WO2021254409A1 - Composition pharmaceutique de complexe et son procédé de préparation - Google Patents

Composition pharmaceutique de complexe et son procédé de préparation 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
Prior art date
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PCT/CN2021/100465
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English (en)
Chinese (zh)
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 CN202180004442.1A priority Critical patent/CN114096530B/zh
Priority to CN202211269494.4A priority patent/CN116036079A/zh
Publication of WO2021254409A1 publication Critical patent/WO2021254409A1/fr

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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.

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Abstract

La présente invention appartient au domaine technique des préparations médicinales, concerne une composition pharmaceutique d'un complexe et son procédé de préparation, et concerne en particulier une composition pharmaceutique d'un complexe d'un métabolite antagoniste du récepteur de l'angiotensine II et d'un inhibiteur de NEP et un procédé de préparation associé.
PCT/CN2021/100465 2020-06-18 2021-06-17 Composition pharmaceutique de complexe et son procédé de préparation WO2021254409A1 (fr)

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WO2024027779A1 (fr) * 2022-08-04 2024-02-08 深圳信立泰药业股份有限公司 Nouvelle forme cristalline de composé arni, son procédé de préparation et son utilisation

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CN115444829B (zh) * 2022-10-25 2023-08-22 南京康川济医药科技有限公司 一种沙库巴曲缬沙坦钠胃滞留缓释片及其制备方法

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WO2020238885A1 (fr) * 2019-05-30 2020-12-03 深圳信立泰药业股份有限公司 Procédé de traitement de complexe d'un métabolite antagoniste du récepteur de l'angiotensine ii et d'un inhibiteur de nep

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WO2007056546A1 (fr) * 2005-11-09 2007-05-18 Novartis Ag Combinaison pharmaceutiques d'un antagoniste de recepteur d'angiotensine et d'un inhibiteur de nep
CN105503760A (zh) * 2014-10-10 2016-04-20 上海翰森生物医药科技有限公司 结晶型ARB-NEPi双阳离子复合物及其制备方法和应用
CN110801452A (zh) * 2015-03-12 2020-02-18 深圳信立泰药业股份有限公司 一种含有阿利沙坦酯水解产物或其水解产物盐的药物组合物及其用途
CN106146472A (zh) * 2015-04-15 2016-11-23 苏州朗科生物技术有限公司 一种双重作用的阿利沙坦复合物
CN106138041A (zh) * 2015-04-15 2016-11-23 苏州朗科生物技术有限公司 一种双重作用的氯沙坦复合物
CN105669581A (zh) * 2015-11-09 2016-06-15 成都苑东生物制药股份有限公司 一种血管紧张受体拮抗剂和中性内肽酶抑制剂复合物
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WO2024027779A1 (fr) * 2022-08-04 2024-02-08 深圳信立泰药业股份有限公司 Nouvelle forme cristalline de composé arni, son procédé de préparation et son utilisation

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