WO2018133563A1 - 一种人参属植物提取物及其药物组合物和应用 - Google Patents

一种人参属植物提取物及其药物组合物和应用 Download PDF

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WO2018133563A1
WO2018133563A1 PCT/CN2017/114497 CN2017114497W WO2018133563A1 WO 2018133563 A1 WO2018133563 A1 WO 2018133563A1 CN 2017114497 W CN2017114497 W CN 2017114497W WO 2018133563 A1 WO2018133563 A1 WO 2018133563A1
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ginsenoside
ginseng
plant extract
present application
ginseng plant
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PCT/CN2017/114497
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English (en)
French (fr)
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高尚先
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上海弘医堂生物医药科技有限公司
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Priority to JP2019539897A priority Critical patent/JP2020506909A/ja
Priority to AU2017394430A priority patent/AU2017394430B2/en
Priority to KR1020197024215A priority patent/KR20190105635A/ko
Priority to US16/479,221 priority patent/US11541091B2/en
Priority to EP17892996.4A priority patent/EP3572088B1/en
Publication of WO2018133563A1 publication Critical patent/WO2018133563A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
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    • 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
    • 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)
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A—HUMAN NECESSITIES
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    • 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

Definitions

  • the present application relates to a traditional Chinese medicine extract and a preparation method thereof, and in particular to a ginseng plant extract, a pharmaceutical composition thereof and an application thereof.
  • Ginseng is the root of the ginseng of the Araliaceae plant. It is known as the "King of Herbs” and has the reputation of "Universal Sacred Medicine”. It is a famous herbal medicine that is well-known both at home and abroad. It has been used in China and East Asia for thousands of years. The study found that ginseng mainly contains saponins, peptides, amino acids, vitamins, etc. Among them, ginsenoside (Ginsenoside) is the main component of ginseng efficacy, which acts extensively on the cardiovascular, nervous, and immune systems of the human body, in cardiovascular diseases and metabolism. Treatments such as diseases and tumors show unique and unique effects. There are about 40 kinds of ginsenoside monomers which have been clarified, such as Rb1, Rb2, Rb3, Rc, Rd, Rg1, Rg2, Rg3, Rh1, Rh2 and Re and the like.
  • ginsenosides can be metabolized under the action of specific physical and chemical conditions or biological enzymes into secondary saponins with less sugar and can be directly absorbed by the human body, such as Rg3, Rg5, Rh1, Rk1, Rh2, Rg2. CK and so on, and play a therapeutic role. Therefore, Rg3, Rg5, Rk1, Rh2, Rg2, C-K, etc. are the main active ingredients of ginseng to exert its medical and health care functions.
  • Ginsenoside Rg3, Ginsenoside Rg5 and/or Rk1 are partial saponins of ginsenoside hydrolyzed, which remove some glycosyl degradation products and have strong biopharmacological activity.
  • a first object of the present application is to provide a ginseng plant extract.
  • a second object of the present application is to provide the pharmaceutical composition containing the extract of the Panax species plant.
  • a third object of the present application is to provide the use of the extract of the genus Panax species.
  • the present application relates to a ginseng plant extract containing ginsenoside Rg3, ginsenoside Rk1 and ginsenoside Rg5, the mass ratio of the ginsenoside Rk1 to the ginsenoside Rg5 is 1:1.0 ⁇ 1.5, preferably 1:1.0 to 1.3.
  • the mass percentage content of the ginsenoside Rg5, the ginsenoside Rk1 and the ginsenoside Rg3 satisfies: 0.5 ⁇ (Rg5+Rk1)/Rg3 ⁇ 1.5,
  • the ginsenoside Rg3 comprises 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3, the quality of the 20(R)-ginsenoside Rg3 and the 20(S)-ginsenoside Rg3
  • the ratio is from 1 to 1.5, preferably from 1.1 to 1.2.
  • the Panax species plant extract further comprises ginsenoside Rg2, ginsenoside Rh1 and ginsenoside Rh2; the ginsenoside Rg3, the ginsenoside Rg5, the ginsenoside Rk1, the ginsenoside Rg2,
  • the mass percentage content of ginsenoside Rh1 and ginsenoside Rh2 is as follows:
  • the ginsenoside Rg2 comprises 20(S)-ginsenoside Rg2 and 20(R)-ginsenoside Rg2, the quality of the 20(R)-ginsenoside Rg2 and the 20(S)-ginsenoside Rg2 The ratio is from 1.5 to 2.5, preferably from 1.8 to 2.0.
  • the ginseng plant is at least one selected from the group consisting of ginseng, red ginseng, Korean ginseng, notoginseng, bamboo ginseng, and American ginseng.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the extract of Panax species of the present application and a pharmaceutically acceptable carrier.
  • the dosage form of the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, an oral liquid, a buccal agent, a granule, a granule, a pill, a powder, a plaster, a dandruff, a suspension, a powder, a solution, an injection, A suppository, a spray, a drop, a patch, and the tablet is preferably an orally disintegrating tablet.
  • the ginseng plant extract of the present application is prepared for treating chronic heart failure, coronary heart disease, stable angina pectoris, arrhythmia, diabetes and its complications, Meniere's syndrome, hyperlipidemia, fat Liver, Alzheimer's disease, dysmenorrhea, metabolic syndrome, gout, tumor Or the application of drugs for vascular leakage syndrome.
  • the ginsenoside Rg3, ginsenoside Rg5 and ginsenoside Rk1 of the Panax species plant extract provided by the present application have a specific ratio content and have more excellent biological activity.
  • Figure 1 is a high performance liquid chromatogram of a total ginsenoside sample of ginseng
  • Figure 2 is a high performance liquid chromatogram of a mixture of ginsenoside standards.
  • the present application relates to a ginseng plant extract, mainly composed of ginsenoside (Ginsenoside), when -Glc-Glc or -Glc-Ara(pyr) is deglycosylated at position 20, the original ginseng diol type Ginsenosides Rb1 and Rb2 produce 20(S)-Rg3 and 20(R)-Rg3, and when dehydration occurs at positions 20 of 20(S)-Rg3 and 20(R)-Rg3, Rg5 and Rk1 can be produced.
  • ginsenoside mainly composed of ginsenoside (Ginsenoside)
  • -Glc-Glc or -Glc-Ara(pyr) is deglycosylated at position 20
  • the original ginseng diol type Ginsenosides Rb1 and Rb2 produce 20(S)-Rg3 and 20(R)-Rg3, and when dehydration occurs at positions 20 of 20(
  • the ginseng plant extract of the examples of the present application mainly contains ginsenoside Rg3, ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg2, ginsenoside Rh1 and ginsenoside Rh2.
  • the ginseng plant may be selected from the group consisting of ginseng, red ginseng, Korean ginseng, notoginseng, bamboo ginseng, American ginseng and the like; the usable part is the root of the ginseng plant. , whiskers, stems, flowers, or leaves, and preferably roots and whiskers of the ginseng plant.
  • Ginsenoside Rg3 -H Rg5 and Rk1 is ortho -OH on C-20 in H 2 O in off is formed between C-20 and C-22 double bond positional isomers. Its structural formula is:
  • the mass ratio of ginsenoside Rk1 to ginsenoside Rg5 is 1:1.0 to 1.5, more preferably 1:1.0 to 1.3, and most preferably 1:1.15.
  • the plant extract of Panax species of the present application greatly improves its physiological activity by controlling the mass ratio of ginsenoside Rk1 to ginsenoside Rg5.
  • the sum of the contents of the ginseng saponin Rg5 and the ginsenoside Rk1 of the ginseng plant extract of the present application is such that the ginsenoside Rg3 satisfies the above ratio relationship, and the sum of the contents of the ginsenoside Rg5 and the ginsenoside Rk1 is sufficiently increased, thereby further improving the ratio thereof.
  • Physiological activity is such that the ginsenoside Rg3 satisfies the above ratio relationship, and the sum of the contents of the ginsenoside Rg5 and the ginsenoside Rk1 is sufficiently increased, thereby further improving the ratio thereof.
  • Ginsenoside Rg3 includes 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3, which are C-20 enantiomers; their structural formulas are:
  • the mass ratio of 20(R)-ginsenoside Rg3 to 20(S)-ginsenoside Rg3 is from 1 to 1.5, preferably from 1.1 to 1.2, more preferably 1.13.
  • Ginsenoside Rg2 includes 20(S)-ginsenoside Rg2 and 20(R)-ginsenoside Rg2, which are C-20 enantiomers; their structural formulas are:
  • the mass ratio of 20(R)-ginsenoside Rg2 to 20(S)-ginsenoside Rg2 is from 1.5 to 2.5, preferably from 1.8 to 2.0, more preferably from 1.92.
  • the sum of the masses of Rg5, Rk1, and Rg3 is not less than 80% of the sum of the masses of Rg5, Rk1, Rg3, Rg2, Rh1, and Rh2. That is, the examples of the present application sufficiently increase the sum of the contents of Rg5, Rk1, and Rg3, thereby further improving the physiological activity thereof.
  • the sum of the masses of Rg5, Rk1, Rg3, Rg2, Rh1, Rh2 accounts for 50-80% of the total mass of the extract of the ginseng plant.
  • the remaining components are moisture, ash, pigments, sugars, and the like.
  • the Panax species plant extract in the examples of the present application can be prepared by the following method:
  • the organic solvent may be an alcohol organic solvent, preferably ethanol;
  • the volume percentage concentration of acetic acid the lower limit of the concentration is 20%, 22%, 25%, 27%, 30%, 32%
  • the upper limit of the concentration is 90%, 87%, 85%, 82%, 80%, 75%, 70%, 65%; the specific concentration can be composed of any data of the upper limit and the lower limit.
  • the specific step of resin adsorption is: adsorbing the hydrolyzate through the macroporous resin.
  • the specific step of removing impurities is: the adsorption column passing through the macroporous adsorption resin is eluted by water, eluted with alkaline water, and the concentration is 18%. The following ethanol elution removes impurities.
  • the eluted one is The bulk step is: eluting the adsorption column with ethanol having a concentration of 32% or more.
  • the concentration may be concentrated under reduced pressure
  • the drying may be selected from the group consisting of vacuum drying, drying, spray drying, and freeze drying.
  • the ginseng plant extract prepared by the examples of the present application was analyzed under the following chromatographic conditions:
  • Preparation of reference solution accurately weigh 10mg of each reference substance in a 5ml volumetric flask, dissolve it in methanol and dilute to the mark to make a stock solution with a concentration of 2mg/ml, accurately absorb 500 ⁇ l of each stock solution, and add to the 5ml volumetric flask.
  • the mixture was diluted with methanol to a volume to prepare a mixed solution having a concentration of 0.2 mg/ml.
  • test solution accurately weigh about 10mg of the sample of Panax species plant extract prepared in Example 1 in a 5ml volumetric flask, dissolve it in methanol and dilute to the mark, weigh it, after ultrasonic for 30min, weigh again and make up with methanol. The weight loss was transferred to a 10 ml centrifuge tube and centrifuged at 4500 rpm for 10 min. The supernatant was passed through a 0.45 ⁇ m filter and injected for analysis.
  • Figure 2 is a ginseng saponin mixed standard (). The content is calculated by using the external standard method as shown in Table 1.
  • Fingerprint peak number name Content (wt%) 1 20(S)-ginsenoside Rg2 1.16
  • the ginseng plant material is first subjected to vacuum expansion treatment
  • the vacuum puffing treatment step comprises: placing the ginseng plant material into a puffing pot, heating, so that the temperature in the puffing tank is 30-100 ° C, the pressure is raised to 0.1-0.9 MPa, and the time is maintained for 5-40 minutes. Then, the pressure reducing valve connecting the puffing tank and the vacuum tank is quickly opened, and the pressure is reduced to -0.04 to -0.08 MPa in an instant, cooled, and maintained for 5 to 40 minutes, and the vacuum tank is pre-vacuum.
  • the yield can be increased by 5% to 30%.
  • Embodiments of the present application are also directed to pharmaceutical compositions containing the extracts of the applicant's genus.
  • the pharmaceutical composition of the examples of the present application may contain a pharmaceutically acceptable carrier as needed, wherein the ginsenoside extract is used as a pharmaceutically active ingredient, and the weight percentage in the preparation may be 0.1 to 99.9%, and the rest is pharmaceutically acceptable.
  • the pharmaceutical composition of the examples of the present application is present in unit dosage form, and the unit dosage form refers to a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, each bottle of the oral solution, the granules per bag, and the injection. Every one.
  • the pharmaceutical composition of the examples of the present application may be in any pharmaceutically acceptable dosage form, including: tablets (including orally disintegrating tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets), capsules, and hard Capsule, soft capsule, oral liquid, buccal, granule, granule, pill, powder, ointment, dan, suspension, powder, solution, injection, suppository, ointment, plaster, cream, Sprays, drops, patches.
  • tablets including orally disintegrating tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets
  • capsules and hard Capsule, soft capsule, oral liquid, buccal, granule, granule, pill, powder, ointment, dan, suspension, powder, solution, injection, suppository, ointment, plaster, cream, Sprays, drops, patches.
  • the orally administered preparation may contain common excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent. And humectants, if necessary, the tablets can be coated.
  • common excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent.
  • humectants if necessary, the tablets can be coated.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
  • Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of filler.
  • the oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats.
  • Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters of esters such as glycerol, propylene glycol or ethanol;
  • the agent for example, p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may contain conventional flavoring or coloring agents.
  • the liquid unit dosage form prepared contains the active substance of the examples of the present application and a sterile carrier.
  • This compound can be suspended or dissolved depending on the carrier and concentration.
  • the solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier.
  • the composition can be frozen after filling the vial and the water removed under vacuum.
  • composition of the examples of the present application may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite.
  • the pharmaceutical composition of the embodiment of the present application determines the dosage according to the condition of the patient during use, and can be taken three times a day, each time 1 to 20 doses, such as: 1 to 20 bags or tablets or tablets, each dose of 1 mg to 1000 mg.
  • the embodiment of the present application further relates to the preparation of the extract of the genus Panax species in the treatment of chronic heart failure, coronary heart disease, stable angina pectoris, arrhythmia, diabetes and its complications, Meniere's syndrome, hyperlipidemia, fatty liver, Al Use in drugs for diseases of Alzheimer's disease, dysmenorrhea, metabolic syndrome, gout, tumor or vascular leakage syndrome.
  • Test materials 4 g of the ginseng plant extract of the example of the present application was accurately weighed, and the pharmaceutical adjuvant was added to prepare 100 tablets each containing 40 mg of Panax species extract.
  • MMSE screening for AD Detecting the patient's cognitive function (orientation, memory, computational power, language ability, ability to use spatial segments, etc.);
  • CDR clinical dementia degree scale
  • the Daily Living Self-care Scale measures the patient's ability to take care of daily life.
  • the results of the examination were analyzed by SPSS statistical software before and after treatment with ginsenoside Rg3 nasal drops and placebo.
  • Cognitive function (using MMSE score): After 12 weeks of treatment, there was a significant improvement compared with before treatment, and the MMSE score increased by 4.3 points (P ⁇ 0.01), and the MMSE score was significantly improved at 4 weeks of treatment (P ⁇ 0.05).
  • the degree of dementia (with CDR score): After 12 weeks of treatment, there was a significant decrease from the pre-treatment period, and the CDR score decreased by 0.8 (P ⁇ 0.05).
  • Self-care ability of daily life (using ADL score): After treatment, there was a significant decrease in the ADL score, and the ADL score decreased by 8.3 points (P ⁇ 0.01).
  • the use of the Panax species plant extract of the present application is safe and effective for improving the mild and moderate cognitive dysfunction, the decline of self-care ability and the degree of dementia in AD patients.
  • Test drug the ginseng plant extract prepared in the examples of the present application.
  • Comparative Formulation 1 The composition is as shown in Table 3, and is prepared using standard materials:
  • Component name Content (wt%) 1 20(S)-ginsenoside Rg2 1 2 20(R)-ginsenoside Rg2 2 3 20(R)-ginsenoside Rh1 1 4 20(S)-ginsenoside Rh1 1 5 20(S)-ginsenoside Rg3 8 6 20(R)-ginsenoside Rg3 8 7 Ginsenoside Rk1 2 8 Ginsenoside Rg5 12 9 Ginsenoside Rh2 1 10 Distilled water 64
  • test drug and the comparative preparation 1 were prepared by using 0.5% carboxymethyl cellulose, respectively. In the stomach.
  • Streptozotocin (sigma).
  • Wistar rats weighing 180 ⁇ 20 g, were purchased from Experimental Animal Center of Shandong University Medical Department.
  • Twenty qualified rats were selected and divided into 4 groups: normal control group, model animal group, present application group and control group. Among them, model animal group, present application group and control group rats were 3 days before the start of the experiment. Intravenous injection of streptozotocin 65mg/kg, blood glucose test showed successful modeling.
  • Normal control group Oral administration of equal amount of purified water
  • Model animal group successful model animals were given an equal amount of purified water orally;
  • the application group the model animal was successfully administered to the ginseng plant extract of the example of the present application at 200 mg/kg/d for 14 consecutive days;
  • Control group Successfully modeled animals were given a comparative preparation 1 at 200 mg/kg/d for 14 consecutive days.
  • Test drug the ginseng plant extract of the embodiment of the present application.
  • Comparative Formulation 1 Composition was the same as Experimental Example 1.
  • test drug and the comparative preparation 1 were prepared into a solution for oral administration using 0.5% carboxymethylcellulose, respectively.
  • Wistar rats weighing 180 ⁇ 20 g, were purchased from the Experimental Animal Center of the University of Dadong University.
  • UV85 ultraviolet spectrophotometer (Shanghai Tianmei), Hitachi 7170A automatic biochemical analyzer.
  • Twenty Wistar rats were divided into 4 groups: normal control group, model animal group, present application group and control group. Among them, model animal group, this application group and control group rats were fed with high fat diet, normal control group. Feed ordinary feed. The body weight was weighed once a week. In the 4th, 6th, and 8th week, 1 to 2 animals in the fatty liver model group were randomly selected, 1ml blood was taken from the tail vein to test blood lipids, and the dynamic changes of blood lipids were observed. The blood lipids in the fatty liver model group increased significantly in the 8th week. The liver showed moderate to severe steatosis and was successfully modeled.
  • the high-fat diet formula is: ordinary feed + 1% cholesterol + 14% lard.
  • Normal control group and model animal group distilled water
  • Comparative preparation 1 was administered at 200 m g/kg/d for 14 consecutive days;
  • the application group The Panax species plant extract of the example of the present application was administered at 200 mg/kg/d for 14 consecutive days.
  • Oral feed is given during administration.
  • TC triglyceride
  • TG cholesterol
  • Test drug the ginseng plant extract of the embodiment of the present application.
  • Component name Content (wt%) 1 20(S)-ginsenoside Rg2 1 2 20(R)-ginsenoside Rg2 2 3 20(R)-ginsenoside Rh1 1 4 20(S)-ginsenoside Rh1 1 5 20(S)-ginsenoside Rg3 9 6 20(R)-ginsenoside Rg3 9 7 Ginsenoside Rk1 2
  • Ginsenoside Rg5 1 Ginsenoside Rh2 10 10 Distilled water 64
  • test drug and the comparative preparation 1 were prepared into a solution for oral administration using 0.5% carboxymethylcellulose, respectively.
  • each group of rats was injected subcutaneously with diethylstilbestrol for 10 consecutive days, once a day, 0.8 mg/day on day 1 and day 10, and 0.2 mg/day on day 2-9.
  • the blank control group and the model group were given an equal amount of distilled water.
  • Control group starting from the 5th day, 200mg/kg/d was given to the contrast preparation 2;
  • the application group starting from the fifth day, 200 mg/kg/d was administered to the Panax species plant extract of the examples of the present application.
  • Test drug the ginseng plant extract of the embodiment of the present application.
  • test drug Comparative Formulation 1 and Comparative Formulation 2 were prepared into a solution for oral administration using 0.5% carboxymethylcellulose, respectively.
  • the specific administration situation was as follows:
  • Control group 1 200 mg/kg/d was given to Comparative Formulation 1;
  • Control group 2 200 mg / kg / d to give contrast preparation 2;
  • the above drugs were administered for 7 days.
  • each rat was anesthetized with sodium pentobarbital 30 min after administration, and the left external jugular vein and the right common carotid artery were separated.
  • a cannula consisting of three polyethylene tubes was placed, and the middle segment was placed.
  • the 5 cm surgical line of the root was filled with a polyethylene tube with heparin saline (50 U/ml).
  • heparin saline 50 U/ml
  • Inhibition rate (model group thrombus wet weight - experimental group thrombus wet weight) / model group thrombus wet weight
  • the average value of the thrombus weight of each group was statistically processed, the t test was used to judge the significant effect of the drug, and the inhibition rate was used to determine the action intensity of the drug.
  • Tumor cell strains used A549 human non-small cell lung cancer cells, MGC80-3 human gastric cancer cells, MCF-7 human breast cancer cells, three human tumor cell lines (the cell culture medium used is RPMI 1640 medium, DMEM medium, respectively). , MEM medium).
  • Test drug the ginseng plant extract of the embodiment of the present application.
  • the ginseng plant extract group of the present application example was dissolved in dimethyl sulfoxide (DMSO), and diluted with RPM I-1640 medium, DMEM medium, and MEM medium to the desired concentration: 1, 25, 50, 100, 200 ⁇ g / L for cell culture.
  • DMSO dimethyl sulfoxide
  • the comparative preparation was dissolved in dimethyl sulfoxide (DMSO) and diluted with RPM I-1640 medium, DMEM medium, and MEM medium to the desired concentration: 1, 25, 50, 100, 200 ⁇ g/L for cells. to cultivate.
  • DMSO dimethyl sulfoxide
  • the comparative preparation was dissolved in dimethyl sulfoxide (DMSO), diluted with RPM I-1640 medium, DMEM medium, and MEM medium to the desired concentration: 1, 25, 50, 100, 200 ⁇ g/L for cell culture. .
  • DMSO dimethyl sulfoxide
  • the preparation method of the ginseng plant extract comprises the following steps:
  • the ginseng pieces are extracted three times with 60% ethanol, and the extract is obtained by using 4 times of the solvent for 3 hours each time, and the extracts are combined and concentrated under reduced pressure;
  • the adsorption column through the macroporous adsorption resin is eluted with water, then eluted with 0.5% sodium hydroxide solution, eluted with water to neutrality, and then eluted with 15% ethanol to remove impurities;
  • the prepared Panax species plant extract was analyzed by the above high performance liquid chromatography, and the obtained spectrum was similar to that of FIG.
  • Other ginseng plants: red ginseng, Korean ginseng, notoginseng, bamboo ginseng, American ginseng, etc. were prepared by the specific conditions of the present example, and the obtained high-performance liquid chromatography of the ginseng plant extract was similar to that of FIG.
  • the preparation method of the ginseng plant extract comprises the following steps:
  • Vacuum puffing treatment Put the Sanqi Pieces into a puffing tank and heat it so that the temperature in the puffing tank is 80 ° C, the pressure is raised to 0.5 MPa, the time is maintained for 20 minutes, the vacuum tank is pre-vacuumed, and the connection is quickly opened.
  • the pressure reducing valve of the puffing tank and the vacuum tank is instantly reduced to -0.04 MPa, cooled, and maintained for 20 minutes;
  • the adsorption column through the macroporous adsorption resin is eluted with water, then eluted with 0.5% sodium hydroxide solution, eluted with water to neutrality, and then eluted with 12% ethanol to remove impurities;
  • the prepared Panax species plant extract was analyzed by the above high performance liquid chromatography, and the obtained spectrum was similar to that of FIG.
  • Other ginseng plants: red ginseng, Korean ginseng, bamboo ginseng, American ginseng, etc. were prepared by the specific conditions of the present example, and the obtained high-performance liquid chromatography of the ginseng plant extract was similar to that of FIG.

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Abstract

一种人参属植物提取物及其药物组合物和应用，所述人参属植物提取物中Rk1与Rg5的质量比为1：1.0～1.5，且Rg3、Rg5和Rk1的含量较高，可用于制备治疗慢性心衰、冠心病稳定性心绞痛、心律失常、糖尿病及其并发症、美尼尔氏综合征、高脂血症、脂肪肝、阿尔茨海默病、痛经、代谢综合征、痛风、肿瘤或血管渗漏综合征的药物。

Description

一种人参属植物提取物及其药物组合物和应用 技术领域
本申请涉及一种中药提取物及其制备方法，具体讲，涉及一种人参属植物提取物及其药物组合物和应用。
背景技术
人参为五加科植物人参的根，被人们称为“百草之王”，有“万能圣药”之誉，是驰名中外、的名贵药材，在我国和东亚的应用已有数千年。研究发现，人参主要含有皂甙、肽及氨基酸、维生素等物质，其中人参皂苷(Ginsenoside)是人参功效的主要成分，广泛地作用于人体的心血管、神经、免疫等系统，在心血管疾病、代谢性疾病和肿瘤等的治疗上显示出与众不同的独特效果。现已明确的人参皂苷单体约有40余种，如Rb1、Rb2、Rb3、Rc、Rd、Rg1、Rg2、Rg3、Rh1、Rh2及Re等等。
近年大量研究发现，人参皂苷类成分可在特定的理化条件或生物酶的作用下代谢成为含糖更少、可以被人体直接吸收的次生皂苷如Rg3、Rg5、Rh1、Rk1、Rh2、Rg2、C-K等、而发挥治疗作用。因此，Rg3、Rg5、Rk1、Rh2、Rg2、C-K等，是人参发挥其医疗及保健功能的主要活性成分。
人参皂苷Rg3(GinsenosideRg3)、人参皂苷Rg5(GinsenosideRg5)和/或Rk1(GinsenosideRk1)是人参皂苷部分水解，脱掉部分糖基降解产物的次生皂苷，具有很强的生物药理学活性。
有鉴于此，特提出本申请。
申请内容
本申请的第一发明目的在于提供一种人参属植物提取物。
本申请的第二发明目的在于提供所述的含有该人参属植物提取物的药物组合物。
本申请的第三发明目的在于提供所述的该人参属植物提取物的应用。
为实现本申请的发明目的，本申请采用如下技术方案：
本申请涉及一种人参属植物提取物，所述人参属植物提取物中含有人参皂苷Rg3、人参皂苷Rk1和人参皂苷Rg5，所述人参皂苷Rk1与所述人参皂苷Rg5的质量比为1：1.0～1.5，优选1：1.0～1.3。
优选的，所述人参皂苷Rg5、所述人参皂苷Rk1与所述人参皂苷Rg3的质量百分比含量满足：0.5≤(Rg5+Rk1)/Rg3≤1.5，
优选：0.5≤(Rg5+Rk1)/Rg3≤1.0。
优选的，所述人参皂苷Rg3包括20(S)-人参皂苷Rg3和20(R)-人参皂苷Rg3，所述20(R)-人参皂苷Rg3与所述20(S)-人参皂苷Rg3的质量比为1～1.5，优选1.1～1.2。
优选的，所述人参属植物提取物中还含有人参皂苷Rg2、人参皂苷Rh1和人参皂苷Rh2；所述人参皂苷Rg3、所述人参皂苷Rg5、所述人参皂苷Rk1、所述人参皂苷Rg2、所述人参皂苷Rh1、所述人参皂苷Rh2的质量百分比含量满足：
60％≤(Rg5+Rk1+Rg3)/(Rg5+Rk1+Rg3+Rg2+Rh1+Rh2)<100％。
优选的，所述人参皂苷Rg2包括20(S)-人参皂苷Rg2和20(R)-人参皂苷Rg2，所述20(R)-人参皂苷Rg2与所述20(S)-人参皂苷Rg2的质量比为1.5～2.5，优选1.8～2.0。
优选的，所述人参属植物选自人参、红参、高丽参、三七、竹节参、西洋参中的至少一种。
本申请涉及一种药物组合物，所述药物组合物中含有本申请的人参属植物提取物的以及药学上可接受的载体。
优选的，所述药物组合物的剂型选自片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、喷雾剂、滴剂、贴剂，所述片剂优选口腔崩解片。
本申请的人参属植物提取物、本申请的药物组合物在制备治疗慢性心衰、冠心病稳定性心绞痛、心律失常、糖尿病及其并发症、美尼尔氏综合征、高脂血症、脂肪肝、阿尔茨海默病、痛经、代谢综合征、痛风、肿瘤 或血管渗漏综合征的药物中的应用。
本申请的技术方案所能达到的有益技术效果至少为：
本申请所提供的人参属植物提取物中人参皂苷Rg3、人参皂苷Rg5和人参皂苷Rk1具有特定的比例含量，具有更加优良的生物活性。
附图说明
图1为人参总次苷样品的高效液相色谱；
图2为人参皂苷标准物质混合物的高效液相色谱。
具体实施方式
以下为本申请的具体实施方式，所述的实施例是为了进一步描述本申请，而不是限制本申请。
本申请实施例涉及一种人参属植物提取物，主要由人参皂苷(Ginsenoside)组成，当-Glc-Glc或-Glc-Ara(pyr)在20位被去糖基化时，原人参二醇型人参皂苷Rb1与Rb2可产生20(S)-Rg3和20(R)-Rg3，当20(S)-Rg3和20(R)-Rg3的20位发生脱水时，可产生Rg5和Rk1。本申请实施例的人参属植物提取物主要含有人参皂苷Rg3、人参皂苷Rk1、人参皂苷Rg5、人参皂苷Rg2、人参皂苷Rh1和人参皂苷Rh2。在本申请实施例中的人参属植物提取物中，人参属植物可选自人参、红参、高丽参、三七、竹节参、西洋参等人参属植物；其可用部分为人参属植物的根、须、茎、花、或叶，并优选为人参属植物的根、须。
人参皂苷Rg5与Rk1是Rg3在C-20上的-OH与邻位上的-H脱掉H2O而在C-20和C-22之间形成的双键位置异构体。其结构式分别为：
Figure PCTCN2017114497-appb-000001
在本申请实施例中，人参皂苷Rk1与人参皂苷Rg5的质量比为1：1.0～1.5，更优选1：1.0～1.3，最优选1：1.15。本申请的人参属植物提取物通过对人参皂苷Rk1与人参皂苷Rg5质量比的控制，大大提高了其生理活性。
作为本申请实施例人参属植物提取物的一种改进，人参皂苷Rg5、人参皂苷Rk1与人参皂苷Rg3的质量百分比含量满足：0.5≤(Rg5+Rk1)/Rg3≤1.5；优选0.5≤(Rg5+Rk1)/Rg3≤1.0，更优选(Rg5+Rk1)/Rg3＝0.85。即在本申请的人参属植物提取物人参皂苷Rg5与人参皂苷Rk1的含量之和为人参皂苷Rg3的满足上述比例关系，充分提高了人参皂苷Rg5、人参皂苷Rk1的含量之和，从而进一步提高其生理活性。
人参皂苷Rg3包括20(S)-人参皂苷Rg3和20(R)-人参皂苷Rg3，是C-20位对映异构体；其结构式分别为：
Figure PCTCN2017114497-appb-000002
作为本申请实施例人参属植物提取物的一种改进，20(R)-人参皂苷Rg3与20(S)-人参皂苷Rg3的质量比为1～1.5，优选1.1～1.2，更优选1.13。
人参皂苷Rg2包括20(S)-人参皂苷Rg2和20(R)-人参皂苷Rg2，是C-20位对映异构体；其结构式分别为：
Figure PCTCN2017114497-appb-000003
作为本申请实施例人参属植物提取物的一种改进，20(R)-人参皂苷Rg2与20(S)-人参皂苷Rg2的质量比为1.5～2.5，优选1.8～2.0，更优选1.92。
作为本申请实施例人参属植物提取物的一种改进，人参皂苷Rg3、人参皂苷Rg5、人参皂苷Rk1、人参皂苷Rg2、人参皂苷Rh1、人参皂苷Rh2 满足：
60％≤(Rg5+Rk1+Rg3)/(Rg5+Rk1+Rg3+Rg2+Rh1+Rh2)<100％。
更优选的满足：
80％≤(Rg5+Rk1+Rg3)/(Rg5+Rk1+Rg3+Rg2+Rh1+Rh2)<100％。
即，本申请中Rg5、Rk1、Rg3的质量之和不低于Rg5、Rk1、Rg3、Rg2、Rh1、Rh2质量之和的80％。即，本申请实施例充分提高了Rg5、Rk1、Rg3的含量之和，从而进一步提高其生理活性。
作为本申请实施例人参属植物提取物的一种改进，Rg5、Rk1、Rg3、Rg2、Rh1、Rh2的质量之和占人参属植物提取物总质量的50～80％。其余成分为水分、灰分、色素、糖类物质等。
本申请实施例中的人参属植物提取物可采用以下方法制备：
(1)将人参属植物原料用有机溶剂提取并浓缩；
(2)将浓缩液与20～90％的醋酸混合，在40℃～55℃、0.11Mpa～0.15MPa条件下处理5～60分钟，然后在0℃～5℃、0.13MPa～0.18MPa条件下处理5～60分钟；然后升温至60～110℃加热0.5～5小时；得水解液；
(3)经树脂吸附、脱除杂质后、洗脱、浓缩、干燥后，得所述人参属植物提取物。
作为本申请实施例制备方法的一种改进，在步骤(1)中，有机溶剂可采用醇类有机溶剂，优选乙醇；
作为本申请实施例制备方法的一种改进，在步骤(2)中，醋酸的体积百分比浓度，其浓度为的下限为20％、22％、25％、27％、30％、32％，其浓度上限为90％、87％、85％、82％、80％、75％、70％、65％；其具体浓度可由上限和下限的任意数据组成而成。
作为本申请实施例制备方法的一种改进，在步骤(3)中，树脂吸附具体步骤为：将水解液通过大孔树脂吸附。
作为本申请实施例制备方法的一种改进，在步骤(3)中，脱除杂质的具体步骤为：将通过大孔吸附树脂的吸附柱经水洗脱、碱水洗脱、浓度为18％以下的乙醇洗脱除去杂质。
作为本申请实施例制备方法的一种改进，在步骤(3)中，洗脱的具 体步骤为：用浓度为32％以上的乙醇洗脱吸附柱。
作为本申请实施例制备方法的一种改进，在步骤(3)中，浓缩可选用减压浓缩、
作为本申请实施例制备方法的一种改进，在步骤(3)中，干燥可选自真空干燥、烘干、喷雾干燥、冷冻干燥。
将本申请实施例制备得到人参属植物提取物在以下色谱条件下进行分析：
实验材料：20(S)-人参皂苷Rg2，20(R)-人参皂苷Rg2，20(R)-人参皂苷Rh1，20(S)-人参皂苷Rh1，20(S)-人参皂苷Rg3，20(R)-人参皂苷Rg3，人参皂苷Rk1，人参皂苷Rg5和人参皂苷Rh2对照品，含量98％；甲醇，HPLC级；乙腈，HPLC级；纯化水。
实验仪器：岛津LC-2010A；超声仪；离心机；涡旋仪。
对照品溶液制备：精密称取各对照品10mg置于5ml容量瓶中，用甲醇溶解并稀释至刻度，制成浓度为2mg/ml的储备液，精密吸取各储备液500μl，加至5ml容量瓶中，用甲醇稀释至刻度，制成浓度为0.2mg/ml的混标溶液。
供试品溶液制备：精密称取实施例1制得的人参属植物提取物样品约10mg置于5ml容量瓶中，用甲醇溶解并稀释至刻度，称重，超声30min后再次称重并用甲醇补足损失重量，转移至10ml离心管后4500rpm离心10min，取上清过0.45μm滤膜后进样分析。
色谱柱：Agilent Zorbax SB-C18(250×4.6mm，5μm)；流动相：乙腈(A)-水(B)；梯度：1～10min 18～25％A，10～25min 25～45％A，25～45min45～65％A，45～57min 65～90％A，57～58min 90～18％A，58～65min 18％A；流速：1.0ml/min；柱温：40℃；检测波长：203nm；进样体积：10μl。
分析得到的的指纹图谱如图1所示。其中，图2为人参皂苷混标()。通过采用外标法计算其含量见表1。
表1、人参属植物提取物中人参皂苷含量
指纹图峰号 名称 含量(wt％)
1 20(S)-人参皂苷Rg2 1.16
2 20(R)-人参皂苷Rg2 2.23
3 20(R)-人参皂苷Rh1 0.90
4 20(S)-人参皂苷Rh1 0.96
5 20(S)-人参皂苷Rg3 7.45
6 20(R)-人参皂苷Rg3 8.42
7 人参皂苷Rk1 6.32
8 人参皂苷Rg5 7.23
9 人参皂苷Rh2 0.96
  含量合计 35.63
作为本申请实施例制备方法的一种改进，为了进一步提高产率，在步骤(1)中，先将人参属植物原料进行真空膨化处理；
优选的，真空膨化处理的步骤为：将人参属植物原料放入膨化罐中，加热，使膨化罐内的温度为30～100℃，压力升高至0.1～0.9MPa，时间维持5～40分钟，随后，迅速打开连接膨化罐和真空罐的减压阀，瞬间降压至-0.04～-0.08MPa，冷却，并维持5～40分钟，真空罐预先抽真空。产率可提升5％～30％。
本申请实施例还涉及含有本申请人参属植物提取物的药物组合物。
本申请实施例的药物组合物，根据需要可以含有药物可接受的载体，其中人参次苷提取物作为药物活性成分，其在制剂中所占重量百分比可以是0.1～99.9％，其余为药物可接受的载体。本申请实施例的药物组合物，以单位剂量形式存在，单位剂量形式是指制剂的单位，如片剂的每片，胶囊的每粒胶囊，口服液的每瓶，颗粒剂每袋，注射剂的每支等。
本申请实施例的药物组合物可以是任何可药用的剂型，这些剂型包括：片剂(包括口腔崩解片、糖衣片剂、薄膜衣片剂、肠溶衣片剂)、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。
本申请实施例的药物组合物，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本申请实施例的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本申请实施例的药物组合物，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗 糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本申请实施例的药物组合物在使用时根据病人的情况确定用法用量，可每日服三次，每次1～20剂，如：1～20袋或粒或片，每剂1mg～1000mg。
本申请中，上述药物制剂可以由本领域普通技术人员通过使用本领域中公知的一般方法来制备。
本申请实施例还涉及该人参属植物提取物在制备治疗慢性心衰、冠心病稳定性心绞痛、心律失常、糖尿病及其并发症、美尼尔氏综合征、高脂血症、脂肪肝、阿尔茨海默病、痛经、代谢综合征、痛风、肿瘤或血管渗漏综合征疾病的药物中的应用。
实验例1：阿尔茨海默病有效性实验
1、试验材料：准确称取本申请实施例的人参属植物提取物4g，加入药物辅料，制成100片，每片含人参属植物提取物40mg。
2、试验方法：
轻中度阿尔茨海默症患者99例，男性47例，女性52例，年龄55～85(73.5±7.6)岁，MMSE评分为10～24(16.3±2.6)分。
AD患者均使用片剂，一日三次，每次一片，连续应用12周。
用药前和用药后每4周检查一次，检查方法如下：
(1)MMSE筛查AD。检测患者的认知功能(定向力、记忆力、计算力、语言能力、视空间段运用能力等)；
(2)临床痴呆程度量表(CDR)检测患者的痴呆程度；
(3)日常生活自理量表(ADL)检测患者的日常生活自理能力。检查结果应用SPSS统计软件治疗前后及人参皂苷Rg3滴鼻液组与安慰剂对照均采用t检验。
AD患者的MMSE、CDR及ADL评分结果见表2。
表2、AD患者使用人参属植物提取物片剂治疗前后
MMSE、CDR、ADL评分结果(x±s，分)
量表名 治疗前 治疗4周 治疗12周
MMSE 16.4±2.8 19.2±1.9* 20.7±1.6**
CDR 2.2±0.4 1.7±0.2 1.4±0.2*
ADL 49.8±8.3 47.1±7.8 41.5±7.2*
注：自身对照组在治疗前与治疗后比较，*P<0.05，**P<0.01。
认知功能(用MMSE评分)：治疗12周后较治疗前有很明显提高，MMSE分数提高4.3分(P<0.01)，且在用药4周时MMSE评分已有明显改善(P<0.05)。痴呆程度(用CDR评分)：治疗12周后较治疗前有显著减低，CDR分数减少0.8分(P<0.05)。日常生活自理能力(用ADL评分)：治疗后较治疗前有很明显减低，ADL分数减少8.3分(P<0.01)。
综上，采用本申请的人参属植物提取物对改善AD患者轻、中度认知功能障碍、生活自理能力下降及痴呆程度安全而有效。
实验例2：降糖对比实验
1、实验材料
1.1药物与试剂
试验药物：本申请实施例制得的人参属植物提取物；
对比制剂1：组成如表3所示，采用标准物质配制而成：
表3
组分 名称 含量(wt％)
1 20(S)-人参皂苷Rg2 1
2 20(R)-人参皂苷Rg2 2
3 20(R)-人参皂苷Rh1 1
4 20(S)-人参皂苷Rh1 1
5 20(S)-人参皂苷Rg3 8
6 20(R)-人参皂苷Rg3 8
7 人参皂苷Rk1 2
8 人参皂苷Rg5 12
9 人参皂苷Rh2 1
10 蒸馏水 64
试验药物和对比制剂1分别采用0.5％的羧甲基纤维素制备成溶液用 于灌胃。
链脲霉素：(sigma公司)。
1.2动物
Wistar大鼠，体重180±20g，购自山东大学医学部实验动物中心。
2、实验方法
2.1造高血糖模型
选合格大鼠20只，分为4组：即正常对照组、模型动物组、本申请组和对照组，其中，模型动物组、本申请组和对照组大鼠于实验开始前3日，尾静脉注射链脲霉素65mg/kg，经血糖检测显示造模成功。
2.2给药
正常对照组：口服给予等量纯净水；
模型动物组：造模成功动物口服给予等量纯净水；
本申请组：造模成功动物按200mg/kg/d给予本申请实施例的人参属植物提取物，连续14天；
对照组：造模成功动物按200mg/kg/d给予对比制剂1，连续14天。
实验期间饲料与水自由摄取。各组动物于给药后0天(给药前)、第7天和第14天分别测定血糖。每次上午10：00，在无麻醉条件下，从大鼠尾静脉采血，测定其血液中的血糖浓度。
3、试验结果
采用SPSS11.0处理，所有数据先行正态性和方差齐性检验。各组大鼠血液中血糖浓度测定结果的比较采用单因素方差分析，组间两两比较采用SNK-q检验，检验水准α＝0.05，测定结果如表4所示。
表4、人参属植物提取物对大鼠血糖的影响(mg/dL)(x±s，n＝5)
Figure PCTCN2017114497-appb-000004
Figure PCTCN2017114497-appb-000005
注：与模型组比较#P<0.05，与对照组比较*P<0.05。
实验例3：降血脂对比实验
1、实验材料
1.1药物与试剂
试验药物：本申请实施例的人参属植物提取物；
对比制剂1：组成同实验例1。
试验药物和对比制剂1分别采用0.5％的羧甲基纤维素制备成溶液用于灌胃。
TC、TG试剂盒。
1.2动物
Wistar大鼠，体重180±20g，购自大东大学医学部实验动物中心。
1.3仪器
UV85紫外分光光度计(上海天美)，日立7170A全自动生化分析仪。
2、实验方法
2.1造高血脂模型
Wistar大鼠20只，分为4组：即正常对照组、模型动物组、本申请组和对照组，其中，模型动物组、本申请组和对照组大鼠饲喂高脂饲料，正常对照组饲喂普通饲料。每周称体重一次，其中第4、6、8周随机选取脂肪肝模型组动物1～2只，尾静脉取血1ml化验血脂，观察血脂的动态变化，8周末脂肪肝模型组血脂明显升高，肝脏呈中至重度脂肪变，造模成功。
高脂饲料配方为：普通饲料+l％胆固醇+14％猪油。
2.2给药方法：
正常对照组和模型动物组：蒸馏水灌胃；
对照组：按200m g/kg/d给予对比制剂1，连续14天；
本申请组：按200mg/kg/d给予本申请实施例的人参属植物提取物，连续14天。
给药期间给予普通饲料。
2.3标本制备：
第8周末，于最后一次进食12小时后断头取血，低温离心，分离血清，密封，-20℃冷贮备检。
2.4指标检测：
检测时将冷贮的血清放置于37℃恒温水浴箱解冻，取血清适量，分别依试剂盒的要求，测定TC(甘油三酯)、TG(胆固醇)含量。
3实验结果
按照试剂盒的要求测定大鼠肝内TC、TG的含量，测定结果如表5所示。
表5、人参属植物提取物对实验大鼠肝内TC、TG影响(X±S，n＝6)
组别 TC(mmol/L) TG(mmol/L)
正常对照组 0.76±0.22 1.33±0.26
模型组 1.26±0.23 2.15±0.74
对照组 0.98±0.18# 1.86±0.17#
本申请组 0.81±0.07*# 1.36±0.13*#
注：与模型组比较#P<0.05，与对照组比较*P<0.05。
实验例4：痛经对比实验
1.实验材料
1.1药品与试剂
试验药物：本申请实施例的人参属植物提取物；
对比制剂2，组成如表6所示：
表6：
组分 名称 含量(wt％)
1 20(S)-人参皂苷Rg2 1
2 20(R)-人参皂苷Rg2 2
3 20(R)-人参皂苷Rh1 1
4 20(S)-人参皂苷Rh1 1
5 20(S)-人参皂苷Rg3 9
6 20(R)-人参皂苷Rg3 9
7 人参皂苷Rk1 2
8 人参皂苷Rg5 1
9 人参皂苷Rh2 10
10 蒸馏水 64
试验药物和对比制剂1分别采用0.5％的羧甲基纤维素制备成溶液用于灌胃。
己烯雌酚注射液，上海通用药业有限公司；
催产素注射液，南京生物化学制药厂。
1.2动物
雌性SD大鼠，160～180g，购自山东大学医学部实验动物中心。
1.3仪器
PB303-N电子天平，梅特勒-托利多仪器(上海)有限公司。
PowerLab/8s，连同配套软件由澳大利亚AD Instruments公司提供。
2.方法结果
2.1动物模型制备
雌性SD大鼠40只，随机分为4组，即空白对照组、模型组、对照组、本申请组。除空白对照组外，各组大鼠均皮下注射己烯雌酚，连续10天，每天1次，第1天及第10天注射0.8mg/只，第2～9天注射0.2mg/只。
2.2给药方法：
空白对照组和模型组给予等量蒸馏水。
对照组：第5天开始，200mg/kg/d给予对比制剂2；
本申请组：第5天开始，200mg/kg/d给予本申请实施例的人参属植物提取物。
第9天末次给己烯雌酚后1小时后，大鼠腹腔注射催产素2u/只，观察30分钟内各组大鼠疼痛反应，扭体反应以大鼠腹部收缩内凹，躯干与后肢伸展，臀部与一侧肢体内旋为子宫收缩痛经指标，观察并记录30分钟内各组大鼠痛经扭体只数及平均扭体次数，计算痛经发生率，结果见表7。
表7、人参属植物提取物对大鼠痛经模型的影响
Figure PCTCN2017114497-appb-000006
Figure PCTCN2017114497-appb-000007
与模型组比较#P<0.05，与对照组比较*P<0.05。
实验例5：血栓对比实验
1.实验材料
SD大鼠40只，雌雄各半，体重250～300g，购自山东大学医学部实验动物中心。
试验药物：本申请实施例的人参属植物提取物；
对比制剂1，组成如表3所示：
对比制剂2，组成如表6所示：
试验药物、对比制剂1和对比制剂2分别采用0.5％的羧甲基纤维素制备成溶液用于灌胃。
2.实验方法：
将大鼠随机分成4组(模型组、对照组1、对照组2、实验组)，每组10只，具体给药情况为：
对照组1：200mg/kg/d给予对比制剂1；
对照组2：200mg/kg/d给予对比制剂2；
实验组：200mg/kg/d给予本申请实施例的人参属植物提取物；
模型组：纯水；
将上述药物灌胃7d。
2.血栓形成抑制率的测定：
给药第七天，每只大鼠于给药后30min用戊巴比妥钠麻醉，分离左颈外静脉和右颈总动脉，取三段聚乙烯管组成的套管，其中间段置一根5cm的称重四号手术线，以肝素生理盐水(50U/ml)充满聚乙烯管，当管的一端插入颈外静脉后，夹住管的一端将丝线固定的一端管插入右颈总动脉， 手术完成后立即开放血流，15min后中断血流，迅速取出丝线称重。总重量减去丝线重量即为血栓湿重。
抑制率＝(模型组血栓湿重-实验组血栓湿重)/模型组血栓湿重
对各组血栓重量的平均值进行统计学处理，t检验判断药物的显著性作用，通过抑制率判定药物的作用强度。
3.实验结果
如表8所示：
表8、人参属植物提取物对大鼠血栓模型的影响
Figure PCTCN2017114497-appb-000008
注：与对照组1比较#P<0.05，与对照组2比较*P<0.05。
实验例6：肿瘤对比实验
1、实验材料
使用的肿瘤细胞株：A549人非小细胞肺癌细胞、MGC80-3人胃癌细胞、MCF-7人乳腺癌细胞三种人肿瘤细胞系(采用的细胞培养液分别为RPMI 1640培养液、DMEM培养液、MEM培养液)。
试验药物：本申请实施例的人参属植物提取物；
对比制剂1，组成如表3所示：
对比制剂2，组成如表6所示：
本申请实施例的人参属植物提取物组以二甲基亚砜(DMSO)溶解，分别用RPM I-1640培养液、DMEM培养液、MEM培养液稀释至所需浓度： 1、25、50、100、200μg/L，用于细胞培养。
对比制剂以二甲基亚砜(DMSO)溶解，分别用RPM I-1640培养液、DMEM培养液、MEM培养液稀释至所需浓度：1、25、50、100、200μg/L，用于细胞培养。
对比制剂以二甲基亚砜(DMSO)溶解,用RPM I-1640培养液、DMEM培养液、MEM培养液稀释至所需浓度：1、25、50、100、200μg/L，用于细胞培养。
2、方法
取对数生长期细胞，加入0.25％胰蛋白酶消化，600r/min离心10min，调整细胞浓度为6×104个/mL，接种于96孔培养板中(边缘孔用无菌PBS填充)，每孔90μL。培养24h后，分别加入含有不同浓度的实验样品的培养液，且加入细胞中药液的DMSO终浓度低于1％，每组均设3个平行孔。于37℃5％CO2培养箱共同培养48h。每孔加入20μL MTT溶液(5mg/mL，溶解于PBS中)，继续培养4h后，终止培养。小心吸弃上清液，每孔加入150μL DMSO，震荡10min，使结晶物充分溶解。用酶标仪在570nm处测每孔的吸光值(A)，计算出细胞存活率：
细胞存活率％＝加样品A值/对照细胞A值×100％。
3、结果
实验结果表明，本申请的人参属植物提取物对三种人肿瘤细胞系均具有较强的细胞杀伤作用，与比较例的人参属植物提取物相比，作用明显增强。结果见表9-11。
表9、人参属植物提取物对A549人非小细胞肺癌细胞的影响
Figure PCTCN2017114497-appb-000009
Figure PCTCN2017114497-appb-000010
表10、人参属植物提取物对MGC80-3人胃癌细胞的影响
Figure PCTCN2017114497-appb-000011
表11、人参属植物提取物对MCF-7人乳腺癌细胞的影响
Figure PCTCN2017114497-appb-000012
Figure PCTCN2017114497-appb-000013
实施例1
人参属植物提取物的制备方法，包括如下步骤：
(1)将人参饮片用60％的乙醇回流提取3次，每次用4倍量的溶剂，每次3小时，得提取液，合并提取液并减压浓缩；
(2)将浓缩液与60％的醋酸等体积混合，在40℃、0.11MPa条件下浸泡20分钟，然后在5℃、0.15MPa条件下浸泡20分钟，升温至90℃加热2小时，得水解液；
(3)将水解液通过D101大孔树脂柱；
(4)将通过大孔吸附树脂的吸附柱经水洗脱，然后用0.5％的氢氧化钠溶液洗脱，用水洗脱至中性后用15％的乙醇洗脱除去杂质；
(5)用50％乙醇洗脱，收集洗脱液，减压浓缩至浸膏，在70℃真空干燥，得到本申请的人参属植物提取物。
制备得到的人参属植物提取物采用上述高效液相色谱进行分析，获得的图谱与图1类似。采用其他人参类植物：红参、高丽参、三七、竹节参、西洋参等，采用本实施例的具体条件进行制备，所获得的人参属植物提取物的高效液相色谱与图1类似。
实施例2
人参属植物提取物的制备方法，包括如下步骤：
(1)真空膨化处理：将三七饮片放入膨化罐中，加热，使膨化罐内的温度为80℃，压力升高至0.5MPa，时间维持20分钟，真空罐预先抽真空，迅速打开连接膨化罐和真空罐的减压阀，瞬间降压至-0.04MPa，冷却，并维持20分钟；
(2)将膨化后的三七饮片用50％的乙醇回流提取3次，每次用2倍量的溶剂，每次2小时，得提取液；
(3)将提取液与80％的醋酸等体积混合，在55℃、0.15MPa条件下浸泡 15分钟，然后在0℃、0.18MPa条件下浸泡25分钟；
(3)将水解液通过D101大孔树脂柱；
(4)将通过大孔吸附树脂的吸附柱经水洗脱，然后用0.5％的氢氧化钠溶液洗脱，用水洗脱至中性后用12％的乙醇洗脱除去杂质；
(5)用55％乙醇洗脱，收集洗脱液，减压浓缩至浸膏，在70℃真空干燥，得到本申请的人参属植物提取物。
制备得到的人参属植物提取物采用上述高效液相色谱进行分析，获得的图谱与图1类似。采用其他人参类植物：红参、高丽参、竹节参、西洋参等，采用本实施例的具体条件进行制备，所获得的人参属植物提取物的高效液相色谱与图1类似。
本申请虽然以较佳实施例公开如上，但并不是用来限定权利要求，任何本领域技术人员在不脱离本申请构思的前提下，都可以做出若干可能的变动和修改，因此本申请的保护范围应当以本申请权利要求所界定的范围为准。

Claims (9)

  1. 一种人参属植物提取物，其特征在于，所述人参属植物提取物中含有人参皂苷Rg3、人参皂苷Rk1和人参皂苷Rg5，所述人参皂苷Rk1与所述人参皂苷Rg5的质量比为1：1.0～1.5，更优选1：1.0～1.3。
  2. 根据权利要求1所述的人参属植物提取物，其特征在于，所述人参皂苷Rg5、所述人参皂苷Rk1与所述人参皂苷Rg3的质量百分比含量满足：0.5≤(Rg5+Rk1)/Rg3≤1.5，
    优选：0.5≤(Rg5+Rk1)/Rg3≤1.0。
  3. 根据权利要求1所述的人参属植物提取物，其特征在于，所述人参皂苷Rg3包括20(S)-人参皂苷Rg3和20(R)-人参皂苷Rg3，所述20(R)-人参皂苷Rg3与所述20(S)-人参皂苷Rg3的质量比为1～1.5，优选1.1～1.2。
  4. 根据权利要求1～3任一权利要求所述的人参属植物提取物，其特征在于，所述人参属植物提取物中还含有人参皂苷Rg2、人参皂苷Rh1和人参皂苷Rh2；所述人参皂苷Rg3、所述人参皂苷Rg5、所述人参皂苷Rk1、所述人参皂苷Rg2、所述人参皂苷Rh1、所述人参皂苷Rh2的质量百分比含量满足：80％≤(Rg5+Rk1+Rg3)/(Rg5+Rk1+Rg3+Rg2+Rh1+Rh2)<100％。
  5. 根据权利要求4所述的人参属植物提取物，其特征在于，所述人参皂苷Rg2包括20(S)-人参皂苷Rg2和20(R)-人参皂苷Rg2，所述20(R)-人参皂苷Rg2与所述20(S)-人参皂苷Rg2的质量比为1.5～2.5，优选1.8～2.0。
  6. 根据权利要求1所述的人参属植物提取物，其特征在于，所述人参属植物选自人参、红参、高丽参、三七、竹节参、西洋参中的至少一种。
  7. 一种药物组合物，其特征在于，所述药物组合物中含有如权利要求1～6任一权利要求所述的人参属植物提取物的以及药学上可接受的载体。
  8. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合 物的剂型选自片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、喷雾剂、滴剂或贴剂，所述片剂优选口腔崩解片。
  9. 一种如权利要求1～6任一权利要求所述的人参属植物提取物、如权利要求7或8所述的药物组合物在制备治疗慢性心衰、冠心病稳定性心绞痛、心律失常、糖尿病及其并发症、美尼尔氏综合征、高脂血症、脂肪肝、阿尔茨海默病、痛经、代谢综合征、痛风、肿瘤或血管渗漏综合征的药物中的应用。
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