Solid dispersion including heterocycle derivative, method for preparing same, and pharmaceutical composition including same

Abstract

The present invention relates to a solid dispersion including a heterocycle derivative, a method for preparing same, and a pharmaceutical composition including same. The solid dispersion including a heterocycle derivative comprises: as an active ingredient, a compound, which is a STAT3 inhibitor, represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and one polymer among hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and a methacrylic acid-methyl methacrylate copolymer.

Description

Description of the Invention

Title of invention

Technical Field

【Background Kishi STAT (signal transducer and activator of transcription) proteins are transcription factors that transmit signals from various extracellular cytokines and growth factors to the nucleus. Currently, seven isoforms of STAT proteins (i.e., STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) are known, which are generally composed of approximately 750 to 850 amino acids. In particular, STAT3 protein is known to play a key role in the IL-6 and EGF signaling systems. STAT3 protein has also been reported to be persistently activated in patients with solid tumors arising in the prostate, stomach, breast, lung, pancreas, kidney, uterus, ovary, head and neck, and in patients with hematological malignancies such as acute and chronic leukemia and multiple myeloma. Many studies have observed apoptosis induced by anti-STAT3 in various cancer cell lines, and therefore, STAT3 is considered a very promising novel anti-cancer target. In contrast, unlike STAT3, STAT1 has the same intracellular response pathways for cytokines and growth factors as STAT3, but has been reported to increase innate and adaptive immunity, thereby inhibiting cancer cell proliferation or inducing pro-apoptotic responses. A heterocyclic derivative compound as a STAT3 inhibitor that has an excellent effect of selectively inhibiting STAT3 compared to STAT1 and exhibits an excellent growth inhibitory effect on various cancer cells is disclosed in Korean Patent Publication No. 2017-0081708.

Prior Art Documents

Patent Document

Contents of the invention

Technical solution

Effect of the Invention

Brief description of drawings

[0633] 7.58 (s, 1H) , 7.52 (d, 2H, J=8.80Hz), 7.31 (s, 1H) , 7.27 (d, 2H, J=8.80Hz), 4.82 (m, 1H) , 4.45-4.51 (m, 1H) , 4.30-4.34 (m, 1H) , 3.16 (s, 3H) , 2.60- 2.64 (m, 1H), 2.29-2.39 (m, 1H); LC / MS ESI (+): 549 (M+l). Examples 1 to 8 - Preparation of solid dispersions A mixed solvent was prepared by using dichloromethane and methanol in a volume ratio of 8:2, and compound 1a and a polymer were dissolved in the prepared mixed solvent according to the components and compositions shown in Table 1 below, and then a solid dispersion was prepared using a spray dryer (Buchi B-290 Spray Dryer & B-295 Inert Loop Unit). Secondary drying was performed at a temperature of 40 °C and a vacuum of 300 mbar for approximately 20 hours. [Table 1] Evaluation 1 - Decision PXRD analysis was performed on each of the solid dispersions according to Examples 1 to 8, and the results are shown in FIGS. 1 and 2. FIGS. 1 and 2 are diagrams showing PXRD analysis graphs of the solid dispersions according to the embodiments of the present invention. Referring to FIGS. 1 and 2, it can be confirmed that both the solid dispersions and compound la according to the present invention are amorphous. Evaluation 2 - DSC DSC evaluation was performed on each of the solid dispersions according to Examples 1 to 8, and the Tg values ​​obtained thereby are shown in Table 2 below. [Table 2] Referring to Table 2, it can be confirmed that the solid dispersions according to the present invention all exhibit a single glass transition temperature, except for Example 5, in which the main glass transition occurred at 127°C and a slight thermal change occurred at 108°C. This means that the solid dispersions according to the present invention have high miscibility and excellent stability. Evaluation 3 - Solubility The solubility of the obtained solid dispersion was confirmed in FaSSIF pH 6.5 eluate using a Pion Micro Diss instrument. The measuring instrument and settings are shown in Table 3 below. [Table 3] After 12 hours, the concentration (ug / mL) of compound la dissolved in the FaSSIF pH 6.5 eluate is shown in Table 4, Figures 3 and 4 below. [Table 4] Referring to Table 4, Figures 3 and 4, it can be confirmed that the solubility of compound la is improved by at least 1.7 times or more and at most 4 times or more by the solid dispersion according to the present invention. Example 9 - Preparation of composition A solid dispersion was prepared using the same type of polymer, weight ratio of compound la and polymer, mixed solvent, and solid content as described in Example 4, and samples 1 to 3 were prepared as compositions containing the solid dispersion according to the components and contents of Table 5 below. In Table 5, the unit of each content is w / w%, and means the weight of each component with respect to 100 of the total weight of the tablet. [Table 5] Evaluation 4 - Stability (Recrystallization / Flexible Matter) For each of Samples 1 to 3, the flexible matter was measured by HPLC analysis after 2 and 4 weeks of storage under accelerated (40°C / 75% RH) and temperature harsh conditions (60°C) compared to the initial state, and XRPD analysis was performed to confirm whether the active ingredient recrystallized and the amorphous state was lost. The results of the flexible matter measurement are shown in Table 6 below. [Table 6] Referring to Table 6, it can be confirmed that practically no flexible substances were generated even under accelerated and harsh conditions. In addition, the XRPD analysis results also confirmed that the active ingredient did not recrystallize even after 2 weeks and 4 weeks and maintained its amorphous state. Example 10 - Preparation of tablets A solid dispersion was prepared using the same polymer type, weight ratio of compound la and polymer, mixed solvent, and solid content as described in Example 4, and tablets having the components and contents of Table 7 below were prepared using the same. In Table 7 below, the unit of each content is w / w%, which means the weight of each component with respect to 100 of the total tablet weight, and 50 w / w% of the solid dispersion means that the content of compound la is 200 mg among the total tablet weight of 800 mg. [Table 7] The procedure for manufacturing the tablets was as follows. (1) The unused mixture was sieved through an 850-μm sieve mesh and then put into a mixing container as follows. After stacking the materials layer by layer in a mixing container (drum blender), they were mixed for 15 minutes at 30 rpm. The order of adding each component as the unused mixture into the mixing container was as follows: Weighed and added 33% of the excipient (microcrystalline cellulose), weighed and added 50% of the solid dispersion, weighed and added 50% of the disintegrant in granules (sodium croscarmellose), weighed and added 33% of the excipient (microcrystalline cellulose), then weighed and added 50% of the solid dispersion, weighed and added 50% of the disintegrant in granules, and finally weighed and added 33% of the excipient (microcrystalline cellulose). (Here, "x% of the component in granules" means x% of the weight of the component contained in the granules when the total weight of the components in the granules shown in Table 7 is taken as 100%). (2) The lubricant in granules (sodium stearyl fumarate) was sieved through a 500-μm sieve and then put into the above mixing container, and then mixed for 3 minutes at 30 rpm, and tablets were manufactured by a dry granulation process. (3) After adding the post-mixing disintegrant (sodium croscarmellose), it was mixed for 6 minutes at 30 rpm, and then after adding the post-mixing lubricant (sodium stearyl fumarate), it was mixed for 3 minutes at 30 rpm. (4) Tablets were manufactured by tableting at 10 rpm with a target mass of 800 ± 5% and a hardness of 20 ± 5 kP using a rotary tablet press. (5) The tablets manufactured as above were coated with Opadry QX yellow (321A220055) to manufacture coated tablets. Evaluation 5 - Dissolution rate evaluation The dissolution rates of the tablets and coated tablets manufactured as above were evaluated, and the evaluation method was based on Table 8 below. The results are shown in Figure 5. [Table 8] Referring to Fig. 5, it can be confirmed that both the uncoated tablet and the coated tablet exhibit excellent dissolution rates. In particular, both the uncoated tablet and the coated tablet manufactured in this way exhibit substantially the same dissolution rate as the solid dispersion itself. Although the present invention has been described above with reference to preferred embodiments, those skilled in the art will understand that the present invention can be variously modified and changed within the spirit and scope of the present invention as set forth in the claims below.

Claims

24 【Scope of Claims】 【 Claim 11 A solid dispersion containing a heterocycle derivative, comprising a heterocycle derivative represented by the following chemical formula 1 as an effective ingredient, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and one polymer among hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and a methacrylic acid-methyl methacrylate copolymer: <화학식 1> In the above chemical formula 1, Ri is -S(=O)(=Ra)Rb, Ra is =0 or =NH, Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, ¬mino, or amino C1-6 alkyl, At least one of Ra or Rb is independently substituted with F, Br, Cl or I. R 2 and R3 are each independently F, Br, Cl or I. 【

2. A solid dispersion containing a heterocycle derivative, wherein the heterocycle derivative represented by chemical formula 1 in claim 1 is N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromen-7-boxamide. 【

3. In claim 1, the heterocycle derivative represented by chemical formula 1 is A solid dispersion containing a heterocycle derivative, which is one of (4S)-N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromen-7-carboxamide, (4R)-N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromen-7-boxamide, and a mixture thereof. 【

4. A solid dispersion containing a heterocycle derivative, wherein the heterocycle derivative represented by chemical formula 1, a stereoisomer thereof, or a chemically acceptable salt thereof is an amorphous substance. 【

5. In claim 1, A solid dispersion containing a heterocycle derivative, wherein the weight ratio of the heterocycle derivative represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to the polymer is 1:1 to 1:

10. 【

6. A solid dispersion containing a heterocycle derivative having an average particle size of 5 um to 15 um according to claim 1. 【

7. A method for producing a solid dispersion containing a heterocycle derivative, comprising: preparing a mixed solution containing a heterocycle derivative represented by the following chemical formula 1, a stereoisomer thereof, or a chemically acceptable salt thereof; and one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl cellulose, and a methacrylic acid-methyl methacrylate copolymer; and preparing a solid dispersion using the mixed solution: <화학식 1> In the above chemical formula 1, Ri is -S(=O)(=Ra)Rb, 27 Ra is =0 or =NH, Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl, At least one of Ra or Rb is independently substituted with F, Br, Cl or I. R 2 and R3 are each independently F, Br, Cl or I. 【

8. A method for producing a solid dispersion containing a heterocycle derivative, wherein the step of producing the solid dispersion in claim 7 is performed by a spray drying method. 【A method for producing a solid dispersion containing a heterocycle derivative, wherein the mixed solution is a mixed solvent of dichloromethane and an alcohol having 1 to 5 carbon atoms, wherein the mixed solvent comprises dichloromethane.

10. A method for producing a solid dispersion containing a heterocycle derivative, wherein the mixed solution in claim 7 comprises a mixed solvent containing dichloromethane and an alcohol having 1 to 5 carbon atoms in a weight ratio of 6:4 to :

1.

11. 28 An oral pharmaceutical composition comprising a heterocycle derivative represented by the following chemical formula 1 as an effective ingredient, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; a polymer selected from among hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and a methacrylic acid-methyl methacrylate copolymer; and a pharmaceutically acceptable carrier: <화학식 1> In the above chemical formula 1, Ri is -S(=O)(=Ra)Rb, Ra is =0 or =NH, Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, ¬mino, or amino C1-6 alkyl, At least one of Ra or Rb is independently substituted with F, Br, Cl or I. R 2 and R3 are each independently F, Br, Cl or I.

12. An oral pharmaceutical composition according to claim 29, wherein the pharmaceutically acceptable carrier comprises at least one selected from an excipient, a disintegrant, a lubricant and a binder.

13. An oral pharmaceutical composition according to claim 11, which is a mixture of a compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and a heterocycle-conductor-containing solid dispersion comprising one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and a hydroxyacrylic acid-methyl methacrylate copolymer, and the pharmaceutically acceptable carrier.

14. An oral pharmaceutical composition according to claim 11, wherein the pharmaceutically acceptable carrier comprises at least one selected from microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, lospovidone, sodium starch glycolate, polyvinylpyrrolidone vinyl acetate, sodium lauryl phosphate, magnesium stearate, and sodium stearyl fumarate.

15. In claim 11, the pharmaceutically acceptable carrier is: An oral pharmaceutical composition comprising 30 microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and sodium stearyl fumarate.

16. An oral pharmaceutical composition according to claim 11, which is a solid preparation of any one of granules, tablets, capsules, dry syrup, and powder.

17. In any one of claims 11 to 16, An oral pharmaceutical composition for the prevention or treatment of a disease mediated by activation of STAT3 protein.

18. A solid dispersion containing a heterocycle derivative according to any one of claims 1 to 6, comprising administering an effective amount of an oral pharmaceutical composition according to any one of claims 11 to 16 to a subject in need thereof. Method for preventing or treating a disease mediated by activation of STAT3 protein. 【Claim 1 Use of a solid dispersion containing a heterocycle derivative according to any one of claims 1 to 6 or an oral pharmaceutical composition according to any one of claims 11 to 16 for the prevention or treatment of a disease mediated by activation of STAT3 protein.

20. 31 Use of a solid dispersion containing a heterocycle derivative according to any one of claims 1 to 6 or an oral pharmaceutical composition according to any one of claims 11 to 16 for the manufacture of a medicament for preventing or treating a disease mediated by activation of STAT3 protein.

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