WO2020108343A1 - 以4'-硫代核苷类化合物为活性成分的口服药物组合物、其制备方法及其用途 - Google Patents

以4'-硫代核苷类化合物为活性成分的口服药物组合物、其制备方法及其用途 Download PDF

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WO2020108343A1
WO2020108343A1 PCT/CN2019/119342 CN2019119342W WO2020108343A1 WO 2020108343 A1 WO2020108343 A1 WO 2020108343A1 CN 2019119342 W CN2019119342 W CN 2019119342W WO 2020108343 A1 WO2020108343 A1 WO 2020108343A1
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pharmaceutical composition
oral pharmaceutical
group
component
weight
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PCT/CN2019/119342
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English (en)
French (fr)
Inventor
蔡孟锬
王梦馨
李岩
葛鹏金
周丹
宋宏梅
蔡家强
赵曦
赵栋
王利春
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201980063524.6A priority Critical patent/CN112770731A/zh
Publication of WO2020108343A1 publication Critical patent/WO2020108343A1/zh

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention relates to an oral pharmaceutical composition containing a 4'-thionucleoside compound, a capsule containing the same, a preparation, a preparation method and use thereof.
  • the main oral preparations are capsules and tablets.
  • Its prescription composition generally includes the active ingredient and one or more excipients. Due to the different properties of various excipients and compounds, a large amount of research work is generally required for a specific compound to determine the appropriate prescription composition.
  • Nucleoside drugs have been widely used to treat various cancers.
  • WO 2016/155593 A1 discloses a new type of 4'-thionucleoside compound, which has superior drug efficacy (including anti-tumor/cancer effect), increased fat solubility, increased bioavailability, and reduced irritation As well as improved absorption, it also has significantly reduced toxicity and increased safety.
  • the present invention provides an oral pharmaceutical composition containing a 4'-thionucleoside compound, which has good stability (the contained active ingredient has good stability, and the amount of impurity growth during preparation and storage is small), good Pharmacokinetic properties (such as good dissolution and bioavailability), which is easy to prepare (the mixing uniformity of intermediate materials in the preparation process is good, and the final formulation indicators such as content uniformity meet the requirements of the Pharmacopoeia), It can meet the needs of clinical and commercial use.
  • the present invention provides an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising the following component (1), and one or more groups selected from components (2), (3), (4) and (5) Minute:
  • Component (1) an active ingredient, which is one or more 4'-thionucleoside compounds of formula (I), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer thereof , Or any of their crystal forms or racemates, or their metabolite forms, or their mixtures:
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycle Group and optionally substituted heteroaryl, wherein both R 2 and R 6 may be connected to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O, and S and It can be saturated ring, unsaturated ring or aromatic ring;
  • R 3 is selected from optionally substituted aryl and optionally substituted heteroaryl
  • R 4 is selected from hydrogen and optionally substituted C 1-10 acyl
  • Q is a pyrimidine base or purine base with the following structure:
  • R 5 is independently selected from hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Group, alkoxyalkyl group, amido group, sulfonamide group, cyano group, nitro group, nitroso group, azido group, aldehyde group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, aralkyl group, aryl group Oxygen, heteroaryl, heteroaryloxy, acyl, carboxyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and carboxylic acid ester groups; the substituents may be connected to each other to constitute 0-3 selected 3-8 membered saturated ring, unsaturated ring or aromatic ring of hetero atoms of N, O
  • Component (3) one or more selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, magnesium lauryl sulfate, talc, polyethylene glycol, and stearic acid Sodium fumarate;
  • Component (4) one or more selected from the following: low-substituted hydroxypropyl cellulose, low-substituted hypromellose, sodium carboxymethyl cellulose, croscarmellose sodium, carboxyl Sodium methyl starch and crospovidone; and
  • Component (5) one or more selected from the following: silica and tricalcium phosphate;
  • the total content of components (1), (2), (3), (4) and (5) is ⁇ 100% by weight of the oral pharmaceutical composition, preferably 100% by weight.
  • the present invention provides a capsule comprising the oral pharmaceutical composition of the present invention and a capsule shell containing the oral pharmaceutical composition.
  • the present invention provides a method of preparing the oral pharmaceutical composition of the present invention or the capsule of the present invention.
  • the present invention provides an article comprising the oral pharmaceutical composition of the present invention or the capsule of the present invention and a separately present desiccant.
  • the present invention provides the use of the oral pharmaceutical composition, capsule, or preparation of the present invention in the preparation of a medicament for preventing or treating a disease with abnormal cell proliferation.
  • the present invention provides an oral pharmaceutical composition, capsule, or preparation of the present invention for use in the prevention or treatment of cell proliferation abnormalities.
  • the present invention provides a method for preventing or treating a cell proliferation abnormality disease, which comprises administering to a subject (preferably a mammal) in need thereof a prophylactic or therapeutically effective amount of the oral pharmaceutical composition, capsule or product.
  • metabolite form refers to a compound produced in vivo after administration to an individual in need thereof.
  • “Pharmaceutically acceptable salts” as used herein refers to those salts that retain the biological effectiveness and properties of the parent compound, which can be prepared by accepting partial protonation of protons and/or deprotonating partial proton donations . It should be noted that partial protonation of the protons leads to the formation of cationic species, where the cationic charge is balanced by the presence of physiological anions, while partial deprotonation of the proton supply results in the formation of anionic species, where the anionic charge is caused by the presence of physiological balance.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts.
  • Suitable acid addition salts are formed from acids that form non-toxic salts, including inorganic and organic acids.
  • suitable inorganic acids are, for example, those defined in the chemical field, such as hydrochloric acid, sulfuric acid or phosphoric acid.
  • suitable organic acids include organic sulfonic acids, organic carboxylic acids or amino acids, etc.
  • Suitable organic sulfonic acids such as C 6-16 aryl sulfonic acid, C 6-16 heteroaryl sulfonic acid and C 1-16 alkyl sulfonic acid
  • Suitable organic carboxylic acids are, for example, mono- or polycarboxylic acids, including C 1-16 alkyl carboxylic acids, C 6-16 aryl carboxylic acids, and C 4-16 heteroaryl carboxylic acids.
  • the organic carboxylic acid may also be, for example, an amino acid, and there are many suitable amino acids, especially natural amino acids found as protein components.
  • salts formed by the above acids include acetate, adipic acid salt, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, Borate, camphorsulfonate, citrate, cyclohexasulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucose Uronic acid salt, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, cis Mellitic acid salt, malonic acid salt, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate , Palmitate, pam
  • Suitable base addition salts are formed from bases that form non-toxic salts, including inorganic bases and organic bases. Specific examples include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, ethanolamine salt , Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • the “isomer” described herein refers to different compounds having the same molecular formula, which includes stereoisomers.
  • stereoisomer refers to isomers that differ only in the way the atoms are arranged in space.
  • ⁇ - and ⁇ - refer to the specific stereochemical configuration of substituents on asymmetric carbon atoms in the chemical structure shown.
  • the compounds of the invention have one or more chiral centers and can exist in various stereoisomeric configurations. Due to the presence of these chiral centers, the compounds of the present invention can exist in the form of racemates, mixtures of enantiomers and individual enantiomers, and mixtures of diastereomers and diastereomers. All such racemates, enantiomers and diastereomers fall within the scope of "compounds of the invention”. "R” and "S” are commonly used in organic chemistry to denote specific configurations of chiral centers.
  • the compound of the present invention may exist in the form of a hydrate or a solvate, wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • the amount of polar solvents, especially water can be present in stoichiometric or non-stoichiometric ratios.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • substitution refers to the existence or non-existence of the corresponding circumstances or conditions, the term includes the presence or absence of the substituent; the “optional” also includes the presence of a Or multiple examples of substitution of the substituents.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the designated atom does not exceed Normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only allowed when such combinations form stable compounds.
  • the term "optionally substituted” includes the case where there is substitution by one or more substituents, and when “optionally substituted” refers to the presence of multiple substituents, the Can be properly connected to each other to form a saturated ring, unsaturated ring or aromatic ring containing 0-3 heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S), the saturated ring, not A saturated ring or an aromatic ring may also form a ring together with a substituted group.
  • substituents oxygen (O), nitrogen (N) and sulfur (S)
  • alkyl as used herein means an unbranched or branched chain or cyclic saturated monovalent hydrocarbon residue, preferably containing 1 to 14 carbon atoms (C 1-14 alkyl), more preferably containing 1 Up to 10 carbon atoms (C 1-10 alkyl), more preferably 1 to 6 carbon atoms (C 1-6 alkyl), particularly preferably 1 to 4 carbon atoms (C 1-4 alkyl).
  • alkyl groups include, but are not limited to lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl , Heptyl (eg hept-4-yl) and octyl.
  • lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl , Heptyl (eg hept-4-yl) and octyl.
  • cycloalkyl refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring. When it is composed of two or more rings, the rings may be connected together in a fused manner.
  • the cycloalkyl group can contain 3 to 10 atoms (C 3-10 cycloalkyl) in the ring, preferably 3 to 8 ring atoms (C 3-8 cycloalkyl), and more preferably 3 to 6 ring atoms ( C 3-6 cycloalkyl), particularly preferably containing 3-4 ring atoms (C 3-4 cycloalkyl).
  • Cycloalkyl includes, but is not limited to, monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridge Systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalin, etc.), which are optionally Substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridge Systems (such as bicycl
  • alkenyl as used herein means a hydrocarbon residue having 2 to 10 carbon atoms and having one or two olefinic double bonds, preferably containing 2 to 8 carbon atoms (C 2-8 alkenyl), more It preferably contains 2 to 6 carbon atoms (C 2-6 alkenyl), and particularly preferably contains 2 to 4 carbon atoms (C 2-4 alkenyl), unless otherwise specified.
  • alkenyl include vinyl, 1-propenyl, 2-propenyl, 2-butenyl, and the like.
  • alkynyl as used herein means an unbranched or branched hydrocarbon chain group having 2 to 10 carbon atoms (C 2-10 alkynyl) and having one or two triple bonds, preferably containing 2 to 8 carbon atoms (C 2-8 alkynyl), more preferably containing 2 to 6 carbon atoms (C 2-6 alkynyl), particularly preferably containing 2 to 4 carbon atoms (C 2-4 alkynyl), in addition Except where specified.
  • alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.
  • amino means -NH 2
  • alkylamino represents -NR'R ", R 'and R" are the same or different and are alkyl or cycloalkyl is H or as defined above.
  • alkoxy as used herein means -O-alkyl, wherein alkyl is as defined above (eg, C 1-14 alkyl, C 1-10 alkyl, C 1-6 alkyl, or C 1-4 alkyl Radicals), such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, and also including Constructs etc.
  • halogen or "halo" as used herein means fluorine, chlorine, bromine or iodine.
  • haloalkyl denotes an alkyl group as defined above, wherein 1, 2, 3 or more hydrogen atoms are replaced by halogen.
  • Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl Group, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloro Ethyl, 3-bromopropyl or 2,2,2-trifluoroethyl, etc.
  • haloalkoxy as used herein means an alkoxy group as defined above, wherein 1, 2, 3 or more hydrogen atoms are replaced by halogen.
  • alkyl denotes a group of formula -R-OH, where R is an alkylene group.
  • alkylene as used herein means containing 1 to 10 carbon atoms (C 1-10 alkylene), more preferably 1 to 6 carbon atoms (C 1-6 alkylene), and particularly preferably 1 A divalent saturated linear hydrocarbon group of up to 4 carbon atoms (C 1-4 alkylene) or 3 to 10 carbon atoms (C 3-10 alkylene), more preferably containing 3 to 8 carbon atoms (C 3-8 alkylene), particularly preferably branched saturated divalent hydrocarbon groups containing 3 to 5 carbon atoms (C 3-5 alkylene), unless otherwise indicated.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
  • aryl refers to a group having at least one aromatic ring, that is, having a conjugated ⁇ -electron system, including monocyclic aryl groups and bicyclic aryl groups. It contains 6-14 carbon atoms (C 6-14 aryl), for example: phenyl, naphthyl and so on.
  • the optionally substituted aryl group includes an aryl group substituted with a plurality of substituents, and the substituents may be appropriately connected to form a saturated ring, an unsaturated ring containing 0-3 heteroatoms selected from oxygen, nitrogen and sulfur /Or aromatic ring.
  • the aryl group preferably includes the following groups:
  • aralkyl refers to the group R'R"-, where R'is an aryl group as defined herein and R" is an alkylene group as defined herein, it being understood that the The point of attachment will be on the alkylene group.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, 4-fluorobenzyl, phenylethyl, phenylpropyl, and phenylbutyl.
  • aryloxy as used herein means -O-R, and R is an aryl group as defined above.
  • heterocyclyl refers to a 3- containing 1-4 (eg, one, two, three, or four) heteroatoms selected from N, O, S, and P and the remaining atoms are carbon atoms.
  • 1-4 eg, one, two, three, or four
  • heteroatoms selected from N, O, S, and P and the remaining atoms are carbon atoms.
  • the 3-10 membered heterocyclic group is a group having 3-10 carbon atoms and hetero atoms in the ring, such as but not limited to ethylene oxide, aziridinyl, and azetidinyl ( azetidinyl), oxetanyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridine Furyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heteroaryl refers to a cyclic aromatic group having 1 to 3 heteroatoms selected from N, O, and S as ring atoms and the remaining ring atoms being carbon, wherein the ring is 4-
  • the 16-membered single ring or fused ring is preferably a 5-12 membered single ring or fused ring, and a 5-8 membered single ring or fused ring.
  • heteroaryl groups include, but are not limited to: furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrrole Group, pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyridazinyl, phthalazinyl, phthalazin-1-(2H)-1-yl, pyrido[3,2 -d]pyridazin-5(6H)-8-yl, triazinyl, etc. and their benzo derivatives.
  • heteroaryloxy denotes a group of the formula heteroaryl-O-, wherein the heteroaryl group is as defined above.
  • sulfonamido refers to a group of formula -SO 2 NR'R" where R'and R" are the same or different, and each independently is hydrogen or an alkyl or cycloalkyl group as defined above.
  • carboxy refers to a group of formula -COOH, and the term “carboxylate group” as used herein denotes -COOR, wherein each of said R independently represents an alkyl group as defined above.
  • each group or atom or ion group includes groups or atoms or ion groups substituted by its isotope, for example, the "hydrogen” includes H, 2 H (deuterium), 3 H (tritium); the C 1-14 alkyl group includes one or more carbon atoms or all of which are 12 C, 13 C, and 14 C, and other examples include N, P, and O isotopes.
  • the "hydrogen” includes H, 2 H (deuterium), 3 H (tritium);
  • the C 1-14 alkyl group includes one or more carbon atoms or all of which are 12 C, 13 C, and 14 C, and other examples include N, P, and O isotopes.
  • particle size refers to the size of the particles, where D v 50 represents the median particle size of the distribution, ie 50% of the particles are smaller than the size and 50% of the particles are larger than the size. D v 10 represents the particle size of 10% of all particles smaller than the stated size. Similarly, D v 90 represents a particle size in which 90% of all particles are smaller than the stated size. D[4,3] refers to the volume-weighted average particle size.
  • pulverization refers to an operation process of pulverizing large-sized solid materials to a suitable degree by mechanical force or air flow, which includes dry pulverization, wet pulverization, low temperature pulverization, and ultrafine pulverization.
  • the crushing equipment includes mortar, universal crusher, ball mill and jet mill.
  • screening refers to passing crushed particles or powder through a certain mesh screen to meet the needs of preparing a formulation, while having a mixing effect to ensure component uniformity.
  • Screening equipment includes shaking screen, vibrating screen, rotating screen and drum screen.
  • the term “content uniformity” refers to the degree to which the content of each tablet (piece) of a small dose or a single dose of solid preparation, semi-solid preparation, and heterogeneous liquid preparation conforms to the indicated weight.
  • grade mixing refers to mixing an active ingredient with equal weight of excipients (single excipient or premix of multiple excipients) to obtain a first mixture, and then adding an equal weight of excipients to the resulting first mixture (Single auxiliary material or pre-mixture of multiple auxiliary materials) and mix to obtain the second mixture. Continue to add auxiliary materials according to the same method until all auxiliary materials are added.
  • a/a% refers to the area percentage calculated according to the area normalization method in the obtained spectrum (eg, HPLC spectrum).
  • the present invention provides an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising the following component (1), and one or more selected from components (2), (3), (4) and (5) Components:
  • Component (1) an active ingredient, which is one or more compounds of formula (I), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystalline form thereof or Racemates, or their metabolite forms, or their mixtures:
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycle Group and optionally substituted heteroaryl, wherein both R 2 and R 6 may be connected to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O, and S and It can be saturated ring, unsaturated ring or aromatic ring;
  • R 3 is selected from optionally substituted aryl and optionally substituted heteroaryl
  • R 4 is selected from hydrogen and optionally substituted C 1-10 acyl
  • Q is a pyrimidine base or purine base with the following structure:
  • R 5 is independently selected from hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Group, alkoxyalkyl group, amido group, sulfonamide group, cyano group, nitro group, nitroso group, azido group, aldehyde group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, aralkyl group, aryl group Oxygen, heteroaryl, heteroaryloxy, acyl, carboxyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and carboxylic acid ester groups; the substituents may be connected to each other to constitute 0-3 selected 3-8 membered saturated ring, unsaturated ring or aromatic ring of hetero atoms of N, O
  • Component (3) one or more selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, magnesium lauryl sulfate, talc, polyethylene glycol, and stearic acid Sodium fumarate;
  • Component (4) one or more selected from the following: low-substituted hydroxypropyl cellulose, low-substituted hypromellose, sodium carboxymethyl cellulose, croscarmellose sodium, carboxyl Sodium methyl starch and crospovidone; and
  • Component (5) one or more selected from the following: silica and tricalcium phosphate;
  • the total content of components (1), (2), (3), (4) and (5) is ⁇ 100% by weight of the oral pharmaceutical composition, preferably 100% by weight.
  • the present invention provides an oral pharmaceutical composition, wherein the active ingredient is one or more compounds selected from the group consisting of pharmaceutically acceptable salts, esters, solvates, hydrates, and isomers thereof, Or any of their crystal forms or racemates, or their metabolite forms, or their mixtures:
  • the present invention provides an oral pharmaceutical composition, wherein the content of the active ingredient is 0.1-50% by weight of the oral pharmaceutical composition, more preferably 0.5-30% by weight.
  • the present invention provides an oral pharmaceutical composition, wherein the component (2) is one or more selected from the group consisting of microcrystalline cellulose, pregelatinized starch, and anhydrous lactose.
  • the present invention provides an oral pharmaceutical composition, wherein the content of the component (2) is 1-99.9% by weight of the oral pharmaceutical composition, more preferably 50-99.5% by weight.
  • the present invention provides an oral pharmaceutical composition, wherein the component (3) is one or more selected from the group consisting of magnesium stearate, sodium stearate fumarate, and calcium stearate .
  • the present invention provides an oral pharmaceutical composition, wherein the content of the component (3) is 0-10% by weight of the oral pharmaceutical composition, preferably 0-5% by weight, more preferably 0.5 -5% by weight.
  • the present invention provides an oral pharmaceutical composition, wherein the component (4) is one or more selected from the group consisting of: low-substituted hypromellose, sodium carboxymethyl cellulose, cross-linked Sodium carboxymethyl cellulose and sodium carboxymethyl starch.
  • the present invention provides an oral pharmaceutical composition, wherein the content of the component (4) is 0-15% by weight of the oral pharmaceutical composition, preferably 0-10% by weight, more preferably 0.5 -10% by weight.
  • the present invention provides an oral pharmaceutical composition, wherein the component (5) is silica.
  • the present invention provides an oral pharmaceutical composition, wherein the content of the component (5) is 0-5% by weight of the oral pharmaceutical composition, preferably 0-3% by weight, more preferably 0.1 -3% by weight.
  • the present invention provides an oral pharmaceutical composition comprising the following components:
  • the active ingredient which is compound C8, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystalline form or racemate thereof, or their metabolite form,
  • the content of the active ingredient is 0.5-30% by weight of the oral pharmaceutical composition
  • Component (2) which is microcrystalline cellulose
  • the content of the component (2) is 50-99.5% by weight of the oral pharmaceutical composition.
  • Component (5) which is silica
  • the content of the component (5) is 0.1-3% by weight of the oral pharmaceutical composition.
  • the present invention provides an oral pharmaceutical composition comprising the following components:
  • the active ingredient which is compound C8, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystalline form or racemate thereof, or their metabolite form,
  • the content of the active ingredient is 0.5-30% by weight of the oral pharmaceutical composition
  • Component (2) which is pregelatinized starch
  • the content of the component (2) is 50-99.5% by weight of the oral pharmaceutical composition.
  • Component (3) which is magnesium stearate
  • the content of the component (3) is 0.5-5% by weight of the oral pharmaceutical composition.
  • the present invention provides an oral pharmaceutical composition comprising the following components:
  • the active ingredient which is compound C8, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystalline form or racemate thereof, or their metabolite form,
  • the content of the active ingredient is 0.75-25% by weight of the oral pharmaceutical composition
  • Component (2) which is microcrystalline cellulose
  • the content of the component (2) is 70-99% by weight of the oral pharmaceutical composition.
  • Component (5) which is silica
  • the content of the component (5) is 0.5-1.5% by weight of the oral pharmaceutical composition.
  • the present invention provides an oral pharmaceutical composition comprising the following components:
  • the active ingredient which is compound C8, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystalline form or racemate thereof, or their metabolite form,
  • the content of the active ingredient is 0.5-20% by weight of the oral pharmaceutical composition
  • Component (2) which is pregelatinized starch
  • the content of the component (2) is 70-99% by weight of the oral pharmaceutical composition.
  • Component (3) which is magnesium stearate
  • the content of the component (3) is 0.5-1.5% by weight of the oral pharmaceutical composition.
  • the present invention provides a method of preparing an oral pharmaceutical composition of the present invention, which includes the following steps:
  • the active ingredient is optionally crushed, and the particle size range of the crushed active ingredient is as follows:
  • D v (90) is 1-500 ⁇ m, preferably 5-100 ⁇ m;
  • D v (50) is 1-100 ⁇ m, preferably 1-20 ⁇ m;
  • D v (10) is 0.1-10 ⁇ m, preferably 0.5-5 ⁇ m; and/or
  • D[4,3] is 1-50 ⁇ m, preferably 5-25 ⁇ m;
  • the present invention provides a capsule comprising the oral pharmaceutical composition of the present invention and a capsule shell containing the oral pharmaceutical composition, the capsule shell is preferably a gelatin hollow capsule shell, hypromellose (HPMC) hollow capsule shell or starch hollow capsule shell, more preferably HPMC hollow capsule shell.
  • the capsule shell is preferably a gelatin hollow capsule shell, hypromellose (HPMC) hollow capsule shell or starch hollow capsule shell, more preferably HPMC hollow capsule shell.
  • the capsule contains 50-600 mg of the oral pharmaceutical composition of the present invention per capsule; preferably 100-300 mg of the oral pharmaceutical composition of the present invention.
  • the present invention provides a method of preparing the capsule of the present invention, which includes the following steps:
  • the active ingredient is optionally crushed, and the particle size range of the crushed active ingredient is as follows:
  • D v (90) is 1-500 ⁇ m, preferably 5-100 ⁇ m;
  • D v (50) is 1-100 ⁇ m, preferably 1-20 ⁇ m;
  • D v (10) is 0.1-10 ⁇ m, preferably 0.5-5 ⁇ m; and/or
  • D[4,3] is 1-50 ⁇ m, preferably 5-25 ⁇ m;
  • the oral pharmaceutical composition of the present invention is filled into a capsule shell.
  • the present invention provides an article comprising the oral pharmaceutical composition of the present invention or the capsule of the present invention, and an independently present desiccant, preferably the desiccant is anhydrous silica gel, molecular sieve, alumina or chlorine Calcium, the product is preferably in a packaging material, the packaging material is aluminum-plastic blister packaging or high-density polyethylene bottle packaging.
  • the preparation is a pharmaceutical preparation.
  • the present invention provides the use of the oral pharmaceutical composition, capsule or preparation of the present invention in the preparation of a medicament for the prevention or treatment of cell proliferation abnormalities.
  • the present invention provides an oral pharmaceutical composition, capsule, or preparation of the present invention for use in the prevention or treatment of cell proliferation abnormalities.
  • the present invention provides a method for preventing or treating a disease with abnormal cell proliferation, which comprises administering to a subject in need thereof (preferably a mammal) a prophylactic or therapeutically effective amount of the oral pharmaceutical composition, capsule of the present invention Or products.
  • the cell proliferation abnormality disease is, for example, cancer and/or tumor and related disorders.
  • the tumor and/or cancer includes esophagus, stomach, intestine, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone , Connective tissue, skin, eyes, brain and central nervous system and other tumors and/or cancers and related disorders, as well as thyroid cancer, leukemia, Hodgkin's disease, lymphoma and myeloma.
  • the present invention also provides the use of the oral pharmaceutical composition, capsule, or preparation of the present invention for simultaneous, separate, and sequential combination with other therapeutic agents (eg, other anti-cancer/tumor agents).
  • other therapeutic agents eg, other anti-cancer/tumor agents.
  • the dosage range of the active ingredients contained in the oral pharmaceutical composition, capsule or preparation of the present invention is 0.1-1000 mg/kg body weight/day, the preferred dosage range is 1-800 mg/kg body weight/day, and the preferred dosage range It is 10-600 mg/kg body weight/day, a particularly preferred dosage range is 100-400 mg/kg body weight/day, and the most preferred dosage range is 120-250 mg/kg body weight/day.
  • the precise dosage required to treat the patient is determined by the doctor based on the stage and severity of the disease and the specific needs and responses of the individual patient.
  • treating originally means reversing, alleviating, inhibiting a condition or condition to which such terms apply or the progression of one or more symptoms of such condition or condition, or preventing Such a disorder or condition or one or more symptoms of such disorder or condition.
  • “Mammal” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease or disorder (eg, the diseases or disorders described herein).
  • non-human animals include non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).
  • Preparation process 1 Gradient mixing of raw and auxiliary materials; 2 Passing through a 60 mesh sieve once; 3 Mixing again for 30 minutes; 4 Filling capsules.
  • the high-density polyethylene bottle was used to seal the various preparations in a sealed package, and the stability was investigated under the condition of 60 °C.
  • Preparation process 1 Gradient mixing of raw and auxiliary materials; 2 Passing through a 60 mesh sieve once; 3 Mixing again for 30 minutes; 4 Filling capsules.
  • the high-density polyethylene bottle was used to seal the various preparations in a sealed package, and the stability was investigated under the condition of 60 °C.
  • Preparation process 1 Gradient mixing of raw and auxiliary materials; 2 Passing through a 60 mesh sieve once; 3 Mixing again for 30 minutes; 4 Filling capsules.
  • the high-density polyethylene bottle was used to seal the various preparations in a sealed package, and the stability was investigated under the condition of 60 °C.
  • prescription 3-2 By examining the stability of prescription 3-2, the maximum single miscellaneous (a/a%) level in prescription 3-2 was 0.12% at 0 days and 0.47% at 30 days. Comparing the test results of prescription 3-1 and prescription 3-2, it can be seen that the prescription containing pregelatinized starch at the same time compared with the prescription of magnesium stearate alone can further reduce the formation of impurities.
  • the capsule preparation was prepared according to the prescription shown in Table 3-1 and the following preparation process, and the influence of the desiccant on the stability of the preparation was investigated.
  • Table 3-1 The dosage of each ingredient of prescription 4 (1.5mg specification)
  • Preparation process 1 Gradient mixing of raw and auxiliary materials; 2 Once through 60 mesh sieve; 3 Mix again for 30min; 4 Filling capsules; One capsule is packed in a packing material containing a molecular sieve desiccant, and the other capsule is packed in a packing material without a desiccant, which is sealed and labeled separately.
  • the packaging material with molecular sieve desiccant is used for prescription 4. Compared with the packaging without desiccant, the amount of impurity growth is significantly reduced. This shows that the inclusion of a desiccant in the packaging material can further improve the stability of the formulation.
  • the capsule preparation was prepared according to the prescription shown in Table 4-1 and the following preparation process, and the effect of CCNa on the dissolution of the preparation was investigated.
  • Preparation process 1 Gradient mixing of raw and auxiliary materials; 2 Once through 60 mesh sieve; 3 Mix again for 30 min; 4 Fill capsules.
  • the dissolution of two prescription capsules was determined by the method of "Chinese Pharmacopoeia” (2015 edition) basket method, 900 ml of hydrochloric acid aqueous solution at pH 2.0 as the dissolution medium, 100 rpm.
  • the capsule preparation was prepared according to the prescription shown in Table 5-1 and the following preparation process, and the influence of API particle size distribution on the dissolution of the preparation was investigated.
  • Preparation process 1Pulverize API mechanically to obtain APIs with different particle sizes, see Table 5-2 for particle size information; 2Gradient mixing of raw and auxiliary materials; 3Once through a 60 mesh sieve; 4Mix again for 30min; 5Fill capsules to obtain API particles Three batches of products with different diameters are represented by prescription 7-1, prescription 7-2 and prescription 7-3.
  • the dissolution of two prescription capsules was determined by the method of "Chinese Pharmacopoeia” (2015 edition) basket method, 900ml of hydrochloric acid aqueous solution at pH 2.0 as the dissolution medium, 75rpm, the results are shown in Table 5-3.
  • the dissolution test method is "Chinese Pharmacopoeia” (2015 version) basket method, the measurement time is 30 minutes, 900ml, pH 2.0 aqueous solution of hydrochloric acid is used as the dissolution medium, the rotation speed is 75rpm.
  • 5Capsule filling Calculate the filling amount of capsules according to the content of intermediate materials; use a capsule machine to fill, the capsule shell is HPMC hollow capsule shell 1#; adjust the filling volume of the capsule machine, and monitor the filling volume in real time during the filling process. After filling, the finished product is obtained, and the content of the finished product is tested.
  • the weight percentage of the measured value and the theoretical value of the API content of the intermediate material of 15 mg specification is: 97.18%; mixing uniformity (RSD): 0.95%.
  • the weight percentage of the measured value and the theoretical value of the API content of the intermediate material of 1.5 mg specification is: 94.58%; mixing uniformity (RSD): 0.99%.
  • the weight percentage of the measured value and the indicated value of API content of the finished 15mg capsules is 96.4%;
  • the weight percentage of the measured value and the marked value of API content of the finished 1.5mg capsules is: 96.5%; and the content uniformity (A+2.2S) of the finished capsules of the above two specifications is less than 15.
  • API content (%) refers to the weight percentage of the measured value of the API content and the marked value
  • API content (%) refers to the weight percentage of the measured value of the API content and the marked value
  • the total impurity content (a/a%) of the 1.5mg product at 0 days is 0.2, and the total impurity content (a/a%) at 30 days is 0.3; 1.5mg specification The dissolution rate (%) of the product at day 0 was 91.6, and the dissolution rate (%) at 30 days was 85.7; the total impurity content (a/a%) of the 15mg product at day 0 was 0.3, and the total impurity content (a/ a%) is also 0.3; the dissolution rate (%) at 0 days of the 15mg specification product is 97.3, and the dissolution rate (%) at 30 days is 93.0.
  • the total impurity content (a/a%) of the 1.5mg product at 0 days is 0.2, and the total impurity content (a/a%) at 30 days is 0.3; 15mg product The total miscellaneous content (a/a%) at day 0 is 0.3, and the total miscellaneous content (a/a%) at day 30 is also 0.3; the dissolution rate (%) at 15 days for the 15 mg product is 97.3 at day 30, and the dissolution rate at 30 days (%) is 97.2.
  • the high-density polyethylene bottle and the high-density polyethylene bottle moisture-proof combination lid packaging preparation were used for stability investigation. The results are shown in Table 6-4 to Table 6-6.
  • API content (%) refers to the weight percentage of the measured value of the API content and the marked value
  • API content (%) refers to the weight percentage of the measured value of the API content and the marked value
  • API content (%) refers to the weight percentage of the measured value of the API content and the marked value.
  • the dissolution test method is "Chinese Pharmacopoeia” (2015 version) basket method, the measurement time is 30 minutes, 900ml, pH 2.0 aqueous solution of hydrochloric acid is used as the dissolution medium, the rotation speed is 75rpm.
  • Capsule filling Calculate the filling amount of the capsule according to the result of the intermediate content; fill the capsule to get the finished product, and test the content of the finished product.
  • the weight percentage of the measured value and the theoretical value of the API content of the intermediate material of 15 mg specification is: 107.19%; mixing uniformity (RSD): 0.59%.
  • the weight percentage between the measured value and the theoretical value of the API content of the 1.5 mg intermediate material is 99.51%; the mixing uniformity (RSD): 1.23%.
  • the weight percentage of the measured value and the theoretical value of the API content of the 50 mg intermediate material is: 100.23%; mixing uniformity (RSD): 0.48%.
  • the weight percentage of the API content measured value and the marked value of the finished 50 mg capsule product is: 94.0%; content uniformity (A+2.2S): 5.62.
  • the weight percentage of the measured value and the marked value of API content of the finished 15mg capsule is 96.8%; content uniformity (A+2.2S): 3.72.
  • the weight percentage of the measured value and marked value of API content of the finished 1.5mg capsules is: 105.0%; content uniformity (A+2.2S): 3.41.
  • High-density polyethylene bottles and high-density polyethylene caps are used as packaging materials for the three specifications of capsules, respectively at a temperature of 30°C ⁇ 2°C/humidity of 65% ⁇ 5% and a temperature of 25°C ⁇ 2°C/humidity of After 6 months under 60% ⁇ 5%, the stability of the product was examined. The results are shown in Tables 7-2 and 7-3.
  • Content determination (%) refers to the weight percentage of the actual measured value of the API content and the indicated value.
  • Content determination (%) refers to the weight percentage of the actual measured value of the API content and the indicated value.

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Abstract

（I）包含式(I)的4'-硫代核苷类化合物的口服药物组合物、包含其的胶囊剂、制品及其制备方法和用途，所述口服药物组合物具有良好的稳定性(所包含的活性成分具有良好的稳定性，且杂质生成量较小)、良好的药物代谢动力学性质，且便于制备，可以满足临床和商业使用的需求。

Description

以4’-硫代核苷类化合物为活性成分的口服药物组合物、其制备方法及其用途 发明领域
本发明涉及包含4’-硫代核苷类化合物的口服药物组合物、包含其的胶囊剂、制品及其制备方法和用途。
发明背景
目前主要的口服制剂形式为胶囊剂和片剂。其处方组成一般包括活性成分和一种或多种赋形剂。由于各种辅料和化合物的性质各不相同，针对特定的化合物一般需要经过大量的研究工作，才能确定合适的处方组成。
核苷类药物已被广泛用于治疗各种癌症。WO 2016/155593 A1中公开了新型4’-硫代核苷类化合物，其具有优越的药效(包括抗肿瘤/癌症的效果)，增加的脂溶性，提高的生物利用度，减少的刺激性以及改善的吸收，同时具有显著降低的毒性和提高的安全性。
尽管研究表明，该新型4’-硫代核苷类化合物的口服生物利用度良好，具有良好的临床应用前景，但是，对于用于给药此类化合物的具体组合物、制剂和制品目前尚无报道。
发明概述
本发明提供包含4’-硫代核苷类化合物的口服药物组合物，其具有良好的稳定性(所包含的活性成分具有良好的稳定性，且制备和储存期间杂质增长量较小)、良好的药物代谢动力学性质(例如良好的溶出度以及生物利用度)，其便于制备(制备过程中中间体物料的混合均匀度良好，且最终制剂的各项指标如含量均匀度符合药典要求)，其可以满足临床和商业使用的需求。
在一些方面中，本发明提供口服药物组合物，其包含以下组分(1)，以及选自组分(2)、(3)、(4)和(5)中的一种或多种组分：
组分(1)：活性成分，其为一种或多种式(I)的4’-硫代核苷类化合物，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，或者它们的混合物：
Figure PCTCN2019119342-appb-000001
其中
X为氢、C 1-6烷基、卤素、N 3、OH、CN或SH；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
R 4选自氢和任选取代的C 1-10酰基；
Q为结构如下的嘧啶碱基或嘌呤碱基：
Figure PCTCN2019119342-appb-000002
R 5每次出现时独立地选自氢、任选取代的C 1-10烷基和任选取代的环烷基；并且
Z为氢、任选取代的C 1-10烷基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷 胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；组分(2)：选自下列中的一种或多种：甘露醇、微晶纤维素、淀粉、预胶化淀粉、一水乳糖、无水乳糖、磷酸二氢钙、磷酸氢钙、磷酸钙和碳酸钙，条件是当组分(2)为甘露醇时，组分(3)、(4)和(5)中的至少一种含量不是0，优选组分(3)的含量不是0；
组分(3)：选自下列中的一种或多种：硬脂酸、硬脂酸镁、硬脂酸钙、氢化植物油、十二烷基硫酸镁、滑石粉、聚乙二醇和硬脂富马酸钠；
组分(4)：选自下列中的一种或多种：低取代羟丙基纤维素、低取代羟丙甲纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮；以及
组分(5)：选自下列中的一种或多种：二氧化硅和磷酸三钙；
其中组分(1)、(2)、(3)、(4)和(5)的含量总和为所述口服药物组合物的≤100重量％，优选为100重量％。
在一些方面中，本发明提供胶囊剂，其包含本发明的口服药物组合物以及包含所述口服药物组合物的胶囊壳。
在一些方面中，本发明提供制备本发明的口服药物组合物或者本发明的胶囊剂的方法。
在一些方面中，本发明提供制品，其包含本发明的口服药物组合物或者本发明的胶囊剂以及独立存在的干燥剂。
在一些方面中，本发明提供本发明的口服药物组合物、胶囊剂或制品在制备用于预防或治疗细胞增殖异常性疾病的药物中的用途。
在一些方面中，本发明提供本发明的口服药物组合物、胶囊剂或制品，其用于预防或治疗细胞增殖异常性疾病。
在一些方面中，本发明提供预防或治疗细胞增殖异常性疾病的方法，其包括向需要其的个体(优选哺乳动物)给药预防或治疗有效量的本发明的口服药物组合物、胶囊剂或制品。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
表述“如上所定义”表示在申请中提供的第一和/或最广泛的定义，以及上下文适宜的情况。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
本文中所述的“式(I)的化合物”涵盖上述式(I)所限定化合物的范围，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，或者它们的混合物。
本文中所述的术语“代谢物形式”是指在施用至需要其的个体后体内产生的化合物。
本文中所述的“药学可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐，其可通过下列方式制备：使质子接受部分质子化和/或使质子供给部分去质子化。应该注意，质子接受部分质子化导致形成阳离子类物质，其中该阳离子电荷通过生理阴离子的存在而平衡，而质子供给部分去质子化导致形成阴离子类物质，其中该阴离子电荷通过生理阳离子的存在而平衡。
本发明的化合物的药学可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成无毒盐的酸来形成，其包括无机酸和有机酸。在本发明中，合适的无机酸例如是化学领域定义的无机酸，例如盐酸、硫酸或磷酸等。合适的有机酸包括有机磺酸、有机羧酸或氨基酸等，合适的有机磺酸例如C 6-16芳基磺酸、C 6-16杂芳基磺酸和C 1-16烷基磺酸，合适的有机羧酸例如是一元或多元羧酸，包括C 1-16烷基羧酸、C 6-16芳基羧酸和C 4-16杂芳基羧酸。所述有机羧酸还可以例如是氨基酸，合适的氨基酸有许多，特别是作为蛋白质组分而发现的天然氨基酸。由上述酸所成盐的具体实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、 氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成无毒盐的碱来形成，其包括无机碱和有机碱。具体实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学可接受的盐的方法为本领域技术人员已知的。
本文中所述的“异构体”是指具有相同分子式的不同化合物，其包括立体异构体。术语“立体异构体”表示仅在原子的空间排列的方式上不同的异构体。“α-”、“β-”是指所示化学结构中不对称碳原子上取代基的特定立体化学构型。
本发明的化合物具有一个或多个手性中心，并且可以存在各种立体异构体构型。由于这些手性中心的存在，本发明的化合物可以外消旋物、对映体混合物和各对映体以及非对映异构体和非对映异构体混合物的形式存在。所有这种外消旋物、对映体和非对映异构体均属于“本发明的化合物”的范围。“R”和“S”在有机化学中通常用于表示手性中心的具体构型。
本发明的化合物可以水合物或溶剂化物的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
术语“任选的”或“任选”是指在相应情况或条件下可以存在但不一定存在，该术语包括所述取代基存在或不存在的实例；所述“任选”也包括存在一个或多个所述取代基取代的实例。术语“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。在本发明的式(I)的化合物中，术语“任选取代”包括存在被一个或多个取代基取代的情形，并且当“任选取代”是指存在多个取代基时，取代基之间可以适当地彼此相连构成含有选自0-3个选自氧(O)、氮(N)和硫(S)的杂原子的饱和环、不饱和环或芳香环，所述饱和环、不饱和环或芳香环还可以与被取代基团一起构成环，例如，术语“任选取代的芳基”具体实例包括苯并二氢噻吩基以及具有以下结构的基团：
Figure PCTCN2019119342-appb-000003
本文所用的术语“烷基”表示未分支或分支的链状或环状的饱和一价烃残基，优选地含有1至14个碳原子(C 1-14烷基)，更优选地含有1至10个碳原子(C 1-10烷基)，更优选含有1至6个碳原子(C 1-6烷基)，特别优选含有1至4个碳原子(C 1-4烷基)。烷基的实例包括但不限于低级烷基，包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或者戊基、异戊基、新戊基、己基、庚基(例如庚-4-基)和辛基。
本文所用的术语“环烷基”指饱和的非芳族单环或多环(诸如双环)烃环。当其由两个或以上的环组成时，所述环可以稠合的方式连接在一起。环烷基能够在环中含有3至10个原子(C 3-10环烷基)，优选3至8个环原子(C 3-8环烷基)，更优选含有3-6个环原子(C 3-6环烷基)，特别优选含有3-4个环原子(C 3-4环烷基)。环烷基包括但不限于单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。
本文所用的术语“烯基”表示具有2至10个碳原子并且具有一个或两个烯属双键的烃残基，优选地含有2至8个碳原子(C 2-8烯基)，更优选含有2至6个碳原子(C 2-6烯基)，特别优选含有2至4个碳原子(C 2-4烯基)，另有指定除外。烯基的实例包括乙烯基、1-丙烯基、2-丙烯基或2-丁烯基等。
本文所用的术语“炔基”表示未分支或分支的烃链基团，其具有2至10个碳原子(C 2-10炔基)，并且具有一或者两个叁键，优选地含有2至8个碳原子(C 2-8炔基)，更优选含有2至6个碳原子(C 2-6炔基)，特别优选含有2至4个碳原子(C 2-4炔基)，另有指定除外。炔基的实例是乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基或3-丁炔基等。
本文所用的术语“氨基”表示-NH 2，烷胺基表示-NR′R″，R′和R″相同或不同并且为H或如上所定义的烷基或环烷基。
本文所用的术语“烷氧基”表示-O-烷基，其中烷基如上所定义(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基，还包括它们的异构体等。
本文所用的术语“卤素”或“卤代”表示氟、氯、溴或碘。
本文所用的术语“卤代烷基”表示如上所定义的烷基，其中1、2、3或多个氢原子被卤素取代。实例是1-氟甲基、1-氯甲基、1-溴甲基、1-碘甲基、三氟甲基、三氯甲基、三溴甲基、三碘甲基、1-氟乙基、1-氯乙基、1-溴乙基、1-碘乙基、2-氟乙基、2-氯乙基、2-溴乙基、2-碘乙基、2，2-二氯乙基、3-溴丙基或2，2，2-三氟乙基等。
本文所用的术语“卤代烷氧基”表示如上所定义的烷氧基，其中1、2、3或多个氢原子被卤素取代。
本文所用的术语“酰基”表示式-C(＝O)R的基团，其中R是氢或者如上述所定义的烷基(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)。
本文所用的术语“烷基羰基”表示式-C(＝O)R的基团，其中R是如上述所定义的烷基(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)。
本文所用的术语“酰胺基”表示式-NC(＝O)R′R″基团，其中R′和R″相同或不同，并且是氢或者如上述所定义的烷基(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)。
本文所用的术语“羟基烷基”表示式-R-OH的基团，其中R是亚烷基。本文所用的术语“亚烷基”表示含有1至10个碳原子(C 1-10亚烷基)，更优选含有1至6个碳原子(C 1-6亚烷基)，特别优选含有1至4个碳原子(C 1-4亚烷基)的二价饱和直链烃基团或者3至10个碳原子(C 3-10亚烷基)，更优选含有3至8个碳原子(C 3-8亚烷基)，特别优选含有3至5个碳原子(C 3-5亚烷基)的支链饱和二价烃基团，另有指示除外。亚烷基的实例包括但不限于亚甲基、亚乙基、亚丙基、2-甲基-亚丙基、亚丁基和2-乙基亚丁基等。
本文所用的术语“芳基”是指具有至少有一个芳环的基团，即有一个共轭π-电子系统，包括单环芳基和双环芳基等。其包含6-14个碳原子(C 6-14芳基)，例如：苯基、萘基等。任选取代的芳基包括被多个取代基取代的芳基，且取代基之间可以适当地相连构成含有0-3个选自氧、氮和硫的杂原子的饱和环、不饱环和/或芳香环。所述芳基优选包括以下基团：
Figure PCTCN2019119342-appb-000004
本文所用的术语“芳烷基”表示基团R′R″-，其中R′是如本文所定义的芳基，R″是如本文所定义的亚烷基，可以理解，芳烷基部分的连接点将位于亚烷基上。通常，所述芳基可具有6-14个碳原子， 并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、4-氟苄基、苯基乙基、苯基丙基和苯基丁基。
本文所用的术语“芳氧基”表示-O-R，R为如上所定义的芳基。
本文所用的术语“芳基羰基”表示式-C(＝O)Ar的基团，其中Ar是如上所定义的芳基。
本文所用的术语“杂环基”是指含有1-4个(例如一个、两个、三个或四个)选自N、O、S和P的杂原子且其余原子为碳原子的3-16元饱和环或不饱和环的基团。特别地，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
本文所用的术语“杂芳基”是指具有1至3个选自N、O和S的杂原子作为环原子且剩余环原子为碳的环状芳族基团，其中所述环为4-16元单环或稠合环，优选5-12元单环或稠合环、5-8元单环或稠合环。杂芳基的实例包括但不限于：呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、吡咯基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、哒嗪基、酞嗪基、酞嗪-1-(2H)-1-基、吡啶并[3，2-d]哒嗪-5(6H)-8-基、三嗪基等以及它们的苯并衍生物。
本文所用的术语“杂芳基羰基”定义类似于“芳基羰基”，其表示式-C(＝O)R的基团，其中R是如上所定义的杂芳基。
本文所用的术语“杂芳基氧基”表示式杂芳基-O-的基团，其中所述杂芳基如上述所定义。
本文所用的术语“磺酰胺基”是指式-SO 2NR′R″的基团，其中R′和R″相同或不同，并且各自独立地是氢或如上定义的烷基或环烷基。
本文所用的术语“羧基”是指式-COOH的基团，本文所用的术语“羧酸酯基”表示-COOR，其中所述的R各自独立地表示如上所定义的烷基。
本发明所述的通式或具体化合物中，各基团或原子或离子团均包括其同位素替代的基团或原子或离子团，例如所述“氢”包括H、 2H(氘)、 3H(氚)；所述C 1-14烷基包括其中一个或多个碳原子或全部为 12C、 13C、 14C，其他示例包括N、P、O同位素的情况。
如本文中所使用，术语“粒径”是指颗粒的大小，其中D v50代表分布的中值粒度，即50％颗粒小于所述尺寸而50％颗粒大于所述尺寸。D v10代表所有颗粒中10％小于所述尺寸的粒度。类似地，D v90代表所有粒子中90％小于所述尺寸的粒度。D[4，3]是指体积加权平均粒度。
如本文中所使用，术语“粉碎”是指借助机械力或气流将大尺寸的固体物质粉碎成适用程度的操作过程，其包括干法粉碎、湿法粉碎、低温粉碎以及超微粉碎。粉碎的设备包括研钵、万能粉碎机、球磨机以及气流粉碎机。
如本文中所使用，术语“过筛”是指将粉碎好的颗粒或粉末等通过一定目数的筛网，以满足制备制剂的需要，同时具有混合作用，以保证组分均匀性。过筛的设备包括摇动筛、振动筛、旋动筛以及滚筒筛。
如本文中所使用，术语“含量均匀度”是指小剂量或单剂量的固体制剂、半固体制剂和非均相液体制剂的每片(个)含量符合标示重量的程度。
如本文中所使用，术语“磷酸钙”和术语“磷酸三钙”均是指化学式为Ca 3(PO 4) 2的物质。其中，“磷酸三钙”具有4μm的粒径、7.0的pH值以及0.2g/cm 3的松密度。
如本文中所使用，术语“梯度混合”是指将活性成分与相等重量的辅料(单一辅料或者多种辅料的预先混合物)混合得到第一混合物，然后再加入与所得第一混合物相等重量的辅料(单一辅料或者多种辅料的预先混合物)并混合得到第二混合物，依照相同的方法继续加入辅料直至将辅料全部加入。
如本文中所使用，术语“a/a％”是指在所得谱图(例如HPLC谱图)中依照面积归一化法计算得到的面积百分比。
药物组合物、包含其的胶囊剂及其制备方法
在一些实施方案中，本发明提供口服药物组合物，其包含以下组分(1)，以及选自组分(2)、(3)、(4)和(5)中的一种或多种组分：
组分(1)：活性成分，其为一种或多种式(I)的化合物，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，或者它们的混合物：
Figure PCTCN2019119342-appb-000005
其中
X为氢、C 1-6烷基、卤素、N 3、OH、CN或SH；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
R 4选自氢和任选取代的C 1-10酰基；
Q为结构如下的嘧啶碱基或嘌呤碱基：
Figure PCTCN2019119342-appb-000006
R 5每次出现时独立地选自氢、任选取代的C 1-10烷基和任选取代的环烷基；并且
Z为氢、任选取代的C 1-10烷基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；组分(2)：选自下列中的一种或多种：甘露醇、微晶纤维素、淀粉、预胶化淀粉、一水乳糖、无水乳糖、磷酸二氢钙、磷酸氢钙、磷酸钙和碳酸钙，条件是当组分(2)为甘露醇时，组分(3)、(4)和(5)中的至少一种含量不是0，优选组分(3)的含量不是0；
组分(3)：选自下列中的一种或多种：硬脂酸、硬脂酸镁、硬脂酸钙、氢化植物油、十二烷基硫酸镁、滑石粉、聚乙二醇和硬脂富马酸钠；
组分(4)：选自下列中的一种或多种：低取代羟丙基纤维素、低取代羟丙甲纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮；以及
组分(5)：选自下列中的一种或多种：二氧化硅和磷酸三钙；
其中组分(1)、(2)、(3)、(4)和(5)的含量总和为所述口服药物组合物的≤100重量％，优选为100重量％。
在一些实施方案中，本发明提供口服药物组合物，其中所述活性成分为选自下列的一种或多种化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，或者它们的混合物：
Figure PCTCN2019119342-appb-000007
Figure PCTCN2019119342-appb-000008
Figure PCTCN2019119342-appb-000009
上述活性成分(例如式(I)的各个基团定义)及其制备和用途均记载于WO 2016/155593 A1国际专利申请中。上述国际专利申请以其整体援引加入本文。
在一些实施方案中，本发明提供口服药物组合物，其中所述活性成分的含量为所述口服药物组合物的0.1-50重量％，更优选为0.5-30重量％。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(2)为选自下列中的一种或多种：微晶纤维素、预胶化淀粉和无水乳糖。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(2)的含量为所述口服药物组合物的1-99.9重量％，更优选为50-99.5重量％。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(3)为选自下列中的一种或多种：硬脂酸镁、硬脂富马酸钠和硬脂酸钙。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(3)的含量为所述口服药物组合物的0-10重量％，优选为0-5重量％，更优选为0.5-5重量％。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(4)为选自下列中的一种或多种：低取代羟丙甲纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠和羧甲基淀粉钠。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(4)的含量为所述口服药物组合物的0-15重量％，优选为0-10重量％，更优选为0.5-10重量％。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(5)为二氧化硅。
在一些实施方案中，本发明提供口服药物组合物，其中所述组分(5)的含量为所述口服药物组合物的0-5重量％，优选为0-3重量％，更优选为0.1-3重量％。
在一些实施方案中，本发明提供口服药物组合物，其包含以下组分：
活性成分，其为化合物C8，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，
其中所述活性成分的含量为所述口服药物组合物的0.5-30重量％；
组分(2)，其为微晶纤维素，
其中所述组分(2)的含量为所述口服药物组合物的50-99.5重量％；以及
组分(5)，其为二氧化硅；
其中所述组分(5)的含量为所述口服药物组合物的0.1-3重量％。
在一些实施方案中，本发明提供口服药物组合物，其包含以下组分：
活性成分，其为化合物C8，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，
其中所述活性成分的含量为所述口服药物组合物的0.5-30重量％；
组分(2)，其为预胶化淀粉，
其中所述组分(2)的含量为所述口服药物组合物的50-99.5重量％；以及
组分(3)，其为硬脂酸镁；
其中所述组分(3)的含量为所述口服药物组合物的0.5-5重量％。
在一些实施方案中，本发明提供口服药物组合物，其包含以下组分：
活性成分，其为化合物C8，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，
其中所述活性成分的含量为所述口服药物组合物的0.75-25重量％；
组分(2)，其为微晶纤维素，
其中所述组分(2)的含量为所述口服药物组合物的70-99重量％；以及
组分(5)，其为二氧化硅；
其中所述组分(5)的含量为所述口服药物组合物的0.5-1.5重量％。
在一些实施方案中，本发明提供口服药物组合物，其包含以下组分：
活性成分，其为化合物C8，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，
其中所述活性成分的含量为所述口服药物组合物的0.5-20重量％；
组分(2)，其为预胶化淀粉，
其中所述组分(2)的含量为所述口服药物组合物的70-99重量％；以及
组分(3)，其为硬脂酸镁；
其中所述组分(3)的含量为所述口服药物组合物的0.5-1.5重量％。
在一些实施方案中，本发明提供制备本发明的口服药物组合物的方法，其包括以下步骤：
1).任选地将所述活性成分粉碎，粉碎后的活性成分粒径范围如下：
D v(90)为1-500μm，优选5-100μm；
D v(50)为1-100μm，优选1-20μm；
D v(10)为0.1-10μm，优选0.5-5μm；和/或
D[4，3]为1-50μm，优选5-25μm；
2).将所述粉碎后的活性成分与其余组分混合、过筛(优选过60目筛或者40目筛)并再次混合。
在一些实施方案中，本发明提供胶囊剂，其包含本发明的口服药物组合物以及包含所述口服药物组合物的胶囊壳，所述胶囊壳优选为明胶空心胶囊壳、羟丙甲纤维素(HPMC)空心胶囊壳或淀粉空心胶囊壳，更优选为HPMC空心胶囊壳。
在一些实施方案中，所述胶囊剂每粒包含50-600mg本发明的口服药物组合物；优选包含100-300mg本发明的口服药物组合物。
在一些实施方案中，本发明提供制备本发明的胶囊剂的方法，其包括以下步骤：
1).任选地将所述活性成分粉碎，粉碎后的活性成分粒径范围如下：
D v(90)为1-500μm，优选5-100μm；
D v(50)为1-100μm，优选1-20μm；
D v(10)为0.1-10μm，优选0.5-5μm；和/或
D[4，3]为1-50μm，优选5-25μm；
2).将所述粉碎后的活性成分与其余组分混合、过筛(优选过60目筛或者40目筛)并再次混合，以得到本发明的口服药物组合物；以及
3).将本发明的口服药物组合物填充入胶囊壳中。
在一些实施方案中，本发明提供制品，其包含本发明的口服药物组合物或者本发明的胶囊剂，以及独立存在的干燥剂，所述干燥剂优选为无水硅胶、分子筛、氧化铝或氯化钙，所述制品优选在包装材料中，所述包装材料为铝塑泡罩包装或高密度聚乙烯瓶包装。在优选的实施方案中，所述制品为药物制品。
制药用途和治疗方法
在一些实施方案中，本发明提供本发明的口服药物组合物、胶囊剂或制品在制备用于预防或治 疗细胞增殖异常性疾病的药物中的用途。
在一些实施方案中，本发明提供本发明的口服药物组合物、胶囊剂或制品，其用于预防或治疗细胞增殖异常性疾病。
在一些实施方案中，本发明提供预防或治疗细胞增殖异常性疾病的方法，其包括向需要其的个体(优选哺乳动物)给药预防或治疗有效量的本发明的口服药物组合物、胶囊剂或制品。
在一些实施方案中，所述细胞增殖异常性疾病是例如癌症和/或肿瘤及其相关病症。所述的肿瘤和/或癌症包括食道、胃、肠、直肠、口腔、咽、喉、肺、结肠、乳腺、子宫、子宫内膜、卵巢、前列腺、睾丸、膀胱、肾、肝、胰腺、骨、结缔组织、皮肤、眼、脑和中枢神经系统等部位发生的肿瘤和/或癌症以及相关病症，以及甲状腺癌、白血病、霍杰金氏病、淋巴瘤和骨髓瘤等。
在一些实施方案中，本发明还提供本发明的口服药物组合物、胶囊剂或制品用于同时、单独和依次与其他治疗剂(例如其他抗癌症/肿瘤剂)联用的用途。
本发明的口服药物组合物、胶囊剂或制品中所包含的活性成分的施用剂量范围是0.1-1000mg/kg体重/天，优选的剂量范围是1-800mg/kg体重/天，优选的剂量范围是10-600mg/kg体重/天，特别优选的剂量范围是100-400mg/kg体重/天，最优选的剂量范围是120-250mg/kg体重/天。由医生根据疾病的阶段和严重性以及患者个体的特定需求和反应确定治疗患者所需的精确剂量。
除非另外说明，否则如本文中所使用，术语“治疗(treating)本意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“哺乳动物”包括人或非人动物。示例性人个体包括患有疾病或病症(例如本文所述的疾病或病症)的人个体(称为患者)或正常个体。本发明中“非人动物”包括非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
具体实施方式
下面结合实施例及具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明内容所实现的技术方案均属于本发明的范围。
实施例1甘露醇为组分(2)的处方考察
表1-1甘露醇为组分(2)的处方制剂
Figure PCTCN2019119342-appb-000010
制备工艺：①原辅料梯度混合；②过60目筛一次；③再次混合30min；④灌装胶囊。
采用高密度聚乙烯瓶密封包装各处方制剂，进行稳定性考察，考察条件为60℃。
表1-2稳定性考察结果
Figure PCTCN2019119342-appb-000011
结果显示，在处方1(对比例)中，在第10天总杂含量超过10a/a％，说明API(活性药物成分)与甘露醇存在明显的相容性问题，甘露醇可能促进了API的降解。在处方2中，制备完后(0天)，总杂仅为0.22a/a％，与处方1(对比例)在第0天总杂相比，有明显减小，同时，在处方2中在第10天总杂含量为约5a/a％，表明本发明的组合物中杂质生成显著降低。
实施例2预胶化淀粉为组分(2)的处方(处方3-1、处方3-2)考察
表2-1处方3-1各成分用量
成分 用量(mg/粒)
化合物C8 1.5
预胶化淀粉 196.5
硬脂酸镁 2.0
HPMC空心胶囊壳2# 1粒
制备工艺：①原辅料梯度混合；②过60目筛一次；③再次混合30min；④灌装胶囊。
采用高密度聚乙烯瓶密封包装各处方制剂，进行稳定性考察，考察条件为60℃。
表2-2处方3-1稳定性考察结果
时间(d) 0 30
最大单杂(a/a％) 0.11 0.20
总杂(a/a％) 0.21 0.34
将处方3-1和实施例1中处方2的测试结果进行对比可知，用预胶化淀粉替代甘露醇进一步降低了杂质的生成。
表2-3处方3-2各成分用量
成分 用量(mg/粒)
化合物C8 1.5
预胶化淀粉 198.5
HPMC空心胶囊壳2# 1粒
制备工艺：①原辅料梯度混合；②过60目筛一次；③再次混合30min；④灌装胶囊。
采用高密度聚乙烯瓶密封包装各处方制剂，进行稳定性考察，考察条件为60℃。
通过对处方3-2进行稳定性考察，处方3-2中的最大单杂(a/a％)水平0天时为0.12％，30天时为0.47％。将处方3-1和处方3-2的测试结果进行对比可知，同时含有预胶化淀粉与硬脂酸镁的处方相比单独使用预胶化淀粉的处方可以进一步降低杂质的生成。
实施例3干燥剂对处方稳定性的作用
按照表3-1所示处方以及以下制备工艺制备胶囊制剂，考察干燥剂对制剂稳定性的影响。
表3-1处方4各成分用量(1.5mg规格)
成分 用量(mg/粒)
化合物C8 1.5
预胶化淀粉 246
硬脂酸镁 2.5
明胶空心胶囊壳1# 1粒
内容物总重 250
制备工艺：①原辅料梯度混合；②过60目筛一次；③再次混合30min；④灌装胶囊；⑤依照处方4的成分、用量及第①-④步骤的工艺制备2粒胶囊剂，将其中1粒装入含有分子筛干燥剂包装材料中，另1粒装入无干燥剂的包装材料中，分别封口，贴签。
在60℃条件下进行稳定性考察，结果如表3-2所示。
表3-2稳定性考察结果
Figure PCTCN2019119342-appb-000012
对于处方4，采用带分子筛干燥剂的包装材料，相对于不带干燥剂的包装，杂质增长量明显减小。这表明，在包装材料中包含干燥剂能够进一步提高制剂的稳定性。
实施例4含交联羧甲基纤维素钠(CCNa)的处方
按照表4-1所示处方以及以下制备工艺制备胶囊制剂，考察CCNa对制剂溶出度的影响。
表4-1处方各成分用量
Figure PCTCN2019119342-appb-000013
Figure PCTCN2019119342-appb-000014
制备工艺：①原辅料梯度混合；②过60目筛一次；③再次混合30min；④填充胶囊。
测定两种处方胶囊溶出，测定方法为《中国药典》(2015版)篮法，900ml，pH 2.0的盐酸水溶液作为溶出介质，100rpm。
表4-2含CCNa与不含CCNa的处方的溶出结果
Figure PCTCN2019119342-appb-000015
结果表明处方中加入CCNa，可以进一步提高溶出速率。
实施例5不同API粒径的处方
按照表5-1所示处方以及以下制备工艺制备胶囊制剂，考察API粒径分布对制剂溶出度的影响。
表5-1处方7各成分用量
成分 用量(mg/粒)
化合物C8 50
预胶化淀粉 197.5
硬脂酸镁 2.5
HPMC空心胶囊壳1# 1粒
内容物总重 250
制备工艺：①将API机械粉碎，获得不同粒径的API，粒径信息见表5-2；②原辅料梯度混合；③过60目筛一次；④再次混合30min；⑤填充胶囊，获得API粒径不同的三个批次产品，分别用处方7-1、处方7-2和处方7-3表示。
表5-2 API粒径信息
Figure PCTCN2019119342-appb-000016
测定两种处方胶囊溶出，测定方法为《中国药典》(2015版)篮法，900ml，pH 2.0的盐酸水溶液作为溶出介质，75rpm，结果见表5-3。
表5-3不同API粒径制备的制剂的溶出(pH 2.0，n＝6)
Figure PCTCN2019119342-appb-000017
结果表明，通过将API粒径控制在适当范围内，获得了具有优异溶出度的制剂产品，三个批次60min内的溶出度均达到94％以上。
实施例6
按照表6-1所示处方及用量以及下述制备工艺分别制备活性成分含量分别为15mg和1.5mg两种不同规格的胶囊，并考察其API含量、混合均匀度、溶出度、稳定性等性质。溶出度测定方法为《中国药典》(2015版)篮法，测定时间30分钟，900ml，pH 2.0的盐酸水溶液作为溶出介质，转速75rpm。
表6-1. 15mg规格和1.5mg规格(处方8)胶囊
Figure PCTCN2019119342-appb-000018
制备工艺：
①将原料药气流粉碎；经测定，粉碎后API粒径的D v(90)为17.806μm；D v(50)为4.139μm；
②称取处方量的预胶化淀粉和硬脂酸镁，混合10min；
③梯度混合：称取处方量的原料药，将②中混合辅料分三次加入，与原料药混合，每次混合10min，得混合物料1；
④将混合物料1过40目筛，使用混合机混合30min，得混合物料2，即为中间体物料；取三个不同位置样品，对中间体物料含量进行检测；
⑤胶囊填充：根据中间体物料含量结果，计算胶囊填充量；使用胶囊机进行填充，胶囊壳为HPMC空心胶囊壳1#；调节胶囊机灌装量，填充过程中实时监测灌装量。灌装后得到制剂成品，对制剂成品含量进行检测。
混合均匀度及含量均匀度检测结果
分别检测两种规格中间体物料的API含量以及混合均匀度，结果如下：
15mg规格的中间体物料的API含量实测值与理论值的重量百分比为：97.18％；混合均匀度(RSD)：0.95％。
1.5mg规格的中间体物料的API含量实测值与理论值的重量百分比为：94.58％；混合均匀度(RSD)：0.99％。
分别检测两种规格胶囊成品的API含量以及含量均匀度，结果如下：
15mg规格的胶囊成品的API含量实测值与标示值的重量百分比为：96.4％；
1.5mg规格的胶囊成品的API含量实测值与标示值的重量百分比为：96.5％；且上述两种规格胶囊成品的含量均匀度(A+2.2S)均小于15。
以上结果显示，中间体物料混合均匀度良好(RSD＜2％)，这表明，合理控制API的粒径，采用本发明中的制备工艺可以实现中间体均匀混合，且能够确保制备过程API的稳定，制剂成品符合药典相关要求。
影响因素检测结果
采用不带包装的制剂，在不同条件下进行稳定性考察。结果如下。
在光照条件(4500lx±500lx)条件下放置30天，考察光照影响因素下药物的稳定性，考察结果如表6-2所示：
表6-2光照条件(4500lx±500lx)下的稳定性考察结果
Figure PCTCN2019119342-appb-000019
1API含量(％)是指API含量实测值与标示值的重量百分比
在高温条件(60℃±2℃)下放置30天，考察高温影响因素下药物的稳定性，考察结果如表6-3所示：
表6-3高温60℃±2℃条件下的稳定性考察结果
Figure PCTCN2019119342-appb-000020
1API含量(％)是指API含量实测值与标示值的重量百分比
另外，在高湿(75％±5％)及高湿(92.5％±5％)条件下放置30天，考察高湿影响因素下药物的稳定性：
在高湿(75％±5％)条件下，1.5mg规格产品0天时的总杂含量(a/a％)为0.2，30天时的总杂含量(a/a％)为0.3；1.5mg规格产品0天时的溶出度(％)为91.6，30天时的溶出度(％)为85.7；15mg规格产品0天时的总杂含量(a/a％)为0.3，30天时的总杂含量(a/a％)也为0.3；15mg规格产品0天时的溶出度(％)为97.3，30天时的溶出度(％)为93.0。
在高湿(92.5％±5％)条件下，1.5mg规格产品0天时的总杂含量(a/a％)为0.2，30天时的总杂含量(a/a％)为0.3；15mg规格产品0天时的总杂含量(a/a％)为0.3，30天时的总杂含量(a/a％)也为0.3；15mg规格产品0天时的溶出度(％)为97.3，30天时的溶出度(％)为97.2。
以上结果显示：该处方制剂在不带包装的情况下，在光照、高温(60℃)或高湿条件下(RH 75％或RH 92.5％)条件下有关物质未显著增加，溶出度及API含量保持稳定，说明制剂稳定性好。
稳定性检测结果
采用高密度聚乙烯瓶和高密度聚乙烯瓶防潮组合盖包装制剂(含硅胶干燥剂)，进行稳定性考察。结果见表6-4至表6-6。
表6-4 40℃±2℃/RH 75％±5％条件下的稳定性考察结果
Figure PCTCN2019119342-appb-000021
1API含量(％)是指API含量实测值与标示值的重量百分比
表6-5 30℃±2℃/RH 65％±5％条件下的稳定性考察结果
Figure PCTCN2019119342-appb-000022
1API含量(％)是指API含量实测值与标示值的重量百分比
表6-6 25℃±2℃/RH 60％±5％条件下的稳定性考察结果
Figure PCTCN2019119342-appb-000023
1API含量(％)是指API含量实测值与标示值的重量百分比。
以上结果显示：该处方制剂在各个考察条件下均未出现显著的杂质增长，溶出度及API含量基本保持稳定，显示在该包装条件下，制剂稳定性良好。
实施例7
按照表7-1所示处方及用量以及下述制备工艺分别制备活性成分含量分别为50mg、15mg和1.5mg三种不同规格的胶囊，并考察其API含量、混合均匀度、溶出度、稳定性等性质。溶出度测定方法为《中国药典》(2015版)篮法，测定时间30分钟，900ml，pH 2.0的盐酸水溶液作为溶出介质，转速75rpm。
表7-1.不同规格胶囊处方组成(处方9)
Figure PCTCN2019119342-appb-000024
制备工艺：
①将原料药机械粉碎；经测定，粉碎后API粒径的D v(90)为73.636μm；D v(50)为5.956μm；
②称取处方量的微晶纤维素和二氧化硅，混合10min；
③梯度混合：称取处方量的粉碎后的原料药，将②中混合辅料分三次加入，与原料药混合，每次混合10min，得混合物料1；
④将混合物料1过40目筛，再次混合30min，得混合物料2，即为中间体物料；取三个不同位置样品，对中间体含量进行检测；
⑤胶囊填充：根据中间体含量结果，计算胶囊填充量；填充胶囊，得到成品，对成品含量进行检测。
混合均匀度及含量均匀度检测结果
分别检测三种规格中间体物料的API含量以及混合均匀度，结果如下：
15mg规格的中间体物料的API含量实测值与理论值的重量百分比为：107.19％；混合均匀度(RSD)：0.59％。
1.5mg规格的中间体物料的API含量实测值与理论值的重量百分比为：99.51％；混合均匀度(RSD)：1.23％。
50mg规格的中间体物料的API含量实测值与理论值的重量百分比为：100.23％；混合均匀度(RSD)：0.48％。
分别检测三种规格胶囊成品的API含量以及含量均匀度，结果如下：
50mg规格的胶囊成品的API含量实测值与标示值的重量百分比为：94.0％；含量均匀度(A+2.2S)：5.62。
15mg规格的胶囊成品的API含量实测值与标示值的重量百分比为：96.8％；含量均匀度(A+2.2S)：3.72。
1.5mg规格的胶囊成品的API含量实测值与标示值的重量百分比为：105.0％；含量均匀度(A+2.2S)：3.41。
以上结果显示，中间体物料混合均匀度良好(RSD＜2％)，且成品含量均匀度均较高，远低于药典规定的A+2.2S含量均匀度要求。这表明，合理控制API的粒径，采用本发明中的制备工艺可以实现中间体均匀混合，且能够确保制备过程API的稳定，制剂成品符合药典相关要求。
稳定性检测结果
对三种规格的胶囊采用高密度聚乙烯瓶和高密度聚乙烯盖作为包装材料，分别在温度为30℃±2℃/湿度为65％±5％以及温度为25℃±2℃/湿度为60％±5％的条件下放置6个月，考察制品的稳定性，结果如表7-2、7-3所示。
表7-2 30℃±2℃/RH 65％±5％条件下的稳定性考察结果
Figure PCTCN2019119342-appb-000025
1含量测定(％)是指API含量实际测定值与标示值的重量百分比。
表7-3 25℃±2℃/RH 60％±5％条件下的稳定性考察结果
Figure PCTCN2019119342-appb-000026
1含量测定(％)是指API含量实际测定值与标示值的重量百分比。
以上结果显示：该处方制剂在各个考察条件下均未出现显著的杂质增长，显示在该包装条件下，制剂稳定性良好。
上述实施例不以任何方式限定本申请的方案。除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (16)

  1. 口服药物组合物，其包含以下组分(1)，以及选自组分(2)、(3)、(4)和(5)中的一种或多种组分：
    组分(1)：活性成分，其为一种或多种式(I)的化合物，或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，或者它们的混合物：
    Figure PCTCN2019119342-appb-100001
    其中
    X为氢、C 1-6烷基、卤素、N 3、OH、CN或SH；
    Y为氧或硫；
    R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
    R 3选自任选取代的芳基和任选取代的杂芳基；
    R 4选自氢和任选取代的C 1-10酰基；
    Q为结构如下的嘧啶碱基或嘌呤碱基：
    Figure PCTCN2019119342-appb-100002
    R 5每次出现时独立地选自氢、任选取代的C 1-10烷基和任选取代的环烷基；并且
    Z为氢、任选取代的C 1-10烷基或卤素；
    上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；组分(2)：选自下列中的一种或多种：甘露醇、微晶纤维素、淀粉、预胶化淀粉、一水乳糖、无水乳糖、磷酸二氢钙、磷酸氢钙、磷酸钙和碳酸钙，条件是当组分(2)为甘露醇时，组分(3)、(4)和(5)中的至少一种含量不是0，优选组分(3)的含量不是0；
    组分(3)：选自下列中的一种或多种：硬脂酸、硬脂酸镁、硬脂酸钙、氢化植物油、十二烷基硫酸镁、滑石粉、聚乙二醇和硬脂富马酸钠；
    组分(4)：选自下列中的一种或多种：低取代羟丙基纤维素、低取代羟丙甲纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮；以及
    组分(5)：选自下列中的一种或多种：二氧化硅和磷酸三钙；
    其中组分(1)、(2)、(3)、(4)和(5)的含量总和为所述口服药物组合物的≤100重量％，优选为100重量％。
  2. 权利要求1的口服药物组合物，其中所述活性成分为选自下列的一种或多种化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，或它们的任意晶型或消旋物，或它们的代谢物形式，或者它们的混合物：
    Figure PCTCN2019119342-appb-100003
    Figure PCTCN2019119342-appb-100004
  3. 权利要求1或2的口服药物组合物，其中所述活性成分的含量为所述口服药物组合物的0.1-50重量％，更优选为0.5-30重量％。
  4. 权利要求1-3中任一项的口服药物组合物，其中所述组分(2)为选自下列中的一种或多种：微晶纤维素、预胶化淀粉和无水乳糖。
  5. 权利要求1-4中任一项的口服药物组合物，其中所述组分(2)的含量为所述口服药物组合物的1-99.9重量％，更优选为50-99.5重量％。
  6. 权利要求1-5中任一项的口服药物组合物，其中所述组分(3)为选自下列中的一种或多种：硬脂酸镁、硬脂富马酸钠和硬脂酸钙。
  7. 权利要求1-6中任一项的口服药物组合物，其中所述组分(3)的含量为所述口服药物组合物的0-10重量％，优选为0-5重量％，更优选为0.5-5重量％。
  8. 权利要求1-7中任一项的口服药物组合物，其中所述组分(4)为选自下列中的一种或多种：低取代羟丙甲纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠和羧甲基淀粉钠。
  9. 权利要求1-8中任一项的口服药物组合物，其中所述组分(4)的含量为所述口服药物组合物的0-15重量％，优选为0-10重量％，更优选为0.5-10重量％。
  10. 权利要求1-9中任一项的口服药物组合物，其中所述组分(5)为二氧化硅。
  11. 权利要求1-10中任一项的口服药物组合物，其中所述组分(5)的含量为所述口服药物组合物的0-5重量％，优选为0-3重量％，更优选为0.1-3重量％。
  12. 制备权利要求1-11中任一项的口服药物组合物的方法，其包括以下步骤：
    1).任选地将所述活性成分粉碎，粉碎后的活性成分粒径范围如下：
    D v(90)为1-500μm，优选5-100μm；
    D v(50)为1-100μm，优选1-20μm；
    D v(10)为0.1-10μm，优选0.5-5μm；和/或
    D[4，3]为1-50μm，优选5-25μm；
    2).将所述粉碎后的活性成分与其余组分混合、过筛并再次混合。
  13. 胶囊剂，其包含权利要求1-11中任一项的口服药物组合物以及包含所述口服药物组合物的胶囊壳，所述胶囊壳优选为明胶空心胶囊壳、羟丙甲纤维素(HPMC)空心胶囊壳或淀粉空心胶囊壳，更优选为HPMC空心胶囊壳。
  14. 制备权利要求13的胶囊剂的方法，其包括以下步骤：
    1).任选地将所述活性成分粉碎，粉碎后的活性成分粒径范围如下：
    D v(90)为1-500μm，优选5-100μm；
    D v(50)为1-100μm，优选1-20μm；
    D v(10)为0.1-10μm，优选0.5-5μm；和/或
    D[4，3]为1-50μm，优选5-25μm；
    2).将所述粉碎后的活性成分与其余组分混合、过筛并再次混合，以得到权利要求1-11中任一项的口服药物组合物；以及
    3).将权利要求1-11中任一项的口服药物组合物填充入胶囊壳中。
  15. 制品，其包含权利要求1-11中任一项的口服药物组合物或者权利要求13的胶囊剂，以及独立存在的干燥剂。
  16. 权利要求1-11中任一项的口服药物组合物、权利要求13的胶囊剂或权利要求15的制品在制备用于预防或治疗细胞增殖异常性疾病的药物中的用途。
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