Pharmaceutical composition for oral administration comprising aminopyrimidine derivative or pharmaceutically acceptable salt, hydrate, or solvate thereof

Abstract

SOLUTION: Provided is a pharmaceutical composition for oral administration comprising, as an active ingredient, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and, as diluents, a combination of (i) a cellulose derivative and (ii) a sugar or polyol.EFFECT: The disclosed composition is characterized by improved manufacturability, while maintaining pharmaceutical benefits of minimizing the effect due to changes in pH environment in the stomach, possessing excellent stability, and exhibiting good bioavailability.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is filed on April 14, 2020, the entire contents of which are incorporated herein by reference. No. 63 / 009,623, filed April 23, 2020. This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 014,277.

[0002] FIELD OF THE INVENTION The present disclosure relates to an aminopyrimidine derivative or a pharmaceutically acceptable salt, hydrate, or More specifically, the present disclosure relates to pharmaceutical compositions for oral administration comprising N- (5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole- 1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)a acrylamide (lasertinib), its pharmaceutically acceptable salts, hydrates, or solvates. The present invention relates to a pharmaceutical composition comprising: [Background technology]

[0003] WO 2016 / 060443 describes aminopyrimidine derivatives, such as N-(5 -(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole-1- (yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acryl amide (lasertinib) or a pharmaceutically acceptable salt, hydrate, or solvate thereof Disclosed is lazertinib or a pharmaceutically acceptable salt, hydrate, or solvate thereof. selected protein kinases, especially mutant epidermal growth factor receptor protein kinases. This provides an effective and safe treatment method for, for example, non-small cell lung cancer. Lazertinib or a pharmaceutically acceptable salt, hydrate, or solvent thereof The monohydrate is less effective against wild-type EGFR and the T790M single activating mutation (EGFR Irreversible EGFR with strong inhibitory activity and excellent selectivity against EGFRm and double mutations Known as TKIs, they are used to treat primary advanced non-small cell lung cancer and advanced non-small cell lung cancer with brain metastases. It is expected to show therapeutic benefits in the treatment of patients with small cell lung cancer. .

[0004] Lazertinib or a pharmaceutically acceptable salt, hydrate, or solvate thereof for oral administration When formulated as a composition, the active ingredient is released immediately in the stomach, then passes into the small intestine and is absorbed. and lazertinib or its derivatives in the form of an immediate release pharmaceutical composition having a mechanism for allowing the drug to be absorbed. It may be considered to incorporate a physiologically acceptable salt, hydrate, or solvate. In the formulation of such immediate release pharmaceutical compositions, for example, food or co-administered drugs (e.g. It is necessary to minimize the effects of changes in stomach pH caused by drugs such as antacids. The pH of the stomach at the time of eating is not constant within the range of pH 1 to pH 3.5, and the average pH of the stomach after eating is Since the pH is 4 (pH 3-5), the dissolution rate varies depending on the physicochemical properties of the active ingredient. This may result in changes in absorption rate and bioavailability. It can be achieved. Summary of the Invention [Means for solving the problem]

[0005] The present inventors have discovered that N-(5-(4-(4-((dimethylamino)methyl)-3-((dimethylamino)methyl)- (phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy- 2-morpholinophenyl)acrylamide (lasertinib) or its pharmaceutically acceptable salts The salts, hydrates, or solvates of the compounds are prepared using specific combinations of diluents in specific relative proportions. When formulated with PEG, it minimizes the effects of changes in the stomach pH environment and provides excellent stability. While maintaining the pharmaceutical benefits of good bioavailability, It has been found that it is possible to prepare immediate release pharmaceutical compositions with improved manufacturability.

[0006] According to one aspect of the present disclosure, N-(5-(4-(4-((dimethylamino) )methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino )-4-methoxy-2-morpholinophenyl)acrylamide or a pharmaceutically acceptable salt thereof and (i) a cellulose derivative and (ii) a salt, hydrate, or solvate thereof as a diluent. A pharmaceutical composition for oral administration comprising a combination of cellulose and a sugar or polyol. A pharmaceutical composition in which a sugar derivative and a sugar or polyol are present in a weight ratio of 1:0.10 to 1:0.40. Pharmaceutical compositions are provided.

[0007] Also provided are methods for treating non-small cell lung cancer in a subject in need thereof. Also disclosed are methods of administering to a subject a pharmaceutical composition of the type described above. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 shows the results of a compression force profile study comparing compositions according to the present disclosure with prior art formulations. [Figure 2] FIG. 1 illustrates the results of compression force profile testing of compositions according to the present disclosure. [Figure 3] FIG. 10 shows the results of compression force profile testing of further compositions according to the present disclosure. [Figure 4] FIG. 10 shows the results of compression force profile testing of further compositions according to the present disclosure. [Figure 5] FIG. 10 shows the results of compression force profile testing of further compositions according to the present disclosure. [Figure 6] FIG. 10 shows the results of compression force profile testing of further compositions according to the present disclosure. [Figure 7] FIG. 10 shows the results of compression force profile testing of further compositions according to the present disclosure. [Figure 8] FIG. 10 shows the results of compression force profile testing of further compositions according to the present disclosure. [Figure 9] FIG. 10 shows the results of a compression force profile study of a further composition according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure provides N-(5-(4-((dimethylamino)methyl)-3-hydroxybenzoates as the active ingredient. -phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy ci-2-morpholinophenyl)acrylamide (lasertinib) or its pharmaceutically acceptable salts and (i) cellulose derivatives and (ii) cellulose derivatives as diluents. ) a pharmaceutical composition for oral administration comprising a combination of a sugar or a polyol, The sucrose derivative and the sugar or polyol are mixed in a ratio of 1:0.10 to 1:0.40 in the pharmaceutical composition. The pharmaceutical composition is provided in which the components are present in an amount ratio of:

[0010] As used herein, the terms "diluent" and "additive" have the same meaning and may be used interchangeably. According to the present disclosure, lazertinib or a pharmaceutically acceptable salt, hydrate, or Solvates are formed by combining specific diluents in specific proportions, i.e., cellulose derivatives and When formulated using a combination of sugars or polyols, the pH of the stomach can change. To prepare an immediate release pharmaceutical composition with excellent manufacturability that can minimize the influence of It was found that this is possible. The pH environment of the stomach changes due to meals. and drug-induced pH changes, e.g., proton pump inhibitors such as emeprazole, or These include, but are not limited to, H2 receptor antagonists such as cimetidine, and antacids. .

[0011] Lazertinib and methods for manufacturing lazertinib are described, for example, in US Pat. No. 6,413,999, which is incorporated herein by reference. This is described in US Patent No. 9,593,098.

[0012] In the pharmaceutical compositions of the present disclosure, N-(5-(4-(4-((dimethylamino)methyl)-3 -phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy ci-2-morpholinophenyl)acrylamide (lasertinib) or its pharmaceutically acceptable salts Acceptable salts, hydrates, or solvates can be used in therapeutically effective amounts. Zertinib or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in a unit dosage form. The dosage range for lazertinib (e.g., per tablet) is 10 to 320 mg. For example, 10mg, 20mg, 40mg, 80mg, 100mg, 120mg, 160mg It can be used in amounts of 240 mg, 240 mg, or 320 mg.

[0013] The pharmaceutical compositions of the present disclosure include those containing a combination of a cellulose derivative and a sugar or a polyol. The cellulose derivative and the sugar or polyol in the composition may be combined with a diluent. When the weight ratio is 1:0.1 to 1:0.40, the resulting composition has a It has now been discovered that the compositions have excellent manufacturability. When the ingredients are combined, mixed, and compressed to form a compressed tablet dosage form, A broad hardness profile is obtained within a specific range of compression forces. Compatible with a wider range of compression forces compared to prior art formulations (i.e., a wider range of compression forces) (This results in an acceptable hardness profile within the range.) This property is explained in the examples below. At the same time, in this composition, lazertinib or its pharmaceutical The commercially acceptable salts, hydrates, or solvates are minimally affected by changes in the pH environment in the stomach. can be kept to.

[0014] According to the present composition, the weight ratio of the cellulose derivative to the sugar or polyol in the composition is: 1:0.1 to 1:0.40, e.g., 1:0.15 to 1:0.40, 1:0.20 to 1: 0.30, or in the range of 1:0.20 to 1:0.25.

[0015] Exemplary cellulose derivatives include cellulose esters and cellulose ethers. Cellulose esters include cellulose acetate (CA), cellulose acetate phthalate, Cellulose acetate butyrate (CAP), cellulose acetate butyrate (CAB), cellulose acetate trimellitate (Cell cellulose acetate trimelitate (CAT), and hydroxypropyl methylcellulose Examples include hydroxupropylmethyl cellulose phthalate (HPMCP). Cellulose ethers include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, Pyrcellulose (HPC), Hydroxyethylcellulose (HEC), Hydroxypropyl HPMC, sodium carboxymethylcellulose (NaCMC) ), and carboxymethyl cellulose (CMC). The term is intended to include other forms of cellulose, such as microcrystalline cellulose (MCC). Microcrystalline cellulose is available in many different forms, called grades. The mechanical properties of grades are greatly influenced by their particle size and crystallinity. Siliconized MCC (SMCC) and second generation MCC grades or MCC Type II (MCC- New grades of MCC with improved pharmaceutical properties, such as II), have been prepared. These grades are made by co-processing cellulose with other materials such as colloidal silicon dioxide. or prepared by special chemical methods. Other types of pure cellulose available These include powdered cellulose (PC) and low crystallinity powdered cellulose (LCPC), These are also included within the intended meaning of the term "cellulose derivatives."

[0016] Sugars that can be used in the present composition include, for example, galactose, glucose, maize, and the like. Sugars, fructose, xylose, fucose, arabinose, sucrose, maltose Polyols include either monosaccharides or disaccharides, including sugars, saccharides, and lactose. Contains low molecular weight compounds such as alcohols, maltitol, sorbitol, mannitol, Xylitol, erythritol, ethylene glycol, glycerol, threitol, Lavitol, ribitol, galactitol, fucitol, iditol, inositol, la Cititol and isomalt represent exemplary sugar alcohols. The polyols include polyethylene oxide or polyethylene glycol (PEG) and and polymer polyols such as polypropylene glycol (PPG).

[0017] Any combination of cellulose derivatives and sugars or polyols may be used in the composition. In some embodiments, the cellulose derivative is microcrystalline cellulose. In some embodiments, the sugar / polyol is mannitol. The weight ratio of microcrystalline cellulose to mannitol in the product is 1:0.1 to 1:0.40, for example For example, 1:0.15 to 1:0.40, 1:0.20 to 1:0.30, or 1:0.20 to 1 : It can be in the range of 0.25.

[0018] The total amount of diluents (cellulose derivatives and sugars or polyols) in the composition is based on the total weight of the composition. For example, the total amount of diluent may be about 55 to 80% by weight based on the amount of the composition. Approximately 57-78% by weight, 58-77% by weight, 60-77% by weight, 6% by weight, based on the total weight of the product 2 to 77% by weight, or about 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 , 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, It can be 78, 79 or 80% by weight.

[0019] The pharmaceutical compositions according to the present disclosure may contain, in addition to the diluent, a disintegrant, a lubricant, a glidant, a coloring agent, or other additives. Additional excipients, such as common excipients, may also be included.

[0020] If present, the disintegrant may be a conventional disintegrant used in the pharmaceutical field. However, according to the present disclosure, among various disintegrants, a specific disintegrant, namely, croscarmellose, is used. When mellose sodium is used, the drug disintegrates / dissolves in the stomach and moves to the intestine. Therefore, the pharmaceutical composition of the present disclosure contains croscarmellose as a disintegrant. It is preferred that the composition contains croscarmellose sodium. About 0.5 to 10% by weight, for example 1 to 10% by weight, 1 to 5% by weight, based on the total weight of the composition; It may be present in an amount of 2-5 wt%, 2-3 wt%, or 2.5-3 wt%.

[0021] When present, the lubricant may be a conventional lubricant used in the pharmaceutical industry. However, according to the present disclosure, among various lubricants, a specific lubricant, namely stearin magnesium phosphate is lazertinib or a pharmaceutically acceptable salt, hydrate, or solvent thereof Therefore, the compatibility of the present invention with the hydrates of the present invention is particularly excellent, thereby ensuring excellent stability. Preferably, the pharmaceutical composition contains magnesium stearate as a lubricant. Magnesium phosphate may be used in an amount sufficient to provide a sufficient lubricating effect. About 0.4 to 2% by weight, for example, 0.5 to 2% by weight, 0.75 to 1. It may be present in an amount of, but not limited to, 25% by weight, or 1-2% by weight. In an embodiment, a lubricant such as magnesium stearate is present in an amount of about 1% by weight.

[0022] The dosage form may further comprise a lubricant. Lubricants are conventional examples used in the pharmaceutical industry. According to some embodiments, the lubricant can be selected from among colloidal diacid In some embodiments, the colloidal silicon dioxide is a hydrophobic silicon dioxide. The lubricant, such as hydrophobic colloidal silicon dioxide, is present in an amount of, based on the total weight of the composition: The lubricant may be present in an amount of about 0.25 to 0.75% by weight. For example, the lubricant may be present in an amount of 0.25, 0.30 , 0.40, 0.50, 0.60, 0.70, or 0.75 wt %. In certain embodiments, the lubricant is hydrophobic colloidal silicon dioxide present in an amount of 0.5% by weight. It is natural.

[0023] In certain embodiments, the pharmaceutical compositions of the present disclosure contain N-(5-(4-(4- ((Dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin (2-amino-4-methoxy-2-morpholinophenyl)acrylamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and microcrystalline cellulose as a diluent. and mannitol, croscarmellose sodium as a disintegrant, and a lubricant. In certain embodiments, the composition comprises a sparsely packed granule containing magnesium stearate. Further included is aqueous colloidal silicon dioxide.

[0024] In this composition, lazertinib mesylate exhibits superior efficacy compared to the free base form of the compound. It has stability, solubility, and bioavailability and can be prepared in high purity. Furthermore, lazertinib mesylate may be effective when co-administered with, for example, antacids, or alone. Even in the case of oral administration, it has the advantage of having excellent bioavailability. Therefore, in the pharmaceutical composition of the present disclosure, the active ingredient is lazertinib mesylate. In certain embodiments, the composition contains 15 to 40% by weight of N-(5-(4-(4 -((Dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin (2-(Dimethylamino)-4-methoxy-2-morpholinophenyl)acrylamide methionine a combination of 55 to 80% by weight of microcrystalline cellulose and mannitol; and 3% by weight of croscarmellose sodium and 0.5 to 2% by weight of magnesium stearate In some embodiments, the pharmaceutical composition comprises 17-38% by weight of N-(5 -(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole-1- (yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acryl A combination of methylparaben mesylate and 60-77% by weight of microcrystalline cellulose and mannitol. Combined with 2.5 to 3% by weight of croscarmellose sodium and 0.75 to 1.25% by weight of % magnesium stearate by weight of the total composition. colloidal silicon dioxide, e.g., hydrophobic colloidal silicon dioxide, in an amount of, for example, about 0.50% by weight based on the amount of It may further comprise loidal silicon dioxide.

[0025] The lazertinib mesylate may be in crystalline form. Silyl salts: 5.614, 12.394, 14.086, 17.143, 18.020; 19.104, 21.585, 22.131, and 22.487°2θ ±0.2°2θ In another embodiment, the compound may be in a crystalline form having a PXRD pattern with a peak at Lazertinib mesylate exhibits an endothermic peak at 210 to 230°C, preferably at 217±2°C. The compound may be in a crystalline form having a differential scanning calorimeter (DSC) thermogram having a Tinib mesylate may have an onset temperature of 214±2°C. For example, see WO 2018 / 194356, which is incorporated herein by reference. It is written.

[0026] Lazertinib mesylate is prepared by dissolving lazertinib free base in a single organic solvent or a mixture of solvents. and then adding methanesulfonic acid to form lazertinib mesylate. and (b) adding an organic solvent to the mixture of step (a) to obtain lazertinib mesylate. and crystallizing the salt.

[0027] The single organic solvent in step (a) is not particularly limited, but may be acetone, methyl ethyl ketone, The mixed solvent in step (a) may be selected from the group consisting of water and one or more The solvent may be a mixture of water with an appropriate organic solvent. A mixed solvent containing one or more organic solvents selected from the group consisting of methyl ethyl ketone and methyl ethyl ketone is preferred, but is not limited to this. The mixing ratio of water to organic solvent is 1:1 to 1:10 by volume, specifically 1:4. The step (a) can be carried out at a temperature of 20 to 70°C, Preferably, the reaction can be carried out at a temperature of 45 to 60°C.

[0028] The crystallization in step (b) is carried out by adding an organic solvent to the mixture obtained in step (a), stirring, and cooling. This can be done by cooling the mixture, filtering the mixture, and then drying the resulting solid. The organic solvent in step (b) may be the same as or different from the single organic solvent in step (a). Specifically, the organic solvent in step (b) may be acetone, methyl ethyl ketone, and and ethyl acetate. The organic solvent is 3 mL to 20 mL per 1 g of lazertinib free base used in step (a). Specifically, the organic solvent may be added by volume to the lazertin used in step (a). A volume of 5 mL to 20 mL per gram of benzodiazepine free base, more specifically 5 mL to 10 mL. The mixture obtained by adding the organic solvent may be, but is not limited to, added in a volume of 1000 ml. After cooling to a temperature of 0 to 30°C, preferably 0 to 10°C, the mixture is dried at a temperature of 30 to 70°C. Lazertinib mesylate can be isolated by

[0029] The lazertinib active ingredient may be provided in the composition as a salt, hydrate, or solvate. As noted above, an exemplary salt form is lazertinib mesylate. WO 2018 / 194356 describes the mesylate salt of lazertinib and its crystalline form. In this composition, the crystalline lazertinib may be a hydrate. .

[0030] The compositions may contain the active ingredient in a specific weight ratio to the diluent combination. For example, the active ingredient may be mixed with the pharmaceutical composition in a weight ratio of 1:1.5 to 1:4 to the diluent combination. It may be present in the formulation. In certain embodiments, the active ingredient is present in a ratio of 1:1.6 to 1:4 to the diluent combination. or in a weight ratio of 1:1.8 to 1:3.9 in the pharmaceutical preparation.

[0031] The active ingredient may be present in an amount of 15 to 35% by weight based on the total weight of the pharmaceutical formulation. In an embodiment, the active ingredient is present in an amount of 18-35% by weight based on the total weight of the pharmaceutical formulation. For example, the active ingredient may be present in an amount of about 18, 19, 20, 21, 22, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 1 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 It may be present in an amount of % by weight.

[0032] The pharmaceutical compositions of the present disclosure are useful for treating allograft rejection, graft-versus-host disease, diabetic retinopathy, age-related Choroidal neovascularization due to blindness, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, and arthritis Pannus invasion of the synovial membrane, multiple sclerosis, myasthenia gravis, diabetes, diabetic vascular disease, and immature Infantile retinopathy, infantile hemangioma, non-small cell lung cancer, bladder cancer, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, stomach cancer Cancer, pancreatic cancer, psoriasis, fibrosis, atherosclerosis, restenosis, autoimmune diseases, allergies, respiratory Respiratory disease, asthma, graft rejection, inflammation, thrombosis, retinal duct proliferation, inflammatory bowel disease, Cancer, ulcerative colitis, bone disease, graft or bone marrow transplant rejection, lupus, chronic pancreatitis, malignant Fluid disorders, septic shock, fibrotic and differentiated skin diseases or disorders, central nervous system diseases, neurodegeneration Diseases, Alzheimer's disease, Parkinson's disease, brain or spinal cord injury, and neurological damage after exon transformation Related disorders or conditions, such as acute or chronic cancer, eye disease, viral infection, heart disease, lung disease, or kidney disease The pharmaceutical composition of the present disclosure can be used for the prevention or treatment of bronchitis. or acute or chronic cancer, more preferably lung cancer, most preferably non-small cell lung cancer or brain metastasis. The present invention can be used for, but is not limited to, the prevention or treatment of advanced non-small cell lung cancer.

[0033] The present disclosure will now be described in more detail by way of examples intended to illustrate the present disclosure. However, the present disclosure is not limited to these examples.

[0034] In the following examples, "lasertinib mesylate" refers to N-(5-(4-(4-( (Dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidine (2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate Refers to acid salts.

[0035] Numbered Embodiments Exemplary numbered embodiments of the present invention are set forth below.

[0036] 1. N-(5-(4-((dimethylamino)methyl)-3-phenyl)-2-phenyl-2-propanol as the active ingredient (1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2 -morpholinophenyl)acrylamide (lasertinib) or its pharmaceutically acceptable salts and salts, hydrates, or solvates thereof, and (i) cellulose derivatives and (ii) sugars or A pharmaceutical composition for oral administration comprising a cellulose acetate copolymer in combination with a polyol. The derivative and the sugar or polyol are contained in the pharmaceutical composition in a weight ratio of 1:0.10 to 1:0.40. A pharmaceutical composition. 2. The weight ratio of the cellulose derivative to the sugar or polyol is 1:0.15 to 1:0.40. 2. The pharmaceutical composition of embodiment 1, wherein the compound is present in the pharmaceutical composition at 3. The weight ratio of the cellulose derivative to the sugar or polyol is 1:0.20 to 1:0.30. 2. The pharmaceutical composition of embodiment 1, wherein the compound is present in the pharmaceutical composition at 4. The weight ratio of the cellulose derivative to the sugar or polyol is 1:0.20 to 1:0.25. 2. The pharmaceutical composition of embodiment 1, wherein the compound is present in the pharmaceutical composition at 5. Any one of embodiments 1 to 4, wherein the cellulose derivative is microcrystalline cellulose. The pharmaceutical composition described. 6. Any one of embodiments 1 to 5, wherein the sugar or polyol is mannitol. A pharmaceutical composition comprising: 7. The medicament of embodiment 1, further comprising croscarmellose sodium as a disintegrant. composition. 8. Croscarmellose sodium is present in an amount of 2 to 3% by weight based on the total weight of the composition. 8. The pharmaceutical composition of embodiment 7, wherein 9. The pharmaceutical composition of embodiment 1, further comprising magnesium stearate as a lubricant. thing. 10. Croscarmellose sodium is used as a disintegrant and magnesium stearate as a lubricant. 2. The pharmaceutical composition of embodiment 1, further comprising nesium. 11. The active ingredient is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl)- (1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2 Any of embodiments 1 to 10, wherein the compound is (-morpholinophenyl)acrylamide mesylate. 1. The pharmaceutical composition described in Item 1. 12.N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H- (pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholino Phenyl)acrylamide mesylate was 5.614, 12.394, 14.086, 1 7.143, 18.020, 19.104, 21.585, 22.131, and 22.4 It is a crystalline form having a PXRD pattern with a peak at 87° 2θ ± 0.2° 2θ. , The pharmaceutical composition according to embodiment 11. 13.N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H- (1-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholino Phenyl)acrylamide mesylate exhibited a differential scan with an endothermic peak at 210-230°C. 12. The pharmaceutical composition of embodiment 11, which is in a crystalline form having a differential scanning calorimetry (DSC) thermogram. Finished product. 14. 15 to 40% by weight of N-(5-(4-(4-((dimethylamino)methyl)-3 -phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy (2-morpholinophenyl) acrylamide mesylate and 55-80% by weight of microcrystalline A combination of cellulose and mannitol with 2-3% by weight of croscarmellose sodium and 0.5 to 2 wt. % magnesium stearate. Pharmaceutical compositions. 15.17-38% by weight of N-(5-(4-(4-((dimethylamino)methyl)-3 -phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy (2-morpholinophenyl) acrylamide mesylate and 60-77% by weight of microcrystalline A combination of cellulose and mannitol and 2.5 to 3% by weight of croscarmellose thorium and 0.75 to 1.25 wt. % magnesium stearate. The pharmaceutical composition according to aspect 1. 16. The medicament according to any one of embodiments 1 to 15, further comprising colloidal silicon dioxide. formulation. 17. Embodiment 1, wherein the colloidal silicon dioxide is hydrophobic colloidal silicon dioxide. 7. The pharmaceutical formulation according to claim 6. 18. Colloidal silicon dioxide is present in an amount of about 0.50% by weight, based on the total weight of the pharmaceutical formulation. 18. The pharmaceutical formulation of embodiment 16 or embodiment 17, wherein the pharmaceutical formulation is present in an amount of 19.N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H- (1-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholino Phenyl)acrylamide mesylate has an endothermic peak at 217±2°C. 16. The pharmaceutical composition of embodiment 15, which is in a crystalline form having a differential scanning calorimeter (DSC) thermogram . 20. The active ingredient is used in a pharmaceutical preparation in a weight ratio of 1:1.5 to 1:4 with respect to the diluent combination. 20. The pharmaceutical formulation according to any one of embodiments 1 to 19, wherein the compound is present in a pharmaceutical formulation. 21. The active ingredient is mixed with the diluent in a weight ratio of 1:1.8 to 1:3.9. 21. The pharmaceutical formulation according to any one of embodiments 1 to 20, which is present in a pharmaceutical formulation. 22. The active ingredient is present in an amount of 15 to 35% by weight based on the total weight of the pharmaceutical formulation. 22. A pharmaceutical formulation according to any one of Forms 1 to 21. 23. The active ingredient is present in an amount of 18 to 35% by weight based on the total weight of the pharmaceutical formulation. 23. The pharmaceutical formulation of any one of Forms 1 to 22. 24. An embodiment in which the active ingredient is present in an amount of about 20% by weight, based on the total weight of the pharmaceutical formulation. 24. The pharmaceutical formulation according to any one of 1 to 23. 25. An embodiment in which the active ingredient is present in an amount of about 25% by weight, based on the total weight of the pharmaceutical formulation. 24. The pharmaceutical formulation according to any one of 1 to 23. 26. Approximately 80 mg, preferably approximately 95 to 98 mg, more preferably approximately 96.48 mg an amount of lazertinib mesylate (e.g., lazertinib) equivalent to an amount of lazertinib free base bumesilate monohydrate) and Microcrystalline cellulose in an amount of about 216 to 219 mg, more preferably about 218.32 mg. , Mannitol in an amount of about 48-52 mg, more preferably about 50 mg; Croscarmellose sodium in an amount of about 7 to 10 mg, more preferably about 9.5 mg; , Colloidal silicon dioxide in an amount of about 1 to 3 mg, more preferably about 1.9 mg; and magnesium stearate in an amount of about 2 to 5 mg, more preferably about 3.8 mg. 24. The pharmaceutical formulation of any one of embodiments 1 to 23. 27. An amount of about 80 mg, preferably about 95 to 98 mg, more preferably 96.48 mg of lazertinib free base equivalent to lazertinib mesylate (e.g., lazertinib mesylate monohydrate), and Microcrystalline cellulose in an amount of about 286 to 290 mg, more preferably about 288.47 mg. , Mannitol in an amount of about 64 to 68 mg, more preferably about 66 mg; Croscarmellose sodium in an amount of about 10 to 14 mg, more preferably about 12 mg; , Colloidal silicon dioxide in an amount of about 1 to 4 mg, more preferably about 2.35 mg; and magnesium stearate in an amount of about 3 to 6 mg, more preferably about 4.7 mg. 24. The pharmaceutical formulation of any one of embodiments 1 to 23. 28. Approximately 240 mg, preferably approximately 287 to 291 mg, more preferably approximately 289.4 an amount of lazertinib mesylate (e.g., lazertinib mesylate) equivalent to a 4 mg amount of lazertinib free base Zertinib mesylate monohydrate) and Microcrystalline cellulose in an amount of about 652 to 656 mg, more preferably about 654.96 mg; , Mannitol in an amount of about 148-152 mg, more preferably about 150 mg; Croscarmellose sodium in an amount of about 26 to 30 mg, more preferably about 28.5 mg And, Colloidal silicon dioxide in an amount of about 4-7 mg, more preferably about 5.7 mg; magnesium stearate in an amount of about 9 to 13 mg, more preferably about 11.4 mg; 24. The pharmaceutical formulation of any one of embodiments 1 to 23, comprising: 29. Lazertinib mesylate (e.g., lazertinib mesylate monohydrate) is used in the treatment of PX In the RD (powder X-ray diffraction) graph, the values ​​were 5.614±0.2, 12.394±0.2, and 1 4.086±0.2, 17.143±0.2, 18.020±0.2, 19.104±0 .2, 21.585±0.2, 22.131±0.2, and 22.487±0.2° Any of embodiments 26 to 28, which is a crystalline form having a diffraction peak at θ (theta) angle. A pharmaceutical formulation according to any one of the preceding items. 30. Lazertinib mesylate (e.g., lazertinib mesylate monohydrate) is used in 5. 614, 12.394, 14.086, 17.143, 18.020, 19.104, 2 Peaks at 1.585, 22.131, and 22.487° 2θ ± 0.2° 30. The method of any one of embodiments 26 to 29, wherein the compound is in a crystalline form having a PXRD pattern Pharmaceutical preparations. 31. Lazertinib mesylate (e.g., lazertinib mesylate monohydrate) is used in 21 A differential scanning calorimeter (DSC) having an endothermic peak at 0 to 230°C, preferably 217±2°C 31. The pharmaceutical composition of any one of embodiments 26 to 30, wherein the compound is in a crystalline form having a thermogram of Drug formulations. 32. Embodiment 2, in the form of a tablet, the tablet optionally further comprising a coating material. 32. The pharmaceutical formulation according to any one of 6 to 31. 33A. A method of treating cancer in a patient, comprising administering to the patient a therapeutic agent according to any one of embodiments 1 to 32. Administering a pharmaceutical formulation of 33B. Embodiment 1 for use in treating cancer (e.g., lung cancer, such as non-small cell lung cancer) 33. The pharmaceutical formulation according to any one of claims 1 to 32. 33C. In the manufacture of a medicament for treating cancer (e.g., lung cancer, such as non-small cell lung cancer). , Use of a pharmaceutical formulation according to any one of embodiments 1 to 32. 34. Any of embodiments 33A, 33B, or 33C, wherein the patient has been diagnosed with lung cancer. The method or use according to any one of claims 1 to 4. 35. The method of embodiment 33A, 33B, or 33C, wherein the patient has been diagnosed with non-small cell lung cancer. Any method or use as described above. 36. A patient is diagnosed with advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer. The method or use of any of embodiments 33A, 33B, or 33C, as described above. 37. The patient has not received any prior epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) ) Patients of embodiments 33A, 33B, or 33C, or 3 37. The method or use according to any one of 4 to 36. 38. The patient has one or more EGFR mutations, e.g., the EGFR T790M mutation , the method according to any one of embodiments 33A, 33B or 33C, or 34 to 37; use. 39. Embodiments 33A, 33B or 33C, comprising administering the pharmaceutical formulation daily; or the method or use according to any one of 34 to 38. 40. The method of embodiment 33A, 33B or 33, comprising administering the pharmaceutical formulation once a day. C, or the method or use according to any one of 34 to 38. 41. Administer the pharmaceutical formulation in an amount that provides approximately 240 mg of lazertinib free base per day. (e.g., each tablet containing the equivalent of about 80 mg of lazertinib free base) In this case, administration of 3 tablets per day or approximately 240 mg of lazertinib (by administering one tablet per day if it contains a corresponding amount of free base), embodiment 33 A method or use according to any one of A, 33B or 33C, or 34 to 40. 42. Administer the pharmaceutical formulation in an amount that provides approximately 80 mg of lazertinib free base per day. (e.g., where a tablet contains the equivalent of about 80 mg of lazertinib free base) , by administering one tablet per day), embodiment 33A, 33B or 33C, or 34 to 40. A method or use according to any one of claims 34 to 40. 43. Administer the pharmaceutical formulation in an amount that provides approximately 160 mg of lazertinib free base per day. (e.g., each tablet containing the equivalent of about 80 mg of lazertinib free base) by administering two tablets per day if desired), in embodiment 33A, 33B or 33C or the method or use according to any one of items 34 to 40. 44. Administer the pharmaceutical formulation in an amount that provides approximately 320 mg of lazertinib free base per day. (e.g., each tablet containing the equivalent of about 80 mg of lazertinib free base) In this case, four tablets per day or approximately 240 mg of lazertinib per tablet may be administered. Each tablet contains approximately 80 mg of lazertinib free base. by administering two tablets per day if desired), in embodiment 33A, 33B or 33C or the method or use according to any one of items 34 to 40. 45. Administering a pharmaceutical preparation as part of a combination regimen with one or more additional anticancer drugs any of embodiments 33A, 33B, or 33C, or 34-44, comprising Method or use. 46. ​​The one or more additional anti-cancer agents include a bispecific anti-EGFR / c-Met antibody. 46. ​​The method or use according to embodiment 45. 47. Bispecific anti-EGFR / c-Met antibody is available from JNJ-61186372 (JNJ -372) (U.S. Pat. No. 9,593,164, which are incorporated herein by reference, and U.S. Pat. No. 6,223,969, which are incorporated herein by reference). As described in embodiment 46, the compound is a compound described in patent application publication no. 2020 / 0360394. The method or use of. [Example]

[0037] Example 1 - Preparation of pharmaceutical compositions and compression testing Preparation of Comparative Compositions. Previously developed dosage forms were manufactured and subjected to compression testing to determine the composition of the present disclosure. The manufacturability of the pharmaceutical composition was evaluated.

[0038] The formulas of the comparative compositions are shown in Table 1 below. As used herein, the core tablet preferably refers to a tablet containing a core. As used herein, coated tablets refer to tablets without any coating material. preferably refers to a tablet comprising a core tablet and further a coating material.

[0039] [Table 1] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0040] The manufacturing process for the comparative composition was as follows. i. A weighed amount of lazertinib mesylate per batch is passed through a No. 20 mesh screen. The mixture was then passed through a filter and transferred to a bottle. ii. Add a weighed amount of microcrystalline cellulose (Vivapur 112) to step i. The ingredients were blended using a suitable blender at a set speed. iii. Add the measured amounts of mannitol and croscarmellose sodium to the blend of step ii. The measured amounts were added and the mixture was blended at a set speed using a suitable blender. iv. Pass magnesium stearate through a suitable screen and blend with the blend of step iii. Added. v. The ingredients of step iv were blended using a suitable blender at a predetermined speed. vi. The blend of step v is compressed into tablets of average weight using a rotary compressor and suitable tableting tooling. The tablets were compressed into tablets weighing 235 mg. vii. Using a suitable container equipped with a mixer, mix Opadry amb 80W62 680 Coating material was dispersed in a vortex of purified water. After a specified time, no lumps were present. Mixed until viii. The core tablets of step vi are coated with the coating suspension of step vii onto the perforated tablets. The film was coated using a film coating device until the specified weight was gained. ix. The film coated tablets were removed and packaged appropriately.

[0041] Compression Testing of Comparative Compositions. Compression testing was performed on certain batches of the comparative composition. Compression was carried out using a rotary tablet press. Generally, the pre-compression force, compression force, and compression speed were adjusted. The process parameters are used to control the in-process properties of the tablets, such as hardness, thickness, disintegration time, and friability. Therefore, the results of this compression test are indicative of the robustness of the process. and identify reasonable and acceptable improvisations for scale-up and commercial manufacturability. Tablet samples can be prepared for each challenge. The samples were collected during the compression test profile run and evaluated for the IPC mentioned above.

[0042] The following IPC test methods were used to evaluate tablet properties: A. Appearance: Visual inspection B. Weight: Weighing, measure the weight of the tablets using an analytical balance C. Thickness: Thickness measurement, the thickness of the tablets is measured using a micrometer. D. Hardness: Hardness measurement: A tablet is placed on an anvil (or a pressure plate) with enough force to break the tablet. The tablet is placed between two platens (adding pressure to the two plates) and the crushing strength at which the tablet just breaks is recorded. E. Friability: Ph.Eur.2.9.7 / USP test <1216> :650mg or less For tablets with a unit weight, take a whole tablet sample as close to 6.5 g as possible, and For tablets with a unit weight of more than 100 mg, a sample of 10 whole tablets is taken. Carefully remove dust prior to testing. Accurately weigh the tablet sample and place the tablets in the drum. After rotating the machine 100 times, remove the tablet. If any cracks or splits are evident, remove the specimen and weigh it accurately. Generally, the test is carried out once. If tablets are broken or crushed, the sample should be considered untested. If the results are difficult to interpret or the weight loss is greater than the target value, the test is considered to be a pass. Repeat twice and calculate the average of the three tests. The maximum average weight loss obtained from the three samples is calculated. is considered acceptable for most products if it is 1.0% or less. F. Disintegration Test: In this test, a tablet disintegrates at a predetermined time when placed in a liquid medium under experimental conditions. The test is carried out to determine whether the dosage unit disintegrates within the six tubes in the basket. Add discs as needed. The time for complete disintegration of the tablets is recorded.

[0043] Tables 2 and 3 below show the performance of comparative compositions in compression tests relative to the IPC of the core tablets. An experimental example related to this is shown below.

[0044] [Table 2]

[0045] [Table 3]

[0046] Preparation of the Compositions of the Invention. Exemplary compositions according to the present disclosure were prepared from the ingredients shown in Table 4 below. Prepared.

[0047] [Table 4] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0048] The process for preparing the composition of the present invention was as follows. i. Weighed amount of lazertinib mesylate and Aerosil R972 per batch Pass the amount through a suitable screen, transfer to a jar and blend at the specified speed using a suitable blender. Blended. ii. Add mannitol, microcrystalline cellulose, and croscarmellose to the blend of step i. Add the weighed amount of sodium and blend the mixture at the specified speed using a suitable blender. Blended. iii. Pass magnesium stearate through a suitable screen and blend with the blend from step ii. Added. iv. Blend the ingredients of step iii using a suitable blender at a predetermined speed. Ta. v. The blend of step iv is compressed to an average weight using a rotary press and suitable tableting tooling. Compressed into 470 mg tablets. vi. Using a suitable container equipped with a mixer, mix Opadry amb 80W626 80 The coating material was dispersed in a vortex of purified water. Mixed with. vii. The core tablets of step v are coated with a perforated film coating using the coating suspension of step vi. The film was coated with a coating device until the desired weight was gained. viii. The film coated tablets were removed and packaged accordingly.

[0049] An alternative process for preparing the composition of the present invention is as follows. i. Lazertinib mesylate, Aerosil R972, mannitol, microcrystalline cellulose The weighed amounts per batch of croscarmellose and croscarmellose sodium are added to the appropriate screen. Pass the mixture through a strainer, transfer to a jar and blend using a suitable blender at the specified speed. ii. Pass magnesium stearate through a suitable screen and add it to the blend from step ii. Add. iii. Blend the ingredients of step iii using a suitable blender at the specified rotation speed. do. iv. The blend of step iv is compressed to an average weight using a rotary press and suitable tableting tooling. Compress into tablets of 470 mg each. v.Opadry amb 80W62680 coating material was mixed with a mixer Disperse the sample in a suitable container by vortexing the purified water. Mix with. vi. The core tablets of step v are perforated film coated with the coating suspension of step vi. The film is coated using a coating device until the specified weight is gained. vii. Remove the film coated tablets and package accordingly.

[0050] Compression Testing of the Compositions of the Invention. Compression testing was performed on several batches of the formulations of the invention. Compression was performed using a power-assisted rotary tablet press. Generally, pre-compression force, compression force, and compression force were Process parameters such as speed affect tablet properties such as hardness, thickness, disintegration time, and friability. This compression test result can affect process control. and whether it was reasonably acceptable for scale-up and commercial manufacturability. This ensures a range of in-process control (IPC) that can be achieved. The samples were taken from each challenge compression test profile run and evaluated for the IPCs listed above.

[0051] The following test methods are used to evaluate in-process tablet properties: A. Appearance: Visual inspection B. Weight: Weighing, measure the weight of the tablets using an analytical balance C. Thickness: Thickness measurement, the thickness of the tablets is measured using a micrometer. D. Hardness: Hardness measurement: A tablet is placed on an anvil (or a pressure plate) with enough force to break the tablet. The tablet is placed between two platens (adding pressure to the two plates) and the crushing strength at which the tablet just breaks is recorded. E. Friability: Ph.Eur.2.9.7 / USP test <1216> :650mg or less For tablets with a unit weight, take a whole tablet sample as close to 6.5 g as possible, and For tablets with a unit weight of more than 100 mg, a sample of 10 whole tablets is taken. Carefully remove dust prior to testing. Accurately weigh the tablet sample and place the tablets in the drum. After rotating the machine 100 times, remove the tablet. If any cracks or splits are evident, remove the specimen and weigh it accurately. Generally, the test is carried out once. If tablets are broken or crushed, the sample should be considered untested. If the results are difficult to interpret or the weight loss is greater than the target value, the test is considered to be a pass. Repeat twice and calculate the average of the three tests. The maximum average weight loss obtained from the three samples is calculated. is considered acceptable for most products if it is 1.0% or less. G. Disintegration Time of Tablets: Disintegration Test: In this test, tablets are placed in a liquid medium under experimental conditions. The test is to determine whether the dosage unit disintegrates within a specified time when placed in the six baskets. Place the discs into each tube and add as needed. The apparatus is run using water and the time for complete disintegration of the tablets is recorded.

[0052] Tables 5 to 7 below show the tested compositions of the present invention in relation to the IPC of the core tablets in the compression test. The experimental examples of the performance of each composition are shown below. All the compositions tested were in the amounts shown in Table 4. I obeyed.

[0053] [Table 5]

[0054] [Table 6]

[0055] [Table 7]

[0056] FIG. 1 shows the relationship between the comparative formulation and the formulation according to the present disclosure in terms of tablet hardness versus measured compression force. The comparative formulation of the prior art exhibited an average tablet hardness of 5 to 16 kN in the compression force range. The compressive strength-hardness profile window was very narrow, ranging from 3 to 9 kN. Within the range of compression forces, the formulations of the present invention have a wide hardness profile with an average tablet hardness of 14 to 25 kp. The file window was displayed.

[0057] Examples 2-11 - Preparation and Compression Testing of Further Compositions of the Invention Example 2 Using the manufacturing and compression test procedures described for the composition of the present invention in Example 1 (see " A further embodiment of the present invention represents an 80 mg lazertinib tablet (using an alternative manufacturing process). The compositions were prepared and tested. Table 8 shows the ingredients and their amounts in the tablets, and Table 9 shows the 1 shows the results of compression testing of compositions prepared from medium-sized batches (approximately 14.6 kg).

[0058] [Table 8] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0059] [Table 9] NT = Not Tested

[0060] FIG. 2 shows the results of compression force profile testing of the compositions according to Table 8.

[0061] Example 3 Using the manufacturing and compression testing procedures described for the composition of the present invention in Example 1, 80 mg Additional compositions of the present invention representing lazertinib tablets were prepared and tested. Table 10 shows the results of the tablet formulation. Table 11 shows the results of compression testing of the compositions.

[0062] [Table 10] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0063] [Table 11] * For a compressive force of 15 kN, n = 6. For compressive forces of 10 and 20 kN, n = 3.

[0064] FIG. 3 shows the results of compression force profile testing of the compositions according to Table 10.

[0065] Example 4 Using the manufacturing and compression test procedures described for the inventive composition of Example 1, an additional 80 Additional compositions of the invention representing mg lazertinib tablets were prepared and tested. Table 12 shows: The ingredients and their amounts in the tablets are listed, and Table 13 shows the results of compression testing of the compositions.

[0066] [Table 12] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0067] [Table 13] * At a compressive force of 11 kN, n = 6. At compressive forces of 9 and 15 kN, n = 3.

[0068] FIG. 4 shows the results of compression force profile testing of the compositions according to Table 12.

[0069] Example 5 Using the manufacturing and compression test procedures described for the inventive composition of Example 1, an additional 80 Additional compositions of the invention representing mg lazertinib tablets were prepared and tested. Table 14 shows: The ingredients and their amounts in the tablets are listed, and Table 15 shows the results of compression testing of the compositions.

[0070] [Table 14] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0071] [Table 15] * At a compressive force of 7.5 kN, n = 6. At compressive forces of 5.0 and 10.0 kN, n = 3.

[0072] FIG. 5 shows the results of compression force profile testing of the compositions according to Table 14.

[0073] Example 6 Using the manufacturing and compression test procedures described for the inventive composition of Example 1, an additional 80 Additional compositions of the invention representing mg lazertinib tablets were prepared and tested. Table 16 shows: Each ingredient and its amount in the tablet is listed, and Table 17 shows the results of compression testing of the compositions.

[0074] [Table 16] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0075] [Table 17] * At a compressive force of 13 kN, n = 6. At compressive forces of 9 and 15 kN, n = 3.

[0076] FIG. 6 shows the results of compression force profile testing of the compositions according to Table 16.

[0077] Example 7 Using the manufacturing and compression test procedures described for the inventive composition of Example 1, an additional 80 Additional compositions of the invention representing 100 mg lazertinib tablets were prepared and tested. Table 18 shows: The ingredients and their amounts in the tablets are listed, and Table 19 shows the results of compression testing of the compositions.

[0078] [Table 18] 1 80 mg of lazertinib per tablet equals 93.86 mg of lazertinib mesylate Equivalent.

[0079] [Table 19] * NT = Not Tested

[0080] FIG. 7 shows the results of compression force profile testing of the compositions according to Table 18.

[0081] Example 8 Using the manufacturing and compression test procedures described for the composition of the present invention in Example 1, 160 mg Additional compositions of the present invention were prepared and tested, representing lazertinib tablets of Tablet 20. Table 21 shows the proposed results of compression testing of the compositions. (i.e., compression is expressed at the target condition only, and no compression profile is generated at this scale.) (There was none).

[0082] [Table 20] 1 160 mg lazertinib per tablet contains 187.72 mg lazertinib mesylate Equivalent to salt.

[0083] [Table 21]

[0084] Example 9 Using the manufacturing and compression test procedures described for the composition of the present invention in Example 1 (see " A further invention representing a 240 mg lazertinib tablet (using an "alternative manufacturing process"). The following compositions were prepared and tested. Table 22 shows the ingredients and their amounts in the tablets. 3 shows the results of compression testing of compositions prepared from medium-sized batches (approximately 20 kg).

[0085] [Table 22] 1 240 mg lazertinib per tablet contains 281.58 mg lazertinib mesylate Equivalent to salt.

[0086] [Table 23] * n=6, NT=not tested

[0087] FIG. 8 shows the results of compression force profile testing of the compositions according to Table 22.

[0088] Example 10 Using the manufacturing and compression test procedures described for the composition of the present invention in Example 1, 240 mg Additional compositions of the present invention representing lazertinib tablets were prepared and tested. Table 24 shows the tablet Table 25 shows the results of compression testing of the compositions.

[0089] [Table 24] 1 240 mg lazertinib per tablet contains 281.58 mg lazertinib mesylate Equivalent to salt.

[0090] [Table 25] NT = Not Tested

[0091] FIG. 9 shows the results of compression force profile testing of compositions according to Table 24.

[0092] Example 11 Using the manufacturing and compression test procedures described for the composition of the present invention in Example 1, 120 mg Additional compositions of the invention representing lazertinib tablets were prepared and tested. Table 26 shows the tablet Table 27 shows the proposed results of compression testing of the compositions. (i.e., compression is expressed at the target condition only, and no compression profile is generated at this scale.) (There was none).

[0093] [Table 26] 1 120 mg lazertinib per tablet contains 140.79 mg lazertinib mesylate Equivalent to salt.

[0094] [Table 27] * NT = Not Tested

[0095] Example 12 Using the manufacturing and compression testing procedures described above in Example 1, the following compositions were obtained: Further compositions according to the present disclosure are prepared using the ingredients and their respective proportions.

[0096] [Table 28] 1 160 mg lazertinib per tablet contains 187.72 mg lazertinib mesylate Equivalent to salt.

[0097] [Table 29] 1 160 mg lazertinib per tablet contains 187.72 mg lazertinib mesylate Equivalent to salt.

[0098] [Table 30] 1 160 mg lazertinib per tablet contains 187.72 mg lazertinib mesylate Equivalent to salt.

[0099] [Table 31] 1 160 mg lazertinib per tablet contains 187.72 mg lazertinib mesylate Equivalent to salt.

[0100] Example 13 Using the manufacturing and compression testing procedures described above in Example 1, the following compositions were obtained: Further compositions according to the present disclosure are prepared using the ingredients and their respective proportions.

[0101] [Table 32] 1 240 mg lazertinib per tablet contains 281.58 mg lazertinib mesylate Equivalent to salt.

[0102] [Table 33] 1 240 mg lazertinib per tablet contains 281.58 mg lazertinib mesylate Equivalent to salt.

[0103] [Table 34] 1 240 mg lazertinib per tablet contains 281.58 mg lazertinib mesylate Equivalent to salt.

[0104] Example 14 Using the manufacturing and compression testing procedures described above in Example 1, the following compositions were obtained: Further compositions according to the present disclosure are prepared using the ingredients and their respective proportions.

[0105] [Table 35] 1 120 mg lazertinib per tablet contains 140.79 mg lazertinib mesylate Equivalent to salt.

[0106] [Table 36] 1 120 mg lazertinib per tablet contains 140.79 mg lazertinib mesylate Equivalent to salt.

[0107] [Table 37] 1 120 mg lazertinib per tablet contains 140.79 mg lazertinib mesylate Equivalent to salt.

[0108] [Table 38] 1 120 mg lazertinib per tablet contains 140.79 mg lazertinib mesylate Equivalent to salt.

[0109] Example 15 Using the manufacturing and compression testing procedures described above in Example 1, the following compositions were obtained: Further compositions according to the present disclosure are prepared using the ingredients and their respective proportions shown in Tables 39-4. Each of the 1000 micrometers was coated with Opadry® QX3 21A220024 or Opadry® AMB Yellow 80W626 80 tablets, each containing lazertinib mesylate monohydrate, microcrystalline cellulose, mannitol, tallow, croscarmellose sodium, colloidal silicon dioxide, and malic acid stearate A pharmaceutical formulation of a film-coated core tablet containing magnesium in the indicated amount. show.

[0110] [Table 39] 1 Each 80 mg tablet of lazertinib contains 96.48 mg of lazertinib mesylate. It corresponds to a hydrate.

[0111] [Table 40] 1 Each 80 mg tablet of lazertinib contains 96.48 mg of lazertinib mesylate. It corresponds to a hydrate.

[0112] [Table 41] 1 240 mg lazertinib per tablet contains 289.44 mg lazertinib mesylate It corresponds to the salt monohydrate.

Claims

1. A pharmaceutical composition for oral administration comprising N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (lasertinib) or a pharmaceutically acceptable salt, hydrate, or solvate thereof as an active ingredient, and a combination of (i) a cellulose derivative and (ii) a sugar or polyol as a diluent, wherein the cellulose derivative and the sugar or polyol are present in the pharmaceutical composition in a weight ratio of 1:0.20 to 1:0.30, the cellulose derivative is microcrystalline cellulose, and the sugar or polyol is mannitol.

2. The pharmaceutical composition described in claim 1, wherein the cellulose derivative and the sugar or polyol are present in the pharmaceutical composition in a weight ratio of 1:0.20 to 1:0.

25.

3. The pharmaceutical composition of claim 1, further comprising croscarmellose sodium as a disintegrant.

4. A pharmaceutical composition as described in claim 3, wherein the croscarmellose sodium is present in a range of 2 to 3 weight percent relative to the total weight of the composition.

5. The pharmaceutical composition of claim 1, further comprising magnesium stearate as a lubricant.

6. The pharmaceutical composition of claim 1, further comprising croscarmellose sodium as a disintegrant and magnesium stearate as a lubricant.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the active ingredient is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the active ingredient is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate monohydrate.

9. The pharmaceutical composition of claim 8, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate monohydrate is in a crystalline form having a PXRD pattern with peaks at 2θ of 5.614, 12.394, 14.086, 17.143, 18.020, 19.104, 21.585, 22.131, and 22.487°2θ±0.2°.

10. The pharmaceutical composition of claim 8, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate monohydrate is in a crystalline form having a differential scanning calorimeter (DSC) thermogram with an endothermic peak at 210 to 230°C.

11. The pharmaceutical composition of claim 1, comprising 15 to 40% by weight of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate, 55 to 80% by weight of a combination of microcrystalline cellulose and mannitol, 2 to 3% by weight of croscarmellose sodium, and 0.5 to 2% by weight of magnesium stearate.

12. The pharmaceutical composition of claim 1, comprising 17 to 38% by weight of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate, 60 to 77% by weight of a combination of microcrystalline cellulose and mannitol, 2.5 to 3% by weight of croscarmellose sodium, and 0.75 to 1.25% by weight of magnesium stearate.

13. A pharmaceutical composition according to any one of claims 1 to 12, further comprising colloidal silicon dioxide.

14. The pharmaceutical composition of claim 13, wherein the colloidal silicon dioxide is hydrophobic colloidal silicon dioxide.

15. The pharmaceutical composition of claim 13 or 14, wherein the colloidal silicon dioxide is present in an amount of about 0.50% by weight, based on the total weight of the pharmaceutical composition.

16. The pharmaceutical composition of claim 12, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate is in a crystalline form having a differential scanning calorimeter (DSC) thermogram with an endothermic peak at 217±2°C.

17. A pharmaceutical composition described in any one of claims 1 to 16, wherein the active ingredient is present in the pharmaceutical composition in a weight ratio of 1:1.5 to 1:4 relative to the diluent combination.

18. A pharmaceutical composition described in any one of claims 1 to 17, wherein the active ingredient is present in the pharmaceutical composition in a weight ratio of 1:1.8 to 1:3.9 relative to the diluent combination.

19. A pharmaceutical composition described in any one of claims 1 to 18, wherein the active ingredient is present in an amount of 15 to 35 weight % based on the total weight of the pharmaceutical composition.

20. A pharmaceutical composition according to any one of claims 1 to 19, wherein the active ingredient is present in an amount of 18 to 35% by weight relative to the total weight of the pharmaceutical composition.

21. A pharmaceutical composition according to any one of claims 1 to 20, wherein the active ingredient is present in an amount of about 20% by weight based on the total weight of the pharmaceutical composition.

22. A pharmaceutical composition according to any one of claims 1 to 20, wherein the active ingredient is present in an amount of approximately 25% by weight based on the total weight of the pharmaceutical composition.

23. The pharmaceutical composition of claim 13, wherein lazertinib or a pharmaceutically acceptable salt, hydrate, or solvate thereof is combined with colloidal silicon dioxide prior to the addition of the combination of the cellulose derivative and the sugar or polyol.

24. (a) N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (lasertinib) or a pharmaceutically acceptable salt, hydrate, or solvate thereof as an active ingredient; (b) hydrophobic colloidal silicon dioxide; (c) croscarmellose sodium as a disintegrant; (d) magnesium stearate; and (e) a combination of (i) a cellulose derivative and (ii) a sugar or polyol as a diluent, wherein the cellulose derivative and the sugar or polyol are present in the pharmaceutical composition in a weight ratio of 1:0.20 to 1:0.30, and the cellulose derivative is microcrystalline cellulose and the sugar or polyol is mannitol; 10. A pharmaceutical composition for oral administration comprising:

25. A method for producing a pharmaceutical composition, comprising: (a) blending N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (lasertinib) or a pharmaceutically acceptable salt, hydrate, or solvate thereof with colloidal silicon dioxide; (b) adding mannitol, microcrystalline cellulose, and croscarmellose sodium to the mixture of (a) and blending; (c) adding magnesium stearate to the mixture of (b); and (d) compressing the mixture of step (c) into tablets. Including, The method of manufacturing, wherein the microcrystalline cellulose and mannitol are provided in a weight ratio of 1:0.20 to 1:0.30.

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