WO2021208976A1 - 固体药物制剂及其制备方法和用途 - Google Patents

固体药物制剂及其制备方法和用途 Download PDF

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Publication number
WO2021208976A1
WO2021208976A1 PCT/CN2021/087262 CN2021087262W WO2021208976A1 WO 2021208976 A1 WO2021208976 A1 WO 2021208976A1 CN 2021087262 W CN2021087262 W CN 2021087262W WO 2021208976 A1 WO2021208976 A1 WO 2021208976A1
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active ingredient
content
solid pharmaceutical
pharmaceutical preparation
particle size
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PCT/CN2021/087262
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English (en)
French (fr)
Inventor
江涛涛
王吉标
杨菡
李利
但招陵
朱科屹
曾振亚
苏波
陈曦
Original Assignee
上海海雁医药科技有限公司
扬子江药业集团有限公司
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Application filed by 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Priority to JP2022562168A priority Critical patent/JP7478839B2/ja
Priority to AU2021256788A priority patent/AU2021256788B2/en
Priority to EP21788226.5A priority patent/EP4137124A4/en
Priority to US17/919,402 priority patent/US20230149402A1/en
Priority to CN202180027685.7A priority patent/CN115379830A/zh
Priority to CA3174409A priority patent/CA3174409A1/en
Priority to KR1020227033065A priority patent/KR20220145876A/ko
Publication of WO2021208976A1 publication Critical patent/WO2021208976A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a solid pharmaceutical preparation containing an orexin receptor antagonist compound, a preparation method thereof, and application in the preparation of a medicine for treating orexin-related diseases.
  • Orexin includes two neuropeptides produced in the hypothalamus: Orexin A (OX-A) (33 amino acid peptide) and Orexin B (OX-B) (28 amino acid peptide) ( Sakurai T. et al., Cell, 1998, 92, 573-585). It has been found that orexin can stimulate food consumption in rats, which indicates that these peptides have a physiological role as a mediator in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585) . Orexin can regulate the state of sleep and insomnia, potentially presenting a new method for treating patients with narcolepsy or insomnia (Chemelli R.M.
  • Orexin also plays a role in awakening, motivation, learning and memory (Harris, et al., Trends Neurosc1., 2006, 29(10), 571-577).
  • two orexin receptors have been cloned and characterized: orexin-1 receptor and orexin-2 receptor. They belong to the superfamily of G protein-coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585), in which orexin-1 receptor (OX or OX1R) is selective for OX-A, and orexin-2
  • the receptor (OX2 or OX2R) can bind to OX-A and OX-B. It is believed that the physiological role of orexin is achieved through the expression of one or both of OX1 receptor and OX2 (two subtypes of orexin receptor).
  • Orexin receptors can be found in the brains of warm-blooded animals, and orexin receptors are associated with, for example, the following pathologies: depression; anxiety; addiction; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety sexual neurosis; mental depressive disorders; behavioral disorders; mood disorders; sexual dysfunction; sexual psychological dysfunction; gender disorders; schizophrenia; manic depression; mental disorders; dementia; severe mental retardation and movement disorders, Such as Huntington’s disease and Tourette’s disease; eating disorders, such as anorexia, bulimia, cachexia and obesity; addictive feeding behavior; binge eating and diarrhea feeding behavior; cardiovascular disease; diabetes; appetite/ Taste disorders; vomiting, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; pituitary tumor/adenoma; Hypothalamic disease; Inflammatory bowel disease; Stomach dysfunction; Gastric ulcer; Obese
  • CN106414439A discloses a class of piperidine derivatives as orexin receptor antagonists, which have a significant inhibitory effect on OX1 and OX2GPCR receptors. It has been found in research that when it is prepared into a solid pharmaceutical composition, there is a dissolution rate and Low dissolution rate, low bioavailability and high half-life in the body are insufficient. For the treatment of insomnia drugs, a longer half-life obviously has an adverse effect, such as a residual effect on the second day, which may cause patients Adverse consequences. Therefore, it is necessary to develop it into a solid pharmaceutical dosage form with a higher dissolution rate and dissolution rate, as well as a higher bioavailability and a lower half-life to meet a wider range of clinical administration needs.
  • the purpose of the present invention is to provide a solid pharmaceutical preparation containing the compound of formula I with good stability, good dissolution effect and good bioavailability.
  • the first aspect of the present invention provides a solid pharmaceutical preparation, wherein the solid pharmaceutical preparation contains an active ingredient, and the active ingredient is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a mixture of the two;
  • R a is hydrogen, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
  • Z is N or CR 0 ;
  • R 0 is hydrogen, halogen or C 1-3 alkyl;
  • n 0, 1 or 2;
  • the particle size of the active ingredient is D90 ⁇ 50 ⁇ m.
  • the compound represented by formula (I) is a compound of formula (II):
  • OX2GPCR and OX2GPCR receptors are 20nM (hOX1R) and 36nM (hOX2R) respectively.
  • the pharmaceutically acceptable salts of the present invention include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable acid addition salts refer to salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts include, but are not limited to, formate, acetate, propionate, glycolate, and gluconate , Lactate, oxalate, maleate, succinate, fumarate, tartrate, citrate, glutamate, aspartate, benzoate, methanesulfonate , P-toluenesulfonate and salicylate, etc. These salts can be prepared by methods known in the art.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium, magnesium, and the like. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like. These salts can be prepared by methods known in the art.
  • the compounds represented by formula (I) and formula (II) or their pharmaceutically acceptable salts in the present invention may be in any form, and specific forms include, but are not limited to, amorphous, arbitrary crystal forms, hydrates, solvates, etc. .
  • the compound represented by formula (II) exists in crystalline form A, and its Cu-K ⁇ radiation XRPD spectrum is analyzed as follows, and its structure is shown in FIG. 6.
  • the compound represented by formula (II) exists in crystalline form B, and its Cu-K ⁇ radiation XRPD spectrum is analyzed as follows, and its structure is shown in FIG. 7.
  • the crystalline form A and crystalline form B mentioned in the present invention can be prepared and characterized by referring to the method described in the patent CN107709318A.
  • the compound of formula (II) exists in crystalline form, and its single crystal X-ray diffraction shows that the compound of formula (II) has a three-dimensional structure ellipsoid diagram as shown in FIG. 10.
  • the content of the active ingredient is 1%-15%, more preferably 4%-10%, more preferably 9.5%-10%, and the percentage is the total solid pharmaceutical preparation Dry weight.
  • the solid pharmaceutical preparation further includes a binder selected from the group consisting of hypromellose, hydroxypropyl cellulose, povidone, sodium alginate, carbopol, polyethylene One or more of alcohols, the content of the binder is 0.5%-10%, more preferably 1.5%-3%, and the percentage is based on the total dry weight of the solid pharmaceutical preparation.
  • a binder selected from the group consisting of hypromellose, hydroxypropyl cellulose, povidone, sodium alginate, carbopol, polyethylene
  • the content of the binder is 0.5%-10%, more preferably 1.5%-3%, and the percentage is based on the total dry weight of the solid pharmaceutical preparation.
  • the binder is selected from one of hypromellose-E5, hypromellose-K4M, hypromellose-E50, carbopol, polyvinyl alcohol, or Many kinds.
  • the binder is selected from hypromellose-E5.
  • the solid pharmaceutical preparation further includes a filler selected from one of microcrystalline cellulose, lactose, cellulose lactose complex, pregelatinized starch, calcium hydrogen phosphate, and calcium carbonate.
  • a filler selected from one of microcrystalline cellulose, lactose, cellulose lactose complex, pregelatinized starch, calcium hydrogen phosphate, and calcium carbonate.
  • the content of the filler is 60% to 90%, more preferably 73% to 85%, more preferably 73%-82.5%, and the percentage is the total dry weight of the solid pharmaceutical preparation count.
  • the filler is microcrystalline cellulose and lactose.
  • the solid pharmaceutical preparation further includes a disintegrant selected from the group consisting of croscarmellose sodium, hypromellose-K4M, crospovidone, carboxymethyl One or more of the sodium starch base, the content of the disintegrant is 5%-15%, and the percentage is based on the total dry weight of the solid pharmaceutical preparation.
  • a disintegrant selected from the group consisting of croscarmellose sodium, hypromellose-K4M, crospovidone, carboxymethyl One or more of the sodium starch base, the content of the disintegrant is 5%-15%, and the percentage is based on the total dry weight of the solid pharmaceutical preparation.
  • the disintegrant is selected from croscarmellose sodium and hypromellose-K4M.
  • the solid pharmaceutical preparation further includes a lubricant
  • the lubricant is selected from one of magnesium stearate, talc, glyceryl monostearate, and sodium fumarate stearate.
  • the content of the lubricant is 0.1%-1%, more preferably 0.4%-0.5%, more preferably 0.48%-0.5%, and the percentage is based on the total dry weight of the solid pharmaceutical preparation.
  • the solid pharmaceutical preparation is a tablet, capsule, powder, granule, dripping pill or film, preferably a tablet.
  • the solid pharmaceutical preparation contains the following components based on the total dry weight of the solid pharmaceutical preparation: a) Active ingredient: ((1S, 2R, 5S)-2-(((5-fluoro (Pyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octane-8-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone , Or a pharmaceutically acceptable salt thereof, or a mixture of the two; the content of the active ingredient is 1%-15%, more preferably 4%-10%, more preferably 9.5%-10%;
  • Filling agent selected from one or more of microcrystalline cellulose, lactose, cellulose lactose complex, pregelatinized starch, calcium hydrogen phosphate, calcium carbonate, and the content of the filler is 60%-90 %, more preferably 73%-85%, more preferably 73%-82.5%;
  • Binder selected from one or more of hypromellose, hydroxypropyl cellulose, povidone, sodium alginate, carbopol, polyvinyl alcohol, and the content of the binder is 0.5%-10%, more preferably 1.5%-3%;
  • a disintegrant selected from one or more of croscarmellose sodium, hypromellose-K4M, crospovidone, sodium carboxymethyl starch, the disintegrant The content is 5%-15%;
  • Lubricant selected from one or more of magnesium stearate, talc, glyceryl monostearate, sodium stearate fumarate, and the content of the lubricant is 0.1%-1 %, more preferably 0.4%-0.5%, more preferably 0.48%-0.5%;
  • the particle size of the active ingredient is D90 ⁇ 35 ⁇ m.
  • the solid preparation is a tablet.
  • the content of the active ingredient is 5 mg-100 mg. In another preferred example, the content of the active ingredient is 10 mg-50 mg. In another preferred example, the content of the active ingredient is 10 mg, 20 mg or 40 mg.
  • the binder is selected from one of hypromellose-E5, hypromellose-K4M, hypromellose-E50, carbopol, polyvinyl alcohol, or Many kinds.
  • the binder is selected from hypromellose-E5.
  • the filler is microcrystalline cellulose and lactose.
  • the disintegrant is selected from croscarmellose sodium and hypromellose-K4M.
  • the solid pharmaceutical preparation contains the following components based on the total dry weight of the solid pharmaceutical preparation: a) Active ingredient: ((1S, 2R, 5S)-2-(((5-fluoro (Pyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octane-8-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone Or a pharmaceutically acceptable salt thereof, or a mixture of the two; the content of the active ingredient is 4%-10%;
  • Microcrystalline cellulose the content is 24%-27.5%
  • Lactose the content is 48.5%-56.5%;
  • Hypromellose-E5 the content is 1.5%-3%;
  • Croscarmellose sodium or hypromellose-K4M the content is 5%-15%;
  • the following components are included based on the total dry weight of the solid pharmaceutical preparation:
  • Active ingredient ((1S,2R,5S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octane-8- Yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone or a pharmaceutically acceptable salt thereof, or a mixture of the two; the content of the active ingredient is 9.5%-10%;
  • Microcrystalline cellulose the content is 24%-27.5%
  • Lactose the content is 48.5%-56.5%;
  • Hypromellose-E5 the content is 1.5%-3%;
  • Croscarmellose sodium or hypromellose-K4M the content is 5%-15%;
  • the lactose is 200 mesh, 100 mesh, 50 mesh and the like. More preferably, the lactose is 200 mesh.
  • the filler is microcrystalline cellulose and lactose; the weight ratio of microcrystalline cellulose to lactose is (24-27.5): (48.5-56.5).
  • the solid pharmaceutical preparation includes any tablet in the preparation example.
  • the present invention provides a unit dosage form. Based on the total weight of the unit dosage form, the unit dosage form contains: about 10 mg, about 20 mg, or about 40 mg of an active ingredient, and the active ingredient is a compound of formula (II); About 25 mg to about 150 mg of microcrystalline cellulose (e.g. microcrystalline cellulose PH101); about 50 mg to about 300 mg of lactose (e.g.
  • hypromellose e.g., hypromellose E5
  • croscarmellose sodium such as croscarmellose sodium SD711
  • HPMC-K4M hypromellose
  • the present invention provides a unit dosage form, based on the total weight of the unit dosage form, the unit dosage form contains: about 20 mg of active ingredient, the active ingredient is a compound of formula (II); about 51 mg of microcrystalline fiber (E.g. microcrystalline cellulose PH101); about 102mg lactose (e.g. Granulac 200); about 6mg hypromellose (e.g. hypromellose E5); about 20mg croscarmellose sodium (e.g.
  • the present invention provides a unit dosage form, based on the total weight of the unit dosage form, the unit dosage form contains: about 40 mg of active ingredient, the active ingredient is a compound of formula (II); about 102 mg of microcrystalline fiber (E.g. microcrystalline cellulose PH101); about 204mg lactose (e.g. Granulac 200); about 12mg hypromellose (e.g. hypromellose E5); about 40mg croscarmellose sodium (e.g.
  • the active ingredient is a compound of formula (II); 20 mg to 30 mg of micro Crystalline cellulose (such as micro
  • the active ingredient is a compound of formula (II); 46 mg to 56 mg of micro Crystalline cellulose (such
  • the compound of formula (II) as an active ingredient may exist in any form, including amorphous, any crystalline form, hydrate, solvate, and the like. In some embodiments, the compound of formula (II) as an active ingredient exists in an amorphous form, crystalline form A, or crystalline form B. In some embodiments, the compound of formula (II) as the active ingredient exists in crystalline form A.
  • the aforementioned unit dosage form is a tablet or capsule. In some embodiments, the aforementioned unit dosage form is a tablet. In some embodiments, the aforementioned unit dosage form is a tablet and further comprises a coating.
  • Tablets can be prepared by conventional compression, wet granulation or dry granulation methods.
  • the dosage form of the present invention is a tablet prepared by a wet granulation method.
  • the tablets may also include one or more surface coatings, such as clear coatings and/or colored coatings.
  • Various coatings and methods of application are known in the art, including those disclosed in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Company, Easton, Pa., 1985).
  • the weight of the tablet will generally increase by 2% to 3%, so the tablet can generally be between about 50 mg to about 1000 mg.
  • the weight of the tablet is about 100 mg. About 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, etc., depending on the dose required for the therapeutic use.
  • the word "about” used before the weight value in the above unit dosage form of the present invention means ⁇ 10mg, or ⁇ 5mg, or ⁇ 2mg, or ⁇ 1mg, or ⁇ 0.5mg, or ⁇ 0.2mg, or ⁇ 0.1mg .
  • the particle size D90 of the active ingredient in the present invention represents the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 90%.
  • the film coatings that can be used in the formulations of the present invention are known in the art and usually contain a polymer (usually a cellulosic polymer), a coloring agent, and a plasticizer. Additional ingredients such as sugars, flavors, oils, and lubricants can be included in the film coating formulation to impart certain characteristics to the film coating.
  • a polymer usually a cellulosic polymer
  • additional ingredients such as sugars, flavors, oils, and lubricants can be included in the film coating formulation to impart certain characteristics to the film coating.
  • the compositions and formulations herein can also be combined and processed into a solid, and then placed in a capsule form such as a gelatin capsule.
  • a given component can be used as both a filler and a disintegrant.
  • the function of a given component may be considered single, although its properties may allow for versatility.
  • lactose may be selected from commercially available lactose applicable to the field of pharmacy, including Flow100, Granulac 200, Tableffose 100, Spherolac 100, and the like.
  • Microcrystalline cellulose can be selected from commercially available microcrystalline cellulose in the field of pharmacy, including pH101, pH102, pH301, pH302, KG1000, KG802, UF702, UF711 and the like.
  • Pregelatinized starch also called modified starch
  • Hypromellose may be selected from commercially available hypromellose suitable for the field of pharmacy, including HPMC E3, HPMC E5, HPMC K4M, HPMC E15, and the like.
  • Povidone can be selected from commercially available povidones in the field of pharmacy, including povidone K30 and povidone K90.
  • the cross-linked povidone can be selected from commercially available cross-linked povidone in the field of pharmacy, including PVPP XL-10, PVPP VL-10, PVPP XL.
  • the croscarmellose sodium can be selected from commercially available croscarmellose sodium in the field of pharmacy, including RC-A591NF, SD-711 and the like.
  • the second aspect of the present invention provides a method for preparing a tablet, the method comprising the following steps:
  • step (c) dry mixing the product obtained in step (b), the second disintegrant and the lubricant;
  • step (d) compressing the product obtained in step (c) into tablets
  • the active ingredient is ((1S,2R,5S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octane-8-yl ) (5-Methyl-2-(pyrimidin-2-yl)phenyl)methanone or a pharmaceutically acceptable salt thereof, or a mixture of the two;
  • the particle size of the active ingredient particles is D90 ⁇ 50 ⁇ m.
  • the first disintegrant and the second disintegrant may be the same or different.
  • the filler is selected from one or more of microcrystalline cellulose, lactose, cellulose lactose complex, pregelatinized starch, dibasic calcium phosphate, and calcium carbonate.
  • the binder is selected from one or more of hypromellose, hypromellose, povidone, sodium alginate, carbopol, and polyvinyl alcohol.
  • the first and second disintegrants are each independently selected from croscarmellose sodium, hypromellose-K4M, crospovidone, sodium carboxymethyl starch One or more of.
  • the lubricant is selected from one or more selected from magnesium stearate, talc, glyceryl monostearate, and sodium stearate fumarate.
  • the content of the active ingredient is 4%-10% based on the total dry weight of the mixture obtained in step (c).
  • the content of the filler is 73%-82.5%.
  • the content of the binder is 1.5%-3%.
  • the content of the first disintegrant is 2%-10%, more preferably 5%-6%; according to step (c) The content of the second disintegrant is 5%-10% based on the total dry weight of all the components in the product.
  • the content of the lubricant is 0.1%-1%, more preferably 0.4%-0.5%, more preferably 0.48%- 0.5%.
  • the method further includes step (e), coating the product of step (d).
  • the coating material in the step (e) is a gastric-soluble film coating premix, and the concentration of the coating liquid is 10%-20%.
  • the present invention also provides the product of the method described herein.
  • the third aspect of the present invention provides the application of the solid pharmaceutical preparation described in the first aspect of the present invention in the preparation of a medicine for treating orexin-related diseases.
  • the orexin-related diseases include insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, drowsiness, anxiety, compulsiveness, panic, nicotine dependence or eating disorder.
  • Figure 1 shows the dissolution profiles of the formulations of Preparation Examples 1-1, 1-2, 1-3 and 1-4.
  • Figure 2 shows the dissolution profile of the formulations of Preparation Examples 2-1, 2-2, 2-6 and 2-7.
  • Figure 3 shows the dissolution profile of the formulations of Preparation Examples 2-1, 2-2, 2-3, 2-4 and 2-5.
  • Figure 4 shows the dissolution profiles of the formulations of Preparation Examples 3, 2-1 and 2-4.
  • Figure 5 shows the dissolution profiles of the formulations of Preparation Examples 4-1, 4-2 and 4-3.
  • FIG. 6 is an XRPD spectrum of Cu-K ⁇ radiation of the compound of formula (II) in crystalline form A.
  • FIG. 7 is an XRPD spectrum of Cu-K ⁇ radiation of the compound of formula (II) in crystalline form B.
  • Figure 8 is a graph showing the in vitro dissolution curves of the formulations of Preparation Examples 2-8 and Preparation Example 6 using a pH 6.8 phosphate buffer as the dissolution medium.
  • Figure 9 shows the in vitro dissolution curves of preparations 2-8 and 6 with 0.1N HCl as the dissolution medium.
  • Fig. 10 is an ellipsoid diagram of a single crystal three-dimensional structure of a compound of formula II.
  • the solid pharmaceutical preparations of the present invention can be prepared by methods known in the art.
  • the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, as well as excipients, binders, disintegrating agents, wetting agents, etc. can be mixed as required It can be manufactured by stirring granulation, extrusion granulation, rotating granulation, spray one-step granulation, etc. Direct dry granulation is also possible.
  • it can also be prepared by applying pellets.
  • sizing and crushing can be carried out as needed.
  • excipients, disintegrating agents, binders, antioxidants, coloring agents, etc. may be further added to the above-mentioned granules for tableting.
  • the uncoated tablets (plain tablets) or coated tablets of the present invention can be prepared according to different prescriptions, by changing the addition amount or corresponding ingredients and using the following preparation process.
  • the preparation process includes: pulverization of raw materials, sieving of auxiliary materials, weighing, mixing and granulation, wet granulation, drying, dry granulation, final mixing, tabletting, and coating (required when preparing coated tablets).
  • Crushed raw materials Qualified raw materials (compounds of formula (I) or formula (II), pharmaceutically acceptable salts, or a mixture of the two) have a particle size of 120-150 ⁇ m, which can be achieved by adjusting different parameters of the crushing equipment Raw material particle size requirements.
  • Particle size control D90 ⁇ 10 ⁇ m, D90 ⁇ 20 ⁇ m or D90 ⁇ 30 ⁇ m take qualified APIs (compounds of formula (I) or formula (II), their pharmaceutically acceptable salts, or a mixture of the two) After sieving, add the jet mill to pulverize, control the feeder speed 100 ⁇ 500rpm, adjust the feed pressure 3 ⁇ 7bar, the crushing pressure 2 ⁇ 7bar, control the pulverization to detect the particle size of the raw material, and measure the particle size distribution with the laser particle size distribution meter Should meet the particle size D90 ⁇ 10 ⁇ m, D90 ⁇ 20 ⁇ m, D90 ⁇ 30 ⁇ m; (2) particle size control D90 ⁇ 50 ⁇ m: take qualified API (formula (I) or formula (II)) and use a laboratory shear grinder Crush, crush for 3 minutes, intermittently for 5 minutes, after crushing for a certain period of time, take a sample to detect the particle size of the bulk drug. The particle size distribution measured by the laser particle size distribution meter should satisfy D90 ⁇ 50 ⁇ m.
  • Excipients sieved Receive the qualified excipient lactose (Granulac 200 mesh).
  • Weighing Weigh the crude drug (crushed), microcrystalline cellulose (PH101), lactose (Granulac 200 mesh) (sieved), hypromellose-E5, croscarmellose sodium or hydroxy Propyl Methyl Cellulose-K4M (with internal disintegrant).
  • pulping that is, binder preparation: weigh 300g of purified water, add 30g of hypromellose-E5 while stirring, continue stirring until it dissolves, and prepare a 10% hypromellose-E5 aqueous solution , Pass through a 60-mesh sieve and set aside.
  • Mixing that is: adding the raw material (crushed) and lactose (sieved) to the wet mixing granulator to start stirring and mixing, the stirring speed is 300-500 rpm (for example, 300 rpm or 400 rpm), and the chopping speed is 350-400 rpm or 400 ⁇ 500rpm (e.g.
  • the stirring speed is 300-500 rpm (for example, 350 rpm or 400 rpm)
  • the cutting speed is 400-500 rpm (preferably 400 rpm)
  • the stirring time is 600 seconds.
  • Making soft material the whole soft material making is divided into two stages.
  • the first stage After starting the preset parameters in the wet mixing granulator, set the stirring speed to 350 ⁇ 500rpm (for example, 350rpm), and the cutting speed to 1000 ⁇ 1500rpm (For example, 1000rpm), after running for 10S, slowly add all 10% (w/w) hypromellose-E5 aqueous binder into the wet mixing granulator, and continue to turn on the stirring paddle after adding the binder solution And the chopper to make the wet particles uniform without obvious clumps.
  • 350 ⁇ 500rpm for example, 350rpm
  • 1000 ⁇ 1500rpm for example, 1000rpm
  • the granulation time is ⁇ 300 seconds (for example, 60s); the second stage: set the stirring speed to 500rpm or 350rpm, and the cutting speed to 1500rpm or 1000rpm, while turning on the stirring and cutting, continue stirring and cutting for 60s to make suitable wet granules.
  • wet granulation use a swing type granulator to granulate the obtained wet granules through an 18-mesh stainless steel sieve or use a 20-mesh sieve for manual wet granulation.
  • Drying Spread the whole wet granules evenly in the baking pan.
  • the thickness of the spreading pan should be 1.5cm ⁇ 0.5cm. Push the spreading wet granules into the oven to start drying, so that the drying temperature is 65.0°C ⁇ 5.0°C . After drying for 30 minutes, turn over the plate and check the moisture of the particles. The end of the drying is that the moisture of the particles after drying should be ⁇ 2.0%.
  • Dry granulation The dried granules are sized through a 20-mesh stainless steel sieve with a swing granulator.
  • Tableting receive the final mixed granules of the raw material tablets, and compress them with a rotary tablet press.
  • Coating Coating the plain tablets obtained by pressing, and the target coating weight gain is 2% to 3%.
  • the gastric-soluble film coating premix is selected as the coating material, and the concentration of the coating solution is 15%.
  • the specific preparation method is: weigh 30g of the coating powder, add it to 200g of purified water, stir to make the dispersion uniform. It is formulated according to 200% of the weight gain of 3%), and then coated with a high-efficiency coating machine. The coating can be carried out using the following process parameters.
  • the single crystal structure was tested with D8 Venture X-ray single crystal diffractometer.
  • Light source Cu target
  • resolution Current and voltage 50kV, 1.2mA, exposure time 10s
  • the distance between the surface detector and the sample is 40mm
  • the test temperature is 150(2)K.
  • the weight percentages of the active ingredients, filler components, binder components, disintegrant components, and lubricant components of the solid pharmaceutical preparations disclosed herein are the percentages of each component in the final solid drug.
  • the percentage of the formulation does not include any surface coverings, such as tablet coatings (such as any clear or colored coatings) or capsules.
  • tablet coatings such as any clear or colored coatings
  • the coated tablets in the following specific examples include the weight of the coating, the weight percentages of the active ingredient, filler component, binder component, disintegrant component, and lubricant component are calculated There are slight changes, but this is only used to illustrate the present invention and cannot be used to limit the scope of the present invention.
  • the active ingredients of the formula (II) in the following preparation examples are in crystalline form A, microcrystalline cellulose is selected from microcrystalline cellulose PH101, lactose is selected from lactose Granulac 200 mesh, croscarmellose The sodium base cellulose is selected from croscarmellose sodium SD711.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to the jet mill.
  • the crushing pressure is set to 6-7bar
  • the inlet pressure is 7-8bar
  • the feeding pressure is 6-7bar
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • Add D90 ⁇ 20 ⁇ m (D90 17.89 ⁇ m) the compound of formula (II) and lactose into the wet mixing granulator and stir and mix, then add the microcrystalline cellulose and croscarmellose sodium, stir and mix, and then mix to the wet method.
  • a 10% (mass percentage) hypromellose-E5 aqueous solution is slowly added to the granulator to perform wet granulation, wet granulation, and oven drying. After drying, the moisture of the granules is less than 2.0%. Then, dry granulation is performed, and the obtained dried granules, croscarmellose sodium and magnesium stearate are finally mixed in a mixer, and the total granule moisture content after the final mixing is less than or equal to 3.0%. Tablet.
  • An uncoated plain tablet with a specification of 500 mg was prepared.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to the jet mill.
  • the crushing pressure is set to 2 to 4 bar
  • the inlet pressure is 4 to 5 bar
  • the feeding pressure is 3 to 4 bar
  • the feeding speed It is 300-400rpm
  • Add the compound of formula (II) with particle size D90 ⁇ 150 ⁇ m (D90 144.5 ⁇ m) and lactose into a wet mixing granulator and stir and mix, then add microcrystalline cellulose and croscarmellose sodium, stir and mix, and then add to A 10% (mass percentage) hypromellose-E5 aqueous solution is slowly added to the wet mixing granulator to perform wet granulation, wet granulation, and oven drying.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • Add D90 ⁇ 20 ⁇ m (D90 17.89 ⁇ m) the compound of formula (II) and lactose into the wet mixing granulator and stir and mix, then add the microcrystalline cellulose and croscarmellose sodium, stir and mix, and then mix to the wet method.
  • a 10% (mass percentage) hypromellose-E5 aqueous solution is slowly added to the granulator to perform wet granulation, wet granulation, and oven drying. After drying, the moisture of the granules is less than 2.0%. Then, dry granulation is performed, and the obtained dried granules, croscarmellose sodium and magnesium stearate are finally mixed in a mixer, and the total granule moisture content after the final mixing is less than or equal to 3.0%. Tablets were compressed and coated with a gastric-soluble film-coating premix to prepare tablets with a specification of 410 mg.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to the jet mill.
  • the crushing pressure is set to 6-7bar
  • the inlet pressure is 7-8bar
  • the feeding pressure is 6-7bar
  • Add the compound of formula (II) with a particle size of D90 ⁇ 150 ⁇ m (D90 144.5 ⁇ m) and lactose into a wet mixing granulator and stir and mix, then add microcrystalline cellulose and croscarmellose sodium, stir and mix, and then add to A 10% (mass percentage) hypromellose-E5 aqueous solution is slowly added to the wet mixing granulator to perform wet granulation, wet granulation, and oven drying.
  • the sieved crude drug is added to the jet mill, and the crushing pressure is set to 4-6bar, the inlet pressure is 6-7bar, and the feed pressure is 5-6bar.
  • the sieved crude drug is added to the jet mill, and the crushing pressure is set to 4-6bar, the inlet pressure is 6-7bar, and the feed pressure is 5-6bar.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to the jet mill.
  • the crushing pressure is set to 6-7bar
  • the inlet pressure is 7-8bar
  • the feeding pressure is 6-7bar
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to the jet mill.
  • the crushing pressure is set to 6-7bar
  • the inlet pressure is 7-8bar
  • the feeding pressure is 6-7bar
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • the compound of formula (II) is passed through a 20-mesh sieve, and the raw drug after sieving is added to a jet mill.
  • Add D90 ⁇ 20 ⁇ m (D90 17.89 ⁇ m) the compound of formula (II) and lactose into the wet mixing granulator and stir and mix, then add the microcrystalline cellulose and croscarmellose sodium, stir and mix, and then mix to the wet method.
  • a 10% (mass percentage) hypromellose-E5 aqueous solution is slowly added to the granulator to perform wet granulation, wet granulation, and oven drying. After drying, the moisture of the granules is less than 2.0%. Then, dry granulation is performed, and the obtained dried granules, croscarmellose sodium and magnesium stearate are finally mixed in a mixer, and the total granule moisture content after the final mixing is less than or equal to 3.0%. Tablets were compressed and coated with a gastric-soluble film-coating premix to prepare tablets with a specification of 102 mg.
  • the compound of formula (II) (in crystalline form B) is passed through a 20-mesh sieve, and the sieved crude drug is added to a jet mill.
  • the in vitro dissolution test of the tablet formulation prepared in the above preparation example was carried out to detect its dissolution in a phosphate buffer of pH 6.8, and the dissolution device was the paddle method.
  • the dissolution medium is pH6.8 buffer
  • the water bath temperature is 37.0 ⁇ 0.5°C
  • the dissolution volume is 900ml
  • the speed is 50 revolutions per minute
  • the sampling time is 5min, 10min, 15min, 20min, 30min, 45min, 60min
  • the sampling volume is 5ml
  • the filter membrane is a polyethersulfone filter.
  • the oral bioavailability of dogs was studied on the prepared samples. Designed in accordance with the technical guidelines for non-clinical pharmacokinetic research of drugs of the former China Food and Drug Administration (CFDA) and ICH M3 (R2).
  • the tablet specification is 20 mg, 1 tablet per dog, according to the design time point Collect samples, use HPLC-MS/MS method to detect the concentration of active ingredients in the samples, and calculate the pharmacokinetic parameters.
  • the specific test content is as follows:
  • Animals and administration Ordinary Beagle dogs aged 7-14 months, weighing 9.51kg-11.14kg. Oral administration, a single dose on each dosing day, dosing time 8:00-12:00, all animals fasted overnight before each dosing, and continue to fast for 2-3 hours after the dosing, but the total is forbidden Eating time did not exceed 24 hours.
  • Blood collection blood collection from the vein of the forelimb, the blood collection time is each administration day (i.e., 1 day, 5 days, 8 days, 12 days and 15 days).
  • the blood sampling time points were before administration (0h), 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration.
  • ⁇ -65°C ultra-low temperature refrigerator

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Abstract

本发明涉及一种固体药物制剂及其制备方法，具体地，公开了一种包含食欲素受体拮抗剂化合物的固体药物制剂及其制备方法，所述固体药物制剂包含活性成分式I化合物、填充剂、粘合剂、崩解剂、润滑剂。该固体药物制剂具有良好的溶出度、稳定性以及体内生物利用度。

Description

固体药物制剂及其制备方法和用途 技术领域
本发明属于药物制剂领域，具体地，涉及一种包含食欲素受体拮抗剂化合物的固体药物制剂及其制备方法和在制备治疗与食欲素有关疾病的药物中的应用。
背景技术
食欲素(食欲肽)包括下丘脑中所产生的两种神经肽：食欲素A(OX-A)(33个氨基酸的肽)和食欲素B(OX-B)(28个氨基酸的肽)(SakuraiT.等人，Cell,1998,92,573-585)。人们发现，食欲素能够在大鼠中刺激食物消耗，这说明，在调节摄食行为的中心反馈机制中，这些肽具有作为介质的生理学作用(Sakurai T.等人，Cell,1998,92,573-585)。食欲素能够调节睡眠和失眠的状态，潜在地提出了治疗发作性睡眠或失眠症患者的新方法(Chemelli R.M.等人，Cell,1999,98,437-451)。食欲素还在觉醒、激励、学习和记忆中起一定作用(Harris，等人，Trends Neurosc1.,2006,29(10),571-577)。在哺乳动物中，已经克隆和表征了两种食欲素受体：食欲素-1受体和食欲素-2受体。它们属于G蛋白偶联受体超家族(Sakurai T.等人，Cell,1998,92,573-585)，其中食欲素-1受体(OX或OX1R)对OX-A具有选择性，食欲素-2受体(OX2或OX2R)能够与OX-A以及OX-B结合。人们认为，食欲素所参与的生理作用是通过OX1受体和OX2(作为食欲素受体的两个亚型)的其中一个或两个的表达来实现的。
在温血动物脑中可以发现食欲素受体，并且食欲素受体与例如下列病变有关：忧郁症；焦虑症；成瘾；强迫性的强制病症；情感性神经症；抑郁性神经症；焦虑性神经症；精神抑郁病症；行为失常；心情病症；性功能紊乱；性心理的功能紊乱；性别病症；精神分裂症；躁狂性忧郁症；精神错乱；痴呆；严重的智力迟钝和运动障碍，例如亨丁顿舞蹈症和妥瑞症；进食障碍，例如厌食，贪食症，恶病体质和肥胖症；上瘾性摄食行为；狂吃狂泻的摄食行为；心血管性疾病；糖尿病；食欲/味觉失调；呕吐，呕，恶心；哮喘；癌症；帕金森氏症；库兴氏综合症/疾病；嗜碱细胞腺瘤；泌乳素瘤；高催乳素血症；脑下垂体肿瘤/腺瘤；下丘脑疾病；炎症性肠病；胃机能障碍；胃溃疡；肥胖性生殖器退化；腺垂体疾病；脑下垂体疾病；腺垂体机能减退；腺垂体机能亢进；下丘脑的性腺机能减退；卡尔曼氏综合症(嗅觉缺失，嗅觉减退)；功能性或心因性闭经；垂体机能减退；下丘脑的甲状腺机能减退；下丘脑-肾上腺功能紊乱；突发性的高催乳素血症；下丘脑病的生长激素缺乏；突发性的生长缺乏；侏儒症；巨人症；肢端肥大症；受到干扰的生物和昼夜节律；与疾病例如神经错乱、神经性疼痛和多动腿综 合征相关的睡眠障碍；心脏和肺疾病，急性和充血性心力衰竭；低血压；高血压症；尿储留；骨质疏松症；心绞痛；急性心肌梗死；缺血性或出血性中风；蛛网膜出血；溃疡；变态反应；良性前列腺肥大；慢性肾衰竭；肾病；葡糖耐量削弱；偏头痛；痛觉过敏；疼痛；对疼痛敏感性增强或夸张，例如痛觉过敏、灼痛和触摸痛；急性疼痛；灼伤性疼痛；非典型性的面部疼痛；神经性疼痛；背痛；复合区域疼痛综合症I和II；关节炎疼痛；运动创伤疼痛；与感染例如HIV相关的疼痛，化疗后疼痛；中风后的疼痛；手术后的疼痛；神经痛；呕吐，恶心，呕；与内脏疼痛相关的病症，例如过敏性肠综合症和心绞痛；偏头痛；膀胱失禁，例如急迫性尿失禁；对麻醉剂或戒除麻醉剂的耐受性；睡眠障碍；睡眠呼吸暂停；嗜眠病；失眠；深眠状态；时差综合症；和神经变性的病症，包括疾病分类实体，例如抑制解除-痴呆-震颤性麻痹-肌萎缩综合征；癫痫；癫痫发作病症及其它与普通食欲素系统功能紊乱相关的疾病。
CN106414439A公开了一类作为食欲素受体拮抗剂的哌啶衍生物，其对OX1和OX2GPCR受体具有明显的抑制作用，在研究中发现，将其制备成固体药物组合物时，存在溶出速率和溶出度较低，以及生物利用度较低和体内半衰期较高的不足，而对于治疗失眠类药物而言较长的半衰期显然存在不利的影响，例如会产生第二天残留效应，从而对患者造成不良后果。因此有必要将其开发成具有较高溶出速率和溶出度，以及较高的生物利用度和较低的半衰期的固体药物剂型以满足更广泛的临床给药需求。
发明内容
本发明的目的是提供一种稳定性好、溶出效果好且具有良好生物利用度的包含式I化合物的固体药物制剂。
本发明第一方面提供了一种固体药物制剂，其中，所述固体药物制剂包含活性成分，该活性成分为式(I)所示的化合物或其药学上可接受盐，或二者的混合物；
Figure PCTCN2021087262-appb-000001
其中R a为氢、氟、氯、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或 异丙氧基；
Z为N或CR 0；R 0为氢、卤素或C 1-3烷基；
n为0、1或2；
并且所述活性成分的粒径为D90≤50μm。
在另一优选例中，所述活性成分的粒径为D90≤35μm。在另一优选例中，所述活性成分的粒径为D90≤30μm。在另一优选例中，所述活性成分的粒径为D90≤20μm。在另一优选例中，所述活性成分的粒径为D90≤10μm。在另一优选例中，所述活性成分的粒径为D90＝1μm～30μm。在另一优选例中，所述活性成分的粒径为D90＝1μm～20μm。在另一优选例中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一优选例中，式(I)所示的化合物为式(II)化合物：
Figure PCTCN2021087262-appb-000002
((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基
-2-(嘧啶-2-基)苯基)甲酮。如专利CN106414439A中所记载的，通过FLIPR检
测细胞内钙信号变化，以化合物的IC50值为指标，来评价式(II)化合物对OX1
和OX2GPCR受体的抑制作用，其活性分别为20nM(hOX1R)和36nM(hOX2R)。
本发明所述药学上可接受的盐包括药学可接受的酸加成盐和药学可接受的碱加成盐。其中药学上可接受的酸加成盐是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、丙酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐和水杨酸盐等。这些盐可通过本技术领域已知的方法制备。药学可接受的碱加成盐包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。这些盐可通过本技术领域已知的方法制备。
本发明所述的式(I)和式(II)所示化合物或其药学上可接受的盐可以是任意形式，具体形式包括但不限于无定形、任意晶型、水合物、溶剂合物等。在一些实施方案中，式(II) 所示化合物以结晶形式A存在，其Cu-Kα辐射的XRPD谱图解析如下，其结构如图6所示。
衍射角2θ 相对强度(％) 衍射角2θ 相对强度(％)
10.428 60.0 25.533 8.2
11.968 100.0 26.083 11.0
13.542 17.8 27.133 3.1
14.238 3.4 27.506 17.7
14.767 12.1 28.316 3.0
15.851 73.9 29.557 2.2
16.818 72.0 30.740 4.2
18.003 9.2 31.846 5.1
19.087 2.1 32.550 2.0
19.755 47.6 33.775 3.1
20.900 25.7 34.682 2.2
22.652 2.9 36.422 3.4
23.858 49.2 36.953 3.4
24.844 23.2 38.569 3.0
在一些实施方案中，式(II)所示化合物以结晶形式B存在，其Cu-Kα辐射的XRPD谱图解析如下，其结构如图7所示。
衍射角2θ 相对强度(％) 衍射角2θ 相对强度(％)
8.611 100.0 23.953 2.6
10.330 70.6 24.370 32.3
12.284 13.4 26.501 29.4
13.703 23.9 26.915 8.7
14.057 5.6 27.663 11.0
14.351 4.8 27.939 15.5
14.848 9.2 29.499 2.6
15.576 7.5 30.604 2.2
16.602 31.6 31.727 13.3
17.250 71.3 32.969 2.6
17.902 90.7 33.378 2.8
18.277 42.4 33.777 3.0
19.149 6.5 34.825 1.6
20.625 21.7 36.399 5.3
21.550 42.7 37.366 4.3
22.124 2.3 39.357 3.3
23.307 33.4    
本发明中提及的结晶形式A和结晶形式B可参照专利CN107709318A中记载的方法进行制备和表征。在一些实施方案中，式(II)所示化合物以结晶形式存在，其单晶X射线衍射表明式(II)化合物具有如图10所示的一种立体结构椭球图。
在另一优选例中，所述活性成分的含量为1％–15％，更佳地为4％–10％，更佳地为9.5％–10％，所述百分比是以固体药物制剂的总干燥重量计。
在另一优选例中，所述固体药物制剂还包括粘合剂，所述粘合剂选自羟丙甲纤维素、羟丙纤维素、聚维酮、海藻酸钠、卡波普、聚乙烯醇中的一种或多种，所述粘合剂的含量为0.5％–10％，更佳地为1.5％–3％，所述百分比是以固体药物制剂的总干燥重量计。
在另一优选例中，所述粘合剂选自羟丙甲纤维素-E5、羟丙甲纤维素-K4M、羟丙甲纤维素-E50、卡波普、聚乙烯醇中的一种或多种。
在另一优选例中，所述粘合剂选自羟丙甲纤维素-E5。
在另一优选例中，所述固体药物制剂还包括填充剂，所述填充剂选自微晶纤维素、乳糖、纤维素乳糖复合物、预胶化淀粉、磷酸氢钙、碳酸钙中的一种或多种，所述填充剂的含量为60％至90％，更佳地为73％至85％，更佳地为73％–82.5％，所述百分比是以固体药物制剂的总干燥重量计。
在另一优选例中，所述填充剂为微晶纤维素和乳糖。
在另一优选例中，所述固体药物制剂还包括崩解剂，所述崩解剂选自交联羧甲基纤维素钠、羟丙甲纤维素-K4M、交联聚维酮、羧甲基淀粉钠中的一种或多种，所述崩解剂的含量为5％–15％，所述百分比是以固体药物制剂的总干燥重量计。
在另一优选例中，所述崩解剂选自交联羧甲基纤维素钠和羟丙甲纤维素-K4M。
在另一优选例中，所述固体药物制剂还包括润滑剂，所述润滑剂选自硬脂酸镁、滑石粉、单硬脂酸甘油酯、硬脂酸富马酸钠中的一种或多种，所述润滑剂的含量为0.1％–1％，更佳地为0.4％–0.5％，更佳地为0.48％–0.5％，所述百分比是以固体药物制剂的总干燥重量计。
在另一优选例中，所述固体药物制剂为片剂、胶囊剂、散剂、颗粒剂、滴丸剂或膜剂，优选为片剂。
在另一优选例中，所述固体药物制剂包含以固体药物制剂的总干燥重量计的下述组分：a)活性成分：((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮，或其药学上可接受的盐，或二者的混合物；所述活性成分的含量为1％–15％，更佳地为4％–10％，更佳地为9.5％–10％；
b)填充剂，选自微晶纤维素、乳糖、纤维素乳糖复合物、预胶化淀粉、磷酸氢钙、碳酸钙中的一种或多种，所述填充剂的含量为60％–90％，更佳地为73％–85％，更佳地为 73％–82.5％；
c)粘合剂，选自羟丙甲纤维素、羟丙纤维素、聚维酮、海藻酸钠、卡波普、聚乙烯醇中的一种或多种，所述粘合剂的含量为0.5％–10％，更佳地为1.5％–3％；
d)崩解剂，选自交联羧甲基纤维素钠、羟丙甲纤维素-K4M、交联聚维酮、羧甲基淀粉钠中的一种或多种，所述崩解剂的含量为5％–15％；
e)润滑剂，选自选自硬脂酸镁、滑石粉、单硬脂酸甘油酯、硬脂酸富马酸钠中的一种或多种，所述润滑剂的含量为0.1％–1％，更佳地为0.4％–0.5％，更佳地为0.48％–0.5％；
其中所述活性成分的粒径为D90≤35μm。
在另一优选例中，所述活性成分的粒径为D90≤30μm。在另一优选例中，所述活性成分的粒径为D90≤20μm。在另一优选例中，所述活性成分的粒径为D90≤10μm。在另一优选例中，所述活性成分的粒径为D90＝1μm～30μm。在另一优选例中，所述活性成分的粒径为D90＝1μm～20μm。在另一优选例中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一优选例中，所述固体制剂为片剂。
在另一优选例中，所述活性成分的含量为5mg～100mg。在另一优选例中，所述活性成分的含量为10mg～50mg。在另一优选例中，所述活性成分的含量为10mg、20mg或40mg。
在另一优选例中，所述粘合剂选自羟丙甲纤维素-E5、羟丙甲纤维素-K4M、羟丙甲纤维素-E50、卡波普、聚乙烯醇中的一种或多种。
在另一优选例中，所述粘合剂选自羟丙甲纤维素-E5。
在另一优选例中，所述填充剂为微晶纤维素和乳糖。
在另一优选例中，所述崩解剂选自交联羧甲基纤维素钠和羟丙甲纤维素-K4M。
在另一优选例中，所述固体药物制剂包含以固体药物制剂的总干燥重量计的下述组分：a)活性成分：((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮或其药学上可接受的盐，或二者的混合物；所述活性成分的含量为4％–10％；
b)微晶纤维素，含量为24％–27.5％；
c)乳糖，含量为48.5％–56.5％；
d)羟丙甲纤维素-E5，含量为1.5％–3％；
e)交联羧甲基纤维素钠或羟丙甲纤维素-K4M，含量为5％–15％；
f)硬脂酸镁，含量为0.4％–0.5％；
其中所述活性成分的粒径为D90≤35μm，或为D90≤30μm，或为D90≤20μm，或为D90≤10μm，或为D90＝1μm～30μm，或为D90＝1μm～20μm，或为D90＝1μm～10μm，或为 D90＝10μm～20μm。
在另一优选例中，包含以固体药物制剂的总干燥重量计的下述组分：
a)活性成分：((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮或其药学上可接受的盐，或二者的混合物；所述活性成分的含量为9.5％–10％；
b)微晶纤维素，含量为24％–27.5％；
c)乳糖，含量为48.5％–56.5％；
d)羟丙甲纤维素-E5，含量为1.5％–3％；
e)交联羧甲基纤维素钠或羟丙甲纤维素-K4M，含量为5％–15％；
f)硬脂酸镁，含量为0.48％–0.5％；
其中所述活性成分的粒径为D90＝1μm～30μm，或为D90＝1μm～20μm，或为D90＝1μm～10μm，或为D90＝10μm～20μm，所述固体制剂为片剂。
在另一优选例中，所述乳糖为200目、100目、50目等。更佳的是乳糖为200目。
在另一优选例中，所述填充剂为微晶纤维素和乳糖；微晶纤维素和乳糖的重量比为(24–27.5):(48.5–56.5)。
在另一优选例中，所述固体药物制剂包括制备例中的任一片剂。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：约10mg、约20mg或约40mg的活性成分，该活性成分为式(II)化合物；约25mg至约150mg的微晶纤维素(例如微晶纤维素PH101)；约50mg至约300mg的乳糖(例如Granulac 200)；约1mg至约15mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；约10mg至约50mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)或羟丙甲纤维素(例如HPMC-K4M)；约0.5mg至约3mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：约10mg的活性成分，该活性成分为式(II)化合物；约25mg至约26mg的微晶纤维素(例如微晶纤维素PH101)；约51mg的乳糖(例如Granulac 200)；约3mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；约10mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)；约0.5mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：约20mg的活性成分，该活性成分为式(II)化合物；约51mg的微晶纤维素(例如 微晶纤维素PH101)；约102mg的乳糖(例如Granulac 200)；约6mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；约20mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)；约1mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：约40mg的活性成分，该活性成分为式(II)化合物；约102mg的微晶纤维素(例如微晶纤维素PH101)；约204mg的乳糖(例如Granulac 200)；约12mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；约40mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)；约2mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：8mg至12mg的活性成分，该活性成分为式(II)化合物；20mg至30mg的微晶纤维素(例如微晶纤维素PH101)；46mg至56mg的乳糖(例如Granulac 200)；2mg至4mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；5mg至15mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)；0.3mg至0.7mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：18mg至22mg的活性成分，该活性成分为式(II)化合物；46mg至56mg的微晶纤维素(例如微晶纤维素PH101)；97mg至107mg的乳糖(例如Granulac 200)；5mg至7mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；15mg至25mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)；0.8mg至1.2mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在另一方面，本发明提供了一种单位剂型，以该单位剂型的总重量计，该单位剂型包含：38mg至42mg的活性成分，该活性成分为式(II)化合物；97mg至107mg的微晶纤维素(例如微晶纤维素PH101)；199mg至209mg的乳糖(例如Granulac 200)；11mg至13mg的羟丙甲纤维素(例如羟丙甲纤维素E5)；35mg至45mg交联羧甲基纤维素钠(例如交联羧甲基纤维素钠SD711)；1.8mg至2.2mg的硬脂酸镁，其中所述活性成分的粒径为D90＝1μm～20μm；在一些实施方案中，所述活性成分的粒径为D90＝1μm～10μm或为D90＝10μm～20μm。
在一些实施方案中，本发明所提供的上述任一单位剂型中，作为活性成分的式(II) 化合物可以任意形式存在，包括无定形、任意结晶形式、水合物、溶剂合物等。在一些实施方案中，作为活性成分的式(II)化合物是以无定形形式、结晶形式A或结晶形式B存在。在一些实施方案中，作为活性成分的式(II)化合物以结晶形式A存在。
在一些实施方案中，上述单位剂型为片剂或胶囊剂。在一些实施方案中，上述单位剂型为片剂。在一些实施方案中，上述单位剂型为片剂并且进一步包含包衣。
片剂可以通过常规的压制、湿法制粒或干法制粒方法来制备。在一些实施方案中，本发明的剂型是湿法制粒方法制备得到的片剂。片剂还可以包括一种或多种表面包衣，例如澄清包衣和/或有颜色的包衣。各种包衣及其应用方法是本领域已知的，包括在Remington′s Pharmaceutical Sciences(第17版，马克(Mack)出版公司，伊斯顿，Pa.，1985)中公开的那些。当存在适量的包衣时，片剂的重量通常会增重2％～3％，因此片剂通常可以在约50mg至约1000mg之间，在一些实施方案中，片剂的重量为约100mg、约150mg、约200mg、约250mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg等，这取决于治疗用途所需的剂量。
本发明上述单位剂型中的重量数值前所使用的“约”字表示±10mg，或±5mg，或±2mg，或±1mg，或±0.5mg，或±0.2mg，或±0.1mg的范围值。
本发明中活性成分的粒径D90表示一个样品的累计粒度分布百分数达到90％时所对应的粒径。
可用于本发明制剂的薄膜包衣是本领域已知的并且通常包含聚合物(通常是纤维素型聚合物)、着色剂和增塑剂。另外的成分如糖、矫味剂、油和润滑剂可以包括在薄膜包衣配制物中以给予薄膜包衣某些特性。还可以将本文的组合物和制剂合并和处理为固体，然后置于胶囊形式如明胶胶囊中。
应当理解，本发明的制剂的一些组分可以具有多重功能。例如，给定的组分既可以用作填充剂，又可以用作崩解剂。在一些这类情况中，给定组分的功能可以被认为是单一的，尽管其性质可以允许多功能性。
本发明中，乳糖可以选自适用药学领域的可市购的乳糖，包括Flow100、Granulac 200、Tableffose 100、Spherolac 100等。微晶纤维素可以选自适用药学领域的可市购的微晶纤维素，包括pH101、pH102、pH301、pH302、KG1000、KG802、UF702、UF711等。预胶化淀粉(又称改性淀粉)可以选自适用药学领域的可市购的预胶化淀粉，包括Starch 1500、PC10等。羟丙甲纤维素可以选自适用药学领域的可市购的羟丙甲纤维素，包括HPMC E3、HPMC E5、HPMC K4M、HPMC E15等。聚维酮可以选自适用药学领域的可市购的聚维酮，包括聚维酮K30、聚维酮K90。交联聚维酮可以选自适用药学领域的可市购的交联聚维酮，包括PVPP XL-10、PVPP VL-10、PVPP XL。交联羧甲基纤维素 钠可以选自适用药学领域的可市购的交联羧甲基纤维素钠，包括RC-A591NF、SD-711等。
本发明第二方面提供了一种片剂的制备方法，所述方法包括下述步骤：
(a)将活性成分颗粒、填充剂、粘合剂和第一崩解剂混合后湿法制粒；
(b)将步骤(a)所得产物干燥；
(c)将步骤(b)所得产物、第二崩解剂和润滑剂干混合；和
(d)将步骤(c)所得产物压制成片；
其中活性成分为((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮或其药学上可接受盐，或二者的混合物；
活性成分颗粒的粒径为D90≤50μm。
第一崩解剂和第二崩解剂可以相同，也可以不同。
在另一优选例中，活性成分颗粒的粒径为D90≤35μm。在另一优选例中，活性成分颗粒的粒径为D90≤30μm。在另一优选例中，活性成分颗粒的粒径为D90≤20μm。在另一优选例中，活性成分颗粒的粒径为D90≤10μm。在另一优选例中，活性成分颗粒的粒径为D90＝1μm～30μm。在另一优选例中，活性成分颗粒的粒径为D90＝1μm～20μm。在另一优选例中，活性成分颗粒的粒径为D90＝1μm～10μm。在另一优选例中，活性成分颗粒的粒径为D90＝10μm～20μm。
在另一优选例中，所述填充剂选自微晶纤维素、乳糖、纤维素乳糖复合物、预胶化淀粉、磷酸氢钙、碳酸钙中的一种或多种。
在另一优选例中，所述粘合剂选自羟丙甲纤维素、羟丙纤维素、聚维酮、海藻酸钠、卡波普、聚乙烯醇中的一种或多种。
在另一优选例中，所述第一和第二崩解剂各自独立地选自交联羧甲基纤维素钠、羟丙甲纤维素-K4M、交联聚维酮、羧甲基淀粉钠中的一种或多种。
在另一优选例中，所述润滑剂选自选自硬脂酸镁、滑石粉、单硬脂酸甘油酯、硬脂酸富马酸钠中的一种或多种。
在另一优选例中，按照步骤(c)所得混合物的总干燥重量计，活性成分的含量为4％–10％。
在另一优选例中，按照步骤(c)所得混合物的总干燥重量计，填充剂的含量为73％–82.5％。
在另一优选例中，按照步骤(c)所得混合物的总干燥重量计，粘合剂的含量为1.5％–3％。
在另一优选例中，按照步骤(a)中所有组分的干燥重量计，第一崩解剂的含量为 2％–10％，更佳地为5％–6％；按照步骤(c)中所有组分的总干燥重量计，第二崩解剂的含量为5％–10％。
在另一优选例中，按照步骤(c)中所有组分的总干燥重量计，润滑剂的含量为0.1％–1％，更佳地为0.4％–0.5％，更佳地为0.48％–0.5％。
在另一优选例中，所述方法还包括步骤(e)，对步骤(d)的产物进行包衣。
在另一优选例中，所述步骤(e)中包衣材料为胃溶型薄膜包衣预混剂，包衣液浓度为10％-20％。
在另一方面，本发明还提供了本文所述方法的产物。
本发明第三方面提供了本发明第一方面所述的固体药物制剂在制备治疗与食欲素有关疾病的药物中的应用。
更佳地，所述与食欲素有关疾病包括失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍。
本文提出的材料、方法和实例意欲是说明性的，而非意欲限制本发明的范围。本文提到的所有出版物、专利申请、专利和其它参考文献整体引入作为参考。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为制备例1-1、1-2、1-3和1-4处方的溶出曲线图。
图2为制备例2-1、2-2、2-6和2-7处方的溶出曲线图。
图3为制备例2-1、2-2、2-3、2-4和2-5处方的溶出曲线图。
图4为制备例3、2-1和2-4处方的溶出曲线图。
图5为制备例4-1、4-2和4-3处方的溶出曲线图。
图6为以结晶形式A存在的式(II)化合物的Cu-Kα辐射的XRPD谱图。
图7为以结晶形式B存在的式(II)化合物的Cu-Kα辐射的XRPD谱图。
图8为制备例2-8和制备例6处方以pH6.8的磷酸盐缓冲液作为溶出介质的体外溶出曲线图。
图9为制备例2-8和制备例6处方以0.1N HCl作为溶出介质的体外溶出曲线图。
图10为一种式II化合物单晶立体结构椭球图。
制备方法
本发明所述的固体药物制剂可以通过本领域公知的方法进行制备。例如在颗粒剂的情况下，可根据需要将式(I)或式(II)所示化合物或其药学上可接受的盐以及赋形剂、粘合剂、崩解剂、润湿剂等混合进行搅拌制粒、挤出制粒、转动制粒、喷雾一步制粒等来制造，直接干法制粒亦可。此外也可采用微丸上药方式制备。此外也可根据需要进行整粒、粉碎。进而也可进一步向上述颗粒剂中加入赋形剂、崩解剂、粘合剂、抗氧剂、着色剂等进行压片。
为进一步说明，本发明的未包衣片剂(素片)或包衣片剂可根据处方不同，改变加入量或对应成分采用以下制备工艺进行制备。所述制备工艺包括：原料药粉碎，辅料过筛，称量，混合制粒，湿整粒，干燥，干整粒，终混，压片，包衣(制备包衣片剂时需要)。
原料药粉碎：合格的原料药(式(I)或式(II)化合物、其药学上可接受的盐，或二者的混合物)自身粒径为120～150μm，通过粉碎设备不同的参数调节达到原料粒径需求。(1)粒径控制D90≤10μm、D90≤20μm或D90≤30μm：取合格的原料药(式(I)或式(II)化合物、其药学上可接受的盐，或二者的混合物)过筛后加入气流粉碎机粉碎，通过控制加料机转速100～500rpm，调节进料压力3～7bar，粉碎压力2～7bar，控制粉碎后检测原料药的粒径，用激光粒度分布仪测量粒径分布应满足粒径D90≤10μm、D90≤20μm、D90≤30μm；(2)粒径控制D90≤50μm：取合格的原料药(式(I)或式(II))，用实验室剪切粉碎机粉碎，粉碎3min，间歇5min，粉碎一定时间后，取样检测原料药粒径。用激光粒度分布仪测量粒径分布应满足D90≤50μm。
辅料过筛：领取检验合格的辅料乳糖(Granulac 200目)。
称量：称取原料药(已粉碎)、微晶纤维素(PH101)、乳糖(Granulac 200目)(已过筛)、羟丙甲纤维素-E5、交联羧甲基纤维素钠或羟丙甲纤维素-K4M(内加崩解剂)。
混合制粒：制浆，即粘合剂配制：称取300g纯化水，边搅拌边加入羟丙甲纤维素-E5 30g，持续搅拌直至溶解，配制得到的10％羟丙甲纤维素-E5水溶液，过60目筛，备用。混合，即：将原料药(已粉碎)、乳糖(已过筛)依次加入至湿法混合制粒机开始搅拌混合，搅拌速度300～500rpm(例如300rpm或400rpm)，切碎速度350～400rpm或400～500rpm(例如400rpm)，搅拌时间300秒；打开物料锅盖，继续将交联羧甲基纤维素钠或羟丙甲纤维素-K4M(内加崩解剂)，微晶纤维素(PH101)依次加入锅内；开始搅拌混合，搅拌速度300～500rpm(例如350rpm或400rpm)，切碎速度400～500rpm(优选400rpm)，搅拌时间600秒。制软材，整个制软材分为两个阶段，第一阶段：开启湿法混合制粒机中预先设定参数后，设置搅拌速度为350～500rpm(例如350rpm)，切割速度为1000～1500rpm(例如1000rpm)，运行10S后向湿法混合制粒机中缓慢加入全部的 10％(w/w)羟丙甲纤维素-E5水溶液粘合剂，加完粘合剂溶液后继续开启搅拌桨和切碎刀使制成的湿颗粒均匀，且无明显团块，制粒时间(加浆时间)为≤300秒(例如60s)；第二阶段：设置搅拌速度为500rpm或350rpm，切割速度为1500rpm或1000rpm，同时开启搅拌切割，继续搅拌切割60s，制成适宜湿颗粒。
湿整粒：将制得的湿颗粒用摇摆式整粒机经18目不锈钢筛整粒或用20目筛网进行手工湿整粒。
干燥：将整粒后的湿颗粒均匀摊布于烘盘中，铺盘厚度应为1.5cm±0.5cm，将铺好湿颗粒烘盘推入烘箱开始干燥，使干燥温度在65.0℃±5.0℃。每干燥30min分别进行翻盘及颗粒水分检测，干燥终点为干燥后颗粒水分应≤2.0％。
干整粒：将干燥后的颗粒用摇摆式整粒机经20目不锈钢筛整粒。
终混：将交联羧甲基纤维素钠或羟丙甲纤维素-K4M(外加崩解剂)、干整后的颗粒、硬脂酸镁同时投入到混合机中混合300秒，混合桶转速16rpm。总混后，总颗粒水分应≤3.0％。
压片：领取原料药片终混颗粒，用旋转压片机进行压片。
包衣：对压制得到的素片进行包衣，目标包衣增重为2％～3％。选用胃溶型薄膜包衣预混剂为包衣材料，包衣液浓度为15％，具体配制方法为：称取30g的包衣粉，加入到200g的纯化水中，搅拌使分散均匀即得(按照增重3％的200％配制)，然后运用高效包衣机进行包衣。包衣可采用如下工艺参数进行。
进风温度(℃) 55.0～65.0
出风温度(℃) 45.0～50.0
加热(℃) 70.0～75.0
风量(m 3/h) 80.0～85.0
流速(g/min) 85～90
主机转速(rpm) 3.0～5.5
喷枪压力(bar) 0.11或0.9
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
单晶结构采用D8 Venture X射线单晶衍射仪测试。光源：Cu靶，X射线：
Figure PCTCN2021087262-appb-000003
探测器：CMOS面探测器，分辨率
Figure PCTCN2021087262-appb-000004
电流电压：50kV，1.2mA，曝光时间10s，面探测器至样品距离40mm，测试温度150(2)K。
除非另有说明，对本文公开的固体药物制剂的活性成分、填充剂组分、粘合剂组分、崩解剂组分和润滑剂组分所提出的重量百分数是各组分占最终固体药物制剂的百分数，而不包括任意表面覆盖物，例如片剂包衣(如任意澄清或有颜色的包衣)或胶囊。尽管以下具体实施例中的包衣片剂因将包衣重量计算在内，使得其中活性成分、填充剂组分、粘合剂组分、崩解剂组分和润滑剂组分的重量百分数计算稍有变化，但这仅用于说明本发明而不能用于限制本发明的范围。除非另有说明，以下制备例中具体处方中的活性成分式(II)化合物均以结晶形式A存在，微晶纤维素选自微晶纤维素PH101，乳糖选自乳糖Granulac200目，交联羧甲基纤维素钠选自交联羧甲基纤维素钠SD711。
制备例1-1未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000005
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为6～7bar，进气压力为7～8bar，进料压力为6～7bar，进料转速为100～150rpm，粉碎结束后，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤10μm(D90＝7.461μm)。将粒径D90≤10μm(D90＝7.461μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片。制得规格为500mg的未包衣的素片片剂。
制备例1-2未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000006
Figure PCTCN2021087262-appb-000007
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将D90≤20μm(D90＝17.89μm)式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片。制得规格为500mg的未包衣的素片片剂。
制备例1-3未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000008
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为2～4bar，进气压力为4～5bar，进料压力为3～4bar，进料转速为300～400rpm，粉碎结束后，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤35μm(D90＝30.7μm)。将D90≤35μm(D90＝30.7μm)式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片。制得规格为500mg的未包衣的素片片剂。
制备例1-4未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000009
将式(II)化合物过20目筛后，用激光粒度分布仪测量粒径分布满足粒径D90≤150μm(D90＝144.5μm)。将粒径D90≤150μm(D90＝144.5μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片。制得规格为500mg的未包衣的素片片剂。
制备例2-1包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000010
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将粒径D90≤20μm(D90＝17.89μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为205mg的片剂。
制备例2-2包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000011
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将D90≤20μm(D90＝17.89μm)式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为410mg的片剂。
制备例2-3包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000012
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为6～7bar，进气压力为7～8bar，进料压力为6～7bar，进料转速为100～150rpm，粉碎结束后，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤10μm(D90＝7.461μm)。将粒径D90≤10μm(D90＝7.461μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥， 干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为205mg的片剂。
制备例2-4包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000013
将式(II)化合物过20目筛，用实验室剪切粉碎机粉碎，粉碎3min，间歇5min，粉碎10min后，用激光粒度分布仪测量粒径分布满足粒径D90≤50μm(D90＝45.71μm)。将粒径D90≤50μm(D90＝45.71μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为205mg的片剂。
制备例2-5包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000014
将式(II)化合物过20目筛后，用激光粒度分布仪测量粒径分布满足粒径D90≤150μm(D90＝144.5μm)。将粒径D90≤150μm(D90＝144.5μm)的式(II)化合物、 乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为205mg的片剂。
制备例2-6未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000015
将式(II)化合物过20目筛后，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将粒径D90≤20μm(D90＝17.89μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片。制得规格为200mg的未包衣片剂。
制备例2-7未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000016
将式(II)化合物过20目筛后，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检 测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将粒径D90≤20μm(D90＝17.89μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，制得规格为400mg的未包衣片剂。
制备例2-8包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000017
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为6～7bar，进气压力为7～8bar，进料压力为6～7bar，进料转速为100～150rpm粉碎结束后，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤10μm(D90＝8.93μm)。将粒径D90≤10μm(D90＝8.93μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为205mg的片剂。
制备例3未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000018
Figure PCTCN2021087262-appb-000019
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为6～7bar，进气压力为7～8bar，进料压力为6～7bar，进料转速为100～150rpm，粉碎结束后，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤10μm(D90＝7.461μm)。将粒径D90≤10μm(D90＝7.461μm)的式(II)化合物、乳糖、微晶纤维素加入湿法混合制粒机搅拌混合，再缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％，压片。制得规格为500mg的片剂。
制备例4-1未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000020
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将D90≤20μm(D90＝17.89μm)式(II)化合物、乳糖、微晶纤维素、羟丙甲纤维素-K4M加入湿法混合制粒机搅拌混合，再缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，羟丙甲纤维素-K4M和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％，压片。制得规格为200mg的片剂。
制备例4-2未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000021
Figure PCTCN2021087262-appb-000022
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将D90≤20μm(D90＝17.89μm)式(II)化合物、乳糖、微晶纤维素、羟丙甲纤维素-K4M加入湿法混合制粒机搅拌混合，再缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，羟丙甲纤维素-K4M和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％，压片。制得规格为200mg的片剂。
制备例4-3未包衣的素片处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000023
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将D90≤20μm(D90＝17.89μm)式(II)化合物、乳糖、微晶纤维素、羟丙甲纤维素-K4M加入湿法混合制粒机搅拌混合，再缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，羟丙甲纤维素-K4M和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％，压片。制得规格为200mg的片剂。
制备例5包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000024
Figure PCTCN2021087262-appb-000025
将式(II)化合物过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为4～6bar，进气压力为6～7bar，进料压力为5～6bar，进料转速为200～300rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝17.89μm)。将D90≤20μm(D90＝17.89μm)式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为102mg的片剂。
制备例6包衣的片剂处方
包含式(II)化合物的片剂处方(质量百分比)：
Figure PCTCN2021087262-appb-000026
将式(II)化合物(以结晶形式B存在)过20目筛，过筛后的原料药加入气流粉碎机中，设置粉碎压力为6～7bar，进气压力为7～8bar，进料压力为6～7bar，进料转速为100～150rpm，取样检测，用激光粒度分布仪测量粒径分布满足粒径D90≤20μm(D90＝10.09μm)。将粒径D90≤20μm(D90＝10.09μm)的式(II)化合物、乳糖加入湿法混合制粒机搅拌混合，再加入微晶纤维素、交联羧甲基纤维素钠搅拌混合，然后向湿法混合制粒机中缓慢加入10％(质量百分比)羟丙甲纤维素-E5水溶液进行湿法制粒，湿整粒，烘箱干燥，干燥后颗粒水分≤2.0％。然后进行干整粒，将所得干整后的颗粒，交联羧甲基纤维素钠和硬脂酸镁在混合机中进行终混，终混后总颗粒水分≤3.0％。压片，用胃溶型薄膜包衣预混剂包衣，制得规格为205mg的片剂。
测试例1体外溶出测试
根据中国药典2015年版四部通则0931第二法，对上述制备例中制得的片剂处方进行体外溶出试验，检测其在pH6.8的磷酸缓冲液中的溶出情况，其中溶出装置为桨法， 溶出介质为pH6.8缓冲液，水浴温度为37.0±0.5℃，溶出体积为900ml，转速为每分钟50转，取样时间为5min、10min、15min、20min、30min、45min、60min，取样体积为5ml，滤膜为聚醚砜过滤器。试验结果如下表1-1至1-5和图1至图5所示。
表1-1制备例1-1至1-4的体外溶出结果
Figure PCTCN2021087262-appb-000027
表1-2制备例2-1、2-2、2-6和2-7的体外溶出结果
Figure PCTCN2021087262-appb-000028
表1-3制备例2-1至2-5的体外溶出结果
Figure PCTCN2021087262-appb-000029
表1-4制备例3、2-1和2-4的体外溶出结果
Figure PCTCN2021087262-appb-000030
表1-5制备例4-1至4-3的体外溶出结果
Figure PCTCN2021087262-appb-000031
表1-6制备例2-8和制备例6的体外溶出结果
Figure PCTCN2021087262-appb-000032
测试例2稳定性测试
将制备样品放入高温60℃和加速(40℃/75％RH)条件下一定时间后，样品根据中国药典2015年版四部通则0512和0931第二法，检测含量、有关物质和溶出度，考察其稳定性。测试结果如表2-1所示。
表2-1制备例2-1、2-2和2-4的稳定性结果
Figure PCTCN2021087262-appb-000033
测试例3狗口服生物利用度测试
对制备样品进行了狗口服生物利用度研究。按照原国家食品药品监督管理总局(CFDA)的药物非临床药代动力学研究技术指导原则和ICH M3(R2)进行设计，片剂规格为20mg，1片/1只犬，按照设计的时间点采集样品，采用HPLC-MS/MS方法检测样品中活性成分浓度，并计算药代参数。具体试验内容如下：
动物和给药：普通级7-14月龄Beagle犬，体重9.51kg-11.14kg。口服给药，每个给药日单次给药，给药时间8:00-12:00，所有动物每次给药前隔夜禁食，给药后继续禁 食2-3小时，但总禁食时间未超过24小时。
采血：前肢静脉采血，采血时间为每个给药日(即1天，5天，8天，12天和15天)。采血时间点为给药前(0h)、给药后5min，15min，30min，1h，2h，4h，6h，8h和24h。收集约1mL血液于EDTA二钾盐抗凝真空采血管中。采集血液后，轻轻振摇使血液与抗凝剂充分混匀。血液采集后置碎冰中，并于采集后1h内离心(4℃，2000g，10min)。离心后收集血浆约400μL于一棕色塑料管中，并立即暂存于装有干冰的容器中，之后再转入超低温冰箱(≤-65℃)，避光存放。
样品分析：采用HPLC-MS/MS方法检测样品中活性成分浓度，采用微软Excel2013进行数据的处理及计算。分析测定样品在血浆中的浓度后，采用WinNonlin6.3软件绘制浓度-时间曲线，并按非房室模型计算药代动力学参数。相应处方的药代参数结果分别见下表3-1，表3-2和表3-3，同一表中的结果为同一批次下测试得到的，不同表中的结果为不同批次下测试得到的。
表3-1制备例1-1、1-2和2-4的口服生物利用度
Figure PCTCN2021087262-appb-000034
表3-2制备例2-1、2-3和2-5的口服生物利用度
Figure PCTCN2021087262-appb-000035
表3-3制备例3、2-1、2-3和2-4的口服生物利用度
制备例 T 1/2(h) T max(h) C max(ng/mL) AUC 0-t(ng*h/mL)
制备例3 1.38 0.875 436 1000
制备例2-1 1.88 1.25 708 1060
制备例2-4 6.17 0.875 393 901
制备例2-3 0.79 1.25 613 927
从上表可以看出处方中活性成分的不同粒径对Beagle犬体内的药代参数有不同的影响，例如延长的半衰期或降低的暴露量。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (26)

  1. 一种固体药物制剂，其特征在于，所述固体药物制剂包含活性成分，该活性成分为式(I)所示的化合物或其药学上可接受的盐，或二者的混合物；
    Figure PCTCN2021087262-appb-100001
    其中R a为氢、氟、氯、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基；Z为N或CR 0；R 0为氢、卤素或C 1-3烷基；n为0、1或2；
    并且所述活性成分的粒径为D90≤50μm。
  2. 如权利要求1所述的固体药物制剂，其特征在于，式(I)所示的化合物为式(II)化合物：
    Figure PCTCN2021087262-appb-100002
  3. 如权利要求1所述的固体药物制剂，其特征在于，所述活性成分的含量为1％–15％，更佳地为4％–10％，更佳地为9.5％–10％，所述百分比是以固体药物制剂的总干燥重量计。
  4. 如权利要求1所述的固体药物制剂，其特征在于，所述固体药物制剂还包括粘合剂，所述粘合剂选自羟丙甲纤维素、羟丙纤维素、聚维酮、海藻酸钠、卡波普、聚乙烯醇中的一种或多种，所述粘合剂的含量为0.5％–10％，更佳地为1.5％–3％，所述百分比是以固体药物制剂的总干燥重量计。
  5. 如权利要求1所述的固体药物制剂，其特征在于，所述固体药物制剂还包括填充剂，所述填充剂选自微晶纤维素、乳糖、纤维素乳糖复合物、预胶化淀粉、磷酸氢钙、碳酸钙中的一种或多种，所述填充剂的含量为60％至90％，更佳地为73％至85％，更佳地为73％–82.5％，所述百分比是以固体药物制剂的总干燥重量计。
  6. 如权利要求1所述的固体药物制剂，其特征在于，所述固体药物制剂还包括崩解剂，所述崩解剂选自交联羧甲基纤维素钠、羟丙甲纤维素-K4M、交联聚维酮、羧甲基淀粉钠中的一种或多种，所述崩解剂的含量为5％–15％，所述百分比是以固体药物制剂的总干燥重量计。
  7. 如权利要求1所述的固体药物制剂，其特征在于，所述固体药物制剂还包括润滑剂，所述润滑剂选自硬脂酸镁、滑石粉、单硬脂酸甘油酯、硬脂酸富马酸钠中的一种或多种，所述润滑剂的含量为0.1％–1％，更佳地为0.4％–0.5％，更佳地为0.48％–0.5％，所述百分比是以固体药物制剂的总干燥重量计。
  8. 如权利要求1所述的固体药物制剂，其特征在于，所述固体药物制剂为片剂、胶囊剂、散剂、颗粒剂、滴丸剂或膜剂，优选为片剂。
  9. 如权利要求1所述的固体药物制剂，其特征在于，包含以固体药物制剂的总干燥重量计的下述组分：
    a)活性成分：((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮，或其药学上可接受的盐，或二者的混合物；所述活性成分的含量为1％–15％，更佳地为4％–10％，更佳地为9.5％–10％；
    b)填充剂，选自微晶纤维素、乳糖、纤维素乳糖复合物、预胶化淀粉、磷酸氢钙、碳酸钙中的一种或多种，所述填充剂的含量为60％–90％，更佳地为73％–85％，更佳地为73％–82.5％；
    c)粘合剂，选自羟丙甲纤维素、羟丙纤维素、聚维酮、海藻酸钠、卡波普、聚乙烯醇中的一种或多种，所述粘合剂的含量为0.5％–10％，更佳地为1.5％–3％；
    d)崩解剂，选自交联羧甲基纤维素钠、羟丙甲纤维素-K4M、交联聚维酮、羧甲基淀粉钠中的一种或多种，所述崩解剂的含量为5％–15％；和
    e)润滑剂，选自选自硬脂酸镁、滑石粉、单硬脂酸甘油酯、硬脂酸富马酸钠中的一种或多种，所述润滑剂的含量为0.1％–1％，更佳地为0.4％–0.5％，更佳地为0.48％–0.5％；
    其中所述活性成分的粒径为D90≤35μm，或为D90≤30μm，或为D90≤20μm，或为D90≤10μm，或为D90＝1μm～30μm，或为D90＝1μm～20μm，或为D90＝1μm～10μm,或为D90＝10μm～20μm。
  10. 如权利要求1所述的固体药物制剂，其特征在于，包含以固体药物制剂的总干燥重量计的下述组分：
    a)活性成分：((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮或其药学上可接受的盐，或二者的混合物；所述活性成分的含量为4％–10％；
    b)微晶纤维素，含量为24％–27.5％；
    c)乳糖，含量为48.5％–56.5％；
    d)羟丙甲纤维素-E5，含量为1.5％–3％；
    e)交联羧甲基纤维素钠或羟丙甲纤维素-K4M，含量为5％–15％；和
    f)硬脂酸镁，含量为0.4％–0.5％；
    其中所述活性成分的粒径为D90≤35μm，或为D90≤30μm，或为D90≤20μm，或为D90≤10μm，或为D90＝1μm～30μm，或为D90＝1μm～20μm，或为D90＝1μm～10μm,或为D90＝10μm～20μm。
  11. 如权利要求1所述的固体药物制剂，其特征在于，包含以固体药物制剂的总干燥重量计的下述组分：
    a)活性成分：((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮或其药学上可接受的盐，或二者的混合物；所述活性成分的含量为9.5％–10％；
    b)微晶纤维素，含量为24％–27.5％；
    c)乳糖，含量为48.5％–56.5％；
    d)羟丙甲纤维素-E5，含量为1.5％–3％；
    e)交联羧甲基纤维素钠或羟丙甲纤维素-K4M，含量为5％–15％；和
    f)硬脂酸镁，含量为0.48％–0.5％；
    其中所述活性成分的粒径为D90＝1μm～30μm，或为D90＝1μm～20μm，或为D90＝1μm～10μm，或为D90＝10μm～20μm，所述固体制剂为片剂。
  12. 一种片剂的制备方法，所述方法包括下述步骤：
    (a)将活性成分颗粒、填充剂、粘合剂和第一崩解剂混合后湿法制粒；
    (b)将步骤(a)所得产物干燥；
    (c)将步骤(b)所得产物、第二崩解剂和润滑剂干混合；和
    (d)将步骤(c)所得产物压制成片；
    其中活性成分为((1S,2R,5S)-2-(((5-氟吡啶-2-基)氧基)甲基)-8-氮杂双环[3.2.1]辛烷-8-基)(5-甲基-2-(嘧啶-2-基)苯基)甲酮或其药学上可接受的盐，或二者的混合物；
    活性成分颗粒的粒径为D90≤50μm。
  13. 如权利要求12所述的制备方法，其特征在于，按照步骤(c)所得混合物的总干燥重量计，活性成分的含量为4％–10％。
  14. 如权利要求12所述的制备方法，其特征在于，按照步骤(c)所得混合物的总干燥重量计，填充剂的含量为73％–82.5％。
  15. 如权利要求12所述的制备方法，其特征在于，按照步骤(c)所得混合物的总干燥重量计，粘合剂的含量为1.5％–3％。
  16. 如权利要求12所述的制备方法，其特征在于，按照步骤(a)中所有组分的干燥重量计，第一崩解剂的含量为2％–10％，更佳地为5％–6％；按照步骤(c)中所有组分的总干燥重量计，第二崩解剂的含量为5％–10％。
  17. 如权利要求12所述的制备方法，其特征在于，按照步骤(c)中所有组分的总干燥重量计，润滑剂的含量为0.1％–1％，更佳地为0.4％–0.5％，更佳地为0.48％–0.5％。
  18. 如权利要求12所述的制备方法，其特征在于，所述方法还包括：
    (e)将步骤(d)所得产物进行包衣。
  19. 一种单位剂型，其特征在于，以所述单位剂型的总重量计，所述单位剂型包含：
    约10mg、约20mg或约40mg的活性成分，该活性成分为式(II)化合物；
    Figure PCTCN2021087262-appb-100003
    约25mg至约150mg的微晶纤维素；
    约50mg至约300mg的乳糖；
    约1mg至约15mg的羟丙甲纤维素；
    约10mg至约50mg交联羧甲基纤维素钠；和
    约0.5mg至约3mg的硬脂酸镁，
    其中所述活性成分的粒径为D90＝1μm～20μm。
  20. 一种单位剂型，其特征在于，以所述单位剂型的总重量计，所述单位剂型包含：
    8mg至12mg的活性成分，该活性成分为式(II)化合物；
    Figure PCTCN2021087262-appb-100004
    20mg至30mg的微晶纤维素；
    46mg至56mg的乳糖；
    2mg至4mg的羟丙甲纤维素；
    5mg至15mg交联羧甲基纤维素钠；和
    0.3mg至0.7mg的硬脂酸镁，
    其中所述活性成分的粒径为D90＝1μm～20μm。
  21. 一种单位剂型，其特征在于，以所述单位剂型的总重量计，所述单位剂型包含：
    18mg至22mg的活性成分，该活性成分为式(II)化合物；
    Figure PCTCN2021087262-appb-100005
    46mg至56mg的微晶纤维素；
    97mg至107mg的乳糖；
    5mg至7mg的羟丙甲纤维素；
    15mg至25mg交联羧甲基纤维素钠；和
    0.8mg至1.2mg的硬脂酸镁，
    其中所述活性成分的粒径为D90＝1μm～20μm。
  22. 一种单位剂型，其特征在于，以所述单位剂型的总重量计，所述单位剂型包含：
    38mg至42mg的活性成分，该活性成分为式(II)化合物；
    Figure PCTCN2021087262-appb-100006
    97mg至107mg的微晶纤维素；
    199mg至209mg的乳糖；
    11mg至13mg的羟丙甲纤维素；
    35mg至45mg交联羧甲基纤维素钠；和
    1.8mg至2.2mg的硬脂酸镁，
    其中所述活性成分的粒径为D90＝1μm～20μm。
  23. 根据权利要求2所述的固体药物制剂或根据权利要求19～22任意一项所述的单位剂型，其特征在于，作为活性成分的式(II)化合物以结晶形式A或结晶形式B存在。
  24. 根据权利要求19～22任意一项所述的单位剂型，其特征在于，所述单位剂型为片剂或胶囊。
  25. 根据权利要求1～11任意一项所述固体药物制剂或权利要求19～22任意一项所述的单位剂型在制备治疗与食欲素有关疾病的药物中的应用。
  26. 根据权利要求25所述的应用，其中所述与食欲素有关疾病包括失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍。
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