WO2022247952A1 - Nifedipine-metoprolol sustained-release composition, preparation method therefor and use thereof - Google Patents

Nifedipine-metoprolol sustained-release composition, preparation method therefor and use thereof Download PDF

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WO2022247952A1
WO2022247952A1 PCT/CN2022/095871 CN2022095871W WO2022247952A1 WO 2022247952 A1 WO2022247952 A1 WO 2022247952A1 CN 2022095871 W CN2022095871 W CN 2022095871W WO 2022247952 A1 WO2022247952 A1 WO 2022247952A1
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sustained
nifedipine
metoprolol
pharmaceutically acceptable
coating
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PCT/CN2022/095871
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French (fr)
Chinese (zh)
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郭桢
陈丽娜
陈祖佑
成明轩
谢文凤
王婷婷
应述欢
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上海博志研新药物技术有限公司
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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K9/2072—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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a nifedipine-metoprolol sustained-release composition, a preparation method and application thereof, and belongs to the field of pharmaceutical compositions.
  • Nifedipine chemical name is 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic Acid Dimethyl Ester, molecular formula: C 17 H 18 N 2 O 6 , molecular weight : 346.33500.
  • nifedipine blocks calcium ion channels on the cell membranes of cardiac muscle and vascular smooth muscle cells, inhibits the influx of extracellular calcium ions, thereby dilating vascular smooth muscle and relaxing coronary vessels. Lower blood pressure and improve myocardial blood supply.
  • Nifedipine can inhibit the calcium inflow of sinoatrial node and atrioventricular node at the same time, so that the self-discipline of sinoatrial node decreases, the atrioventricular conduction slows down, and the ventricular rate decreases, so as to reduce myocardial oxygen consumption.
  • calcium channel blockers relax arteries and lower blood pressure, which can reflexively cause heart rate to increase. Clinically, they are not suitable for patients with hypertension complicated with tachyarrhythmia.
  • Metoprolol The chemical name of Metoprolol is 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol, its molecular formula is C 15 H 25 NO 3 , and its molecular weight is: 267.36400.
  • Metoprolol usually uses two salt forms, namely metoprolol succinate and metoprolol tartrate, the latter is more soluble and is usually used in immediate release formulations.
  • Metoprolol succinate is ( ⁇ )1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate(2:1)(salt), and its molecular formula is: C 34 H 56 N 2 O 10 , molecular weight: 652.81600.
  • Metoprolol tartrate chemical name 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L(+)-tartrate, molecular formula : C 34 H 56 N 2 O 12 , molecular weight: 684.81500.
  • metoprolol As a common selective beta 1 receptor blocker, metoprolol has negative cardiac effects, clinically manifested as slowed heart rate, weakened myocardial contractility, decreased cardiac output, decreased blood pressure and myocardial oxygen consumption reduce.
  • Nifedipine is a BCS class II drug with extremely poor water solubility, but metoprolol is a BCS class I drug, resulting in a large difference in solubility and a large difference in release curves between the two drugs, making it difficult to achieve synchronous release.
  • the present invention provides a sustained-release composition, characterized in that, the sustained-release composition comprises:
  • the dissolution release curve of the sustained-release composition has the following characteristics:
  • the dissolution is no more than 10% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is no more than 10% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
  • the dissolution is not less than 70% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 70% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
  • the dissolution release profile of the sustained-release composition has the following characteristics:
  • dissolution is no more than 8% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 8% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
  • the dissolution is not less than 80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 80% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
  • the dissolution release profile of the sustained-release composition has the following characteristics:
  • dissolution is no more than 6% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 6% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
  • the dissolution is not less than 85% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 85% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
  • the dissolution release profile of the sustained release composition has the following characteristics:
  • dissolution is no more than 25% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 25% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
  • the dissolution is not less than 80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 80% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
  • said (i) is selected from nifedipine or a pharmaceutically acceptable salt thereof.
  • said (ii) is selected from metoprolol or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a sustained-release composition, characterized in that, the sustained-release composition comprises:
  • the drug-containing layer tablet core contains pharmaceutical active ingredients and carriers
  • the pharmaceutical active ingredient comprises one or more of nifedipine, its pharmaceutically acceptable salt or solvate, and one of metoprolol, its pharmaceutically acceptable salt or solvate or more.
  • the release composition comprises a drug-containing layer tablet core, or comprises a drug-containing layer tablet core and a booster layer tablet core.
  • the coating film may be selected from functional coating films and/or water-soluble film coatings.
  • the carrier in the drug-containing layer tablet core may be selected from one or more of solubilizers, thickeners, binders, glidants and lubricants.
  • the booster layer tablet core may contain one or more of an osmotic pressure regulator, a swelling agent, a binder, a colorant and a lubricant.
  • the functional coating film is a semi-permeable film.
  • the water-soluble film coating is a stomach-soluble film coating.
  • the pharmaceutically acceptable salt of metoprolol is preferably metoprolol succinate and/or metoprolol tartrate.
  • the total mass percentage content of the nifedipine, its pharmaceutically acceptable salts and solvates may be 1% to 1%. 30%, such as 5%-22%, and its examples can be 8.57%, 9.09%, 12.00%, 12.60%, 13.20% or 21.43%.
  • the total mass percentage content of metoprolol, its pharmaceutically acceptable salts and solvates can be 1 % ⁇ 15%, such as 2% ⁇ 10%, its example can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% %, 13%, 14% or 15%.
  • the drug-containing layer tablet core contains metoprolol succinate or metoprolol tartrate, based on the mass of metoprolol succinate or metoprolol tartrate, it is included in the drug-containing layer tablet
  • the mass percentage content in the core can be 4.99%, 7.20%, 9.98%, 13.57%, 14.29%, 19.00%, 19.95%, 20.90% or 22.62%.
  • the solubilizing agent in the drug-containing layer tablet core, can be a conventional surfactant with solubilizing effect in the art, preferably sodium lauryl sulfate and Tween 80 one or more of .
  • the mass percentage content of the solubilizer may be 1% to 15%, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10.00%, 11%, 12%, 13%, 14% or 15%.
  • the thickener in the drug-containing layer tablet core, can be a conventional one in the art that can increase the viscosity of the dispersion medium to reduce the particle size.
  • the settling speed or the additive for increasing the hydrophilicity of the microparticles is preferably one or more of polyoxyethylene, hypromellose, hydroxyethylcellulose, copovidone, gum arabic, polyvinylpyrrolidone and sodium alginate.
  • the mass percent content of the thickener may be 1% to 85%, such as 1% to 80%, and its examples may be 71.43%, 5.43% %, 57.14%, 19.71%, 74.29%, 1.86%, 59.40%, 7.60%, 76.95%, 5.76%, 52.38%, 2.38%, 58.00%, 9.00%, 52.80%, 13.20%, 49.50%, 16.50%, 44.50%, 11.50%, 47.95%, 46.40%, 36.29%, 48.03%, 53.90%, 19.18%, 44.88%, 20.52%, or 49.17%.
  • the binder in the drug-containing layer tablet core, can be a conventional substance in the art that can be dissolved in a solvent to produce viscosity, preferably copovidone, polyvinylpyrrolidone, pre- One or more of gelatinized starch and hydroxypropyl cellulose.
  • the mass percent content of the binder may be 2% to 15%, such as 5% to 10%, and its examples may be 8.66%, 6.90% %, 6.02%, 7.37%, or 6.72%.
  • the glidant in the drug-containing layer tablet core, can be a conventional excipient in the art that can reduce the friction between particles and improve the fluidity of powder or granules, preferably talc One or more of powder, micropowder silica gel, colloidal silicon dioxide.
  • the mass percentage content of the glidant may be 0.10%-5.00%, such as 0.50%-2.00%, and an example may be 1.00%.
  • the lubricant in the drug-containing layer tablet core, may be a conventional substance with a lubricating effect in the art, preferably metal stearate, stearic acid, talcum powder, hard One or more of fatty acid ester, stearyl fumarate and micropowder silica gel.
  • metal stearate is preferably magnesium stearate and/or calcium stearate.
  • stearic acid ester is preferably glyceryl stearate.
  • Described stearyl fumarate is preferably sodium stearyl fumarate.
  • the mass percentage content of the lubricant may be 0.10% to 10.00%, such as 0.50% to 8.00%, and its examples may be 1.00%, 1.19% , 2.00% or 5.00%.
  • the osmotic pressure regulator in the booster layer tablet core, can be a substance conventional in the art that can regulate osmosis, preferably sodium chloride, potassium chloride, mannitol , sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose and lactose in one or more.
  • the mass percent content of the osmotic pressure regulator may be 5.00% to 50.00%, such as 10.00% to 45.00%, and an example may be 32.29%, 43.71%, 16.14%, 28.00%, 21.52%, 10.76%, 24.21%, 8.07%, 20.00%, 18.50%, or 10.00%.
  • the swelling agent (also used as a thickener, also referred to as a propellant) can be a conventional one in the art that can absorb solvents and change after hydration.
  • the sticky and swollen substance is preferably one or more of carbomer, sodium starch glycolate, hypromellose, gum arabic, sodium alginate and polyoxyethylene.
  • the mass percentage content of the swelling agent may be 5.00% to 75.00%, such as 9.00% to 70.00%, and its examples may be 65.71%, 54.29% , 65.72%, 70.00%, 39.00%, 29.25%, 9.75%, 50.00%, 10.00%, 58.00%, 29.00%, 43.50%, or 24.00%.
  • the binder in the booster layer tablet core, can be a conventional substance in the art that can be dissolved in a solvent to generate viscosity, preferably copovidone, polyvinylpyrrolidone, hydroxyl One or more of ethyl cellulose.
  • the mass percentage content of the binder may be 1.00%-10.00%, for example 3.00%-8.00%, and an example may be 5.00%.
  • the coloring agent in the booster layer tablet core, may be a conventional substance in the art that can achieve the purpose of coloring, preferably red iron oxide and/or iron oxide yellow.
  • the mass percentage content of the colorant may be 0.10%-5.00%, such as 0.50%-2.00%, and an example may be 1.00%.
  • the lubricant in the booster layer tablet core, may be a conventional substance with a lubricating effect in the art, preferably metal stearate, stearic acid, talcum powder, hard One or more of fatty acid ester, stearyl fumarate and micropowder silica gel.
  • metal stearate is preferably magnesium stearate and/or calcium stearate.
  • stearic acid ester is preferably glyceryl stearate.
  • Described stearyl fumarate is preferably sodium stearyl fumarate.
  • the mass percentage content of the lubricant may be 0.10% to 5.00%, such as 0.50% to 2.00%, and its example may be 1.00% or 2.00%. .
  • the semi-permeable membrane includes one or more of a membrane-forming material, a porogen and a plasticizer.
  • the film-forming material in the functional coating film, can be a conventional material in the art that can be dispersed on a solid surface and solidified to form a film, preferably cellulose acetate, ethyl cellulose , one or more of cellulose acetate phthalate, acrylic resin and methacrylic resin.
  • the porogen in the functional coating film, can be a conventional substance in the art that can make the material pore-forming, preferably polyethylene glycol and/or hydroxypropyl cellulose and/or povidone.
  • the plasticizer in the functional coating film, can be a conventional substance in the art that can increase the plasticity of the polymer, preferably polyethylene glycol, glyceryl triacetate, One or more of glyceryl citrate, glycerides and phthalates.
  • the water-soluble film is a gastric-soluble film coating premix commercially available from Colorcon.
  • the functional coating film of the present invention can also be selected from commercially available cellulose acetate full formula coating premix ( CA).
  • the sustained-release composition of the present invention is dissolved in a 0.5% SDS-pH6.8 phosphate citrate buffer solution with a volume of 900ml, and the dissolution test is carried out at a speed of 50rpm according to the second method of USP. , that is, the 24-hour cumulative release of nifedipine, its pharmaceutically acceptable salt or solvate and metoprolol, its pharmaceutically acceptable salt or solvate can reach more than 85%.
  • the drug-containing layer tablet core can be selected from any of the following formulations:
  • Formula 1 8.57% nifedipine, 13.57% metoprolol succinate, 71.43% polyoxyethylene, 5.43% hypromellose, 1.00% magnesium stearate;
  • Formula 2 8.57% nifedipine, 13.57% metoprolol succinate, 57.14% polyoxyethylene, 19.71% hypromellose, 1.00% magnesium stearate;
  • Formula 3 8.57% nifedipine, 14.29% metoprolol tartrate, 74.29% polyoxyethylene, 1.86% hypromellose, 1.00% magnesium stearate;
  • Formula 4 12.00% nifedipine, 19.00% metoprolol succinate, 59.40% polyoxyethylene, 1.00% colloidal silicon dioxide, 7.60% hypromellose, 1.00% magnesium stearate;
  • Formula 5 9.09% nifedipine, 7.20% metoprolol succinate, 76.95% polyoxyethylene, 5.76% hypromellose, 1.00% magnesium stearate;
  • Formula 6 21.43% nifedipine, 22.62% metoprolol succinate, 52.38% polyoxyethylene, 2.38% hypromellose, 1.19% magnesium stearate;
  • Formula 7 12.00% nifedipine, 19.00% metoprolol succinate, 58.00% povidone, 1.00% colloidal silicon dioxide, 9.00% copovidone, 1.00% magnesium stearate;
  • Formula 8 12.00% nifedipine, 19.00% metoprolol succinate, 52.80% copovidone, 13.20% hydroxyethyl cellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate;
  • Formula 9 12.00% nifedipine, 19.00% metoprolol succinate, 49.50% copovidone, 16.50% hydroxyethylcellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate;
  • Formulation 10 12.00% nifedipine, 19.00% metoprolol succinate, 44.50% copovidone, 11.50% hydroxyethyl cellulose, 10.00% sodium lauryl sulfate, 1.00% colloidal silicon dioxide, 2.00% Sodium stearyl fumarate;
  • Formula 11 12.60% nifedipine, 19.95% metoprolol succinate, 47.95% copovidone, 16.50% hydroxyethylcellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate (remarks: Both nifedipine and metoprolol succinate were fed in excess, and were fed according to 105% of the labeled amount);
  • Formula 12 13.20% nifedipine, 20.90% metoprolol succinate, 46.40% copovidone, 16.50% hydroxyethyl cellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate (remarks: Both nifedipine and metoprolol succinate were fed in excess, and were fed according to 110% of the marked amount);
  • Formula 13 12.60% nifedipine, 19.95% metoprolol succinate, 8.66% copovidone (internal addition), 16.50% hydroxyethylcellulose, 36.29% copovidone (external addition), 1.00% colloidal dioxide Silicon, 5.00% sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate were fed in excess, and were fed according to 105% of the labeled amount);
  • Formula 14 12.60% nifedipine, 9.98% metoprolol succinate, 6.90% copovidone (internal addition), 16.50% hydroxyethylcellulose, 48.03% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount);
  • Formula 15 12.60% nifedipine, 4.99% metoprolol succinate, 6.02% copovidone (internal addition), 16.50% hydroxyethylcellulose, 53.90% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount);
  • Formula 16 12.60% nifedipine, 9.98% metoprolol succinate, 7.37% copovidone (internal addition), 19.18% hydroxyethylcellulose, 44.88% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount);
  • Formula 17 12.60% nifedipine, 4.99% metoprolol succinate, 6.72% copovidone (internal addition), 20.52% hydroxyethylcellulose, 49.17% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount).
  • the booster layer tablet core can be selected from any of the following prescriptions:
  • Prescription 1 65.71% polyoxyethylene, 32.29% sodium chloride, 1.00% iron oxide red, 1.00% magnesium stearate;
  • Prescription 2 54.29% polyoxyethylene, 43.71% sorbitol, 1.00% iron oxide red, 1.00% magnesium stearate;
  • Prescription 3 65.71% polyoxyethylene, 16.14% sorbitol, 16.14% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
  • Prescription 4 65.72% polyoxyethylene, 16.14% sorbitol, 16.14% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
  • Prescription 5 70.00% polyoxyethylene, 28.00% sodium chloride, 1.00% iron oxide red, 1.00% magnesium stearate;
  • Prescription 6 65.72% polyoxyethylene, 21.52% sorbitol, 10.76% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
  • Prescription 7 65.72% polyoxyethylene, 24.21% sorbitol, 8.07% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
  • Prescription 8 39.00% sodium starch glycolate, 29.25% hypromellose, 9.75% carbomer, 20.00% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
  • Prescription 9 50.00% polyoxyethylene, 10.00% carbomer, 18.50% sorbitol, 18.50% sodium chloride, 1.00% red iron oxide, 2.00% sodium stearyl fumarate;
  • Prescription 10 58.00% polyoxyethylene, 29.00% hypromellose, 10.00% sodium chloride, 1.00% red iron oxide, 2.00% sodium stearyl fumarate;
  • Prescription 11 43.50% polyoxyethylene, 43.50% hypromellose, 10.00% sodium chloride, 1.00% red iron oxide, 2.00% sodium stearyl fumarate;
  • Prescription 12 58.00% polyoxyethylene, 24.00% hypromellose, 10.00% sodium chloride, 5.00% copovidone, 1.00% red iron oxide, 2.00% sodium stearyl fumarate.
  • the dissolution release profile of the sustained release composition has the characteristics described above.
  • the present invention also provides a preparation method of the sustained-release composition, comprising the steps of:
  • the nifedipine-metoprolol sustained-release composition can be obtained by wrapping it with a common film coat.
  • the preparation method may include the following steps:
  • Step 2) sieving and mixing the ingredients in the booster layer tablet core except the lubricant, and then mixing with the lubricant to obtain the booster layer mixture;
  • Step 3) compressing the drug-containing layer mixture obtained in step 1) and the booster layer mixture obtained in step 2) to obtain a double-layer tablet core;
  • Step 4) coating and aging the double-layer tablet core obtained in step 3) to obtain a coated tablet;
  • Step 5) The coated tablets obtained in step 4) are sequentially punched and film-coated to obtain nifedipine-metoprolol sustained-release tablets.
  • the sieving can be a 30-mesh sieve.
  • step 1) and step 2) the mixing can be carried out in a mixer, such as a mixing tank.
  • the mixing frequency may be 30 Hz
  • the mixing time may be 1 minute to 2 hours, such as 5 minutes or 15 minutes.
  • the coating is preferably coated with a weight gain of 6% to 20%, and the percentage refers to (the weight of the nifedipine metoprolol coated tablet-the weight of the double-layer tablet core)/double The weight of the ply core*100%.
  • the aging temperature is preferably 20°C to 60°C, for example 40°C.
  • the aging time is preferably 10 hours to 30 hours, such as 20 hours.
  • the perforation can be perforated at the center of the drug-containing surface.
  • the hole diameter of the perforated holes may be 0.4mm-1.0mm.
  • the preferred coating weight gain of the coating is 2% to 10%, and the percentage refers to (the weight of the nifedipine metoprolol sustained-release tablet-the weight of the film-coated front tablet)/ The weight of the film-coated front tablet*100%.
  • Step 1) Sieve together the fluidized granulation internally added excipients in the drug-containing layer tablet core, premix, fluidize granulate, granulate, convert and add all external excipients except lubricant to continue mixing, convert and adding a lubricant for total mixing to obtain a drug-containing layer mixture;
  • Step 2) Screening and/or pre-mixing, fluidizing granulation, sizing, converting the amount of all external excipients except lubricant in the core of the booster layer, and jointly sieving the external excipients Finally, add the granulated materials and mix together, convert and add a lubricant for total mixing to obtain the booster layer mixture;
  • Step 3) compressing the drug-containing layer mixture obtained in step 1) and the booster layer mixture obtained in step 2) to obtain a double-layer tablet core;
  • Step 4) coating and aging the double-layer tablet core obtained in step 3) to obtain a coated tablet;
  • Step 5) The coated tablets obtained in step 4) are sequentially punched and film-coated to obtain nifedipine-metoprolol sustained-release tablets.
  • the sieving can be 45 mesh and/or 40 mesh sieve.
  • the sieving can be a 30-mesh sieve.
  • step 1) and step 2) the mixing can be carried out in a mixer, such as a mixing tank.
  • the mixing frequency may be 30 Hz or 50 Hz, and the mixing time may be 1 minute to 2 hours, such as 5 minutes, 10 minutes, 20 minutes, 25 minutes or 40 minutes.
  • the preferred coating weight gain of the coating is 6% to 20%, and the percentage refers to (the weight of the nifedipine metoprolol coated tablet-the weight of the double-layer tablet core)/double The weight of the ply core*100%.
  • the aging temperature is preferably 20°C to 60°C, for example 40°C.
  • the aging time is preferably 10 hours to 30 hours, such as 16 hours.
  • the perforation can be perforated at the center of the drug-containing surface.
  • the hole diameter of the perforated holes may be 0.4mm-1.0mm.
  • the preferred coating weight gain of the coating is 2% to 10%, and the percentage refers to (the weight of the nifedipine metoprolol sustained-release tablet-the weight of the film-coated front tablet)/ The weight of the film-coated front tablet*100%.
  • the present invention also provides a sustained-release preparation comprising the above-mentioned sustained-release composition.
  • the sustained-release preparation may be a sustained-release tablet.
  • the present invention also provides the application of the sustained-release composition or sustained-release preparation in the preparation of medicine, wherein the medicine is used for preventing and/or treating hypertension or its related symptoms, such as arrhythmia or angina pectoris.
  • the present invention also provides a method for preventing and/or treating hypertension or its related symptoms, such as arrhythmia or angina pectoris, comprising administering a therapeutically effective amount of the sustained-release composition or sustained-release preparation to a patient in need.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the sustained-release composition of the present invention overcomes the huge difference in solubility of the two drugs of nifedipine, its pharmaceutically acceptable salt or solvate and metoprolol, its pharmaceutically acceptable salt or solvate, Using the release mechanism of single-chamber double-layer osmotic pump, two antihypertensive drugs with complementary action mechanisms are prepared into a once-a-day long-acting compound preparation, so that the two drugs can achieve long-acting synchronous release, and the 24-hour cumulative release of the two drugs All can reach more than 85%. Moreover, the preparation process of the sustained-release composition of the present invention is stable, the production is convenient, and it is beneficial to industrialized production.
  • Fig. 1 shows in 0.5%SDS-pH6.8 phosphate citrate buffer solution, the stripping curve figure of nifedipine in the prescription of embodiment II-1 ⁇ embodiment II-15;
  • Fig. 2 shows in 0.5%SDS-pH6.8 phosphate citrate buffer solution, the stripping profile of metoprolol succinate in the prescription of embodiment II-1 ⁇ embodiment II-15;
  • Fig. 3 shows in the pharmacokinetic evaluation test of the beagle dog oral administration of embodiment II-16, the blood drug concentration-time graph of nifedipine;
  • Fig. 4 shows the blood drug concentration-time curve of metoprolol succinate in the pharmacokinetic evaluation test of oral administration to beagle dogs of Example II-16.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 6% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 20 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, and the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer or 0.75% SDS-pH6. 8 phosphate citrate buffer solution, the rotating speed is 50rpm to measure, and the release results in vitro are as follows:
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 20%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 3% to 8%.
  • Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, and the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer or 0.75% SDS-pH6. 8 phosphate citrate buffer solution, the rotating speed is 50rpm to measure, and the release results in vitro are as follows:
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • Sorbitol is pretreated through a 30-mesh sieve for subsequent use, and sodium chloride is pretreated through an 80-mesh sieve for subsequent use.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, and the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer or 0.75% SDS-pH6. 8 phosphate citrate buffer solution, the rotating speed is 50rpm to measure, and the release results in vitro are as follows:
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • Sorbitol is pretreated through a 30-mesh sieve for subsequent use
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 10%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 24 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 10%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 6% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 6% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Example I-7 From the results of Example I-1 to Example I-7, it can be seen that in the in vitro dissolution of the sustained-release tablet of the present invention, the two raw materials can achieve long-acting synchronous release, meeting the requirement of once-a-day administration.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 210 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 18 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 800 tablets.
  • the sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
  • the sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
  • the sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
  • the sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
  • the sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is dried and aged in a blast drying oven at 40°C for about 16 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Example II-10 scale up the batch to 10,000 pieces for production and preparation.
  • the plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 10% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
  • the perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
  • Reference Example 1 One-time imported commercially available nifedipine controlled-release tablets (30 mg specification) were used as the control drug, and the licensed manufacturer was Bayer Pharma AG/Bayer AG.
  • Reference example 2 One-time imported commercially available metoprolol succinate sustained-release tablets (47.5 mg specification) were used as the control drug, and the licensed manufacturer was AstraZeneca AB.
  • nifedipine metoprolol pharmaceutical composition of embodiment II-15 gained and the nifedipine controlled-release tablet of reference example 1 and the metoprolol succinate sustained-release tablet of reference example 2 to carry out oral administration to beagle dogs A comparative study of drug pharmacokinetic evaluation tests.
  • a total of 6 Beagle dogs were used in the test, half male and half male, and divided into 2 groups according to gender, with 3 dogs in each group.
  • the first group and the second group were orally administered with 1 tablet of the self-made preparation of Example II-15 and 2 tablets of the reference preparation. (reference example 1+reference example 2 each 1 tablet, single administration), after the 7-day washout period at intervals, the first group and the second group in the second cycle were orally given 2 tablets of the reference preparation respectively (reference example 1+reference Example 2 each 1 tablet, single administration) and Example II-15 self-made preparation 1 tablet, plasma was collected after administration according to the set time points.
  • sampling time points of the two groups in the two cycles are 0.5hr, 1hr, 1.5hr, 2hr, 3hr, 4hr, 5hr, 6hr, 8hr, 12hr, 16hr, 24hr, 36hr and 48hr after administration, a total of 14 time points;
  • test results suggest that there is no significant difference (P>0.05) in the pharmacokinetic parameters between the self-made preparation of Example II-15 and the 2 tablets of the reference preparation (reference example 1 + reference example 2 each 1 tablet, single administration).
  • Embodiment II-1 ⁇ embodiment II-15 is shown in Fig. 1 and Fig. 2 in the stripping curve figure in 0.5%SDS-pH6.8 phosphate citrate buffer solution; Kinetic evaluation test results are shown in Table 1 and Table 2; the pharmacokinetic evaluation test plasma concentration-time curves of Beagle dog oral administration are shown in Fig. 3 and Fig. 4; The pharmacokinetics of Beagle dog oral administration The T-test results of the pharmacokinetic parameters of the pharmacokinetic evaluation test are shown in Table 3 and Table 4.
  • Table 1 The average pharmacokinetic parameters of metoprolol after oral administration of embodiment II-15 preparation and reference preparation in Beagle dogs
  • Table 2 The average pharmacokinetic parameters of nifedipine after Beagle dog oral administration embodiment II-15 preparation and reference preparation
  • embodiment I-1 ⁇ embodiment I-7 and embodiment II-1 ⁇ embodiment II-16 result as seen, in in vitro dissolution, in nifedipine succinic acid/metoprolol tartrate slow-release tablet of the present invention
  • the two APIs can achieve long-acting synchronous release, meeting the requirement of once-a-day dosing.
  • Tmax of the currently commercially available reference preparation Nifedipine Sustained-release Tablets and Metoprolol Succinate Sustained-release Tablets is quite different, while the two components of Example II-15 are close to Tmax in Beagle dogs, A significant synchronous sustained-release effect has been achieved.

Abstract

Disclosed are a nifedipine-metoprolol sustained-release composition, a preparation method therefor and the use thereof. The sustained-release composition overcomes the huge differences in the solubility of the two drugs of nifedipine, a pharmaceutically acceptable salt or solvate thereof, and metoprolol, a pharmaceutically acceptable salt or solvate thereof, the two antihypertensive drugs with complementary action mechanisms are prepared into a daily long-acting compound preparation by means of a single-chamber double-layer osmotic pump drug release mechanism, so that the two drugs achieve long-acting synchronous release, and the 24-hour cumulative release degree of the two drugs can reach at least 85%. The sustained-release composition has a stable preparation process, convenience in terms of production and a conduciveness to industrial production.

Description

硝苯地平美托洛尔缓释组合物、其制备方法及应用Nifedipine and metoprolol sustained-release composition, its preparation method and application
本申请要求享有申请人2021年5月28日向中国国家知识产权局提交的申请号为202110594245.1的在先中国专利申请的优先权权益。上述在先申请的全文以引用的方式结合至本申请中。This application claims the priority of the prior Chinese patent application with application number 202110594245.1 submitted by the applicant to the State Intellectual Property Office of China on May 28, 2021. The entirety of the aforementioned prior application is incorporated into the present application by reference.
技术领域technical field
本发明涉及硝苯地平美托洛尔缓释组合物、其制备方法及应用，属于药物组合物领域。The invention relates to a nifedipine-metoprolol sustained-release composition, a preparation method and application thereof, and belongs to the field of pharmaceutical compositions.
背景技术Background technique
硝苯地平(Nifedipine)化学名为1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic Acid Dimethyl Ester，分子式：C 17H 18N 2O 6，分子量：346.33500。作为首个二氢吡啶类钙通道阻滞剂，硝苯地平通过阻断心肌和血管平滑肌细胞膜上的钙离子通道，抑制细胞外钙离子内流，从而扩张血管平滑肌，舒张冠脉血管，起到降压和改善心肌供血的作用。硝苯地平可同时抑制窦房结和房室结的钙内流，使窦房结自律性下降，房室传导减慢，心室率降低，以降低心肌氧耗。钙通道阻滞剂在降压过程中，舒张动脉血管降低血压，可反射性引起心率加快，临床上不适用于高血压合并快速心率失常患者。 Nifedipine chemical name is 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic Acid Dimethyl Ester, molecular formula: C 17 H 18 N 2 O 6 , molecular weight : 346.33500. As the first dihydropyridine calcium channel blocker, nifedipine blocks calcium ion channels on the cell membranes of cardiac muscle and vascular smooth muscle cells, inhibits the influx of extracellular calcium ions, thereby dilating vascular smooth muscle and relaxing coronary vessels. Lower blood pressure and improve myocardial blood supply. Nifedipine can inhibit the calcium inflow of sinoatrial node and atrioventricular node at the same time, so that the self-discipline of sinoatrial node decreases, the atrioventricular conduction slows down, and the ventricular rate decreases, so as to reduce myocardial oxygen consumption. In the process of lowering blood pressure, calcium channel blockers relax arteries and lower blood pressure, which can reflexively cause heart rate to increase. Clinically, they are not suitable for patients with hypertension complicated with tachyarrhythmia.
美托洛尔(Metoprolol)化学名为1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol，分子式：C 15H 25NO 3，分子量为：267.36400。美托洛尔通常使用两种盐型，即琥珀酸美托洛尔和酒石酸美托洛尔，后者溶解度较大，通常用于速释制剂中。琥珀酸美托洛尔(Metoprolol succinate)化学名为(±)1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate(2:1)(salt),分子式：C 34H 56N 2O 10，分子量：652.81600。酒石酸美托洛尔(Metoprolol tartrate)，化学名为1-异丙氨基-3-[对-(2-甲氧乙基)苯氧基]-2-丙醇L(+)-酒石酸盐，分子式：C 34H 56N 2O 12，分子量：684.81500。 The chemical name of Metoprolol is 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol, its molecular formula is C 15 H 25 NO 3 , and its molecular weight is: 267.36400. Metoprolol usually uses two salt forms, namely metoprolol succinate and metoprolol tartrate, the latter is more soluble and is usually used in immediate release formulations. The chemical name of Metoprolol succinate is (±)1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate(2:1)(salt), and its molecular formula is: C 34 H 56 N 2 O 10 , molecular weight: 652.81600. Metoprolol tartrate, chemical name 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L(+)-tartrate, molecular formula : C 34 H 56 N 2 O 12 , molecular weight: 684.81500.
美托洛尔作为一种常见的选择性β 1受体阻断剂，具有负性心力作用，临床表现为心率减慢，心肌收缩力减弱，心排血量下降，血压降低和心肌氧耗量降低。硝苯地平为BCS II类药物，水溶性极差，但美托洛尔为BCS I类药物，导致两种药物的溶解性差异较大，释放曲线相差很大，很难达到同步释放。 As a common selective beta 1 receptor blocker, metoprolol has negative cardiac effects, clinically manifested as slowed heart rate, weakened myocardial contractility, decreased cardiac output, decreased blood pressure and myocardial oxygen consumption reduce. Nifedipine is a BCS class II drug with extremely poor water solubility, but metoprolol is a BCS class I drug, resulting in a large difference in solubility and a large difference in release curves between the two drugs, making it difficult to achieve synchronous release.
因此，寻找临床效果好、副作用小、高血压患者顺应性好的包含硝苯地平和美托洛尔的药物剂型是目前急需解决的技术问题。Therefore, finding a pharmaceutical dosage form containing nifedipine and metoprolol with good clinical effect, few side effects, and good compliance of hypertensive patients is an urgent technical problem to be solved at present.
发明内容Contents of the invention
本发明提供了一种缓释组合物，其特征在于，所述缓释组合物包含：The present invention provides a sustained-release composition, characterized in that, the sustained-release composition comprises:
(i)硝苯地平、其药学上可接受的盐或溶剂合物中的一种或多种；和(i) one or more of nifedipine, its pharmaceutically acceptable salt or solvate; and
(ii)美托洛尔、其药学上可接受的盐或溶剂合物中的一种或多种；(ii) one or more of metoprolol, its pharmaceutically acceptable salt or solvate;
其中，所述缓释组合物的溶出释放曲线具有以下特征：Wherein, the dissolution release curve of the sustained-release composition has the following characteristics:
A)在2小时内，溶出不超过10％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过10％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 2 hours, the dissolution is no more than 10% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is no more than 10% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
B)在9小时内，溶出20％～70％所述得硝苯地平、其药学上可接受的盐或溶剂合物，和溶出20％～70％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括20％和70％两个点值；和/或，B) within 9 hours, dissolve 20%～70% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 20%～70% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 20% and 70%; and/or,
C)在24小时内，溶出均不低于70％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不低于70％所述的美托洛尔、其药学上可接受的盐或溶剂合物。C) within 24 hours, the dissolution is not less than 70% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 70% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
根据本发明优选的实施方案，所述缓释组合物的溶出释放曲线具有以下特征：According to a preferred embodiment of the present invention, the dissolution release profile of the sustained-release composition has the following characteristics:
A)在2小时内，溶出不超过8％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过8％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 2 hours, dissolution is no more than 8% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 8% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
B)在9小时内，溶出25％～65％所述得硝苯地平、其药学上可接受的盐或溶剂合物，和溶出25％～65％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括25％和65％两个点值；和/或，B) within 9 hours, dissolve 25%～65% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 25%～65% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 25% and 65%; and/or,
C)在24小时内，溶出均不低于80％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不低于80％所述的美托洛尔、其药学上可接受的盐或溶剂合物。C) within 24 hours, the dissolution is not less than 80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 80% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
根据本发明优选的实施方案，所述缓释组合物的溶出释放曲线具有以下特征：According to a preferred embodiment of the present invention, the dissolution release profile of the sustained-release composition has the following characteristics:
A)在2小时内，溶出不超过6％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过6％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 2 hours, dissolution is no more than 6% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 6% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
B)在9小时内，溶出30％～60％所述得硝苯地平、其药学上可接受的盐或溶剂合物，和溶出30％～60％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括30％和60％两个点值；和/或，B) within 9 hours, dissolve 30%～60% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 30%～60% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 30% and 60%; and/or,
C)在24小时内，溶出均不低于85％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不低于85％所述的美托洛尔、其药学上可接受的盐或溶剂合物。C) within 24 hours, the dissolution is not less than 85% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 85% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
根据本发明更优选的实施方案，所述缓释组合物的溶出释放曲线具有以下特征：According to a more preferred embodiment of the present invention, the dissolution release profile of the sustained release composition has the following characteristics:
A)在4小时内，溶出不超过25％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过25％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 4 hours, dissolution is no more than 25% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 25% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
B)在12小时内，溶出45％～80％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出45％～80％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括45％和80％两个点值；和/或B) within 12 hours, dissolve 45%～80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 45%～80% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 45% and 80%; and/or
C)在24小时内，溶出均不低于80％所述的硝苯地平、其药学上可接受的盐或溶剂 合物，和溶出不低于80％所述的美托洛尔、其药学上可接受的盐或溶剂合物。C) within 24 hours, the dissolution is not less than 80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 80% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
根据本发明更优选的实施方案，所述(i)选自硝苯地平或其药学上可接受的盐。According to a more preferred embodiment of the present invention, said (i) is selected from nifedipine or a pharmaceutically acceptable salt thereof.
根据本发明更优选的实施方案，所述(ii)选自美托洛尔或其药学上可接受的盐。According to a more preferred embodiment of the present invention, said (ii) is selected from metoprolol or a pharmaceutically acceptable salt thereof.
本发明还提供一种缓释组合物，其特征在于，所述缓释组合物包括：The present invention also provides a sustained-release composition, characterized in that, the sustained-release composition comprises:
含药层片芯和/或助推层片芯，其中在所述含药层片芯的一侧打孔；以及A drug-containing layer core and/or a booster layer core, wherein holes are perforated on one side of the drug-containing layer core; and
包衣膜；Coating film;
所述的含药层片芯包含药物活性成分以及载体；The drug-containing layer tablet core contains pharmaceutical active ingredients and carriers;
所述的药物活性成分包含硝苯地平、其药学上可接受的盐或溶剂合物中的一种或多种，和美托洛尔、其药学上可接受的盐或溶剂合物中的一种或多种。The pharmaceutical active ingredient comprises one or more of nifedipine, its pharmaceutically acceptable salt or solvate, and one of metoprolol, its pharmaceutically acceptable salt or solvate or more.
根据本发明的实施方案，所述释组合物包括含药层片芯，或包括含药层片芯和助推层片芯。According to an embodiment of the present invention, the release composition comprises a drug-containing layer tablet core, or comprises a drug-containing layer tablet core and a booster layer tablet core.
根据本发明的实施方案，所述包衣膜可以选自功能性包衣膜和/或水溶性薄膜衣。According to an embodiment of the present invention, the coating film may be selected from functional coating films and/or water-soluble film coatings.
根据本发明的实施方案，所述含药层片芯中的载体可以选自增溶剂、增稠剂、粘合剂、助流剂和润滑剂中的一种或多种。According to an embodiment of the present invention, the carrier in the drug-containing layer tablet core may be selected from one or more of solubilizers, thickeners, binders, glidants and lubricants.
根据本发明的实施方案，所述的助推层片芯可以包含渗透压调节剂、溶胀剂、粘合剂、着色剂和润滑剂中的一种或多种。According to an embodiment of the present invention, the booster layer tablet core may contain one or more of an osmotic pressure regulator, a swelling agent, a binder, a colorant and a lubricant.
根据本发明的实施方案，所述的功能性包衣膜为半渗透膜。According to an embodiment of the present invention, the functional coating film is a semi-permeable film.
根据本发明的实施方案，所述的水溶性薄膜衣为胃溶型薄膜衣。According to an embodiment of the present invention, the water-soluble film coating is a stomach-soluble film coating.
根据本发明的实施方案，所述的美托洛尔药学上可接受的盐优选琥珀酸美托洛尔和/或酒石酸美托洛尔。According to an embodiment of the present invention, the pharmaceutically acceptable salt of metoprolol is preferably metoprolol succinate and/or metoprolol tartrate.
根据本发明的实施方案，所述的含药层片芯中，以硝苯地平计，所述硝苯地平、其药学上可接受的盐和溶剂合物的总质量百分比含量可以为1％～30％，例如5％～22％，其实例可以为8.57％、9.09％、12.00％、12.60％、13.20％或21.43％。According to an embodiment of the present invention, in the drug-containing layer tablet core, based on nifedipine, the total mass percentage content of the nifedipine, its pharmaceutically acceptable salts and solvates may be 1% to 1%. 30%, such as 5%-22%, and its examples can be 8.57%, 9.09%, 12.00%, 12.60%, 13.20% or 21.43%.
根据本发明的实施方案，所述的含药层片芯中，以美托洛尔计，所述美托洛尔、其药学上可接受的盐和溶剂合物的总质量百分比含量可以为1％～15％，如2％～10％，其实例可以为1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％或15％。According to an embodiment of the present invention, in the drug-containing layer tablet core, based on metoprolol, the total mass percentage content of metoprolol, its pharmaceutically acceptable salts and solvates can be 1 %～15%, such as 2%～10%, its example can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% %, 13%, 14% or 15%.
优选地，当所述含药层片芯中包含琥珀酸美托洛尔或酒石酸美托洛尔时，以琥珀酸美托洛尔或酒石酸美托洛尔的质量计，其在含药层片芯中的质量百分比含量可以为4.99％、7.20％、9.98％、13.57％、14.29％、19.00％、19.95％、20.90％或22.62％。Preferably, when the drug-containing layer tablet core contains metoprolol succinate or metoprolol tartrate, based on the mass of metoprolol succinate or metoprolol tartrate, it is included in the drug-containing layer tablet The mass percentage content in the core can be 4.99%, 7.20%, 9.98%, 13.57%, 14.29%, 19.00%, 19.95%, 20.90% or 22.62%.
根据本发明的实施方案，所述的含药层片芯中，所述的增溶剂可以为本领域中常规的具有增溶作用的表面活性剂，优选十二烷基硫酸钠和吐温80中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the solubilizing agent can be a conventional surfactant with solubilizing effect in the art, preferably sodium lauryl sulfate and Tween 80 one or more of .
根据本发明的实施方案，所述的含药层片芯中，所述的增溶剂的质量百分比含量可以为1％～15％，如1％、2％、3％、4％、5％、6％、7％、8％、9％、10.00％、11％、12％、 13％、14％或15％。According to an embodiment of the present invention, in the drug-containing layer tablet core, the mass percentage content of the solubilizer may be 1% to 15%, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10.00%, 11%, 12%, 13%, 14% or 15%.
根据本发明的实施方案，所述的含药层片芯中，所述的增稠剂(也可以称为混悬剂)可以为本领域中常规的能够增加分散介质的黏度，以降低微粒的沉降速度或增加微粒亲水性的附加剂，优选聚氧乙烯、羟丙甲纤维素、羟乙纤维素、共聚维酮、阿拉伯胶、聚乙烯吡咯烷酮和海藻酸钠中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the thickener (also referred to as a suspending agent) can be a conventional one in the art that can increase the viscosity of the dispersion medium to reduce the particle size. The settling speed or the additive for increasing the hydrophilicity of the microparticles is preferably one or more of polyoxyethylene, hypromellose, hydroxyethylcellulose, copovidone, gum arabic, polyvinylpyrrolidone and sodium alginate.
根据本发明的实施方案，所述的含药层片芯中，所述的增稠剂的质量百分比含量可以为1％～85％，例如1％～80％，其实例可以为71.43％、5.43％、57.14％、19.71％、74.29％、1.86％、59.40％、7.60％、76.95％、5.76％、52.38％、2.38％、58.00％、9.00％、52.80％、13.20％、49.50％、16.50％、44.50％、11.50％、47.95％、46.40％、36.29％、48.03％、53.90％、19.18％、44.88％、20.52％或49.17％。According to the embodiment of the present invention, in the drug-containing layer tablet core, the mass percent content of the thickener may be 1% to 85%, such as 1% to 80%, and its examples may be 71.43%, 5.43% %, 57.14%, 19.71%, 74.29%, 1.86%, 59.40%, 7.60%, 76.95%, 5.76%, 52.38%, 2.38%, 58.00%, 9.00%, 52.80%, 13.20%, 49.50%, 16.50%, 44.50%, 11.50%, 47.95%, 46.40%, 36.29%, 48.03%, 53.90%, 19.18%, 44.88%, 20.52%, or 49.17%.
根据本发明的实施方案，所述的含药层片芯中，所述的粘合剂可以为本领域中常规的能够溶于溶剂中产生粘性的物质，优选共聚维酮、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基纤维素中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the binder can be a conventional substance in the art that can be dissolved in a solvent to produce viscosity, preferably copovidone, polyvinylpyrrolidone, pre- One or more of gelatinized starch and hydroxypropyl cellulose.
根据本发明的实施方案，所述的含药层片芯中，所述的粘合剂的质量百分比含量可以为2％～15％，例如5％～10％，其实例可以为8.66％、6.90％、6.02％、7.37％或6.72％。According to an embodiment of the present invention, in the drug-containing layer tablet core, the mass percent content of the binder may be 2% to 15%, such as 5% to 10%, and its examples may be 8.66%, 6.90% %, 6.02%, 7.37%, or 6.72%.
根据本发明的实施方案，所述的含药层片芯中，所述的助流剂可以为本领域中常规的能够降低粒子间的摩擦力而能改善粉末或颗粒流动性的辅料，优选滑石粉、微粉硅胶、胶态二氧化硅中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the glidant can be a conventional excipient in the art that can reduce the friction between particles and improve the fluidity of powder or granules, preferably talc One or more of powder, micropowder silica gel, colloidal silicon dioxide.
根据本发明的实施方案，所述的含药层片芯中，所述的助流剂的质量百分比含量可以为0.10％～5.00％，例如0.50％～2.00％，其实例可以为1.00％。According to an embodiment of the present invention, in the drug-containing layer tablet core, the mass percentage content of the glidant may be 0.10%-5.00%, such as 0.50%-2.00%, and an example may be 1.00%.
根据本发明的实施方案，所述的含药层片芯中，所述的润滑剂可以为本领域中常规的具有润滑作用的物质，优选硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬脂富马酸盐和微粉硅胶中的一种或多种。所述的硬脂酸金属盐优选硬脂酸镁和/或硬脂酸钙。所述的硬脂酸酯优选硬脂酸甘油酯。所述的硬脂富马酸盐优选硬脂富马酸钠。According to an embodiment of the present invention, in the drug-containing layer tablet core, the lubricant may be a conventional substance with a lubricating effect in the art, preferably metal stearate, stearic acid, talcum powder, hard One or more of fatty acid ester, stearyl fumarate and micropowder silica gel. Described metal stearate is preferably magnesium stearate and/or calcium stearate. Described stearic acid ester is preferably glyceryl stearate. Described stearyl fumarate is preferably sodium stearyl fumarate.
根据本发明的实施方案，所述的含药层片芯中，所述的润滑剂的质量百分比含量可以为0.10％～10.00％，例如0.50％～8.00％，其实例可以为1.00％、1.19％、2.00％或5.00％。According to an embodiment of the present invention, in the drug-containing layer tablet core, the mass percentage content of the lubricant may be 0.10% to 10.00%, such as 0.50% to 8.00%, and its examples may be 1.00%, 1.19% , 2.00% or 5.00%.
根据本发明的实施方案，所述的助推层片芯中，所述的渗透压调节剂可以为本领域中常规的，可以调节渗透作用的物质，优选氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种。According to an embodiment of the present invention, in the booster layer tablet core, the osmotic pressure regulator can be a substance conventional in the art that can regulate osmosis, preferably sodium chloride, potassium chloride, mannitol , sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose and lactose in one or more.
根据本发明的实施方案，所述的助推层片芯中，所述的渗透压调节剂的质量百分比含量可以为5.00％～50.00％，例如10.00％～45.00％，其实例可以为32.29％、43.71％、16.14％、28.00％、21.52％、10.76％、24.21％、8.07％、20.00％、18.50％或10.00％。According to an embodiment of the present invention, in the booster layer tablet core, the mass percent content of the osmotic pressure regulator may be 5.00% to 50.00%, such as 10.00% to 45.00%, and an example may be 32.29%, 43.71%, 16.14%, 28.00%, 21.52%, 10.76%, 24.21%, 8.07%, 20.00%, 18.50%, or 10.00%.
根据本发明的实施方案，所述的助推层片芯中，所述的溶胀剂(同时作为增稠剂，也可以称为推动剂)可以为本领域中常规的能够吸收溶剂水化后变粘并发生膨胀的物质， 优选卡波姆、羧甲淀粉钠、羟丙甲纤维素、阿拉伯胶、海藻酸钠和聚氧乙烯中的一种或多种。According to an embodiment of the present invention, in the booster layer tablet core, the swelling agent (also used as a thickener, also referred to as a propellant) can be a conventional one in the art that can absorb solvents and change after hydration. The sticky and swollen substance is preferably one or more of carbomer, sodium starch glycolate, hypromellose, gum arabic, sodium alginate and polyoxyethylene.
根据本发明的实施方案，所述的助推层片芯中，所述的溶胀剂的质量百分比含量可以为5.00％～75.00％，例如9.00％～70.00％，其实例可以为65.71％、54.29％、65.72％、70.00％、39.00％、29.25％、9.75％、50.00％、10.00％、58.00％、29.00％、43.50％或24.00％。According to an embodiment of the present invention, in the booster layer tablet core, the mass percentage content of the swelling agent may be 5.00% to 75.00%, such as 9.00% to 70.00%, and its examples may be 65.71%, 54.29% , 65.72%, 70.00%, 39.00%, 29.25%, 9.75%, 50.00%, 10.00%, 58.00%, 29.00%, 43.50%, or 24.00%.
根据本发明的实施方案，所述的助推层片芯中，所述的粘合剂可以为本领域中常规的能够溶于溶剂中产生粘性的物质，优选共聚维酮、聚乙烯吡咯烷酮、羟乙纤维素中的一种或多种。According to an embodiment of the present invention, in the booster layer tablet core, the binder can be a conventional substance in the art that can be dissolved in a solvent to generate viscosity, preferably copovidone, polyvinylpyrrolidone, hydroxyl One or more of ethyl cellulose.
根据本发明的实施方案，所述的助推层片芯中，所述的粘合剂的质量百分比含量可以为1.00％～10.00％，例如3.00％～8.00％，其实例可以为5.00％。According to an embodiment of the present invention, in the booster layer core, the mass percentage content of the binder may be 1.00%-10.00%, for example 3.00%-8.00%, and an example may be 5.00%.
根据本发明的实施方案，所述的助推层片芯中，所述的着色剂可以为本领域中常规的能够达到着色目的的物质，优选红氧化铁和/或氧化铁黄。According to an embodiment of the present invention, in the booster layer tablet core, the coloring agent may be a conventional substance in the art that can achieve the purpose of coloring, preferably red iron oxide and/or iron oxide yellow.
根据本发明的实施方案，所述的助推层片芯中，所述的着色剂的质量百分比含量可以为0.10％～5.00％，例如0.50％～2.00％，其实例可以为1.00％。According to an embodiment of the present invention, in the booster layer tablet core, the mass percentage content of the colorant may be 0.10%-5.00%, such as 0.50%-2.00%, and an example may be 1.00%.
根据本发明的实施方案，所述的助推层片芯中，所述的润滑剂可以为本领域中常规的具有润滑作用的物质，优选硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬脂富马酸盐和微粉硅胶中的一种或多种。所述的硬脂酸金属盐优选硬脂酸镁和/或硬脂酸钙。所述的硬脂酸酯优选硬脂酸甘油酯。所述的硬脂富马酸盐优选硬脂富马酸钠。According to an embodiment of the present invention, in the booster layer tablet core, the lubricant may be a conventional substance with a lubricating effect in the art, preferably metal stearate, stearic acid, talcum powder, hard One or more of fatty acid ester, stearyl fumarate and micropowder silica gel. Described metal stearate is preferably magnesium stearate and/or calcium stearate. Described stearic acid ester is preferably glyceryl stearate. Described stearyl fumarate is preferably sodium stearyl fumarate.
根据本发明的实施方案，所述的助推层片芯中，所述的润滑剂的质量百分比含量可以为0.10％～5.00％，例如0.50％～2.00％，其实例可以为1.00％或2.00％。According to an embodiment of the present invention, in the booster layer core, the mass percentage content of the lubricant may be 0.10% to 5.00%, such as 0.50% to 2.00%, and its example may be 1.00% or 2.00%. .
根据本发明的实施方案，所述的半渗透膜包含成膜材料、致孔剂和增塑剂中的一种或多种。According to an embodiment of the present invention, the semi-permeable membrane includes one or more of a membrane-forming material, a porogen and a plasticizer.
根据本发明的实施方案，所述的功能性包衣膜中，所述的成膜材料可以为本领域中常规的能够分散在固体表面固化成膜的材料，优选醋酸纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素、丙烯酸树脂和甲基丙烯酸树脂中的一种或多种。According to an embodiment of the present invention, in the functional coating film, the film-forming material can be a conventional material in the art that can be dispersed on a solid surface and solidified to form a film, preferably cellulose acetate, ethyl cellulose , one or more of cellulose acetate phthalate, acrylic resin and methacrylic resin.
根据本发明的实施方案，所述的功能性包衣膜中，所述的致孔剂可以为本领域中常规的能够使材料成孔性的物质，优选聚乙二醇和/或羟丙基纤维素和/或聚维酮。According to an embodiment of the present invention, in the functional coating film, the porogen can be a conventional substance in the art that can make the material pore-forming, preferably polyethylene glycol and/or hydroxypropyl cellulose and/or povidone.
根据本发明的实施方案，所述的功能性包衣膜中，所述的增塑剂可以为本领域中常规的能使聚合物塑性增加的物质，优选聚乙二醇、三醋酸甘油酯、柠檬酸甘油酯、甘油酯和邻苯二甲酸酯中的一种或多种。According to an embodiment of the present invention, in the functional coating film, the plasticizer can be a conventional substance in the art that can increase the plasticity of the polymer, preferably polyethylene glycol, glyceryl triacetate, One or more of glyceryl citrate, glycerides and phthalates.
根据本发明的实施方案，所述的水溶性薄膜为可商购自卡乐康的一种胃溶型薄膜包衣预混剂。According to an embodiment of the present invention, the water-soluble film is a gastric-soluble film coating premix commercially available from Colorcon.
根据本发明的实施方案，本发明的功能性包衣膜也可选择可商购自卡乐康的醋酸纤维素全配方包衣预混剂(
Figure PCTCN2022095871-appb-000001
CA)。 According to an embodiment of the present invention, the functional coating film of the present invention can also be selected from commercially available cellulose acetate full formula coating premix (
Figure PCTCN2022095871-appb-000001
CA).
根据本发明的实施方案，本发明的缓释组合物在体积为900ml的0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液中，采用USP第二法转速50rpm进行溶出实验，两种药物，即硝苯地平、其药学上可接受的盐或溶剂合物和美托洛尔、、其药学上可接受的盐或溶剂合物的24小时累积释放度均可达85％以上。According to an embodiment of the present invention, the sustained-release composition of the present invention is dissolved in a 0.5% SDS-pH6.8 phosphate citrate buffer solution with a volume of 900ml, and the dissolution test is carried out at a speed of 50rpm according to the second method of USP. , that is, the 24-hour cumulative release of nifedipine, its pharmaceutically acceptable salt or solvate and metoprolol, its pharmaceutically acceptable salt or solvate can reach more than 85%.
根据本发明的实施方案，所述的含药层片芯可以选自以下任一配方：According to an embodiment of the present invention, the drug-containing layer tablet core can be selected from any of the following formulations:
配方1：8.57％硝苯地平、13.57％琥珀酸美托洛尔、71.43％聚氧乙烯、5.43％羟丙甲基纤维素、1.00％硬脂酸镁；Formula 1: 8.57% nifedipine, 13.57% metoprolol succinate, 71.43% polyoxyethylene, 5.43% hypromellose, 1.00% magnesium stearate;
配方2：8.57％硝苯地平、13.57％琥珀酸美托洛尔、57.14％聚氧乙烯、19.71％羟丙甲基纤维素、1.00％硬脂酸镁；Formula 2: 8.57% nifedipine, 13.57% metoprolol succinate, 57.14% polyoxyethylene, 19.71% hypromellose, 1.00% magnesium stearate;
配方3：8.57％硝苯地平、14.29％酒石酸美托洛尔、74.29％聚氧乙烯、1.86％羟丙甲基纤维素、1.00％硬脂酸镁；Formula 3: 8.57% nifedipine, 14.29% metoprolol tartrate, 74.29% polyoxyethylene, 1.86% hypromellose, 1.00% magnesium stearate;
配方4：12.00％硝苯地平、19.00％琥珀酸美托洛尔、59.40％聚氧乙烯、1.00％胶态二氧化硅、7.60％羟丙甲基纤维素、1.00％硬脂酸镁；Formula 4: 12.00% nifedipine, 19.00% metoprolol succinate, 59.40% polyoxyethylene, 1.00% colloidal silicon dioxide, 7.60% hypromellose, 1.00% magnesium stearate;
配方5：9.09％硝苯地平、7.20％琥珀酸美托洛尔、76.95％聚氧乙烯、5.76％羟丙甲基纤维素、1.00％硬脂酸镁；Formula 5: 9.09% nifedipine, 7.20% metoprolol succinate, 76.95% polyoxyethylene, 5.76% hypromellose, 1.00% magnesium stearate;
配方6：21.43％硝苯地平、22.62％琥珀酸美托洛尔、52.38％聚氧乙烯、2.38％羟丙甲基纤维素、1.19％硬脂酸镁；Formula 6: 21.43% nifedipine, 22.62% metoprolol succinate, 52.38% polyoxyethylene, 2.38% hypromellose, 1.19% magnesium stearate;
配方7：12.00％硝苯地平、19.00％琥珀酸美托洛尔、58.00％聚维酮、1.00％胶态二氧化硅、9.00％共聚维酮、1.00％硬脂酸镁；Formula 7: 12.00% nifedipine, 19.00% metoprolol succinate, 58.00% povidone, 1.00% colloidal silicon dioxide, 9.00% copovidone, 1.00% magnesium stearate;
配方8:12.00％硝苯地平、19.00％琥珀酸美托洛尔、52.80％共聚维酮、13.20％羟乙纤维素、1.00％胶态二氧化硅、2.00％硬脂富马酸钠；Formula 8: 12.00% nifedipine, 19.00% metoprolol succinate, 52.80% copovidone, 13.20% hydroxyethyl cellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate;
配方9：12.00％硝苯地平、19.00％琥珀酸美托洛尔、49.50％共聚维酮、16.50％羟乙纤维素、1.00％胶态二氧化硅、2.00％硬脂富马酸钠；Formula 9: 12.00% nifedipine, 19.00% metoprolol succinate, 49.50% copovidone, 16.50% hydroxyethylcellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate;
配方10:12.00％硝苯地平、19.00％琥珀酸美托洛尔、44.50％共聚维酮、11.50％羟乙纤维素、10.00％十二烷基硫酸钠、1.00％胶态二氧化硅、2.00％硬脂富马酸钠；Formulation 10: 12.00% nifedipine, 19.00% metoprolol succinate, 44.50% copovidone, 11.50% hydroxyethyl cellulose, 10.00% sodium lauryl sulfate, 1.00% colloidal silicon dioxide, 2.00% Sodium stearyl fumarate;
配方11：12.60％硝苯地平、19.95％琥珀酸美托洛尔、47.95％共聚维酮、16.50％羟乙纤维素、1.00％胶态二氧化硅、2.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的105％进行投料)；Formula 11: 12.60% nifedipine, 19.95% metoprolol succinate, 47.95% copovidone, 16.50% hydroxyethylcellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate (remarks: Both nifedipine and metoprolol succinate were fed in excess, and were fed according to 105% of the labeled amount);
配方12：13.20％硝苯地平、20.90％琥珀酸美托洛尔、46.40％共聚维酮、16.50％羟乙纤维素、1.00％胶态二氧化硅、2.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的110％进行投料)；Formula 12: 13.20% nifedipine, 20.90% metoprolol succinate, 46.40% copovidone, 16.50% hydroxyethyl cellulose, 1.00% colloidal silicon dioxide, 2.00% sodium stearyl fumarate (remarks: Both nifedipine and metoprolol succinate were fed in excess, and were fed according to 110% of the marked amount);
配方13：12.60％硝苯地平、19.95％琥珀酸美托洛尔、8.66％共聚维酮(内加)、16.50％羟乙纤维素、36.29％共聚维酮(外加)、1.00％胶态二氧化硅、5.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的105％进行投料)；Formula 13: 12.60% nifedipine, 19.95% metoprolol succinate, 8.66% copovidone (internal addition), 16.50% hydroxyethylcellulose, 36.29% copovidone (external addition), 1.00% colloidal dioxide Silicon, 5.00% sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate were fed in excess, and were fed according to 105% of the labeled amount);
配方14：12.60％硝苯地平、9.98％琥珀酸美托洛尔、6.90％共聚维酮(内加)、16.50％羟乙纤维素、48.03％共聚维酮、1.00％胶态二氧化硅、5.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的105％进行投料)；Formula 14: 12.60% nifedipine, 9.98% metoprolol succinate, 6.90% copovidone (internal addition), 16.50% hydroxyethylcellulose, 48.03% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount);
配方15：12.60％硝苯地平、4.99％琥珀酸美托洛尔、6.02％共聚维酮(内加)、16.50％羟乙纤维素、53.90％共聚维酮、1.00％胶态二氧化硅、5.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的105％进行投料)；Formula 15: 12.60% nifedipine, 4.99% metoprolol succinate, 6.02% copovidone (internal addition), 16.50% hydroxyethylcellulose, 53.90% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount);
配方16：12.60％硝苯地平、9.98％琥珀酸美托洛尔、7.37％共聚维酮(内加)、19.18％羟乙纤维素、44.88％共聚维酮、1.00％胶态二氧化硅、5.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的105％进行投料)；Formula 16: 12.60% nifedipine, 9.98% metoprolol succinate, 7.37% copovidone (internal addition), 19.18% hydroxyethylcellulose, 44.88% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount);
配方17：12.60％硝苯地平、4.99％琥珀酸美托洛尔、6.72％共聚维酮(内加)、20.52％羟乙纤维素、49.17％共聚维酮、1.00％胶态二氧化硅、5.00％硬脂富马酸钠(备注：硝苯地平和琥珀酸美托洛尔均过量投料，均按照标示量的105％进行投料)。Formula 17: 12.60% nifedipine, 4.99% metoprolol succinate, 6.72% copovidone (internal addition), 20.52% hydroxyethylcellulose, 49.17% copovidone, 1.00% colloidal silicon dioxide, 5.00 % sodium stearyl fumarate (remarks: both nifedipine and metoprolol succinate are fed in excess, and are fed according to 105% of the labeled amount).
根据本发明的实施方案，所述的助推层片芯可以选自以下任一处方：According to an embodiment of the present invention, the booster layer tablet core can be selected from any of the following prescriptions:
处方1：65.71％聚氧乙烯、32.29％氯化钠、1.00％氧化铁红、1.00％硬脂酸镁；Prescription 1: 65.71% polyoxyethylene, 32.29% sodium chloride, 1.00% iron oxide red, 1.00% magnesium stearate;
处方2：54.29％聚氧乙烯、43.71％山梨醇、1.00％氧化铁红、1.00％硬脂酸镁；Prescription 2: 54.29% polyoxyethylene, 43.71% sorbitol, 1.00% iron oxide red, 1.00% magnesium stearate;
处方3：65.71％聚氧乙烯、16.14％山梨醇、16.14％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁；Prescription 3: 65.71% polyoxyethylene, 16.14% sorbitol, 16.14% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
处方4：65.72％聚氧乙烯、16.14％山梨醇、16.14％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁；Prescription 4: 65.72% polyoxyethylene, 16.14% sorbitol, 16.14% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
处方5：70.00％聚氧乙烯、28.00％氯化钠、1.00％氧化铁红、1.00％硬脂酸镁；Prescription 5: 70.00% polyoxyethylene, 28.00% sodium chloride, 1.00% iron oxide red, 1.00% magnesium stearate;
处方6：65.72％聚氧乙烯、21.52％山梨醇、10.76％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁；Prescription 6: 65.72% polyoxyethylene, 21.52% sorbitol, 10.76% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
处方7：65.72％聚氧乙烯、24.21％山梨醇、8.07％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁；Prescription 7: 65.72% polyoxyethylene, 24.21% sorbitol, 8.07% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
处方8：39.00％羧甲淀粉钠、29.25％羟丙甲纤维素、9.75％卡波姆、20.00％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁；Prescription 8: 39.00% sodium starch glycolate, 29.25% hypromellose, 9.75% carbomer, 20.00% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate;
处方9：50.00％聚氧乙烯、10.00％卡波姆、18.50％山梨醇、18.50％氯化钠、1.00％红氧化铁、2.00％硬脂富马酸钠；Prescription 9: 50.00% polyoxyethylene, 10.00% carbomer, 18.50% sorbitol, 18.50% sodium chloride, 1.00% red iron oxide, 2.00% sodium stearyl fumarate;
处方10：58.00％聚氧乙烯、29.00％羟丙甲纤维素、10.00％氯化钠、1.00％红氧化铁、2.00％硬脂富马酸钠；Prescription 10: 58.00% polyoxyethylene, 29.00% hypromellose, 10.00% sodium chloride, 1.00% red iron oxide, 2.00% sodium stearyl fumarate;
处方11：43.50％聚氧乙烯、43.50％羟丙甲纤维素、10.00％氯化钠、1.00％红氧化铁、2.00％硬脂富马酸钠；Prescription 11: 43.50% polyoxyethylene, 43.50% hypromellose, 10.00% sodium chloride, 1.00% red iron oxide, 2.00% sodium stearyl fumarate;
处方12：58.00％聚氧乙烯、24.00％羟丙甲纤维素、10.00％氯化钠、5.00％共聚维酮、 1.00％红氧化铁、2.00％硬脂富马酸钠。Prescription 12: 58.00% polyoxyethylene, 24.00% hypromellose, 10.00% sodium chloride, 5.00% copovidone, 1.00% red iron oxide, 2.00% sodium stearyl fumarate.
根据本发明的实施方案，所述缓释组合物的溶出释放曲线具有上文描述的特征。According to an embodiment of the present invention, the dissolution release profile of the sustained release composition has the characteristics described above.
本发明还提供所述缓释组合物的制备方法，包括如下步骤：The present invention also provides a preparation method of the sustained-release composition, comprising the steps of:
(a)将上述含药层片芯与助推层片芯各自的成分分别混合，其中各层混合粉的制备工艺可以选自例如粉末直压、流化制粒、干法制粒、湿法制粒等；(a) Mix the respective components of the drug-containing layer core and the booster layer core respectively, wherein the preparation process of the mixed powder of each layer can be selected from, for example, powder direct compression, fluidized granulation, dry granulation, wet granulation Wait;
(b)压制双层片芯；(b) compressing the double-layer tablet core;
(c)将双层片芯包衣(如半透膜包衣)；(c) coating the double-layer tablet core (such as semi-permeable membrane coating);
(d)在所述含药层片芯的一侧打孔；(d) punch holes on one side of the drug-containing layer tablet core;
(e)包上普通薄膜衣即可得到所述的硝苯地平美托洛尔缓释组合物。(e) The nifedipine-metoprolol sustained-release composition can be obtained by wrapping it with a common film coat.
根据本发明的实施方案，所述制备方法可以包括如下步骤：According to an embodiment of the present invention, the preparation method may include the following steps:
步骤1)：将含药层片芯中除了润滑剂之外的成分过筛、混合，然后再与润滑剂混合，得到含药层混合物；Step 1): sieving and mixing the ingredients in the drug-containing layer tablet core except the lubricant, and then mixing with the lubricant to obtain the drug-containing layer mixture;
步骤2)：将助推层片芯中除了润滑剂之外的成分过筛、混合，然后再与润滑剂混合，得到助推层混合物；Step 2): sieving and mixing the ingredients in the booster layer tablet core except the lubricant, and then mixing with the lubricant to obtain the booster layer mixture;
步骤3)：将步骤1)得到的含药层混合物与步骤2)中得到的助推层混合物进行压片得到双层片芯；Step 3): compressing the drug-containing layer mixture obtained in step 1) and the booster layer mixture obtained in step 2) to obtain a double-layer tablet core;
步骤4)将步骤3)得到的双层片芯进行包衣、老化，得到包衣片；Step 4) coating and aging the double-layer tablet core obtained in step 3) to obtain a coated tablet;
步骤5)将步骤4)得到的包衣片依次进行打孔和薄膜包衣，得到硝苯地平美托洛尔缓释片。Step 5) The coated tablets obtained in step 4) are sequentially punched and film-coated to obtain nifedipine-metoprolol sustained-release tablets.
步骤1)和步骤2)中，所述的过筛，可以为30目的筛。In step 1) and step 2), the sieving can be a 30-mesh sieve.
步骤1)和步骤2)中，所述的混合可以在混合机，例如混合罐中进行。所述的混合的频率可以为30Hz，所述的混合的时间可以为1分钟～2小时，例如5分钟或15分钟。In step 1) and step 2), the mixing can be carried out in a mixer, such as a mixing tank. The mixing frequency may be 30 Hz, and the mixing time may be 1 minute to 2 hours, such as 5 minutes or 15 minutes.
步骤4)中，所述的包衣优选包衣增重6％～20％，所述的百分比是指(硝苯地平美托洛尔包衣片的重量-双层片芯的重量)/双层片芯的重量﹡100％。In step 4), the coating is preferably coated with a weight gain of 6% to 20%, and the percentage refers to (the weight of the nifedipine metoprolol coated tablet-the weight of the double-layer tablet core)/double The weight of the ply core*100%.
步骤4)中，所述的老化的温度优选20℃～60℃，例如40℃。In step 4), the aging temperature is preferably 20°C to 60°C, for example 40°C.
步骤4)中，所述的老化的时间优选10小时～30小时，例如20小时。In step 4), the aging time is preferably 10 hours to 30 hours, such as 20 hours.
步骤5)中，所述的打孔可以在含药面中心位置打孔。所述的打孔的孔径可以为0.4毫米～1.0毫米。In step 5), the perforation can be perforated at the center of the drug-containing surface. The hole diameter of the perforated holes may be 0.4mm-1.0mm.
步骤5)中，所述的包衣优选包衣增重2％～10％，所述的百分比是指(硝苯地平美托洛尔缓释片的重量-薄膜包衣前片的重量)/薄膜包衣前片的重量﹡100％。In step 5), the preferred coating weight gain of the coating is 2% to 10%, and the percentage refers to (the weight of the nifedipine metoprolol sustained-release tablet-the weight of the film-coated front tablet)/ The weight of the film-coated front tablet*100%.
和/或and / or
步骤1)：将含药层片芯中的流化制粒内加辅料共同过筛、预混合、流化制粒、整粒、折算并加入除润滑剂外的所有外加辅料继续混合、折算并加入润滑剂进行总混，得到含药层混合物；Step 1): Sieve together the fluidized granulation internally added excipients in the drug-containing layer tablet core, premix, fluidize granulate, granulate, convert and add all external excipients except lubricant to continue mixing, convert and adding a lubricant for total mixing to obtain a drug-containing layer mixture;
步骤2)：将助推层片芯中流化制粒内加辅料共同过筛和/或预混合、流化制粒、整粒、折算除润滑剂外的所有外加辅料量、外加辅料共同过筛后加入整粒后物料中共同混合、折算并加入润滑剂进行总混，得到助推层混合物；Step 2): Screening and/or pre-mixing, fluidizing granulation, sizing, converting the amount of all external excipients except lubricant in the core of the booster layer, and jointly sieving the external excipients Finally, add the granulated materials and mix together, convert and add a lubricant for total mixing to obtain the booster layer mixture;
步骤3)：将步骤1)得到的含药层混合物与步骤2)中得到的助推层混合物进行压片得到双层片芯；Step 3): compressing the drug-containing layer mixture obtained in step 1) and the booster layer mixture obtained in step 2) to obtain a double-layer tablet core;
步骤4)将步骤3)得到的双层片芯进行包衣、老化，得到包衣片；Step 4) coating and aging the double-layer tablet core obtained in step 3) to obtain a coated tablet;
步骤5)将步骤4)得到的包衣片依次进行打孔和薄膜包衣，得到硝苯地平美托洛尔缓释片。Step 5) The coated tablets obtained in step 4) are sequentially punched and film-coated to obtain nifedipine-metoprolol sustained-release tablets.
步骤1)中，所述的过筛，可以为45目和/或40目的筛。In step 1), the sieving can be 45 mesh and/or 40 mesh sieve.
步骤2)中，所述的过筛，可以为30目的筛。In step 2), the sieving can be a 30-mesh sieve.
步骤1)和步骤2)中，所述的混合可以在混合机，例如混合罐中进行。所述的混合的频率可以为30Hz或50Hz，所述的混合的时间可以为1分钟～2小时，例如5分钟、10分钟、20分钟、25分钟或40分钟。In step 1) and step 2), the mixing can be carried out in a mixer, such as a mixing tank. The mixing frequency may be 30 Hz or 50 Hz, and the mixing time may be 1 minute to 2 hours, such as 5 minutes, 10 minutes, 20 minutes, 25 minutes or 40 minutes.
步骤4)中，所述的包衣优选包衣增重6％～20％，所述的百分比是指(硝苯地平美托洛尔包衣片的重量-双层片芯的重量)/双层片芯的重量﹡100％。In step 4), the preferred coating weight gain of the coating is 6% to 20%, and the percentage refers to (the weight of the nifedipine metoprolol coated tablet-the weight of the double-layer tablet core)/double The weight of the ply core*100%.
步骤4)中，所述的老化的温度优选20℃～60℃，例如40℃。In step 4), the aging temperature is preferably 20°C to 60°C, for example 40°C.
步骤4)中，所述的老化的时间优选10小时～30小时，例如16小时。In step 4), the aging time is preferably 10 hours to 30 hours, such as 16 hours.
步骤5)中，所述的打孔可以在含药面中心位置打孔。所述的打孔的孔径可以为0.4毫米～1.0毫米。In step 5), the perforation can be perforated at the center of the drug-containing surface. The hole diameter of the perforated holes may be 0.4mm-1.0mm.
步骤5)中，所述的包衣优选包衣增重2％～10％，所述的百分比是指(硝苯地平美托洛尔缓释片的重量-薄膜包衣前片的重量)/薄膜包衣前片的重量﹡100％。In step 5), the preferred coating weight gain of the coating is 2% to 10%, and the percentage refers to (the weight of the nifedipine metoprolol sustained-release tablet-the weight of the film-coated front tablet)/ The weight of the film-coated front tablet*100%.
本发明还提供了一种缓释制剂，其包含上文所述的缓释组合物。The present invention also provides a sustained-release preparation comprising the above-mentioned sustained-release composition.
根据本发明的实施方案，所述的缓释制剂可以为缓释片。According to an embodiment of the present invention, the sustained-release preparation may be a sustained-release tablet.
本发明还提供所述缓释组合物或缓释制剂在制备药物中的应用，其中所述药物用于预防和/或治疗高血压或与其相关的症状，如心率失常或心绞痛。The present invention also provides the application of the sustained-release composition or sustained-release preparation in the preparation of medicine, wherein the medicine is used for preventing and/or treating hypertension or its related symptoms, such as arrhythmia or angina pectoris.
本发明还提供一种预防和/或治疗高血压或与其相关的症状，如心率失常或心绞痛的方法，包括将治疗有效量的所述缓释组合物或缓释制剂给予有需要的患者。The present invention also provides a method for preventing and/or treating hypertension or its related symptoms, such as arrhythmia or angina pectoris, comprising administering a therapeutically effective amount of the sustained-release composition or sustained-release preparation to a patient in need.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
有益效果Beneficial effect
本发明的缓释组合物克服了硝苯地平、其药学上可接受的盐或溶剂合物和美托洛尔、其药学上可接受的盐或溶剂合物这两种药物溶解性的巨大差异，利用单室双层渗透泵释药机理，将两种作用机制互补的降压药制备成一日一次的长效复方制剂，使两种药物达到长效同步释放，两种药物的24小时累积释放度均可达85％以上。并且，本发明的缓释 组合物的制备工艺稳定，生产方便，有利于工业化生产。The sustained-release composition of the present invention overcomes the huge difference in solubility of the two drugs of nifedipine, its pharmaceutically acceptable salt or solvate and metoprolol, its pharmaceutically acceptable salt or solvate, Using the release mechanism of single-chamber double-layer osmotic pump, two antihypertensive drugs with complementary action mechanisms are prepared into a once-a-day long-acting compound preparation, so that the two drugs can achieve long-acting synchronous release, and the 24-hour cumulative release of the two drugs All can reach more than 85%. Moreover, the preparation process of the sustained-release composition of the present invention is stable, the production is convenient, and it is beneficial to industrialized production.
附图说明Description of drawings
图1示出了在0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液中，实施例II-1～实施例II-15处方中硝苯地平的溶出曲线图；Fig. 1 shows in 0.5%SDS-pH6.8 phosphate citrate buffer solution, the stripping curve figure of nifedipine in the prescription of embodiment II-1～embodiment II-15;
图2示出了在0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液中，实施例II-1～实施例II-15处方中琥珀酸美托洛尔的溶出曲线图；Fig. 2 shows in 0.5%SDS-pH6.8 phosphate citrate buffer solution, the stripping profile of metoprolol succinate in the prescription of embodiment II-1 ~ embodiment II-15;
图3示出了实施例II-16的比格犬口服给药的药代动力学评价试验中，硝苯地平的血药浓度-时间曲线图；Fig. 3 shows in the pharmacokinetic evaluation test of the beagle dog oral administration of embodiment II-16, the blood drug concentration-time graph of nifedipine;
图4示出了实施例II-16的比格犬口服给药的药代动力学评价试验中，琥珀酸美托洛尔的血药浓度-时间曲线图。Fig. 4 shows the blood drug concentration-time curve of metoprolol succinate in the pharmacokinetic evaluation test of oral administration to beagle dogs of Example II-16.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.
实施例I-1Example I-1
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000002
Figure PCTCN2022095871-appb-000002
Figure PCTCN2022095871-appb-000003
Figure PCTCN2022095871-appb-000003
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、氯化钠、氧化铁红，共同过30目筛网处理。5) Weigh the polyoxyethylene, sodium chloride, and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重175mg，含药层理论片重350mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 175mg, the theoretical tablet weight of the drug-containing layer is 350mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000004
Figure PCTCN2022095871-appb-000004
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在6％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约20小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 6% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 20 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.6毫米～0.8毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.6 mm to 0.8 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为2％～6％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液或0.75％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, and the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer or 0.75% SDS-pH6. 8 phosphate citrate buffer solution, the rotating speed is 50rpm to measure, and the release results in vitro are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000005
Figure PCTCN2022095871-appb-000005
Figure PCTCN2022095871-appb-000006
Figure PCTCN2022095871-appb-000006
0.75％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.75% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000007
Figure PCTCN2022095871-appb-000007
实施例I-2Example I-2
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000008
Figure PCTCN2022095871-appb-000008
Figure PCTCN2022095871-appb-000009
Figure PCTCN2022095871-appb-000009
Figure PCTCN2022095871-appb-000010
Figure PCTCN2022095871-appb-000010
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟，进行干法制粒。3) Add magnesium stearate, continue mixing for about 5 minutes, and carry out dry granulation.
II助推层混合II boost layer mix
4)将山梨醇过30目筛网预处理备用4) Pass the sorbitol through a 30-mesh sieve for pretreatment
5)按顺序分别称取处方量的聚氧乙烯、山梨醇、氧化铁红，共同过30目筛网处理。5) Weigh respectively the polyoxyethylene, sorbitol, and iron oxide red in the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重175mg，含药层理论片重350mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 175mg, the theoretical tablet weight of the drug-containing layer is 350mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000011
Figure PCTCN2022095871-appb-000011
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素和聚乙二醇，搅拌60min至包衣液澄清。9) Weigh the purified water of the prescribed amount for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate and polyethylene glycol, and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～20％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约15小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 20%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.6毫米～0.8毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.6 mm to 0.8 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为3％～8％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 3% to 8%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液或0.75％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, and the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer or 0.75% SDS-pH6. 8 phosphate citrate buffer solution, the rotating speed is 50rpm to measure, and the release results in vitro are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000012
Figure PCTCN2022095871-appb-000012
0.75％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.75% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000013
Figure PCTCN2022095871-appb-000013
实施例I-3Example I-3
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000014
Figure PCTCN2022095871-appb-000014
Figure PCTCN2022095871-appb-000015
Figure PCTCN2022095871-appb-000015
Figure PCTCN2022095871-appb-000016
Figure PCTCN2022095871-appb-000016
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将山梨醇过30目筛网预处理备用，将氯化钠过80目筛网预处理备用。4) Sorbitol is pretreated through a 30-mesh sieve for subsequent use, and sodium chloride is pretreated through an 80-mesh sieve for subsequent use.
5)按顺序分别称取处方量的聚氧乙烯、山梨醇、氯化钠、氧化铁红，共同过30目筛网处理。5) Weigh the prescribed amounts of polyoxyethylene, sorbitol, sodium chloride, and iron oxide red in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重175mg，含药层理论片重350mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 175mg, the theoretical tablet weight of the drug-containing layer is 350mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000017
Figure PCTCN2022095871-appb-000017
9)称取包衣处方量的纯化水置于烧杯中，加入部分的乙醇，搅拌5min，再缓慢加入处方量的羟丙甲纤维素、聚乙二醇，再加入剩下的乙醇，加入乙基纤维素、搅拌60min 至包衣液澄清。9) Weigh the purified water of the prescription amount for coating and place it in a beaker, add part of ethanol, stir for 5 minutes, then slowly add hypromellose and polyethylene glycol of the prescription amount, then add the remaining ethanol, add ethyl alcohol Base cellulose and stir for 60 minutes until the coating liquid is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～12％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约15小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.6毫米～0.8毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.6 mm to 0.8 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为2％～6％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液或0.75％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, and the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer or 0.75% SDS-pH6. 8 phosphate citrate buffer solution, the rotating speed is 50rpm to measure, and the release results in vitro are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000018
Figure PCTCN2022095871-appb-000018
0.75％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.75% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000019
Figure PCTCN2022095871-appb-000019
实施例I-4Example I-4
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000020
Figure PCTCN2022095871-appb-000020
Figure PCTCN2022095871-appb-000021
Figure PCTCN2022095871-appb-000021
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、酒石酸美托洛尔、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol tartrate, and hypromellose in order, and pass through a 30-mesh sieve for processing.
2)将上述物料湿法制粒，干燥，整粒。2) The above materials are wet granulated, dried, and granulated.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将山梨醇过30目筛网预处理备用；4) Sorbitol is pretreated through a 30-mesh sieve for subsequent use;
5)按顺序分别称取处方量的聚氧乙烯、山梨醇、氧化铁红，共同过30目筛网处理。5) Weigh respectively the polyoxyethylene, sorbitol, and iron oxide red in the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重175mg，含药层理论片重350mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 175mg, the theoretical tablet weight of the drug-containing layer is 350mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000022
Figure PCTCN2022095871-appb-000022
Figure PCTCN2022095871-appb-000023
Figure PCTCN2022095871-appb-000023
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～10％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约24小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 10%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 24 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.6毫米～1.0毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.6 mm to 1.0 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为2％～6％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平酒石酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Tartrate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement, in vitro The release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000024
Figure PCTCN2022095871-appb-000024
实施例I-5Example I-5
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000025
Figure PCTCN2022095871-appb-000025
Figure PCTCN2022095871-appb-000026
Figure PCTCN2022095871-appb-000026
Figure PCTCN2022095871-appb-000027
Figure PCTCN2022095871-appb-000027
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、羟丙甲基纤维素、胶态二氧化硅，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, hypromellose, and colloidal silicon dioxide in order, and pass them through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将甘露醇过30目筛网预处理备用，将氯化钠过80目筛网预处理备用。4) Pass mannitol through a 30-mesh sieve for pretreatment, and pass sodium chloride through a 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、甘露醇、氯化钠、氧化铁红，共同过30目筛网处理。5) Weigh the polyoxyethylene, mannitol, sodium chloride, and iron oxide red in the prescribed quantities respectively in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm或9mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重125mg，含药层理论片重250mg，压制双层片芯。8) Press with a circular shallow-arc die (or other suitable size die) with a diameter of 10mm or 9mm. The theoretical tablet weight of the booster layer is 125mg, and the theoretical tablet weight of the drug-containing layer is 250mg. Press the double-layer tablet core.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000028
Figure PCTCN2022095871-appb-000028
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢 加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the purified water of the prescribed amount of coating and place it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clarified.
10)素片包功能衣膜，理论包衣增重控制在7％～10％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约15小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 10%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.8毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.8 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为2％～6％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000029
Figure PCTCN2022095871-appb-000029
实施例I-6Example I-6
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000030
Figure PCTCN2022095871-appb-000030
Figure PCTCN2022095871-appb-000031
Figure PCTCN2022095871-appb-000031
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用；4) Sodium chloride is passed through 80 mesh sieves for pretreatment for subsequent use;
5)按顺序分别称取处方量的聚氧乙烯、氯化钠、氧化铁红，共同过30目筛网处理。5) Weigh the polyoxyethylene, sodium chloride, and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重175mg，含药层理论片重330mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 175mg, the theoretical tablet weight of the drug-containing layer is 330mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000032
Figure PCTCN2022095871-appb-000032
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在6％～12％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约15小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 6% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.8毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.8 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为2％～6％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000033
Figure PCTCN2022095871-appb-000033
实施例I-7Example I-7
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000034
Figure PCTCN2022095871-appb-000034
Figure PCTCN2022095871-appb-000035
Figure PCTCN2022095871-appb-000035
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、氯化钠、氧化铁红，共同过30目筛网处理。5) Weigh the polyoxyethylene, sodium chloride, and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径12mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重200mg，含药层理论片重420mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 12mm, the theoretical tablet weight of the booster layer is 200mg, the theoretical tablet weight of the drug-containing layer is 420mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000036
Figure PCTCN2022095871-appb-000036
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在6％～12％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约15小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 6% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 15 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.6毫米～1.0毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.6 mm to 1.0 mm.
VI薄膜包衣VI film coating
12)打孔片进行薄膜包衣，控制包衣增重为2％～6％。12) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000037
Figure PCTCN2022095871-appb-000037
Figure PCTCN2022095871-appb-000038
Figure PCTCN2022095871-appb-000038
由实施例I-1～实施例I-7结果可见，本发明的缓释片在体外溶出中，两种原料药可达到长效同步释放，满足一日一次的给药需求。From the results of Example I-1 to Example I-7, it can be seen that in the in vitro dissolution of the sustained-release tablet of the present invention, the two raw materials can achieve long-acting synchronous release, meeting the requirement of once-a-day administration.
实施例II-1Example II-1
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000039
Figure PCTCN2022095871-appb-000039
Figure PCTCN2022095871-appb-000040
Figure PCTCN2022095871-appb-000040
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、山梨醇、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh respectively the polyoxyethylene, sorbitol, sodium chloride, and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重125mg，含药层理论片重250mg，压制双层片芯。8) Press with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 125mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000041
Figure PCTCN2022095871-appb-000041
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000042
Figure PCTCN2022095871-appb-000042
Figure PCTCN2022095871-appb-000043
Figure PCTCN2022095871-appb-000043
实施例II-2Example II-2
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000044
Figure PCTCN2022095871-appb-000044
Figure PCTCN2022095871-appb-000045
Figure PCTCN2022095871-appb-000045
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚氧乙烯、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟丙甲基纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of polyoxyethylene, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hypromellose in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、山梨醇、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh respectively the polyoxyethylene, sorbitol, sodium chloride, and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片 重125mg，含药层理论片重250mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 125mg, the theoretical tablet weight of the drug-containing layer is 250mg, and press the double-layer tablet core.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000046
Figure PCTCN2022095871-appb-000046
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000047
Figure PCTCN2022095871-appb-000047
实施例II-3Example II-3
含有以下成分的基质片剂按如下方法生产，批量约为210片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 210 tablets.
Figure PCTCN2022095871-appb-000048
Figure PCTCN2022095871-appb-000048
Figure PCTCN2022095871-appb-000049
Figure PCTCN2022095871-appb-000049
Figure PCTCN2022095871-appb-000050
Figure PCTCN2022095871-appb-000050
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的聚维酮、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、共聚维酮，共同过30目筛网处理。1) Weigh the prescribed amounts of povidone, nifedipine, metoprolol succinate, colloidal silicon dioxide, and copovidone in sequence, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂酸镁，继续混合约5分钟。3) Add magnesium stearate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用。4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的羧甲淀粉钠、羟丙甲纤维素、卡波姆、氯化钠、红氧化铁红氧化铁共同过30目筛网处理。5) Weigh the prescribed amount of sodium carboxymethyl starch, hypromellose, carbomer, sodium chloride, red iron oxide and red iron oxide in order and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂酸镁，继续混合约5分钟。7) Add magnesium stearate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重125mg，含药层理论片重250mg，压制双层片芯。8) Press with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 125mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000051
Figure PCTCN2022095871-appb-000051
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢 加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the purified water of the prescribed amount of coating and place it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clarified.
10)素片包功能衣膜，理论包衣增重控制在7％～12％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约18小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 12%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 18 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000052
Figure PCTCN2022095871-appb-000052
实施例II-4Example II-4
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000053
Figure PCTCN2022095871-appb-000053
Figure PCTCN2022095871-appb-000054
Figure PCTCN2022095871-appb-000054
Figure PCTCN2022095871-appb-000055
Figure PCTCN2022095871-appb-000055
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的共聚维酮、胶态二氧化硅、羟乙纤维素，共同过30目筛网处理。1) Weigh respectively the copovidone, colloidal silicon dioxide, and hydroxyethyl cellulose of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
2)称量处方量的硝苯地平及琥珀酸美托洛尔分别过30目筛网备用。2) Weigh the prescribed amount of nifedipine and metoprolol succinate through a 30-mesh sieve for later use.
3)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。3) Put the above materials in a mixing tank, set the frequency to 30Hz (about 20rpm), and mix for about 15 minutes.
4)加入硬脂富马酸钠，继续混合约5分钟。4) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
5)将氯化钠过80目筛网预处理备用5) Sodium chloride is passed through 80 mesh sieve for pretreatment for later use
6)按顺序分别称取处方量的聚氧乙烯、卡波姆、山梨醇、氯化钠、红氧化铁，共同过30目筛网处理。6) Weigh the prescribed amounts of polyoxyethylene, carbomer, sorbitol, sodium chloride, and red iron oxide in order, and pass through a 30-mesh sieve for processing.
7)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。7) Put the above materials in a mixing tank, set the frequency to 30Hz (about 20rpm), and mix for about 15 minutes.
8)加入硬脂富马酸钠，继续混合约5分钟。8) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
9)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。9) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000056
Figure PCTCN2022095871-appb-000056
10)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。10) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
11)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。11) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
12)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫 米。12) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000057
Figure PCTCN2022095871-appb-000057
实施例II-5Example II-5
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000058
Figure PCTCN2022095871-appb-000058
Figure PCTCN2022095871-appb-000059
Figure PCTCN2022095871-appb-000059
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的共聚维酮、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟乙纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of copovidone, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hydroxyethyl cellulose in order, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂富马酸钠，继续混合约5分钟。3) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、羟丙甲纤维素、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh the prescribed quantities of polyoxyethylene, hypromellose, sodium chloride, and red iron oxide in sequence, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂富马酸钠，继续混合约5分钟。7) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000060
Figure PCTCN2022095871-appb-000060
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000061
Figure PCTCN2022095871-appb-000061
Figure PCTCN2022095871-appb-000062
Figure PCTCN2022095871-appb-000062
实施例II-6Example II-6
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000063
Figure PCTCN2022095871-appb-000063
Figure PCTCN2022095871-appb-000064
Figure PCTCN2022095871-appb-000064
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的共聚维酮、十二烷基硫酸钠、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟乙纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of copovidone, sodium lauryl sulfate, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hydroxyethyl cellulose in order, and pass through a 30-mesh sieve for processing .
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂富马酸钠，继续混合约5分钟。3) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、羟丙甲纤维素、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh the prescribed quantities of polyoxyethylene, hypromellose, sodium chloride, and red iron oxide in sequence, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂富马酸钠，继续混合约5分钟。7) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000065
Figure PCTCN2022095871-appb-000065
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000066
Figure PCTCN2022095871-appb-000066
Figure PCTCN2022095871-appb-000067
Figure PCTCN2022095871-appb-000067
实施例II-7Example II-7
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000068
Figure PCTCN2022095871-appb-000068
Figure PCTCN2022095871-appb-000069
Figure PCTCN2022095871-appb-000069
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的共聚维酮、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟乙纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of copovidone, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hydroxyethyl cellulose in order, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂富马酸钠，继续混合约5分钟。3) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、羟丙甲纤维素、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh the prescribed quantities of polyoxyethylene, hypromellose, sodium chloride, and red iron oxide in sequence, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂富马酸钠，继续混合约5分钟。7) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000070
Figure PCTCN2022095871-appb-000070
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000071
Figure PCTCN2022095871-appb-000071
实施例II-8Example II-8
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000072
Figure PCTCN2022095871-appb-000072
Figure PCTCN2022095871-appb-000073
Figure PCTCN2022095871-appb-000073
Figure PCTCN2022095871-appb-000074
Figure PCTCN2022095871-appb-000074
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的共聚维酮、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟乙纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of copovidone, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hydroxyethyl cellulose in order, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂富马酸钠，继续混合约5分钟。3) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through an 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、羟丙甲纤维素、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh the prescribed quantities of polyoxyethylene, hypromellose, sodium chloride, and red iron oxide in sequence, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂富马酸钠，继续混合约5分钟。7) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000075
Figure PCTCN2022095871-appb-000075
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000076
Figure PCTCN2022095871-appb-000076
实施例II-9Example II-9
含有以下成分的基质片剂按如下方法生产，批量约为200片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 200 tablets.
Figure PCTCN2022095871-appb-000077
Figure PCTCN2022095871-appb-000077
Figure PCTCN2022095871-appb-000078
Figure PCTCN2022095871-appb-000078
Figure PCTCN2022095871-appb-000079
Figure PCTCN2022095871-appb-000079
工艺步骤：Process steps:
I含药层混合I Drug-containing layer mixed
1)按顺序分别称取处方量的共聚维酮、硝苯地平、琥珀酸美托洛尔、胶态二氧化硅、羟乙纤维素，共同过30目筛网处理。1) Weigh the prescribed amounts of copovidone, nifedipine, metoprolol succinate, colloidal silicon dioxide, and hydroxyethyl cellulose in order, and pass through a 30-mesh sieve for processing.
2)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。2) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
3)加入硬脂富马酸钠，继续混合约5分钟。3) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层混合II boost layer mix
4)将氯化钠过80目筛网预处理备用4) Sodium chloride is passed through a 80-mesh sieve for pretreatment.
5)按顺序分别称取处方量的聚氧乙烯、羟丙甲纤维素、氯化钠、红氧化铁，共同过30目筛网处理。5) Weigh the prescribed quantities of polyoxyethylene, hypromellose, sodium chloride, and red iron oxide in sequence, and pass through a 30-mesh sieve for processing.
6)将上述物料置于混合罐中，设置频率为30Hz(约20rpm)，混合约15分钟。6) Put the above materials in a mixing tank, set the frequency at 30Hz (about 20rpm), and mix for about 15 minutes.
7)加入硬脂富马酸钠，继续混合约5分钟。7) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
8)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。8) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000080
Figure PCTCN2022095871-appb-000080
9)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。9) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
10)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。10) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
11)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。11) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml， 溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the rotation speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000081
Figure PCTCN2022095871-appb-000081
实施例II-10Example II-10
含有以下成分的基质片剂按如下方法生产，批量约为800片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 800 tablets.
Figure PCTCN2022095871-appb-000082
Figure PCTCN2022095871-appb-000082
Figure PCTCN2022095871-appb-000083
Figure PCTCN2022095871-appb-000083
工艺步骤：Process steps:
I含药层制备Preparation of I drug-containing layer
1)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。1) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
2)称取处方量的羟乙基纤维素、硝苯地平、琥珀酸美托洛尔共同过45目筛网后，置于混合罐中，设置频率30Hz，混合25分钟。2) Weigh the prescribed amount of hydroxyethylcellulose, nifedipine, and metoprolol succinate and pass through a 45-mesh sieve together, then place them in a mixing tank, set the frequency to 30 Hz, and mix for 25 minutes.
3)将混合结束后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。3) Place the mixed material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for sizing.
4)根据处方量折算并称量共聚维酮(外加)、胶态二氧化硅、硬脂富马酸钠的理论量，将整粒后物料、共聚维酮(外加)、胶态二氧化硅加入混合罐中，设置频率30Hz，混合10分钟。4) Convert and weigh the theoretical amounts of copovidone (extra), colloidal silicon dioxide, and sodium stearyl fumarate according to the prescription amount, and mix the material, copovidone (extra), colloidal silica Add to the mixing tank, set the frequency to 30Hz, and mix for 10 minutes.
5)加入硬脂富马酸钠，继续混合约5分钟。5) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层制备II booster layer preparation
6)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。6) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for future use.
7)按顺序分别称取处方量的聚氧乙烯、红氧化铁，共同过30目筛网处理。7) Weigh the polyoxyethylene and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
8)将过筛后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。8) The sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
9)根据处方量折算并称量羟丙甲纤维素、氯化钠、硬脂富马酸钠的理论量，将整粒后物料、羟丙甲纤维素、氯化钠加入混合罐中，设置频率30Hz，混合10分钟。9) Convert and weigh the theoretical amount of hypromellose, sodium chloride, and sodium stearyl fumarate according to the prescription amount, add the granulated material, hypromellose, and sodium chloride into the mixing tank, set Frequency 30Hz, mix for 10 minutes.
10)加入硬脂富马酸钠，继续混合约5分钟。10) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
11)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。11) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000084
Figure PCTCN2022095871-appb-000084
12)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。12) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
13)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。13) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
14)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫 米。14) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
VI薄膜包衣VI film coating
Figure PCTCN2022095871-appb-000085
Figure PCTCN2022095871-appb-000085
15)称取包衣处方量的纯化水置于烧杯中，缓慢加入处方量的薄膜包衣预混剂，搅拌45分钟至包衣液澄清。15) Weigh the purified water of the prescribed amount for coating and place it in a beaker, slowly add the prescribed amount of film coating premix, and stir for 45 minutes until the coating solution is clear.
16)打孔片进行薄膜包衣，控制包衣增重为2％～6％。16) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000086
Figure PCTCN2022095871-appb-000086
实施例II-11Example II-11
含有以下成分的基质片剂按如下方法生产，批量约为400片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
Figure PCTCN2022095871-appb-000087
Figure PCTCN2022095871-appb-000087
Figure PCTCN2022095871-appb-000088
Figure PCTCN2022095871-appb-000088
Figure PCTCN2022095871-appb-000089
Figure PCTCN2022095871-appb-000089
工艺步骤：Process steps:
I含药层制备Preparation of I drug-containing layer
1)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。1) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
2)称取处方量的羟乙基纤维素、硝苯地平、琥珀酸美托洛尔共同过45目筛网后，置于混合罐中，设置频率30Hz，混合25分钟。2) Weigh the prescribed amount of hydroxyethylcellulose, nifedipine, and metoprolol succinate and pass through a 45-mesh sieve together, then place them in a mixing tank, set the frequency to 30 Hz, and mix for 25 minutes.
3)将混合结束后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。3) Place the mixed material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for sizing.
4)根据处方量折算并称量共聚维酮(外加)、胶态二氧化硅、硬脂富马酸钠的理论量，将整粒后物料、共聚维酮(外加)、胶态二氧化硅加入混合罐中，设置频率30Hz，混合10分钟。4) Convert and weigh the theoretical amounts of copovidone (extra), colloidal silicon dioxide, and sodium stearyl fumarate according to the prescription amount, and mix the material, copovidone (extra), colloidal silica Add to the mixing tank, set the frequency to 30Hz, and mix for 10 minutes.
5)加入硬脂富马酸钠，继续混合约5分钟。5) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层制备II booster layer preparation
6)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。6) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for future use.
7)按顺序分别称取处方量的聚氧乙烯、红氧化铁，共同过30目筛网处理。7) Weigh the polyoxyethylene and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
8)将过筛后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。8) The sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
9)根据处方量折算并称量羟丙甲纤维素、氯化钠、硬脂富马酸钠的理论量，将整粒后物料、羟丙甲纤维素、氯化钠加入混合罐中，设置频率30Hz，混合10分钟。9) Convert and weigh the theoretical amount of hypromellose, sodium chloride, and sodium stearyl fumarate according to the prescription amount, add the granulated material, hypromellose, and sodium chloride into the mixing tank, set Frequency 30Hz, mix for 10 minutes.
10)加入硬脂富马酸钠，继续混合约5分钟。10) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
11)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。11) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000090
Figure PCTCN2022095871-appb-000090
Figure PCTCN2022095871-appb-000091
Figure PCTCN2022095871-appb-000091
12)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。12) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
13)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。13) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
14)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。14) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
VI薄膜包衣VI film coating
Figure PCTCN2022095871-appb-000092
Figure PCTCN2022095871-appb-000092
15)称取包衣处方量的纯化水置于烧杯中，缓慢加入处方量的薄膜包衣预混剂，搅拌45分钟至包衣液澄清。15) Weigh the purified water of the prescribed amount for coating and place it in a beaker, slowly add the prescribed amount of film coating premix, and stir for 45 minutes until the coating solution is clear.
16)打孔片进行薄膜包衣，控制包衣增重为2％～6％。16) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000093
Figure PCTCN2022095871-appb-000093
实施例II-12Example II-12
含有以下成分的基质片剂按如下方法生产，批量约为400片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
Figure PCTCN2022095871-appb-000094
Figure PCTCN2022095871-appb-000094
Figure PCTCN2022095871-appb-000095
Figure PCTCN2022095871-appb-000095
工艺步骤：Process steps:
I含药层制备Preparation of I drug-containing layer
1)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。1) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
2)称取处方量的羟乙基纤维素、硝苯地平、琥珀酸美托洛尔共同过45目筛网后，置于混合罐中，设置频率30Hz，混合25分钟。2) Weigh the prescribed amount of hydroxyethylcellulose, nifedipine, and metoprolol succinate and pass through a 45-mesh sieve together, then place them in a mixing tank, set the frequency to 30 Hz, and mix for 25 minutes.
3)将混合结束后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。3) Place the mixed material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for sizing.
4)根据处方量折算并称量共聚维酮(外加)、胶态二氧化硅、硬脂富马酸钠的理论量，将整粒后物料、共聚维酮(外加)、胶态二氧化硅加入混合罐中，设置频率30Hz，混合10分钟。4) Convert and weigh the theoretical amounts of copovidone (extra), colloidal silicon dioxide, and sodium stearyl fumarate according to the prescription amount, and mix the material, copovidone (extra), colloidal silica Add to the mixing tank, set the frequency to 30Hz, and mix for 10 minutes.
5)加入硬脂富马酸钠，继续混合约5分钟。5) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层制备II booster layer preparation
6)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。6) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for future use.
7)按顺序分别称取处方量的聚氧乙烯、红氧化铁，共同过30目筛网处理。7) Weigh the polyoxyethylene and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
8)将过筛后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后 过24目筛网进行整粒。8) The sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
9)根据处方量折算并称量羟丙甲纤维素、氯化钠、硬脂富马酸钠的理论量，将整粒后物料、羟丙甲纤维素、氯化钠加入混合罐中，设置频率30Hz，混合10分钟。9) Convert and weigh the theoretical amount of hypromellose, sodium chloride, and sodium stearyl fumarate according to the prescription amount, add the granulated material, hypromellose, and sodium chloride into the mixing tank, set Frequency 30Hz, mix for 10 minutes.
10)加入硬脂富马酸钠，继续混合约5分钟。10) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
11)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。11) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000096
Figure PCTCN2022095871-appb-000096
12)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。12) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
13)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。13) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
14)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。14) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
VI薄膜包衣VI film coating
Figure PCTCN2022095871-appb-000097
Figure PCTCN2022095871-appb-000097
15)称取包衣处方量的纯化水置于烧杯中，缓慢加入处方量的薄膜包衣预混剂，搅拌45分钟至包衣液澄清。15) Weigh the purified water of the prescribed amount for coating and place it in a beaker, slowly add the prescribed amount of film coating premix, and stir for 45 minutes until the coating solution is clear.
16)打孔片进行薄膜包衣，控制包衣增重为2％～6％。16) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000098
Figure PCTCN2022095871-appb-000098
Figure PCTCN2022095871-appb-000099
Figure PCTCN2022095871-appb-000099
实施例II-13Example II-13
含有以下成分的基质片剂按如下方法生产，批量约为400片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
Figure PCTCN2022095871-appb-000100
Figure PCTCN2022095871-appb-000100
Figure PCTCN2022095871-appb-000101
Figure PCTCN2022095871-appb-000101
工艺步骤：Process steps:
I含药层制备Preparation of I drug-containing layer
1)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。1) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
2)称取处方量的羟乙基纤维素、硝苯地平、琥珀酸美托洛尔共同过45目筛网后，置于混合罐中，设置频率30Hz，混合25分钟。2) Weigh the prescribed amount of hydroxyethylcellulose, nifedipine, and metoprolol succinate and pass through a 45-mesh sieve together, then place them in a mixing tank, set the frequency to 30 Hz, and mix for 25 minutes.
3)将混合结束后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完 成后过24目筛网进行整粒。3) Place the mixed material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
4)根据处方量折算并称量共聚维酮(外加)、胶态二氧化硅、硬脂富马酸钠的理论量，将整粒后物料、共聚维酮(外加)、胶态二氧化硅加入混合罐中，设置频率30Hz，混合10分钟。4) Convert and weigh the theoretical amounts of copovidone (extra), colloidal silicon dioxide, and sodium stearyl fumarate according to the prescription amount, and mix the material, copovidone (extra), colloidal silica Add to the mixing tank, set the frequency to 30Hz, and mix for 10 minutes.
5)加入硬脂富马酸钠，继续混合约5分钟。5) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层制备II booster layer preparation
6)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。6) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for future use.
7)按顺序分别称取处方量的聚氧乙烯、红氧化铁，共同过30目筛网处理。7) Weigh the polyoxyethylene and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
8)将过筛后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。8) The sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
9)根据处方量折算并称量羟丙甲纤维素、氯化钠、硬脂富马酸钠的理论量，将整粒后物料、羟丙甲纤维素、氯化钠加入混合罐中，设置频率30Hz，混合10分钟。9) Convert and weigh the theoretical amount of hypromellose, sodium chloride, and sodium stearyl fumarate according to the prescription amount, add the granulated material, hypromellose, and sodium chloride into the mixing tank, set Frequency 30Hz, mix for 10 minutes.
10)加入硬脂富马酸钠，继续混合约5分钟。10) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
11)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。11) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000102
Figure PCTCN2022095871-appb-000102
12)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。12) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
13)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。13) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
14)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。14) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
VI薄膜包衣VI film coating
Figure PCTCN2022095871-appb-000103
Figure PCTCN2022095871-appb-000103
15)称取包衣处方量的纯化水置于烧杯中，缓慢加入处方量的薄膜包衣预混剂，搅 拌45分钟至包衣液澄清。15) Weigh the purified water of the prescribed amount of coating and place it in a beaker, slowly add the prescribed amount of film coating premix, and stir for 45 minutes until the coating solution is clear.
16)打孔片进行薄膜包衣，控制包衣增重为2％～6％。16) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000104
Figure PCTCN2022095871-appb-000104
实施例II-14Example II-14
含有以下成分的基质片剂按如下方法生产，批量约为400片。Matrix tablets containing the following ingredients were produced as follows in batches of approximately 400 tablets.
Figure PCTCN2022095871-appb-000105
Figure PCTCN2022095871-appb-000105
Figure PCTCN2022095871-appb-000106
Figure PCTCN2022095871-appb-000106
Figure PCTCN2022095871-appb-000107
Figure PCTCN2022095871-appb-000107
工艺步骤：Process steps:
I含药层制备Preparation of I drug-containing layer
1)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。1) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
2)称取处方量的羟乙基纤维素、硝苯地平、琥珀酸美托洛尔共同过45目筛网后，置于混合罐中，设置频率30Hz，混合25分钟。2) Weigh the prescribed amount of hydroxyethylcellulose, nifedipine, and metoprolol succinate and pass through a 45-mesh sieve together, then place them in a mixing tank, set the frequency to 30 Hz, and mix for 25 minutes.
3)将混合结束后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。3) Place the mixed material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for sizing.
4)根据处方量折算并称量共聚维酮(外加)、胶态二氧化硅、硬脂富马酸钠的理论量，将整粒后物料、共聚维酮(外加)、胶态二氧化硅加入混合罐中，设置频率30Hz，混合10分钟。4) Convert and weigh the theoretical amounts of copovidone (extra), colloidal silicon dioxide, and sodium stearyl fumarate according to the prescription amount, and mix the material, copovidone (extra), colloidal silica Add to the mixing tank, set the frequency to 30Hz, and mix for 10 minutes.
5)加入硬脂富马酸钠，继续混合约5分钟。5) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
II助推层制备II booster layer preparation
6)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。6) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for future use.
7)按顺序分别称取处方量的聚氧乙烯、红氧化铁，共同过30目筛网处理。7) Weigh the polyoxyethylene and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
8)将过筛后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后过24目筛网进行整粒。8) The sieved material is placed in a fluidized granulator, sprayed into the binder solution for fluidized granulation; after the granulation is completed, pass through a 24-mesh screen for granulation.
9)根据处方量折算并称量羟丙甲纤维素、氯化钠、硬脂富马酸钠的理论量，将整粒后物料、羟丙甲纤维素、氯化钠加入混合罐中，设置频率30Hz，混合10分钟。9) Convert and weigh the theoretical amount of hypromellose, sodium chloride, and sodium stearyl fumarate according to the prescription amount, add the granulated material, hypromellose, and sodium chloride into the mixing tank, set Frequency 30Hz, mix for 10 minutes.
10)加入硬脂富马酸钠，继续混合约5分钟。10) Add sodium stearyl fumarate and continue mixing for about 5 minutes.
III压片III Tablet
11)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。11) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10mm, the theoretical tablet weight of the booster layer is 100mg, the theoretical tablet weight of the drug-containing layer is 250mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000108
Figure PCTCN2022095871-appb-000108
12)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。12) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
13)素片包功能衣膜，理论包衣增重控制在7％～15％，包衣完成后将成品放置于40℃ 鼓风干燥箱中干燥老化约16小时。13) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 7% to 15%. After the coating is completed, the finished product is dried and aged in a blast drying oven at 40°C for about 16 hours.
V包衣片打孔V-coated tablets punched
14)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.4毫米～0.6毫米。14) Use a laser punching machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.4 mm to 0.6 mm.
VI薄膜包衣VI film coating
Figure PCTCN2022095871-appb-000109
Figure PCTCN2022095871-appb-000109
15)称取包衣处方量的纯化水置于烧杯中，缓慢加入处方量的薄膜包衣预混剂，搅拌45分钟至包衣液澄清。15) Weigh the purified water of the prescribed amount for coating and place it in a beaker, slowly add the prescribed amount of film coating premix, and stir for 45 minutes until the coating solution is clear.
16)打孔片进行薄膜包衣，控制包衣增重为2％～6％。16) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000110
Figure PCTCN2022095871-appb-000110
实施例II-15Example II-15
参照实施例II-10的处方，放大批量至1万片进行生产制备。Referring to the prescription of Example II-10, scale up the batch to 10,000 pieces for production and preparation.
工艺步骤：Process steps:
I含药层制备Preparation of I drug-containing layer
1)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。1) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
2)称取处方量的羟乙基纤维素、硝苯地平、琥珀酸美托洛尔共同过40目筛网后，置于混合罐中，设置频率50Hz，混合40分钟。2) Weigh the prescribed amount of hydroxyethylcellulose, nifedipine, and metoprolol succinate and pass through a 40-mesh sieve together, then place them in a mixing tank, set the frequency to 50 Hz, and mix for 40 minutes.
3)将混合结束后的物料使用整粒机进行整粒。3) The material after mixing is granulated using a granulator.
4)将整粒后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后使用整粒机再次进行整粒。4) Place the sized material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, use the granulator to perform granulation again.
5)根据处方量折算并称量共聚维酮(外加)、胶态二氧化硅、硬脂富马酸钠的理论量，将整粒后物料、共聚维酮(外加)、胶态二氧化硅加入混合罐中，设置频率50Hz，混合25分钟。5) Convert and weigh the theoretical amounts of copovidone (extra), colloidal silicon dioxide, and sodium stearyl fumarate according to the prescription amount, and mix the material, copovidone (extra), and colloidal silica Add to the mixing tank, set the frequency to 50Hz, and mix for 25 minutes.
6)加入硬脂富马酸钠，继续混合约3分钟后使用整粒机再次整粒。6) Add sodium stearyl fumarate, continue mixing for about 3 minutes, and then use a granulator to granulate again.
7)整粒完成后，继续混合5分钟。7) After the granulation is completed, continue to mix for 5 minutes.
II助推层制备II booster layer preparation
8)称取处方量的共聚维酮，加入无水乙醇中，配制成10％固含量的粘合剂溶液备用。8) Weigh the prescribed amount of copovidone, add it to absolute ethanol, and prepare an adhesive solution with a solid content of 10% for later use.
9)按顺序分别称取处方量的聚氧乙烯、红氧化铁，共同过30目筛网处理。9) Weigh the polyoxyethylene and red iron oxide of the prescribed amount in order, and pass through a 30-mesh sieve for processing.
10)将过筛后的物料置于混合机中，设置频率50Hz，混合20分钟。10) Put the sieved material in a mixer, set the frequency to 50Hz, and mix for 20 minutes.
11)将混合后的物料置于流化制粒机中，喷入粘合剂溶液进行流化制粒；制粒完成后使用整粒机进行整粒。11) Put the mixed material in a fluidized granulator, spray into the binder solution for fluidized granulation; after the granulation is completed, use a granulator for granulation.
12)根据处方量折算并称量羟丙甲纤维素、氯化钠、硬脂富马酸钠的理论量，将整粒后物料、羟丙甲纤维素、氯化钠加入混合罐中，设置频率50Hz，混合20分钟。12) Convert and weigh the theoretical amount of hypromellose, sodium chloride, and sodium stearyl fumarate according to the prescription amount, add the granulated material, hypromellose, and sodium chloride into the mixing tank, set Frequency 50Hz, mixing for 20 minutes.
13)加入硬脂富马酸钠，继续混合约3分钟后使用整粒机再次进行整粒。13) Add sodium stearyl fumarate, continue mixing for about 3 minutes, and then use a granulator to granulate again.
14)整粒完成后继续混合5分钟。14) Continue mixing for 5 minutes after the granulation is completed.
III压片III Tablet
15)采用直径10mm圆形浅弧型冲模(或其他合适尺寸的模具)压制，助推层理论片重100mg，含药层理论片重250mg，压制双层片芯。15) Compress with a circular shallow arc die (or other suitable size die) with a diameter of 10 mm, the theoretical tablet weight of the booster layer is 100 mg, the theoretical tablet weight of the drug-containing layer is 250 mg, and the double-layer tablet core is pressed.
IV功能衣包衣IV functional coat coating
Figure PCTCN2022095871-appb-000111
Figure PCTCN2022095871-appb-000111
16)称取包衣处方量的纯化水置于烧杯中，加入处方量的丙酮，搅拌5min，再缓慢加入处方量的醋酸纤维素(欧巴代CA)，搅拌60min至包衣液澄清。16) Weigh the prescribed amount of purified water for coating and put it in a beaker, add the prescribed amount of acetone, stir for 5 minutes, then slowly add the prescribed amount of cellulose acetate (Opadry CA), and stir for 60 minutes until the coating solution is clear.
17)素片包功能衣膜，理论包衣增重控制在10％～15％，包衣完成后将成品放置于40℃鼓风干燥箱中干燥老化约16小时。17) The plain tablet is coated with a functional coating film, and the theoretical coating weight gain is controlled at 10% to 15%. After the coating is completed, the finished product is placed in a blast drying oven at 40°C for drying and aging for about 16 hours.
V包衣片打孔V-coated tablets punched
18)使用激光打孔机于包衣片的含药面中心位置打孔，孔径控制在0.6毫米～0.8毫米。18) Use a laser drilling machine to punch a hole in the center of the drug-containing surface of the coated tablet, and the hole diameter is controlled at 0.6 mm to 0.8 mm.
VI薄膜包衣VI film coating
Figure PCTCN2022095871-appb-000112
Figure PCTCN2022095871-appb-000112
19)称取包衣处方量的纯化水置于烧杯中，缓慢加入处方量的薄膜包衣预混剂，搅拌45分钟至包衣液澄清。19) Weigh the purified water of the prescribed amount for coating and place it in a beaker, slowly add the prescribed amount of film coating premix, and stir for 45 minutes until the coating solution is clear.
20)打孔片进行薄膜包衣，控制包衣增重为2％～6％。20) The perforated tablet is film-coated, and the weight gain of the coating is controlled to be 2% to 6%.
硝苯地平琥珀酸美托洛尔缓释片体外释放采用USP溶出第II法，介质体积900ml，溶出介质为0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液，转速为50rpm进行测量，体外释放结果如下：The in vitro release of Nifedipine Metoprolol Succinate Sustained-release Tablets adopts USP dissolution method II, the medium volume is 900ml, the dissolution medium is 0.5% SDS-pH6.8 phosphate citrate buffer, and the speed is 50rpm for measurement. The in vitro release results are as follows:
0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液：0.5% SDS-pH6.8 Phosphate Citrate Buffer:
Figure PCTCN2022095871-appb-000113
Figure PCTCN2022095871-appb-000113
实施例II-16Example II-16
参照例1：一次性进口市售硝苯地平控释片(30mg规格)作为对照药，持证商为Bayer Pharma AG/Bayer AG。Reference Example 1: One-time imported commercially available nifedipine controlled-release tablets (30 mg specification) were used as the control drug, and the licensed manufacturer was Bayer Pharma AG/Bayer AG.
参照例2：一次性进口市售琥珀酸美托洛尔缓释片(47.5mg规格)作为对照药，持证商为AstraZeneca AB。Reference example 2: One-time imported commercially available metoprolol succinate sustained-release tablets (47.5 mg specification) were used as the control drug, and the licensed manufacturer was AstraZeneca AB.
使用实施例II-15所得自制硝苯地平美托洛尔药物组合物和参照例1的硝苯地平控释片以及参照例2的琥珀酸美托洛尔缓释片进行了比格犬口服给药药代动力学评价试验的比较研究。Use the self-made nifedipine metoprolol pharmaceutical composition of embodiment II-15 gained and the nifedipine controlled-release tablet of reference example 1 and the metoprolol succinate sustained-release tablet of reference example 2 to carry out oral administration to beagle dogs A comparative study of drug pharmacokinetic evaluation tests.
试验共采用6只Beagle犬，雌雄各半，根据性别分成2组，每组3只，第一周期第1组和第2组分别口服给予实施例II-15自制制剂1片和参照制剂2片(参照例1+参照例2各1片，单次给药)，间隔7天洗脱期后，第二周期第1组和第2组分别口服给予片参 照制剂2片(参照例1+参照例2各1片，单次给药)和实施例II-15自制制剂1片，根据设定的时间点分别于给药后采集血浆。A total of 6 Beagle dogs were used in the test, half male and half male, and divided into 2 groups according to gender, with 3 dogs in each group. In the first cycle, the first group and the second group were orally administered with 1 tablet of the self-made preparation of Example II-15 and 2 tablets of the reference preparation. (reference example 1+reference example 2 each 1 tablet, single administration), after the 7-day washout period at intervals, the first group and the second group in the second cycle were orally given 2 tablets of the reference preparation respectively (reference example 1+reference Example 2 each 1 tablet, single administration) and Example II-15 self-made preparation 1 tablet, plasma was collected after administration according to the set time points.
两个周期两组采样时间点均为给药后0.5hr、1hr、1.5hr、2hr、3hr、4hr、5hr、6hr、8hr、12hr、16hr、24hr、36hr和48hr，一共14个时间点；The sampling time points of the two groups in the two cycles are 0.5hr, 1hr, 1.5hr, 2hr, 3hr, 4hr, 5hr, 6hr, 8hr, 12hr, 16hr, 24hr, 36hr and 48hr after administration, a total of 14 time points;
根据设定的时间点，前肢头静脉或其它合适静脉采集约500μL全血至含K 2EDTA的抗凝离心管中，离心前放于湿冰上保存，样品采集及保存过程避光或在黄光条件下。采样后2hr内离心样品(以3000g离心力在2-8℃下离心5min)获得血浆。血浆样品先置于干冰中冻存，然后放于低于-60℃冰箱长期保存直至样品分析。 According to the set time point, about 500 μL of whole blood was collected from the cephalic vein of the forelimb or other suitable veins into anticoagulant centrifuge tubes containing K 2 EDTA, and stored on wet ice before centrifugation. under light conditions. The samples were centrifuged within 2 hours after sampling (centrifugation at 2-8° C. for 5 minutes with a centrifugal force of 3000 g) to obtain plasma. Plasma samples were first frozen in dry ice, and then stored in a refrigerator below -60°C for long-term storage until sample analysis.
血样采集完毕后，采用已验证的液相色谱串联质谱(LC-MS/MS)分析方法定量测定Beagle犬血浆中美托洛尔和硝苯地平的浓度。通过WinNonlin 8.2软件，按非房室模型计算药动学参数，再用Microsoft Excel 2007对药动学参数Cmax、AUC last、AUC INF、T 1/2和MRT INF进行配对双尾T检验。 After blood sample collection, the concentrations of metoprolol and nifedipine in Beagle dog plasma were quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) analytical method. The pharmacokinetic parameters were calculated according to the non-compartmental model by WinNonlin 8.2 software, and then paired two-tailed T-test was performed on the pharmacokinetic parameters Cmax, AUC last , AUC INF , T 1/2 and MRT INF with Microsoft Excel 2007.
检验结果提示，实施例II-15自制制剂和参照制剂2片(参照例1+参照例2各1片，单次给药)的药动学参数没有显著性差异(P>0.05)。The test results suggest that there is no significant difference (P>0.05) in the pharmacokinetic parameters between the self-made preparation of Example II-15 and the 2 tablets of the reference preparation (reference example 1 + reference example 2 each 1 tablet, single administration).
实施例II-1～实施例II-15于0.5％SDS-pH6.8磷酸盐枸橼酸盐缓冲液中的溶出曲线图见图1和图2；本实施例比格犬口服给药的药代动力学评价试验结果见表1和表2；比格犬口服给药的药代动力学评价试验血药浓度-时间曲线图见图3和图4；比格犬口服给药的药代动力学评价试验药动学参数T-test检验结果如表3和表4所示。Embodiment II-1～embodiment II-15 is shown in Fig. 1 and Fig. 2 in the stripping curve figure in 0.5%SDS-pH6.8 phosphate citrate buffer solution; Kinetic evaluation test results are shown in Table 1 and Table 2; the pharmacokinetic evaluation test plasma concentration-time curves of Beagle dog oral administration are shown in Fig. 3 and Fig. 4; The pharmacokinetics of Beagle dog oral administration The T-test results of the pharmacokinetic parameters of the pharmacokinetic evaluation test are shown in Table 3 and Table 4.
表1：Beagle犬口服给予实施例II-15制剂及参照制剂后美托洛尔的平均药动学参数Table 1: The average pharmacokinetic parameters of metoprolol after oral administration of embodiment II-15 preparation and reference preparation in Beagle dogs
Figure PCTCN2022095871-appb-000114
Figure PCTCN2022095871-appb-000114
表2：Beagle犬口服给予实施例II-15制剂及参照制剂后硝苯地平的平均药动学参数Table 2: The average pharmacokinetic parameters of nifedipine after Beagle dog oral administration embodiment II-15 preparation and reference preparation
Figure PCTCN2022095871-appb-000115
Figure PCTCN2022095871-appb-000115
Figure PCTCN2022095871-appb-000116
Figure PCTCN2022095871-appb-000116
表3：Beagle犬口服给予实施例II-15制剂及参照制剂后美托洛尔药动学参数T-test结果Table 3: Metoprolol pharmacokinetic parameters T-test results after oral administration of Example II-15 preparations and reference preparations to Beagle dogs
Figure PCTCN2022095871-appb-000117
Figure PCTCN2022095871-appb-000117
表4：Beagle犬口服给予实施例II-15制剂及参照制剂后硝苯地平药动学参数T-test结果Table 4: Nifedipine pharmacokinetic parameters T-test results after oral administration of Example II-15 preparation and reference preparation to Beagle dogs
Figure PCTCN2022095871-appb-000118
Figure PCTCN2022095871-appb-000118
由实施例I-1～实施例I-7和实施例II-1～实施例II-16结果可见，在体外溶出中，本发明的硝苯地平琥珀酸/酒石酸美托洛尔缓释片中的两种原料药可达到长效同步释放，满足一日一次的给药需求。在动物实验中，目前市售的参照制剂硝苯地平缓释片和琥珀酸美托洛尔缓释片的Tmax相差较大，而实施例II-15两种成分在比格犬体内Tmax接近，达到了显著的同步缓释效果。By embodiment I-1 ~ embodiment I-7 and embodiment II-1 ~ embodiment II-16 result as seen, in in vitro dissolution, in nifedipine succinic acid/metoprolol tartrate slow-release tablet of the present invention The two APIs can achieve long-acting synchronous release, meeting the requirement of once-a-day dosing. In animal experiments, the Tmax of the currently commercially available reference preparation Nifedipine Sustained-release Tablets and Metoprolol Succinate Sustained-release Tablets is quite different, while the two components of Example II-15 are close to Tmax in Beagle dogs, A significant synchronous sustained-release effect has been achieved.

Claims (10)

  1. 一种缓释组合物，其特征在于，所述缓释组合物包含：A sustained-release composition, characterized in that, the sustained-release composition comprises:
    (i)硝苯地平、其药学上可接受的盐或溶剂合物中的一种或多种；和(i) one or more of nifedipine, its pharmaceutically acceptable salt or solvate; and
    (ii)美托洛尔、其药学上可接受的盐或溶剂合物中的一种或多种；(ii) one or more of metoprolol, its pharmaceutically acceptable salt or solvate;
    其中，所述缓释组合物的溶出释放曲线具有以下特征：Wherein, the dissolution release curve of the sustained-release composition has the following characteristics:
    A)在2小时内，溶出不超过10％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过10％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 2 hours, the dissolution is no more than 10% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is no more than 10% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
    B)在9小时内，溶出20％～70％所述得硝苯地平、其药学上可接受的盐或溶剂合物，和溶出20％～70％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括20％和70％两个点值；和/或，B) within 9 hours, dissolve 20%～70% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 20%～70% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 20% and 70%; and/or,
    C)在24小时内，溶出均不低于70％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不低于70％所述的美托洛尔、其药学上可接受的盐或溶剂合物；C) within 24 hours, the dissolution is not less than 70% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 70% of the described metoprolol, its pharmaceutical acceptable salts or solvates;
    优选地，所述缓释组合物的溶出释放曲线具有以下特征：Preferably, the dissolution release profile of the sustained-release composition has the following characteristics:
    A)在2小时内，溶出不超过8％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过8％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 2 hours, dissolution is no more than 8% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 8% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
    B)在9小时内，溶出25％～65％所述得硝苯地平、其药学上可接受的盐或溶剂合物，和溶出25％～65％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括25％和65％两个点值；和/或，B) within 9 hours, dissolve 25%～65% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 25%～65% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 25% and 65%; and/or,
    C)在24小时内，溶出均不低于80％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不低于80％所述的美托洛尔、其药学上可接受的盐或溶剂合物。C) within 24 hours, the dissolution is not less than 80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 80% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
  2. 根据权利要求1所述的缓释组合物，其特征在于，所述缓释组合物的溶出释放曲线具有以下特征：The sustained-release composition according to claim 1, wherein the release profile of the sustained-release composition has the following characteristics:
    A)在4小时内，溶出不超过25％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不超过25％所述的美托洛尔、其药学上可接受的盐或溶剂合物；A) within 4 hours, dissolution is no more than 25% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolution is no more than 25% of the described metoprolol, its pharmaceutically acceptable salts or solvates of
    B)在12小时内，溶出45％～80％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出45％～80％所述的美托洛尔、其药学上可接受的盐或溶剂合物，包括45％和80％两个点值；和/或B) within 12 hours, dissolve 45%～80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and dissolve 45%～80% of the described metoprolol, its pharmaceutically Acceptable salts or solvates, including both point values of 45% and 80%; and/or
    C)在24小时内，溶出均不低于80％所述的硝苯地平、其药学上可接受的盐或溶剂合物，和溶出不低于80％所述的美托洛尔、其药学上可接受的盐或溶剂合物。C) within 24 hours, the dissolution is not less than 80% of the described nifedipine, its pharmaceutically acceptable salt or solvate, and the dissolution is not less than 80% of the described metoprolol, its pharmaceutical acceptable salts or solvates.
  3. 一种缓释组合物，其特征在于，所述缓释组合物包括：A sustained-release composition, characterized in that, the sustained-release composition comprises:
    含药层片芯和/或助推层片芯，其中在所述含药层片芯的一侧打孔；以及A drug-containing layer core and/or a booster layer core, wherein holes are perforated on one side of the drug-containing layer core; and
    包衣膜；Coating film;
    所述的含药层片芯包含药物活性成分以及载体；The drug-containing layer tablet core contains pharmaceutical active ingredients and carriers;
    所述的药物活性成分包含硝苯地平、其药学上可接受的盐或溶剂合物中的一种或多种，和美托洛尔、其药学上可接受的盐或溶剂合物中的一种或多种；优选地，所述的美托洛尔药学上可接受的盐选自琥珀酸美托洛尔和/或酒石酸美托洛尔；The pharmaceutical active ingredient comprises one or more of nifedipine, its pharmaceutically acceptable salt or solvate, and one of metoprolol, its pharmaceutically acceptable salt or solvate or more; preferably, the pharmaceutically acceptable salt of metoprolol is selected from metoprolol succinate and/or metoprolol tartrate;
    优选地，所述缓释组合物的溶出释放曲线具有权利要求1或2所述的特征。Preferably, the dissolution release profile of the sustained-release composition has the characteristics described in claim 1 or 2.
  4. 根据权利要求3所述的缓释组合物，其特征在于：The sustained-release composition according to claim 3, characterized in that:
    所述释组合物包括含药层片芯，或包括含药层片芯和助推层片芯；The release composition includes a drug-containing layer tablet core, or includes a drug-containing layer tablet core and a booster layer tablet core;
    所述包衣膜可以选自功能性包衣膜和/或水溶性薄膜衣；The coating film can be selected from a functional coating film and/or a water-soluble film coating;
    所述含药层片芯中的载体可以选自增溶剂、增稠剂、粘合剂、助流剂和润滑剂中的一种或多种；The carrier in the drug-containing layer tablet core can be selected from one or more of solubilizers, thickeners, binders, glidants and lubricants;
    所述的助推层片芯可以包含渗透压调节剂、溶胀剂、粘合剂、着色剂和润滑剂中的一种或多种；The booster layer tablet core may contain one or more of osmotic pressure regulators, swelling agents, binders, coloring agents and lubricants;
    所述的功能性包衣膜为半渗透膜；例如，所述的半渗透膜包含成膜材料、致孔剂和增塑剂中的一种或多种；和/或，The functional coating film is a semi-permeable membrane; for example, the semi-permeable membrane contains one or more of film-forming materials, porogens and plasticizers; and/or,
    所述的水溶性薄膜衣为胃溶型薄膜衣。The water-soluble film coating is stomach-soluble film coating.
  5. 根据权利要求3或4所述的缓释组合物，其特征在于：The sustained-release composition according to claim 3 or 4, characterized in that:
    所述的含药层片芯中，以硝苯地平计，所述硝苯地平、其药学上可接受的盐和溶剂合物的总质量百分比含量可以为1％～30％；和/或，In the drug-containing layer tablet core, based on nifedipine, the total mass percentage content of the nifedipine, its pharmaceutically acceptable salts and solvates may be 1% to 30%; and/or,
    所述的含药层片芯中，以美托洛尔计，所述美托洛尔、其药学上可接受的盐和溶剂合物的总质量百分比含量可以为1％～15％。In the drug-containing layer tablet core, based on metoprolol, the total mass percentage of metoprolol, its pharmaceutically acceptable salts and solvates may be 1%-15%.
  6. 根据权利要求3-5任一项所述的缓释组合物，其特征在于：The sustained-release composition according to any one of claims 3-5, characterized in that:
    所述的含药层片芯中：In the described drug-containing layer tablet core:
    所述的增溶剂选自十二烷基硫酸钠和吐温80中的一种或多种；优选地，所述的增溶剂的质量百分比含量可以为1％～15％；The solubilizer is selected from one or more of sodium lauryl sulfate and Tween 80; preferably, the mass percentage content of the solubilizer can be 1% to 15%;
    所述的增稠剂选自聚氧乙烯、羟丙甲纤维素、羟乙纤维素、共聚维酮、阿拉伯胶、聚乙烯吡咯烷酮和海藻酸钠中的一种或多种；优选地，所述的增稠剂的质量百分比含量可以为1％～85％；The thickener is selected from one or more of polyoxyethylene, hypromellose, hydroxyethylcellulose, copovidone, gum arabic, polyvinylpyrrolidone and sodium alginate; preferably, the The mass percent content of the thickener can be 1% to 85%;
    所述的粘合剂选自共聚维酮、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基纤维素中的一种或多种；优选地，所述的粘合剂的质量百分比含量可以为2％～15％；The binder is selected from one or more of copovidone, polyvinylpyrrolidone, pregelatinized starch, and hydroxypropyl cellulose; preferably, the mass percent content of the binder can be 2 %～15%;
    所述的助流剂选自滑石粉、微粉硅胶、胶态二氧化硅中的一种或多种；优选地，所述的助流剂的质量百分比含量可以为0.10％～5.00％；The glidant is selected from one or more of talcum powder, micropowder silica gel, and colloidal silicon dioxide; preferably, the mass percentage content of the glidant can be 0.10% to 5.00%;
    所述的润滑剂选自硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬脂富马酸盐和微粉 硅胶中的一种或多种；优选地，所述的润滑剂的质量百分比含量可以为0.10％～10.00％；Described lubricant is selected from one or more in metal stearate, stearic acid, talcum powder, stearic acid ester, stearyl fumarate and micropowder silica gel; Preferably, described lubricant The mass percentage content can be 0.10% to 10.00%;
    和/或，and / or,
    所述的助推层片芯中：In the described booster layer core:
    所述的渗透压调节剂选自氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种；优选地，所述的渗透压调节剂的质量百分比含量可以为5.00％～50.00％；The osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose and lactose; preferably, the The mass percent content of the osmotic pressure regulator can be 5.00% to 50.00%;
    所述的溶胀剂选自卡波姆、羧甲淀粉钠、羟丙甲纤维素、阿拉伯胶、海藻酸钠和聚氧乙烯中的一种或多种；优选地，所述的溶胀剂的质量百分比含量可以为5.00％～75.00％；Described swelling agent is selected from one or more in carbomer, sodium starch glycolate, hypromellose, gum arabic, sodium alginate and polyoxyethylene; Preferably, the quality of described swelling agent The percentage content can be 5.00% to 75.00%;
    所述的粘合剂选自共聚维酮、聚乙烯吡咯烷酮、羟乙纤维素中的一种或多种；优选地，所述的粘合剂的质量百分比含量可以为1.00％～10.00％；The binder is selected from one or more of copovidone, polyvinylpyrrolidone, and hydroxyethyl cellulose; preferably, the mass percent content of the binder can be 1.00% to 10.00%;
    所述的着色剂选自红氧化铁和/或氧化铁黄；优选地，所述的着色剂的质量百分比含量可以为0.10％～5.00％；The coloring agent is selected from red iron oxide and/or iron oxide yellow; preferably, the mass percentage content of the coloring agent can be 0.10% to 5.00%;
    所述的润滑剂可以选自硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬脂富马酸盐和微粉硅胶中的一种或多种；优选地，所述的润滑剂的质量百分比含量可以为0.10％～5.00％。Described lubricant can be selected from one or more in metal stearate, stearic acid, talcum powder, stearic acid ester, stearyl fumarate and micropowder silica gel; Preferably, described lubricant The mass percentage content of the agent can be 0.10%-5.00%.
  7. 根据权利要求4所述的缓释组合物，其特征在于：The sustained-release composition according to claim 4, characterized in that:
    所述的成膜材料选自醋酸纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素、丙烯酸树脂和甲基丙烯酸树脂中的一种或多种；The film-forming material is selected from one or more of cellulose acetate, ethyl cellulose, cellulose acetate phthalate, acrylic resin and methacrylic resin;
    所述的致孔剂选自聚乙二醇和/或羟丙基纤维素和/或聚维酮；The porogen is selected from polyethylene glycol and/or hydroxypropyl cellulose and/or povidone;
    所述的增塑剂选自聚乙二醇、三醋酸甘油酯、柠檬酸甘油酯、甘油酯和邻苯二甲酸酯中的一种或多种。The plasticizer is selected from one or more of polyethylene glycol, glyceryl triacetate, glyceryl citrate, glyceride and phthalate.
  8. 权利要求3-7任一项所述的缓释组合物的制备方法，其特征在于，所述制备方法包括如下步骤：The preparation method of the sustained-release composition described in any one of claims 3-7, is characterized in that, described preparation method comprises the steps:
    (a)将上述含药层片芯与助推层片芯各自的成分分别混合，其中各层混合粉的制备工艺可以选自例如粉末直压、流化制粒、干法制粒、湿法制粒等；(a) Mix the respective components of the drug-containing layer core and the booster layer core respectively, wherein the preparation process of the mixed powder of each layer can be selected from, for example, powder direct compression, fluidized granulation, dry granulation, wet granulation Wait;
    (b)压制双层片芯；(b) compressing the double-layer tablet core;
    (c)将双层片芯包衣(如半透膜包衣)；(c) coating the double-layer tablet core (such as semi-permeable membrane coating);
    (d)在所述含药层片芯的一侧打孔；(d) punch holes on one side of the drug-containing layer tablet core;
    (e)包上普通薄膜衣即可得到所述的硝苯地平美托洛尔缓释组合物。(e) The nifedipine and metoprolol sustained-release composition can be obtained by wrapping it with a common film coat.
  9. 一种缓释制剂，其特征在于，所述缓释制剂包含权利要求1-7任一项所述的缓释组合物；A sustained-release preparation, characterized in that, the sustained-release preparation comprises the sustained-release composition according to any one of claims 1-7;
    优选地，所述缓释制剂为缓释片。Preferably, the sustained-release preparation is a sustained-release tablet.
  10. 权利要求1-7任一项所述的缓释组合物或权利要求9的缓释制剂在制备药物中的应用，其中所述药物用于预防和/或治疗高血压或与其相关的症状，如心率失常或心绞痛。The application of the sustained-release composition according to any one of claims 1-7 or the sustained-release formulation of claim 9 in the preparation of medicines, wherein the medicines are used to prevent and/or treat hypertension or symptoms related thereto, such as Arrhythmia or angina.
PCT/CN2022/095871 2021-05-28 2022-05-30 Nifedipine-metoprolol sustained-release composition, preparation method therefor and use thereof WO2022247952A1 (en)

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