WO2021136507A1 - 一种二肽基肽酶4抑制剂的药物组合物及其制备方法和应用 - Google Patents

一种二肽基肽酶4抑制剂的药物组合物及其制备方法和应用 Download PDF

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WO2021136507A1
WO2021136507A1 PCT/CN2020/142147 CN2020142147W WO2021136507A1 WO 2021136507 A1 WO2021136507 A1 WO 2021136507A1 CN 2020142147 W CN2020142147 W CN 2020142147W WO 2021136507 A1 WO2021136507 A1 WO 2021136507A1
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pharmaceutical composition
tablet
microcrystalline cellulose
sodium
active ingredient
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PCT/CN2020/142147
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English (en)
French (fr)
Inventor
刘翠艳
陈金平
荀浩华
王尹珊
白晶
吕高星
安立鑫
李海霞
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石药集团中奇制药技术（石家庄）有限公司
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Priority to CN202310673958.6A priority Critical patent/CN116509844B/zh
Priority to CN202080075053.3A priority patent/CN114641277B/zh
Publication of WO2021136507A1 publication Critical patent/WO2021136507A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition for a dipeptidyl peptidase 4 (DPP-4) inhibitor, and a preparation method and application thereof.
  • DPP-4 dipeptidyl peptidase 4
  • DPP-4 inhibitors are a new type of clinically commonly used drugs for the treatment of type II diabetes [Cai Wei et al., Analysis of the pharmacochemical properties of DPP-4 inhibitors of hypoglycemic drugs, North Pharmaceutical, 2018, 15 (8): 158-159.].
  • DPP-4 is a transmembrane serine protease composed of 766 amino acids, which can degrade various inflammatory chemokines and peptide hormones to exert biological effects.
  • the main substrates of DPP-4 are glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), growth hormone, etc. , GIP and GLP-1 secretion increase after ingestion, promote insulin secretion in a glucose-dependent manner, inhibit glucagon secretion to maintain normal blood sugar levels, but they can be degraded by DPP-4.
  • DPP-4 inhibitors competitively inhibit DPP-4 complex, reduce substrate degradation, increase substrate concentration, promote insulin secretion, and inhibit glucagon at the same time, thereby lowering blood sugar and reducing blood sugar. Adverse reactions such as blood sugar and weight gain.
  • DPP-4 inhibitors there are 5 common DPP-4 inhibitors on the global market, namely sitagliptin, linagliptin, saxagliptin, alogliptin and vildagliptin [Li Chunxing, etc., 5 DPP-4 Molecular structure differences and pharmacokinetic properties of inhibitors, Drug Evaluation, 2019, 16(8): 3-9.; Cai Wei et al., Analysis of the pharmacological properties of DPP-4 inhibitor antidiabetic drugs, North China Pharmaceutical, 2018 , 15(8):158-159.].
  • Compound I is a DPP-4 inhibitor with the chemical name (2S, 4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propyl Amino)-acetyl]-4-fluoro-2-cyano-pyrrolidine, its structural formula is as follows:
  • Patent CN101970402B discloses compound I and its use in treating diabetes, but does not provide relevant information on the formulation of compound I.
  • a pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof with excellent formulation properties has become an urgent problem for those skilled in the art.
  • a technical problem to be solved by the present invention is to provide a pharmaceutical composition containing Compound I as an active ingredient or a pharmaceutically acceptable salt thereof, which meets the needs of oral administration.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition containing Compound I as an active ingredient or a pharmaceutically acceptable salt thereof, which has a simple preparation method and is suitable for industrial production.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition suitable for direct compression tableting containing Compound I as an active ingredient or a pharmaceutically acceptable salt thereof.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition containing Compound I as an active ingredient or a pharmaceutically acceptable salt thereof, which can be used to prepare a pharmaceutical composition with favorable appearance, substrate hardness, and friability.
  • the disintegration time limit and the uniformity of the content of the active ingredient are solid oral preparations.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition containing compound I as an active ingredient or a pharmaceutically acceptable salt thereof, which has excellent stability and is suitable for long-term storage.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical combination containing two or more of the above characteristics (preferably having all of the above characteristics) containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient Things.
  • the present invention provides the following preferred embodiments:
  • a pharmaceutical composition comprising:
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof and excipients include fillers and lubricants, and optionally, further include disintegrants,
  • the filler is: (1) microcrystalline cellulose, (2) microcrystalline cellulose and lactose, or (3) microcrystalline cellulose and calcium phosphate.
  • the filler is microcrystalline cellulose; or the filler is microcrystalline cellulose and lactose, and the weight ratio of microcrystalline cellulose and lactose is 1:9-10 :1, preferably 1:3 to 3:1, more preferably 1:1.5; or the filler is microcrystalline cellulose and calcium phosphate, and the weight ratio of microcrystalline cellulose and calcium phosphate is 1 : 9-10:1, preferably 1:3-3:1, more preferably 1:1.5; preferably, the calcium phosphate is calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate or their hydrates, Calcium hydrogen phosphate or a hydrate thereof is preferable, and calcium hydrogen phosphate anhydrous is more preferable.
  • lubricant is selected from stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, lauryl sulfate
  • stearic acid magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, lauryl sulfate
  • the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, lauryl sulfate
  • the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, lauryl sulfate
  • composition according to any one of the schemes 1-3, wherein the pharmaceutical composition does not include a disintegrant; or the pharmaceutical composition includes a disintegrant, and the disintegrant is selected from carboxymethyl Base cellulose, powdered cellulose, methyl cellulose, pollacrine potassium, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crosslinked One or more of bispovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or croscarmellose sodium, preferably corn starch, pregelatinized starch, crospovidone, One or more of low-substituted hydroxypropyl cellulose, sodium starch glycolate, or croscarmellose sodium, more preferably sodium starch glycolate or croscarmellose sodium.
  • the disintegrant is selected from carboxymethyl Base cellulose, powdered cellulose, methyl cellulose, pollacrine potassium
  • the weight percentage of the active ingredient is 1.00%-90.00%, preferably 5.00%-80.00%, 10.00%-65.00%, 20.00%-50.00%, 25.00%-45.00% or 28.00%-35.00%;
  • the weight percentage of the filler is 10.00%-95.00%, preferably 25.00%-90.00%, 40.00%-90.00%, 50.00%-80.00% or 60.00%-70.00%;
  • the weight percentage of the disintegrant is 0.00% to 25.00%, preferably 0.00% to 15.00%, 0.00% to 6.00%, 0.00% to 5.00% or 0.00% to 2.00%;
  • the weight percentage of the lubricant is 0.10% to 5.00%, preferably 0.50% to 4.00%, 0.50% to 3.00%, 0.50% to 2.00% or 0.50% to 1.50%;
  • the weight percentage is 0.00% to 25.00%, preferably 0.00% to 15.00%, 0.00% to 10.00%, 0.00% to 5.00% or 0.00% to 2.00%;
  • the weight ratio of microcrystalline cellulose to anhydrous calcium hydrogen phosphate or lactose is 1:9-10:1, more preferably 1:3-3:1, and further Preferably it is 1:1.5.
  • the coating composition, the weight gain of the film coating accounts for 1 to 5% of the weight of the tablet core, preferably 2 to 4%, more preferably 2.5 to 3%, and most preferably 3%.
  • a method for preparing the pharmaceutical composition according to any one of schemes 1-7 which comprises: (1) combining a compound represented by formula I or a pharmaceutically acceptable salt thereof and a compound other than a lubricant Other excipients are mixed in a mixing container to produce a premix; (2) the lubricant and the premix are mixed together to obtain the pharmaceutical composition.
  • a method for preparing the solid oral preparation as described in Scheme 8 or 9, which comprises: filling the pharmaceutical composition obtained by the preparation method as described in Scheme 10 into a packaging bag at a packaged dose to prepare a powder; or Fill the pharmaceutical composition into a capsule to form a capsule; or use a suitable tablet press to further compress the pharmaceutical composition into a tablet; preferably, use a suitable tablet press to compress the pharmaceutical composition It is directly compressed into a tablet; further preferably, the tablet is further made into a coated tablet, preferably a film-coated tablet, and more preferably a gastric-soluble film-coated tablet.
  • the therapeutically effective amount of the pharmaceutically acceptable salt thereof is 1 mg to 500 mg, preferably 25 mg to 200 mg, preferably 50 mg to 150 mg, and more preferably 100 mg.
  • the compound or a pharmaceutically acceptable salt thereof is the only active ingredient for the treatment of type II diabetes, or combined with other active ingredients as an active ingredient for the treatment of type II diabetes, wherein the other active ingredient is selected from insulin and metformin Or one or more of its pharmaceutically acceptable salts, sulfonylurea hypoglycemic agents, and thiazolidinedione hypoglycemic agents, preferably metformin, more preferably metformin hydrochloride.
  • a method for treating type II diabetes which comprises administering the pharmaceutical composition according to any one of schemes 1-7 or the solid oral preparation according to scheme 8 or 9 to a subject in need thereof.
  • the therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof is 1 mg to 500 mg, preferably 25 mg to 200 mg, preferably 50 mg to 150 mg, and further Preferably it is 100 mg.
  • the preparation method of the pharmaceutical composition is simple and has no strict requirements on the equipment and operating technology used, and is more suitable for industrial production; (2) The pharmaceutical composition is suitable for direct compression tableting, so it can Greatly simplify the preparation process of tablets; (3) Solid oral preparations such as tablets made from the pharmaceutical composition have favorable appearance, base tablet hardness, friability, disintegration time limit and uniformity of active ingredient content , Meet the preparation standards; and (4) the pharmaceutical composition also has excellent stability, in the influencing factor test, accelerated stability test and long-term stability test, the largest single impurities, total impurities, There is no obvious change in content, moisture and crystal form, so it is suitable for long-term storage.
  • the first aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: as an active ingredient, a compound represented by formula I or a pharmaceutically acceptable salt thereof and excipients, the excipients comprising fillers And a lubricant, optionally, further comprising a disintegrant,
  • the filler is: (1) microcrystalline cellulose, (2) microcrystalline cellulose and lactose, or (3) microcrystalline cellulose and calcium phosphate.
  • the "active ingredient” in the present invention refers to a compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the weight percentage of the active ingredient in the pharmaceutical composition is 1.00%-90.00%, preferably 5.00%-80.00%, 10.00%-65.00%, 20.00%-50.00%, 25.00%-45.00 % Or 28.00% ⁇ 35.00%.
  • the "other active ingredient” in the present invention refers to a pharmaceutically active agent used in combination with a compound represented by formula I or a pharmaceutically acceptable salt thereof for the treatment of type II diabetes, which includes, but is not limited to, insulin and metformin Or one or more of its pharmaceutically acceptable salts, sulfonylurea hypoglycemic agents, and thiazolidinedione hypoglycemic agents, preferably metformin, more preferably metformin hydrochloride.
  • excipients refer to the general term for all additional materials used in formulating prescriptions and producing medicines, except for the active ingredients. They are also called excipients. They are generally pharmaceutically acceptable inert ingredients. In terms of safety A reasonable assessment has been made. Examples of excipients include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers (or diluents), as well as flavoring agents, thickening agents, dispersing agents, and coloring agents. Agents and spices and other substances. Excipients can enhance the handling characteristics of the pharmaceutical formulation, for example by increasing fluidity and/or adhesion to make the formulation more suitable for direct compression.
  • the "excipient" should have good compatibility with the active ingredient, that is, the excipient itself or the impurities contained in it will not chemically react with the structural groups in the active ingredient or cause the active ingredient to degrade, resulting in The content of active ingredients decreases.
  • the excipients include fillers and lubricants and optionally further include disintegrants.
  • the excipients consist of fillers and lubricants. In another embodiment, the excipients consist of fillers, lubricants and disintegrants.
  • the “filler” in the present invention refers to an excipient used to increase the weight and volume of a pharmaceutical composition to facilitate molding and dosage.
  • the filler described in the present invention can be a single filler or a mixture of two fillers.
  • the filler is a single filler, it is microcrystalline cellulose, especially microcrystalline cellulose MCC102.
  • the two fillers are microcrystalline cellulose (especially microcrystalline cellulose MCC102) and lactose (especially lactose F100), or microcrystalline cellulose (especially lactose F100).
  • Is microcrystalline cellulose (MCC102) and calcium phosphate such as calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate or their hydrates, preferably calcium hydrogen phosphate or its hydrates, more preferably anhydrous calcium hydrogen phosphate
  • the weight ratio of the two is 1:9-10:1, preferably 1:3-3:1, more preferably 1:1.5.
  • the weight percentage of the filler in the pharmaceutical composition is 10.00%-95.00%, preferably 25.00%-90.00%, 40.00%-90.00%, 50.00%-80.00% or 60.00%-70.00 %.
  • the "lubricant” in the present invention refers to an excipient used to reduce the friction between the particles of the pharmaceutical composition and between the particles and the die holes, and to improve the transmission and distribution of force.
  • the lubricant of the present invention is selected from stearic acid or its salts (for example, magnesium stearate, calcium stearate, zinc stearate), palmitic acid, glyceryl palmitate stearate, sodium benzoate, lauryl One or more of sodium sulfate, hydrogenated vegetable oil, talc, silica, micronized silica gel, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate or polyethylene glycol; preferably It is one or more of micronized silica gel, talc, calcium stearate, magnesium stearate or polyethylene glycol; more preferably, it is magnesium stearate.
  • the weight percentage of the lubricant in the pharmaceutical composition is 0.10% to 5.00%, preferably 0.50% to 4.00%, 0.50% to 3.00%, 0.50% to 2.00% or 0.50% to 1.50 %.
  • the "disintegrant” in the present invention refers to an excipient used to promote the disintegration of the pharmaceutical composition in the gastrointestinal tract and increase the dissolution of the active ingredient.
  • the disintegrant of the present invention is selected from carboxymethyl cellulose, powdered cellulose, methyl cellulose, Pollacrine potassium, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, silicic acid
  • aluminum magnesium corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, preferably corn starch , Pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or croscarmellose sodium, more preferably sodium starch glycolate or cross-linked sodium starch Sodium carboxymethyl cellulose.
  • the weight percentage of the disintegrant in the pharmaceutical composition is 0.00% to 25.00%, preferably 0.00% to 15.00%, 0.00% to 6.00%, 0.00% to 5.00% or 0.00% to 2.00%.
  • the pharmaceutical composition of the present invention may also contain other excipients besides fillers, lubricants and disintegrants. Specific examples thereof include adhesives, flavoring agents, thickening agents, dispersing agents, coloring agents, fragrances, and the like.
  • the weight percentage of other excipients in the pharmaceutical composition is 0.00% to 25.00%, preferably 0.00% to 15.00%, 0.00% to 10.00%, 0.00% to 5.00% or 0.00% ⁇ 2.00%.
  • the components and weight percentages of a typical pharmaceutical composition are as follows:
  • the components and weight percentages of the pharmaceutical composition are as follows:
  • the components and weight percentages of the pharmaceutical composition are as follows:
  • the second aspect of the present invention provides a solid oral preparation made from the above-mentioned pharmaceutical composition.
  • the "solid oral preparation” in the present invention refers to a solid pharmaceutical preparation for oral administration.
  • the present invention relates to a solid oral preparation made from the above pharmaceutical composition.
  • the specific dosage form is preferably powder, capsule, tablet, granule, fine granule, etc., more preferably powder, capsule or tablet, more preferably tablet, It is more preferably a coated tablet, and most preferably a film-coated tablet.
  • the "film-coated tablet” in the present invention refers to a tablet with a film (coated) coated on a tablet core (which is made of the pharmaceutical composition of the present invention through compression).
  • the film coating can be prepared using coating materials and methods commonly used in the art.
  • the film coating material includes one or more of polymer materials, plasticizers, porogens, and certain solid materials, among which the polymer materials can be selected from hypromellose, hydroxypropyl cellulose , Methyl cellulose, hydroxyethyl cellulose, acrylic resin, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl phthalate, cellulose acetate trimellitate, hypromellose Phthalates, etc.; plasticizers can be selected from glycerin, propylene glycol, polyethylene glycol, glycerol monoacetate, glycerol triacetate, dibutyl sebacate, dibutyl phthalate, phthalic acid Diethyl, castor oil, corn oil, liquid paraffin, etc.; porogen (also called release rate regulator) can be selected from sucrose, sodium chloride, surfactant, polyethylene glycol, etc.; solid material can be selected from talc Powder, magnesium stearate,
  • the coating material can also be directly selected commercially available pre-mixed coating powder, for example Series coating powder, Series coating powder, Series coating powder, Series coating powder, Series of coating powder, etc.
  • the coating material may be a gastric-soluble coating material or an enteric-soluble coating material.
  • the weight gain of the film coating accounts for 1 to 5% of the weight of the tablet core, preferably 2 to 4%, more preferably 2.5 to 3%, and most preferably 3%.
  • the coating solvent is preferably water, which can be removed during drying without remaining in the final product.
  • the pharmaceutical composition of the present invention or its solid oral preparation may contain 0.001-1000 mg, preferably 0.1-800 mg, preferably 1-500 mg, more preferably 25-500 mg of the compound represented by formula I or a pharmaceutically acceptable salt thereof in a dosage range .
  • the content of the compound represented by formula I or its pharmaceutically acceptable salt in a single-dose pharmaceutical composition or its solid oral preparation may be 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg , 5mg, 10mg, 20mg, 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 500mg, etc.
  • the third aspect of the present invention provides a method for preparing the above-mentioned pharmaceutical composition, which comprises: (1) mixing the active ingredient and other excipients except lubricants in a mixing container to produce a premix; (2) mixing the lubricant The agent and the premix are mixed together to obtain the pharmaceutical composition.
  • the method for preparing the pharmaceutical composition of the present invention includes: (1) Preparation: Weigh the compound represented by formula I or its pharmaceutically acceptable salt (ie the above-mentioned active ingredient) and corresponding (2) Mix the active ingredients, fillers and optional disintegrants in a mixing container to produce a premix; (3) Mix the lubricant and the premix together to obtain the Pharmaceutical composition.
  • an exemplary method for preparing the pharmaceutical composition of the present invention includes: 1) Preparation: Weigh the compound of Formula I or a pharmaceutically acceptable salt thereof (i.e., the above-mentioned active ingredient) according to the prescription amount, and Corresponding excipients (for example, fillers, disintegrants and lubricants); 2) Pre-mixing: add the disintegrant to the filler by adding the same amount 3 times, shake the bag and mix; then add the active Ingredients (API), shake the bag and mix; 3) Total mixing: Add the lubricant to the above-mentioned mixed powder by adding the same amount 3 times, shake the bag and mix uniformly to obtain the pharmaceutical composition.
  • Preparation Weigh the compound of Formula I or a pharmaceutically acceptable salt thereof (i.e., the above-mentioned active ingredient) according to the prescription amount, and Corresponding excipients (for example, fillers, disintegrants and lubricants); 2) Pre-mixing: add the disintegrant to the filler by adding the same
  • an exemplary method for preparing the pharmaceutical composition of the present invention includes: 1) Preparation: Weigh the compound of Formula I or a pharmaceutically acceptable salt thereof (i.e., the above-mentioned active ingredient) according to the prescription amount, and Corresponding excipients (for example, fillers, disintegrants and lubricants); 2) Pre-mixing: add the disintegrant to a filler by adding the same amount 3 times, and shake the bag to mix; Add the compound represented by formula I or its pharmaceutically acceptable salt (that is, the above-mentioned active ingredient) and another filler, shake the bag and mix; 3) Total mixing: Add the lubricant to the same amount by adding 3 times In the above powder mixing, shake the bag and mix uniformly to obtain the pharmaceutical composition.
  • Preparation Weigh the compound of Formula I or a pharmaceutically acceptable salt thereof (i.e., the above-mentioned active ingredient) according to the prescription amount, and Corresponding excipients (for example, fillers, disintegrants and lubricants
  • an exemplary method for preparing the pharmaceutical composition of the present invention includes: 1) Preparation: Weigh the compound of Formula I or a pharmaceutically acceptable salt thereof (i.e., the above-mentioned active ingredient) according to the prescription amount, and Corresponding excipients (for example, fillers, disintegrants and lubricants); 2) Pre-mixing: Add the two fillers in the same amount 3 times in sequence, and shake the bag to mix. Add the same amount 3 times, add the disintegrant to the mixed powder after shaking the bag, shake the bag to mix, and then add the compound represented by formula I or its pharmaceutically acceptable salt (ie, the above-mentioned active ingredient). Bag mixing; 3) Total mixing: Add the lubricant to the above-mentioned mixed powder by adding the same amount 3 times, shake the bag and mix uniformly to obtain the pharmaceutical composition.
  • the above-mentioned method for preparing the pharmaceutical composition of the present invention may further include other unmentioned steps.
  • mixing container should be understood in a broad sense, which includes both flexible mixing containers (including but not limited to flexible bags such as clean plastic bags, ziplock bags, etc.) and rigid mixing containers (including but not limited to hopper mixers, etc.) ). Those skilled in the art can select a suitable mixing container according to the batch size and weight to perform the corresponding pre-mixing and total mixing operations.
  • the fourth aspect of the present invention provides a preparation method of the above-mentioned solid oral preparation, which comprises: filling the pharmaceutical composition obtained by the above-mentioned preparation method into a packaging bag according to a packaged dose to prepare a powder; or filling the pharmaceutical composition to In the capsule, it is made into a capsule; or the pharmaceutical composition is further compressed into a tablet using a suitable tablet press.
  • the pharmaceutical composition is directly compressed into tablets using a suitable tablet press.
  • the tablet has a target core weight, appropriate size and compression resistance.
  • direct compression refers to a method of directly compressing the ingredients (ie, active ingredients and excipients) of a pharmaceutical preparation without changing the physical and chemical properties of the active ingredients.
  • An exemplary direct compression method includes: mixing the active ingredients and excipients in powder form in a mixing device; then filling the mixed composition into a mold and directly compressing it with a punch.
  • Excipients useful in the direct compression method include, without limitation, fillers and lubricants.
  • the tablets are further made into coated tablets, preferably film-coated tablets.
  • the tablet ie, the base tablet prepared from the aforementioned pharmaceutical composition
  • An exemplary method for preparing a film-coated tablet includes: (1) preparing a coating liquid; (2) putting the tablet core into a coating pan and rotating, and spraying the coating liquid evenly to obtain a film coating Tablets; and (3) drying the resulting film-coated tablets.
  • the coating liquid can be prepared by dispersing (e.g., dissolving or suspending) a coating material (e.g., film coating premix) in a coating solvent (e.g., water, preferably purified water) (e.g., at ambient temperature with suitable In the mixer) preparation.
  • a coating material e.g., film coating premix
  • a coating solvent e.g., water, preferably purified water
  • the fifth aspect of the present invention provides the application of the above-mentioned pharmaceutical composition or the above-mentioned solid oral preparation in the preparation of a medicament for the treatment of type II diabetes.
  • the therapeutically effective amount of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is 1 mg to 500 mg, preferably 25 mg to 200 mg, more preferably 50 mg to 150 mg, and still more preferably 100mg.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof can be used as the sole active ingredient of the drug for the treatment of type II diabetes, or can be combined with other active ingredients as the An active ingredient of a medicine for the treatment of type II diabetes, wherein the other active ingredient is selected from insulin, metformin or a pharmaceutically acceptable salt thereof, sulfonylurea hypoglycemic agents, and thiazolidinedione hypoglycemic agents One or more, preferably metformin, more preferably metformin hydrochloride.
  • the sixth aspect of the present invention provides the above-mentioned pharmaceutical composition or the above-mentioned solid oral preparation, which is used for the treatment of type II diabetes.
  • the therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof is 1 mg to 500 mg, preferably 25 mg to 200 mg, more preferably 50 mg to 150 mg, and further Preferably it is 100 mg.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof may be the only active ingredient for the treatment of type II diabetes , Or can be combined with other active ingredients as an active ingredient for the treatment of type II diabetes, wherein the other active ingredient is selected from insulin, metformin or a pharmaceutically acceptable salt thereof, sulfonylurea hypoglycemic agents, thiazolidine two One or more of the ketone hypoglycemic agents is preferably metformin, more preferably metformin hydrochloride.
  • the seventh aspect of the present invention provides a method for treating type II diabetes, which comprises administering the above-mentioned pharmaceutical composition or the above-mentioned solid oral preparation to a subject in need thereof.
  • the therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof is 1 mg to 500 mg, preferably 25 mg to 200 mg, and more preferably 50 mg to 150 mg, More preferably, it is 100 mg.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof may be administered as the sole active ingredient for the treatment of type II diabetes, or may be combined with other active ingredients It is administered as an active ingredient for the treatment of type II diabetes, wherein the other active ingredient is selected from insulin, metformin or a pharmaceutically acceptable salt thereof, sulfonylurea hypoglycemic agents, and thiazolidinedione hypoglycemic agents
  • the other active ingredient is selected from insulin, metformin or a pharmaceutically acceptable salt thereof, sulfonylurea hypoglycemic agents, and thiazolidinedione hypoglycemic agents
  • One or more of is preferably metformin, more preferably metformin hydrochloride.
  • the subject of administration may be a human or a non-human mammal, more preferably a human.
  • a pharmaceutical composition comprising: as an active ingredient a compound represented by formula I or a pharmaceutically acceptable salt and excipients thereof
  • a pharmaceutical composition comprising as an active ingredient
  • the compound represented by formula I or its pharmaceutically acceptable salt and excipients is composed of "in the case of ".
  • the dosage of the compound represented by formula I or its pharmaceutically acceptable salt in the formulation can be adjusted appropriately, or the ratio (mass ratio) with the excipient can be adjusted to obtain Pharmaceutical compositions or solid oral preparations containing different specifications or different drug weights also fall within the scope of the present invention.
  • a pharmaceutical composition comprising as an active ingredient the DPP-4 inhibitor represented by formula I or a pharmaceutically acceptable salt thereof and excipients, the excipients comprising fillers and lubricants, Optionally, further comprising a disintegrant,
  • the filler is selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose or anhydrous calcium hydrogen phosphate, preferably micro One or more of crystalline cellulose, lactose or anhydrous calcium hydrogen phosphate;
  • the disintegrant is selected from corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl One or more of sodium starch or croscarmellose sodium, preferably sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, and micropowder Silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate.
  • the filler is a single filler or a mixture of two fillers; when the filler is a mixture of two fillers, the ratio of filler A to filler B is selected from 1:9-10: 1, preferably 1:3 to 3:1, more preferably 1:1.5; wherein the filler A is preferably microcrystalline cellulose, and the filler B is preferably lactose or anhydrous calcium hydrogen phosphate.
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the disintegrant is selected from one or more of corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium croscarmellose, Preferably it is sodium starch glycolate or croscarmellose sodium;
  • the lubricant is selected from talc, magnesium stearate, micronized silica gel, calcium stearate or polyethylene glycol, preferably magnesium stearate;
  • the drug is used in combination with other active ingredients or drugs for the treatment of diabetes, and the other active ingredients or drugs are selected from insulin, metformin, sulfonylurea hypoglycemic agents, thiazolidinedione hypoglycemic agents, preferably metformin .
  • a preparation method for preparing the pharmaceutical composition according to any one of schemes 1-5 which comprises: (1) mixing the active ingredient and other excipients except lubricants in a suitable mixer to produce Premix; (2) Totally mix the lubricant and the premix to obtain the total mixture.
  • a method for preparing the solid oral preparation as described in Scheme 6, which comprises: filling the total mixture obtained by the preparation method as described in Scheme 9 into a packaging bag according to the packaged dose to prepare a powder; or combining the total mixture
  • the compound is filled into a capsule to form a capsule; or a suitable tablet press is used to further form the total mixture into a tablet; preferably, the total mixture is directly compressed into a tablet; preferably, the tablet is further It is made into coated tablets, preferably film-coated tablets.
  • the compound I of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Say obvious equivalent replacements. Preferred embodiments include but are not limited to the preparation examples of the present invention.
  • the crude compound I was prepared by referring to the method of Example 1 in CN101970402B. Add the crude product (1000g, 3.083mol) to 6 times the volume (v/w) of methanol, heat and stir to dissolve, filter, and concentrate the filtrate under reduced pressure to about 2 times the volume (v/w) of methanol, change it to 25 ⁇ 30°C and stir. 1h, cooled to 0 ⁇ 5°C, stirred and crystallized for 1h, filtered. The obtained solid was washed with ethyl acetate and dried in vacuum to obtain 674 g of white crystalline powder. The yield was 67.4%, the purity of the liquid phase was 99.88%, and the melting point was 166.3-167.8°C.
  • Example 1 Tablets of Compound I (using microcrystalline cellulose as a single filler)
  • Example 1 The tablet formulation of Example 1 is shown in Table 1 below:
  • the tablet of Example 1 was prepared using a direct compression process, and the specific method was: 1) Preparation: weigh the active ingredient (API) compound I and the corresponding fillers, disintegrants and lubricants according to the prescription; 2) premix : Add the disintegrant to the filler 3 times in the same amount, shake the bag and mix; add the active ingredient (API), shake the bag and mix; 3) Total mixing: Add 3 times in the same amount , Add the lubricant to the above mixed powder, shake the bag and mix evenly; 4) Pressing: The punch is compressed with a single-punch tablet machine.
  • Examples 2-5 were prepared according to the prescription composition and preparation method of Example 1, but the single filler microcrystalline cellulose was replaced with lactose, pregelatinized starch, mannitol or anhydrous calcium hydrogen phosphate.
  • the specific prescriptions and test results of the tablets of Examples 2-5 are shown in Table 3 below.
  • Example 1 Replace the single filler with two fillers, refer to the recipe composition and preparation method of Example 1 (wherein, the pre-mixing step is changed to: add the disintegrant to the microcrystalline cellulose by adding the same amount three times , Shake the bag and mix; then add the active ingredient and lactose, shake the bag and mix) to obtain the following composition (1000 tablets).
  • the specific prescription is shown in Table 4, and the test results are shown in Table 5.
  • Example 7-10 Compound I tablets (comparative experiments conducted for different types of combined fillers)
  • Example 6 Replace the combined filler with microcrystalline cellulose + anhydrous calcium hydrogen phosphate, microcrystalline cellulose + pregelatinized starch, microcrystalline cellulose + mannitol or mannitol + lactose, refer to the prescription composition and preparation method of Example 6 (Among them, the pre-mixing step is changed to: add the disintegrant to the microcrystalline cellulose or mannitol in the same amount three times, shake the bag and mix; then add the active ingredient and another filler (anhydrous Calcium hydrogen phosphate, pregelatinized starch, mannitol or lactose), shake the bag and mix) to prepare the tablets of Examples 7-10.
  • Table 6 The specific prescriptions and test results of the tablets of Examples 7-10 are shown in Table 6 below.
  • the combined filler is preferably microcrystalline cellulose + lactose and microcrystalline cellulose + anhydrous calcium hydrogen phosphate.
  • Example 11-13 Compound I tablets (screening of combined filler dosage)
  • Example 6 Refer to the prescription composition and preparation method of Example 6 to prepare the tablets of Examples 14-15, but adjust the type or amount of disintegrant, that is, only replace the disintegrant in Example 6 from sodium starch glycolate to cross-linking.
  • disintegrant sodium starch glycolate
  • the weight percentage of each component remains unchanged to obtain the formulation of Example 14; or on the basis of the formulation of Example 6, without adding the disintegrant sodium starch glycolate, its weight percentage is determined by the filler Microcrystalline cellulose was supplemented to obtain the prescription of Example 15 to observe its influence on the effect of the preparation.
  • Table 9 The specific prescriptions and test results of the tablets of Examples 14-15 are shown in Table 9 below.
  • Exemplary prescriptions suitable for the present invention also include those listed in Tables 10-11 (made in 1000 tablets):
  • Example 17 Compound I tablets (prescriptions containing active ingredients of different specifications)
  • compositions of the present invention can also be made into preparations containing active ingredients of different specifications.
  • Exemplary prescriptions include those listed in Tables 12-13 (made into 1000 tablets):
  • the pharmaceutical composition of the present invention can be prepared into a film-coated tablet, and the specific preparation method is as follows: 1) Use the prescription composition and preparation method described in any one of Examples 1-17 to prepare a tablet of Compound I (ie Substrate) as the tablet core; 2) Weigh the prescribed amount of film coating premix, and suspend the film coating premix in purified water in a suitable mixer at ambient temperature to produce a coating liquid; 3 ) Put the tablet core into the coating pan and rotate, after preheating and edging, spray the coating liquid evenly; 4) Dry the obtained film-coated tablet.
  • the tablet weight increase caused by film coating is about 2% to 4% of the tablet core weight.
  • Exemplary formulations include those listed in Table 14:
  • the coating material is a gastric-soluble film coating premix 85F28751-CN.
  • Example 18-1 Select the film-coated tablets of Example 18-1 (containing 100mg of compound I, the total weight of the coated tablets is 329.60mg), remove the packaging, and put them under the conditions of illumination 4500Lx ⁇ 500Lx, high humidity 92.5%RH, and high temperature 60°C.
  • the influencing factor test was carried out under the conditions of slightly low light intensity, so samples were taken at 6 days and 12 days under the light conditions, and samples were taken at 5 days and 10 days under the conditions of high humidity and 92.5% RH and high temperature of 60°C.
  • the test results of influencing factors are shown in Table 15.
  • Example 18-1 Select the film-coated tablets of Example 18-1 (containing 100mg of compound I, the total weight of the coated tablets is 329.600mg), and pack them (aluminum foil and polyamide/aluminum/polyvinyl chloride cold stamping forming solid medicinal
  • the coated tablets of composite hard tablets were placed at 40°C ⁇ 2°C and relative humidity of 75%RH ⁇ 5%RH for 6 months. Samples were taken at 1, 2, 3, and 6 months. The results are shown in the table. 16.
  • Example 18-1 Select the film-coated tablets of Example 18-1 (containing 100mg of compound I, the total weight of the coated tablets is 329.600mg), and pack them (aluminum foil and polyamide/aluminum/polyvinyl chloride cold stamping into solid medicinal Compound hard tablets) coated tablets are placed for 36 months under the conditions of 25°C ⁇ 2°C and relative humidity of 60%RH ⁇ 10%RH, and at 3, 6, 9, 12, 18, 24, 36 months Sampling, the results are shown in Table 17.

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Abstract

一种含二肽基肽酶4抑制剂的药物组合物及其制备方法和应用。所述药物组合物包含作为活性成分的如式I所示的化合物或其药学上可接受的盐及赋形剂，所述赋形剂包含填充剂、润滑剂，任选包含崩解剂，所述填充剂是：(1)微晶纤维素，(2)微晶纤维素和乳糖，或(3)微晶纤维素和钙的磷酸盐。该药物组合物的制备方法简便、适于直压制片，且由该药物组合物制成的片剂具有有利的外观、基片硬度、脆碎度、崩解时限和活性成分的含量均匀度等制剂性质和优良的稳定性。

Description

一种二肽基肽酶4抑制剂的药物组合物及其制备方法和应用 技术领域
本发明属于药物制剂技术领域，具体涉及一种二肽基肽酶4(dipeptidyl peptidase 4，DPP-4)抑制剂的药物组合物及其制备方法和应用。
背景技术
随着近年来高血糖类疾病对人类健康的威胁日趋严重，糖尿病的治疗及其治疗药物的研发逐渐受到重视。在糖尿病新药研发领域，DPP-4抑制剂是一种临床常用的治疗II型糖尿病的新型药物[蔡蕤等，DPP-4抑制剂类降糖药的药化性质分析，北方药学，2018，15(8)：158-159.]。
DPP-4是一种由766个氨基酸组成的跨膜丝氨酸蛋白酶，可降解各种炎症趋化因子和肽类激素而发挥生物学效应。DPP-4的主要底物有胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)、葡萄糖依赖性胰岛素释放肽(glucose-dependent insulinotropic peptide，GIP)、生长素等，其中，GIP和GLP-1在摄食后分泌增加，以葡萄糖依赖形式促进胰岛素分泌，抑制胰高糖素分泌以维持血糖正常水平，但可被DPP-4降解失效。DPP-4抑制剂竞争性抑制DPP-4复合体，减少底物降解，使底物浓度升高，促进胰岛素分泌，同时抑制胰高血糖素，从而起到降低血糖的治疗效果，同时不易导致低血糖及体重增加等不良反应。目前，全球上市的常见DPP-4抑制剂有5种，分别是西格列汀、利格列汀、沙格列汀、阿格列汀和维格列汀[李春杏等，5种DPP-4抑制剂分子结构差异及药代动力学特性，药品评价，2019，16(8)：3-9.；蔡蕤等，DPP-4抑制剂类降糖药的药化性质分析，北方药学，2018，15(8)：158-159.]。
化合物I是一种DPP-4抑制剂，化学名称为(2S，4S)-1-[2-(1，1-二甲基-3-氧代-3-吡咯烷-1-基-丙基氨基)-乙酰基]-4-氟-2-氰基-吡咯烷，其结构式如下所示：
Figure PCTCN2020142147-appb-000001
专利CN101970402B公开了化合物I及其治疗糖尿病的用途，但并未给出化合物I制剂处方的相关信息。鉴于化合物I在糖尿病的治疗中具有巨大的应用前景，寻求一种具有优异的制剂性质的包含化合物I或其药学上可接受的盐的药物组合物成为了本领域技术人员亟待解决的问题。
发明内容
[技术问题]
本发明所要解决的一个技术问题是提供一种满足口服给药需要的包含作为活性成分的化合物I或其药学上可接受的盐的药物组合物。
本发明所要解决的另一个技术问题是提供一种制备方法简便且适合于工业化生产的包含作为活性成分的化合物I或其药学上可接受的盐的药物组合物。
本发明所要解决的另一个技术问题是提供一种适于直压制片的包含作为活性成分的化合物I或其药学上可接受的盐的药物组合物。
本发明所要解决的另一个技术问题是提供一种包含作为活性成分的化合物I或其药学上可接受的盐的药物组合物，其能够用于制备具有有利的外观、基片硬度、脆碎度、崩解时限和活性成分的含量均匀度等制剂性质的固体口服制剂。
本发明所要解决的另一个技术问题是提供一种具备优良的稳定性且适宜长期储存的包含作为活性成分的化合物I或其药学上可接受的盐的药物组合物。
本发明所要解决的另一个技术问题是提供一种具有以上特性中的两种或更多种(优选具有全部以上特性)的包含作为活性成分的化合物I或其药学上可接受的盐的药物组合物。
[问题的解决方案]
在探索合乎需要的包含化合物I或其药学上可接受的盐的药物组 合物及其固体口服制剂的持续研究的过程中，本申请的发明人对药物组合物的成分进行了缜密的筛选实验，并且已经发现特定的药物组合物的处方组成能够解决以上技术问题，从而完成了本发明。
具体地，本发明提供以下优选实施方案：
1.一种药物组合物，其包含：
作为活性成分的如式I所示的化合物或其药学上可接受的盐及赋形剂，所述赋形剂包含填充剂及润滑剂，任选地，进一步包含崩解剂，
Figure PCTCN2020142147-appb-000002
其特征在于，所述填充剂是：(1)微晶纤维素，(2)微晶纤维素和乳糖，或(3)微晶纤维素和钙的磷酸盐。
2.根据方案1的药物组合物，其中所述填充剂是微晶纤维素；或者所述填充剂是微晶纤维素和乳糖，且微晶纤维素和乳糖的重量比为1∶9～10∶1，优选1∶3～3∶1，进一步优选为1∶1.5；或者所述填充剂是微晶纤维素和钙的磷酸盐，且微晶纤维素和钙的磷酸盐的重量比为1∶9～10∶1，优选1∶3～3∶1，进一步优选为1∶1.5；优选地，所述钙的磷酸盐是磷酸钙、磷酸氢钙、磷酸二氢钙或它们的水合物，优选磷酸氢钙或其水合物，更优选无水磷酸氢钙。
3.根据方案1或2的药物组合物，其中所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、二氧化硅、硬脂酸锌、微粉硅胶、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁或聚乙二醇中的一种或多种；优选为微粉硅胶、滑石粉、硬脂酸钙、硬脂酸镁或聚乙二醇中的一种或多种；进一步优选为硬脂酸镁。
4.根据方案1-3中任一项的药物组合物，其中所述药物组合物中不包含崩解剂；或者所述药物组合物包含崩解剂，且所述崩解剂选自羧甲基纤维素、粉状纤维素、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠、聚乙烯吡咯烷酮、麦芽糖糊精、硅酸铝镁、玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联 羧甲基纤维素钠中的一种或多种，优选为玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，进一步优选为羧甲淀粉钠或交联羧甲基纤维素钠。
5.根据方案1-4中任一项的药物组合物，其中所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1.00％～90.00％，优选5.00％～80.00％、10.00％～65.00％、20.00％～50.00％、25.00％～45.00％或28.00％～35.00％；
填充剂，其重量百分比为10.00％～95.00％，优选25.00％～90.00％、40.00％～90.00％、50.00％～80.00％或60.00％～70.00％；
崩解剂，其重量百分比为0.00％～25.00％，优选0.00％～15.00％、0.00％～6.00％、0.00％～5.00％或0.00％～2.00％；
润滑剂，其重量百分比为0.10％～5.00％，优选0.50％～4.00％、0.50％～3.00％、0.50％～2.00％或0.50％～1.50％；
其它赋形剂，其重量百分比为0.00％～25.00％，优选0.00％～15.00％、0.00％～10.00％、0.00％～5.00％或0.00％～2.00％；且
以上各组分重量百分比之和为100％。
6.根据方案1-5中任一项的药物组合物，其中所述药物组合物的各组分及其重量百分比为：
Figure PCTCN2020142147-appb-000003
或者，
Figure PCTCN2020142147-appb-000004
或者，
Figure PCTCN2020142147-appb-000005
Figure PCTCN2020142147-appb-000006
以上各组分重量百分比之和为100％。
7.根据方案1-6中任一项的药物组合物，其中所述药物组合物的各组分及其重量百分比为：
Figure PCTCN2020142147-appb-000007
或者，
Figure PCTCN2020142147-appb-000008
或者，
Figure PCTCN2020142147-appb-000009
或者，
Figure PCTCN2020142147-appb-000010
或者，
Figure PCTCN2020142147-appb-000011
Figure PCTCN2020142147-appb-000012
或者，
Figure PCTCN2020142147-appb-000013
或者，
Figure PCTCN2020142147-appb-000014
或者，
Figure PCTCN2020142147-appb-000015
或者，
Figure PCTCN2020142147-appb-000016
或者，
Figure PCTCN2020142147-appb-000017
或者，
Figure PCTCN2020142147-appb-000018
或者，
Figure PCTCN2020142147-appb-000019
或者，
Figure PCTCN2020142147-appb-000020
或者，
Figure PCTCN2020142147-appb-000021
Figure PCTCN2020142147-appb-000022
或者，
Figure PCTCN2020142147-appb-000023
其中以上各组分重量百分比之和为100％，并且微晶纤维素和无水磷酸氢钙或乳糖的重量比为1∶9～10∶1，进一步优选1∶3～3∶1，更进一步优选为1∶1.5。
8.一种由方案1-7任一项所述的药物组合物制成的固体口服制剂，优选散剂、胶囊剂、片剂、颗粒剂或细粒剂，更优选散剂、胶囊剂或片剂，更优选片剂，更优选包衣片剂，最优选薄膜包衣片剂，其中所述薄膜包衣片剂由作为片芯的方案1-7任一项所述的药物组合物和薄膜包衣组成，所述薄膜包衣增重占片芯重量的1～5％，优选2～4％，更优选2.5～3％，最优选为3％。
9.根据方案1-7任一项所述的药物组合物或方案8所述的固体口服制剂，其中所述药物组合物或固体口服制剂包含0.001～1000mg，优选0.1～800mg，优选1～500mg，更优选25～200mg如式I所示的化合物或其药学上可接受的盐。
10.一种制备如方案1-7任一项所述的药物组合物的方法，其包括：(1)将如式I所示的化合物或其药学上可接受的盐及除润滑剂以外的其它赋形剂于混合容器中混合以产生预混物；(2)将润滑剂与预混物进行总混，得到所述的药物组合物。
11.一种制备如方案8或9所述的固体口服制剂的方法，其包括：将由方案10中所述的制备方法得到的药物组合物按包装剂量装入包装袋中，制成散剂；或将所述药物组合物填充至胶囊中，制成胶囊剂；或使用适当的压片机将所述药物组合物进一步压制成片剂；优选地，使用适当的压片机将所述药物组合物直接压缩成为片剂；进一步优选地，将所述片剂进一步制成包衣片剂，优选薄膜包衣片剂，更优选胃溶性薄膜包衣片剂。
12.如方案1-7任一项所述的药物组合物或方案8或9所述固体口 服制剂在制备用于治疗II型糖尿病的药物中的应用。
13.如方案12所述的应用，其中所述如式I所示的化合物或其药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，进一步优选为50mg～150mg，更进一步优选为100mg。
14.如方案12或13所述的应用，其中所述如式I所示的化合物或其药学上可接受的盐作为所述用于治疗II型糖尿病的药物的唯一活性成分，或者与其它活性成分联合作为所述用于治疗II型糖尿病的药物的活性成分，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
15.如方案1-7任一项所述的药物组合物或方案8或9所述固体口服制剂，其用于治疗II型糖尿病。
16.如方案15所述的用于治疗II型糖尿病的如方案1-7任一项所述的药物组合物或方案8或9所述固体口服制剂，其中所述如式I所示的化合物或其药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，优选为50mg～150mg，进一步优选为100mg。
17.如方案15或16所述的用于治疗II型糖尿病的如方案1-7任一项所述的药物组合物或方案8或9所述固体口服制剂，其中所述如式I所示的化合物或其药学上可接受的盐是用于治疗II型糖尿病的唯一活性成分，或者与其它活性成分联合作为用于治疗II型糖尿病的活性成分，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
18.一种治疗II型糖尿病的方法，其包括向需要其的对象施用如方案1-7任一项所述的药物组合物或方案8或9所述固体口服制剂。
19.如方案18所述的方法，其中所述如式I所示的化合物或其药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，优选为50mg～150mg，进一步优选为100mg。
20.如方案18或19所述的方法，其中所述如式I所示的化合物或其药学上可接受的盐作为用于治疗II型糖尿病的唯一活性成分而施用，或者与其它活性成分联合作为用于治疗II型糖尿病的活性成分而施用，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接 受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
[发明的有益效果]
本发明取得了以下有益的技术效果：
(1)所述药物组合物的制备方法简便，对所采用的仪器设备和操作工艺均无苛刻的要求，更适合于工业化生产；(2)所述药物组合物适于直压制片，故可以极大地简化片剂的制备过程；(3)由所述药物组合物制成的固体口服制剂如片剂具有有利的外观、基片硬度、脆碎度、崩解时限和活性成分的含量均匀度，符合制剂标准；和(4)所述药物组合物还具备优良的稳定性，在影响因素试验、加速稳定性试验和长期稳定性试验中，被考察药物组合物的最大单杂、总杂、含量、水分和晶型均无明显变化，故适宜长期储存。
[实施方案的详细描述]
本发明的第一个方面提供了一种药物组合物，其包含：作为活性成分的如式I所示的化合物或其药学上可接受的盐及赋形剂，所述赋形剂包含填充剂及润滑剂，任选地，进一步包含崩解剂，
Figure PCTCN2020142147-appb-000024
其中，所述填充剂是：(1)微晶纤维素，(2)微晶纤维素和乳糖，或(3)微晶纤维素和钙的磷酸盐。
本发明所述的“活性成分”是指如式I所示的化合物或其药学上可接受的盐。在本发明的实施方案中，活性成分在所述药物组合物中的重量百分比为1.00％～90.00％，优选5.00％～80.00％、10.00％～65.00％、20.00％～50.00％、25.00％～45.00％或28.00％～35.00％。
本发明所述的“其它活性成分”是指用于与如式I所示的化合物或其药学上可接受的盐联合用于治疗II型糖尿病的药学活性剂，其包括但不限于胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
本发明所述的“赋形剂”是指除活性成分以外，在调配处方和生产药品时使用的所有附加物料的总称，也称作辅料，一般为可药用的惰性成分，在安全性方面已进行了合理的评估。赋形剂的实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂(或称稀释剂)，以及矫味剂、增稠剂、分散剂、着色剂及香料等物质。赋形剂能增强药物制剂的操作特性，例如通过增加流动性和/或粘着性而使制剂更适于直接压缩。进一步的，所述“赋形剂”应具备与活性成分良好的相容性，即赋形剂本身或所含杂质不会与活性成分中的结构基团产生化学反应或导致活性成分降解，造成活性成分含量下降。
在本发明的实施方案中，所述赋形剂包含填充剂及润滑剂并任选地进一步包含崩解剂。在一个实施方案中，所述赋形剂由填充剂及润滑剂组成。在另一个实施方案中，所述赋形剂由填充剂、润滑剂和崩解剂组成。
本发明所述的“填充剂”是指用于增加药物组合物的重量和体积，以便于成型和分剂量的赋形剂。本发明所述的填充剂可以为单一填充剂，也可为两种填充剂的混合物。当所述填充剂为单一填充剂时，其是微晶纤维素，特别是微晶纤维素MCC102。当所述填充剂为两种填充剂的混合物时，两种填充剂分别为微晶纤维素(特别是微晶纤维素MCC102)和乳糖(特别是乳糖F100)，或者为微晶纤维素(特别是微晶纤维素MCC102)和钙的磷酸盐(例如磷酸钙、磷酸氢钙、磷酸二氢钙或它们的水合物，优选磷酸氢钙或其水合物，更优选无水磷酸氢钙)，且两者的重量比为1∶9～10∶1，优选1∶3～3∶1，进一步优选为1∶1.5。
在本发明的实施方案中，填充剂在所述药物组合物中的重量百分比为10.00％～95.00％，优选25.00％～90.00％、40.00％～90.00％、50.00％～80.00％或60.00％～70.00％。
本发明所述的“润滑剂”是指用于减少药物组合物的颗粒间及颗粒与模孔间的摩擦力，改善力的传递和分布的赋形剂。本发明所述的润滑剂选自硬脂酸或其盐(例如，硬脂酸镁、硬脂酸钙、硬脂酸锌)、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、二氧化硅、微粉硅胶、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁或聚乙二醇中的一种或多种；优选为微粉硅胶、滑石粉、硬脂酸钙、硬脂酸镁或聚乙二醇中的一种或多种；进一步优选 为硬脂酸镁。
在本发明的实施方案中，润滑剂在所述药物组合物中的重量百分比为0.10％～5.00％，优选0.50％～4.00％、0.50％～3.00％、0.50％～2.00％或0.50％～1.50％。
本发明所述的“崩解剂”是指用于促进药物组合物在胃肠道中的崩解和增加活性成分的溶出的赋形剂。本发明所述的崩解剂选自羧甲基纤维素、粉状纤维素、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠、聚乙烯吡咯烷酮、麦芽糖糊精、硅酸铝镁、玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，进一步优选为羧甲淀粉钠或交联羧甲基纤维素钠。
在本发明的实施方案中，崩解剂在所述药物组合物中的重量百分比为0.00％～25.00％，优选0.00％～15.00％、0.00％～6.00％、0.00％～5.00％或0.00％～2.00％。
本发明的药物组合物还可含有除填充剂、润滑剂和崩解剂以外的其它赋形剂。作为其具体实例，可以举出：粘合剂、矫味剂、增稠剂、分散剂、着色剂及香料等。在本发明的实施方案中，其它赋形剂在所述药物组合物中的重量百分比为0.00％～25.00％，优选0.00％～15.00％、0.00％～10.00％、0.00％～5.00％或0.00％～2.00％。
除非另外指出，否则所有的百分数都以药物组合物及其固体口服制剂的总重量的重量％给出。
在本发明的一些实施方案中，典型的药物组合物的组分及重量百分比如下：
Figure PCTCN2020142147-appb-000025
或者，
Figure PCTCN2020142147-appb-000026
或者，
Figure PCTCN2020142147-appb-000027
在本发明的另一些实施方案中，所述药物组合物的组分及重量百分比如下：
Figure PCTCN2020142147-appb-000028
或者，
Figure PCTCN2020142147-appb-000029
Figure PCTCN2020142147-appb-000030
或者，
Figure PCTCN2020142147-appb-000031
或者，
Figure PCTCN2020142147-appb-000032
在本发明的另一些实施方案中，所述药物组合物的组分及重量百分比如下：
Figure PCTCN2020142147-appb-000033
或者，
Figure PCTCN2020142147-appb-000034
或者，
Figure PCTCN2020142147-appb-000035
或者，
Figure PCTCN2020142147-appb-000036
Figure PCTCN2020142147-appb-000037
或者，
Figure PCTCN2020142147-appb-000038
或者，
Figure PCTCN2020142147-appb-000039
或者，
Figure PCTCN2020142147-appb-000040
Figure PCTCN2020142147-appb-000041
或者，
Figure PCTCN2020142147-appb-000042
或者，
Figure PCTCN2020142147-appb-000043
或者，
Figure PCTCN2020142147-appb-000044
Figure PCTCN2020142147-appb-000045
或者，
Figure PCTCN2020142147-appb-000046
本发明的第二个方面提供由上述的药物组合物制成的固体口服制剂。
本发明所述的“固体口服制剂”是指用于口服施用的呈固态的药物制剂。本发明涉及由上述药物组合物制成的固体口服制剂，其具体剂型优选散剂、胶囊剂、片剂、颗粒剂、细粒剂等，更优选散剂、胶囊剂或片剂，更优选片剂，更优选为包衣片剂，最优选薄膜包衣片剂。
本发明所述的“薄膜包衣片剂”是指在片芯(其由本发明的药物组合物经压片制成)外包上薄膜(包)衣的片剂。所述薄膜包衣可使用本领域常用的包衣材料和方法制备。例如，薄膜包衣材料包括高分子材料、增塑剂、致孔剂和某些固体物料等中的一种或多种成分，其中高分子材料可选自羟丙甲纤维素、羟丙纤维素、甲基纤维素、羟乙基纤维素、丙烯酸树脂、乙基纤维素、醋酸纤维素、醋酸纤维素酞酸酯、聚乙烯醇酞酸酯、醋酸纤维素苯三酸酯、羟丙甲纤维素酞酸酯等；增塑剂可选自甘油、丙二醇、聚乙二醇、甘油单醋酸酯、甘油三醋酸酯、癸二酸二丁酯、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、蓖麻油、玉米油、液状石蜡等；致孔剂(也称释放速度调节剂)可选自蔗糖、氯化钠、表面活性剂、聚乙二醇等；固体物料可选自滑石粉、硬脂酸镁、微粉 硅胶等。还可视情况使用本领域常规的增光剂、色料等。包衣材料也可直接选用市售预混包衣粉，例如
Figure PCTCN2020142147-appb-000047
系列包衣粉、
Figure PCTCN2020142147-appb-000048
系列包衣粉、
Figure PCTCN2020142147-appb-000049
系列包衣粉、
Figure PCTCN2020142147-appb-000050
系列包衣粉、
Figure PCTCN2020142147-appb-000051
系列包衣粉等。所述包衣材料可以是胃溶性包衣材料，也可以是肠溶性包衣材料。所述薄膜包衣增重占片芯重量的1～5％，优选2～4％，更优选2.5～3％，最优选为3％。包衣溶剂优选为水，其可在干燥期间去除而并不保留于最终产物中。
本发明的药物组合物或其固体口服制剂可含有0.001-1000mg，优选0.1～800mg，优选1～500mg，更优选25～500mg剂量范围的如式I所示的化合物或其药学上可接受的盐。例如，单剂量药物组合物或其固体口服制剂中如式I所示的化合物或其药学上可接受的盐的含量可以为0.1mg、0.2mg、0.25mg、0.5mg、1mg、2mg、2.5mg、5mg、10mg、20mg、25mg、50mg、100mg、150mg、200mg、250mg、300mg、500mg等。
本发明的第三方面提供上述药物组合物的制备方法，其包括：(1)将活性成分及除润滑剂以外的其它赋形剂于混合容器中混合以产生预混物；(2)将润滑剂与预混物进行总混，得到所述的药物组合物。
在一些实施方案中，用于制备本发明的药物组合物的方法包括：(1)备料：按照处方量称取式I所示化合物或其药学上可接受的盐(即上述活性成分)及相应的赋形剂；(2)将活性成分、填充剂及任选的崩解剂于混合容器中混合以产生预混物；(3)将润滑剂与预混物进行总混，得到所述的药物组合物。
在一些实施方案中，用于制备本发明的药物组合物的示例性方法包括：1)备料：按照处方量称取式I所示化合物或其药学上可接受的盐(即上述活性成分)以及相应的赋形剂(例如，填充剂、崩解剂和润滑剂)；2)预混：按等量递加3次的方式，将崩解剂加入填充剂中，抖袋混合；再加入活性成分(API)，抖袋混合；3)总混：按等量递加3次的方式，将润滑剂加入上述混粉中，抖袋混合均匀，得到所述的药物组合物。
在一些实施方案中，用于制备本发明的药物组合物的示例性方法包括：1)备料：按照处方量称取式I所示化合物或其药学上可接受的盐(即上述活性成分)以及相应的赋形剂(例如，填充剂、崩解剂和 润滑剂)；2)预混：按等量递加3次的方式，将崩解剂加入一种填充剂中，抖袋混合；再加入式I所示化合物或其药学上可接受的盐(即上述活性成分)和另一种填充剂，抖袋混合；3)总混：按等量递加3次的方式，将润滑剂加入上述混粉中，抖袋混合均匀，得到所述的药物组合物。
在一些实施方案中，用于制备本发明的药物组合物的示例性方法包括：1)备料：按照处方量称取式I所示化合物或其药学上可接受的盐(即上述活性成分)以及相应的赋形剂(例如，填充剂、崩解剂和润滑剂)；2)预混：按等量递加3次的方式，将两种填充剂依次置于袋中，抖袋混合，按等量递加3次的方式，将崩解剂加入抖袋混合后的混粉中，抖袋混合，再加入式I所示化合物或其药学上可接受的盐(即上述活性成分)，抖袋混合；3)总混：按等量递加3次的方式，将润滑剂加入上述混粉中，抖袋混合均匀，得到所述的药物组合物。
上述用于制备本发明的药物组合物的方法还可进一步包括其它未提及的步骤。
上述“混合容器”应做广义的理解，其既包括柔性的混合容器(包括但不限于柔性的袋如洁净塑料袋、自封袋等)也包括刚性的混合容器(包括但不限于料斗混合机等)。本领域技术人员可根据批量和重量选择适宜的混合容器进行相应的预混和总混操作。本发明的第四方面提供上述固体口服制剂的制备方法，其包括：将由上述制备方法得到的药物组合物按包装剂量装入包装袋中，制成散剂；或将所述的药物组合物填充至胶囊中，制成胶囊剂；或使用适当的压片机将所述的药物组合物进一步压制成片剂。
在一些优选的实施方案中，使用适当的压片机将所述的药物组合物直接压缩成为片剂。所述片剂具有目标片芯重量、适当尺寸及抗压程度。
用于本文的术语“直接压缩”是指直接压缩药物制剂的成分(即，活性成分和赋形剂)而不改变活性成分的物理和化学特性的方法。一种示例性的直接压缩方法包括：将活性成分和赋形剂以粉末的形式在混合设备中混合；然后将混合的组合物填入模具中，并通过冲头直接压缩。在直接压缩方法中有用的赋形剂非限制性地包括填充剂和润滑剂。
在一些进一步优选的实施方案中，将所述片剂进一步制成包衣片 剂，优选薄膜包衣片剂。在这些实施方案中，所述片剂(即由前述药物组合物制备的基片)充当所述包衣片剂的片芯。一种示例性的制备薄膜包衣片剂的方法包括：(1)配制包衣液；(2)将片芯放入包衣锅内转动，将包衣液均匀喷入，即得薄膜包衣片剂；和(3)干燥所得薄膜包衣片剂。所述包衣液可以通过将包衣材料(例如薄膜包衣预混剂)分散(例如溶解或悬浮)于包衣溶剂(例如水，优选纯净水)中(例如，在环境温度下与合适的混合器中)制备。
本发明的第五方面提供上述的药物组合物或上述的固体口服制剂在制备用于治疗II型糖尿病的药物中的应用。
所述药物在发挥治疗作用时，如式I所示的化合物或其药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，进一步优选为50mg～150mg，更进一步优选为100mg。
在所述应用中，所述如式I所示的化合物或其药学上可接受的盐可以作为所述用于治疗II型糖尿病的药物的唯一活性成分，或者可以与其它活性成分联合作为所述用于治疗II型糖尿病的药物的活性成分，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
本发明的第六方面提供上述的药物组合物或上述的固体口服制剂，其用于治疗II型糖尿病。
在治疗II型糖尿病的应用中，所述如式I所示的化合物或其药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，进一步优选为50mg～150mg，更进一步优选为100mg。
在用于治疗II型糖尿病的上述的药物组合物或上述的固体口服制剂中，所述如式I所示的化合物或其药学上可接受的盐可以是用于治疗II型糖尿病的唯一活性成分，或者可以与其它活性成分联合作为用于治疗II型糖尿病的活性成分，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
本发明的第七方面提供一种治疗II型糖尿病的方法，其包括向需要其的对象施用上述的药物组合物或上述的固体口服制剂。
在所述治疗II型糖尿病的方法中，所述如式I所示的化合物或其 药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，进一步优选为50mg～150mg，更进一步优选为100mg。
在所述治疗II型糖尿病的方法中，所述如式I所示的化合物或其药学上可接受的盐可以作为用于治疗II型糖尿病的唯一活性成分而施用，或者可以与其它活性成分联合作为用于治疗II型糖尿病的活性成分而施用，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
在本发明的实施方案中，给药对象可以是人或非人哺乳动物，更优选人。
在本发明的实施方案中，术语“包含”、“包括”和“含有”一般表示开放性的含义，但是在其范围内也包括“由......组成”所限定的封闭性的情况。例如，“一种药物组合物，其包含：作为活性成分的如式I所示的化合物或其药学上可接受的盐及赋形剂”也包括“一种药物组合物，其由作为活性成分的如式I所示的化合物或其药学上可接受的盐及赋形剂组成”的情况。
在本发明的范围中，任一特征的各种选项可以与其它特征的各种选项相互组合，从而构成许多不同的实施方案。本发明意欲包括由所有技术特征的各种选项所组成的所有可能的实施方案。
在本发明的范围中，可对如式I所示的化合物或其药学上可接受的盐在处方中的用量进行适当的调整，或者与赋形剂的比例(质量比)进行调整，以得到含有不同规格或不同药物重量的药物组合物或固体口服制剂，其也落入本发明的范围。
[其它实施方案]
本发明还涉及以下实施方案：
1.一种药物组合物，其包含作为活性成分的如式I所示的DPP-4抑制剂或其药学上可接受的盐及赋形剂，所述赋形剂包含填充剂及润滑剂，任选地，进一步包含崩解剂，
Figure PCTCN2020142147-appb-000052
2.如方案1所述的药物组合物，其特征在于，所述填充剂选自预胶化淀粉、乳糖、微晶纤维素或无水磷酸氢钙中的一种或多种，优选为微晶纤维素、乳糖或无水磷酸氢钙中的一种或多种；所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁。
3.如方案2所述的药物组合物，其特征在于，各组分的重量百分比为：
Figure PCTCN2020142147-appb-000053
以上各组分重量百分比之和为100％；
或者，
Figure PCTCN2020142147-appb-000054
以上各组分重量百分比之和为100％；
或者，
Figure PCTCN2020142147-appb-000055
以上各组分重量百分比之和为100％；
优选地，所述填充剂为单一填充剂或两种填充剂的混合物；当所述填充剂为两种填充剂的混合物时，填充剂A和填充剂B的比例选自1∶9～10∶1，优选1∶3～3∶1，进一步优选为1∶1.5；其中填充剂A优选为微晶纤维素，填充剂B优选为乳糖或无水磷酸氢钙。
4.如方案3所述的药物组合物，其特征在于，所述药物组合物的组分及重量百分比如下：
Figure PCTCN2020142147-appb-000056
以上各组分重量百分比之和为100％，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000057
以上各组分重量百分比之和为100％，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000058
以上各组分重量百分比之和为100％，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000059
Figure PCTCN2020142147-appb-000060
以上各组分重量百分比之和为100％。
5.如方案3所述的药物组合物，其特征在于，所述药物组合物的组分及重量百分比如下：
Figure PCTCN2020142147-appb-000061
以上各组分重量百分比之和为100％；微晶纤维素∶无水磷酸氢钙或乳糖＝1∶9～10∶1，优选为1∶1.5，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000062
以上各组分重量百分比之和为100％；微晶纤维素∶无水磷酸氢钙或乳糖＝1∶9～10∶1，优选1∶1.5，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000063
Figure PCTCN2020142147-appb-000064
以上各组分重量百分比之和为100％；微晶纤维素∶无水磷酸氢钙或乳糖＝1∶1.5，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000065
以上各组分重量百分比之和为100％；微晶纤维素∶无水磷酸氢钙或乳糖＝1∶1.5，
所述崩解剂选自玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为羧甲淀粉钠或交联羧甲基纤维素钠；所述润滑剂选自滑石粉、硬脂酸镁、微粉硅胶、硬脂酸钙或聚乙二醇，优选为硬脂酸镁；
或者，
Figure PCTCN2020142147-appb-000066
以上各组分重量百分比之和为100％；微晶纤维素∶无水磷酸氢钙或乳糖＝1∶1.5。
6.一种由方案1-5任一项所述的药物组合物制成的固体口服制剂，其特征在于，所述固体口服制剂选自散剂、胶囊或片剂；所述片剂优选薄膜包衣片剂，其中，薄膜包衣增重占片芯重量的2％～4％，优选为3％。
7.如方案1-5任一项所述的药物组合物或方案6所述固体口服制剂，其包含所述DPP-4抑制剂或其药学上可接受的盐0.001～1000mg，优选0.1～800mg，优选1～500mg，更优选25～200mg。
8.如方案1-5任一项所述的药物组合物或方案6所述固体口服制剂在制备治疗II型糖尿病药物中的应用，其中所述DPP-4抑制剂或其药学上可接受盐的治疗有效量为25mg～200mg，优选为50mg～150mg，进一步优选为100mg；
任选地，所述药物与其它活性成分或药物联合用于治疗糖尿病，其它活性成分或药物选自胰岛素、二甲双胍、磺酰脲类降糖药、噻唑烷二酮类降糖药，优选为二甲双胍。
9.一种制备如方案1-5任一项所述的药物组合物的制备方法，其包含：(1)将活性成分及除润滑剂以外的其它赋形剂于合适混合器中混合以产生预混物；(2)将润滑剂与预混物进行总混，得到总混物。
10.一种制备如方案6所述的固体口服制剂的方法，其包含：将由方案9中所述制备方法得到的总混物按包装剂量装入包装袋中，制成散剂；或将总混物填充至胶囊中，制成胶囊剂；或使用适当压片机将总混物进一步制成片剂；优选地，将所述总混物直接压缩成为片剂；优选地，所述片剂进一步制成包衣片剂，优选薄膜包衣片剂。
具体实施方式
下面通过部分实施例对本发明进行详细说明，但本发明并不限于下述实施例。对于本领域技术人员显而易见的修改意图落入本发明权利要求的范围内。
实施例中未注明具体条件者，按照常规条件或制造商建议条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。除非另行定义，否则文中所使用的所有专业与科学用语的意义与本领域技术人员所熟悉的意义相同。
本发明的化合物I可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及对于本领域技术上人员来说显而易见的等同替换方式。优选的实施方式包括但不限于本发明的制备例。
为了获得本发明的化合物，有时需要本领域技术人员在已有实施 方式的基础上对合成步骤或者反应流程进行修改或选择。
制备例 化合物I的制备
参照CN101970402B中实施例1的方法制备得到化合物I的粗品。将粗品(1000g，3.083mol)加入6倍体积(v/w)甲醇中，加热搅拌至溶解，过滤，滤液减压浓缩至约2倍体积(v/w)甲醇，改为25～30℃搅拌1h，降温至0～5℃搅拌析晶1h，过滤。所得固体用乙酸乙酯洗涤，真空干燥，得白色晶状粉末674g。收率为67.4％，液相纯度为99.88％，熔点为166.3-167.8℃。
实施例1化合物I的片剂(采用微晶纤维素作为单一填充剂)
实施例1的片剂处方如下表1中所示：
表1实施例1的处方(制成1000片)
Figure PCTCN2020142147-appb-000067
使用直接压缩工艺制备实施例1的片剂，其具体方法为：1)备料：按照处方量称取活性成分(API)化合物I以及相应的填充剂、崩解剂和润滑剂；2)预混：按等量递加3次的方式，将崩解剂加入填充剂中，抖袋混合；再加入活性成分(API)，抖袋混合；3)总混：按等量递加3次的方式，将润滑剂加入上述混粉中，抖袋混合均匀；4)压片：采用
Figure PCTCN2020142147-appb-000068
冲头，以单冲压片机进行压片。
结果显示：采用微晶纤维素作为单一填充剂，压片过程顺利，所得片剂样品的脆碎度及含量均匀度结果均符合要求，具体结果见下表2：
表2实施例1的检测结果
Figure PCTCN2020142147-appb-000069
注：A：标示量与均值差值的绝对值，S：标准差，下同。
实施例2-5化合物I的片剂(针对不同的单一填充剂种类进行的 对比实验)
参照实施例1的处方组成及制备方法制备实施例2-5的片剂，但是将单一填充剂微晶纤维素替换为乳糖、预胶化淀粉、甘露醇或无水磷酸氢钙。实施例2-5的片剂的具体处方及检测结果见下表3。
表3实施例2-5的处方及检测结果
Figure PCTCN2020142147-appb-000070
结果显示：对于使用单一填充剂的处方，采用乳糖作为填充剂时，所得基片脆碎度值结果偏大，片子磨损较严重；采用预胶化淀粉作为填充剂时，所得基片可压性差，片子虽能成型，但硬度太小，手掰易断，且崩解太慢(大于10分钟)；采用甘露醇作为填充剂时，脆碎度值偏大，片子磨损较严重；采用无水磷酸氢钙作为填充剂时，所得基片硬度略小，脆碎度结果偏大，片子磨损较严重。综上所述，采用乳糖、预胶化淀粉、甘露醇和无水磷酸氢钙作为单一填充剂不能制备合格的片剂，所得到的片剂的质量相对于采用微晶纤维素作为单一填充剂制备的片剂的质量较差。
实施例6化合物I的片剂(使用微晶纤维素和乳糖作为组合填充剂)
将单一填充剂替换为两种填充剂，参照实施例1的处方组成及制 备方法(其中，预混步骤变更为：按等量递加3次的方式，将崩解剂加入微晶纤维素中，抖袋混合；再加入活性成分与乳糖，抖袋混合)，可得以下组合物(1000片)。具体处方见表4，检测结果见表5。
表4实施例6的处方
Figure PCTCN2020142147-appb-000071
表5实施例6的检测结果
Figure PCTCN2020142147-appb-000072
结果显示：采用微晶纤维素和乳糖作为组合填充剂，压片过程顺利，所得片剂的样品的脆碎度及含量均匀度结果均符合要求。
实施例7-10化合物I的片剂(针对不同的组合填充剂种类进行的对比实验)
将组合填充剂替换为微晶纤维素+无水磷酸氢钙、微晶纤维素+预胶化淀粉、微晶纤维素+甘露醇或甘露醇+乳糖，参照实施例6的处方组成及制备方法(其中，预混步骤变更为：按等量递加3次的方式，将崩解剂加入微晶纤维素或甘露醇中，抖袋混合；再加入活性成分与另一种填充剂(无水磷酸氢钙、预胶化淀粉、甘露醇或乳糖)，抖袋混合)制备实施例7-10的片剂。实施例7-10的片剂的具体处方及检测结果见下表6。
表6实施例7-10的处方及检测结果
Figure PCTCN2020142147-appb-000073
结果显示：对于使用组合填充剂的处方，将微晶纤维素与预胶化淀粉配伍使用作为填充剂时，所得基片硬度偏小，脆碎度试验后，片子磨损与其它处方相比较明显；将乳糖与甘露醇配伍使用作为填充剂时，基片硬度适中，但脆碎度试验后，边缘磨损较为严重；将微晶纤维素与甘露醇配伍使用作为填充剂时，尽管所得基片硬度、脆碎度及含量均匀度结果均合格，但是在原辅料相容性试验中发现，当活性成分与甘露醇一起放样时，杂质增长明显，故甘露醇与活性成分的相容性较差。因此，采用微晶纤维素与预胶化淀粉、乳糖与甘露醇、或者微晶纤维素与甘露醇配伍作为组合填充剂，得到的片剂效果较差。然而，将微晶纤维素与无水磷酸氢钙配伍使用作为填充剂时，所得基片硬度、脆碎度及含量均匀度结果均合格。
综合以上结果，组合填充剂优选微晶纤维素+乳糖及微晶纤维素+ 无水磷酸氢钙。
实施例11-13化合物I的片剂(对组合填充剂用量的筛选)
改变两种组合填充剂的用量比例，参照实施例6的处方组成及制备方法(其中，预混步骤变更为：按等量递加三次的方式，将处方量的两种填充剂加入自封袋中，抖袋混合；按等量递加三次的方式，加入崩解剂，抖袋混合；再加入活性成分，抖袋混合)制备实施例11-13的片剂，以探究组合填充剂比例对压片效果的影响。实施例11-13的片剂的具体处方及检测结果见下表7和8。
表7实施例11-13的处方
Figure PCTCN2020142147-appb-000074
表8实施例11-13的检测结果
Figure PCTCN2020142147-appb-000075
结果显示：组合填充剂采用微晶纤维素与乳糖时，乳糖与微晶纤维素比例10∶1时，含量均匀度结果显示，10片中有1片含量不合格，A+2.2S偏大。乳糖与微晶纤维素比例调为9∶1时，基片硬度、含量均匀度及脆碎度均有改善，处方更优。微晶纤维素与乳糖比例为10∶1时，基片硬度、脆碎度、含量均匀度结果均合格。
实施例14-15化合物I的片剂(对崩解剂的筛选)
参照实施例6的处方组成及制备方法制备实施例14-15的片剂，但是调整崩解剂的种类或用量，即仅将实施例6中的崩解剂由羧甲淀粉 钠替换为交联羧甲纤维素钠，各组分的重量百分比保持不变，得到实施例14的处方；或者在实施例6处方的基础上，不添加崩解剂羧甲淀粉钠，其重量百分比份额由填充剂微晶纤维素补足，得到实施例15的处方，以观察其对制剂效果的影响。实施例14-15的片剂的具体处方及检测结果见下表9。
表9实施例14-15的处方及检测结果
Figure PCTCN2020142147-appb-000076
结果显示：乳糖与微晶纤维素的比例为1.5∶1时，崩解剂采用交联羧甲纤维素钠或不加崩解剂，基片的硬度、脆碎度、崩解时限、含量均匀度结果均合格。
实施例16化合物I的片剂(其它示例性处方)
适用于本发明的示例性处方还包括表10-11中所列出的那些(制成1000片)：
表10实施例16的处方(使用单一填充剂)
Figure PCTCN2020142147-appb-000077
表11实施例16的处方(使用组合填充剂)
Figure PCTCN2020142147-appb-000078
实施例17化合物I的片剂(含有不同规格的活性成分的处方)
还可以将本发明的药物组合物制成含有不同规格的活性成分的制剂，其示例性处方包括表12-13中所列出的那些(制成1000片)：
表12实施例17的处方(使用单一填充剂)
Figure PCTCN2020142147-appb-000079
表13实施例17的处方(使用组合填充剂)
Figure PCTCN2020142147-appb-000080
实施例18化合物I的薄膜包衣片剂
可以将本发明的药物组合物制备成薄膜包衣片剂，其具体制备方法如下：1)使用实施例1-17中的任一个所述的处方组成和制备方法制 备化合物I的片剂(即基片)作为片芯；2)称取处方量的薄膜包衣预混剂，在环境温度下与合适的混合器中，将薄膜包衣预混剂悬浮于纯化水中以产生包衣液；3)将片芯放入包衣锅内转动，预热与磨边结束后，将包衣液均匀喷入；4)干燥所得薄膜包衣片剂。薄膜包衣所致的片剂重量增加约为片芯重量的2％～4％。示例性的配方包括表14中所列出的那些：
表14实施例18的处方(薄膜包衣片剂)
Figure PCTCN2020142147-appb-000081
注：包衣材料为胃溶型薄膜包衣预混剂
Figure PCTCN2020142147-appb-000082
85F28751-CN。
实施例19薄膜包衣片剂的稳定性考察
1.影响因素试验
选取实施例18-1的薄膜包衣片剂(含有100mg化合物I，包衣片剂的总重量为329.60mg)，去除包装，分别于光照4500Lx±500Lx、高湿92.5％RH、高温60℃条件下进行影响因素试验，由于光照度略低，因此光照条件于6天、12天取样，高湿92.5％RH、高温60℃条件于5天、10天取样。影响因素试验结果见表15。
表15光照、高湿和高温影响因素试验结果
Figure PCTCN2020142147-appb-000083
结果显示：将化合物I的薄膜包衣片剂在光照4500Lx±500Lx条件下放置12天，在高温60℃、高湿92.5％RH条件下放置10天后，有关物质的含量基本不变，未显示明显的变化趋势。以上结果说明本发明的化合物I的薄膜包衣片剂稳定性较好。
2.加速稳定性试验
选取实施例18-1的薄膜包衣片剂(含有100mg化合物I，包衣片剂的总重量为329.600mg)，将经包装(铝箔和聚酰胺/铝/聚氯乙烯冷冲压成型固体药用复合硬片)的包衣片剂置于40℃±2℃、相对湿度为75％RH±5％RH的条件下放置6个月，于1、2、3、6个月取样，结果见表16。
表16加速试验结果
Figure PCTCN2020142147-appb-000084
结果显示：将包装的化合物I的薄膜包衣片剂在40±2℃、相对湿度为75％RH±5％RH的条件下放置6个月后有关物质无显著增长；各时间点的其它考察项目均符合规定，符合质量标准要求。
3.长期稳定性试验
选取实施例18-1的薄膜包衣片剂(含有100mg化合物I，包衣片剂的总重量为329.600mg)，将经包装(铝箔和聚酰胺/铝/聚氯乙烯冷冲压成型固体药用复合硬片)的包衣片剂在25℃±2℃、相对湿度为60％RH±10％RH的条件下放置36个月，于3、6、9、12、18、24、36个月取样，结果见表17。
表17长期试验结果
Figure PCTCN2020142147-appb-000085
结果显示：将包装的化合物I的薄膜包衣片剂在25±2℃、相对湿度为60％RH±10％RH的条件下放置36个月后有关物质无显著增长；各时间点的其它考察项目均符合规定，符合质量标准要求。

Claims (14)

  1. 一种药物组合物，其包含：
    作为活性成分的如式I所示的化合物或其药学上可接受的盐及赋形剂，所述赋形剂包含填充剂及润滑剂，任选地，进一步包含崩解剂，
    Figure PCTCN2020142147-appb-100001
    其特征在于，所述填充剂是：(1)微晶纤维素，(2)微晶纤维素和乳糖，或(3)微晶纤维素和钙的磷酸盐。
  2. 根据权利要求1的药物组合物，其中所述填充剂是微晶纤维素；或者所述填充剂是微晶纤维素和乳糖，且微晶纤维素和乳糖的重量比为1∶9～10∶1，优选1∶3～3∶1，进一步优选为1∶1.5；或者所述填充剂是微晶纤维素和钙的磷酸盐，且微晶纤维素和钙的磷酸盐的重量比为1∶9～10∶1，优选1∶3～3∶1，进一步优选为1∶1.5；优选地，所述钙的磷酸盐是磷酸钙、磷酸氢钙、磷酸二氢钙或它们的水合物，优选磷酸氢钙或其水合物，更优选无水磷酸氢钙。
  3. 根据权利要求1或2的药物组合物，其中所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、二氧化硅、硬脂酸锌、微粉硅胶、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁或聚乙二醇中的一种或多种；优选为微粉硅胶、滑石粉、硬脂酸钙、硬脂酸镁或聚乙二醇中的一种或多种；进一步优选为硬脂酸镁。
  4. 根据权利要求1-3中任一项的药物组合物，其中所述药物组合物中不包含崩解剂；或者所述药物组合物包含崩解剂，且所述崩解剂选自羧甲基纤维素、粉状纤维素、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠、聚乙烯吡咯烷酮、麦芽糖糊精、硅酸铝镁、玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种，优选为玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙基纤维素、羧甲淀粉钠或交联羧甲基纤 维素钠中的一种或多种，进一步优选为羧甲淀粉钠或交联羧甲基纤维素钠。
  5. 根据权利要求1-4中任一项的药物组合物，其中所述药物组合物的各组分及其重量百分比为：
    活性成分，其重量百分比为1.00％～90.00％，优选5.00％～80.00％、10.00％～65.00％、20.00％～50.00％、25.00％～45.00％或28.00％～35.00％；
    填充剂，其重量百分比为10.00％～95.00％，优选25.00％～90.00％、40.00％～90.00％、50.00％～80.00％或60.00％～70.00％；
    崩解剂，其重量百分比为0.00％～25.00％，优选0.00％～15.00％、0.00％～6.00％、0.00％～5.00％或0.00％～2.00％；
    润滑剂，其重量百分比为0.10％～5.00％，优选0.50％～4.00％、0.50％～3.00％、0.50％～2.00％或0.50％～1.50％；
    其它赋形剂，其重量百分比为0.00％～25.00％，优选0.00％～15.00％、0.00％～10.00％、0.00％～5.00％或0.00％～2.00％；且
    以上各组分重量百分比之和为100％。
  6. 根据权利要求1-5中任一项的药物组合物，其中所述药物组合物的各组分及其重量百分比为：
    Figure PCTCN2020142147-appb-100002
    或者，
    Figure PCTCN2020142147-appb-100003
    或者，
    Figure PCTCN2020142147-appb-100004
    Figure PCTCN2020142147-appb-100005
    以上各组分重量百分比之和为100％。
  7. 根据权利要求1-6中任一项的药物组合物，其中所述药物组合物的各组分及其重量百分比为：
    Figure PCTCN2020142147-appb-100006
    或者，
    Figure PCTCN2020142147-appb-100007
    或者，
    Figure PCTCN2020142147-appb-100008
    或者，
    Figure PCTCN2020142147-appb-100009
    或者，
    Figure PCTCN2020142147-appb-100010
    Figure PCTCN2020142147-appb-100011
    或者，
    Figure PCTCN2020142147-appb-100012
    或者，
    Figure PCTCN2020142147-appb-100013
    或者，
    Figure PCTCN2020142147-appb-100014
    或者，
    Figure PCTCN2020142147-appb-100015
    或者，
    Figure PCTCN2020142147-appb-100016
    Figure PCTCN2020142147-appb-100017
    或者，
    Figure PCTCN2020142147-appb-100018
    或者，
    Figure PCTCN2020142147-appb-100019
    或者，
    Figure PCTCN2020142147-appb-100020
    或者，
    Figure PCTCN2020142147-appb-100021
    或者，
    Figure PCTCN2020142147-appb-100022
    其中以上各组分重量百分比之和为100％，并且微晶纤维素和无水磷酸氢钙或乳糖的重量比为1∶9～10∶1，进一步优选1∶3～3∶1，更进一步优选为1∶1.5。
  8. 一种由权利要求1-7任一项所述的药物组合物制成的固体口服制剂，优选散剂、胶囊剂、片剂、颗粒剂或细粒剂，更优选散剂、胶囊剂或片剂，更优选片剂，更优选包衣片剂，最优选薄膜包衣片剂，其中所述薄膜包衣片剂由作为片芯的方案1-7任一项所述的药物组合物和薄膜包衣组成，所述薄膜包衣增重占片芯重量的1～5％，优选2～4％，更优选2.5～3％，最优选为3％。
  9. 根据权利要求1-7任一项所述的药物组合物或权利要求8所述的固体口服制剂，其中所述药物组合物或固体口服制剂包含0.001～1000mg，优选0.1～800mg，优选1～500mg，更优选25～200mg如式I所示的化合物或其药学上可接受的盐。
  10. 一种制备如权利要求1-7任一项所述的药物组合物的方法，其包括：(1)将式I所示的化合物或其药学上可接受的盐及除润滑剂以外的其它赋形剂于混合容器中混合以产生预混物；(2)将润滑剂与预混物进行总混，得到所述的药物组合物。
  11. 一种制备如权利要求8或9所述的固体口服制剂的方法，其包括：将由方案10中所述的制备方法得到的药物组合物按包装剂量装入包装袋中，制成散剂；或将所述药物组合物填充至胶囊中，制成胶囊剂；或使用适当的压片机将所述药物组合物进一步压制成片剂；优选地，使用适当的压片机将所述药物组合物直接压缩成为片剂；进一步优选地，将所述片剂进一步制成包衣片剂，优选薄膜包衣片剂，更优选胃溶性薄膜包衣片剂。
  12. 如权利要求1-7任一项所述的药物组合物或权利要求8或9所述固体口服制剂在制备用于治疗II型糖尿病的药物中的应用。
  13. 如权利要求12所述的应用，其中所述如式I所示的化合物或其药学上可接受的盐的治疗有效量为1mg～500mg，优选为25mg～200mg，进一步优选为50mg～150mg，更进一步优选为100mg。
  14. 如权利要求12或13所述的应用，其中所述如式I所示的化合物或其药学上可接受的盐作为所述用于治疗II型糖尿病的药物的唯一活性成分，或者与其它活性成分联合作为所述用于治疗II型糖尿病的药物的活性成分，其中所述其它活性成分选自胰岛素、二甲双胍或其药学上可接受的盐、磺酰脲类降糖药、噻唑烷二酮类降糖药中的一种或多种，优选为二甲双胍，更优选为盐酸二甲双胍。
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