Solid dispersion of EED inhibitor, oral formulation containing the same, and method for manufacturing the same.

Abstract

The present invention relates to the field of pharmaceutical formulations, and more specifically to a solid dispersion containing an extraembryonic ectoderm development (EED) inhibitor having good dissolution and good bioavailability, and a method for producing the same; a solid dispersion composition comprising the solid dispersion and an excipient; an oral formulation comprising the solid dispersion or solid dispersion composition, and a method for producing the same; and the use of the solid dispersion, solid dispersion composition, or oral formulation for the treatment and / or prevention of EED-mediated diseases.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical formulations and specifically relates to a solid dispersion containing an extraembryonic developmental protein (EED) inhibitor having good dissolution and good bioavailability, a solid dispersion composition comprising the solid dispersion and an excipient, an oral formulation comprising the solid dispersion or solid dispersion composition and a method for producing the same, and the use of the solid dispersion, solid dispersion composition or oral formulation for the treatment and / or prevention of EED-mediated diseases. [Background technology]

[0002] Polycomb group (PcG) proteins are a series of transcription inhibitors that regulate target genes through chromatin modification. They not only control the normal developmental modes of an individual but are also closely involved in cell proliferation, differentiation, and tumor development. PcG proteins can be broadly classified into two types: PRC1 (Polycomb inhibitory complex 1 with E3 ubiquitin ligase activity) and PRC2 (Polycomb inhibitory complex 2 with methyltransferase activity).

[0003] PRC2, a representative member of the PcG, is a multi-subunit complex that maintains a chromatin inhibitory state by silently suppressing the expression of specific genes. It plays a crucial role in development, tissue differentiation, and regeneration, and its core subunits include histone methyltransferase 2 (EZH2), EED, zeste 12 inhibitor (SUZ12), and retinoblastoma inhibitor-related protein 46 / 48 (RbAp46 / 48). PRC2 dysfunction has been found in many human cancers. For example, EZH2 is highly expressed in several types of human cancers and promotes cancer development and malignancy. EZH2 mutations occur in as many as 25% of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and are associated with poor patient prognosis.

[0004] Although targeting and inhibiting the methyltransferase activity of EZH2 has proven to be a successful cancer treatment strategy, secondary mutations in EZH2 can lead to acquired resistance, and its homolog EZH1 also possesses methyltransferase activity, both of which limit the activity of EZH2 inhibitors. On the other hand, EED can activate the methyltransferase activity of EZH2, so allosteric inhibition targeting EED is also an effective anticancer method. Furthermore, it can overcome resistance to EZH2 inhibitors and produce a stronger antitumor effect by simultaneously inhibiting EZH2 and EZH1. Previous research has clearly demonstrated that EED inhibitors have enormous therapeutic potential in hematological malignancies, solid tumors, and non-tumor indications.

[0005] To date, EED inhibitors that have entered clinical research include MAK683 developed by Novartis and FTX-6058 developed by Fulcrum Therapeutics. Furthermore, there is a novel, potent, selective small molecule EED inhibitor being developed by Yashen Pharmaceutical that has high EED binding affinity and is expected to overcome tumor resistance and achieve complete and sustained tumor regression by modulating tumor epigenetics and the tumor microenvironment. This compound has already received clinical trial approval from the US FDA on June 29 and November 10, 2022, and from the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China, respectively, and is currently conducting Phase I clinical trials for the treatment of advanced solid tumors or hematological malignancies. It is also the first original EED inhibitor to enter clinical trials in China.

[0006] The compound with the chemical name 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one is a member of a series of imidazopyrimidine-based EED inhibitors disclosed in WO2021 / 011713 (CN114127073A), and its structural formula is as follows: [ka] Preclinical data demonstrated that compound A possesses in vitro antitumor cell proliferation activity in multiple tumor cell lines and exhibits antitumor activity in EZH2-mutated B-cell non-Hodgkin lymphoma, INI1-negative malignant rhabdoid tumor, BAP1-mutated mesothelioma, and PDX / CDX models of prostate cancer.

[0007] Given the enormous therapeutic potential of EED inhibitors in the field of oncology, the early development of EED inhibitor pharmaceutical formulations that are easy to manufacture, convenient to use, and possess favorable formulation characteristics will benefit more oncology patients as soon as possible. At the same time, in light of the safety issues that have long been a focus in the field of oncology drugs, namely toxicity and side effects, there is a great need for anticancer drugs that can exert therapeutic effects at relatively low doses by having improved bioavailability even during practical application.

[0008] Compound A is an anhydrous crystalline powder that is slightly hygroscopic, practically insoluble in water, and has a solubility of 0.39-0.08 μg / mL (37°C / 24h) in aqueous buffer solutions with a pH of 1.2-7.4, indicating poor fluidity. For drugs with such poor water solubility, the dissolution of the drug in gastrointestinal fluid is the rate-limiting step in its bioavailability. Poor water solubility inevitably leads to low dissolution rates, and consequently, relatively low bioavailability. Therefore, to improve the bioavailability of the drug, it is necessary to specially design the dosage form, formulation composition, and process to alter the drug's dispersion state and promote its dissolution in the gastrointestinal tract.

[0009] To meet the above needs and solve the above problems, as a result of extensive research and screening by the present inventors, a stable solid dispersion of an EED inhibitor that can provide good dissolution and good bioavailability has been developed. Further, through formulation design, the solid dispersion has been manufactured into an oral formulation having good formulation properties, achieving the object of the invention.

Summary of the Invention

[0010] In one aspect, the present invention provides a stable solid dispersion having good dissolution and bioavailability, its EED inhibitor (particularly compound A), and a carrier substance.

[0011] In another aspect, the present invention provides a stable solid dispersion composition having good dissolution and bioavailability, the solid dispersion composition comprising the solid dispersion of the present invention and one or more pharmaceutically acceptable excipients.

[0012] In another aspect, the present invention provides an oral formulation (e.g., a tablet) having good dissolution and bioavailability, which comprises the solid dispersion or solid dispersion composition of the present invention, wherein the EED inhibitor is in the solid dispersion.

[0013] In another aspect, the present invention provides a method for producing the solid dispersion of the present invention.

[0014] In another aspect, the present invention provides a method for producing the oral formulation of the present invention.

[0015] In another aspect, the present invention provides a method for treating or preventing a disease (e.g., cancer or tumor) promoted by EED inhibition, the method comprising administering a therapeutically effective amount of the solid dispersion, solid dispersion composition or oral formulation of the present invention to a subject in need thereof.

[0016] In another embodiment, the present invention provides the use of a solid dispersion, solid dispersion composition, or oral formulation of the present invention for treating or preventing diseases (e.g., cancer or tumors) promoted by EED inhibition.

[0017] In another embodiment, the present invention provides the use of a solid dispersion, solid dispersion composition, or oral formulation of the present invention in the manufacture of a drug for treating or preventing a disease (e.g., cancer or tumor) promoted by EED inhibition.

[0018] Detailed description of the invention definition As used herein, the term "approximately" allows for a variation of ±10% of the numbers it is used with. With respect to ratios, the term "approximately" is used to limit each number in a given ratio. For example, a ratio of approximately 1:1 means that the ratio is 0.9 to 1.1:0.9 to 1.1.

[0019] A "solid dispersion" refers to a highly dispersed system formed by uniformly dispersing a drug in a highly dispersed state, such as molecular, colloidal, amorphous, or microcrystalline, on an inert auxiliary material or carrier. Its characteristics include delaying the hydrolysis and oxidation of the drug, masking unpleasant odors and irritants, solidifying liquid drugs, and accelerating or delaying drug dissolution to achieve rapid or sustained release. However, the highly dispersed state also brings the problem of poor physical stability of the solid dispersion, making it prone to aging after long-term storage. Different types of solid dispersions exist depending on differences in carrier materials, manufacturing methods, and composition ratios, and include, but are not limited to, simple low-eutectic mixtures, solid solutions, and coprecipitates. There are multiple methods for manufacturing solid dispersions, including melting, solvent methods, solvent-melting, solvent-spray drying, and polishing. Means for verifying the state of existence of drugs and identifying the formation of solid dispersions include thermal analysis (including differential thermal analysis (DTA) or differential scanning calorimetry (DSC)), X-ray diffraction (XRPD), infrared spectroscopy, and polarizing microscope (PLM).

[0020] However, given the diversification of carrier materials and their properties, the diversification of manufacturing methods, and the frequent incompatibility between carrier materials and manufacturing methods and specific drug molecules, the advantages of solid dispersions described above are often not realized. In other words, it is often not possible to obtain a solid dispersion that yields good formulation properties solely through the molecular structure and physicochemical properties of a particular drug and conventional technical means of solid dispersions.

[0021] A "solid dispersion carrier" is a material in which a drug in a solid dispersion is dispersed in a highly dispersed state such as molecular, colloidal, amorphous, or microcrystalline state. The properties of the carrier material have a very significant impact on the properties of the solid dispersion, and it should have basic characteristics such as being non-toxic, non-carcinogenic, not affecting the stability of the drug, not undergoing chemical reactions with the drug, and not affecting the monitoring of the drug's efficacy and content.

[0022] Commonly used solid dispersion carrier materials can be divided into water-soluble carrier materials, including polyethylene glycol (PEG)-based, polyvinylpyrrolidone (PVP)-based, surfactant-based, organic acid-based, and sugar (alcohol)-based materials; poorly soluble carrier materials, including cellulose-based, polyacrylic resin-based, and lipid-based materials; and enteric-coated carrier materials, including enteric-coated cellulose-based and polyacrylic resin-based materials. Generally, water-soluble carriers can increase the solubility and elution rate of poorly soluble drugs, thereby improving the bioavailability of drugs; poorly soluble carriers can delay or control drug release; and enteric-coated carriers can control drug release in the small intestine.

[0023] Among these, polyethylene glycol-based carriers are one of the most commonly used water-soluble carriers, characterized by low toxicity, a low melting point, and good water solubility. After being manufactured as a solid dispersion, the drug molecules can be dispersed in a molecular state, thereby accelerating the drug dissolution rate. Generally, PEG with a molecular weight of 1,000 to 20,000 is selected as the solid dispersion carrier, with PEG4000 and PEG6000 being the most commonly used.

[0024] Povidone-based carriers are amorphous polymers that are stable to heat, readily soluble in water and polar organic solvents such as ethanol, and exhibit relatively strong crystallization inhibitory activity against several types of drugs.

[0025] Polyacrylic resin carriers are a general term for copolymers of acrylic acid, methacrylic acid, and their derivatives. The most commonly used product is traded under the name Eudragit, which includes methacrylic acid copolymers and methacrylic acid ester copolymers, and is divided into different model numbers depending on the composition, ratio, and degree of polymerization. Of these, Eudragit E is a copolymer of dimethylaminoethyl methacrylate and other neutral methacrylic acid esters, while Eudragit L and Eudragit S are copolymers of methacrylic acid with acrylic acid esters in different ratios, and include methacrylic acid-ethyl acrylate (1:1) copolymer, methacrylic acid-methyl methacrylate (1:1) copolymer, and methacrylic acid-methyl methacrylate (1:2) copolymer. Specific examples include, but are not limited to, Eudragit E100, Eudragit EPO, Eudragit L100-55, Eudragit L30D-55, Eudragit L100, and Eudragit S100.

[0026] Examples of cellulosic carriers include ethylcellulose, hydroxypropylcellulose, and hypromellose, and further include enteric-coated celluloses such as cellulose acetate phthalate, hypromellose phthalate, and hypromellose acetate succinate.

[0027] As used herein, the terms “formulation” or “pharmaceutical composition” refer to a composition suitable for administration to animals, preferably mammals (including humans), comprising at least one active ingredient and at least one inactive ingredient, such as a medicinal excipient. The formulations of the present invention may be any formulation applicable in this art, such as tablets, capsules, or liquid formulations.

[0028] As used herein, the term “pharmaceutically acceptable excipient” refers to a component in a pharmaceutical formulation other than the active ingredient that is non-toxic to the organism. Examples of pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.

[0029] As used herein, the term “EED inhibitor” refers to a bioactive agent that can interact with EED proteins directly or indirectly to reduce the signaling activity of EED, specifically the series of imidazopyrimidine-based EED inhibitors having formula (I) as described in CN114127073A, more specifically, EED inhibitor compounds having formula (III) thereof, most preferably the compounds of Example 73, or pharmaceutically acceptable salts or solvates thereof. The entire contents of CN114127073A are incorporated herein by reference.

[0030] As used herein, the terms “EED-mediated disease” or “EED inhibition-promoted disease” refer to a disease or disorder in which EED is involved in its development, the appearance of one or more disease symptoms or markers, its severity, or its progression. Alternatively, they refer to a disease or disorder in which the incidence of the disease is reduced, or the disease symptoms are diminished or eliminated by inhibition of EED. These diseases or disorders include, but are not limited to, cancer and proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections, of which cancer and proliferative disorders are of the most important importance. Those skilled in the art can easily determine, for example, whether a compound treats any particular cell type disease or condition mediated by an EED inhibitor by analyses conveniently available for evaluating the activity of a particular compound. See, for example, Yue and Turkson, Expert Opinion Invest Drugs, 18:45-56 (2009).

[0031] As used herein, the terms “patient,” “subject,” “subject,” or “individual” refer to mammalian and non-mammalian individuals requiring the EED inhibitors of the present invention. Examples include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), horses, cattle, sheep, cats, dogs, rabbits, and rodents (e.g., mice and rats), and are not limited to specific ages or sexes. In some embodiments, the above terms refer to humans, including children, adolescents, or adults.

[0032] As used herein, the term “treatment” refers to administering the EED inhibitor solid dispersion of the present invention or a pharmaceutical composition containing it to an individual having a related disease or its symptoms, or an individual having a predisposition to a related disease, in order to cure, alleviate, or improve the disease or its symptoms, or to prevent the individual from contracting the disease. In specific embodiments of the present invention, the disease is an EED-mediated disease as defined above, in particular tumor or cancer.

[0033] As used herein, the term “prevention” means delaying the onset of a disease or reducing the risk of developing a disease by administering to a subject suspected of or susceptible to an EED-mediated disease, particularly cancer or tumor, as defined herein, to a mammal such as a human, by solid dispersion of the EED inhibitor of the present invention or a pharmaceutical composition containing the same. The term “prevention” includes using the solid dispersion or pharmaceutical composition of the present invention before diagnosing or confirming any clinical and / or pathological symptoms.

[0034] As used herein, the term “effective dose” refers to the amount of a pharmacoactive agent sufficient to prevent the onset of one or more symptoms of the disease or disorder being treated, or to alleviate such symptoms to some extent, when administered alone or in combination with other therapeutic agents to a particular patient or patient population. The effective dose of the EED inhibitor in the solid dispersion or pharmaceutical composition of the present invention is generally about 1 μg / kg to 100 mg / kg / day, for example, a daily dose of about 1 mg / kg to about 10 mg / kg. In some cases, the effective dose of the EED inhibitor of the present invention may be higher than the upper limit of the above dose range or lower than the lower limit of the above dose range. Those skilled in the art can determine the effective dose of the EED inhibitor pharmaceutical composition of the present invention by combining conventional methods (e.g., modeling, dose escalation studies or clinical trials) with conventional influencing factors (e.g., method of administration, pharmacokinetics of the compound, severity and course of the disease, medical history of the individual, health status of the individual, degree of response of the individual to the drug, etc.).

[0035] The term "AUC" used in this specification last The term "area under the plasma concentration-time curve" refers to the area under the plasma concentration-time curve from the time of administration to the last point, and its unit is ng·h·mL. -1 That is the case.

[0036] The term "AUC" used in this specification INF The term "area under the plasma concentration-time curve" refers to the area under the plasma concentration-time curve when the measured administration time is extrapolated from 0h to infinity, and the unit is ng·h·mL. -1 That is the case.

[0037] The term "C" used herein max The term "highest concentration" refers to the peak concentration of a drug in plasma after administration, and its unit is ng / mL.

[0038] The term "T" used in this specification max The term "C" refers to the term used after administration. max This refers to the time at which the phenomenon occurs, and its unit is time (h).

[0039] The term "T" used in this specification 1 / 2The term "equilibrium" refers to the time required for the plasma drug concentration to be halved after the in vivo distribution of the drug has reached equilibrium, and its unit is hours (h).

[0040] A typical acceptable standard for the term “stable” as used herein when describing the solid dispersions or oral formulations of the present invention is that the total impurity content measured by the HPLC method described herein is about 1% or less, preferably about 0.5% or less, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%, and / or that, as detected by XRPD, DTA, DSC, or PLM, the physical form of the active ingredient in the solid dispersion / oral formulation remains amorphous, with no apparent crystals present and no aging.

[0041] In this specification, when describing the content of each component, the expression "by weight of the oral formulation" refers to calculating the content of the active ingredient and other types of excipients by weight of the core, excluding the coating agent.

[0042] Any designation of an EED inhibitor appearing herein is intended to include the free compound and its pharmaceutically acceptable salts, hydrates, or solvates.

[0043] As used herein, the term “pharmaceutically acceptable salt” refers to a salt or amphoteric form of an EED inhibitor compound relating to this disclosure. A pharmaceutically acceptable salt of an EED inhibitor relating to this disclosure may be an acid addition salt formed with a pharmaceutically acceptable acid, examples of which include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Non-exclusive examples of salts of EED inhibitors relating to this disclosure include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipine, alginate, aspartate, benzoate, hydrogen sulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptaneate, caproate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethylsulfonate, salicylate, methanesulfonate, and mesinate. This includes, but is not limited to, ethylene sulfonate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate. Furthermore, the usable amino groups present in the EED inhibitor compounds according to this disclosure may be quaternarily ammoniumated with chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; sulfates of dimethyl, diethyl, dibutyl, and dipentyl groups; chlorides, bromides, and iodides of decyl, lauryl, myristyl, and sterol groups; and bromides of benzyl and phenethyl groups.

[0044] As used herein, the term "solvate" refers to a combination, physical association and / or fusion of an EED inhibitor compound according to the present disclosure and solvent molecules, for example, a disolvate, a monosolvate or a hemisolvate, wherein the ratio of solvent molecules to the compound according to the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. Solvates can generally function as pharmacological equivalents. The EED inhibitor compounds according to the present disclosure may exist in the form of solvates together with pharmaceutically acceptable solvents (e.g., water, methanol and ethanol). One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates where the solvent molecule is water.

[0045] The EED inhibitors according to the present disclosure cover any compound according to the present disclosure that is isotopically labeled (i.e., radioactively labeled) by substituting one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H (or deuterium (D)), 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, for example, 3 H, 11 C and 14It is C. In one embodiment, virtually all atoms at a certain position in the EED inhibitor of the present disclosure are replaced with atoms having different atomic masses or mass numbers. In another embodiment, virtually all atoms at a certain position in the EED inhibitor of the present disclosure are replaced with deuterium atoms, for example, all hydrogen atoms of the -CH3 group are replaced with deuterium atoms to obtain the -CD3 group. In another embodiment, some atoms at a certain position in the EED inhibitor of the present disclosure are replaced with atoms having different atomic masses or mass numbers. In another embodiment, none of the atoms of the EED inhibitor of the present disclosure are replaced with atoms having different atomic masses or mass numbers. The isotope-labeled EED inhibitor of the present disclosure can be prepared by methods known in the art.

[0046] The EED inhibitors relating to this disclosure may contain one or more chiral centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomers. This disclosure covers all such possible forms, as well as the use of their racemic and analytical forms and mixtures thereof.

[0047] Technical and scientific terms used herein that are not specifically defined have the meanings that are ordinarily understood by those skilled in the art.

[0048] Detailed description of the invention In a first aspect, the present invention provides a solid dispersion comprising an EED inhibitor or a pharmaceutically acceptable salt or solvate thereof and a polymer carrier.

[0049] In one embodiment, the present invention provides the above-mentioned solid dispersion, in which the EED inhibitor is the EED inhibitor described in CN114127073A, all of which are incorporated herein by reference. Specifically, the EED inhibitor according to the present invention has the following formula, i.e., [ka] Eventually, R 1 It is an aralkyl group, R 2The alkyl groups are selected from H and C1-C4 alkyl groups. X is -C(R 5a )(R 5b )-, -C(=O)- and -S(=O)2- are selected, R 5a and R 5b These are independently selected from H and C1-C4 alkyl groups. Y is -C(R 6a )(R 6b )-, -S-, -O- and -N(R 7 )- Selected from, Z is -C(R 6c )(R 6d ) m -and, R 6a and R 6b These are independently selected from H and C1-C4 alkyl groups. R 6c and R 6d Each is independently selected from H and C1-C4 alkyl groups, and m is 0, 1, or 2. R 7 These are selected from C1-C6 alkyl groups, C1-C6 haloalkyl groups, and optionally substituted C3-C8 cycloalkyl groups. L is -C(R 8b )= and -N= are selected, R 8a is selected from -CF3, -CH3, -CHF2, -CD3 and cyclopropyl groups, and R 8b and R 8c It is hydrogen, Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0050] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the above-mentioned EED inhibitor is [Table 1] Alternatively, it may be selected from its pharmaceutically acceptable salts or solvates.

[0051] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the EED inhibitor is compound A [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0052] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the above-mentioned EED inhibitor, for example, compound A, can form a salt with an acid to obtain a medicinal salt. The above-mentioned acid may be well known to those skilled in the art or may be determined in the usual manner, and is not limited to, for example, hydrochloric acid, methanesulfonic acid, fumaric acid, trifluoroacetic acid or phosphoric acid, sulfuric acid, 2-hydroxyethanesulfonic acid, acetic acid, benzoic acid, succinic acid, maleic acid, oxalic acid, p-toluenesulfonic acid, citric acid, tartaric acid and benzenesulfonic acid.

[0053] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from a cellulose-based polymer, a polyacrylic resin-based polymer, or a mixture thereof.

[0054] In one embodiment, the present invention provides the above-mentioned solid dispersion, the polymer carrier being selected from cellulose esters such as cellulose acetate and cellulose acetate phthalate, cellulose ethers such as ethylcellulose, hydroxypropylcellulose, and hypromellose (HPMC), and cellulose ether esters such as hypromellose phthalate (HPMCP) and hypromellose acetate succinate (HPMCAS).

[0055] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is an ester of cellulose ether, for example, hypromellose phthalate such as HP-55, HP-55S, and HP-50, and for example, hypromellose acetate succinate.

[0056] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the cellulose ether ester polymer carrier is preferably hypromellose acetate succinate (HPMCAS), which is a mixture of hypromellose acetate and succinate, and is amphiphilic, with the acetyl group providing hydrophobicity and the succinyl group providing hydrophilicity. Depending on the difference in the content of acetyl and succinyl groups and the granule size, HPMCAS usable in the solid dispersion of the present invention includes HPMCAS L, HPMCAS LG, HPMCAS M, HPMCAS MG, and HPMCAS H (L, M, and H represent the content of progressively increasing acetyl groups and progressively decreasing succinyl groups, respectively, G indicates a coarse particle size, and F indicates a fine particle size), and HPMCAS LG is more preferred.

[0057] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is a polyacrylic resin polymer, selected from methacrylic acid copolymers and methacrylic acid ester copolymers.

[0058] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the polymer carrier is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate, methacrylate-ethyl acrylate copolymer, methacrylate-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer, ethyl acrylate-methyl methacrylate copolymer, methacrylate-methyl acrylate-methyl methacrylate copolymer, and methacrylate-butyl acrylate copolymer.

[0059] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the polymer carrier is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1), methacrylate-ethyl acrylate (1:1), methacrylate-methyl methacrylate (1:1 or 1:2), ethyl methacrylate-methyl trimethylammonium methacrylate chloride (1:2:0.1 or 1:2:0.2), ethyl acrylate-methyl methacrylate (2:1), methacrylate-butyl acrylate (35:65) copolymer, and mixtures thereof in any ratio.

[0060] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from Eudragit. In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from Eudragit E, Eudragit L, Eudragit S, Eudragit RL, and Eudragit RS.

[0061] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from Eudragit E100, Eudragit EPO, Eudragit L100-55, Eudragit L30D-55, Eudragit L100, Eudragit S100, or a mixture thereof in any ratio.

[0062] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from a copolymer of methacrylate-ethyl acrylate (1:1) and / or a copolymer of methacrylate-methyl methacrylate (1:1). In one embodiment, the polymer carrier in the solid dispersion of the present invention is Eudragit E100. In one embodiment, the polymer carrier in the solid dispersion of the present invention is Eudragit L100. In one embodiment, the polymer carrier in the solid dispersion of the present invention is Eudragit L100-55.

[0063] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is a mixture of a cellulose-based polymer and a polyacrylic resin-based polymer.

[0064] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is a mixture of a cellulosic polymer and a polyacrylic resin polymer, wherein the cellulosic polymer is selected from the general or specific cellulosic polymers mentioned in the above embodiment, preferably an ester of cellulose ether, more preferably hypromellose acetate succinate (HPMCAS), and most preferably HPMCAS LG, wherein the polyacrylic resin polymer is selected from the general or specific polyacrylic resin polymers mentioned in the above embodiment, for example Eudragit such as Eudragit L100, Eudragit E100, Eudragit L100-55, or a mixture thereof in any ratio, preferably a methacrylate-ethyl acrylate (1:1) copolymer such as Eudragit L100-55.

[0065] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is a mixture of the above-mentioned general or specific cellulosic polymer and the above-mentioned general or specific polyacrylic resin polymer, wherein the weight ratio between the cellulosic polymer and the polyacrylic resin polymer is about 10:1 to 5:1, for example, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, preferably about 8:1 to 5:1, about 7:1 to 5:1, 7:1 to 6:1, about 6:1 to 5:1, or any integer or non-integer weight ratio between them.

[0066] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the weight ratio (drug carrying ratio) of the above-mentioned EED inhibitor (e.g., compound A) to the polymer carrier is at least about 1:1. This allows for the production of a homogeneous dispersion of the active ingredient and the carrier by the production method of the present invention, completely converting the active ingredient to an amorphous state, thereby improving the solubility and absorption of the drug, and thereby improving the bioavailability of the drug after oral administration. Furthermore, the solid dispersion thus produced is stable, does not undergo aging under accelerated conditions, and shows no significant changes in any of the indicators. While a higher carrier content facilitates the dissolution and absorption of the active ingredient, a low drug load increases the mass of the formulation and the difficulty of formulation. Considering all these factors, the drug load ratio in the solid dispersion of the present invention is approximately 1:1 to 1:5, for example, approximately 1:1, approximately 1:1.5, approximately 1:2, approximately 1:2.5, approximately 1:3, approximately 1:3.5, approximately 1:4, approximately 1:4.5, approximately 1:5, or any integer or non-integer weight ratio between these, preferably approximately 1:1 to 1:2, approximately 1:1 to 1:3, approximately 1:1 to 1:4, approximately 1:2 to 1:3, approximately 1:2 to 1:4, and approximately 1:3 to 1:4, and more preferably approximately 1:3 to 1:4.

[0067] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the above-mentioned EED inhibitor (e.g., compound A) constitutes about 10 to 50% by weight of the solid dispersion, or any integer or non-integer point value between those, for example, about 5% by weight, 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, or any integer or non-integer weight ratio between those.

[0068] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the content range of the EED inhibitor (e.g., compound A) in the solid dispersion is, for example, about 10-50% by weight, 10-40% by weight, 10-30% by weight, 10-20% by weight, 15-50% by weight, 15-40% by weight, 15-30% by weight, 15-35% by weight, 15-20% by weight, 20-50% by weight, 20-40% by weight, and 20-35% by weight. The values ​​are weight%, 20-30 weight%, 25-50 weight%, 25-40 weight%, 25-35 weight%, 25-30 weight%, 30-50 weight%, 30-45 weight%, 30-40 weight%, 30-35 weight%, or any integer or non-integer range value between them, preferably about 10-40 weight%, 15-40 weight%, 15-35 weight%, 20-50 weight%, 20-40 weight%, and 20-35 weight%.

[0069] In one embodiment, the present invention provides the above-mentioned solid dispersion, of which the polymer carrier accounts for about 40% to 90% by weight of the solid dispersion, or any integer or non-integer point value between those, for example, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, and about 90% by weight.

[0070] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the content range of the polymer carrier in the solid dispersion is, for example, about 40-90% by weight, 40-80% by weight, 40-70% by weight, 40-60% by weight, 40-50% by weight, 45-90% by weight, 45-80% by weight, 45-70% by weight, 45-60% by weight, 50-90% by weight, 50-80% by weight, 50-70% by weight, and 50-60% by weight. %, 55-90% by weight, 55-80% by weight, 55-70% by weight, 55-65% by weight, 60-90% by weight, 60-80% by weight, 60-70% by weight, 65-90% by weight, 65-80% by weight, 65-75% by weight, 70-90% by weight, 70-80% by weight, or any integer, non-integer point value or range value between them, preferably about 40-80% by weight, 50-80% by weight, 60-80% by weight.

[0071] In one embodiment, the present invention provides a solid dispersion comprising an EED inhibitor (e.g., compound A) and a polymer carrier, wherein the EED inhibitor is an EED inhibitor as generally or preferably described above, most preferably compound A, and the polymer carrier is a polymer carrier as generally or preferably described above, more preferably HPMCAS and / or Eudragit (e.g., methacrylate-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55), most preferably HPMCAS LG. In one embodiment, the weight ratio between the EED inhibitor and the polymer carrier constituting the solid dispersion and the weight ratio of each to the solid dispersion are as generally or specifically defined above.

[0072] In one embodiment, the present invention provides the above-mentioned solid dispersion, wherein the content range of the EED inhibitor (e.g., compound A) is 20 to 50% by weight, the content range of the polymer support is 50 to 80% by weight, preferably the content range of the EED inhibitor (e.g., compound A) is 20 to 40% by weight, and the content range of the polymer support is 60 to 80% by weight.

[0073] The solid dispersion provided in the present invention is confirmed by methods such as PLM and / or XRPD and / or DSC to have the active ingredient, an EED inhibitor (e.g., compound A), in an amorphous state and to have undergone complete crystalline conversion.

[0074] The solid dispersion provided in the present invention is stable under conditions selected from high temperature (60°C), high humidity (25°C / RH90%), accelerated conditions (40°C / RH75%), refrigeration (2-8°C), polishing (5-15 min / room temperature), polishing and refrigeration (5-15 min / 2-8°C), and tableting (room temperature or refrigerated). That is, it has chemical stability and solid stability, and by methods such as PLM and / or XRPD and / or DSC, it is confirmed that the active ingredient, the EED inhibitor, is in an amorphous state, there is no aging phenomenon, and there is no clear change in the active ingredient content or impurities.

[0075] The solid dispersion provided in the present invention maintains stable solubility for at least 24 hours in fasting-simulated intestinal fluid (FaSSIF) at pH 6.5, and its solubility is at least about 10 times that of the EED inhibitor active pharmaceutical ingredient (e.g., compound A) under the same conditions, for example, about 10 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 50 times, and about 60 times.

[0076] In one embodiment, the present invention provides a solid dispersion comprising an EED inhibitor (e.g., compound A) and a polymer carrier consisting of a cellulose ether ester system (e.g., HPMCAS) and a polyacrylic resin system (e.g., Eudragit, e.g., methacrylate-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55), wherein the EED inhibitor, its drug-loading amount, the cellulose ether ester system and the polyacrylic resin polymer carrier, and their content and weight ratios are as generally and specifically defined above for the corresponding features, and the solubility of the solid dispersion in a fetal intestinal fluid (FeSSIF) at pH 5.8 is maintained stably for at least 24 hours, and the EED inhibitor maintains a non-crystalline state for at least 24 hours.

[0077] In one embodiment, first, an EED inhibitor (e.g., compound A) and a cellulose ether ester polymer carrier (e.g., HPMCAS) are prepared as a solid dispersion according to the method of the present invention, and a polyacrylic resin polymer (e.g., Eudragit, e.g., methacrylate-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55) may be added. The mixture containing the solid dispersion thus prepared can similarly make the active ingredient, the EED inhibitor, amorphous, and possesses the above-mentioned chemical stability and solid stability. Its solubility in fasting-simulated intestinal fluid (FaSSIF) at pH 6.5 can be maintained stably for at least 24 hours, and is far higher than the solubility of the EED inhibitor active pharmaceutical ingredient under the same conditions. Furthermore, its solubility in feeding-simulated intestinal fluid (FeSSIF) at pH 5.8 can be maintained stably for at least 24 hours, and it maintains an amorphous state for at least 24 hours.

[0078] In animal pharmacokinetic experiments (such as the Beagle dog pharmacokinetic study shown in the examples), the solid dispersion provided in the present invention has been shown to have an in vivo exposure level equivalent to that of the EED inhibitor solution when administered at the same dose, with an AUC value reaching at least 80% of that of the solution.

[0079] The solid dispersions provided in the present invention can be used directly or manufactured into different dosage forms as needed for treatment or prevention.

[0080] In a second aspect, the present invention provides a method for producing the EED inhibitor solid dispersion of the present invention. The solid dispersion of the present invention can be obtained by widely known production methods such as melting, solvent, solvent-melting, spray drying, fluidized bed drying, and melt extrusion.

[0081] In one specific embodiment, the present invention preferably produces an EED inhibitor solid dispersion by a spray-drying method, which is described below. (1) Dissolve an EED inhibitor (e.g., compound A) in an organic solvent, add a polymer support, stir to dissolve, and prepare a spray-dried solution. (2) The step of removing the organic solvent by spray-drying the solution obtained in step (1).

[0082] In one embodiment, a method for producing the EED inhibitor solid dispersion further comprises step (3) of vacuum drying the spray-dried powder obtained in step (2).

[0083] In step (1), the organic solvent used is not strictly limited, but should be able to sufficiently dissolve the EED inhibitor. Examples include methanol, anhydrous ethanol, isopropanol, isobutanol, ethyl acetate, acetone, dichloromethane, n-hexane, n-heptane, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dimethyl sulfoxide, dimethylformamide, and N,N-dimethylacetamide, but are not limited to these. Preferably, it is dichloromethane, methanol, or a mixture thereof in any ratio, and more preferably a dichloromethane / methanol mixed solvent of about 2:1 to 3:1.

[0084] In step (1), the amount of organic solvent used should be sufficient to dissolve the EED inhibitor, and the solid content concentration of the appropriate solution should be 120 mg / mL or less, preferably in the range of 20 to 80 mg / mL, and more preferably in the range of 40 to 60 mg / mL.

[0085] In step (1), the form of the EED inhibitor is not strictly limited; amorphous or crystalline forms may be used, and any EED inhibitor of a different crystalline form can be converted to an amorphous form in the solid dispersion system of the present invention.

[0086] In step (2), the drying conditions and means are not strictly limited, as long as the organic solvent can be removed. In one embodiment, the drying in step (2) is carried out by spray drying, and those skilled in the art can determine the parameters of the spray drying, for example, by controlling the intake air temperature of the spray drying to within the range of 65 to 95°C, for example, 70°C. In one specific embodiment, the spray drying is carried out under light-shielding conditions.

[0087] In one embodiment, after step (2), vacuum drying in step (3) is optionally performed to further remove the organic solvent, and the conditions for vacuum drying are not strictly limited and can be determined by those skilled in the art. In one specific embodiment, vacuum drying is performed at a temperature of 25 to 50°C (e.g., 50°C) and under reduced pressure of 0 to -0.1 MPa (e.g., -0.1 MPa) for an appropriate amount of time, for example, 2 to 5 hours, for example, 4 hours, but is not limited thereto.

[0088] In the method for producing a solid dispersion according to this embodiment of the present invention, the yield of the solid dispersion reaches at least 75%, and it exhibits good pressure resistance.

[0089] In a third aspect, the present invention provides a solid dispersion composition comprising the solid dispersion and excipients of the present invention, wherein the solid dispersion is as generally or specifically defined herein for the solid dispersion of the present invention, and the excipients are one or more selected from diluents, flavorings, surfactants, fillers, binders, disintegrants, lubricants, flow promoters / anti-tackifiers, stabilizers, emulsifiers, coatings and / or release modifiers.

[0090] In one embodiment, the present invention provides a solid dispersion composition which may be in the form of tablets, capsules, granules, powders, or pills.

[0091] In a fourth aspect, the present invention relates to a method for producing the solid dispersion composition of the present invention, (1) A step of uniformly mixing the EED inhibitor solid dispersion of the present invention with a filler, binder, disintegrant, stabilizer and / or flow enhancer, (2) A step of optionally granulating the mixture from step (1), (3) A manufacturing method comprising the step of optionally thoroughly mixing the granules produced in step (2) with a lubricant.

[0092] In one embodiment, the composition produced as described above may be manufactured in the form of pills, granules, powders, etc., or it may be further pressed into tablet form, or the resulting mixture or granules may be directly filled into capsule shells to produce capsules.

[0093] In a fifth embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A) comprising a solid dispersion or solid dispersion composition of the present invention and an optional excipient.

[0094] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which is a solid oral formulation selected from tablets, capsules, granules, powders, lozenges and pills, preferably tablets or capsules, and more preferably tablets.

[0095] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which comprises a solid dispersion of the present invention, and further comprises one or more of the following: fillers, stabilizers, binders, disintegrants, lubricants, flow promoters, and coating agents.

[0096] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which comprises a solid dispersion of the present invention, and further comprises a filler, a binder, a disintegrant, and a lubricant.

[0097] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which comprises a solid dispersion of the present invention, and further comprises a filler, a binder, a disintegrant, a lubricant, and a flow enhancer.

[0098] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which comprises a solid dispersion of the present invention, and further comprises a filler, binder, disintegrant, lubricant, stabilizer, and flow enhancer.

[0099] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which comprises a solid dispersion of the present invention, and further comprises a filler, binder, disintegrant, lubricant, stabilizer, flow enhancer, and coating agent.

[0100] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the content of the EED inhibitor is about 5 to 40% by weight of the oral formulation, or any integer, non-integer point, or range between these values, for example, about 5 to 30% by weight, about 5 to 20% by weight, about 10 to 40% by weight, about 10 to 30% by weight, about 10 to 20% by weight, about 15 to 40% by weight, about 15 to 30% by weight, about 15 to 25% by weight, about 20 to 40% by weight, about 20 to 30% by weight, about 25 to 40% by weight, about 25 to 35% by weight, and about 30 to 40% by weight, but is not limited to these, preferably about 10 to 30%, and more preferably about 10 to 20%.

[0101] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the amount of the EED inhibitor in a unit formulation is approximately 5 to 500 mg, for example, approximately 5 to 400 mg, approximately 5 to 300 mg, approximately 5 to 200 mg, approximately 10 to 500 mg, approximately 10 to 400 mg, and approximately 10 to 200 mg, but is not limited to these amounts, and is preferably approximately 10 to 200 mg, for example, approximately 200 mg, approximately 150 mg, approximately 100 mg, approximately 75 mg, approximately 50 mg, approximately 25 mg, approximately 15 mg, and approximately 10 mg, and more preferably approximately 10 mg, approximately 50 mg, and approximately 200 mg.

[0102] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the solid dispersion accounts for about 10-80% of the weight of the oral formulation, or any integer, non-integer point, or range value between these, for example, about 10-70%, about 10-50%, about 20-80%, about 20-70%, about 20-60%, about 30-80%, about 30-70%, about 30-50%, about 40-80%, about 40-70%, about 50-80%, and about 50-70%, but is not limited to these, and is preferably about 30-80%, about 40-80%, about 40-70%, about 50-80%, and more preferably about 50-70%.

[0103] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the filler may be selected from lactose, sucrose, calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, starch, mannitol, etc., preferably the filler is microcrystalline cellulose, and the amount of the filler occupies about 10 to 80% of the weight of the oral formulation, or any integer, non-integer point, or range value between them, e.g. For example, approximately 10-70%, approximately 10-60%, approximately 10-50%, approximately 10-40%, approximately 10-30%, approximately 15-35%, approximately 15-40%, approximately 20-80%, approximately 20-70%, approximately 20-60%, approximately 20-50%, approximately 20-40%, approximately 30-80%, approximately 30-70%, approximately 30-60%, approximately 30-50%, and approximately 30-40%, but not limited to these. Preferably, approximately 10-60%, approximately 15-40%, approximately 20-60%, approximately 20-40%, and approximately 20-30%, more preferably approximately 20-40%, and most preferably approximately 20-30%.

[0104] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the binder may be selected from polyvinylpyrrolidone, starch, methylcellulose, hydroxypropylcellulose, hypromellose, alginate, etc., preferably the binder is selected from polyvinylpyrrolidone or hypromellose, and the dose of the binder is 0.5 to 10% of the weight of the oral formulation, or any intermediate amount between these. These values ​​occupy a number, a non-integer point, or a range of values, for example, approximately 0.5-9%, 0.5-8%, 0.5-5%, 1-10%, 1-9%, 1-8%, 1-5%, 1-3%, 1.5-2.5%, 2-10%, 2-8%, 2-5%, and 2-4%, but are not limited to these. Preferably, they are approximately 0.5-5%, 1-3%, and 1.5-2.5%, more preferably 1-3%, and most preferably 1.5-2.5%.

[0105] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the disintegrant may be selected from croscarmellose sodium, crospovidone, carboxymethyl starch sodium, starch, pregelatinized starch, etc., preferably the disintegrant is croscarmellose sodium, and the dose of the disintegrant is 1 to 20% of the weight of the oral formulation, or any integer between these amounts or non- The values ​​occupy integer points or ranges, for example, about 1.0%, about 2.0%, about 5.0%, about 7.0%, about 10%, about 15%, about 20%, about 1-10%, about 1-8%, about 2-10%, about 2-8%, about 2-7%, about 3-10%, about 3-8%, about 3-7%, about 4-10%, and about 4-8%, but are not limited to these. Preferably, they are about 1-10%, about 2-8%, and about 3-7%, more preferably about 2-8%, and most preferably about 3-7%.

[0106] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), wherein the lubricant may be selected from stearic acid, magnesium stearate, calcium stearate, zinc stearate, palmitic acid, glyceryl palmitate stearate, talc, carnauba wax, sodium lauryl sulfate, sodium stearyl fumarate, and the like, preferably the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, and zinc stearate, and the dose of the lubricant is 0.1 to 5% of the weight of the oral formulation, or any integer between these amounts. These values ​​may occupy non-integer points or range values, such as approximately 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 0.5-5%, 0.5-4%, 0.5-3%, 0.5-2%, 0.5-2.5%, 0.5-1.5%, 1-5%, 1-4%, 1-3%, 1-2.5%, and 1-2%, but are not limited to these. Preferably, they are approximately 0.5-3%, 0.5-2%, 0.5-1.5%, 1-3%, and 1-2%, more preferably approximately 0.5-2%, and most preferably approximately 0.5-1.5%.

[0107] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), further comprising a stabilizer, the stabilizer of which may be selected from hypromellose, sodium dodecyl sulfate, polyacrylic resin polymers, and preferably a polyacrylic resin polymer, for example, the general or specific polyacrylic resin polymers referred to in the above embodiments, for example, Eudragit, for example, Eudragit L100, Eudragit E100, Eudragit L100-55, or a mixture thereof in any ratio, and preferably a methacrylate-ethyl acrylate (1:1) copolymer, for example, Eudragit The L100-55 is the amount of the stabilizer, which accounts for 1-20% of the weight of the oral preparation, or any integer, non-integer point, or range value between these, for example, about 1.0%, about 2.0%, about 3.0%, about 5.0%, about 7.0%, about 10%, about 12%, about 15%, about 1-10%, about 1-8%, about 2-10%, about 2-8%, about 3-10%, about 3-8%, about 4-10%, about 4-8%, about 5-10%, and about 5-8%, but is not limited to these. Preferably, it is about 1-10%, about 5-10%, about 2-8%, and about 4-8%, more preferably about 2-8%, and most preferably about 4-8%.

[0108] In one embodiment, the present invention provides an oral formulation of an EED inhibitor (e.g., compound A) further comprising a flow enhancer, the flow enhancer may be selected from talc, silica, fine silica gel (colloidal silica), and other medicinal forms of silica, preferably colloidal silica, and the dose of the flow enhancer shall occupy 0 to 5% of the weight of the oral formulation, or any integer, non-integer point, or range between them, e.g. For example, these include 0%, approximately 0.5%, approximately 1.0%, approximately 1.5%, approximately 2.0%, approximately 2.5%, approximately 3.0%, approximately 3.5%, approximately 4.0%, approximately 4.5%, approximately 0.5-5%, 0.5-4%, 0.5-3%, 0.5-2%, 0.5-1.5%, 1-3%, and 1-2%, but are not limited to these. Preferably, they are approximately 0.5-4%, 0.5-3%, 0.5-2%, and 0.5-1.5%, more preferably approximately 0.5-2%, and most preferably approximately 0.5-1.5%.

[0109] In one embodiment, the present invention provides an oral formulation of the above-mentioned EED inhibitor (e.g., compound A), for example, a tablet, which is... 1) A general or specifically defined solid dispersion as described herein, comprising approximately 5 to 500 mg of a general or specifically defined EED inhibitor as described herein (e.g., compound A), and the general or specifically defined polymer carrier as described above, 2) Approximately 10 to 80% by weight of the general or specifically defined fillers described herein, 3) Approximately 0.5 to 10% by weight of a general or specifically defined binder as described herein, 4) Approximately 1 to 20% by weight of a general or specifically defined disintegrant as described herein, 5) comprising approximately 0.1 to 5% by weight of a general or specifically defined lubricant as described herein, Preferably, 1) A general or specifically defined solid dispersion as described herein, comprising approximately 10 to 500 mg of a general or specifically defined EED inhibitor as described herein (e.g., compound A), and the general or specifically defined polymer carrier described above, 2) Approximately 20-60% by weight of the general or specifically defined fillers described herein, 3) Approximately 0.5 to 5% by weight of a general or specifically defined binder as described herein, 4) Approximately 1 to 10% by weight of a general or specifically defined disintegrant as described herein, 5) comprising approximately 0.5 to 3% by weight of a general or specifically defined lubricant as described herein, more, 1) A general or specifically defined solid dispersion as described herein, comprising approximately 10 to 200 mg of a general or specifically defined EED inhibitor as described herein (e.g., compound A), and the general or specifically defined polymer carrier described above, 2) Approximately 20-40% by weight of the general or specifically defined fillers described herein, 3) Approximately 1-3% by weight of a general or specifically defined binder as described herein, 4) Approximately 2-8% by weight of a general or specifically defined disintegrant as described herein, 5) comprising approximately 0.5 to 2% by weight of a general or specifically defined lubricant as described herein, Most preferably, 1) A general or specifically defined solid dispersion as described herein, comprising approximately 10 to 200 mg of a general or specifically defined EED inhibitor as described herein (e.g., compound A), and the general or specifically defined polymer carrier described above, 2) Approximately 20-30% by weight of the general or specifically defined fillers described herein, 3) Approximately 1.5 to 2.5% by weight of a general or specifically defined binder as described herein, 4) Approximately 3-7% by weight of a disintegrant as described herein, 5) comprising approximately 0.5 to 1.5% by weight of a general or specifically defined lubricant as described herein, The above general, preferred, more preferred, or most preferred oral formulations can each be further optionally selected as follows: 6) comprising about 1 to 20% by weight, preferably about 1 to 10% by weight, more preferably about 2 to 8% by weight, and most preferably about 4 to 8% by weight of a general or specifically defined stabilizer as specified herein, and / or The above general, preferred, more preferred, or most preferred oral formulations can each be further optionally selected as follows: 7) comprising about 0 to 5% by weight, preferably about 0.5 to 3% by weight, more preferably about 0.5 to 2% by weight, and most preferably about 0.5 to 1.5% by weight of a general or specifically defined flow promoter as described herein.

[0110] What should be explained is that in the oral formulation of the EED inhibitor (e.g., compound A) of the present invention as generally or preferably defined above, the solid dispersion, the selection of each component, the content of each component, and the mixing ratios between them (e.g., drug loading ratio, mixing ratio between polymer carriers) are all as defined in the first aspect of the present invention, that is, it covers technical proposals for solid dispersions configured with the general or preferred definitions of each technical feature, as well as technical proposals for solid dispersions configured with any combination of the general or preferred definitions of each technical feature.

[0111] In one embodiment, the present invention provides an oral formulation of the above-mentioned EED inhibitor, for example, a tablet, wherein the EED inhibitor is compound A or a pharmaceutically acceptable salt or solvate thereof, and the polymer carrier in the solid dispersion is hypromellose acetate succinate (HPMCAS).

[0112] In one embodiment, the present invention provides an oral formulation of the above-mentioned EED inhibitor, for example, a tablet, wherein the EED inhibitor is compound A or a pharmaceutically acceptable salt or solvate thereof, and the polymer carrier in the solid dispersion is a mixture of cellulose ether ester-based (e.g., HPMCAS) and polyacrylic resin-based (e.g., Eudragit, e.g., methacrylate-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55) polymers as generally or specifically defined herein.

[0113] In one embodiment, the present invention provides an oral formulation of the above-mentioned EED inhibitor, for example, a tablet, wherein the EED inhibitor is compound A or a pharmaceutically acceptable salt or solvate thereof, and the polymer carrier in the solid dispersion is a polyacrylic resin-based polymer as generally or specifically defined herein (e.g., Eudragit, e.g., methacrylate-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55).

[0114] In one embodiment, the present invention provides an oral formulation of the above-mentioned EED inhibitor (e.g., compound A), such as a tablet, wherein the filler is microcrystalline cellulose, the binder is hypromellose, the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, the stabilizer is a methacrylate-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55), and the flow enhancer is colloidal silica.

[0115] In one embodiment, the present invention provides an oral formulation of the above-mentioned EED inhibitor (e.g., compound A), for example, a tablet, of which the tablet may be a coated tablet, of which the coating agent is well known to those skilled in the art, for example, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, hypromellose phthalate, methacrylic acid copolymer, gelatin, medicinal glaze, polyethylene glycol, polyvinyl acetate phthalate, sodium dodecyl sulfate, shellac, sucrose, titanium dioxide The coating agent may be a mixture of ointment, carnauba wax, zein, opa-dry, or other common film coating premixtures well known to those skilled in the art, but is not limited thereto. The amount of the coating agent may be 0-10% of the weight of the oral formulation, or any range between these, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, or about 10%, but is not limited thereto. Preferably, it is about 1-5%, 2-4%, and more preferably about 2-4%.

[0116] The oral formulation of the above-mentioned EED inhibitor (e.g., compound A) provided in the present invention, such as a tablet, exhibits rapid and complete dissolution, and under aqueous media conditions of 0.15% sodium dodecyl sulfate (SDS) at pH 6-7, the dissolution rate of the active ingredient is maintained at approximately 75% or more, preferably approximately 80% or more, more preferably 85% or more, after 30 minutes, and at approximately 85% or more, preferably approximately 90% or more, after 45 minutes.

[0117] The oral formulation of the EED inhibitor (e.g., compound A) provided in the present invention is a tablet with a tablet hardness between approximately 50 and 400 N. In one specific embodiment, a 10 mg tablet has a hardness between approximately 30 and 90 N, preferably between approximately 30 and 80 N. In one specific embodiment, a 50 mg tablet has a hardness between approximately 50 and 200 N, preferably between approximately 70 and 150 N. In one specific embodiment, a 200 mg tablet has a hardness between approximately 150 and 400 N, preferably between approximately 200 and 360 N.

[0118] The oral formulation of the EED inhibitor (e.g., compound A) provided in the present invention is a tablet, wherein the abrasion of the tablet is less than about 1% by weight, preferably less than about 0.5% by weight, for example less than about 0.2% by weight, and more preferably less than about 0.1% by weight.

[0119] The oral formulation of the EED inhibitor (e.g., compound A) provided in the present invention is a tablet, which has a disintegration time limit of less than about 15 minutes, preferably less than about 5 minutes, for example, about 0.5 to 5 minutes.

[0120] The oral formulation of the above-mentioned EED inhibitor (e.g., compound A) provided in the present invention exhibits good stability in the mixture of raw materials and auxiliary materials. When left for 0 / 5 / 10 / 30 days under high temperature (60°C), high humidity (25°C / RH90%±5%), accelerated conditions (40°C±2°C / RH75%±5%), and light-shielded conditions, there is no apparent change in appearance and no apparent increase in related substances.

[0121] The oral formulation of the above-mentioned EED inhibitor (e.g., compound A) provided in the present invention is in the form of a tablet. The finished formulation, after being packaged in ordinary packaging materials, exhibits good stability. When left for one month under conditions of 40°C±2°C / RH75%±5%, 30°C±2°C / RH65%±5%, and 25°C±2°C / RH60%±5%, no significant changes were observed in the appearance, moisture content, related substances, content, or dissolution rate of the test sample.

[0122] In a sixth embodiment, the present invention is a method for producing an oral formulation in tablet form as described above, (1) A step of uniformly mixing the EED inhibitor solid dispersion, filler, binder, disintegrant, stabilizer and / or flow enhancer of the present invention in a mixer, (2) A step of granulating the mixture from step (1), (3) A step of thoroughly mixing the granules produced in step (2) with a lubricant, (4) A manufacturing method comprising the step of compressing the mixture produced in step (3) into tablets is provided.

[0123] In one preferred embodiment, step (1) involves uniformly mixing the EED inhibitor solid dispersion, filler, stabilizer, binder, disintegrant, and flow enhancer of the present invention.

[0124] In one preferred embodiment, the mixture from step (1) is sieved and then mixed.

[0125] In one preferred embodiment, the sieved mixture from step (1) is remixed.

[0126] In one preferred embodiment, before granulation in step (2), the mixture from step (1) is thoroughly mixed with a portion of the lubricant, the portion of the lubricant added may preferably be about 40-70% of the total weight of the lubricant in the formulation, and more preferably about 50-70%. Adding a portion of the lubricant at this stage helps to further improve the adhesion phenomenon in the subsequent granulation process and the sticking phenomenon in the tableting process.

[0127] In step (2), the conditions and means of granulation are not strictly limited, and wet granulation may be used, as well as dry granulation or melt granulation.

[0128] In one preferred embodiment, the granulation in step (2) employs dry granulation and can be carried out by a conventional method known in the art, for example, the roll press method can be used, for example, refer to "Pharmaceutical Science," edited by Fang Liang, 3rd edition, July 2015, China Pharmaceutical and Technology Press.

[0129] In one preferred embodiment, the pressure for dry granulation may be 6 to 8 kPa, preferably 4 to 6 kPa. Adopting this pressure range further reduces the adhesion of the dry granulation material to the press rolls, further improves the fluidity of the produced granules, and further reduces the sticking phenomenon during tableting.

[0130] Tablets manufactured according to the above method have a degree of abrasion of less than 1%, preferably less than about 0.5%, a disintegration time limit of less than 15 minutes, preferably less than 10 minutes or less than 5 minutes, and a dissolution rate of 75% or more in 30 minutes and 85% or more in 45 minutes in an SDS solution at pH 6.8.

[0131] In one embodiment, the method for producing an oral formulation in tablet form according to this aspect of the present invention further includes step (5) of coating the tablets produced in step (4) with a coating material.

[0132] In step (5), the coating material used is not particularly limited, but it should not significantly affect the tablet content and dissolution rate, and should also provide light-shielding properties to further improve the storage stability of the tablet formulation.

[0133] In one embodiment, the coating material of step (5) accounts for about 1-5%, preferably 2-4%, of the total weight of the oral tablet formulation and increases the weight of the core by about 1-5%, preferably 2-4%.

[0134] It should be explained that in the manufacturing methods of the second, fourth, and sixth aspects of the present invention described above, the selection and dosage of the EED inhibitor (e.g., compound A), polymer carrier, solid dispersion, and various excipients are all as generally, specifically, or preferably defined above for the corresponding technical proposals, the most preferred EED inhibitor being compound A or a pharmaceutically acceptable salt or solvate thereof, the polymer carrier being hypromellose acetate succinate (HPMCAS) and / or methacrylate-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55), the filler being microcrystalline cellulose, the stabilizer being methacrylate-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55), the binder being hypromellose, the disintegrant being croscarmellose sodium, the lubricant being magnesium stearate, and the flow enhancer being colloidal silica.

[0135] In a seventh aspect, the present invention provides the use of the solid dispersion, solid dispersion composition, or oral formulation of the present invention for the treatment or prevention of diseases (e.g., cancer or tumors) promoted by EED inhibition.

[0136] In an eighth aspect, the present invention provides the use of the above-described solid dispersion, solid dispersion composition, or oral formulation of the present invention in the manufacture of a drug for treating or preventing diseases (e.g., cancer or tumors) promoted by EED inhibition.

[0137] In a ninth embodiment, the present invention provides a method for treating or preventing a disease (e.g., cancer or tumor) that is promoted by EED inhibition in a patient, comprising administering a therapeutically effective amount of the solid dispersion, solid dispersion composition or oral formulation of the present invention to a subject in need thereof.

[0138] For explanation purposes, the "diseases promoted by EED inhibition" described in the seventh to ninth aspects of the present invention above are selected from cancer and proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections, and are preferably cancer and proliferative disorders. For specific examples, please refer to the corresponding content in CN114127073A.

[0139] In one embodiment, the "diseases promoted by EED inhibition" described in the seventh to ninth aspects of the present invention are cancers selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, mixed lineage chronic lymphocytic leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovarian cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0140] Each of the above-described technical proposals of the present invention involves producing a solid dispersion of a poorly soluble EED inhibitor active ingredient, such as compound A, on a specific type of polymer carrier. The drug active ingredient maintains a stable, formless state in the solid dispersion environment while simultaneously improving the solubility and dissolution of the drug in gastrointestinal fluid, thereby enhancing the oral bioavailability of the drug. The formulation performance of tablets produced using this solid dispersion in combination with specific excipients is excellent, with abrasion resistance, hardness, disintegration time limitation, and dissolution rate simultaneously reaching excellent levels. Furthermore, the manufacturing method employed is simple, the parameters are easily controllable, it is highly reproducible, and industrial production is easily achieved. [Brief explanation of the drawing]

[0141] [Figure 1] Figure 1A shows the DSC patterns of compound A (hereinafter abbreviated as API), a typical polymer carrier (Figure 1B), and a mixture of compound A and a typical polymer carrier (drug loading ratio 1:3) (Figure 1C). [Figure 2] PLM images of solid dispersions prepared with different carriers (hypromellose acetate succinate-LG, copovidone VA64, or hydroxypropylcellulose EXF) and APIs are shown. [Figure 3A] The XRPD patterns of solid dispersions prepared with different carriers (hypromellose acetate succinate-LG, copovidone VA64, or hydroxypropylcellulose EXF) and APIs are shown. [Figure 3B] The XRPD patterns of solid dispersions prepared with different carriers (Eudragit L100-55 or Eudragit L100-55 + HPMCAS-LG) and API are shown. [Figure 3C] The XRPD patterns of solid dispersions with different drug loading ratios (API: HPMCAS-LG) are shown. [Figure 4A-4D] The DSC patterns of solid dispersions with different drug loading ratios (API: HPMCAS-LG) are shown. [Figure 5A] This shows the dynamic solubility of compound A solid dispersions prepared with different polymer supports in FaSSIF-V2 solution. [Figure 5B] This shows the dynamic solubility of solid dispersions with different drug loading ratios (API: HPMCAS-LG) in FeSSIF-V2 solution when Eudragit L100-55 is further added. [Figure 6] The pharmacokinetic properties of the solid dispersion of the present invention administered orally to beagle dogs are shown. [Figure 7] The dissolution characteristics of the solid oral formulation of the present invention are shown. [Modes for carrying out the invention]

[0142] The present invention will be further described and interpreted below with reference to examples, but this will not limit the scope of the claims.

[0143] Unless otherwise specified, all auxiliary materials and reagents used in the examples are commercially available, and their quality standards and dosages meet the standards of the Chinese Pharmacopoeia. The EED inhibitors used in the present invention can be prepared by referring to the method described in CN114127073A, for example, compound A or its pharmaceutically acceptable salt can be prepared by referring to the method in Example 73 thereof.

[0144] General experimental methods 1. X-ray powder diffraction (XRPD): A D8 Advance instrument was used, equipped with a Lynxeye detector, and patterns were recorded under the following conditions: X-ray (Cu, Kα(Å): 1.54), 45kV / 40mA, step size (°2θ) 0.02, scan speed (s / step) 0.1, and scan range (°2θ) 3-40.

[0145] 2. Polarizing Microscope (PLM): An Axiolab5 instrument was used. Under room temperature conditions, an appropriate amount of sample awaiting measurement was placed on a glass slide, a small amount of paraffin was dropped onto it to disperse the sample, a coverslip was placed over it to further disperse the sample, the coverslip was removed, and the sample was observed under a 20x objective lens (200x magnification).

[0146] 3. Modulated Differential Scanning Calorimetry (mDSC): A Discovery DSC 2500 was used, with linear heating (10°C / min), and patterns were recorded from 25°C using nitrogen gas.

[0147] 4. Measurement of active ingredient content: A high-performance liquid chromatograph (HPLC) equipped with an ultraviolet detector or diode array detector and an autosampler was used. The column was a Waters Xbridge C18 (4.6 × 150 mm, 3.5 μm, column temperature 30°C), the mobile phase was (A:B = 40:60, A: 0.05% aqueous phosphoric acid solution, B: 0.05% phosphoric acid solution in methanol:acetonitrile (1:9)), and the flow rate was 0.8 mL / min. The sample was diluted with methanol, injected in 10 μL, and the change in absorption value at UV 249 nm over time was recorded.

[0148] 5. Measurement of dissolution rate, tablet abrasion rate, hardness, and disintegration time limit: This was carried out by methods commonly used in this field, for example, by the corresponding measurement methods in the Chinese Pharmacopoeia 2015 edition.

[0149] 6. Fasting-like simulated intestinal fluid (FaSSIF), feeding-like simulated intestinal fluid (FeSSIF), and simulated gastric fluid (SGF) can be obtained using commercially available products or prepared as follows.

[0150] Preparation of FaSSIF-V2 solution: 1.39 g of sodium hydroxide, 2.22 g of maleic acid, and 4.01 g of sodium chloride were weighed out, the volume was adjusted to 1000 mL, dissolved by sonication, and the pH was adjusted to 6.5 for use. Then, 1.79 g of FaSSIF-V2 powder was added and dissolved for use.

[0151] Preparation of FeSSIF-V2 solution: 1.64 g of sodium hydroxide, 3.19 g of maleic acid, and 3.67 g of sodium chloride were weighed and dissolved in 500 mL of pure water. The pH was adjusted to 5.8, and 4.88 g of FeSSIF-V2 solution was added. The solution was then sonicated until completely dissolved, and the solution was prepared for use.

[0152] Preparation of simulated gastric juice (SGF): 0.96 mL of concentrated hydrochloric acid was taken, 150 mL of water and 2.5 g of pepsin were added, and after shaking uniformly, water was added to dilute it to 250 mL, and it was prepared for use.

[0153] 7. Preparation of Solid Dispersion: Compound A in the prescribed amount was weighed and added to a solvent (e.g., a mixed solvent of dichloromethane and methanol), stirred until dissolved, then the carrier material in the prescribed amount was added, stirred until dissolved, placed in a spray dryer, and spray drying was performed by selecting appropriate parameters such as intake temperature, intake volume, absorption rate, and pressure to obtain the solid dispersion of the present invention. The spray drying equipment applicable to the present invention includes, but is not limited to, corresponding equipment from Niro GEA Process Engineering Inc., Buchi Labortechnik AG., ProCept and SPX ANHYDROUS, and the present invention exemplifies the use of a BUCHI290 spray dryer and was carried out within the following parameter range. [Table 2]

[0154] The powder obtained by the above spray drying may be subjected to further secondary drying. For example, vacuum drying may be carried out at a temperature of 25 to 50°C (e.g., 50°C) and under reduced pressure of 0 to -0.1 MPa (e.g., -0.1 MPa) for an appropriate time, for example, 2 to 5 hours, or for example, 4 hours.

[0155] Example 1 Using a standard solubility measurement method well-known in this field, the solubility (at 25°C) of compound A, the active ingredient, in various solvents was measured, and the results are shown in Table 1 below.

[0156] [Table 3]

[0157] Based on the results of the above experiments, and after comprehensively considering factors such as economic efficiency, dissolution efficiency, and toxicity, the present invention employs a mixed solvent of dichloromethane and methanol as the solvent system for producing solid dispersions.

[0158] Example 2 12 mg of each carrier material was weighed and placed in a 2 mL liquid-phase vial with 8 mg of free base crystals of compound A. 1 mL of dichloromethane:methanol (2:1) solvent was then added to each vial, and the mixture was stirred for 30 minutes at 1500 rpm in a magnetic stirrer until completely dissolved, preparing a suspension solution with a solid content of 20 mg / mL. 20 μL of each formulation solution was pipetteed onto a glass slide, the droplets were dispersed with a coverslip, and the solutions were dried at 50°C. The solutions were then observed using a polarizing microscope (PLM). Eudragit L100-55 was detected using XRPD. The results are shown in Table 2.

[0159] [Table 4]

[0160] As shown in Table 2, polyethylene glycol and hypromellose E4M were clearly unsuitable as the measured carrier materials, and all other types of carriers were capable of completely transcrystalline conversion of compound A.

[0161] Example 3 According to the method for producing the solid dispersion described above, the following solid dispersions (ASDs) were produced using dichloromethane:methanol (2:1) as the solvent system, employing different carriers and compound A. [Table 5]

[0162] Using dichloromethane:methanol (3:1) as the solvent system, the following solid dispersions (ASDs) were prepared using different carriers and compound A. [Table 6] Note: "External addition" means adding the above substance to the solid dispersion obtained by preparing it with the carrier and compound A listed in the table, and the final ratio of compound A to HPMCAS-LG in * is 1:7.

[0163] The experimental results showed that when a solid dispersion of compound A was produced using different carriers and drug loading ratios, the yield was 75% or higher in all cases, indicating that all methods are feasible.

[0164] Example 4 The crystal transformation status of compound A in the solid dispersion of the present invention was investigated using the X-ray powder diffraction (XRPD) and polarized light microscopy (PLM) measurement methods described herein, and the results are shown in Table 3 and Figures 2, 3A, 3B, and 3C below.

[0165] [Table 7]

[0166] As shown in Table 3, when solid dispersions were prepared using HPMCAS-LG, copovidone VA64, hydroxypropylcellulose EXF, and / or Eudragit L100-55 as supports, compound A was completely transcrystalline in all cases, and no clear crystals were present.

[0167] Table 3 shows that the PLM detection results indicated that only very small amounts of birefringent granules were observed in all solid dispersions with different drug loading ratios. The XRPD results also showed that none of the samples had a crystal diffraction peak for compound A, suggesting that compound A can undergo complete crystallization at all different drug loading ratios.

[0168] Furthermore, the dynamic crystallization status of representative solid dispersions of the present invention in FeSSIF-V2 solution and / or FsSSIF-V2 solution was investigated. Of these, each solid dispersion was dispersed in FeSSIF-V2 solution to prepare a suspension containing approximately 1 mg / mL of compound A, or dispersed in FaSSIF-V2 solution to prepare a suspension containing approximately 2 mg / mL of compound A. Each suspension was then placed in a magnetic stirrer and dispersed at 1500 rpm at room temperature, while stirring was maintained at 1000 rpm. A 1.5 mL sample was taken at a certain point and observed according to the polarized light microscopy (PLM) measurement method described herein. The results are shown in Table 4.

[0169] [Table 8]

[0170] As shown in Table 4, each solid dispersion (ASD-11, ASD-12, ASD-13) prepared with compound A using HPMCAS-LG as a support could be maintained stably in FeSSIF-V2 solution for approximately 6 hours. PLM testing revealed no obvious birefringence granules in any of the dispersions, indicating that no crystal transmutation occurred. Longer-term stability in the FeSSIF-V2 solution can be achieved by further adding specific polymers to the solid dispersion. For example, the addition of HPMC-E4M, SDS, and HPMCAS-LG did not improve the stability in the solution over relatively long periods, and a large amount of birefringent granules (ASD-14, ASD-15, ASD-16) were still observable after 19 hours. However, by further adding Eudragit L100-55 to each drug-loading ratio of ASD, the solid dispersion could be maintained stably in the FeSSIF-V2 solution for 24 hours, and PLM testing showed no obvious birefringent granules and no crystal transmutation occurred.

[0171] As further shown in Table 4, solid dispersions (ASD-4, ASD-5, ASD-6, ASD-7, and ASD-8) can also be obtained by using Eudragit L100-55 or (Eudragit L100-55 + HPMCAS-LG) as a support and preparing them together with compound A. These solid dispersions remained stable in FeSSIF-V2 solution for 24 hours, and PLM testing did not reveal any obvious birefringence granules, indicating that no crystal transmutation occurred. Furthermore, these solid dispersions also remained stable in FaSSIF-V2 solution for 24 hours, and PLM testing at each time point did not reveal any obvious birefringence granules, indicating that no crystal transmutation occurred.

[0172] Furthermore, the crystallization status of compound A in the solid dispersions of the present invention (ASD-10, ASD-11, ASD-12, and ASD-13) with different drug loading ratios was investigated according to the modulated differential scanning calorimetry (mDSC) measurement method described herein. As shown in Figures 4A to 4D, none of the samples showed a crystallization peak for compound A, and as the drug loading ratio decreased, the glass transition temperature decreased, and the intensity of the crystallization peak at around 230°C weakened.

[0173] Example 5 Following the description of the general experimental method described above, the dynamic solubility of the solid dispersions of the present invention in FaSSIF, FeSSIF, and SGF solutions was investigated. Of these, each solid dispersion was dispersed in FeSSIF-V2 solution to prepare a suspension containing approximately 1 mg / mL of compound A, or dispersed in FaSSIF-V2 solution to prepare a suspension containing approximately 2 mg / mL of compound A. Each suspension was stirred to disperse, 1 to 1.5 mL was sampled at a certain point, centrifuged, the supernatant was taken, filtered through a membrane, and the content of compound A was measured according to the HPLC method described in the general experimental method described above. The results are shown in Table 5 and Figures 5A and 5B.

[0174] [Table 9]

[0175] As shown in Table 5, in the FaSSIF-V2 solution, the amount of compound A solid dispersion with different carriers and drug loading ratios dissolved at each time point was always much greater than the amount of compound A raw material dissolved, and the 24-hour dissolution amounts of compound A solid dispersion with different drug loading ratios were basically similar.

[0176] As further shown in Table 5, the API solubility of solid dispersions prepared using HPMCAS and / or Eudragit L100-55 or Copovidone VA64 in FaSSIF-V2 solution remains stable or increases over time. Of these, the API solubility of the solid dispersion prepared using HPMCAS with internal addition of Eudragit L100-55 is relatively superior to that of solid dispersions prepared using Copovidone VA64 and Hydroxypropylcellulose EXF.

[0177] As further shown in Table 5, the solid dispersions of FaSSIF-V2 solution and FeSSIF-V2 solution to which Eudragit L100-55 was added internally or externally showed a different degree of increase in API solubility compared to the solid dispersion to which HPMCAS was the only polymer support.

[0178] As further shown in Table 5, in the FeSSIF-V2 solution, the lower the drug load, the greater the solubility. Furthermore, the solid dispersions with only HPMCAS as the polymer support showed a significant decrease in solubility after 24 hours. However, when Eudragit L100-55 was further added to the solid dispersion, the solubility was able to maintain a balance over time, and the solubility of the API also increased as the proportion of Eudragit L100-55 added increased.

[0179] The comparison results in Table 5 further demonstrate that, under the same conditions, the amount of API dissolved in the FeSSIF-V2 solution was essentially the same whether Eudragit L100-55 was added internally or externally.

[0180] Furthermore, using SGF solution, the solid dispersion of the present invention was prepared as a suspension containing approximately 2 mg / mL of compound A, and its dynamic solubility was investigated. As a result, the solid dispersions with different drug loading ratios (e.g., ASD10-13) all had API solubility of less than 0.005 mg / mL at each time point between 1 and 24 hours, and even less than 0.0001 mg / mL.

[0181] Example 6 The solid dispersion ASD-12 (API: HPMCAS-LG=1:3) produced in Example 3 was subjected to high temperature (60°C), high humidity (25°C / RH90%±5%), and accelerated conditions (40°C±2°C / RH75%±5%) for 0 / 5 / 10 / 30 days. Samples were taken, and the chemical stability of ASD was evaluated using purity and related substances (maximum single impurity and total impurities) as indicators. The results are shown in Table 6.

[0182] [Table 10]

[0183] As shown in Table 6, ASD showed no apparent change in appearance and no apparent increase in related substances under high temperature, high humidity, and accelerated conditions, demonstrating good chemical stability of ASD.

[0184] Furthermore, the solid morphological stability (mDSC, XRPD, and PLM) of samples taken from the solid dispersion ASD-1 at each of the above time points was further investigated. As a result, on day 30, the XRPD patterns of all samples showed no clear crystal diffraction, the PLM examination showed no clear birefringence granules, and the mDSC patterns of all samples under all conditions showed no clear change from day 0.

[0185] Furthermore, the content of ASD-1 in the solid dispersion, impurities (single impurities and total impurities), and solid morphological stability (mDSC, XRPD, and PLM) in samples on day 0, day 5, day 10, and day 30 under the following conditions: refrigeration (2-8°C), 5 min polishing (room temperature), 5 min polishing and refrigeration (2-8°C), 15 min polishing (room temperature), 15 min polishing and refrigeration (2-8°C), tableting (room temperature), tableting and refrigeration (2-8°C), tableting with PH102 at room temperature (solid dispersion:PH102=1:5), and tableting with PH102 at 2-8°C (solid dispersion:PH102=1:5). As a result, no significant changes were observed in the content or impurities of any of the samples under each test condition. The XRPD patterns of all samples showed no clear crystal diffraction, and PLM testing revealed no clear birefringence granules. Furthermore, the mDSC patterns of all samples under all conditions showed no significant change compared to day 0.

[0186] As shown by the results above, the solid dispersion of the present invention has desirable stability properties and exhibits excellent chemical stability and solid stability under all measurement conditions, thus having the potential to be developed as a practical and convenient pharmaceutical product.

[0187] Example 7 In this experiment, a 2.5 mg / mL solution of compound A in a 0.5% SDS aqueous solution was used as a control (prepared within 2 hours prior to use), and the pharmacokinetic properties of the solid dispersion of the present invention (ASD-22, filled in a capsule shell) were investigated in beagle dogs.

[0188] Specifically, 15 male beagle dogs (weighing approximately 8-11 kg) were randomly divided into 5 groups of 3 dogs each. After an overnight fast, the test sample was orally administered to two of the groups at doses of 2.5 mg / kg and 10 mg / kg, respectively. In addition, a 10 mg / kg dose of the test sample was orally administered to a beagle dog in another group after 0.5 hours of feeding, and two other groups of beagle dogs that had been fasted overnight were orally administered 2.5 mg / kg and 50 mg / kg of compound A solution as controls. 0.5 mL of blood was collected from the cephalic vein of each group before administration (0 h) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. After removing the blood samples, they were immediately placed in heparinized EP tubes, centrifuged at 3000 g (RCF: relative centrifugal force) for 5 minutes to separate the plasma, and frozen in a refrigerator at -70°C for measurement.

[0189] During measurement, after thawing the plasma, 20 μL was precisely aspirated and placed in a plugged centrifuge tube. 200 μL of internal standard solution (60 ng / mL diclofenac, 70% methanol aqueous solution) was precisely added, and the mixture was homogenized by vortexing for 10 minutes. The mixture was then centrifuged at 5800 rpm for 10 minutes, and the supernatant was taken and analyzed by LC-MS / MS (Waters ACQUITY UPLC BEH C18 2.1×50 mm, mobile phase A: 0.025% formic acid (1 mM ammonium acetate aqueous solution), mobile phase B: 0.025% phosphoric acid (1 mM ammonium acetate methanol solution), gradient: 10%B (The concentration increased to 95% B at 0.2 min, then 0.2-1 min, maintained for 0.5 min, decreased to 10% B at 1.50-1.51 min, maintained up to 2 min, with a flow rate of 0.60 mL / min, autosampler temperature control / column temperature of 5°C / 60°C, and injection volume of 4 μL) The main pharmacokinetic parameters are shown in Table 7, and the plasma drug concentration-time curve is shown in Figure 6. Of these, the AUC values ​​were calculated using WinNonLin software.

[0190] [Table 11]

[0191] As shown in Table 7 and Figure 6, the solid dispersion of this invention resulted in comparable exposure in beagle dogs to the solution formulation under the same dosage and conditions, and no significant food effect was observed. This demonstrates that compound A, which is almost insoluble in water, can be successfully manufactured in a solid form with bioavailability comparable to that of the solution formulation, overcoming the common drawback of poorly soluble drugs—low bioavailability—and expanding the drug's potential uses.

[0192] Example 8 The solid dispersion (ASD-12) of the present invention was uniformly mixed with the excipients shown in Table 8 below, sieved, and dry-granulated. The resulting granules were then uniformly mixed with magnesium stearate, and the entire mixture of granules was pressed into tablets.

[0193] [Table 12]

[0194] As shown in Table 8, the tablets of formulations T1, T3, T4, and T5 exhibited relatively good dissolution characteristics, with dissolution reaching over 80% in 45 minutes. In particular, the tablets manufactured with microcrystalline cellulose alone as a filler had the best overall performance, good compressibility, acceptable disintegration time limitations, and the most complete dissolution.

[0195] Furthermore, the solid dispersion (ASD-12) of the present invention was uniformly mixed with the excipients shown in Table 9 below, sieved, and dry-granulated. The resulting granules were then uniformly mixed with magnesium stearate, and the entire mixture of granules was pressed into tablets.

[0196] [Table 13]

[0197] Each tablet manufactured according to the above formulation has an acceptable off-white appearance (with occasional spots).

[0198] As shown in Table 9, the disintegrant content is directly proportional to the disintegration time. Croscarmellose sodium, a disintegrant present in an amount of approximately 1-10% by weight, can rapidly disintegrate the above formulations, with a disintegration time of 1-10 minutes. Of these, the disintegration time for approximately 2-8% by weight, and especially approximately 3-7% by weight, is the most appropriate. Furthermore, the dry-granulated granules produced by each formulation method all have an appropriate hardness, with a wear rate (4 min) between approximately 0.05-0.15% and a wear rate (8 min) between approximately 0.1-0.3%.

[0199] As further shown in Table 9, any of the measured binder content ranges can moderately adjust the hardness of the dry-granulated granules, preferably about 1-3% by weight of binder, most preferably about 1.5-2.5% by weight of binder, resulting in pressed tablets with good formulation characteristics, for example, abrasion rate of less than 0.2% by weight and moderate disintegration time.

[0200] As demonstrated in the experimental process of the formulation, adding the above-mentioned amount of magnesium stearate to the initial dry granulation powder mixture and mixing it uniformly before dry granulation helps improve the adhesion phenomenon. Adding the prescribed amount of magnesium stearate after dry granulation and mixing before tableting also helps improve the sticking phenomenon.

[0201] Furthermore, when formulation T15 from the table above was adopted and the dry granulation pressure was changed from 6-8 kPa to 4-6 kPa, it was observed that the granules did not adhere to the press rolls, the fluidity after granulation was good, there was no sticking during tableting, the tablet surface was flat and smooth, the abrasion rate was acceptable (less than 0.1% in all cases), the disintegration time limit was less than 10 minutes (disintegration time for 50 mg tablets was 6 min 8 s, and disintegration time for 200 mg tablets was 3 min), dissolution (pH 6.8 + 0.1% SDS) reached 89.1% (50 mg tablets) and 90.7% (200 mg tablets) in 45 minutes, and dissolution (pH 6.8 + 0.1% SDS) reached 93.9% (50 mg tablets) and 91.7% (200 mg tablets) in 60 minutes.

[0202] Example 9 Based on the findings of Example 8, the solid dispersion of the present invention was prepared into tablets of 10 mg, 50 mg, and 200 mg in size, together with a stabilizer, filler, binder, disintegrant, flow promoter, lubricant, and film coating premixing agent, and the characteristics of each tablet were examined.

[0203] Specifically, according to Table 10 below, the formulation amounts of the solid dispersion ASD-12 and the methacrylate-ethyl acrylate copolymer (e.g., Eudragit) are used. In L100-55), microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silica, and a film coating premixture, as well as magnesium stearate, were weighed and sieved (50-60 mesh). ASD-12, methacrylate-ethyl acrylate copolymer, microcrystalline cellulose, hypromellose, croscarmellose sodium, and colloidal silica were mixed in a mixer, then sieved, and this step may be repeated one more time (premixture). Then, magnesium stearate (approximately 0.5% w / w) was added as an internal additive and mixed uniformly. The premixture with magnesium stearate was added to a dry granulator and dry granulated, controlling the pressure to 4-6 kPa. The resulting granules were uniformly mixed with the remaining magnesium stearate (approximately 0.5% w / w), and the entire resulting mixed granules were pressed into tablets. The appearance, abrasion resistance, hardness, dissolution characteristics, and stability of the resulting tablets were then examined.

[0204] [Table 14]

[0205] As shown in Table 10, when poorly soluble compound A was produced as a solid dispersion according to the present invention, and then further produced as an oral solid dosage form according to the present invention, it exhibited excellent dissolution performance (Figure 7) and good formulation characteristics, and had improved bioavailability. This makes it possible to provide an anticancer agent that can exert therapeutic effects at relatively low doses, and is expected to meet the medical needs in the field of cancer treatment.

[0206] Furthermore, the 10 mg, 50 mg, and 200 mg tablets were packaged in commonly used packaging materials (for example, 45 mL or 100 mL medicinal high-density polyethylene bottles with 33 mm or 38 mm medicinal polyethylene / polypropylene pediatric safety combination caps). The stability of these tablets was then further investigated under conditions of 40°C±2°C / RH75%±5% and 30°C±2°C / RH65%±5%, respectively. The appearance, moisture content, related substances, content, and dissolution rate of the test samples were examined, and no significant changes were observed in any of these areas. The results showed that the manufactured tablet formulations had good stability and good compatibility with the packaging materials. The results are shown in Table 11.

[0207] [Table 15-1] [Table 15-2]

[0208] Of these, the elution values ​​represent the experimental results after 45 minutes in a pH 6.8 phosphate buffer + 0.15% sodium dodecyl sulfate medium. The "related substances" value is the sum of all impurities in the HPLC pattern under the HPLC detection conditions described in the general experimental method, and "moisture content" is the result measured by the Karl Fischer method.

[0209] The specific embodiments described herein are for illustrative purposes only and do not limit the scope defined in the claims. Based on the disclosure herein, those skilled in the art will be able to clearly understand equivalent variations of the present invention, and these variations are also covered within the scope of this application.

Claims

1. A solid dispersion comprising an EED inhibitor or a pharmaceutically acceptable salt or solvate thereof, and a polymer carrier, wherein the EED inhibitor is a compound of the following formula: 【Chemistry 1】 Eventually, R １ It is an aralkyl group, R ２ H and C １ ~C ４ Selected from alkyl groups, X is selected from -C(R ５ａ )(R ５ｂ )-, -C(=O)-, and -S(=O) ２ -, and R ５ａ and R ５ｂ are independently selected from H and C １ to C ４ alkyl groups, Y is -C(R ６ａ ) (Caution ６ｂ )-, -S-, -O- and -N(R ７ ) - Selected from, Z is -C(R ６ｃ ) (Caution ６ｄ ) ｍ - and R ６ａ and R ６ｂ H and C １ ~C ４ Selected independently from alkyl groups, R ６ｃ and R ６ｄ H and C, respectively. １ ~C ４ It is independently selected from alkyl groups, and m is 0, 1, or 2. R ７ C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl groups, optionally substituted C ３ ~C ８ Selected from cycloalkyl groups, L is -C(R ８ｂ ) = and -N = are selected, R ８ａ -CF ３ ien-CH ３ ,-CHF ２ , -CD ３ and selected from the cyclopropyl group, R ８ｂ and R ８ｃ It is hydrogen, or a pharmaceutically acceptable salt or solvate thereof, Solid dispersion.

2. The aforementioned EED inhibitor is compound A, 【Chemistry 2】 or a pharmaceutically acceptable salt or solvate thereof, The solid dispersion according to claim 1.

3. The polymer carrier is selected from cellulose ether esters, preferably hypromellose acetate succinate. The solid dispersion according to claim 1 or 2.

4. The polymer carrier is selected from polyacrylic resins, preferably a methacrylate-ethyl acrylate (1:1) copolymer, and preferably Eudragit L100-55. The solid dispersion according to claim 1 or 2.

5. The polymer carrier is a mixture of cellulose ether ester and polyacrylic resin, preferably a mixture of hypromellose acetate succinate and a copolymer of methacrylic acid and ethyl acrylate (1:1), and more preferably a mixture of hypromellose acetate succinate and Eudragit L100-55. The solid dispersion according to claim 1 or 2.

6. The weight ratio of the EED inhibitor or its pharmaceutically acceptable salt or solvate to the polymer carrier is approximately 1:1 to 1:

5. A solid dispersion according to any one of claims 1 to 5.

7. An oral solid formulation comprising a solid dispersion according to any one of claims 1 to 6 and one or more medicinal excipients.

8. A tablet comprising a solid dispersion according to any one of claims 1 to 6, and one or more of the following: fillers, binders, disintegrants, lubricants, flow promoters, stabilizers, and coating agents. The oral solid formulation according to claim 7.

9. Medicinal excipients include fillers, binders, disintegrants, lubricants, flow enhancers, and stabilizers. An oral solid formulation according to claim 7 or 8.

10. The content of the aforementioned EED inhibitor is approximately 10 to 30% by weight, preferably approximately 10 to 20% by weight. An oral solid formulation according to any one of claims 7 to 9.

11. The solid dispersion accounts for approximately 30-80%, preferably approximately 50-70%, of the weight of the oral formulation. An oral solid formulation according to any one of claims 7 to 9.

12. 1) A solid dispersion comprising approximately 30 to 80% by weight, containing approximately 10 to 200 mg of the EED inhibitor and the polymer carrier, 2) A filler of approximately 20-40% by weight, 3) Approximately 1-3% by weight of a binder, 4) Approximately 2-8% by weight of a disintegrant, 5) A lubricant in an amount of approximately 0.5 to 2% by weight, 6) Approximately 2-8% by weight of a stabilizer, 7) A mixture containing approximately 0.5 to 2% by weight of a flow promoter, An oral solid formulation according to any one of claims 7 to 9.

13. 1) A solid dispersion comprising approximately 10 to 200 mg of the EED inhibitor and the polymer carrier, in an amount of approximately 50 to 70% by weight, 2) Approximately 20-30% by weight of filler, 3) Approximately 1.5 to 2.5% by weight of a binder, 4) Approximately 3-7% by weight of a disintegrant, 5) A lubricant in an amount of approximately 0.5 to 1.5% by weight, 6) Approximately 4-8% by weight of a stabilizer, 7) A mixture containing approximately 0.5 to 1.5% by weight of a flow promoter, An oral solid formulation according to any one of claims 7 to 9.

14. The EED inhibitor is compound A or a pharmaceutically acceptable salt or solvate thereof, and the polymer carrier in the solid dispersion is selected from hypromellose acetate succinate, methacrylate-ethyl acrylate (1:1) copolymer, or a mixture thereof. An oral solid formulation according to any one of claims 8 to 13.

15. The stabilizer is a methacrylate-ethyl acrylate (1:1) copolymer, preferably Eudragit L100-55. An oral solid formulation according to any one of claims 8 to 14.

16. The filler is microcrystalline cellulose, the binder is hypromellose, the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, and the flow enhancer is colloidal silica. An oral solid formulation according to any one of claims 8 to 15.

17. Use of the solid dispersion according to any one of claims 1 to 6 or the solid oral formulation according to any one of claims 7 to 16 for treating or preventing diseases promoted by EED inhibition.

18. Use of a solid dispersion according to any one of claims 1 to 6 or a solid oral formulation according to any one of claims 7 to 16 in the manufacture of a drug for treating or preventing diseases promoted by EED inhibition.

19. A method for treating or preventing a disease promoted by EED inhibition in a patient who requires it, comprising administering to the patient a therapeutically effective amount of a solid dispersion according to any one of claims 1 to 6 or a solid oral formulation according to any one of claims 7 to 16.

20. Diseases promoted by EED inhibition include selected cancers from among acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, mixed lineage chronic lymphocytic leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma. The use described in claim 17 or 18, or the method described in claim 19.

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