WO2019101151A1 - Composition pharmaceutique de hs-25 et d'inhibiteur de la hmg-coa réductase - Google Patents

Composition pharmaceutique de hs-25 et d'inhibiteur de la hmg-coa réductase Download PDF

Info

Publication number
WO2019101151A1
WO2019101151A1 PCT/CN2018/117087 CN2018117087W WO2019101151A1 WO 2019101151 A1 WO2019101151 A1 WO 2019101151A1 CN 2018117087 W CN2018117087 W CN 2018117087W WO 2019101151 A1 WO2019101151 A1 WO 2019101151A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
granules
granulating
pharmaceutical composition
povidone
Prior art date
Application number
PCT/CN2018/117087
Other languages
English (en)
Chinese (zh)
Inventor
丁立
代军
冯春荣
代常亮
Original Assignee
浙江海正药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江海正药业股份有限公司 filed Critical 浙江海正药业股份有限公司
Priority to CN202311288927.5A priority Critical patent/CN117085011A/zh
Priority to CN201880073253.8A priority patent/CN111836620B/zh
Publication of WO2019101151A1 publication Critical patent/WO2019101151A1/fr

Links

Classifications

    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a composition of Heze Maibu and HMG-CoA reductase inhibitor and application thereof.
  • Cardiovascular disease is one of the most common and serious diseases that endanger human health (especially in the elderly).
  • Dyslipidemia is an important risk factor for atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases.
  • Lipid-lowering drugs are very important for the prevention and treatment of cardiovascular diseases.
  • statins are the most widely used and most effective clinically recommended lipid-lowering drugs.
  • Commonly used drugs are: lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, long-acting fluvastatin sustained-release tablets, rosuvastatin, pitavastatin and the like.
  • atorvastatin the highest market share is atorvastatin.
  • statins are less than those of other hypolipidemic drugs.
  • the most common symptoms are mild gastrointestinal reactions, rhinitis, sinusitis, headache, sore throat, flu syndrome, arthritis, chest pain, insomnia, etc.
  • the haize wheat cloth of the present invention is a novel intestinal cholesterol absorption inhibitor disclosed in Chinese Patent No. CN101993403A.
  • Haize Maibu has the following structural formula:
  • one of the technical solutions of the present invention is to provide a pharmaceutical composition comprising 0.5 to 20% by weight of Haize Maibu; and 1 to 80% by weight of at least one HMG-CoA reductase Inhibitor.
  • the compositions of the invention are stable.
  • the HMG-CoA reductase inhibitor is a statin or a salt thereof
  • the statin is, for example, lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluoride
  • the salt of the statin is pharmaceutically acceptable, and the salt is not particularly limited; preferably , in which lovastatin, simvastatin, atorvastatin, rosuvastatin, pitavastatin and rosuvastatin are in the form of calcium salts; pravastatin, fluvastatin, cerivastatin are in the form of sodium salts .
  • statin is atorvastatin, rosuvastatin or simvastatin.
  • the pharmaceutical composition may further contain an excipient which is an excipient conventionally used in the art; preferably, the excipient may be a stabilizer, a surfactant, a filler, a binder, disintegration One or more of a agent and a lubricant.
  • an excipient which is an excipient conventionally used in the art; preferably, the excipient may be a stabilizer, a surfactant, a filler, a binder, disintegration One or more of a agent and a lubricant.
  • the stabilizer may be a stabilizer conventionally used in the art, and may be, for example, a carbonate, a hydrogencarbonate or a phosphate, or an antioxidant such as butylated hydroxyanisole, citric acid or butylated hydroxytoluene. And the like, preferably, the stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid or butylated hydroxytoluene.
  • the surfactant may be a surfactant conventionally used in the art, and may be, for example, an anionic surfactant or a nonionic surfactant; examples of anionic surfactants are: sodium stearate, potassium stearate , sodium oleate, calcium stearate, sodium lauryl sulfate, etc.; examples of nonionic surfactants are: fatty acid sorbitan (span), polysorbate, meze (myrj), benzze (brij ), poloxamer, etc.; preferably, the surfactant is at least one of sodium lauryl sulfate or polysorbate.
  • anionic surfactants are: sodium stearate, potassium stearate , sodium oleate, calcium stearate, sodium lauryl sulfate, etc.
  • examples of nonionic surfactants are: fatty acid sorbitan (span), polysorbate, meze (myrj), benzze (brij ), poloxamer
  • the filler may be a filler conventionally used in the art, such as starch, sugar, cellulose, inorganic salts and the like; preferably, the filler is lactose, microcrystalline cellulose, pre-glue At least one of the starches.
  • the binder may be a binder conventionally used in the art, and may be, for example, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, povidone, gum arabic, sucrose, etc.;
  • the binder is at least one of hydroxypropylcellulose and povidone.
  • the disintegrant may be a disintegrator conventionally used in the art, and may be, for example, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, sodium alginate, corn starch, Low-substituted hydroxypropylcellulose; preferably, the disintegrant is at least one of croscarmellose sodium and crospovidone.
  • the lubricant may be a lubricant conventionally used in the art, and may be, for example, magnesium stearate, stearic acid, sodium fumarate, PEG 6000, glyceryl behenate, talc, etc.; preferably, The lubricant is at least one of magnesium stearate and talc.
  • the composition of the present invention may comprise 1 to 25% by weight of calcium carbonate, 0.005 to 0.1% by weight of butylated hydroxytoluene, 0.1 to 10% by weight of sodium lauryl sulfate, 0.05 to 1.0% by weight.
  • Polysorbate 1 to 10% by weight of croscarmellose sodium, 1 to 10% by weight of crospovidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of poly-dimensional A ketone, one or more of 0.1 to 5% by weight of hydroxypropylcellulose, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.
  • a second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 0.5 to 20% by weight of hydra zenet and 1 to 80% by weight of atorvastatin.
  • the pharmaceutical composition contains from 1 to 10% by weight of Hazel malt and from 1 to 30% by weight of atorvastatin.
  • the composition may also optionally comprise a stabilizer.
  • the stabilizer may be a stabilizer conventionally used in the art; for example, it may be a carbonate, a hydrogencarbonate, a phosphate or a butylated hydroxytoluene; etc.; preferably, the stabilizer is at least one of calcium carbonate or butylated hydroxytoluene.
  • the addition of calcium carbonate or butylated hydroxytoluene to the composition of the present invention is advantageous for the stability of the formulation. More preferably, the pharmaceutical composition may comprise 5 to 25% by weight of calcium carbonate and 0.005% to 0.05% by weight of butoxyl. Toluene.
  • the pharmaceutical composition may also optionally comprise a surfactant.
  • the surfactant may be a surfactant conventionally used in the art, and may be, for example, an anionic surfactant or a nonionic surfactant.
  • anionic surfactants are: sodium stearate, potassium stearate, sodium oleate, calcium stearate, sodium lauryl sulfate, and the like;
  • nonionic surfactants are: fatty acid sorbitan Disk), polysorbate, myrj, brij, poloxamer, etc.; preferably, the surfactant is at least one of sodium lauryl sulfate or polysorbate.
  • compositions of the present invention may be more beneficial to the efficacy of the pharmaceutical compositions. More preferably, the pharmaceutical composition may contain 0.1 to 5% by weight of sodium lauryl sulfate and 0.05 to 0.5% by weight of polysorbate.
  • the pharmaceutical composition is in an oral form comprising, for example, an oral dosage unit having a total weight of from 100 to 800 mg, and further comprising: a filler, a binder, a disintegrant, and a lubricant.
  • a filler may be a filler conventionally used in the art, for example, may be starch, sugar, cellulose, inorganic salts, etc.; preferably, the filler is lactose, microcrystalline cellulose At least one of them.
  • the binder may be a binder conventionally used in the art, and may be, for example, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, povidone, acacia, sucrose, etc.; preferably, The binder is at least one of hydroxypropylcellulose and povidone.
  • the disintegrant may be a disintegrator conventionally used in the art, and may, for example, be croscarmellose sodium, crospovidone, sodium carboxymethyl starch, sodium alginate, corn starch, low substitution. Hydroxypropylcellulose; preferably, the disintegrant is at least one of croscarmellose sodium and crospovidone.
  • the lubricant may be a lubricant conventionally used in the art, and may be, for example, magnesium stearate, stearic acid, sodium fumarate, PEG 6000, glyceryl behenate, talc, etc.; preferably, the lubrication
  • the agent is magnesium stearate.
  • the pharmaceutical composition may contain 1 to 10% by weight of croscarmellose sodium, 1 to 10% by weight of crospovidone, and 10 to 50% by weight of microcrystalline cellulose. 0.1 to 5% by weight of povidone, 0.1 to 5% by weight of hydroxypropylcellulose, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.
  • a third aspect of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising 0.5 to 20% by weight of haize wheat cloth and 1 to 80% by weight of rosuvastatin.
  • the pharmaceutical composition contains from 1 to 10% by weight of hexagram and from 1 to 30% by weight of rosuvastatin.
  • the composition may also optionally comprise a stabilizer.
  • the stabilizer may be a stabilizer conventionally used in the art, and may be, for example, a carbonate, a hydrogencarbonate or a phosphate; etc.; preferably, the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene.
  • the addition of calcium carbonate or butylated hydroxytoluene to the composition of the present invention is advantageous for the stability of the formulation. More preferably, the pharmaceutical composition may comprise from 1 to 15% by weight of calcium carbonate and from 0.005 to 0.05% by weight of butylated hydroxytoluene. .
  • the pharmaceutical composition may also optionally comprise a surfactant.
  • the surfactant may be a surfactant conventionally used in the art, and may be, for example, an anionic surfactant or a nonionic surfactant.
  • anionic surfactants are: sodium stearate, potassium stearate, sodium oleate, calcium stearate, sodium lauryl sulfate, etc.
  • nonionic surfactants are: fatty acid sorbitan Disk), polysorbate, mezer (myrj), benzze (brij), poloxamer, and the like.
  • the surfactant is sodium lauryl sulfate.
  • the addition of sodium lauryl sulfate to the compositions of the present invention may be more beneficial to the efficacy of the pharmaceutical compositions. More preferably, the pharmaceutical composition may contain 0.1 to 6% by weight of sodium lauryl sulfate.
  • the pharmaceutical composition may contain 1 to 10% by weight of crospovidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of povidone, and 10 to 50% by weight.
  • a fourth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising a haize wheat cloth and an HMG-CoA reductase inhibitor, the method comprising the HMG-CoA reductase inhibitor, Heze Mai Mai Combined with optional excipients.
  • a fifth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising a haize wheat cloth and an HMG-CoA reductase inhibitor, comprising the steps of:
  • the HMG-CoA reductase inhibitor granule portion of the step (1) can be granulated with water as a solvent
  • the portion of the haize mai granules of the step (2) can be granulated with water, an organic solvent or a mixture thereof; preferably
  • the portion of the Hezemeat granules of the step (2) may be granulated with water, an alcohol, chloroform, acetone, acetonitrile or the like, and a mixture thereof, preferably granulated with water, an alcohol or a mixture thereof, more preferably with an alcohol and
  • the mixture of water is granulated, and a mixture of ethanol and water is preferably used for granulation.
  • a method for preparing a pharmaceutical composition comprising haize wheat cloth and atorvastatin, comprising the steps of:
  • the preparation method comprises the following steps:
  • the granules after the step (3) and the step (6) are granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate, and tableted.
  • a seventh aspect of the present invention provides a method for preparing a pharmaceutical composition comprising Heiser Maibu and Atorvastatin, comprising the steps of:
  • the preparation method comprises the following steps:
  • the granules after the step (3) is granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate to obtain a first total mixed granule;
  • step (6) granules after the step (6) is granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate to obtain a second total mixed granule;
  • Eighth of the technical solution of the present invention is to provide a method for preparing a pharmaceutical composition comprising haize wheat cloth and rosuvastatin, comprising the following steps:
  • the preparation method comprises the following steps:
  • the granules after the granulation in the step (3) and the step (6) are mixed, optionally mixed with the crospovidone, and then uniformly mixed with magnesium stearate, and tableted.
  • the preparation method comprises the following steps:
  • the granules after the granulation in the step (3) and the step (6) are mixed, optionally mixed with the crospovidone, and then uniformly mixed with magnesium stearate, and tableted.
  • a ninth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising haize malbe and rosuvastatin, comprising the steps of:
  • the preparation method comprises the following steps:
  • the granules after the step (3) is granulated, optionally mixed with crospovidone, and then uniformly mixed with magnesium stearate to obtain a first total mixed granule;
  • the granules after the step (6) are optionally mixed with crospovidone, and then uniformly mixed with magnesium stearate to obtain a second total mixed granule;
  • a pharmaceutical dosage unit comprising 5 to 20 mg of methadone and 5 to 80 mg of atorvastatin.
  • the dose of the Hazel malt is 5 mg, 10 mg or 20 mg; and the dose of the atorvastatin is 5 mg, 10 mg, 20 mg, 40 mg or 80 mg.
  • the pharmaceutical dosage unit is an oral dosage unit.
  • the dosage unit can optionally contain calcium carbonate as a component.
  • the dosage unit may contain from 5 to 100 mg of calcium carbonate.
  • the dosage unit can optionally contain calcium carbonate, butylated hydroxytoluene as a component.
  • the dosage unit may contain 5 to 100 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.
  • the dosage unit can optionally contain sodium lauryl sulfate as a component.
  • the dosage unit may contain from 0.5 to 5 mg of sodium lauryl sulfate.
  • the dosage unit can optionally contain sodium lauryl sulfate, polysorbate as a component.
  • the dosage unit may contain from 0.5 to 5 mg of sodium lauryl sulfate, from 0.1 to 5 mg of polysorbate.
  • the dosage unit may further comprise 1 to 50 mg of croscarmellose sodium, 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg of povidone, and 0.5 to 10 mg of hydroxy group.
  • croscarmellose sodium 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg of povidone, and 0.5 to 10 mg of hydroxy group.
  • Propylcellulose 10 to 250 mg of lactose, 0.1 to 10 mg of magnesium stearate.
  • the dosage unit may further comprise 1 to 50 mg of croscarmellose sodium, 1 to 30 mg of crospovidone, 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg.
  • crospovidone 0.5 to 10 mg of hydroxypropylcellulose, 10 to 250 mg of lactose, 0.1 to 10 mg of magnesium stearate.
  • a pharmaceutical dosage unit comprising 5 to 20 mg of methadone and 5 to 80 mg of rosuvastatin, preferably, the dose of the granule is 5 mg, 10 mg or 20 mg; and the dose of the rosuvastatin is 5 mg, 10 mg, 20 mg or 40 mg.
  • the pharmaceutical dosage unit is an oral dosage unit.
  • the dosage unit can optionally contain calcium carbonate as a component.
  • the dosage unit may contain from 1 to 50 mg of calcium carbonate.
  • the dosage unit can optionally contain calcium carbonate, butylated hydroxytoluene as a component.
  • the dosage unit may contain from 1 to 50 mg of calcium carbonate and from 0.01 to 0.2 mg of butylated hydroxytoluene.
  • the dosage unit can optionally contain sodium lauryl sulfate as a component.
  • the dosage unit may contain from 0.5 to 10 mg of sodium lauryl sulfate.
  • the dosage unit may further comprise 5 to 40 mg of crospovidone, 20 to 250 mg of microcrystalline cellulose, 1 to 20 mg of povidone, 20 to 250 mg of lactose, 0.1 to 5 mg of magnesium stearate.
  • the povidone is preferably povidone K30.
  • the pharmaceutical composition or the pharmaceutical dosage unit of the present invention may be in the form of a capsule, a tablet, a granule, a powder, a solution or a tablet.
  • composition of the haize wheat cloth and the HMG-CoA reductase inhibitor of the present invention may be in various forms, such as a tablet, and the composition of the invention is reasonable in design, easy to prepare a suitable preparation, and the preparation has good stability. The quality is controllable.
  • the pharmaceutical composition containing the haize wheat cloth and the HMG-CoA reductase inhibitor according to the present invention has the following advantages:
  • the present invention combines Heze Metz with an HMG-CoA reductase inhibitor, particularly when the HMG-CoA reductase inhibitor is a statin, and has a good synergistic effect. It can have important clinical benefit by reducing the incidence of myocardial toxicity and the incidence of cardiovascular events by reducing the dose of statins.
  • the pharmaceutical composition provided by the invention not only reduces the adverse reaction by reducing the dose of the statin by synergistic effect, but has higher safety and clinical adverse reaction than the combination of the similar mechanism drug and the statin drug. Fewer, the patient's medication compliance is also better.
  • the pharmaceutical composition provided by the present invention has stable properties, and the prepared preparation product can achieve stable storage requirements by using ordinary packaging.
  • excipients can be used in the pharmaceutical composition of the present invention, and the excipients can be all common excipients, and the prepared preparation has controllable quality and good stability.
  • the preparation method of the pharmaceutical composition of the invention is simple in process, convenient in operation, and suitable for industrialized large-scale production.
  • Heze Metz combined with statins and ezetimibe combined with statins are pharmacologically equivalent, but the safety of Heze Maibu combined with statins is significantly better than that of ezetimibe combined with statins. Drugs are better and have greater advantages in clinical applications.
  • the Herzet Maibu (HS-25), Ezetimibe, atorvastatin, rosuvastatin and simvastatin used in the following examples were derived from Zhejiang Sea. Zheng Pharmaceutical Co., Ltd., or prepared according to the methods of the prior art.
  • atorvastatin, rosuvastatin and simvastatin used in the following examples are in the form of calcium salts, and the contents thereof refer to the contents of atorvastatin, rosuvastatin and simvastatin.
  • the weight of tovatatin calcium is 10.83 mg.
  • Example 6 the specification is 20 mg/20 mg of Herzema mazulastatin tablets, of which 20 mg refers to the weight of rosuvastatin, and if the weight of rosuvastatin in the prescription is converted to rosuvastatin
  • the weight of calcium is 20.83 mg.
  • Example 1 Haazawa Maibu Atorvastatin tablets, specifications: 5 mg/10 mg, each weighing 92.25 mg, the composition is shown in Table 1.
  • Example 2 Azevastatin tablets of Heze Mbe, specifications: 5 mg / 20 mg, each piece weighing 143.50 mg, see Table 2 for the composition.
  • Example 3 Azevastatin tablets of Heze Mbe, specifications: 10 mg/10 mg, each piece weighing 133.25 mg, see Table 3 for the composition.
  • Example 4 Azevastatin tablets of Heze Mbe, specifications: 10 mg / 20 mg, each tablet weighs 184.50 mg, see Table 4 for the composition.
  • Example 5 Azevastatin tablets of Heze Mbe, specifications: 10 mg/80 mg, each weighing 492.00 mg, and the composition is shown in Table 5.
  • Example 6 Hazel Maibrizalvastatin tablets, specifications: 20 mg / 20 mg, each tablet weight 460.00 mg, see Table 6 for the composition.
  • Example 7 Hazel Maibrizalvastatin tablets, specifications: 10 mg / 20 mg, each piece weighing 297.00 mg, see Table 7 for the composition.
  • Example 8 Hazel Maibrizalvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 393.00 mg, and the composition is shown in Table 8.
  • Example 9 Herzema mazulastatin tablets, specifications: 10 mg/10 mg, each weighing 230.00 mg, see Table 9 for the composition.
  • Example 10 Heze Metz simvastatin tablets, specifications: 6 mg / 20 mg, each tablet weighs 100.00 mg, the composition is shown in Table 10.
  • Example 11 Stability study of Azevastatin tablets of Haize Maibu (5 mg/10 mg specification)
  • Method 1 The tablets prepared in Example 1 were packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed at a temperature of 40 ° C ⁇ 2 ° C and a humidity (RH) of 75% ⁇ 5%. Conduct stability studies, the test results are shown in Table 11:
  • Method 2 The tablet prepared in Example 1 was packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed at a temperature of 25 ° C ⁇ 2 ° C and a humidity of 60% ⁇ 5% for stability. Study, the test results are shown in Table 12:
  • Example 12 Stability study of azevastatin tablets of Heze Mbe (5mg/20mg specification)
  • Method 1 The tablets prepared in Example 2 were packaged in a high-density polyethylene bottle (containing 2 g of desiccant) and placed at a temperature of 40 ° C ⁇ 2 ° C and a humidity of 75% ⁇ 5% for stability. Study, the test results are shown in Table 13:
  • Method 2 The tablet prepared in Example 2 was packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed at a temperature of 25 ° C ⁇ 2 ° C and a humidity of 60% ⁇ 5% for stability. Study, the test results are shown in Table 14:
  • Example 13 Stability study of auzestatin tablets of Heze Mbe (10 mg/10 mg specification)
  • Method 1 The tablets prepared in Example 3 were packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed under conditions of 40 ° C ⁇ 2 ° C and RH 75% ⁇ 5% for stability studies. The test results are shown in Table 15:
  • Method 2 The tablets prepared in Example 3 were packaged in a high-density polyethylene bottle (containing 2 g of desiccant), placed at 25 ° C ⁇ 2 ° C, humidity 60% ⁇ 5%, for stability study The test results are shown in Table 16:
  • Method 1 The tablets prepared in Example 4 were packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed under the conditions of 40 ° C ⁇ 2 ° C and RH 75% ⁇ 5% for stability study. See Table 17:
  • Method 2 The tablet prepared in Example 4 was packaged in a high-density polyethylene bottle (containing 2 g of a desiccant), and placed under the conditions of 25 ° C ⁇ 2 ° C and a humidity of 60% ⁇ 5% for stability study. The results are shown in Table 18:
  • Example 15 Stability study of azevastatin tablets of Heze Mbe (10 mg/80 mg size)
  • Example 5 The tablet prepared in Example 5 was packaged in a high-density polyethylene bottle (containing 2 g of a desiccant) and placed at a temperature (40 ° C ⁇ 2 ° C) and humidity (RH 75% ⁇ 5%) for stabilization. Sex studies, the results are shown in Table 19:
  • Example 6 The tablets prepared in Example 6 were placed in a bare piece (without packaging) at 50 ° C and a humidity of 75% for stability studies. The results are shown in Table 20:
  • Example 17 Stability study of Heze Metz simvastatin tablets (6 mg/20 mg size)
  • Example 10 The tablets prepared in Example 10 were placed in a high temperature (60 ° C), high humidity (humidity 92.5%, 25 ° C), strong light (4500 Lx ⁇ 500 Lx) conditions for stability studies without measurement.
  • the stability data obtained are shown in Table 21:
  • Rhesus monkeys with primary hyperlipidemia blood lipid index: TC>6.22mmol/L, LDL>4.91mmol/L, HDL ⁇ 1.55mmol/L, TG>1.0mmol/L
  • high fat diet to induce blood lipids Levels continued to stabilize for at least 2 weeks (see pre-dose data)
  • oral administration of Heiszema Maibu (ie HS-25) or simvastatin and oral administration of ezetimibe for 4 weeks.
  • the experimental grouping and testing indicators are shown in Table 22:
  • HS-25 and ezetimibe alone or in combination with simvastatin had no significant effect on body weight, blood biochemistry, blood routine, and blood glucose of hyperlipidemic rhesus monkeys, and no abnormal clinical manifestations were observed.
  • the HS-25 single-use group and the ezetimibe alone group had a significant effect on reducing TC, which was superior to the simvastatin single-use group, compared with the model group, P ⁇ 0.01, indicating significant statistical differences.
  • the pharmacodynamic effect gradually increased with the administration time, suggesting that HS-25 and ezetimibe have a certain persistence for the reduction of TC.
  • the animal model of primary hyperlipidemia rhesus monkey was selected (the blood lipid index was: TC>6.22mmol/L, LDL>4.91mmol/L, HDL ⁇ 1.55mmol/L, TG>1.0mmol/L), plus high fat diet. After induced, high blood lipid levels continued to be stable, oral administration of atorvastatin or combined with Heze Maibu (HS-25) or ezetimibe animals for 3 months, observed HS-25 and ezetimibe The effect of combined atorvastatin on blood lipids.
  • the experimental grouping and testing indicators are shown in Table 25:
  • Atorvastatin alone or atorvastatin combined with HS-25 or ezetimibe had no significant effect on rhesus monkey weight, blood biochemistry, blood routine and blood glucose, and no abnormal clinical manifestations were observed.
  • the TC content of the model group was relatively stable during the test period, and no significant fluctuations were observed, which proved that the model was stable.
  • Example 20 Repeated dose toxicity study of Heze Metz combined with atorvastatin in Beagle dogs
  • This beagle dog has drooling and is associated with atorvastatin.
  • Other indicators such as body weight, food intake, electrocardiogram, blood routine, gross anatomy and pathology were not abnormal; the decrease in blood lipids was dose-related to atorvastatin.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • HS-25 combined with atorvastatin only showed an increase in ALT, and there was no abnormality in AST.
  • the toxicity of Zetia combined with atorvastatin was not only increased in ALT at 3/10 and 30/10 mg/kg, but also increased in AST. high.
  • HS-25 combined with atorvastatin (30/10 mg/kg) was ALT: 112.8; the toxicity of Zetia combined with atorvastatin (0.3/1 mg/kg) was: ALT: 112.8; suggesting that HS-25 combined with Ato
  • the safety of statin is at least 10 times greater than the safety of Zetia combined with atorvastatin.
  • HS-25 combined with atorvastatin was 30/10, 100/10, 100/30 mg/kg ALT: 112.8, 188.3, 242.8, respectively, and the increase of ALT was small; Zetia combined with Ato
  • the toxicity of statin was 0.3/1, /3/1, 3/10, 30/10 mg/kg for ALT: female 112.8, 156.3, 990.3, 657.0; male 88.8, 106.3, 391.5, 1133.5, ALT increased with dose. The increase was significantly greater, suggesting that hepatotoxicity is more pronounced.
  • the combination of HS-25 and atorvastatin is significantly safer than the combination of Zetia and atorvastatin, and the safety factor is about 10 times that of Beagle dogs.
  • Example 21 Azevastatin tablets of Heze Mbe, specifications: 20 mg / 20 mg, each tablet weighs 480 mg, and the composition is shown in Table 31.
  • Example 22 Azevastatin tablets of Heze Mbe, specifications: 20 mg/10 mg, each tablet weighing 480 mg, see Table 32 for the composition.
  • Example 23 Azevastatin tablets of Haize Maibu, specifications: 10 mg / 20 mg, each tablet weighs 315 mg, and the composition is shown in Table 33.
  • Example 24 Hazel mai atorvastatin tablets, specifications: 10 mg/10 mg, each tablet weighing 315 mg, see Table 34 for the composition.
  • Example 25 Heze Mesobruvastatin Tablets, Specification: 20 mg/20 mg, each weighing 460 mg, see Table 35 for the composition.
  • Example 26 Hazel Maibresulvastatin tablets, specifications: 20 mg/10 mg, each weighing 460 mg, see Table 36 for the composition.
  • Example 27 Herzema mazulastatin tablets, specifications: 10 mg / 20 mg, each tablet weighs 295 mg, see Table 37 for the composition.
  • Example 28 Hessian Maibresulvastatin tablets, specifications: 10 mg/10 mg, each tablet weighing 295 mg, see Table 38 for the composition.
  • Example 29 Hazel Maibresulvastatin tablets, specifications: 20 mg / 20 mg, each tablet weighs 460 mg, see Table 39 for the composition.
  • Example 30 Stability study of atorvastatin calcium tablets of Haize Maibu (20 mg/10 mg specification)
  • Example 22 The tablets prepared in Example 22 were placed in bottles and placed under accelerated conditions (40 ° C / 75% RH) for stability study. The stability data measured are shown in Table 40:
  • Example 31 Azerbaijan and atorvastatin tablets, specifications: 20 mg/10 mg, each tablet weighing 480 mg, see Table 41 for the composition.
  • Example 32 Hazel mai atorvastatin tablets, specifications: 20 mg / 20 mg, each tablet weighs 630 mg, the composition is shown in Table 42.
  • Example 33 Azerbaijan and atorvastatin tablets, specifications: 10 mg / 20 mg, each tablet weighing 465 mg, see Table 43 for the composition.
  • Example 34 Stability study of auzestatin tablets of Heze Mbe (20 mg/20 mg size)
  • Method 1 The tablets prepared in Example 21 were placed in a double aluminum package and placed under the conditions of 40 ° C ⁇ 2 ° C and RH 75% ⁇ 5% for stability studies. The test results are shown in Table 44:
  • Method 2 The tablets prepared in Example 21 were placed in a double aluminum package and placed under the conditions of 25 ° C ⁇ 2 ° C and a humidity of 60% ⁇ 5% for stability studies. The test results are shown in Table 45:
  • Example 35 Stability study of auzestatin tablets of Heze Mbe (20 mg/10 mg size)
  • Method 1 The tablets prepared in Example 22 were placed in a double aluminum package and placed under the conditions of 40 ° C ⁇ 2 ° C and RH 75% ⁇ 5% for stability studies. The test results are shown in Table 46:
  • Method 2 The tablets prepared in Example 22 were placed in a double aluminum package and placed under the conditions of 25 ° C ⁇ 2 ° C and a humidity of 60% ⁇ 5% for stability studies. The test results are shown in Table 47:
  • Example 36 Stability study of auzestatin tablets of Heze Mbe (10 mg/20 mg size)
  • Method 1 The tablets prepared in Example 23 were placed in a double aluminum package and placed under the conditions of 40 ° C ⁇ 2 ° C and RH 75% ⁇ 5% for stability study. The test results are shown in Table 48:
  • Method 2 The tablets prepared in Example 23 were placed in a double aluminum package and placed under the conditions of 25 ° C ⁇ 2 ° C and a humidity of 60 % ⁇ 5% for stability studies. The test results are shown in Table 49:
  • Example 37 Stability study of haize mappa atorvastatin tablets (10 mg/10 mg specification)
  • Method 1 The tablets prepared in Example 24 were placed in a double aluminum package and placed under the conditions of 40 ° C ⁇ 2 ° C and RH 75% ⁇ 5% for stability study. The test results are shown in Table 50:
  • Method 2 The tablets prepared in Example 24 were placed in a double aluminum package and placed under the conditions of 25 ° C ⁇ 2 ° C and a humidity of 60% ⁇ 5% for stability studies. The test results are shown in Table 51:
  • Example 38 Hazel Maibrizalvastatin tablets, specifications: 20 mg/10 mg, each tablet weighing 320 mg, see Table 52 for the composition.
  • Example 39 Haize Maibrizalvastatin tablets, specifications: 20 mg/5 mg, each tablet weighing 270 mg, see Table 53 for the composition.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Inorganic Chemistry (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique, qui comprend HS-25 et un inhibiteur de la HMG-CoA réductase, et qui peut en outre comprendre un ou plusieurs matériaux auxiliaires parmi le carbonate de calcium, l'hydroxyanisole butylé, l'hydroxytoluène butylé, l'acide citrique, le laurylsulfate de sodium, le polysorbate, la carboxyméthylcellulose sodique réticulée, la povidone réticulée, la cellulose microcristalline, la povidone, l'hydroxypropylcellulose, le lactose, l'amidon prégélatinisé, le stéarate de magnésium et le talc. La composition peut être transformée en une variété de formes posologiques, et une préparation de celle-ci présente une bonne stabilité et une qualité contrôlable.
PCT/CN2018/117087 2017-11-23 2018-11-23 Composition pharmaceutique de hs-25 et d'inhibiteur de la hmg-coa réductase WO2019101151A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202311288927.5A CN117085011A (zh) 2017-11-23 2018-11-23 一种海泽麦布和HMG-CoA还原酶抑制剂的药物组合物
CN201880073253.8A CN111836620B (zh) 2017-11-23 2018-11-23 一种海泽麦布和HMG-CoA还原酶抑制剂的药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711183715 2017-11-23
CN201711183715.5 2017-11-23

Publications (1)

Publication Number Publication Date
WO2019101151A1 true WO2019101151A1 (fr) 2019-05-31

Family

ID=66631288

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/117087 WO2019101151A1 (fr) 2017-11-23 2018-11-23 Composition pharmaceutique de hs-25 et d'inhibiteur de la hmg-coa réductase

Country Status (2)

Country Link
CN (2) CN111836620B (fr)
WO (1) WO2019101151A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101993403A (zh) * 2009-08-11 2011-03-30 浙江海正药业股份有限公司 氮杂环丁酮类化合物及医药应用
CN103566373A (zh) * 2012-07-19 2014-02-12 北京普惠康投资有限公司 包含胆固醇吸收抑制剂和HMG-CoA还原酶抑制剂的药物组合物及其制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3071198A1 (fr) * 2013-11-20 2016-09-28 Cymabay Therapeutics, Inc. Traitement de l'hypercholestérolémie familiale homozygote
CN104013617A (zh) * 2014-05-13 2014-09-03 万特制药(海南)有限公司 一种含有依折麦布和阿托伐他汀钙的组合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101993403A (zh) * 2009-08-11 2011-03-30 浙江海正药业股份有限公司 氮杂环丁酮类化合物及医药应用
CN103566373A (zh) * 2012-07-19 2014-02-12 北京普惠康投资有限公司 包含胆固醇吸收抑制剂和HMG-CoA还原酶抑制剂的药物组合物及其制备方法和用途

Also Published As

Publication number Publication date
CN111836620B (zh) 2023-11-03
CN111836620A (zh) 2020-10-27
CN117085011A (zh) 2023-11-21

Similar Documents

Publication Publication Date Title
JP7187488B2 (ja) 固定用量製剤
CA2740146C (fr) Formes posologiques a liberation immediate d'oxybate de sodium
CN103800280B (zh) 氟伐他汀钠药物组合物
CA2751313C (fr) Procede de preparation d'une composition pharmaceutique contenant de l'ezetimibe
EP2797584B1 (fr) Combinaisons de diacéréine et d'anti-inflammatoires non stéroïdiens
US20230414578A1 (en) Pharmaceutical composition
CN101972260B (zh) 一种瑞舒伐他汀钙口服药物组合物
JP2013541572A (ja) Ｓ−［２−（［［１−（２−エチルブチル）シクロヘキシル］カルボニル］アミノ）フェニル］２−メチルプロパンチオアート及びクロスカルメロースナトリウムを含む組成物
ES2387913T3 (es) Preparaciones de combinación de sales del ácido O-acetilsalicílico
US20180344648A1 (en) Clobazam tablet formulation and process for its preparation
WO2019101151A1 (fr) Composition pharmaceutique de hs-25 et d'inhibiteur de la hmg-coa réductase
US20140363508A1 (en) Pharmaceutical formulations of flurbiprofen and glucosamin
US20220184095A1 (en) Meloxicam co-crystal compositions
WO2022138717A1 (fr) Préparation solide orale
WO2023172958A1 (fr) Formulations stables de talabostat
JP2022536955A (ja) ジクロフェナミド組成物及び使用方法
JP2017210455A (ja) エゼチミブ含有医薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18882244

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18882244

Country of ref document: EP

Kind code of ref document: A1