A PHARMACEUTICAL PREPARATION COMPRISING AN AMIDE DERIVATIVE THAT INHIBITS THE GROWTH OF CANCER CELLS AND A PHARMACEUTICAL PRODUCT CONTAINING THE PREPARATION.

Abstract

The present invention relates to a pharmaceutical preparation comprising granules containing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent. The pharmaceutical preparation exhibits high productivity due to its excellent tablet-forming properties, friability, and mass uniformity. The preparation also exhibits low impurity generation and high stability.

Description

A PHARMACEUTICAL PREPARATION COMPRISING AN AMIDE DERIVATIVE THAT INHIBITS THE GROWTH OF CANCER CELLS AND A PHARMACEUTICAL PRODUCT CONTAINING THE PREPARATION. [Technical Field] The present invention relates to a pharmaceutical preparation comprising an amide derivative that inhibits the growth of cancer cells and a pharmaceutical product containing the preparation. Specifically, the present invention relates to a pharmaceutical preparation comprising granules containing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent, and a pharmaceutical product containing the preparation. This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0132809 filed on October 24, 2019, and Korean Patent Application No. 102020-0137829 filed on October 22, 2020, and all the contents disclosed in the references of these Korean Patent Applications are incorporated herein in their entirety by reference as part of this specification. [Background] The Epidermal Growth Factor Receptor (EGFR) is known to be present in four receptor subtypes: EGFR / ErbB1, Her2 / ErbB2, Her3 / ErbB3, and Her4 / ErbB4, and is abnormally overexpressed in most solid cancer cells. Furthermore, ligand-mediated receptor activation is known to activate cell signaling systems that induce cancer cell growth, differentiation, neovascularization, metastasis, and resistance expression (Wells A., Int J Biochem Cell Biol., 1999, 31, 637-643). Consequently, regarding the conjecture that the anticancer effect will be excellent if the signal transduction of cancer cells is blocked through epithelial growth factor receptors, research is underway to develop anticancer agents targeting epithelial growth factor receptors. These anticancer agents targeting epidermal growth factor receptors are classified into monoclonal antibody drugs that target the extracellular region of the receptors and small-molecule drugs that target the intracellular tyrosine kinase. Monoclonal antibody drugs have the advantages of few adverse effects and excellent efficacy by selectively binding to epidermal growth factor receptors. However, these drugs have disadvantages, as they are not only expensive but must also be administered by injection. In contrast, small-molecule drugs targeting tyrosine kinase are relatively affordable, can be administered orally, and have excellent efficacy by acting selectively or simultaneously on epidermal growth factor receptor subtypes (EGFR, Her-2, Her-3, and Her-4). Small molecule drugs targeting epidermal growth factor receptors include Iressa (ingredient: gefitinib; AstraZeneca), Tarceva (ingredient: erlotinib; Roche), which are selective inhibitors for EGFR, and Tykerv (ingredient: lapatinib; GlaxoSmithKline), which is a dual inhibitor that simultaneously blocks EGFR and Her-2, and are used as therapeutic agents to treat advanced Her-2-positive lung cancer and breast cancer, respectively, and are undergoing clinical trials to expand indications into the treatment of other solid cancers. In this regard, Korean Patent Application Open to Public Inspection Number 10-2008-0107294 reveals a compound of the following Chemical Formula 1 that has fewer side effects, while selectively and effectively inhibiting the growth of cancer cells and drug resistance produced by EGFR and mutations thereof: [Chemical Formula 1] However, with respect to pharmaceutical compositions containing this compound, specialists have encountered productivity and stability issues when preparing tablets and capsules. Specifically, such compositions, prepared using conventional production methods, typically achieve uniform purity, stability, and a predictable shelf life. Furthermore, these compositions frequently experience significant encapsulation inconsistencies and abrasion during manufacturing, potentially exposing patients to situations where they may receive inadequate doses. Consequently, to develop more suitable preparations and improve patient outcomes, ongoing research is being conducted on pharmaceutical compositions containing this compound. [References to the previous technique] [Patent Documents] (Patent Literature 1) Korean Patent Application Open for Public Inspection Number 10-2008-0107294 [Divulgation] [Technical Problem] With respect to a pharmaceutical preparation comprising the preceding Chemical Formula 1, its purpose is to provide a pharmaceutical preparation with greater productivity due to its improved properties for tablet making, friability and mass uniformity, and high stability due to a reduced amount of impurities generated even under extreme conditions. [Technical Solution] The present invention addresses shortcomings in the prior art. With respect to a first aspect of the present invention, the present invention provides a pharmaceutical preparation comprising granules containing a compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent: [Chemical Formula 1] In one embodiment of the present invention, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is included in the pharmaceutical preparation in an amount of 2.0% or more and less than 20% by weight based on the total weight of the pharmaceutical preparation. In one embodiment of the present invention, the diluent is included in the pharmaceutical preparation in an amount of 20% to 50% by weight based on the total weight of the pharmaceutical preparation. In one embodiment of the present invention, the diluent is mannitol, microcrystalline cellulose, or a mixture of both. In one embodiment of the present invention, the diluent is a mixture of mannitol and microcrystalline cellulose in a weight ratio of 0.50:1 to 3.2:1. In one embodiment of the present invention, the pharmaceutical preparation further comprises a lubricant. In one embodiment of the present invention, the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, sodium lauryl sulfate, zinc stearate, sodium benzoate, and mixtures thereof. In one embodiment of the present invention, the lubricant is included in the pharmaceutical preparation in an amount of 0.5% to 1.5% by weight based on the total weight of the pharmaceutical preparation. With respect to a second aspect of the present invention, the present invention provides a method for preparing the aforementioned pharmaceutical preparation, the method comprising the following steps: 1) mixing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive and then developing the granulation to prepare granules; 2) mixing the granule with a pharmaceutically acceptable additive and then adding a diluent to prepare a mixed granule; and 3) formulating the mixed granule. With respect to the third aspect of the present invention, the present invention provides methods for reducing impurities in a pharmaceutical preparation containing the compound of Formula 1, by mixing granules containing the compound of Formula 1 with pharmaceutically acceptable amounts of at least two diluents in appropriate proportions and compressing such combinations into tablet form, characterized in that the amount of such impurities, including compounds of Formula 2 (also referred to herein as Impurity IV), would be less than 1%, 0.5%, more preferably less than 0.2% of the total weight of the preparation. [Chemical Formula 2] n ci CU,NH With respect to a fourth aspect of the present invention, the present invention provides a pharmaceutical product in which the aforementioned pharmaceutical preparation is packaged in a packaging material. In one embodiment of the present invention, the packaging material is selected from the group consisting of glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cycloolefin polymer (COP), cycloolefin copolymer (COC), polyolefin (PO), aluminum (Al), and combinations thereof, and the shape of the packaging material is selected from the group consisting of bottles, blisters, and bags. In one embodiment of the present invention, the packaging material is composed of a moisture absorbent. In one embodiment of the present invention, the moisture absorbent is calcium oxide or silica gel. In one embodiment of the present invention, the silica gel is included in the packaging material in an amount of 2 to 5 g based on a 125 ml high-density polyethylene bottle. With respect to the fifth aspect of the present invention, the present invention provides a method for the treatment of cancer in a subject who needs it. In one embodiment of the present invention, it has been determined that the subject has one or more activating mutations of EGFR or HER2. In one embodiment of the present invention, the method for treating the tumor includes administering an effective therapeutic amount of a pharmaceutical preparation comprising granules containing a compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent, according to the present invention. In one embodiment of the present invention, the cancer is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, gastric cancer, brain cancer, cervical cancer, bladder cancer, bile duct cancer, ovarian cancer, pancreatic cancer, and testicular cancer. In one embodiment of the present invention, the cancer is metastatic. [Beneficial Effects] The pharmaceutical preparation, with respect to the present invention, is a pharmaceutical preparation comprising a compound of Chemical Formula 1, and the productivity of the preparation is high due to the excellent properties of the tablets, friability, and mass uniformity when adding granules containing a compound of Chemical Formula 1 as an active ingredient and a specific diluent. Furthermore, the present invention can provide a pharmaceutical product with a reduced amount of generated impurities and high stability by specifying the use of a metallic salt lubricant in a pharmaceutical preparation and packaging the pharmaceutical preparation with a specific packaging material. [Description of the illustrations] Figure 1 is a graph showing the amount of impurity IV generated compared to experimental example 6. The tablets from example 1 and comparative examples 7 and 8 were packaged with Blister Formpack Dessiflex (where to obtain: amcor) and left for 1, 2, and 4 weeks at 40 °C / 75% relative humidity under accelerated conditions, respectively, and then impurity IV of Chemical Formula 2 was measured by liquid chromatography. Figure 2 is a graph showing the amount of impurity IV generated compared to experimental example 7. Each of the tablets from examples 6 to 9 and comparative example 9 above was packaged in a Dessiflex Formpack blister pack (available from amcor), and HM781-36B from comparative example 11 was packaged in a high-density polyethylene bottle. These were then stored for 1, 2, and 4 weeks at a critical temperature of 60 °C. The impurity IV of Chemical Formula 2 was measured for the samples stored during the aforementioned period compared to the analytical conditions of Experimental Example 6. Figure 3 is a graph showing the amount of impurity IV generated compared to experimental example 8. Each of the tablets compared to example 1 was packaged either in an AlA1 blister, an Al-PO+CaO-Al blister, or an HDPE bottle (5 different wrappers, each fitted with a polypropylene cap, including in any of the cases 0.5, 2.0, 3.0, 4.0, or 5.0 g of silica gel and a polypropylene cap), characterized in that TEKNILID' 1207 (Tekniplex) was used for the Al-Al blister, Formpack'-' Dessiflex blister (Amcor) was used for the AlPO+CaO-Al blister, BTH-250 (Ewha Engineering) was used for the HDPE bottles, and the polypropylene cap (including silica gel) was also from Ewha Engineering with the trademarks MH-Cap (0.5 g), MH-Cap (2.0 g), and MH-Cap (2.0 g). g), MH-Cap (3.0 g), MH-Cap (4.0 g) and MH-Cap (5.0 g).The packaged products were left for 1, 2, and 4 weeks at 40 °C / 75% relative humidity under accelerated conditions, respectively, and then the impurity IV of Chemical Formula 2 was measured against the analysis conditions of experimental example 6. [Optimal Conditions] From here on, the present invention will have a more detailed description. A compound of the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof, is very stable on its own, but a pharmaceutical preparation comprising it exhibits a highly unstable profile under critical conditions. Although the instability problem was partially improved through enhancements to the packaging material, the fundamental stability of the pharmaceutical preparation was not improved. [Chemical Formula 1] Thus, with respect to the pharmaceutical preparation comprising Chemical Formula 1 mentioned above in the present invention, its purpose is to provide a pharmaceutical preparation with greater productivity due to its improved properties for tablet formation, friability and mass uniformity, and high stability due to a low amount of impurities generated such as the impurity that the structure of Formula 2 has even under extreme conditions (60°C for 1 month). The present invention provides a pharmaceutical preparation comprising granules containing the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent to be mixed with the granule. The compound of Chemical Formula 1 (hereafter referred to by the key code HM781-36B) is a compound that has fewer adverse effects, while selectively and effectively inhibiting the growth of cancer cells and drug resistance produced by EGFR and mutations thereof, as described in Korean Patent Application Open to Public Inspection Number 10-2008-0107294. The pharmaceutically acceptable salt of the compound of Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt derived from an organic or inorganic acid. Examples of salts may be salts with inorganic acids such as hydrochloric acid, sulfuric acid, diasulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, and the like; or salts with organic acids such as salts of formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, malic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, italic acid, embonic acid, aspartic acid, glutamic acid, camsylic acid, benzylic acid, or acetylsalicylic acid (aspirin).In addition, the pharmaceutically acceptable salt may be in the form of a metallic salt obtained from a reaction with an alkali metal such as calcium, sodium, magnesium, strontium, potassium, and the like. The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be included in an amount of 1.5% or more and less than 25% by weight, 2.0% or more and less than 20% by weight, 2.5% or more and less than 20% by weight, or 5% or more and less than 20% by weight preferably 3.5% up to 15% by weight, and more preferably 5% up to 8% by weight based on the total weight of the pharmaceutical preparation. If the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is included in an amount less than 2.0% by weight, the properties of the tablets and the dissolution rate are excellent, but the stability is too poor to generate impurities quickly, and if they are included in an amount of 20% by weight or more, the total content of the tablet decreases to a mass (less than 70 mg) at which it is impossible to formulate a tablet, and therefore there is a problem where it is impossible to formulate tablets. In addition, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 100 mg, preferably 0.5 to 50 mg. The pharmaceutical preparation may be, for example, in the form of a powder, tablet, pill, capsule, liquid, suspension, emulsion, syrup, or granule, and preferably may be a tablet or capsule, but is not limited to these. 10 The pharmaceutical preparation may further comprise a diluent, a binder, a disintegrant, and a lubricant as a pharmaceutically acceptable additive. In some embodiments, the diluent may be a combination of at least two different diluents. In one embodiment of the present invention, the pharmaceutical preparation may contain the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof prepared in granule form. The granule may be prepared by mixing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof with a diluent, and then subjecting it to wet granulation in a binding solution in which a binder is dissolved in purified water. The diluent may be one or more of the following selected from the group consisting of mannitol, microcrystalline cellulose, lactose, and calcium phosphate, and preferably may be mannitol, microcrystalline cellulose, or a mixture of both. Furthermore, the diluent may be included in an amount of 50% to 99% by weight, preferably 60% to 95% by weight, and more preferably 70% to 90% by weight, based on the total weight of the granule. In some embodiments, the diluent may be a combination of mannitol and microcrystalline cellulose. The binding agent may be one or more substances selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and carboxymethylcellulose, and preferably, but not limited to, povidone. The binding agent may be included in the granule in an amount of 0.5% to 10% by weight, preferably 1% to 7% by weight, and more preferably 2% to 5% by weight based on the total weight of the granule. The granule can be mixed with an additional diluent and then purified to prepare a pharmaceutical formulation. The diluent for mixing with the granule is physically separate from the diluent used in the granule preparation and has a different function; thus, they are kept separate and used independently. The diluent for mixing with the granule can preferably be mannitol, microcrystalline cellulose, or a mixture of both, and more preferably a mixture of mannitol and microcrystalline cellulose. The mannitol and microcrystalline cellulose mixture can be a mixture of mannitol and microcrystalline cellulose in a weight ratio of 0.25:2 to 4:1.5, 0.75:1.25 to 3.5:1.25, or 0.50:1 to 3.2:1, preferably 1:1 to 2:1. The diluent to be mixed with the granule may be included in an amount of 20% to 50% by weight, and preferably 30% to 40% by weight based on the total weight of the pharmaceutical preparation.The choice of diluent to be mixed with the granule can significantly impact the productivity of the pharmaceutical preparation. Specifically, by selecting the diluent mentioned above, tablet properties and friability can be improved, resulting in a tablet with a uniform mass. In at least one embodiment, the diluent that is mixed with the granule may contain two types of diluents. In some embodiments, the first type of diluent is selected from the group consisting of lactose, mannitol, calcium sulfate, sucrose, dextrose, sorbitol, maltitol, and starch, while the second diluent is a cellulose derivative such as microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and the like. In at least one embodiment, the first diluent is mannitol and the second diluent is microcrystalline cellulose, characterized in that the weight ratio of mannitol to microcrystalline cellulose is in the range of 0.25:2 to 4:1.5; or 0.75:1.25 to 3.5:1.25; or preferably 0.50:1 to 3.2:1. In some embodiments, the granule may be mixed with a disintegrant along with the diluent mentioned above, and then purified to prepare a pharmaceutical preparation. The disintegrant may be one or more selected from the group consisting of crospovidone, croscarmellose sodium, and sodium starch glycolate, preferably crospovidone, but not limited to these. The disintegrant may be included in an amount of 1% to 10% by weight, preferably 3% to 7% by weight, based on the total weight of the pharmaceutical preparation. In some embodiments, a lubricant may be added to the pharmaceutical preparation before purification. With respect to one embodiment of the present invention, the lubricant may be a metallic salt lubricant. The lubricant may be one or more selected from the group consisting of calcium stearate, magnesium stearate, sodium lauryl sulfate, zinc stearate, and sodium benzoate, and preferably magnesium stearate. The lubricant may be included in an amount of 0.5% or more and less than 5% by weight, preferably less than 2% by weight, and more preferably from 0.5% to 15% by weight based on the total weight of the pharmaceutical preparation.The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may have slight stability when a lubricant in the form of a metallic salt is used, but the stability of the pharmaceutical preparation may be improved by including the lubricant in an amount of 0.5% or more and less than 5% by weight. In some embodiments, the present invention is substantially free (less than 1% by weight) from acidic additives such as acetic acid, adipic acid, citric acid, ascorbic acid, erythorbic acid, lactic acid, propionic acid, tartaric acid, fumaric acid, formic acid, oxalic acid, camsylic acid, malic acid, maleic acid, edicylic acid, palmitic acid, stearic acid, or silicon dioxide. In some embodiments, the pharmaceutical preparation of the present invention contains less than 0.25% by weight of any acidic additive. In some embodiments, the pharmaceutical preparation is free from any acidic additive. In addition, the pharmaceutical preparation may have an external surface covered by a coating base selected from the group consisting of an immediate-release film-forming agent, an enteric coating base, and a prolonged-release coating base, in order to prevent direct contact of the active pharmaceutical ingredient with the hands or human skin during handling. The immediate-release film-forming agent may be one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl alcohol polyethylene glycol graft polymer alcohol; the enteric base of the coating may be one or more selected from the group consisting of methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate; and the prolonged-release base of the coating may be one or more selected from the group consisting of cellulose acetate, ethyl cellulose, and polyvinyl acetate, but without limitation to the same. The coating base may be included in an amount of 1% to 10% by weight, preferably 2% to 5% by weight, based on the total weight of the pharmaceutical preparation. In one embodiment, the coating layer is approximately 0.5% to approximately 5% of the total weight of the formulation, characterized in that the coating layer has less than 18% by weight of titanium dioxide and no more than 25% by weight of polyvinyl alcohol, and optionally no more than 25% by weight of lactose or talc. In some embodiments, the coating base may be a polyvinyl acetate substrate consisting solely of polyvinyl alcohol of any molecular weight or may be contained in a copolymer, for example, Kollicoat·’ IR (BASF, NJ USA) or as part of a polyvinyl alcohol-based coating system such as the various film-coated products available under the trade name Opadry- (Cclorcon, PA, USA), for example, Opadry II’385F ​​series, Opadry’ II 89F series or Opadry3white. The pharmaceutical preparation of the present invention comprises the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, characterized in that the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be included in an amount of 5% or more and less than 20% by weight based on the total weight of the pharmaceutical preparation. At least one notable feature is the improved stability, in particular the stability of the pharmaceutical preparation by suppressing the generation of impurities under critical conditions, without affecting the properties of the tablets and the dissolution rate. In some embodiments, the critical condition may include storage at 40°C and 75% relative humidity under accelerated conditions for a duration of 1, 2, or 4 weeks, or 2, 3, 4, 5, or 6 months.In certain embodiments, the storage condition may include storage at 30°C and 55% RH [relative humidity] for a duration of 6 to 12 months. The stability in at least some embodiments of the present invention is evaluated in tests based on more than 5% of the changes from the initial value of the Formula 1 compound or non-compliance with accepted criteria for potency when used in a biological or immunological procedure with a specific use, any degradation product that exceeds accepted criteria such as the existence of an impurity, or non-compliance with physical attributes, functional analysis such as color, phase separation, coverage, hardness of the final preparation. In some embodiments, the present pharmaceutical preparation is presented in tablet form, with a hardness of 4 to 20 kp, or preferably 6 to 17 kp by using suitable equipment. The present invention provides a method for preparing the aforementioned pharmaceutical preparation. The method comprises the following steps: 1) mixing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive and then developing the granulation to prepare granules; 2) mixing the granule with a pharmaceutically acceptable additive and then adding a diluent to prepare a mixed granule; and 3) formulating the mixed granule. Each step of the preparation method is specified with respect to the contents of the aforementioned pharmaceutical preparation. The present invention provides a pharmaceutical product in which the aforementioned pharmaceutical preparation is packaged in a packaging material. The packaging material is intended to protect the preparation from light, heat, moisture, and the like, and the packaging material may be selected from the group consisting of glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cycloolefin polymer (COP), cycloolefin copolymer (COC), polyolefin (PO), aluminum (Al), and combinations thereof. The packaging material may contain the aforementioned material and may be prepared in a form selected from the group consisting of bottles, blister packs, and bags.With respect to an embodiment of the present invention, the bottle may be a bottle made of HDPE, and the blister may be made of an upper plate comprising one, two, or more materials selected from the group consisting of PVC, PVDC, PCTFE, PP, PE, COP, COC, PO, Al, and combinations thereof, and a lower plate comprising an Al material. The upper plate and / or the lower plate may have a single structure or a double structure or more structures. The glass, HDPE, PP, PVC, PVDC, PCTFE, COP, COC, PO, and Al used in the present invention may be the same as those normally used for pharmaceutical packaging. For example, HDPE may have an average molecular weight of approximately 50,000 to 150,000 and a density of approximately 0.941 g / cm³ to 0.965 g / cm³. PP may have an average molecular weight of approximately 200,000 to 600,000, and PVC may have a molecular weight distribution (Mw / Mn) [Mw / Mn refers to: mass average molecular weight / number average molecular weight] of approximately 1.7 to 2.0 and a density of approximately 1.16 g / cm³ to 1.35 g / cm³. PVDC can have a density of approximately 0.65 g / cm3 to 172 g / cm3, PCTFE can have a specific gravity of approximately 2.12, and PO, COP, and COC can have a density of approximately 1.02 g / cm3 or less. The packaging material according to the present invention may contain a moisture absorbent. The moisture absorbent serves to increase the stability of the pharmaceutical preparation by controlling the humidity within the packaging material. The moisture absorbent may be used without limitation as long as it is generally used in the relevant technical field, and preferably calcium oxide or silica gel may be used in relation to the active ingredient of the present invention. The moisture absorbent may be mixed with the packaging material and may be applied to the packaging material in various ways. With respect to one embodiment of the present invention, when using silica gel as the moisture absorbent, the silica gel may preferably be included in an amount of 2 to 5 g, preferably 3 to 5 g, in the packaging material.The silica gel content is a value established based on a packaging material for packaging a preparation comprising approximately 480 mg of the active ingredient (HM78136B) or an HDPE bottle with a capacity of approximately 125 ml. When the silica gel content is less than 2 g, the stability of the pharmaceutical preparation within the packaging material may decrease due to the inability to adequately control the humidity inside the packaging material, and when the silica gel content is greater than 5 g, the dissolution rate of the pharmaceutical preparation may decrease, affecting the moisture content of the pharmaceutical preparation itself. The present invention also provides a method for treating cancer in a subject in need. In some embodiments, the method for treating cancer includes administering an effective therapeutic amount of a pharmaceutical preparation comprising granules containing a compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent, with respect to the present invention. In some embodiments, the pharmaceutical preparation is substantially free from impurity IV. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, gastric cancer, brain cancer, cervical cancer, bladder cancer, bile duct cancer, ovarian cancer, pancreatic cancer, and testicular cancer. In some embodiments, the cancer is metastatic. In some implementations, the subject has been found to have one or more activating mutations of EGFR or HER2. In some implementations, the subject has been found to have one or more activating mutations of HER2 in one or more locations. From here on, preferred examples will be provided to facilitate understanding of the present invention, but the following examples are not provided to limit the present invention but to facilitate understanding of the present invention. Examples Example 1 The tablets containing the compound of Chemical Formula 1 (hereafter referred to as HM781-36B, manufactured by Dongwoo Syntech Co., Ltd.) as the active ingredient were prepared with respect to the composition described in Table 1 below. Specifically, HM781-36B and D-mannitol (manufactured by Roquette) were wet-granulated using a high-level shear mixer. The wet-granulation mixture was screened while distributing the HM781-36B with D-mannitol using a No. 35 (500 µm) sieve. Povidone dissolved in an appropriate amount of purified water (manufactured by BASF) was then added to prepare a granulated portion. The granules obtained by wet-granulation were screened using a No. 20 (850 µm) sieve and then dried using a fluidized bed dryer (Fluidized Bed Granulator). The processes described above were repeated until a result of approximately 0.5% or less was obtained, based on a numerical value of the loss on drying. The granulated portion prepared through the processes already mentioned was mixed with a blend of mannitol and microcrystalline cellulose (manufactured by Mingtai Chemical), and crospovidone (manufactured by BASF). Magnesium stearate (manufactured by Peter Greven, Netherlands) was then added and the mixture was blended. The resulting final mixture was formed into a tablet with a hardness of approximately 5 to 10 kp using a conventional tablet forming machine (manufactured by Sejong). Examples 2 to 5 The tablets containing HM781-36B as the active ingredient, with respect to the composition described in Table 1 below, were prepared in the same manner as in Example 1. [Table 1] Processes Raw material Example 1 Example 2 Example 3 Example 4 Example 5 Granulation Mixture HM781-36B 8 8 8 8 8 Mannitol 50 50 50 50 50 Povidone Solution 2 2 2 2 2 wet binding<Agua purificada> <8> <8> <8> <8> <8> Post-mixing Manitol 17 20 22.5 17.5 17 Microcrystalline cellulose 17 14 11.5 17 16.5 Crospovidone 5 5 5 5 5 Lubricant Magnesium stearate 1 1 1 0.5 1.5 Total mass 100 100 100 100 100 * The unit of numerical value is mg / tablet, and purified water is extracted during the process. Comparative examples 1 to 8 The tablets containing HM781-36B as the active ingredient, with respect to the composition described in Table 2 below, were prepared in the same manner as in Example 1. In Table 2 below, Pruv;stearyl fumarate sodium from JRS PHARMA, dibasic calcium phosphate from Lian yungang Debang Fine Chemical, and pregelatinized starch from Roquette were used. [Table 2] Processes Raw material And now on a comparative basis 1 And now on a comparative basis 2 And on a comparative basis 3 And on a comparative basis 4 And on a comparative basis 5 And on a comparative basis 6 And on a comparative basis 7 And on a comparative basis 8 Humid granulation from Mezclado HM781-36B 8 8 8 8 8 8 8 8 Mannitol 50 50 50 50 50 50 50 50 Agglutinant solution and Povidone 2 2 2 2 2 2 2 2<Agua purifica da> <8> <8> <8> <8> <8> <8> <8> <8> Post-mixed Mannitol 11 26 - - - - 17 17 Cellulose microcrystalline 23 8 34 16 17 Lactose - - - 34 — - - - Dibasic calcium phosphate 34 Pregelatinized starch 34 Crospovidone 5 5 5 5 5 5 5 5 Lubricant Magnesium stearate 1 1 1 1 1 1 2 Sodium stearate 1 Total mass 100 100 100 100 100 100 100 100 The unit of numerical value is mg / tablet, and purified water is extracted during the process. Examples 6 to 9 and comparative examples 9 to 10 The tablets were prepared as in Example 1, and then coated with Opadary'-03F180000, and finally the coated tablets containing HM781-36B or a pharmaceutically acceptable salt were prepared. The compositions of Examples 6 to 9 and Comparative Examples 9 and 10 are shown in Table 3 below. [Table 3] Processes Raw material Example 6 Example 7 Example 8 Example 9 Comparative example 9 Comparative example 10 Wet granulation Mixing HM781-36B 4 6 8 16 2 16 D-Mannitol 35.2 37.5 50 100 50 34 Binding solution Povidone 1.4 1.5 2 4 1.5 1<Agua puri ficada> <5,6> <6> <8> <16> <6> <4> Post-mixed D-Mannitol 12.5 12.8 17 34 23.5 12 Microcrystalline cellulose 12.5 12.8 17 34 17 12 Crospovidone 3.6 3.8 5 10 5 2.5 Lubricant Magnesium stearate 0.8 0.8 1 2 1 0.5 Coating Opadry 03F180000 2 2.3 3 6 3 2 Total mass 72.0 77.5 103 206 103 80 * The unit of numerical value is mg / tablet, and purified water is extracted during the process. HM781-36B was included in Examples 6 to 9 and the above-mentioned comparative examples 9 and 10 in amounts of 5.6%, 7.7%, 7.8%, 7.8%, 1.9% and 20% by weight, respectively, based on the total weight of the pharmaceutical preparation. Experimental examples Experimental Example 1: Evaluation of the properties of the tablets from examples 1 to 5 and comparative examples 1 to 6 For Examples 1 to 5 and the comparative examples 1 to 6 above, the buoyancy (Hausner index calculated by the formula H=ρτ / ρB where p» is the settled density (g / mL) of the powder, and p? is the compaction density (g / mL) of the powder) of the final granules was determined before tablet formation as well as the encapsulation and bonding properties in 100 tablets after the tablet formation stage and the results are shown in Table 4 below. The buoyancy of the final granules before tablet formation is an indicator of how well the tablets float. The better the buoyancy, the higher the overall buoyancy in the process, which can be confirmed by demonstrating easy productivity. This is generally a pharmaceutical index and is evaluated using a value called the Hausner index; the closer this value is to 1, the better the buoyancy. The settled density (g / mL) in the Hausner index was calculated by weighing approximately 10 g of the final granules, placing them in a 50 mL measuring cylinder, and measuring the volume, and the compaction density (g / mL) was calculated by measuring the settled density, tapping the measuring cylinder on the floor, and measuring the volume where it no longer decreased. The properties of the tablets were tested by visually determining whether encapsulation and bonding occurred in each tablet for 100 tablets after the formation of each tablet using the final granules. [Table 4] Hausner Index Encapsulated (number) Glued (number) Example 1 1, 15 0 0 Example 2 1,23 0 0 Example 3 1,22 0 0 Example 4 1, 14 0 0 Example 5 1, 15 0 0 Comparative example 1 1.24 0 0 Comparative example 2 1.17 0 0 Comparative example 3 1.38 0 0 Comparative example 4 1.35 2 0 Comparative example 5 1.28 21 25 Comparative example 6 1.40 12 27 Regarding Table 4 above, when using a diluent of mannitol, microcrystalline cellulose, or a mixture of both during post-mixing (Examples 1 to 5 and Comparative Examples 1 to 3), no encapsulation or sticking occurred. However, when using other diluents (Comparative Examples 4 to 6), encapsulation or sticking was confirmed. In particular, when using a dibasic calcium phosphate or pregelatinized starch diluent (Comparative Examples 5 and 6), encapsulation or sticking occurred in approximately 10% to 30% of cases, resulting in less desirable outcomes. Furthermore, it was determined that when lactose diluents, dibasic calcium phosphate or pregelatinized starch (Comparative Examples 4 to 6) as well as microcrystalline cellulose (Comparative Example 3) were used in isolation as the only component, an unexpected loss of flowability was observed in the tablets prepared with a Hausner index of 1.26 or more. Experimental Example 2: Evaluation of Tablet Properties from Examples 6 to 9 and Comparative Examples 9 and 10 The Hausner index, encapsulation, and gluing were confirmed in the same way as in Experimental Example 1. [Table 5] Hausner index Encapsulated (number) Glued (number) Example 6 1, 18 0 0 Example Ί 1, 9 0 0 Example 8 1, 5 0 0 Example 9 1,20 0 0 Comparative example 9 1.23 0 0 Comparative example 10 1.24 Based on the results in Table 5 above, it could be confirmed that all examples 6 to 9 and comparative examples 9 and 10 obtained a Hausner index measurement of less than 1.26, and therefore had excellent buoyancy. Furthermore, after tablet formation, the encapsulation and gluing of the tablets in Examples 6 through 9 and Comparative Example 9 could not be observed. However, in the case of Comparative Example 10, the total tablet mass was 80 mg, which is 40% of the weight of Example 9, which comprises the same HM781-36B. Therefore, it was confirmed that this mass is not unsuitable for the minimum number of final granules required to prepare a tablet. Consequently, Comparative Example 10 was a final mixture in which tablet formulation was impossible, and therefore, the other evaluations, except for the granule evaluation, were not performed. Based on the above results, it is surprising to observe that even if the HM781-36B content included in the pharmaceutical preparation was increased, the tablet properties were not affected to the point where the buoyancy and compression of the granules were acceptable. Experimental Example 3: Friability Assessment of Examples 1 to 5 and Comparative Examples 1 to 4 For the 65 tablets with respect to examples 1 to 5 and comparative examples 1 to 4 mentioned above, friability was measured with a friability meter (TAR 200 manufactured by ERWEKA, condition: 25 rpm, 4 minutes) and the results are shown in Table 6 below. [Table 6] Mass before measurement (mg) Mass after measurement (mg) Friability Example 1 6521.0 6516.4 0.07 Example 2 6518.1 6510.3 0.12 Example 3 6511.4 6507.5 0.06 Example 4 6553.2 6546.6 0.10 Example 5 6526.9 6523.6 0.05 Comparative example 1 6541.1 6533.3 0.12 Comparative example 2 6527.4 6513.7 0.21 Comparative example 3 6614.8 6608.2 0.10 Comparative example 4 6435.8 6383.0 0.82 Regarding Table 6 above, all tablets in examples 1 to 5 and comparative examples 1 to 4 showed a friability of 1% or less, but if a diluent of mannitol, microcrystalline cellulose, or a mixture of both is used after mixing (Examples 1 to 5 and comparative examples 1 to 3), it could be confirmed that excellent friability is evident. Experimental Example 4: Mass Deviation Analysis of Examples 1 to 5 and Comparative Examples 1 to 4 For 10 tablets with respect to examples 1 to 5 and comparative examples 1 to 4, the mass deviation was measured, and the results are shown in Table 7 below. [Table 7] Average mass (mg) Mean mass deviation (%) Mass deviation of 5% or more (number) Example 1 99.94 1.08 0 Example 2 100.21 1.63 0 Example 3 99.68 1.42 0 Example 4 100.41 1.34 0 Example 5 99.99 1.46 0 Comparative example 1 98.17 4.23 3 Comparative example 2 100.54 4.56 2 Comparative example 3 99.83 4.72 3 Comparative example 4 97.12 5.21 5 Regarding Table 7 above, if a mixture of mannitol and microcrystalline cellulose is used in a weight ratio of 1:1 to 2:1 as a diluent (Examples 1 to 5), it could be confirmed that tablets with a uniform mass could be obtained. Experimental Example 5: Evaluation of the dissolution of Examples 6 to 9 and Comparative Example 9 The dissolution of the tablets from examples 6 to 9 and comparative example 9 mentioned above was evaluated using the dissolution conditions and analytical methods described below. The results of the evaluation are shown in Table 8 below. <Condiciones de disolución> Dissolution solution: take 2 tablets and analyze them in 900 mL of buffer solution, pH 1.2. - buffer solution, pH 1.2: 7.0 mL of HCl was dissolved in 2.0 g of NaCl to form 1000 mL. Device: Apparatus 2 method (paddle dissolution method) between USP <711> Dissolution items. Dissolution temperature: 37 ± 0.5 °C Rotation speed: 50 ± 2 rpm<Condiciones de análisis para HPLC> Detector: Ultraviolet absorption spectrometer (measurement wavelength: 254 nm) Column: Inertsil ODS-2, 4.6 x 150 nm, 5 pm or equivalent column. Mobile phase: Acetonitrile:phosphate buffer solution (pH 2.5) = 40:60 (phosphate buffer solution, pH 2.5: prepared by dissolving 7.0 g of NaClO4 and 1.7 g of KH2PO4 in 1 L of purified water and adjusting the pH to 2.5 with phosphoric acid.) Analysis time: 10 minutes Column temperature: 30 °C Flow rate: 1.0 mL / min Injection volume: 50 pL Based on the results in Table 8 above, when the dissolution pattern of the tablets in examples 6 to 9 and the comparative example 9 mentioned above were observed with pH 1.2, even if the HM781-36B content of examples 6 to 9 was higher than that of comparative example 9, it could be confirmed that both the dissolution pattern and the final dissolution index were not affected. Experimental example 6: Stability analysis for packaged tablets (Example 1 and comparative examples 7 and 8) The tablets from example 1 and comparative examples 7 and 8 were blister-packed with Formpack-Dessiflex (where to obtain: amcor) and left for 1, 2, and 4 weeks at 40°C / 75% relative humidity under accelerated conditions, respectively, and then the impurity IV of Chemical Formula 2 below was measured by liquid chromatography (see analysis conditions below), and the results are shown in figure 1 and table 9.<Condiciones de análisis> Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 254 nm) Column: XTerra RP18, 4.6 mm x 150 mm, 3.5 pm or equivalent column Mobile phase: A - acetonitrile: phosphate buffer solution (pH 2.5) = 40:60 β-acetonitrile: phosphate buffer solution (pH 2.5) = 70:30 Column temperature: 30 °C Analysis time: 45 minutes; flow rate: 1.0 mL / min Injection volume: 50 pL [Chemical Formula 2] [Table 9] Amount of impurity IV (%) Initial 1 Week of acceleration 2 Weeks of acceleration 4 Weeks of acceleration Example 1 0.071 0.132 0.170 0.172 Comparative example 7 0.091 0.411 0.681 0.921 Comparative example 8 0.121 0.342 0.610 0.821 Regarding Figure 1 and Table 9, when using magnesium stearate lubricant at a concentration of 2% by weight or more (Comparative Example 7), the amount of impurity IV increased steadily in proportion to the time it was exposed to acceleration conditions. Similarly, when using sodium stearyl fumarate, another metal salt lubricant, at a concentration of 1% by weight (Comparative Example 8), the amount of impurity IV also increased steadily in proportion to the time it was exposed to acceleration conditions. Specifically, when exposed to acceleration conditions for 4 weeks at 40°C / 75% relative humidity, the amount of impurity IV increased by 4 or more times in the tables of Comparative Examples 7 and 8 compared to the tablets in Example 1, respectively. Based on the above results, it is surprising to observe that the type and content of lubricant included in the pharmaceutical formulation can affect the amount of impurity IV. Experimental Example 7: Stability analysis for packaged tablets (Examples 6 to 9 and comparative examples 9 and 11) The stability of the tablets in examples 6 to 9 and the comparative example 9 mentioned above was evaluated. In addition, stability was evaluated using HM781-36B itself as comparative example 11. Specifically, each of the tablets in Examples 6 through 9 and the comparative example 9 mentioned above was packaged in Formpack-Dessiflex blister packs (available from Amcor), and the HM78136B tablet in comparative example 11 was packaged in a high-density polyethylene bottle. These tablets were then stored for 1, 2, and 4 weeks at a critical temperature of 60 °C. A stability assessment was performed on the samples stored for the aforementioned period against the analytical conditions of experimental example 6. The stability assessment was conducted to measure impurity IV of Chemical Formula 2 below, and the results are shown in Figure 2 and Table 10. [Table 10] Amount of impurity IV (%) Initial 1 Week of acceleration 2 Weeks of acceleration 4 Weeks of acceleration Comparative Example 9 0.07 0.28 0.53 0.75 Example 6 0.05 0.11 0.14 0.18 Example 7 0.05 0.09 0.13 0.17 Example 8 0.05 0.09 0.13 0.17 Example 9 0.07 0.11 0.15 0.18 Comparative Example 11 0.06 0.06 0.07 0.07 Regarding Figure 2 and Table 10, since Comparative Example 11 only includes HM781-36B, it showed very stable results for 4 weeks under critical conditions. However, it was determined that the tablets in examples 6 to 9 and comparative example 9, which were prepared by mixing HM781-36B with a pharmaceutically acceptable additive, generated the impurity of Chemical Formula 2 mentioned above. Specifically, comparative example 9 includes HM781-36B in an amount less than 2.0% by weight based on the total weight of the pharmaceutical preparation. Therefore, it was determined that the amount of impurity generated from Chemical Formula 2 mentioned above increased significantly over time, even when packaged in a stable packaging material. In other words, although the stability increased slightly with the addition of the packaging material, the results showed no improvement in the stability of HM781-36B itself. However, examples 6 to 9, which include HM781-36B in an amount of 5% or more and less than 20% by weight based on the total weight of the pharmaceutical preparation, showed that the amount generated from the impurity of Chemical Formula 2 above did not increase significantly. Specifically, when left for 4 weeks under critical conditions of 60°C, the amount of impurity IV was found to increase at a rate of 3.5 or more times in the comparative example 9 tablet compared to the tablets in examples 6 to 9, respectively. Based on the previous results, it is surprising to observe that the HM781-36B content in the pharmaceutical formulation can affect the amount of impurity IV. Experimental Example 8: Stability analysis for each tablet packaging material with respect to Example 1. Each of the tablets with respect to example 1 was packaged either in an Al-Al blister, an Al-PO+CaO-Al blister, or an HDPE bottle (5 different packages, each fitted with a polypropylene cap including 0.5, 2.0, 3.0, 4.0, or 5.0 g of silica gel and a polypropylene cap), characterized in that TEKNILID® 1207 (Tekniplex) was used for the Al-Al blister, Formpack® Dessiflex blister (Amcor) was used for the Al-PO+CaO-Al blister, BTH-250 (Ewha Engineering) was used for the HDPE bottles, and the polypropylene cap (including silica gel) was also from Ewha Engineering with the trademarks MH-Cap (0.5 g), MH-Cap (2.0 g), MH-Cap (3.0 g), MH-Cap (4.0 g), and MH-Cap (5.0 g). (5.0 g).The packaged products were left for 1, 2, and 4 weeks at 40°C / 75% relative humidity under accelerated conditions, respectively, and then the impurity IV of the above-mentioned Chemical Formula 2 was measured by liquid chromatography (see analysis conditions in Experimental Example 6), and the results are shown in Figure 3 and Table 11. [Table 11] Amount of impurity IV (%) Initial 1 Week of acceleration 2 Weeks of acceleration 4 Weeks of acceleration Al-Al 0.071 0.229 0.285 0.391 Al-PO+CaO-Al 0.071 0.132 0.170 0.172 HDPE / Silica 0.5g 0.071 0.187 0.248 0.325 HDPE / Silica 2.0g 0.071 0.142 0.181 0.207 HDPE / Silica 3.Og 0.071 0.138 0.180 0.191 HDPE / Silica 4, Og 0.071 0, 131 0, 176 0, 181 HDPE / Silica 5, Og 0.071 0, 135 0, 172 0.17 Ί Regarding Figure 3 and Table 11, when using an Al-PO+CaO-Al blister pack containing CaO, a moisture absorbent, instead of an Al-Al blister pack, the increased amount of impurity IV decreased in proportion to the time it was exposed to acceleration conditions. Specifically, in the Al-PO+CaO-Al blister pack, the increased amount of impurity IV decreased significantly after two weeks of acceleration. Furthermore, when using the HDPE bottle, the increased amount of impurity IV decreased in proportion to the time it was exposed to acceleration conditions, while the amount of silica gel, a moisture absorbent, increased in the cap.In particular, in the HDPE bottle packaging material using a cap that includes 2g more of silica gel, the increased amount of impurity IV decreased markedly over time. Experimental Example 9: Dissolution Analysis after 4 Weeks under Acceleration Conditions. Under the dissolution and analysis conditions of experimental example 5, the dissolution indices of the tablets left for 4 weeks under acceleration conditions were measured compared to experimental example 8, respectively, and the results are shown in Table 12, [Table 12] Time (min) 0 5 10 15 30 45 60 Al-Al Average 7 2.13 81.35 86.72 89.23 90. 12 90. 63 Standard deviation (SD) 3. 0 2.2 1. 5 0.7 0.5 0. 3 Al-PO + CaO-Al Average - 7 6.76 82.28 84.87 87. 15 8 7.58 88. 09 Deviation 2. 5 2.2 1.1 0.8 0. 5 0.8 Standard deviation (SD) HDPE / Silic e 0.5 g Average - 70.05 82.38 85.34 87.83 88.30 88.63 Standard deviation (SD) 2.7 1.9 1.4 1.0 0.8 0.9 HDPE / Silic e 2.0 g Average - 72.84 82.34 85.71 86.96 8 7.99 87.97 Standard deviation (SD) 1.9 1.8 1.9 0.9 0.9 0.7 HDPE / Silic e 3.G g Average — 74.47 79.97 82.72 85.89 88.66 90.24 Standard deviation (SD) 3.4 2.7 2.1 1.8 1.5 0.4 HDPE / Silic e 4.0 g Average — 68.32 80.43 83.68 85.51 87.29 87.04 Standard deviation (SD) 4.1 2.5 1.5 0.8 1.3 1.i Average — 50.13 67.20 7 7.23 82.04 85.67 86.13 HDPE / Silic e 5.0 g Standard deviation (SD) 8.0 3.7 2.8 1.7 1.4 1.3 Regarding Table 12 above, when using HDPE packaging material with a cap containing 5.0 g of silica gel, it could be confirmed that tablets left for 4 weeks under accelerated conditions exhibited slow initial disintegration and a lower dissolution rate. However, after approximately 60 minutes, the difference in the dissolution rate of each tablet was negligible. Note that all simple variations and modifications of the present invention are within the scope of the present invention, and the specific scope of the present invention to be protected will be defined through the attached claims.

Claims

1. A pharmaceutical preparation comprising a granule comprising a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof and a diluent for mixing with the granule: [Chemical Formula 1] 2. The pharmaceutical preparation according to claim 1, characterized in that the compound of Chemical Formula 1 or the pharmaceutically acceptable salt thereof is included in the pharmaceutical preparation in an amount of 2.0% or more and less than 20% by weight based on the total weight of the pharmaceutical preparation.

3. The pharmaceutical preparation according to claim 1, characterized in that the diluent is included in the pharmaceutical preparation in an amount of 20% to 50% by weight based on the total weight of the pharmaceutical preparation.

4. The pharmaceutical preparation according to claim 1, characterized in that the diluent is mannitol, microcrystalline cellulose, or a mixture of both. 5.The pharmaceutical preparation according to claim 4, characterized in that the diluent is a mixture of mannitol and microcrystalline cellulose in a weight ratio of 0.50:1 to 3.2:

1.

6. The pharmaceutical preparation according to claim 1, characterized in that the pharmaceutical preparation further comprises a lubricant.

7. The pharmaceutical preparation according to claim 6, characterized in that the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, sodium lauryl sulfate, zinc stearate, sodium benzoate, and mixtures thereof.

8. The pharmaceutical preparation according to claim 6, characterized in that the lubricant is included in the pharmaceutical preparation in an amount of 0.5% to 1.5% by weight based on the total weight of the pharmaceutical preparation. 9.A method for preparing the pharmaceutical preparation according to claim 1, the method comprising the following steps: 1) mixing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive and then developing the granulation to prepare a granule; 2) mixing the granule with a pharmaceutically acceptable additive and then adding a diluent to prepare a mixed granule; and 3) formulating the mixed granule.

10. A pharmaceutical product wherein the pharmaceutical preparation of claim 1 is packaged in a presentation material.

11. The pharmaceutical product of claim 10, characterized in that the packaging material is selected from the group consisting of glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cycloolefin polymer (COP), cycloolefin copolymer (COC), polyolefin (PO), aluminum (Al), and combinations thereof, and the packaging material shape is selected from the group consisting of bottles, blisters, and pouches. 12.The pharmaceutical product of claim 10, characterized in that the packaging material is composed of a moisture absorbent.

13. The pharmaceutical product of claim 12, characterized in that the moisture absorbent is calcium oxide or silica gel.

14. The pharmaceutical product of claim 13, characterized in that the silica gel is included in the packaging material in an amount of 2 to 5 g based on a 125 ml high-density polyethylene bottle. 15.A method for improving the stability of a pharmaceutical preparation by reducing the formation of impurities comprising the pharmaceutical preparation of claim 1, the method comprising the following steps: 1) mixing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive and then developing the granulation to prepare a granule; 2) mixing the granule with a pharmaceutically acceptable additive and then adding a diluent to prepare a mixed granule, characterized in that the diluent is a mixture of mannitol and microcrystalline cellulose in a weight ratio of 0.50:1 to 3.2:1; and. 3) formulating mixed granules.

16. A method for treating cancer in a subject, comprising administering an effective therapeutic amount of the pharmaceutical preparation of claim 1, characterized in that the subject has been determined to have one or more activating mutations of EGFR or HER2.

17. The method of claim 16, characterized in that the subject has been determined to have one or more activating mutations of HER2 selected from the group consisting of S310F / Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H / N / Y, V773M, V777L / M, L786V, V842I, and L869R.

18. The method of claim 16, characterized in that the subject has one or more EGFR activating mutations selected from the group consisting of EGFRvIII, R108K, R222C, A289T, P596L, G598V, Exon 20 Insertion, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.