WO2023088231A1 - 一种rock2抑制剂的纳米晶制剂及其制备方法 - Google Patents

一种rock2抑制剂的纳米晶制剂及其制备方法 Download PDF

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WO2023088231A1
WO2023088231A1 PCT/CN2022/131872 CN2022131872W WO2023088231A1 WO 2023088231 A1 WO2023088231 A1 WO 2023088231A1 CN 2022131872 W CN2022131872 W CN 2022131872W WO 2023088231 A1 WO2023088231 A1 WO 2023088231A1
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nanocrystal
preparation
rock2 inhibitor
polysorbate
rock2
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PCT/CN2022/131872
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English (en)
French (fr)
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卢迪
朱朝露
张志兵
牛生盼
卢永杰
徐佳佳
张莎莎
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北京泰德制药股份有限公司
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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
    • A61K31/33—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/20—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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the invention relates to the field of medicine, in particular, the invention relates to a nanocrystal preparation of a ROCK2 inhibitor and a preparation method thereof.
  • Idiopathic pulmonary fibrosis is a progressive respiratory disease characterized by pulmonary fibrosis and reduction and loss of lung function. The median survival period is 2.5-3 years.
  • IPF Idiopathic pulmonary fibrosis
  • ROCK2-targeted drugs the United States is conducting a phase 2 clinical study for IPF (Kadmon, USA), and preliminary results have confirmed the safety and effectiveness of ROCK2 inhibitors in the treatment of IPF.
  • [6-[4-[[4-(1H-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]-1-methyl-1H-indol-2-yl](3,3 -Difluoroazetidin-1-yl)methanone is a new type of highly selective ROCK2 inhibitor with a new target and a new structure type completely independently developed by Beijing Tide Pharmaceutical Co., Ltd., from the perspective of patient compliance From this point of view, choose oral preparations for the treatment of IPF.
  • the high selectivity of its target greatly reduces the safety risk.
  • Our company has obtained the compound patent in the United States, and has applied for compound patents in China, the European Union, Japan, South Korea, India, Canada, Australia and other countries and regions.
  • [6-[4-[[4-(1H-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]-1-methyl-1H-indol-2-yl](3,3 -Difluoroazetidin-1-yl)methanone is a light yellow to yellow solid powder with poor solubility and is insoluble in water and pH1.0 ⁇ pH6.8 cache salt solution. Poor physical properties, easy stickiness, static electricity, aggregation. Therefore, how to prepare the preparation of the compound and improve the dissolution rate of the product has become a technical problem to be solved urgently by those skilled in the art.
  • An object of the present invention is to provide a nanocrystal preparation of a ROCK2 inhibitor and a preparation method thereof, so as to improve the dissolution rate of the ROCK2 inhibitor.
  • the specific technical scheme is as follows:
  • the present invention firstly provides a nanocrystalline preparation comprising a ROCK2 inhibitor and a stabilizer, the ROCK2 inhibitor being a compound of formula (I),
  • Ring A is The above group is connected to the pyrimidine ring through one of the two positions marked with * or **, and the other position is connected to the carbonyl;
  • n is independently at each occurrence an integer of 0, 1, 2 or 3;
  • n each occurrence is independently an integer of 0, 1 or 2;
  • Ring A is The above group is connected to the pyrimidine ring through the position marked with *, and connected to the carbonyl group through the position marked with **, wherein R 10 is selected from H and C 1-6 alkyl, preferably H or methyl;
  • R is selected from H and C 1-6 alkyl
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 is independently selected from H, halogen, -NR 5 R 6 , -OH, C 1-6 alkyl and -OR 5 ;
  • alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally selected at each occurrence by one or more independently selected from halogen, C Substituents of -6 alkyl and -OR 5 ;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • the present invention also provides a preparation method of the nanocrystal preparation, which comprises grinding the ROCK2 inhibitor and the stabilizer.
  • Another object of the present invention is the method and application of the nanocrystal preparation in the prevention, alleviation and/or treatment of idiopathic pulmonary fibrosis.
  • Fig. 1 and Fig. 2 are the stripping curves of comparative examples 1-3 of the present invention.
  • Fig. 3 is the stripping curve of embodiment 8-9 of the present invention and comparative example
  • Fig. 4 ⁇ Fig. 6 are respectively the stripping curve of embodiment 8 nano-suspension of the present invention, embodiment 10-15 nano-tablet formulation and comparative example;
  • Fig. 7 is the dissolution curve of the nanosuspension of Example 8, the nanochip tablet of Example 15, the nanocrystalline capsules of Examples 24-25 and the comparative example of the present invention.
  • nanocrystal refers to nanocrystals, and also to nanosuspension, which means a stable colloidal dispersion system formed by dispersing nanoscale drug particles in water in the presence of a stabilizer.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl radical, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally replaced by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution in which case the group is called "haloalkyl”
  • haloalkyl for example CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH 2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-butenyl, -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenylene group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl,
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclopropyl) of 3 to 6 ring-forming carbon atoms. hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., with one or more double bond and/or triple bond) cyclic group.
  • a "3-10 membered (sub)heterocyclic (group)” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocyclic ring (group) of one or more (for example, 1, 2, 3 or 4) heteroatoms of , O and S.
  • heterocyclylene and heterocycle include, but are not limited to: ()oxiranyl, () aziridinyl, (azetidinyl), ()oxy Heterocyclobutyl (oxetanyl), (sub)tetrahydrofuranyl, (sub)dioxolinyl (dioxolinyl), (sub)pyrrolidinyl, (sub)pyrrolidinyl, (sub)imidazolidinyl, (sub) ) pyrazolidinyl, (sub)pyrrolinyl, (sub)tetrahydropyranyl, (sub)piperidinyl, (sub)morpholinyl, (sub)dithianyl (dithianyl), (sub) Thiomorpholinyl, piperazinyl or trithianyl.
  • the groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycle(yl) groups may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring).
  • ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • heteroarylene and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom which may be the same or different (the heteroatoms are for example oxygen, nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
  • “(y)heteroaryl” or “heteroaromatic ring” is selected from (y)thienyl, (y)furyl, (y)pyrrolyl, (y)oxazolyl, ()thiazolyl, (Yellow) imidazolyl, (lower) pyrazolyl, (lower) isoxazolyl, (lower) isothiazolyl, (lower) oxadiazolyl, (lower) triazolyl, (lower) thiadiazolyl etc., and their benzo derivatives; or (sub)pyridyl, (sub)pyridazinyl, (sub)pyrimidinyl, (sub)pyrazinyl, (sub)triazinyl, etc. derivative.
  • aralkyl preferably denotes an aryl or heteroaryl substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the heteroaryl group can have 5-14 ring atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ).
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N); , 17 O and 18 O
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
  • stereoisomer means isomers formed as a result of at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
  • Solid lines can be used in this article solid wedge or imaginary wedge Depicts the chemical bonds of the compounds of the invention.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist.
  • solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
  • the present invention covers 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 proportion.
  • compositions of the invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to patients in need thereof Following administration, the compound of the invention or its metabolites or residues can be provided directly or indirectly. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pam
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium, sodium, tromethamine and zinc salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperbenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "effective amount” refers to the amount sufficient to achieve the desired therapeutic effect under the administration conditions, which leads to the improvement of pathological symptoms, disease progression, physiological conditions related thereto or induces resistance to the aforementioned diseases.
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • the present invention relates to a nanocrystalline formulation comprising a ROCK2 inhibitor and a stabilizer.
  • the present invention relates to a nanocrystalline preparation, wherein the ROCK2 inhibitor is a compound of formula (I),
  • Ring A is The above group is connected to the pyrimidine ring through one of the two positions marked with * or **, and the other position is connected to the carbonyl;
  • n is independently at each occurrence an integer of 0, 1, 2 or 3;
  • n each occurrence is independently an integer of 0, 1 or 2;
  • Ring A is The above group is connected to the pyrimidine ring through the position marked with *, and connected to the carbonyl group through the position marked with **, wherein R 10 is selected from H and C 1-6 alkyl, preferably H or methyl;
  • R is selected from H and C 1-6 alkyl
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 is independently selected from H, halogen, -NR 5 R 6 , -OH, C 1-6 alkyl and -OR 5 ;
  • alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally selected at each occurrence by one or more independently selected from halogen, C Substituents of -6 alkyl and -OR 5 ;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • the present invention relates to a nanocrystalline preparation
  • the ROCK2 inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof substances, N-oxides, isotope labels, metabolites or prodrugs,
  • each group is as defined above.
  • the present invention relates to a nanocrystalline preparation
  • the ROCK2 inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof substances, N-oxides, isotope labels, metabolites or prodrugs,
  • R 10 is H or methyl, preferably methyl.
  • the present invention relates to a nanocrystalline preparation
  • the ROCK2 inhibitor is a compound of formula (IV), or a pharmaceutically acceptable salt (especially hydrochloride), ester, stereoisomer thereof , polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs,
  • the chemical name of the compound of formula (IV) is: [6-[4-[[4-(1H-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]-1-methyl-1H-ind Indol-2-yl](3,3-difluoroazetidin-1-yl)methanone.
  • the compound of formula (IV) can be prepared by a known method as a bulk drug, and can also be obtained through commercial channels, no matter which method is used, it is easy for those skilled in the art to realize, Therefore, the present invention will not be described in detail here.
  • nano-micronization can significantly increase the specific surface area of drug particles, which also increases the free energy of the entire preparation preparation system, resulting in system instability;
  • the action temperature caused by the mechanical energy during the grinding process, the newly formed nanoparticles will re-agglomerate and recrystallize under the influence of the free energy change.
  • the stabilizer is adsorbed on the surface of the drug particles to block the re-aggregation of the drug particles, thereby increasing the effective surface area and significantly improving the stability of the nanosuspension.
  • the stabilizer in addition to improving the wettability of the drug and stabilizing the particle size of the drug, can also improve the dissolution rate by improving the particle size stability of the ROCK2 inhibitor nanocrystal after solidification, drying and reconstitution.
  • a person skilled in the art can select a suitable stabilizer according to the description of the function of the stabilizer herein in the present invention.
  • polysorbate 20 Including but not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, povidone K29/32, polyoxyethylene fatty acid ester, polo Sharm 188, Poloxamer 407, Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC 3cps), Polyvinylpyrrolidone (PVP K30), Poloxamer (Pluronic F68 and Pluronic F127) , sodium dodecyl sulfate (SDS), docusate sodium (DSS), polyethylene glycol 15-hydroxystearate, polyoxyethylene castor oil, copovidone, etc.
  • HPC Hydroxypropylcellulose
  • HPMC 3cps Hydroxypropylmethylcellulose
  • PVP K30 Polyvinylpyrrolidone
  • Poloxamer Poloxamer (Pluronic F68 and Pluronic F127) , sodium dodecyl s
  • the present invention relates to a nanocrystalline preparation, wherein the stabilizer is selected from polysorbate, povidone, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyoxyethylene castor One or more of sesame oil, poloxamer, sodium lauryl sulfate, lactose, and mannitol.
  • the stabilizer is selected from polysorbate, povidone, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyoxyethylene castor One or more of sesame oil, poloxamer, sodium lauryl sulfate, lactose, and mannitol.
  • the present invention relates to a nanocrystal preparation
  • the particle size D90 of the nanocrystal preparation is 50-1500nm, preferably 50-1000nm, preferably 50-500nm, preferably 80-300nm, more preferably 50nm, 100nm, 150nm, 200nm, 250nm, 300nm, 400nm, 500nm, 600nm, 700nm, 800nm, 900nm or 1000nm.
  • the present invention relates to a nanocrystalline preparation, and the particle size range of the ROCK2 inhibitor is preferably D 90 5-300 ⁇ m, preferably 10-100 ⁇ m, more preferably 10-50 ⁇ m.
  • the present invention relates to a nanocrystal preparation, based on the total weight of the nanocrystal preparation, the weight percentage of the ROCK2 inhibitor can be 1%-55%, 4%-50%, 1%- 10%, 10%-40%, 10%-35%, 20%-30% or 30%-40%, can also be 1%, 2%, 3%, 4%, 4.5%, 5%, 6% , 7%, 8%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 15%, 16%, 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%.
  • the present invention relates to a nanocrystal preparation, based on the total weight of the nanocrystal preparation, the weight percentage of the stabilizer can be 0.1%-55%, 0.1%-30%, 0.5%-1 %, 1%-10%, 10%-20% or 20%-30%, can also be 1%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 15%, 16%, 18%, 19%, 20%, 21%, 22%, 23%, 24% , 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40%.
  • the present invention relates to a nanocrystalline formulation, wherein the weight ratio of ROCK2 inhibitor and stabilizer can be 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8: 1. 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1; can also be 4:1 to 1:1 or 1:1 to 1:2; can also be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 5:4, 5:3, or 5:2.
  • the weight ratio of ROCK2 inhibitor and stabilizer can be 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8: 1. 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1; can also be 4:1 to 1:1 or 1:1 to 1:2; can also be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1
  • the present invention relates to a nanocrystal formulation further comprising excipients.
  • the present invention relates to a nanocrystalline formulation, wherein said excipient is selected from the group consisting of fillers; wetting agents; sweeteners or flavoring agents; surfactants; Glidants or anti-adherents; release modifiers; coating agents; emulsifiers; solubilizers;
  • the present invention relates to a nanocrystalline preparation, wherein the excipient comprises a filler; the filler can improve the material properties of the active ingredient, improve stickiness and electrostatic properties, thereby facilitating the subsequent shaping of the composition, such as pressing Tablets, filled capsules, etc., play an important role in the preparation of solid preparations.
  • Fillers can also adjust the dissolution rate of the formulation.
  • fillers commonly used in the technical field can be selected, including but not limited to microcrystalline cellulose, mannitol, lactose, starch, pregelatinized starch, dextrin, calcium phosphate dihydrate, anhydrous phosphoric acid One or at least two kinds of calcium hydrogen.
  • the weight percentage of the filler can be 1%-80%; more specifically, in some embodiments, the weight percentage of the filler can be 20%-70%, 30%-60% or 50-70%, etc., such as 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% etc.
  • the filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol. Preferably, the filler is mannitol.
  • the present invention is directed to a nanocrystalline formulation wherein the excipients comprise lubricants which facilitate various processing steps including mixing of components, tabletting; for example lubricants allow pressure distribution during tabletting Uniformity, and make the density of the tablet uniform; the force required to push the tablet out of the die hole is reduced.
  • lubricants allow pressure distribution during tabletting Uniformity, and make the density of the tablet uniform; the force required to push the tablet out of the die hole is reduced.
  • Another possible function of the lubricant is to improve the appearance of the tablet, making the surface of the tablet bright and smooth.
  • lubricants commonly used in the technical field can be selected, including but not limited to magnesium stearate, talcum powder, micropowder silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol One or a combination of at least two, more preferably magnesium stearate.
  • the weight percentage of the lubricant can be 0.1% to 5%, 0.1%-1.5% or 0.5%-1%, etc., such as 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%, etc.
  • Described lubricant is selected from magnesium stearate, talcum powder, micropowder silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol.
  • the present invention relates to a nanocrystalline formulation, wherein the excipient comprises a disintegrant.
  • disintegrants commonly used in the technical field can be selected, including but not limited to one or more of croscarmellose sodium and crospovidone.
  • the weight percentage of the disintegrant can be 0 to 20%, preferably 0 to 10%, more preferably 2 to 10%, For example 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
  • the present invention relates to a nanocrystalline formulation, wherein the excipient comprises a glidant.
  • commonly used glidants in the technical field can be selected, including but not limited to silicon dioxide and the like.
  • the weight percentage of the glidant may be 0 to 20%, preferably 0 to 15%, more preferably 2 to 12%, For example 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or 11%.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation further contains a solvent.
  • solvents commonly used in the technical field can be selected, including but not limited to water, etc., preferably pure water.
  • the weight percentage of the solvent may be 0 to 99%, preferably 80 to 99%, more preferably 85% to 95%, for example 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation further contains a bacteriostatic agent.
  • bacteriostatic agents commonly used in the technical field can be selected, including but not limited to one or more of methylparaben and propylparaben.
  • the weight percentage of the bacteriostat can be 0 to 5%, preferably 0 to 1%, more preferably 0.01% to 0.5% , such as 0.1%, 0.2%, 0.3%, 0.4% or 0.5%.
  • the present invention relates to a nanocrystalline formulation, wherein the nanocrystalline formulation is selected from suspensions, tablets, capsules, granules, powders, lozenges and pills; preferably suspensions, tablets doses or capsules.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a suspension comprising:
  • ROCK2 inhibitor preferably 1%, 2%, 3%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9% or 10% ROCK2 inhibitor, more preferably 4%, 4.5%, 5% ROCK2 inhibitors;
  • - 1-10% stabilizer preferably 1%, 1.5%, 2%, 2.5%, 5%, 9%, 9.5% or 10% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 5.00g of povidone K29/32 and 233.10 g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 2.50g of povidone K29/32 and 235.60 g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 2.50g of hypromellose and 235.60g of Purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 5.00g of hypromellose and 233.10g of Purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 250.08g ROCK2 inhibitor, 17.40g polysorbate 80, 111.60g povidone K29/32, 10.00g g methylparaben, 1.10g propylparaben and 5189.82g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 55.19g ROCK2 inhibitor, 18.61g polysorbate 80, 99.25g polyoxyethylene castor oil, 2.23g Methylparaben, 0.25g propylparaben and 1065.09g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm .
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a tablet, comprising:
  • ROCK2 inhibitor preferably 20-30% ROCK2 inhibitor, preferably 20%, 22%, 25%, 28% or 30% ROCK2 inhibitor;
  • - 1-20% stabilizer preferably 5-20% stabilizer, more preferably 5%, 8%, 10%, 13%, 15%, 18% or 20% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 11.70g ROCK2 inhibitor, 3.15g polysorbate 80, 5.26g lactose, 1.05g polyethylene glycol 6000 , 16.03g mannitol, 4.94g silicon dioxide, 2.47g sodium lauryl sulfate, 2.96g microcrystalline cellulose, 2.96g croscarmellose sodium and 0.32g magnesium stearate, preferably, the The particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 32.71g ROCK2 inhibitor, 14.81g polysorbate 80, 14.71g lactose, 2.94g polyethylene glycol 6000 , 43.63g mannitol, 16.00g silicon dioxide, 8.00g sodium lauryl sulfate, 12.80g microcrystalline cellulose, 12.80g croscarmellose sodium and 1.60g sodium stearyl fumarate, preferably , the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 3.34g ROCK2 inhibitor, 0.89g polysorbate 80, 1.80g lactose, 0.30g polyethylene glycol 6000 , 0.75g silicon dioxide, 0.75g sodium lauryl sulfate, 5.82g microcrystalline cellulose, 1.20g croscarmellose sodium and 0.15g sodium stearyl fumarate, preferably, the ROCK2 inhibitor
  • the particle size of the agent is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 3.34g ROCK2 inhibitor, 0.89g polysorbate 80, 1.80g lactose, 0.30g polyethylene glycol 6000 , 0.75g silicon dioxide, 0.45g sodium lauryl sulfate, 4.50g microcrystalline cellulose, 1.62g pregelatinized starch, 1.20g croscarmellose sodium and 0.15g sodium stearyl fumarate,
  • the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 11.14g ROCK2 inhibitor, 2.97g polysorbate 80, 6.01g lactose, 1.00g polyethylene glycol 6000 , 1.00g silicon dioxide, 27.38g spray-dried mannitol and 0.50g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, Most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 111.20g of ROCK2 inhibitor, 30.04g of polysorbate 80, 59.99g of lactose, 10.00g of polyethylene glycol 6000 , 10.00g silicon dioxide, 273.78g spray-dried mannitol and 5.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, Most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a tablet, comprising:
  • ROCK2 inhibitor preferably 20-30% ROCK2 inhibitor, more preferably 20%, 22%, 25%, 28% or 30% ROCK2 inhibitor;
  • - 10-30% stabilizer preferably 20-30% stabilizer, more preferably 20%, 22%, 25%, 28% or 30% stabilizer.
  • the present invention relates to a nanocrystal formulation, wherein the nanocrystal is a tablet comprising 22.22g ROCK2 inhibitor, 20.00g polysorbate 80, 54.80g mannitol, 2.00g silicon dioxide and 1.00 g of sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g povidone K29/32, 44.80g Mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50- 150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g polyethylene glycol 6000, 44.80g manna Alcohol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm .
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet, comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g poloxamer 188, 44.80g manna Alcohol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm .
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g polyvinyl alcohol, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 16.00g povidone K29/32, 4.00g Poloxamer 188, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet, comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 4.00g povidone K29/32, 16.00g Poloxamer 188, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet, comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 10.00g povidone K29/32, 10.00g Poloxamer 188, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a capsule, comprising:
  • ROCK2 inhibitor preferably 20-40% ROCK2 inhibitor, more preferably 20%, 25%, 30%, 35% or 40% ROCK2 inhibitor;
  • stabilizer preferably 20-30% stabilizer, more preferably 20%, 22%, 25%, 28% or 30% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a capsule, comprising 22.20g ROCK2 inhibitor, 6.00g polysorbate 80, 8.00g povidone K29/32, 4.00g Poloxamer and 20.00g of mannitol, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a capsule comprising 4.45g ROCK2 inhibitor, 1.20g polysorbate 80, 1.20g povidone K32/29, 0.80g Poloxamer 188 and 6.80 g of mannitol.
  • the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric preparation selected from enteric-coated tablets or enteric-coated capsules.
  • the present invention relates to a nanocrystalline preparation, wherein the nanocrystalline preparation is a nanocrystalline enteric coated tablet, wherein the enteric coating material is selected from the group consisting of shellac, polyvinyl alcohol benzene diacetate Formate ester (PVAP), methacrylic acid copolymer, cellulose and its derivatives (cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose phthalate ( One or more of HPMCP)), acrylic resins (EuS100, EuL100).
  • the enteric coating material is selected from the group consisting of shellac, polyvinyl alcohol benzene diacetate Formate ester (PVAP), methacrylic acid copolymer, cellulose and its derivatives (cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose phthalate ( One or more of HPMCP)), acrylic resins (EuS100, EuL100).
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated capsule, wherein the enteric-coated capsule is selected from gelatin enteric-coated capsules or hypromellose enteric-coated capsules,
  • the composition of the capsule material is selected from shellac, polyvinyl alcohol acetate phthalate (PVAP), methacrylic acid copolymer, cellulose and its derivatives (cellulose acetate phthalate (CAP), cellulose acetate trimellitate One or more of esters (CAT), hydroxypropyl cellulose phthalate (HPMCP)), acrylic resins (EuS100, EuL100).
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated tablet, comprising:
  • ROCK2 inhibitor preferably 5-15% ROCK2 inhibitor, more preferably 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% ROCK2 inhibitor;
  • - 1-90% stabilizer preferably 10-40% stabilizer, more preferably 15-25% stabilizer, for example, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22% %, 23%, 24% or 25% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated tablet, comprising 5.56g ROCK2 inhibitor, 1.50g polysorbate 80, 1.00g porol Sham, 1.50g povidone K29/32, 5.00g mannitol, 1.00g silicon dioxide, 4.00g crospovidone, 29.94g microcrystalline cellulose, 0.50g magnesium stearate and 5g film coating pre Mixture (enteric-coated type), preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated tablet, comprising 5.56g ROCK2 inhibitor, 1.50g polysorbate 80, 1.00g porol Sham, 1.50g povidone K29/32, 38.94g mannitol, 1.00g silicon dioxide, 0.50g magnesium stearate and 5g film coating premix (enteric coating type), preferably, the ROCK2 inhibitor
  • the particle size of the agent is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated capsule, comprising:
  • ROCK2 inhibitor preferably 10-20% ROCK2 inhibitor, more preferably 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% ROCK2 inhibitor; and
  • - 10-50% stabilizer preferably 20-40% stabilizer, more preferably 30-40% stabilizer, eg 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% %, 38%, 39% or 40% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric capsule, comprising 11.1g of ROCK2 inhibitor, 3.0g of polysorbate 80, 2.0g of poloxamer, 3.0g povidone K29/32, 20.0g mannitol, 2.00g silicon dioxide, 8.0g crospovidone, 29.9g microcrystalline cellulose, 1.0g magnesium stearate and enteric-coated capsules, preferably, all
  • the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the ROCK2 inhibitor may comprise, in addition to the compound of formula (I), (II), (III) or formula (IV), or a pharmaceutically acceptable salt or hydrate thereof, Optionally at least one other compound that has a synergistic therapeutic effect with the compound is included.
  • the present invention relates to a method for preparing the above-mentioned nanocrystal preparation, which comprises grinding a ROCK2 inhibitor and a stabilizer.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the weight ratio of ROCK2 inhibitor and stabilizer during grinding is 1:15 to 15:1, 1:14 to 14:1, 1:13 to 13:1, 1:12 to 12:1, 1:11 to 11:1, 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8:1, 1:7 to 7 :1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1; preferably,
  • the weight ratio of ROCK2 inhibitor to stabilizer when grinding is 15:1 to 2:1, more preferably 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 10:3 , 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the grinding medium is selected from ceramic balls, glass balls, zirconia beads, steel balls or ice beads; preferably, the grinding medium is zirconia beads .
  • the present invention relates to a method for preparing the above-mentioned nanocrystalline preparation, wherein the particle size of the grinding medium is in the range of 0.1-1 mm, preferably 0.1-0.5 mm, more preferably 0.2 mm.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein the grinding time is 0.1-6h, preferably 0.5-6h, preferably 4-6h, more preferably 10min, 20min, 30min, 40min, 1h , 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h or 6h.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the grinding speed is 1000-6000rpm, preferably 1500rpm-4500rpm, more preferably 1500rpm, 2000rpm, 2500rpm, 3000rpm, 3500rpm, 4000rpm, 4500rpm, 5000rpm , 5500rpm or 6000rpm.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein the filling amount of grinding beads is 50-95%, preferably 70%-90%, more preferably 70%, 80% or 90%.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein, before grinding the ROCK2 inhibitor and the stabilizer, a pre-grinding step is further included.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein, the pre-grinding speed is 3000-6000rpm, preferably 3000rpm, 3500rpm, 4000rpm, 4500rpm, 5000rpm, 5500rpm or 6000rpm, more preferably 4000rpm;
  • the pre-grinding time is 1-30 min, preferably 2-20 min, preferably 3 min, 4 min, 5 min, 6 min, 8 min, 10 min, 12 min, 15 min, 18 min or 20 min, more preferably 5 min.
  • the present invention relates to a method for preparing the above-mentioned nanocrystalline preparation, wherein stabilizers and/or excipients are optionally added after grinding.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein, the stabilizer added after grinding is selected from polysorbate, povidone, polyoxyethylene fatty acid ester, polyethylene glycol, polyvinyl alcohol , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poloxamer, sodium lauryl sulfate, docusate sodium, 15-hydroxystearic acid polyethylene glycol, polyoxyethylene One or more of castor oil, copovidone, lactose, mannitol.
  • the stabilizer added after grinding is selected from polysorbate, povidone, polyoxyethylene fatty acid ester, polyethylene glycol, polyvinyl alcohol , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poloxamer, sodium lauryl sulfate, docusate sodium, 15-hydroxystearic acid polyethylene glycol, polyoxyethylene
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein, the stabilizer added after grinding is selected from povidone K29/32, poloxamer 188, polyvinyl alcohol, lactose and mannitol one or more.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the stabilizer added after grinding is a mixture of povidone K29/32 and poloxamer 188, and the mixing ratio of the two is 1:10 to 10:1, preferably 1:9 to 9:1, preferably 1:8 to 8:1, preferably 1:7 to 7:1, preferably 1:6 to 6:1, preferably 1:5 to 5:1, preferably 1:4 to 4:1, preferably 1:3 to 3:1, preferably 1:2 to 2:1, preferably 1:1; more preferably, the mixing ratio of the two is 1:4, 4:1 or 1:1.
  • the stabilizer added after grinding is a mixture of povidone K29/32 and poloxamer 188
  • the mixing ratio of the two is 1:10 to 10:1, preferably 1:9 to 9:1, preferably 1:8 to 8:1, preferably 1:7 to 7:1, preferably 1:6 to 6:1, preferably 1:5 to 5:1, preferably 1:4 to 4:1, preferably 1:3 to 3:1
  • the present invention relates to the preparation method of above-mentioned nanocrystal preparation, it comprises:
  • the active ingredient, part of the stabilizer and purified water are ground with a nano-grinding machine to obtain a nano-suspension, and then adding a stabilizer and/or a filler to obtain a nano-crystal suspension.
  • a nano-grinding machine to obtain a nano-suspension
  • a stabilizer and/or a filler to obtain a nano-crystal suspension.
  • the nanosuspension is obtained by grinding, it is solidified by spray drying or freeze drying to obtain a solid nanocrystalline mixture, then adding fillers for mixing, adding a lubricant, and then molding.
  • the molding process may include granulation, optionally sizing, and tableting or capsule filling.
  • the key process in the present invention is the nano-grinding process.
  • the mixing and the subsequent molding process are all conventional processes and operations in the technical field, and the present invention is not specifically limited here.
  • the inventors investigated the effects of grinding speed, filling amount of grinding beads, sample amount and grinding time on the particle size of ROCK2 inhibitors.
  • the results show that the particle size of ROCK2 inhibitor decreases gradually with the increase of grinding time, but the decreasing speed gradually slows down; as the grinding speed increases, the grinding efficiency increases; at the same speed, the grinding bead filling increases, and the grinding efficiency also increases .
  • the sample size had no significant effect on the grinding efficiency.
  • the grinding parameters and particle size study results are shown in Table 8. Based on this, in some embodiments of the present invention, in the grinding process, 0.2mm zirconia grinding beads are used, and the filling amount of the grinding beads is 50%-95%, preferably 70%-90%.
  • the grinding speed is 1000 rpm to 4500 rpm, preferably 1500 rpm to 3500 rpm.
  • the grinding time is 2h-6h, preferably 4h-5h.
  • the ground nanosuspension when the nanocrystalline preparation composition contains a lubricant, the ground nanosuspension needs to be spray-dried or freeze-dried to remove moisture, and then directly or crushed with optional filler mix, then
  • the present invention relates to a method for preventing, alleviating and/or treating idiopathic pulmonary fibrosis, fatty liver disease and/or steatohepatitis, graft-versus-host disease or viral infection after hematopoietic stem cell transplantation, which It includes administering to the subject a therapeutically effective amount of the nanocrystal preparation or the nanocrystal preparation prepared by the method; preferably, the method is to prevent, alleviate and/or treat fatty liver disease and/or steatohepatitis method; preferably, the fatty liver disease is alcoholic fatty liver disease (ALFD) or nonalcoholic fatty liver disease (NALFD), and the steatohepatitis is alcoholic hepatitis (ASH) or nonalcoholic steatohepatitis (NASH), the hematopoietic stem cell transplantation is allogeneic hematopoietic stem cell transplantation, the graft-versus-host disease is acute graft-versus-host disease
  • the present invention relates to the use of the nanocrystal preparation or the nanocrystal preparation prepared by the method for preventing, alleviating and/or treating idiopathic pulmonary fibrosis, fatty liver disease and/or fatty liver disease Hepatitis, graft-versus-host disease or viral infection after hematopoietic stem cell transplantation; preferably, the nanocrystal preparation is used to prevent, relieve and/or treat fatty liver disease and/or steatohepatitis; preferably, the steatohepatitis
  • the liver disease is alcoholic fatty liver disease (ALFD) or nonalcoholic fatty liver disease (NALFD)
  • the steatohepatitis is alcoholic hepatitis (ASH) or nonalcoholic steatohepatitis (NASH)
  • the hematopoietic stem cell transplantation It is allogeneic hematopoietic stem cell transplantation, the graft-versus-host disease is acute graft-versus-host disease or chronic
  • the present invention relates to the preparation of the nanocrystal preparation or the nanocrystal preparation prepared by the method for preventing, alleviating and/or treating idiopathic pulmonary fibrosis, fatty liver disease and/or fatty Graft-versus-host disease or virus infection after hematopoietic stem cell transplantation; preferably, the use is to prepare a drug for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis purposes in; preferably, the fatty liver disease is alcoholic fatty liver disease (ALFD) or nonalcoholic fatty liver disease (NALFD), and the steatohepatitis is alcoholic hepatitis (ASH) or nonalcoholic fatty liver disease Hepatitis (NASH), the hematopoietic stem cell transplantation is allogeneic hematopoietic stem cell transplantation, the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease, and the virus infection is cor
  • the present invention will be further described below in conjunction with specific embodiments.
  • the specific conditions of the test methods are usually implemented according to the conventional conditions or the conditions suggested by the manufacturer; the raw materials and reagents are all obtained from the market or prepared using public information.
  • the active ingredient (API) used in the following comparative examples, examples and tests is the compound of formula (IV).
  • Preparation method Weigh the prescription amount of API hydrochloride, lactose, microcrystalline cellulose and croscarmellose sodium, mix, dry granulate, add magnesium stearate after granulation, mix, and compress into tablets.
  • Preparation method first micronize API hydrochloride to obtain API hydrochloride with a particle size of D 90 of about 2 ⁇ m, weigh the prescription amount of micronized API hydrochloride, lactose, microcrystalline cellulose and croscarmellose Sodium cellulose is mixed, dry granulated, after granulation, magnesium stearate is added, mixed, and tabletted.
  • Preparation method Weigh the prescription amount of API hydrochloride, silicon dioxide, pregelatinized starch 1500, microcrystalline cellulose, crospovidone and magnesium stearate half of the prescription, mix, dry granulate, and add after granulation The other half is mixed with crospovidone and magnesium stearate, and compressed into tablets.
  • Preparation method take recipe quantity API hydrochloride, polysorbate 80 and part of purified water, grind with nano grinder (0.2mm grinding beads, filling capacity 70%), grinding speed 1500rpm, time 10min, obtain average particle size 1868nm Add the solution of povidone K29/32 again, dilute to 250g, obtain final product concentration 40mg/mL (calculated as free base), product particle diameter 1875nm.
  • the grinding speed is 1500rpm, and the time is 20min to obtain a nanosuspension with an average particle diameter of 1006nm, then add the solution of povidone K29/32, and dilute to 250g to obtain a final product concentration of 40mg/mL (in the form of free Alkali meter), product particle size 1080nm.
  • the grinding speed is 1500rpm, and the time is 40min to obtain a nanosuspension with an average particle diameter of 512nm, then add the solution of povidone K29/32, and dilute to 250g to obtain a final product concentration of 40mg/mL (in the form of free Alkali meter), product particle size 540nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of povidone K29/32, dilute to 250g, obtain final product concentration 40mg/mL (calculated as free base), product particle diameter 300nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of povidone K29/32 again, dilute to 250g, obtain final product concentration 40mg/mL (calculated as free base), product particle diameter 302nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of hypromellose to dilute to 250g to obtain the final product concentration of 40mg/mL (in terms of free base), and the product particle size is 336nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of hypromellose to dilute to 250g to obtain the final product concentration of 40mg/mL (calculated as free base), and the product particle size is 442nm.
  • Preparation method take the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 4h to obtain an average particle size of 281nm
  • a nano grinder 0.2mm grinding beads, filling capacity 70%
  • grind at a speed of 1500rpm and take 4h to obtain an average particle size of 281nm
  • the particle size is 283nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 90%), grind at a speed of 3000rpm, and take 4h to obtain an average particle size of 100nm Add the solution of methylparaben, propylparaben and polyoxyethylene castor oil prepared in advance, and dilute to 1240.62g to obtain a final product concentration of 40mg/mL (calculated as free base). The particle size is 106nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 4500 rpm, and take 6 hours to obtain a nanocrystal suspension Liquid, particle size 58nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, carry out spray-drying, air inlet temperature 120 °C, spray speed 40rpm, get spray-dried powder.
  • a nano grinder 0.2 mm grinding beads, filling capacity 90%
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 4500 rpm, and take 6 hours to obtain a nanocrystal suspension Liquid, particle size 58nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, carry out spray-drying, air inlet temperature 120 °C, spray speed 40rpm, get spray-dried powder.
  • a nano grinder 0.2 mm grinding beads, filling capacity 90%
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension Liquid, particle size 89nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, spray drying, air inlet temperature 120 °C, spray speed 40rpm, to obtain spray-dried powder.
  • a nano grinder 0.2 mm grinding beads, filling capacity 90%
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano-grinding machine (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 4 hours to obtain a nanocrystal suspension Liquid, particle size 128nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, freeze-dry (solid content of sample solution is about 20%), pre-freeze at -40°C for 5h, main dry at -5°C for 13h, vacuum 0.18mbar, secondary drying at 10 ⁇ 15°C for 16h, vacuum degree 0.18mbar.
  • the sample was pulverized and granulated with a pulverizing and granulating machine, mixed with silicon dioxide, spray-dried mannitol and sodium stearyl fumarate (internal addition), dry granulated, mixed with externally added sodium stearyl fumarate, and pressed Tablets, weighing about 1g (specification 200mg, based on anhydrous API).
  • the sample was pulverized and granulated with a granulator, and then mixed with silicon dioxide, spray-dried mannitol and sodium stearyl fumarate, and pressed into tablets with a weight of about 1 g (specification 200 mg, based on anhydrous API).
  • Embodiment 26 enteric-coated nanochip tablet
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension solution, particle size 109nm, and then add pre-prepared poloxamer, povidone K29/32, and mannitol solution, freeze-dry (solid content of sample solution is about 20%), pre-freeze at -40°C for 5h, and main dry -5°C for 13h, vacuum degree 0.18mbar, secondary drying at 10-15°C for 16h, vacuum degree 0.18mbar.
  • the sample is pulverized and granulated with a pulverizing and granulating machine, mixed with silicon dioxide, microcrystalline cellulose, crospovidone and magnesium stearate, and compressed into tablets.
  • the weight of the tablet is about 1g (specification 100mg, according to water API meter).
  • Use the film coating premix (enteric-coated type) for enteric coating prepare a coating material with a solid content of 20%, and coat under stirring.
  • the inlet air temperature is 45°C
  • the air volume is 200m3/min
  • the tablet bed temperature is 31°C.
  • the rotating speed of the coating pan is 15-18 rpm
  • the spraying speed of the coating solution is 5g/min
  • the weight gain of the coating is 9.9%.
  • Embodiment 27 enteric-coated nanochip tablet
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension solution, particle size 109nm, then add pre-prepared poloxamer, povidone K29/32, and mannitol solution (mannitol accounts for 15%), and freeze-dry (the solid content of the sample solution is about 20%). Freezing at -40°C for 5h, main drying at -5°C for 13h, vacuum at 0.18mbar, secondary drying at 10-15°C for 16h, vacuum at 0.18mbar.
  • the sample was pulverized and granulated with a granulator, and mixed with silicon dioxide, mannitol (33.94g) and magnesium stearate, and pressed into tablets. .
  • film coating premix enteric-coated type
  • enteric coating prepare a coating material with a solid content of 20%, and coat under stirring.
  • the inlet air temperature is 48°C
  • the air volume is 200m3/min
  • the tablet bed temperature is 36°C.
  • the rotating speed of the coating pan is 15-20 rpm
  • the spraying speed of the coating solution is 5g/min
  • the coating weight gain is 10.0%.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension solution, particle size 109nm, then add pre-prepared poloxamer, povidone K29/32, and mannitol solution (mannitol accounts for 15%), and freeze-dry (the solid content of the sample solution is about 20%). Freezing at -40°C for 5h, main drying at -5°C for 13h, vacuum at 0.18mbar, secondary drying at 10-15°C for 16h, vacuum at 0.18mbar.
  • the sample was pulverized and granulated with a pulverizer and granulator, and silicon dioxide, microcrystalline cellulose, mannitol (15g), crospovidone and magnesium stearate (0.25g) were added, mixed, and dry granulated , passed through a 24-mesh sieve for granulation, added magnesium stearate (0.25g) and mixed, manually filled enteric-coated capsules, size 00, with a filling amount of 800mg (specification 100mg, calculated according to anhydrous API).
  • Dissolution medium purified water, 0.3SDS aqueous solution, 0.5% SDS aqueous solution, 0.8% SDS aqueous solution, 1.0% SDS aqueous solution, pH2.0 hydrochloric acid solution+1.0%SDS, pH4.5 acetate solution+1.0%SDS, pH6 .8 phosphate solution + 1.0% SDS, 3% Tween solution; 900ml;
  • Reference substance solution preparation Take about 25mg of the reference substance, weigh it accurately, place it in a 100mL volumetric flask, add about 2mL DMSO, dissolve it by ultrasonication, then dilute to the mark with the diluent of the corresponding medium, and shake well.
  • the API ordinary sheet prepared by Comparative Example 3 of the present invention is insoluble in pure water, and is insoluble in water containing different concentrations of sodium dodecyl sulfate (SDS) and at different pHs.
  • SDS sodium dodecyl sulfate
  • the dissolution rate of the tablets prepared by micronizing the API was not significantly improved.
  • Adding an appropriate amount of silicon dioxide and optimizing the formulation showed a greater improvement in the product dissolution rate, but at SDS concentration ⁇ 0.5 % dissolution rate in the medium is still low.
  • the dissolution rate of the nanocrystalline suspension preparation prepared by the embodiments of the present invention 8-9 is significantly higher than that of the common tablet, and it is 15min in the low SDS concentration (3%) medium. The dissolution rate reaches more than 85%. But when the SDS concentration was further reduced to 2%, the sample precipitated out in the late stage of dissolution. Using 3% Tween medium instead, the dissolution rates of the two nanocrystal suspensions in Example 8 and Example 9 were significantly improved, and the samples were stable without precipitation.
  • the dissolution rate of the nano-chip preparations prepared by Examples 10-15 of the present invention is significantly improved compared with the dissolution rate of ordinary tablets. Slower, 2h dissolution rate is similar.
  • the dissolution rate of the nanocrystalline capsule prepared by the embodiment of the present invention 24-25 is significantly improved compared with the dissolution rate of the common tablet, and compared with the nano-chip tablet, the dissolution is accelerated in 1h and before, and the dissolution rate is faster after 1h.
  • the post-dissolution rates were similar. Compared with the nanocrystal suspension, the dissolution rate is slower at 15 minutes and before, and the dissolution rate is similar after 15 minutes.
  • the product specification was changed from 200mg to 100mg, and the corresponding dissolution medium volume was changed from 900ml to 500ml.
  • the average particle diameter result of the suspension before and after drying the nanocrystalline powder that adds different stabilizers after table 7 grinding
  • the inventors investigated the influence of grinding speed, filling amount of grinding beads, sample amount and grinding time on the particle size of API.

Abstract

一种纳米晶制剂及其制备方法，所述纳米晶制剂包含ROCK2抑制剂和稳定剂。还涉及所述纳米晶制剂在用于预防、缓解和/或治疗所选疾病及医学病症，尤其是特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染等疾病中的用途。

Description

一种ROCK2抑制剂的纳米晶制剂及其制备方法 技术领域
本发明涉及医药领域，具体地，本发明涉及一种ROCK2抑制剂的纳米晶制剂及其制备方法。
背景技术
特发性肺纤维化(IPF)为进行性呼吸***疾病，以肺组织纤维化和肺功能的降低和丧失为主要临床特征，中位生存期2.5-3年。针对ROCK2靶点药物，美国正在开展针对IPF的临床2期研究(美国Kadmon公司)，初步结果证实了ROCK2抑制剂治疗IPF的安全性和有效性。
[6-[4-[[4-(1H-吡唑-4-基)苯基]氨基]嘧啶-2-基]-1-甲基-1H-吲哚-2-基](3,3-二氟氮杂环丁烷-1-基)甲酮是北京泰德制药制药股份有限公司完全自主研发的全新靶点和全新结构类型的一种新型高选择性ROCK2抑制剂，从患者依从性角度出发，选择口服制剂用于IPF的治疗。其靶点的高度选择性大大降低了安全性风险。我公司已在美国取得该化合物专利，并已在中国、欧盟、日本、韩国、印度、加拿大、澳大利亚等国家和地区申请化合物专利。
[6-[4-[[4-(1H-吡唑-4-基)苯基]氨基]嘧啶-2-基]-1-甲基-1H-吲哚-2-基](3,3-二氟氮杂环丁烷-1-基)甲酮为一种浅黄色至黄色固体粉末，溶解度很差，在水和pH1.0～pH6.8缓存盐溶液中均不溶。物理性质较差，易粘涩、静电、聚集。因此如何制备该化合物的制剂并提高产品溶出度成为本领域技术人员亟待解决的技术问题。
发明内容
本发明的一个目的在于提供一种ROCK2抑制剂的纳米晶制剂及其制备方法，以提高ROCK2抑制剂的溶出度。具体技术方案如下：
本发明首先提供了一种纳米晶制剂，其包含ROCK2抑制剂和稳定剂，所述ROCK2抑制剂为式(I)的化合物，
Figure PCTCN2022131872-appb-000001
其中，
环A为
Figure PCTCN2022131872-appb-000002
以上基团通过*或**标记的两个位置之一与嘧啶环连接，并且另一位置与羰基连接；
R 9和R 10在每次出现时各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5和-C 1-6亚烷基-O(P＝O)(OH) 2；
m在每次出现时各自独立地为0、1、2或3的整数；并且
n在每次出现时各自独立地为0、1或2的整数；
优选地，环A为
Figure PCTCN2022131872-appb-000003
以上基团通过*标记的位置与嘧啶环连接，并且通过**标记的位置与羰基连接，其中R 10选自H和C 1-6烷基，优选为H或甲基；
R选自H和C 1-6烷基；
R 1为
Figure PCTCN2022131872-appb-000004
R 2选自H和C 1-6烷基；
R 3、R 4、R 7和R 8在每次出现时各自独立地选自H、卤素、-NR 5R 6、-OH、C 1-6烷基和-OR 5；
上述亚烷基、烷基、烯基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自卤素、C 1-6烷基和-OR 5的取代基取代；
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药。
本发明还提供了一种纳米晶制剂的制备方法，其包含将ROCK2抑制剂和稳定剂研磨。
本发明的又一目的是所述纳米晶制剂在预防、缓解和/或治疗特发性肺纤维化的疾病的方法和用途。
本领域技术人员通过上下文说明以及通过实施例可明了本发明的其它目的。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1和图2为本发明对比例1-3的溶出曲线；
图3为本发明实施例8-9及对比例的溶出曲线；
图4～图6分别为本发明实施例8纳米混悬液、实施例10-15纳米晶片剂及对比例的溶出曲线；
图7为本发明实施例8纳米混悬液、实施例15纳米晶片剂、实施例24～25纳米晶胶囊及对比例的溶出曲线。
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。
术语“纳米晶”指纳米结晶，又指纳米混悬液，表示在稳定剂存在的条件下，将纳米尺度的药物粒子分散在水中形成的稳定胶体分散体系。
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。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，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***(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。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环***，包括螺环、稠合或桥连***(诸如8-氮杂螺[4.5]癸烷、3,9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子***的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-10(亚)芳基”和“C 6-10芳环”意指含有6至10个碳原子的芳族基团，诸 如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)***基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，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、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
术语“取代”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。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该 目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2022131872-appb-000005
实楔形
Figure PCTCN2022131872-appb-000006
或虚楔形
Figure PCTCN2022131872-appb-000007
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
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。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上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药学可接受盐的酸来形成。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、海苯酸盐、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药学可接受盐的碱来形成。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上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)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。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
术语“有效量”是指在施用条件下足以达到所需治疗效果的量，其导致病理学症状、疾病进展、与之相关的生理状况改善或诱导对前述疾病进行的抵抗力。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”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“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖 动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
具体实施方式
在一个实施方式中，本发明涉及一种纳米晶制剂，其包含ROCK2抑制剂和稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中所述的ROCK2抑制剂为式(I)的化合物，
Figure PCTCN2022131872-appb-000008
其中，
环A为
Figure PCTCN2022131872-appb-000009
以上基团通过*或**标记的两个位置之一与嘧啶环连接，并且另一位置与羰基连接；
R 9和R 10在每次出现时各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5和-C 1-6亚烷基-O(P＝O)(OH) 2；
m在每次出现时各自独立地为0、1、2或3的整数；并且
n在每次出现时各自独立地为0、1或2的整数；
优选地，环A为
Figure PCTCN2022131872-appb-000010
以上基团通过*标记的位置与嘧啶环连接，并且通过**标记的位置与羰基连接，其中R 10选自H和C 1-6烷基，优选为H或甲基；
R选自H和C 1-6烷基；
R 1为
Figure PCTCN2022131872-appb-000011
R 2选自H和C 1-6烷基；
R 3、R 4、R 7和R 8在每次出现时各自独立地选自H、卤素、-NR 5R 6、-OH、C 1-6烷基和-OR 5；
上述亚烷基、烷基、烯基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自卤素、C 1-6烷基和-OR 5的取代基取代；
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药。
在一个实施方式中，本发明涉及一种纳米晶制剂，所述ROCK2抑制剂为式(II)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药，
Figure PCTCN2022131872-appb-000012
其中，各基团如前述所定义。
在一个实施方式中，本发明涉及一种纳米晶制剂，所述ROCK2抑制剂为式(III)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药，
Figure PCTCN2022131872-appb-000013
其中，R 10为H或甲基，优选为甲基。
在一个实施方式中，本发明涉及一种纳米晶制剂，所述ROCK2抑制剂为式(IV)的化合物，或其药学上可接受的盐(尤其是盐酸盐)、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药，
Figure PCTCN2022131872-appb-000014
式(IV)化合物的化学名为：[6-[4-[[4-(1H-吡唑-4-基)苯基]氨基]嘧啶-2-基]-1-甲基-1H-吲哚-2-基](3,3-二氟氮杂环丁烷-1-基)甲酮。
在本发明中，式(IV)的化合物作为原料药可以采用已知的方法来制备，也可以通过商业途径获得，无论采用何种方式获得，对于所属领域技术人员来说都是容易实现的，因此本发明在此不进行赘述。
一般地，纳米晶制备过程中需要添加稳定剂，主要原因为：一方面，纳米微粉化可显著增加药物粒子比表面积，这也使得整个制剂制备体系的自由能上升，导致体系的不稳定性；另一方面，随着研磨过程中机械产能所引起的作用温度升高，新形成的纳米粒子会受到自由能变化的影响而重新发生聚集和重结晶现象。这些因素均可能使得本已减小的粒径重新回复到较大水平，使得溶解的表面积减小，从而影响体内生物利用度。稳定剂通过吸附在药物粒子表面以阻滞药物粒子的重聚集，从而增加有效表面积，显著提高纳米混悬液的稳定性。
在本发明中，稳定剂除可以提高药物的润湿性，稳定药物的粒径外，还可通过改善ROCK2抑制剂纳米晶固化干燥复溶后的粒径稳定性以提高溶出度。本领域技术人员可以根据本发明在此对于稳定剂的作用的描述来选择合适的稳定剂。包括但不限于聚山梨酯20，聚山梨酯40，聚山梨酯60，聚山梨酯65，聚山梨酯80，聚山梨酯85，聚维酮K29/32，聚氧乙烯脂肪酸酯，泊洛沙姆188，泊洛沙姆407，羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC 3cps)、聚乙烯吡咯烷酮(PVP K30)、泊洛沙姆(Pluronic F68和Pluronic F127)、十二烷基硫酸钠(SDS)、多库酯钠(DSS)、15-羟基硬脂酸聚乙二醇脂、聚氧乙烯蓖麻油、共聚维酮等。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，稳定剂选自聚山梨酯、聚维酮、羟丙基甲基纤维素、聚乙二醇、聚乙烯醇、聚氧乙烯蓖麻油、泊洛沙姆和十二烷基硫酸钠、乳糖、甘露醇中的一种或几种。
在一个实施方式中，本发明涉及一种纳米晶制剂，所述纳米晶制剂的粒径D 90为50-1500nm，优选为 50-1000nm，优选为50-500nm，优选为80-300nm，更优选为50nm、100nm、150nm、200nm、250nm、300nm、400nm、500nm、600nm、700nm、800nm、900nm或1000nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，所述ROCK2抑制剂的粒径范围优选D 905～300μm，优选10～100μm，更优选10～50μm。
在一个实施方式中，本发明涉及一种纳米晶制剂，基于所述纳米晶制剂的总重量，所述ROCK2抑制剂的重量百分数可以为1％-55％、4％-50％、1％-10％、10％-40％、10％-35％、20％-30％或30％-40％，还可以为1％、2％、3％、4％、4.5％、5％、6％、7％、8％、9％、9.5％、10％、11％、12％、13％、14％、15％、15％、16％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％或40％。
在一个实施方式中，本发明涉及一种纳米晶制剂，基于所述纳米晶制剂的总重量，所述稳定剂的重量百分数可以为0.1％-55％、0.1％-30％、0.5％-1％、1％-10％、10％-20％或20％-30％，还可以为1％、2％、2.5％、3％、4％、5％、6％、7％、8％、9％、9.5％、10％、11％、12％、13％、14％、15％、15％、16％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％或40％。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，ROCK2抑制剂和稳定剂的重量比可以为1:10至10:1、1:9至9:1、1:8至8:1、1:7至7:1、1:6至6:1、1:5至5:1、1:4至4:1、1:3至3:1、1:2至2:1、1:1；还可以为4:1至1:1或1:1至1:2；还可以为10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、5:4、5:3或5:2。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中还含有赋形剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中所述赋形剂选自填充剂；润湿剂；甜味剂或调味剂；表面活性剂；粘合剂；崩解剂；润滑剂；助流剂或抗粘附剂；释放改性剂；包衣剂；乳化剂；增溶剂；和香料中的一种或多种。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中赋形剂包含填充剂；填充剂可改善活性成分的物料性质，改善粘涩和静电特性，从而便于组合物后续的成型，例如压片，填充胶囊等，对于制备固体制剂有重要作用。填充剂也可调整制剂的溶出速度。在本发明的技术方案中，可以选择所属技术领域常用的填充剂，包括但不限于微晶纤维素、甘露醇、乳糖、淀粉、预胶化淀粉、糊精、二水合磷酸钙、无水磷酸氢钙中的一种或至少两种。在本发明的一些具体实施方式中，基于所述纳米晶制剂的总重量，填充剂的重量百分数可以为1％-80％；更为具体地，在一些实施方式中，填充剂的重量百分数可以为20％-70％、30％-60％或50-70％等，例如20％、25％、30％、35％、40％、45％、50％、55％、60％、65％或70％等。在本发明的一些具体实施例中，填充剂选自微晶纤维素、乳糖、甘露醇中的一种或多种，优选地，填充剂为甘露醇。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中赋形剂包含润滑剂，其有助于包括组分混合、压片等各种加工步骤；例如润滑剂可使压片时压力分布均匀，并使片剂的密度均匀；将片剂由模孔中推出所需之力减小。润滑剂可能存在的另一个作用是改善片剂的外观，使片剂表面光亮、平整。在本发明的技术方案中，可以选择所属技术领域常用的润滑剂，包括但不限于硬脂酸镁、滑石粉、微粉硅胶、硬脂富马酸钠、山嵛酸甘油酯和聚乙二醇中的一种或至少两种的组合，更优选为硬脂酸镁。在本发明的一些具体实施方式中，基于所述纳米晶制剂的总重量，所述润滑剂的重量百分数可以为0.1％至5％、0.1％-1.5％或0.5％-1％等，例如0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％或1.5％等。所述润滑剂选自硬脂酸镁、滑石粉、微粉硅胶、硬脂富马酸钠、山嵛酸甘 油酯和聚乙二醇。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，赋形剂包含崩解剂。在本发明的技术方案中，可以选择所属技术领域常用的崩解剂，包括但不限于交联羧甲基纤维素钠和交联聚维酮等中的一种或几种。在本发明的一些具体实施方式中，基于所述纳米晶制剂的总重量，所述崩解剂的重量百分数可以为0至20％，优选为0至10％，更优选为2至10％，例如3％、4％、5％、6％、7％、8％、9％或10％。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，赋形剂包含助流剂。在本发明的技术方案中，可以选择所属技术领域常用的助流剂，包括但不限于二氧化硅等。在本发明的一些具体实施方式中，基于所述纳米晶制剂的总重量，所述助流剂的重量百分数可以为0至20％，优选为0至15％，更优选为2至12％，例如2％、2.5％、3％、4％、5％、6％、7％、8％、9％、10％或11％。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂中还含有溶剂。在本发明的技术方案中，可以选择所属技术领域常用的溶剂，包括但不限于水等，优选纯净水。在本发明的一些具体实施方式中，基于所述纳米晶制剂的总重量，所述溶剂的重量百分数可以为0至99％，优选为80至99％，更优选为85％至95％，例如86％、87％、88％、89％、90％、91％、92％、93％、94％或95％。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂中还含有抑菌剂。在本发明的技术方案中，可以选择所属技术领域常用的抑菌剂，包括但不限于羟苯甲酯和羟苯丙酯等中的一种或几种。在本发明的一些具体实施方式中，基于所述纳米晶制剂的总重量，所述抑菌剂的重量百分数可以为0至5％，优选为0至1％，更优选为0.01％至0.5％，例如0.1％、0.2％、0.3％、0.4％或0.5％。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中所述纳米晶制剂选自混悬剂、片剂、胶囊剂、颗粒剂、散剂、锭剂和丸剂；优选为混悬剂、片剂或胶囊剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为混悬剂，包含：
-1-10％ROCK2抑制剂，优选为1％、2％、3％、4％、4.5％、5％、6％、7％、8％、9％或10％ROCK2抑制剂，更优选为4％、4.5％、5％ROCK2抑制剂；和
-1-10％稳定剂，优选为1％、1.5％、2％、2.5％、5％、9％、9.5％或10％稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、5.00g聚维酮K29/32和233.10g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、2.50g聚维酮K29/32和235.60g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、2.50g羟丙甲纤维素和235.60g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、5.00g羟丙甲纤维素和233.10g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为混悬剂，包含250.08g ROCK2抑制剂、17.40g聚山梨酯80、111.60g聚维酮K29/32、10.00g羟苯甲酯、1.10g羟苯丙酯和5189.82g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为混悬剂，包含55.19g ROCK2抑制剂、18.61g聚山梨酯80、99.25g聚氧乙烯蓖麻油、2.23g羟苯甲酯、0.25g羟苯丙酯和1065.09g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为片剂，包含：
-10-30％ROCK2抑制剂，优选为20-30％ROCK2抑制剂，优选为20％、22％、25％、28％或30％ROCK2抑制剂；
-1-20％稳定剂，优选为5-20％稳定剂，更优选为5％、8％、10％、13％、15％、18％或20％稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含11.70g ROCK2抑制剂、3.15g聚山梨酯80、5.26g乳糖、1.05g聚乙二醇6000、16.03g甘露醇、4.94g二氧化硅、2.47g十二烷基硫酸钠、2.96g微晶纤维素、2.96g交联羧甲基纤维素钠和0.32g硬脂酸镁，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含32.71g ROCK2抑制剂、14.81g聚山梨酯80、14.71g乳糖、2.94g聚乙二醇6000、43.63g甘露醇、16.00g二氧化硅、8.00g十二烷基硫酸钠、12.80g微晶纤维素、12.80g交联羧甲基纤维素钠和1.60g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含3.34g ROCK2抑制剂、0.89g聚山梨酯80、1.80g乳糖、0.30g聚乙二醇6000、0.75g二氧化硅、0.75g十二烷基硫酸钠、5.82g微晶纤维素、1.20g交联羧甲基纤维素钠和0.15g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含3.34g ROCK2抑制剂、0.89g聚山梨酯80、1.80g乳糖、0.30g聚乙二醇6000、0.75g二氧化硅、0.45g十二烷基硫酸钠、4.50g微晶纤维素、1.62g预胶化淀粉、1.20g交联羧甲基纤维素钠和0.15g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含11.14g ROCK2抑制剂、2.97g聚山梨酯80、6.01g乳糖、1.00g聚乙二醇6000、1.00g二氧化硅、27.38g喷雾干燥甘露醇和0.50g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含111.20g ROCK2抑制剂、30.04g聚山梨酯80、59.99g乳糖、10.00g聚乙二醇6000、10.00g二氧化硅、273.78g喷雾干燥甘露醇和5.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为片剂，包含：
-10-30％ROCK2抑制剂，优选为20-30％ROCK2抑制剂，更优选为20％、22％、25％、28％或30％ROCK2抑制剂；
-10-30％稳定剂，优选为20-30％稳定剂，更优选为20％、22％、25％、28％或30％稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.22g ROCK2抑制剂、20.00g聚山梨酯80、54.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑 制剂、10.00g聚山梨酯80、20.00g聚维酮K29/32、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g聚乙二醇6000、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g聚乙烯醇、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、16.00g聚维酮K29/32、4.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、4.00g聚维酮K29/32、16.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、10.00g聚维酮K29/32、10.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为胶囊剂，包含：
-10-50％ROCK2抑制剂，优选为20-40％ROCK2抑制剂，更优选为20％、25％、30％、35％或40％ROCK2抑制剂；
-10-40％稳定剂，优选为20-30％稳定剂，更优选为20％、22％、25％、28％或30％稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为胶囊剂，包含22.20g ROCK2抑制剂、6.00g聚山梨酯80、8.00g聚维酮K29/32、4.00g泊洛沙姆和20.00g甘露醇，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶为胶囊剂，包含4.45g ROCK2抑制剂、1.20g聚山梨酯80、1.20g聚维酮K32/29、0.80g泊洛沙姆188和6.80g甘露醇，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶制剂，选自肠溶包衣片剂或肠溶胶囊。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，其中，肠溶包衣材料选自虫胶、聚乙烯醇乙酸苯二甲酸酯(PVAP)、甲基丙烯酸共聚物、纤维素及其衍生物(醋酸纤维素酞酸酯(CAP)、醋酸纤维素苯三酸酯(CAT)、羟丙基纤维素酞酸酯(HPMCP))、丙烯酸树脂类(EuS100、EuL100)中的一种或多种。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶胶囊，其中，肠溶胶囊选自明胶肠溶胶囊或羟丙甲纤维素肠溶胶囊，囊材组成选自虫胶、聚乙烯醇乙酸苯二甲酸酯(PVAP)、甲基丙烯酸共聚物、纤维素及其衍生物(醋酸纤维素酞酸酯(CAP)、醋酸纤维素苯三酸酯(CAT)、羟丙基纤维素酞酸酯(HPMCP))、丙烯酸树脂类(EuS100、EuL100)中的一种或多种。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，包含：
-1-20％ROCK2抑制剂，优选5-15％ROCK2抑制剂，更优选为5％、6％、7％、8％、9％、10％、11％、12％、13％、14％或15％ROCK2抑制剂；和
-1-90％稳定剂，优选10-40％稳定剂，更优选为15-25％稳定剂，例如，15％、16％、17％、18％、19％、20％、21％、22％、23％、24％或25％稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，包含5.56g ROCK2抑制剂、1.50g聚山梨酯80、1.00g泊洛沙姆、1.50g聚维酮K29/32、5.00g甘露醇、1.00g二氧化硅、4.00g交联聚维酮、29.94g微晶纤维素、0.50g硬脂酸镁和5g薄膜包衣预混剂(肠溶型)，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，包含5.56g ROCK2抑制剂、1.50g聚山梨酯80、1.00g泊洛沙姆、1.50g聚维酮K29/32、38.94g甘露醇、1.00g二氧化硅、0.50g硬脂酸镁和5g薄膜包衣预混剂(肠溶型)，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶胶囊，包含：
-5-30％ROCK2抑制剂，优选10-20％ROCK2抑制剂，更优选为10％、11％、12％、13％、14％、15％、16％、17％、18％、19％或20％ROCK2抑制剂；和
-10-50％稳定剂，优选20-40％稳定剂，更优选为30-40％稳定剂，例如，30％、31％、32％、33％、34％、35％、36％、37％、38％、39％或40％稳定剂。
在一个实施方式中，本发明涉及一种纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶胶囊，包含11.1g ROCK2抑制剂、3.0g聚山梨酯80、2.0g泊洛沙姆、3.0g聚维酮K29/32、20.0g甘露醇、2.00g二氧化硅、8.0g交联聚维酮、29.9g微晶纤维素、1.0g硬脂酸镁和肠溶胶囊，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
在本发明的一些具体实施方式中，ROCK2抑制剂除了包含式(I)、(II)、(III)或式(IV)化合物、或其药学上可接受的盐、或水合物以外，还可以任选地包括至少一种与所述化合物具有协同治疗作用的其它化合物。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其包含将ROCK2抑制剂和稳定剂研磨。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨时ROCK2抑制剂和稳定剂的重量比为1:15至15:1、1:14至14:1、1:13至13:1、1:12至12:1、1:11至11:1、1:10至10:1、1:9至9:1、1:8至8:1、1:7至7:1、1:6至6:1、1:5至5:1、1:4至4:1、1:3至3:1、1:2至2:1、1:1；优选地，研磨时ROCK2抑制剂和稳定剂的重量比为15:1至2:1，更优选为15:1、14:1、13:1、12：1、11:1、10:1、10:3、9:1、8:1、7:1、 6:1、5:1、4:1、3:1或2:1。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨介质选自瓷球、玻璃球、氧化锆珠、钢球或冰珠；优选地，所述研磨介质为氧化锆珠。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨介质的粒径范围为0.1-1mm，优选为0.1-0.5mm，更优选为0.2mm。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨时间为0.1-6h，优选为0.5-6h，优选为4-6h，更优选为10min、20min、30min、40min、1h、1.5h、2h、2.5h、3h、3.5h、4h、4.5h、5h、5.5h或6h。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨速度为1000～6000rpm，优选为1500rpm～4500rpm，更优选为1500rpm、2000rpm、2500rpm、3000rpm、3500rpm、4000rpm、4500rpm、5000rpm、5500rpm或6000rpm。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨珠的填充量为50～95％，优选70％～90％，更优选为70％、80％或90％。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，在将ROCK2抑制剂和稳定剂研磨前，还包括预研磨步骤。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，所述预研磨速度为3000～6000rpm，优选为3000rpm、3500rpm、4000rpm、4500rpm、5000rpm、5500rpm或6000rpm，更优选为4000rpm；预研磨时间为1-30min，优选为2-20min，优选为3min、4min、5min、6min、8min、10min、12min、15min、18min或20min，更优选为5min。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨后可选地加入稳定剂和/或赋形剂。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨后加入的稳定剂选自聚山梨酯、聚维酮、聚氧乙烯脂肪酸酯、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、泊洛沙姆、十二烷硫酸钠、多库酯钠、15-羟基硬脂酸聚乙二醇脂、聚氧乙烯蓖麻油、共聚维酮、乳糖、甘露醇中的一种或多种。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨后加入的稳定剂选自聚维酮K29/32、泊洛沙姆188、聚乙烯醇、乳糖和甘露醇中的一种或多种。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其中，研磨后加入的稳定剂为聚维酮K29/32和泊洛沙姆188的混合物，二者的混合比例为1:10至10:1、优选为1:9至9:1、优选为1:8至8:1、优选为1:7至7:1、优选为1:6至6:1、优选为1:5至5:1、优选为1:4至4:1、优选为1:3至3:1、优选为1:2至2:1、优选为1:1；更优选地，二者的混合比例为1:4、4:1或1:1。
在一个实施方式中，本发明涉及上述纳米晶制剂的制备方法，其包括：
将活性成分、部分稳定剂和纯化水采用纳米研磨机进行研磨，研磨后得到纳米混悬液，再添加稳定剂和或填充剂得到纳米晶混悬液。或者在研磨得到纳米混悬液后通过喷雾干燥或者冷冻干燥固化得到固体纳米晶混合物，再添加填充剂混合，加入润滑剂，然后成型处理。在具体实施过程中，成型处理可以包括制粒，任选地整粒以及压片或灌装胶囊等工序。本发明中关键工艺为纳米研磨工艺，当活性成分平均粒径达到50nm～1000nm时，进一步优选为80nm～500nm，更优选为80nm～300nm时，研磨结束。需要说明的是，混合以及其后的成型工序，均是所属技术领域的常规工序、操作，本发明在此不进行具体限定。
发明人在制备ROCK2抑制剂纳米晶的过程中，考察了研磨转速、研磨珠填充量、样品量和研磨时间对ROCK2抑制剂粒径的影响。结果表明ROCK2抑制剂粒径随着研磨时间的增加逐渐减小，但减小速度逐渐变慢；随研磨转速提高，研磨效率提高；相同转速下，研磨珠填充量提高，研磨效率也随之提高。样品量对研磨效率影响不显著。研磨参数和粒径研究结果见表8。基于此，在本发明的一些具体实施方式中，研磨工艺中，采用0.2mm氧化锆研磨珠，研磨珠填充量为50％～95％，优选70％～90％。研磨转速1000rpm～4500rpm，优选1500rpm～3500rpm。研磨时间为2h～6h，优选4h～5h。
在本发明的一些具体实施方式中，当纳米晶制剂组合物中含有润滑剂时，需将研磨后的纳米混悬剂通过喷雾干燥或者冷冻干燥方式除去水分，再直接或粉碎后同任选地填充剂混合，然后
A：再与全部的润滑剂混合，然后进行成型工艺；
或者，
B：先与部分的润滑剂混合，再经过制粒、任选地整粒后，再加入剩余部分的润滑剂，再进行其它的成型工序，例如压片、灌装胶囊。
在一个实施方式中，本发明涉及预防、缓解和/或治疗特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染的方法，其包括向受试者给予治疗有效量的所述纳米晶制剂或者由所述方法制备得到的纳米晶制剂；优选地，所述方法为预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎的方法；优选地，所述脂肪性肝病为酒精性脂肪性肝病(ALFD)或非酒精性脂肪性肝病(NALFD)，所述脂肪性肝炎为酒精性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)，所述的造血干细胞移植是同种异体造血干细胞移植，所述的移植物抗宿主病为急性移植物抗宿主病或者慢性移植物抗宿主病，所述病毒感染为冠状病毒感染；优选地，所述冠状病毒选自SARA-CoV、SARA-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43和HCoV-HKU1；优选地，所述冠状病毒引起的疾病为中东呼吸综合征、严重急性呼吸***综合征或者COVID-19；优选地，所述冠状病毒引起的是严重急性呼吸综合征冠状病毒2(SARA-CoV-2或者2019-nCoV)，其导致的疾病为COVID-19。
在一个实施方式中，本发明涉及将所述纳米晶制剂或由所述方法制备得到的纳米晶制剂用于预防、缓解和/或治疗特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染；优选地，所述纳米晶制剂用于预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎；优选地，所述脂肪性肝病为酒精性脂肪性肝病(ALFD)或非酒精性脂肪性肝病(NALFD)，所述脂肪性肝炎为酒精性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)，所述的造血干细胞移植是同种异体造血干细胞移植，所述的移植物抗宿主病为急性移植物抗宿主病或者慢性移植物抗宿主病，所述病毒感染为冠状病毒感染；优选地，所述冠状病毒选自SARA-CoV、SARA-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43和HCoV-HKU1；优选地，所述冠状病毒引起的疾病为中东呼吸综合征、严重急性呼吸***综合征或者COVID-19；优选地，所述冠状病毒引起的是严重急性呼吸综合征冠状病毒2(SARA-CoV-2或者2019-nCoV)，其导致的疾病为COVID-19。
在一个实施方式中，本发明涉及所述纳米晶制剂或由所述方法制备得到的纳米晶制剂在制备用于预防、缓解和/或治疗特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染的药物中的用途；优选地，所述用途为制备用于预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎的药物中的用途；优选地，所述脂肪性肝病为酒精性脂肪性肝病(ALFD)或非酒精性脂肪性肝病(NALFD)，所述脂肪性肝炎为酒精性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)，所述的造血干细胞移植是同种异体造血干细胞移植，所述的移植物抗宿主病为急性移植物抗宿主病或者慢 性移植物抗宿主病，所述病毒感染为冠状病毒感染；优选地，所述冠状病毒选自SARA-CoV、SARA-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43和HCoV-HKU1；优选地，所述冠状病毒引起的疾病为中东呼吸综合征、严重急性呼吸***综合征或者COVID-19；优选地，所述冠状病毒引起的是严重急性呼吸综合征冠状病毒2(SARA-CoV-2或者2019-nCoV)，其导致的疾病为COVID-19。
为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合具体实施例，对本发明作进一步的说明。下述实施例中，除非另有说明，所述的试验方法具体条件通常按照常规条件或制造厂商建议的条件实施；所述原料、试剂均通过市售获得或者使用***息制备。
实施例
以下对比例、实施例以及测试中采用的活性成分(API)均为前述式(IV)化合物。
I.对比例的制备
对比例1
处方：
Figure PCTCN2022131872-appb-000015
制备方法：称取处方量API盐酸盐、乳糖、微晶纤维素和交联羧甲基纤维素钠混合，干法制粒，整粒后加入硬脂酸镁混合，压片。
对比例2
处方：
Figure PCTCN2022131872-appb-000016
制备方法：先将API盐酸盐进行微粉化处理，得到D 90约2μm粒径的API盐酸盐，称取处方量微粉化的API盐酸盐、乳糖、微晶纤维素和交联羧甲基纤维素钠混合，干法制粒，整粒后加入硬脂酸镁混合，压片。
对比例3
处方：
Figure PCTCN2022131872-appb-000017
Figure PCTCN2022131872-appb-000018
制备方法：称取处方量API盐酸盐、二氧化硅、预胶化淀粉1500、微晶纤维素和处方一半的交联聚维酮、硬脂酸镁混合，干法制粒，整粒后加入另一半交联聚维酮、硬脂酸镁混合，压片。
II.纳米晶制剂(混悬液)的制备
实施例1
处方：
Figure PCTCN2022131872-appb-000019
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量70％)，研磨转速1500rpm，时间10min，得到平均粒径1868nm的纳米混悬液，再加入聚维酮K29/32的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径1875nm。
实施例2
在实施例1处方上，研磨转速1500rpm，时间20min，得到平均粒径1006nm的纳米混悬液，再加入聚维酮K29/32的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径1080nm。
实施例3
在实施例1处方上，研磨转速1500rpm，时间40min，得到平均粒径512nm的纳米混悬液，再加入聚维酮K29/32的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径540nm。
实施例4
处方：
Figure PCTCN2022131872-appb-000020
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量70％)，研磨转速1500rpm，时间6h，得到平均粒径268nm的纳米混悬液，再加入聚维酮K29/32的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径300nm。
实施例5
处方：
Figure PCTCN2022131872-appb-000021
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量70％)，研磨转速1500rpm，时间6h，得到平均粒径268nm的纳米混悬液，再加入聚维酮K29/32的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径302nm。
实施例6
处方：
Figure PCTCN2022131872-appb-000022
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量70％)，研磨转速1500rpm，时间6h，得到平均粒径268nm的纳米混悬液，再加入羟丙甲纤维素的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径336nm。
实施例7
处方：
Figure PCTCN2022131872-appb-000023
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量70％)，研磨转速1500rpm，时间6h，得到平均粒径268nm的纳米混悬液，再加入羟丙甲纤维素的溶液，稀释至250g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径442nm。
实施例8
处方：
Figure PCTCN2022131872-appb-000024
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量70％)，研磨转速1500rpm，时间4h，得到平均粒径281nm的纳米混悬液，再加入事先配好的羟苯甲酯、羟苯丙酯和聚维酮K29/32的溶液，稀释至5580g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径283nm。
实施例9
处方：
Figure PCTCN2022131872-appb-000025
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间4h，得到平均粒径100nm的纳米混悬液，再加入事先配好的羟苯甲酯、羟苯丙酯和聚氧乙烯蓖麻油的溶液，稀释至1240.62g，得到终产品浓度40mg/mL(以游离碱计)，产品粒径106nm。
III.纳米晶制剂(片剂)的制备
实施例10
处方：
Figure PCTCN2022131872-appb-000026
Figure PCTCN2022131872-appb-000027
制备方法：称取处方量API盐酸盐、部分聚山梨酯80(API游离碱：聚山梨酯80＝1:0.1)和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间4h，得到平均粒径为105nm的纳米混悬液，再加入事先配好的聚山梨酯80、聚乙二醇6000和乳糖溶液(API游离碱：聚山梨酯80：乳糖：聚乙二醇6000＝1:0.3:0.5:0.1)，进行喷雾干燥，进风温度120℃，喷速40rpm，得到喷雾干燥粉末。取适量上述喷干粉末，向其中加入甘露醇、二氧化硅、十二烷基硫酸钠、微晶纤维素、交联羧甲基纤维素钠和硬脂酸镁混合，直接压片，片重约1g(规格200mg，按无水API计)。
实施例11
处方：
Figure PCTCN2022131872-appb-000028
制备方法：称取处方量API盐酸盐、部分聚山梨酯80(API游离碱：聚山梨酯80＝1:0.1)和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间4h，得到平均粒径为105nm的纳米混悬液，再加入事先配好的聚山梨酯80、聚乙二醇6000、部分甘露醇和乳糖溶液(API游离碱：聚山梨酯80：乳糖：甘露醇：聚乙二醇6000＝1:0.3:0.5:0.3:0.1)，进行喷雾干燥，进风温度120℃，喷速40rpm，得到喷雾干燥粉末。取适量上述喷干粉末加入二氧化硅混合过35目筛，再加入十二烷基硫酸钠、甘露醇、微晶纤维素、交联羧甲基纤维素钠(内加)混合，用10％十二烷基硫酸钠的水溶液进行湿法制粒，干燥整粒后再和交联羧甲基纤维素钠(外加)、硬脂富马酸钠混合，压片，片重约1g(规格200mg，按无水API计)。
实施例12
处方：
Figure PCTCN2022131872-appb-000029
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速4500rpm，时间6h，得到纳米晶混悬液，粒径58nm，再加入事先配好的聚乙二醇6000和乳糖溶液，进行喷雾干燥，进风温度120℃，喷速40rpm，得到喷雾干燥粉末。取适量上述喷干粉末加入二氧化硅混合过35目筛，再加入微晶纤维素、交联羧甲基纤维素钠(内加)、硬脂富马酸钠(内加)混合，干法制粒，24目筛整粒后加入交联羧甲基纤维素钠(外加)、硬脂富马酸钠(外加)混合，压片，片重约1g(规格200mg，按无水API计)。
实施例13
处方：
Figure PCTCN2022131872-appb-000030
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速4500rpm，时间6h，得到纳米晶混悬液，粒径58nm，再加入事先配好的聚乙二醇6000和乳糖溶液，进行喷雾干燥，进风温度120℃，喷速40rpm，得到喷雾干燥粉末。取适量上述喷干粉末加入二氧化硅混合过35目筛，再加入微晶纤维素、预胶化淀粉、交联羧甲基纤维素钠(内加)、硬脂富马酸钠(内加)混合，干法制粒，24目筛整粒后加入交联羧甲基纤维素钠(外加)、硬脂富马酸钠(外加)混合，压片，片重约1g(规格200mg，按无水API计)。
实施例14
处方：
Figure PCTCN2022131872-appb-000031
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间6h，得到纳米晶混悬液，粒径89nm，再加入事先配好的聚乙二醇6000和乳糖溶液，进行喷雾干燥，进风温度120℃，喷速40rpm，得到喷雾干燥粉末。取适量上述喷干粉末加入二氧化硅、喷雾干燥甘露醇和硬脂富马酸钠混合，压片，片重约1g(规格200mg，按无水API计)。
实施例15
处方：
Figure PCTCN2022131872-appb-000032
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间4h，得到纳米晶混悬液，粒径128nm，再加入事先配好的聚乙二醇6000和乳糖溶液，进行冷冻干燥(样品溶液固含量约20％)，预冻-40℃ 5h，主干燥-5℃ 13h，真空度0.18mbar，二次干燥10～15℃ 16h，真空度0.18mbar。冻干结束后样品用粉碎整粒机进行粉碎整粒，加入二氧化硅、喷雾干燥甘露醇和硬脂富马酸钠(内加)混合，干法制粒，外加硬脂富马酸钠混合，压片，片重约1g(规格200mg，按无水API计)。
实施例16
处方：
Figure PCTCN2022131872-appb-000033
Figure PCTCN2022131872-appb-000034
制备方法：称取处方量API盐酸盐、部分聚山梨酯80和部分纯化水(API游离碱：聚山梨酯80＝1:0.3)，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间4.5h，得到纳米晶混悬液，粒径102nm，再加入事先配好的聚山梨酯80和甘露醇溶液，进行冷冻干燥(样品溶液固含量约10％)，预冻-40℃ 5h，主干燥-5℃ 13h，真空度0.18mbar，二次干燥10～15℃℃ 16h，真空度0.18mbar。冻干结束后样品用粉碎整粒机进行粉碎整粒，加入二氧化硅、喷雾干燥甘露醇和硬脂富马酸钠混合，压片，片重约1g(规格200mg，按无水API计)。
实施例17-23
参照实施例16的制备方法，研磨处方均为API游离碱：聚山梨酯80＝1:0.3，在研磨后向研磨液中加入以下表中的稳定剂分散均匀进行冷冻干燥，干燥后按以下表中的处方加入填充剂和润滑剂等，完成实施例17-23，各实施例研磨后粒径记载于表7。
Figure PCTCN2022131872-appb-000035
IV.纳米晶制剂(胶囊剂)的制备
实施例24
处方：
Figure PCTCN2022131872-appb-000036
Figure PCTCN2022131872-appb-000037
制备方法：称取处方量API盐酸盐、聚山梨酯80和纯化水(API游离碱:聚山梨酯80＝1:0.3)，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间5h，得到纳米晶混悬液，平均粒径93nm，再加入事先配好的聚维酮K29/32、泊洛沙姆188和甘露醇溶液，使得终样品中API游离碱：聚山梨酯80：聚维酮K29/32：泊洛沙姆188：甘露醇＝1:0.3:0.4:0.2:1，进行冷冻干燥(样品溶液固含量约10％)，预冻-40℃ 5h，主干燥-5℃ 13h，真空度0.18mbar，二次干燥10～15℃ 16h，真空度0.18mbar。冻干结束后样品过40目筛，称取301.2mg冻干粉末直接灌装胶囊，规格100mg。
实施例25
处方：
Figure PCTCN2022131872-appb-000038
制备方法：称取处方量API盐酸盐、聚山梨酯80和纯化水(API游离碱：聚山梨酯80＝1:0.3)，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间5h，得到纳米晶混悬液，平均粒径103nm，再加入事先配好的聚维酮K29/32、泊洛沙姆188和甘露醇溶液，使得终样品中API游离碱：聚山梨酯80：聚维酮K29/32：泊洛沙姆188：甘露醇＝1:0.3:0.3:0.2:1.7，进行冷冻干燥(样品溶液固含量约10％)，预冻-40℃ 5h，主干燥-5℃ 13h，真空度0.18mbar，二次干燥10～15℃ 16h，真空度0.18mbar。冻干结束后样品过40目筛，称取361mg冻干粉末直接灌装胶囊，规格100mg。
V.肠溶纳米晶制剂(片剂或胶囊剂)的制备
实施例26肠溶纳米晶片剂
处方：
Figure PCTCN2022131872-appb-000039
Figure PCTCN2022131872-appb-000040
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间6h，得到纳米晶混悬液，粒径109nm，再加入事先配好的泊洛沙姆和聚维酮K29/32、甘露醇溶液，进行冷冻干燥(样品溶液固含量约20％)，预冻-40℃5h，主干燥-5℃13h，真空度0.18mbar，二次干燥10～15℃16h，真空度0.18mbar。冻干结束后样品用粉碎整粒机进行粉碎整粒，加入二氧化硅、微晶纤维素、交联聚维酮和硬脂酸镁混合，压片，片重约1g(规格100mg，按无水API计)。使用薄膜包衣预混剂(肠溶型)进行肠溶包衣，配制固含量20％的包衣材料，搅拌下进行包衣，进风温度45℃，风量200m3/min，片床温度31℃，包衣锅转速15～18转/min，包衣液喷速5g/min，包衣增重9.9％。
实施例27肠溶纳米晶片剂
处方：
Figure PCTCN2022131872-appb-000041
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间6h，得到纳米晶混悬液，粒径109nm，再加入事先配好的泊洛沙姆和聚维酮K29/32、甘露醇溶液(甘露醇占比15％)，进行冷冻干燥(样品溶液固含量约20％)，预冻-40℃5h，主干燥-5℃13h，真空度0.18mbar，二次干燥10～15℃16h，真空度0.18mbar。冻干结束后样品用粉碎整粒机进行粉碎整粒，加入二氧化硅、甘露醇(33.94g)和硬脂酸镁混合，压片，片重约1g(规格100mg，按无水API计)。使用薄膜包衣预混剂(肠溶型)进行肠溶包衣，配制固含量20％的包衣材料，搅拌下进行包衣，进风温度48℃，风量200m3/min，片床温度36℃，包衣锅转速15～20转/min，包衣液喷速5g/min，包衣增重10.0％。
实施例28肠溶纳米晶胶囊
处方：
Figure PCTCN2022131872-appb-000042
Figure PCTCN2022131872-appb-000043
制备方法：称取处方量API盐酸盐、聚山梨酯80和部分纯化水，纳米研磨机进行研磨(0.2mm研磨珠，填充量90％)，研磨转速3000rpm，时间6h，得到纳米晶混悬液，粒径109nm，再加入事先配好的泊洛沙姆和聚维酮K29/32、甘露醇溶液(甘露醇占比15％)，进行冷冻干燥(样品溶液固含量约20％)，预冻-40℃5h，主干燥-5℃13h，真空度0.18mbar，二次干燥10～15℃16h，真空度0.18mbar。冻干结束后样品用粉碎整粒机进行粉碎整粒，加入二氧化硅、微晶纤维素、甘露醇(15g)、交联聚维酮和硬脂酸镁(0.25g)混合，干法制粒，过24目筛整粒，加入硬脂酸镁(0.25g)混合，手工填充肠溶胶囊，00号，填充量800mg(规格100mg，按无水API计)。
药物溶出测试
测试一
对比例1～3的片剂溶出测试
1.溶出方法：
1)方法：溶出度测定法(中国药典2020年版第四部通则“0931溶出度与释放度测定法”第二法(桨法))；
2)溶出介质：纯化水，0.3SDS水溶液，0.5％SDS水溶液，0.8％SDS水溶液，1.0％SDS水溶液，pH2.0盐酸溶液+1.0％SDS，pH4.5醋酸盐溶液+1.0％SDS，pH6.8磷酸盐溶液+1.0％SDS，3％吐温溶液；900ml；
3)转速：75转/分钟；
4)取样时间：5min、15min、30min、45min、60min、90min、120min、180min；
5)检测方法：高效液相色谱法，检测波长：254nm；
6)供试品溶液配制：于各时间点取溶液5ml，滤过。
对照品溶液配制：取对照品约25mg，精密称定，置于100mL容量瓶中，加入约2mL DMSO，超声使其溶解，然后用相应介质的稀释液稀释至刻度，摇匀。
2.仪器型号：
名称 厂家/型号 仪器编号
智能溶出仪 瑞士SOTAX AT Xtend Ⅱ050-808
智能溶出仪 瑞士SOTAX AT Xtend Ⅱ050-809
3.溶出结果
各介质中对比例1～3的溶出结果，见表1及图1～图2：
表1对比例1～3的溶出结果
Figure PCTCN2022131872-appb-000044
注：表中的溶出结果均以百分数计。“ND”表示未检出。
从表1及图1～图2中可以看出，本发明对比例3制备出的API普通片，在纯水中不溶，在含不同浓度十二烷基硫酸钠(SDS)的水和不同pH值介质中溶出度有显著差异。随SDS比例增加，溶出度增加，在pH较低时药物聚集较为严重，溶出度较低。比较对比例1～3，将API微粉化后制备的片剂溶出度改善不明显，添加适量二氧化硅并优化处方(对比例3)，产品溶出度有较大改善，但在SDS浓度≤0.5％的介质中溶出度依然较低。
测试二
实施例8和9纳米晶混悬液的溶出测试
各介质中溶出结果见表2及图3：
表2实施例8和9纳米晶混悬液的溶出结果
Figure PCTCN2022131872-appb-000045
注：表中的溶出结果均以百分数计。
从表2及图3中可以看出，本发明实施例8-9制备出的纳米晶混悬液制剂溶出度显著较普通片剂溶出度高，且在低SDS浓度(3％)介质中15min溶出度达到85％以上。但当SDS浓度进一步降低至2％时，溶出度后期样品析出。换用3％吐温介质，实施例8和实施例9两种纳米晶混悬液溶出度显著提高，且样品稳定无析出。
测试三
实施例10-15纳米晶片的溶出测试
各介质中溶出结果，见表3及图4～图6：
表3实施例10-15纳米晶片溶出结果
Figure PCTCN2022131872-appb-000046
注：表中的溶出结果均以百分数计。
从表3及图4～图6中可以看出，本发明实施例10-15制备出的纳米晶片剂溶出度较普通片剂溶出度显著提高，同纳米晶混悬液相比，前期溶出度较慢，2h溶出度相近。
测试四
实施例24-25纳米晶胶囊的溶出测试
各介质中溶出结果，见表4及图7：
表4实施例24-25纳米晶胶囊的溶出结果
时间 介质 5min 15min 30min 60min 90min 120min
对比例3 3％吐温 1.1 2.1 3.8 6.1 8.4 8.5
实施例8 3％吐温 94.9 95.2 96.3 99.1 100.1 101.0
实施例15 3％吐温 11.9 51.2 83.0 91.9 94.1 94.9
实施例24 3％吐温 61.1 95.6 96.3 96.2 96.4 96.6
实施例25 3％吐温 50.7 90.1 94.8 93.8 94.5 95.5
从表4及图7中可以看出，本发明实施例24-25制备出的纳米晶胶囊剂溶出度较普通片剂溶出度显著 提高，同纳米晶片剂相比，1h及以前溶出加快，1h后溶出度相近。同纳米晶混悬液相比，15min及以前溶出度较慢，15min后溶出度相近。
测试五
实施例26-28纳米晶肠溶制剂的溶出测试
在该测试中，相比于其他实施例和对比例，产品规格由200mg变为100mg，相应溶出介质体积由900ml变为500ml。
各介质中溶出结果，见表5：
表5实施例24-25纳米晶胶囊的溶出结果
Figure PCTCN2022131872-appb-000047
粒径稳定性测试
发明人在制备纳米晶混悬剂的过程中，考察了不同稳定剂对产品粒径稳定性的影响；具体试验结果详见表6和表7。
表6纳米晶混悬液在不同稳定剂中的粒径分布
Figure PCTCN2022131872-appb-000048
表7研磨后加入不同稳定剂的纳米晶粉末干燥前后混悬液的平均粒径结果
Figure PCTCN2022131872-appb-000049
Figure PCTCN2022131872-appb-000050
注：“--”为未检测。
发明人在制备纳米晶的过程中，考察了研磨转速、研磨珠填充量、样品量和研磨时间对API粒径的影响。
Figure PCTCN2022131872-appb-000051

Claims (68)

  1. 一种纳米晶制剂，其包含ROCK2抑制剂和稳定剂，所述ROCK2抑制剂为式(I)的化合物，
    Figure PCTCN2022131872-appb-100001
    其中，
    环A为
    Figure PCTCN2022131872-appb-100002
    以上基团通过*或**标记的两个位置之一与嘧啶环连接，并且另一位置与羰基连接；
    R 9和R 10在每次出现时各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5和-C 1-6亚烷基-O(P＝O)(OH) 2；
    m在每次出现时各自独立地为0、1、2或3的整数；并且
    n在每次出现时各自独立地为0、1或2的整数；
    优选地，环A为
    Figure PCTCN2022131872-appb-100003
    以上基团通过*标记的位置与嘧啶环连接，并且通过**标记的位置与羰基连接，其中R 10选自H和C 1-6烷基，优选为H或甲基；
    R选自H和C 1-6烷基；
    R 1为
    Figure PCTCN2022131872-appb-100004
    R 2选自H和C 1-6烷基；
    R 3、R 4、R 7和R 8在每次出现时各自独立地选自H、卤素、-NR 5R 6、-OH、C 1-6烷基和-OR 5；
    上述亚烷基、烷基、烯基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自卤素、C 1-6烷基和-OR 5的取代基取代；
    R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
    或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药。
  2. 权利要求1的纳米晶制剂，其中，所述ROCK2抑制剂为式(II)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药，
    Figure PCTCN2022131872-appb-100005
    其中，各基团如权利要求1所定义。
  3. 权利要求1-2中任意一项的纳米晶制剂，其中，所述ROCK2抑制剂为式(III)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药，
    Figure PCTCN2022131872-appb-100006
    其中，R 10为H或甲基，优选为甲基。
  4. 权利要求1-3中任意一项的纳米晶制剂，其中，所述ROCK2抑制剂为式(IV)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记物、代谢物或前药，
    Figure PCTCN2022131872-appb-100007
  5. 权利要求1-4中任意一项的纳米晶制剂，其中，所述稳定剂选自聚山梨酯、聚维酮、聚氧乙烯脂肪酸酯、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、泊洛沙姆、十二烷基硫酸钠、多库酯钠、15-羟基硬脂酸聚乙二醇脂、聚氧乙烯蓖麻油、共聚维酮、乳糖、甘露醇中的一种或多种；优选地，稳定剂选自聚山梨酯、聚维酮、羟丙基甲基纤维素、聚乙二醇6000、聚乙烯醇、聚氧乙烯蓖麻油、泊洛沙姆和十二烷基硫酸钠、乳糖和甘露醇中的一种或几种。
  6. 权利要求1-5中任意一项的纳米晶制剂，所述纳米晶制剂的粒径D 90为50-1500nm，优选为50-1000nm，优选为50-500nm，优选为80-300nm，更优选为50nm、100nm、150nm、200nm、250nm、300nm、400nm、500nm、600nm、700nm、800nm、900nm或1000nm。
  7. 权利要求1-6中任意一项的纳米晶制剂，其中，所述ROCK2抑制剂的重量百分数为1％-55％，优选为4％-50％，优选为1％-10％，优选为10％-40％，优选为10％-35％，优选为20％-30％，优选为30％-40％，更优选为4％、4.5％、5％、10％、15％、20％、25％、30％、35％或40％。
  8. 权利要求1-7中任意一项的纳米晶制剂，其中，所述稳定剂的重量百分数为0.1％-55％，优选为0.1％-30％，优选为0.5％-1％、1％-10％、10％-20％或20％-30％，更优选为1％、2％、5％、10％、15％、20％或30％。
  9. 权利要求1-8中任意一项的纳米晶制剂，其中，ROCK2抑制剂和稳定剂的重量比为1:10至10:1、优选为1:9至9:1、优选为1:8至8:1、优选为1:7至7:1、优选为1:6至6:1、优选为1:5至5:1、优选为1:4至4:1、优选为1:3至3:1、优选为1:2至2:1、优选为1:1；优选地，ROCK2抑制剂和稳定剂的重量比为4:1至1:1或1:1至1:2，更优选为5:4、5:3、4:1、3:1、2:1、1:1、1:2或1:3。
  10. 权利要求1-9中任意一项的纳米晶制剂，其中，所述纳米晶制剂中含有赋形剂。
  11. 权利要求10的纳米晶制剂，其中，所述赋形剂选自填充剂；润湿剂；甜味剂或调味剂；表面活性剂；粘合剂；崩解剂；润滑剂；助流剂或抗粘附剂；释放改性剂；包衣剂；乳化剂；增溶剂；和香料中的一种或多种。
  12. 权利要求10或11所述的纳米晶制剂，其中，赋形剂包含填充剂，所述填充剂选自微晶纤维素、甘露醇、乳糖、淀粉、预胶化淀粉、糊精、二水合磷酸钙和无水磷酸氢钙中的一种或几种。
  13. 权利要求10-12中任意一项的纳米晶制剂，其中，赋形剂包含填充剂，所述填充剂的用量为1％至80％，优选为20％至70％，更优选为30％至60％或50％至70％。
  14. 权利要求11-13中任意一项的纳米晶制剂，其中，赋形剂包含润滑剂，所述润滑剂选自硬脂 酸镁、滑石粉、微粉硅胶、硬脂富马酸钠、山嵛酸甘油酯和聚乙二醇中的一种或几种。
  15. 权利要求11-14中任意一项的纳米晶制剂，其中，赋形剂包含润滑剂，所述润滑剂的用量为0.1％至5％，优选为0.1％至1.5％，更优选为0.5％至1％。
  16. 权利要求11-15中任意一项的纳米晶制剂，其中，赋形剂包含崩解剂，所述崩解剂选自交联羧甲基纤维素钠和交联聚维酮中一种或两种；
    优选地，所述崩解剂的用量为0至20％，优选为0至10％，更优选为2至10％。
  17. 权利要求11-16中任意一项的纳米晶制剂，其中，赋形剂包含助流剂，所述助流剂选自二氧化硅；
    优选地，所述助流剂的用量为0至20％，优选为0至15％，更优选为2至12％。
  18. 权利要求1-17中任意一项的纳米晶制剂，其中，所述纳米晶制剂中还含有溶剂；
    优选地，所述溶剂选自水，优选纯净水；
    优选地，所述溶剂的用量为0至99％，优选为80至99％，更优选为85％至95％。
  19. 权利要求1-18中任意一项的纳米晶制剂，其中，所述纳米晶制剂中还含有抑菌剂；
    优选地，所述抑菌剂选自羟苯甲酯和羟苯丙酯中一种或两种；
    优选地，所述抑菌剂的用量为0至5％，优选为0至1％，更优选为0.01％至0.5％。
  20. 权利要求1-19中任意一项的纳米晶制剂，其中，所述纳米晶制剂选自混悬剂、片剂、胶囊剂、颗粒剂、散剂、锭剂和丸剂；优选为混悬剂、片剂或胶囊剂。
  21. 权利要求1-20中任意一项的纳米晶制剂，其中，所述纳米晶制剂为混悬剂，包含：
    -1-10％ROCK2抑制剂，优选为1％、2％、3％、4％、4.5％、5％、6％、7％、8％、9％或10％ROCK2抑制剂，更优选为4％、4.5％、5％ROCK2抑制剂；和
    -1-10％稳定剂，优选为1％、1.5％、2％、2.5％、5％、9％、9.5％或10％稳定剂。
  22. 权利要求21所述的纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、5.00g聚维酮K29/32和233.10g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
  23. 权利要求21所述的纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、2.50g聚维酮K29/32和235.60g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
  24. 权利要求21所述的纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、2.50g羟丙甲纤维素和235.60g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
  25. 权利要求21所述的纳米晶制剂，其中，所述纳米晶为混悬剂，包含11.13g ROCK2抑制剂、0.77g聚山梨酯80、5.00g羟丙甲纤维素和233.10g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
  26. 权利要求21所述的纳米晶制剂，其中，所述纳米晶为混悬剂，包含250.08g ROCK2抑制剂、17.40g聚山梨酯80、111.60g聚维酮K29/32、10.00g羟苯甲酯、1.10g羟苯丙酯和5189.82g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm。
  27. 权利要求21所述的纳米晶制剂，其中，所述纳米晶为混悬剂，包含55.19g ROCK2抑制剂、18.61g聚山梨酯80、99.25g聚氧乙烯蓖麻油、2.23g羟苯甲酯、0.25g羟苯丙酯和1065.09g纯化水，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  28. 权利要求1-20中任意一项的纳米晶制剂，其中，所述纳米晶制剂为片剂，包含：
    -10-30％ROCK2抑制剂，优选为20-30％ROCK2抑制剂，优选为20％、22％、25％、28％或30％ROCK2抑制剂；
    -1-20％稳定剂，优选为5-20％稳定剂，更优选为5％、8％、10％、13％、15％、18％或20％稳定剂。
  29. 权利要求28所述的纳米晶制剂，其中，所述纳米晶为片剂，包含11.70g ROCK2抑制剂、3.15g聚山梨酯80、5.26g乳糖、1.05g聚乙二醇6000、16.03g甘露醇、4.94g二氧化硅、2.47g十二烷基硫酸钠、2.96g微晶纤维素、2.96g交联羧甲基纤维素钠和0.32g硬脂酸镁，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  30. 权利要求28所述的纳米晶制剂，其中，所述纳米晶为片剂，包含32.71g ROCK2抑制剂、14.81g聚山梨酯80、14.71g乳糖、2.94g聚乙二醇6000、43.63g甘露醇、16.00g二氧化硅、8.00g十二烷基硫酸钠、12.80g微晶纤维素、12.80g交联羧甲基纤维素钠和1.60g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  31. 权利要求28所述的纳米晶制剂，其中，所述纳米晶为片剂，包含3.34g ROCK2抑制剂、0.89g聚山梨酯80、1.80g乳糖、0.30g聚乙二醇6000、0.75g二氧化硅、0.75g十二烷基硫酸钠、5.82g微晶纤维素、1.20g交联羧甲基纤维素钠和0.15g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  32. 权利要求28所述的纳米晶制剂，其中，所述纳米晶为片剂，包含3.34g ROCK2抑制剂、0.89g聚山梨酯80、1.80g乳糖、0.30g聚乙二醇6000、0.75g二氧化硅、0.45g十二烷基硫酸钠、4.50g微晶纤维素、1.62g预胶化淀粉、1.20g交联羧甲基纤维素钠和0.15g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  33. 权利要求28所述的纳米晶制剂，其中，所述纳米晶为片剂，包含11.14g ROCK2抑制剂、2.97g聚山梨酯80、6.01g乳糖、1.00g聚乙二醇6000、1.00g二氧化硅、27.38g喷雾干燥甘露醇和0.50g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  34. 权利要求28所述的纳米晶制剂，其中，所述纳米晶为片剂，包含111.20g ROCK2抑制剂、30.04g聚山梨酯80、59.99g乳糖、10.00g聚乙二醇6000、10.00g二氧化硅、273.78g喷雾干燥甘露醇和5.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  35. 权利要求1-20中任意一项的纳米晶制剂，其中，所述纳米晶制剂为片剂，包含：
    -10-30％ROCK2抑制剂，优选为20-30％ROCK2抑制剂，更优选为20％、22％、25％、28％或30％ROCK2抑制剂；
    -10-30％稳定剂，优选为20-30％稳定剂，更优选为20％、22％、25％、28％或30％稳定剂。
  36. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.22g ROCK2抑制剂、20.00g聚山梨酯80、54.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  37. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g聚维酮K29/32、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  38. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g聚乙二醇6000、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  39. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  40. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、20.00g聚乙烯醇、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  41. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、16.00g聚维酮K29/32、4.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  42. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、4.00g聚维酮K29/32、16.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  43. 权利要求35所述的纳米晶制剂，其中，所述纳米晶为片剂，包含22.20g ROCK2抑制剂、10.00g聚山梨酯80、10.00g聚维酮K29/32、10.00g泊洛沙姆188、44.80g甘露醇、2.00g二氧化硅和1.00g硬脂富马酸钠，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  44. 权利要求1-20中任意一项的纳米晶制剂，其中，所述纳米晶制剂为胶囊剂，包含：
    -10-50％ROCK2抑制剂，优选为20-40％ROCK2抑制剂，更优选为20％、25％、30％、35％或40％ROCK2抑制剂；
    -10-40％稳定剂，优选为20-30％稳定剂，更优选为20％、22％、25％、28％或30％稳定剂。
  45. 权利要求44所述的纳米晶制剂，其中，所述纳米晶为胶囊剂，包含22.20g ROCK2抑制剂、6.00g聚山梨酯80、8.00g聚维酮K29/32、4.00g泊洛沙姆和20.00g甘露醇，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  46. 权利要求44所述的纳米晶制剂，其中，所述纳米晶为胶囊剂，包含4.45g ROCK2抑制剂、1.20g聚山梨酯80、1.20g聚维酮K32/29、0.80g泊洛沙姆188和6.80g甘露醇，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  47. 权利要求1-19中任意一项的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶制剂，选自肠溶包衣片剂或肠溶胶囊。
  48. 权利要求47的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，其中，肠溶包衣材料选自虫胶、聚乙烯醇乙酸苯二甲酸酯(PVAP)、甲基丙烯酸共聚物、纤维素及其衍生物(醋酸纤维素酞酸酯(CAP)、醋酸纤维素苯三酸酯(CAT)、羟丙基纤维素酞酸酯(HPMCP))、丙烯酸树脂类(EuS100、EuL100)中的一种或多种。
  49. 权利要求47的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶胶囊，其中，肠溶胶囊选自明胶肠溶胶囊或羟丙甲纤维素肠溶胶囊，囊材组成选自虫胶、聚乙烯醇乙酸苯二甲酸酯(PVAP)、甲 基丙烯酸共聚物、纤维素及其衍生物(醋酸纤维素酞酸酯(CAP)、醋酸纤维素苯三酸酯(CAT)、羟丙基纤维素酞酸酯(HPMCP))、丙烯酸树脂类(EuS100、EuL100)中的一种或多种。
  50. 权利要求1-19、47-48中任一项的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，包含：
    -1-20％ROCK2抑制剂，优选5-15％ROCK2抑制剂，更优选为5％、6％、7％、8％、9％、10％、11％、12％、13％、14％或15％ROCK2抑制剂；和
    -1-90％稳定剂，优选10-40％稳定剂，更优选为15-25％稳定剂，例如，15％、16％、17％、18％、19％、20％、21％、22％、23％、24％或25％稳定剂。
  51. 权利要求50所述的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，包含5.56g ROCK2抑制剂、1.50g聚山梨酯80、1.00g泊洛沙姆、1.50g聚维酮K29/32、5.00g甘露醇、1.00g二氧化硅、4.00g交联聚维酮、29.94g微晶纤维素、0.50g硬脂酸镁和5g薄膜包衣预混剂(肠溶型)，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  52. 权利要求50所述的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶包衣片剂，包含5.56g ROCK2抑制剂、1.50g聚山梨酯80、1.00g泊洛沙姆、1.50g聚维酮K29/32、38.94g甘露醇、1.00g二氧化硅、0.50g硬脂酸镁和5g薄膜包衣预混剂(肠溶型)，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  53. 权利要求1-19、47和49中任一项的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶胶囊，包含：
    -5-30％ROCK2抑制剂，优选10-20％ROCK2抑制剂，更优选为10％、11％、12％、13％、14％、15％、16％、17％、18％、19％或20％ROCK2抑制剂；和
    -10-50％稳定剂，优选20-40％稳定剂，更优选为30-40％稳定剂，例如，30％、31％、32％、33％、34％、35％、36％、37％、38％、39％或40％稳定剂。
  54. 权利要求53所述的纳米晶制剂，其中，所述纳米晶制剂为纳米晶肠溶胶囊，包含11.1g ROCK2抑制剂、3.0g聚山梨酯80、2.0g泊洛沙姆、3.0g聚维酮K29/32、20.0g甘露醇、2.00g二氧化硅、8.0g交联聚维酮、29.9g微晶纤维素、1.0g硬脂酸镁和肠溶胶囊，优选地，所述ROCK2抑制剂的粒径为50-1000nm，优选为50-500nm，更优选50-300nm，最优选50-150nm。
  55. 权利要求1-54所述纳米晶制剂的制备方法，其包含将ROCK2抑制剂和稳定剂研磨。
  56. 权利要求55的制备方法，其中，研磨时ROCK2抑制剂和稳定剂的重量比为1:15至15:1、1:14至14:1、1:13至13:1、1:12至12:1、1:11至11:1、1:10至10:1、1:9至9:1、1:8至8:1、1:7至7:1、1:6至6:1、1:5至5:1、1:4至4:1、1:3至3:1、1:2至2:1、1:1；优选地，研磨时ROCK2抑制剂和稳定剂的重量比为15:1至2:1，更优选为15:1、10:1、10:3、5:1、4:1、3:1或2:1。
  57. 权利要求55-56中任意一项的制备方法，其中，研磨介质选自瓷球、玻璃球、氧化锆珠、钢球或冰珠；优选地，所述研磨介质为氧化锆珠。
  58. 权利要求55-57中任意一项的制备方法，其中，研磨介质的粒径范围为0.1-1mm，优选为0.1-0.5mm，更优选为0.2mm。
  59. 权利要求55-58中任意一项的制备方法，其中，研磨时间为0.1-6h，优选为0.5-6h，优选为4-6h，更优选为10min、20min、30min、40min、1h、1.5h、2h、2.5h、3h、3.5h、4h、4.5h、5h、5.5h或6h。
  60. 权利要求55-59中任意一项的制备方法，其中，研磨速度为1000～6000rpm，优选为 1500rpm～4500rpm，更优选为1500rpm、2000rpm、2500rpm、3000rpm、3500rpm、4000rpm、4500rpm、5000rpm、5500rpm或6000rpm。
  61. 权利要求55-60中任意一项的制备方法，其中，研磨珠的填充量为50～95％，优选70％～90％，更优选为70％、80％或90％。
  62. 权利要求55-61中任意一项的制备方法，其中，在将ROCK2抑制剂和稳定剂研磨前，还包括预研磨步骤。
  63. 权利要求62的制备方法，其中，所述预研磨速度为3000～6000rpm，优选为3000rpm、3500rpm、4000rpm、4500rpm、5000rpm、5500rpm或6000rpm，更优选为4000rpm；预研磨时间为1-30min，优选为2-20min，优选为3min、4min、5min、6min、8min、10min、12min、15min、18min或20min，更优选为5min。
  64. 权利要求55-63中任意一项的制备方法，其中，研磨后可选地加入稳定剂和/或赋形剂。
  65. 权利要求64的制备方法，其中，所述稳定剂选自聚山梨酯、聚维酮、聚氧乙烯脂肪酸酯、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、泊洛沙姆、十二烷硫酸钠、多库酯钠、15-羟基硬脂酸聚乙二醇脂、聚氧乙烯蓖麻油、共聚维酮、乳糖、甘露醇中的一种或多种；优选地，稳定剂选自聚维酮K29/32、泊洛沙姆188和聚乙烯醇、乳糖、甘露醇；优选地，稳定剂为聚维酮K29/32和泊洛沙姆188的混合物，二者的混合比例为1:10至10:1、优选为1:9至9:1、优选为1:8至8:1、优选为1:7至7:1、优选为1:6至6:1、优选为1:5至5:1、优选为1:4至4:1、优选为1:3至3:1、优选为1:2至2:1、优选为1:1；更优选地，二者的混合比例为1:4、4:1或1:1。
  66. 预防、缓解和/或治疗特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染的方法，其包括向受试者给予治疗有效量的权利要求1-54的纳米晶制剂或者由权利要求55-65的方法制备得到的纳米晶制剂；优选地，所述方法为预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎的方法；优选地，所述脂肪性肝病为酒精性脂肪性肝病(ALFD)或非酒精性脂肪性肝病(NALFD)，所述脂肪性肝炎为酒精性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)，所述的造血干细胞移植是同种异体造血干细胞移植，所述的移植物抗宿主病为急性移植物抗宿主病或者慢性移植物抗宿主病，所述病毒感染为冠状病毒感染；优选地，所述冠状病毒选自SARA-CoV、SARA-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43和HCoV-HKU1；优选地，所述冠状病毒引起的疾病为中东呼吸综合征、严重急性呼吸***综合征或者COVID-19；优选地，所述冠状病毒引起的是严重急性呼吸综合征冠状病毒2，其导致的疾病为COVID-19。
  67. 权利要求1-54所述的纳米晶制剂或由权利要求55-65的方法制备得到的纳米晶制剂，其用于预防、缓解和/或治疗特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染；优选地，所述纳米晶制剂用于预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎；优选地，所述脂肪性肝病为酒精性脂肪性肝病(ALFD)或非酒精性脂肪性肝病(NALFD)，所述脂肪性肝炎为酒精性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)，所述的造血干细胞移植是同种异体造血干细胞移植，所述的移植物抗宿主病为急性移植物抗宿主病或者慢性移植物抗宿主病，所述病毒感染为冠状病毒感染；优选地，所述冠状病毒选自SARA-CoV、SARA-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43和HCoV-HKU1；优选地，所述冠状病毒引起的疾病为中东呼吸综合征、严重急性呼吸***综合征或者COVID-19；优选地，所述冠状病毒引起的是严重急性呼吸综合征冠状病毒2，其导致的疾病为COVID-19。
  68. 权利要求1-54所述的纳米晶制剂或由权利要求55-65的方法制备得到的纳米晶制剂在制备用 于预防、缓解和/或治疗特发性肺纤维化、脂肪性肝病和/或脂肪性肝炎、造血干细胞移植后的移植物抗宿主病或者病毒感染的药物中的用途；优选地，所述用途为制备用于预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎的药物中的用途；优选地，所述脂肪性肝病为酒精性脂肪性肝病(ALFD)或非酒精性脂肪性肝病(NALFD)，所述脂肪性肝炎为酒精性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)，所述的造血干细胞移植是同种异体造血干细胞移植，所述的移植物抗宿主病为急性移植物抗宿主病或者慢性移植物抗宿主病，所述病毒感染为冠状病毒感染；优选地，所述冠状病毒选自SARA-CoV、SARA-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43和HCoV-HKU1；优选地，所述冠状病毒引起的疾病为中东呼吸综合征、严重急性呼吸***综合征或者COVID-19；优选地，所述冠状病毒引起的是严重急性呼吸综合征冠状病毒2，其导致的疾病为COVID-19。
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