profile. Figure 38 The Pareto plot of the two-way interaction is shown, indicating that low drug loading and low copovidone content lead to a high dissolution rate of the 90N core measured in the basket method at 100 rpm.

[0560] Dissolution profile of 120N tablet core in a paddle at 50 rpm (pH 3)

[0561] As previously stated, the drug substance (compound (A)) is a Class 2 compound in the Biopharmaceutics Classification System, a weak base exhibiting strong pH-dependent solubility (3 mg / mL at pH 1.2 and 0.003 mg / mL at pH 3). The dissolution rate of the 120N tablet core was evaluated at pH 3 using a paddle at 50 rpm in 900 mL of 0.001 M HCl at pH 3. Low variability (RSD < 5%) was observed in all batches.

[0562] The Pareto plot (Figure 37) shows the dissolution rate of the 120N core at 15 min and 30 min. Although only slight differences were observed between batches, the Pareto plot showed that all four factors had a significant effect on the dissolution rate at 15 min at pH 3 and a paddle speed of 50 rpm. At 30 min, the main influencing factor was the amount of SLS.

[0563] Conclusions from all experiments on the qualitative and quantitative composition of particles.

[0564] The excipient ratio in the granular composition is based on the amount of solids to be sprayed onto the carrier to form the matrix (i.e., copovidone, sodium lauryl sulfate, mannitol, and drug loading). For these experiments, the excipient composition was fixed at 50%, as this is considered a good amount for tablet disintegration, dispersion, and associated dissolution rates.

[0565] The properties of particles, the final blend (i.e., flowability, density, particle size distribution), and the core (i.e., compressibility, disintegration time, dissolution rate) were evaluated. Tables 30-1 and 30-2 summarize the main factors that had statistical significance for the responses of particles, the final blend, and the core.

[0566] Table 30-1. Summary of the factors with the greatest impact on particle response (difference between high and low values)

[0567]

[0568] Table 30-2. Summary of the most influential factors on the final blend and core response (difference between high and low values)

[0569]

[0570]

[0571] Based on statistical analysis, this experiment revealed that the ratio of copovidone to sodium lauryl sulfate and the drug loading were the main factors affecting the properties of particles, the final blend, and the tablet core. Mannitol had a relatively small effect on the response. High copovidone content resulted in coarse particles and low fineness. High sodium lauryl sulfate content and low drug loading contributed to a faster dissolution rate. For all batches, the flowability of the final blend was acceptable, and the final blend exhibited good compressibility in terms of tensile strength and low extrusion force.

[0572] Based on the above experiments, the following particle composition was selected (Table 31):

[0573] • A povidone ratio of 0.5 indicates a good balance between finer particle size, lower push force, and faster core DT and DR.

[0574] • Sodium dodecyl sulfate: A higher ratio level of 0.04 is required for a high dissolution rate.

[0575] • Mannitol SD 200 ratio (from spray suspension): The presence of mannitol has a relatively low impact on the physical properties of the granules, final blend, and tablets. The decision was made to remove mannitol from the granule composition for development.

[0576] • Drug loading: Lower ratio levels (below 35%) contribute to a rapid dissolution rate.

[0577] Table 31. Particle composition

[0578]

[0579] The drug ratio [compound (A): copovidone: SLS] corresponds to [2:1:0.08]

[0580] Example 8: Film-coated tablets

[0581] Using all optimized parameters from the experiments in the previous example, the following film-coated formulation was prepared as the optimal variant and a good balance among all variables.

[0582] Compound (A) spray suspension

[0583] flow chart

[0584]

[0585]

[0586] Manufacturing formula

[0587]

[0588] Composition of the final product

[0589]

[0590] The ratio of compound (A) / copovidone / SLS is 2:1:0.08.

[0591] Example 9: Manufacturing

[0592] The final blend of capsules and tablets was prepared according to a procedure similar to that described in the flowchart above.

[0593] a. Dissolve an adhesive, such as a polyvinylpyrrolidone-vinyl acetate copolymer, in water with stirring.

[0594] b. Add a surfactant, such as sodium dodecyl sulfate (SLS), to the solution from step a and dissolve it with stirring.

[0595] c. Add compound (A) to the solution from step b and suspend it under stirring.

[0596] d. Grind the suspension from step c, for example, by wet media grinding.

[0597] e. Dissolve the required amounts of SLS and polyvinylpyrrolidone-vinyl acetate copolymer in separately purified water with stirring.

[0598] f. Weigh the required amount of the suspension from step d and add it to the solution from step e to complete the suspension for spraying, such as spray granulation.

[0599] g. Load an inert matrix (carrier particles), such as mannitol SD.

[0600] h. Spray granulation, for example, by spraying the suspension from step e onto an inert matrix, such as mannitol SD200, from step g.

[0601] i. The particles from step h are further mixed with some pharmaceutically acceptable excipients such as mannitol DS, sodium glycolate starch, polyvinylpyrrolidone-vinyl acetate copolymer, and crosslinked sodium carboxymethyl cellulose.

[0602] j. Introduce the blend from step i into capsules or compress it to form tablets.

[0603] flow chart

[0604]

[0605] Example 10: Stability Experiment

[0606] Stability data of capsules in Example 4

[0607] Stability data for hard gelatin capsules (10 mg, 25 mg, and 50 mg) in Example 4 over a period of up to 24 months

[0608] Stability program:

[0609] The stability procedure tested the hard gelatin capsules (10 mg, 25 mg, and 50 mg) of Example 4 under the following storage conditions, packaged in square high-density polyethylene bottles (175 ml, 30 capsules) with aluminum induction seals and child-safe screw caps: 5°C / ambient RH; 25°C / 60% RH; 30°C / 75% RH; 40°C / 75% RH; and 50°C / 75% RH (RH is relative humidity).

[0610] Light stability study :

[0611] Using ICH Q1B Option 2 as the light source, photostability tests were performed on unpackaged hard gelatin capsules (10 mg, 25 mg, and 50 mg) of Example 4 according to the ICH guideline 'Photo stability testing of new active substances and medicinal products' [ICH Q1B]. Light-protected samples, tested in parallel with the exposed samples, served as controls.

[0612] The photostable sample load is at least 1.2 million lux-hours of total illuminance and at least 200 watt-hours / square meter of near-ultraviolet energy.

[0613] Open the bottle :

[0614] The test was performed on the hard gelatin capsules of Example 4 stored in open glass containers. The samples were stored at 25°C / 60% RH for up to one month. The chemical and physical properties of the samples were then analyzed.

[0615] Freeze-thaw cycle:

[0616] The test was conducted using hard gelatin capsules (10 mg, 25 mg, and 50 mg) from Example 4, packaged in square high-density polyethylene (HDPE) bottles (175 ml, 30 capsules) with aluminum induction seals and child-safe screw caps. Stability samples were stored for four complete freeze-thaw cycles (6 days at -20°C / ambient RH, then 1 day at 25°C / 60% RH). Samples were taken after 28 days for chemical and physical properties analysis.

[0617] Test method:

[0618] Perform the following tests as described in the table below:

[0619]

[0620] Stability results of hard gelatin capsules

[0621] When stored for up to 24 months at 5°C / ambient RH, 25°C / 60% RH, or 30°C / 75% RH, the hard gelatin capsules (10 mg, 25 mg, and 50 mg) in HDPE bottles exhibited good physical and chemical stability. No significant changes in chemical and physical properties were observed.

[0622] When stored at 40°C / 75% RH for up to 6 months, the hard gelatin capsules (10 mg, 25 mg, and 50 mg) in HDPE bottles exhibited good physical and chemical stability. No significant changes in chemical and physical properties were observed.

[0623] When stored at 50°C / 75% RH for up to 1 month, the hard gelatin capsules (10 mg, 25 mg, and 50 mg) in HDPE bottles exhibited good physical and chemical stability. No significant changes in chemical and physical properties were observed.

[0624] The photostability samples of hard gelatin capsules (10 mg, 25 mg, and 50 mg) in HDPE bottles showed good physical and chemical stability.

[0625] Freeze-thaw cycle samples of hard gelatin capsules (10 mg, 25 mg, and 50 mg) in HDPE bottles showed good physical and chemical stability.

[0626] Open vessel studies of hard gelatin capsules (10 mg, 25 mg, and 50 mg) in HDPE bottles showed good physical and chemical stability.

[0627] Stability data for film-coated tablets (50 mg) in Example 8

[0628] Stability program :

[0629] The stability procedure tested the film-coated tablets (10 mg, 25 mg, 50 mg, and 100 mg) of Example 8 for up to 18 months under the following storage conditions: the film-coated tablets were packaged in square high-density polyethylene bottles (175 ml, 30 capsules) with aluminum induction seals and child-safe screw caps.

[0630] 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 is relative humidity)

[0631] The light stability test and freeze-thaw cycle test were conducted according to the tests described above for the capsule.

[0632] The testing method was as described above for the capsules.

[0633] Stability test results :

[0634] When stored at 5°C / ambient RH, 25°C / 60% RH, and 30°C / 75% RH, the film-coated tablets of Example 8 (10, 25, 50, and 100 mg) exhibited good chemical and physical stability for up to 18 months.

[0635] No significant changes were observed in chemical (content determination and degradation products) and physical (appearance, thickness, diameter, dissolution rate, water content) properties.

[0636] When stored in HDPE bottles at 40°C / 75% RH, the film-coated tablets of Example 8 (10, 25, 50, and 100 mg) exhibited good chemical and physical stability for up to 6 months. A slight increase in particle size (177.6 nm) was observed in the 10 mg and 25 mg tablets after storage in HDPE bottles at 40°C / 75% RH compared to the initial value (150.1 nm). This slight increase is not expected to have any impact.

[0637] When stored in HDME bottles at 50°C / 75% RH, the film-coated tablets of Example 8 (10, 25, 50, and 100 mg) exhibited good chemical and physical stability for up to 1.5 months. No significant changes in chemical (content assays and degradation products) or physical (appearance, thickness, diameter, dissolution rate, water content) properties were observed, except for particle size in the 10 mg clinical batch. After 1.5 months of storage in HDPE bottles at 50°C / 75% RH, a slight increase in particle size was observed in the 10 mg tablets (from 150.5 nm at the initial time point to 196.0 nm). However, this slight increase is not expected to have any impact.

[0638] When stored in open HDME bottles at 25°C / 60% and 30°C / 75% RH, the film-coated tablets of Example 8 (10, 25, 50, and 100 mg) exhibited good chemical and physical stability for up to 3 months. No significant changes were observed in chemical (content determination and degradation products) or physical (appearance, thickness, diameter, dissolution rate, and water content) properties. For the 100 mg tablets, a slight increase in dissolution rate (105%) was observed after 3 months of storage in open HDME bottles at 30°C / 75% RH. A slight increase in particle size was observed for tablets stored in open HDPE bottles at 30°C / 75% RH for 3 months compared to the initial values. For the 10 mg tablets, the particle size increased from 150.5 nm to 201.1 nm, while for the 25 mg tablets, the particle size increased from 150.1 nm to 181.4 nm. Similarly, for the 50 mg tablets, the particle size showed an increase from 148.9 nm to 178.7 nm, while for the 100 mg tablets, it increased from 140.7 nm to 177.0 nm. This slight increase is not expected to have any impact.

[0639] Film-coated tablets (10, 25, 50, and 100 mg) in HDPE bottles exhibited good physical and chemical stability. No significant changes were observed in chemical (content determination and degradation products) or physical (appearance, thickness, diameter, dissolution rate, water content, and particle size) properties. Light had no effect on the stability of the film-coated tablets.

[0640] Freeze-thaw cycle samples of film-coated tablets (10, 25, 50, and 100 mg) in HDPE bottles showed good physical and chemical stability.

[0641] Assessing crystal stability using XRPD:

[0642] When stored for 9 months at 5°C / ambient RH, 25°C / 60% RH, and 30°C / 75% RH, no change in the XRPD pattern was observed in the film-coated tablets (10 mg, 25 mg, 50 mg, and 100 mg) of Example 8. The crystalline form (A) described in WO 2020 / 234779 remained stable under those conditions. No conversion to other crystalline forms was observed.

Claims

1. A pharmaceutical composition for oral administration, the pharmaceutical composition comprising particulate particles, the particulate particles comprising: (a) An inert matrix comprising a material selected from lactose and mannitol or mixtures thereof, and (b) A mixture comprising N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof or its free form, an adhesive and a surfactant, said adhesive being a polyvinylpyrrolidone-vinyl acetate copolymer, said surfactant being sodium dodecyl sulfate, wherein the mixture of (b) is added to the inert matrix of (a), and in N The weight ratio of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide to polyvinylpyrrolidone-vinyl acetate copolymer is in the range of [3:1] to [1:3], and Sodium dodecyl sulfate is based on N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is present in an amount of 1% w / w to 10% w / w by weight, and in N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide has a particle size of less than 500 nm.

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

3. The pharmaceutical composition according to claim 1, wherein the mixture (b) is added to the inert matrix (a) by lamination using spray granulation.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the (a) inert matrix comprises a material, said material being mannitol.

5. The pharmaceutical composition according to claim 2 or 3, wherein... N The weight ratio of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide to polyvinylpyrrolidone-vinyl acetate copolymer is [3:1], [2:1], [1:1], [1:2] or [1:3].

6. The pharmaceutical composition according to claim 5, wherein... N The weight ratio of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide to polyvinylpyrrolidone-vinyl acetate copolymer is [1:1] or [2:1].

7. The pharmaceutical composition according to claim 5, wherein... N The weight ratio of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide to polyvinylpyrrolidone-vinyl acetate copolymer is [2 : 1].

8. The pharmaceutical composition according to claim 2 or 3, wherein... N The weight ratio of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, polyvinylpyrrolidone-vinyl acetate copolymer, and sodium dodecyl sulfate is [3:1:0.1], or [2:1:0.1], or [2:1:0.08], or [2:1:0.05], or [2:1:0.04], or [2:1:0.03], or [2:1:0.02], or [1:1:0.1], or [1:1:0.07], or [1:1:0.05], or [1:1:0.05]. [0.04] or [1:1:0.02].

9. The pharmaceutical composition according to claim 8, wherein... N The weight ratio of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, polyvinylpyrrolidone-vinyl acetate copolymer and sodium dodecyl sulfate is either [2:1:0.08], or [2:1:0.1], or [2:1:0.05], or [2:1:0.04], or [2:1:0.03], or [2:1:0.02].

10. The pharmaceutical composition according to any one of claims 1-3, wherein the polyvinylpyrrolidone-vinyl acetate copolymer is based on N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is present in the mixture described in (b) in an amount of 25% w / w to 100% w / w by weight.

11. The pharmaceutical composition of claim 10, wherein the polyvinylpyrrolidone-vinyl acetate copolymer is based on... N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is present in the mixture described in (b) in an amount of 50% w / w to 100% w / w by weight.

12. The pharmaceutical composition of claim 1, wherein sodium dodecyl sulfate is based on... N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is present in the mixture described in (b) in an amount of 4% w / w or 5% w / w by weight.

13. The pharmaceutical composition according to claim 1, wherein... N The particle size of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is less than 350 nm.

14. The pharmaceutical composition according to claim 1, wherein... N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide has a particle size of less than 250 nm.

15. The pharmaceutical composition according to claim 1, wherein the content measured by PCS N The particle size of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is 100 nm to 350 nm.

16. The pharmaceutical composition according to claim 1, wherein the content measured by PCS N The particle size of -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is 110 nm to 180 nm.

17. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition further comprises an external phase, wherein the external phase comprises a pharmaceutically acceptable excipient: - A filler, wherein the filler is lactose, mannitol, or cellulose. - A lubricant, wherein the lubricant is sodium stearate fumarate or magnesium stearate. - A disintegrant, wherein the disintegrant is croscarmellose sodium, sodium carbonate, or sodium glycolate starch.

18. The pharmaceutical composition of claim 17, wherein the exogenous phase is present in an amount of 20-50% w / w of the total weight of the composition.

19. The pharmaceutical composition of claim 17, wherein the external phase is present in an amount of 40% w / w of the total weight of the composition.

20. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition is optionally further formulated into a final dosage form in the presence of at least one pharmaceutically acceptable excipient, and wherein the final dosage form is a capsule or a tablet.

21. The pharmaceutical composition of claim 20, wherein the capsule is selected from hard-shell capsules, soft-shell capsules, or mixtures thereof, and wherein the tablet is a film-coated tablet.

22. The pharmaceutical composition of claim 20, wherein the capsule is a plant-based shell capsule.

23. A final dosage form, said final dosage form being a capsule formulation comprising a pharmaceutical composition according to any one of claims 1-19.

24. A final dosage form, said final dosage form being a tablet formulation comprising a pharmaceutical composition according to any one of claims 1-19.

25. The final dosage form according to claim 24, wherein N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is present in an amount of 10% w / w to 25% w / w based on the total weight of the final dosage form.

26. The final dosage form according to claim 24 or 25, wherein the filler is present in an amount of 20% w / w to 40% w / w based on the total weight of the final dosage form.

27. The final dosage form according to claim 24 or 25, wherein the disintegrant is present in an amount of 5% w / w to 10% w / w based on the total weight of the final dosage form.

28. The final dosage form according to claim 24 or 25, wherein the inert matrix is ​​present in an amount of 20% w / w to 40% w / w based on the total weight of the final dosage form.

29. The final dosage form according to claim 24 or 25, wherein the binder is present in an amount of 5% w / w to 25% w / w based on the total weight of the final dosage form.

30. The final formulation according to claim 24 or 25, wherein the lubricant is present in an amount of 0.1% w / w to 2% w / w based on the total weight of the final formulation.

31. The final dosage form according to claim 24 or 25, wherein the surfactant is present in an amount of 0.1% w / w to 2.5% w / w based on the total weight of the final dosage form.

32. The final dosage form according to claim 24 or 25, wherein the final dosage form comprises an amount of 10 mg to 150 mg. N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

33. The final dosage form according to claim 24 or 25, wherein the final dosage form comprises amounts of 10 mg, 25 mg, 35 mg, 50 mg, 75 mg, or 100 mg. N -(3-(6-amino-5-(2-(N-methacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

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