Pharmaceutical composition comprising EGFR inhibitor

Abstract

Provided are a pharmaceutical composition comprising an EGFR inhibitor compound hereinafter referred to as FWD1509 or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation thereof, and a method for preparing same.

Description

Pharmaceutical compositions comprising EGFR inhibitors Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising an EGFR inhibitor compound FWD1509 or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active ingredient"). Background Art

[0002] Epidermal growth factor receptor (EGFR) mutations are common in non-small cell lung cancer (NSCLC). The EGFR mutation rate in Chinese NSCLC patients is approximately 50.3%, more than half of the patients. The human epidermal growth factor receptor (EGFR) mutation gene is the most common driver gene in Asian NSCLC patients, mainly manifested as two sensitive mutations: exon 19 deletion and exon 21 mutation. EGFR exon 20 insertion mutations account for 5% to 12% of EGFR gene mutations. [2] The incidence of EGFR exon 20 insertion mutations in Chinese patients with EGFR-mutant NSCLC is lower than that in Western populations (4.8%-5.1% vs 9%-12%).

[0003] EGFR exon 20 insertion mutations have numerous subtypes and strong heterogeneity due to the different locations and lengths of the inserted fragments. Currently, more than 100 mutation subtypes have been found worldwide. Most EGFR exon 20 insertion mutations will change the conformation of the C helix, causing permanent activation of the EGFR protein; on the other hand, the active conformation of the C helix and the phosphate binding loop simultaneously occupy the binding pocket of 1-3 generation EGFR-TKI drugs. This steric hindrance effect prevents 1-3 generation EGFR-TKIs from entering this active conformation domain to exert their therapeutic effects, thereby reducing their affinity for 1-3 generation EGFR-TKIs. Therefore, the vast majority of EGFR exon 20 insertion mutation NSCLCs are insensitive to 1-3 generation EGFR-TKIs. [3] The conformation of the EGFR exon 20 insertion mutant is very similar to that of wild-type EGFR, with similar binding modes and apparent affinities. This similar structure results in low drug selectivity, a narrow safe therapeutic window, and difficulty balancing the drug's clinical efficacy and side effects. Therefore, the development of new drugs targeting the EGFR exon 20 insertion mutation is extremely difficult.

[0004] In this regard, CN116075504A [1]Disclosed is an active ingredient that selectively and potently inhibits some mutant forms of the epidermal growth factor receptor (EGFR), and provides relevant experimental data. The active ingredient has good activity against common EGFR mutations (L858R, exon 19 deletion) and T790M drug-resistant mutations. It also has excellent drug activity against EGFR exon 20 insertion mutations and has good selectivity for wild-type EGFR. In addition, the active ingredient has good inhibitory activity against HER2 exon 20 insertion mutations and HER4. Therefore, the active ingredient can be used for targeted treatment of patients with non-small cell lung cancer (NSCLC) carrying EGFR exon 20 insertion mutations or HER2 exon 20 insertion mutations, thereby addressing unmet clinical needs in clinical treatment.

[0005] To this end, the present invention has developed a convenient and easy-to-use preparation, preferably an oral preparation, which is used to provide a treatment plan for patients with EGFR mutations. Specifically, the present invention relates to a novel pharmaceutical composition comprising the above-mentioned FWD1509 (hereinafter also referred to as the active ingredient). The preparation of the pharmaceutical composition of the present invention can be a tablet or capsule. The pharmaceutical composition and / or preparation provided by the present invention exhibits good solubility and bioavailability, and the solubility is less affected by factors such as light, high temperature, and high humidity, and can be better used in the aforementioned clinical treatment. Summary of the Invention

[0006] The present invention relates to a pharmaceutical composition comprising:

[0007] a) from 2 to 60 parts of an active ingredient, which is compound FWD1509 or a pharmaceutically acceptable salt thereof;

[0008] b) from 39 to 92 parts of one or more diluents;

[0009] c) from 0 to 10 parts of one or more disintegrants;

[0010] d) from 0 to 5 parts of one or more solubilizing agents;

[0011] e) from 0 to 5 parts of one or more glidants;

[0012] f) from 0.5 to 8 parts of one or more lubricants which is sodium stearyl fumarate; and

[0013] g) Optional binder.

[0014] All parts are calculated by weight. In one embodiment, the pharmaceutical composition consists of the above ingredients.

[0015] In one embodiment, the active ingredient is the mesylate, hydrochloride, and maleate salt of FWD1509, preferably the mesylate salt. In one embodiment, the active ingredient is present in an amount of 2 to 60 wt%, 5 to 55 wt%, 10 to 50 wt%, 15 to 40 wt%, or 20 to 30 wt%, based on the total weight of the pharmaceutical composition, inclusive or not.

[0016] In one embodiment, the diluent in the pharmaceutical composition of the present application is selected from one or more combinations of the following substances: starch, lactose, anhydrous lactose, fructose, xylitol, mannitol, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch and lactose-cellulose. In a preferred embodiment, the diluent in the pharmaceutical composition of the present application can be selected from lactose, microcrystalline cellulose, mannitol and combinations thereof. In one embodiment, the content of the diluent in the pharmaceutical composition of the present application is 39 to 92wt%, 50 to 85wt%, 55 to 75wt%, 60 to 70wt%, 63 to 68wt% based on the total weight of the pharmaceutical composition, which may or may not contain endpoint values.

[0017] In one embodiment, the disintegrant in the pharmaceutical composition of the present application is selected from a combination of one or more of the following substances: starch, sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone (cross-linked polyvinylpyrrolidone), hydroxypropyl methylcellulose and other pharmaceutical disintegrants. In a preferred embodiment, the disintegrant in the pharmaceutical composition of the present application can be selected from sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and a combination thereof. In one embodiment, the content of the disintegrant in the pharmaceutical composition of the present application is 0 to 10wt%, 1 to 9wt%, 2 to 8.5wt%, 3 to 8wt% based on the total weight of the pharmaceutical composition, and may or may not contain endpoint values.

[0018] In one embodiment, the binder in the pharmaceutical composition of the present application is selected from one or more combinations of the following substances: pharmaceutical binders such as polyvinylpyrrolidone, starch slurry, dextrin, glucose and its syrup, sucrose and its syrup, fructose and its syrup, sorbitol, hydroxypropyl methylcellulose, etc. In one embodiment, the binder in the pharmaceutical composition of the present application may be hydroxypropyl methylcellulose. In one embodiment, the pharmaceutical composition of the present application may not contain a binder. In one embodiment, the content of the binder in the pharmaceutical composition of the present application is 0 to 5wt%, 1 to 3wt%, 1.5 to 2wt% by weight of the total weight of the pharmaceutical composition, and may or may not contain endpoint values.

[0019] In one embodiment, the glidant in the pharmaceutical composition of the present application is selected from a combination of one or more of the following substances: colloidal silicon dioxide, talc. In one embodiment, the pharmaceutical composition of the present application may not contain a glidant. In one embodiment, the content of the glidant in the pharmaceutical composition of the present application is 0 to 5wt%, 0.25 to 3wt%, or 0.5 to 2wt%, based on the total weight of the pharmaceutical composition, which may or may not include the endpoint values.

[0020] In one embodiment, the solubilizer in the pharmaceutical composition of the present application is selected from a combination of one or more of the following substances: pharmaceutical solubilizers such as poloxamer, sodium lauryl sulfate, polysorbate, cyclodextrin, and hydrogenated castor oil. In one embodiment, the glidant in the pharmaceutical composition of the present application may be poloxamer. In one embodiment, the pharmaceutical composition of the present application may not contain a solubilizer. In one embodiment, the content of the solubilizer in the pharmaceutical composition of the present application is 0 to 5wt%, 1 to 4.5wt%, or 2 to 4wt% based on the total weight of the pharmaceutical composition, which may or may not contain endpoint values.

[0021] The lubricant in the pharmaceutical composition of the present application is sodium stearyl fumarate. In one embodiment, the content of the lubricant in the pharmaceutical composition of the present application is 0.5 to 8 wt %, 0.8 to 5 wt %, 1.0 to 4.5 wt %, 1.5 to 4 wt %, 2.0 to 3.5 wt %, based on the total weight of the pharmaceutical composition, which may or may not include the endpoint values. DETAILED DESCRIPTION

[0022] Throughout this specification, the terms 'wt%' or 'weight percent' have their ordinary meaning as used in the art. Thus, 'wt%' refers to the proportion of component X within component Y, calculated in each case based on the weight of component X and component Y (as distinct from other physical parameters, such as volume or number of moles present). By way of example, if there are 2g of component X in 20g of component Y, then component X constitutes 10wt% of component Y. As described, describing the components of a pharmaceutical composition in terms of 'parts', where 'all parts are by weight,' such language simply defines the relative ratios of these components, where the ratios are defined in terms of relative weight (as distinct from other physical parameters, such as volume or number of moles). For example, if there is 1g of component X and 4g of component Z in a mixture, and the sum of the parts of component X and component Z is defined as equal to 100, then in this example, there are 20 parts of component X and 80 parts of component Z in the mixture.

[0023] The chemical name of compound FWD1509 is N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide.

[0024] In one embodiment, the pharmaceutical composition of the present application can be prepared into a formulation. In one embodiment, the pharmaceutical composition of the present application can be prepared into tablets or capsules by a wet formulation process or a wet formulation process. Preparation methods 1-3 used in the examples of the present application are as follows:

[0025] Preparation method 1 of the present invention: (wet preparation process)

[0026] The active ingredient and a suitable diluent and / or disintegrant and / or solubilizer are mixed in a certain order and proportion, wet granulated, dried, and granulated to form a whole. A glidant and / or lubricant is added for total mixing, and the resulting granules are compressed into tablets or filled into capsules.

[0027] Preparation method 2 of the present invention: (dry process)

[0028] The active ingredient is mixed with a suitable diluent and / or disintegrant and / or solubilizer in a certain order and proportion, a glidant and / or lubricant is added for total mixing, and the resulting mixture is compressed into tablets or filled into capsules.

[0029] Preparation method 3 of the present invention: (dry granulation process)

[0030] The active ingredient is mixed with a suitable diluent and / or disintegrant and / or solubilizer in a certain order and proportion, followed by dry granulation, and a glidant and / or lubricant is added for total mixing. The resulting granules are then compressed into tablets or filled into capsules.

[0031] For tablets, coating can be further applied to protect the core from moisture ingress and light degradation. Colorants such as titanium dioxide, ferric oxide, iron oxide, or aluminum tartrate can also be used to enhance patient recognition.

[0032] The coating method of the present invention comprises preparing an appropriate amount of a gastric-soluble film coating premix into a coating solution, sieving the solution, and spray coating the solution to achieve the desired coating weight gain. The gastric-soluble film coating premix comprises Opadry II coating powder or Opadry I coating powder.

[0033] During the preparation of the FWD1509 drug formulation, the inventors unexpectedly discovered that the use of different lubricants significantly impacted the dissolution and bioavailability of the resulting formulations. In terms of dissolution, sodium stearyl fumarate significantly improved dissolution compared to the commonly used magnesium stearate, reaching or approaching 100% dissolution at 30 minutes. This dissolution was also less affected by factors such as light, high temperature, and high humidity. In terms of bioavailability, oral bioavailability studies in beagle dogs showed that formulations using magnesium stearate (1.5%, 2.0%, 2.5%, and 3.5%) as a lubricant achieved bioavailability of approximately 39% to 46%. Under the same conditions, formulations using sodium stearyl fumarate (1.5%, 2.0%, 2.5%, and 3.5%) as a lubricant achieved bioavailability of approximately 65% ​​to 67%. The sodium stearyl fumarate formulation exhibited significantly improved bioavailability compared to the magnesium stearate formulation. The mechanism of this difference is unclear, but it may be related to the interaction between the lubricant and the active ingredient.

[0034] Example

[0035] The following provides examples of the present invention. It should be understood that the examples are merely illustrative and do not constitute any form of limitation on the scope of protection of this patent application.

[0036] According to the preparation method below, the components in the proportions (by weight) described in Table 1 are prepared into preparations. The lactose used in each embodiment and comparative example is sourced from Megler GmbH & Co. KG, Germany; silicified microcrystalline cellulose and sodium stearyl fumarate are sourced from Reidenmeier & Sons GmbH, Germany; microcrystalline cellulose is sourced from DuPont (Shanghai) Industrial Co., Ltd.; low-substituted hydroxypropyl cellulose and hydroxypropyl methylcellulose are sourced from Shin-Etsu Chemical Industry Co., Ltd.; mannitol and magnesium stearate are sourced from Roquette, France; sodium starch glycolate is sourced from Yongri Chemical Industry Co., Ltd.; cross-linked polyvinylpyrrolidone is sourced from Ashland Chemical (Nanjing) Co., Ltd.; poloxamer is sourced from Merck Chemical Technology (Shanghai) Co., Ltd.; colloidal silicon dioxide is sourced from Evonik Specialty Chemicals (Shanghai) Co., Ltd.; talc is sourced from Guilin Guiguang Talc Development Co., Ltd. The beagle used in the present invention is provided by Beijing Mas Biotechnology Co., Ltd.

[0037] Table 1

[0038] Comparative Example 1

[0039] Using the preparation method 2 described in the present invention, 60 parts of FWD1509 mesylate and 39 parts of silicified microcrystalline cellulose were mixed evenly, and then 1 part of magnesium stearate was added for total mixing. The mixture was then filled into capsules.

[0040] Comparative Example 2

[0041] Using the preparation method 1 of the present invention, FWD1509 mesylate was mixed with mannitol, microcrystalline cellulose, and hypromellose for 15 minutes, and then water was added for wet granulation. The wet granules were sieved and then dried with hot air. After the granules were dried, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were added to the granules and mixed for 5 minutes. The mixture was then tableted.

[0042] Comparative Example 3

[0043] Using the preparation method 2 of the present invention, FWD1509 mesylate was mixed with the excipients described in Table 1 (except lubricant and glidant) for 30 minutes, and then magnesium stearate was added to the mixture and mixed for another 5 minutes. The mixture was then tableted.

[0044] Comparative Example 4

[0045] Using Preparation Method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except lubricant) for 30 minutes, magnesium stearate was then added to the mixture and mixed for another 5 minutes, and the mixture was tableted.

[0046] Comparative Example 5

[0047] Using Preparation Method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except lubricant) for 30 minutes, magnesium stearate was then added to the mixture and mixed for another 5 minutes, and the mixture was tableted.

[0048] Comparative Example 6

[0049] Using Preparation Method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except lubricant) for 30 minutes, magnesium stearate was then added to the mixture and mixed for another 5 minutes, and the mixture was tableted.

[0050] Example 1

[0051] Using the preparation method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except lubricant and glidant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for another 5 minutes. The mixture was then tableted.

[0052] Example 2

[0053] Using the preparation method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except the lubricant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for another 10 minutes. The mixture was then tableted.

[0054] Example 3

[0055] Using the preparation method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except the lubricant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for another 10 minutes. The mixture was then tableted.

[0056] Example 4

[0057] Using the preparation method 2 of the present invention, FWD1509 mesylate was mixed with the excipients listed in Table 1 (except the lubricant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for another 10 minutes. The mixture was then tableted.

[0058] Example 5

[0059] Using the preparation method 2 described in the present invention, FWD1509 mesylate was mixed with the excipients described in Table 1 (except the lubricant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for another 10 minutes. The mixture was then compressed into tablets or filled into capsules.

[0060] Example 6

[0061] Using Preparation Method 3 of the present invention, FWD1509 mesylate was mixed with the excipients described in Table 1 (excluding the lubricant) for 30 minutes, the mixture was dry-granulated, sodium stearyl fumarate was added to the mixture and mixing was continued for 5 minutes, and the mixture was tableted or filled into capsules.

[0062] Example 7

[0063] Using Preparation Method 2 of the present invention, FWD1509 mesylate was mixed with the excipients described in Table 1 (excluding the lubricant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for a further 10 minutes. The mixture was then compressed into tablets or filled into capsules.

[0064] Example 8

[0065] Using the preparation method 2 described in the present invention, FWD1509 mesylate was mixed with the excipients described in Table 1 (except the lubricant) for 30 minutes, and then sodium stearyl fumarate was added to the mixture and mixed for another 10 minutes. The mixture was then compressed into tablets or filled into capsules.

[0066] Test Example 1: Determination of sample stability

[0067] Taking the tablets prepared in Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, Comparative Example 6, Example 1, Example 2, Example 3, Example 4, Example 5 and Example 6 as examples, the changes in dissolution and content of this product after being placed at a high temperature of 60°C for 10 days were studied. The detailed results are shown in the following table. Among them, Comparative Example 2 adopts a wet granulation process, and the dissolution of the pharmaceutical composition prepared therefrom tends to decrease. Among them, the dosage of magnesium stearate in Comparative Examples 3 to 6 is different, which has a certain effect on the dissolution of the product. In Examples 1 to 6, the dosage of sodium stearyl fumarate is different, which has no obvious effect on the dissolution of the product.

[0068] Table 2

[0069] Test Example 2: Dissolution Determination

[0070] The solid preparations prepared above were subjected to dissolution testing. Dissolution was measured according to the following test conditions: dissolution medium: 900 ml of 0.01 N hydrochloric acid, dissolution conditions: 37°C, 50 rpm, and dissolution was measured at 280 nm using an ultraviolet spectrophotometer (UV). The data for each example are shown in Table 3 below.

[0071] Table 3

[0072] Test Example 3: Drug Absorption Test

[0073] Intravenous (IV) Injection: Three healthy beagle dogs weighing approximately 10 kg were intravenously administered the mesylate salt of compound FWD1509 (0.5 mg / kg). Blood samples were collected before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours after administration. The concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). Drug concentration-time curves were obtained, and the main pharmacokinetic parameters are shown in Table 4 below:

[0074] Table 4

[0075] Oral Administration (PO): Three healthy beagle dogs weighing approximately 10 kg were orally administered 2 mg / kg of the formulations obtained in Comparative Examples 3-6 and Examples 1-4. Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours after administration. Blood samples were analyzed using validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). Drug concentration-time curves were obtained, and the main pharmacokinetic parameters are shown in Table 5 below:

[0076] Table 5

[0077] Test Example 4: Study on factors affecting dissolution

[0078] Taking the tablets prepared in Example 2 (white film-coated tablets, appearing off-white after removing the coating) as an example, the stability of the formulation samples obtained by this formulation process under high temperature, high humidity, and light was studied. The product was exposed to a cool white fluorescent lamp and a near-ultraviolet lamp at an illumination of 4500 lx ± 500 lx for 10 days, placed at a high temperature of 60°C for 30 days, or placed at a relative humidity of 92.5% for 30 days. After that, the dissolution test was performed according to the method of Test Example 2. The results showed that there was no significant change in the dissolution rate. The detailed results are shown in Table 6 below. This shows that the dissolution rate of the formulation of the present invention is less affected by factors such as light, high temperature, and high humidity.

[0079] Table 6

[0080] References

[0081] [1] Chinese patent application CN116075504A.

[0082] [2]Russo A, Franchina T, Ricciardi G, et al.Heterogeneous Responses to Epidermal Growth Factor Receptor(EGFR)Tyrosine Kinase Inhibitors(TKIs) in Patients with Uncommon EGFR Mutations:New Insights and Future Perspectives in this Complex Clinical Scenario[J].Int J Mol Sci, 2019, 20(6):1431.

[0083] [3] Zhu Xiaoying, Huang Jian. Current status of treatment for non-small cell lung cancer with EGFR exon 20 insertion mutation[J]. Medical Review, 2022, 28(14): 2801-2807.

Claims

1. A pharmaceutical composition comprising: a) 2 to 60 wt% of active ingredient based on the total weight of the pharmaceutical composition; b) 39 to 92 wt % of one or more diluents based on the total weight of the pharmaceutical composition; c) 0 to 10 wt % of one or more disintegrants based on the total weight of the pharmaceutical composition; d) 0 to 5 wt % of one or more solubilizing agents based on the total weight of the pharmaceutical composition; e) 0 to 5 wt % of one or more glidants based on the total weight of the pharmaceutical composition; f) 0.5 to 8 wt % of one or more lubricants based on the total weight of the pharmaceutical composition; and g) optionally a binder, The active ingredient is compound FWD1509 or a pharmaceutically acceptable salt thereof: The lubricant is sodium stearyl fumarate.

2. A pharmaceutical composition, which consists of the following components: a) 2 to 60 wt% of active ingredient based on the total weight of the pharmaceutical composition; b) 39 to 92 wt % of one or more diluents based on the total weight of the pharmaceutical composition; c) 0 to 10 wt % of one or more disintegrants based on the total weight of the pharmaceutical composition; d) 0 to 5 wt % of one or more solubilizing agents based on the total weight of the pharmaceutical composition; e) 0 to 5 wt % of one or more glidants based on the total weight of the pharmaceutical composition; f) 0.5 to 8 wt % of one or more lubricants based on the total weight of the pharmaceutical composition; and g) optionally a binder, The active ingredient is compound FWD1509 or a pharmaceutically acceptable salt thereof: The lubricant is sodium stearyl fumarate.

3. The pharmaceutical composition according to claim 1 or 2, wherein the active ingredient is the mesylate salt of FWD1509; and / or The content of the active ingredient is 5 to 55 wt%, 10 to 50 wt%, 15 to 40 wt% or 20 to 30 wt% based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the diluent is selected from one or more of the following: starch, lactose, anhydrous lactose, fructose, xylitol, mannitol, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch and lactose-cellulose; and / or The content of the diluent is 50 to 85 wt%, 55 to 75 wt%, 60 to 70 wt%, or 63 to 68 wt% based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the disintegrant is selected from one or more of the following: starch, sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl methylcellulose; and / or The content of the disintegrant is 0 to 10 wt %, 1 to 9 wt %, 2 to 8.5 wt %, or 3 to 8 wt % based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the binder is selected from one or more of the following: polyvinylpyrrolidone, starch slurry, dextrin, glucose and its syrup, sucrose and its syrup, fructose and its syrup, sorbitol, hydroxypropyl methylcellulose; and / or The binder may be present in an amount of 0 to 5 wt %, 1 to 3 wt %, or 1.5 to 2 wt % based on the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the glidant is selected from one or more of the following: colloidal silicon dioxide, talc; and / or The content of the glidant is 0.25 to 3 wt % or 0.5 to 2 wt % based on the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the solubilizing agent is selected from one or more of the following: poloxamer, sodium lauryl sulfate, polysorbate, cyclodextrin, hydrogenated castor oil; and / or The solubilizer is present in an amount of 1 to 4.5 wt % or 2 to 4 wt % based on the total weight of the pharmaceutical composition.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the content of the lubricant is 0.8 to 5 wt%, 1.0 to 4.5 wt%, 1.5 to 4 wt% or 2.0 to 3.5 wt% based on the total weight of the pharmaceutical composition.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition does not contain a binder; and / or the pharmaceutical composition does not contain a glidant; and / or the pharmaceutical composition does not contain a solubilizer.

11. A preparation comprising the pharmaceutical composition according to any one of claims 1 to 10.

12. The preparation according to claim 11, wherein the preparation is a tablet or a capsule.

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