PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION COMPRISING AN AMINOPYRIMIDINE DERIVATIVE OR ITS SALT

Abstract

The present description provides a pharmaceutical composition for oral administration comprising: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

Description

PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION WHICH COMPRISES AN AMINOPYRIMIDINE DERIVATIVE OR ITS SALT Cross-referencing of related applications This application claims priority to Korean patent application no. 10-2018-0124171, filed on October 18, 2018, the full content of which is incorporated herein by reference. TECHNICAL FIELD This description relates to a pharmaceutical composition for oral administration comprising an aminopyrimidine derivative or its salt. More particularly, this description relates to a pharmaceutical composition comprising N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1yl)pyrimidine-2-ylamino)-4-methoxy-2-morphol-1-phenyl) aorylamide (Lazertinib) or its salt and a combination of microcrystalline cellulose and mannitol as a diluent. BACKGROUND Patent No. WO 2016 / 060443 describes an aminopyrimidine derivative, for example, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-ylpyrimidina-2-ylamino)-4-methoxy-2-morpholinophenyl)aminoamide (Lazertinib) or its pharmaceutically acceptable salt. Lazertinib or its pharmaceutically acceptable salt has selective protein kinase inhibitory activity, particularly the protein kinase for a mutating epidermal growth factor receptor, and may provide, for example, an effective and safe treatment method for non-small cell lung cancer. Lazertinib or its pharmaceutically acceptable salt is known as an irreversible EGFR TKI that has less effect on type 1 EGFR. IF-2020-07123170-APN-ANP#INPI Page 1 of 31 wild-type, strong inhibitory activity on the single active T790M mutation (EGFRm) and double mutation, and excellent selectivity, and are expected to exhibit a therapeutically effective effect in the treatment of patients with primary cancer of progressive non-small cell lung cancer and progressive non-small cell lung cancer accompanied by brain metastasis. When lazertinib or its salt is formulated as an oral composition, it may be considered as an immediate-release pharmaceutical composition. This type of formulation involves the immediate release of the active ingredient in the stomach, which is then transferred to the small intestine for absorption. In formulating such an immediate-release pharmaceutical composition, it is necessary to minimize the effect of pH changes in the stomach, such as those caused by food or other drugs administered concurrently (e.g., an antacid). For example, since the pH in the empty stomach is not constant, ranging from pH 1 to pH 3.5, and the average pH in a postprandial stomach is pH 4 (pH 3 to 5), deviations in the dissolution index can occur depending on the physicochemical properties of the active ingredient. These deviations can result in changes in the absorption index and bioavailability. SUMMARY The present inventors discovered that when N-(5-(4-(4((dim eti lam i no) m et il)-3 -fe ni I-1 H-pyrazol-1 -yl)pyrimid ina-2-ylamino)-4-methoxy-2-morpholinophenyljacrylamide (Lazertinib) or its derivative are formulated using a combination of specific diluents, it is possible to prepare an immediate-release pharmaceutical composition capable of minimizing the effect in accordance with the changes in IF-2020-07123170-APN-ANP#INPI Page 2 of 31 pH environment in the stomach Furthermore, the present inventors discovered that the pharmaceutical composition can be formulated to ensure excellent stability and exhibit significantly greater bioavailability. Therefore, one objective of the present description is to provide a pharmaceutical composition for oral administration of Lazertinib or its pharmaceutically acceptable salt comprising a combination of specific diluents. According to one aspect of the present description, a pharmaceutical composition for oral administration is provided comprising N-(5-(4-(4"d-methylamino)methyl)-3-phenyl-1H-plrazol-1-yl)primidine-2-ylaminoH-methoxy-2-morpholinophenylacrylamide or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent. In the pharmaceutical composition of the present description, the weight ratio of microcrystalline cellulose to mannitol may be in the range of 1:0.9 to 1:3 and preferably 1:0.9 to 1:1.5. The pharmaceutical composition of the present description may further include croscarmellose sodium as a disintegrating agent, and the croscarmellose sodium may be present in a range of 0.5 to 10% by weight, preferably 2 to 5% by weight, with respect to the total weight of the composition. In addition, the pharmaceutical composition of the present description may further include magnesium stearate as a lubricant. In one embodiment, the pharmaceutical composition of the present description includes N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide or a pharmaceutically acceptable salt thereof as an active ingredient; a combination of IF-2020-07123170-APN-ANP#INPI Page 3 of 31 microcrystalline cellulose and mannitol as a diluent; croscarmellose sodium as a disintegrating agent; and magnesium stearate as a lubricant In the pharmaceutical composition of the present invention, the active ingredient may be Ν-(5-(4-(4-((όΪΓΤΐ6ίϊΐ3ΐΊηίηο)ΓπβίίΙ)-3-ίθηίΙ-1Η-ρίΓ3ζοΙ) mesylate 1'yl)pyrimidine-2-ylamino)-4-methoxy-2-morphoiinophenyl)acrylannide. In one embodiment, N-(5-(4-(4-((dimethylamino)methyl)-3-phenylpyrazo(yl)pyrimidine-2-amino)-4-methoxy-2-morpholinophenyl)acrylamide mesylate can be a crystalline form having a PXRD pattern with peaks at 5,614, 12,394, 14,086, 17,143, 18,020, 19,104, 21,585, 22,131, and 22,487°20 ± 0.2c28. In another embodiment, N-(5-(4-(4-((dimethylamino)methyl)-3-phenylpyrazo(yl)pyrazo(yl)) mesylate -yl)pyrimidine-2ylamino)-4-methoxy'2-morpholinofen¡l)acr¡lamide may be a crystalline form that has a differential scanning calorimetry (DSC) thermogram with anendothermic peaks at 210 to 230 °C, preferably 217±2C. According to the present description, it was discovered that when N-(5-(4(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidine-2-ylamine)-4-methoxy-2-morpholmophenyl)acrylamide (Lazertinib) or its salt is formulated using a combination of specific diluents, namely a combination of microcrystalline cellulose and mannitol, it is possible to prepare an immediate-release pharmaceutical composition capable of minimizing the effect according to changes in the pH environment in the stomach. Furthermore, the pharmaceutical composition of the present description can be formulated to ensure excellent stability and can achieve significantly improved bioavailability. BRIEF DESCRIPTION OF THE FIGURES IF-2020-07123170-APN-ANP#INPI Page 4 of 31 Figure 1 is a powder X-ray diffraction (PXRD) plot of Lazertinib mesylate prepared in Reference Example 1. Figure 2 is a differential scanning calorimetry (DSC) plot of Lazertinib mesylate prepared in Reference Example 1. Figure 3 is a photograph illustrating the results of the stability test performed under a stress condition with respect to Lazertinib mesylate prepared in Reference Example 1 (Initial: at the start, 2 weeks: after 2 weeks, 4 weeks: after 4 weeks) Figure 4 is a photograph illustrating the results of the stability test performed under an accelerated condition with respect to Lazertinib mesylate prepared in Reference Example 1 (Initial: at the beginning, 1 month: after 1 month, 3 months: after 3 months, 6 months: after 6 months) Figure 5 illustrates the results of the comparative pharmacokinetic test for Lazertinib mesylate and Lazertinib free base, performed in normal rats. Figure 6 illustrates the results of the comparative pharmacokinetic test for Lazertinib mesylate and Lazertinib free base, performed in esomeprazole-treated rats Figure 7 illustrates the results of the comparative pharmacokinetic test for Lazertinib mesylate and Lazertinib free base, performed in Beagle dogs Figure 8 illustrates the results obtained by performing the dissolution test under a pH 1.2 condition with respect to the tablet (Example 5) obtained according to the present description and the tablet from the comparative example (Comparative Example 1). IF-2020-07123170-APN-ANP#INPI Page 5 of 31 Figure 9 illustrates the results obtained by performing the dissolution test under a pH 4.0 condition with respect to the tablet (Example 5) obtained according to the present description and the tablet from the comparative example (Comparative Example 1). Figure 10 illustrates an enlarged result of the dissolution test from Figure 9. Figure 11 illustrates the results obtained by performing the dissolution test under a pH 4.0 condition with respect to the tablets (Examples 1 and 2) obtained according to the present description and the comparative example tablet (Comparative Example 3). Figure 12 illustrates the results obtained by performing the dissolution test under a continuous condition of an acidic phase (pH 1.0) and a buffer phase (pH 6.8) with respect to the tablet (Example 7) obtained according to the present description and the tablets of the comparative examples (Comparative Examples 5 and 6). Figure 13 illustrates a blood concentration profile obtained by performing a pharmacokinetic test with the tablet (Example 7) obtained according to the present description and the comparative example tablet (Comparative Example 2). DETAILED DESCRIPTION OF ILLUSTRATIVE MODALITIES This description provides a pharmaceutical composition for oral administration comprising N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H IF-2020-07123170-APN-ANP#INPI Page 6 of 31 pyrazol-1-11)pyrimidine2-ylamino-4-methoxy-2-morpholinophenylacrylamide (Lazertinib) or its pharmaceutically acceptable salt as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent. In this specification, “diluent” and “additive” have the same meaning and may be used interchangeably. According to the present description, it was found that when lazertinib or its salt is formulated using a combination of specific diluents, i.e., a combination of microcrystalline cellulose and mannitol, it is possible to prepare an immediate-release pharmaceutical composition capable of minimizing the effect of changes in the pH environment in the stomach. These changes include changes in pH due to diet and changes in pH due to drugs, such as a proton pump inhibitor like esomeprazole or an H2 receptor antagonist like cimetidine, an antacid, and similar, but not limited to, these. In the pharmaceutical composition of the present description, N-(5-(4-(4-(d-methylamino)methyl)'3-phenyl-1H-pyrazol-Vyl)pyrimidine-2-ylamino)'4-methoxy-2-morpholinophenyljacrylamide (Lazertinib) or its pharmaceutically acceptable salt may be used in therapeutically effective amounts. For example, Lazertinib or its pharmaceutically acceptable salt may be used in a range of 10 to 320 mg as Lazertinib per formulation unit (e.g., per tablet unit), and may be used in amounts of, for example, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 160 mg, 240 mg, or 320 mg The pharmaceutical composition described herein includes a combination of specific diluents, namely, a combination of microcrystalline cellulose and mannitol. According to this description, it was found that when the weight ratio of mannitol to cellulose IF-2020-07123170-APN-ANP#INPI Page 7 of 31. The weight ratio of microcrystalline cellulose to mannitol is 0.5 to 3 times. Lazertinib or its salt may minimize the effect according to changes in the pH environment in the stomach. Therefore, the weight ratio of microcrystalline cellulose to mannitol may be in the range of preferably 1:0.5 to 1:3, more preferably 1:0.9 to 1:3, much more preferably 1:0.9 to 1:1.5, and particularly preferably approximately 1:0.95 to 1:1.2 The pharmaceutical composition of the present description may include a disintegrating agent and / or a lubricant (or a gluing agent), in addition to the diluent. The disintegrating agent may be a conventional disintegrating agent used in the pharmaceutical field. However, according to the present description, it was found that when using a specific disintegrating agent, namely croscarmellose sodium among various disintegrating agents, precipitation is significantly delayed when the drug, disintegrated / dissolved in the stomach, is transferred to the intestine. Therefore, it is preferred that the pharmaceutical composition of the present description include croscarmellose sodium as a disintegrating agent. Croscarmellose sodium may be present, for example, in a range of 0.5 to 10% by weight, preferably 2 to 5% by weight, with respect to the total weight of the composition. The lubricant (or slip) may be a conventional lubricant used in the pharmaceutical field. However, according to the present description, it was found that a specific lubricant, namely magnesium stearate, among various lubricants, has particularly excellent compatibility with Lazertinib or its salt, thus ensuring excellent stability. Therefore, it is preferred that the pharmaceutical composition of the present description include magnesium stearate as a lubricant (or slip). IF-2020-07 f 23 f70-APN-ANP#INPI Page 8 of 3 f Magnesium stearate can be used in a sufficient quantity to achieve a sufficient lubricating effect, and for example, it can exist in a range of 0.4 to 2% by weight, with respect to the total weight of the composition, but is not limited to this. In one embodiment, the pharmaceutical composition of the present description includes N-(5-(4-(4-((d-dimethylammomethyl)-3-phen-1H-pyrazol-11)pyrimidine-2-lamino)-4-methoxy-2-morpholinophenyl)anamide or its pharmaceutically acceptable salt as an active ingredient; a combination of microcrystalline cellulose and mannitol as a diluent; croscarmellose sodium as a disintegrant agent; and magnesium stearate as a lubricant. Lazertinib mesylate was found to be excellent in stability, solubility, and bioavailability compared to the free-base compound and can be prepared with high purity. Furthermore, it was found that lazertinib mesylate has an advantage because it exhibits excellent bioavailability even when co-administered with, for example, an antacid, as well as when administered alone. Therefore, in the pharmaceutical composition of the present invention, the active ingredient may be lazertinib mesylate.In one embodiment, the pharmaceutical composition of the present description may consist of 5 to 54% by weight of Lazertinib mesylate; 45 to 87% by weight of a combination of microcrystalline cellulose and mannitol; 0.5 to 10% by weight of croscarmellose sodium; and 0.4 to 2% by weight of magnesium stearate. In another embodiment, the pharmaceutical composition of the present description may consist of 7 to 46% by weight of Lazertinib mesylate; 50 to 87% by weight of a combination of microcrystalline cellulose and mannitol; 2 to 5% by weight of croscarmellose sodium; and 0.5 to 1.5% by weight of magnesium stearate. IF-2020-07123170-APN-ANP#INPI Page 9 of 31 Lazertinib mesylate may have a crystalline form. In one embodiment, Lazertinib mesylate may have a crystalline form that has a PXRD pattern with peaks at 5,614, 12,394, 14,086, 17,143, 18,020, 19,104, 21,585, 22,131, and 22,487°20 + 0.2'29. In another embodiment, Lazertinib mesylate may have a crystalline form that has a differential scanning calorimetry (DSC) pattern with endothermic peaks at 210 to 230 °C, preferably 217+2 °C. Lazertinib mesylate may have an onset of 214±2 °C. Lazertinib mesylate can be prepared by a preparation method comprising (a) mixing Lazertinib free base with a single organic solvent or a mixed solvent, followed by the addition of methanesulfonic acid to form Lazertinib mesylate, and (b) crystallizing the Lazertinib mesylate by adding an organic solvent to the mixture from step (a). The single organic solvent in step (a) is not particularly restricted, but may be selected from the group consisting of acetone, methyl ethyl ketone, and ethyl acetate. The mixed solvent in step (a) may be a solvent mixed with water and one or more suitable organic solvents. Specifically, a solvent mixed with water and one or more organic solvents selected from acetone and methyl ethyl ketone are preferred, but not limited to these. A mixing ratio of water to the organic solvent may be from 1:1 to 1:10 by volume, and specifically 1:4 to 1:6, but is not limited to this. Step (a) may be carried out at a temperature of 20 to 70 °C, preferably 45 to 60 °C. The crystallization in step (b) can be carried out by adding the organic solvent to the mixture obtained in step (a), stirring, cooling, and filtering the mixture, and then drying it to obtain the resulting solid. The organic solvent in step (b) can be the same as or different from the single organic solvent used in step (a). Specifically, the IF-2020-07123170-APN-ANP#INPI Page 10 of 31. The organic solvent in step (b) may be at least one selected from the group consisting of acetone, methyl ethyl ketone, and ethyl acetate. The organic solvent in step (b) may be added in a volume of 3 mL to 20 mL per 1 g of Lazertinib freebase used in step (a). Specifically, the organic solvent may be added in a volume of 5 mL to 20 mL per 1 g of Lazertinib freebase used in step (a), and more specifically, in a volume of 5 mL to 10 mL, but is not limited to these. The mixture obtained by adding the organic solvent may be cooled to a temperature of 0 to 30 °C, preferably 0 to 10 °C, and then dried at a temperature of 30 to 70 °C to isolate Lazertinib mesylate. The pharmaceutical composition of the present description can be used to prevent or treat allograft rejection, graft-versus-host disease, diabetic retinopathy, ceroid angiogenesis due to age-related vision loss, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, pannus invasion of the synovial membrane in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic vascular disease, retinopathy of prematurity, infantile hemangioma, non-small cell lung cancer, bladder cancer, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, psoriasis, fibrosis, atherosclerosis, recurrent stenosis, autoimmune disease, allergy, respiratory disease, asthma, transplant rejection, inflammation, thrombosis, retinal canal proliferation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone disease.rejection of graft or bone marrow transplant, lupus, chronic pancreatitis, cachexia, septic shock, fibrosis and differentiating skin diseases or disorders, diseases of the central nervous system, neurodegenerative diseases, Alzheimer's disease, IF-2020-07123170-APN-ANP#INPI disease, Page 11 of 31 Parkinson's disease, disorders or symptoms associated with nerve damage following brain or spinal cord injury and exon metamorphosis, acute or chronic cancer, eye disease, viral infection, heart disease, lung disease, or kidney disease and bronchitis. The pharmaceutical composition of the present description may be used for the prevention or treatment of, preferably, acute or chronic cancer, most preferably lung cancer, most preferably non-small cell lung cancer or non-small cell lung cancer with brain metastases, but is not limited to these. From this point forward, the present description will be further explained through examples and test samples. However, these examples and test samples are for illustrative purposes only, and the present description is not limited to them. In the following examples and test examples, “Lazertinib” refers to N(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimide na-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, and Lazertinib mesylate refers to the mesyl acid salt N(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimide na-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide Reference Example 1: Preparation of Lazertinib A compound prepared in the same manner as the method described in patent no. WO 2016 / 060443, namely N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1-Hyrazol-1-yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) (1100.0 g, 1983.2 mmol), acetone (4.4 L), and purified water (1.1 L), was placed in a reactor and heated to 45–55°C under stirring. Methanesulfonic acid (186.8 g, 1943.6 mmol) was diluted in purified water (0.55 L) and then the solution IF-2020-07123170-APN-ANP#INPI Page 12 of 31 The resulting mixture was added to it while maintaining a temperature of 45 °C or higher. The resulting mixture was stirred for 30 minutes or more to prepare a mixture containing mesyl acid salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1Hp i razo I-1 - i I )pir¡ m id in a-2 - i lam ln o)-4-methoxy-2-mo río I in ofe nil)ac ri la m id a. After that, to crystallize the mesylate compound from the mixture, acetone (8.8 L) was added while maintaining a temperature of 40 to 50 °C. The resulting mixture was stirred for 30 minutes or more, cooled to 0 to 5 °C, and then stirred for 3 hours or more. The reaction mixture was filtered under reduced pressure, a wet cake was washed with acetone (5.5 L), and then the resulting solid was dried at 55 °C under vacuum to obtain 1095.8 g of Lazertinib mesylate (yield: 84.9%). The results of measuring Lazertinib mesylate by 'H-NMR (400 MHz, DMSO-de) were as follows. 1H-NMR(400 MHz, DMSO-d6) δ 9.79(s, 1H), 9.35(s, 1H), 9.21(s, 1H), 8.78(s. 1H). 8.59(d, 1H), 8:33(s, 1H), 7.77(d, 2H), 7.55(m, 3H), 7.34(d, 1H), 6.94(s, 1H), 6.71-6.76(q, 1H), 6.28-6.31(dr1H). 5.81-5.83(d, 1H), 4.48(s, 2H), 3.90(s, 3H), 3.81-3.830, 4H), 2.86-2.88(1 4H), 2.66(s_ 6H), 2.35(s, 3H). As a result of measuring the PXRD of the obtained Lazertinib mesylate, a PXRD pattern was shown with peaks at 5,614, 12,394, 14,086, 17,143, 18,020, 19,104, 21,585, 22,131 and 22,487 Θ ± 0.202 Θ (Figure 1). The PXRD spectrum was measured using Broker D8 advance (X-ray source: CuKa, tube voltage: 40 kV / tube current: 40 mA, emission slit: 0.3, and scatter slit: 0.3). As a result of measuring the Lazertinib mesylate obtained by DSC, an endothermic peak was shown at approximately 217 °C in a graph of IF-2020-07123170-APN-ANP#INPI Page 13 of 31 DSC (Figure 2). DSC was measured using Mettler Toíedo DSC 1 STAR (sample container: sealed aluminum tray, nitrogen condition 99%, and increasing 10SC per minute from 30 °C to 300 °C). Reference Example 2: Evaluation of properties and pharmacokinetic testing of Lazertinib mesylate (1) Solubility test The solubility according to pH and the solubility in artificial gastric juice, artificial intestinal fluid, water, and ethanol were compared with each other with respect to Lazertinib mesylate and Lazertinib free base. 120 mg of lazertinib mesylate (100 mg as lazertinib) prepared according to Reference Example 1 was added to 5 mL of buffer solution having each pH described in Table 1 below, artificial gastric juice, artificial intestinal fluid, water, or ethanol, and then stirred under conditions of 37 °C, water bath, and 50 rpm for 12 hours. In addition, 100 mg of lazertinib freebase (prepared in the same manner as the method described in patent no. WO 2016 / 060443) was tested under the same conditions. After 12 hours of stirring, the concentration of the dissolved lazertinib was measured and compared with the solubility. The results are shown in Table 1 below. [Table 1] Solubility (mg / mt) IF-2020-07123170-APN-ANP#INPI Page 14 of 31 pH 1.2 pH 2.0 pH 3.0 pH 4.0 pH 5.0 pH 6.0 pH 7.0 Artificial gastric juice (FaSSGF) Artificial intestinal fluid (FaSSIF) Water Ethanol Lazertinib 4,4-free base 3.7 1.9 1.0 0.01 0.003 0.001 1.5 0.027 0.001 0.599 Lazertinib 1dn Mesiiate 14.1 17.9 20.9 16.4 1.2 0.013 10.1 0.63 21.6 17.3 As illustrated in Table 1, Lazertinib mesiiate had a water solubility 20,000 times greater than Lazertinib free base, an artificial gastric juice solubility (FaSSGF) approximately 10 times greater than Lazertinib free base, and an artificial intestinal fluid solubility (FaSSIF) approximately 25 times greater than Lazertinib free base. (2) Stability test A stability test was performed for Lazertinib mesiiate under a stress condition and an accelerated condition, and each condition was as shown in Table 2 below. [Table 2] Classification Stress Condition Accelerated Condition Temperature 60-12°C 40-12°C Humidity 75-15% (relative humidity) 75-5% (relative humidity) Container 10 mt glass vial and rubber stopper double polyethylene bag, high-density polyethylene (HDPE) bottle Sampling time Initial, after 2 weeks, and after 4 weeks Initial, after 1 month, after 3 months, and after 6 months IF-2020-07123170-APN-ANP#INPI Page 15 of 31 (2-1) Stability test under stress conditions The stability for Lazertinib mesylate was tested under the stress conditions described in Table 2 above, and the results are illustrated in Figure 3 and Tables 3 and 4 below. The measurement conditions for PXRD and DSC are the same as those described in Reference Example 1. [Table 3] PXRD Pattern DSC CC Start) Appearance (to be jealous) Starts 2 weeks 4 weeks Starts 2 weeks 4 weeks Starts 2 weeks 4 weeks - Same pattern Same pattern 214 214 214 White White White Furthermore, the results of the high-performance liquid chromatography (HPLC) measurements are shown in Table 4 below, and the measurement conditions are as follows. Mobile phase regulator: 250 mM ammonium acetate in water (Mobile phase A: regulator / water / acetonitrile, Mobile phase B: acetonitrile, column: Xbridge BEH C18XP) [Table 4] Initial Purity (%) Variation Content (%) Variation Water Content {%} 2 4 weeks weeks initial 2 weeks 4 weeks initial 2 weeks 4 u ___„„1 Variation δθΓΪΤΒΠ35| 99.2 99.3 | 93.3 +0.1 Ί 98.8 97.7 98.9 +0.1 2.48 2.71 2.70 ' +0.22 IF-2020-07123170-APN-ANP#INPI Page 16 of 31 (2-2) Stability test under accelerated conditions The stability for Lazertinib mesyoate was tested under the accelerated conditions described in Table 2 above, and the results are illustrated in Figure 4 and Tables 5 and 6 below. The measurement conditions for PXRD and DSC are the same as those described in Example 1. [Table 51 PXRD Pattern DSC Onset (°C) Appearance (Heat) Onset 1 month 3 months 6 months Onset 1 month 3 months 6 months Onset 1 month 3 months 6 months - Same pattern Same pattern Same pattern 214 214 Ξ14 214 White White White White Furthermore, the results of the high-performance liquid chromatography (HPLC) measurement are shown in Table 6 below, and the measurement conditions are the same as those described in (2-2). [Table 6] Purity (%) Content (%) Water content (%) Start | 1 month | 6 months 99.3 1 3 Variation Start month 6 months Variation Start 2.48 1 month 2.73 3 | 6 months months Variation 99.2 | 99.3 99.3 +0.1 98.6 90.9 98.9 99.1 +0.3 3.19 3.01 +0.53 From the stability test results, Lazertinib mesioate showed a slight change in purity and water content between the initial and final points of the stability test; no changes in the pattern were observed. IF-2020-07123170-APN-ANP#INPI Page 17 of 31 of PXRD, and no changes in appearance were shown by color, and therefore, the stability of these was excellent. (3} Comparative pharmacochemical trial of Lazertinib mesylate and Lazertinib free base in normal rats and esomeprazole-treated rats Regarding lazertinib mesylate and lazertinib freebase, the pharmacokinetics were compared in normal rats and rats treated with esomeprazole, a proton pump inhibitor. Specifically, in normal rats and esomeprazole-treated rats, peak blood concentrations (Cmax) and areas under the blood concentration curve (AUCuTi) were compared to assess drug absorption in the animals. For the comparative pharmacokinetic test, 8-week-old male rats (SD rats) of approximately 250 g were selected as test animals, and Lazertinib mesylate and Lazertinib free base were suspended in 0.5% methylcellulose, and then administered orally to normal rats at a dose of 30 mg / 5 ml / kg. In addition, esomeprazole (esomeprazole magnesium dihydrate, manufactured by Sigma-Alcfrich) was administered intravenously to 8-week-old male rats weighing approximately 250 g at a dose of 5 mg / 2 ml / kg for 3 days, and then lazertinib mesyoate and lazertinib free base were administered orally at the same dose (30 mg / 5 ml / kg) as the dose administered to normal rats. The results (peak blood concentration and area) IF-2020-07123170-APN-ANP#INPI Page 18 of 31 (under the blood concentration curve) of the comparative pharmacokinetic test obtained from these are shown in Table 7 and in Figures 5 and 6. [Table 7] Pharmacological parameters Normal rat Esomeprazole-treated rat Lazertinib mesylate Lazertinib free base Lazertinib mesylate Lazertinib free base Peak blood concentration (δ™*., ng / ml!) 815.6 725.7 427.5 223 0 Area under the blood concentration curve (AUC, ng.h / ml) 3139.0 7293.6 5210.3 2036.7 As shown in the previous results, for lazertinib freebase, the peak blood concentration and area under the blood concentration curve were 11.0% and 10.4% lower than for lazertinib mesylate in normal rats, respectively, and the peak blood concentration and area under the blood concentration curve were 47.0% and 49.4% lower than for lazertinib mesylate in esomeprazole-treated rats, respectively. This indicates that lazertinib freebase has a lower body exposure than lazertinib mesylate. Furthermore, in rats treated with esomeprazole, for lazertinib mesylate, the peak blood concentration and area under the blood concentration curve were reduced by 47.6% and 36.0%, respectively, compared to normal rats. However, for lazertinib freebase, the peak blood concentration and area under the blood concentration curve were reduced by 69.3% and 63.8%, respectively, compared to IF-2020-07123170-APN-ANP#INPI Page 19 of 31 normal rats, respectively From these results, it can be observed that Lazertinib mesylate shows less change in pharmacokinetics according to the administration of esomeprazole than Lazertinib free base, thus maintaining a high blood concentration in the rats (4) Pharmacokinetic test of Lazertinib mesylate and Lazertinib free base in Beagle dogs For a comparative pharmacokinetic trial, male Beagle dogs aged 15 to 17 months and weighing approximately 10 kg were selected as test animals. Lazertinib mesylate and Lazertinib freebase were suspended in 0.5% methylcellulose and then administered orally to a Beagle dog at a dose of 5 mg / 2 ml / kg. The results (peak blood concentration and area under the blood concentration curve) of the comparative pharmacokinetic trial obtained from these dogs are shown in Table 8 and Figure 7. [Table 8] Lazertinib Mesilaio Lazertinib Free Base Peak Blood Concentration (0. ng / ml) 134.7 60.7 Area under the blood concentration curve (AUC™, ng.h / ml) 311.5 379.1 As shown in the previous results, in a trial for Beagle dogs, the free base of Lazertinib showed the highest blood concentration and the area under the blood concentration curve, which were 40.1% and 50.4% lower than Lazertinib mesylate, respectively. (IF-2020-07123170-APN-ANP#INPI) Page 20 of 31 These results show that Lazertinib mesylate maintains a higher blood concentration than Lazertinib free base in Beagle dogs. As such, Lazerlinib mesylate is excellent in solubility and bioavailability, compared to Lazerlinib freebase. Lazerlinib mesylate has improved stability, solubility, and bioavailability, and is excellent in terms of its high purity. Examples 1 to 8. Tablet preparation According to the ingredients and contents in Table 9, a tablet containing Lazertlnlb mesylate was prepared. The contents in Table 9 represent mg ​​per tablet unit. Specifically, an active ingredient, an additive, and a disintegrant were mixed using a mixer, and then a lubricant was further mixed in. The resulting mixture was compressed using a tablet press machine (Corsch Corporation XP1) to prepare a tablet. [Table 9] Ingredient 1 Examples (mg / cap) 2 3 4 5 6 7 6 Active ingredient Lazertinib mesylate (as Lazertinib) 11.73 11.73 23.47 23.47 46.93 46.93 93.56 93.86 (10.00) (16.00) (20.00) (20.00) (40.00) (40.00) (80.00) (50.00) Additive Microcrystalline cellulose 65.27 42.55 67.53 35.38 65.07 32.52 67.14 33.29 D-rnarsitd 65.00 37.72 66.00 98.15 65.00 97.55 66.00 99.85 Disintegrating agent Croscarmellose sodium 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Lubricant Magnesium stearate 2.00 2.00 2.00 2.00 2.00 2 00 2.00 2.00 IF-2020-07123170-APN-ANP#INPI Page 21 of 31 Total weight I 150.00 150.00 165.00 | 165.00 | 185.00 185.00 , 235.00 235.00 Examples 9 to 13. Tablet preparation According to the ingredients and contents listed in Table 10, a tablet containing lazertinib mesylate was prepared. The contents in Table 10 represent mg ​​per tablet unit. Specifically, an active ingredient, an additive, and a disintegrant were mixed using a mixer, and then a lubricant was added. The resulting mixture was compressed using a tablet press (Corsch Corporation XP1) to prepare a tablet. [Table 10] Ingredient Examples (rng / ciimprimidn) 9 10 11 12 13 Active ingredient Lazertinib mesylate (as Lazertinib) 117.33 140.79 187.72 281.58 375.44 (100.00) (120.00) (160.00) (240.00) (320.00) Additive Cellulose mareen alanine 67.67 100.71 134.28 201.42 268.56 i D-mannitol 67.00 99.00 132.00 198.00 264.00 Disintegrant agent Croscarmellose sodium 6.00 9.0D 12.00 18.00 24.00 Lubricant 1 Magnesium ester 2.00 3.00 4.00 6.00 8.00 Total weight 260.00 352.50 470.00 705.00 940.00 Comparative examples 1 to 6. Tablet preparation According to the ingredients and contents in Table 11, a tablet containing lazertinib mesylate was prepared. The contents in Table 11 represent mg ​​per tablet unit. Specifically, one ingredient IF-2020-07123170-APN-ANP#INPI Page 22 of 31 The active ingredient, an additive, and a disintegrant were mixed using a mixer, and then a lubricant was further mixed in. The resulting mixture was compressed using a tablet press machine (XP1 from Corsch Corporation) to prepare a tablet. [Table 11] Ingredient Comparative Examples (mg / camprinide) 1 2 3 4 5 6 Active ingredient Lazertinib mesylate (as Lazertinib) 46.93 (40.00) 93.96 (80.00) 11.73 (10.00) 11.73 (10.00) 93.86 (80.00) 93.86 (80.00) Microcrystalline cellulose 35.07 36.14 - - - - Lactose hydrate 95.00 97.00 - - Additive Microcrystalline cellulose - - 98.00 - 67.14 67.14 D-mannilol - 32.27 - 66.00 66.00 Microshellac - - - 130.27 - Croscarmellose Sodium 6.00 6.00 6.00 6.00 - Disintegrating agent Crospovidone - - - - 6.00 - Sodium starch glycolate - - - 6.00 Lubricant Magnesium stearal 2.00 2.00 2.00 2.00 2.00 2.00 Total weight 165.00 235.00 150.00 150.00 235.00 235.00 * Microshellac; Additive consisting of 73 to 77% lactose hydrate and 23 to 27% microcrystalline cellulose Example test 1. Compatibility test with mesylate of La ze rt jnib / lub ri ca nte / dis I iza nte A mixture (Mixture A) of 1000 mg of Lazertinib mesylate and 1000 mg of magnesium stearate, a mixture (Mixture B) of 1000 mg of Lazertinib mesylate and 1000 mg of sodium stearyl fumarate, and a mixture (Mixture C) of IF-2020-07123170-APN-ANP#INPI Page 23 of 31 1000 mg of lazertinib mesylate and 1000 mg of colloidal silicon dioxide (i.e., Aerosil 200) were compressed at a pressure of 1 kN to prepare a compression material. The contents of an unknown maximum impurity and a total impurity were measured in the mixture before compression and in the resulting compression material. The resulting compression material was then placed in an HDPE glass bottle and stored under severe conditions (60 ± 2 °C, 75 ± 5% RH) for 1 week, after which the contents of the unknown maximum impurity and the total impurity were measured. The impurity content was analyzed by ultra-performance liquid chromatography (UPLG) under the following conditions. "HPLC conditions" Column: ACQUITY UPLC(R) HSS T3, 1.8 μ particle size, 2.1 x 100 mm Mobile phase A: Regulator / acetonitrile = 95 / 5 (v / v %) - Mobile phase B: Regulator / acetonitrile - 5 / 95 (v / v %) * regulator: 20 mM ammonium bicarbonate (adjusted to pH 7.0 with formic acid) flow rate: 0.4 ml / min; Column temperature: 40DC Wavelength: 285 nm As such, the results of performing the compatibility test are shown in Table 12 below. [Table 12] IF-2020-07123170-APN-ANP#INPI Page 24 of 31 Maximum unknown impurity (%) Total impurity (%) Initial 1 week Initial 1 week Before compression After compression Before compression I After compression I Mixture A 0.14 0.13 0.13 0.4 0.5 0.4 i Mixture B 0.14 0.30 0.29 0.4 0.6 0.7 Mixture C 0.13 0.14 0.19 0.4 0.5 0.5 As can be seen from the results in Table 12 above, in the mixture of lazertinib mesylate and magnesium stearate, no significant increase in the amount of impurities was observed either before or after compression and during storage for one week under severe conditions. However, in the mixture of lazertinib mesylate and sodium stearyl fumarate, a significant increase in the amount of impurities was observed during the compression process. Furthermore, in the mixture of lazertinib mesylate and colloidal silicon dioxide, a significant increase in the amount of impurities was observed during storage for one week under severe conditions. Therefore, it can be observed that magnesium stearate has particularly excellent compatibility with lazertinib mesylate. Example test 2. Tablet dissolution test (1) A dissolution test was performed according to the following conditions with respect to the tablets from Example 5 and Comparative Example 1, and each sample was analyzed by HPLC <Condiciones de la prueba de disolución^ Solution to the dissolution test: IF-2020-07123170-APN-ANP#INPI Page 25 of 31 1) pH 1.2 solution - First solution of the Korean Pharmacopoeia disintegration test 2) pH 4.0 solution - Acetate buffer solution (mixture of 0.05 mol / l acetic acid solution and 0.05 mol / l sodium acetate solution (41:9, v / v), and adjusted to pH 4.0) Quantity of the dissolution test solution: 900 ml Temperature of the dissolution test solution: 37±0.5 °C Dissolution test method: Second method of the Korean pharmacopoeia dissolution test (50 rpm) Sample collection time: 1) pH 1.2 solution - 5 minutes, 10 minutes, 15 minutes, 30 minutes 2) pH 4.0 solution - 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes cHPLC conditions> Column: Luna C18 (2), particle size of 5 pm, 4.6 * 50 mm Mobile phase: Regulator / acetonitrile - 40 / 60 (v / v %) * Regulator: 20 mM ammonium bicarbonate (adjusted to pH 7.2 with formic acid) flow rate: 2.0 ml / min; Column temperature: 50 X Wavelength: 298 nm The results of the previous dissolution test are shown in Figures 8 to 9. Additionally, an enlarged dissolution pattern from Figure 9 is shown in Figure 10. As illustrated in Figures 8 to 10, the tablet from Example 5 showed no significant difference in the dissolution index at pH 1.2, indicating an IF-2020-07123170-APN-ANP#INPI Page 26 of 31 state before food and the dissolution index at pH 4.0 indicating a state after food. In contrast, in the tablet of Comparative Example 1, the dissolution index at pH 4.0 was significantly reduced, compared to the Dissolution Index at pH 1.2. Therefore, the tablet of the present description can minimize deviations in dissolution according to changes in pH according to food or drugs (e.g. antacids, etc.). Example test 3. Tablet dissolution test (2) A dissolution test was performed under the following conditions with respect to the tablets from Examples 1 and 2 and Comparative Example 3, and each sample was analyzed by HPLC. The HPLC analysis conditions are the same as in Test Example 2. ^Conditions of the solution test> Dissolution test solution: pH 4.0 solution - Acetate buffer solution (mixture of 0.05 mol / l acetic acid solution and 0.05 mol / l sodium acetate solution (41:9, v / v), adjusted to pH 4.0) Quantity of dissolution test solution: 900 ml Dissolution test solution temperature: 37+0.5CC Dissolution test method: Second method of the Korean pharmacopoeia dissolution test (50 rpm) Sample collection time; 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes The results of the previous dissolution test are shown in Figure 11. As illustrated in Figure 11, when using a larger quantity (approximately 3 times) of microcrystalline cellulose than mannitol, IF-2020-07123170-APN-ANP#INPI Page 27 of 31 Dissolution index at pH 4.0 is significantly reduced. Conversely, it can be observed that the tablet of the present description shows a uniform dissolution index. Example test 4. Tablet dissolution test f3) A dissolution test was performed according to the following conditions with respect to the tablets from Example 7 and Comparative Examples 5 and 6, and each sample was analyzed by HPLC. The HPLC analysis conditions are the same as in Test Example 2. "Conditions of the dissolution test* Solution to the dissolution test: 1) Acid phase - 750 ml of 0.1 N hydrochloric acid solution 2) Regulator phase - 1) Acid phase 750 ml + 0.2 M sodium triphosphate solution 250 ml Dissolution test solution temperature: 37±0.5CC Dissolution test method: Second method of dissolution test of the Korean pharmacopoeia (50 rpm) (After performing a dissolution test for 30 minutes in the dissolution solution (750 ml) of an acid phase, 250 ml of a 0.2 M sodium triphosphate solution were added to become a dissolution solution (1000 ml) of the buffer phase, and then the dissolution test was further performed for 60 minutes). Sample collection time: 1) Acid phase - 5 minutes, 10 minutes, 15 minutes, 30 minutes IF-2020-07123170-APN-ANP#INPI Page 28 of 31 2) Regulatory phase - 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes The results of the previous dissolution test are shown in Figure 12. From the results in Figure 12, it can be observed that in the tablet obtained using croscarmellose sodium as a disintegrating agent, the precipitation of a drug in the regulatory phase is delayed further. Example test 5. Stability test The tablets from Example 1 and Comparative Example 4 were placed in an aluminum pouch and stored for 2 weeks under a severe condition (60 ± 2 °C, 75 ± 5% RH). The contents of an unknown maximum impurity and a total impurity were then measured, respectively. The impurity content was analyzed by ultra-performance liquid chromatography (UPLC). The UPLC analysis conditions were the same as in Test Example 1. As such, the results of performing the stability test are shown in Table 13 below. [Table 13] Sample Maximum unknown impurity (%) Total impurity (%) Initial 1 week 2 weeks Initial 1 week 2 weeks Example 1 0.01 0.04 0.05 0.4 0.3 0.4 Comparative example 4 0.01 0.10 0.10 0.4 0.4 0.4 IF-2020-07123170-APN-ANP#INPI Page 29 of 31 As can be seen from the results in Table 13 above, the tablet obtained according to the present description did not show a significant increase in impurity. However, in the tablet from Comparative Example 4, the unknown impurity increased significantly. Example test 6. Pharmacokinetic test With respect to the tablets in Example 7 and Comparative Example 2, the pharmacokinetic characteristics in a Beagle dog were compared with each other, respectively. The tablets (composition containing 80 mg as YH25448) prepared in Example 7 and Comparative Example 2 were administered orally to Beagle dogs under a 14-hour fasting condition on the day before the test, and a pharmacokinetic test was then performed. A blood concentration profile obtained by performing the above pharmacokinetic test is shown in Figure 13. In addition, the pharmacokinetic parameters obtained from the blood concentration profile, namely a maximum blood concentration and an area under the blood concentration curve (AUC maximum), are shown in Table 14 below. [Table 14] Example 7 Comparative Example 2 Maximum blood concentration (ng / ml) 2353.0 3420.0 Area under the curve of kanguinea concentration (AUCliiiiii-iS[ ng.h / mlj । 19.&57.8 17.000,4 IF-2020-07123170-APN-ANP#INPI Page 30 of 31 As shown in Table 14 and Figure 13, the tablet obtained according to this description has a high AUC value and excellent bioavailability. Furthermore, the maximum blood concentration can be reduced, thus minimizing the risk of toxicity. IF-2020-07123170-APN-ANP#INPI Page 31 of 31 Argentine Republic - National Executive Branch 2020 - Year of General Manuel Belgrano Additional Signature Sheet Graphic Report Number: IF-2020-07123170-APN-ANP#INPI CITY OF BUENOS AIRES Friday, January 31, 2020 Reference: 20190102972 The document was imported by the GEDO system with a total of 31 page(s). Digitally signed by GESTION DOCUMENTAL ELECTRONICA- GDE Date: 2020.01.31 15:20:26-03:00 Mariela Flavia Gonnet Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by DOCUMENTAL MANAGEMENT ELECTRONICS-GDE Date: 2020.01.31 15:20:51 -03:00

Claims

1. A pharmaceutical composition for oral administration characterized in that it comprises: an N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinephenyl)acrylamide mesylate salt (Lazertinib) as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent, wherein the combination is a dry mixture of the microcrystalline cellulose and mannitol in the absence of a solvent, and wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinephenyl)acrylamide mesylate is a crystalline form having a PXRD pattern with peaks at 5.614, 17.143 and 21.585°2θ ± 0.2°2θ. Seventeen claims follow.