WO2021254409A1 - 一种复合物的药物组合物及其制备方法 - Google Patents

一种复合物的药物组合物及其制备方法 Download PDF

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Publication number
WO2021254409A1
WO2021254409A1 PCT/CN2021/100465 CN2021100465W WO2021254409A1 WO 2021254409 A1 WO2021254409 A1 WO 2021254409A1 CN 2021100465 W CN2021100465 W CN 2021100465W WO 2021254409 A1 WO2021254409 A1 WO 2021254409A1
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Prior art keywords
pharmaceutical composition
exp3174
ahu377
composite
composition according
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PCT/CN2021/100465
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English (en)
French (fr)
Inventor
蔡燕霞
叶冠豪
Original Assignee
深圳信立泰药业股份有限公司
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Application filed by 深圳信立泰药业股份有限公司 filed Critical 深圳信立泰药业股份有限公司
Priority to CN202211269494.4A priority Critical patent/CN116036079A/zh
Priority to CN202180004442.1A priority patent/CN114096530B/zh
Publication of WO2021254409A1 publication Critical patent/WO2021254409A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/2806—Coating materials
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and relates to a compound pharmaceutical composition and a preparation method thereof, and in particular to a pharmaceutical composition of a compound of an angiotensin II receptor antagonist metabolite and a NEP inhibitor and a preparation method thereof method.
  • Hypertension is a clinical syndrome characterized by increased systemic arterial pressure, and is the most common cardiovascular disease. Most hypertension has a slow onset and lack of special clinical manifestations, leading to a delay in diagnosis. It is only discovered when blood pressure is measured or when complications such as heart, brain, and kidney occur. There is a close causal relationship between long-term hypertension and the risk of morbidity and death from cardiovascular and cerebrovascular diseases.
  • hypertension is not effectively controlled and treated, it can cause coronary atherosclerosis, coronary heart disease, angina pectoris, and serious complications such as hypertensive heart disease and heart failure.
  • long-term high blood pressure can cause damage to the kidneys, brain, cardiovascular and other organs.
  • Heart failure is a serious manifestation or late stage of various heart diseases. It is an important part of the prevention and treatment of chronic cardiovascular diseases in the world. The mortality rate and rehospitalization rate remain high. European and American epidemiological data show that the prevalence of adult heart failure is 1.5% to 2.0%, and with the increase of age, the prevalence of heart failure also increases, and the prevalence of people ⁇ 70 years old is ⁇ 10%. An epidemiological survey in China in 2003 showed that the prevalence of heart failure among adults aged 35 to 74 in my country was 0.9%. "China Cardiovascular Disease Report 2016" pointed out that the prevalence of cardiovascular disease in my country is on the rise, and the mortality rate of cardiovascular disease ranks first, higher than that of tumors and other diseases.
  • WO2007056546A1 discloses a valsartan (Sacubitril, AHU377) sodium salt complex (LCZ696) and a preparation method thereof. It was approved for marketing in China in 2017, and its trade name is Nucinto (Foreign listed product name 2015) for heart failure. Its molecular structure units are as follows:
  • Patent WO2009061713 discloses a preparation of sacubitril and valsartan sodium and a preparation method thereof. By mixing a therapeutic agent with at least one pharmaceutically acceptable excipient, a preparation composed of a variety of prescriptions is disclosed, and then the mixture is used Suitable equipment, such as a tablet press, is directly compressed or the mixture is prepared by pressing a suitable equipment, such as a roller press.
  • the prescription composition contains microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, magnesium stearate, talc and colloidal silicon dioxide.
  • the film coating composition contains hypromellose, titanium dioxide (E 171), polyethylene glycol 4000, talc and iron oxide red (E 172).
  • WO2017125031A1 discloses a series of complexes composed of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), and exhibits a certain effect on heart failure HFpEF with retention of ejection fraction. Its molecular structural units are as follows :
  • the present invention provides a new compound pharmaceutical composition and a preparation method thereof,
  • the present invention is realized by the following technical solutions, a pharmaceutical composition of a complex, the structural units of the complex are as follows:
  • x is a value between 0.5 ⁇ 3;
  • A refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, Acetonitrile, toluene, dichloromethane;
  • n is a value between 0 and 3;
  • the pharmaceutical composition contains one or a mixture of two or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, sodium croscarmellose, and pregelatinized starch in any ratio ,
  • the amount used in the pharmaceutical composition is 4%-50%; and one or more other excipients.
  • the pharmaceutical composition contains low-substituted hydroxypropyl cellulose and crospovidone, and the amount of low-substituted hydroxypropyl cellulose used in the pharmaceutical composition is preferably 17%-30% The amount of crospovidone used in the pharmaceutical composition is preferably 8%-20%.
  • the ratio of low-substituted hydroxypropyl cellulose and crospovidone is preferably 1:1-3:1, and the total weight of the two is preferably 25% in the pharmaceutical composition. -40%. More preferably, when the ratio of the complex in the pharmaceutical composition is 25%-30%, the ratio of low-substituted hydroxypropylcellulose and crospovidone is 1.75:1 to 2.25:1, more preferably 2:1.
  • the pharmaceutical composition contains sodium starch glycolate, croscarmellose sodium and crospovidone, wherein the sodium starch glycolate is used in the pharmaceutical composition in an amount
  • the amount of croscarmellose sodium used in the pharmaceutical composition is 4%-12%, and the amount of crospovidone used in the pharmaceutical composition is 4%-12%; the three
  • the weight sum is preferably used in the pharmaceutical composition in an amount of 15%-35%. More preferably, when the proportion of the complex in the pharmaceutical composition is 40%-50%, the amount of sodium starch glycolate used in the pharmaceutical composition is 8-12%, and the sodium croscarmellose is used in the pharmaceutical composition.
  • the usage amount is 8-12%, and the usage amount of crospovidone in the pharmaceutical composition is 8-12%.
  • the low-substituted hydroxypropyl cellulose of the aforementioned ratio has a large surface area and porosity, has strong water-absorbing swellability, and exhibits a significant disintegration effect; moreover, the cross-linked povidone of the aforementioned ratio is in this
  • the invention has good fluidity, quickly exhibits capillary activity and excellent hydration ability in water, and also has good disintegration properties.
  • the combined use of low-substituted hydroxypropyl cellulose and cross-linked povidone can make this product disintegrate rapidly in the dissolution medium to achieve rapid release.
  • more than one other auxiliary materials include more than one filler, lubricant, coating agent and the like.
  • the filler includes one or a mixture of two or more of microcrystalline cellulose, lactose, mannitol, and dibasic calcium phosphate in any ratio, and the usage amount is 16%-by weight of the pharmaceutical composition. 60%, preferably 17%-45%.
  • the filler comprises a mixture of microcrystalline cellulose and lactose, preferably the mass ratio of microcrystalline cellulose and lactose is 1:1-5:1, preferably microcrystalline cellulose and lactose
  • the total mass of is 16%-60% by weight of the pharmaceutical composition, more preferably 17%-45%.
  • the lactose is preferably anhydrous lactose.
  • the anhydrous lactose and microcrystalline cellulose of the present invention constitute more than 40% of the total preparation part.
  • As a filler in the formulation it has good fluidity and Compressibility, stable properties, smooth appearance, good hardness and disintegration. It can also be used in direct pressure process and dry granulation process.
  • the proportion of the compound in the pharmaceutical composition is 25%-30% (specifically, the compound is calculated as 60 or 120 mg of free acid)
  • the ratio of the microcrystalline cellulose and lactose is 1.5:1 to 5:1, preferably the total mass of microcrystalline cellulose and lactose is 17% to 45% of the weight of the pharmaceutical composition.
  • the proportion of the compound in the pharmaceutical composition is 40%-50% (specifically, the compound is 240 mg based on the free acid)
  • the mass ratio of the microcrystalline cellulose and lactose is 1.8:1-2.2:1 (specifically such as 1.9:1, 2:1, 2.1:1, etc.), preferably the total mass of microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.
  • the mass of the complex ( calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) is 20%-50% of the weight of the pharmaceutical composition, and the specific usage amount is preferably 30 mg , 60mg, 90mg, 120mg, 150mg, 180mg, 210mg, 240mg, 270mg, 300mg, etc.
  • the lubricant includes one or a mixture of two or more of silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol, and hydrogenated castor oil.
  • the mass of the agent is 1%-3% of the weight of the pharmaceutical composition.
  • the lubricant is a combination of silica and magnesium stearate.
  • Silica mainly acts as a glidant and also has a lubricating effect.
  • Magnesium stearate is a hydrophobic material.
  • it is easy to mix with the particles and adhere to the surface of the particles, which can reduce the friction between the particles and the die.
  • the two are used in the pharmaceutical composition of the present invention in the aforementioned ratio, which can obviously increase the fluidity of the material, and the sheet surface is smooth and beautiful after tableting.
  • the sum of the percentages of the aforementioned raw and auxiliary materials in the pharmaceutical composition is 95%-100%, and the usage amounts are all mass usage amounts.
  • the coating agent includes any gastric-soluble coating.
  • the gastric soluble coating includes 85G640059-CN, and the gastric soluble coating adopts a solvent mixture such as water (preferably, the gastric soluble coating agent and purified water are mixed in a mass ratio of 1:5-1:8 and then coated. Coating), the weight gain after coating is about 0.1%-4%.
  • the molecular formula of EXP3174 is C 22 H 21 ClN 6 O 2 and the molecular weight is about 436.9; the molecular formula of AHU377 is C 24 H 29 NO 5 and the molecular weight is about 411.5.
  • the complex of the drug can be obtained by a method known in the prior art, wherein the complex disclosed in WO2017125031A1 and the preparation method thereof are introduced into the present invention.
  • the value of a:b includes 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4.
  • the structural units of the composite are as follows:
  • x includes 0.5, 1, 1.5, and 2.
  • the structural units of the composite are as follows:
  • n is any value between 1 and 3.
  • n includes 0.5, 1, 1.5, 2, 2.5, and 3.
  • the composite includes:
  • the supramolecular complex (complex) of the present invention is different from a mixture obtained by simple physical mixing of two active ingredients.
  • EXP3174 and AHU377 in the complex molecule and pharmaceutically acceptable calcium cations are combined to obtain supramolecular complexes (complexes) through non-covalent bonds, and the non-covalent bonds are well known to those of ordinary skill in the art.
  • the XRD spectrum of the obtained supramolecular complex (complex) is obviously different from the XRD spectrum of EXP3174 and AHU377 calcium salt. , Ethanol, ethanol-water, etc.).
  • solubility properties and there are obvious differences in other physical and chemical properties such as hygroscopicity, melting point, infrared spectrum, etc.
  • the pharmaceutical composition is a solid preparation suitable for oral administration, preferably a tablet or capsule for oral administration.
  • the present invention further provides a preparation method of the pharmaceutical composition.
  • the raw and auxiliary materials are prepared by a direct compression process or a dry granulation process and then compressed, and then coated with a coating agent to obtain a coated pharmaceutical composition.
  • the present invention further provides that the pharmaceutical composition can be used in medicines for preventing and/or treating hypertension, heart failure, hypertension and heart failure.
  • the embodiment of the present invention can effectively ensure the disintegration and dissolution of the drug, and has good granulation fluidity and other effects.
  • the pharmaceutical composition obtained by the present invention through clinical verification, can effectively reach the drug concentration in the body, and is used in drugs for the prevention and/or treatment of hypertension, heart failure, hypertension and heart failure;
  • the present invention greatly reduces the composition of the raw and auxiliary materials of the prescription, has a simple process, is environmentally friendly and economical, and is beneficial to large-scale industrial application.
  • the present invention effectively controls the weight of the tablet, ensures the dissolution and effect of the drug, and is beneficial to the clinical use of the drug.
  • Example 5 Disintegrant and its dosage selection
  • the amount of low-substituted hydroxypropyl cellulose used in the pharmaceutical composition is 17%-30%, and the amount of crospovidone used in the pharmaceutical composition is 8%-20%. Preferably, both are used in the pharmaceutical composition.
  • the usage amount is 25%-40%.
  • Example 5 On the basis of Example 5, crystalline cellulose (Type 102) and anhydrous lactose (DTHV) are selected as fillers in the formulation of this product.
  • the experimental results found that different proportions of fillers may affect the disintegration and dissolution of the tablet core. Combining the disintegration time and the dissolution curve of the pH 6.8 medium, a suitable prescription ratio was screened out. See Table 3 for details. The mixed use of the two fillers can ensure that the core appearance, weight difference, and friability meet the requirements.
  • the ratio of microcrystalline cellulose/lactose is 2:1, and the angle of repose (°) is about 40°, which can meet the requirements of fluidity.
  • the thickness of the tablet is thicker, which may affect the effect of swallowing and compliance.
  • the mass ratio of microcrystalline cellulose and anhydrous lactose is more preferably 1:1-5:1, and the total mass of microcrystalline cellulose and lactose is preferably 18%-60% by weight of the pharmaceutical composition.
  • the disintegration time is fast, and a fast dissolution effect can be obtained.
  • the mass ratio of microcrystalline cellulose and lactose is 1.5:1 to 5:1, and the dissolution effect is 30min ⁇ 85%.
  • Example 7 To study the pharmacokinetics of different in vitro dissolved samples in animals.
  • the enteric coating formula contains: Eudragit L30D-55, talc, triethyl citrate, and purified water according to the mass ratio of 1:6 and then the coating is mixed, and the weight gain after coating is about 3%.
  • LBQ657 is an active metabolite of sacubitril.
  • the F value of the three prescription tablets of sacubitril is more than 90%, indicating that sacubitril is mainly absorbed in the distal small intestine, while the EXP3174 enteric-coated tablet is combined with the mixed Compared with the suspension, the bioavailability of the suspension is only about 60% of that of the suspension.
  • the F value of the other two groups without enteric-coated tablets is above 90%, indicating that EXP3174 is absorbed at the proximal and distal ends of the small intestine.
  • the gastric soluble coating includes 85G640059-CN.
  • the gastric soluble coating adopts a solvent mixture such as water, and the weight gain after coating is about 0.1%-4%.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed.
  • the tablets obtained by direct compression of the coating mixed powder (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: dry granulation of the aforementioned raw and auxiliary materials, and then compression;
  • the tablets obtained by coating, granulating and tableting (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: mixing the aforementioned raw and auxiliary materials directly with powder;
  • the tablets obtained by direct compression of the coating mixed powder (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: dry granulation of the aforementioned raw and auxiliary materials, and then compression;
  • the tablets obtained by coating, granulating and tableting (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: mixing the aforementioned raw and auxiliary materials directly with powder;
  • the tablets obtained by direct compression of the coating mixed powder (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: dry granulation of the aforementioned raw and auxiliary materials, and then compression;
  • the tablets obtained by coating, granulating and tableting (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: dry granulation of the aforementioned raw and auxiliary materials, and then compression;
  • the tablets obtained by coating, granulating and tableting (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a compound pharmaceutical composition and a preparation method thereof include:
  • the preparation method is: dry granulation of the aforementioned raw and auxiliary materials, and then compression;
  • the tablets obtained by coating, granulating and tableting (wherein, the purified water used for coating is in After coating, it is dried and finally removed) to obtain a coated tablet with a weight gain of about 3% after coating.
  • a indicates that the amount of the complex described in Examples 8-15 is based on the anhydrous free acid C 46 H 50 ClN 7 O 7 .
  • Examples 16-23 are the same as those of Examples 8-15, except that the raw material used is the compound a of Example 2.
  • Example 24 Using the pharmaceutical composition of Example 8 to conduct a clinical phase I trial
  • the composite tablet of the present invention has completed single-center, randomized, double-blind, placebo-controlled multi-dose, single, multiple-dose tolerance and pharmacokinetic phase I clinical trials in healthy subjects.
  • the exposure of EXP3174 in the human body was not lower than the total active ingredient exposure in the human body after 100 mg of losartan was taken orally, and the human body was exposed to LBQ657
  • the amount of exposure to LBQ657 in the human body after oral administration of LCZ696 200 mg; the exposure of EXP3174 in the human body after oral administration of 480 mg of the compound of the present invention is not less than the total active ingredient exposure in the human body after oral administration of Losartan 200 mg, and the exposure of LBQ657 in the human body is not Lower than the human body exposure to LBQ657 after oral administration of LCZ696 400 mg.
  • the complex of the present invention is applied to patients with heart failure and hypertension, the pharmacokinetics and pharmacodynamics in the body are consistent with the expected clinical treatment effect.
  • Granulation process dry granulation.
  • Granulation process dissolve the compound of Example 3 and Poloxamer 188 in dichloromethane, place crospovidone XL and microcrystalline cellulose in a fluidized bed to control the inlet air temperature of 50-70°C, and the material temperature of 40 -50°C, spray dried, then mixed with magnesium stearate and compressed into tablets.
  • the obtained tablets were stored at 40°C ⁇ 2°C and 75% ⁇ 5% RH for 2 months, and the impurity detection was carried out by the HPLC method.
  • the results are as follows, which shows that the stability of the products of the prescription process is poor.
  • Example 11 EXP3174 Unit Mean Mean Mean AUC last h*ng/mL 4,644.9 3729.2 4,271.1 LBQ657 Unit Mean Mean Mean AUC last h*ng/mL 4002.5 3,473.5 3827.8
  • LBQ657 is an active metabolite of sacubitril, *2 means 2 tablets.
  • the compound a when the compound a is 60 mg or 120 mg in the pharmaceutical composition, when microcrystalline cellulose and lactose are selected as support agents, low-substituted hydroxypropyl cellulose and cross-linked cellulose are preferred.
  • the combination of bispovidone has a better dissolution effect than croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, single use or combination of other ratios; and from batch 305 According to the comparison results between 306 and Examples 9, 11, the mass ratio of low-substituted hydroxypropyl cellulose and crospovidone is preferably 1.75-2.25:1, more preferably 2:1.
  • LBQ657 is the active metabolite of sacubitril, *4 means 4 tablets.
  • the applicant found that when the compound a is 240 mg in the pharmaceutical composition, microcrystalline
  • the ratio of cellulose and lactose is 1.8:1-2.2:1 (specifically 1.9:1, 2:1, 2.1:1), it preferably contains sodium starch glycolate, croscarmellose sodium and crospovidone
  • the amount of sodium starch glycolate used in the pharmaceutical composition is 8-12%
  • the amount of croscarmellose sodium used in the pharmaceutical composition is preferably 8-12%
  • the amount of crospovidone used in the pharmaceutical composition is 8-12%.
  • the usage amount is 8-12%, compared with other ratios of the combination of sodium starch glycolate, croscarmellose sodium and crospovidone, or the combination of crospovidone and low-substituted hydroxypropyl cellulose
  • the combination, and other ratios of microcrystalline cellulose and lactose on this basis, is difficult to achieve the corresponding dissolution, and it is expected that it is difficult to achieve the corresponding in vivo dissolution effect.

Abstract

属于医药制剂技术领域，涉及一种复合物的药物组合物及其制备方法，特别涉及一种血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的药物组合物及其制备方法。

Description

一种复合物的药物组合物及其制备方法 技术领域
本发明属于医药制剂技术领域，涉及一种复合物的药物组合物及其制备方法，特别涉及一种血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的药物组合物及其制备方法。
背景技术
高血压是以体循环动脉压增高为主要表现的临床综合征，是最常见的心血管疾病。高血压大多数起病缓慢，缺乏特殊临床表现，导致诊断延迟，仅在测量血压时或发生心、脑、肾等并发症时才被发现。长期的高血压与心脑血管病发病和死亡风险之间存在密切的因果关系。
据统计，目前全世界有超过十亿人高血压未得到控制，预计到2030年会增加到15亿。在我国，2012～2015年中国高血压调查(CHS)调查结果显示：中国≥18岁成人高血压患病率为27.9％(加权率为23.2％)，知晓率、治疗率和控制率分别为51.6％，45.8％和16.8％，治疗控制率为37.5％。高血压的发病率呈不断上升的趋势，据统计，我国心血管病患者约为2.9亿人(《中国心血管病报告2013》)。高血压如果得不到有效的控制和治疗，可以引起冠状动脉硬化，出现冠心病、心绞痛，还可能造成高血压性心脏病、心力衰竭等严重并发症。另外，长期高血压可导致肾、脑、心血管等器官损伤。
心衰是各种心脏疾病的严重表现或晚期阶段，是全球慢性心血管疾病防治的重要内容，死亡率和再住院率居高不下。欧美流行病学数据显示，成人心衰患病率为1.5％～2.0％，并且随着年龄增加，心力衰竭的患病率也随之增加，≥70岁人群患病率≥10％。2003年中国流行病学调查显示，我国35～74岁成人心衰患病率为0.9％。《中国心血管病报告2016》提出我国心血管病患病率处于持续上升阶段，心血管病死亡率居首位，高于肿瘤和其他疾病。我国人口老龄化加剧，冠心病、高血压、糖尿病、肥胖等慢性病的发病呈上升趋势，医疗水平的提高使心脏疾病患者生存期延长，导致我国心衰患病率呈持续升高趋势。对国内10714例住院心衰患者的调查显示：1980、1990、2000年心衰患者住院期间病死率分别为15.4％、12.3％和6.2％，主要死亡原因依次为左心衰竭(59％)、心律失常(13％)和心脏性猝死(13％)。China-HF研究显示，住院心衰患者的病死率为4.1％。
WO2007056546A1公开了一种缬沙坦(Valsartan)-沙库巴曲(Sacubitril，AHU377)的钠盐复合物(LCZ696)及其制备方法，于2017年在中国获批上市，商品名：诺欣妥
Figure PCTCN2021100465-appb-000001
(国外上市商品名为
Figure PCTCN2021100465-appb-000002
2015年)用于心力衰竭。其分子结构单元如下：
Figure PCTCN2021100465-appb-000003
专利WO2009061713公开了一种沙库巴曲缬沙坦钠的制剂及其制备方法，通过将治疗剂与至少一种可药用赋形剂混合，公开了多种处方组成的制剂，接着将混合物用适合的设备如压片机直接压缩或将混合物用适合的设备如滚压机压制而制备。
已上市的
Figure PCTCN2021100465-appb-000004
的处方组成含有微晶纤维素，低取代羟丙基纤维素，交联聚维酮， 硬脂酸镁，滑石粉和胶体二氧化硅。薄膜衣组成包含羟丙甲纤维素，二氧化钛(E 171)，聚乙二醇4000，滑石粉和氧化铁红(E 172)。
另外，WO2017125031A1公开了一系列由血管紧张素受体拮抗剂代谢产物(EXP3174)与NEP抑制剂(Sacubitril)的复合物，且对射血分数保留的心力衰竭HFpEF表现一定效果，其分子结构单元如下：
Figure PCTCN2021100465-appb-000005
但是由于化合物组成的不同，如何寻找符合临床使用的制剂方案至关重要，需进一步研究开发。
发明内容
鉴于现有技术存在的问题，本发明的提供了一种新的复合物药物组合物及其制备方法，
本发明通过以下技术方案来实现，一种复合物的药物组合物，所述复合物的结构单元如下：
(aEXP3174·bAHU377)·xCa·nA
其中a:b＝1:0.25～4；x为0.5～3之间的数值；A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-叔-丁基醚、乙腈、甲苯、二氯甲烷；n为0～3之间的数值；
所述药物组合物中含有低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠、交联羧甲基纤维素钠、预胶化淀粉中的一种或者两种以上任意比例的混合物，在药物组合物中使用量为4％-50％；和一种以上的其他辅料。
作为本发明的一种优选技术方案，所述药物组合物中含有低取代羟丙纤维素和交联聚维酮，低取代羟丙纤维素在药物组合物中使用量为优选17％-30％，交联聚维酮在药物组合物中使用量为优选8％-20％。
作为本发明的一种优选技术方案，优选低取代羟丙纤维素和交联聚维酮的比例为1：1-3：1，二者重量之和优选在药物组合物中使用量为25％-40％。更优选当复合物在药物组合物中的比例为25％-30％，低取代羟丙纤维素和交联聚维酮的比例为1.75：1-2.25：1，更优选2：1。
作为本发明的一种优选技术方案，所述药物组合物中含有羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮，其中，羧甲淀粉钠在药物组合物中使用量为4％-12％，交联羧甲基纤维素钠在药物组合物中使用量为4％-12％，交联聚维酮在药物组合物中使用量为4％-12％；三者重量之和优选在药物组合物中使用量为15％-35％。更优选当复合物在药物组合物中的比例为40％-50％时，羧甲淀粉钠在药物组合物中使用量为8-12％，交联羧甲基纤维素钠在药物组合物中使用量为8-12％，交联聚维酮在药物组合物中使用量为8-12％。
在本发明中，前述比例的低取代羟丙纤维素具有很大的表面积和孔隙率，具有很强的吸水膨胀性，展现明显的崩解效果；而且，前述比例的交联聚维酮在本发明中具有良好的流动性，在水中迅速表现出毛细管活性和优异的水化能力，也具有良好的崩解性能。联合使用低取代羟丙纤维素和交联聚维酮，可使本品在溶出介质中迅速崩解，达到快速释放的作用。
作为本发明的一种优选技术方案，一种以上的其他辅料包括一种以上的填充剂、润滑剂和包衣剂等。
作为本发明的一种优选技术方案，所述填充剂包括微晶纤维素、乳糖、甘露醇、磷酸氢钙一种或者两种以上任意比例的混合物，使用量为药物组合物重量的16％-60％，优选17％-45％。
作为本发明的一种优选技术方案，所述填充剂包含微晶纤维素和乳糖的混合物，优选微晶纤维素和乳糖的质量比为1：1-5：1，优选微晶纤维素和乳糖的总质量为药物组合物重量的16％-60％，更优选为17％-45％。
作为本发明的一种优选技术方案，所述乳糖优选无水乳糖，本发明无水乳糖和微晶纤维素构成约40％以上的总制剂部分，作为处方中的填充剂具有良好的流动性和可压缩性，其性质稳定，制成的片剂外观光洁，硬度、崩解较好。也可用于直压工艺、干法制粒工艺。
作为本发明的一种优选技术方案，当复合物在药物组合物中的比例为25％-30％(具体如复合物以游离酸计如60、120mg)，所述微晶纤维素和乳糖的质量比为1.5：1-5：1，优选微晶纤维素和乳糖的总质量为药物组合物重量的17％-45％。
作为本发明的一种优选技术方案，当复合物在药物组合物中的比例为40％-50％(具体如复合物以游离酸计240mg)，所述微晶纤维素和乳糖的质量比为1.8：1-2.2：1(具体如如1.9：1，2：1，2.1：1等)，优选微晶纤维素和乳糖的总质量为药物组合物重量的17％-45％。
作为本发明的一种优选技术方案，所述复合物(以无水游离酸C 46H 50ClN 7O 7计)的质量为药物组合物重量的20％-50％，优选具体使用量为30mg、60mg、90mg、120mg、150mg、180mg、210mg、240mg、270mg、300mg等。
作为本发明的一种优选技术方案，所述润滑剂包括二氧化硅，硬脂酸，硬脂酸镁、聚乙二醇、氢化蓖麻油中的一种或者两种以上的混合物，所述润滑剂的质量为药物组合物重量的1％-3％。
作为本发明的一种优选技术方案，润滑剂选择二氧化硅和硬脂酸镁的组合物，二氧化硅主要发挥助流剂并兼有润滑的作用，硬脂酸镁属于疏水性物料，在本发明中易与颗粒混匀并附着于颗粒表面，可以减少颗粒与冲模之间的摩擦力。两者按前述比例合用于本发明药物组合物中，能明显增加物料的流动性，压片后片面光滑美观。
除另有说明外，前述原辅料在药物组合物中的百分比之和为95％-100％，所述使用量均为质量使用量。
作为本发明的一种优选技术方案，所述包衣剂包括任意的胃溶性包衣。具体地，例如胃溶性包衣包括85G640059-CN，所述胃溶性包衣的采用水等溶剂混合物(优选胃溶性包衣剂与纯化水按质量比为1：5-1：8混合后进行包衣)，包衣后增重约0.1％-4％。
本发明复合物的组成中，EXP3174的分子式为C 22H 21ClN 6O 2，分子量约为436.9；AHU377的分子式为C 24H 29NO 5，分子量约为411.5。
所述药物的所述复合物可以通过现有技术已知的方法获得，其中，WO2017125031A1公开的复合物及其制备方法引入本发明。
作为本发明的一种更为优选技术方案，a:b的值包括1:0.25，1:0.5，1:1，1:1.5，1:2，1:2.5，1:3，1:3.5，1:4。
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：
(EXP3174·AHU377)·xCa·nH 2O
或者
Figure PCTCN2021100465-appb-000006
其中x为0.5～2之间的数值；n为0～3之间的数值。
作为本发明的一种更为优选技术方案，x包括0.5、1、1.5、2。
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：
(EXP3174·AHU377)·1.5Ca·nH 2O
或者
(EXP3174·AHU377)·2Ca·nH 2O
其中n为1～3之间的任意数值。
作为本发明的一种更为优选技术方案，n包括0.5、1、1.5、2、2.5、3。
作为本发明的一种更为优选技术方案，所述复合物包括：
(EXP3174·AHU377)·1.5Ca·1H 2O；
(EXP3174·AHU377)·1.5Ca·1.5H 2O；
(EXP3174·AHU377)·1.5Ca·2H 2O；
(EXP3174·AHU377)·1.5Ca·2.5H 2O；
(EXP3174·AHU377)·1.5Ca·3H 2O；
(EXP3174·AHU377)·2Ca·1H 2O；
(EXP3174·AHU377)·2Ca·1.5H 2O；
(EXP3174·AHU377)·2Ca·2H 2O；
(EXP3174·AHU377)·2Ca·2.5H 2O；
(EXP3174·AHU377)·2Ca·3H 2O。
本领域的技术人员可以理解，在超分子络合物(复合物)的单位晶胞中，所述阿利沙坦酯代谢产物(EXP3174)、AHU377、钙离子(Ca 2+)和溶剂分子会以数个结构单元的形式填充于其中。
本发明所述超分子络合物(复合物)区别于两种活性成分通过简单的物理混合得到的混合物。所述复合物分子中EXP3174和AHU377和药学上可接受的钙阳离子，通过非共价键结合得到超分子络合物(复合物)，所述非共价键为本领域普通技术人员所熟知，包含但不限于氢键、配位键、离子键等等，所得超分子络合物(复合物)的XRD谱图明显区别于EXP3174和AHU377钙盐的XRD谱图，其在各溶剂(诸如水、乙醇、乙醇-水等)中的溶解性能也存在明显区别，在其他各项理化性质诸如吸湿性、熔点、红外谱图等均存在明显差异。
所述药物组合物是适于口服的固体制剂，优选口服的片剂或胶囊。
本发明进一步提供了所述的药物组合物的制备方法，所述原辅料采用直压工艺，或者干法制粒工艺制备后压片，然后采用包衣剂包衣，得到包衣的药物组合物。
本发明进一步提供了所述的药物组合物可以应用于预防和/或治疗高血压、心衰、高血压和心衰的药物中使用。
本发明相对于现有技术的有益效果包括：
(1)本发明实施方案可以有效保证药物的崩解和溶出，具有良好的制粒流动性等效果。
(2)本发明获得的药物组合物，通过临床验证，可以有效的达到体内用药浓度，应用于预防和/或治疗高血压、心衰、高血压和心衰的药物中使用；
(3)本发明大大减少处方的原辅料组成，不仅工艺简单，环保经济，利于大规模产业化应用。
(4)本发明在药物组合物活性成分占比较高的情况下，有效控制片重的情况，保证了药物的溶出和效果，有利于该药物的临床使用。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。
实施例1
AHU377游离酸的制备：
将2.1g AHU377钙盐、40mL醋酸异丙酯加入250mL的单口瓶中，室温下加入2mol/L盐酸4.5mL搅拌溶清。分液，收集有机层，使用20mL水洗涤有机层两次；35℃下减压脱溶，得AHU377游离酸。
实施例2
复合物的制备：(按照专利WO2017125031A1的实施例2制备)
Figure PCTCN2021100465-appb-000007
室温下，将依据实施例1方法所得的AHU377游离酸2.36g、EXP3174 2g与40mL丙酮 加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.3当量的氢氧化钙固体和1mL水，室温搅拌10h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，35℃下真空烘8h，烘干得到固体3.5g(EXP3174·AHU377) 3-·1.5Ca 2+·2.5H 2O，HPLC检测纯度为99％。重复试验，以获得足够的药效实验用量。
实施例3
复合物的制备：(按照专利WO2017125031A1的实施例3制备)
Figure PCTCN2021100465-appb-000008
室温下，将依据实施例1方法所得的AHU377游离酸2.36g、EXP3174 2g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU377 1.6当量的氢氧化钙固体和0.6mL水，35℃搅拌6h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，50℃下真空烘8h，烘干得到固体3.1g(EXP3174·AHU377) 3-·1.5Ca 2+·2H 2O。重复试验，以获得足够的药效实验用量。
实施例4
参照实施例2和3的制备方法，分别制备得到以下复合物：
(EXP3174·AHU377)·1.5Ca·1H 2O；
(EXP3174·AHU377)·1.5Ca·1.5H 2O；
(EXP3174·AHU377)·1.5Ca·3H 2O；
(EXP3174·AHU377)·2Ca·1H 2O；
(EXP3174·AHU377)·2Ca·1.5H 2O；
(EXP3174·AHU377)·2Ca·2H 2O；
(EXP3174·AHU377)·2Ca·2.5H 2O；
(EXP3174·AHU377)·2Ca·3H 2O。
实施例5崩解剂及其用量选择
通过测定pH6.8介质的溶出曲线，考察不同崩解剂种类，筛选较佳崩解剂用量。处方设计内容见表1，溶出曲线结果见表2。
表1不同崩解剂及用量处方实验
Figure PCTCN2021100465-appb-000009
表2不同崩解剂及用量溶出曲线研究结果
Figure PCTCN2021100465-appb-000010
由崩解剂选择结果可知，使用低取代羟丙纤维素和交联聚维酮比单独使用低取代羟丙纤维素更能促进溶出，低取代羟丙纤维素和交联聚维酮的使用量分别达17.8％和8.9％时，溶出能在15min达85％以上。
所以，优选低取代羟丙纤维素在药物组合物中使用量为17％-30％，交联聚维酮在药物组合物中使用量为8％-20％，优选二者在药物组合物中使用量为25％-40％。
实施例6填充剂及其用量选择
在实施例5的基础上，本品制剂中填充剂选择晶纤维素(Type102)和无水乳糖(DTHV)。实验结果发现，不同配比的填充剂可能影响片芯的崩解及溶出情况，结合崩解时间及pH6.8 介质的溶出曲线筛选出适合的处方比例，具体见表3。两者填充剂混合使用能保证片芯外观、重量差异、脆碎度符合要求。
表3微晶纤维素/乳糖不同比例的处方设计
Figure PCTCN2021100465-appb-000011
表4微晶纤维素/乳糖不同比例的崩解时间的研究结果
Figure PCTCN2021100465-appb-000012
表5微晶纤维素/乳糖不同比例的溶出曲线的研究结果
Figure PCTCN2021100465-appb-000013
另外，混粉流动性考察结果：采用微晶纤维素/乳糖配比为2：1，休止角(°)为40°左右，可以满足流动性的要求。
由于微晶纤维素/乳糖配比为6：1时，药片厚度较厚，可能影响吞咽和依从效果。
综合以上结果可知，进一步优选微晶纤维素和无水乳糖的质量比为1：1-5：1，优选微晶纤维素和乳糖的总质量为药物组合物重量的18％-60％，不仅崩解时间快，而且能得到快速溶出效果，更优选微晶纤维素和乳糖的质量比为1.5：1-5：1，溶出效果30min≥85％。
实施例7研究不同体外溶出的样品在动物体内的药动学情况。
通过实施例5、6优选的技术方案，制备出三个具有不同的样品，进行犬PK试验，具体处方组成如表6中所示，溶出曲线结果见表7。
表6不同处方组成
Figure PCTCN2021100465-appb-000014
*肠溶包衣配方中含：Eudragit L30D-55、滑石粉、柠檬酸三乙酯，和纯化水按照质量比1：6混合后进行包衣，包衣后增重约3％。
表7不同处方的体外溶出结果
Figure PCTCN2021100465-appb-000015
结果：由于3C批次选择了肠溶包衣，在pH5.5以下的酸性介质中肠溶衣膜不会被破坏，因此，未检测3C批次片剂在pH1.2及pH5.0中的溶出曲线。
以原料药的混悬液作为对照，采用这3A、3B和3C三批样品进行犬PK试验，考察不同体外溶出行为的处方在比格犬体内的药动学情况，结果如表8所示。
表8不同处方样品在比格犬的体内药动学结果
Figure PCTCN2021100465-appb-000016
Figure PCTCN2021100465-appb-000017
注：LBQ657为沙库巴曲活性代谢产物。
由以上结果可知，与混悬液比较，沙库巴曲三种处方片剂F值均有90％以上，说明沙库巴曲主要在小肠远端吸收，而EXP3174肠溶包衣片剂与混悬液相比生物利用度只有混悬液的60％左右，其他2组别没有包肠溶衣片剂F值均有90％以上，说明而EXP3174在小肠近端及远端均有吸收。
上述实验显示肠溶包衣样品与混悬液比较吸收降低，因此我们选择胃溶包衣。具体地，例如胃溶性包衣包括85G640059-CN，所述胃溶性包衣的采用水等溶剂混合物，包衣后增重约0.1％-4％。
在前述实验例5-7的技术方案的基础上，本发明进一步得到以下优选的实施例。
实施例8
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000018
Figure PCTCN2021100465-appb-000019
制备方法为：将前述原辅料进行混粉直压。
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：7混合后，包衣混粉直压得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例9
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000020
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：7混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例10
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000021
生产工艺：制备方法为：将前述原辅料进行混粉直压；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：6混合后，包衣混粉直压得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例11
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000022
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例12
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000023
生产工艺：制备方法为：将前述原辅料进行混粉直压；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：6混合后，包衣混粉直压得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例13
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000024
Figure PCTCN2021100465-appb-000025
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例14
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000026
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
实施例15
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：
Figure PCTCN2021100465-appb-000027
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1：6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。
注： a表示实施例8-15所述复合物的用量以无水游离酸C 46H 50ClN 7O 7计。
前述部分实施例的溶出效果如下：
Figure PCTCN2021100465-appb-000028
各实施例的溶出符合标准要求，并在动物实验中体现足够的药物暴露量。
实施例16-23
实施例16-23分别与实施例8-15的处方一致，所不同的是，所使用的原料药为实施例2的复合物 a。
注： a表示所述复合物的用量以无水游离酸C 46H 50ClN 7O 7计。
实施例24采用实施例8的药物组合物进行临床I期试验
本发明复合物片已完成在健康受试者中单中心、随机、双盲、安慰剂对照的多剂量、单次、多次给药的耐受性、药代动力学Ⅰ期临床试验。单次给药设置60mg、180mg、360mg、540mg、720mg、960mg、1080mg，共7个剂量组；多次给药设置180mg、360mg、540mg、720mg，共4个剂量组；在480mg剂量组开展食物影响试验，同时在食物影响试验第一周期采集尿样和粪样，用于回收率和药物代谢转化研究；以评价本发明复合物片在健康受试者中单次、多次给药的耐受性、药代动力学、药物代谢转化及回收率以及食物对其药代动力学的影响，并初步评价药效学。
根据单次给药和多次给药的PK结果进行推算，口服本发明复合物240mg后，人体内EXP3174暴露量不低于口服氯沙坦100mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 200mg后人体内LBQ657暴露量；口服本发明复合物480mg后，人体内EXP3174暴露量不低于口服氯沙坦200mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 400mg后人体内LBQ657暴露量。
所以，本发明复合物在应用于心衰和高血压疾病患者后，从体内药代和药效上均表现符合预期的临床治疗效果。
对比实施例1
Figure PCTCN2021100465-appb-000029
Figure PCTCN2021100465-appb-000030
制粒工艺：干法制粒。
该处方测定pH1.2的溶出结果，溶出缓慢，具体如下表所示：
Figure PCTCN2021100465-appb-000031
对比实施例2
Figure PCTCN2021100465-appb-000032
制粒工艺：将实施例3复合物和泊洛沙姆188溶于二氯甲烷，将交联聚维酮XL和微晶纤维素置于流化床控制进风温度50-70℃，物料温度40-50℃，进行喷雾干燥，然后与硬脂酸镁混合后压片。
所得片剂进行40℃±2℃，75％±5％RH下保存2个月，采用HPLC法进行杂质检测，结果如下，可见该处方工艺的产品的稳定性较差。
Figure PCTCN2021100465-appb-000033
Figure PCTCN2021100465-appb-000034
对比实施例3
采用以下处方与实施例处方进行对比，采用本发明处方，在pH1.2下的溶出明显好于301-305的对比例，并且，实施例9和实施例11的溶出性质接近，并通过犬pK实验发现，其体内代谢物的效果AUC last接近，可以有效保证药效。
实验处方及结果如下：
Figure PCTCN2021100465-appb-000035
Figure PCTCN2021100465-appb-000036
Figure PCTCN2021100465-appb-000037
比格犬体内pk数据
PK parameters   实施例9*2 305 实施例11
EXP3174 Unit Mean Mean Mean
AUC last h*ng/mL 4644.9 3729.2 4271.1
LBQ657 Unit Mean Mean Mean
AUC last h*ng/mL 4002.5 3473.5 3827.8
备注：LBQ657为沙库巴曲活性代谢产物，*2为2片。
从上述实验结果可见，在本发明处方中，当复合物 a在药物组合物中为60mg或者120mg时，选择微晶纤维素和乳糖作为支持剂的情况下，优选低取代羟丙纤维素和交联聚维酮的组合，其溶出效果优于交联羧甲基纤维素钠、低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠单一使用或者其他比例组合；并且从批次305、306和实施例9、11的对比结果，优选低取代羟丙纤维素和交联聚维酮质量比为1.75-2.25:1，更优选2:1。
a表示所述复合物的用量以无水游离酸C 46H 50ClN 7O 7计
对比实施例4
采用以下处方与实施例9通过猴pK实验发现，其体内代谢物的效果AUC last接近，可以有效保证相应药效。
实验处方及结果如下：
Figure PCTCN2021100465-appb-000038
动物(猴)体内pk数据
Figure PCTCN2021100465-appb-000039
备注：LBQ657为沙库巴曲活性代谢产物，*4为4片。
动物的体内PK数据结果表明，401批EXP3174暴露量和4片实施例9工艺60mg样品更接近。
对比实施例5
实验处方及结果如下：
  402 比例％ 403 比例％
实施例3复合物 266.4 52.35 266.4 52.35
微晶纤维素 83 16.31 83 16.31
无水乳糖 53 10.41 53 10.41
羧甲淀粉钠 27 5.31 / /
交联羧甲基纤维素钠 33 6.48 / /
交联聚维酮 33 6.48 33 6.48
低取代羟丙纤维素 / / 60 11.79
二氧化硅 8 1.57 8 1.57
硬脂酸镁 5.5 1.08 5.5 1.08
Figure PCTCN2021100465-appb-000040
综合对比实施例4和5的效果，基于实施例14和15(批次401)、以及402和403的处方，本发明申请人研究发现，当复合物 a在药物组合物中为240mg，微晶纤维素和乳糖的1.8：1-2.2：1(具体如1.9：1，2：1，2.1：1)时，优选含有羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮，羧甲淀粉钠在药物组合物中使用量为8-12％，交联羧甲基纤维素钠在药物组合物中使用量为优选8-12％，交联聚维酮在药物组合物中使用量为8-12％，相对于选择其他比例的羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮的组合，或者交联聚维酮和低取代羟丙纤维素的组合，以及在此基础上微晶纤维素和乳糖的其他比例，难以达到相应的溶出，预期难以达到相应的体内溶出效果。
a表示所述复合物的用量以无水游离酸C 46H 50ClN 7O 7计
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (16)

  1. 一种复合物药物组合物，其特征在于，所述复合物的结构单元如下：
    (aEXP3174·bAHU377)·xCa·nA
    其中a:b＝1:0.25～4；x为0.5～3之间的数值；A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-叔-丁基醚、乙腈、甲苯、二氯甲烷；n为0～3之间的数值；
    所述药物组合物中含有低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠、交联羧甲基纤维素钠、预胶化淀粉中的一种或者两种以上任意比例的混合物，在药物组合物中使用量为4％-50％；和一种以上的其他辅料。
  2. 根据权利要求1所述的一种复合物药物组合物，其特征在于，所述药物组合物中含有低取代羟丙纤维素和交联聚维酮，低取代羟丙纤维素在药物组合物中使用量为17％-30％，交联聚维酮在药物组合物中使用量为8％-20％；或者所述药物组合物中含有羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮，羧甲淀粉钠在药物组合物中使用量为4％-12％，交联羧甲基纤维素钠在药物组合物中使用量为4％-12％，交联聚维酮在药物组合物中使用量为4％-12％。
  3. 根据权利要求2所述的一种复合物药物组合物，其特征在于，低取代羟丙纤维素和交联聚维酮的比例为1：1-3：1，二者重量之和优选在药物组合物中使用量为25％-40％；或者羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮三者重量之和在药物组合物中使用量为15％-35％。
  4. 根据权利要求3所述的一种复合物药物组合物，其特征在于，当复合物在药物组合物中的比例为25％-30％，优选低取代羟丙纤维素和交联聚维酮的比例为1.75：1-2.25：1，更优选2：1；或者当复合物在药物组合物中的比例为40％-50％，所述药物组合物中含有羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮，羧甲淀粉钠在药物组合物中使用量为8-12％，交联羧甲基纤维素钠在药物组合物中使用量为优选8-12％，交联聚维酮在药物组合物中使用量为8-12％。
  5. 根据权利要求1-4任一权利要求所述的一种复合物药物组合物，其特征在于，所述一种以上的其他辅料包括一种以上的填充剂、润滑剂和包衣剂；
    所述填充剂包括微晶纤维素、乳糖、甘露醇、磷酸氢钙一种或者两种以上任意比例的混合物，使用量为药物组合物重量的16％-60％；
    所述润滑剂包括二氧化硅，硬脂酸，硬脂酸镁、聚乙二醇、氢化蓖麻油中的一种或者两种以上的混合物，所述润滑剂的质量为药物组合物重量的1％-3％；
    所述包衣剂包括胃溶型包衣剂。
  6. 根据权利要求5所述的一种复合物药物组合物，其特征在于，所述填充剂包括微晶纤维素和乳糖的混合物，微晶纤维素和乳糖的质量比为1：1-5：1，微晶纤维素和乳糖的总质量为药物组合物重量的16％-60％。
  7. 根据权利要求5所述的一种复合物药物组合物，其特征在于，当复合物在药物组合物中的比例为25％-30％，所述微晶纤维素和乳糖的质量比为1.5：1-5：1，优选微晶纤维素和乳糖的总质量为药物组合物重量的17％-45％。
  8. 根据权利要求5所述的一种复合物药物组合物，其特征在于，当复合物在药物组合物中的比例为40％-50％，所述微晶纤维素和乳糖的质量比为1.8：1-2.2：1，优选微晶纤维素和 乳糖的总质量为药物组合物重量的17％-45％。
  9. 根据权利要求1-8任一权利要求所述的一种复合物药物组合物，其特征在于，所述复合物(以无水游离酸C 46H 50ClN 7O 7计)的质量为药物组合物重量的20％-50％。
  10. 根据权利要求1-8任一权利要求所述的一种复合物药物组合物，其特征在于，所述复合物(以无水游离酸C 46H 50ClN 7O 7计)的使用量为30mg、60mg、90mg、120mg、150mg、180mg、210mg、240mg、270mg、300mg。
  11. 根据权利要求1-10任一权利要求所述的一种复合物药物组合物，其特征在于，所述药物组合物是适于口服的固体制剂，优选口服的片剂或胶囊。
  12. 根据权利要求1-11任一权利要求所述的一种复合物药物组合物，其特征在于，a：b的值包括1：0.25，1：0.5，1：1，1：1.5，1：2，1：2.5，1：3，1：3.5，1：4；
    进一步优选所述复合物的结构单元如下：
    (EXP3174·AHU377)·xCa·nH 2O
    或者
    Figure PCTCN2021100465-appb-100001
    其中x为0.5～2之间的数值；n为0～3之间的数值；进一步优选x包括0.5、1、1.5、2。
  13. 根据权利要求1-11任一权利要求所述的一种复合物药物组合物，其特征在于，所述复合物的结构单元如下：
    (EXP3174·AHU377)·1.5Ca·nH 2O
    或者
    (EXP3174·AHU377)·2Ca·nH 2O
    其中n为1～3之间的任意数值，进一步优选：n包括0.5、1、1.5、2、2.5、3。
  14. 根据权利要求1-11任一权利要求所述的一种复合物药物组合物，其特征在于，所述复合物包括：
    (EXP3174·AHU377)·1.5Ca·1H 2O；
    (EXP3174·AHU377)·1.5Ca·1.5H 2O；
    (EXP3174·AHU377)·1.5Ca·2H 2O；
    (EXP3174·AHU377)·1.5Ca·2.5H 2O；
    (EXP3174·AHU377)·1.5Ca·3H 2O；
    (EXP3174·AHU377)·2Ca·1H 2O；
    (EXP3174·AHU377)·2Ca·1.5H 2O；
    (EXP3174·AHU377)·2Ca·2H 2O；
    (EXP3174·AHU377)·2Ca·2.5H 2O；
    (EXP3174·AHU377)·2Ca·3H 2O。
  15. 根据权利要求1-11任一权利要求所述的一种复合物药物组合物，其特征在于，所述药物组合物采用直压工艺，或者干法制粒工艺制备。
  16. 种药物组合物的用途，其特征在于，根据权利要求1-15任一项所述的药物组合物在制备预防和/或治疗高血压、心衰、高血压和心衰的药物中的应用。
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