WO2015081702A1 - 药物组合物及其制备方法和用途 - Google Patents

药物组合物及其制备方法和用途 Download PDF

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WO2015081702A1
WO2015081702A1 PCT/CN2014/082233 CN2014082233W WO2015081702A1 WO 2015081702 A1 WO2015081702 A1 WO 2015081702A1 CN 2014082233 W CN2014082233 W CN 2014082233W WO 2015081702 A1 WO2015081702 A1 WO 2015081702A1
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Prior art keywords
desmodium
extract
ethanol
pharmaceutical composition
alcohol extract
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PCT/CN2014/082233
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English (en)
French (fr)
Inventor
王学海
李�杰
李莉娥
许勇
涂荣华
陈刚
曹儒宾
冯芸
杨仲文
范昭泽
余艳平
肖强
黄璐
杨成兵
黄天赐
田华
杨菁
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人福医药集团股份公司
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Priority to US15/101,917 priority Critical patent/US20160303178A1/en
Priority to KR1020167017637A priority patent/KR20160110369A/ko
Priority to JP2016536889A priority patent/JP2016539955A/ja
Publication of WO2015081702A1 publication Critical patent/WO2015081702A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/48Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/3533,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893Tablet coating processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833Encapsulating processes; Filling of capsules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4875Compounds of unknown constitution, e.g. material from plants or animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/04Drugs for disorders of the urinary system for urolithiasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30Extraction of the material
    • A61K2236/33Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30Extraction of the material
    • A61K2236/33Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30Extraction of the material
    • A61K2236/37Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30Extraction of the material
    • A61K2236/39Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50Methods involving additional extraction steps
    • A61K2236/51Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50Methods involving additional extraction steps
    • A61K2236/55Liquid-liquid separation; Phase separation

Definitions

  • the invention belongs to the field of traditional Chinese medicine, and in particular relates to a pharmaceutical composition, a preparation method thereof and use thereof. More specifically, the present invention provides pharmaceutical compositions, uses of the pharmaceutical compositions in the preparation of medicaments, and methods of preparing pharmaceutical compositions. Background technique
  • Guangcaocao is a leguminous plant, and the dried aerial part of dium ⁇ yra «;/ tom (Osb.) Merr. is a traditional Chinese medicine contained in the 2010 edition of the Chinese Pharmacopoeia. Yellow, the effect of diuretic Tonglin.
  • the prescription preparation of Shilintong tablets is mainly composed of broad-leaf grass, which is used for bladder dampness, stone drenching pain, urinary calculi, and urinary tract infection is hepatobiliary bladder damp heat.
  • the preparation of the raw material of Shilintong Tablet is a crude extract of Dianthus chinensis obtained by the traditional water extraction and alcohol precipitation extraction process.
  • the drug still has a clear basis for the pharmacodynamic substance and the clinical dose is too large. (6 times a day, 3 tablets each time, sugar-coated tablets or film-coated tablets, each containing 0.12 g of dry extract), and the quality control standards are not perfect.
  • Western medicine is commonly used in the treatment of urinary calculi, such as potassium citrate, thiazide diuretics, magnesium, acetylcysteine, etc., and its efficacy is not ideal, and the toxicity and side effects are obvious.
  • Chinese patent medicines such as Shishitong, Paishi Granules, and Shilintong tablets are commonly used drugs with exact curative effects.
  • these traditional Chinese patent medicines like Shilintong tablets, still have problems such as primitive pharmaceutical technology, difficult quality control, inaccurate quantitative detection methods, and large doses. They are far from international standards and do not conform to modern clinical practice. Medication requirements.
  • the present invention is directed to solving at least some of the above technical problems or at least providing a useful commercial choice. Therefore, the present invention provides a pharmaceutical composition, a preparation method thereof and a medical use for the case where the drug for treating urinary calculi is insufficient at the present stage.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an extract of total flavonoids of Rhododendron chinense as an active ingredient, and a pharmaceutically acceptable pharmaceutical excipient, wherein the broad The 5% to 95% by weight of the total flavonoids of the extract of the medicinal composition of the medicinal composition.
  • the pharmaceutically acceptable pharmaceutical excipient is selected from the group consisting of corn starch, dextrin, lactose, pregelatinized starch, sucrose, microcrystalline cellulose, mannitol, sorbitol, xylitol, Calcium hydrogen phosphate, calcium carbonate, starch paste, hypromellose, povidone K 3 Q, povidone K 25 , polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, tannic acid , succinic acid, dextran, galactose, sucrose, glucose, modified starch, microcrystalline cellulose, poloxamer 188, D-mannitol, methylcellulose, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carboxymethyl Cellulose calcium, coconut oil amine polyglycol ether, glycerol ethoxylate, Twe
  • the total flavonoid extract of Herba Lysimachia is prepared by the following steps: adding alcohol extract to alcohol extract to obtain the extract of Herba Lysimachia, and purifying the extract of Herba Lysimachia, In order to obtain the total flavonoid extract of the broadbread.
  • the obtained extract after obtaining the total flavonoid extract of Herba Lysimachia, the obtained extract can be dried as needed to obtain a solid substance.
  • the alcohol extraction of the polysaccharides further comprises: heating and refluxing the medicinal herbs with 50% to 95% ethanol of 8 to 14 times the weight of the medicinal materials, and extracting 1 to 3 times, each 1 to 3 hours, and the alcohol extract is combined to obtain the extract of the broad-leaved grass.
  • purifying the extract of the broad-leaf grass extract further comprises: concentrating the extract of the broad-leaf grass extract to remove ethanol; and performing the macroporous adsorption resin column on the extract of the broad-leaf grass extract Treatment to obtain purified total flavonoid extract of Herba Lysimachia.
  • the method for preparing a total flavonoid extract of Dioscorea opposita L. may comprise the following steps:
  • the alcohol extract is concentrated to a certain volume, so that the volume of the liquid is 2 to 8 times the amount of the medicine, and after standing and filtering, the filtrate is obtained; c the filtrate is passed through the AB-8 at a flow rate of 1 to 3 times per minute of the bed volume.
  • the pore adsorption resin column after the adsorption is completed, first elute with 8 ⁇ 12 times of resin amount of water, and then use 6 ⁇ 10 times the bed volume of 40% ⁇ 95% ethanol to 2 ⁇ 4 times of bed bed per hour. The flow rate of the volume is eluted to obtain an eluent;
  • the eluate is recovered from ethanol, and concentrated to a relative density of 1. 10 ⁇ 1.
  • 30 concentrated liquid the concentrated liquid is dried and pulverized to obtain a fine powder of total flavonoid extract of the broadbread, the fine powder has a particle size of 50- 100 mesh.
  • the content of the total flavonoids in the extract can reach 50% ⁇ 80%, and the content of the sulphate is 3. 0% ⁇ 12. 0%. Collect the dried extract, seal, weigh, and store in a dry place.
  • the ethanol concentration referred to in the present invention means the volume fraction (V/V) of ethanol contained in a 100 mL volume of aqueous ethanol solution.
  • V/V volume fraction of ethanol contained in a 100 mL volume of aqueous ethanol solution.
  • the method for preparing the total flavonoid extract of Herba Lysimachia can be Includes the following steps:
  • the alcohol extract is concentrated to a certain volume, so that the volume of the liquid is 5 times the amount of the drug, and after standing and filtering, the filtrate is obtained; c the filtrate passes through the AB-8 macroporous adsorption resin column at a flow rate of 3 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount of water, and then eluted with 8 times of bed volume of 60% ethanol at a flow rate of 3 times of bed volume per hour to obtain an eluent;
  • the eluate is recovered from ethanol, concentrated to a concentrate having a relative density of 1.22, and the concentrate is dried under reduced pressure at 75 ° C, and pulverized to obtain a total flavonoid extract of Herba fuliginea, and the fine powder has a particle size of 80 mesh.
  • the invention improves the content of active ingredients and effective substances in the medicinal herbs of the medicinal herbs, and the total flavonoid content of the cynomolgus sinensis (in terms of dry products) is 50% ⁇ 80%, wherein the buddha is The content of glucoside (% by dry product) is 3.0% ⁇ 12 ⁇ 0% ⁇
  • the pharmaceutical composition of the present invention is composed of a total flavonoid extract of Dianthus chinensis and a pharmaceutically acceptable pharmaceutical excipient, thereby enabling the pharmaceutical composition to exhibit a form suitable for administration of a clinical pharmaceutical preparation.
  • the pharmaceutical composition of the present invention may be in the form of an oral preparation selected from the group consisting of at least one of a tablet, an effervescent capsule, a hard capsule, a soft capsule, a granule, a granule, a pill, and a powder, wherein the tablet is a sugar-coated tablet. , film-coated tablets, enteric-coated tablets, dispersible tablets, sustained-release tablets, controlled-release tablets or effervescent tablets.
  • a pharmaceutical composition according to an embodiment of the present invention for the preparation of a medicament, which pharmaceutical composition can be used for treating urinary calculi, that is, the medicament of the present invention can be effectively used for removal Damp heat, diuretic row stones, leaching and pain caused by damp heat accumulation, urinary calculi and the above-mentioned syndromes, and can be used for the preparation of clinical therapeutic drugs for the treatment of moist heat removal and diuretic drainage (damp heat accumulation).
  • Total flavonoids of Rhododendron chinense can significantly inhibit the amount of calcium oxalate crystal aggregates in the kidney, reduce the formation rate of kidney stones and serum creatinine and uric acid content, and improve rat kidney Function; It has the function of dissolving stone and reducing the formation of new stones; It has the effect of diuresis; and the total flavonoids of Radix Paeoniae Alba can alleviate the swelling degree and swelling rate caused by the injection of fresh egg white in rats, suggesting that the total flavonoid capsule of Desmodium styracifolium has certain Anti-inflammatory effect, and has a significant inhibitory effect on granulation tissue proliferation.
  • the medicament may be in the form of an oral preparation selected from the group consisting of at least one of a tablet, an effervescent capsule, a hard capsule, a soft capsule, a granule, a granule, a pill, and a powder, wherein the tablet is a sugar coating. Tablets, film-coated tablets, enteric-coated tablets, dispersible tablets, sustained-release tablets, controlled-release tablets or effervescent tablets.
  • the present invention provides a method of preparing a pharmaceutical composition.
  • the method comprises: providing an extract of oleracea alcohol, the extract of the polysaccharide of Lysimachia glabra L. containing as an active ingredient.
  • the method further comprises the step of adding a pharmaceutically acceptable pharmaceutical excipient, wherein the total flavonoid content of the broad-leaved grass is 2.5 to 95% by weight based on the total weight of the pharmaceutical composition.
  • the preparation of the total flavonoid extract of Rhododendron chinense comprises: extracting alcohol extracts to obtain the extract of Dianthus chinensis, and purifying the extract of Dianthus chinensis to obtain the total flavonoids of the broadbread An extract, wherein the concentration of the ethanol is 50 to 95%, and the weight of the ethanol is 8 to 14 times that of the polysaccharide material; the extract of the polysaccharide of Lysimachia chinensis is concentrated to remove ethanol; And the concentrated Lysimachia chinensis extract is subjected to a macroporous adsorption resin column to obtain the extract of the polysaccharide.
  • the obtained extract may be dried as needed to obtain a solid substance.
  • the alcohol extraction of the polysaccharides may further comprise: heating and refluxing the medicinal herbs with 50% to 95% ethanol of 8 to 14 times the weight of the medicinal materials, and extracting 1 to 3 times, Each time for 1 to 3 hours, the alcohol extract is combined to obtain the extract of the broad-leaved grass.
  • purifying the extract of the broad-leaf grass extract further comprises: concentrating the extract of the broad-leaf grass extract to remove ethanol; and performing the macroporous adsorption resin column on the extract of the broad-leaf grass extract Treatment to obtain purified total flavonoid extract of Herba Lysimachia.
  • the preparation method of the extract of the broadgrass extract according to the embodiment of the present invention may be as follows:
  • the extract of the extract of Dianthus chinensis as follows: take 50 grams of medicinal herbs, add the first 80 times of the amount of 80% ethanol, and heat and reflux at 55 ° C for 2 hours, second. Adding 10 times of the amount of 80% ethanol, and heating and refluxing at 55 ° C for 1.5 hours, combining the alcohol extract; concentrating the alcohol extract to a certain volume, so that the volume of the liquid is 5 times the amount of the drug, and static filtration. The filtrate (as the sample solution) was obtained and used. Will be 100 kg of pharmaceutical grade AB-8 The macroporous resin is soaked in an appropriate amount of ethanol, packed in a wet manner, and disposed of after use.
  • the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
  • the bed volume of 60% ethanol is eluted at a flow rate of 2 times the bed volume per hour to obtain an eluate; the eluate is recovered from ethanol, and concentrated to a concentration of 1.22, which is reduced by 75 ° C. ⁇
  • the dried whey extract product 1. 10 grams.
  • the method for producing a medicament of the present invention may further comprise the step of adding a pharmaceutically acceptable pharmaceutical excipient to prepare a traditional Chinese medicine preparation.
  • the method for preparing a medicament of the present invention may further comprise the steps of: forming the medicament into at least one selected from the group consisting of a tablet, an effervescent capsule, a hard capsule, a soft capsule, a granule, a granule, a pill, and a powder.
  • An oral preparation form, wherein the tablet is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a dispersible tablet, a sustained-release tablet, a controlled release tablet or an effervescent tablet.
  • the preparation method thereof may include: dissolving a prescribed amount of the binder in water, stirring and uniformly formulating the solution, and standby; and prescribing the amount of the total flavonoid extract of the broadbread
  • the filler is mixed, put into the fluidized bed, and the binder solution is sprayed into the fluidized bed by using a spray gun to perform granulation; after the granulation is finished, the mixture is dried and discharged, and the mixed powder is obtained, and the obtained mixed powder is filled.
  • a pharmaceutical composition in the form of granules may include: dissolving a prescribed amount of the binder in water, stirring and uniformly formulating the solution, and standby; and prescribing the amount of the total flavonoid extract of the broadbread
  • the filler is mixed, put into the fluidized bed, and the binder solution is sprayed into the fluidized bed by using a spray gun to perform granulation; after the granulation is finished, the mixture is dried and discharged, and the mixed powder is obtained, and the obtained
  • the preparation method may further comprise: respectively, prescribing a total amount of the total flavonoid extract raw material of the polysaccharide, and a pharmaceutically acceptable pharmaceutical excipient, through a 60-100 mesh sieve;
  • the binder is dissolved in a solvent and stirred to prepare a solution for use; according to the prescription, the material is put into a fluidized bed, preheated for 5 to 60 minutes, and preheated to 35 ° C - 55 ° C; adjust the parameters, and use
  • the inlet air temperature of 50 ° C -65 ° C, keep the material temperature at 40 ° C -55 ° C, spray the adhesive after 5-60 minutes; after the granulation is finished, adjust the parameters to dry, through adjustment
  • the air temperature is 60 ° C - 7 (TC, the temperature of the material is raised to 40 ° C - 55 ° C, and the drying is carried out for 5 to 60 minutes; the dried particles are cooled and discharged, and the mixed powder is obtained, and the obtained mixed powder is granulated.
  • the agent is filled to obtain a pharmaceutical composition in the form of granules.
  • the granule preparation method of the composition product of the present invention is as follows: The binder povidone K 3 is used . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, ready for use; 133 g of total flavonoid extract of D. chinensis, 110 g of microcrystalline cellulose and 60 g of lactose are mixed and put into a fluidized bed, preheated for 20 minutes. , preheating to 45 ° C; adjust the parameters, and use a spray gun to spray the binder solution into the fluidized bed for granulation, maintaining the atomization pressure of 0.
  • the spray speed is 20 rev / min, through Adjust the inlet air temperature to 55 °C, keep the material temperature at 45 °C, and spray the adhesive for 15 minutes. After the granulation is finished, adjust the parameters for drying. Adjust the inlet air temperature to 65 °C to raise the material temperature to 45 °. C, drying for 10 minutes; the dried granules were cooled and discharged to obtain a mixed powder, and the obtained mixed powder was granulated to obtain 1000 bags of the pharmaceutical composition in the form of granules.
  • the preparation method thereof may include: dissolving a prescribed amount of the binder In water, stir and mix into a solution, and set aside; mix the prescribed amount of the total flavonoid extract of the cynomolgus extract with the filler, put it into the fluidized bed, and spray the binder solution into the fluidized bed using a spray gun. After the granulation is finished, the mixture is dried and discharged to obtain a mixed powder, and the obtained mixed powder is filled on a capsule machine to obtain a composition in the form of a capsule.
  • the preparation method may further comprise: separately applying a prescribed amount of the total flavonoid extract raw material of the polysaccharide, and a pharmaceutically acceptable pharmaceutical excipient, through a 60-100 mesh sieve;
  • the binder is dissolved in a solvent and stirred to prepare a solution for use; according to the prescription, the material is put into a fluidized bed, preheated for 5 to 60 minutes, and preheated to 35 ° C - 55 ° C; adjust the parameters, and use
  • the capsule preparation method of the composition product of the present invention is as follows: The adhesive povidone K 3 is used . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, ready for use; 133 g of total flavonoid extract of D. chinensis, 30 g of microcrystalline cellulose and 37 g of lactose are mixed and put into a fluidized bed, preheated for 20 minutes. , preheating to 45 ° C; adjust the parameters, and use a spray gun to spray the binder solution into the fluidized bed for granulation, maintaining the atomization pressure of 0.
  • the spray speed is 20 rev / min, through Adjust the inlet air temperature to 55 °C, keep the material temperature at 45 °C, and spray the adhesive for 15 minutes. After the granulation is finished, adjust the parameters for drying. Adjust the inlet air temperature to 65 °C to raise the material temperature to 45 °. C, drying for 10 minutes; the dried granules were cooled and discharged to obtain a mixed powder, and the obtained mixed powder was filled on a capsule machine to obtain 1000 tablets of the pharmaceutical composition in the form of a capsule.
  • the preparation method may include: prescribing a total amount of the total flavonoids of the polysaccharide, a solid dispersion carrier, and a surfactant, sieving, adding 50% ethanol, heating and stirring to dissolve The solvent is evaporated under reduced pressure, dried in a vacuum, and pulverized to obtain a solid dispersion of total flavonoids of Rhododendron chinense; a filler, a disintegrant is weighed, and after being sieved, it is uniformly mixed with the solid dispersion of total flavonoids of Herba fuliginea , granulating, drying, granulating, adding a lubricant to mix uniformly, in order to obtain granules of total flavonoids of cynomolgus, and granules are pressed on a tableting machine to obtain a pharmaceutical composition in the form of a tablet. Further, the above tablets are sugar coated or film coated to obtain a pharmaceutical
  • the preparation method thereof may further include: separately weighing a prescribed amount of the total flavonoids of the polysaccharide, the solid dispersion carrier, and the surfactant, and after adding the 40-100 mesh sieve, adding 50% ethanol, heated to 50 ° C ⁇ 75 ° C stir to dissolve, 30 ° C ⁇ 75 ° C under reduced pressure evaporation to remove the solvent, 30 ° C ⁇ 6 (TC vacuum drying, after drying, smashed through 40-200 mesh sieve , spare; weigh filler, disintegrant, after 40-100 mesh sieve, with broad money grass
  • the solid flavonoid solid dispersion is uniformly mixed, made into a soft material, granulated with a 10-30 mesh sieve, dried at 30 ° C to 75 ° C, whole granules, and uniformly mixed with a lubricant to obtain a total flavonoid granule of Compressed on a tablet machine to obtain a pharmaceutical composition in the form
  • the tablet preparation method of the composition product of the present invention is as follows: a prescribed amount of total flavonoids of P. chinensis 66.5 g, povidone K 3Q 266 g, poloxamer 188 133 g, and 39.9 g of sodium decyl sulfate, after passing through a mesh of 80 mesh, adding 50% ethanol, heating to 65 ° C, stirring and dissolving, evaporating the solvent under reduced pressure at 50 ° C, vacuum drying at 4 CTC, after drying, smashing through 80 mesh sieve , Decopolysaccharide total flavonoid solid dispersion spare; Weigh 10g of lactose, 15g of croscarmellose sodium, after 80 mesh sieve, mix with the obtained solid dispersion of total flavonoids of Herba fuliginea, use appropriate amount of water The soft material was granulated with a 20-mesh sieve, dried at 55 ° C, and granulated,
  • the total flavonoid granules of D. chinensis were compressed on a tablet machine to obtain 1000 tablets of the pharmaceutical composition in the form of tablets. Further, the above tablets are sugar coated or film coated to obtain a pharmaceutical composition in the form of a sugar-coated tablet or a film-coated tablet.
  • the preparation method may include: adding a prescribed amount of the oil phase, a surfactant, and a co-surfactant by stirring or ultrasonically, and uniformly mixing the mixture, and then adding a wide prescription amount.
  • the total flavonoid extract of Lysimachia chinensis is dissolved by stirring or sonication, and then potted in a soft capsule to obtain a composition in the form of a soft capsule.
  • the preparation method may include: 40 g of a prescribed amount of soybean oil, 80 g of polyoxyethylene (40) hydrogenated castor oil, and 30 g of polyethylene glycol 400, by stirring or ultrasonication. The method is to stir the mixture evenly, and then add 133 g of the total amount of the total flavonoid extract of Herba fuliginea, and stir it at 37 ° C or ultrasonic to dissolve it, and evacuate the air bubbles to prepare a content material liquid.
  • the content material liquid is placed in a soft capsule pilling machine, filled into soft capsules, and then dried into a drum drying device to dry and soften the soft capsules, and then sterilized by ethanol and scrubbed the pellets, so that the capsule shell moisture and ethanol are naturally evaporated. Drop, drying time for 20 hours, until the surface of the capsule is dry and smooth, slightly elastic, and dry. Finally, the unqualified soft capsules such as the appearance and the joint are sorted and discarded, and the selected qualified soft capsules are packaged in the form of a bottle or a blister sheet to obtain 1000 compositions in the form of soft capsules.
  • a medicament prepared by the method for producing a medicament of the present invention can be used for the treatment of urinary calculi.
  • the present invention also provides a medicament which is produced by the above method for preparing a medicament. As described above, with this drug, urinary calculi can be effectively treated.
  • composition of the present invention its preparation method and use are completed by the inventor of the present application through arduous creative labor and optimization work.
  • the invention has the following advantages: 1.
  • ethanol is used as an extraction solvent to extract the medicinal materials of the medicinal herbs, and the extract is purified by macroporous adsorption resin to obtain the total flavonoids of the medicinal herb of the genus Lysimachia chinensis, and the oleoresin
  • the effective material basis of the extract is clear, the quality standard is controllable, the clinical dose of the drug is reduced, and the clinical adverse reaction is reduced.
  • the present invention can directly purify the macroporous resin by recovering the ethanol to a certain volume (5 times the amount of the medicinal material), without concentrating and drying to the extract, saving Production time; Secondly, after the macroporous resin is used, the higher concentration of the active ingredient can be obtained by eluting with the same concentration of ethanol. Compared with the gradient elution with different concentrations of ethanol, the process flow is simple and the operability is strong; After the eluent recovers the ethanol, it is directly dried under reduced pressure. Without the need of adding a suitable solvent for treatment, the total flavonoids of the active part of the broad-leaved grass can be obtained, which saves the production monthly energy. From the perspective of large-scale production, the new extraction and purification process reduces the production cost, shortens the production cycle, and the process is simple and feasible, and meets the requirements of the modernization industry of traditional Chinese medicine.
  • the invention adopts AB-8 macroporous adsorption resin technology to extract and purify the effective part, has the advantages of simple process, low cost, reusable resin, and is suitable for industrial production. Moreover, the present invention has carefully and carefully examined the corresponding technical parameters, optimized the optimal conditions, and conducted a pilot test. The method of the present invention can be transitioned to industrialization and the content of the effective portion is improved.
  • the pharmaceutical composition of total flavonoids of Radix Paeoniae Alba obtained by the invention has the advantages of advanced production technology, clear basis of effective drug substance, controllable quality standard, relatively accurate clinical indication, and pharmacological efficacy. Significant, less medication, safe and convenient to take, and low adverse reactions, so that it has the advantages of adapting to modern manufacturing technology and quality standards.
  • Figure 2 shows the elution profile of total flavonoids in a resin column eluted with 60% ethanol as an eluent according to one embodiment of the present invention.
  • Extraction method According to the solubility properties of flavonoids, free flavonoids and flavonoid glycosides can be extracted by organic solvents, and industrial production is usually extracted with higher concentration of ethanol. This study draws on the industrial extraction method of general flavonoids. On the basis of the selection, 60%-95% ethanol is selected as the extraction solvent, and the extraction times are economically and practically extracted twice by the usual methods of production.
  • Ethanol reflux extraction process experiment Using L9 ( 3 4 ) orthogonal test method, taking the total flavonoids of Lysimachia chinensis as an indicator to determine the process parameters of ethanol concentration, ethanol dosage (multiple of Guangqian herbal material) and extraction time.
  • the content of total flavonoids in the extract was determined by UV-visible spectrophotometry, and the total flavonoid content and the net weight of total flavonoids in the dry paste were used as the evaluation indexes.
  • the experimental factors and O level arrangement are shown in Table 1, and the results are shown in Table 2.
  • the macroporous resin purification process is carried out by extracting the extract of Dianthus chinensis obtained by the above preferred extraction conditions: 1) screening test of macroporous resin
  • Resin source AB-8 resin (Nankai University), D101 resin (Shandong Lukang), HPD100 resin (Hebei Baodi Co., Ltd.).
  • Saturated adsorption amount [(initial concentration - concentration after adsorption) X adsorbent volume] / resin amount]
  • elution rate (eluent concentration X eluent volume) / saturation
  • the adsorption amount is X 100%, and the results are shown in Table 3.
  • the experimental results are shown in Table 4.
  • the test results show that: AB-8 macroporous resin has better specific adsorption and elution rate of total flavonoids of D. It has high safety and is one of the most widely used macroporous resins in the domestic pharmaceutical production industry. Therefore, this study used AB-8 macroporous resin to simultaneously purify total flavonoids from Herba Lysimachia.
  • the orthogonal test method is used to determine the concentration of the above liquid (based on the amount of the original drug contained in the sample), the adsorption flow rate and the aspect ratio as the investigation factor, and apply the (3 4 ) orthogonal table arrangement test. 5.
  • the total flavonoid content was determined for the following 9 groups of tests, and the specific adsorption amount was calculated and comprehensively evaluated. The results of the analysis are shown in Table 6.
  • the sample was adsorbed according to the above optimal adsorption conditions, the sample loading was 50 mL, and then rinsed with purified water, and the column liquid was 1 part per 20 mL, and the ⁇ -naphthol reaction was detected, and the dry paste weight was measured, and the water was washed. After 300 mL, the ct-naphthol reaction was negative, and the dry paste weight did not change. The results showed that the sugar on the resin column was substantially removed after washing with 300 mL of water (about 15 times the amount of resin).
  • the impurity is eluted with 10 times of resin amount, and then 8 times column is used. Bed volume of 60% ethanol, 2 times bed volume per hour The flow rate is eluted to obtain an eluate; the eluate is recovered to ethanol, and concentrated to a relative density of 1.22, dried at 75 ° C under reduced pressure, and pulverized to obtain a total flavonoid extract product of Herba Lysimachia. . 10 grams.
  • the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
  • the bed volume of 60% ethanol was eluted at a flow rate of 2 times the bed volume per hour to obtain an eluate; the eluate was recovered to ethanol, concentrated to a concentrate having a relative density of 1.22, and dried under reduced pressure at 75 ° C. , crushed, and obtained 4.03 g of total flavonoid extract product of Lysimachia chinensis (preserved in a cool place).
  • the extract product was measured by ultraviolet-visible spectrophotometry to obtain the content of the substance in the extract, and the total flavonoid content (% by dry product) was 63.31%, and the content of safflower glycoside (% by dry product) was 5.38%. .
  • the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
  • the bed volume of 60% ethanol was eluted at a flow rate of 2 times the bed volume per hour to obtain an eluate; the eluate was recovered to ethanol, concentrated to a concentrate having a relative density of 1.22, and dried under reduced pressure at 75 ° C. , crushed, obtained 1.12 kg of total flavonoids extract of Herba Lysimachia (stored in a cool place).
  • the extract product was measured by ultraviolet-visible spectrophotometry to obtain the content of the substance in the extract, and the total flavonoid content (% by dry product) was 59.49%, and the content of safflower glycoside (% by dry product) was 5.10%. .
  • the above filtrate (loading solution) is passed through the AB-8 macroporous adsorption resin column at a flow rate of 2 times the bed volume per hour. After the adsorption is completed, the impurity is eluted with 10 times of resin amount, and then 8 times column is used.
  • the bed volume of 60% ethanol was eluted at a flow rate of 2 bed volumes per hour to obtain an eluate; the eluate was recovered from ethanol and concentrated to a relative density of 1.22.
  • the concentrated solution was dried under reduced pressure at 75 ° C and pulverized to obtain 1.14 kg of total flavonoid extract product of Lysimachia chinensis (preserved in a cool place).
  • the extract product was measured by ultraviolet-visible spectrophotometry to obtain the content of the substance in the extract, and the total flavonoid content (% by dry product) was 59.37%, and the content of safflower glycoside (% by dry product) was 5.01%. .
  • the binder povidone K 3 . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, and used;
  • the dried granules are cooled and discharged to obtain a mixed powder, and the obtained mixed powder is filled on a capsule machine to obtain a total flavonoid capsule of Herba fuliginea.
  • Micro powder silica gel lg Water 120g is made into a total of 1000 tablets: same as in Example 6
  • the binder povidone K 3 . 1 g is dissolved in 120 g of water, stirred and evenly mixed into a solution, and used;
  • the dried granules are cooled and discharged to obtain a mixed powder, and the obtained mixed powder is filled with granules to obtain granules of total flavonoids of Herba fuliginea.
  • drying time is 20 hours, until the surface of the capsule is dry and smooth, slightly elastic, dry carry out.
  • unqualified soft capsules such as the appearance and the joint are sorted and discarded, and the selected qualified soft capsules are packaged in the form of a bottle or a blister board to obtain 1000 compositions in the form of soft capsules.
  • Laboratory animals and administration Kunming mice, female, weighing 18-22 g, provided by the Experimental Animal Center of the Academy of Military Medical Sciences, Laboratory Animal Quality License No.: SCXK (Military) 2002-001, animal words raised in the center Rat laboratory, laboratory facility certification number is SYXK (Army) 2002-001.
  • Experimental group The experiment was divided into 4 groups, namely, the control group (administered 0.5% sodium carboxymethylcellulose), the low-dose group of total flavonoids of Radix Paeoniae Alba (75 mg/kg), and the middle dose of total flavonoids of Radix Paeoniae Alba (150 mg/ Kg), high-dose total flavonoids (300mg/kg) o 10-20 per group.
  • the administration route was a one-time gavage, and the administration volume was 0.6 ml/mouse.
  • mice in each group were observed 15 minutes after gavage. The observation included mental, gait, eyes, tail, fur and feces, and observed continuously for 60 minutes. Observe 1 more hour.
  • mice After observing the general state and behavior of the mice, the mice were given small, medium and large doses of total flavonoids (75 mg/kg, 150 mg/kg, 300 mg/kg) on animal behavior, response, activity, mood, There was no significant change in gait, and there was no significant difference compared with the control group.
  • the specific data are shown in Table 9.
  • mice were fed with the total flavonoids of the herb, the appropriate amount of normal saline was applied to the ears of the animals, and the tip of the ear was clamped with a fish mouth clamp.
  • the voltage was 110 volts, and the stimulating time was 0.3 seconds. duration.
  • mice Effects of total flavonoids from Lysimachia chinensis on central nervous system excitability in mice Number of animals (only) Body weight (g) Dosage (mg/kg) Duration of convulsion (seconds)
  • mice in each group were tested. The mice were fasted for 12 hours before the experiment. After 1 hour of total flavonoids of Herba Lysimachia, a suspension made of 5% carbon powder and 10% gum arabic was administered, 0.2 ml. /only. The animals were sacrificed 20 minutes after the gavage, and the entire gastrointestinal tract was taken out and placed on a glass plate. The distance between the pylorus and the leading edge of the carbon was measured with a ruler, and the percentage of the gastrointestinal tract was calculated. The results showed that total flavonoids from Herba Lysimachia had no significant effect on gastrointestinal motility in mice. The specific data is shown in Table 11.
  • the four doses of total flavonoids of Lysimachia chinensis can significantly inhibit the amount of calcium oxalate crystal aggregates in the kidney, dose-effect relationship (P ⁇ 0.05-0.01), reduce the formation rate of kidney stones and serum creatinine and uric acid content (P ⁇ 0.05-0.01), Improve renal function in rats.
  • control group rats were given 0.5% sodium carboxymethylcellulose
  • three doses of total flavonoids of Lysimachia chinensis 50mg/kg/day, 100mg/kg/day, 200mg/kg/day
  • the three doses of total flavonoids (100 mg/kg/day, 200 mg/kg/day, 400 mg/kg/day) It has the function of dissolving stone and reducing the formation of new stones.
  • the weight of stones in the 100 mg/kg group was reduced (P ⁇ 0.05)
  • the weight of stones in the 200 mg/kg group was reduced (P ⁇ 0.05)
  • 20% of the stones were dissolved
  • the weight of stones in the 400 mg/kg group was reduced (P ⁇ 0.01), and 30% of the stones were dissolved.
  • the control group was administered with 0.5% sodium carboxymethylcellulose
  • the three doses of total flavonoids 50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day
  • the total amount of urine excretion was 6 hours after administration, and the total amount of normal control was 48.1 ml.
  • the drug group 76.4-89.5 ml was 29-36 ml higher than the normal control group.
  • 12 Urinary excretion increased significantly during the hour, an increase of 12-36% over the model group.
  • the control group was given 0.5% sodium carboxymethylcellulose
  • the three doses of total flavonoids 100 mg/kg/day, 200 mg/kg/day, 400 mg/kg/day were all It can alleviate the swelling degree and swelling rate caused by injection of fresh egg white in rats, suggesting that the total flavonoids of Radix Paeoniae Alba have certain anti-inflammatory effects and have obvious inhibitory effects on granulation tissue proliferation.
  • Example 19 Animal acute toxicity test of total flavonoids from Herba Lysimachia
  • the test was divided into 6 groups, 20 animals in each group, half male and half female, with a distance between the groups of 0.85. After the drug, the animals showed reduced activity, unstable gait, and weak breathing. Most of the dead animals were distributed within 1 hour after the drug, and individual dead animals were distributed 1-6 hours after the drug.
  • the LD50 of female animals is 18.162g/kg, 95% confidence limit
  • the upper limit is 20.199g/kg
  • the lower limit is 16.326g/kg
  • the male animal LD50 is 17.084g/kg
  • 95% confidence limit The upper limit is 18.975g/kg and the lower limit is 15.301g/kg. There was no significant difference in LD50 between females and males. Based on the above results, it can be considered that the total flavonoids of Lysimachia chinensis is a substantially non-toxic test drug.
  • the test was carried out according to the "single oral fixed dose method".
  • the rats were administered at 2000 mg/kg, and there was no obvious acute toxicity after the drug was administered. Therefore, a formal test was conducted at a fixed dose of 2000 mg/kg.
  • the test was divided into the control group and the total flavonoids group of D. chinensis, with 10 animals in each group, half male and half female.
  • the animals in the administration group were intragastrically administered with total flavonoids of 2000 mg/kg, and the volume was 2.0 ml/100 g body weight.
  • the control animals were intragastrically administered with 0.5% sodium carboxymethylcellulose 2.0 ml/100 g body weight.
  • the lazy movement occurred within 3 hours after the drug was administered.
  • the stool was grayish-black on the 1st day after the drug, the food intake decreased slightly, and the body weight growth was slightly inhibited.
  • the drug returned to the control level 7 days after the drug.

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Abstract

提供了一种药物组合物及其制备方法和用途。所述药物组合物由广金钱草总黄酮提取物作为活性成分,与药学上可接受的辅料组成。该药物组合物可制成片剂、颗粒剂、胶囊剂、丸剂、粉剂等。该药物组合物具有清除湿热,利尿,排石的作用,能用于治疗尿路结石。

Description

药物组合物及其制备方法和用途
技术领域
本发明属于中药领域, 具体地涉及药物组合物及其制备方法和用途。 更具体地, 本发 明提供了药物组合物、 药物组合物在制备药物中的用途以及制备药物组合物的方法。 背景技术
广金钱草为豆科植物, 广金钱草 De画 dium ^yra«;/ tom(Osb.)Merr.的干燥地上部分, 为 《中国药典》 2010年版一部收载的传统中药, 具有利湿退黄, 利尿通淋的功效。 同时收 载的成方制剂石淋通片,其主要成分即为广金钱草,用于膀胱湿热, 石淋涩痛, 尿路结石, 泌尿系感染属肝胆膀胱湿热者。 但是, 对石淋通片的原料的制备, 是经传统的水提醇沉法 提取工艺制备得到的广金钱草粗提取物, 该药物尚存在着药效物质基础不明确、 临床服用 剂量过大 (每日 6次, 每次 3片, 糖衣片或薄膜衣片, 每片含干浸膏 0.12g)、 质量控制标 准不完善。 临床上西医治疗尿路结石常用枸橼酸钾、 噻嗪类利尿剂、 镁剂、 乙酰半胱酸 等促排剂,其疗效不甚理想,且毒副反应明显。中成药如泌石通、排石冲剂、石淋通片, 都是常用的疗效确切的药物。 但是以上这些传统的中成药, 同石淋通片一样, 仍存在制 药工艺原始、 质量控制难、 定量检测方法不准确、 服用量大等问题, 与国际接轨有较大 距离, 且不符合现代临床用药要求。
目前,用于治疗尿路结石的药物仍有待改进。 发明内容
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选择。 因此, 针对现阶段用于治疗尿路结石的药物不足的情况, 本发明提供了一种药物组合物及 其制备方法和医药用途。
根据本发明的一个方面, 本发明提供了一种药物组合物, 该药物组合物是由广金钱草 总黄酮提取物作为活性成分, 与药学上可接受的药用辅料组成, 其中,所述广金钱草总黄酮 是以广金钱草醇提取物的形式提供的, 基于所述药物组合物的总重量, 广金钱草总黄酮提 取物所占的重量百分比为 2. 5%-95%。
本发明的药物组合物中, 所述药物可接受的药用辅料为选自玉米淀粉、 糊精、 乳糖、 预 胶化淀粉、 蔗糖、 微晶纤维素、 甘露醇、 山梨醇、 木糖醇、 磷酸氢钙、 碳酸钙、 淀粉糊、 羟丙甲纤维素、 聚维酮 K3Q、 聚维酮 K25、 聚乙二醇 2000、 聚乙二醇 4000、 聚乙二醇 6000、 枸橼酸、 琥珀酸、 右旋糖酐、 半乳糖、 蔗糖、 葡萄糖、 改性淀粉、 微晶纤维素、 泊洛沙姆 188、 D-甘露醇、 甲基纤维素、 羧甲基淀粉钠、 低取代羟丙基纤维素、 交联聚维酮、 羧甲基 淀粉钠、交联羧甲基纤维素钠、羧甲基纤维素钙、椰子油胺聚乙二醇醚、甘油聚氧乙烯醚、 吐温 20、 吐温 40、 吐温 60、 吐温 80、 卖泽 40、 苄泽 30、 聚乙二醇单甲醚、 十二垸基硫酸 钠、 硬脂酸镁、 滑石粉、 微粉硅胶、 十二垸基硫酸镁、 苯甲酸钠、 硬脂酰富马酸钠的至少 一种。
利用该药物组合物, 能够对尿路结石的疾病进行有效地治疗。
根据本发明的实施例, 广金钱草总黄酮提取物是通过下列步骤制备的: 将广金钱草进 行加醇提取, 以便获得广金钱草提取液, 以及将所述广金钱草提取液进行纯化, 以便获得 所述广金钱草总黄酮提取物。 根据本发明的实施例, 在得到广金钱草总黄酮提取物之后, 可以根据需要, 对所得到的提取物进行干燥得到固体物质。
根据本发明的实施例, 将广金钱草进行加醇提取进一步包括: 将所述广金钱草药材用 8〜14倍药材重量的 50%〜95%乙醇进行加热回流, 提取 1〜3次, 每次 1〜3小时, 并合并 醇提取液, 以便获得所述广金钱草提取液。 根据本发明的具体示例, 将所述广金钱草提取 液进行纯化进一步包括: 将所述广金钱草提取液进行浓缩处理, 以便除去乙醇; 将所述广 金钱草提取液进行大孔吸附树脂柱处理, 以便获得经过纯化的广金钱草总黄酮提取物。
具体地, 根据本发明的实施例, 本发明的制备广金钱草总黄酮提取物的方法可以包括 以下步骤:
a. 称取广金钱草药材, 加入 8〜14倍药材量的 50%〜95%乙醇, 50_6(TC加热回流, 提 取 1〜3次, 每次 1〜3小时, 以便获得广金钱草的醇提取液, 然后合并醇提液;
b. 将醇提液浓缩至一定体积,使药液体积为 2〜8倍药材量,静置过滤后,得到滤液; c 滤液以每小时 1〜3倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先 用 8〜12倍树脂量的水洗脱除杂,再用 6〜10倍柱床体积的 40%〜95 %的乙醇,以每小时 2〜 4倍柱床体积的流速进行洗脱, 得到洗脱液;
d. 将洗脱液回收乙醇, 浓缩至相对密度为 1. 10〜1. 30的浓缩液, 浓缩液经干燥, 粉 碎, 得到广金钱草总黄酮提取物细粉, 细粉的粒度为 50-100目。 提取物中的广金钱草总黄 酮含量可达 50%〜80%, 其中夏佛塔苷含量为 3. 0%〜12. 0%。 收集干燥的提取物, 密封, 称 重, 置干燥处保存。
本发明中所述的乙醇浓度是指 lOOmL体积乙醇水溶液中含乙醇体积分数 (V/V)。 具体地, 根据本发明的一些实施例, 本发明对广金钱草总黄酮提取物的制备工艺及技 术参数进行了细致周密的考察和研究, 优选出了最佳条件, 并进行了中试工艺验证, 成功 过渡到了工业化生产。
具体地, 根据本发明的一个实施例, 本发明的制备广金钱草总黄酮提取物的方法可以 包括以下步骤:
a. 称取广金钱草药材, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2小 时, 第二次加入 10倍药材量的 80%乙醇, 55°C加热回流提取 1. 5小时, 以便获得广金钱草 的醇提取液, 然后合并醇提液;
b. 将醇提液浓缩至一定体积, 使药液体积为 5倍药材量, 静置过滤后, 得到滤液; c 滤液以每小时 3倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60 %乙醇, 以每小时 3倍柱床体积的流速 进行洗脱, 得到洗脱液;
d. 将洗脱液回收乙醇, 浓缩至相对密度为 1. 22 的浓缩液, 浓缩液经 75°C减压干燥, 粉碎, 得到广金钱草总黄酮提取物, 细粉的粒度为 80目。
本发明提高了广金钱草药物中有效成分及有效物质的含量, 该广金钱草总黄酮提取物 产品中,广金钱草总黄酮含量(以干燥品计)为 50%〜80%,其中夏佛塔苷含量(以干燥品计,%) 为 3· 0%〜12· 0%ο
根据本发明的实施例, 本发明的药物组合物由广金钱草总黄酮提取物与药学上可接受 的药用辅料组成, 从而可以使得药物组合物能够呈现临床用药物制剂适于给药的形式。 优 选本发明的药物组合物可以呈选自片剂、 泡腾胶囊、 硬胶囊、 软胶囊、 颗粒剂、 冲剂、 丸 剂、 粉剂的至少一种的口服制剂形式, 其中, 所述片剂为糖衣片、 薄膜衣片、 肠溶片、 分 散片、 缓释片、 控释片或泡腾片。 由此, 可以方便使得所述药物组合物适于为对象进行给 药。
根据本发明的又一方面, 本发明提供了根据本发明实施例的药物组合物在制备药物中 的用途, 该药物组合物能够用于治疗尿路结石, 即本发明的药物能够有效用于清除湿热、 利尿排石, 湿热蕴结所致的淋沥涩痛, 尿路结石和上述证候者, 并且可用于制备成治疗 清除湿热、 利尿排石 (湿热蕴结) 的临床治疗药物。
根据本发明所做的一般药理学实验, 广金钱草总黄酮用药后, 对动物行为、 反应、 活 动、 情绪、 步态正常无明显变化, 对动物自发活动无影响、 对动物中枢神经系统兴奋性无 明显影响、对小鼠胃肠道运动无明显影响。根据本发明的实施例的动物药效学的实验结果: 广金钱草总黄酮能明显抑制肾脏中草酸钙结晶聚合体数量, 降低肾结石形成率和血清中的 肌酐和尿酸含量, 改善大鼠肾功能; 具有溶石和减少新结石形成的作用; 具有利尿作用作 用; 并且广金钱草总黄酮能减轻大鼠足跖注射新鲜蛋清引起的肿胀度和肿胀率, 提示广金 钱草总黄酮胶囊具有一定的消炎作用, 并对肉芽组织增生有明显的抑制作用。 并且, 在动 物的急性毒性试验中, 小鼠灌胃广金钱草总黄酮急性毒性试验结果表明广金钱草总黄酮 是一种基本无毒的受试药。大鼠灌胃广金钱草总黄酮急性毒性试验结果表明广金钱草总 黄酮是一种无严重急性中毒危险的受试药。 动物的长期毒性试验结果也证明了广金钱草 总黄酮是安全的。 根据本发明实施例, 该药物可以呈选自片剂、 泡腾胶囊、 硬胶囊、 软胶 囊、 颗粒剂、 冲剂、 丸剂、 粉剂的至少一种的口服制剂形式, 其中, 所述片剂为糖衣片、 薄膜衣片、 肠溶片、 分散片、 缓释片、 控释片或泡腾片。
根据本发明的再一方面, 本发明提供了一种制备药物组合物的方法。 根据本发明的实 施例, 该方法包括: 提供广金钱草醇提取物, 所述广金钱草醇提取物含有广金钱草总黄酮 作为活性成分。 根据本本发明的一些实施例, 进一步包括添加药学上可接受的药用辅料的 步骤, 其中, 基于所述药物组合物的总重量, 所述广金钱草总黄酮的含量为 2.5~95重量%。 其中, 制备广金钱草总黄酮提取物包括: 将广金钱草进行加醇提取, 以便获得广金钱草提 取液, 以及将所述广金钱草提取液进行纯化, 以便获得所述广金钱草总黄酮提取物, 其中, 所述乙醇的浓度为 50~95%, 所述乙醇的重量是所述广金钱草药材的 8~14倍; 将所述广金 钱草提取液进行浓缩处理, 以便除去乙醇; 以及将经过浓缩处理的广金钱草提取液进行大 孔吸附树脂柱处理, 以便获得所述广金钱草醇提取物。 根据本发明的实施例, 在得到广金 钱草总黄酮提取物之后, 可以根据需要, 对所得到的提取物进行干燥得到固体物质。
利用上述制备药物的方法所得到的药物组合物,能够对尿路结石疾病进行有效地治疗。 根据本发明的实施例, 将广金钱草进行加醇提取可以进一步包括: 将所述广金钱草药 材用 8〜14倍药材重量的 50%〜95%乙醇进行加热回流, 提取 1〜3次, 每次 1〜3小时, 并 合并醇提取液, 以便获得所述广金钱草提取液。 根据本发明的具体示例, 将所述广金钱草 提取液进行纯化进一步包括: 将所述广金钱草提取液进行浓缩处理, 以便除去乙醇; 将所 述广金钱草提取液进行大孔吸附树脂柱处理, 以便获得经过纯化的广金钱草总黄酮提取物。
具体地, 根据本发明实施例的广金钱草提取物的制备方法可以为如下:
广金钱草药材加入 8〜14倍药材量的 50%〜95%乙醇, 50-60°C加热回流,提取 1〜3次, 每次 1〜3小时, 以便获得广金钱草的醇提取液, 然后合并醇提液; 将醇提液浓缩至一定体 积, 使药液体积为 2〜8倍药材量, 静置过滤后, 得到滤液; 滤液以每小时 1〜3倍柱床体 积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 8〜12倍树脂量的水洗脱除杂, 再 用 6〜 10倍柱床体积的 40%〜95 %的乙醇, 以每小时 2〜4倍柱床体积的流速进行洗脱, 得 到洗脱液; 将洗脱液回收乙醇, 浓缩至相对密度为 1. 10〜1. 30的浓缩液, 浓缩液经干燥, 粉碎, 得到广金钱草总黄酮提取物细粉。
根据本发明的具体示例,优选广金钱草提取物的制备方法如下:取广金钱草药材 50克, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2小时, 第二次加入 10倍药材量 的 80%乙醇, 55°C加热回流提取 1. 5小时, 合并醇提液; 将醇提液浓缩至一定体积, 使药 液体积为 5倍药材量, 静置过滤, 得到滤液(为上样药液), 备用。 将 100千克药用级 AB-8 型大孔树脂用适量乙醇浸泡, 湿法装柱, 处理后备用。 将上述滤液 (上样药液) 以每小时 2倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 10倍树脂量的水洗脱 除杂, 再用 8倍柱床体积的 60 %乙醇, 以每小时 2倍柱床体积的流速进行洗脱, 得到洗脱 液; 将洗脱液回收乙醇, 浓缩至相对密度为 1. 22 的浓缩液, 经 75°C减压干燥, 粉碎, 得 到广金钱草总黄酮提取物产品 1. 10克。
根据本发明的实施例, 本发明的制备药物的方法可以进一步包括添加药学上可接受的 药用辅料制备而成的中药制剂的步骤。 根据本发明的实施例, 本发明的制备药物的方法可 以进一步包括下列步骤: 将药物制成选自片剂、 泡腾胶囊、 硬胶囊、 软胶囊、 颗粒剂、 冲 剂、 丸剂、 粉剂的至少一种的口服制剂形式, 其中, 所述片剂为糖衣片、 薄膜衣片、 肠溶 片、 分散片、 缓释片、 控释片或泡腾片。
具体地, 对于颗粒剂形式的药物组合物, 其制备方法可以包括: 将处方量的粘合剂溶 于水中,搅拌均匀配成溶液,备用;将处方量的广金钱草总黄酮提取物原料和填充剂混合, 投入流化床中, 并使用喷枪将粘合剂溶液喷入流化床中进行制粒; 制粒结束后, 干燥、 出 料, 得混合粉, 将所得到的混合粉灌装, 以便得到呈颗粒剂形式的药物组合物。
具体地, 对于颗粒剂形式的药物组合物, 其制备方法可以进一步包括: 分别将处方量 的广金钱草总黄酮提取物原料、 以及药学上可接受的药用辅料, 过 60-100目筛; 将粘合剂 溶于溶剂中搅拌, 配成溶液备用; 按照处方, 将物料投入流化床中, 预热 5-60分钟, 使预 热至 35°C-55°C ; 调整参数, 并使用喷枪将粘合剂溶液喷入流化床中进行制粒, 保持雾化压 力为 0. 7-1. 0巴(1巴 =0. 1兆帕),喷液速度为 15-25转 /分钟,通过调节进风温度 50°C-65°C, 将物料温度保持在 40°C-55°C, 5-60分钟喷完粘合剂; 制粒结束后, 调整参数进行干燥, 通过调节进风温度 60°C-7(TC, 提升物料温度至 40°C-55°C, 干燥 5-60分钟; 将干燥后的颗 粒降温、 出料, 得混合粉, 将所得到的混合粉进行颗粒剂灌装, 以便得到呈颗粒剂形式的 药物组合物。
根据本发明的一个具体示例, 本发明的组合物产品的颗粒剂制备方法如下: 将粘合剂 聚维酮 K3。 1克溶于 120克水中, 搅拌均匀配成溶液, 备用; 将广金钱草总黄酮提取物 133 克、以及微晶纤维素 110克、乳糖 60克混合,投入流化床中,预热 20分钟,使预热至 45°C ; 调整参数, 并使用喷枪将粘合剂溶液喷入流化床中进行制粒, 保持雾化压力为 0. 9 巴, 喷 液速度为 20转 /分钟, 通过调节进风温度 55°C, 将物料温度保持在 45°C, 15分钟喷完粘 合剂; 制粒结束后, 调整参数进行干燥, 通过调节进风温度 65°C, 提升物料温度至 45°C, 干燥 10分钟;将干燥后的颗粒降温、出料,得混合粉,将所得到的混合粉进行颗粒剂灌装, 以便得到呈颗粒剂形式的药物组合物 1000袋。
具体地, 对于硬胶囊形式的药物组合物, 其制备方法可以包括: 将处方量的粘合剂溶 于水中,搅拌均匀配成溶液,备用;将处方量的广金钱草总黄酮提取物原料和填充剂混合, 投入流化床中, 并使用喷枪将粘合剂溶液喷入流化床中进行制粒; 制粒结束后, 干燥、 出 料, 得混合粉, 将所得到的混合粉, 在胶囊机上进行灌装, 以便得到呈胶囊剂形式的组合 物。
具体地, 对于胶囊剂形式的药物组合物, 其制备方法可以进一步包括: 分别将处方量 的广金钱草总黄酮提取物原料、 以及药学上可接受的药用辅料, 过 60-100目筛; 将粘合剂 溶于溶剂中搅拌, 配成溶液备用; 按照处方, 将物料投入流化床中, 预热 5-60分钟, 使预 热至 35°C-55°C ; 调整参数, 并使用喷枪将粘合剂溶液喷入流化床中进行制粒, 保持雾化压 力为 0. 7-1. 0巴(1巴 =0. 1兆帕),喷液速度为 15-25转 /分钟,通过调节进风温度 50°C-65°C, 将物料温度保持在 40°C-55°C, 5-60分钟喷完粘合剂; 制粒结束后, 调整参数进行干燥, 通过调节进风温度 60°C-7(TC, 提升物料温度至 40°C-55°C, 干燥 5-60分钟; 将干燥后的颗 粒降温、 出料, 得混合粉, 将所得到的混合粉进行胶囊灌装, 以便得到呈胶囊剂形式的药 物组合物。
根据本发明的一个具体示例, 本发明的组合物产品的胶囊剂制备方法如下: 将粘合剂 聚维酮 K3。 1克溶于 120克水中, 搅拌均匀配成溶液, 备用; 将广金钱草总黄酮提取物 133 克、以及微晶纤维素 30克、乳糖 37克混合,投入流化床中,预热 20分钟,使预热至 45°C ; 调整参数, 并使用喷枪将粘合剂溶液喷入流化床中进行制粒, 保持雾化压力为 0. 9 巴, 喷 液速度为 20转 /分钟, 通过调节进风温度 55°C, 将物料温度保持在 45°C, 15分钟喷完粘 合剂; 制粒结束后, 调整参数进行干燥, 通过调节进风温度 65°C, 提升物料温度至 45°C, 干燥 10分钟; 将干燥后的颗粒降温、 出料, 得混合粉, 将所得到的混合粉在胶囊机上进行 灌装, 以便得到呈胶囊剂形式的药物组合物 1000粒。
具体地, 对于片剂形式的药物组合物, 其制备方法可以包括: 将处方量的广金钱草总 黄酮、 固体分散体载体、 以及表面活性剂, 过筛后, 加入 50%乙醇, 加热搅拌溶解, 减压 蒸发除去溶剂, 真空干燥, 粉碎过筛, 以便得到广金钱草总黄酮的固体分散体; 称取填充 剂、 崩解剂, 过筛后, 与广金钱草总黄酮固体分散体混合均匀, 制粒, 烘干, 整粒, 加入 润滑剂混合均匀, 以便得到广金钱草总黄酮颗粒, 颗粒在压片机上压制, 以便得到呈片剂 形式的药物组合物。 更进一步的, 上述片剂经包糖衣、 或包薄膜衣, 以便得到呈糖衣片、 或薄膜衣片形式的药物组合物。
具体地, 对于片剂形式的药物组合物, 其制备方法可以进一步包括: 分别称取处方量 的广金钱草总黄酮、固体分散体载体、以及表面活性剂,过 40-100目筛后,加入 50%乙醇, 加热至 50°C〜75°C搅拌溶解, 30°C〜75°C减压蒸发除去溶剂, 30°C〜6(TC真空干燥, 干燥 完毕后, 粉碎过 40-200目筛, 备用; 称取填充剂、 崩解剂, 过 40-100目筛后, 与广金钱草 总黄酮固体分散体混合均匀, 制软材, 用 10-30 目筛网制粒, 30°C〜75°C烘干, 整粒, 加 入润滑剂混合均匀, 得到的广金钱草总黄酮颗粒在压片机上压制, 以便得到呈片剂形式的 药物组合物。 更进一步的, 上述片剂经包糖衣、 或包薄膜衣, 以便得到呈糖衣片、 或薄膜 衣片形式的药物组合物。
根据本发明的一个具体示例, 本发明的组合物产品的片剂制备方法如下: 分别称取处 方量的广金钱草总黄酮 66.5g、聚维酮 K3Q 266g、 泊洛沙姆 188 133g、 以及十二垸基硫酸 钠 39.9g, 过 80 目筛后, 加入 50%乙醇, 加热至 65°C搅拌溶解, 50°C减压蒸发除去溶剂, 4CTC真空干燥, 干燥完毕后, 粉碎过 80目筛, 得广金钱草总黄酮固体分散体备用; 称取乳 糖 10g、 交联羧甲基纤维素钠 15g, 过 80目筛后, 与所得的广金钱草总黄酮固体分散体混 合均匀, 采用适量水制软材, 用 20 目筛网制粒, 55°C烘干, 整粒, 加入硬脂酰富马酸钠 6g混合均匀。 将广金钱草总黄酮颗粒在压片机上压制, 以便得到呈片剂形式的药物组合物 1000片。 更进一步的, 上述片剂经包糖衣、 或包薄膜衣, 以便得到呈糖衣片、 或薄膜衣片 形式的药物组合物。
具体地, 对于软胶囊形式的组合物, 其制备方法可以包括: 将处方量的油相、 表面活 性剂和助表面活性剂, 通过搅拌或超声的方法使混合物搅拌均匀, 再加入处方量的广金钱 草总黄酮提取物, 搅拌或者超声使其溶解, 然后灌封在软胶囊中, 以便得到呈软胶囊形式 的组合物。
具体地, 对于软胶囊形式的组合物, 其制备方法可以包括: 将处方量的大豆油 40克、 聚氧乙烯 (40)氢化蓖麻油 80克和聚乙二醇 400 30克,通过搅拌或超声的方法使混合物搅 拌均匀, 再加入处方量的广金钱草总黄酮提取物 133克, 37°C搅拌或者超声使其溶解, 抽 真空脱尽气泡,制成内容物料液。将内容物料液置于软胶囊压丸机中,填充压制成软胶囊, 进入滚筒干燥设备进行吹风干燥, 使软胶囊硬化成型, 再经过乙醇杀菌、 擦洗丸, 使胶囊 囊壳水分和乙醇自然蒸发掉, 干燥时间 20小时, 至囊皮表面干燥光洁、 稍有弹性, 干燥完 成。 最后将外型、 合缝等不合格的软胶囊拣选出来弃掉, 将拣选出来的合格软胶囊采用瓶 装或泡罩板等形式进行包装, 以便得到呈软胶囊形式的组合物 1000粒。
根据本发明的实施例, 利用本发明制备药物的方法制备的药物, 可以用于治疗尿路结 石。
根据本发明的又一方面, 本发明还提出了一种药物, 其是通过上述制备药物的方法制 备的。 如前所述, 利用该药物, 能够对尿路结石进行有效地治疗。
需要说明的是, 本发明的药物组合物及其制备方法和用途是本申请的发明人经过艰苦 的创造性劳动和优化工作才完成的。
本发明相对于现有技术, 具有如下优势: 1、 本发明的药材提取纯化工艺中, 用乙醇作为提取溶媒提取广金钱草药材, 提取液用 大孔吸附树脂纯化得到广金钱草的有效部位广金钱草总黄酮, 与广金钱草水提醇沉的传统 提取工艺法比较, 其提取物的有效物质基础明确, 质量标准可控, 降低了药物的临床服用 量、 减少了临床的不良反应。
2、本发明与现有的乙醇提取-大孔树脂纯化法比较, 提取液回收乙醇至一定体积(5倍 药材量) 即可直接上大孔树脂纯化, 而不需要浓缩干燥至浸膏, 节省了生产时间; 其次, 上大孔树脂后, 采用等浓度的乙醇进行洗脱也能得到较高含量的有效成分, 相比采用不同 浓度乙醇梯度洗脱, 工艺流程简便, 可操作性强; 再次,洗脱液回收乙醇后直接减压干燥, 不需加适当溶剂进行处理, 便可得到广金钱草的有效部位广金钱草总黄酮, 节约了生产月 能。 从规模化生产来看, 新的提取纯化工艺降低了生产成本, 缩短了生产周期, 工艺简便 可行, 符合中药现代化产业要求。
3、本发明采用 AB-8大孔吸附树脂技术提取纯化有效部位,具有工艺简单,成本较低, 树脂可反复使用, 适合工业生产的特点。 而且本发明对相应的技术参数进行了细致周密的 考察, 优选出最佳条件, 进行了中试验证, 本发明的方法可过渡到产业化, 提高了有效部 位的含量。
4、本发明所得的广金钱草总黄酮药物组合物与市售同用途药物比较, 具有生产工艺先 进、有效部位药效物质基础明确、质量标准可控、临床适应病证较为确切、药理药效显著、 用药量少、 服用安全方便、 不良反应小等特点, 从而具有适应现代制造业的工艺技术和质 量标准的优势。
本发明的附加方面和优点将在下面的描述中部分给出, 部分将从下面的描述中变得明 显, 或通过本发明的实践了解到。 附图说明
本发明的上述和 /或附加的方面和优点从结合下面附图对实施例的描述中将变得明显 和容易理解, 其中:
图 1显示了根据本发明的一个实施例的广金钱草样品溶液上 AB-8大孔树脂柱吸附总 黄酮的泄露曲线;
图 2显示了根据本发明的一个实施例的 60%乙醇为洗脱剂洗脱树脂柱中总黄酮的洗脱 曲线。 具体实施方式
下面详细描述本发明的实施例, 所述实施例的示例在附图中示出, 其中自始至终相同 或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。 下面通过参考附图描 述的实施例是示例性的, 仅用于解释本发明, 而不能理解为对本发明的限制。
实施例 1、 广金钱草总黄酮的制备
( 1 )提取方法: 根据黄酮类化合物的溶解性能, 游离的黄酮类及黄酮苷类化合物一般 可用有机溶剂提取, 工业化生产常用较高浓度的乙醇提取, 本研究在借鉴一般黄酮类化合 物工业化提取方法的基础上, 选择 60%-95%乙醇作为提取溶剂, 提取次数按生产常用方法 提取两次比较经济实用。
乙醇回流提取工艺实验: 采用 L9 ( 34) 正交试验法, 以广金钱草总黄酮为考察指标, 确定乙醇浓度、 乙醇用量 (广金钱草药材量的倍数) 及提取时间等因素的工艺参数, 并采 用紫外 -可见分光光度法对提取物中总黄酮的含量进行测定,并以总黄酮含量及干膏中总黄 酮的净重为评价指标进行比较分析。 实验因素及 O水平安排见表 1, 结果分析见表 2。 表 1 实验因素水平表
A B C D
水平 \因素 乙醇浓度 乙醇用量 (倍) 空白 提取时间 (h )
( ) 第 1次 第 2次 第 1次 第 2次
1 60 8 6 一 1. 0 1. 0
2 80 10 8 一 1. 5 1. 0
3 95 12 10 一 2. 0 1. 5 表 2 正交试验设计及结果分析
实验序号 A B C D 总黄酮含量(%) 总黄酮净重(g)
1 1 1 1 1 19. 0 0. 67
2 1 2 2 2 23. 8 1. 01
3 1 3 3 3 23. 0 1. 11
4 2 1 2 3 27. 4 1. 05
5 2 2 3 1 25. 5 1. 03
6 2 3 1 2 30. 7 1. 15
7 3 1 3 2 15. 0 0. 45
8 3 2 1 3 16. 0 0. 48
9 3 3 2 1 16. 8 0. 49
K1 2. 790 2. 170 2. 300
K2 3. 230 2. 520 2. 550 2. 610 K3 1. 420 2. 750 2. 590 2. 640
kl 0. 930 0. 723 0. 767 0. 730
k2 1. 077 0. 840 0. 850 0. 870
k3 0. 473 0. 917 0. 863 0. 880
R 0. 604 0. 194 0. 096 0. 150 直观分析: 由表 2的 R值可知, RA>RB>RD,表明影响因素顺序为 A>B>D。 由 k值可知, A2>A1>A3, B3>B2>B1 , D3>D2>D1 , 因此, 各因素的最佳水平组合为 A2B3D3。 即广金钱草总 黄酮的最佳提取工艺为: 用 80%乙醇提取两次, 第一次提取 2小时, 加 12倍量乙醇, 第二 次 1. 5小时, 加 10倍量乙醇。
( 2 )用上述述优选的提取条件提取得到的广金钱草提取液进行大孔树脂纯化工艺试验: 1 ) 大孔树脂的筛选试验
树脂来源: AB-8型树脂 (南开大学)、 D101型树脂 (山东鲁抗)、 HPD100型树脂 (河 北宝沧有限责任公司)。
a) 不同大孔吸附树脂对样品溶液中总黄酮的静态饱和吸附和解吸附洗脱试验 精密称取已处理好的大孔吸附树脂 2g (抽滤至不滴水为止),置 lOOmL磨口三角瓶中, 精密加入供试品药液 50mL, 置振荡器上持续振摇 24h, 使其充分吸附后, 取上层液分别测 定总黄酮的浓度。 并按下式计算树脂饱和吸附量: 饱和吸附量 = [ (初始浓度-吸附后浓度) X吸附液体积] /树脂量], 洗脱率 = (洗脱液浓度 X洗脱液体积) /饱和吸附量 X 100 %, 结 果见表 3。
表 3 三种树脂静态饱和吸附与解吸附测定结果 总黄酮
树脂种类
饱和吸附量 (mg/g) 洗脱率 (%)
AB-8 58. 36 89. 75
D101 49. 27 81. 23
HPD100 52. 41 85. 35 结果表明, 在静态吸附和解吸附试验中, AB-8、 D101、 HPD100型大孔吸附树脂对样品 中总黄酮的饱和吸附量以及洗脱量和洗脱率比较接近, 对这三种树脂进行进一步的动态吸 附和解吸附性能的考察。
b ) 三种大孔树脂对样品溶液中总黄酮的动态饱和吸附及解吸附性能试验
精密称取已处理好的上述三种大孔吸附树脂各 2g, 上柱备用, 分别用 lOOmL供试品药 液以 lmL/min通过树脂柱, 过柱液重复吸附一次, 再用一定体积的水洗, 分别测量流出液 中总黄酮的含量, 并按下式计算树脂比吸附量: 比吸附量= [ (上柱液中物质的含量一下柱 液中物质的含量 -水洗脱液中物质的含量) /树脂量], 比洗脱量= [洗脱液浓度 X吸附液体 积 /树脂量]。 实验结果见表 4。
表 4 三种树脂饱和吸附与解吸附测定结果 总黄酮
树脂种类
比吸附量 (mg/g) 洗脱率 (%)
AB-8 50. 24 86. 52 D101 40. 78 78. 34 HPD100 45. 02 80. 19 试验结果表明: AB-8型大孔树脂对广金钱草总黄酮比吸附量和洗脱率均较好, 且安全 性较高, 是目前国内药品生产行业应用最多的一种大孔树脂, 故本研究选用 AB-8型大孔树 脂同时纯化广金钱草总黄酮。
2 ) AB-8型大孔树脂纯化工艺试验
a) 吸附条件优选试验
采用正交试验方法以上样药液浓度(以样品中所含有的原药材量计)、吸附流速及径高 比作为考察因数, 应用 ( 34) 正交表安排试验, 因素及水平安排见表 5。 对以下 9组试验 分别测定总黄酮含量, 计算其比吸附量, 并进行综合评价。 分析结果见表 6。
表 5 试验因素水平表
A B
水平 \因素 上样药液浓度 吸附流速
Figure imgf000012_0001
比 ( g/mL) (倍柱体积 /h)
1 0. 1 2 1 : 4 2 0. 2 4 1 : 8 3 0. 4 6 1 : 12 正交试验设计及结果分析
实验序 总黄酮净重 总黄酮含量 (%)
( g) 1 1 1 1 1 70. 35 0. 28
2 1 2 2 2 66. 75 0. 22
3 1 3 3 3 63. 08 0. 26
4 2 1 2 3 69. 21 0. 25
5 2 2 3 1 66. 06 0. 24
6 2 3 1 2 68. 54 0. 28
7 3 1 3 2 60. 97 0. 27
8 3 2 1 3 61. 21 0. 24
9 3 3 2 1 66. 09 0. 20
Kl 0. 760 0. 800 0. 800 0. 720
K2 0. 770 0. 700 0. 670 0. 770
K3 0. 710 0. 740 0. 770 0. 750
kl 0. 253 0. 267 0. 267 0. 240
k2 0. 257 0. 233 0. 223 0. 257
k3 0. 237 0. 247 0. 257 0. 250
R 0. 020 0. 034 0. 044 0. 017
结果分析: 由表 2的 R值可知, RB > RA> RD,表明影响因素顺序为 B > A> D。 由 k值可 知, A2> A > A3, B1>B3>B2 , D2> D3> D1 o 因此, 各因素的最佳水平组合为 A2BJ)2。 因此优选 总黄酮的最佳吸附条件为: 上样药液浓度为 0. 2g/ml,吸附流速为 2BV/h (即: 以每小时 2倍 柱床体积的流速进行洗脱), 径高比为 1 : 8。
b ) 上样量考察
取 0. 2g/mL样品溶液,加于 20gAB-8树脂柱中(20mm X 400mm), 以 2Bv/h的流速通过。 每个流份收集 10mL, 测定并计算流份中总黄酮的浓度, 并绘制泄露曲线, 结果见图 1。 图 中可以看出当上样量为 50mL时(即 10g生药量), 总黄酮开始泄漏, 上样量为 600mL时(约 为 30倍树脂量) 达到吸附饱和状态。
c ) 水洗条件考察
按上述最佳吸附条件进行上样吸附, 上样量为 50 mL, 再用纯化水冲洗, 每 20mL下柱 液为 1流份, 用 α -萘酚反应检识, 同时测定干膏重, 水洗 300mL后 ct -萘酚反应呈阴性, 干膏重量不再变化, 结果表明, 用 300mL水洗(约 15倍树脂量)后树脂柱上的糖类可以基 本除去。
d) 乙醇洗脱浓度考察
另取 20g树脂共五份上柱,按上述吸附条件和水洗条件进行吸附和去杂,再各用 30%, 45%, 60%, 75%, 90%的乙醇 400mL, 以相同的流速进行洗脱,测定, 计算总黄酮的含量及解 吸率, 结果见表 7。
表 7 广金钱草总黄酮乙醇洗脱浓度考察结果 乙醇浓度 (%) 30 45 60 75 90 解吸率 (%) 38. 16 59. 25 85. 63 81. 56 79. 21 干膏重 (mg) 87. 23 178. 5 231. 6 216. 2 209. 3 总黄酮含量 (%) 35. 21 42. 06 58. 63 55. 45 56. 82 以上试验结果表明,当乙醇浓度为 60 %以上时,总黄酮解吸率和含量都较高,且 60 %、 75%和 90 %乙醇解吸能力相当, 考虑到生产成本, 故本试验选 60%乙醇为洗脱溶剂。
e ) 洗脱速率考察
按上述条件进行动态吸附, 以 60%乙醇为洗脱剂, 分别以 1, 3, 5倍柱体积 /小时的速 度洗脱, 收集乙醇洗脱液, 测定, 计算总黄酮的含量与解吸率, 结果见表 8。
表 8 广金钱草总黄酮乙醇洗脱流速考察结果
洗脱流速 解吸率 (%) 干膏中总黄酮含量 (%) lBV/h 88. 31 57. 92
3BV/h 87. 45 56. 37
5BV/h 80. 16 50. 08
结果表明:洗脱速率为 1倍柱体积 /小时 3倍柱体积 /小时相差不大, 考虑生产效率, 选 用 3Bv/h的洗脱流速较合理。
f ) 乙醇洗脱量考察
按上述条件进行动态吸附, 以 60%乙醇为洗脱剂进行洗脱, 定量收集流出液并测定其 中总黄酮的含量。 结果见图 2。 结果表明: 用 240mL ( 8倍树脂柱体积) 60%乙醇可以完全 洗脱 20g树脂所吸附的黄酮类成分。 因此, 采用 240mL ( 8倍树脂柱体积) 60%乙醇以 3Bv/h 的流速可以使 20g树脂所吸附的黄酮类成分完全洗脱。
实施例 2、 广金钱草总黄酮的制备
取广金钱草药材 50克, 第一次加入 12倍药材量的 80%乙醇, 55 °C加热回流提取 2小 时, 第二次加入 10倍药材量的 80%乙醇, 55 °C加热回流提取 1. 5小时, 合并醇提液; 将醇 提液浓缩至一定体积, 使药液体积为 5倍药材量, 静置过滤, 得到滤液(为上样药液), 备 用。 将 100千克药用级 AB-8型大孔树脂用适量乙醇浸泡, 湿法装柱, 处理后备用。 将上述 滤液 (上样药液) 以每小时 2倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60 %乙醇, 以每小时 2倍柱床体积 的流速进行洗脱, 得到洗脱液; 将洗脱液回收乙醇, 浓缩至相对密度为 1. 22的浓缩液, 经 75°C减压干燥, 粉碎, 得到广金钱草总黄酮提取物产品 1. 10克。
实施例 3、 广金钱草总黄酮的制备
取广金钱草药材 200克, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2小 时, 第二次加入 10倍药材量的 80%乙醇, 55°C加热回流提取 1.5小时, 合并醇提液; 将醇 提液浓缩至一定体积, 使药液体积为 5倍药材量, 静置过滤, 得到滤液(为上样药液), 备 用。 将 400克药用级 AB-8型大孔树脂用适量乙醇浸泡, 湿法装柱, 处理后备用。
将上述滤液 (上样药液) 以每小时 2倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60%乙醇, 以每小时 2 倍柱床体积的流速进行洗脱, 得到洗脱液; 将洗脱液回收乙醇, 浓缩至相对密度为 1.22的 浓缩液,经 75°C减压干燥,粉碎,得到广金钱草总黄酮提取物产品 4.03克(置阴凉处保存)。 提取物产品采用紫外一可见分光光度法测量提取物中物质的含量, 得总黄酮含量 (以干燥品 计, %)为 63.31%, 夏佛塔苷含量 (以干燥品计, %)为5.38%。
实施例 4、 广金钱草总黄酮的制备
取广金钱草药材 50千克, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2 小时, 第二次加入 10倍药材量的 80%乙醇, 55°C加热回流提取 1.5小时, 合并醇提液; 将 醇提液浓缩至一定体积, 使药液体积为 5倍药材量, 静置过滤, 得到滤液 (为上样药液), 备用。 将 100千克药用级 AB-8型大孔树脂用适量乙醇浸泡, 湿法装柱, 处理后备用。
将上述滤液 (上样药液) 以每小时 2倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60%乙醇, 以每小时 2 倍柱床体积的流速进行洗脱, 得到洗脱液; 将洗脱液回收乙醇, 浓缩至相对密度为 1.22的 浓缩液, 经 75°C减压干燥, 粉碎, 得到广金钱草总黄酮提取物产品 1.12千克 (置阴凉处保 存)。 提取物产品采用紫外一可见分光光度法测量提取物中物质的含量, 得总黄酮含量 (以 干燥品计, %)为 59.49%, 夏佛塔苷含量 (以干燥品计, %)为5.10%。
实施例 5、 广金钱草总黄酮的制备
取广金钱草药材 50千克, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2 小时, 第二次加入 10倍药材量的 80%乙醇, 55°C加热回流提取 1.5小时, 合并醇提液; 将 醇提液浓缩至一定体积, 使药液体积为 5倍药材量, 静置过滤, 得到滤液 (为上样药液), 备用。 将 100千克药用级 AB-8型大孔树脂用适量乙醇浸泡, 湿法装柱, 处理后备用。
将上述滤液 (上样药液) 以每小时 2倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后, 先用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60%乙醇, 以每小时 2 倍柱床体积的流速进行洗脱, 得到洗脱液; 将洗脱液回收乙醇, 浓缩至相对密度为 1.22的 浓缩液, 经 75°C减压干燥, 粉碎, 得到广金钱草总黄酮提取物产品 1.14千克 (置阴凉处保 存)。 提取物产品采用紫外一可见分光光度法测量提取物中物质的含量, 得总黄酮含量 (以 干燥品计, %)为 59.37%, 夏佛塔苷含量 (以干燥品计, %)为5.01%。
结果表明: 本实验研究的工艺参数可行, 工艺条件经中试进一步调整后, 可顺利过渡 到产业化生产。
实施例 6、 广金钱草总黄酮胶囊的制备
处方:
广金钱草总黄酮 133g
乳糖 37g
微晶纤维素 30g
聚维酮 K30 lg
水 120g
制成 1000粒
制法:
a. 广金钱草总黄酮提取物按实施例 5的方法制备;
b. 将粘合剂聚维酮 K3。 1克溶于 120克水中, 搅拌均匀配成溶液, 备用;
c 将广金钱草总黄酮提取物 133克、 以及微晶纤维素 30克、乳糖 37克混合, 投入 化床中, 预热 20分钟, 使预热至 45°C ; 调整参数, 并使用喷枪将粘合剂溶液喷入流化床 中进行制粒, 保持雾化压力为 0. 9巴, 喷液速度为 20转 /分钟, 通过调节进风温度 55°C, 将物料温度保持在 45°C, 15分钟喷完粘合剂;
d. 制粒结束后,调整参数进行干燥,通过调节进风温度 65°C,提升物料温度至 45°C, 干燥 10分钟;
e. 将干燥后的颗粒降温、出料,得混合粉,将所得到的混合粉,在胶囊机上进行灌装, 得广金钱草总黄酮胶囊剂。
实施例 7、 广金钱草总黄酮胶囊的制备
处方:
广金钱草总黄酮 133g
微晶纤维素 30g
乳糖 37g
聚维酮 κ30 lg
交联羧甲基纤维素钠 20 g
微粉硅胶 lg 水 120g 共计 制成 1000粒 制法: 同实施例 6
实施例 8、 广金钱草总黄酮胶囊的制备 处方:
广金钱草总黄酮 100g 乳糖 60g 交联羧甲基纤维素钠 35g 羟丙甲纤维素 O.lg 微粉硅胶 2g 乙醇 100 g 水 lOg 共计 制成 1000粒 制法: 同实施例 6。
实施例 9、 广金钱草总黄酮胶囊的制备 处方:
广金钱草总黄酮 66.5g 乳糖 50g 微晶纤维素 50g 聚维酮 K3o ig 水 120g 共计 制成 1000粒 制法: 同实施例 6。
实施例 10、 广金钱草总黄酮颗粒剂的制备 处方:
广金钱草总黄酮 133g 乳糖 HOg 微晶纤维素 60g 聚维酮 K3Q ig 水 120g 共计 制成 1000袋 制法: a. 广金钱草总黄酮提取物按实施例 5的方法制备;
b. 将粘合剂聚维酮 K3。 1克溶于 120克水中, 搅拌均匀配成溶液, 备用;
c 将广金钱草总黄酮提取物 133克、 以及微晶纤维素 60克、 乳糖 110克混合, 投入 流化床中, 预热 20分钟, 使预热至 45°C ; 调整参数, 并使用喷枪将粘合剂溶液喷入流化 床中进行制粒,保持雾化压力为 0. 9巴,喷液速度为 20转 /分钟,通过调节进风温度 55°C, 将物料温度保持在 45°C, 15分钟喷完粘合剂;
d. 制粒结束后,调整参数进行干燥,通过调节进风温度 65°C,提升物料温度至 45°C, 干燥 10分钟;
e. 将干燥后的颗粒降温、 出料, 得混合粉, 将所得到的混合粉, 进行颗粒剂灌装, 得 广金钱草总黄酮颗粒剂。
实施例 11、 广金钱草总黄酮颗粒的制备
处方:
广金钱草总黄酮 150g
微晶纤维素 60g
乳糖 100g
交联聚维酮 20g
聚乙二醇 6000 5g
硬脂酰富马酸钠 5g
乙醇 100 g
水 40g
共计 制成 1000袋
制法: 同实施例 10。
实施例 12、 广金钱草总黄酮片的制备
处方:
广金钱草总黄酮 66.5g
聚维酮 K3o 266g
泊洛沙姆 188 133g
十二垸基硫酸钠 39.9g
乳糖 10g
交联羧甲基纤维素钠 15 g
硬脂酰富马酸钠 6g
共计 制成 1000片 制法:分别称取处方量的广金钱草总黄酮 66.5g、聚维酮 K3Q 266g、泊洛沙姆 188 133g、 以及十二垸基硫酸钠 39.9g, 过 80目筛后, 加入 50%乙醇, 加热至 65°C搅拌溶解, 50°C减 压蒸发除去溶剂, 40°C真空干燥, 干燥完毕后, 粉碎过 80目筛, 得广金钱草总黄酮固体分 散体备用; 称取乳糖 10g、 交联羧甲基纤维素钠 15g, 过 80 目筛后, 与所得的广金钱草总 黄酮固体分散体混合均匀, 采用适量水制软材, 用 20目筛网制粒, 55°C烘干, 整粒, 加入 硬脂酰富马酸钠 6g混合均匀。将广金钱草总黄酮颗粒在压片机上压制, 以便得到呈片剂形 式的药物组合物 1000片。
实施例 13、 广金钱草总黄酮片的制备
处方:
广金钱草总黄酮 50g
聚维酮 K3Q 200g
泊洛沙姆 188 100g
十二垸基硫酸钠 30g
乳糖 50g
交联羧甲基纤维素钠 20 g
硬脂酰富马酸钠 5g
共计 制成 1000片
制法: 同实施例 12。
实施例 14、 广金钱草总黄酮软胶囊的制备
处方:
广金钱草总黄酮 133g
大豆油 40g
聚氧乙烯(40)氢化蓖麻油 80g
聚乙二醇 400 30g
药用明胶 300
甘油 120g
水 300g
共计 制成 1000粒
制法: 将明胶、 甘油、 水浸泡膨胀, 制备成胶液, 备用; 将处方量的大豆油 40克、 聚 氧乙烯 (40)氢化蓖麻油 180克和聚乙二醇 400 30克, 通过搅拌或超声的方法使混合物搅 拌均匀, 再加入处方量的广金钱草总黄酮提取物 133克, 37°C搅拌或者超声使其溶解, 抽 真空脱尽气泡,制成内容物料液。将内容物料液置于软胶囊压丸机中,填充压制成软胶囊, 进入滚筒干燥设备进行吹风干燥, 使软胶囊硬化成型, 再经过乙醇杀菌、 擦洗丸, 使胶囊 囊壳水分和乙醇自然蒸发掉, 干燥时间 20小时, 至囊皮表面干燥光洁、 稍有弹性, 干燥完 成。 最后将外型、 合缝等不合格的软胶囊拣选出来弃掉, 将拣选出来的合格软胶囊采用瓶 装或泡罩板等形式进行包装, 以便得到呈软胶囊形式的组合物 1000粒。
实施例 15、 广金钱草总黄酮软胶囊的制备
处方:
广金钱草总黄酮 133g
大豆油 30g
聚氧乙烯(40)氢化蓖麻油 100g
聚乙二醇 400 20g
药用明胶 300
甘油 120g
水 300g
共计 制成 1000粒
制法: 同实施例 14。
实施例 16、 广金钱草总黄酮软胶囊的制备
处方:
广金钱草总黄酮 66.5g
大豆油 30g
聚氧乙烯(40)氢化蓖麻油 100g
聚乙二醇 400 20g
药用明胶 300
甘油 120g
水 300g
共计 制成 1000粒
制法: 同实施例 14。
实施例 17、 广金钱草总黄酮的一般药理学实验
实验目的: 观察广金钱草总黄酮对动物一般行为、 状态、 中枢神经系统、 消化系统等 的药理作用。
实验动物及给药: 昆明种小鼠, 雌性, 体重 18-22克, 由军事医学科学院实验动物中 心提供, 实验动物质量许可证号: SCXK (军) 2002-001, 动物词养于该中心小鼠实验房, 实验设施证明编号为 SYXK (军) 2002-001。 实验分组: 实验分 4个组, 即对照组 (灌服 0.5%羧甲基纤维素钠)、 广金钱草总黄酮 小剂量组 (75mg/kg)、 广金钱草总黄酮中剂量组 (150mg/kg)、 广金钱草总黄酮高剂量组 (300mg/kg)o 每组 10-20只。 给药途径为一次性灌胃, 给药容量为 0.6毫升 /鼠。
观察指标及结果:
1.1 广金钱草总黄酮对小鼠一般状态及行为的影响
采用 Bastian分级法对动物一般行为进行观察, 每组 10只小鼠, 于灌胃后 15分钟开始 观察, 观察内容包括精神、 步态、 眼睛、 尾巴、 皮毛及粪便等, 连续观察 60分钟, 24小 时再观察 1次。
经对小鼠一般状态及行为的观察,小鼠灌服广金钱草总黄酮小、中、大剂量组 (75mg/kg、 150mg/kg、 300mg/kg) 对动物行为、 反应、 活动、 情绪、 步态正常无明显变化, 与对照组 相比无明显差别。
1.2 广金钱草总黄酮对自发活动的影响
用光电管法记录的结果表明, 小鼠灌服不同剂量的广金钱草总黄酮, 用药动物自发活 动与对照组无明显差异, 具体数据见表 9。
表 9 小鼠灌服广金钱草总黄酮对自发活动的影响 动物数 (只) 给药剂量 药前 (次 /3 药后 (次 /3分钟)
(mg/kg) 分钟) 30分钟 60分钟 120分钟
20 0 43.5±7· 2 41.8±3· 3 40.3±3· 1 37.8±2· 2
20 75 43.8±5.0 41.3±3· 1 39.8±3· 3 38.5±1· 3
20 150 44.8±5.0 39.8±2· 2 39.3±1· 7 39.5±1· 3
20 300 43.5±4.2 40.5±1· 9 39.8±2· 2 39.5±1· 9
1.3 广金钱草总黄酮对小鼠中枢神经系统兴奋性的影响
小鼠灌服广金钱草总黄酮后, 在动物双耳涂上适量的生理盐水, 以鱼嘴夹夹住双侧耳 尖部通电, 电压为 110伏, 剌激时间为 0.3秒, 观察小鼠惊厥持续时间。
结果显示: 广金钱草总黄酮小、 中、 大剂量组 (75mg/kg、 150mg/kg 300mg/kg) 与对 照组比较, 对小鼠电剌激所致惊厥持续时间无明显延长或缩短, 惊厥发生率也无变化 (具体数据见表 10)。提示小鼠灌胃广金钱草总黄酮对动物中枢神经系统兴奋性无明显 影响。
表 10 小鼠灌服广金钱草总黄酮对小鼠中枢神经系统兴奋性的影响 动物数 (只) 体重 (克) 给药剂量 (mg/kg) 惊厥持续时间 (秒)
10 21.1±0· 6 0 32.8±5· 3 10 20.9±0· 8 75 37.1±8· 1 10 20.3±0.7 150 37.7±6.0
10 21.0±0· 9 300 35.5±8.7
1.4 广金钱草总黄酮对小鼠消化系统的影响
每组实验 10只小鼠, 实验前小鼠禁食 12小时, 灌胃广金钱草总黄酮 1小时后, 再用 5%碳末和 10%阿拉伯胶制成的混悬液灌胃, 0.2毫升/只。 灌胃后 20分钟处死动物, 取出全 部胃肠道, 将其展放在玻璃板上, 用尺测量幽门距碳末的前沿的距离, 计算其与胃肠道全 长的百分比。结果显示:广金钱草总黄酮对小鼠胃肠道运动无明显影响。具体数据见表 11。
表 11 小鼠灌服广金钱草总黄酮对肠推进率的影响
给药剂量(mg/kg) 胃肠全长 (厘米) 幽门距碳末前沿的距离 (厘米) 推进率 (%)
0 52.2±1.9 30.2±2.4 57.8±4.2
75 52.5±1.7 31.6±2.4 58.1±3· 5
150 52.3±2.3 28.8±3· 5 56.8±5.0
300 52.0±1.9 29.8±2.9 58.0±3· 4 实施例 18、 广金钱草总黄酮的动物药效学实验
1.1广金钱草总黄酮对大鼠乙二醇性草酸钙肾结石治疗作用实验
与对照组 (对照组大鼠灌服 0.5%羧甲基纤维素钠)相比, 广金钱草总黄酮四个剂量组 (50mg/kg/天、 100mg/kg/天、 200mg/kg/天、 400mg/kg/天) 能明显抑制肾脏中草酸钙结晶 聚合体数量, 量效关系 (P<0.05-0.01), 降低肾结石形成率和血清中的肌酐和尿酸含量 (P<0.05-0.01), 改善大鼠肾功能。
1.2广金钱草总黄酮大鼠乙二醇中毒性草酸钙肾结石预防作用实验
与对照组 (对照组大鼠灌服 0.5%羧甲基纤维素钠)相比, 广金钱草总黄酮三个剂量组 (50mg/kg/天、 100mg/kg/天、 200mg/kg/天)均能减轻肾盂扩张, 降低结石形成率, 减少肾 草酸钙结聚合体 (P<0.01-0.001), 降低血清中肌酐和尿酸含量 (P<0.05-0.01)。
1.3广金钱草总黄酮对植入大鼠膀胱内人的膀胱结石溶石作用实验
与对照组 (对照组大鼠灌服 0.5%羧甲基纤维素钠) 比, 广金钱草总黄酮三个剂量组 ( 100mg/kg/天、 200mg/kg/天、 400mg/kg/天)均具有溶石和减少新结石形成的作用。 100mg/kg 组结石重量减轻 (P<0.05), 200mg/kg组结石重量减轻 (P<0.05), 20%结石溶解, 400mg/kg组 结石重量减轻 (P<0.01), 30%结石溶解。
1.4广金钱草总黄酮对乙二醇性肾结石大鼠和正常大鼠的利尿作用实验。
与对照组 (对照组大鼠灌服 0.5%羧甲基纤维素钠) 比, 广金钱草总黄酮三个剂量组 (50mg/kg/天、 100mg/kg/天、 200mg/kg/天) 一次给药后 6h尿排出总量, 正常对照排出总 量 48.1ml, 用药组 76.4-89.5ml比正常对照组高出 29-36ml。 结石大鼠给药 4周治疗后, 12 小时内尿排出明显增加, 比模型组增加 12-36%。
1.5广金钱草总黄酮大鼠足跖注射新鲜蛋清肿胀度和肿胀率实验
与对照组 (对照组大鼠灌服 0.5%羧甲基纤维素钠) 比, 广金钱草总黄酮三个剂量组 ( 100mg/kg/天、 200mg/kg/天、 400mg/kg/天) 均能减轻大鼠足跖注射新鲜蛋清引起的肿胀 度和肿胀率, 提示广金钱草总黄酮具有一定的消炎作用, 并对肉芽组织增生有明显的抑制 作用。
实施例 19、 广金钱草总黄酮的动物急性毒性实验
1.1小鼠灌胃广金钱草总黄酮急性毒性实验
试验分 6组, 每组 20只动物, 雌雄各半, 组间间距为 0.85。 药后动物出现活动减 少, 步态不稳, 呼吸微弱, 多数死亡动物分布在药后 1小时内, 个别死亡动物分布在药 后 1-6小时。 用 Bliss法统计, 雌性动物 LD50为 18.162g/kg, 95%的可信限, 上限为 20.199g/kg,下限为 16.326g/kg; 雄性动物 LD50为 17.084g/kg, 95%的可信限, 上限为 18.975g/kg,下限为 15.301g/kg。 雌性和雄性动物 LD50无明显差别。 根据上述结果, 可 以认为广金钱草总黄酮是一种基本无毒的受试药。
1.2大鼠灌胃广金钱草总黄酮急性毒性实验
按《单次口服固定剂量法》进行试验。 预备试验中大鼠以 2000mg/kg给药, 药后动 物无明显急性毒性反应, 故以 2000mg/kg固定剂量做正式试验。
试验分对照组和广金钱草总黄酮组, 每组 10只动物, 雌雄各半。 给药组动物一次 灌胃广金钱草总黄酮 2000mg/kg, 容积为 2.0ml/100g体重。 对照组动物一次灌胃 0.5% 羧甲基纤维素钠 2.0ml/100g体重。
给药组动物药后 3小时内出现懒动, 药后 1天大便呈灰黑色, 进食量稍有下降, 体 重增长受到轻度抑制, 药后 7天恢复至对照组水平。 根据上述结果, 可以认为广金钱草 总黄酮是一种无严重急性中毒危险的受试药。 在本说明书的描述中, 参考术语"一个实施例"、 "一些实施例"、 "示例"、 "具体示例"、 或"一些示例"等的描述意指结合该实施例或示例描述的具体特征、 结构、 材料或者特点包 含于本发明的至少一个实施例或示例中。 在本说明书中, 对上述术语的示意性表述不一定 指的是相同的实施例或示例。 而且, 描述的具体特征、 结构、 材料或者特点可以在任何的 一个或多个实施例或示例中以合适的方式结合。
尽管已经示出和描述了本发明的实施例, 本领域的普通技术人员可以理解: 在不脱离 本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、 修改、 替换和变型, 本发 明的范围由权利要求及其等同物限定。

Claims

权利要求书
1、 一种药物组合物, 其含有广金钱草总黄酮作为活性成分,
其中, 所述广金钱草总黄酮是以广金钱草醇提取物的形式提供的。
2、 根据权利要求 1所述的药物组合物, 其特征在于, 所述药物组合物进一步包含药学 上可接受的药用辅料。
3、 根据权利要求 1或 2所述的药物组合物, 其特征在于, 基于所述药物组合物的总重 量, 所述广金钱草总黄酮的含量为 2.5~95重量%。
4、 根据权利要求 1-3任一项所述的药物组合物, 其特征在于, 所述广金钱草醇提取物 是通过下列步骤获得的:
利用乙醇对广金钱草药材进行加热回流, 以便获得广金钱草提取液, 其中, 所述乙醇 的浓度为 50~95%, 所述乙醇的重量是所述广金钱草药材的 8~14倍;
将所述广金钱草提取液进行浓缩处理, 以便除去乙醇; 以及
将经过浓缩处理的广金钱草提取液进行大孔吸附树脂柱处理, 以便获得所述广金钱草 醇提取物。
5、 根据权利要求 4所述的药物组合物, 其特征在于, 所述广金钱草提取液是通过将所 述广金钱草药材用 8〜14倍药材重量的 50%〜95%乙醇进行加热回流,提取 1-3次,每次 1〜 3小时, 并合并醇提取液而获得的。
6、 根据权利要求 1-3任一项所述的药物组合物, 其特征在于, 所述金钱草醇提取物是 通过下列步骤制备的:
称取广金钱草药材, 加入 8〜14倍药材量的 50%〜95%乙醇, 50-6CTC加热回流, 提取
1〜3次, 每次 1〜3小时, 以便获得广金钱草的醇提取液, 然后合并醇提液;
将所述醇提液浓缩至体积为 2〜8倍药材量, 静置过滤后, 得到滤液;
将所述滤液以每小时 1〜3倍柱床体积的流速通过 AB-8大孔吸附树脂柱,吸附完毕后, 先用 8〜12倍树脂量的水洗脱除杂, 再用 6〜10倍柱床体积的 40%〜95 %的乙醇, 以每小 时 2〜4倍柱床体积的流速进行洗脱, 得到洗脱液;
将所述洗脱液浓缩至相对密度为 1.10〜1.30的浓缩液,并将所述浓缩液 经干燥,粉碎, 以便得到所述广金钱草醇提取物。
7、 根据权利要求 6所述的药物组合物, 其特征在于, 所述广金钱草醇提取物的粒度为 50-100目。
8、 根据权利要求 1-3任一项所述的药物组合物, 其特征在于, 所述金钱草醇提取物是 通过下列步骤制备的:
称取广金钱草药材, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2小时, 第二次加入 10倍药材量的 80%乙醇, 55°C加热回流提取 1.5小时, 以便获得广金钱草的醇 提取液, 然后合并醇提液;
将所述醇提液浓缩至体积为 5倍药材量, 静置过滤后, 得到滤液;
将所述滤液以每小时 3倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后,先 用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60%乙醇, 以每小时 3倍柱床体积的 流速进行洗脱, 得到洗脱液;
将所述洗脱液浓缩至相对密度为 1.22的浓缩液, 浓缩液经 75°C减压干燥, 粉碎, 得到 所述广金钱草醇提取物。
9、 根据权利要求 8所述的药物组合物, 其特征在于, 所述广金钱草醇提取物的粒度为 50-100目。
10、 根据权利要求 1-9任一项所述的药物组合物, 其特征在于, 所述药物组合物是以 片剂、 泡腾胶囊、 硬胶囊、 软胶囊、 颗粒剂、 冲剂、 丸剂或粉剂的形式提供的。
11、根据权利要求 10所述的药物组合物, 其特征在于, 所述片剂为糖衣片、薄膜衣片、 肠溶片、 分散片、 缓释片、 控释片或泡腾片。
12、 根据权利要求 2-11任一项所述的药物组合物, 其特征在于, 所述药学上可接受的 药用辅料为选自玉米淀粉、 糊精、 乳糖、 预胶化淀粉、 蔗糖、 微晶纤维素、 甘露醇、 山梨 醇、 木糖醇、 磷酸氢钙、 碳酸钙、 淀粉糊、 羟丙甲纤维素、 聚维酮 K3Q、 聚维酮 κ25、 聚乙 二醇 2000、 聚乙二醇 4000、 聚乙二醇 6000、 枸橼酸、 琥珀酸、 右旋糖酐、 半乳糖、 蔗糖、 葡萄糖、 改性淀粉、 微晶纤维素、 泊洛沙姆 188、 D-甘露醇、 甲基纤维素、 羧甲基淀粉钠、 低取代羟丙基纤维素、 交联聚维酮、 羧甲基淀粉钠、 交联羧甲基纤维素钠、 羧甲基纤维素 钙、 椰子油胺聚乙二醇醚、 甘油聚氧乙烯醚、 吐温 20、 吐温 40、 吐温 60、 吐温 80、 卖泽 40、 苄泽 30、 聚乙二醇单甲醚、 十二垸基硫酸钠、 硬脂酸镁、 滑石粉、 微粉硅胶、 十二垸 基硫酸镁、 苯甲酸钠、 硬脂酰富马酸钠的至少之一。
13、 一种制备药物组合物的方法, 其特征在于, 包括:
提供广金钱草醇提取物, 所述广金钱草醇提取物含有广金钱草总黄酮作为活性成分。
14、 根据权利要求 13所述的方法, 其特征在于, 进一步包括:
添加药学上可接受的药用辅料的步骤。
15、 根据权利要求 13或 14所述的方法, 其特征在于, 基于所述药物组合物的总重量, 所述广金钱草总黄酮的含量为 2.5~95重量%。
16、 根据权利要求 13-15 任一项所述的方法, 其特征在于, 所述广金钱草醇提取物是 通过下列步骤获得的:
利用乙醇对广金钱草药材进行加热回流, 以便获得广金钱草提取液, 其中, 所述乙醇 的浓度为 50~95%, 所述乙醇的重量是所述广金钱草药材的 8~14倍;
将所述广金钱草提取液进行浓缩处理, 以便除去乙醇; 以及
将经过浓缩处理的广金钱草提取液进行大孔吸附树脂柱处理, 以便获得所述广金钱草 醇提取物。
17、 根据权利要求 16所述的方法, 其特征在于, 所述广金钱草提取液是通过将所述广 金钱草药材用 8〜14倍药材重量的 50%〜95%乙醇进行加热回流, 提取 1-3次, 每次 1〜3 小时, 并合并醇提取液而获得的。
18、 根据权利要求 13-15 任一项所述的方法, 其特征在于, 所述金钱草醇提取物是通 过下列步骤制备的:
称取广金钱草药材, 加入 8〜14倍药材量的 50%〜95%乙醇, 50-6CTC加热回流, 提取
1〜3次, 每次 1〜3小时, 以便获得广金钱草的醇提取液, 然后合并醇提液;
将所述醇提液浓缩至体积为 2〜8倍药材量, 静置过滤后, 得到滤液;
将所述滤液以每小时 1〜3倍柱床体积的流速通过 AB-8大孔吸附树脂柱,吸附完毕后, 先用 8〜12倍树脂量的水洗脱除杂, 再用 6〜10倍柱床体积的 40%〜95 %的乙醇, 以每小 时 2〜4倍柱床体积的流速进行洗脱, 得到洗脱液;
将所述洗脱液浓缩至相对密度为 1.10〜1.30的浓缩液,并将所述浓缩液 经干燥,粉碎, 以便得到所述广金钱草醇提取物。
19、根据权利要求 18所述的方法,其特征在于,所述广金钱草醇提取物的粒度为 50-100 巨。
20、 根据权利要求 13-15 任一项所述的方法, 其特征在于, 所述金钱草醇提取物是通 过下列步骤制备的:
称取广金钱草药材, 第一次加入 12倍药材量的 80%乙醇, 55°C加热回流提取 2小时, 第二次加入 10倍药材量的 80%乙醇, 55°C加热回流提取 1.5小时, 以便获得广金钱草的醇 提取液, 然后合并醇提液;
将所述醇提液浓缩至体积为 5倍药材量, 静置过滤后, 得到滤液;
将所述滤液以每小时 3倍柱床体积的流速通过 AB-8大孔吸附树脂柱, 吸附完毕后,先 用 10倍树脂量的水洗脱除杂, 再用 8倍柱床体积的 60%乙醇, 以每小时 3倍柱床体积的 流速进行洗脱, 得到洗脱液;
将所述洗脱液浓缩至相对密度为 1.22的浓缩液, 浓缩液经 75°C减压干燥, 粉碎, 得到 所述广金钱草醇提取物。
21、根据权利要求 20所述的方法,其特征在于,所述广金钱草醇提取物的粒度为 50-100 巨。
22、 根据权利要求 14-21 所述的方法, 其特征在于, 所述药学上可接受的药用辅料为 选自玉米淀粉、 糊精、 乳糖、 预胶化淀粉、 蔗糖、 微晶纤维素、 甘露醇、 山梨醇、 木糖醇、 磷酸氢钙、 碳酸钙、 淀粉糊、 羟丙甲纤维素、 聚维酮 K3Q、 聚维酮 K25、 聚乙二醇 2000、 聚 乙二醇 4000、 聚乙二醇 6000、 枸橼酸、 琥珀酸、 右旋糖酐、 半乳糖、 蔗糖、 葡萄糖、 改性 淀粉、 微晶纤维素、 泊洛沙姆 188、 D-甘露醇、 甲基纤维素、 羧甲基淀粉钠、 低取代羟丙 基纤维素、 交联聚维酮、 羧甲基淀粉钠、 交联羧甲基纤维素钠、 羧甲基纤维素钙、 椰子油 胺聚乙二醇醚、 甘油聚氧乙烯醚、 吐温 20、 吐温 40、 吐温 60、 吐温 80、卖泽 40、苄泽 30、 聚乙二醇单甲醚、 十二垸基硫酸钠、 硬脂酸镁、 滑石粉、 微粉硅胶、 十二垸基硫酸镁、 苯 甲酸钠、 硬脂酰富马酸钠的至少之一。
23、 根据权利要求 13-22任一项所述的方法, 其特征在于, 进一步包括:
将所述药物组合物配制为片剂、 泡腾胶囊、 硬胶囊、 软胶囊、 颗粒剂、 冲剂、 丸剂或 粉剂。
24、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤将所述药物组合物配制 为颗粒剂:
将广金钱草醇提取物和填充剂混合, 投入流化床中, 并使用喷枪将粘合剂喷入流化床 中进行制粒;
制粒结束后, 干燥、 出料, 得到混合粉;
将所述混合粉进行罐装, 以便得到颗粒剂。
25、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤将所述药物组合物配制 为颗粒剂:
分别将所述广金钱草醇提取物以及所述药学上可接受的药用辅料, 过 60-100目筛后, 投入流化床中, 预热 5-60分钟, 使温度达到 35°C-55°C ;
使用喷枪将粘合剂喷入流化床中进行制粒, 保持雾化压力为 0.07-0.1 兆帕, 喷液速度 为 15-25转 /分钟, 通过调节进风温度 50°C-65°C, 将物料温度保持在 40°C-55°C, 5-60分钟 喷完所述粘合剂;
制粒结束后, 通过调节进风温度 60°C-7(TC, 提升物料温度至 40°C-55°C, 干燥 5-60分 钟;
将干燥后的颗粒降温、 出料, 得到混合粉, 将所得到的混合粉进行颗粒剂灌装, 以便 得到所述颗粒剂。
26、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤按照下列比例将所述药 物组合物配制为颗粒剂:
将粘合剂聚维酮 K3Q 1克溶于 120克水中, 搅拌均匀配成粘合剂溶液, 备用; 将广金钱草总黄酮提取物 133克、 以及微晶纤维素 110克、 乳糖 60克混合, 投入流化 床中, 预热 20分钟, 使温度达到 45 °C ;
使用喷枪将所述粘合剂溶液喷入流化床中进行制粒, 保持雾化压力为 0.09兆帕, 喷液 速度为 20转 /分钟, 通过调节进风温度 55°C, 将物料温度保持在 45°C, 15分钟喷完所述粘 合剂溶液;
制粒结束后, 通过调节进风温度 65°C, 提升物料温度至 45°C, 干燥 10分钟; 将干燥后的颗粒降温、 出料, 得混合粉, 将所述混合粉进行颗粒剂灌装, 以便得到呈 颗粒剂形式的药物组合物 1000袋。
27、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤制备将所述药物组合物 配制为硬胶囊:
将广金钱草醇提取物和填充剂混合, 投入流化床中, 并使用喷枪将粘合剂喷入流化床 中进行制粒;
制粒结束后, 干燥、 出料, 得到混合粉;
将所述混合分在胶囊机上进行灌装, 以便得到呈胶囊剂形式的组合物。
28、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤制备将所述药物组合物 配制为硬胶囊:
分别将所述广金钱草醇提取物以及所述药学上可接受的药用辅料, 过 60-100目筛后, 投入流化床中, 预热 5-60分钟, 使温度达到 35°C-55°C ;
使用喷枪将粘合剂喷入流化床中进行制粒, 保持雾化压力为 0.07-0.1 兆帕, 喷液速度 为 15-25转 /分钟, 通过调节进风温度 50°C-65°C, 将物料温度保持在 40°C-55°C, 5-60分钟 喷完所述粘合剂;
制粒结束后, 通过调节进风温度 60°C-7(TC, 提升物料温度至 40°C-55°C, 干燥 5-60分 钟;
将干燥后的颗粒降温、 出料, 得到混合粉, 将所得到的混合粉进行胶囊灌装, 以便得 到所述硬胶囊。
29、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤按照下列比例将所述药 物组合物配制为硬胶囊:
将粘合剂聚维酮 K3Q 1克溶于 120克水中, 搅拌均匀配成粘合剂溶液, 备用; 将广金钱草总黄酮提取物 133克、 以及微晶纤维素 30克、 乳糖 37克混合, 投入流化 床中, 预热 20分钟, 使温度达到 45 °C ;
使用喷枪将所述粘合剂溶液喷入流化床中进行制粒, 保持雾化压力为 0.09兆帕, 喷液 速度为 20转 /分钟, 通过调节进风温度 55°C, 将物料温度保持在 45°C, 15分钟喷完所述粘 合剂溶液;
制粒结束后, 通过调节进风温度 65°C, 提升物料温度至 45°C, 干燥 10分钟; 将干燥后的颗粒降温、 出料, 得混合粉, 将所述混合粉进行在胶囊机上进行灌装, 以 便得到呈硬胶囊剂形式的药物组合物 1000粒。
30、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤将所述药物组合物配制 为糖衣片或薄膜衣片:
将广金钱草醇提取物、 固体分散体载体、 以及表面活性剂与 50%乙醇混合, 加热搅拌 溶解, 减压蒸发除去溶剂, 真空干燥, 粉碎过筛, 以便得到广金钱草总黄酮的固体分散体; 称取填充剂、 崩解剂与所述广金钱草总黄酮固体分散体混合均匀, 制粒, 烘干, 整粒, 加入润滑剂混合均匀, 以便得到广金钱草总黄酮颗粒;
将所述广金钱草总黄酮颗粒在压片机上压制, 以便得到片剂; 以及
将所述片剂进行包糖衣或包薄膜衣, 以便得到糖衣片或薄膜衣片。
31、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤将所述药物组合物配制 为糖衣片或薄膜衣片:
将广金钱草醇提取物、 固体分散体载体、 以及表面活性剂过 40-100目筛后与 50%乙醇 混合, 加热至 50°C〜75°C搅拌溶解, 30°C〜75°C减压蒸发除去溶剂, 30°C〜6(TC真空干燥, 干燥完毕后, 粉碎过 40-200目筛, 以便得到广金钱草总黄酮的固体分散体;
称取填充剂和崩解剂,过 40-100目筛后,与所述广金钱草总黄酮固体分散体混合均匀, 制软材, 用 10-30 目筛网制粒, 30°C〜75°C烘干, 整粒, 加入润滑剂混合均匀, 得到广金 钱草总黄酮颗粒;
将所述广金钱草总黄酮颗粒在压片机上压制, 以便得到片剂; 以及
将所述片剂进行包糖衣或包薄膜衣, 以便得到糖衣片或薄膜衣片。
32、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤按照下列比例将所述药 物组合物配制为糖衣片或薄膜衣片:
将广金钱草醇提取物 66.5g、 聚维酮 K3Q 266g、 泊洛沙姆 188 133g、 以及十二垸基硫 酸钠 39.9g, 过 80目筛后与 50%乙醇混合,加热至 65°C搅拌溶解, 50°C减压蒸发除去溶剂, 4CTC真空干燥, 干燥完毕后, 粉碎过 80目筛, 得广金钱草总黄酮固体分散体;
称取乳糖 10g、 交联羧甲基纤维素钠 15g, 过 80 目筛后, 与所述广金钱草总黄酮固体 分散体混合均匀, 制软材, 用 20 目筛网制粒, 55°C烘干, 整粒, 加入硬脂酰富马酸钠 6g 混合, 得到广金钱草总黄酮颗粒;
将所述广金钱草总黄酮颗粒在压片机上压制, 以便得到片剂 1000片; 以及
将所述片剂进行包糖衣或包薄膜衣, 以便得到糖衣片或薄膜衣片。
33、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤, 将所述组合物配制成 软胶囊:
将油相、 表面活性剂和助表面活性剂, 通过搅拌或超声处理使混合物搅拌均匀; 向所得到的混合物中加入广金钱草醇提取物, 通过搅拌或超声处理溶解, 然后灌封在 软胶囊中, 以便得到所述软胶囊。
34、 根据权利要求 23所述的方法, 其特征在于, 通过下列步骤按照下列比例将所述组 合物配制成软胶囊:
将大豆油 40克、聚氧乙烯 (40)氢化蓖麻油 80克和聚乙二醇 400 30克, 通过搅拌或超 声处理使混合物搅拌均匀;
向所得到的混合物中添加广金钱草总黄酮提取物 133克, 在 37°C搅拌或者超声处理, 使其溶解, 抽真空脱尽气泡, 得到内容物料液,
将所述内容物料液置于软胶囊压丸机中, 填充压制成软胶囊, 以便呈软胶囊 1000粒。
35、 一种药物组合物, 其是通过权利要求 13-34任一项所述方法制备的。
36、 权利要求 1-12和 35任一项所述的药物组合物在制备药物中的用途, 所述药物用 于治疗尿路结石。
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