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WO2024251197A1 - Eed抑制剂固体分散体、包含其的口服制剂及其制备方法 - Google Patents

Eed抑制剂固体分散体、包含其的口服制剂及其制备方法 Download PDF

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WO2024251197A1
WO2024251197A1 PCT/CN2024/097747 CN2024097747W WO2024251197A1 WO 2024251197 A1 WO2024251197 A1 WO 2024251197A1 CN 2024097747 W CN2024097747 W CN 2024097747W WO 2024251197 A1 WO2024251197 A1 WO 2024251197A1
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solid dispersion
weight
eed
present
solid
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PCT/CN2024/097747
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English (en)
French (fr)
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林艳琼
郭宏涛
徐峰
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苏州亚盛药业有限公司
亚盛医药集团(香港)有限公司
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Publication of WO2024251197A1 publication Critical patent/WO2024251197A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, and specifically relates to a solid dispersion having good solubility and good bioavailability and comprising an embryonic ectodermal development protein (EED) inhibitor, a solid dispersion composition comprising the solid dispersion and an excipient, an oral preparation comprising the solid dispersion or the solid dispersion composition and a preparation method thereof, and use of the solid dispersion, the solid dispersion composition or the oral preparation for treating and/or preventing EED-mediated diseases.
  • EED embryonic ectodermal development protein
  • PcG proteins are a group of transcriptional repressors that regulate target genes through chromatin modification. They not only control the normal developmental pattern of individuals, but are also closely related to cell proliferation, differentiation and tumorigenesis. PcG proteins can be divided into two major categories: PRC1 (polycomb repressive complex 1, with E3 ubiquitin ligase activity) and PRC2 (polycomb repressive complex 2, with methyltransferase activity).
  • PRC2 as a representative member of PcG, is a multi-subunit complex that maintains the repressive state of chromatin by silencing specific gene expression. It plays a key role in development, tissue differentiation and regeneration. Its core subunits include histone methyltransferase 2 (EZH2), EED, suppressor of zeste 12 (SUZ12) and retinoblastoma suppressor-associated protein 46/48 (RbAp46/48). PRC2 dysregulation has been found in many human cancers. For example, EZH2 is highly expressed in a variety of human cancers and promotes cancer occurrence and malignant transformation. EZH2 mutations occur in up to 25% of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and are associated with poor patient prognosis.
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • EED can activate the methyltransferase activity of EZH2, so allosteric targeted inhibition of EED is also an effective anti-cancer method, and can produce stronger anti-tumor effects by overcoming resistance to EZH2 inhibitors and inhibiting EZH2 and EZH1 at the same time.
  • Previous research results have indeed shown that EED inhibitors have great therapeutic potential in hematological tumors, solid tumors and non-tumor indications.
  • EED inhibitors that have entered clinical research include MAK683 developed by Novartis and FTX-6058 developed by Fulcrum Therapeutics.
  • Ascentage Pharmaceuticals which has a high EED binding affinity and is expected to overcome tumor resistance and achieve complete and lasting tumor regression by regulating tumor epigenetics and tumor microenvironment.
  • the compound has obtained clinical trial approval from the U.S. FDA and the China National Medical Products Administration (NMPA) Drug Review Center (CDE) on June 29 and November 10, 2022, respectively, to conduct Phase I clinical trials for the treatment of advanced solid tumors or hematological malignancies. It is also the first original EED inhibitor to enter the clinical stage in China.
  • compound A has in vitro anti-tumor cell proliferation activity in multiple tumor cell lines, as well as anti-tumor activity in PDX/CDX models of EZH2-mutated B-cell non-Hodgkin's lymphoma, INI1-negative malignant rhabdoid tumor, BAP1-mutated mesothelioma, and prostate cancer.
  • EED inhibitors In view of the great therapeutic potential of EED inhibitors in the field of tumor treatment, the early development of EED inhibitor pharmaceutical preparations that are easy to prepare, convenient to use, and have good formulation properties can benefit more tumor patients as soon as possible. At the same time, in view of the long-standing safety issues in the field of tumor treatment drugs, namely toxic side effects, there is also a great demand in practice for anticancer drugs with enhanced bioavailability, which can exert therapeutic effects at lower doses.
  • the raw material of compound A is anhydrous crystalline powder, which is slightly hygroscopic and almost insoluble in water. Its solubility in aqueous buffer solution with a pH range of 1.2 to 7.4 is 0.39 to 0.08 micrograms/mL (37°C/24h), and its fluidity is poor. For such a poorly water-soluble drug, the dissolution of the drug in gastrointestinal fluid is the rate-limiting step of its bioavailability. Poor water solubility will inevitably lead to low dissolution, which in turn leads to lower bioavailability. Therefore, if you want to improve the bioavailability of the drug, you need to specially design the dosage form, prescription composition and process to change the dispersion state of the drug and promote its dissolution in the gastrointestinal tract.
  • the inventors have developed a stable EED inhibitor solid dispersion that can provide good solubility and good bioavailability after extensive research and screening, and prepared the solid dispersion into an oral preparation with good formulation properties through prescription design, thereby achieving the purpose of the invention.
  • the present invention provides a stable solid dispersion of an EED inhibitor (particularly Compound A) and a carrier material with good dissolution and bioavailability.
  • the present invention provides a stable solid dispersion composition having good dissolution and bioavailability, comprising the solid dispersion of the present invention and one or more pharmaceutically acceptable excipients.
  • the present invention provides an oral formulation (eg, tablet) having good dissolution and bioavailability, comprising the solid dispersion or solid dispersion composition of the present invention, wherein the EED inhibitor is in the solid dispersion.
  • an oral formulation eg, tablet having good dissolution and bioavailability
  • the present invention provides a method for preparing the solid dispersion of the present invention.
  • the present invention provides a method for preparing the oral formulation of the present invention.
  • the present invention provides a method for treating or preventing a disease (eg, cancer or tumor) for which inhibition of EED provides benefits, comprising administering a therapeutically effective amount of a solid dispersion, solid dispersion composition, or oral formulation of the present invention to a subject in need thereof.
  • a disease eg, cancer or tumor
  • a therapeutically effective amount of a solid dispersion, solid dispersion composition, or oral formulation of the present invention comprising administering a therapeutically effective amount of a solid dispersion, solid dispersion composition, or oral formulation of the present invention to a subject in need thereof.
  • the present invention provides use of the solid dispersion, solid dispersion composition or oral formulation of the present invention for treating or preventing a disease that benefits from EED inhibition (eg, cancer or tumor).
  • EED inhibition eg, cancer or tumor
  • the present invention provides use of the solid dispersion, solid dispersion composition or oral formulation of the present invention in the preparation of a medicament for treating or preventing a disease (eg, cancer or tumor) for which inhibition of EED provides benefits.
  • a disease eg, cancer or tumor
  • a ratio of about 1:1 means a ratio of 0.9-1.1:0.9-1.1.
  • Solid dispersion refers to a highly dispersed system formed by uniformly dispersing drugs in molecular, colloidal, amorphous, microcrystalline and other highly dispersed states in inactive excipients or carriers. Its characteristics include delaying the hydrolysis and oxidation of drugs, masking bad odors and irritation, solidifying liquid drugs, accelerating or delaying the dissolution of drugs, and achieving the purpose of rapid release or sustained release.
  • the highly dispersed state also brings about the problem of poor physical stability of solid dispersions and easy aging after long-term storage.
  • solid dispersions Due to differences in carrier materials, preparation methods, composition ratios, etc., there are different types of solid dispersions, including but not limited to simple eutectic mixtures, solid solutions, and coprecipitates. There are many methods for preparing solid dispersions, including melting methods, solvent methods, solvent-melting methods, solvent-spray drying methods, grinding methods, etc.
  • the means for verifying and analyzing the presence 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, polarizing microscopy (PLM), etc.
  • DTA differential thermal analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray diffraction
  • PLM polarizing microscopy
  • Solid dispersion carrier is the material in which the drug is dispersed in a highly dispersed state such as molecular, colloidal, amorphous, or microcrystalline in the solid dispersion.
  • the properties of the carrier material have a great influence on the properties of the solid dispersion. It should have basic properties such as being non-toxic, non-carcinogenic, not affecting the stability of the drug, not undergoing chemical changes with the drug, and not affecting the efficacy and content monitoring of the drug.
  • Solid dispersion carrier materials can be divided into: water-soluble carrier materials, including polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), surfactants, organic acids, sugars (alcohols), etc.; poorly soluble carrier materials, including cellulose, polyacrylic acid resins, lipids, etc.; enteric carrier materials, including enteric cellulose and polyacrylic acid resins, etc. It is generally believed that water-soluble carriers can increase the solubility and dissolution rate of poorly soluble drugs, which helps to improve the bioavailability of drugs; poorly soluble carriers can delay or control drug release; enteric carriers can control drug release in the small intestine.
  • water-soluble carrier materials including polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), surfactants, organic acids, sugars (alcohols), etc.
  • poorly soluble carrier materials including cellulose, polyacrylic acid resins, lipids, etc.
  • enteric carrier materials including enteric cellulose and polyacrylic acid resins,
  • polyethylene glycol carriers are one of the most commonly used water-soluble carriers, which are characterized by low toxicity, low melting point, and good water solubility. After being made into solid dispersions, they can disperse drug molecules in a molecular state, thereby accelerating the dissolution rate of drugs.
  • PEG with a molecular weight of 1000-20000 is selected as a solid dispersion carrier.
  • the most commonly used are PEG4000 and PEG6000.
  • Povidone carriers are amorphous high molecular polymers that are heat stable, easily soluble in polar organic solvents such as water and ethanol, and have a strong inhibitory effect on a variety of drugs.
  • Polyacrylic acid resin carriers are a general term for copolymers of acrylic acid, methacrylic acid and their derivatives.
  • the most commonly used product is called Eudragit, which includes methacrylic acid copolymers and methacrylate copolymers. They are divided into different models according to their composition, proportion and degree of polymerization.
  • Eudragit E is a copolymer of dimethylaminoethyl methacrylate and other neutral methacrylates
  • Eudragit L and Eudragit S are copolymers of methacrylic acid and acrylic esters in different proportions, including 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, Eudragit S100, etc.
  • cellulose carriers examples include ethyl cellulose, hydroxypropyl cellulose, and hypromellose, and also include enteric celluloses such as cellulose acetate phthalate, hypromellose phthalate, and hypromellose acetate succinate.
  • preparation refers 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 pharmaceutically acceptable excipient.
  • the preparation of the present invention can be any preparation suitable in the art, such as tablets, capsules, liquid preparations, etc.
  • pharmaceutically acceptable excipient refers to an ingredient in a pharmaceutical preparation other than the active ingredient, which is non-toxic to an individual.
  • pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives or flavoring agents, etc.
  • EED inhibitor refers to a bioactive agent that can interact with the EED protein directly or indirectly and reduce the signal transduction activity of EED, specifically a group of imidazopyrimidine EED inhibitors with formula (I) described in CN114127073A, more specifically an EED inhibitor compound with formula (III), most preferably the compound of Example 73, or a pharmaceutically acceptable salt or solvate thereof.
  • CN114127073A The entire contents of CN114127073A are incorporated herein by reference.
  • EED-mediated disease or “disease that benefits from EED inhibition” refers to a disease or disorder in which EED is involved in the occurrence, appearance, severity or progression of one or more disease symptoms or markers. Or a disease or disorder in which inhibition of EED will reduce the incidence of the disease, reduce or eliminate the symptoms of the disease.
  • diseases or disorders include, but are not limited to, cancer and proliferative diseases, inflammatory diseases, sepsis, autoimmune diseases and viral infections, the most important of which are cancer and proliferative diseases.
  • a person of ordinary skill in the art can readily determine whether a compound treats a disease or condition of any particular cell type mediated by an EED inhibitor, for example, by an assay that can be conveniently used to assess the activity of a particular compound. See, for example, Yue and Turkson, Expert Opinion Invest Drugs 18:45-56 (2009).
  • patient refers to mammals and non-mammalian individuals in need of the EED inhibitor 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, rabbits, and rodents (e.g., mice and rats), and are not limited to a specific age or sex.
  • the term is human, including children, adolescents, or adults.
  • treatment refers to administering the EED inhibitor solid dispersion of the present invention or a pharmaceutical composition comprising the same to an individual with a relevant disease or its symptoms or an individual with a physique susceptible to a relevant disease, in order to cure, alleviate, improve the disease or its symptoms or prevent the individual from suffering from the disease.
  • the disease is an EED-mediated disease as defined above, especially a tumor or cancer.
  • prevention refers to the administration of the EED inhibitor solid dispersion of the present invention or a pharmaceutical composition comprising the same to a subject, such as a mammal, such as a human, suspected of suffering from or susceptible to an EED-mediated disease as defined herein, especially cancer or a tumor, to delay the onset of the disease or reduce the risk of suffering from the disease.
  • prevention includes the use of the solid dispersion or pharmaceutical composition of the present invention before the diagnosis or determination of any clinical and/or pathological symptoms.
  • the term "effective amount” as used herein refers to the amount of a pharmaceutically active agent that is sufficient to prevent one or more symptoms of the disease or disorder being treated or to alleviate the symptoms of the disease to a certain extent when administered alone or in combination with other therapeutic agents to a specific patient or patient population.
  • the effective amount of the EED inhibitor in the solid dispersion or pharmaceutical composition of the present invention is generally about 1 ⁇ g/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 amount of the EED inhibitor of the present invention may be higher than the upper limit of the above dosage range or lower than the lower limit of the above dosage range.
  • EED inhibitor pharmaceutical composition of the present invention can determine the effective amount of the EED inhibitor pharmaceutical composition of the present invention by conventional methods (e.g., modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, individual response to the drug, etc.).
  • conventional influencing factors e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, individual response to the drug, etc.
  • AUC last refers to the area under the plasma concentration-time curve from the start of administration to the last point, and the unit is ng ⁇ h ⁇ ml -1 .
  • AUC INF refers to the area under the plasma concentration-time curve measured from 0 h to infinity after administration, and the unit is ng ⁇ h ⁇ ml -1 .
  • C max refers to the maximum concentration value of a drug in plasma after administration, and the unit is ng/ml.
  • T max refers to the time after administration when C max occurs, expressed in hours (h).
  • T 1/2 refers to the time required for half of the plasma drug concentration to be eliminated after the drug distribution in the body reaches equilibrium, and the unit is hour (h).
  • Typical acceptable standards for the term "stable" used herein to describe the solid dispersion or oral formulation of the present invention are: the total impurity content measured by the HPLC method described herein does not exceed about 1%, preferably does not exceed about 0.5%, for example, it can be 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%; and/or the physical form of the active ingredient in the solid dispersion/oral formulation remains amorphous, no obvious crystals are present, and no aging occurs when detected by XRPD or DTA or DSC or PLM.
  • the expression "based on the weight of the oral preparation" used herein to describe the content of each ingredient means that the content of the active ingredient and other types of excipients are calculated based on the weight of the tablet core excluding the coating agent.
  • EED inhibitor Any reference to an EED inhibitor appearing herein is intended to include the free compound, as well as a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • pharmaceutically acceptable salt refers to a salt or zwitterion form of the EED inhibitor compound involved in the present disclosure.
  • the pharmaceutically acceptable salt of the EED inhibitor involved in the present 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; and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.
  • Non-limiting examples of salts of EED inhibitors contemplated by the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylprop
  • available amino groups present in the EED inhibitor compounds of the present disclosure may be quaternized with methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl and sterol chlorides, bromides and iodides; and benzyl and phenethyl bromides.
  • solvate is a combination, physical association and/or dissolution of an EED inhibitor compound of the present disclosure with a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate, wherein the ratio of solvent molecules to the compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively.
  • Solvates can generally act as pharmacological equivalents.
  • the EED inhibitor compounds of the present disclosure can exist in a solvated form with a pharmaceutically acceptable solvent such as water, methanol and ethanol.
  • a pharmaceutically acceptable solvent such as water, methanol and ethanol.
  • solvate is a hydrate.
  • “Hydrate” refers to a specific subgroup of solvates in which the solvent molecule is water.
  • the EED inhibitors involved in the present disclosure encompass any compounds of the present disclosure that are isotopically labeled (i.e., radiolabeled) by replacing one or more atoms with atoms having different atomic masses or mass numbers.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 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 , respectively, such as 3 H, 11 C, and 14 C.
  • substantially all atoms at a certain position of the EED inhibitor involved in the present disclosure are replaced by atoms having different atomic masses or mass numbers.
  • substantially all atoms at a certain position of the EED inhibitor involved in the present disclosure are replaced by deuterium atoms, such as all hydrogen atoms of a -CH 3 group are replaced by deuterium atoms to obtain a -CD 3 group.
  • a portion of the atoms at a certain position of the EED inhibitor involved in the present disclosure are replaced by atoms with different atomic masses or mass numbers.
  • none of the atoms of the EED inhibitor involved in the present disclosure are replaced by atoms with different atomic masses or mass numbers.
  • the isotopically labeled EED inhibitor involved in the present disclosure can be prepared by methods known in the art.
  • the EED inhibitors contemplated by the present disclosure may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms.
  • the present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
  • the present invention provides a solid dispersion comprising an EED inhibitor or a pharmaceutically acceptable salt or solvate thereof and a polymer carrier.
  • the present invention provides the above-mentioned solid dispersion, wherein the EED inhibitor is the EED inhibitor described in CN114127073A, the entire contents of which are incorporated herein.
  • the EED inhibitor involved in the present invention has the following formula:
  • R1 is an aralkyl group
  • R 2 is selected from H and C 1 -C 4 alkyl
  • X is selected from -C(R 5a )(R 5b )-, -C( ⁇ O)- and -S( ⁇ O) 2 -;
  • R 5a and R 5b are independently selected from H and C 1 -C 4 alkyl;
  • Y is selected from -C(R 6a )(R 6b )-, -S-, -O- and -N(R 7 )-;
  • Z is -C(R 6c )(R 6d ) m -;
  • R 6a and R 6b are independently selected from H and C 1 -C 4 alkyl
  • R 6c and R 6d are each independently selected from H and C 1 -C 4 alkyl; m is 0, 1 or 2;
  • R7 is selected from C1 - C6 alkyl, C1 - C6 haloalkyl, and optionally substituted C3 - C8 cycloalkyl;
  • R 8a is selected from -CF 3 , -CH 3 , -CHF 2 , -CD 3 and cyclopropyl;
  • R 8b and R 8c are hydrogen
  • the present invention provides the above-mentioned solid dispersion, wherein the EED inhibitor is selected from:
  • the present invention provides the above-mentioned solid dispersion, wherein the EED inhibitor is compound A or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides the above solid dispersion, wherein the EED inhibitor, such as compound A, can be salified with an acid to obtain a pharmaceutically acceptable salt.
  • the acid is well known to those skilled in the art or can be routinely determined, such as but not limited to 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.
  • the present invention provides the above solid dispersion, wherein the polymer carrier is selected from cellulose polymers, polyacrylic acid resin polymers or mixtures thereof.
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from cellulose esters, such as cellulose acetate, cellulose acetate phthalate; cellulose ethers, such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC); esters of cellulose ethers, such as hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).
  • cellulose esters such as cellulose acetate, cellulose acetate phthalate
  • cellulose ethers such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC)
  • esters of cellulose ethers such as hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).
  • the present invention provides the above solid dispersion, wherein the polymer carrier is an ester of cellulose ether, such as hydroxypropylmethylcellulose phthalate, such as HP-55, HP-55S and HP-50; and, for example, hypromellose acetate succinate.
  • the polymer carrier is an ester of cellulose ether, such as hydroxypropylmethylcellulose phthalate, such as HP-55, HP-55S and HP-50; and, for example, hypromellose acetate succinate.
  • the present invention provides the above-mentioned solid dispersion, wherein the ester polymer carrier of the cellulose ether is preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS), which is a mixture of acetate and succinate of hydroxypropyl methylcellulose, and has amphiphilicity, wherein the acetyl group provides hydrophobicity and the succinyl group provides hydrophilicity.
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • the HPMCAS that can be used in the solid dispersion of the present invention includes HPMCAS L, HPMCAS LG, HPMCAS M, HPMCAS MG and HPMCAS H, etc. (L, M and H represent gradually increasing acetyl content and gradually decreasing succinyl content, respectively, G represents coarse particle size, and F represents fine particle size), and HPMCAS LG is more preferred.
  • the present invention provides the above solid dispersion, wherein the polymer carrier is a polyacrylic resin polymer selected from methacrylic acid copolymers and methacrylate copolymers.
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from the copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate; methacrylic acid-ethyl acrylate copolymer; methacrylic acid methyl methacrylate copolymer; ethyl acrylate-methyl methacrylate-methacrylic acid chloride trimethylaminoethyl ester copolymer; ethyl acrylate-methyl methacrylate copolymer; methacrylic acid-methyl acrylate-methyl methacrylate copolymer; methacrylic acid-butyl acrylate copolymer.
  • the polymer carrier is selected from the copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate; methacrylic acid-ethyl acrylate copolymer; methacryl
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1); a methacrylic acid-ethyl acrylate (1:1) copolymer; a methacrylic acid-methyl methacrylate (1:1 or 1:2) copolymer; an ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride (1:2:0.1 or 1:2:0.2) copolymer; an ethyl acrylate-methyl methacrylate (2:1) copolymer; a methacrylic acid-butyl acrylate (35:65) copolymer, and mixtures thereof in any proportion.
  • the polymer carrier is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl
  • 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, Eudragit RS.
  • 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 proportion.
  • 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 proportion.
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is selected from a copolymer of methacrylic acid-ethyl acrylate (1:1), and/or a copolymer of methacrylic acid-methyl methacrylate (1:1).
  • the polymer carrier in the solid dispersion of the present invention is Eudragit E100.
  • the polymer carrier in the solid dispersion of the present invention is Eudragit L100.
  • the polymer carrier in the solid dispersion of the present invention is Eudragit L100-55.
  • the present invention provides the above solid dispersion, wherein the polymer carrier is a mixture of a cellulose-based polymer and a polyacrylic acid resin-based polymer.
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is a mixture of a cellulose polymer and a polyacrylic acid resin polymer, wherein the cellulose polymer is selected from the general or specific cellulose polymers mentioned in the above-mentioned embodiment, preferably esters of cellulose ethers, more preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS), and most preferably HPMCAS LG; wherein the polyacrylic acid resin polymer is selected from the general or specific polyacrylic acid resin polymers mentioned in the above-mentioned embodiment, such as Eudragit, such as Eudragit L100, Eudragit E100, Eudragit L100-55 or a mixture thereof in any proportion, preferably methacrylic acid-ethyl acrylate (1:1) copolymer, such as Eudragit L100-55.
  • the polymer carrier is a mixture of a cellulose polymer and a polyacrylic acid resin polymer
  • the cellulose polymer is selected
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier is a mixture of the above-mentioned general or specific cellulose polymer and the above-mentioned general or specific polyacrylic resin polymer, wherein the weight ratio between the cellulose 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 therebetween.
  • the present invention provides the above-mentioned solid dispersion, wherein the weight ratio (drug loading ratio) of the EED inhibitor (e.g., compound A) to the polymer carrier is at least about 1:1, so that a uniform dispersion of the active ingredient and the carrier is obtained by the preparation method of the present invention, so that the active ingredient is completely crystallized and converted into an amorphous form, thereby improving the solubility and absorption of the drug, thereby improving the bioavailability of the drug after oral administration, and the solid dispersion obtained in this way is itself stable, does not show aging phenomenon under accelerated conditions, and there is no obvious change in various indicators.
  • the EED inhibitor e.g., compound A
  • the drug loading ratio in the solid dispersion of the present invention is about 1:1 to 1:5, for example, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, or any integer or non-integer weight ratio therebetween; preferably about 1:1 to 1:2, about 1:1 to 1:3, about 1:1 to 1:4, about 1:2 to 1:3, about 1:2 to 1:4, about 1:3 to 1:4; more preferably about 1:3 to 1:4.
  • the present invention provides the above-mentioned solid dispersion, wherein the EED inhibitor (e.g., Compound A) accounts for about 10 to 50% by weight of the solid dispersion, or any integer or non-integer point value therebetween, such as 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 % therebetween.
  • the EED inhibitor e.g., Compound A
  • the present invention provides the above-mentioned solid dispersion, wherein the content of the EED inhibitor (e.g., Compound A) in the solid dispersion is, for example, in the range of 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, 20-3 %, 20-30% by weight, 25-50% by weight, 25-40% by weight, 25-35% by weight, 25-30% by weight, 30-50% by weight, 30-45% by weight, 30-40% by weight, 30-35% by weight, or any integer or non-integer range value therebetween; preferably about 10-40% by weight, 15-40% by weight, 15-35% by weight, 20-50% by weight, 20-40% by weight, 20-35% by weight.
  • the EED inhibitor e.g., Compound A
  • the present invention provides the above-mentioned solid dispersion, wherein the polymer carrier accounts for about 40% to 90% by weight of the solid dispersion, or any integer or non-integer point value therebetween, such as 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, about 90% by weight.
  • the present invention provides the above-mentioned solid dispersion, wherein the content of the polymer carrier in the solid dispersion is, for example, in the range of 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, 50-60% by weight.
  • % 55-90 wt%, 55-80 wt%, 55-70 wt%, 55-65 wt%, 60-90 wt%, 60-80 wt%, 60-70 wt%, 65-90 wt%, 65-80 wt%, 65-75 wt%, 70-90 wt%, 70-80 wt%, or any integer or non-integer point or range therebetween; preferably about 40-80 wt%, 50-80 wt%, 60-80 wt%.
  • the present invention provides the above-mentioned solid dispersion, wherein the solid dispersion is composed of an EED inhibitor (e.g., compound A) and a polymer carrier, wherein the EED inhibitor is the EED inhibitor generally or preferably described above, most preferably compound A, and the polymer carrier is the polymer carrier generally or preferably described above, more preferably HPMCAS and/or Eudragit (e.g., methacrylic acid-ethyl acrylate (1:1) copolymer, such as Eudragit L100-55), and most preferably HPMCAS LG.
  • 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 respectively as generally or specifically defined above.
  • the present invention provides the above-mentioned solid dispersion, wherein the content of the EED inhibitor (e.g., compound A) is in the range of 20 to 50% by weight, and the content of the polymer carrier is in the range of 50 to 80% by weight, based on the total weight of the solid dispersion; preferably, the content of the EED inhibitor (e.g., compound A) is in the range of 20 to 40% by weight, and the content of the polymer carrier is in the range of 60 to 80% by weight.
  • the content of the EED inhibitor e.g., compound A
  • the content of the polymer carrier is in the range of 60 to 80% by weight.
  • the solid dispersion provided by the present invention is confirmed by PLM and/or XRPD and/or DSC methods that the active ingredient EED inhibitor (eg compound A) is in an amorphous state and is completely transformed into crystals.
  • EED inhibitor eg compound A
  • the above-mentioned solid dispersion provided by the present invention is stable under the following conditions, that is, it has chemical stability and solid stability: high temperature (60°C), high humidity (25°C/RH90%), accelerated conditions (40°C/RH75%), refrigeration (2-8°C), grinding (5-15min/room temperature), grinding and refrigeration (5-15min/2-8°C), tableting (room temperature or refrigeration), and it is confirmed by PLM and/or XRPD and/or DSC methods that the active ingredient EED inhibitor is in an amorphous state and has no aging phenomenon, and the active ingredient content and impurities do not change significantly.
  • the solid dispersion provided by the present invention has a solubility in fasting simulated intestinal fluid (FaSSIF) at pH 6.5 that can remain stable for at least 24 hours, and its solubility is at least about 10 times, for example, about 10 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 50 times, or about 60 times that of the original EED inhibitor (e.g., compound A) under the same conditions.
  • FaSSIF fasting simulated intestinal fluid
  • the present invention provides the above-mentioned solid dispersion, which comprises an EED inhibitor (e.g., compound A) and a polymer carrier cellulose ether ester (e.g., HPMCAS) and a polyacrylic acid resin (e.g., Eudragit, e.g., methacrylic acid-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55), wherein the EED inhibitor, its drug loading, the cellulose ether ester and polyacrylic acid resin polymer carriers and their contents and the weight ratio between the two are as generally and specifically defined above for the corresponding characteristics, and the solubility of the solid dispersion in fed state simulated intestinal fluid (FeSSIF) at pH 5.8 remains stable for at least 24 hours, and the EED inhibitor remains free of crystallization for at least 24 hours.
  • EED inhibitor e.g., compound A
  • a polymer carrier cellulose ether ester e.g., HPMCAS
  • the EED inhibitor e.g., compound A
  • a cellulose ether ester polymer carrier e.g., HPMCAS
  • a polyacrylic resin e.g., Eudragit, e.g., methacrylic acid-ethyl acrylate (1:1) copolymer, e.g., Eudragit L100-55
  • the mixture containing the solid dispersion prepared in this way can also make the active ingredient EED inhibitor in an amorphous state, have the above-mentioned chemical stability and solid stability, and its solubility in fasting state simulated intestinal fluid (FaSSIF) at pH 6.5 can remain stable for at least 24 hours and is much higher than the solubility of the EED inhibitor original drug under the same conditions, and its solubility in fed state simulated intestinal fluid (FeSSIF) at pH 5.8 remains stable for at least 24 hours and remains without crystallization for at least 24 hours.
  • simulated intestinal fluid FeSSIF
  • the solid dispersion provided by the present invention shows in animal pharmacokinetic experiments (such as the beagle dog pharmacokinetic study shown in the examples) that when administered at the same dose, the in vivo exposure of the EED inhibitor solid dispersion of the present invention is equivalent to that of the EED inhibitor solution, and the AUC value reaches at least 80% of that of the solution.
  • the solid dispersion provided by the present invention can be used directly, or prepared into different dosage forms according to the needs of treatment or prevention.
  • the present invention provides a method for preparing the solid dispersion of the EED inhibitor of the present invention.
  • the solid dispersion of the present invention can be obtained by widely known preparation methods, such as melting method, solvent method, solvent-melting method, spray drying method, fluidized bed drying method, melt extrusion method, etc.
  • the present invention preferably prepares the EED inhibitor solid dispersion by a spray drying method, which comprises the following steps:
  • the method for preparing a solid dispersion of an EED inhibitor further comprises step (3): drying the spray-dried powder obtained in step (2) under reduced pressure.
  • step (1) there is no strict limitation on the organic solvent used, but it should be able to fully dissolve the EED inhibitor, such as but not limited to methanol, anhydrous ethanol, isopropanol, isobutanol, ethyl acetate, acetone, dichloromethane, n-hexane, n-heptane, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetamide; preferably dichloromethane, methanol or a mixture thereof in any proportion; more preferably a dichloromethane/methanol mixed solvent of about 2:1 to 3:1.
  • the EED inhibitor such as but not limited to methanol, anhydrous ethanol, isopropanol, isobutanol, ethyl acetate, acetone, dichloromethane, n-hexane, n
  • the amount of organic solvent used should be an amount that can fully dissolve the EED inhibitor; the solid content concentration of the suitable solution is not more than 120 mg/mL, preferably in the range of 20-80 mg/mL, and more preferably in the range of 40-60 mg/mL.
  • step (1) there is no strict limitation on the form of the EED inhibitor, and either an amorphous form or a crystalline form can be used. EED inhibitors in different crystalline forms can be converted into an amorphous form in the solid dispersion system of the present invention.
  • step (2) there is no strict restriction on the conditions and means of drying, as long as the organic solvent can be removed.
  • the drying in step (2) is carried out by spray drying.
  • the air inlet temperature of spray drying can be controlled within the range of 65 to 95° C., for example, at 70° C.
  • spray drying is carried out under light-proof conditions.
  • the reduced pressure drying of step (3) is optionally performed to further remove the organic solvent; the conditions of the reduced pressure drying are not strictly limited and can be determined by those skilled in the art.
  • the reduced pressure drying is performed at a temperature of 25 to 50° C. (e.g., 50° C.) and a reduced pressure of 0 to -0.1 MPa (e.g., -0.1 MPa) for a suitable time, such as but not limited to 2 to 5 hours, such as 4 hours.
  • the yield of the solid dispersion reaches at least 75% and has good compressibility.
  • the present invention provides a solid dispersion composition
  • a solid dispersion composition comprising a solid dispersion of the present invention and an excipient, wherein the solid dispersion is as generally or specifically defined herein for the solid dispersion of the present invention, and wherein the excipient is selected from one or more of a diluent, a flavoring agent, a surfactant, a filler, a binder, a disintegrant, a lubricant, a glidant/antiadherent, a stabilizer, an emulsifier, a coating agent and/or a release modifier.
  • the present invention provides a solid dispersion composition, which can be in the form of tablets, capsules, granules, powders or pills.
  • the present invention provides a method for preparing the solid dispersion composition of the present invention, comprising the following steps:
  • step (1) optionally granulating the mixture of step (1);
  • step (3) the granules obtained in step (2) are thoroughly mixed with a lubricant.
  • the composition prepared above can be prepared in the form of pills, granules, powders, etc., or can be further compressed into tablets, or the obtained mixture or granules can be directly filled into capsule shells to prepare capsules.
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A), comprising the solid dispersion of the present invention or the solid dispersion composition of the present invention, and optionally an excipient.
  • an EED inhibitor eg, Compound A
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A), which is a solid oral formulation selected from tablets, capsules, granules, powders, lozenges and pills, preferably tablets or capsules, more preferably tablets.
  • EED inhibitor eg, Compound A
  • Compound A is a solid oral formulation selected from tablets, capsules, granules, powders, lozenges and pills, preferably tablets or capsules, more preferably tablets.
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A) comprising a solid dispersion of the present invention and one or more of a filler, a stabilizer, a binder, a disintegrant, a lubricant, a glidant, and a coating agent.
  • an EED inhibitor eg, Compound A
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A) comprising the solid dispersion of the present invention, and further comprising a filler, a binder, a disintegrant, and a lubricant.
  • EED inhibitor eg, Compound A
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A) comprising a solid dispersion of the present invention, and further comprising a filler, a binder, a disintegrant, a lubricant, and a glidant.
  • an EED inhibitor eg, Compound A
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A) comprising a solid dispersion of the present invention, and further comprising a filler, a binder, a disintegrant, a lubricant, a stabilizer, and a glidant.
  • an EED inhibitor eg, Compound A
  • the present invention provides an oral formulation of an EED inhibitor (eg, Compound A) comprising a solid dispersion of the present invention, and further comprising a filler, a binder, a disintegrant, a lubricant, a stabilizer, a glidant, and a coating agent.
  • an EED inhibitor eg, Compound A
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), wherein the content of the EED inhibitor is about 5-40% by weight, or any integer or non-integer point or range value therebetween, such as but not limited to about 5-30% by weight, about 5-20% by weight, about 10-40% by weight, about 10-30% by weight, about 10-20% by weight, about 15-40% by weight, about 15-30% by weight, about 15-25% by weight, about 20-40% by weight, about 20-30% by weight, about 25-40% by weight, about 25-35% by weight, about 30-40% by weight, preferably about 10-30%, more preferably about 10-20%, based on the weight of the oral formulation.
  • an EED inhibitor e.g., Compound A
  • the content of the EED inhibitor is about 5-40% by weight, or any integer or non-integer point or range value therebetween, such as but not limited to about 5-30% by weight, about 5-20% by weight, about 10-40% by weight, about 10-30%
  • 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 preparation is about 5-500 mg, for example, but not limited to, about 5-400 mg, about 5-300 mg, about 5-200 mg, about 10-500 mg, about 10-400 mg, about 10-200 mg, preferably about 10-200 mg, for example, about 200 mg, about 150 mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg, about 15 mg, about 10 mg, more preferably about 10 mg, about 50 mg, about 200 mg.
  • an EED inhibitor e.g., Compound A
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), wherein the solid dispersion accounts for about 10-80% by weight of the oral formulation, or any integer or non-integer point or range value therebetween, such as but not limited to 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%, about 50-70%, preferably about 30-80%, about 40-80%, about 40-70%, about 50-80%, about 50-70%, preferably about 30-80%, about 40-80%, about 40-70%, about 50-80%, about 50-70%, and more preferably about 50-70%.
  • an EED inhibitor e.g., Compound A
  • the solid dispersion accounts for about 10-80% by weight of the oral formulation, or any integer or non-integer point or range value therebetween, such as but not limited to about 10-70%, about 10-50%, about 20-80%, about 20
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), wherein the filler can 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; the amount of the filler accounts for about 10-80% by weight of the oral formulation, or any integer or non-integer point value or range value therebetween, such as but not limited to about 10-70%, about 10-60%, about 10 ⁇ 50%, about 10 ⁇ 40%, about 10 ⁇ 30%, about 15 ⁇ 35%, about 15 ⁇ 40%, about 20 ⁇ 80%, about 20 ⁇ 70%, about 20 ⁇ 60%, about 20 ⁇ 50%, about 20 ⁇ 40%, about 30 ⁇ 80%, about 30 ⁇ 70%, about 30 ⁇ 60%, about 30 ⁇ 50%, about 30 ⁇ 40%, preferably about 10 ⁇ 60%, about
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), wherein the binder can be selected from polyvinyl pyrrolidone, starch, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginate, etc.; preferably, the binder is selected from polyvinyl pyrrolidone or hydroxypropyl methylcellulose; the amount of the binder is 0.5-10% by weight of the oral formulation, or any integer or non-integer point value or range value therebetween, such as but not limited to about 0.5-9%, about 0.5-8%, about 0.5-5%, about 1-10%, about 1-9%, about 1-8%, about 1-5%, about 1-3%, about 1.5-2.5%, about 2-10%, about 2-8%, about 2-5%, about 2-4%, preferably about 0.5-5%, about 1-3%, about 1.5-2.5%, more preferably about 1-3%, and most preferably about 1.5-2.5%.
  • the binder can be selected from polyvinyl pyr
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), wherein the disintegrant can be selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, starch, pregelatinized starch, etc.; preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose; the amount of the disintegrant is 1-20% by weight of the oral formulation, or any integer or non-integer point value or range value therebetween, such as but not limited to 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%, about 4-8%, preferably about 1-10%, about 2-8%, about 3-7%, more preferably about 2-8%, and most preferably about 3-7%.
  • an EED inhibitor e.g., Compound A
  • the disintegrant can
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), wherein the lubricant can be selected from stearic acid, magnesium stearate, calcium stearate, zinc stearate, palmitic acid, palmitostearylglycerol, talc, carnauba wax, sodium lauryl sulfate, sodium stearyl fumarate, etc.; preferably, the lubricant is selected from stearic acid, magnesium stearate, calcium stearate and zinc stearate; the amount of the lubricant is 0.1-5% by weight of the oral formulation, or any integer or non-integer point value or range value therebetween, such as but not limited to about 0.1%, about 0.5%, 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 0.5-5%, about 0.5-4%, about 0.5-3%, about 0.5-2%,
  • the present invention provides an oral formulation of an EED inhibitor (e.g., compound A), which further comprises a stabilizer, which can be selected from hydroxypropyl methylcellulose, sodium lauryl sulfate, polyacrylic acid resin polymers, etc., preferably polyacrylic acid resin polymers, such as the general or specific polyacrylic acid resin polymers mentioned in the above embodiments, such as Eudragit, such as Eudragit L100, Eudragit E100, Eudragit L100-55 or a mixture thereof in any proportion, preferably methacrylic acid-ethyl acrylate (1:1) copolymer such as Eudragit ragit L100-55; the amount of the stabilizer accounts for 1 to 20% by weight of the oral preparation, or any integer or non-integer point value or range value therebetween, such as but not limited to about 1.0%, about 2.0%, about 3.0%, about 5.0%, about 7.0%, about 10%, about 12%, about 15%, about 1 to 10%, about 1 to 8%, about 2 to 10%,
  • the present invention provides an oral formulation of an EED inhibitor (e.g., Compound A), which further comprises a glidant, which can be selected from talc, silicon dioxide, micropowdered silica (colloidal silicon dioxide) and other pharmaceutically acceptable forms of silicon dioxide; preferably, the glidant is colloidal silicon dioxide; the amount of the glidant is 0 to 5% by weight of the oral formulation, or any integer or non-integer point value or range value therebetween, such as but not limited to 0%, about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%
  • the present invention provides an oral formulation of the above-mentioned EED inhibitor (eg, Compound A), such as a tablet, comprising:
  • a solid dispersion as generally or specifically defined herein, comprising about 5-500 mg of an EED inhibitor as generally or specifically defined herein (e.g., Compound A), and a polymer carrier as generally or specifically defined herein;
  • a solid dispersion as generally or specifically defined herein, comprising about 10-500 mg of an EED inhibitor as generally or specifically defined herein (e.g., Compound A), and a polymer carrier as generally or specifically defined herein;
  • a solid dispersion as generally or specifically defined herein, comprising about 10-200 mg of an EED inhibitor as generally or specifically defined herein (e.g., Compound A), and a polymer carrier as generally or specifically defined herein;
  • Most preferably comprises:
  • a solid dispersion as generally or specifically defined herein, comprising about 10-200 mg of an EED inhibitor as generally or specifically defined herein (e.g., Compound A), and a polymer carrier as generally or specifically defined herein;
  • compositions further optionally contain:
  • compositions further optionally contain:
  • the solid dispersion in the oral preparations of the EED inhibitor of the present invention (e.g., compound A) generally or preferably defined above, the solid dispersion, the selection of its components, the content of each component and the ratio between them (e.g., drug loading ratio, ratio between polymer carriers) are all as defined in the first aspect of the present invention above, that is, the solid dispersion technical solution constituted by the general or preferred definition of each technical feature, and also the solid dispersion technical solution constituted by any combination of one or preferred definitions of each technical feature.
  • the present invention provides an oral formulation of the above-mentioned EED inhibitor, such as 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 hydroxypropyl methylcellulose acetate succinate (HPMCAS).
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • the present invention provides an oral formulation of the above-mentioned EED inhibitor, such as 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 esters (such as HPMCAS) and polyacrylic acid resins (such as Eudragit, such as methacrylic acid-ethyl acrylate (1:1) copolymer, such as Eudragit L100-55) polymers generally or specifically defined herein.
  • HPMCAS cellulose ether esters
  • polyacrylic acid resins such as Eudragit, such as methacrylic acid-ethyl acrylate (1:1) copolymer, such as Eudragit L100-55
  • the present invention provides an oral formulation of the above-mentioned EED inhibitor, such as 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 acid resin (such as Eudragit, such as methacrylic acid-ethyl acrylate (1:1) copolymer, such as Eudragit L100-55) polymer generally or specifically defined herein.
  • a polyacrylic acid resin such as Eudragit, such as methacrylic acid-ethyl acrylate (1:1) copolymer, such as Eudragit L100-55
  • 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 cross-linked sodium carboxymethyl cellulose, the lubricant is magnesium stearate, the stabilizer is methacrylic acid-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55), and the glidant is colloidal silicon dioxide.
  • the above-mentioned EED inhibitor e.g., compound A
  • the filler is microcrystalline cellulose
  • the binder is hypromellose
  • the disintegrant is cross-linked sodium carboxymethyl cellulose
  • the lubricant is magnesium stearate
  • the stabilizer is methacrylic acid-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55)
  • the glidant is colloidal silicon dioxide.
  • the present invention provides an oral formulation of the above-mentioned EED inhibitor (e.g., Compound A), such as a tablet, wherein the tablet can be a coated tablet, wherein the coating agent is well known to those skilled in the art, such as but not limited to sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, gelatin, pharmaceutical glaze, polyethylene glycol, polyvinyl acetate phthalate, sodium lauryl sulfate, shellac, sucrose, titanium dioxide, carnauba wax, corn alcohol soluble protein, Opadry, etc.
  • the coating agent is well known to those skilled in the art, such as but not limited to sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, methylcellulose, ethylcellulose, hydroxypropy
  • the amount of the coating agent is 0-10% by weight of the oral formulation, or any range therebetween, for example but not limited to 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%, about 10%, preferably about 1-5%, 2-4%, more preferably about 2-4%, based on the weight of the oral formulation.
  • the oral preparations of the above-mentioned EED inhibitors such as compound A provided by the present invention, such as tablets, dissolve rapidly and completely.
  • the solubility of the active ingredient is maintained at about 75% or higher in 30 minutes, preferably about 80% or higher, more preferably 85% or higher; and maintained at about 85% or higher in 45 minutes, preferably about 90% or higher.
  • the oral preparation of the above-mentioned EED inhibitor (e.g., compound A) provided by the present invention is a tablet, and the tablet hardness is between about 50 and 400 N.
  • the hardness is between about 30 and 90 N, preferably between about 30 and 80 N.
  • the hardness is between about 50 and 200 N, preferably between about 70 and 150 N.
  • the hardness is between about 150 and 400 N, preferably between about 200 and 360 N.
  • the oral preparation of the above-mentioned EED inhibitor (such as compound A) provided by the present invention is a tablet, and its tablet friability is less than about 1% by weight, preferably less than about 0.5% by weight, such as less than about 0.2% by weight, and more preferably less than about 0.1% by weight.
  • the oral preparation of the EED inhibitor (eg, compound A) provided by the present invention is a tablet having a disintegration time of less than about 15 minutes, preferably less than about 5 minutes, such as about 0.5 to 5 minutes.
  • the oral preparation of the above-mentioned EED inhibitor (such as compound A) provided by the present invention has a mixture of raw materials and excipients with good stability.
  • high temperature 60°C
  • high humidity 25°C/RH90% ⁇ 5%
  • accelerated 40°C ⁇ 2°C/RH75% ⁇ 5%
  • light-proof conditions for 0/5/10/30 days
  • the oral preparation of the above-mentioned EED inhibitor (e.g., compound A) provided by the present invention is a tablet.
  • the finished preparation after being packaged with conventional packaging materials has good stability. After being placed under 40°C ⁇ 2°C/RH75% ⁇ 5%, 30°C ⁇ 2°C/RH65% ⁇ 5% and 25°C ⁇ 2°C/RH60% ⁇ 5% conditions for 1 month, the appearance, moisture, related substances, content and solubility of the tested samples did not change significantly.
  • the present invention provides a method for preparing the oral preparation in the form of a tablet of the present invention, comprising the following steps:
  • step (1) (2) granulating the mixture of step (1);
  • step (3) fully mixing the particles obtained in step (2) with a lubricant
  • step (1) the EED inhibitor solid dispersion of the present invention, a filler, a stabilizer, a binder, a disintegrant and a glidant are uniformly mixed.
  • the mixture of step (1) is sieved before mixing.
  • the screened mixture of step (1) is mixed again.
  • the mixture of step (1) is fully mixed with a portion of lubricant; the portion of lubricant added may be suitably about 40-70% of the total weight of the lubricant in the formulation, preferably about 50-70%. Adding a portion of lubricant at this stage helps to further improve the adhesion phenomenon in the subsequent granulation process and the sticking phenomenon in the tableting process.
  • step (2) there is no strict limitation on the conditions and means of granulation, and the granulation may be wet granulation, dry granulation or melt granulation.
  • the granulation in step (2) is performed by dry granulation, which can be performed by conventional methods known in the art, such as roller compaction.
  • roller compaction for example, see “Pharmaceutics”, edited by Fang Liang, third edition, July 2015, China Medical Science and Technology Press.
  • the pressure of dry granulation can be 6-8 KPa, preferably 4-6 KPa. Adopting the pressure range can further reduce the adhesion of dry granulated materials on the roller, further improve the fluidity of the prepared granules, and further reduce the sticking phenomenon during tableting.
  • the tablets prepared according to the above method have a friability of less than 1%, preferably less than about 0.5%; a disintegration time of less than 15 minutes, preferably less than 10 minutes, less than 5 minutes; and a solubility in an SDS solution of pH 6.8 of more than 75% in 30 minutes and more than 85% in 45 minutes.
  • the method for preparing an oral preparation in tablet form according to this aspect of the invention further comprises step (5): coating the tablet prepared in step (4) with a coating material.
  • step (5) there is no particular limitation on the coating material used, but it should have no significant effect on the content and dissolution of the tablets and play a light-shielding role to further improve the storage stability of the tablet preparation.
  • the coating material of step (5) accounts for about 1-5%, preferably 2-4%, of the total weight of the oral tablet formulation, and adds about 1-5%, preferably 2-4% to the weight of the tablet core.
  • the selection and dosage of the EED inhibitor e.g., compound A
  • polymer carrier e.g., polymer carrier
  • solid dispersion e.g., solid dispersion
  • various excipients e.g., solid dispersion, and various excipients are as generally, specifically or preferably defined above for the corresponding technical scheme.
  • the most preferred EED inhibitor is compound A or a pharmaceutically acceptable salt or solvate thereof
  • the polymer carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS) and/or methacrylic acid-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55)
  • the filler is microcrystalline cellulose
  • the stabilizer is methacrylic acid-ethyl acrylate (1:1) copolymer (e.g., Eudragit L100-55)
  • the binder is hypromellose
  • the disintegrant is cross-linked sodium carboxymethyl cellulose
  • the lubricant is magnesium stearate
  • the glidant is colloidal silicon dioxide.
  • the present invention provides use of the above-mentioned solid dispersion, solid dispersion composition or oral formulation of the present invention for treating or preventing a disease (eg, cancer or tumor) for which inhibition of EED provides benefits.
  • a disease eg, cancer or tumor
  • the present invention provides use of the above-mentioned solid dispersion, solid dispersion composition or oral formulation of the present invention in the preparation of a medicament for treating or preventing a disease (eg, cancer or tumor) for which inhibition of EED provides benefits.
  • a disease eg, cancer or tumor
  • the present invention provides a method for treating or preventing a disease (e.g., cancer or tumor) in a patient for which inhibition of EED provides benefits, comprising administering a therapeutically effective amount of a solid dispersion, solid dispersion composition, or oral formulation of the present invention to a subject in need thereof.
  • a disease e.g., cancer or tumor
  • a therapeutically effective amount of a solid dispersion, solid dispersion composition, or oral formulation of the present invention comprising administering a therapeutically effective amount of a solid dispersion, solid dispersion composition, or oral formulation of the present invention to a subject in need thereof.
  • the "diseases that benefit from EED inhibition” described in the seventh to ninth aspects of the present invention are selected from cancer and proliferative diseases, inflammatory diseases, sepsis, autoimmune diseases and viral infections, preferably cancer and proliferative diseases.
  • cancer and proliferative diseases inflammatory diseases, sepsis, autoimmune diseases and viral infections, preferably cancer and proliferative diseases.
  • the "disease that benefits from EED inhibition" described in the seventh to ninth aspects of the present invention is cancer, selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's 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.
  • the various technical solutions of the present invention described above prepare the EED inhibitor active ingredient, such as compound A, which is poorly soluble in water into a solid dispersion using a specific type of polymer carrier, and the active drug ingredient maintains a stable invisible state in the solid dispersion environment, while improving the dissolution and solubility of the drug in the gastrointestinal fluid, thereby improving the oral bioavailability of the drug.
  • the tablets prepared using the solid dispersion and a specific excipient combination have good preparation properties, and the friability, hardness, disintegration time and solubility have reached excellent levels at the same time.
  • the preparation method adopted is simple in process, the parameters are easy to control, the reproducibility is good, and it is easy to industrialize production.
  • FIG1A , FIG1B , and FIG1C show the DSC spectra of compound A (hereinafter also referred to as API), a representative polymer carrier, and a mixture of compound A and a representative polymer carrier (drug loading ratio 1:3).
  • FIG. 2 shows PLM images of solid dispersions prepared with different carriers (hydroxypropyl methylcellulose acetate succinate-LG, copovidone VA64 or hydroxypropylcellulose EXF) and API.
  • Figure 3A shows the XRPD patterns of solid dispersions prepared from different carriers (hydroxypropyl methylcellulose acetate succinate-LG, copovidone VA64 or hydroxypropyl cellulose EXF) and API;
  • Figure 3B shows the XRPD patterns of solid dispersions prepared from different carriers (Eutrac L100-55 or Eudragit L100-55+HPMCAS-LG) and API;
  • Figure 3C shows the XRPD patterns of solid dispersions with different drug loading ratios (API:HPMCAS-LG).
  • Figure 5A shows the dynamic solubility of solid dispersions of compound A prepared with different polymer carriers in FaSSIF-V2 solution
  • Figure 5B shows the dynamic solubility of solid dispersions with different drug loading ratios (API:HPMCAS-LG) in FeSSIF-V2 solution when Eudragit L100-55 was additionally added.
  • FIG6 shows the pharmacokinetic properties of the solid dispersion of the present invention following oral administration in beagle dogs.
  • FIG. 7 shows the dissolution properties of the solid oral dosage form of the present invention.
  • the excipients and reagents used in the examples are from commercial sources, and their quality standards and dosages are in compliance with the standards of the Chinese Pharmacopoeia;
  • the EED inhibitor used in the present invention can be prepared by referring to the method described in CN114127073A, for example, compound A or a pharmaceutically acceptable salt thereof can be prepared by referring to the method of Example 73 therein.
  • X-ray powder diffraction D8 Advance instrument equipped with Lynxeye detector was used to analyze the X-ray (Cu, :1.54), 45kV/40mA, step size (°2 ⁇ ) 0.02, scan rate (s/step) 0.1, and scan range (°2 ⁇ ) 3-40.
  • PLM Polarized light microscope
  • Modulated differential scanning calorimetry Using Discovery DSC 2500, linear temperature increase (10°C/min), and recording spectra from 25°C under nitrogen.
  • Fasting state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF) and gastric simulated fluid (SGF) can use commercially available products, or be prepared as follows:
  • FaSSIF-V2 solution weigh 1.39 g of sodium hydroxide, 2.22 g of maleic acid, and 4.01 g of sodium chloride, dilute to 1000 ml, dissolve by ultrasonication, adjust the pH to 6.5 for later use, add 1.79 g of FaSSIF-V2 powder, dissolve and set aside.
  • FeSSIF-V2 solution weigh 1.64 g of sodium hydroxide, 3.19 g of maleic acid, and 3.67 g of sodium chloride, dissolve them in 500 ml of pure water, adjust the pH to pH 5.8, add 4.88 g of FeSSIF-V2 solution, sonicate until all dissolved, and set aside.
  • SGF gastric simulation solution
  • Preparation of solid dispersion Weigh the prescribed amount of compound A, add a solvent (e.g., a mixed solvent of dichloromethane and methanol), stir until dissolved, add the prescribed amount of carrier material, stir to dissolve, place in a spray dryer, select appropriate parameters such as inlet temperature, inlet volume, liquid inlet speed and pressure for spray drying, and obtain the solid dispersion of the present invention.
  • Spray drying equipment suitable for the present invention includes but is not limited to corresponding equipment produced by Niro GEA Process Engineering Inc., Buchi Labortechnik AG., ProCept and SPX ANHYDROUS.
  • the present invention exemplarily uses a BUCHI290 spray dryer within the following parameter range:
  • the powder obtained by the spray drying can also be further subjected to secondary drying, such as reduced pressure drying, for example, at a temperature of 25 to 50° C. (e.g. 50° C.) and a reduced pressure of 0 to -0.1 MPa (e.g. -0.1 MPa) for a suitable time, such as 2-5 hours, such as 4 hours.
  • secondary drying such as reduced pressure drying, for example, at a temperature of 25 to 50° C. (e.g. 50° C.) and a reduced pressure of 0 to -0.1 MPa (e.g. -0.1 MPa) for a suitable time, such as 2-5 hours, such as 4 hours.
  • the present invention adopts a mixed solvent of dichloromethane and methanol as the solvent system for preparing the solid dispersion.
  • Table 2 shows that among the carrier substances tested, polyethylene glycol and hypromellose E4M are obviously not suitable, and other types of carriers can completely crystallize compound A.
  • Table 3 shows that when HPMCAS-LG, copovidone VA64, hydroxypropylcellulose EXF and/or Eudragit L100-55 are used as carriers to prepare solid dispersions, compound A can be completely crystallized without obvious crystals.
  • the PLM test results in Table 3 show that only a very small amount of birefringent particles were observed in the solid dispersions with different drug loading ratios.
  • the XRPD results also show that all samples have no crystal diffraction peaks of compound A, indicating that compound A can be completely crystallized at different drug loading ratios.
  • Table 4 shows that each solid dispersion (ASD-11, ASD-12, ASD-13) prepared using HPMCAS-LG as a carrier and compound A can remain stable in FeSSIF-V2 solution for about 6 hours, and no obvious birefringent particles are observed in PLM inspection, and no crystal transformation occurs.
  • Longer stability in FeSSIF-V2 solution can be achieved by adding specific polymers to the solid dispersion.
  • HPMC-E4M, SDS and HPMCAS-LG failed to improve the stability after a long time in the solution.
  • a large number of birefringent particles (ASD-14, ASD-15, ASD-16) can still be observed after 19 hours.
  • Table 4 also shows that solid dispersions (ASD-4, ASD-5, ASD-6, ASD-7 and ASD-8) can also be prepared using Eudragit L100-55 or (Eudragit L100-55+HPMCAS-LG) as carriers with compound A.
  • This group of solid dispersions remained stable in FeSSIF-V2 solution for 24 hours, and no obvious birefringent particles were observed in the PLM inspection, and no crystal transformation occurred.
  • this group of solid dispersions also remained stable in FaSSIF-V2 solution for 24 hours, and no obvious birefringent particles were observed in the PLM inspection at each time point, and no crystal transformation occurred.
  • FaSSIF, FeSSIF and SGF solutions were used to investigate the dynamic solubility of the solid dispersion of the present invention in each solution, wherein each solid dispersion was dispersed in FeSSIF-V2 solution to prepare a suspension containing about 1 mg/mL of compound A, or dispersed in FaSSIF-V2 solution to prepare a suspension containing about 2 mg/mL of compound A.
  • Each suspension was stirred and dispersed, 1 to 1.5 ml was sampled at a fixed time point, centrifuged, the supernatant was taken, the membrane was filtered, and the content of compound A was determined by HPLC according to the general experimental method described above. The results are shown in Table 5 and Figures 5A and 5B.
  • Table 5 shows that in the FaSSIF-V2 solution, the dissolution amount of the solid dispersions of Compound A with different carriers and different drug loading ratios at each time point is much greater than the dissolution amount of the raw material of Compound A, and the 24-hour dissolution amount of the solid dispersions of Compound A with different drug loading ratios is basically similar.
  • Table 5 also shows that in FaSSIF-V2 solution, the API solubility of the solid dispersions prepared with HPMCAS and/or Eudragit L100-55, or copolyvidone VA64 remains stable or increases over time, among which the API solubility of the solid dispersions prepared with HPMCAS and Eudragit L100-55 has a greater advantage over the API solubility of the solid dispersions prepared with copolyvidone VA64 and hydroxypropylcellulose EXF.
  • Table 5 also shows that in FaSSIF-V2 solution and FeSSIF-V2 solution, the addition of Eudragit Compared with the solid dispersion of HPMCAS as the polymer carrier, the solubility of API in the solid dispersion of L100-55 showed an increase to varying degrees.
  • Table 5 also shows that in FeSSIF-V2 solution, the lower the drug loading, the greater the dissolution amount, and the dissolution amount of the solid dispersion with HPMCAS as the only polymer carrier is significantly reduced in 24 hours.
  • adding Eudragit L100-55 to the solid dispersion can keep the dissolution amount basically balanced over time, and as the addition ratio of Eudragit L100-55 increases, the dissolution amount of API also increases accordingly.
  • the solid dispersion of the present invention was formulated into a suspension containing about 2 mg/mL of compound A using SGF solution, and the dynamic solubility was investigated.
  • the results showed that the API solubility of solid dispersions with different drug loading ratios (e.g., ASD10-13) at each time point during the period of 1 to 24 hours was less than 0.005 mg/ml, and even less than 0.0001 mg/ml.
  • the chemical stability of ASD was evaluated based on purity and related substances (maximum single impurity and total impurities). The results are shown in Table 6.
  • Table 6 shows that under high temperature, high humidity and accelerated conditions, the appearance of ASD has no obvious change, and the related substances have no obvious increase, indicating that ASD has good chemical stability.
  • 15 beagle dogs male, weighing about 8-11 kg
  • 15 beagle dogs were randomly divided into 5 groups, 3 in each group.
  • two of the groups were orally administered with the test sample, at doses of 2.5 mg/kg and 10 mg/kg, respectively, and another group of beagle dogs were orally administered with 10 mg/kg of the test sample after eating for 0.5 h; the other two groups of beagle dogs that had fasted for one night were orally administered with 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 before administration (0 h) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration.
  • the main pharmacokinetic parameters are shown in Table 7, and the plasma drug concentration-time curve is shown in Figure 6, where the AUC value was calculated using WinNonLin software.
  • Table 7 and Figure 6 show that the solid dispersion of the present application has comparable exposure to the solution in beagle dogs at the same dosage and under the same conditions, and no obvious food effect was observed. This indicates that compound A, which is almost insoluble in water, has been successfully prepared into a solid form with comparable bioavailability to the solution, overcoming the common defect of low bioavailability of poorly soluble drugs and expanding the use space of drugs.
  • the solid dispersion of the present invention (ASD-12) is mixed uniformly with the excipients shown in Table 8 below, sieved, and dry granulated.
  • the obtained granules are mixed uniformly with magnesium stearate, and the obtained total mixed granules are pressed into tablets.
  • Table 8 shows that the tablets of prescriptions T1, T3, T4, and T5 exhibit good dissolution characteristics, with dissolution reaching more than 80% in 45 minutes.
  • the tablets prepared using microcrystalline cellulose alone as a filler have the best overall performance, good compressibility, acceptable disintegration time, and the most complete dissolution.
  • the solid dispersion of the present invention (ASD-12) was mixed uniformly with the excipients according to the formulation shown in Table 9 below, sieved, and dry granulated.
  • the obtained granules were mixed uniformly with magnesium stearate, and the obtained total mixed granules were pressed into tablets.
  • the pressure of dry granulation is 5-6KPa, and the others are 6-8KPa.
  • Each tablet prepared by the above prescription has an acceptable off-white (occasionally spotted) appearance.
  • Table 9 shows that the content of disintegrant is proportional to the disintegration time.
  • About 1 to 10 wt % of the disintegrant cross-linked carboxymethyl cellulose sodium can make the preparation disintegrate rapidly, and the disintegration time is within 1 to 10 minutes.
  • the disintegration time of about 2 to 8 wt %, especially about 3 to 7 wt % of the disintegrant is the most moderate.
  • the granules of the dry granulation of each formulation have moderate hardness, friability (4 min) is between about 0.05 and 0.15%, and friability (8 min) is between about 0.1 and 0.3%.
  • Table 9 also shows that the tested binder content range can make the hardness of dry granules moderate, among which about 1-3% by weight of binder is preferred, and about 1.5-2.5% by weight of binder is most preferred.
  • the compressed tablets have good formulation properties, such as friability less than 0.2% by weight and moderate disintegration time.
  • the preparation experiment process shows that adding the above-prescribed amount of magnesium stearate to the dry granulation initial mixed powder and performing dry granulation after mixing can help improve the adhesion phenomenon. Adding the prescribed amount of magnesium stearate after dry granulation and performing tableting after mixing can help improve the sticking phenomenon.
  • the prescription T15 in the above table was used, and the dry granulation pressure was changed from 6-8KPa to 4-6KPa. It was observed that the granules basically did not stick to the rollers and had good fluidity after granulation, the tablets did not stick to the punches, the tablet surface was flat and smooth, the friability was qualified (all less than 0.1%), the disintegration time was less than 10 minutes (the disintegration time of 50mg tablets was 6min8s, and the disintegration time of 200mg tablets was 3min), the dissolution in 45 minutes (pH6.8+0.1% SDS) reached 89.1% (50mg tablets) and 90.7% (200mg tablets), and the dissolution in 60 minutes (pH6.8+0.1% SDS) reached 93.9% (50mg tablets) and 91.7% (200mg tablets).
  • the solid dispersion of the present invention together with a stabilizer, a filler, a binder, a disintegrant, a glidant, a lubricant, and a film coating premix, were formulated into tablets of 10 mg, 50 mg, and 200 mg, respectively, and their tablet properties were examined.
  • the solid dispersion ASD-12 methacrylic acid-ethyl acrylate copolymer (e.g., Eudragit L100-55), microcrystalline cellulose, hypromellose, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and film coating premix, and magnesium stearate in the prescribed amount, and sieve (50-60 mesh); mix ASD-12, methacrylic acid-ethyl acrylate copolymer, microcrystalline cellulose, hypromellose, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and film coating premix.
  • methacrylic acid-ethyl acrylate copolymer e.g., Eudragit L100-55
  • microcrystalline cellulose hypromellose
  • cross-linked sodium carboxymethyl cellulose colloidal silicon dioxide and film coating premix
  • magnesium stearate magnesium stearate
  • the mixture is sieved, and the step can be repeated once more (premix); then, magnesium stearate (about 0.5% w/w) is added and mixed evenly; the premix with magnesium stearate is added into a dry granulator for dry granulation, and the pressure is controlled at 4-6 KPa; the obtained granules are mixed evenly with the remaining magnesium stearate (about 0.5% w/w), and the obtained total mixed granules are pressed into tablets, and the appearance, friability, hardness, dissolution properties and stability of the obtained tablets are examined.
  • Table 10 shows that the poorly soluble compound A is prepared into a solid dispersion according to the present invention, and further prepared into an oral solid preparation according to the present invention, which has excellent dissolution performance (Figure 7) and shows good various preparation properties. It is expected to provide an anticancer drug with enhanced bioavailability, thereby being able to exert therapeutic efficacy at a lower dose, thereby meeting the medical needs in the field of cancer treatment.
  • the solubility value represents the experimental result after 45 minutes in pH 6.8 phosphate buffer + 0.15% sodium dodecyl sulfate medium; the "related substances” value is the sum of all impurities in the HPLC spectrum under the HPLC detection conditions described in the general experimental method; and the "water content” is the result determined by the Karl Fischer method.

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Abstract

一种具有良好溶出度和良好生物利用度、包含胚胎外胚层发育(EED)抑制剂的固体分散体及其制备方法、包含所述固体分散体和赋形剂的固体分散体组合物、包含所述固体分散体或固体分散体组合物的口服制剂及其制备方法、以及所述固体分散体、固体分散体组合物或口服制剂用于治疗和/或预防EED介导的疾病的用途。

Description

EED抑制剂固体分散体、包含其的口服制剂及其制备方法
交叉引用
本申请要求国际申请日为2023年6月6日、国际申请号为PCT/CN2023/098642的PCT专利申请的优先权。
技术领域
本发明属于药物制剂领域，具体地涉及一种具有良好溶出度和良好生物利用度、包含胚胎外胚层发育蛋白(EED)抑制剂的固体分散体、包含所述固体分散体和赋形剂的固体分散体组合物、包含所述固体分散体或固体分散体组合物的口服制剂及其制备方法、以及所述固体分散体、固体分散体组合物或口服制剂用于治疗和/或预防EED介导的疾病的用途。
技术背景
多梳家族(PcG)蛋白是一组通过染色质修饰来调控靶基因的转录抑制子，不仅控制个体正常的发育模式，而且与细胞的增殖、分化和肿瘤发生密切相关。PcG蛋白可以分为两大类：PRC1(多梳抑制复合物1，具有E3泛素连接酶活性)和PRC2(多梳抑制复合物2，具有甲基转移酶活性)。
PRC2作为PcG的代表性成员，是一种通过静默特定基因表达来维持染色质抑制状态的多亚基复合物，在发育、组织分化和再生中发挥关键作用，其核心亚单位包括组蛋白甲基转移酶2(EZH2)、EED、zeste 12抑制子(SUZ12)和视网膜母细胞瘤抑制因子相关蛋白46/48(RbAp46/48)。在许多人类癌症中都发现了PRC2的失调。例如，EZH2在多种人类癌症中呈现高表达且促进癌症发生和恶变，EZH2突变发生在多达25％的弥漫性大B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤(FL)中，并且与患者预后不良有关。
靶向抑制EZH2的甲基转移酶活性已被证明是一种成功的癌症治疗策略，尽管如此，EZH2的二次突变可产生获得性耐药，且其同源性EZH1也具有甲基转移酶活性，均会导致EZH2抑制剂活性受限。而EED可激活EZH2的甲基转移酶活性，故变构靶向抑制EED也是一种有效抗癌方法，并且可通过克服对EZH2抑制剂的耐药性、同时抑制EZH2和EZH1而产生更强的抗肿瘤作用。既往研究结果的确已经表明，EED抑制剂在血液肿瘤、实体瘤和非肿瘤适应症中有着极大的治疗潜力。
迄今为止，进入临床研究的EED抑制剂，包括诺华研发的MAK683和Fulcrum Therapeutics开发的FTX-6058，此外还有亚盛医药在研的一种新型强效的选择性小分子EED抑制剂，具有高度EED结合亲和性，通过调节肿瘤表观遗传学及肿瘤微环境，有望克服肿瘤耐药，实现完全和持久的肿瘤消退，该化合物已分别于2022年6月29日和11月10日获得美国FDA临床试验许可和中国国家药品监督管理局(NMPA)药品审评中心(CDE)的临床试验许可，开展治疗晚期实体瘤或血液系统恶性肿瘤的I期临床试验，也是在中国首个进入临床阶段的原研EED抑制剂。
化学名为12-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-4-异丙基-7-(三氟甲基)-4,5-二氢-3H-2,4,8,11,12a-五氮杂苯并[4,5]环辛并[1,2,3-cd]茚-3-酮的化合物，是公开于WO2021/011713(CN114127073A)中的一组咪唑并嘧啶类EED抑制剂中的一员，结构式如下所示：
(以下简称“化合物A”)
临床前数据已经证明了化合物A在多个肿瘤细胞系具有体外抗肿瘤细胞增殖活力，以及在EZH2突变的B细胞非霍奇金淋巴瘤、INI1-阴性恶性横纹肌样瘤、BAP1突变的间皮瘤和前列腺癌的PDX/CDX模型中具有抗肿瘤活性。
鉴于EED抑制剂在肿瘤治疗领域中极大的治疗潜力，及早开发易于制备、使用方便、具有良好制剂性质的EED抑制剂药物制剂，可以让更多的肿瘤患者早日受益。同时，鉴于肿瘤治疗药物领域长久以来关注的安全性问题即毒副作用，因此，实践中也对具有增强的生物利用度、从而能够以较低的剂量发挥治疗功效的抗癌药物存在极大的需求。
化合物A的原料为无水结晶性粉末，略有吸湿性，在水中几乎不溶，在pH1.2至7.4的水性缓冲溶液中的溶解度在0.39～0.08微克/mL(37℃/24h)，流动性差。对于这种水溶性差的药物，药物在胃肠液中的溶出是其生物利用度的限速步骤， 水溶性差必将导致溶出度低，继而导致较低的生物利用度。因此，若欲提高该药物的生物利用度，需要特别地设计剂型、处方组成和工艺过程来改变药物的分散状态，促进其在胃肠道的溶出。
为了满足以上需求和解决以上问题，本发明人经过广泛的研究和筛选，开发出能够提供良好溶出度和良好生物利用度的稳定的EED抑制剂固体分散体，并通过处方设计、将该固体分散体制备成具有良好制剂性质的口服制剂，实现了发明的目的。
发明概述
一方面，本发明提供了具有良好溶出度和生物利用度的稳定的固体分散体，其EED抑制剂(特别是化合物A)和载体物质。
另一方面，本发明提供了具有良好溶出度和生物利用度的稳定的固体分散体组合物，其包含本发明的固体分散体和一种或多种可药用赋形剂。
另一方面，本发明提供了具有良好溶出度和生物利用度的口服制剂(例如片剂)，其包含本发明的固体分散体或固体分散体组合物，其中所述EED抑制剂处于固体分散体中。
另一方面，本发明提供了用于制备本发明固体分散体的方法。
另一方面，本发明提供了用于制备本发明口服制剂的方法。
另一方面，本发明提供了用于治疗或预防抑制EED提供益处的疾病(例如癌症或肿瘤)的方法，包括将治疗有效量的本发明的固体分散体、固体分散体组合物或口服制剂施用于有需要的对象。
另一方面，本发明提供了本发明的固体分散体、固体分散体组合物或口服制剂用于治疗或预防得益于EED抑制的疾病(例如癌症或肿瘤)的用途。
另一方面，本发明提供了本发明的固体分散体、固体分散体组合物或口服制剂在制备用于治疗或预防抑制EED提供益处的疾病(例如癌症或肿瘤)的药物中的用途。
发明详述
定义
本文所用的术语“约”将与其联用的数值浮动±10％。对于比例而言，术语“约”用于限定所给出的比例的每个数字。例如，比例约1:1是指比例为0.9～1.1:0.9～1.1。
“固体分散体”是指将药物以分子、胶态、无定型、微晶态等高度分散状态均匀分散在无活性的辅料或载体中形成的高度分散系统。其特点包括，可以延缓药物的水解和氧化、掩盖不良气味和刺激性、使液态药物固体化，也可以加快或延缓药物的溶出、达到速释或缓释的目的，但高度分散状态同时也带来固体分散体物理稳定性不好、久贮后容易老化的问题
因载体材料、制备方法、组成比例等的不同，存在不同类型的固体分散体，包括但不限于简单低共熔混合物、固态溶液和共沉淀物。制备固体分散体的方法有多种，包括熔融法、溶剂法、溶剂-熔融法、溶剂-喷雾干燥法、研磨法等等。验证分析药物存在状态和鉴定固体分散体的形成的手段包括热分析法(包括差示热分析法(DTA)或差示扫描量热法(DSC))、X-射线衍射法(XRPD)、红外光谱法、偏光显微镜(PLM)等。
但是，鉴于载体物质类型和性质的多样化、制备方法的多样化、载体物质和制备方法与特定药物分子之间常常不相容，上述固体分散体的优势经常无法实现，即仅仅根据特定药物的分子结构和理化性质以及固体分散体的常规技术手段，常常无法获得能够带来良好制剂性质的固体分散体。
“固体分散体载体”是固体分散体中药物以分子、胶态、无定型、微晶态等高度分散状态分散于其中的材料，该载体材料的性质对固体分散体的性质有很大影响，其应当具有无毒、无致癌性、不影响药物稳定性、不与药物发生化学变化、不影响药物的药效与含量监测等基本性质。
常用的固体分散体载体材料可以分为：水溶性载体材料，包括聚乙二醇(PEG)类、聚乙烯基吡咯烷酮(PVP)类、表面活性剂类、有机酸类、糖(醇)类等；难溶性载体材料，包括纤维素类、聚丙烯酸树脂类、脂质类等；肠溶性载体材料，包括肠溶型纤维素类和聚丙烯酸树脂类等。通常认为，水溶性载体可增加难溶性药物的溶解度和溶出速率，有助于提高药物的生物利用度；难溶性载体可延缓或控制药物释放；肠溶性载体可控制药物于小肠释放。
其中，聚乙二醇类载体是最常用的水溶性载体之一，特点是毒性小、熔点低、水溶性良好，制成固体分散体后能使药物分子以分子状态分散，从而加快药物的溶出速率。一般选用分子量为1000-20000的PEG作为固体分散体载体， 最常用的是PEG4000和PEG6000。
聚维酮类载体为无定型高分子聚合物，对热稳定，易溶于水和乙醇等极性有机溶剂，对多种药物有较强的抑晶作用。
聚丙烯酸树脂类载体是丙烯酸、甲基丙烯酸及其衍生物的共聚物的总称。最常用产品的商品名为Eudragit(尤特奇)，包括甲基丙烯酸共聚物和甲基丙烯酸酯共聚物，按照构成、比例和聚合度不同而分为不同的型号，其中Eudragit E为甲基丙烯酸二甲胺基乙酯与其他中性甲基丙烯酸酯的共聚物，Eudragit L和Eudragit S为甲基丙烯酸与不同比例的丙烯酸酯类共聚物，包括甲基丙烯酸-丙烯酸乙酯(1:1)共聚物、甲基丙烯酸-甲基丙烯酸甲酯(1:1)共聚物、甲基丙烯酸-甲基丙烯酸甲酯(1:2)共聚物。具体的实例包括但不限于Eudragit E100、Eudragit EPO、Eudragit L100-55、Eudragit L30D-55、Eudragit L100、Eudragit S100等。
纤维素类载体的实例包括乙基纤维素、羟丙基纤维素、羟丙甲纤维素，还包括肠溶性纤维素，例如醋酸纤维素酞酸酯、羟丙甲纤维素酞酸酯、醋酸羟丙甲纤维素琥珀酸酯等。
本文所用的术语“制剂”或“药物组合物”指适合于向动物、优选哺乳动物(包括人)施用的包含至少一种活性成分和至少一种非活性成分、例如可药用赋形剂的组合物。本发明的制剂可以是本领域适用的任意制剂，例如片剂、胶囊剂、液体制剂等。
本文所用的术语“药学上可接受的赋形剂”指药物制剂中除活性成分以外的成分，其对个体是无毒的。可药用载体的实例包括但不限于粘合剂、崩解剂、润滑剂、溶剂、分散介质、缓冲剂、赋形剂、抗氧化剂、防腐剂或矫味剂等。
本文所用的术语“EED抑制剂”是指能通过直接或间接方式与EED蛋白相互作用、降低EED的信号传导活性的生物活性剂，具体地指CN114127073A中描述的一组具有式(I)的咪唑并嘧啶类EED抑制剂、更具体地是其中具有式(III)的EED抑制剂化合物、最优选为实施例73化合物，或它们药学上可接受的盐或溶剂合物。CN114127073A的全部内容以引用方式并入本文。
本文所用的术语“EED介导的疾病”或“得益于EED抑制的疾病”是指EED参与其发生、一种或多种疾病症状或标记物的出现、严重性或进展的疾病或障碍。或抑制EED将降低疾病的发生率、减少或消除疾病病状的疾病或障碍。这些疾病或障碍包括但不限于癌症和增生性疾病、炎性疾病、败血症、自体免疫疾病和病毒感染，其中最重要的是癌症和增生性疾病。所属领域的一般技术人员能够容易地确定化合物是否治疗由EED抑制剂介导的任何特定细胞类型的疾病或病况，例如通过可方便地用于评定特定化合物活性的分析。参见例如Yue和Turkson,《调研药物专家评论(Expert Opinion Invest Drugs)》18:45-56(2009)。
本文所用的术语“患者”、“对象”、“受试者”或“个体”是指需要本发明的EED抑制剂的哺乳动物和非哺乳动物个体。实例包括但不限于灵长类(例如人和非人灵长类动物如猴)、马、牛、羊、猫、狗、兔、兔以及啮齿类(例如小鼠和大鼠)，并不限定特定的年龄或性别。在一些实施方案中，所述术语是人，包括儿童、青少年或成人。
本文所用的术语“治疗”是指给具有相关疾病或其症状的个体或者具有易患相关疾病的体质的个体施用本发明的EED抑制剂固体分散体或包含其的药物组合物，用以治愈、减轻、改善所述疾病或其症状或者防止个体罹患疾病。在本发明具体的实施方案中，所述疾病是上文所定义的EED介导的疾病、尤其是肿瘤或癌症。
本文所用的术语“预防”是给怀疑患上或易感于如本文所定义的EED介导的疾病、尤其是癌症或肿瘤的受试者、例如哺乳动物、例如人施用本发明的EED抑制剂固体分散体或包含其的药物组合物，延迟疾病的发生或使得罹患所述疾病的风险降低。术语“预防”包含在诊断或确定任何临床和/或病理症状以前使用本发明的固体分散体或药物组合物。
本文所用的术语“有效量”是指当单独或与其他治疗剂组合施用于特定的患者或患者人群中时足以防止所治疗疾病或障碍的一种或多种症状发生或在一定程度上减轻所述疾病症状的药物活性剂的量。本发明的固体分散体或药物组合物中的EED抑制剂的有效量一般为约1μg/kg～100mg/kg/天，例如日剂量约1mg/kg～约10mg/kg。在一些情况下，本发明的EED抑制剂的有效量有可能高于上述剂量范围的上限或低于上述剂量范围的下限。相关领域的技术人员可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药方式、化合物的药代动力学、疾病的严重程度和病程、个体的病史、个体的健康状况、个体对药物的响应程度等)来确定本发明的EED抑制剂药物组合物的有效量。
本文所用的术语“AUClast”是指从给药时间开始到最后一个点期间血浆浓度-时间曲线下面积，单位是ng·h·ml-1。
本文所用的术语“AUCINF”是指测定的给药时间由0h外推至无穷远的血浆浓度-时间曲线下面积，单位是ng·h·ml-1。
本文所用的术语“Cmax”是指给药后药物在血浆中的最高浓度值，单位是ng/ml。
本文所用的术语“Tmax”是指给药后出现Cmax的时间，单位是小时(h)。
本文所用的术语“T1/2”是指药物在体内分布达到平衡后，血浆药物浓度消除一半所需的时间，单位是小时(h)。
本文描述本发明的固体分散体或口服制剂时所用的术语“稳定”的典型可接受标准是：通过本文所述的HPLC方法测定的总杂质含量不超过约1％，优选不超过约0.5％，例如可以为0.01％、0.05％、0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％；和/或通过XRPD或DTA或DSC或PLM法检测，固体分散体/口服制剂中活性成分物理形态保持无定型、无明显晶体存在、未发生老化。
本文描述各成分含量时所用的表述“以口服制剂的重量计”是指以不包含包衣剂的片芯重量计算活性成分和其他种类赋形剂的含量。
本文中出现的任何EED抑制剂的称谓意图包括游离化合物、以及其药学上可接受的盐、水合物或溶剂化物。
本文所用的术语“药学上可接受的盐”是指本公开所涉及的EED抑制剂化合物的盐或两性离子形式。本公开所涉及的EED抑制剂的药学上可接受的盐可为与药学上可接受的酸形成的酸加成盐，实例包括无机酸，如硝酸、硼酸、盐酸、氢溴酸、硫酸和磷酸；以及有机酸，如草酸、马来酸、琥珀酸和柠檬酸。本公开所涉及的EED抑制剂的盐的非限制性实例包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟基乙烷磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、褐藻酸盐、天冬氨酸盐、苯甲酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、抗坏血酸盐、羟乙磺酸盐、水杨酸盐、甲烷磺酸盐、均三甲苯磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、 十一烷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡糖酸盐、甲烷磺酸盐、乙烷二磺酸盐、苯磺酸盐和对甲苯磺酸盐。另外，存在于本公开所涉及的EED抑制剂化合物中的可用氨基可用甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；二甲基、二乙基、二丁基和二戊基硫酸盐；癸基、月桂基、肉豆蔻基和固醇氯化物、溴化物和碘化物；以及苯甲基和苯乙基溴化物季铵化。
本文所用的术语“溶剂化物”为本公开所涉及的EED抑制剂化合物与溶剂分子的组合、物理缔合和/或溶合，例如二溶剂化物、单溶剂化物或半溶剂化物，其中溶剂分子与本公开的化合物的比率分别为约2:1、约1:1或约1:2。溶剂化物通常可充当药理学等效物。本公开所涉及的EED抑制剂化合物可与药学上可接受的溶剂(如水、甲醇和乙醇)一起以溶剂化形式存在。一种类型的溶剂化物为水合物。“水合物”是指溶剂化物的特定亚组，其中溶剂分子为水。
本公开所涉及的EED抑制剂涵盖通过将一个或多个原子置换为具有不同原子质量或质量数的原子而经同位素标记(即放射性标记)的任何本公开的化合物。可并入所公开的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素，如分别为2H(或氘(D))、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl，例如3H、11C和14C。在一个实施例中，本公开所涉及的EED抑制剂的某一位置处的基本上所有原子被具有不同原子质量或质量数的原子置换。在另一个实施例中，本公开所涉及的EED抑制剂的某一位置处的基本上所有原子经氘原子置换，例如-CH3基团的所有氢原子经氘原子置换得到-CD3基团。在另一个实施例中，本公开所涉及的EED抑制剂的某一位置处的一部分原子经具有不同原子质量或质量数的原子置换。在另一个实施例中，本公开所涉及的EED抑制剂的原子均未经具有不同原子质量或质量数的原子置换。经同位素标记的本公开所涉及的EED抑制剂可通过所属领域中已知的方法制备。
本公开所涉及的EED抑制剂可含有一个或多个不对称中心，并且因此可产生对映异构体、非对映异构体和其它立体异构形式。本公开涵盖使用所有此类可能的形式，以及其外消旋和解析形式和其混合物。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
发明详述
在第一个方面，本发明提供了一种固体分散体，其包含EED抑制剂或其可药用盐或溶剂合物和聚合物载体。
在一个实施方案中，本发明提供了上述固体分散体，其中所述的EED抑制剂为CN114127073A中所述的EED抑制剂，其全部内容并入本文。具体地，本发明中涉及的EED抑制剂具有下式：
其中：
R1是芳烷基；
R2选自H和C1-C4烷基；
X选自-C(R5a)(R5b)-、-C(＝O)-和-S(＝O)2-；R5a和R5b独立地选自H和C1-C4烷基；
Y选自-C(R6a)(R6b)-、-S-、-O-和-N(R7)-；
Z是-C(R6c)(R6d)m-；
R6a和R6b独立地选自H和C1-C4烷基；
R6c和R6d各自独立地选自H和C1-C4烷基；m是0、1或2；
R7选自C1-C6烷基、C1-C6卤代烷基、任选取代的C3-C8环烷基；
L选自-C(R8b)＝和-N＝；
R8a选自-CF3、-CH3、-CHF2、-CD3和环丙基；并且
R8b和R8c为氢；
或其药学上可接受的盐或溶剂化物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述的EED抑制剂选自：

或其药学上可接受的盐或溶剂化物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述的EED抑制剂为化合物A或其药学上可接受的盐或溶剂化物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述的EED抑制剂、例如化合物A可与酸成盐，以获得可药用盐。所述酸为本领域技术人员所熟知或可以常规确定的，例如但不限于盐酸、甲磺酸、富马酸、三氟乙酸或磷酸、硫酸、2-羟基乙烷磺酸、乙酸、苯甲酸、琥珀酸、马来酸、草酸、对甲苯磺酸、柠檬酸、酒石酸和苯磺酸。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自纤维素类聚合物、聚丙烯酸树脂类聚合物或其混合物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自纤维素酯类，例如醋酸纤维素、醋酸纤维素酞酸酯；纤维素醚类，例如乙基纤维素、羟丙基纤维素、羟丙甲纤维素(HPMC)；纤维素醚的酯类，例如羟丙甲纤维素酞酸酯(HPMCP)和醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体为纤维素醚的酯类，例如羟丙甲纤维素酞酸酯，例如HP-55、HP-55S和HP-50； 和例如醋酸羟丙甲纤维素琥珀酸酯。
在一个实施方案中，本发明提供了上述固体分散体，其中所述纤维素醚的酯类聚合物载体优选醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)，其是羟丙甲纤维素的乙酸酯和琥珀酸酯的混合物，具有两亲性，其中乙酰基提供疏水性，琥珀酰基提供亲水性。因乙酰基和琥珀酰基含量的不同以及颗粒的粗细，可用于本发明固体分散体的HPMCAS包括HPMCAS L、HPMCAS LG、HPMCAS M、HPMCAS MG和HPMCAS H等(L、M和H分别代表逐渐增加的乙酰基含量和逐渐降低的琥珀酰基含量，G表示粗粒径，F表示细粒径)，更优选HPMCAS LG。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体为聚丙烯酸树脂类聚合物，选自甲基丙烯酸共聚物和甲基丙烯酸酯共聚物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自甲基丙烯酸丁酯-甲基丙烯酸二甲胺基乙酯-甲基丙烯酸甲酯的共聚物；甲基丙烯酸-丙烯酸乙酯共聚物；甲基丙烯酸甲基丙烯酸甲酯共聚物；丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯的共聚物；丙烯酸乙酯-甲基丙烯酸甲酯共聚物；甲基丙烯酸-丙烯酸甲酯-甲基丙烯酸甲酯的共聚物；甲基丙烯酸-丙烯酸丁酯共聚物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自甲基丙烯酸丁酯-甲基丙烯酸二甲胺基乙酯-甲基丙烯酸甲酯(1:2:1)的共聚物；甲基丙烯酸-丙烯酸乙酯(1:1)共聚物；甲基丙烯酸-甲基丙烯酸甲酯(1:1或1:2)共聚物；丙烯酸乙酯甲基丙烯酸甲酯甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1或1:2:0.2)共聚物；丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物；甲基丙烯酸-丙烯酸丁酯(35:65)共聚物，以及其任意比例的混合物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自Eudragit。在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自Eudragit E、Eudragit L、Eudragit S、Eudragit RL、Eudragit RS。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自Eudragit E100、Eudragit EPO、Eudragit L100-55、Eudragit L30D-55、Eudragit L100、Eudragit S100，或其任意比例的混合物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体选自甲基丙烯酸-丙烯酸乙酯(1:1)的共聚物，和/或甲基丙烯酸-甲基丙烯酸甲酯(1:1)共聚物。在一个实施方案中，本发明固体分散体中的聚合物载体为Eudragit E100。在一个实施方案中，本发明固体分散体中的聚合物载体为Eudragit L100。在一个实施方案中，本发明固体分散体中的聚合物载体为Eudragit L100-55。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体为纤维素类聚合物和聚丙烯酸树脂类聚合物的混合物。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体为纤维素类聚合物和聚丙烯酸树脂类聚合物的混合物，其中的纤维素类聚合物选自上述实施方案中所提及的一般或具体的纤维素聚合物，优选纤维素醚的酯类，更优选醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)，最优选HPMCAS LG；其中的聚丙烯酸树脂类聚合物选自上述实施方案中所提及的一般或具体的聚丙烯酸树脂类聚合物，例如Eudragit，例如Eudragit L100、Eudragit E100、Eudragit L100-55或其任意比例的混合物，优选甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，例如Eudragit L100-55。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体为上述一般或具体的纤维素类聚合物和上述一般或具体的聚丙烯酸树脂类聚合物的混合物，其中所述纤维素类聚合物和聚丙烯酸树脂类聚合物之间的重量比为约10:1至5:1，例如约10:1、约9:1、约8:1、约7:1、约6:1、约5:1，优选约8:1至5:1、约7:1至5:1、7:1至6:1、约6:1至5:1，或其间的任何整数或非整数重量比。
在一个实施方案中，本发明提供了上述固体分散体，其中所述EED抑制剂(例如化合物A)与聚合物载体的重量比(载药比)至少为约1:1，以通过本发明的制备方法得到活性成分与载体的均匀分散体，使得活性成分转晶完全，转化为无定型，提高药物的溶解度和吸收，从而提高药物口服后的生物利用度，且这样制得的固体分散体本身稳定，在加速条件下不会出现老化现象，各项指标没有明显变化。尽管载体含量越高，越容易使活性成分溶解和吸收，但是低载药率会增加制剂质量，增加制剂难度，综合考量后的本发明固体分散体中的载药比为约1:1至1:5，例如约1:1、约1:1.5、约1:2、约1:2.5、约1:3、约1:3.5、约1:4、约1:4.5、约1:5，或其间的任何整数或非整数重量比；优选约1:1至1:2、约1:1至1:3、约1:1至1:4、约1:2至1:3、约1:2至1:4、约1:3至1:4；更优选约1:3至1:4。
在一个实施方案中，本发明提供了上述固体分散体，其中所述EED抑制剂(例如化合物A)占所述固体分散体的约10～50重量％，或其间的任何整数或非整数点值，例如约5重量％、10重量％、约15重量％、约20重量％、约25重量％、约30重量％、约35重量％、约40重量％、约45重量％、约50重量％，或其间的任何整数或非整数重量％。
在一个实施方案中，本发明提供了上述固体分散体，其中EED抑制剂(例如化合物A)在固体分散体中的含量范围为例如约10～50重量％、10～40重量％、10～30重量％、10～20重量％、15～50重量％、15～40重量％、15～30重量％、15～35重量％、15～20重量％、20～50重量％、20～40重量％、20～35重量％、20～30重量％、25～50重量％、25～40重量％、25～35重量％、25～30重量％、30～50重量％、30～45重量％、30～40重量％、30～35重量％，或其间的任何整数或非整数范围值；优选约10～40重量％、15～40重量％、15～35重量％、20～50重量％、20～40重量％、20～35重量％。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体占所述固体分散体的约40重量％至90重量％，或其间的任何整数或非整数点值，例如约40重量％、约45重量％、约50重量％、约55重量％、约60重量％、约65重量％、约70重量％、约75重量％、约80重量％、约85重量％、约90重量％。
在一个实施方案中，本发明提供了上述固体分散体，其中所述聚合物载体在固体分散体中的含量范围为例如约40～90重量％、40～80重量％、40～70重量％、40～60重量％、40～50重量％、45～90重量％、45～80重量％、45～70重量％、45～60重量％、50～90重量％、50～80重量％、50～70重量％、50～60重量％、55～90重量％、55～80重量％、55～70重量％、55～65重量％、60～90重量％、60～80重量％、60～70重量％、65～90重量％、65～80重量％、65～75重量％、70～90重量％、70～80重量％，或其间的任何整数或非整数点值或范围值；优选约40～80重量％、50～80重量％、60～80重量％。
在一个实施方案中，本发明提供了上述固体分散体，其中所述固体分散体由EED抑制剂(例如化合物A)和聚合物载体组成，其中所述EED抑制剂为上文一般或优选所述的EED抑制剂，最优选化合物A，所述聚合物载体为上文一般或优选所述的聚合物载体，更优选HPMCAS和/或Eudragit(例如甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，例如Eudragit L100-55)，最优选HPMCAS LG。在一种实施方案中，组成所述固体分散体的EED抑制剂和聚合物载体之间的重量比以及各自占固体分散体的重量比分别如上文一般或具体所定义。
在一个实施方案中，本发明提供了上述固体分散体，其中以固体分散体的总重量计，EED抑制剂(例如化合物A)的含量范围为20～50重量％，聚合物载体的含量范围为50～80重量％；优选EED抑制剂(例如化合物A)的含量范围为20～40重量％，聚合物载体的含量范围为60～80重量％。
本发明提供的上述固体分散体，通过PLM和/或XRPD和/或DSC等方法确认活性成分EED抑制剂(例如化合物A)呈无定型状态，转晶完全。
本发明提供的上述固体分散体，其在选自以下的条件下是稳定的，即具有化学稳定性和固体稳定性：高温(60℃)、高湿(25℃/RH90％)、加速条件(40℃/RH75％)、冷藏(2～8℃)、研磨(5～15min/室温)、研磨和冷藏(5～15min/2～8℃)、压片(室温或冷藏)，通过PLM和/或XRPD和/或DSC等方法确认活性成分EED抑制剂呈无定型状态、无老化现象，且活性成分含量、杂质没有明显变化。
本发明提供的上述固体分散体，其在pH6.5的禁食状态模拟肠液(FaSSIF)中的溶解度可保持稳定至少达24小时，且其溶解度是相同条件下EED抑制剂原药(例如化合物A)的溶解度的至少约10倍，例如约10倍、约20倍、约25倍、约30倍、约35倍、约40倍、约50倍、约60倍。
在一个实施方案中，本发明提供了上述固体分散体，其包含EED抑制剂(例如化合物A)和聚合物载体纤维素醚酯类(例如HPMCAS)和聚丙烯酸树脂类(例如Eudragit，例如甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，例如Eudragit L100-55)，其中EED抑制剂、其载药量、纤维素醚酯类和聚丙烯酸树脂类聚合物载体及其含量以及二者之间的重量比如上文对相应特征一般和具体所定义，该固体分散体在pH5.8的进食状态模拟肠液(FeSSIF)中的溶解度保持稳定至少达24小时，且EED抑制剂保持无转晶至少达24小时。
在一个实施方案中，可以先将EED抑制剂(例如化合物A)和纤维素醚酯类聚合物载体(例如HPMCAS)按照本发明的方法制备成固体分散体，然后再加入聚丙烯酸树脂类(例如Eudragit，例如甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，例如Eudragit L100-55)聚合物，这样制备的包含固体分散体的混合物，同样能够使活性成分EED抑制剂呈无定型状态、具有上述化学稳定性和固体稳定性、在pH6.5的禁食状态模拟肠液(FaSSIF)中的溶解度可保持稳定至少达24小时且远远高于相同条件下EED抑制剂原药的溶解度，且在pH5.8的进食状态模拟肠液(FeSSIF)中的溶解度保持稳定至少达24小时、保持无转晶至少达24小时。
本发明提供的上述固体分散体，其在动物药动学实验中(如实施例所示比格狗药动学研究)显示，当以相同剂量施用时，本发明的EED抑制剂固体分散体的体内暴露量与EED抑制剂溶液剂相当，AUC值达到溶液剂的至少80％。
本发明提供的上述固体分散体，其可以直接使用，或者根据治疗或预防的需要制备成不同的剂型。
在第二个方面，本发明提供了本发明EED抑制剂固体分散体的制备方法。本发明的固体分散体可通过广泛已知的制备方法获得，如熔融法、溶剂法、溶剂-熔融法、喷雾干燥法、流化床干燥法、熔融挤出法等。
在一个具体实施方案中，本发明优选通过喷雾干燥法制备EED抑制剂固体分散体，其包括以下步骤：
(1)将EED抑制剂(例如化合物A)溶于有机溶剂，然后加入聚合物载体，搅拌溶解，制备喷雾干燥溶液；
(2)喷雾干燥步骤(1)得到的溶液，以除去有机溶剂。
在一个实施方案中，上述制备EED抑制剂固体分散体的方法还包括步骤(3)：减压干燥步骤(2)得到的喷雾干燥粉末。
在步骤(1)中，对所使用的有机溶剂没有严格限制，但应当为能够充分溶解EED抑制剂，例如但不限于甲醇、无水乙醇、异丙醇、异丁醇、乙酸乙酯、丙酮、二氯甲烷、正己烷、正庚烷、四氢呋喃、乙腈、苯、甲苯、二甲苯、二甲亚砜、二甲基甲酰胺、N,N-二甲基乙酰胺；优选二氯甲烷、甲醇或其任意比例的混合物；更优选约2:1～3:1的二氯甲烷/甲醇混合溶剂。
在步骤(1)中，所使用的有机溶剂的量应当为能够充分溶解EED抑制剂的量；适合的溶液的固含物浓度不大于120mg/mL，优选在20～80mg/mL范围内，更优选在40～60mg/mL范围内。
在步骤(1)中，对EED抑制剂的形式没有严格限制，可以使用无定型，也可以使用结晶形式，不同结晶形式的EED抑制剂均可以在本发明固体分散体体系中转化为无定型形式。
在步骤(2)中，对干燥的条件和手段没有严格限制，能除去有机溶剂即可。在一个实施方案中，步骤(2)中的干燥采用喷雾干燥法进行，本领域技术人员能够确定喷雾干燥的各项参数，例如喷雾干燥的进风温度可以控制在65～95℃的范围内，例如在70℃进行。在一个具体的实施方案中，喷雾干燥在避光条件下进行。
在一个实施方案中，在步骤(2)之后任选进行步骤(3)的减压干燥，以进一步除去有机溶剂；减压干燥的条件没有严格限制，可以由本领域技术人员确定。在一个具体的实施方案中，减压干燥于25～50℃的温度(例如50℃)和降低的压力0～-0.1Mpa(例如-0.1Mpa)下进行适合的时间，例如但不限于2-5小时，例如4小时。
在本发明该方面的固体分散体制备方法中，固体分散体的收率达到至少75％，且可压性良好。
在第三个方面，本发明提供了一种固体分散体组合物，其包含本发明的固体分散体和赋形剂，其中的固体分散体如本文对本发明固体分散体一般或具体所定义，其中的赋形剂选自稀释剂、调味剂、表面活性剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂/抗粘附剂、稳定剂、乳化剂、包衣剂和/或释放改性剂中的一种或多种。
在一个实施方案中，本发明提供了固体分散体组合物，其可为片剂、胶囊、颗粒剂、散剂或丸剂等形式。
在第四个方面，本发明提供了上述本发明固体分散体组合物的制备方法，包括以下步骤：
(1)将本发明的EED抑制剂固体分散体与填充剂、粘合剂、崩解剂、稳定剂和/或助流剂均匀混合；
(2)任选地将步骤(1)的混合物制粒；
(3)任选地将步骤(2)制得的颗粒与润滑剂充分混合。
在一个实施方案中，上述制备得到的组合物可以制备为丸剂、颗粒剂、散剂等形式，也可以进一步压制为片剂形式，或者将所得混合物或颗粒直接填充至胶囊壳中制成胶囊形式。
在第五个方面，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其包含本发明的固体分散体或本发明的固体分散体组合物，以及任选的赋形剂。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其为固体口服制剂，选自片剂、胶囊、颗粒剂、散剂、锭剂和丸剂，优选片剂或胶囊，更优选片剂。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其包含本发明的固体分散体，还包含填充剂、稳定剂、粘合剂、崩解剂、润滑剂、助流剂和包衣剂中的一种或多种。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其包含本发明的固体分散体，还包含填充剂、粘合剂、崩解剂和润滑剂。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其包含本发明的固体分散体，还包含填充剂、粘合剂、崩解剂、润滑剂和助流剂。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其包含本发明的固体分散体，还包含填充剂、粘合剂、崩解剂、润滑剂、稳定剂和助流剂。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其包含本发明的固体分散体，还包含填充剂、粘合剂、崩解剂、润滑剂、稳定剂、助流剂和包衣剂。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中所述EED抑制剂的含量为约5～40重量％，或其间的任何整数或非整数点值或范围值，例如但不限于约5～30重量％、约5～20重量％、约10～40重量％、约10～30重量％、约10～20重量％、约15～40重量％、约15～30重量％、约15～25重量％、约20～40重量％、约20～30重量％、约25～40重量％、约25～35重量％、约30～40重量％，优选约10～30％、更优选约10～20％，以口服制剂的重量计。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中单位制剂中所述EED抑制剂的量为约5～500mg，例如但不限于约5～400mg、约5～300mg、约5～200mg、约10～500mg、约10～400mg、约10～200mg，优选约10～200mg，例如约200mg、约150mg、约100mg、约75mg、约50mg、约25mg、约15mg、约10mg，更优选约10mg、约50mg、约200mg。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中所述固体分散体占所述口服制剂重量的约10～80％，或其间的任何整数或非整数点值或范围值，例如但不限于约约10～70％、约10～50％、约20～80％、约20～70％、约20～60％、约30～80％、约30～70％、约30～50％、约40～80％、约40～70％、约50～80％、约50～70％，优选约30～80％、约40～80％、约40～70％、约50～80％、约50～70％，更优选约50～70％。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中所述填充剂可以选自乳糖、蔗糖、磷酸钙、磷酸氢钙、无水磷酸氢钙、微晶纤维素、硅化微晶纤维素、预胶化淀粉、淀粉、甘露醇等；优选地，所述填充剂为微晶纤维素；所述填充剂的用量占口服制剂重量的约10～80％，或其间的任何整数或非整数点值或范围值，例如但不限于约10～70％、约10～60％、约10～50％、约10～40％、约10～30％、约15～35％、约15～40％、约20～80％、约20～70％、约20～60％、约20～50％、约20～40％、约30～80％、约30～70％、约30～60％、约30～50％、约30～40％，优选约10～60％、约15～40％、约20～60％、约20～40％、约20～30％，更优选约20～40％，最优选约20～30％。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中所述粘合剂可以选自聚乙烯吡咯烷酮、淀粉、甲基纤维素、羟丙基纤维素、羟丙甲纤维素、海藻酸盐等；优选地，所述粘合剂选自聚乙烯吡咯烷酮或羟丙甲纤维素；所述粘合剂的用量占口服制剂重量的0.5～10％，或其间的任何整数或非整数点值或范围值，例如但不限于约0.5～9％、约0.5～8％、约0.5～5％、约1～10％、约1～9％、约1～8％、约1～5％、约1～3％、约1.5～2.5％、约2～10％、约2～8％、约2～5％、约2～4％，优选约0.5～5％、约1～3％、约1.5～2.5％，更优选约1～3％，最优选约1.5～2.5％。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中所述崩解剂可以选自交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、淀粉、预胶化淀粉等；优选地，所述崩解剂剂为交联羧甲基纤维素钠；所述崩解剂的用量占口服制剂重量的1～20％，或其间的任何整数或非整数点值或范围值，例如但不限于约1.0％、约2.0％、约5.0％、约7.0％、约10％、约15％、约20％、约1～10％、约1～8％、约2～10％、约2～8％、约2～7％、约3～10％、约3～8％、约3～7％、约4～10％、约4～8％，优选约1～10％、约2～8％、约3～7％，更优选约2～8％，最优选约3～7％。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其中所述润滑剂可以选自硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸锌、棕榈酸、棕榈酸硬脂酸甘油酯、滑石粉、巴西棕榈蜡、月桂基硫酸钠、硬脂富马酸钠等；优选地，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙和硬脂酸锌；所述润滑剂的用量占口服制剂重量的0.1～5％，或其间的任何整数或非整数点值或范围值，例如但不限于约0.1％、约0.5％、约1.0％、约1.5％、约2.0％、约2.5％、约3.0％、约3.5％、约4.0％、约4.5％、约5.0％、约0.5～5％、约0.5～4％、约0.5～3％、约0.5～2％、约0.5～2.5％、约0.5～1.5％、约1～5％、约1～4％、约1～3％、约1～2.5％、约1～2％，优选约约0.5～3％、约0.5～2％、约0.5～1.5％、约1～3％、约1～2％，更优选约0.5～2％，最优选约约0.5～1.5％。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其还包含稳定剂，所述稳定剂可以选自羟丙甲纤维素、十二烷基硫酸钠、聚丙烯酸树脂类聚合物等，优选聚丙烯酸树脂类聚合物，例如上述实施方案中所提及的一般或具体的聚丙烯酸树脂类聚合物，例如Eudragit，例如Eudragit L100、Eudragit E100、Eudragit L100-55或其任意比例的混合物，优选甲基丙烯酸-丙烯酸乙酯(1:1)共聚物例如Eudragit L100-55；所述稳定剂的用量占口服制剂重量的1～20％，或其间的任何整数或非整数点值或范围值，例如但不限于约1.0％、约2.0％、约3.0％、约5.0％、约7.0％、约10％、约12％、约15％、约1～10％、约1～8％、约2～10％、约2～8％、约3～10％、约3～8％、约4～10％、约4～8％、约5～10％、约5～8％，优选约1～10％、约5～10％、约2～8％、约4～8％，更优选约2～8％，最优选约4～8％。
在一个实施方案中，本发明提供了EED抑制剂(例如化合物A)的口服制剂，其还包含助流剂，所述助流剂可以选自滑石粉、二氧化硅、微粉硅胶(胶态二氧化硅)以及其他可药用形式的二氧化硅；优选地，所述助流剂为胶态二氧化硅；所述助流剂的用量占口服制剂重量的0～5％，或其间的任何整数或非整数点值或范围值，例如但不限于0％、约0.5％、约1.0％、约1.5％、约2.0％、约2.5％、约3.0％、约3.5％、约4.0％、约4.5％、约0.5～5％、0.5～4％、0.5～3％、0.5～2％、0.5～1.5％、1～3％、1～2％，优选约0.5～4％、0.5～3％、0.5～2％、0.5～1.5％，更优选约0.5～2％，最优选约0.5～1.5％。
在一个实施方案中，本发明提供了上述EED抑制剂(例如化合物A)的口服制剂，例如片剂，其包含：
1)约10～80重量％的本文所述一般或具体定义的固体分散体，包含约5-500mg本文所述一般或具体定义的EED抑制剂(例如化合物A)，以及所述一般或具体定义的聚合物载体；
2)约10～80重量％的本文所述一般或具体定义的填充剂；
3)约0.5～10重量％的本文所述一般或具体定义的粘合剂；
4)约1～20重量％的本文所述一般或具体定义的崩解剂；和
5)约0.1～5重量％的本文所述一般或具体定义的润滑剂；
优选地包含：
1)约50～80重量％的本文所述一般或具体定义的固体分散体，包含约10-500mg本文所述一般或具体定义的EED抑制剂(例如化合物A)，以及所述一般或具体定义的聚合物载体；
2)约20～60重量％的本文所述一般或具体定义的填充剂；
3)约0.5～5重量％的本文所述一般或具体定义的粘合剂；
4)约1～10重量％的本文所述一般或具体定义的崩解剂；和
5)约0.5～3重量％的本文所述一般或具体定义的润滑剂；
更优选地包含：
1)约30-80重量％的本文所述一般或具体定义的固体分散体，包含约10-200mg本文所述一般或具体定义的EED抑制剂(例如化合物A)，以及所述一般或具体定义的聚合物载体；
2)约20～40重量％的本文所述一般或具体定义的填充剂；
3)约1～3重量％的本文所述一般或具体定义的粘合剂；
4)约2～8重量％的本文所述一般或具体定义的崩解剂；和
5)约0.5～2重量％的本文所述一般或具体定义的润滑剂；
最优选地包含：
1)约50-70重量％的本文所述一般或具体定义的固体分散体，包含约10-200mg本文所述一般或具体定义的EED抑制剂(例如化合物A)，以及所述一般或具体定义的聚合物载体；
2)约20～30重量％的本文所述一般或具体定义的填充剂；
3)约1.5～2.5重量％的本文所述一般或具体定义的粘合剂；
4)约3～7重量％的本文所述一般或具体定义的崩解剂；和
5)约0.5～1.5重量％的本文所述一般或具体定义的润滑剂；
上述一般、优选、更优选或最优选的口服制剂进一步分别任选地包含：
6)约1～20重量％、优选约1-10重量％、更优选约2-8重量％、最优选约4～8重量％的本文所述一般或具体定义的稳定剂；和/或
上述一般、优选、更优选或最优选的口服制剂进一步分别任选地包含：
7)约0～5重量％、优选约0.5～3重量％、更优选约0.5～2重量％、最优选约0.5～1.5重量％的本文所述一般或具体定义的助流剂。
需要说明的是，在上文一般或优选定义的本发明EED抑制剂(例如化合物A)的口服制剂中，所述固体分散体、其各个组份的选择、各个组份的含量和相互之间的配比(例如载药比、聚合物载体之间的配比)均如上文本发明第一方面所定义，即涵盖每个技术特征的一般或优选定义所构成的固体分散体技术方案，也涵盖各个技术特征的一本或优选定义的任意组合所构成的固体分散体技术方案。
在一个实施方案中，本发明提供了上述EED抑制剂的口服制剂，例如片剂，其中EED抑制剂为化合物A或其药学上可接受的盐或溶剂合物，且所述固体分散体中的聚合物载体为醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)。
在一个实施方案中，本发明提供了上述EED抑制剂的口服制剂，例如片剂，其中EED抑制剂为化合物A或其药学上可接受的盐或溶剂合物，且所述固体分散体中的聚合物载体为本文一般或具体定义的纤维素醚酯类(例如HPMCAS)和聚丙烯酸树脂类(例如Eudragit，例如甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，例如Eudragit L100-55)聚合物的混合物。
在一个实施方案中，本发明提供了上述EED抑制剂的口服制剂，例如片剂，其中EED抑制剂为化合物A或其药学上可接受的盐或溶剂合物，且所述固体分散体中的聚合物载体为本文一般或具体定义的聚丙烯酸树脂类(例如Eudragit，例如甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，例如Eudragit L100-55)聚合物。
在一个实施方案中，本发明提供了上述EED抑制剂(例如化合物A)的口服制剂，例如片剂，其中所述填充剂为微晶纤维素，所述粘合剂为羟丙甲纤维素，所述崩解剂为交联羧甲基纤维素钠，所述润滑剂为硬脂酸镁，所述稳定剂为甲基丙烯酸-丙烯酸乙酯(1:1)共聚物(例如Eudragit L100-55)，所述助流剂为胶态二氧化硅。
在一个实施方案中，本发明提供了上述EED抑制剂(例如化合物A)的口服制剂，例如片剂，其中所述片剂可以为包衣片剂，其中所述包衣剂为本领域技术人员所熟知，例如但不限于羧甲基纤维素钠、醋酸纤维素、醋酸邻苯二甲酸纤维素、甲基纤维素、乙基纤维素、羟丙纤维素、羟丙甲纤维素、羟丙甲纤维素邻苯二甲酸酯、甲基丙烯酸共聚物、明胶、药用釉料、聚乙二醇、聚醋酸乙烯邻苯二甲酸酯、十二烷基硫酸钠、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、玉米醇溶蛋白、欧巴代等或其混合物，或本领域技术人员熟知的常规薄膜包衣预混物；所述包衣剂的用量占口服制剂重量的0～10％，或其间的任何范围，例如但不限于约0.5％、约0.6％、约0.7％、约0.8％、约0.9％、约1.0％、约1.5％、约2.0％、约2.5％、约3.0％、约3.5％、约4.0％、约4.5％、约5.0％、约6.0％、约7.0％、约8.0％、约9.0％、约10％，优选约1～5％、2～4％，更优选约2～4％。
本发明提供的上述EED抑制剂(例如化合物A)的口服制剂，例如片剂，其溶出迅速且完全，在pH 6～7的0.15％十二烷基硫酸钠(SDS)水性介质条件下，活性成分的溶出度在30分钟保持在约75％或更高，优选约80％或更高，更优选85％或更高；在45分钟保持在约85％或更高，优选约90％或更高。
本发明提供的上述EED抑制剂(例如化合物A)的口服制剂，其为片剂，其片剂硬度在约50～400N之间。在一个具体的实施方案中，对于10mg规格的片剂，硬度为约30～90N之间，优选约30～80N之间。在一个具体的实施方案中，对于50mg规格的片剂，硬度为约50～200N之间，优选约70～150N之间。在一个具体的实施方案中，对于200mg规格的片剂，硬度为约150～400N之间，优选约200～360N之间。
本发明提供的上述EED抑制剂(例如化合物A)的口服制剂，其为片剂，其片剂脆碎度低于约1重量％，优选低于约0.5重量％，例如低于约0.2重量％，更优选低于约0.1重量％。
本发明提供的上述EED抑制剂(例如化合物A)的口服制剂，其为片剂，其具有低于约15分钟的崩解时限，优选低于约5分钟，例如约0.5～5分钟。
本发明提供的上述EED抑制剂(例如化合物A)的口服制剂，其原辅料混合物具有良好的稳定性，在高温(60℃)、高湿(25℃/RH90％±5％)、加速(40℃±2℃/RH75％±5％)和避光条件下放置0/5/10/30天，外观无明显变化，有关物质无明显增长。
本发明提供的上述EED抑制剂(例如化合物A)的口服制剂，其为片剂，在经常规包装材料包装后的成品制剂具有良好的稳定性，在40℃±2℃/RH75％±5％、30℃±2℃/RH65％±5％和25℃±2℃/RH60％±5％条件下放置1个月，受试样品的外观、水分、有关物质、含量及溶出度均无显著变化。
在第六个方面，本发明提供了上述本发明片剂形式的口服制剂的制备方法，包括以下步骤：
(1)在混合机内均匀混合本发明的EED抑制剂固体分散体、填充剂、粘合剂、崩解剂、稳定剂和/或助流剂；
(2)将步骤(1)的混合物制粒；
(3)将步骤(2)制得的颗粒与润滑剂充分混合；
(4)将步骤(3)制得的混合物压片。
在一个优选的实施方案中，在步骤(1)中，将本发明的EED抑制剂固体分散体、填充剂、稳定剂、粘合剂、崩解剂和和助流剂均匀混合。
在一个优选的实施方案中，将步骤(1)的该混合物过筛后再混合。
在一个优选的实施方案中，将步骤(1)的经过筛的混合物再次混合。
在一个优选的实施方案中，在进行步骤(2)的制粒之前，将步骤(1)的混合物与部分润滑剂充分混合；其中所加入的部分润滑剂可以适宜地为处方中润滑剂总重量的约40～70％，优选约50～70％。在该阶段加入部分润滑剂，有助于进一步改善随后的制粒过程中的粘附现象以及压片过程中的粘冲现象。
在步骤(2)中，对制粒的条件和手段没有严格限制，可以为湿法制粒，也可以采取干法制粒或熔融制粒。
在一个优选的实施方案中，该步骤(2)的制粒采用干法制粒，可以采用本领域已知的常规方法进行，例如应用辊压法，可以参见例如《药剂学》，方亮主编，第三版，2015年7月，中国医药科技出版社。
在一个优选的实施方案中，干法制粒的压力可以为6～8Kpa，优选4～6KPa。采用所述的压力范围，能够进一步减少干法制粒的物料在压辊上的粘附，所制备的颗粒流动性进一步改善，压片时的粘冲现象进一步减少。
依照上述方法所制备得到的片剂的脆碎度低于1％，优选低于约0.5％；崩解时限小于15分钟，优选小于10分钟、小于5分钟；溶出度pH6.8的SDS溶液中在30分钟能够达到75％以上，在45分钟能够得到85％以上。
在一个实施方案中，本发明该方面的片剂形式的口服制剂的制备方法还包括步骤(5)：用包衣材料将步骤(4)制得的片剂包衣。
在步骤(5)中，对所用的包衣材料没有特别的限制，但应当对片剂的含量和溶出度无显著影响，并起到避光作用，以进一步提高片剂制剂的储存稳定性。
在一个实施方案中，步骤(5)的包衣材料占口服片剂处方总重量的约1～5％，优选2～4％，且为片芯增重约1～5％，优选2～4％。
需要说明的是，上述本发明第二方面、第四方面和第六方面的制备方法中，所述EED抑制剂(例如化合物A)、聚合物载体、固体分散体、各类赋形剂的选择和用量均如上文对于相应技术方案所一般、具体或优选所定义，最优选EED抑制剂为化合物A或其药学上可接受的盐或溶剂合物，所述聚合物载体为醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)和/或甲基丙烯酸-丙烯酸乙酯(1:1)共聚物(例如Eudragit L100-55)，所述填充剂为微晶纤维素，所述稳定剂为甲基丙烯酸-丙烯酸乙酯(1:1)共聚物(例如Eudragit L100-55)，所述粘合剂为羟丙甲纤维素，所述崩解剂为交联羧甲基纤维素钠，所述润滑剂为硬脂酸镁，所述助流剂为胶态二氧化硅。
在第七个方面，本发明提供了上述本发明固体分散体、固体分散体组合物或口服制剂的用途，用于治疗或预防抑制EED提供益处的疾病(例如癌症或肿瘤)。
在第八个方面，本发明提供了上述本发明固体分散体、固体分散体组合物或口服制剂在制备用于治疗或预防抑制EED提供益处的疾病(例如癌症或肿瘤)的药物中的用途。
在第九个方面，本发明提供了一种在患者中治疗或预防抑制EED提供益处的疾病(例如癌症或肿瘤)的方法，包括将治疗有效量的本发明的固体分散体、固体分散体组合物或口服制剂施用于有需要的对象。
需要说明的是，上述本发明第七方面至第九方面中所述的“得益于EED抑制的疾病”选自癌症和增生性疾病、炎性疾病、败血症、自体免疫疾病和病毒感染，优选癌症和增生性疾病，具体示例参见CN114127073A的相应内容。
在一个实施方案中，上述本发明第七方面至第九方面中所述的“得益于EED抑制的疾病”为癌症，选自急性单核细胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴细胞性白血病混合谱系白血病、NUT-中线癌、多发性骨髓瘤、小细胞肺癌、非小细胞肺癌、成神经细胞瘤、伯基特氏淋巴瘤、宫颈癌、食道癌、卵巢癌、结肠直肠癌、前列腺癌、乳癌、膀胱癌、卵巢癌、胶质瘤、肉瘤、食道鳞状细胞癌和甲状腺乳头状癌。
以上所述的本发明各项技术方案，将难溶于水的EED抑制剂活性成分例如化合物A用特定类型的聚合物载体制备成固体分散体，药物活性成分在该固体分散体环境中保持稳定的无形性状态，同时改善了药物在胃肠液中的溶解、溶出度从而提高了药物的口服生物利用度。使用该固体分散体、配合特定的赋形剂组合所制备的片剂的各项制剂性能良好，脆碎度、硬度、崩解时限和溶出度同时达到了优异的水平，且所采用的制备方法工艺简单，参数易控制，重现性练好，易于工业化生产。
附图说明
图1A、图1B和图1C显示：化合物A(下文亦简称API)、代表性聚合物载体以及化合物A和代表性聚合物载体的混合物(载药比1:3)的DSC图谱。
图2显示不同载体(醋酸羟丙甲纤维素琥珀酸酯-LG、共聚维酮VA64或羟丙纤维素EXF)和API所制备固体分散体的PLM照相。
图3A显示不同载体(醋酸羟丙甲纤维素琥珀酸酯-LG、共聚维酮VA64或羟丙纤维素EXF)和API所制备固体分散体的XRPD图谱；图3B显示不同载体(尤特奇L100-55或尤特奇L100-55+HPMCAS-LG)和API所制备固体分散体的XRPD图谱；图3C显示不同载药比(API:HPMCAS-LG)的固体分散体的XRPD图谱。
图4A-图4D显示不同载药比(API:HPMCAS-LG)的固体分散体的DSC图谱。
图5A显示不同聚合物载体所制备的化合物A固体分散体在FaSSIF-V2溶液中的动态溶解度；图5B显示另外添加尤特奇L100-55时不同载药比(API:HPMCAS-LG)的固体分散体在FeSSIF-V2溶液中的动态溶解度。
图6显示在比格犬中口服施用本发明固体分散体的药代动力学性质。
图7显示本发明固体口服制剂的溶出性质。
具体实施方式
以下通过实施例进一步说明和解释本发明，但不构成对本发明所要求保护的范围的限制。
如果没有特别说明，则实施例中所使用的辅料和试剂均来自商业途径，质量标准和用量均符合中国药典的标准；本发明所使用的EED抑制剂可以参照CN114127073A所述方法制备，例如化合物A或其可药用盐可参照其中的实施例73的方法制备。
通用实验方法
1.X射线粉末衍射(XRPD)：采用D8 Advance仪器，配备Lynxeye检测器，在X射线(Cu，:1.54)、45kV/40mA、步长(°2θ)0.02、扫描速率(s/step)0.1、扫描范围(°2θ)3-40条件下记录图谱。
2.偏光显微镜(PLM)：采用Axiolab5仪器，在室温条件下，取适量待测样品于载玻片上，滴加少量石蜡分散样品，盖上盖玻片分散样品后移除盖玻片，于20倍物镜(放大200倍)下观察。
3.调制差示扫描量热测定(mDSC)：采用Discovery DSC 2500，线性升温(10℃/min)，在氮气下自25℃记录图谱。
4.活性成分含量测定：采用配有紫外检测器或二极管阵列检测器和自动进样器的高效液相色谱仪(HPLC)，色谱柱Waters Xbridge C18(4.6×150mm,3.5μm，柱温30℃)，流动相(A:B＝40:60，A：0.05％磷酸水溶液，B：0.05％磷酸在甲醇:乙腈(1:9)中的溶液)，流速0.8mL/min，以甲醇稀释样品，进样10μL，记录UV 249nm处的吸收值随时间的变化。
5.溶出度、片剂脆碎度、硬度和崩解时限的测定：按照本领域常规方法进行，例如参照中国药典2015版中相应的测定方法进行。
6.禁食状态模拟肠液(FaSSIF)、进食状态模拟肠液(FeSSIF)和胃模拟溶液(SGF)可以使用商购产品，或按照以下方式配制：
FaSSIF-V2溶液的配制：称取氢氧化钠1.39g、2.22g顺丁烯二酸、4.01g氯化钠、定容至1000ml，超声溶解，调节pH至6.5备用，加入FaSSIF-V2粉末1.79g，溶解备用。
FeSSIF-V2溶液的配制：称取氢氧化钠1.64g，顺丁烯二酸3.19g，氯化钠3.67g在500ml纯水中溶解，调节pH至pH5.8，加入FeSSIF-V2溶液4.88g，超声至全部溶解，备用。
胃模拟溶液(SGF)的配制：取浓盐酸0.96ml，加水150ml与胃蛋白酶2.5g，摇匀后加水稀释成250ml，备用。
7.固体分散体的制备：称取处方量的化合物A加入溶剂(例如二氯甲烷和甲醇的混合溶剂)，搅拌直至溶解，加入处方量的载体物质，搅拌溶解，置于喷雾干燥机中、选择合适的进风温度、进风量、进液速度和压力等参数进行喷雾干燥，得到本发明的固体分散体。适用于本发明的喷雾干燥设备包括但不限于Niro GEA Process Engineering Inc.、Buchi Labortechnik AG.、ProCept和SPX ANHYDROUS公司生产的相应设备，本发明示例性采用BUCHI290喷雾干燥机，在以下参数范围内进行：
还可以将上述喷雾干燥所得粉末进一步进行二次干燥，例如减压干燥，例如在25～50℃的温度(例如50℃)和降低的压力0至-0.1Mpa(例如-0.1Mpa)下进行适合的时间，例如2-5小时，例如4小时。
实施例1
采用本领域熟知的标准溶解度测定法，测定了活性成分化合物A在各类溶剂中的溶解度(25℃)，结果见下表1：
表1
基于以上实验结果，综合考量经济、溶解效率和毒性等因素，本发明采用二氯甲烷和甲醇的混合溶剂作为制备固体分散体的溶剂系统。
实施例2
称取12mg各类载体物质，分别与8mg化合物A游离碱晶体置于2ml液相小瓶中，再分别加1ml溶剂二氯甲烷:甲醇(2:1)，于磁力搅拌器上1500rpm搅拌30min至全部溶解，配置成固含物20mg/ml的混悬溶液。移取20μl各处方溶液滴在载玻片上，用盖玻片将液滴分散，于50℃烘干溶液，使用偏光显微镜PLM观察。尤特奇L100-55采用XRPD进行相应检测。结果见表2：
表2
表2显示，所测试的载体物质中，聚乙二醇和羟丙甲纤维素E4M明显不适用，其他类型的载体均能将化合物A转晶完全。
实施例3
根据上文所述固体分散体制备方法，以二氯甲烷:甲醇(2:1)作为溶剂系统，采用不同载体和化合物A分别制备如下固体分散体(ASD)：
以二氯甲烷:甲醇(3:1)作为溶剂系统，采用不同载体和化合物A分别制备如下固体分散体(ASD)：
注：“外加”意指将所述物质添加到用表中所列载体和化合物A已制备得到的固体分散体中；*中化合物A和HPMCAS-LG的最终比例为1:7。
实验结果显示，使用不同载体和载药比制备化合物A固体分散体，收率均在75％以上，均具有可制备性。
实施例4
按照本文所述X射线粉末衍射(XRPD)和偏光显微镜(PLM)测定法，考察了本发明固体分散体中化合物A的转晶情况，结果见下表3及图2、3A、3B、3C：
表3
表3显示，以HPMCAS-LG、共聚维酮VA64、羟丙纤维素EXF和/或尤特奇L100-55作为载体制备固体分散体，化合物A均能转晶完全，无明显晶体存在。
表3的PLM检测结果显示，不同载药比的固体分散体，均仅观察到极少量双折射颗粒，XRPD结果也显示，所有样品均无化合物A晶体衍射峰，说明在不同载药比下，化合物A均能转晶完全。
还考察了本发明代表性固体分散体在FeSSIF-V2溶液和/或FsSSIF-V2溶液中的动态转晶情况，其中将各个固体分散体分散于FeSSIF-V2溶液中，配制含化合物A约1mg/mL的混悬液，或分散于FaSSIF-V2溶液中，配制含化合物A约2mg/mL的混悬液；将各个混悬液置于磁力搅拌器初步分散后，常温1500rpm分散，1000rpm保持搅拌，在固定的时间点取样1.5ml，按照本文所述偏光显微镜(PLM)测定法观察。结果见表4：
表4
表4显示，使用HPMCAS-LG作为载体与化合物A制备的各个固体分散体(ASD-11、ASD-12、ASD-13)，在FeSSIF-V2溶液中能保持稳定约6小时，在PLM检查中均未观察到明显双折射颗粒，未发生转晶。在FeSSIF-V2溶液中更长时间的稳定性，可通过向所述固体分散体另外添加特定的聚合物来实现，例如另外添加HPMC-E4M、SDS和HPMCAS-LG均未能改善在溶液中较长时间后的稳定性，19小时仍能观察到大量双折射颗粒(ASD-14、ASD-15、ASD-16)，但是在各个载药比的ASD中另外添加尤特奇L100-55，使得所述固体分散体在FeSSIF-V2溶液中能够保持稳定达24小时，在PLM检查中未出现明显双折射颗粒，未发生转晶。
表4还显示，还可以使用尤特奇L100-55或(尤特奇L100-55+HPMCAS-LG)作为载体与化合物A制备得到固体分散体(ASD-4、ASD-5、ASD-6、ASD-7和ASD-8)，该组固体分散体在FeSSIF-V2溶液中保持稳定达24小时，在PLM检查中均未观察到明显双折射颗粒，未发生转晶。此外，该组固体分散体，在FaSSIF-V2溶液中也保持稳定达24小时，在各个时间点的PLM检查中均未观察到明显双折射颗粒，未发生转晶。
还按照本文所述调制差示扫描量热测定(mDSC)测定法，考察了不同载药比的本发明固体分散体(ASD-10、ASD-11、ASD-12和ASD-13)中化合物A的转晶情况，结果如图4A～4D所示，各个样品均未显示化合物A晶体峰，随着载药比降低，玻璃化转化温度降低，230℃左右的转晶峰强度变弱。
实施例5
按照上文通用实验方法所述，使用FaSSIF、FeSSIF和SGF溶液，考察了本发明固体分散体在各个溶液中的动态溶解度，其中将各个固体分散体分散于FeSSIF-V2溶液中，配制含化合物A约1mg/mL的混悬液，或分散于FaSSIF-V2溶液中，配制含化合物A约2mg/mL的混悬液。将各个混悬液搅拌分散，在固定的时间点取样1～1.5ml，离心，取上清液，过滤膜，按照上文通用实验方法所述HPLC法测定化合物A的含量，结果见表5和图5A、图5B。
表5

*：FeSSIF-V2混悬液的API浓度为2mg/ml。
表5显示，在FaSSIF-V2溶液中，不同载体和不同载药比的化合物A固体分散体在各个时间点的溶解量均远远大于化合物A原料的溶解量，且不同载药比的化合物A固体分散体的24小时溶解量基本相似。
表5还显示，在FaSSIF-V2溶液中，用HPMCAS和/或尤特奇L100-55、或共聚维酮VA64所制备的固体分散体的API溶解度随着时间保持稳定或不断上升，其中用HPMCAS、内加尤特奇L100-55所制备的固体分散体的API溶解度，相对于用共聚维酮VA64和羟丙纤维素EXF所制备固体分散体的API溶解度，有较大优势。
表5还显示，在FaSSIF-V2溶液和FeSSIF-V2溶液中，内加或外加Eudragit  L100-55的固体分散体，相比聚合物载体仅为HPMCAS的固体分散体，API的溶解度均显示有不同程度的增加。
表5还显示，在FeSSIF-V2溶液中，载药量越低，溶解量越大，且聚合物载体仅为HPMCAS的固体分散体在24h的溶解量均显著降低，但是向固体分散体另外添加Eudragit L100-55即均能使溶解量随时间基本保持平衡，且随着Eudragit L100-55的添加比例增加，API的溶解量也随之增加。
表5中的对比结果还显示，在保持其他条件相同的情况下，将Eudragit L100-55内加或外加，API在FeSSIF-V2溶液中的溶解量基本一致。
此外，还使用SGF溶液，将本发明固体分散体配制成含化合物A约2mg/mL的混悬液，考察了动态溶解度。结果显示，不同载药比的固体分散体(例如ASD10～13)在1～24小时期间各个时间点的API溶解度均小于0.005mg/ml，甚至低于0.0001mg/ml。
实施例6
将实施例3制备的固体分散体ASD-12(API:HPMCAS-LG＝1:3)于高温(60℃)、高湿(25℃/RH90％±5％)、加速(40℃±2℃/RH75％±5％)条件下放置0/5/10/30天，取样，以纯度、有关物质(最大单一杂质和总杂质)为考察指标，评价ASD的化学稳定性，结果见表6。
表6
表6显示：ASD在高温、高湿、加速条件下，外观无明显变化，有关物质无明显增长，表明ASD化学稳定性良好。
此外，还考察了固体分散体ASD-1在上述各个时间点所取样品的固体形态稳定性(mDSC、XRPD和PLM)。结果显示，在30天时，所有样品的XRPD图谱均未发现有明显晶体衍射，PLM检查无明显双折射颗粒，且:所有条件样品的mDSC图谱与第0天均无明显变化。
此外，还考察了固体分散体ASD-1在冷藏(2～8℃)、研磨5min(室温)、研磨5min冷藏(2～8℃)、研磨15min(室温)、研磨15min冷藏(2～8℃)、压片(室温)、压片冷藏(2～8℃)、与PH102压片室温(固体分散体:PH102＝1:5)、与PH102压片2～8℃(固体分散体:PH102＝1:5)条件下于第0天、第5天、第10天和第30天样品的含量、杂质(单一杂质和总杂质)和固体形态稳定性(mDSC、XRPD和PLM)。结果显示，各试验条件下样品均未见含量、杂质明显变化，所有样品的XRPD图谱均未发现有明显晶体衍射，PLM检查无明显双折射颗粒，且:所有条件样品的mDSC图谱与第0天均无明显变化。。
以上结果显示，本发明的固体分散体具有令人满意的稳定性质，在所有所测试的条件下均表现出优异的化学稳定性和固态稳定性，使得其有潜力开发为实用便捷的制剂产品。
实施例7
本实验采用化合物A在0.5％ SDS水溶液中的2.5mg/ml溶液作为对照(使用前2小时内配制)，在比格犬中考察了本发明固体分散体(ASD-22，灌装于胶囊壳中)的药代动力学性质。
具体地，将15只比格犬(雄性，体重约8～11kg)随机分为5组，每组3只。禁食一晚后，对其中两组分别通过口服给予供试样品，剂量分别为2.5mg/kg和10mg/kg，并对另一组进食0.5h后的比格犬口服给予10mg/kg供试样品；另外两组禁食一晚的比格犬口服给予2.5mg/kg和50mg/kg的化合物A溶液作为对照。分别于给药前(0h)和给药后0.083、0.25、0.5、1、2、4、6、8、24h由头静脉采血0.5ml。血样取出后立即置于肝素化的EP管中，3000g(RCF：相对离心力)离心5min，分离血浆，冷冻保存于-70℃冰箱待测。
测定时，将血浆解冻后，精密吸取20μL置于具塞的离心管中，精密加入内标溶液200μL(60ng/mL双氯芬酸70％甲醇水溶液)，涡旋混匀10分钟，5800rpm离心10分钟，取上清液进行LC-MS/MS分析(Waters ACQUITY UPLC BEH C182.1×50mm；流动相A：0.025％甲酸(1mM醋酸铵水溶液)溶液，流动相B：0.025％磷酸(1mM醋酸铵甲醇溶液)溶液；梯度：10％B 0.2min，0.2～1min升至95％B，保持0.5min，1.50～1.51min降至10％B，保持至2min；流速0.60mL/min；自动进样器控温/柱温5℃/60℃；进样体积4μL)
主要药动学参数见表7，血浆药物浓度-时间曲线见图6，其中AUC值是用WinNonLin软件计算得到。
表7
表7和图6显示，本申请的固体分散体与相同给药剂量、相同条件下的溶液剂形式在比格犬体内的暴露量相当，且未见有明显食物效应。这表明，在水中几乎不溶的化合物A，被成功地制备为生物利用度与溶液剂相当的固体形式，克服了难溶性药物普遍的生物利用度低的缺陷，扩展了药物的使用空间。
实施例8
将本发明固体分散体(ASD-12)按照下表8所示处方，与所示赋形剂混合均匀，过筛，进行干法制粒，将所制得的颗粒与硬脂酸镁混合均匀，将得到的总混颗粒压制成片剂。
表8

表8显示，处方T1、T3、T4、T5的片剂展现出较好的溶出特性，45分钟溶出可达80％以上，尤其是单独使用微晶纤维素作为填充剂制得的片剂综合性能最佳，可压性良好，崩解时限可接受，溶出最为完全。
还将本发明固体分散体(ASD-12)按照下表9所示处方，与所示赋形剂混合均匀，过筛，进行干法制粒，将所制得的颗粒与硬脂酸镁混合均匀，将得到的总混颗粒压制成片剂。
表9
*：干法制粒压力为5-6KPa，其余均为6-8KPa。
以上处方制备的各个片剂，均具有可接受的类白色(间或斑点)外观。
表9显示，崩解剂的含量与崩解时间成正比，约1～10重量％的崩解剂交联羧甲基纤维素钠能够使所述制剂迅速崩解，崩解时间在1～10分钟内，其中约2～8重量％、尤其约3～7重量％的崩解剂的崩解时间最为适中，且各个配方的干法制粒的颗粒均硬度适中，脆碎度(4min)在约0.05～0.15％之间，脆碎度(8min)在约0.1～0.3％之间。
表9还显示，所测试的含量范围的粘合剂均能使得干法制粒的颗粒硬度适中，其中优选约1～3重量％的粘合剂，最优选约1.5～2.5重量％的粘合剂，所压制的片剂具有良好的制剂性质，例如脆碎度均小于0.2重量％，且崩解时间适中。
制剂实验过程显示，在干法制粒初混粉中加入上述处方量的硬脂酸镁，混匀后进行干法制粒，有助于改善粘附现象。干法制粒后加入处方量的硬脂酸镁，混合后进行压片，有助于改善黏冲现象。
此外，还采用上表处方T15，将干法制粒压力由6～8KPa更改为4-6KPa，观察到制粒物基本不黏压辊且制粒后的流动性良好，压片不粘冲，片面平整光滑，脆碎度合格(均小于0.1％)，崩解时限小于10分钟(50mg规格片剂崩解时间为6min8s，200mg规格片剂崩解时间为3min)，45分钟溶出(pH6.8+0.1％SDS)达到89.1％(50mg规格片剂)和90.7％(200mg规格片剂)，60分钟溶出(pH6.8+0.1％SDS)达到93.9％(50mg规格片剂)和91.7％(200mg规格片剂)。
实施例9
基于实施例8的考察结果，将本发明的固体分散体、连同稳定剂、填充剂、粘合剂、崩解剂、助流剂、润滑剂、薄膜包衣预混剂分别配制成10mg、50mg、200mg规格的片剂，考察其各项片剂性质。
具体地，按照下表10称取处方量的固体分散体ASD-12、甲基丙烯酸-丙烯酸乙酯共聚物(例如Eudragit L100-55)、微晶纤维素、羟丙甲纤维素、交联羧甲基纤维素钠、胶态二氧化硅和薄膜包衣预混物，以及硬脂酸镁，过筛(50～60目)；将ASD-12、甲基丙烯酸-丙烯酸乙酯共聚物、微晶纤维素、羟丙甲纤维素、交联羧甲基纤维素钠、胶态二氧化硅在混合机中混合后，过筛，该步骤可再重复一次(预混物)；然后加入内加硬脂酸镁(约0.5％w/w)，混合均匀；将加入硬脂酸镁的预混物加入干法制粒机中进行干法制粒，压力控制在4-6KPa；将所制得的颗粒与剩余的硬脂酸镁(约0.5％w/w)混合均匀，将得到的总混颗粒压制成片剂，并考察所得片剂的外观、脆碎度、硬度、溶出性质和稳定性。
表10
注：该表中括号内的溶出数据在pH6.8+0.1％SDS中测试获得。
表10显示，将难溶性的化合物A根据本发明制备成固体分散体，并按照本发明进一步制备成口服固体制剂，其溶出性能优异(附图7)，且显示良好的各项制剂性质，预期能够提供具有增强的生物利用度、从而能够以较低的剂量发挥治疗功效的抗癌药物，满足了癌症治疗领域的医疗需求。
此外，还考察了上述10mg、50mg和200mg规格的片剂用常用包装材料包装(例如药用高密度聚乙烯瓶45ml或100ml、33mm或38mm药用聚乙烯/聚丙烯儿童安全组合瓶盖)后分别在40℃±2℃/RH75％±5％、30℃±2℃/RH65％±5％条件下的稳定性，检查受试样品的外观、水分、有关物质、含量及溶出度，结果显示均无显著变化，表明所制备的片剂制剂具有良好的稳定性，且与包装材料相容性良好。结果见表11：
表11

其中，溶出度数值表示在pH6.8磷酸盐缓冲液+0.15％十二烷基硫酸钠介质中45min后的实验结果，“有关物质”数值是在通用实验方法所述HPLC检测条件下HPLC图谱中所有杂质的总和；“水分”为采用卡尔费休方法测定的结果。
本文所给出的具体实施方案仅用于对本发明进行举例说明，不构成对权利要求所定义的范围的限制。在本申请所公开的内容的基础上，本领域技术人员能显而易见地了解本申请的技术方案的等价变体，这些变体也涵盖在本申请的范围内。

Claims (20)

  1. 固体分散体，其包含EED抑制剂或其药学上可接受的盐或溶剂化物，以及聚合物载体，其中所述的EED抑制剂为下式的化合物：
    其中：
    R1是芳烷基；
    R2选自H和C1-C4烷基；
    X选自-C(R5a)(R5b)-、-C(＝O)-和-S(＝O)2-；R5a和R5b独立地选自H和C1-C4烷基；
    Y选自-C(R6a)(R6b)-、-S-、-O-和-N(R7)-；
    Z是-C(R6c)(R6d)m-；
    R6a和R6b独立地选自H和C1-C4烷基；
    R6c和R6d各自独立地选自H和C1-C4烷基；m是0、1或2；
    R7选自C1-C6烷基、C1-C6卤代烷基、任选取代的C3-C8环烷基；
    L选自-C(R8b)＝和-N＝；
    R8a选自-CF3、-CH3、-CHF2、-CD3和环丙基；并且
    R8b和R8c为氢；
    或其药学上可接受的盐或溶剂化物。
  2. 权利要求1的固体分散体，其中所述EED抑制剂为化合物A：
    或其药学上可接受的盐或溶剂化物。
  3. 权利要求1或2的固体分散体，其中所述聚合物载体选自纤维素醚酯，优选醋酸羟丙甲纤维素琥珀酸酯。
  4. 权利要求1或2的固体分散体，其中所述聚合物载体选自聚丙烯酸树脂，优选甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，优选Eudragit L100-55。
  5. 权利要求1或2的固体分散体，其中所述聚合物载体为纤维素醚酯和聚丙烯酸树脂的混合物，优选醋酸羟丙甲纤维素琥珀酸酯和甲基丙烯酸和丙烯酸乙酯(1:1)共聚物的混合物，更优选醋酸羟丙甲纤维素琥珀酸酯和Eudragit L100-55的混合物。
  6. 权利要求1至5任一项的固体分散体，其中EED抑制剂或其药学上可接受的盐或溶剂化物和聚合物载体的重量比为约1:1至1:5。
  7. 口服固体制剂，其包含权利要求1-6任一项的固体分散体和一种或多种可药用赋形剂。
  8. 权利要求7的口服固体制剂，其为片剂，包含权利要求1-6任一项的固体分散体和填充剂、粘合剂、崩解剂、润滑剂、助流剂、稳定剂和包衣剂中的一种或多种。
  9. 权利要求7或8的口服固体制剂，其中的可药用赋形剂为填充剂、粘合剂、崩解剂、润滑剂、助流剂和稳定剂。
  10. 权利要求7至9任一项的口服固体制剂，其中所述EED抑制剂的含量为约10～30重量％、优选约10～20重量％。
  11. 权利要求7至9任一项的口服固体制剂，其中所述固体分散体占所述口服制剂重量的约30～80％，优选约50～70％。
  12. 权利要求7至9任一项的口服固体制剂，其包含
    1)约30-80重量％的所述固体分散体，包含约10-200mg所述EED抑制剂以及所述聚合物载体；
    2)约20～40重量％的填充剂；
    3)约1～3重量％的粘合剂；
    4)约2～8重量％的崩解剂；
    5)约0.5～2重量％的润滑剂；
    6)约2-8重量％的稳定剂；和
    7)约0.5～2重量％的助流剂。
  13. 权利要求7至9任一项的口服固体制剂，其包含
    1)约50-70重量％的所述固体分散体，包含约10-200mg所述EED抑制剂以及所述聚合物载体；
    2)约20～30重量％的填充剂；
    3)约1.5～2.5重量％的粘合剂；
    4)约3～7重量％的崩解剂；
    5)约0.5～1.5重量％的润滑剂；
    6)约4～8重量％的稳定剂；和
    7)约0.5～1.5重量％的助流剂。
  14. 权利要求8至13任一项的口服固体制剂，其中EED抑制剂为化合物A或其药学上可接受的盐或溶剂合物，且所述固体分散体中的聚合物载体选自醋酸羟丙甲纤维素琥珀酸酯、甲基丙烯酸-丙烯酸乙酯(1:1)共聚物或二者的混合物。
  15. 权利要求8至14任一项的口服固体制剂，其中所述稳定剂是甲基丙烯酸-丙烯酸乙酯(1:1)共聚物，优选Eudragit L100-55。
  16. 权利要求8至15任一项的口服固体制剂，其中所述填充剂为微晶纤维素，所述粘合剂为羟丙甲纤维素，所述崩解剂为交联羧甲基纤维素钠，所述润滑剂为硬脂酸镁，所述助流剂为胶态二氧化硅。
  17. 权利要求1至6任一项的固体分散体或权利要求7-16任一项的固体口服制剂的用途，用于治疗或预防抑制EED提供益处的疾病。
  18. 权利要求1至6任一项的固体分散体或权利要求7-16任一项的固体口服制剂在制备用于治疗或预防抑制EED提供益处的疾病的药物中的用途。
  19. 在有需要的患者中治疗或预防抑制EED提供益处的疾病的方法，包括将治疗有效量的权利要求1至6任一项的固体分散体或权利要求7-16任一项的固体口服制剂施用于所述患者。
  20. 权利要求17或18的用途或权利要求19的方法，其中得益于EED抑制的疾病为癌症，选自急性单核细胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴细胞性白血病混合谱系白血病、NUT-中线癌、多发性骨髓瘤、小细胞肺癌、非小细胞肺癌、成神经细胞瘤、伯基特氏淋巴瘤、宫颈癌、食道癌、卵巢癌、结肠直肠癌、前列腺癌、乳癌、膀胱癌、卵巢癌、胶质瘤、肉瘤、食道鳞状细胞癌和甲状腺乳头状癌。
PCT/CN2024/097747 2023-06-06 2024-06-06 Eed抑制剂固体分散体、包含其的口服制剂及其制备方法 WO2024251197A1 (zh)

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