WO2018010543A1 - 一种用于口服固体制剂的复合崩解剂体系及含有该复合崩解剂体系的口服固体制剂 - Google Patents

一种用于口服固体制剂的复合崩解剂体系及含有该复合崩解剂体系的口服固体制剂 Download PDF

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WO2018010543A1
WO2018010543A1 PCT/CN2017/090374 CN2017090374W WO2018010543A1 WO 2018010543 A1 WO2018010543 A1 WO 2018010543A1 CN 2017090374 W CN2017090374 W CN 2017090374W WO 2018010543 A1 WO2018010543 A1 WO 2018010543A1
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group
content
disintegrant
sodium
solid preparation
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PCT/CN2017/090374
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English (en)
French (fr)
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万耀文
陈永凯
曾弦
王朝东
冯伟
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武汉朗来科技发展有限公司
武汉启瑞药业有限公司
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Priority to EP17826880.1A priority Critical patent/EP3482747A4/en
Priority to US16/312,948 priority patent/US11786471B2/en
Publication of WO2018010543A1 publication Critical patent/WO2018010543A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and in particular to a composite disintegrator system for oral solid preparations and an oral solid preparation containing the composite disintegrant system.
  • the rate of absorption of an oral solid preparation depends on the rate at which the active substance (active ingredient) is dissolved (released) from the solid preparation, and the rate of dissolution (release) of the active ingredient often depends on the rate of disintegration of the solid preparation, and thus basically It is considered that the rate of disintegration of the oral solid preparation is a determining step of the absorption rate of the active ingredient by the body. Most of the disintegrants have good water absorption and swelling.
  • the effect of adding a disintegrant to the oral solid preparation is to eliminate or destroy the binding force due to the adhesive or the high compression, so that it is rapidly cleaved in the dissolution medium.
  • the fine particulate material is formed so that the active ingredient is rapidly dissolved and absorbed to exert a therapeutic effect.
  • disintegrants are dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium (CMC-Na), etc., mainly through capillary action and expansion. The effect is to promote the disintegration of the solid preparation.
  • some active substances have strong hygroscopicity and become sticky after moisture absorption, so that the conventional disintegrating agent cannot effectively disintegrate, resulting in poor dissolution and release properties.
  • the pressure effect has a more obvious and lasting effect of lowering heart rate, and has high safety, and has an ideal protective effect on the heart and kidney function of the patient, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.
  • various conventional disintegrating agents is not effective in disintegrating, resulting in poor dissolution and release properties of the active ingredient. Further studies, Applicants have found that most of these compounds have strong hygroscopicity and become sticky after moisture absorption, making conventional disintegrants unable to effectively disintegrate, resulting in poor release and release properties of the active ingredients.
  • the invention provides a composite disintegrator system for oral solid preparation, which can rapidly disintegrate the oral solid preparation, increase the dissolution rate thereof, thereby improving the bioavailability, and particularly capable of solving the hygroscopicity and after the moisture absorption The problem of the presence of a viscous active substance (active ingredient) which cannot be effectively disintegrated by a conventional disintegrant.
  • Conventional disintegrants mainly introduce moisture into the interior of the solid preparation by capillary action, and at the same time, the disintegrant expands after absorbing water, and eliminates the binding force generated by the binder or the high compression in the solid preparation, thereby achieving the purpose of promoting disintegration of the solid preparation.
  • the pharmaceutically active substance is highly hygroscopic and becomes sticky after moisture absorption, the oral solid preparation will be difficult to disintegrate after being prepared into an oral solid preparation by using a conventional disintegrator, for example, a solid preparation under simulated gastric acid pH conditions. Can not collapse to explain the drug.
  • the reason for this result may be that the active substance is highly hygroscopic and will compete with the disintegrant to absorb water, and at the same time become sticky after water absorption, hinder the expansion of the disintegrant, block the passage of water, and cause the conventional disintegrant. It is difficult to exert its disintegration performance.
  • the disintegrating agent is a hygroscopic swelling type disintegrating agent.
  • the hygroscopic swelling disintegrant is selected from the group consisting of dry starch, croscarmellose sodium, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, methylcellulose, low substitution A mixture of one or more of hydroxypropylcellulose, crospovidone, chitosan, microcrystalline cellulose.
  • the helper is a small molecule easily soluble substance or a gas generating type salt.
  • the gas generating salt is selected from the group consisting of one or more of a carbonate and a hydrogencarbonate. More preferably, the gas-producing salt is selected from the group consisting of sodium carbonate, calcium carbonate, potassium carbonate, calcium magnesium carbonate, zinc carbonate, magnesium carbonate, ammonium carbonate, sodium glycinate, sodium sesquicarbonate, sodium hydrogencarbonate, calcium hydrogencarbonate, hydrogencarbonate. a mixture of one or more of potassium, ammonium hydrogencarbonate.
  • the weight ratio of the disintegrant to the helper is from 10:1 to 1:10, more preferably from 8:1 to 1:8, and most preferably from 5:1 to 1:5.
  • the helper-disintegrating agent refers to an auxiliary agent capable of helping to disintegrate an active material (active ingredient) which is highly hygroscopic and which becomes sticky after moisture absorption. Active substances of this type cannot be effectively disintegrated by conventional disintegrants.
  • the present inventors have found that the addition of a small molecule easily soluble substance or a gas generating type salt can disintegrate such an active substance which cannot be effectively disintegrated. Thus, it is defined as a helper in the present invention.
  • the composite disintegrant system may also be referred to as a composite disintegrant system, a composite disintegrant composition, or a composite disintegrant.
  • the composite disintegrant system of the present invention rapidly dissolves in the preparation of the oral solid preparation, after the dissolution medium is introduced, or as a small molecule easily soluble substance as a helper to form a capillary channel, on the other hand, the oral solid preparation is inside and outside. The osmotic pressure difference is generated, and the combination of the two introduces the dissolution medium into the oral solid preparation to promote the disintegration of the disintegrating agent to cause disintegration, thereby promoting disintegration of the solid preparation; or contacting the gas-producing salt as a disintegrating agent with the dissolution medium.
  • the gas is released to form a space for introducing water, on the one hand, the water disintegration of the disintegrant is promoted to cause disintegration, and on the other hand, gas pressure is generated inside the preparation to promote disintegration, thereby causing the solid preparation to disintegrate.
  • the dissolution medium referred to in the present invention refers to gastric juice, intestinal fluid, simulated gastric juice, or simulated intestinal fluid.
  • the composite disintegrant system provided by the present invention is particularly suitable for an active ingredient which cannot be effectively disintegrated by a conventional disintegrating agent, for example, an active ingredient which is highly hygroscopic and which becomes sticky after moisture absorption, including but not limited to A compound represented by the following formula (I) or formula (II):
  • the R 1 represents a C 2 -C 8 alkyl group, a C 2 -C 8 alkene group, a C 2 -C 8 alkyne group, (CH 2 ) n O(CH 2 ) m , An aryl group (such as a phenyl group), a substituted aryl group (such as a substituted phenyl group), a heteroaryl group or a substituted heteroaryl group, of which Wherein C b and C c represent H or an alkyl group, respectively, wherein b and c represent the number of carbon atoms, each independently selected from 0, 1, 2, 3, 4, 5 or 6; wherein (CH 2 ) n , m in n O(CH 2 ) m are each independently selected from 1, 2, 3, 4, 5 or 6;
  • the R 2 represents hydrogen, halogen, trifluoromethyl, C 1 -C 8 alkoxy, C 1 -C 8 alkyl, nitro, sulfonamide, amino or nitrile;
  • the R 3 represents the absence, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkoxy, C 2 -C 8 alkoxy, (C 1 -C 6 )O(C 1 -C 6 ), An aryl group (such as a phenyl group), a substituted aryl group (such as a substituted phenyl group), a heteroaryl group or a substituted heteroaryl group, of which Wherein C b and C c represent H or an alkyl group, respectively, wherein b and c represent the number of carbon atoms, each independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • the R 4 represents an aryl group such as a phenyl group, a substituted aryl group such as a substituted phenyl group, an arylsulfonyl group such as a benzenesulfonyl group, a 5-6 membered heteroaryl group, and a 5-6 membered substituted heteroaryl group.
  • nitrile group trifluoromethyl group, C 1 -C 8 alkoxy group, C 1 -C 8 nitrate ester, C 1 -C 8 alkyl group, -CH 2 ONO 2 ;
  • the R 5 represents an aryl group (such as a phenyl group), a substituted aryl group (such as a substituted phenyl group), a 5-6 membered heteroaryl group, a 5-6 membered substituted heteroaryl group, a nitrile group, a trifluoromethyl group, a C 1 group. -C 8 alkoxy, C 1 -C 8 nitrate, C 1 -C 8 alkyl, C 1 -C 8 alkene, C 1 -C 8 alkyne, Or (CH 2 ) n O(CH 2 ) m , wherein R 3 , R 4 , a, m, n are as defined above;
  • the R 6 and R 7 represent hydrogen, C 1 -C 8 alkoxy or C 1 -C 8 alkyl
  • the aryl group means an aryl group having a 6-20 membered monocyclic or fused ring such as a phenyl group or a naphthyl group;
  • the substituted aryl group means one or more selected from the group consisting of a hydroxyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen, a nitro group, an amino group, a nitrile group, a trifluoromethyl group, and an oxygen group.
  • the heteroaryl group means a 5-20 membered aryl group (preferably a 5 to 7 membered aryl group) having 1 to 4 hetero atoms, each of which is independently selected from O, S or N; preferably hetero
  • the aryl group is selected from the group consisting of furan, thiophene, pyrrole, pyridine, pyrimidine, thiazole, thiadiazole, quinoline, anthracene, and the like;
  • the substituted heteroaryl group is a heteroaryl group substituted by one or more C 1 -C 6 alkyl groups, C 1 -C 6 alkoxy groups, halogens, and the respective substituents may be the same or different.
  • the compound of formula (I) has the structure shown below:
  • the compound of formula (II) has the structure shown below:
  • the compound represented by the formula (II) can be produced by contacting a compound represented by the formula (I) with a potassium salt reagent.
  • a compound of formula (I) is prepared by contacting a compound of formula (I) with a potassium salt reagent in a solvent.
  • the solvent is selected from a mixture of one or more of a polar solvent and a non-polar solvent, or the solvent is selected from the group consisting of water and an ether solvent (for example, an ether of 1-6 carbon atoms, 1-6 of a hydroxy group) An ether of a carbon atom or a 3-8 membered cyclic ether), a ketone solvent (for example, a ketone of 1 to 6 carbon atoms), an alcohol solvent (for example, a monohydric alcohol, a diol or a triol of 1 to 6 carbon atoms) a mixture of one or more of an ester solvent, an aromatic solvent, an alkane (including a cycloalkane) solvent, a nitrile solvent, and a sulfone.
  • an ether solvent for example, an ether of 1-6 carbon atoms, 1-6 of a hydroxy group
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol Ether, methyl tert-butyl ether, acetone, methyl ethyl ketone, 4-methyl-2-pentanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, acetic acid Butyl ester, tert-butyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, N,N-dimethylformamide, dimethyl sulfoxide, ace
  • the amount of solvent used per gram of the compound of formula (I) is at least about 0.1 ml, further preferably from about 2 to 300 ml, more preferably from about 5 to 100 ml, and most preferably from about 10 to 50 ml.
  • the potassium salt reagent is selected from the group consisting of a mixture of one or more of an organic acid potassium salt and an inorganic acid potassium salt.
  • the potassium salt of an organic acid is selected from the group consisting of potassium hydrogen phthalate, potassium acetate, potassium formate, potassium di-tert-butyl phosphate, dipotassium glycyrrhizinate, potassium 2-ethylhexanoate, potassium ethyl xanthate, sorbic acid.
  • Acid is selected from potassium K or more C3 olefins, preferably C 3 -C 26 acid potassium, such as potassium acrylate, potassium butene, vaccenic acid, potassium and the like.
  • the compound of formula (I) is first placed in a solvent and then the potassium salt reagent is added.
  • the temperature may be between room temperature and the reflux temperature of the solvent; further preferably, after the potassium salt reagent is added, the temperature may be at 0 ° C to the solvent. Between the reflux temperatures, more preferably between room temperature and the reflux temperature of the solvent.
  • room temperature means from about 18 ° C to about 30 ° C, preferably from about 20 ° C to about 24 ° C, more preferably about 22 ° C.
  • the product may be dissolved in the solution or may be directly precipitated from the solution.
  • the product is filtered and dried to give a compound of the formula (II).
  • it is cooled prior to filtration and has a cooling temperature of from about -50 ° C to about 30 ° C, more preferably from about -10 ° C to about 10 ° C, most preferably from about 0 ° C to about 5 ° C.
  • the solvent in the solution is removed to obtain a compound of the formula (II) or an antisolvent is added to the solution, filtered, and dried to give a compound of the formula (II).
  • the method of removing the solvent is, for example, spin drying or the like. Preferably, it is cooled prior to filtration and has a cooling temperature of from about -50 ° C to about 30 ° C, preferably from about -10 ° C to about 10 ° C, most preferably from about 0 ° C to about 5 ° C.
  • the anti-solvent is selected from the group consisting of a reagent in which the solubility is inferior to the selected solvent, such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, and different Propyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, n-hexane, cyclohexane, pentane, n-heptane, benzene, toluene, xylene a mixture of one or more of them.
  • a reagent in which the solubility is inferior to the selected solvent such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-buty
  • the active ingredient is QR01019 or QR01019K as shown in the following structure:
  • composite disintegrator system provided by the present invention is suitable for various active ingredients because it can rapidly disintegrate the oral solid preparation, and is not limited to the formula (I) and formula (II). Compound.
  • the composite disintegrant system provided by the present invention is suitable for the preparation of oral solid preparations, including tablets, capsules, powders, granules, pills, films, and the like.
  • the composite disintegrant system provided by the present invention is particularly suitable for use in the preparation of tablets.
  • an oral solid formulation comprising an active ingredient, a complex disintegrant system as described above, an excipient and a lubricant.
  • the active ingredient is present in an amount of from about 5% to about 50% by weight, from about 1% to about 20% by weight of the disintegrant, from about 0.1% to about 35% by weight of the disintegrant, and from about 20% by weight of the excipient.
  • the lubricant content is about 0.25%-10%
  • the weight ratio of the disintegrant to the helper is 10:1 to 1:10.
  • the active ingredient content is about 8-30%, the disintegrant content is about 2-2-1%, the helper content is about 0.5-30%, the excipient content is about 30-80%, and the lubricant content is About 0.5-8%, the weight ratio of the disintegrant to the helper is 8:1 to 1:8. More preferably, the active ingredient content is about 10-20%, the disintegrant content is about 4-15%, the helper content is about 1-25%, the excipient content is about 50-80%, and the lubricant content is About 1-5%, the weight ratio of the disintegrant to the helper is 5:1 to 1:5.
  • the active ingredient is present in an amount of from about 12% to about 16%
  • the disintegrant content is from about 6% to about 10%
  • the co-cracking agent is present in an amount of from about 2% to about 5%
  • the excipient content is from about 65% to about 8%
  • the lubricant content is About 2-4%.
  • the active ingredient is not particularly limited.
  • the active ingredient is an active ingredient which is not effectively disintegrated by a conventional disintegrating agent, for example, an active ingredient which is highly hygroscopic and which becomes sticky after moisture absorption; further preferably, the active ingredient is of the formula (I), formula (I) II) The compound shown.
  • the active ingredients are QR01005, QR01008, QR01009, QR01011, QR01013, QR01017, QR01019, QR01020, QR01023, QR01026, QR01030, QR01031, QR01032, QR01033, QR01034, QR01035, QR01036, QR01005K, QR01008K, QR01009K, QR01011K, QR01013K, QR01017K, QR01019K, QR01020K, QR01023K, QR01026K, QR01030K, QR01031K, QR01032K, QR01033K, QR01034K, QR01035K, QR01036K.
  • the active ingredient is QR01019 or QR01019K.
  • the excipient is not particularly limited.
  • the excipient is selected from the group consisting of starch, lactose, mannitol, cellulose lactose, microcrystalline cellulose, calcium hydrogen phosphate, a mixture of mannitol-starch complexes.
  • the oral solid preparation of the present invention may further contain a binder and/or a diluent depending on the nature of the active ingredient and/or the method of preparation.
  • the binder is not particularly limited.
  • the binder is selected from the group consisting of starch and its derivatives (including but not limited to In starch, pregelatinized starch, dextrin, maltodextrin, etc.), cellulose derivatives (including but not limited to methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hypromellose , ethyl cellulose, microcrystalline cellulose, etc.), natural rubber and synthetic rubber (including but not limited to gelatin, gum arabic, locust bean gum, peach gum, etc.), polyethylene glycol, povidone, diammonium Glycerides, carbomers, polyvinyl alcohols, poly(meth)acrylic resins, sugar alcohols (including but not limited to sucrose, liquid glucose, maltitol, etc.), corn mash, sodium alginate, monolaurate a mixture of one or more.
  • starch and its derivatives including but not limited to In starch, pregelatinized starch, dextrin,
  • the diluent is not particularly limited.
  • the diluent is selected from the group consisting of lactose (eg, monohydrate, spray dried monohydrate, anhydrate, and the like), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose a mixture of one or more of starch and dicalcium phosphate dihydrate.
  • lactose eg, monohydrate, spray dried monohydrate, anhydrate, and the like
  • mannitol eg., monohydrate, spray dried monohydrate, anhydrate, and the like
  • mannitol eg., mannitol
  • xylitol glucose
  • sucrose sucrose
  • sorbitol microcrystalline cellulose a mixture of one or more of starch and dicalcium phosphate dihydrate.
  • microcrystalline cellulose a mixture of one or more of starch and dicalcium phosphate dihydrate.
  • the oral solid preparation of the present invention may further optionally contain a surfactant, an antioxidant, a coloring agent, a flavoring agent, a preservative, and/or a taste masking agent and the like.
  • a surfactant an antioxidant, a coloring agent, a flavoring agent, a preservative, and/or a taste masking agent and the like.
  • Those skilled in the art will be able to select specific materials and suitable amounts of surfactants, antioxidants, colorants, flavoring agents, preservatives, and/or taste masking agents depending on the active ingredient and the properties of the excipients.
  • the oral solid preparation of the present invention may be a tablet, a capsule, a powder, a granule, a pill, a film, or the like.
  • the oral solid preparation of the present invention is a tablet.
  • the oral solid preparation of the present invention can be used for the preparation of an angiotensin II receptor antagonist or for the preparation of a medicament for preventing and/or treating hypertension, chronic heart failure, and diabetic nephropathy.
  • an oral solid preparation comprising QR01019K and a composite disintegrant system according to the present invention.
  • it further contains an excipient and a lubricant.
  • the content of QR01019K is about 5%-50% by weight, the disintegrant content is about 1%-20%, and the content of the disintegrating agent is about 0.1%-35%.
  • the agent content is from about 20% to about 80%, the lubricant content is from about 0.25% to about 10%, and the weight ratio of the disintegrant to the helper is from 10:1 to 1:10.
  • the QR01019K content is about 8-30%, the disintegrant content is about 2-2-1%, the helper content is about 0.5-30%, the excipient content is about 30-80%, and the lubricant content is about 0.5%.
  • the weight ratio of the disintegrant to the disintegrating agent is from 8:1 to 1:8. More preferably, the QR01019K content is about 10-20%, the disintegrant content is about 4-15%, the helper content is about 1-25%, the excipient content is about 50-80%, and the lubricant content is about 1-5%, the weight ratio of the disintegrant to the helper is 5:1 to 1:5. Most preferably, the QR01019K content is about 12-16%, the disintegrant content is about 6-10%, the helper content is about 2-5%, the excipient content is about 65-78%, and the lubricant content is about 2-4%.
  • the excipient is not particularly limited.
  • the excipient is selected from the group consisting of starch, lactose, mannitol, cellulose lactose, microcrystalline cellulose, calcium hydrogen phosphate, a mixture of mannitol-starch complexes.
  • the lubricant is not particularly limited.
  • the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, colloidal silica, hydrated silica, sodium stearyl fumarate, polyethylene glycol, sodium stearyl fumarate, A mixture of one or more of glyceryl monostearate, hydrogenated vegetable oil.
  • the oral solid preparation of the present invention may further contain a binder and/or a diluent depending on the nature of the active ingredient and/or the method of preparation.
  • the binder is not particularly limited.
  • the binder is selected from the group consisting of starch and derivatives thereof (including but not limited to starch, pregelatinized starch, dextrin, maltodextrin, etc.), cellulose derivatives (including but not limited to methylcellulose, carboxy Sodium methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, microcrystalline cellulose, etc.), natural rubber and synthetic rubber (including but not limited to gelatin, gum arabic, locust bean gum, peach Glue, etc.), polyethylene glycol, povidone, glyceryl dibehenate, carbomer, polyvinyl alcohol, poly(meth)acrylic resin, sugar alcohols (including but not limited to sucrose, liquid glucose, maltose a mixture of one or more of alcohol, etc., corn mash, sodium alginate, monolaurate. Those skilled in the art will be able to select a suitable amount of binder
  • the diluent is not particularly limited.
  • the diluent is selected from the group consisting of lactose (eg, monohydrate, spray dried monohydrate, anhydrate, and the like), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose a mixture of one or more of starch and dicalcium phosphate dihydrate.
  • lactose eg, monohydrate, spray dried monohydrate, anhydrate, and the like
  • mannitol eg., monohydrate, spray dried monohydrate, anhydrate, and the like
  • mannitol eg., mannitol
  • xylitol glucose
  • sucrose sucrose
  • sorbitol microcrystalline cellulose a mixture of one or more of starch and dicalcium phosphate dihydrate.
  • microcrystalline cellulose a mixture of one or more of starch and dicalcium phosphate dihydrate.
  • the oral solid preparation of the present invention may further optionally contain a surfactant, an antioxidant, a coloring agent, a flavoring agent, a preservative, and/or a taste masking agent and the like.
  • a surfactant an antioxidant, a coloring agent, a flavoring agent, a preservative, and/or a taste masking agent and the like.
  • Those skilled in the art will be able to select specific materials and suitable amounts of surfactants, antioxidants, colorants, flavoring agents, preservatives, and/or taste masking agents depending on the active ingredient and the properties of the excipients.
  • the oral solid preparation of the present invention may be a tablet, a capsule, a powder, a granule, a pill, a film, or the like.
  • the oral solid preparation of the present invention is a tablet.
  • the oral solid preparation of the present invention can be used for the preparation of an angiotensin II receptor antagonist or for the preparation of a medicament for preventing and/or treating hypertension, chronic heart failure, and diabetic nephropathy.
  • the oral solid preparation unit preparation of the present invention has a total weight of about 90 mg to 600 mg; and a hardness of about 3 kg to 20 kg.
  • the active ingredient QR01019K is present in an amount from about 10 mg to 100 mg per unit of formulation.
  • the present invention achieves effective disintegration of an active substance (active ingredient) which is highly hygroscopic and becomes sticky after moisture absorption by adding a small molecule easily soluble substance or a gas generating type salt, thereby causing dissolution of the active ingredient and improving the living organism. Utilization.
  • the solid preparation of the present invention is administered by an oral route and is convenient to use.
  • the control group was given 0.5% sodium carboxymethylcellulose (hereinafter referred to as CMC-Na); the OR01019 group and the QR01019K group were dissolved in 0.5% CMC-Na, and the doses were all administered at an effective dose of 1 mg/kg of azilsartan.
  • the drug volume was 4 mL/kg, which was administered by intragastric administration.
  • the systolic blood pressure and heart rate of the animals before administration were used as reference values.
  • the systolic blood pressure and heart rate of SHR were compared before and after administration, and the time was measured three times. take the average. The results are shown in Tables 1 and 2 below.
  • the QR01019K group has a more potent and long-lasting heart rate reduction effect than QR01019.
  • QR01005K, QR01008K, QR01009K, QR01011K, QR01013K, QR01017K, QR01020K, QR01023K, QR01026K, QR01030K, QR01031K, QR01032K, QR01033K, QR01034K, QR01035K, QR01036K were also tested in the same manner as above, and these compounds were found to be similar to QR01019K. Both have a more potent and longer-lasting blood pressure lowering and rhythmic lowering effect than their corresponding unsalted compounds.
  • Preparation Examples 2, 4, 5 and 10, Comparative Examples 2, 4, 5 and 10 were subjected to a wet granulation method: a 60-mesh sieve was selected according to the material properties, and the materials were sieved for use; the active ingredients, excipients, and disintegrants were used.
  • the disintegrating agent (the disintegrating agent in the comparative example) was poured into a granulator and mixed, and an aqueous binder solution was added (in which Preparation Example 2 and Comparative Example 2 used 5% aqueous solution of povidone, Preparation Example 4 and 10% starch slurry was used in the proportion 4, 8% starch slurry was used in the preparation example 5 and the comparative example 5, granulation, fluidized bed drying; the dried granules were placed in a three-dimensional mixer, and then the lubricant was added for total mixing.
  • the total mixed material is tableted in a rotary tablet press.
  • Preparation Examples 3, 6 and 11, Comparative Examples 3, 6 and 11 were subjected to a dry granulation method: a 60 mesh sieve was selected according to the material properties, and the materials were sieved for use; the active ingredients, excipients, disintegrants, and disintegrating agents were used.
  • Comparative disintegration agent in the comparative example is poured into a three-dimensional mixer and mixed, and granulated in a dry granulator; the granules are placed in a three-dimensional mixer, and then a lubricant is added for total mixing; the total mixed material is subjected to a rotary pressure. Tablet in the tablet.

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Abstract

一种用于口服固体制剂的复合崩解剂组合物，包括崩解剂和助崩剂，所述崩解剂为吸湿膨胀型崩解剂，所述助崩剂为小分子易溶性物质或产气型盐。一种口服固体制剂，包含活性成分、所述复合崩解剂组合物、赋形剂和润滑剂。

Description

一种用于口服固体制剂的复合崩解剂体系及含有该复合崩解剂体系的口服固体制剂 技术领域
本发明涉及医药制剂领域，具体涉及一种用于口服固体制剂的复合崩解剂体系及含有该复合崩解剂体系的口服固体制剂。
背景技术
一般情况下，口服固体制剂的吸收速度取决于活性物质(活性成分)从固体制剂溶出(释放)的速度，而活性成分的溶出(释放)速度往往取决于固体制剂的崩解速度，因此基本上可以认为，口服固体制剂的崩解速度是活性成分被机体吸收速度的决定步骤。崩解剂大都具有良好的吸水性和膨胀性，在口服固体制剂中加入崩解剂的作用是消除或破坏因粘合剂或者高度压缩而产生的结合力，使其在溶出介质中迅速裂碎成细小颗粒状物质，从而使活性成分被迅速溶解吸收，发挥治疗作用。崩解剂的崩解机理主要为毛细管作用和膨胀作用，崩解剂在口服固体制剂中形成易于润湿的毛细管通道，当固体制剂置于溶出介质中时，溶出介质迅速的随毛细管进入固体制剂内部，使整个固体制剂润湿，从而口服固体制剂的崩解经历润湿、虹吸、膨胀和破碎过程。
常用的崩解剂有干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠(CMC-Na)等，主要通过毛细管作用和膨胀作用起到促使固体制剂崩解的功效。但有些活性物质吸湿性强，且在吸湿后会变粘，使得常规崩解剂无法有效使之崩解，导致其溶出释放性能较差。
公开号为CN103709154A的中国专利申请首次公开了结构如下式(I)所示的化合物：
Figure PCTCN2017090374-appb-000001
上述化合物是偶联了川芎嗪或NO供体的沙坦类药物，是血管紧张素II受体拮抗剂阿齐沙坦(TAK-536)的前药，该化合物在体内释放出羟基川芎嗪或NO，从而与阿齐沙坦发生有效的协同作用，增强抗高血压疗效，具有一定的降心率作用，减少不良反应，对患者心肾也具有较理想的保护作用。申请人在进一步的研究中发现式(I)化合物的钾盐，即结构如下式(II)所示的化合物，溶解性能更好，生物利用度更高，具有更强效和更长效的降压效果，同时具有更明显且持久的降心率效果，且安全性高，对患者心肾功能具有较理想的保护作用，能够用于预防和/或治疗高血压、慢性心衰、糖尿病肾病等。在将式(I)和式(II)化合物制成口服固体制剂的过程中，使用各种常用崩解剂都无法有效使之崩解，导致活性成分的溶出释放性能较差。进一步研究，申请人发现这些化合物大多具有吸湿性强，且在吸湿后会变粘的特性，使得常规崩解剂无法有效使之崩解，导致活性成分的溶出释放性能较差，
Figure PCTCN2017090374-appb-000002
发明内容
本发明提供了一种用于口服固体制剂的复合崩解剂体系，能够使口服固体制剂迅速崩解、提高其溶出速率，从而提高生物利用度，并特别能够解决吸湿性强且在吸湿后会变粘的活性物质(活性成分)所存在的采用常规崩解剂无法有效使之崩解的问题。
常规崩解剂主要靠毛细管作用将水分导入固体制剂内部，同时崩解剂吸水后膨胀，消除固体制剂中因为粘合剂或高度压缩而产生的结合力，达到促使固体制剂崩解的目的。当药物活性物质吸湿性强，且在吸湿后会变粘时，在采用常规崩解剂将其制成口服固体制剂后，口服固体制剂将难以崩解，例如体现在模拟胃酸pH条件下固体制剂无法崩解释放药物。导致这种结果的原因可能是活性物质吸湿性强，会与崩解剂竞争吸收水分，同时吸水后变粘，阻碍崩解剂的膨胀，阻断了水进入的通道，从而导致常规崩解剂难以发挥其崩解性能。
根据本发明的一个方面，本发明提供了一种用于口服固体制剂的复合崩解剂体系，包括崩解剂和助崩剂。优选，该用于口服固体制剂的复合崩解剂体系由崩解剂和助崩剂组成。
在本发明中，崩解剂为吸湿膨胀型崩解剂。优选，吸湿膨胀型崩解剂选自干淀粉、交联羧甲基纤维素钠、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代 羟丙基纤维素、交联聚维酮、壳聚糖、微晶纤维素中的一种或多种的混合物。
在本发明中，助崩剂为小分子易溶性物质或产气型盐。优选，产气型盐选自碳酸盐、碳酸氢盐中的一种或多种的混合物。更优选，产气型盐选自碳酸钠、碳酸钙、碳酸钾、碳酸钙镁、碳酸锌、碳酸镁、碳酸铵、甘氨酸碳酸钠、倍半碳酸钠、碳酸氢钠、碳酸氢钙、碳酸氢钾、碳酸氢铵中的一种或多种的混合物。
优选，所述小分子易溶性物质选自氯化钠、葡萄糖、果糖、木糖醇中的一种或多种的混合物；更优选，所述小分子易溶性物质选自氯化钠、葡萄糖中的一种或两种的混合物。
在本发明中，优选，崩解剂和助崩剂的重量比为10:1-1:10，更优选8:1-1:8，最优选5:1-1:5。
在本发明中，助崩剂是指能够帮助吸湿性强且在吸湿后会变粘的活性物质(活性成分)崩解的助剂。这一类的活性物质无法采用常规崩解剂进行有效崩解。本发明发现加入小分子易溶性物质或者产气型盐，能够将这一类无法有效崩解的活性物质予以崩解。因而本发明中将其定义为助崩剂。
在本发明中，复合崩解剂体系也可以被称为复合崩解剂系统、复合崩解剂组合物或复合崩解剂。本发明的复合崩解剂体系在制备口服固体制剂时，在溶出介质被引入后，或者作为助崩剂的小分子易溶性物质迅速溶解，一方面形成毛细管通道，另一方面使口服固体制剂内外产生渗透压差，两者结合将溶出介质引入口服固体制剂内部，促进崩解剂吸水膨胀产生崩解作用，从而促使固体制剂崩解；或者作为助崩剂的产气型盐与溶出介质接触反应释放气体，形成引入水的空间，一方面促进崩解剂吸水膨胀产生崩解作用，另一方面在制剂内部产生气体压力促进崩解，从而促使固体制剂崩解。本发明中所提及的溶出介质指的是胃液、肠液、模拟胃液、或模拟肠液。
因此，本发明所提供的复合崩解剂体系，特别适用采用常规崩解剂无法有效使之崩解的活性成分，例如吸湿性强，且在吸湿后会变粘的活性成分，包括但不限于如下述式(I)、式(II)所示的化合物：
Figure PCTCN2017090374-appb-000003
式(I)和式(II)中，R代表
Figure PCTCN2017090374-appb-000004
Figure PCTCN2017090374-appb-000005
Figure PCTCN2017090374-appb-000006
或者
Figure PCTCN2017090374-appb-000007
其中a＝0、1、2、3、4、5或6；
所述R1代表C2-C8烷基、C2-C8烯烃基、C2-C8炔烃基、
Figure PCTCN2017090374-appb-000008
(CH2)nO(CH2)m、
Figure PCTCN2017090374-appb-000009
芳基(如苯基)、取代芳基(如取代苯基)、杂芳基或取代杂芳基，其中的
Figure PCTCN2017090374-appb-000010
中的Cb、Cc分别代表H或者烷基，其中b、c代表碳原子的个数，各自独立地选自0、1、2、3、4、5或6；其中的(CH2)nO(CH2)m中的n、m各自独立地选自1、2、3、4、5或6；
所述R2代表氢、卤素、三氟甲基、C1-C8烷氧基、C1-C8烷基、硝基、磺酰胺基、氨基或腈基；
所述R3代表不存在、C1-C8烷基、C1-C8烷氧基、C2-C8烯烃氧基、C2-C8炔烃氧基、(C1-C6)O(C1-C6)、
Figure PCTCN2017090374-appb-000011
芳基(如苯基)、取代芳基(如取代苯基)、杂芳基或取代杂芳基，其中的
Figure PCTCN2017090374-appb-000012
中的Cb、Cc分别代表H或者烷基，其中b、c代表碳原子的个数，各自独立地选自0、1、2、3、4、5或6；
所述R4代表芳基(如苯基)、取代芳基(如取代苯基)、芳基磺酰基(如苯磺酰基)、5-6元杂芳基、5-6元取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、-CH2ONO2；
所述R5代表芳基(如苯基)、取代芳基(如取代苯基)、5-6元杂芳基、5-6元取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、C1-C8烯烃基、C1-C8炔烃基、
Figure PCTCN2017090374-appb-000013
或(CH2)nO(CH2)m， 其中R3、R4、a、m、n如上所定义；
所述R6和R7代表氢、C1-C8烷氧基或C1-C8烷基；
所述R8和R9代表氢、C1-C8烷氧基、C1-C8硝酸酯或C1-C8烷基；
所述芳基是指含有6-20元的单环或稠合环的芳基，如苯基或萘基；
所述的取代芳基是指被一个或多个选自羟基、C1-C6烷基、C1-C6烷氧基、卤素、硝基、氨基、腈基、三氟甲基、氧代、-CH＝CHCO2R11取代的芳基，各取代基可相同或不同，其中的R11代表氢或C1-C6烷基；
所述的杂芳基是指含有1至4个杂原子的5-20元芳基(优选5至7元芳基)，所述杂原子各自独立的选自O、S或N；优选地杂芳基选自呋喃、噻吩、吡咯、吡啶、嘧啶、噻唑、噻二唑、喹啉、吲哚等；
所述的取代杂芳基为被一个或多个C1-C6烷基、C1-C6烷氧基、卤素取代的杂芳基，各取代基可相同或不同。
在优选的实施方案中，式(I)化合物具有如下式所示结构：
Figure PCTCN2017090374-appb-000014
Figure PCTCN2017090374-appb-000015
在优选的实施方案中，式(II)化合物具有如下式所示结构：
Figure PCTCN2017090374-appb-000016
Figure PCTCN2017090374-appb-000017
其中，式(I)所示的化合物可以通过本领域已知的方法，例如CN103709154A中公开的方法制备得到，在此将CN103709154A全文引入本文作为参考。
式(II)所示的化合物可以通过将如式(I)所示的化合物与钾盐试剂接触反应制备得到。优选，将如式(I)所示的化合物与钾盐试剂在溶剂中接触反应制备得到式(II)化合物。
本领域技术人员可以理解，各种溶剂均可用于制备式(II)化合物。优选，溶剂选自极性溶剂、非极性溶剂中的一种或多种的混合物，或者溶剂选自水、醚类溶剂(例如1-6个碳原子的醚、羟基取代的1-6个碳原子的醚或3-8元环醚)、酮类溶剂(例如1-6个碳原子的酮)、醇类溶剂(例如1-6个碳原子的一元醇、二元醇或三元醇)、酯类溶剂、芳烃类溶剂、烷烃类(包括环烷烃)溶剂、腈类溶剂、砜中的一种或多种的混合物。更优选，溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、甲基四氢呋喃、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、甲基叔丁基醚、丙酮、丁甲乙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、乙酸异丁酯、乙酸仲丁酯、乙酸叔丁酯、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、硝基乙烷、N,N-二甲基甲酰胺、二甲亚砜、乙腈、丙二腈、苯、甲苯、二甲苯、正己烷、环己烷、戊烷、正庚烷中的一种或多种的混合物。本领域技术人员可以理解，式(I)化合物无需完全溶解在溶剂中，甚至是在不使用溶剂的情况下，其与钾盐试剂接触后反应仍然可以发生，因此可以不使用或者使用任意量的溶剂。
在优选的实施方案中，每克式(I)化合物所用溶剂的量至少为约0.1ml，进一步优选约2-300ml，更优选约5-100ml，最优选约10-50ml。
钾盐试剂选自有机酸钾盐、无机酸钾盐中的一种或多种的混合物。优选，有机酸钾盐选自邻苯二甲酸氢钾，乙酸钾，甲酸钾，磷酸二叔丁酯钾，甘草酸二钾、2-乙基己酸钾、乙基黄原酸钾、山梨酸钾、邻苯二甲酰亚胺钾、马来酰亚胺钾、草酸钾、烯酸钾、柠檬酸钾、苹果酸钾、葡萄酸钾、乳酸钾、酒石酸钾、水杨酸钾、富马酸钾、硬脂酸钾、月桂酸钾中的一种或多种的混合物；无机酸钾盐选自硝酸钾，硫酸钾，亚硫酸钾，溴酸钾，碳酸氢钾，硫氰酸钾，磷酸氢二钾，磷酸二氢钾，邻苯二甲酸氢钾中的一种或多种的混合物。烯酸钾选自 C3以上的烯烃酸钾，优选C3-C26的烯酸钾，例如丙烯酸钾、丁烯酸钾、十八碳烯酸钾等等。
本领域技术人员可以理解，钾盐试剂无需事先溶解，当然也可以事先溶解在上述溶剂中，另外，有些钾盐试剂因不稳定或者比较危险而被保存在溶剂中，此时可以直接使用这些被保存在溶剂中的钾盐试剂。在优选的实施方案中，式(I)化合物和钾盐试剂中K的摩尔比为约1:0.3-3，更优选约1:0.9-2，最优选约1:0.95-1.5。
在优选的实施方案中，先将式(I)化合物置于溶剂中，然后再加入钾盐试剂。优选，在将式(I)化合物置于溶剂中后，温度可处于在室温至所述溶剂的回流温度之间；进一步优选，在加入钾盐试剂后，温度可处于在0℃至所述溶剂的回流温度之间，更优选温度在室温至所述溶剂的回流温度之间。术语“室温”指约18℃至约30℃，优选约20℃至约24℃，更优选约22℃。
本领域技术人员可以理解，在本发明中，因产物在不同溶剂中的溶解度不同，以及反应后反应体系的温度不同，产物可能会溶解在溶液中，也可能会从溶液中直接析出。对于产物从溶液中直接析出的情况，在反应后，过滤，干燥得到式(II)化合物。优选，在过滤前冷却，冷却温度为约-50℃至约30℃，更优选约-10℃至约10℃，最优选约0℃至约5℃。对于产物溶解在溶液中的情况，在反应后，过滤去除杂质，去除溶液中的溶剂得到式(II)化合物或者在溶液中加入反溶剂，过滤，干燥得到式(II)化合物。去除溶剂的方式例如旋干等。优选，在过滤前冷却，冷却温度为约-50℃至约30℃，优选约-10℃至约10℃，最优选约0℃至约5℃。优选，反溶剂选自化合物在其中溶解性比所选溶剂差的试剂，例如甲基四氢呋喃、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、甲基叔丁基醚、异丙醚、乙醚、二氯甲烷，1,2-二氯乙烷、氯仿、四氯化碳、硝基乙烷、正己烷、环己烷、戊烷、正庚烷、苯、甲苯、二甲苯中的一种或多种的混合物。
在更优选的实施方案中，活性成分是如下结构所示的QR01019或QR01019K：
Figure PCTCN2017090374-appb-000018
本领域技术人员可以理解，本发明所提供的复合崩解剂体系，因能够使口服固体制剂迅速崩解，适用于各种活性成分，并不限于式(I)、式(II)所示的化合物。
本发明提供的复合崩解剂体系适合用于制备口服固体制剂，包括片剂、胶囊剂、散剂、颗粒剂、滴丸剂、膜剂等。在优选的实施方案中，本发明提供的复合崩解剂体系特别适合用于制备片剂。
根据本发明的另一个方面，本发明提供一种口服固体制剂，含有活性成分、如上文所述的复合崩解剂体系、赋形剂和润滑剂。优选，以重量百分比计，活性成分含量为约5％-50％，崩解剂含量为约1％-20％，助崩剂含量为约0.1％-35％，赋形剂含量为约20％-80％，润滑剂含量为约0.25％-10％，崩解剂和助崩剂的重量比为10:1-1:10。
进一步优选，活性成分含量为约8-30％，崩解剂含量为约2-18％，助崩剂含量为约0.5-30％，赋形剂含量为约30-80％，润滑剂含量为约0.5-8％，崩解剂和助崩剂的重量比为8:1-1:8。更优选，活性成分含量为约10-20％，崩解剂含量为约4-15％，助崩剂含量为约1-25％，赋形剂含量为约50-80％，润滑剂含量为约1-5％，崩解剂和助崩剂的重量比为5:1-1:5。
最优选，活性成分含量为约12-16％，崩解剂含量为约6-10％，助崩剂含量为约2-5％，赋形剂含量为约65-78％，润滑剂含量为约2-4％。
在本发明中，活性成分没有特别限制。优选，活性成分是采用常规崩解剂无法有效使之崩解的活性成分，例如吸湿性强，且在吸湿后会变粘的活性成分；进一步优选，活性成分是如式(I)、式(II)所示的化合物。更优选，活性成分是QR01005、QR01008、QR01009、QR01011、QR01013、QR01017、QR01019、QR01020、QR01023、QR01026、QR01030、QR01031、QR01032、QR01033、QR01034、QR01035、QR01036、QR01005K、QR01008K、QR01009K、QR01011K、QR01013K、QR01017K、QR01019K、QR01020K、QR01023K、QR01026K、QR01030K、QR01031K、QR01032K、QR01033K、QR01034K、QR01035K、QR01036K。最优选，活性成分是QR01019或QR01019K。
在本发明中，赋形剂没有特别限制。优选，赋形剂选自淀粉、乳糖、甘露醇、纤维素乳糖、微晶纤维素、磷酸氢钙、甘露醇-淀粉复合物中的一种或多种的混合物。
在本发明中，润滑剂没有特别限制。优选，润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶体二氧化硅、水合二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂酰富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或多种的混合物。
根据活性成分的性质和/或制剂方法不同，本发明的口服固体制剂中还可以进一步含有粘合剂和/或稀释剂。
在本发明中，粘合剂没有特别限制。优选，粘合剂选自淀粉及其衍生物类(包括但不限 于淀粉、预胶化淀粉、糊精、麦芽糊精等)、纤维素衍生物类(包括但不限于甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、乙基纤维素、微晶纤维素等)、天然胶及合成胶(包括但不限于明胶、阿拉伯胶、角豆胶、桃胶等)、聚乙二醇、聚维酮、二山嵛酸甘油酯、卡波姆、聚乙烯醇、聚(甲基)丙烯酸树脂、糖醇类(包括但不限于蔗糖、液体葡萄糖、麦芽糖醇等)、玉米朊、海藻酸钠、单月桂酸酯中的一种或多种的混合物。本领域技术人员能够根据活性成分和各辅料性能选择粘合剂的合适用量。一般来说，粘合剂含量为约0-15％。
在本发明中，稀释剂没有特别限制。优选，稀释剂选自乳糖(例如，单水合物、喷雾干燥的单水合物、无水物及其类似物)、甘露糖醇、木糖醇、葡萄糖、蔗糖、山梨糖醇、微晶纤维素、淀粉及二水合磷酸氢二钙中的一种或多种的混合物。本领域技术人员能够根据活性成分和各辅料性能选择稀释剂的合适用量。
本发明的口服固体制剂还可以进一步任选含有表面活性剂、抗氧化剂、着色剂、调味剂、防腐剂和/或掩味剂等。本领域技术人员能够根据活性成分和各辅料性能选择表面活性剂、抗氧化剂、着色剂、调味剂、防腐剂和/或掩味剂等的具体物质和合适用量。
本发明的口服固体制剂可以是片剂、胶囊剂、散剂、颗粒剂、滴丸剂、膜剂等。优选，本发明的口服固体制剂为片剂。本发明的口服固体制剂可用于制备血管紧张素II受体拮抗剂，或者用于制备预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物。
根据本发明的另一个方面，本发明提供一种口服固体制剂，含有QR01019K和如本发明所述的复合崩解剂体系。优选，进一步含有赋形剂和润滑剂。
在本发明的口服固体制剂中，以重量百分比计，QR01019K含量为约5％-50％，崩解剂含量为约1％-20％，助崩剂含量为约0.1％-35％，赋形剂含量为约20％-80％，润滑剂含量为约0.25％-10％，崩解剂和助崩剂的重量比为10:1-1:10。优选，QR01019K含量为约8-30％，崩解剂含量为约2-18％，助崩剂含量为约0.5-30％，赋形剂含量为约30-80％，润滑剂含量为约0.5-8％，崩解剂和助崩剂的重量比为8:1-1:8。更优选，QR01019K含量为约10-20％，崩解剂含量为约4-15％，助崩剂含量为约1-25％，赋形剂含量为约50-80％，润滑剂含量为约1-5％，崩解剂和助崩剂的重量比为5:1-1:5。最优选，QR01019K含量为约12-16％，崩解剂含量为约6-10％，助崩剂含量为约2-5％，赋形剂含量为约65-78％，润滑剂含量为约2-4％。
在本发明中，赋形剂没有特别限制。优选，赋形剂选自淀粉、乳糖、甘露醇、纤维素乳糖、微晶纤维素、磷酸氢钙、甘露醇-淀粉复合物中的一种或多种的混合物。
在本发明中，润滑剂没有特别限制。优选，润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶体二氧化硅、水合二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或多种的的混合物。
根据活性成分的性质和/或制剂方法不同，本发明的口服固体制剂中还可以进一步含有粘合剂和/或稀释剂。
在本发明中，粘合剂没有特别限制。优选，粘合剂选自淀粉及其衍生物类(包括但不限于淀粉、预胶化淀粉、糊精、麦芽糊精等)、纤维素衍生物类(包括但不限于甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、乙基纤维素、微晶纤维素等)、天然胶及合成胶(包括但不限于明胶、阿拉伯胶、角豆胶、桃胶等)、聚乙二醇、聚维酮、二山嵛酸甘油酯、卡波姆、聚乙烯醇、聚(甲基)丙烯酸树脂、糖醇类(包括但不限于蔗糖、液体葡萄糖、麦芽糖醇等)、玉米朊、海藻酸钠、单月桂酸酯中的一种或多种的混合物。本领域技术人员能够根据活性成分和各辅料性能选择粘合剂的合适用量。一般来说，粘合剂含量为约0-15％。
在本发明中，稀释剂没有特别限制。优选，稀释剂选自乳糖(例如，单水合物、喷雾干燥的单水合物、无水物及其类似物)、甘露糖醇、木糖醇、葡萄糖、蔗糖、山梨糖醇、微晶纤维素、淀粉及二水合磷酸氢二钙中的一种或多种的混合物。本领域技术人员能够根据活性成分和各辅料性能选择稀释剂的合适用量。
本发明的口服固体制剂还可以进一步任选含有表面活性剂、抗氧化剂、着色剂、调味剂、防腐剂和/或掩味剂等。本领域技术人员能够根据活性成分和各辅料性能选择表面活性剂、抗氧化剂、着色剂、调味剂、防腐剂和/或掩味剂等的具体物质和合适用量。
本发明的口服固体制剂可以是片剂、胶囊剂、散剂、颗粒剂、滴丸剂、膜剂等。优选，本发明的口服固体制剂为片剂。本发明的口服固体制剂可用于制备血管紧张素II受体拮抗剂，或者用于制备预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物。
本发明的口服固体制剂单位制剂总重为约90mg-600mg；硬度为约3Kg-20Kg。活性成分QR01019K的含量为约10mg-100mg/单位制剂。
在最优选的实施方案中，本发明的片剂中活性成分为QR01019K，赋形剂为甘露醇，崩解剂为交联羧甲基纤维素钠，助崩剂为碳酸氢钠，润滑剂为硬脂酸镁；优选，以重量百分比计，活性成分QR01019K含量为约5％-50％，崩解剂交联羧甲基纤维素钠含量为约1％-20％，助崩剂碳酸氢钠含量为约0.1％-35％，赋形剂甘露醇含量为约20％-80％，润滑剂硬脂酸镁含量为约0.25％-10％，崩解剂和助崩剂的重量比为10:1-1:10；进一步优选，活性成分 QR01019K含量为约8-30％，崩解剂交联羧甲基纤维素钠含量为约2-18％，助崩剂碳酸氢钠含量为约0.5-30％，赋形剂甘露醇含量为约30-80％，润滑剂硬脂酸镁含量为约0.5-8％，崩解剂和助崩剂的重量比为8:1-1:8；更优选，活性成分QR01019K含量为约10-20％，崩解剂交联羧甲基纤维素钠含量为约4-15％，助崩剂碳酸氢钠含量为约1-25％，赋形剂甘露醇含量为约50-80％，润滑剂硬脂酸镁含量为约1-5％，崩解剂和助崩剂的重量比为5:1-1:5；最优选，活性成分QR01019K含量为约12-16％，崩解剂交联羧甲基纤维素钠含量为约6-10％，助崩剂碳酸氢钠含量为约2-5％，赋形剂甘露醇含量为约65-78％，润滑剂硬脂酸镁含量为约2-4％。
本发明的有益效果是：
1、本发明的复合崩解剂体系能有效克服活性成分遇水产生的粘性，从而导致固体制剂无法崩解的问题，促进固体制剂崩散，释放药物。
2、本发明的复合崩解剂体系不需要添加额外的酸，仅仅利用酸性环境即可实现快速崩解，使活性成分溶出，提高了生物利用度。
3、本发明通过加入小分子易溶性物质或者产气型盐，实现了吸湿性强且在吸湿后会变粘的活性物质(活性成分)的有效崩解，从而使得活性成分溶出，提高了生物利用度。
4、本发明的固体制剂可用于预防和/或治疗高血压、慢性心衰、糖尿病肾病。
5、本发明的固体制剂通过口服途径给药，使用方便。
6、本发明的复合崩解剂体系能够改善了活性成分的成药性和患者的顺应性。
附图说明
图1是实施例1中QR01019K的H-NMR图谱；
图2是实施例1中QR01019K的X射线粉末衍射图谱。
具体实施方式
下面将结合具体实施例对本发明做更进一步的详细说明。本领域技术人员可以借鉴本文内容，适当更改工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明中。本发明的产品已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的产品进行改动或适当变更与组合，来实现和应用本技术。
实施例1：QR01019K的制备
将QR01019(1.0g)溶于二氯甲烷(5ml)中，室温搅拌形成溶液，往溶液中加入邻苯二甲酰亚胺钾(0.27g)，保温反应4h，冷却至-50℃，过滤，溶剂旋干所得固体为无定型的QR01019K。
熔点：135-145℃。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
1H-NMR(400MHz,DMSO-d6)δ：1.44(t，3H)，1.46(t，3H)，2.38(s，3H)，2.41(s，3H)，2.44(s，3H)，4.64(q，2H)，5.29(d，1H)，5.32(d，1H)，5.52(d，1H)，5.56(d，1H)，6.86(q，1H)，6.90(d，2H)，7.18(m，2H)，7.22(d，2H)，7.33(m，1H)，7.36(m，1H)，7.46(d，1H)，7.52(dd，1H)，7.75(d，1H)。
H-NMR图谱和X射线粉末衍射图谱分别见图1和图2。
实施例2：QR01019K在自发性高血压大鼠上的抗高血压药效试验
取12周龄的自发性高血压大鼠(以下简称SHR，购自北京维通利华实验动物技术有限公司)，以2.5％的戊巴比妥钠进行腹腔注射麻醉，将血压植入子的血压感应导管插入腹主动脉，植入子固定于腹壁，缝合后进行术后日常看护。选取收缩压超过160mm Hg的动物进入分组，每组8只动物，共3组。对照组给予0.5％的羧甲基纤维素钠(下称CMC-Na)；OR01019组和QR01019K组采用0.5％CMC-Na溶解，给药剂量均以1mg/kg阿齐沙坦有效剂量计，给药体积为4mL/kg，均灌胃给药，以给药前动物的收缩压和心率为基准值，比较给药前、后各时间点SHR的收缩压和心率变化，每个时间点测三次取平均值。结果见下表1和表2。
表1.QR01019、QR01019K口服给药前、后各时间点收缩压变化(平均值(mmHg)±标准误差)
Figure PCTCN2017090374-appb-000019
Figure PCTCN2017090374-appb-000020
*P<0.01(相对于对照组)。
从表1结果可以看出，给药3小时后各给药组与对照组比较收缩压均显著下降，在给药 5-7小时药效达峰，QR01019K组具有比QR01019更强效和长效的降压效果。
表2.QR01019、QR01019K口服给药前、后各时间点心率变化(平均值(次/分钟)±标准误差)
Figure PCTCN2017090374-appb-000021
Figure PCTCN2017090374-appb-000022
*P＜0.05(相对于对照组单因素方差比较)。
从表2结果可以看出，QR01019K组具有比QR01019更强效和长效的降心率效果。
还按照上述相同方法测试了QR01005K、QR01008K、QR01009K、QR01011K、QR01013K、QR01017K、QR01020K、QR01023K、QR01026K、QR01030K、QR01031K、QR01032K、QR01033K、QR01034K、QR01035K、QR01036K的药效试验，发现这些化合物与QR01019K类似，均具有比其相应的未成盐化合物更强效和更长效的降血压和降心律效果。
实施例3：口服固体制剂的制备和崩解实验
按照以下三种制备方法分别制备了制备例1-11和对比例1-11的片剂，各制备例和对比例的处方组成、压片硬度和片重差异见下表3。
制备例1、7、8和9，对比例1、7、8和9采用粉末压片法：根据物料性状选择60目筛，将物料过筛备用(制备例7和对比例7中，将活性成分与赋形剂共同过筛，崩解剂与助崩剂混合过筛备用；其余的制备例和对比例分别过筛)；将活性成分、赋形剂、崩解剂、助崩剂(对比例中无助崩剂)倒入三维混合机中混合，再加入润滑剂进行总混；总混物料于旋转压片机中压片。
制备例2、4、5和10，对比例2、4、5和10采用湿法制粒法：根据物料性状选择60目筛，将物料过筛备用；将活性成分、赋形剂、崩解剂、助崩剂(对比例中无助崩剂)倒入制粒机中混合，加入粘合剂水溶液(其中，制备例2和对比例2中采用5％聚维酮水溶液，制备例4和对比例4中采用10％淀粉浆，制备例5和对比例5中采用8％淀粉浆)，制粒，流化床干燥；将干燥后的颗粒放入三维混合机，再加入润滑剂进行总混；总混物料于旋转压片机中压片。
制备例3、6和11，对比例3、6和11采用干法制粒法：根据物料性状选择60目筛，将物料过筛备用；将活性成分、赋形剂、崩解剂、助崩剂(对比例中无助崩剂)倒入三维混合机中混合，在干法制粒机中制粒；将制得颗粒放入三维混合机，再加入润滑剂进行总混；总混物料于旋转压片机中压片。
按照如下实验条件进行崩解实验，各制备例和对比例的崩解时间见下表3。
仪器：ZBS-6E智能崩解试验仪(天津天大天发科技有限公司)
方法：吊篮法
介质：含0.5％吐温80的0.1M HCl介质
往返频率：每分钟30-32次
温度：37℃
表3片剂处方及崩解时间
Figure PCTCN2017090374-appb-000023
Figure PCTCN2017090374-appb-000024
Figure PCTCN2017090374-appb-000025

Claims (10)

  1. 一种用于口服固体制剂的复合崩解剂体系，包括崩解剂和助崩剂，优选由崩解剂和助崩剂组成，所述崩解剂为吸湿膨胀型崩解剂，所述助崩剂为小分子易溶性物质或产气型盐；
    优选，所述吸湿膨胀型崩解剂选自干淀粉、交联羧甲基纤维素钠、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代羟丙基纤维素、交联聚维酮、壳聚糖、微晶纤维素中的一种或多种的混合物；
    优选，所述产气型盐选自碳酸盐、碳酸氢盐中的一种或多种的混合物；更优选，所述产气型盐选自碳酸钠、碳酸钙、碳酸钾、碳酸钙镁、碳酸锌、碳酸镁、碳酸铵、甘氨酸碳酸钠、倍半碳酸钠、碳酸氢钠、碳酸氢钙、碳酸氢钾、碳酸氢铵中的一种或多种的混合物。
    优选，所述小分子易溶性物质选自氯化钠、葡萄糖、果糖、木糖醇中的一种或多种的混合物；更优选，所述小分子易溶性物质选自氯化钠、葡萄糖中的一种或两种的混合物。
  2. 如权利要求1所述的复合崩解剂体系，其特征在于，崩解剂和助崩剂的重量比为10:1-1:10，更优选8:1-1:8，最优选5:1-1:5。
  3. 一种口服固体制剂，含有活性成分、如权利要求1所述的复合崩解剂体系、赋形剂和润滑剂；
    优选，以重量百分比计，活性成分含量为约5％-50％，崩解剂含量为约1％-20％，助崩剂含量为约0.1％-35％，赋形剂含量为约20％-80％，润滑剂含量为约0.25％-10％，崩解剂和助崩剂的重量比为10:1-1:10；
    进一步优选，活性成分含量为约8-30％，崩解剂含量为约2-18％，助崩剂含量为约0.5-30％，赋形剂含量为约30-80％，润滑剂含量为约0.5-8％，崩解剂和助崩剂的重量比为8:1-1:8；
    更优选，活性成分含量为约10-20％，崩解剂含量为约4-15％，助崩剂含量为约1-25％，赋形剂含量为约50-80％，润滑剂含量为约1-5％，崩解剂和助崩剂的重量比为5:1-1:5；
    最优选，所述口服固体制剂为片剂。
  4. 如权利要求3所述的口服固体制剂，其特征在于，活性成分选自如下述式(I)、式(II)所示的化合物：
    Figure PCTCN2017090374-appb-100001
    式(I)和式(II)中，R代表
    Figure PCTCN2017090374-appb-100002
    Figure PCTCN2017090374-appb-100003
    Figure PCTCN2017090374-appb-100004
    其中a＝0、1、2、3、4、5或6；
    所述R1代表C2-C8烷基、C2-C8烯烃基、C2-C8炔烃基、
    Figure PCTCN2017090374-appb-100005
    (CH2)nO(CH2)m、
    Figure PCTCN2017090374-appb-100006
    芳基(如苯基)、取代芳基(如取代苯基)、杂芳基或取代杂芳基，其中的
    Figure PCTCN2017090374-appb-100007
    中的Cb、Cc分别代表H或者烷基，b、c代表碳原子的个数，各自独立地选自0、1、2、3、4、5或6；其中的(CH2)nO(CH2)m中的n、m各自独立地选自1、2、3、4、5或6；
    所述R2代表氢、卤素、三氟甲基、C1-C8烷氧基、C1-C8烷基、硝基、磺酰胺基、氨基或腈基；
    所述R3代表不存在、C1-C8烷基、C1-C8烷氧基、C2-C8烯烃氧基、C2-C8炔烃氧基、(C1-C6)O(C1-C6)、
    Figure PCTCN2017090374-appb-100008
    芳基(如苯基)、取代芳基(如取代苯基)、杂芳基或取代杂芳基，其中的
    Figure PCTCN2017090374-appb-100009
    中的Cb、Cc分别代表H或者烷基，b、c代表碳原子的个数，各自独立地选自0、1、2、3、4、5或6；
    所述R4代表芳基(如苯基)、取代芳基(如取代苯基)、芳基磺酰基(如苯基磺酰基)、 5-6元杂芳基、5-6元取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、-CH2ONO2；
    所述R5代表芳基(如苯基)、取代芳基(如取代苯基)、5-6元杂芳基、5-6元取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、C1-C8烯烃基、C1-C8炔烃基、
    Figure PCTCN2017090374-appb-100010
    或(CH2)nO(CH2)m，其中R3、R4、a、m、n如上所定义；
    所述R6和R7代表氢、C1-C8烷氧基或C1-C8烷基；
    所述R8和R9代表氢、C1-C8烷氧基、C1-C8硝酸酯或C1-C8烷基；
    所述芳基是指含有6-20元的单环或稠合环的芳基，如苯基或萘基；
    所述的取代芳基是指被一个或多个选自羟基、C1-C6烷基、C1-C6烷氧基、卤素、硝基、氨基、腈基、三氟甲基、氧代、-CH＝CHCO2R11取代的芳基，各取代基可相同或不同，其中的R11代表氢或C1-C6烷基；
    所述的杂芳基是指含有1至4个杂原子的5-20元芳基(优选5至7元芳基)，所述杂原子各自独立的选自O、S或N；优选地杂芳基选自呋喃、噻吩、吡咯、吡啶、嘧啶、噻唑、噻二唑、喹啉、吲哚等；
    所述的取代杂芳基为被一个或多个C1-C6烷基、C1-C6烷氧基、卤素取代的杂芳基，各取代基可相同或不同。
    优选，式(I)化合物具有如下式所示结构：
    Figure PCTCN2017090374-appb-100011
    Figure PCTCN2017090374-appb-100012
    优选，式(II)化合物具有如下式所示结构：
    Figure PCTCN2017090374-appb-100013
    Figure PCTCN2017090374-appb-100014
    最优选，活性成分是如下结构所示的QR01019或QR01019K：
    Figure PCTCN2017090374-appb-100015
  5. 如权利要求3或4所述的口服固体制剂，其特征在于，赋形剂选自淀粉、乳糖、甘露醇、纤维素乳糖、微晶纤维素、磷酸氢钙、甘露醇-淀粉复合物中的一种或多种的混合物； 润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶体二氧化硅、水合二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂酰富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或多种的混合物。
  6. 如权利要求3-5任一项所述的口服固体制剂，其特征在于，进一步含有粘合剂；
    优选，粘合剂选自淀粉及其衍生物类(包括但不限于淀粉、预胶化淀粉、糊精、麦芽糊精等)、纤维素衍生物类(包括但不限于甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、乙基纤维素、微晶纤维素等)、天然胶及合成胶(包括但不限于明胶、阿拉伯胶、角豆胶、桃胶等)、聚乙二醇、聚维酮、二山嵛酸甘油酯、卡波姆、聚乙烯醇、聚(甲基)丙烯酸树脂、糖醇类(包括但不限于蔗糖、液体葡萄糖、麦芽糖醇等)、玉米朊、海藻酸钠、单月桂酸酯中的一种或多种的混合物；
    更优选，以重量百分比计，粘合剂含量为约0-15％。
  7. 一种口服固体制剂，含有QR01019K和如权利要求1所述的复合崩解剂体系；
    优选，进一步含有赋形剂和润滑剂；
    进一步优选，以重量百分比计，QR01019K含量为约5％-50％，崩解剂含量为约1％-20％，助崩剂含量为约0.1％-35％，赋形剂含量为约20％-80％，润滑剂含量为约0.25％-10％，崩解剂和助崩剂的重量比为10:1-1:10；
    更优选，QR01019K含量为约8-30％，崩解剂含量为约2-18％，助崩剂含量为约0.5-30％，赋形剂含量为约30-80％，润滑剂含量为约0.5-8％，崩解剂和助崩剂的重量比为8:1-1:8；
    更进一步优选，QR01019K含量为约10-20％，崩解剂含量为约4-15％，助崩剂含量为约1-25％，赋形剂含量为约50-80％，润滑剂含量为约1-5％，崩解剂和助崩剂的重量比为5:1-1:5；
    最优选，所述口服固体制剂为片剂。
  8. 如权利要求7所述的口服固体制剂，其特征在于，赋形剂选自淀粉、乳糖、甘露醇、纤维素乳糖、微晶纤维素、磷酸氢钙、甘露醇-淀粉复合物中的一种或多种的混合物；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶体二氧化硅、水合二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂酰富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或多种的混合物。
  9. 如权利要求7或8所述的口服固体制剂，其特征在于，进一步含有粘合剂；
    优选，粘合剂选自淀粉及其衍生物类(包括但不限于淀粉、预胶化淀粉、糊精、麦芽糊精等)、纤维素衍生物类(包括但不限于甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、乙基纤维素、微晶纤维素等)、天然胶及合成胶(包括但不限于明胶、阿拉伯 胶、角豆胶、桃胶等)、聚乙二醇、聚维酮、二山嵛酸甘油酯、卡波姆、聚乙烯醇、聚(甲基)丙烯酸树脂、糖醇类(包括但不限于蔗糖、液体葡萄糖、麦芽糖醇等)、玉米朊、海藻酸钠、单月桂酸酯中的一种或多种的混合物；
    更优选，以重量百分比计，粘合剂含量为约0-15％。
  10. 如权利要求3-9任一项所述的口服固体制剂在制备血管紧张素II受体拮抗剂中的应用，或者在制备用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物中的应用。
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