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WO2025120552A1 - Dispersion solide comprenant un dérivé hétérocyclique, son procédé de préparation et composition pharmaceutique la comprenant - Google Patents

Dispersion solide comprenant un dérivé hétérocyclique, son procédé de préparation et composition pharmaceutique la comprenant Download PDF

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Publication number
WO2025120552A1
WO2025120552A1 PCT/IB2024/062241 IB2024062241W WO2025120552A1 WO 2025120552 A1 WO2025120552 A1 WO 2025120552A1 IB 2024062241 W IB2024062241 W IB 2024062241W WO 2025120552 A1 WO2025120552 A1 WO 2025120552A1
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Prior art keywords
solid dispersion
heterocycle derivative
chemical formula
pharmaceutical composition
alkyl
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PCT/IB2024/062241
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English (en)
Korean (ko)
Inventor
황규목
엄윤식
진세호
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JW Pharmaceutical Corp
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JW Pharmaceutical Corp
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Publication of WO2025120552A1 publication Critical patent/WO2025120552A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to a solid dispersion containing a heterocycle derivative, a method for producing the same, and a pharmaceutical composition comprising the same, and more specifically, to a solid dispersion containing a heterocycle derivative with improved bioavailability, a method for producing the same, and a pharmaceutical composition comprising the same.
  • STAT signal transducer and activator of transcription
  • STAT proteins are transcription factors that transmit signals from various extracellular cytokines and growth factors to the nucleus.
  • seven isoforms of STAT proteins i.e., STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 are known, which are generally composed of about 750 to 850 amino acids.
  • STAT3 protein is known to play a key role in the IL-6 and EGF signaling systems.
  • STAT3 protein is persistently activated in patients with solid tumors such as those in the prostate, stomach, breast, lung, pancreas, kidney, uterus, ovary, and head and neck, as well as in patients with hematological cancers such as acute and chronic leukemia and multiple myeloma.
  • solid tumors such as those in the prostate, stomach, breast, lung, pancreas, kidney, uterus, ovary, and head and neck
  • STAT3 is considered a very promising novel anticancer target.
  • STAT1 has the same intracellular response pathways for cytokines and growth factors as STAT3, but has been reported to inhibit the proliferation of cancer cells or induce pro-apoptotic responses by increasing innate and adaptive immunity.
  • a heterocycle 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.
  • One object of the present invention is to provide a solid dispersion containing a heterocycle derivative which can improve the solubility of a drug and has improved physicochemical properties.
  • One object of the present invention is to provide a method for producing a solid dispersion containing a heterocycle derivative.
  • One object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion containing a heterocycle derivative.
  • a solid dispersion containing a heterocycle derivative for one purpose of the present invention comprises, as an effective ingredient, a heterocycle derivative represented by the following chemical formula 1, which is a STAT3 inhibitor, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and methacrylic acid- It contains one polymer among methyl methacrylate copolymers (Methacryl ic acid-methyl methacrylate copolymer).
  • 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 may be independently substituted with F, Br, Cl or I.
  • R 2 and R3 are each independently F, Br, Cl or I.
  • the heterocycle derivative represented by the above chemical formula 1 may be the following compound 1.
  • Compound 1 may be referred to as N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide.
  • the heterocycle derivative represented by the chemical formula 1 may be any one of (4S)-N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide, (4R)-N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide, and mixtures thereof.
  • a pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, and is not particularly limited.
  • the pharmaceutically acceptable salt can be a salt with an inorganic acid or an organic acid, wherein the inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, and the like, and the organic acid can be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like.
  • the inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, and the like
  • the organic acid can be acetic acid, methanesulfonic
  • Organic bases that can be used in the preparation of the organic base addition salts can include tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like.
  • Amino acids that can be used in the preparation of the amino acid addition salt may include natural amino acids, such as alanine and glycine.
  • the heterocycle derivative represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the solid dispersion may be amorphous.
  • the solid dispersion may be amorphous.
  • the weight ratio of the heterocycle derivative represented by Chemical Formula 1 according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient and the polymer may be 1:1 to 1:10.
  • the weight ratio may be 1:1 to 1:5, 1:1 to 1:3.
  • the average particle size of the solid dispersion containing the heterocycle derivative according to the present invention may be 5 um to 15 um.
  • the average particle size in the present invention may be a volume-average diameter.
  • the average particle size may be D50, and D50 may be defined as a particle size that accounts for 50% of the cumulative volume when the total particle amount is regarded as 100%.
  • the average particle size may be measured by laser diffraction or dynamic light scattering.
  • the average particle size may be measured by a dry dispersion.
  • the average particle size of the solid dispersion containing the heterocycle derivative according to the present invention may be 5 um to 10 um, 7 um to 9 um, 10 um to 15 um, or 13 um to 15 um.
  • the solubility of the heterocycle derivative in the solid dispersion containing the heterocycle derivative according to the present invention may be at least 40 ug/mL or more in a pH 6.5 eluate, for example, at least 60 ug/mL or more.
  • the solubility of the heterocycle derivative in the solid dispersion containing the heterocycle derivative according to the present invention can be 60 ug/mL to 120 ug/mL in a FaSSIF pH 6.5 solution.
  • the solid dispersion containing the heterocycle derivative according to the present invention may be used for the prevention or treatment of a disease mediated by the activation of STAT3 protein.
  • a method for producing a solid dispersion containing the heterocycle derivative for one purpose of the present invention is as follows.
  • a STAT3 inhibitor comprising a heterocycle derivative represented by the above chemical formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; and a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose and a methacrylic acid-methyl methacrylate copolymer; a step of preparing a mixed solution; and a step of preparing a solid dispersion with the mixed solution. Accordingly, the heterocycle derivative-containing solid dispersion according to the present invention described above can be prepared.
  • the step of preparing the solid dispersion can be performed by a spray drying method, a fluidized bed granulation method, a fluidized bed coating method, a rotary evaporation concentration method, a supercritical fluid method, or a melt extrusion method.
  • the step of preparing the solid dispersion can be performed by a spray drying method.
  • the step of preparing the solid dispersion can include a step of performing a spray drying process on the mixed solution; and a step of drying the solid obtained through the spray drying process.
  • the mixed solution may include a mixed solvent of dichloromethane and an alcohol having 1 to 5 carbon atoms or dichloromethane.
  • the alcohol may be methanol or ethanol.
  • the mixed solution may include a mixed solvent including dichloromethane and an alcohol having 1 to 5 carbon atoms in a weight ratio of 6:4 to 9:1.
  • the weight ratio may be 7:3 to 9:1, or 7:3 to 8:2.
  • the mixed solution can be prepared by mixing a solid comprising a heterocycle derivative represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and a methacrylic acid-methyl methacrylate copolymer, with a solvent.
  • the solvent can include the mixed solvent or dichloromethane.
  • the solid and the solvent can have a weight ratio of 0.5:99, 5 to 20:80 out of 100 of their total weight.
  • the weight ratio of the solid and the solvent can be 0.5:99.5 to 15:85, or 1:99 to
  • a pharmaceutical composition for one purpose of the present invention may include a heterocycle derivative represented by the chemical formula 1 as a STAT3 inhibitor, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; a polymer of one of hydroxypropyl cellulose, hydroxypropyl methylcellulose and a methacrylic acid-methyl methacrylate copolymer; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be a mixture of a heterocycle derivative-containing solid dispersion comprising a heterocycle derivative represented by the chemical formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; and a polymer of one of hydroxypropyl cellulose, hydroxypropyl methylcellulose and a methacrylic acid-methyl methacrylate copolymer, and the pharmaceutically acceptable carrier.
  • the mixture at this time may be in a solid dosage form, for example, may be in the form of granules, tablets, capsules, dry syrup, or powder.
  • the pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention may include excipients, disintegrants, lubricants, binders, etc.
  • Excipients may include lactose, mannitol, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate, silicon dioxide (Si02), cellulose, sodium bicarbonate, and mixtures thereof.
  • Disintegrants may include croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and the like.
  • Lubricants may include sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, sodium lauryl sulfate, and the like.
  • Binders may include glucose syrup, polyvinylpyrrolidone, polyethylene glycol 6000, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, and the like.
  • the above pharmaceutically acceptable carrier can be appropriately selected and used by a person skilled in the art depending on the form of the pharmaceutical composition.
  • the pharmaceutically acceptable carrier can include at least one selected from microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, sodium starch glycolate, polyvinylpyrrolidone vinyl acetate, sodium lauryl sulfate, magnesium stearate, and sodium stearyl fumarate.
  • the pharmaceutical composition according to the present invention can be an oral pharmaceutical composition.
  • the pharmaceutical composition can be in various forms, but includes solid preparations such as granules, tablets, capsules, dry syrups, or powders, and can be, for example, granules, tablets, or capsules. These preparations can be prepared according to methods commonly used in the pharmaceutical art.
  • the tablet is manufactured by mixing the solid dispersion containing the heterocycle derivative with excipients, disintegrants, lubricants, etc., or by adding excipients, etc. to the solid dispersion containing the heterocycle derivative, manufacturing it into granules, and mixing it with excipients, disintegrants, lubricants, etc., and compressing it into tablets. can be.
  • the tablet can be a coated tablet having a film or enteric coating, which includes the solid dispersion containing the heterocycle derivative, an excipient, a disintegrant, a lubricant, etc.
  • the coating can include polyvinyl alcohol, polyvinylacetate, polyethylene glycol, titanium dioxide, iron oxide, etc., or Opadry®, etc.
  • the capsule can be prepared by filling a capsule with a mixture containing the solid dispersion containing the heterocycle derivative, an excipient, a disintegrant, a lubricant, etc. At this time, the mixture can be a granule.
  • the pharmaceutical composition according to the present invention can be a pharmaceutical composition for preventing or treating a disease mediated by activation of STAT3 protein.
  • the present invention also provides a method for preventing or treating a disease mediated by activation of STAT3 protein, comprising administering an effective amount of the solid dispersion containing the heterocycle derivative according to the present invention or the pharmaceutical composition according to the present invention to a subject in need thereof.
  • the present invention also provides a use of a solid dispersion containing a heterocycle derivative according to the present invention or a pharmaceutical composition according to the present invention for the prevention or treatment of a disease mediated by activation of STAT3 protein.
  • the present invention also provides a use of a solid dispersion containing a heterocycle derivative according to the present invention or a pharmaceutical composition according to the present invention for the manufacture of a medicament for the prevention or treatment of a disease mediated by activation of STAT3 protein.
  • the disease mediated by activation of STAT3 protein in the present invention may include cancer.
  • the disease mediated by activation of STAT3 protein may include at least one of a solid cancer, a hematological cancer, a radiation- or drug-resistant cancer, and a metastatic cancer.
  • the disease mediated by the activation of the STAT3 protein in the present invention may include at least one of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B- or T-cell lymphoma, and non-Hodgkin's lymphoma.
  • the solid dispersion containing the heterocycle derivative of the present invention may include at least one of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B- or T-cell lymphoma, and non-Hodgkin's lymphoma.
  • a solid dispersion containing a heterocycle derivative which comprises 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:
  • 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 may be independently replaced by F, Br, Cl or I.
  • R 2 and R3 are each independently F, Br, Cl or I.
  • the heterocycle derivative represented by the chemical formula 1 may be N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide.
  • the heterocycle derivative represented by chemical formula 1 may be one of (4S)-N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide, (4R)-N-[2-chloro-6-(4-chlorophenoxy)pyridin-4-yl]-4-methylsulfonyl-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide, and a mixture thereof.
  • the heterocycle derivative represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be amorphous.
  • the weight ratio of the heterocycle derivative represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and the polymer may be 1:1 to 1:10.
  • the method for producing a solid dispersion containing a heterocycle derivative of the present invention comprises: (7) A method for producing a solid dispersion containing a heterocycle derivative, comprising: a step of producing a mixed solution containing a heterocycle derivative represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and a methacrylic acid-methyl methacrylate copolymer; and a step of producing a solid dispersion using the mixed solution:
  • 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 may be independently substituted with F, Br, Cl or I.
  • R 2 and R3 are each independently F, Br, Cl or I.
  • the step of manufacturing the solid dispersion may be performed by a spray drying method.
  • the mixed solution may include a mixed solvent of dichloromethane and an alcohol having 1 to 5 carbon atoms or dichloromethane.
  • the mixed solution may include a mixed solvent containing dichloromethane and alcohol in a weight ratio of 6:4 to 9:1.
  • the pharmaceutical composition of the present invention in one embodiment, is a mixed solvent containing dichloromethane and alcohol in a weight ratio of 6:4 to 9:1.
  • 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:
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • methacrylic acid-methyl methacrylate copolymer a pharmaceutically acceptable carrier
  • 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 may be independently substituted with F, Br, Cl or I.
  • R 2 and R3 are each independently F, Br, Cl or I.
  • the pharmaceutically acceptable carrier may include at least one selected from among an excipient, a disintegrant, a lubricant, and a binder.
  • the pharmaceutically acceptable carrier may include at least one selected from microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, sodium starch glycolate, polyvinylpyrrolidone vinyl acetate, sodium lauryl sulfate, magnesium stearate, and sodium stearyl fumarate.
  • the pharmaceutically acceptable carrier may include microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and sodium stearyl fumarate.
  • any one of (11) to (15) it may be a solid preparation of any one of granules, tablets, capsules, dry syrup, and powder.
  • the oral pharmaceutical composition may be for the prevention or treatment of a disease mediated by activation of STAT3 protein.
  • the method for prevention or treatment of the present invention is a method for prevention or treatment of a disease mediated by activation of STAT3 protein, comprising administering an effective amount of a solid dispersion containing a heterocycle derivative according to any one of (1) to (6) above or an oral pharmaceutical composition according to any one of (11) to (16) above to a subject in need thereof.
  • the use of the present invention is a use of a solid dispersion containing a heterocycle derivative according to any one of (1) to (6) above or an oral pharmaceutical composition according to any one of (11) to (16) above for the prevention or treatment of a disease mediated by activation of STAT3 protein.
  • the use of the present invention is the use of a solid dispersion containing a heterocycle derivative according to any one of (1) to (6) above or an oral pharmaceutical composition according to any one of (11) to (16) above for the manufacture of a medicament for preventing or treating a disease mediated by activation of STAT3 protein.
  • a solid dispersion containing a heterocycle derivative of the present invention the method for producing the same, and the pharmaceutical composition containing the same, a solid dispersion containing a heterocycle derivative having improved solubility of a STAT3 inhibitor can be provided.
  • a pharmaceutical composition containing the solid dispersion containing a heterocycle derivative can have excellent stability and dissolution characteristics. Accordingly, the bioavailability of the STAT3 inhibitor can be improved.
  • FIG. 1 and FIG. 2 are drawings showing PXRD analysis graphs of solid dispersions according to embodiments of the present invention.
  • FIG. 3 and FIG. 4 are diagrams showing the results of solubility analysis of solid dispersions according to embodiments of the present invention.
  • FIG. 5 is a diagram showing the dissolution rate graphs of each of the uncoated tablet and the coated tablet according to the present invention.
  • 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 la and polymer were dissolved in the prepared mixed solvent with 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). The secondary drying was performed under the conditions of a vacuum of 40 °C and a negative pressure of 300 mbar for about 20 hours.
  • a spray dryer Buchi B-290 Spray Dryer & B-295 Inert Loop Unit
  • FIGS. 1 and 2 are drawings 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 the solid dispersions and compound la according to the present invention are both 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.
  • Example 9 Preparation of composition Using the same type of polymer, weight ratio of compound la and polymer, mixed solvent, and solid content as described in Example 4, a solid dispersion was prepared, and using the same, Samples 1 to 3 were prepared as compositions containing the solid dispersion according to the components and contents of Table 5 below.
  • the unit of each content in Table 5 is w/w%, and means the weight of each component with respect to 100 of the total weight of the tablet.
  • Example 10 Preparation of tablets 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 tablets having the components and contents of Table 7 below were prepared using the same.
  • 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 of the total tablet weight of 800 mg.
  • the unactivated mixture was sieved through an 850 ⁇ m sieve and placed into a mixing container as follows.
  • the materials were layered in the mixing container (drum blender) as follows and mixed at 30 °C for 15 minutes.
  • the order of placing each component into the mixing container as the unactivated mixture is as follows: 33% of the excipient (microcrystalline cellulose) was weighed and placed, 50% of the solid dispersion was weighed and placed, 50% of the intragranular disintegrant (croscarmellose sodium) was weighed and placed, and 33% of the excipient (microcrystalline cellulose) was weighed and placed.
  • the intragranular lubricant sodium stearyl fumarate
  • the intragranular lubricant sodium stearyl fumarate was sieved through a 500 ⁇ m sieve and placed into the mixing container, mixed at 30 rpm for 3 minutes, and granules were manufactured using a dry granulation process.
  • a tablet was manufactured by pressing at 10 rpm using a rotary tablet press with a target mass of 800 ⁇ 5% and a hardness of 20 ⁇ 5 kP.

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Abstract

La présente invention concerne une dispersion solide comprenant un dérivé hétérocyclique, son procédé de préparation et une composition pharmaceutique la comprenant. La dispersion solide comprenant un dérivé hétérocyclique comprend : en tant que principe actif, un composé, qui est un inhibiteur de STAT3, représenté par la formule chimique 1, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci ; et un polymère parmi l'hydroxypropylcellulose (HPC), l'hydroxypropylméthylcellulose (HPMC), et un copolymère d'acide méthacrylique et de méthacrylate de méthyle.
PCT/IB2024/062241 2023-12-07 2024-12-05 Dispersion solide comprenant un dérivé hétérocyclique, son procédé de préparation et composition pharmaceutique la comprenant Pending WO2025120552A1 (fr)

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WO2008124000A2 (fr) * 2007-04-02 2008-10-16 Ligand Pharmaceuticals Incorporated Dérivés de thiazole utilisés comme composés modulateurs de récepteurs d'androgènes
KR20170037670A (ko) * 2014-08-19 2017-04-04 온코에틱스 게엠베하 티에노트리아졸로디아제핀 화합물을 사용한 림프종의 치료 방법
KR20170081708A (ko) * 2014-12-02 2017-07-12 주식회사 씨앤드씨신약연구소 헤테로환형 유도체 및 이의 용도
JP2020512377A (ja) * 2017-03-30 2020-04-23 ボストン バイオメディカル， インコーポレイテッド がんを処置および／または防止するための組成物
KR20220162163A (ko) * 2020-04-01 2022-12-07 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 니클로사미드의 약제학적 조성물

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