Pharmaceutical composition for oral administration comprising aminopyrimidine derivative or its salt

Abstract

The present disclosure provides a pharmaceutical composition for oral administration, which comprises: 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 thereof as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Korean Application No. 10-2018-0124171, filed on October 18, 2018, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to a pharmaceutical composition for oral administration comprising an aminopyrimidine derivative or a salt thereof. More specifically, the present disclosure relates to a pharmaceutical composition comprising: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or a salt thereof; and a combination of microcrystalline cellulose and mannitol as a diluent. Background Art

[0004] WO 2016 / 060443 discloses an aminopyrimidine derivative, such as N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or a pharmaceutically acceptable salt thereof. Lazertinib or a pharmaceutically acceptable salt thereof has the activity of selectively inhibiting protein kinases, particularly protein kinases of mutant epidermal growth factor receptors, and can provide, for example, an effective and safe treatment method for non-small cell lung cancer. Lazertinib or a pharmaceutically acceptable salt thereof is known as an irreversible EGFR TKI that has less effect on wild-type EGFR, has strong inhibitory activity on T790M single active mutations (EGFRm) and double mutations, and has excellent selectivity, and is expected to show a therapeutically effective effect in the treatment of patients with progressive non-small cell lung cancer and progressive non-small cell lung cancer with primary cancers of brain metastases.

[0005] When lazertinib or its salt is formulated as a composition for oral administration, it is contemplated that lazertinib or its salt is formulated into a form of a rapid-release pharmaceutical composition having a mechanism in which the active ingredient is immediately released in the stomach and then transferred to the small intestine to be absorbed. In the preparation of such rapid-release pharmaceutical compositions, it is necessary to minimize the effect of pH changes in the stomach, for example, according to food or drugs (such as antacids, etc.) administered simultaneously. For example, since the pH is not constant when fasting, in the range of pH 1 to pH 3.5, and the average pH in the stomach after a meal is pH 4 (pH 3 to 5), it depends on the physicochemical properties of the active ingredient, and the dissolution rate may deviate, which may result in changes in absorption rate and bioavailability. Summary of the invention

[0006] The present inventors have found that when N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or a salt thereof is formulated using a combination of specific diluents, an immediate-release pharmaceutical composition capable of minimizing the effects of changes in the pH environment in the stomach can be prepared. In addition, the present inventors have found that the pharmaceutical composition can be formulated to ensure excellent stability and show significantly increased bioavailability.

[0007] Therefore, an object of the present disclosure is to provide a pharmaceutical composition of lazertinib or a pharmaceutically acceptable salt thereof for oral administration, the pharmaceutical composition comprising a combination of specific diluents.

[0008] According to one aspect of the present disclosure, there is provided 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 or a pharmaceutically acceptable salt thereof as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

[0009] In the pharmaceutical composition of the present disclosure, 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.

[0010] The pharmaceutical composition of the present disclosure may also include cross-linked carboxymethyl cellulose sodium as a disintegrant, and the cross-linked carboxymethyl cellulose sodium may be present in a range of 0.5% to 10% by weight, preferably 2% to 5% by weight, relative to the total weight of the composition. In addition, the pharmaceutical composition of the present disclosure may also include magnesium stearate as a lubricant. In one embodiment, the pharmaceutical composition of the present disclosure includes: 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 as an active ingredient; a combination of microcrystalline cellulose and mannitol as a diluent; cross-linked carboxymethyl cellulose sodium as a disintegrant; and magnesium stearate as a lubricant.

[0011] In the pharmaceutical composition of the present disclosure, the active ingredient may be N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide methanesulfonate.

[0012] In one embodiment, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide methanesulfonate may be in a crystalline form having a PXRD pattern having peaks at 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, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide methanesulfonate may be in a crystalline form having a differential scanning calorimeter (DSC) thermogram having an endothermic peak at 210°C to 230°C, preferably 217°C±2°C.

[0013] According to the present disclosure, it was found that when N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (lazertinib) or a salt thereof is formulated using a combination of specific diluents, i.e., a combination of microcrystalline cellulose and mannitol, an immediate-release pharmaceutical composition capable of minimizing the effects of changes in the pH environment in the stomach can be prepared. In addition, the pharmaceutical composition of the present disclosure can be formulated to ensure excellent stability and achieve significantly increased bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is the powder X-ray diffraction (PXRD) pattern of lazertinib mesylate prepared in Reference Example 1.

[0015] Figure 2 is a differential scanning calorimeter (DSC) chart of lazertinib mesylate prepared in Reference Example 1.

[0016] Figure 3 are photographs showing the results of a stability test conducted under stress conditions with respect to lazertinib mesylate prepared in Reference Example 1 (Initial: at the beginning, 2 weeks: after 2 weeks, 4 weeks: after 4 weeks).

[0017] Figure 4 The photographs are showing the results of the stability test conducted under accelerated conditions 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).

[0018] Figure 5 Shown are the results of a comparative pharmacokinetic study of lazertinib mesylate and lazertinib free base in normal rats.

[0019] Figure 6 Shown are the results of a comparative pharmacokinetic study of lazertinib mesylate and lazertinib free base in esomeprazole-treated rats.

[0020] Figure 7 Shown are the results of a comparative pharmacokinetic study of lazertinib mesylate and lazertinib free base in beagle dogs.

[0021] Figure 8 Results obtained by conducting a dissolution test under the condition of pH 1.2 with respect to a tablet obtained according to the present disclosure (Example 5) and a tablet of a comparative example (Comparative Example 1) are shown.

[0022] Fig. 9 Results obtained by conducting a dissolution test under the condition of pH 4.0 with respect to a tablet obtained according to the present disclosure (Example 5) and a tablet of a comparative example (Comparative Example 1) are shown.

[0023] Fig.10 Shows Fig. 9 Scale-up results of the dissolution test.

[0024] Fig.11 Results obtained by conducting a dissolution test under the condition of pH 4.0 with respect to tablets obtained according to the present disclosure (Examples 1 and 2) and a tablet of a comparative example (Comparative Example 3) are shown.

[0025] Fig.12 Results obtained by conducting a dissolution test under continuous conditions of an acid phase (pH 1.0) and a buffer phase (pH 6.8) with respect to a tablet obtained according to the present disclosure (Example 7) and tablets of Comparative Examples (Comparative Examples 5 and 6) are shown.

[0026] Fig.13 The blood concentration profiles obtained by conducting a pharmacokinetic test with respect to the tablet obtained according to the present disclosure (Example 7) and the tablet of the comparative example (Comparative Example 2) are shown. DETAILED DESCRIPTION

[0027] The present disclosure provides a pharmaceutical composition for oral administration, which comprises: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (lazertinib) or a pharmaceutically acceptable salt thereof as an active ingredient; and a combination of microcrystalline cellulose and mannitol as a diluent.

[0028] In this specification, "diluent" and "additive" have the same meaning and are used interchangeably. According to the present disclosure, it was found that when lazertinib or its salt is formulated using a combination of a specific diluent, i.e., a combination of microcrystalline cellulose and mannitol, a rapid-release pharmaceutical composition capable of minimizing the effects of changes in the pH environment in the stomach can be prepared. Changes in the pH environment in the stomach include pH changes caused by diet; and pH changes caused by drugs, such as proton pump inhibitors such as esomeprazole or H2 receptor antagonists such as cimetidine, antacids, etc., but are not limited thereto.

[0029] In the pharmaceutical composition of the present disclosure, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) or a pharmaceutically acceptable salt thereof can be used in a therapeutically effective amount. For example, Lazertinib or a pharmaceutically acceptable salt thereof can be used in a range of 10 mg to 320 mg of Lazertinib per unit formulation (e.g., per unit tablet), and can be used in an amount of, for example, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 160 mg, 240 mg or 320 mg.

[0030] The pharmaceutical composition of the present disclosure comprises a combination of specific diluents, i.e., a combination of microcrystalline cellulose and mannitol. According to the present disclosure, it was found that when the weight ratio of mannitol relative to microcrystalline cellulose is 0.5 to three times, lazertinib or its salt can minimize the effect of changes in the pH environment in the stomach. Therefore, the weight ratio of microcrystalline cellulose to mannitol can be preferably 1:0.5 to 1:3, more preferably 1:0.9 to 1:3, even more preferably 1:0.9 to 1:1.5, and particularly preferably about 1:0.95 to 1:1.2.

[0031] The pharmaceutical composition of the present disclosure may further comprise a disintegrant and / or a lubricant (or glidant) in addition to the diluent.

[0032] The disintegrant may be a conventional disintegrant used in the pharmaceutical field. However, according to the present disclosure, it was found that when a specific disintegrant (i.e., various disintegrants such as cross-linked carboxymethyl cellulose sodium) is used, 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 disclosure comprises cross-linked carboxymethyl cellulose sodium as a disintegrant. Cross-linked carboxymethyl cellulose sodium may be present, for example, in a range of 0.5% to 10% by weight, preferably 2% to 5% by weight, relative to the total weight of the composition.

[0033] Lubricant (or glidant) can be a conventional lubricant used in the pharmaceutical field. However, according to the present disclosure, it is found that a specific lubricant (i.e. various lubricants such as magnesium stearate) has particularly excellent compatibility with lazertinib or its salt, thereby ensuring excellent stability. Therefore, it is preferred that the pharmaceutical composition of the present disclosure includes magnesium stearate as a lubricant (or glidant). Magnesium stearate can be used in an amount sufficient to achieve a sufficient lubricating effect, and for example, can be present in a range of 0.4% to 2% by weight relative to the gross weight of the composition, but is not limited thereto.

[0034] In one embodiment, the pharmaceutical composition of the present disclosure comprises: 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 as an active ingredient; a combination of microcrystalline cellulose and mannitol as a diluent; cross-linked carboxymethyl cellulose sodium as a disintegrant; and magnesium stearate as a lubricant.

[0035] It was found that lazertinib mesylate is superior in stability, solubility and bioavailability compared to the compound in the form of free base, and can be prepared in high purity. In addition, it was found that there are the following advantages: even in the case of co-administration with, for example, antacids, and in the case of single administration, lazertinib mesylate has excellent bioavailability. Therefore, in the pharmaceutical composition of the present disclosure, the active ingredient may be lazertinib mesylate. In one embodiment, the pharmaceutical composition of the present disclosure may be composed of the following substances: 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 cross-linked carboxymethyl cellulose sodium; and 0.4% to 2% by weight of magnesium stearate. In another embodiment, the pharmaceutical composition of the present disclosure may be composed of the following substances: 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 cross-linked carboxymethyl cellulose sodium; and 0.5% to 1.5% by weight of magnesium stearate.

[0036] Lazertinib mesylate may be in a crystalline form. In one embodiment, lazertinib mesylate may be in a crystalline form, and its PXRD pattern has peaks at 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, lazertinib mesylate may be in a crystalline form, and its differential scanning calorimeter (DSC) thermogram has an endothermic peak at 210 ° C to 230 ° C, preferably 217 ° C ± 2 ° C. Lazertinib mesylate may have an onset of 214 ° C ± 2 ° C.

[0037] Lazertinib mesylate can be prepared by a preparation method comprising the following steps: (a) mixing lazertinib free base with a single organic solvent or a mixed solvent, and then adding methanesulfonic acid thereto to form lazertinib mesylate, and (b) crystallizing lazertinib mesylate by adding an organic solvent to the mixture of step (a).

[0038] The single organic solvent of step (a) is not particularly limited, but can be selected from the group consisting of acetone, methyl ethyl ketone and ethyl acetate. The mixed solvent of step (a) may be a mixed solvent of water and one or more suitable organic solvents. Specifically, a mixed solvent of water and one or more organic solvents selected from acetone and methyl ethyl ketone is preferred, but not limited thereto. The mixing ratio of water to the organic solvent may be a volume ratio of 1:1 to 1:10, and specifically 1:4 to 1:6, but not limited thereto. Step (a) may be carried out at a temperature of 20°C to 70°C, preferably 45°C to 60°C.

[0039] The crystallization of step (b) can be carried out as follows: an organic solvent is added to the mixture obtained in step (a), the mixture is stirred, cooled and filtered, and then dried to obtain the resulting solid. The organic solvent of step (b) may be the same or different from the single organic solvent of step (a). Specifically, 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) can be added in a volume of 3mL to 20mL per 1g of the free base of lazertinib used in step (a). Specifically, the organic solvent can be added in a volume of 5mL to 20mL and more specifically 5mL to 10mL per 1g of the free base of lazertinib used in step (a), but is not limited thereto. The mixture obtained by adding the organic solvent can be cooled to a temperature of 0°C to 30°C, preferably 0°C to 10°C, and then dried at a temperature of 30°C to 70°C to separate the mesylate of lazertinib.

[0040] The pharmaceutical composition of the present disclosure can be used to prevent or treat allogeneic transplant rejection, graft-versus-host disease, diabetic retinopathy, choroidal neovascularization due to age-related vision loss, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, pannus invasion of synovium in arthritis, multiple sclerosis, myasthenia gravis, diabetes, diabetic angiopathy, 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 Narrow, autoimmune diseases, allergies, respiratory diseases, asthma, transplant rejection, inflammation, thrombosis, retinal ductal hyperplasia, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone disease, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, cachexia, septic shock, fibrotic and differentiated skin diseases or conditions, central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, conditions or symptoms associated with brain or spinal cord injury and nerve damage after exon deformation, acute or chronic cancer, eye disease, viral infection, heart disease, lung disease or kidney disease and bronchitis. The pharmaceutical composition of the present disclosure can be used to prevent or treat preferably acute or chronic cancer, more preferably lung cancer, most preferably non-small cell lung cancer or brain metastatic non-small cell lung cancer, but is not limited thereto.

[0041] Hereinafter, the present disclosure will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples are merely illustrative for the present disclosure, and the present disclosure is not limited to these Examples and Test Examples.

[0042] In the following Examples and Test Examples, “Lazertinib” refers to N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, and “Lazertinib mesylate” refers to the methanesulfonate salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0043] Reference Example 1: Preparation of Lazertinib Mesylate

[0044] A compound prepared in the same manner as the method disclosed in WO 2016 / 060443, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (Lazertinib) (1,100.0 g, 1,983.2 mmol), acetone (4.4 L) and purified water (1.1 L) were added to a reactor and heated to 45° C. to 55° C. under stirring. Methanesulfonic acid (186.8 g, 1,943.6 mmol) was diluted in purified water (0.55 L), and the resulting solution was then added thereto while maintaining a temperature of 45° C. or higher. The resulting mixture was stirred for 30 minutes or longer to prepare a mixture containing the methanesulfonate of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0045] Then, in order to crystallize the mesylate compound in the mixture, acetone (8.8 L) was added thereto while maintaining a temperature of 40° C. to 50° C. The resulting mixture was stirred for 30 minutes or more, cooled to 0° C. to 5° C., and then stirred for 3 hours or more. The reaction mixture was filtered under reduced pressure, the wet cake was washed with acetone (5.5 L), and the resulting solid was then vacuum dried at 55° C. to obtain 1,095.8 g of lazertinib mesylate (yield: 84.9%).

[0046] pass 1 The results of H-NMR (400 MHz, DMSO-d6) measurement of the obtained lazertinib mesylate are as follows.

[0047] 1 H-NMR(400MHz,DMSO-d6)δ9.79(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(d,1H),5.81-5.83(d,1H),4.48(s,2H),3 .90(s,3H),3.81-3.83(t,4H),2.86-2.88(t,4H),2.66(s,6H),2.35(s,3H).

[0048] As a result of measuring the PXRD of the obtained lazertinib mesylate, a PXRD pattern having peaks at 5.614, 12.394, 14.086, 17.143, 18.020, 19.104, 21.585, 22.131, and 22.487°2θ±0.2°2θ was shown. Figure 1 ). The PXRD spectrum was measured using a Bruker D8 advance (X-ray source: CuKα, tube voltage: 40 kV / tube current: 40 mA, emission slit: 0.3, and scattering slit: 0.3).

[0049] As a result of the obtained lazertinib mesylate by DSC measurement, in the DSC graph ( Figure 2 ), an endothermic peak is shown at about 217° C. DSC was measured using Mettler Toledo DSC 1STAR (sample container: sealed aluminum pan, 99% nitrogen condition, and increased from 30° C. to 300° C. at 10° C. / min).

[0050] Reference Example 2: Characteristic evaluation and pharmacokinetic study of lazertinib mesylate

[0051] (1) Solubility test

[0052] The solubility according to pH and in artificial gastric fluid, artificial intestinal fluid, water and ethanol were compared with each other relative to lazertinib mesylate and lazertinib free base.

[0053] 120mg of lazertinib mesylate (100mg, in terms of lazertinib) prepared in Reference Example 1 was added to 5mL of buffer solution, artificial gastric juice, artificial intestinal juice, water or ethanol having each pH value disclosed in Table 1 below, and then stirred for 12 hours at 37°C, water bath and 50rpm. In addition, 100mg of lazertinib free base (prepared in the same manner as described in WO2016 / 060443) was tested under the same conditions. After stirring for 12 hours, the concentration of dissolved lazertinib was measured and the solubility was compared. The results are shown in Table 1 below.

[0054] [Table 1]

[0055]

[0056] As shown in Table 1, the solubility of lazertinib mesylate in water is 20,000 times higher than that of lazertinib free base, the solubility in artificial gastric fluid (FaSSGF) is about 10 times higher than that of lazertinib free base, and the solubility in artificial intestinal fluid (FaSSIF) is about 25 times higher than that of lazertinib free base.

[0057] (2) Stability test

[0058] The stability test of lazertinib mesylate was conducted under stress conditions and accelerated conditions, and each condition is shown in Table 2 below.

[0059] [Table 2]

[0060]

[0061] (2-1) Stability test under stress conditions

[0062] The stability of lazertinib mesylate was tested under the stress conditions described in Table 2 above and the results are shown in Figure 3 And in the following Table 3 and Table 4. The measurement conditions of PXRD and DSC are the same as those described in Reference Example 1.

[0063] [Table 3]

[0064]

[0065] In addition, the measurement results of high performance liquid chromatography (HPLC) are shown in Table 4 below, and the measurement conditions are as follows. Mobile phase buffer: 250 mM ammonium acetate aqueous solution (mobile phase A: buffer / water / acetonitrile, mobile phase B: acetonitrile, column: Xbridge BEHC18 XP)

[0066] [Table 4]

[0067]

[0068] (2-2) Stability test under accelerated conditions

[0069] The stability of lazertinib mesylate was tested under the accelerated conditions described in Table 2 above, and the results are shown in Figure 4 And in the following Table 5 and Table 6. The measurement conditions of PXRD and DSC are the same as those described in Example 1.

[0070] [Table 5]

[0071]

[0072] In addition, the measurement results of high performance liquid chromatography (HPLC) are shown in Table 6 below, and the measurement conditions are the same as those disclosed in (2-2).

[0073] [Table 6]

[0074]

[0075] From the results of the stability test, lazertinib mesylate showed slight changes in purity and water content between the starting point and the end point of the stability test, showed no changes in the PXRD pattern, and showed no changes in appearance by color observation, so its stability was excellent.

[0076] (3) The activity of lazertinib mesylate and lazertinib free base in normal rats and rats treated with esomeprazole Comparative pharmacokinetic trials in

[0077] For lazertinib mesylate and lazertinib free base, the pharmacokinetics were compared in normal rats and rats treated with esomeprazole as a proton pump inhibitor, respectively. Specifically, the maximum blood concentration (C max ) and blood concentration area under the curve (AUC last ) to assess drug absorption in animals.

[0078] For comparative pharmacokinetic studies, 8-week-old male rats (SD rats) weighing about 250 g were selected as test animals, and lazertinib mesylate and lazertinib free base were suspended in 0.5% methylcellulose and then orally administered to normal rats at a dose of 30 mg / 5 mL / kg.

[0079] In addition, esomeprazole (esomeprazole magnesium dihydrate, manufactured by Sigma-Aldrich) was intravenously administered to 8-week-old male rats of about 250 g at a dose of 5 mg / 2 mL / kg for 3 days, and then lazertinib mesylate and lazertinib free base were orally administered at the same dose (30 mg / 5 mL / kg) as that administered to normal rats. The results of the comparative pharmacokinetic test thus obtained (maximum blood concentration and area under the blood concentration curve) are shown in Table 7 and Figure 5 and Figure 6 middle.

[0080] [Table 7]

[0081]

[0082] As shown in the above results, for lazertinib free base, the maximum blood concentration and the area under the blood concentration curve observed in normal rats were 11.0% and 10.4% lower than those of lazertinib mesylate, respectively, and the maximum blood concentration and the area under the blood concentration curve observed in rats treated with esomeprazole were 47.8% and 49.4% lower than those of lazertinib mesylate, respectively. That is, it can be seen that lazertinib free base has a lower body exposure than lazertinib mesylate.

[0083] In addition, in rats treated with esomeprazole, the maximum blood concentration and the area under the blood concentration curve were reduced by 47.6% and 36.0%, respectively, compared with normal rats, for lazertinib mesylate. However, for lazertinib free base, the maximum blood concentration and the area under the blood concentration curve were reduced by 69.3% and 63.8%, respectively, compared with normal rats. From these results, it can be seen that due to the administration of esomeprazole, the pharmacokinetics of lazertinib mesylate changed less than that of lazertinib free base, thereby maintaining high blood concentrations in rats.

[0084] (4) Pharmacokinetic study of lazertinib mesylate and lazertinib free base in beagle dogs

[0085] For comparative pharmacokinetic studies, male beagles aged about 15 to 17 months, weighing about 10 kg, were selected as test animals, and lazertinib mesylate and lazertinib free base were suspended in 0.5% methylcellulose and then orally administered to beagles at a dose of 5 mg / 2 mL / kg. The results of the comparative pharmacokinetic studies thus obtained (maximum blood concentration and area under the blood concentration curve) are shown in Tables 8 and Figure 7 middle.

[0086] [Table 8]

[0087]

[0088] As shown in the above results, as a result of the test in beagle dogs, it was observed that lazertinib free base showed a maximum blood concentration and an area under the blood concentration curve that were 40.1% and 50.4% lower than those of lazertinib mesylate, respectively. From these results, it can be seen that in beagle dogs, lazertinib mesylate maintained a higher blood concentration than lazertinib free base.

[0089] Therefore, compared with lazertinib free base, lazertinib mesylate is superior in solubility and bioavailability. Lazertinib mesylate has improved stability, solubility and bioavailability, and is superior in its high purity.

[0090] Examples 1 to 8. Preparation of tablets

[0091] Tablets containing lazertinib mesylate were prepared according to the ingredients and contents of Table 9 below. The contents in Table 9 represent mg / unit tablets. Specifically, active ingredients, additives and disintegrants were mixed using a stirrer, and lubricants were then additionally mixed. The resulting mixture was compressed using a tablet press (XP1, from Corsch Corporation) to prepare tablets.

[0092] [Table 9]

[0093]

[0094] Examples 9 to 13. Preparation of tablets

[0095] Tablets containing lazertinib mesylate were prepared according to the ingredients and contents of Table 10 below. The contents in Table 10 represent mg / unit tablets. Specifically, active ingredients, additives and disintegrants were mixed using a stirrer, and lubricants were then additionally mixed. The resulting mixture was compressed using a tablet press (XP1, from Corsch Corporation) to prepare tablets.

[0096] [Table 10]

[0097]

[0098]

[0099] Comparative Examples 1 to 6. Preparation of Tablets

[0100] Tablets containing lazertinib mesylate were prepared according to the ingredients and contents of Table 11 below. The contents in Table 11 represent mg / unit tablets. Specifically, active ingredients, additives and disintegrants were mixed using a stirrer, and then lubricants were additionally mixed. The resulting mixture was compressed using a tablet press (XP1, from Corsch Corporation) to prepare tablets.

[0101] [Table 11]

[0102]

[0103] *Microshellac: An additive composed of 73% to 77% lactose hydrate and 23% to 27% microcrystalline cellulose

[0104] Test Example 1. Compatibility test of lazertinib mesylate and / or lubricant / glidant

[0105] A mixture of 1,000 mg of lazertinib mesylate and 1,000 mg of magnesium stearate (mixture A), a mixture of 1,000 mg of lazertinib mesylate and 1,000 mg of sodium stearyl fumarate (mixture B), and a mixture of 1,000 mg of lazertinib mesylate and 1,000 mg of colloidal silicon dioxide (ie, Aerosil 200) (mixture C) were pressed separately by applying a pressure of 1 kN to prepare a pressed material. The contents of the maximum unknown impurities and total impurities in the mixture before pressing and the maximum unknown impurities and total impurities in the obtained pressed material were measured respectively. In addition, the obtained pressed material was placed in a glass bottle made of HDPE and stored under harsh conditions (60°C ± 2°C, 75% ± 5% RH) for 1 week, and then the contents of the maximum unknown impurities and total impurities were measured. The content of impurities was analyzed by ultra-high performance liquid chromatography (UPLC) under the following conditions.

[0106] <ULPC conditions>

[0107] - Column: ACQUITY UPLC(R) HSS T3, 1.8 μm particle size, 2.1×100 mm

[0108] - Mobile phase A: Buffer / acetonitrile = 95 / 5 (v / v%)

[0109] - Mobile phase B: Buffer / acetonitrile = 5 / 95 (v / v%)

[0110] * Buffer: 20 mM ammonium bicarbonate (adjusted to pH 7.0 with formic acid)

[0111] - Flow rate: 0.4 mL / min

[0112] - Column temperature: 40 °C

[0113] - Wavelength: 285 nm

[0114] Therefore, the results of the compatibility test are shown in Table 12 below.

[0115] [Table 12]

[0116]

[0117] 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 before and after compression and during storage under harsh conditions for 1 week. However, in the mixture of lazertinib mesylate and sodium stearoyl fumarate, a significant increase in the amount of impurities was shown during compression. In addition, in the mixture of lazertinib mesylate and colloidal silica, a significant increase in the amount of impurities was shown within 1 week under harsh conditions. Therefore, it can be seen that magnesium stearate has particularly excellent compatibility with lazertinib mesylate.

[0118] Test Example 2. Dissolution test of tablets (1)

[0119] The dissolution test was carried out on the tablets of Example 5 and Comparative Example 1 under the following conditions, and each sample was analyzed by HPLC.

[0120] <Dissolution test conditions>

[0121] Dissolution test solution:

[0122] 1) pH 1.2 solution - The first disintegration test solution of the Korean Pharmacopoeia

[0123] 2) pH 4.0 Solution - Acetate buffer solution (a 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)

[0124] Volume of dissolution test solution: 900 mL

[0125] Temperature of dissolution test solution: 37 °C ± 0.5 °C

[0126] Dissolution test method: The second dissolution test method of the Korean Pharmacopoeia (50 rpm)

[0127] Sample collection time:

[0128] 1) pH 1.2 Solution - 5 minutes, 10 minutes, 15 minutes, 30 minutes

[0129] 2) pH 4.0 Solution - 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes

[0130] <HPLC Conditions>

[0131] - Column: Luna C18(2), 5 μm particle size, 4.6 × 50 mm

[0132] - Mobile phase: Buffer / Acetonitrile = 40 / 60 (v / v%)

[0133] * Buffer: 20 mM Ammonium bicarbonate (adjusted to pH 7.2 with formic acid)

[0134] - Flow rate: 2.0 mL / min

[0135] - Column temperature: 50 °C

[0136] - Wavelength: 298 nm

[0137] The results of the dissolution test conducted as above are shown in Figures 8 to 9 In addition, Fig.10 shows in Fig. 9 the magnified dissolution pattern of Figures 8 to 10 As shown in, there is no significant difference between the dissolution rate of the tablet of Example 5 at pH 1.2 indicating the pre-meal state and the dissolution rate at pH 4.0 indicating the post-meal state. On the contrary, in the tablet of Comparative Example 1, the dissolution rate at pH 4.0 is significantly lower than the dissolution rate at pH 1.2. Therefore, the tablets of the present disclosure can minimize the dissolution deviation caused by pH changes according to food or drugs (such as antacids, etc.).

[0138] Test Example 3. Dissolution test of tablets (2)

[0139] The dissolution test was conducted with respect to the tablets of Examples 1 and 2 and Comparative Example 3 according to the following conditions, and each sample was analyzed by HPLC. The HPLC analysis conditions were the same as those in Test Example 2.

[0140] <Dissolution Test Conditions>

[0141] Dissolution test solution: pH 4.0 solution-acetate buffer solution (a 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)

[0142] Amount of dissolution test solution: 900mL

[0143] Temperature of dissolution test solution: 37℃±0.5℃

[0144] Dissolution test method: The second dissolution test method of the Korean Pharmacopoeia (50rpm)

[0145] Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes

[0146] The results of the dissolution test conducted as above are shown in Fig.11 In. Fig.11 As shown, when a larger amount (about 3 times) of microcrystalline cellulose is used than mannitol, the dissolution rate at pH 4.0 is significantly reduced. In contrast, it can be seen that the tablets of the present disclosure show a uniform dissolution rate.

[0147] Test Example 4. Dissolution test of tablets (3)

[0148] Dissolution tests were conducted with respect to the tablets of Example 7 and Comparative Examples 5 and 6 according to the following conditions, and each sample was analyzed by HPLC. The HPLC analysis conditions were the same as those in Test Example 2.

[0149] <Dissolution Test Conditions>

[0150] Dissolution test solution:

[0151] 1) Acid phase - 750 mL of 0.1 N hydrochloric acid solution

[0152] 2) Buffer phase - 1) Acid phase 750mL + 0.2M sodium triphosphate solution 250mL

[0153] Temperature of dissolution test solution: 37℃±0.5℃

[0154] Dissolution test method: The second dissolution test method of the Korean Pharmacopoeia (50rpm)

[0155] (After the dissolution test was performed in the dissolving solution of the acid phase (750 mL) for 30 minutes, 250 mL of a 0.2 M sodium triphosphate solution was added to become a dissolving solution of the buffer phase (1,000 mL), and then the dissolution test was performed for another 60 minutes.)

[0156] Sample collection time:

[0157] 1) Acid phase - 5 minutes, 10 minutes, 15 minutes, 30 minutes

[0158] 2) Buffer phase - 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes

[0159] The results of the dissolution test conducted as above are shown in Fig.12 In. From Fig.12 The results show that in the tablets obtained using croscarmellose sodium as a disintegrant, the precipitation of the drug in the buffer phase is most delayed.

[0160] Test Example 5. Stability Test

[0161] The tablets of Example 1 and Comparative Example 4 were placed in aluminum bags and stored under harsh conditions (60°C ± 2°C, 75% ± 5% RH) for 2 weeks, and then the contents of the largest unknown impurity and the total impurities were measured, respectively. The content of impurities was analyzed by ultra-high performance liquid chromatography (UPLC). The UPLC analysis conditions were the same as those in Test Example 1.

[0162] Therefore, the stability test was conducted and the results are shown in Table 13 below.

[0163] [Table 13]

[0164]

[0165] As can be seen from the results of Table 13 above, no significant increase in impurities was observed in the tablets obtained according to the present disclosure. However, in the tablets of Comparative Example 4, unknown impurities increased significantly.

[0166] Test Example 6. Pharmacokinetic Test

[0167] For the tablets of Example 7 and Comparative Example 2, the pharmacokinetics in beagle dogs were compared with each other. On the day before the test, the tablets prepared in Example 7 and Comparative Example 2 (compositions containing 80 mg of YH25448) were orally administered to beagle dogs 14 hours before fasting (fasting conditions), and then a pharmacokinetic test was performed.

[0168] The blood concentration profile obtained by the pharmacokinetic test as above is shown in Fig.13In addition, the pharmacokinetic parameters obtained from the blood concentration distribution, namely the maximum blood concentration (C max ) and blood concentration area under the curve (AUC last ) are shown in Table 14 below.

[0169] [Table 14]

[0170]

[0171] As Table 14 and Fig.13 From the results, it can be seen that the tablets obtained according to the present disclosure have high AUC values ​​and excellent bioavailability. In addition, the maximum blood concentration can be reduced, thereby reducing the risk of toxicity.

Claims

1. A pharmaceutical composition for oral administration, the pharmaceutical composition consisting of the following substances: 7 to 46 wt% of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (lazertinib) mesylate as an active ingredient; 50 to 87 wt% of a combination of microcrystalline cellulose and mannitol as a diluent; 2 to 5 wt % of croscarmellose sodium as a disintegrant; and 0.5 wt % to 1.5 wt % magnesium stearate as a lubricant, wherein the weight ratio of the microcrystalline cellulose to the mannitol is in the range of 1:0.9 to 1:1.

5.

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

3. The pharmaceutical composition according to claim 1 or 2, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide methanesulfonate is in a crystalline form and its differential scanning calorimeter (DSC) thermogram has an endothermic peak at 210°C to 230°C.

4. The pharmaceutical composition according to claim 3, wherein N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide methanesulfonate is in a crystalline form, and its differential scanning calorimeter (DSC) thermogram has an endothermic peak at 217°C±2°C.

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