WO2022143252A1 - 一种药物组合物的制备方法 - Google Patents

一种药物组合物的制备方法 Download PDF

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WO2022143252A1
WO2022143252A1 PCT/CN2021/139602 CN2021139602W WO2022143252A1 WO 2022143252 A1 WO2022143252 A1 WO 2022143252A1 CN 2021139602 W CN2021139602 W CN 2021139602W WO 2022143252 A1 WO2022143252 A1 WO 2022143252A1
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powder
extract
preparation
add
ginseng
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林艳和
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云南生物谷药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/79—Schisandraceae (Schisandra family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8968—Ophiopogon (Lilyturf)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation 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
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation 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
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation 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
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation 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
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation 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
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/55—Liquid-liquid separation; Phase separation
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the invention belongs to the field of medicine, and relates to a preparation method of a medicinal composition, in particular to a preparation method of a medicinal composition containing Dengzhan Asarum, ginseng, Ophiopogon japonicus and Schisandra chinensis.
  • Dengzhan Shengmai is a prescription for the treatment of cardiovascular and cerebrovascular diseases, that is, a preparation method of a medicinal composition of Dengzhan Asarum, ginseng, Schisandra and Ophiopogon japonicus based on the traditional classical prescription Shengmai powder.
  • breviscapine can dilate arterioles, reduce blood viscosity, improve cerebral circulation
  • caffeate antioxidant, anti-inflammatory, antiviral, anti-fibrosis contained in breviscapine , inhibit smooth muscle contraction, lower blood lipids
  • lignans in Schisandra chinensis have anti-inflammatory, antioxidant, antiviral, vasodilatory, neuroprotective and ulcer-inhibiting medicinal effects
  • high isoflavones in Ophiopogon japonicus have anti-myocardial effect.
  • ginsenosides in ginseng have the effects of treating neurodegenerative diseases, improving memory function, and protecting brain tissue in the nervous system, and in the cardiovascular system, they have anti-arrhythmic, anti-cardiac hypertrophy, anti-myocardial ischemia, and anti-cardiomyocyte apoptosis. In anti-tumor, it has the functions of inducing apoptosis, inhibiting tumor cell proliferation, regulating signaling pathways, and regulating immune function.
  • the four herbs were mixed and extracted, and n-butanol was extracted. Such a method is simple, but it is difficult to achieve the effect of enriching active ingredients and removing harmful substances and impurities.
  • the present invention discloses a preparation method of a pharmaceutical composition, wherein the pharmaceutical composition contains Asarum brevis, ginseng, Ophiopogon japonicus and Schisandra chinensis, and is characterized in that the preparation method of the pharmaceutical composition is as follows:
  • ginseng Take ginseng, add 80-85% ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure into clear paste, add 3-15 times purified water to ginseng clear paste to prepare adult ginseng clear liquid, use microfiltration membrane for clarification, clarify The liquid is then concentrated with a nanofiltration membrane, and the concentrated solution is for subsequent use;
  • Schisandra chinensis Take Schisandra chinensis, add water to decoct, discard the aqueous solution, add 80-85% ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare Schisandra chinensis clear liquid, and clarify with a microfiltration membrane. The liquid is then concentrated with a nanofiltration membrane, the concentrated clear paste is extracted with ethyl acetate, the ethyl acetate extract is collected, and concentrated under reduced pressure into an extract for subsequent use;
  • the microfiltration membrane of the present invention can be a ceramic microfiltration membrane with a specification of 100 nm or 200 nm, and an organic nanofiltration membrane with a specification of 300-400D can be selected as the nanofiltration membrane.
  • the above-mentioned pharmaceutical composition is added with appropriate amount of auxiliary materials to prepare oral compound medicines such as hard capsules, soft capsules, tablets, dropping pills, oral liquids or granules.
  • Step-by-step extraction the powders 1, 2, and 3 with high active ingredient content can be extracted respectively.
  • This method compared with the conventional method, is more refined, and it is easy to control the content of the active ingredient, whether it is preparing a drug with a reasonable proportion
  • the composition is also a preparation, and has better stability and repeatability in terms of calculation and proportioning.
  • the fingerprints were obtained.
  • the conventional method detected an obvious peak of pyroconic acid at the time of 5.2min, but in this extraction method, there was no such absorption peak at and near the retention time, which proved that the extraction method of the present invention It can effectively remove pyroconic acid and improve the quality of medicines.
  • the ethanol of concentration 75% is selected in the past ethanol backflow, and the ethanol of higher increasing concentration is used in the present invention, and the purpose is to successively improve the ethanol concentration, the amount proposed by the water-soluble component can be reduced, and the subsequent processing is convenient.
  • the effect is more obvious.
  • the invention also provides a preparation method.
  • the weight ratio of the raw materials of the medicinal composition is: 71%-80% of Asarum; 5.2%-7.2% of ginseng, 5.2-7.2% of Schisandra, 10.5-14.3% of wheat winter.
  • Microfiltration membrane 100nm or 200nm ceramic membrane was used to remove macromolecular insoluble substances. It can effectively reduce the energy consumption of concentration and make the subsequent column loading and extraction process more efficient.
  • the pH of the filtrate is adjusted to 7-9, and it is clarified with a ceramic microfiltration membrane, which can remove a large number of macromolecular impurities that are insoluble under neutral conditions; Concentration, on the one hand, can reduce the cost of concentration, and on the other hand, most of the pyroconic acid can be removed. This is because the water solubility of pyroconic acid is much higher than the fat solubility, and the molecular weight is only 112.
  • the membrane concentrate was applied to a 30-60 mesh amide chromatography column in an amount of 1:1 column volume. After overnight adsorption, eluted with water for 4 column volumes, eluted with 55-75% ethanol, collected the ethanol eluent and concentrated. After adjusting the pH to 7-9, spray drying to obtain powder 2. This step is to further remove pyroconic acid and enrich the required caffeic acid esters, especially dicaffeoate.
  • the present invention also provides a preparation method. Calculated by weight percentage, the flavonoid-containing scutellaria scutellariae extract powder 1 and the 4,5-di-O-caffeoylquinic acid-containing scutellaria scutellaria total caffeic acid ester extract are The powder 2 accounts for 50-55%, the extract powder 3 containing ginseng, Ophiopogon japonicus, and Schisandra chinensis accounts for 44-49%, and the sum of the three kinds of powder accounts for 94-99%.
  • the present invention also provides a preparation method.
  • the powder 1 contains 400-600 mg/g of scutellarin, and powder 1, 25-40 g is obtained by taking 2000 g of Asarum radix, 200 g of ginseng, 400 g of Ophiopogon japonicus, and 200 g of Schisandra chinensis.
  • powder 2 contains 4,5-di-O-caffeoylquinic acid 30 ⁇ 60mg/g, and obtains powder 2, 35 ⁇ 55g;
  • powder 3 contains ginsenoside Rg1+Re 2.0 ⁇ 6.0mg/g, schisandrin methyl 3.5 ⁇ 9.0 mg/g, get powder 3, 55 ⁇ 75g; after mixing powder 1, 2, 3, the content of scutellarin is 105mg/g ⁇ 155mg/g, 4,5-di-O-caffeoylquinic acid is 10 ⁇ 16mg /g, ginsenoside Rg1+Re 1.0 ⁇ 2.5mg/g, schisandrin methyl 1.8 ⁇ 4.3mg/g.
  • the present invention also provides a preparation method.
  • the powder 1 contains 450-600 mg/g of baicalin by taking 2000 g of Asarum radix, 200 g of ginseng, 400 g of Ophiopogon japonicus, and 200 g of Schisandra chinensis, and the powder 1 contains 450-600 mg/g of scutellarin, and the powder is 1: 25-40 g; 2 contains 4,5-di-O-caffeoylquinic acid 35 ⁇ 55mg/g, powder 2: 35 ⁇ 55g; powder 3 contains ginsenoside Rg1+Re 3.0 ⁇ 5.0mg/g, schisandrin 5.0 ⁇ 8.0 mg/g, powder 3: 55 ⁇ 75g.
  • the content of scutellarin is 110mg/g ⁇ 135mg/g, 4,5-di-O-caffeoylquinic acid 12 ⁇ 15mg/g, ginsenoside Rg1+Re 2 ⁇ 2.4mg /g, schisandrin methyl 2.0 ⁇ 4.0mg/g.
  • the present invention also provides a preparation method, wherein the alkali used for adjusting the pH value of the solution is NaOH, Na 2 CO 3 , NaHCO 3 , KOH, K 2 CO 3 or KHCO 3 ;
  • the acid is HCl, H 2 SO 4 or H 3 PO 4 ;
  • the ethanol concentration of the polyamide chromatography column used for elution is 50-95%.
  • the invention also provides a preparation method, wherein the microfiltration membrane is a ceramic membrane of 100 or 200 nm, and the nanofiltration membrane is an organic nanofiltration membrane of 300-400D.
  • the scutellaria scutellariae extract obtained by the above process provided by the present invention includes scutellarin and caffeoylquinic acid, and the flavonoids mainly composed of scutellarin are first precipitated by acidification, and then can be purified as required.
  • the acidified supernatant is first adjusted to pH value and then clarified with a microfiltration membrane (100nm or 200nm ceramic membrane), and then concentrated with a nanofiltration membrane (300-400D) to remove a large amount of pyroconic acid and then pass through polyamide column chromatography, First, the water-soluble impurities with high polarity are removed, and at the same time, pyroconic acid, a toxic component with high water-soluble, is removed again, and then the desired caffeic acid esters are eluted with 50-90% ethanol, especially Dicaffeic acid esters.
  • the ginseng obtained by the above process provided by the present invention adopts alcohol extraction, and after alcohol extraction, the ginseng is clarified and concentrated with a membrane to consider the three quantitative components of ginsenosides Rg1+Re and Rb1, and remove macromolecular components such as polysaccharides, proteins, and tannins; After membrane filtration and concentration, the content of ginsenoside Rg1+Re in the extract is increased by 1.5-2.5 times, thereby enriching the ginsenoside in the extract.
  • oligosaccharides were removed by alcohol extraction and water precipitation in Ophiopogon japonicus, and the flavanones of Ophiopogon japonicus were enriched, and the content of flavanones of Ophiopogon japonicus increased by 3 times.
  • the removal of oligosaccharide components is also conducive to the spray drying, otherwise there will be serious sticking to the wall during the production process, resulting in the inevitable loss of effective components.
  • Schisandra chinensis is extracted with water once to remove organic acids, and then extracted with alcohol. After alcohol extraction, the yield of the extract is still about 40% of that of the medicinal material.
  • the macromolecules are first removed with a clarifying membrane, and then removed with a concentrated membrane.
  • Inorganic substances and small molecular organic acids with strong water solubility are extracted with ethyl acetate, and the lignans are concentrated, and the content of lignans is increased by 3-4 times.
  • the active substance of the obtained spray-dried powder has obvious advantages such as high enrichment rate, more definite components of the obtained spray-dried powder, etc., and Most of the harmful substances pyroconic acid are removed, thereby improving the safety of medicines.
  • the produced preparation achieves high content, low dosage, and increased safety, thereby increasing drug compliance.
  • the extraction of Asarum scutellariae adopts two steps to enrich flavonoids and caffeic acid esters respectively: alkali-dissolving and acidifying after water extraction.
  • the ingredients settle out.
  • acidifying the supernatant to adjust the pH value it first removes macromolecular substances, such as chlorophyll, tannin, gum, resin, etc., through a microfiltration membrane, and then passes through an organic nanofiltration membrane for concentration.
  • the flavonoids and caffeic acid esters are extracted and sprayed separately, which is also conducive to the stable content of flavonoids and caffeic acid esters in the preparation, which is conducive to the free ratio of drug compounds.
  • ginseng is clarified and concentrated with a membrane.
  • Rg1+Re and Rb1 Remove macromolecular components such as polysaccharides, proteins, and tannins.
  • Ophiopogon japonicus uses alcohol extraction and water precipitation to remove most of the oligosaccharide components, and enrich the Ophiopogon flavanone components.
  • removing the oligosaccharide components is also conducive to spray drying. Otherwise, there will be serious sticking to the wall; removing the oligosaccharide can also solve the hygroscopic problem of the spray-dried powder.
  • Schisandra chinensis is first extracted with water to remove organic acids, and then extracted with alcohol. After alcohol extraction, the yield of the extract is still about 40% of that of the medicinal material. First, microfiltration membrane is used to clarify and remove macromolecular insoluble substances, and then nanofiltration is used. The membrane is concentrated to further remove water-soluble small molecule acidic substances, and finally extracted with ethyl acetate to concentrate the lignans.
  • the use of membrane separation and concentration not only effectively removes inactive components, but also reduces the cost of concentration and extraction.
  • the spray-dried powder obtained in the refining process has a high content of active substances, and the produced preparation can achieve the effect of high content and low dosage, so as to increase the compliance of medicines.
  • Schisandra chinensis Take 200g of Schisandra chinensis, add water to decoct once, and pour out the water once to remove most of the organic acids, otherwise the extract is too much, which is not conducive to enriching lignin, discard the aqueous solution, add 80-85% ethanol to reflux for extraction twice, Filtration, combined filtrates, concentrated under reduced pressure into extract, added water to prepare Schisandra clear liquid and clarified with 100nm ceramic membrane, the clarified clear liquid was then concentrated with 350D organic membrane to obtain Schisandra clear paste, clear paste with ethyl acetate Ester extraction, the ethyl acetate extract was collected, and concentrated under reduced pressure into an extract for later use.
  • the ginseng concentrate, Ophiopogon japonicus precipitation, and Schisandra chinensis extract were mixed and dissolved, and after spray drying, powder 3 was obtained, and powders 1, 2, and 3 were mixed uniformly to obtain 144 g of brown raw material extract.
  • the content of baicalin in the obtained powder 1 is 520 mg/g, and the powder 1, 34 g is obtained; the powder 2 contains 35 mg/g of 4,5-di-O-caffeoylquinic acid, and the powder 2, 43 g is obtained; the powder 3 contains ginsenosides Rg1+Re 5.5mg/g, schisandrin methyl 3.8mg/g, to obtain powder 3,67g.
  • the content of scutellarin is 129mg/g, 4,5-di-O-caffeoylquinic acid 12.8mg/g, ginsenoside Rg1+Re 2.4mg/g, schisandrin 3.9mg /g.
  • the acidified filtrate was adjusted to pH 7-9, clarified with a 200nm ceramic membrane, and the clarified solution obtained after clarification was concentrated with a 400D organic membrane, and the concentrated solution passed through a 30-60 mesh polyamide chromatography column (diameter to length ratio 1: 4), after eluting with 3 column volumes of water, eluting with 3 column volumes of 70% ethanol, collecting the ethanol eluent, adjusting the pH to 7-9 after concentration, and spray-drying to obtain powder 2;
  • Schisandra chinensis Take 200g of Schisandra chinensis, add water to decoct once, discard the aqueous solution, add 80-85% ethanol for reflux extraction twice, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare Schisandra chinensis clear liquid with 200nm ceramic membrane for clarification , the clarified clear liquid is then concentrated with 400D organic membrane to obtain Schisandra chinensis clear paste, the clear paste is extracted with ethyl acetate, the ethyl acetate extract is collected, and concentrated under reduced pressure to form an extract for later use.
  • the ginseng concentrate, Ophiopogon japonicus precipitation, and Schisandra chinensis extract were dissolved in water, and after spray drying, powder 3 was obtained, and powders 1, 2, and 3 were mixed uniformly to obtain 171 g of brown raw material extract.
  • the content of baicalin in the obtained powder 1 is 478 mg/g, and the powder 1, 42 g is obtained; the powder 2 contains 36 mg/g of 4,5-di-O-caffeoylquinic acid, and the powder 2: 53 g; the powder 3 contains ginsenoside Rg1 +Re 5.1mg/g, schisandrin methyl 4.2mg/g, get powder 3,76g.
  • the content of scutellarin is 117mg/g, 4,5-di-O-caffeoylquinic acid 16mg/g, ginsenoside Rg1+Re2.3mg/g, schisandrin 1.9mg /g.
  • Schisandra chinensis Take 200g of Schisandra chinensis, add water to decoct once, discard the aqueous solution, add 80-85% ethanol to reflux for extraction twice, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare Schisandra chinensis clear liquid with 100nm ceramic membrane for clarification , the clarified clear liquid is then concentrated with a 300D organic membrane to obtain the clear paste of Schisandra chinensis, the clear paste is extracted with ethyl acetate, the ethyl acetate extract is collected, and concentrated under reduced pressure into an extract for later use.
  • the ginseng extract, Ophiopogon japonicus precipitation, and Schisandra extract were dissolved in water, and after spray drying, powder 3 was obtained, and powders 1, 2, and 3 were mixed uniformly to obtain 166 g of brown raw material extract.
  • the content of scutellarin in the obtained powder 1 530 mg/g, the powder 1, 38 g is obtained, the powder 2 contains 38 mg/g of 4,5-di-O-caffeoylquinic acid, and the powder 2, 47 g is obtained; the powder 3 contains ginsenosides Rg1+Re 5.2mg/g, schisandrin methyl 6.3mg/g, to obtain powder 3, 81g.
  • the content of scutellarin is 121mg/g, 4,5-di-O-caffeoylquinic acid 10.8mg/g, ginsenoside Rg1+Re 2.5mg/g, schisandrin 3.1 mg/g.
  • the acidified supernatant of scutellaria scutellariae is adjusted to pH 7-9, clarified with a ceramic microfiltration membrane, and the clarified liquid obtained after clarification is then concentrated with an organic nanofiltration membrane. Determine the content of 5 dicaffeoate before and after membrane filtration, and compare the list:
  • the chromatographic conditions and system suitability test use octadecylsilane-bonded silica gel as the filler; use [A(methanol:acetonitrile 30:70)-B(0.1% trifluoroacetic acid)](18:82) as the mobile phase;
  • the detection wavelength of total caffeate was 327 nm, and the detection wavelength of pyroconic acid was 270 nm.
  • the number of theoretical plates should not be less than 5000 according to the peak of 3,5-O-dicaffeoylquinic acid.
  • Preparation of reference substance solution Take appropriate amount of 3,5-O-dicaffeoylquinic acid and scutellarin reference substance, accurately weigh, add methanol to make each 1ml containing 3,5-O-dicaffeoylquinic acid 30 ⁇ g of mixed solution, as the reference solution.
  • Determination method Precisely draw 10 ⁇ l of the reference solution and the test solution, respectively, and inject them into a liquid chromatograph for determination.
  • Dicaffeoate was compared with the peak area of 3,5-O-dicaffeoylquinic acid reference substance, and the corresponding correction factors in the following table were used to calculate 3,4-O-dicaffeoylquinic acid, 3,4-O-dicaffeoylquinic acid, 3,4-O-dicaffeoylquinic acid
  • the contents of 5-O-dicaffeoylquinic acid, phosphatidyl ester B, 4,5-O-dicaffeoylquinic acid and scutellarin ester were calculated by calculating the total amount of the above five substances.
  • ginseng Take ginseng, add 80-85% ethanol for reflux extraction twice, filter, combine the filtrates, and concentrate under reduced pressure to form a clear paste.
  • the clear paste of ginseng is added with 8 times of purified water to prepare adult ginseng clear liquid, which is clarified with a 100nm ceramic microfiltration membrane.
  • the clarified solution was then concentrated with a 400D organic nanofiltration membrane, and the concentrated solution was used for later use.
  • ginsenosides Rg1, Rb1 and Re were determined in ginseng clear liquid, clear liquid and concentrated liquid, respectively.
  • Chromatographic conditions and system suitability test Use octadecylsilane bonded silica gel as filler; use acetonitrile as mobile phase A, use water as mobile phase B, and carry out gradient elution as specified in the table; detection wavelength is 203nm.
  • the theoretical plate number should not be less than 6000 according to the ginsenoside Rg 1 peak.
  • Preparation of reference solution Precisely weigh ginsenoside Rg 1 reference substance, ginsenoside Re reference substance and ginsenoside Rb 1 reference substance, add methanol to make a mixed solution containing 0.2 mg per 1ml, and shake well.
  • Determination method Precisely draw 10 ⁇ l of the reference solution and 10-20 ⁇ l of the test solution, inject them into the liquid chromatograph, and measure.
  • the ginsenosides Rg1, Rb1 and Re in the ginseng extract were largely retained after being clarified and concentrated by the membrane, and retained 95%, 89% and 96%, respectively.
  • Schisandra chinensis Take Schisandra chinensis, add water to decoct, discard the aqueous solution, add 80-85% ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare Schisandra chinensis clear liquid, and use nanofiltration membrane for clarification. The liquid is then concentrated with a nanofiltration membrane to obtain a concentrated solution of Schisandra chinensis.
  • Preparation of reference substance solution Take an appropriate amount of Schisandrol A reference substance, and make a solution containing 0.3 mg of Schisandrin A per 1ml of methanol, that is.
  • Determination method Precisely draw 10 ⁇ l of the reference solution and the test solution, respectively, inject them into the liquid chromatograph, and measure.
  • This pharmaceutical composition is not only because of the composition ratio, but also because the present invention provides a novel pharmaceutical preparation method.
  • the technical comparison of alcohol extraction method is carried out, and the obtained data are as follows: the same amount of medicinal materials is used for feeding: 2000g of Asarum radix, 200g of ginseng, 400g of Ophiopogon japonicus, and 200g of Schisandra chinensis.
  • the present invention adopts the ratio of Example 1.
  • the beneficial effect obtained by the process method of the present invention has outstanding substantive characteristics and significant progress compared with the effect that can be achieved by the existing process.
  • the scutellaria scutellariae extract which includes scutellarin B and caffeoylquinic acid
  • the scutellaria extract obtained by the prior art extraction method has high chlorophyll content, chlorophyll is an inactive substance, and the caffeic acid ester content is low, and even cannot be extracted or extracted.
  • the present invention adopts polyamide column gradient elution to remove water-soluble impurities to the maximum extent, remove related substances with high polarity and low polarity, completely remove chlorophyll, and also remove pyroconic acid, which is difficult to remove. It improves the extraction rate, enrichment rate and purity of active ingredients and active substances.
  • the ginseng, Ophiopogon japonicus, and Schisandra chinensis extracts obtained by the prior art extraction method have the following disadvantages: the active ingredients are unclear, the impurities are many, the material components are unclear, the organic acid removal rate in the Schisandra chinensis is low, and the active ingredient content is low.
  • Extraction method in which ginseng adopts alcohol extraction and alcohol precipitation method; Ophiopogon japonicus adopts alcohol extraction and water precipitation method to remove oligosaccharides; Schisandra is extracted with water once to remove organic acids, then alcohol extraction, and then ethyl acetate extraction. .
  • the spray-dried powder obtained in the refining process has a clear material composition, removes impurities such as organic acids, and obtains active substances with high content, high extraction rate, enrichment rate, and high purity with clear active ingredient content, which improves drug efficacy and drug safety. It has remarkable technical progress and obtained unexpected technical effects, and the preparation method is innovative. Also using the same combination of traditional Chinese medicines, the preparations prepared by this method will surely have better medicinal effects than those prepared by conventional methods on the basis of preparing the same amount of preparations.

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Abstract

本发明公开了一种药物组合物的制备方法,为灯盏细辛、人参、麦冬、五味子经过提取精制方法得到有效部位提取物喷干粉的方法，灯盏细辛经过水提碱溶酸沉，沉淀物为黄酮类化合物，喷粉，得粉1；酸化上清液进一步去除焦袂康酸，富集咖啡酸酯类成分，喷粉，得粉2；人参富集人参皂苷类成分，麦冬醇提水沉，富集麦冬黄烷酮类成分；五味子水提后弃去水提液，去除大部分有机酸类成分，然后醇提，经过膜过滤浓缩后，乙酸乙酯萃取富集木脂素类成分。将富集的人参皂苷类成分，麦冬黄烷酮类成分，五味子木脂素类成分合并，喷粉，得粉3；将粉1、2、3混合，或者再加一定的辅料，得到所述药物组合物。

Description

一种药物组合物的制备方法 技术领域
本发明属于医药领域，涉及一种药用组合物的制备方法，具体是一种含有灯盏细辛、人参、麦冬、五味子的药物组合物的制备方法。
背景技术
近年来，随着我国人口老龄化加速、城市化程度不断加深以及生活方式的逐步改变，疾病谱也发生了重大变化。高血压病、冠心病、糖尿病等慢性非传染性疾病广泛流行，由此导致的心脑血管疾病的发病率也呈加速上升趋势。
灯盏生脉是一种治疗心脑血管疾病的处方，即在传统经典方剂生脉散基础上加味，以灯盏细辛、人参、五味子、麦冬的药物组合物的制备方法。其中，其中，富集了灯盏细辛中所含的灯盏花素(能扩张微动脉、降低血液粘滞度、改善脑循环)和咖啡酸酯(抗氧化、抗炎、抗病毒、抗纤维化、抑制平滑肌收缩、降血脂)；五味子中木脂素类成分具有抗炎、抗氧化、抗病毒、舒张血管、保护神经及抑制溃疡等药效作用；麦冬中高异黄酮类化合物具有抗心肌缺血活性；人参中人参皂苷人在神经系统有神经退行性疾病的治疗、改善记忆功能、保护脑组织等作用，在心血管系统有抗心律失常、抗心肌肥厚、抗心肌缺血、抗心肌细胞凋亡等作用，在抗肿瘤方面具有诱导细胞凋亡、抑制肿瘤细胞增殖、调控信号通路、调节免疫功能等作用。以往的文献提取方法，采用四味药混合提取，正丁醇萃取的方式。这样的的方法是简单，但是难以达到富集有效成分，去除有害物质及杂质的效果。灯盏细辛中有相对含量在0.5％左右的焦袂康酸，焦袂康酸是一个对肝脏有较大毒性的物质，如果作为长期用药不将此成分去除，将会导致肝损伤。
发明内容
针对上述技术问题，本发明公开了一种药物组合物的制备方法，其中，该药物组合物含有灯盏细辛、人参、麦冬和五味子，其特征在于，该药物组合物的制备方法为：
取灯盏细辛加水提取，提取液浓缩成清膏；清膏加碱调节pH至7～9，滤过，加酸调 节pH至1～3，放置过夜，滤过，收集滤液及沉淀，沉淀乙醇精制，加入碱调节pH至7～8，喷雾干燥得粉1；滤液调节pH至7～9，用微滤膜进行澄清，澄清液再用纳滤膜进行浓缩，浓缩液通过聚酰胺层析柱，用水洗脱后，用乙醇洗脱，收集乙醇洗脱液，浓缩后调pH至7～9，喷雾干燥得粉2；
取人参，加浓度80～85％乙醇回流提取，滤过，合并滤液，减压浓缩成清膏，人参清膏加3-15倍纯化水配制成人参清液，用微滤膜进行澄清，澄清液再用纳滤膜进行浓缩，浓缩液备用；
取麦冬，加80～85％乙醇回流提取，滤过，合并滤液，减压浓缩成浸膏，浸膏加入12-15倍量水沉淀，弃去水层，收集沉淀备用；
取五味子，加水煎煮，弃去水溶液，加入浓度80～85％的乙醇回流提取，滤过，合并滤液，减压浓缩成浸膏，加水配制成五味子清液后用微滤膜进行澄清，澄清液再用纳滤膜进行浓缩，浓缩清膏用乙酸乙酯萃取，收集乙酸乙酯萃取液，减压浓缩成浸膏备用；
本发明所述的微滤膜可为陶瓷微滤膜，规格为100nm或200nm，纳滤膜可选用有机纳滤膜，规格为300-400D的有机纳滤膜。
将人参浓缩液、麦冬沉淀、五味子浸膏混合溶解，喷雾干燥后，混合得粉3，将粉1、粉2、粉3合并，即得所述药用组合物。
上述药物组合物加入适量辅料，制成硬胶囊，软胶囊，片剂，滴丸，口服液或颗粒剂等口服复方药剂。
本方法具有的技术创新性：
1)分步提取，可以分别提取高活性成分含量的粉1、2、3，这种方法，与常规方法相比，更加精细，且便于控制活性成分的含量，无论是制备具有合理比例的药物组合物还是制剂，在计算和配比方面都具有更好的稳定性和重复性。
2)去除有害或无生物活性物质，例如叶绿素、焦袂康酸、寡糖类、有机酸类等成分，制备的药物具有更好的安全性，消除隐患，提高药品质量。
特别是焦袂康酸的检测，通过以下检测方法对常规方法(不经过柱层析)和本发明的提取方法得到的灯盏细辛的浸膏进行检测效果比较：
检测方法：
在色谱柱为十八烷基硅烷为填料，采用梯度洗脱，流动相A为甲醇，流动相B为含0.5％的甲酸水溶液，C为乙腈溶液，梯度洗脱程序如下的色谱条件下，进行洗脱，
0分钟时，5％流动性A，92％流动相B，3％流动相C；
15分钟时，15％流动性A，73.5％流动相B，11.5％流动相C；
45分钟时，15％流动性A，73.5％流动相B，11.5％流动相C；
55分钟时，0％流动性A，55％流动相B，45％流动相C；
65分钟时，0％流动性A，15％流动相B，85％流动相C；
65.1分钟时，5％流动性A，92％流动相B，3％流动相C；
80分钟时，5％流动性A，92％流动相B，3％流动相C。
然后在流速1.0mL/min；检测波长270nm；柱温30℃的检测条件下，得到该的指纹图谱。在指纹图谱上，常规方法在时间5.2min处检测到有明显的焦袂康酸的峰，而在本提取方法中，该保留时间处以及附近，无该吸收峰的出现，证明本发明提取方法可以有效去除焦袂康酸，提高药品质量。
3)修改了现有的萃取方式，不使用正丁醇来萃取，减少溶剂残留，保证药品安全性。
4)以往的乙醇回流选用浓度75％的乙醇，本发明中使用更高递增浓度的乙醇，目的为逐次提高乙醇浓度，可以减少水溶成分提出的量，便于后续处理，这在生脉成分的提取中效果更明显。例如人参的人参皂苷Rg1，Rb1和Re成分的富集过程。本发明还提供了一种制备方法，所述药用组合物的原料重量配比为：71％-80％灯盏细辛；5.2％-7.2％人参，5.2-7.2％五味子，10.5-14.3％麦冬。
5)在灯盏细辛、人参、五味子的提取分离过程中采用了膜分离技术，用微滤膜(100nm或200nm陶瓷膜)去除大分子的不溶性物质，用纳滤膜(350-400D)将无机物及水溶性的有害物质焦袂康酸、有机酸去除，有效降低了浓缩的能耗，且使后续的上柱及萃取过程更为高效。
并且在粉2制备步骤，滤液调节pH至7～9，用陶瓷微滤膜进行澄清，可以去除大量中性条件下不溶解的大分子杂质；澄清后得到的澄清液再用有机纳滤膜进行浓缩，一则可以降低浓缩成本，二则可以去除大部分焦袂康酸，这是由于焦袂康酸的水溶性远高于脂溶性，且分子量较小，仅112。膜浓缩液以1:1柱体积的量上30-60目的酰胺层析柱，吸附过夜后，用水洗脱4个柱体积后，用55-75％乙醇洗脱，收集乙醇洗脱液，浓缩后调节pH至7～9，喷雾干燥得粉2。此步骤是为了进一步去除焦袂康酸，富集所需要的咖啡酸酯类成分，尤其是二咖啡酸酯类成分这一步很关键，保证了提取物的高药物活性。
本发明还提供了一种制备方法，按重量百分比计算，含黄酮的灯盏细辛提取物粉1与含4,5-二-O-咖啡酰奎宁酸的灯盏细辛总咖啡酸酯提取物粉2占50-55％，含人参，麦冬，五味子的提取物粉3占44-49％，三种粉之和占94-99％。
本发明还提供了一种制备方法，以灯盏细辛2000g，人参200g，麦冬400g，五味子200g入药计所述粉1含野黄芩苷400～600mg/g，得粉1，25～40g；粉2含4，5－二－O-咖啡酰奎宁酸30～60mg/g，得粉2，35～55g；粉3含人参皂苷Rg1+Re 2.0～6.0mg/g，五味子醇甲3.5～9.0mg/g，得粉3，55～75g；粉1、2、3混合后，野黄芩苷含量在105mg/g～155mg/g，4，5-二－O-咖啡酰奎宁酸10～16mg/g，人参皂苷Rg1+Re 1.0～2.5mg/g，五味子醇甲1.8～4.3mg/g。
本发明还提供了一种制备方法，以灯盏细辛2000g，人参200g，麦冬400g，五味子200g入药计所述粉1含野黄芩苷450～600mg/g，得粉1：25～40g；粉2含4，5－二－O-咖啡酰奎宁酸35～55mg/g，得粉2：35～55g；粉3含人参皂苷Rg1+Re 3.0～5.0mg/g，五味子醇甲5.0～8.0mg/g，得粉3：55～75g。粉1、2、3混合后，野黄芩苷含量在110mg/g～135mg/g，4，5-二－O-咖啡酰奎宁酸12～15mg/g，人参皂苷Rg1+Re 2～2.4mg/g，五味子醇甲2.0～4.0mg/g。
本发明还提供了一种制备方法，所述的调节溶液pH值用的碱是NaOH、Na 2CO 3、NaHCO 3、KOH、K 2CO 3或者KHCO 3；所述的调节溶液pH值用的酸是HCl、H 2SO 4或者H 3PO 4；所述的聚酰胺层析柱所用乙醇洗脱的乙醇浓度为50-95％。
本发明还提供了一种制备方法，所述的微滤膜为100或200nm的陶瓷膜，纳滤膜为300-400D的有机纳滤膜。
本发明提供的上述工艺得到的灯盏细辛提取物，其中包括灯盏乙素和咖啡酰奎宁酸，灯盏乙素为主的黄酮类成分先通过酸化沉淀下来，然后可以根据需要进行纯化。酸化上清液先调节pH值后用微滤膜(100nm或200nm陶瓷膜)进行澄清，进而用纳滤膜(300-400D)进行浓缩，去除大量焦袂康酸后通过聚酰胺柱层析，先将极性大的水溶性杂质去除，同时将水溶性大的毒性成分焦袂康酸再一次去除，然后再用50-90％的乙醇将所需的咖啡酸酯类成分洗脱，尤其是二咖啡酸酯类成分。
本发明提供的上述工艺得到的人参采用醇提，人参采用醇提后用膜澄清和浓缩是考虑人参皂苷Rg1+Re和Rb1这三个定量成分，去除多糖、蛋白、鞣质等大分子成分；经过膜过滤和浓缩后，浸膏中的人参皂苷Rg1+Re的含量提高1.5-2.5倍，从而富集了浸膏中人参皂苷。麦冬以醇提水沉法去除多数寡糖类成分，并富集麦冬黄烷酮类成分，麦冬黄烷酮类物质含量提高了3倍。经过除了富集麦冬黄烷酮类成分外，除去寡糖类成分还有利于喷雾干燥的进行，否则生产过程中将出现严重沾壁造成不可避免有效成分的损失。五味子采用先水提一次，去除有机酸类物质，然后再醇提，醇提后浸膏得率依然有药材的40％左右，用澄清膜先将大分子的不容物去除，再用浓缩膜去除无机物及水溶性强的小分子有机酸，后采取乙酸乙酯萃取，浓缩其中木脂素类成分，木脂素成分含量提高了3-4倍。这样经过提取，过柱，醇沉，水沉， 萃取等精制过程，所得到的喷干粉的活性物质具有高富集率、所得到的喷干粉明确的成分更多等明显的突出的优点，并且将有害物质焦袂康酸绝大部分去除，从而提高了药品的安全性。所生产的制剂达到高含量，低服用量，安全性增加，从而使药品的依从性增加。
有益效果：
本发明中灯盏细辛的提取采取了两个步骤分别富集黄酮类化合物和咖啡酸酯类化合物：水提后碱溶酸化，碱溶是为了去除不能成盐的杂质，酸化是为了将黄酮类成分沉淀下来。酸化上清液调节pH值后先通过微滤膜去除大分子的物质，例如叶绿素，鞣质，树胶，树脂等，再过一次有机纳滤膜进行浓缩，由于焦袂康酸的水溶性远大于脂溶性，且分子较小，因而可以通过纳滤膜将大部分焦袂康酸去除，同时节约浓缩成本，再上聚酰胺树脂，先以水冲洗，除去水溶性大分子及残余的焦袂康酸，再用50-90％乙醇冲洗，富集咖啡酸酯类成分，尤其是二咖啡酸酯类成分。灯盏细辛采用水提取的原因主要是为了提取出有效成分，叶绿素等脂溶性杂质少提取出来，为后续上层析柱不至于由于叶绿素等成分在层析住上堵塞聚酰胺造成层析不顺畅和再生困难。黄酮类成分及咖啡酸酯类成分分别提取喷粉也有利于制剂中稳定含量的黄酮类成分及咖啡酸酯类成分，有利于药物化合物自由配比，人参采用醇提后用膜澄清和浓缩是考虑人参皂苷Rg1+Re和Rb1这三个定量成分。去除多糖、蛋白、鞣质等大分子成分。麦冬以醇提水沉去除多数寡糖类成分，并富集麦冬黄烷酮类成分，除了富集麦冬黄烷酮类成分外，除去寡糖类成分还有利于喷雾干燥的进行，否则将出现严重沾壁；去除寡糖还可以解决喷干粉的吸湿性问题。五味子采用先水提一次，去除有机酸类物质，然后再醇提，醇提后浸膏得率依然有药材的40％左右，先用微滤膜澄清去除大分子难溶性物质，再用纳滤膜浓缩，进一步去除水溶性小分子酸性物质，最后采取乙酸乙酯萃取，浓缩其中木脂素类成分。采用膜分离和浓缩不仅有效去除非活性成分，并且可以降低浓缩和萃取成本。这样精制过程得到的喷干粉具有高含量活性物质，所生产的制剂可以达到高含量，低服用量的效果，使药品的依从性增加。
具体实施方式：
实施例1：原料药提取物制备
取灯盏细辛2000g加水煎煮两次，每次2小时，滤过，合并滤液，减压浓缩成清膏；清膏搅拌下加入5％氢氧化钠溶液，调节pH至7.5～8.5，滤过，加10％硫酸溶液调节pH至1～3，放置过夜，滤过，收集滤液及沉淀，沉淀乙醇精制，后加入5％氢氧化钠调节pH至7～8，喷雾干燥得粉1；酸化的滤液调节pH至7～9，用100nm陶瓷膜进行澄清，澄清后得到 的澄清液再用350D有机膜进行浓缩，浓缩液通过30-60目聚酰胺层析柱(直径与长度比1:4)，用水洗脱3个柱体积后，用65％乙醇洗脱4个柱体积，收集乙醇洗脱液，浓缩后调节pH至7～9，喷雾干燥得粉2；
取人参200g，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，加10倍水稀释，用100nm陶瓷膜进行澄清，澄清液用350D有机膜进行浓缩，得浓缩液备用。
取麦冬400g，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，浸膏加入12-15倍量水沉淀，弃去水层，收集沉淀备用。
取五味子200g，加水煎煮一次，水提一次倒掉为了去掉大部分的有机酸，否则提取物太多，不利于富集木质素，弃去水溶液，加入80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，加水后配制成五味子清液用100nm陶瓷膜进行澄清，澄清后的澄清液再用350D有机膜进行浓缩，得到五味子清膏，清膏用乙酸乙酯萃取，收集乙酸乙酯萃取液，减压浓缩成浸膏备用。将人参浓缩液，麦冬沉淀，五味子浸膏混合溶解，喷雾干燥后，得粉3，将粉1、2、3混合均匀，得棕色原料提取物144g。
所得粉1中野黄芩苷含量为520mg/g，得粉1，34g；粉2中含4,5－二－O-咖啡酰奎宁酸35mg/g，得粉2，43g；粉3含人参皂苷Rg1+Re 5.5mg/g，五味子醇甲3.8mg/g，得粉3，67g。粉1、2、3混合后野黄芩苷含量在129mg/g，4,5-二－O-咖啡酰奎宁酸12.8mg/g，人参皂苷Rg1+Re 2.4mg/g，五味子醇甲3.9mg/g。
实施例2：原料药提取物制备
取灯盏细辛3000g加入水煎煮两次，每次2小时，滤过，合并滤液，减压浓缩成清膏；清膏搅拌下加入5％氢氧化钠溶液，调节pH至7～9，滤过，加10％盐酸溶液调节pH至1～3，放置过夜，滤过，收集滤液及沉淀，沉淀乙醇精制，加入5％氢氧化钠调节pH至7～8，喷雾干燥得粉1；
酸化的滤液调节pH至7～9，用200nm陶瓷膜进行澄清，澄清后得到的澄清液再用400D有机膜进行浓缩，浓缩液通过30-60目聚酰胺层析柱(直径与长度比1:4)，用3个柱体积的水洗脱后，用3个柱体积的70％乙醇洗脱，收集乙醇洗脱液，浓缩后调节pH至7～9，喷雾干燥得粉2；
取人参200g，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成清膏，加6倍水稀释，用200nm陶瓷膜进行澄清，澄清液用400D有机膜进行浓缩，得浓缩液备用。。取麦冬400g，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，浸膏加入 15倍量水沉淀，弃去水层，收集沉淀备用。取五味子200g，加水煎煮一次，弃去水溶液，加入80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，加水后配制成五味子清液用200nm陶瓷膜进行澄清，澄清后的澄清液再用400D有机膜进行浓缩，得到五味子清膏，清膏用乙酸乙酯萃取，收集乙酸乙酯萃取液，减压浓缩成浸膏备用。将人参浓缩液，麦冬沉淀，五味子浸膏加水溶解，喷雾干燥后，得粉3，将粉1,2,3混合均匀，得棕色原料提取物171g。
所得粉1中野黄芩苷含量为478mg/g，得粉1，42g；粉2中含4,5－二－O-咖啡酰奎宁酸36mg/g，粉2：53g；粉3含人参皂苷Rg1+Re 5.1mg/g，五味子醇甲4.2mg/g，得粉3，76g。粉1、2、3混合后，野黄芩苷含量在117mg/g，4，5-二－O-咖啡酰奎宁酸16mg/g，人参皂苷Rg1+Re2.3mg/g，五味子醇甲1.9mg/g。
实施例3：原料药提取物制备
取灯盏细辛2500g加水煎煮两次，每次2小时，滤过，合并滤液，减压浓缩成清膏；清膏搅拌下加入5％氢氧化钠溶液，调节pH至7.5～9.0，滤过，加10％硫酸溶液调节pH至1～3，放置过夜，滤过，收集滤液及沉淀，沉淀乙醇精制，加入5％氢氧化钠调节pH至7～8，喷雾干燥得粉1；酸化滤液调节pH至7～9，用100nm陶瓷膜进行澄清，澄清后得到的澄清液再用300D有机膜进行浓缩，浓缩液通过30-60目聚酰胺层析柱(直径与长度比1:4)，用3.5个柱体积水洗脱后，用3个柱体积的75％乙醇洗脱，收集乙醇洗脱液，浓缩后调节pH至7～9，喷雾干燥得粉2；
取人参200g，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，加8倍水稀释，用100nm陶瓷膜进行澄清，澄清液用300D有机膜进行浓缩，得浓缩液备用。
取麦冬400g，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，浸膏加入15倍量水沉淀，弃去水层，收集沉淀备用。取五味子200g，加水煎煮一次，弃去水溶液，加入80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成浸膏，加水后配制成五味子清液用100nm陶瓷膜进行澄清，澄清后的澄清液再用300D有机膜进行浓缩，得到五味子清膏，清膏用乙酸乙酯萃取，收集乙酸乙酯萃取液，减压浓缩成浸膏备用。将人参浸膏，麦冬沉淀，五味子浸膏加水溶解，喷雾干燥后，得粉3，将粉1,2,3混合均匀，得棕色原料提取物166g。所得粉1中野黄芩苷含量：530mg/g，得粉1，38g，粉2中含4,5－二－O-咖啡酰奎宁酸38mg/g，得粉2，47g；粉3含人参皂苷Rg1+Re 5.2mg/g，五味子醇甲6.3mg/g，得粉3，81g。粉1、2、3混合后，野黄芩苷含量在121mg/g，4,5-二－O-咖啡酰奎宁酸10.8mg/g， 人参皂苷Rg1+Re 2.5mg/g，五味子醇甲3.1mg/g。
实施例4：膜分离试验
灯盏细辛酸化上清液调节pH至7～9，用陶瓷微滤膜进行澄清，澄清后得到的澄清液再用有机纳滤膜进行浓缩。测定膜过滤前后5个二咖啡酸酯的含量，列表进行对比：
色谱条件与系统适用性试验以十八烷基硅烷键合硅胶为填充剂；以[A(甲醇:乙腈30:70)-B(0.1％三氟乙酸)](18:82)为流动相；总咖啡酸酯检测波长为327nm、焦袂康酸检测波长为270nm。理论板数按3,5-O-二咖啡酰奎宁酸峰计算应不低于5000。
对照品溶液的制备取3,5-O-二咖啡酰奎宁酸和野黄芩苷对照品适量,精密称定,加甲醇制成每1ml各含3,5-O-二咖啡酰奎宁酸30μg的混合溶液,作为对照品溶液。
测定法分别精密吸取对照品溶液与供试品溶液各10μl，注入液相色谱仪，测定。
二咖啡酸酯以3,5-O-二咖啡酰奎宁酸对照品的峰面积为对照，分别按下表相对应的校正因子计算3,4-O-二咖啡酰奎宁酸、3,5-O-二咖啡酰奎宁酸、飞蓬酯乙、4,5-O-二咖啡酰奎宁酸、灯盏细辛酯的含量，计算上述五个物质的总量。用待测成分色谱峰与3,5-O-二咖啡酰奎宁酸色谱峰的相对保留时间确定3,4-O-二咖啡酰奎宁酸、3,5-O-二咖啡酰奎宁酸、飞蓬酯乙、4,5-O-二咖啡酰奎宁酸、灯盏细辛酯的峰位，其相对保留时间应在规定值的±10％范围之内(若相对保留时间偏离超过10％，则应以相应的被替代对照品确证为准)，即得。相对保留时间及校正因子(F)见下表：
表1.二咖啡酸酯相对保留时间及校正因子
Figure PCTCN2021139602-appb-000001
表2.灯盏细辛酸化上清液调pH后膜过滤后成分含量变化表
Figure PCTCN2021139602-appb-000002
从表2可以看出，灯盏细辛酸化上清液调节pH接近中性后过澄清膜和纳滤浓缩膜后有效物质二咖啡酸酯得到较好地保留，而有害物质焦袂康酸的去除84％。
取人参，加80～85％乙醇回流提取两次，滤过，合并滤液，减压浓缩成清膏，人参清膏加8倍纯化水配制成人参清液，用100nm陶瓷微滤膜进行澄清，澄清液再用400D有机纳滤膜进行浓缩，浓缩液备用。
人参清液，澄清液和浓缩液分别测定人参皂苷Rg1,Rb1和Re的含量。
【含量测定】照高效液相色谱法(通则0512)测定
色谱条件与系统适用性试验 以十八烷基硅烷键合硅胶为填充剂；以乙腈为流动相A，以水为流动相B，按下表中的规定进行梯度洗脱；检测波长为203nm。理论板数按人参皂苷Rg 1峰计算应不低于6000。
表3.色谱流动相梯度
Figure PCTCN2021139602-appb-000003
对照品溶液的制备 精密称取人参皂苷Rg 1对照品、人参皂苷Re对照品及人参皂苷Rb 1对照品，加甲醇制成每1ml各含0.2mg的混合溶液，摇匀，即得。
供试品溶液的制备 取人参清液，澄清液和浓缩液滤过，取续滤液即得。
测定法 分别精密吸取对照品溶液10μl与供试品溶液10～20μl，注入液相色谱仪，测定，即得。
表4.人参提取液过膜前后人参皂苷含量变化
Figure PCTCN2021139602-appb-000004
从表4可以看出，人参提取液中人参皂苷Rg1,Rb1和Re通过膜澄清和浓缩后得到较大程度的保留，分别保留了95％，89％和96％。
取五味子，加水煎煮，弃去水溶液，加入浓度80～85％的乙醇回流提取，滤过，合并滤液，减压浓缩成浸膏，加水配制成五味子清液后用纳滤膜进行澄清，澄清液再用纳滤膜进行浓缩，得到五味子浓缩液。
五味子清液，澄清液和浓缩液测定五味子醇甲含量
色谱条件与系统适用性试验 以十八烷基硅烷键合硅胶为填充剂，以甲醇-水(65：35)为 流动相，检测波长为250nm。理论板数按五味子醇甲峰计算应不低于2000。
对照品溶液的制备 取五味子醇甲对照品适量，用甲醇制成每1ml含五味子醇甲0.3mg的溶液，即得。
供试品溶液的制备 取五味子清液，澄清液和浓缩液，滤过，取续滤液，即得。
测定法 分别精密吸取对照品液与供试品溶液各10μl，注入液相色谱仪，测定，即得。
表5.五味子提取液过膜前后五味子醇甲含量变化
品名 代表量(L) 含量(mg/ml) 总量(g)
五味子清液 100 0.27 27.00
五味子澄清液 125 0.17 21.25
五味子浓缩液 32 0.57 18.30
从表5可以看出，五味子醇甲在过澄清膜和浓缩膜后总含量保持67％以上。
实施例5：质量标准试验
本药物组合物，不仅是因为组合物配比的原因，还因为本发明中提供了一种新型的药物制备方法，为进一步证明所述制备方法的高效性，特与常规混合酒精回流，正丁醇萃取方法进行技术对比，所得数据如下：以相同药材量配比投料：灯盏细辛2000g，人参200g，麦冬400g，五味子200g。本发明所采用实施例1的配比。
表6.现有方法与新方法的提取产物对比
Figure PCTCN2021139602-appb-000005
因此，从以上指标数据可以看出，本发明的工艺方法得到的有益效果与已有的工艺所能达到的效果相比，具有突出的实质性特点和显著的进步。灯盏细辛提取物，其中包括灯盏乙素和咖啡酰奎宁酸，现有技术提取方法得到的灯盏提取物叶绿素含量高，叶绿素是非活性物 质，而咖啡酸酯含量低，甚至提不出来或者提取不完全，本发明采用利用聚酰胺柱梯度洗脱，最大限度地除去了水溶性杂质，除去了极性大和极性小的有关物质，完全去除了叶绿素，还除去了焦袂康酸等难以去除的对人体有害的杂质，提高了有效成分活性物质的提取率、富集率和纯度。现有技术提取方法得到的人参、麦冬、五味子提取物，具有如下缺点：有效成分不明确，杂质多，物质成分不清楚，五味子中有机酸去除率低，有效成分含量低，本发明采用分提法，其中人参采用醇提醇沉法；麦冬采用醇提水沉法去除寡糖类成分；五味子采用先水提一次，去除有机酸类物质，然后再醇提，再采取乙酸乙酯萃取。这样精制过程得到的喷干粉明确了物质成分，去除了有机酸等杂质，得到了有效成分含量明确的高含量、高提取率和富集率、高纯度的活性物质，提高药效和药品的安全性，具有显著的技术进步，获取了意想不到的技术效果，本制备方法具有创新性。同样使用相同的中药组合，使用本方法制得的制剂，在制备相同数量制剂的基础上，必将具有优于常规方法制得的药物效果。

Claims (10)

  1. 一种药物组合物的制备方法，其特征在于，该药物组合物含有灯盏细辛、人参、麦冬和五味子，其特征在于，该药物组合物的制备方法为：
    取灯盏细辛加水提取，提取液浓缩成清膏；清膏加碱调节pH至7～9，滤过，加酸调节pH至1～3，放置过夜，滤过，收集滤液及沉淀，沉淀用乙醇精制，加入碱调节pH至7～8，喷雾干燥得粉1；滤液调节pH至7～9，用微滤膜进行澄清，澄清液再用纳滤膜进行浓缩，浓缩液通过聚酰胺层析柱，用水洗脱后，用乙醇洗脱，收集乙醇洗脱液，浓缩后调节pH值至7～9，喷雾干燥得粉2；
    取人参，加浓度80～85％乙醇回流提取，滤过，合并滤液，减压浓缩成清膏，人参清膏加3-15倍纯化水配制成人参清液，用微滤膜进行澄清，澄清液再用纳滤膜进行浓缩，浓缩液备用；
    取麦冬，加80～85％乙醇回流提取，滤过，合并滤液，减压浓缩成浸膏，浸膏加入12-15倍量水沉淀，弃去水层，收集沉淀备用；
    取五味子，加水煎煮，弃去水溶液，加入浓度80～85％的乙醇回流提取，滤过，合并滤液，减压浓缩成浸膏，加水配制成五味子清液后用微滤膜进行澄清，澄清液再用纳滤膜进行浓缩成清膏，浓缩清膏用乙酸乙酯萃取，收集乙酸乙酯萃取液，减压浓缩成浸膏备用；
    将人参浓缩液、麦冬沉淀、五味子浸膏混合溶解，喷雾干燥后，混合得粉3，将粉1、粉2、粉3合并，即得所述药用组合物。
  2. 如权利要求1所述的制备方法，其特征在于，灯盏细辛加水煎煮次数为1-3次。
  3. 如权利要求1或2所述的制备方法，其特征在于，调节溶液pH值所用的碱为NaOH、Na 2CO 3,NaHCO 3、KOH、K 2CO 3或者KHCO 3；调节溶液pH值所用的酸是HCl、H 2SO 4或者H 3PO 4。
  4. 如权利要求1或2所述的制备方法，其特征在于，所述的洗脱聚酰胺层析柱所用乙醇的浓度为50-95％。
  5. 如权利要求1所述的制备方法，其特征在于，人参的乙醇回流提取次数为1-3次；麦冬的乙醇回流提取次数为1-3次；五味子的乙醇回流提取和加水煎煮的次数均为1-3次。
  6. 如权利要求1所述的制备方法，其特征在于，微滤膜为100nm或者200nm陶瓷膜， 纳滤膜为300-400D有机纳滤膜。
  7. 如权利要求1所述的制备方法，其特征在于，所述药用组合物由下列重量配比的原料药制得：71％-80％灯盏细辛、5.2％-7.2％人参、5.2-7.2％五味子、10.5-14.3％麦冬。
  8. 如权利要求7所述的制备方法，其特征在于，按重量百分比计算，含黄酮的灯盏细辛提取物粉1与含4，5-二-O-咖啡酰奎宁酸的灯盏细辛总咖啡酸酯提取物粉2占之和50-55％，含人参、麦冬、五味子的提取物粉3占44-49％，三种粉之和占94-99％。
  9. 如权利要求8所述的制备方法，其特征在于，粉1、2、3混合后野黄芩苷含量在105mg/g～155mg/g，4,5-二－O-咖啡酰奎宁酸10～16mg/g，人参皂苷Rg1+Re 1.0～2.5mg/g，五味子醇甲1.8～4.3mg/g。
  10. 如权利要求8或9所述的制备方法，其特征在于，所述粉1含野黄芩苷400～600mg/g；粉2含4，5－二－O-咖啡酰奎宁酸30～60mg/g；粉3含人参皂苷Rg1+Re 2.0～6.0mg/g，五味子醇甲3.5～9mg/g；粉1、2、3混合后野黄芩苷含量在105mg/g～155mg/g，4,5-二－O-咖啡酰奎宁酸10-16mg/g，人参皂苷Rg1+Re 1.0～2.5mg/g，五味子醇甲1.8～4.3mg/g。
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