TW202128170A - A pharmaceutical preparation comprising an amide derivative inhibiting the growth of cancer cell and a pharmaceutical product containing the same - Google Patents

Abstract

The present invention relates to a pharmaceutical preparation comprising a granule comprising a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a diluent. The pharmaceutical preparation has a high productivity of the preparation due to excellent tableting properties, friability, and mass uniformity. The pharmaceutical preparation has low generated amount of impurities and high stability.

Description

Pharmaceutical preparations containing amide derivatives that inhibit the growth of cancer cells and pharmaceutical products containing them

The present invention relates to pharmaceutical preparations containing amide derivatives that inhibit the growth of cancer cells and pharmaceutical products containing the same. Specifically, the present invention relates to pharmaceutical preparations, which include particles and diluents containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof, and pharmaceutical products containing the same.

This application claims the benefit of priority based on the Korean patent application number 10-2019-0132809 filed on October 24, 2019 and the Korean patent application number 10-2020-0137829 filed on October 22, 2020. The entire content disclosed in the Korean patent application is hereby incorporated in its entirety as a part of this case.

The epidermal growth factor receptor (EGFR) is known to exist as four subtype receptors of EGFR/ErbB1, Her-2/ErbB2, Her-3/ErbB3 and Her-4/ErbB4, and is abnormal in most solid cancer cells Overperformance. In addition, it is known that the receptor activates the cell signaling system through the activation line of the ligand to induce the growth, differentiation, angiogenesis, metastasis and drug resistance of cancer cells (Wells A., Int J Biochem Cell Biol., 1999 , 31, 637-643). Therefore, it is predicted that if the signal transduction of cancer cells via the epidermal growth factor receptor is blocked, the anticancer effect will be excellent, and research is actively being conducted to develop anticancer agents that target the epidermal growth factor receptor.

These anti-cancer agents that target the epidermal growth factor receptor are divided into monoclonal antibody drugs that target the extracellular region of the receptor and low-molecular-weight drugs that target intracellular tyrosine kinase. Monoclonal antibody drugs have the advantage of showing few side effects and excellent efficacy by selectively binding to epidermal growth factor receptors. However, these drugs have the disadvantage of not only being expensive but also having to be used in the form of injections. In contrast, low-molecular-weight drugs targeting tyrosine kinase are relatively inexpensive, can be administered orally, and have selective or simultaneous action on several subtypes of epidermal growth factor receptors (EGFR, Her-2, Her-3). And Her-4) excellent efficacy.

Low-molecular-weight drugs targeting epidermal growth factor receptors include Iressa ^® (ingredient name: gefitinib (gefitinib); AstraZeneca), Tarceva ^® (ingredient name: erlotinib (erlotinib); Roche), which is EGFR Selective inhibitor, and Tykerv ^® (ingredient name: lapatinib; GlaxoSmithKline), which is a dual inhibitor that simultaneously blocks EGFR and Her-2, and these are used for lung cancer and Her-2, respectively Positive therapeutic agents for advanced breast cancer and are undergoing clinical trials to expand the indications for the treatment of other solid cancers.

In this regard, Korean Patent Application Early Publication No. 10-2008-0107294 discloses a compound of the following chemical formula 1, which has fewer side effects, while selectively and effectively inhibiting the growth of cancer cells and the effects caused by EGFR and its mutations. Drug resistance: [Chemical formula 1]

However, with regard to pharmaceutical compositions containing this compound, those skilled in the art have encountered productivity and stability problems in preparing preparations such as tablets and capsules. In particular, such compositions prepared by conventional production steps usually suffer from uniform purity, predictable stability and shelf life. Moreover, such compositions often suffer from obvious capping and inconsistent scratches during the manufacturing stage, leaving patients in a situation where they may receive sub-optimal doses. Accordingly, in order to develop more suitable preparations and improve the prognosis of patients, research on pharmaceutical compositions containing the compound is continuously performed. [Prior Art Reference] [Patent Document] (Patent Document 1) Korean Patent Application Early Publication No. 10-2008-0107294

[Technical issues]

Regarding the pharmaceutical preparation comprising the above chemical formula 1, it is intended to provide a pharmaceutical product with high productivity due to improved tablet properties, pulverization and quality uniformity, and high stability due to low impurity generation even under severe conditions. Preparation. [Technical Solution]

The present invention solves the shortcomings of the prior art. According to the first aspect of the present invention,

The present invention provides a pharmaceutical preparation, which comprises particles comprising the 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% by weight or more and less than 20% by weight based on the total weight of the pharmaceutical preparation middle.

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 thereof.

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 contains a glidant.

In one embodiment of the present invention, the glidant 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 glidant 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.

According 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 the compound of formula 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; Subsequently, granulation is performed to prepare granules; 2) the granules are mixed with pharmaceutically acceptable additives and then a diluent is added to prepare mixed granules; and 3) the mixed granules are formulated.

According to a third aspect of the present invention, the present invention provides a method for reducing impurities in a pharmaceutical preparation containing a compound of formula 1 by mixing particles containing a compound of formula 1 with a pharmaceutically acceptable amount in a suitable amount. The proportions of at least two diluents and the combination of this type are compressed into a tablet form, wherein the amount of such impurities including the compound of formula 2 (also referred to as impurity IV in this case) is less than 1% of the total weight of the preparation, preferably Less than 0.5%, more preferably less than 0.2%. [Chemical formula 2]

According to a fourth aspect of the present invention, the present invention provides a pharmaceutical product, wherein the aforementioned pharmaceutical preparation is packaged in a packaging material.

In one embodiment of the present invention, the material of the packaging material is selected from the group consisting of glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene Vinyl chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyolefin (PO), aluminum (Al) and combinations thereof, the shape of the packaging material Selected from the group consisting of: bottle, blister and pouch.

In one embodiment of the present invention, the packaging material contains 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 silicone gel is included in the packaging material in an amount of 2 to 5 g based on a 125 ml HDPE bottle.

According to the fifth aspect of the present invention, the present invention provides a method of treating cancer in an individual in need thereof.

In one embodiment of the invention, the individual has been tested to have one or more EGFR or HER2 activating mutations.

In one embodiment of the present invention, a method for treating tumors comprises administering a therapeutically effective amount of a pharmaceutical preparation, which comprises particles and dilutions according to the present invention comprising the compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof Agent.

In one embodiment of the present invention, the cancer is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, stomach cancer, brain cancer, cervical cancer, bladder cancer, bile duct cancer, ovarian cancer, pancreatic cancer and Testicular cancer.

In one embodiment of the invention, the cancer is metastatic. [Advantageous effect]

According to the present invention, the pharmaceutical preparation is a pharmaceutical preparation containing the compound of Chemical Formula 1, and by adding particles containing the compound of Chemical Formula 1 as an active ingredient and a specific diluent, due to excellent tablet pressing properties, pulverization and quality uniformity Preparations with high productivity.

In addition, by specifying the metal salt glidant used in pharmaceutical preparations and packaging the pharmaceutical preparations with specific packaging materials, the present invention can provide pharmaceutical products with low impurity generation and high stability.

Hereinafter, the present invention will be explained in more detail.

The compound of the following chemical formula 1 or its pharmaceutically acceptable salt itself is very stable, but the pharmaceutical preparation containing it exhibits extremely unstable properties under severe conditions. Although the problem of instability has been partially improved by the improvement of packaging materials, the basic stability of pharmaceutical preparations has not been improved. [Chemical formula 1]

Therefore, with regard to the pharmaceutical preparation containing the above-mentioned chemical formula 1 in the present invention, it is intended to provide a high productivity due to improved tablet properties, pulverization and quality uniformity, and due to the fact that even under severe conditions (60°C for 1 Month) Pharmaceutical preparations with high stability and low production of impurities such as the structure of Formula 2.

The present invention provides a pharmaceutical preparation comprising particles containing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof and a diluent for mixing with the particles:

The compound of Chemical Formula 1 (hereinafter referred to as HM781-36B) is a compound with fewer side effects, while selectively and effectively inhibiting the growth of cancer cells and drug resistance caused by EGFR and its mutations, such as Korean Patent Application Publication No. Described in 10-2008-0107294.

The pharmaceutically acceptable salt of the compound of Chemical Formula 1 can be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid. Examples of salts may be salts with inorganic acids, such as hydrochloric acid, sulfuric acid, pyrosulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc.; or salts with organic acids, such as 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, gluconic acid, fumaric acid, lactobionic acid, salicylic acid, phthalic acid, palmoic acid, natural Winter amino acid, glutamine acid, camphor sulfonic acid, benzene sulfonic acid or acetylsalicylic acid (aspirin). In addition, pharmaceutically acceptable salts may be in the form of metal salts obtained by reacting with alkali metals, such as calcium, sodium, magnesium, strontium, potassium, and the like.

The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be based on 1.5% by weight or more and less than 25% by weight, 2.0% by weight or more and less than 20% by weight, 2.5% by weight or More and less than 20 wt% or 5 wt% or more and less than 20 wt%, preferably 3.5 wt% to 15 wt%, and more preferably 5 wt% to 8 wt% is included.

If the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is included in an amount of less than 2.0% by weight, the tablet properties and dissolution rate are excellent, but the stability is extremely poor and impurities are quickly generated, and if it is 20% by weight or If more amount is included, the total content of the tablet will be reduced to a mass that cannot be compressed (less than 70 mg), so there is a problem that the tablet cannot be compressed.

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 in the form of, for example, powder, lozenge, pill, capsule, liquid, suspension, emulsion, syrup, or granule, and preferably may be a lozenge or capsule, but is not limited thereto.

The pharmaceutical preparation may further contain diluents, binding agents, disintegrants and glidants as pharmaceutically acceptable additives. In some embodiments, the diluent may be a combination of at least two different diluents.

In an embodiment of the present invention, the pharmaceutical preparation may include the compound of Formula 1 or a pharmaceutically acceptable salt thereof prepared in the form of granules. The granules can be prepared by mixing the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof with a diluent, and then wet granulating it in a binder solution in which the binder is dissolved in pure water.

The diluent may be one or more selected from the group consisting of mannitol, microcrystalline cellulose, lactose and calcium phosphate, and preferably may be mannitol, microcrystalline cellulose or a mixture thereof. In addition, 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 particles. In some embodiments, the diluent may be a combination of mannitol and microcrystalline cellulose.

The binding agent may be one or more selected from the group consisting of: pupvidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, and carboxymethyl cellulose, preferably Puvidone, but not limited to this. The binding agent may be included 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 particles.

The particles can be mixed with additional diluents and then purified to prepare pharmaceutical preparations. The diluent system used for mixing with the particles and the diluent used for preparing the particles are physically separate and have different functions, so they are separated and used independently. The diluent used for mixing with the particles may preferably be mannitol, microcrystalline cellulose or a mixture thereof, and more preferably may be a mixture of mannitol and microcrystalline cellulose. The mixture of mannitol and microcrystalline cellulose may be a mixture of mannitol and microcrystalline cellulose in the following weight ratios: 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 used for mixing with the particles may be included in an amount of 20% to 50% by weight, preferably 30% to 40% by weight, based on the total weight of the pharmaceutical preparation. The choice of diluent used to mix with the particles may actually affect the productivity of the pharmaceutical preparation. Specifically, by selecting the aforementioned diluent, the pressing properties and pulverization properties of the tablets can be improved, and tablets of uniform quality can be obtained.

In at least one embodiment, the diluent mixed with the particles may include 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, and the second diluent is cellulose Derivatives, such as microcrystalline cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and the like.

In at least one embodiment, the first diluent is mannitol and the second diluent is microcrystalline cellulose, wherein the weight ratio of mannitol to upper microcrystalline cellulose is 0.25: 2 to 4: 1.5; or 0.75: 1.25 to 3.5:1.25; or preferably in the range of 0.50:1 to 3.2:1.

In some embodiments, the particles may be mixed with a disintegrant together with the aforementioned diluent, and then purified to prepare a pharmaceutical preparation. The disintegrant may be one or more selected from the group consisting of crosprovidone, croscarmellose sodium and sodium starch glycolate, preferably crosprovidone, but Not limited to this. 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, the glidant may be added to the pharmaceutical preparation prior to purification. According to one embodiment of the present invention, the glidant may be a metal salt glidant. The glidant may be one or more selected from the group consisting of calcium stearate, magnesium stearate, sodium lauryl sulfate, zinc stearate and sodium benzoate, preferably stearin Magnesium acid. The glidant can be included in the pharmaceutical preparation in an amount of 0.5% by weight or more and less than 5% by weight, preferably less than 2% by weight, and more preferably 0.5% to 1.5% by weight based on the total weight of the pharmaceutical preparation. In. When a glidant in the form of a metal salt is used, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may have poor stability, but the glidant is included in an amount of 0.5% by weight or more and less than 5% by weight , Can improve the stability of pharmaceutical preparations.

In some embodiments, the present invention does not substantially contain (less than 1% by weight) any 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, camphorsulfonic acid, malic acid, maleic acid, oxalic acid, palmitic acid, stearic acid or even silicon dioxide. In some embodiments, the pharmaceutical preparations of the present invention contain less than 0.25% by weight of any such acidic additives. In some embodiments, the pharmaceutical preparation does not contain any acidic additives.

In addition, the pharmaceutical preparation may have an outer surface coated with a coating matrix selected from the group consisting of an immediate-release film-forming agent, an enteric coating matrix, and a sustained-release coating matrix, so as to prevent the pharmaceutical active ingredient from being Direct contact with human hands or skin.

The immediate-release film-forming agent may be one or more selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol graft The polymer, the enteric coating base may be one or more selected from the group consisting of (meth)acrylic acid copolymer, hydroxypropyl methyl cellulose phthalate and cellulose acetate The basic phthalate and the sustained-release coating base may be one or more selected from the group consisting of cellulose acetate, ethyl cellulose and polyvinyl acetate, but not limited thereto .

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 certain embodiments, the coating layer accounts for about 0.5 to about 5% of the total weight of the formulation, wherein the coating layer has less than 18 weight percent titanium dioxide and not more than 25 weight percent polyvinyl alcohol, and any Choose no more than 25% by weight of lactose or talc.

In some embodiments, the coating substrate may be a polyvinyl acetate substrate composed solely of polyvinyl alcohol of any molecular weight or contained in a copolymer, for example, Kollicoat ^® IR (BASF, NJ USA) or as a polyvinyl alcohol Alcohol is a part of the coating system of the matrix, such as ^{various film coating products available under the trade name Opadry ®} (Colorcon, PA, USA), such as Opadry II ^® 85F series, Opadry ^® II 89F series or Opadry ^® White.

The pharmaceutical preparation of the present invention comprises the compound of Chemical Formula 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable additives, wherein the compound of Chemical Formula 1 or its pharmaceutically acceptable salt is based on the total weight of the pharmaceutical preparation. An amount of weight% or more and less than 20 weight% is included in the pharmaceutical preparation. At least one surprising observation is that the inhibition of impurity generation under severe conditions improves the stability, especially the stability of pharmaceutical preparations, without affecting the properties of the tablet and the dissolution rate. In some embodiments, the severe conditions may include a storage duration of 4 weeks or five or six months in 40 ^○ C and 75% RH accelerated conditions In certain embodiments, the storage conditions may comprise 30 ^○ C at 55% RH and duration of storage of 6 to 12 months.

In at least some embodiments of the present invention, the stability is evaluated based on the following: The compound of formula 1 has a change of more than 5% from the initial value in the test, or cannot be used for its intended use in a biological or immunological process. To meet the acceptance criteria for efficacy, any degradation product that exceeds the acceptable criteria, such as the presence of impurities, or the final preparation cannot meet physical properties, functional tests, such as color, phase separation, agglomeration, and hardness.

In some embodiments, by using suitable equipment, the pharmaceutical preparation of the present invention is in the form of a lozenge having a hardness of 4 to 20 kp or preferably 6 to 17 kp.

The present invention provides a method for preparing the aforementioned pharmaceutical preparation. The method includes the following steps: 1) mixing the compound of formula 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable additives and then granulating to prepare granules; 2) mixing the granules and pharmaceutically acceptable additives And then add a diluent to prepare mixed particles; and 3) formulate the mixed particles. The various steps of the preparation method are described in accordance with the contents of the aforementioned pharmaceutical preparations.

The present invention provides a pharmaceutical product, wherein the aforementioned pharmaceutical preparation is packaged in a packaging material. The packaging material is used to protect the preparation from light, heat, moisture, etc. The material of the packaging material can be selected from the group consisting of glass, high-density polyethylene (HDPE), polypropylene (PP), poly Vinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cycloolefin polymer (COP), cycloolefin copolymer (COC), polyolefin (PO), aluminum (Al) And its combination. The packaging material may have the foregoing materials and may be prepared in a form selected from the group consisting of a bottle, a blister, and a pouch. According to the embodiment of the present invention, the bottle can be made of HDPE, and the blister can be made of an upper plate and a lower plate containing Al material. The upper plate contains selected from PVC, PVDC, PCTFE, PP, One or two or more materials in the group formed by PE, COP, COC, PO, Al, and combinations thereof. The upper plate and/or the lower plate may have a single structure or a double or more structure.

The glass, HDPE, PP, PVC, PVDC, PCTFE, COP, COC, PO, and Al used in the present invention may be those commonly used for packaging of pharmaceutical products in the pharmaceutical field. For example, HDPE may have a weight average molecular weight of about 50,000 to 150,000, and a density of ^{about 0.941 g/cm 3} to 0.965 g/cm ^3. PP may have a weight average molecular weight of about 200,000 to 600,000, and PVC may have a molecular weight distribution (Mw/Mn) of about 1.7 to 2.0 and a density of ^{1.16 g/cm 3} to 1.35 g/cm ^3. PVDC may have a density of about 0.65 g/cm ³ to 1.72 g/cm ³ , PCTFE may have a specific gravity of about 2.12, and PO, COP, and COC may have a density of ^{about 1.02 g/cm 3 or less.}

The packaging material according to the present invention may contain a moisture absorbent. The hygroscopic agent has the function of increasing the stability of the pharmaceutical preparation by controlling the moisture inside the packaging material. The hygroscopic agent can be used without limitation, as long as it is generally used in the related technical field. Compared with the active ingredient of the present invention, calcium oxide or silica gel can be preferably used. The moisture absorbent can be mixed with the material of the packaging material and applied to the packaging material in various forms. According to an embodiment of the present invention, in the case of using silicone as a moisture absorbent, the silicone may preferably be included in the packaging material in an amount of 2 to 5 g, preferably 3 to 5 g. The content of silicone is based on the value set by the packaging material used to package the preparation containing about 480 mg of the active ingredient (HM781-36B) or the HDPE bottle with a capacity of about 125 ml. When the content of silicone gel is less than 2 g, the stability of the drug preparation inside the packaging material may be reduced due to the inability to properly control the moisture inside the packaging material, and when the content of silicone gel is more than 5 g, the drug preparation will dissolve The rate may be reduced by affecting the moisture content of the drug preparation itself.

The present invention also provides a method of treating cancer in an individual in need thereof. In some embodiments, the method of treating cancer includes administering a therapeutically effective amount of a pharmaceutical preparation comprising particles according to the present invention comprising the compound of Formula 1 below or a pharmaceutically acceptable salt thereof and a diluent. In some embodiments, the pharmaceutical preparation is substantially free of impurity IV.

In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, stomach cancer, brain cancer, cervical cancer, bladder cancer, cholangiocarcinoma, ovarian cancer, pancreatic cancer, and testicular cancer. In some embodiments, the cancer is metastatic.

In some embodiments, the individual has been tested to have one or more EGFR or HER2 activating mutations. In some embodiments, the individual has been tested to have one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. Multiple HER2 activating mutations.

In some embodiments, the individual has been tested to have one or more HER2 activating mutations selected from: S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M , V777L/M, L786V, V842I and L869R.

In some embodiments, the individual has been tested to have a solid tumor with an EGFR activating mutation, where the individual may or may not have NSCLC or high-grade glioma). In some embodiments, EGFR activating mutations are located outside the cell and/or transmembrane, including, for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V. In some embodiments, EGFR activating mutations are located in the kinase domain, including, for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V. Exon 20 insertion, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V. In some embodiments, the individual has not yet received chemotherapy for cancer treatment, biologics, immunotherapy, HER2 targeted therapy, or radiation therapy for curative purposes.

In the following, preferred embodiments will be provided to help understand the present invention, but the following embodiments are not provided to limit the present invention but to promote the understanding of the present invention. Example Example 1

A tablet containing the compound of Chemical Formula 1 (hereinafter referred to as "HM781-36B", manufactured by Dongwoo Syntech Co., Ltd.) as an active ingredient was prepared according to the composition described in Table 1 below.

Specifically, HM781-36B and D-mannitol (manufactured by Roquette) were wet-granulated using a high-shear mixer and a wet granulation sieve, while using a No. 35 sieve (500 μm) to distribute HM781-36B to D-mannitol. Then, Puvidone (manufactured by BASF) dissolved in an appropriate amount of pure water was added thereto to prepare a granular portion. The particles obtained by wet granulation were sieved using a No. 20 sieve (850 μm), and then dried using a fluidized bed dryer (fluid bed granulator). Repeat the above process until a result is obtained by measuring the drying loss of about 0.5% or less.

The granular part prepared by the above method was mixed with a mixture of mannitol and microcrystalline cellulose (manufactured by Mingtai Chemical) and crosprovidone (manufactured by BASF), and then magnesium stearate (Peter Greven, Netherlands) was added. Manufacturing), and finally mixed. Using a tablet press (manufactured by Sejong), the resulting final mixture is prepared into tablets having a hardness of about 5 to 10 kp by a conventional method. Examples 2 to 5

A lozenge containing HM781-36B as an active ingredient according to the composition described in Table 1 below was prepared in the same manner as in Example 1. [Table 1] method raw material Example 1 Example 2 Example 3 Example 4 Example 5 Wet granulation mix HM781-36B 8 8 8 8 8 Mannitol 50 50 50 50 50 Binding solution Puvidone 2 2 2 2 2 ＜Pure water＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ Post-mix Mannitol 17 20 22.5 17.5 17 Microcrystalline cellulose 17 14 11.5 17 16.5 Cross-linked providone 5 5 5 5 5 Glidant Magnesium stearate 1 1 1 0.5 1.5 Total mass 100 100 100 100 100

*The unit of the value is mg/tablet, and pure water is removed during this method. Comparative examples 1 to 8

A lozenge containing HM781-36B as an active ingredient according to the composition described in Table 2 below was prepared in the same manner as in Example 1. Table 2 below, using the product from Pruv ^®, sodium stearyl fumarate JRS PHARMA acyl of from Lian yungang Debang Fine Chemical dibasic calcium phosphate available from Roquette and pregelatinized starch. [Table 2] method raw material Comparative example 1 Comparative example 2 Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Comparative example 7 Comparative example 8 Wet granulation mix HM781-36B 8 8 8 8 8 8 8 8 Mannitol 50 50 50 50 50 50 50 50 Binding solution Puvidone 2 2 2 2 2 2 2 2 ＜Pure water＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ ＜8＞ Post-mix Mannitol 11 26 - - - - 17 17 Microcrystalline cellulose twenty three 8 34 - - - 16 17 lactose - - - 34 - - - - Dicalcium Phosphate - - - - 34 - - - Pregelatinized starch - - - - - 34 - - Cross-linked providone 5 5 5 5 5 5 5 5 Glidant Magnesium stearate 1 1 1 1 1 1 2 - Sodium Stearyl Fumarate - - - - - - - 1 Total mass 100 100 100 100 100 100 100 100

*The unit of the value is mg/tablet, and pure water is removed during this method. Examples 6 to 9 and Comparative Examples 9 to 10

Tablets were prepared as in Example 1, and then ^{coated with Opadary ®} 03F180000, and finally 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] method raw material Example 6 Example 7 Example 8 Example 9 Comparative example 9 Comparative example 10 Wet granulation mix HM781-36B 4 6 8 16 2 16 D-mannitol 35.2 37.5 50 100 50 34 Binding solution Puvidone 1.4 1.5 2 4 1.5 1 ＜Pure water＞ ＜5.6＞ ＜6＞ ＜8＞ ＜16＞ ＜6＞ ＜4＞ Post-mix D-mannitol 12.5 12.8 17 34 23.5 12 Microcrystalline cellulose 12.5 12.8 17 34 17 12 Cross-linked providone 3.6 3.8 5 10 5 2.5 Glidant 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 the value is mg/tablet, and pure water is removed during this method.

The HM781-36B in the foregoing Examples 6 to 9 and Comparative Examples 9 and 10 are based on 5.6% by weight, 7.7% by weight, 7.8% by weight, 7.8% by weight, 1.9% by weight, and 20% by weight based on the total weight of the pharmaceutical preparation, respectively. The amount is included. Experimental exampleExperimental example 1: Evaluation of the pressed properties of Examples 1 to 5 and Comparative Examples 1 to 6

For the above Examples 1 to 5 and Comparative Examples 1 to 6, the fluidity of the final granules before pressing (Hausner ratio calculated _{by the formula H=ρ T} /ρ _{B , where ρ B} is the free powder Settling bulk density (g/mL), ρ _T is the tapped bulk density (g/mL) of the powder) and the capping and sticking properties in 100 tablets after the tablet pressing step. The results are shown in Table 4 below.

The fluidity of the final granules before tableting is an indicator of the fluidity of the tablet. The better the fluidity, the higher the fluidity in the manufacturing process, which can be confirmed by the easy productivity. This is usually a pharmacy index and is evaluated using a value called Hausner Ratio. The closer it is to 1, the better the fluidity that can be exhibited.

By weighing about 10 g of the final particles, placing them in a 50 mL graduated cylinder, and measuring the volume to calculate the free sedimentation bulk density (g/mL) in the Hausner Ratio, and by measuring the free sedimentation bulk density, on the floor Tap the graduated cylinder and measure the volume when the volume no longer decreases to calculate the tapped bulk density (g/mL).

After each tablet was compressed with the final granules, for 100 tablets, the properties of the tablets were tested by visually determining whether the tablets had capped and sticked. [Table 4] Hausner ratio Capping (number) Stick (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 twenty one 25 Comparative example 6 1.40 12 27

According to Table 4 above, in the case of using diluents of mannitol, microcrystalline cellulose or their mixtures during the post-mixing period (Examples 1 to 5 and Comparative Examples 1 to 3), no capping or sticking phenomenon occurred, but In the case of using other diluents (Comparative Examples 4 to 6), capping or sticking can be confirmed. In particular, in the case of using dicalcium phosphate or a diluent of pregelatinized starch (Comparative Examples 5 and 6), about 10% to 30% of capping or sticking occurred, thus leading to more undesirable results .

In addition, it was determined that when lactose, dicalcium hydrogen phosphate or pregelatinized starch (Comparative Examples 4 to 6) and microcrystalline cellulose (Comparative Example 3) are used as a single component alone, the ratio of 1.26 or more An accidental loss of fluidity was observed in lozenges prepared with high Hausnaby. Experimental Example 2: Evaluation of the pressed properties of Examples 6 to 9 and Comparative Examples 9 and 10

In the same manner as in Experimental Example 1, Hausnerby, capping and sticking were confirmed. [table 5] Hausner ratio Capping (number) Stick (number) Example 6 1.18 0 0 Example 7 1.19 0 0 Example 8 1.15 0 0 Example 9 1.20 0 0 Comparative example 9 1.23 0 0 Comparative example 10 1.24 - -

According to the results of Table 5 above, it can be confirmed that Examples 6 to 9 and Comparative Examples 9 and 10 are measured to have a Hausner ratio of less than 1.26, and therefore have excellent fluidity.

In addition, after the tablets were pressed into tablets, no capping or sticking was visually observed in the tablets of Examples 6 to 9 and Comparative Example 9. However, in the case of Comparative Example 10, the total mass of the tablet was 80 mg, which was 40% of the weight of Example 9 containing the same HM781-36B, thus it was confirmed that it was not suitable for the final preparation required for the tablet. The minimum amount of particles. Therefore, Comparative Example 10 was the final mixture that could not be compressed, so no other evaluation was performed except for the particle evaluation.

It is surprisingly observed from the above results that even if the content of HM781-36B included in the pharmaceutical preparation is increased, the properties of the tablet will not be affected, and the fluidity and compressibility of the granules are acceptable. Experimental example 3: Evaluation of crushability of Examples 1 to 5 and Comparative Examples 1 to 4

For the 65 tablets according to the above-mentioned Examples 1 to 5 and Comparative Examples 1 to 4, the pulverability was measured with a pulverization 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) Crushability (%) 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 6,6546.6 0.10 Example 5 6526.9 6,523.6 0.05 Comparative example 1 6541.1 6533.3 0.12 Comparative example 2 6,527.4 6513.7 0.21 Comparative example 3 6614.8 6608.2 0.10 Comparative example 4 6435.8 6383.0 0.82

According to Table 6 above, all tablets according to Examples 1 to 5 and Comparative Examples 1 to 4 showed a pulverability of 1% or less, but after using a diluent of mannitol, microcrystalline cellulose or a mixture thereof In the case of mixing (Examples 1 to 5 and Comparative Examples 1 to 3), it can be confirmed that more excellent pulverization properties are exhibited. Experimental example 4: Quality deviation test of Examples 1 to 5 and Comparative Examples 1 to 4

The mass deviation was measured for 10 tablets according to Examples 1 to 5 and Comparative Examples 1 to 4, and the results are shown in Table 7 below. [Table 7] Average mass (mg) Average quality deviation (%) 5% or higher quality deviation (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

According to Table 7 above, in the case of using a mixture of mannitol and microcrystalline cellulose in a weight ratio of 1:1 to 2:1 as the diluent (Examples 1 to 5), it can be confirmed that tablets with uniform quality can be obtained . Experimental Example 5: Evaluation of the dissolution of Examples 6 to 9 and Comparative Example 9

The following dissolution conditions and analysis methods were used to evaluate the solubility of the tablets of Examples 6 to 9 and Comparative Example 9 above. The evaluation results are shown in Table 8 below. ＜Dissolution conditions＞

Dissolving solution: Take 2 tablets and test in 900 mL buffer solution with pH 1.2.

-Buffer solution, pH 1.2: Dissolve 7.0 mL HCl and water in 2.0 g NaCl to make 1000 mL.

Device: USP <711> Instrument 2 Method (Paddle Method) in the Solubility Project Dissolution temperature: 37 ± 0.5 °C Rotation speed: 50 ± 2 rpm <HPLC analysis conditions> Detector: UV absorption spectrophotometer (measurement wavelength: 254 nm) column: Inertsil ODS-2, 4.6 x 150 nm, 5 μm or equivalent column mobile phase: acetonitrile: phosphate buffer solution (pH 2.5) = 40: 60 (phosphate buffer solution, pH 2.5: 7.0 g of NaClO ₄ and 1.7 g of KH ₂ PO _{4 were} dissolved in 1 L of pure water, and the pH was adjusted to 2.5 with phosphoric acid.) Analysis time: 10 minutes Column temperature: 30 °C Flow rate: 1.0 mL/min Injection volume: 50 μL [Table 8] Time (min) 0 5 10 15 30 45 Comparative example 9 average - 73.5 81.6 88.9 92.1 94.2 Standard deviation (SD) - 3.0 1.8 1.0 0.7 0.7 Example 6 average - 72.1 80.3 84.7 88.4 91.2 Standard deviation (SD) - 0.3 1.4 1.6 1.9 2.2 Example 7 average - 71.7 76.8 86.5 91.5 93.7 Standard deviation (SD) - 0.2 0.9 1.7 1.6 1.4 Example 8 average - 70.9 78.6 84.6 90.8 92.6 Standard deviation (SD) - 1.2 0.9 2.2 2.0 3.6 Example 9 average - 72.6 79.4 84.6 89.9 93.5 Standard deviation (SD) - 6.0 3.1 1.8 2.9 3.1

According to the results of Table 8 above, when observing the dissolution mode of the tablets of Examples 6 to 9 and Comparative Example 9 at pH 1.2, it can be confirmed that even though the content of HM781-36B of Examples 6 to 9 is higher than that of Comparative Example The content of 9, dissolution mode and final dissolution rate are still not affected. Experimental Example 6: Stability Test of Packaged Tablets (Example 1 and Comparative Examples 7 and 8)

[表9]   雜質IV的量(%) 初始 1週加速 2週加速 4週加速 實施例1 0.071 0.132 0.170 0.172 比較例7 0.091 0.411 0.681 0.921 比較例8 0.121 0.342 0.610 0.821 The tablets of Example 1 and Comparative Examples 7 and 8 were packaged with Formpack ^® Dessiflex Blister (how to obtain: amcor), and placed at 40 °C/75% RH accelerated conditions for 1, 2 and 4 weeks, and then subjected to liquid phase The chromatographic measurement has the impurity IV of the following chemical formula 2 (see the following analysis conditions), and the results are shown in Figure 1 and Table 9. <Analysis conditions> Detector: UV absorption spectrophotometer (measurement wavelength: 254 nm) Column: XTerra RP18, 4.6 mm x 150 mm, 3.5 μm or equivalent column Dynamic phase: A-Acetonitrile: phosphate buffer solution (pH 2.5) = 40: 60 B-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 μL [Chemical formula 2 ]

[Table 9] The amount of impurity IV (%) initial 1 week acceleration 2 weeks acceleration 4 weeks 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

According to Fig. 1 and Table 9, in the case of using magnesium stearate glidant in an amount of 2% by weight or more (Comparative Example 7), it was determined that the amount of impurity IV was changed with the storage time under accelerated conditions. The proportion is steadily increasing. In addition, in the case where another metal salt glidant sodium stearyl fumarate was used in an amount of 1% by weight (Comparative Example 8), the amount of impurity IV was measured as the amount of impurity IV increased with the storage time under accelerated conditions. The proportion is steadily increasing. Specifically, when placed for 4 weeks under accelerated conditions of 40 °C/75% RH, it was determined that compared with the tablets of Example 1, the amount of impurity IV in the tablets of Comparative Examples 7 and 8 increased respectively. 4 times or more.

It is surprisingly observed from the above results that the type and content of glidants included in pharmaceutical preparations affect the amount of impurity IV. Experimental Example 7: Stability Test of Packaged Tablets (Examples 6 to 9 and Comparative Examples 9 and 11)

The stability of the tablets of Examples 6 to 9 and Comparative Example 9 described above was evaluated. In addition, HM781-36B itself was used as Comparative Example 11 to evaluate the stability.

Specifically, the tablets of Examples 6 to 9 and Comparative Example 9 described above were packaged with Formpack ^® Dessiflex Blister (how to obtain: amcor), and HM781-36B of Comparative Example 11 was packaged in an HDPE bottle, and then the same Store at 60 °C under severe conditions for 1, 2 and 4 weeks. According to the analysis conditions of Experimental Example 6, the stability evaluation of the samples stored in the above period was performed. The stability evaluation is to measure the impurity IV of the following chemical formula 2, and the results are shown in Fig. 2 and Table 10. [Table 10] The amount of impurity IV (%) initial 1 week acceleration 2 weeks acceleration 4 weeks 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

According to Fig. 2 and Table 10, since Comparative Example 11 only contained HM781-36B, it showed a very stable result under severe conditions for 4 weeks.

However, it was determined that the tablets of Examples 6 to 9 and Comparative Example 9 prepared by mixing HM781-36B with pharmaceutically acceptable additives produced impurities with the above Chemical Formula 2.

Specifically, Comparative Example 9 included HM781-36B in an amount of less than 2.0% by weight based on the total weight of the pharmaceutical preparation, and it was determined that even when a stable packaging material is used for packaging, the amount of impurities with the above chemical formula 2 is also Will increase significantly over time. In other words, even if the stability is slightly increased from the packaging material, it is shown that the stability of HM781-36B itself is not improved.

However, Examples 6 to 9—including HM781-36B in an amount of 5% by weight or more and less than 20% by weight based on the total weight of the pharmaceutical preparation—showed that the generation amount of impurities with the above Chemical Formula 2 did not increase significantly.

Specifically, when placed under severe conditions of 60°C for 4 weeks, it was determined that the amount of impurity IV in the tablets of Comparative Example 9 was increased by 3.5 times or that of the tablets of Comparative Examples 6 to 9, respectively. More times.

It is surprisingly observed from the above results that the content of HM781-36B contained in the pharmaceutical preparations affects the amount of impurity IV.

Experimental example 8: According to Example 1 For lozenges Stability test of various packaging materials.

The tablets according to Example 1 are packaged in Al-Al blister, Al-PO+CaO-Al blister or HDPE bottle (5 different packages, each with a polypropylene cap, including 0.5, 2.0, 3.0, 4.0 Or 5.0 g silicone and polypropylene cover), of which TEKNILID® 1207 (Tekniplex) is used for Al-Al blister, Formpack® Dessiflex Blister (Amcor) is used for Al-PO+CaO-Al blister, BTH-250 (Ewha Engineering ) Is used in HDPE bottles. Polypropylene caps (including silicone) are also from Ewha Engineering. The proprietary names are 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). The packaged products were placed under accelerated conditions of 40 °C/75% RH for 1, 2 and 4 weeks, and then the impurity IV with the above chemical formula 2 was measured by liquid chromatography (see the analysis conditions of Experimental Example 6), and the results showed于图3和表11。 In Figure 3 and Table 11. [Table 11] The amount of impurity IV (%) initial 1 week acceleration 2 weeks acceleration 4 weeks acceleration Al-Al 0.071 0.229 0.285 0.391 Al-PO+CaO-Al 0.071 0.132 0.170 0.172 HDPE/silicon dioxide 0.5g 0.071 0.187 0.248 0.325 HDPE/silicon dioxide 2.0g 0.071 0.142 0.181 0.207 HDPE/silicon dioxide 3.0g 0.071 0.138 0.180 0.191 HDPE/silicon dioxide 4.0g 0.071 0.131 0.176 0.181 HDPE/Silicon Dioxide 5.0g 0.071 0.135 0.172 0.177

According to Figure 3 and Table 11, in the case of using Al-PO+CaO-Al blister including moisture absorbent CaO instead of Al-Al blister as the packaging material, it can be confirmed that it is proportional to the time placed under accelerated conditions The increase in impurity IV is reduced. In particular, in the packaging material of Al-PO+CaO-Al blister shells, after 2 weeks of acceleration, the increase in impurity IV was significantly reduced. In addition, in the case of using an HDPE bottle, it can be confirmed that as the amount of moisture absorbent silicone in the cap increases, the increase in impurity IV in proportion to the time it is left under accelerated conditions decreases. In particular, in packaging materials using HDPE bottles with caps including 2 g or more of silicone, the increase in impurity IV is significantly reduced over time. Experimental Example 9: Dissolution test after 4 weeks under accelerated conditions

Under the dissolution conditions and analysis conditions of Experimental Example 5, the dissolution rates of the tablets left for 4 weeks under accelerated conditions according to Experimental Example 8 were measured, and the results are shown in Table 12. [Table 12] Time (min) 0 5 10 15 30 45 60 Al-Al average - 72.13 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 - 76.76 82.28 84.87 87.15 87.58 88.09 Standard deviation (SD) - 2.5 2.2 1.1 0.8 0.5 0.8 HDPE/silicon dioxide 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/silicon dioxide 2.0 g average - 72.84 82.34 85.71 86.96 87.99 87.97 Standard deviation (SD) - 1.9 1.8 1.9 0.9 0.9 0.7 HDPE/silicon dioxide 3.0 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/silicon dioxide 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 1.1 HDPE/silicon dioxide 5.0 g average - 50.13 67.20 77.23 82.04 85.67 86.13 Standard deviation (SD) - 8.0 3.7 2.8 1.7 1.4 1.3

According to Table 12 above, in the case of using an HDPE packaging material with a lid including 5.0 g of silicone, it can be confirmed that the tablet placed for 4 weeks under accelerated conditions has a slow initial disintegration and a lower dissolution rate. However, after a period of about 60 minutes, there was little difference in the solubility of the tablets.

It should be understood that all simple changes 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 by the scope of the attached patent application.

FIG. 1 is a graph showing the amount of impurity IV produced according to Experimental Example 6. FIG. The tablets of Example 1 and Comparative Examples 7 and 8 were packaged with Formpack ^® Dessiflex Blister (how to obtain: amcor), and placed at 40 °C/75% RH accelerated conditions for 1, 2 and 4 weeks, and then subjected to liquid phase Chromatography measurement has impurity IV of formula 2.

FIG. 2 is a graph showing the amount of impurity IV produced according to Experimental Example 7. FIG. The tablets of Examples 6 to 9 and Comparative Example 9 above were packaged with Formpack ^® Dessiflex Blister (how to obtain: amcor), and HM781-36B of Comparative Example 11 was packaged in an HDPE bottle, which was then placed under severe conditions. Store at 60 °C for 1, 2 and 4 weeks. According to the analysis conditions of Experimental Example 6, the impurity IV of Chemical Formula 2 was measured on the samples stored during the above period.

FIG. 3 is a graph showing the amount of impurity IV produced according to Experimental Example 8. FIG. Each lozenge according to Example 1 is packaged in Al-Al blister, Al-PO+CaO-Al blister or HDPE bottle (5 different packages, each equipped with 0.5, 2.0, 3.0, 4.0 or 5.0 g Silicone polypropylene cover and polypropylene cover), of which TEKNILID ^® 1207 (Tekniplex) is used for Al-Al blister, Formpack ^® Dessiflex Blister (Amcor) is used for Al-PO+CaO-Al blister, BTH-250 (Ewha Engineering) is used for HDPE bottles, polypropylene caps (including silicone) are also from Ewha Engineering, and their proprietary names are 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). The packaged products were placed under accelerated conditions of 40 °C/75% RH for 1, 2 and 4 weeks, and then the impurity IV of chemical formula 2 was measured according to the analysis conditions of Experimental Example 6.

Claims (18)

A pharmaceutical preparation comprising particles containing the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof and a diluent for mixing with the particles: [Chemical Formula 1]

. The pharmaceutical preparation of claim 1, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is included in an amount of 2.0% by weight or more and less than 20% by weight based on the total weight of the pharmaceutical preparation The pharmaceutical preparations. The pharmaceutical preparation of claim 1, wherein 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. The pharmaceutical preparation according to claim 1, wherein the diluent is mannitol, microcrystalline cellulose or a mixture thereof. The pharmaceutical preparation according to claim 4, wherein the diluent is a mixture of mannitol and microcrystalline cellulose, and the weight ratio is 0.50:1 to 3.2:1. The pharmaceutical preparation of claim 1, wherein the pharmaceutical preparation further comprises a glidant. The pharmaceutical preparation of claim 6, wherein the glidant is selected from the group consisting of calcium stearate, magnesium stearate, sodium lauryl sulfate, zinc stearate, sodium benzoate, and mixtures thereof. The pharmaceutical preparation of claim 6, wherein the glidant 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. A method for preparing the pharmaceutical preparation according to claim 1, the method comprising the following steps: 1) Mixing the compound of Chemical Formula 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable additives and then granulating to prepare granules; 2) Mix the granules with pharmaceutically acceptable additives and then add a diluent to prepare mixed granules; and 3) Prepare the mixed particles. A pharmaceutical product in which the pharmaceutical preparation according to claim 1 is packaged in a packaging material. Such as the pharmaceutical product of claim 10, wherein the material of the packaging material is selected from the group consisting of glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene Vinyl chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyolefin (PO), aluminum (Al) and combinations thereof, the shape of the packaging material Selected from the group consisting of: bottle, blister and pouch. The pharmaceutical product of claim 10, wherein the packaging material contains a moisture absorbent. Such as the pharmaceutical product of claim 12, wherein the hygroscopic agent is calcium oxide or silica gel. The pharmaceutical product of claim 13, wherein the silicone gel is included in the packaging material in an amount of 2 to 5 g based on a 125 ml HDPE bottle. A method for improving the stability of a pharmaceutical preparation by reducing the formation of impurities, which comprises preparing the pharmaceutical preparation according to claim 1. The method comprises the following steps: 1) Mixing the compound of Chemical Formula 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable additives and then granulating to prepare granules; 2) Mix the granules with pharmaceutically acceptable additives and then add a diluent to prepare mixed granules, wherein the diluent is a mixture of mannitol and microcrystalline cellulose in a weight ratio of 0.50:1 to 3.2:1; and 3) Prepare the mixed particles. A method of treating cancer in an individual, comprising administering a therapeutically effective amount of the pharmaceutical preparation according to claim 1, wherein the individual has been tested to have one or more EGFR or HER2 activating mutations. The method of claim 16, wherein the individual has been determined to have one or more HER2 activating mutations 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. The method of claim 16, wherein the individual 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.

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