WO2020098831A1 - 一种妇科千金胶囊及其质量控制方法 - Google Patents

一种妇科千金胶囊及其质量控制方法 Download PDF

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WO2020098831A1
WO2020098831A1 PCT/CN2020/072103 CN2020072103W WO2020098831A1 WO 2020098831 A1 WO2020098831 A1 WO 2020098831A1 CN 2020072103 W CN2020072103 W CN 2020072103W WO 2020098831 A1 WO2020098831 A1 WO 2020098831A1
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less
capsule
content
qianjin
andrographolide
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PCT/CN2020/072103
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English (en)
French (fr)
Inventor
蹇顺
龚云
张鹏
李伏君
凌勇根
何娟娟
王康华
杨秀伟
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株洲千金药业股份有限公司
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Priority claimed from CN201811356105.5A external-priority patent/CN109364147A/zh
Priority claimed from CN201811356104.0A external-priority patent/CN109254098A/zh
Application filed by 株洲千金药业股份有限公司 filed Critical 株洲千金药业股份有限公司
Priority to US17/293,920 priority Critical patent/US20220143125A1/en
Publication of WO2020098831A1 publication Critical patent/WO2020098831A1/zh

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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)
    • A61K36/19—Acanthaceae (Acanthus 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • 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)
    • A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/738—Rosa (rose)
    • 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)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/758—Zanthoxylum, e.g. pricklyash
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • 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, 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
    • A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
    • 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
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying

Definitions

  • the invention relates to the technical field of traditional Chinese medicine, and more particularly, to a gynecological Qianjin capsule and its quality control method.
  • Gynecology Qianjin Capsule is a medicine made from 8 herbs such as Qianjinpao, Jinyinggen, Andrographis paniculata, Gong Gong, single-sided needle, angelica, Coprinus chinensis and Codonopsis pilosula. The effect is to clear away heat and dehumidify, tonic qi and blood. Used for diarrhea and abdominal pain caused by dampness and heat stasis. Symptoms include heavy diarrhea, thick yellow color, odor, abdominal pain, lumbosacral pain, fatigue, chronic pelvic inflammatory disease, endometritis, For chronic cervicitis, see the above syndrome.
  • the technical problem to be solved by the present invention is to overcome the above-mentioned defects and deficiencies of the prior art, to provide a gynecological Qianjin capsule and its quality control method.
  • the gynecological Qianjin capsules are more stable in terms of effect consistency, and have better clinical treatment effects than the existing gynecological Qianjin capsules.
  • the object of the present invention is to provide a quality control method for gynecological Qianjin capsules.
  • Another object of the present invention is to provide a gynecological Qianjin capsule.
  • a quality control method for gynecology Qianjin capsules includes the following steps:
  • Qianjinba Gongluo clearing away heat and detoxifying, dryness and dampness, a total of Jun medicine
  • Andrographis paniculata single-sided needles clearing away heat and detoxification, cooling blood and swelling, dryness and dampness, dryness
  • Angelica nourishes and promotes blood circulation
  • Codonopsis pilosula nourishes qi and strengthens the spleen, promotes the transport of water and moisture, and stops
  • the golden cherry root solid essence stops the belt, which is a total of adjuvants.
  • the Chinese herbal compound is an organic whole with layers and structures. Its efficacy is not a simple addition of individual medicines, but a result of the collaboration between multiple active ingredients.
  • the existing pharmacopoeia for gynecological Qianjin capsules stipulates that only two kinds of andrographolide and dehydroandrographolide are from the medicine (from andrographis paniculata), but not the types and contents of other active ingredients. In the actual production process, because of quality testing and control, only andrographolide and dehydroandrographolide were tested, but the types and contents of other active ingredients were not tested.
  • the content of Z-ligustilide per mg of ointment in step S5 is not less than 0.01 mg and / or the content of Z-3-butenylphthalide is not less than 0.00017 mg, and andrographolide and dehydration The total amount of andrographolide is not less than 0.01mg.
  • the content of Z-ligustilide per mg of ointment in step S5 is not less than 0.015 mg and / or the content of Z-3-butenylphthalide is not less than 0.00025 mg, and andrographolide and dehydration The total amount of andrographolide is not less than 0.015mg.
  • the content of Z-ligustilide per milligram of ointment in step S5 is 0.0165 to 0.022 mg and / or the content of Z-3-butenylphthalide is 0.00036 to 0.0006 mg, and andrographolide and dehydration The total amount of andrographolide is not less than 0.02mg.
  • a quality control method for gynecology Qianjin capsules includes the following steps:
  • the content of genistein per mg of ointment in step S5 is not less than 0.00015 mg
  • the content of jatrorrhizine is not less than 0.0004 mg
  • the content of palmatine is not less than 0.00038 mg
  • the content of berberine is not Less than 0.0004mg
  • the content of Z-ligustilide is not less than 0.01mg
  • the content of Z-3-butenylphthalide is not less than 0.00017mg
  • the total amount of andrographolide and dehydroandrographolide is not less than 0.01mg.
  • the content of genistein per milligram of ointment in step S5 is not less than 0.0002mg
  • the content of jatrorrhizine is not less than 0.0006mg
  • the content of palmatine is not less than 0.0006mg
  • the content of berberine is not Less than 0.0006mg
  • Z-ligustilide content is not less than 0.015mg
  • Z-3-butenylphthalide content is not less than 0.00025mg
  • the total amount of andrographolide and dehydroandrographolide is not less than 0.015mg.
  • the content of genistein in each milligram of ointment is 0.0025 to 0.0035 mg
  • the content of jatrorrhizine is 0.009 to 0.015 mg
  • the content of palmatine is 0.007 to 0.01 mg
  • the content of berberine The content is 0.0085 ⁇ 0.01mg
  • the content of Z-ligustilide is 0.0165 ⁇ 0.022mg
  • the content of Z-3-butenylphthalide is 0.00036 ⁇ 0.0006mg
  • the total amount of andrographolide and dehydroandrographolide is not Less than 0.02mg.
  • the genistein in each of the gynecological Qianjin capsules prepared by the method is not less than 0.025 mg, jatrorrhizine no less than 0.08mg, palmatine no less than 0.06mg, berberine no less than 0.08mg, Z-ligustilide no less than 2.0mg, Z-3-butenylphthalide Not less than 0.03mg, the total amount of andrographolide and dehydroandrographolide is not less than 1.6mg.
  • the genistein in each of the gynecological Qianjin capsules prepared by the method is not less than 0.025 mg, jatrorrhizine no less than 0.08mg, palmatine no less than 0.060mg, berberine no less than 0.08mg, Z-ligustilide no less than 2.0mg, Z-3-butenylphthalide Not less than 0.03mg, the total amount of andrographolide and dehydroandrographolide is not less than 1.9mg;
  • the genistein in each of the gynecological Qianjin capsules prepared by the method is not less than 0.032 mg, jatrorrhizine no less than 0.12mg, palmatine no less than 0.075mg, berberine no less than 0.12mg, Z-ligustilide no less than 2.6mg, Z-3-butenylphthalide Not less than 0.04mg, the total amount of andrographolide and dehydroandrographolide is not less than 2.5mg.
  • the total amount of andrographolide and dehydroandrographolide in each gynecological Qianjin capsule is not less than 3.5 mg.
  • each of the gynecological Qianjin capsules prepared by the method contains 0.04 to 0.06 mg of genistein, 0.165 to 0.20 mg of jatrorrhizine, 0.090 to 0.130 mg of palmatine, 0.13 to 0.18 mg of The total amount of berberine, 3.0-3.65 mg of Z-ligustilide, 0.065-0.105 mg of Z-3-butenylphthalide, andrographolide and dehydroandrographolide is not less than 3.5 mg.
  • control is to adjust the extraction process or raw material source of S1, S2, S3, S4, so that the genistein, jatrorrhizine, palmatine after mixing the four clear pastes of S1-S4 , Berberine, Z-ligustilide and Z-3-butenylphthalide reach the required range.
  • the detection method used in step S5 is HPLC detection.
  • the detection step in S5 is: taking 1 g of the paste and dissolving it in 200 mL of 75% methanol aqueous solution, then taking 2 mL of the dissolving solution and diluting it with a 75% methanol aqueous solution to 10 mL, passing through a 0.45 ⁇ m microporous membrane, and taking the filtrate as the test Solution; Kromasil 100-5-C18 column (250mm ⁇ 4.6mm, 5 ⁇ m), mobile phase with acetonitrile as phase A and 0.1% phosphoric acid aqueous solution as phase B, gradient elution, flow rate 1.0mL ⁇ min-1, detection The wavelength was 254 nm, the column temperature was 30 ° C, and the injection volume was 10 ⁇ L.
  • the method of S1 is to pulverize angelica into coarse powder, pass through an 8-mesh sieve, infiltrate with 70% ethanol by mass concentration, put it into a percolating cylinder, soak for 48h, and percolate at a rate of 0.2mL / min, Collect 10 times the amount of percolate and concentrate to obtain a relative density of 1.1 (80 °C), which is Angelica sinensis ointment.
  • the method of S2 is: crushing andrographis paniculata through a 100 mesh sieve, adding ethanol with a mass concentration of 90% according to the material-liquid ratio of 1: 9, heating and refluxing extraction, refluxing for 4h, separating the extraction liquid, and then removing the residue
  • the material-liquid ratio was 1: 8 and refluxed for 3.5 h.
  • the extract was separated, the two extracts were combined, filtered, and concentrated to obtain andrographis paniculata with a relative density of 1.1 (80 ° C.).
  • the method of S3 is to extract boiled wood and single-sided needle twice, add 12 times the total weight of two flavors of traditional Chinese medicine in the first time and boil it for 4 hours, the decoction is released, and the second time is added 10 times The amount of water is decoction for 3 hours, the decoction is released, the decoction is combined, filtered, and the filtrate is concentrated to obtain an ointment with a relative density of 1.1 (80 ° C).
  • the method of S4 is to add Qianjinpa, Jinyinggen, Coprinus chinensis, Codonopsis pilosulae and boiled Codonopsis according to the material-to-liquid ratio of 1:10, add water and boil for 3.5h, extract after one time and filter, and the filtrate is concentrated to obtain a relative density of 1.1 (80 °C).
  • Ointment combine the filtered drug residue with the angelica drug residue generated in step S2, the andrographis paniculata drug residue generated in step S2, and the drug residue generated in step S3, add 4 times the volume of water for 3 hours, filter, and concentrate to obtain a relative density of 1.1 (80 °C) ointment.
  • the genistein is derived from the raw material of the gynecological Qianjin capsule
  • the root of the medicine, palmatine and berberine are derived from the raw material of the gynecological Qianjin capsule
  • the Z-ligustilide and Z- The 3-butenylphthalide comes from the raw material of Angelica sinensis capsules
  • the andrographolide and the dehydroandrographolide come from the raw medicine of Andrographis paniculata capsules.
  • the dosages of angelica, dangshen, andrographis paniculata, and single-sided needles are each 9% of the total amount of gynecological Qianjin capsules; the dosages of Jinyinggen, Codonopsis lanceolata, Gong Gong, and Qianjinba are each 16% of the total gynecological Qianjin capsules. .
  • the invention also protects the gynecology Qianjin capsule prepared by the above quality control method and its application in the preparation of medicine for treating gynecological diseases.
  • the gynecological disease is chronic pelvic inflammatory disease, chronic appendicitis or endometritis.
  • the invention also protects a gynecological Qianjin capsule, which is made of Jinjinba, Gongluo, Andrographis paniculata, single-sided needle, heliotrope, angelica, codonopsis, and golden cherry root.
  • Each gynecological Qianjin capsule contains not less than 2.0mg Z-ligustilide; preferably contains 2.6 mg of Z-ligustilide; more preferably contains 3.0-3.65 mg of Z-ligustilide;
  • the total amount of andrographolide and dehydroandrographolide is not less than 1.9mg; preferably, the total amount of andrographolide and dehydroandrographolide is not less than 2.5mg; preferably, the amount of andrographolide and dehydroandrographolide is not less than 2.5mg; The total amount is not less than 3.5mg.
  • a gynecological Qianjin capsule made of Jinjinba, Gongmu, Andrographis paniculata, single-sided needle, heliotrope, angelica, dangshen, Jinyinggen, and each gynecological Qianjin capsule contains not less than 0.03mg of Z-3 -Butenylphthalide; preferably contains not less than 0.04mg of Z-3-butenylphthalide; preferably contains 0.065 ⁇ 0.105mg of Z-3-butenylphthalide;
  • the total amount of andrographolide and dehydroandrographolide is not less than 1.9mg; preferably, the total amount of andrographolide and dehydroandrographolide is not less than 2.5mg; preferably, the amount of andrographolide and dehydroandrographolide is not less than 2.5mg; The total amount is not less than 3.5mg.
  • each gynecological Qianjin capsule contains not less than 2.0mg of Z-Liu
  • This lactone contains not less than 0.03mg of Z-3-butenylphthalide; and the total amount of andrographolide and dehydroandrographolide is not less than 1.9mg;
  • each of the gynecological Qianjin capsules contains not less than 2.6 mg of Z-ligustilide, not less than 0.04 mg of Z-3-butenylphthalide, and the total amount of andrographolide and dehydroandrographolide The amount is not less than 2.5mg;
  • each of the gynecological Qianjin capsules contains 3.0 to 3.65 mg of Z-ligustilide, 0.065 to 0.105 mg of Z-3-butenylphthalide, and the total amount of andrographolide and dehydroandrographolide is not Less than 3.5mg.
  • a gynecological Qianjin capsule made of Jinjinba, Gongmu, Andrographis paniculata, single-sided needle, heliotrope, angelica, dangshen, Jinyinggen as raw materials, each of the gynecological Qianjin capsules (according to the 2015 edition of the Pharmacopoeia of the People's Republic of China)
  • the quality of each gynecological Qianjin capsule is 0.4mg), containing genistein at least 0.025mg, jatrorrhizine at least 0.08mg, palmatine at least 0.060mg, and berberine at least At 0.08mg
  • Z-ligustilide is not less than 2.0mg
  • Z-3-butenylphthalide is not less than 0.03mg
  • the total amount of andrographolide and dehydroandrographolide is not less than 1.9mg.
  • each of the gynecological Qianjin capsules contains genistein at least 0.032 mg, jatrorrhizine at least 0.12 mg, palmatine at least 0.075 mg, berberine at least 0.12 mg, Z -Ligustilide is not less than 2.6mg, Z-3-butenylphthalide is not less than 0.04mg, and the total amount of andrographolide and dehydroandrographolide is not less than 2.5mg.
  • the total amount of andrographolide and dehydroandrographolide in each gynecological Qianjin capsule is not less than 3.5 mg.
  • each of the gynecological Qianjin capsules contains 0.04 to 0.06 mg of genistein, 0.165 to 0.20 mg of jatrorrhizine, 0.090 to 0.130 mg of palmatine, 0.13 to 0.18 mg of berberine, 3.0 to The total amount of 3.65 mg of Z-ligustilide, 0.065 to 0.105 mg of Z-3-butenylphthalide, andrographolide and dehydroandrographolide is not less than 3.5 mg.
  • each of the gynecological Qianjin capsules contains 0.045 to 0.056 mg of genistein, 0.175 to 0.195 mg of jatrorrhizine, 0.10 to 0.130 mg of palmatine, 0.16 to 0.178 mg of berberine, 3.30 to 3.65 mg of Z-ligustilide, 0.080 to 0.105 mg of Z-3-butenylphthalide, 2.5 to 4.15 mg of andrographolide, and 1.0 to 1.3 mg of dehydroandrographolide.
  • the content of the genistein, jatrorrhizine, palmatine, berberine, Z-ligustilide, Z-3-butenylphthalide, andrographolide and dehydroandrographolide is determined by HPLC detection.
  • the sample detected by the HPLC is prepared by the following method: taking out 1.00g of the contents of the gynecology Qianjin capsule, placing it in a triangular flask, adding 20mL of a 75% methanol aqueous solution precisely, and extracting with ultrasonic (30 ⁇ 5) min, to be reduced to After normal temperature, 75% methanol aqueous solution was used to make up for the loss of mass, and the filter was passed through a 0.45 ⁇ m microporous membrane, and the filtrate was taken as the solution to be tested.
  • the HPLC detection is performed according to the following conditions: a Kromasil 100-5-C18 chromatographic column (250mm ⁇ 4.6mm, 5 ⁇ m) is used, the mobile phase is acetonitrile as phase A and 0.1% phosphoric acid aqueous solution as phase B, and gradient elution, The flow rate was 1.0 mL ⁇ min-1, the detection wavelength was 254 nm, the column temperature was (30 ⁇ 0.5) ° C, and the injection volume was 10 ⁇ L.
  • a Kromasil 100-5-C18 chromatographic column 250mm ⁇ 4.6mm, 5 ⁇ m
  • the mobile phase is acetonitrile as phase A and 0.1% phosphoric acid aqueous solution as phase B
  • gradient elution The flow rate was 1.0 mL ⁇ min-1
  • the detection wavelength was 254 nm
  • the column temperature was (30 ⁇ 0.5) ° C
  • the injection volume was 10 ⁇ L.
  • the genistein is derived from the raw material of the gynecological Qianjin capsule
  • the root of the medicine, palmatine and berberine are derived from the raw material of the gynecological Qianjin capsule
  • the Z-ligustilide and Z- The 3-butenylphthalide comes from the raw material of Angelica sinensis capsules
  • the andrographolide and the dehydroandrographolide come from the raw medicine of Andrographis paniculata capsules.
  • the dosages of angelica, dangshen, andrographis paniculata, and single-sided needles are each 9% of the total amount of gynecological Qianjin capsules; the dosages of Jinyinggen, Codonopsis lanceolata, Gong Gong, and Qianjinba are each 16% of the total amount of gynecological Qianjin capsules. .
  • the invention also protects the application of the gynecology Qianjin capsule in the preparation of medicine for treating gynecological diseases.
  • the gynecological disease is chronic pelvic inflammatory disease, chronic appendicitis or endometritis.
  • the present invention has the following beneficial effects:
  • the present invention establishes a new standard for controlling the quality of gynecological Qianjin capsules by analyzing the chemical components in gynecological Qianjin capsules.
  • This standard adds the limitation of the content of other core components to the existing pharmacopoeia standards.
  • Qianjin capsules the consistency of the effect between different batches is more stable, and as the number of core ingredients is limited, the consistency of the drug effect is more stable; and the gynecological Qianjin capsules provided by the present invention, compared with the prior art, Has better clinical treatment effect.
  • a detection process is added to the preparation process of the product to control genistein, jatrorrhizine, palmatine, berberine, Z -The content of ligustilide and Z-3-butenylphthalide ensures that the content of these six active ingredients in the product is within a certain range, thereby ensuring that the consistency of the drug effect between the different batches is more stable .
  • the present invention adopts the HPLC method for detection, which not only has a high accuracy of the detection result, but also has a fast and simple detection process, which is convenient for the actual production process of the gynecological Qianjin capsule of the present invention, which can be simultaneously detected and monitored in the original preparation process.
  • the content of this active ingredient is conducive to the implementation of the new standard.
  • test methods used in the following examples are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available reagents and materials.
  • the formula of gynecological Qianjin capsules the dosage of Angelica, Codonopsis, Andrographis paniculata and single-sided needles are each 9% of the total amount of medicinal materials; the dosage of Jinyinggen, Coprinus chinensis, Gentiana macrophylla, Gongmu and Qianjinba are each 16% of the total amount of medicinal materials.
  • the total amount of medicinal materials is 500kg.
  • the product is prepared by the following method:
  • Extract andrographis paniculata by ethanol reflux method to make an ointment crush andrographis paniculata through a 100-mesh sieve, add ethanol with a mass concentration of 90% according to the material-liquid ratio of 1: 9, heat to reflux and extract, reflux for 4h, separate the extract, Then, the drug residue is refluxed for 3.5h according to the material-liquid ratio of 1: 8, the extract is separated, the extracts are combined, filtered, and concentrated to obtain a relative density of 1.1 (80 °C), which is Andrographis paniculata;
  • the boiled wood and single-sided needle are boiled and extracted twice.
  • the first time is to add 12 times the total weight of the two flavored Chinese medicines and boil for 4 hours, and the decoction is released;
  • the second time is to add 10 times the total weight of the two flavored Chinese medicines Decoction for 3 hours, the decoction is released, the decoction is combined, filtered, and the filtrate is concentrated to a relative density of 1.1 (80 ° C) at 80 ° C to obtain an ointment of the second flavor medicine;
  • step (5) When the detection results of the mixed ointment in step (5), 6 active ingredients (Z-ligustilide, Z-3-butenylphthalide, genistein, jatrorrhizine, palmatine, berberine When the content of any component in alkali) does not meet the above conditions, some samples are kept for future use.
  • step (5) When the detection results of the mixed ointment in step (5), 6 active ingredients (Z-ligustilide, Z-3-butenylphthalide, genistein, jatrorrhizine, palmatine, berberine When the content of alkali) does not satisfy the above conditions, it is a comparative sample and is reserved.
  • Analysis of the causes of the ointment with fluctuating active ingredient content may be due to the difference in the active ingredient content of the raw materials between different batches.
  • test solution randomly select gynecological Qianjin capsules, take out 1.0g of the contents, place them in a triangular flask with a ground stopper, precisely add 20mL of 75% methanol aqueous solution, weigh, ultrasonically extract for 30min, and wait for normal temperature After that, make up for the loss of quality with 75% methanol aqueous solution, pass through a 0.45 ⁇ m microporous filter membrane, and take the filtrate as the test solution.
  • a Kromasil 100-5-C18 chromatographic column 250mm ⁇ 4.6mm, 5 ⁇ m was used.
  • the mobile phase was acetonitrile (phase A) and 0.1% aqueous phosphoric acid solution (phase B).
  • the wavelength was 254 nm
  • the column temperature was 30 ° C
  • the injection volume was 10 ⁇ L.
  • step (5) controls the content of Z-ligustilide in each milligram of ointment At 0.015 mg, and / or Z-3-butenylphthalide content is not less than 0.00025 mg, and / or genistein content is not less than 0.002 mg, and / or jatrorrhizine content is not less than 0.006
  • the content of mg, and / or palmatine is not less than 0.006mg, and / or the content of berberine is not less than 0.006mg, and the total amount of andrographolide and dehydroandrographolide is not less than 0.015mg, spray After drying, granulation and canning, the gynecological Qianjin capsules are obtained.
  • the content of each milligram of ointment At 0.015 mg, and / or Z-3-butenylphthalide content is not less than 0.00025 mg, and / or genistein content is not less than
  • the gynecological Qianjin capsules were prepared according to the above method, and multiple batches of products were randomly selected from long-term and large-scale products, and each batch of gynecological Qianjin capsule products was tested according to the HPLC detection method in Example 1.
  • Example 1 Six batches were randomly selected from the multiple batch samples tested in Example 1 and six batches were randomly selected in Example 2 for HPLC detection. The test results are shown in Table 1.
  • Table 1 The content of eight components in gynecological Qianjin capsules prepared in Example 1 and Example 2 ( ⁇ g / capsule)
  • Example 1 Choose the balm in which the contents of Z-ligustilide, Z-3-butenylphthalide, genistein, jatrorrhizine, palmatine and berberine in Example 1 do not meet the requirements of Example 1, Directly spray drying, then granulating and canning to obtain the gynecological Qianjin capsules.
  • the content of each gynecological Qianjin capsule is 0.4g.
  • each batch of gynecology Qianjin capsule products were tested by HPLC using the same method.
  • Table 2 The content of eight components in gynecological Qianjin capsules prepared in Comparative Example 1 ( ⁇ g / capsule)
  • Drugs or materials used croton oil, provided by Nanjing Institute of Dermatology; carrageenan, produced by Wako Pure Chemical Industries, Ltd. of Japan; nutrient broth medium, product of Guangdong Huankai Microbiological Technology Co., Ltd .; mold medium, Provided by the China National Institute for the Control of Pharmaceutical and Biological Products.
  • Example 1 Qianjin capsules prepared in Example 1 (Batch 1 and Batch 6) and Comparative Example 1 (Batch 1) were used as samples, respectively.
  • Escherichia coli, Staphylococcus aureus, Streptococcus hemolyticus, and Candida albicans were all isolated from clinical patients and were bacteriologically identified by the bacterial laboratory of the Clinical Laboratory Department of the Third affiliated Hospital of Hunan Medical University.
  • E.coli 32 10 5 ⁇ 10 6 50.0 ⁇ 25.0 Staphylococcus aureus twenty three 10 5 ⁇ 10 6 12.5 ⁇ 3.13 Streptococcus hemolyticus 20 10 5 ⁇ 10 6 50.0 ⁇ 25.0 Candida albicans 27 10 5 ⁇ 10 6 12.5 ⁇ 3.13
  • Table 7 The results of the bacteriostasis experiment of batch 6 gynecology Qianjin capsules of Example 1 on clinical isolation (liquid test tube method)
  • E.coli 32 10 5 ⁇ 10 6 50.0 ⁇ 25.0 Staphylococcus aureus twenty three 10 5 ⁇ 10 6 12.5 ⁇ 3.13 Streptococcus hemolyticus 20 10 5 ⁇ 10 6 50.0 ⁇ 25.0 Candida albicans 27 10 5 ⁇ 10 6 12.5 ⁇ 3.13
  • E.coli 32 10 5 ⁇ 10 6 50.0 ⁇ 25.0 Staphylococcus aureus twenty three 10 5 ⁇ 10 6 12.5 ⁇ 3.13 Streptococcus hemolyticus 20 10 5 ⁇ 10 6 50.0 ⁇ 25.0 Candida albicans 27 10 5 ⁇ 10 6 12.5 ⁇ 3.13
  • Five groups of gynecological Qianjin capsules used in batch 6 of Example 1 and five groups of gynecological Qianjin capsules used in comparative example 1 of batch 1 were dosed at 17.3, 24.7, 35.3, 50.4, and 72.0 g crude drug / kg, respectively.
  • the volume of intragastric administration was 0.5mL / 20g, and each group was injected with 0.5mL of E. coli (10 6FGu / mL) Rongtang broth one hour after the administration. Twelve hours and After 24 hours, dosing twice more, then observe for seven days, and record the number of animal deaths. The peak of animal death is between 24 hours and 48 hours.
  • Drug configuration for use Take the contents of the gynecological Qianjin capsules, and use distilled water to prepare suspensions of different concentrations for mice, and give them intragastric administration once a day. The liquid for intragastric administration is now used.
  • 2% croton oil 20% absolute ethanol, 5% distilled water, and 73% ether
  • Seventy SD rats, male, were divided into seven groups (n 10). They were given different concentrations of liquid by intragastric administration. The control group was given an equal volume of distilled water by intragastric administration once a day for seven days. The last administration was 1 hour. 0.1 mL / carrageenan was injected into the bottom of the plantar of the right foot of the rat to cause inflammation. The drug was given again 2 hours after the inflammation. In addition to measuring the normal foot and plantar size before the inflammation, the foot and plantar size was measured every 1 hour after the inflammation, a total of 6 times, and the degree of swelling was calculated.
  • mice The pain threshold of mice was measured as follows: At room temperature of 20 ⁇ 1 ° C, the mice were placed on a 55 ⁇ 0.5 ° C hot plate, and the time from contacting the hot plate to licking the hind feet was taken as the pain threshold.
  • the pain threshold was measured at 55 ⁇ 0.5 ° C before and 30, 60 and 90 minutes after administration. The results are shown in Table 13.
  • blood was taken to measure the normal values of RBC and HB.
  • each mouse The orbital venous plexus was bleed 0.5 mL.
  • blood was taken to measure the value of RBC and HB in the mice.
  • different doses of medicine were given by gavage once a day for seven days.
  • Blood was taken to measure RBC and HB values. The results are shown in Table 14.
  • Example 1 the Qianjin Capsules of Example 1 and Comparative Example 1 have a minimum inhibitory concentration in vitro against E. coli, Staphylococcus aureus, Hemolytic Streptococcus type B and Candida albicans, as well as the above four clinically isolated bacteria
  • the minimum inhibitory concentration is the same.
  • Example 1 in vivo experiments in mice, the two batches of Example 1 and the gynecological Qianjin Capsule of Comparative Example 1 can significantly inhibit the swelling of mouse ears caused by croton oil and the swelling of rat feet caused by carrageenan;
  • the number of writhings in mice can improve the pain threshold of hot plate-induced painful mice; it can also have a significant blood-enriching effect on mice with hemorrhagic blood deficiency; however, the above-mentioned efficacy of gynecological Qianjin capsules prepared in 2 batches in Example 1 Compared with the gynecological Qianjin capsule of Comparative Example 1, it has a certain degree of improvement, and the effect is better than the gynecological Qianjin capsule of Comparative Example 1.
  • each test site formulated the principles of clinical research, established diagnostic criteria, inclusion criteria, and rejection criteria, and used this as a guide to collect observation cases.
  • the instructions attached to the drug in the use of the drug take the drug at the time of treatment, 7 days as a course of treatment, two consecutive courses of medication, and collect clinical symptoms and physical changes according to the proposed clinical observation form.
  • Table 15 shows the clinical changes of the Second affiliated Hospital of Hunan College of Traditional Chinese Medicine, Hunan Provincial Institute of Traditional Chinese Medicine, and the First affiliated Hospital of Hunan Medical University after taking Qianjin Capsule for 240 patients with chronic pelvic inflammatory disease. There are 80 patients in each group. See Table 15 for specific results.
  • Table 16 to Table 18 list the effect statistics of 240 patients with appendicitis taking gynecological Qianjin capsules, of which Table 16 is the gynecological examination of 240 patients with appendicitis, table 17 efficacy statistics, and Table 18 is the change of symptoms before and after taking gynecological Qianjin capsule behaveing.
  • Example 1 The observation group was given the gynecological Qianjin Capsule of Example 1 (3 batches) and Example 2 (3 batches) on the basis of the blank control group, and the control group was given the comparative example 1 (3 batches) on the basis of the blank control group.
  • Batch) prepared gynecological Qianjin capsules. The treatment results are shown in Table 19-21.
  • the present invention controls genistein, and / or jatrorrhizine, and / or palmatine, and / or
  • the gynecological Qianjin capsules with berberine content have improved the efficacy of gynecological Qianjin capsules in the treatment of endometritis.
  • the specific performance is that the efficiency and obvious efficiency are improved, which means that the control of genistein, and / or jatrorrhizine, and / or With the content of palmatine and / or berberine, Fujin Qianjin Capsule can better interact with antibiotics and progesterone.

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Abstract

一种妇科千金胶囊及其质量控制方法。该胶囊是以千金拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，每粒妇科千金胶囊，含有的Z-藁本内酯不少于2.0mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg。该质量控制方法保证了胶囊的生产质量。通过对妇科千金胶囊中化学成分的分析，建立了控制妇科千金胶囊质量的新标准，该标准在现有的药典标准上，增加了其他核心成分含量的限定，依据该范围制成的妇科千金胶囊，不同批次之间效果一致性更稳定，而且随着核心成分种类限定的越多，药效一致性更为稳定；该妇科千金胶囊具有更好的临床治疗效果。

Description

一种妇科千金胶囊及其质量控制方法 技术领域
本发明涉及中药技术领域，更具体地，涉及一种妇科千金胶囊及其质量控制方法。
背景技术
妇科千金胶囊是由千斤拔、金樱根、穿心莲、功劳木、单面针、当归、鸡血藤、党参8味药材制成的药物。功效为清热除湿，补益气血。用于湿热瘀阻所致的带下病、腹痛，症见带下量多、色黄质稠、臭秽，小腹疼痛，腰骶酸疼，神疲乏力；慢性盆腔炎、子宫内膜炎，慢性宫颈炎见上述证候者。
现有的中国药典中，对于妇科千金胶囊的含量鉴别，仅仅是限定了其中穿心莲内酯与脱水穿心莲内酯的总含量，具体是在每粒胶囊中，含穿心莲以穿心莲内酯(C 20H 30O 5)和脱水穿心莲内酯(C 20H 28O 4)的总量计，不得少于1.6mg。而在妇科千金胶囊的配伍成分中，穿心莲仅仅作为其中的臣药，显然，现有的标准并未对千金胶囊中的其他重要成分进行规定，使得控制妇科千金胶囊不同批次产品之间的效果一致性存在困难。虽然已经通过配方及制备方法获得相对具有一致性的产品，但依然需要一种更有效的手段来提高妇科千金胶囊的治疗效果。
发明内容
本发明要解决的技术问题是克服上述现有技术的缺陷和不足，提供一种妇科千金胶囊及其质量控制方法。所述妇科千金胶囊相对于现有的妇科千金胶囊在效果一致性方面表现更稳定，并且相对于现有的妇科千金胶囊，具有更好的临床治疗效果。
本发明的目的在于提供一种妇科千金胶囊的质量控制方法。
本发明的另一目的是提供一种妇科千金胶囊。
本发明的上述目的是通过以下方案予以实现的：
一种妇科千金胶囊的质量控制方法，包括如下步骤：
以千斤拔、金樱根、穿心莲、当归、功劳木、单面针、鸡血藤和党参为原料；
S1.首先将当归用乙醇渗漉法提取制成清膏；
S2.将穿心莲用乙醇回流法提取制成清膏；
S3.将功劳木、单面针水煮提取两次，经过滤后将两者滤液合并制成清膏；
S4.将千斤拔、金樱根、鸡血藤、党参水煮提取一次后过滤，将过滤后的药渣与步骤S1产生的当归药渣、步骤S2产生的穿心莲药渣以及步骤S3产生的功劳木和单面针药渣一起水煮，过滤，合并滤液并制成清膏；
S5.合并上述S1、S2、S3、S4四种清膏，混匀，控制清膏中Z-藁本内酯和Z-3-丁烯基苯酞中至少一种的含量、以及穿心莲内酯与脱水穿心莲内酯的总量均达到标准含量，进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊。按照2015版《中华人民共和国药典》中的规定，每粒妇科千金胶囊的质量为0.4mg。
所述妇科千金胶囊中，千斤拔、功劳木清热解毒，燥湿止带，共为君药；穿心莲、单面针清热解毒，凉血消肿，燥湿止带，为臣药；鸡血藤、当归养血活血；党参益气健脾，促进水湿运化而止带；金樱根固精止带，共为佐药。
中药复方是一个有层次和结构的有机整体，其功效并不是各单味药的简单加和，而是多个活性成分相互之间共同协作的结果，而现有的药典中对于妇科千金胶囊的标准规定仅限定了穿心莲内酯和脱水穿心莲内酯两种来自于臣药(来自于穿心莲)，而未限定其他有效成分的种类和含量。而在实际生产过程中，由于在质量检测与控制中，仅检测了穿心莲内酯和脱水穿心莲内酯，而未检测其他有效成分的种类和含量。而众所周知，中药材提取物中有效成分的含量是受到药材的种植地域以及提取方法的影响的，因此即使是按照相同的原料配方制备的提取物，其中具体某种有效成分的含量是不相同的。因此，不同批次生产的妇科千金胶囊之间未检测的其他有效成分的含量是不统一的，则导致其药效存在较大的差异。
为了保证在实际生产过程中，制备的妇科千金胶囊的药效一致，发明人经过多次试验发现，除了穿心莲内酯和脱水穿心莲内酯之外，还保证产品中染料木苷、药根碱、巴马汀、小檗碱、Z-藁本内酯和Z-3-丁烯基苯酞这6种有效成分的含量在一定范围内时，生产的产品的效果较好，且不同批次之间的药效具有一致性，并且临床治疗效果得到提升。由于中药制备过程中存在多种影响因素，对于中药中的核心成分含量控制，可以克服不同批次之间，成分含量波动的问题。
优选地，步骤S5中每毫克清膏中Z-藁本内酯的含量不少于0.01mg和/或Z-3-丁烯基苯酞的含量不少于0.00017mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.01mg。
优选地，步骤S5中每毫克清膏中Z-藁本内酯的含量不少于0.015mg和/或Z-3-丁烯基苯酞的含量不少于0.00025mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.015mg。
优选地，步骤S5中每毫克清膏中Z-藁本内酯的含量为0.0165～0.022mg和/或Z-3-丁烯基苯酞的含量为0.00036～0.0006mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.02mg。
一种妇科千金胶囊的质量控制方法，包括如下步骤：
以千斤拔、金樱根、穿心莲、当归、功劳木、单面针、鸡血藤和党参为原料；
S1.首先将当归用乙醇渗漉法提取制成清膏；
S2.将穿心莲用乙醇回流法提取制成清膏；
S3.将功劳木、单面针水煮提取两次，经过滤后将两者滤液合并制成清膏；
S4.将千斤拔、金樱根、鸡血藤、党参水煮提取一次后过滤，将过滤后的药渣与步骤S1产生的当归药渣、步骤S2产生的穿心莲药渣以及步骤S3产生的功劳木和单面针药渣一起水煮，过滤，合并滤液并制成清膏；
S5.合并上述S1、S2、S3、S4四种清膏，混匀，控制清膏中Z-藁本内酯的含量、和/或Z-3-丁烯基苯酞的含量、和/或染料木苷的含量、和/或药根碱的含量、和/或巴马汀的含量、和/或小檗碱的含量、以及穿心莲内酯与脱水穿心莲内酯的总量均达到标准含量，进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊。
优选地，步骤S5中每毫克清膏中染料木苷的含量不少于0.00015mg、药根碱的含量不少于0.0004mg、巴马汀的含量不少于0.00038mg、小檗碱的含量不少于0.0004mg、Z-藁本内酯的含量不少于0.01mg、Z-3-丁烯基苯酞的含量不少于0.00017mg、穿心莲内酯与脱水穿心莲内酯的总量不少于0.01mg。
优选地，步骤S5中每毫克清膏中染料木苷的含量不少于0.0002mg、药根碱的含量不少于0.0006mg、巴马汀的含量不少于0.0006mg、小檗碱的含量不少 于0.0006mg、Z-藁本内酯的含量不少于0.015mg、Z-3-丁烯基苯酞的含量不少于0.00025mg、穿心莲内酯与脱水穿心莲内酯的总量不少于0.015mg。
优选地，S5中控制每毫克清膏中所述染料木苷的含量为0.0025～0.0035mg、药根碱的含量为0.009～0.015mg、巴马汀的含量为0.007～0.01mg、小檗碱的含量为0.0085～0.01mg、Z-藁本内酯的含量为0.0165～0.022mg、Z-3-丁烯基苯酞的含量为0.00036～0.0006mg、穿心莲内酯与脱水穿心莲内酯的总量不少于0.02mg。
优选地，由所述方法制备的每粒所述妇科千金胶囊(按照2015版《中华人民共和国药典》中的规定，每粒妇科千金胶囊的质量为0.4mg)中的染料木苷不少于0.025mg、药根碱不少于0.08mg、巴马汀不少于0.06mg、小檗碱不少于0.08mg、Z-藁本内酯不少于2.0mg、Z-3-丁烯基苯酞不少于0.03mg、穿心莲内酯与脱水穿心莲内酯的总量不少于1.6mg。
优选地，由所述方法制备的每粒所述妇科千金胶囊(按照2015版《中华人民共和国药典》中的规定，每粒妇科千金胶囊的质量为0.4mg)中的染料木苷不少于0.025mg、药根碱不少于0.08mg、巴马汀不少于0.060mg、小檗碱不少于0.08mg、Z-藁本内酯不少于2.0mg、Z-3-丁烯基苯酞不少于0.03mg、穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；
优选地，由所述方法制备的每粒所述妇科千金胶囊(按照2015版《中华人民共和国药典》中的规定，每粒妇科千金胶囊的质量为0.4mg)中的染料木苷不少于0.032mg、药根碱不少于0.12mg、巴马汀不少于0.075mg、小檗碱不少于0.12mg、Z-藁本内酯不少于2.6mg、Z-3-丁烯基苯酞不少于0.04mg、穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg。
优选地，每粒所述妇科千金胶囊中穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
优选地，由所述方法制备的每粒所述妇科千金胶囊中含有0.04～0.06mg的染料木苷、0.165～0.20mg的药根碱、0.090～0.130mg的巴马汀、0.13～0.18mg的小檗碱、3.0～3.65mg的Z-藁本内酯、0.065～0.105mg的Z-3-丁烯基苯酞、穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
优选地，在S5中，所述控制为通过调整S1、S2、S3、S4的提取工艺或原料来源，使得S1～S4的四种清膏混合后的染料木苷、药根碱、巴马汀、小檗碱、Z-藁本内酯和Z-3-丁烯基苯酞的含量达到需要的范围。
步骤S5中采用的检测方法为HPLC检测。
优选地，S5中所述检测步骤为：取1g清膏加200mL 75％甲醇水溶液溶解，再取2mL溶解液用75％甲醇水溶液稀释至10mL，过0.45μm微孔滤膜，取滤液作为待测溶液；采用Kromasil 100-5-C18色谱柱(250mm×4.6mm，5μm)，流动相以乙腈作为A相和0.1％磷酸水溶液作为B相，梯度洗脱，流速为1.0mL·min-1，检测波长为254nm，柱温为30℃，进样量为10μL。
优选地，所述S1的方法为当归粉碎成粗粉，过8目筛，以质量浓度为70％的乙醇浸润，装入渗漉筒中，浸渍48h，以0.2mL/min的速度进行渗漉，收集10倍量的渗漉液，浓缩得到相对密度为1.1(80℃)，即为当归清膏。
优选地，所述S2的方法为：将穿心莲粉碎过100目筛，按照料液比为1：9加入质量浓度为90％的乙醇加热回流提取，回流4h，分离提取液，然后药渣再按照料液比为1：8回流3.5h，分离提取液，合并两次提取液，过滤，浓缩得到相对密度为1.1(80℃)的穿心莲清膏。
优选地，所述S3的方法为将功劳木、单面针水煮提取两次，第一次加两味中药总重量12倍量的水煎煮4h，煎液放出，第二次加10倍量的水，煎煮3小时，煎液放出，合并煎液，滤过，滤液浓缩得到相对密度为1.1(80℃)的清膏。
优选地，所述S4的方法为将千斤拔、金樱根、鸡血藤、党参按照料液比1：10加水煮3.5h，提取一次后过滤，滤液浓缩得到相对密度为1.1(80℃)的清膏，将过滤后的药渣与步骤S2产生的当归药渣、步骤S2产生的穿心莲药渣、步骤S3产生的药渣合并，加4倍体积水煎煮3h，过滤，浓缩得到相对密度为1.1(80℃)的清膏。
优选地，所述染料木苷来自妇科千金胶囊原料药材千斤拔，所述药根碱、巴马汀和小檗碱来自妇科千金胶囊原料药材功劳木，所述Z-藁本内酯和Z-3-丁烯基苯酞来自妇科千金胶囊原料药材当归，所述穿心莲内酯与脱水穿心莲内酯来自妇科千金胶囊原料药材穿心莲。
优选地，当归、党参、穿心莲和单面针的用量各为妇科千金胶囊药材总量的9％；金樱根、鸡血藤、功劳木和千斤拔的用量各为妇科千金胶囊药材总量的16％。
本发明同时还保护由上述质量控制方法制备的妇科千金胶囊及其在制备治疗妇科疾病的药物中的应用。
优选地，所述妇科疾病为慢性盆腔炎、慢性附件炎或子宫内膜炎。
本发明还保护一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，每粒所述妇科千金胶囊含有不少于2.0mg的Z-藁本内酯；优选含有2.6mg的Z-藁本内酯；更优选含有3.0～3.65mg的Z-藁本内酯；
以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；优选地，穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg；优选地，穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，每粒所述妇科千金胶囊含有不少于0.03mg的Z-3-丁烯基苯酞；优选含有不少于0.04mg的Z-3-丁烯基苯酞；优选含有0.065～0.105mg的Z-3-丁烯基苯酞；
以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；优选地，穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg；优选地，穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，每粒所述妇科千金胶囊含有不少于2.0mg的Z-藁本内酯，含有不少于0.03mg的Z-3-丁烯基苯酞；以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；
优选每粒所述妇科千金胶囊含有不少于2.6mg的Z-藁本内酯，含有不少于0.04mg的Z-3-丁烯基苯酞，以及穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg；
优选每粒所述妇科千金胶囊含有3.0～3.65mg的Z-藁本内酯，含有0.065～0.105mg的Z-3-丁烯基苯酞，以及穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，每粒所述妇科千金胶囊(按照2015版《中华人民共和国药典》中的规定，每粒妇科千金胶囊的质量为0.4mg)，含有的染料木苷不少于0.025mg、药根碱不少于0.08mg、巴马汀不少于0.060mg、小檗碱不少于0.08mg、Z-藁本内酯不少于2.0mg、Z-3-丁烯基苯酞不少于0.03mg、穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg。
优选地，每粒所述妇科千金胶囊，含有的染料木苷不少于0.032mg、药根碱不少于0.12mg、巴马汀不少于0.075mg、小檗碱不少于0.12mg、Z-藁本内酯不少于2.6mg、Z-3-丁烯基苯酞不少于0.04mg、穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg。
优选地，每粒所述妇科千金胶囊，穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
优选地，每粒所述妇科千金胶囊，含有0.04～0.06mg的染料木苷、0.165～0.20mg的药根碱、0.090～0.130mg的巴马汀、0.13～0.18mg的小檗碱、3.0～3.65mg的Z-藁本内酯、0.065～0.105mg的Z-3-丁烯基苯酞、穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
优选地，每粒所述妇科千金胶囊，含有0.045～0.056mg的染料木苷、0.175～0.195mg的药根碱、0.10～0.130mg的巴马汀、0.16～0.178mg的小檗碱、3.30～3.65mg的Z-藁本内酯、0.080～0.105mg的Z-3-丁烯基苯酞、2.5～4.15mg的穿心莲内酯、1.0～1.3mg的脱水穿心莲内酯。
另外优选地，所述染料木苷、药根碱、巴马汀、小檗碱、Z-藁本内酯、Z-3-丁烯基苯酞的含量、穿心莲内酯与脱水穿心莲内酯的总量通过HPLC检测确定。
优选地，所述HPLC检测的样品经如下方法制备：取出妇科千金胶囊内容物1.00g，置于三角瓶中，精密加入20mL的75％甲醇水溶液，超声提取(30±5)min，待降至常温后，用75％甲醇水溶液补足减失质量，过0.45μm微孔滤膜，取滤液作为待测溶液。
优选地，所述HPLC检测依照如下条件进行：采用Kromasil 100-5-C18色谱柱(250mm×4.6mm，5μm)，流动相以乙腈作为A相和0.1％磷酸水溶液作为B 相，梯度洗脱，流速为1.0mL·min-1，检测波长为254nm，柱温为(30±0.5)℃，进样量为10μL。
优选地，所述染料木苷来自妇科千金胶囊原料药材千斤拔，所述药根碱、巴马汀和小檗碱来自妇科千金胶囊原料药材功劳木，所述Z-藁本内酯和Z-3-丁烯基苯酞来自妇科千金胶囊原料药材当归，所述穿心莲内酯与脱水穿心莲内酯来自妇科千金胶囊原料药材穿心莲。
优选地，当归、党参、穿心莲和单面针的用量各为妇科千金胶囊药材总量的9％；金樱根、鸡血藤、功劳木和千斤拔的用量各为妇科千金胶囊药材总量的16％。
本发明同时还保护所述妇科千金胶囊在制备治疗妇科疾病的药物中的应用。优选地，所述妇科疾病为慢性盆腔炎、慢性附件炎或子宫内膜炎。
与现有技术相比，本发明具有以下有益效果：
本发明通过对妇科千金胶囊中化学成分的分析，建立了控制妇科千金胶囊质量的新标准，该标准在现有的药典标准上，增加了其他核心成分含量的限定，依据该范围制成的妇科千金胶囊，不同批次之间效果一致性更稳定，而且随着核心成分种类限定的越多，药效一致性更为稳定；并且本发明所提供的妇科千金胶囊，相较于现有技术，具有更好的临床治疗效果。
进一步地，除控制产品中穿心莲内酯与脱水穿心莲内酯的含量外，在产品的制备过程中加入了检测过程，控制产品中染料木苷、药根碱、巴马汀、小檗碱、Z-藁本内酯和Z-3-丁烯基苯酞的含量，保证产品中这6种有效成分的含量在一定范围内，从而保证了不同批次之间的产品的药效一致性更稳定。
同时，本发明采用HPLC方法进行检测，不仅检测结果准确度高，检测过程快速、简单，便于本发明所述妇科千金胶囊的实际生产过程中，在原有的制备工艺中即可同时检测和监控多种有效成分的含量，有利于新标准的执行。
具体实施方式
下面结合具体实施例对本发明做出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1妇科千金胶囊
妇科千金胶囊的配方：当归、党参、穿心莲和单面针的用量各为药材总量的9％；金樱根、鸡血藤、功劳木和千斤拔的用量各为药材总量的16％。药材总量为500kg。通过以下方法制备产品：
(1)首先将当归用乙醇渗漉法提取制成清膏：当归粉碎成粗粉，过8目筛，以质量浓度为70％的乙醇浸润，装入渗漉筒中，浸渍48h，以0.2mL/min的速度进行渗漉，收集10倍量的渗漉液，浓缩得到相对密度为1.1(80℃)，即为当归清膏；
(2)将穿心莲用乙醇回流法提取制成清膏：将穿心莲粉碎过100目筛，按照料液比为1:9加入质量浓度为90％的乙醇加热回流提取，回流4h，分离提取液，然后药渣再按照料液比为1:8回流3.5h，分离提取液，合并提取液，过滤，浓缩得到相对密度为1.1(80℃)，即为穿心莲清膏；
(3)将功劳木、单面针水煮提取两次，第一次加两味中药总重量12倍量的水煎煮4h，煎液放出；第二次加两味中药总重量10倍量的水，煎煮3小时，煎液放出，合并煎液，滤过，滤液浓缩至80℃时相对密度为1.1(80℃)，得二味药的清膏；
(4)将千斤拔、金樱根、鸡血藤、党参按照料液比为1:10加水煮3.5h，提取一次后过滤，滤液浓缩至80℃时相对密度为1.1(80℃)的清膏；然后将过滤后的药渣与步骤(1)产生的当归药渣、步骤(2)产生的穿心莲药渣和步骤(3)产生的功劳木、单面针药渣合并后加4倍体积水煎煮3h，过滤，滤液浓缩至80℃时相对密度为1.1(80℃)的清膏；
(5)合并上述(1)、(2)、(3)、(4)四种清膏，混匀，并进行HPLC检测，控制每毫克清膏中所述Z-藁本内酯的含量不少于0.01mg、和/或Z-3-丁烯基苯酞的含量不少于0.00017mg、和/或染料木苷的含量不少于0.00015mg、和/或药根碱的含量不少于0.0004mg、和/或巴马汀的含量不少于0.0038mg、和/或小檗碱的含量不少于0.0004mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.01mg，进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊，2015版《中华人民共和国药典》的规定，每粒妇科千金胶囊的内容物为0.4g。
当步骤(5)的混合清膏的检测结果中，6种有效成分(Z-藁本内酯、Z-3-丁烯基苯酞、染料木苷、药根碱、巴马汀、小檗碱)中的任一成分的含量不满足上述条件时，保留部分样品备用。
当步骤(5)的混合清膏的检测结果中，6种有效成分(Z-藁本内酯、Z-3-丁烯基苯酞、染料木苷、药根碱、巴马汀、小檗碱)的含量全部不满足上述条件时，为对比样品，备用。
分析有效成分含量波动的清膏产生的原因，可能由于不同批次之间的原料药材有效成分含量不同所致。
参照上述方法进行制备妇科千金胶囊，从长期、大量的产品中随机选取多个批次的产品，并对各批次的妇科千金胶囊产品进行HPLC检测：
供试品溶液的制备：随机选取妇科千金胶囊，取出内容物1.0g，置于具磨口塞的三角瓶中，精密加入20mL的75％甲醇水溶液，称定，超声提取30min，待降至常温后，用75％甲醇水溶液补足减失质量，过0.45μm微孔滤膜，取滤液作为供试品溶液。
采用Kromasil 100-5-C18色谱柱(250mm×4.6mm，5μm)，流动相为乙腈(A相)和0.1％磷酸水溶液(B相)，梯度洗脱，流速为1.0mL·min-1，检测波长为254nm，柱温为30℃，进样量为10μL。
实施例2
一种妇科千金胶囊，其制备过程中步骤(1)至(4)同实施例1，不同之处在于步骤(5)，控制每毫克清膏中所述Z-藁本内酯的含量不少于0.015mg、和/或Z-3-丁烯基苯酞的含量不少于0.00025mg、和/或染料木苷的含量不少于0.002mg、和/或药根碱的含量不少于0.006mg、和/或巴马汀的含量不少于0.006mg、和/或小檗碱的含量不少于0.006mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.015mg，进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊，2015版《中华人民共和国药典》的规定，每粒妇科千金胶囊的内容物为0.4g。
参照上述方法进行制备妇科千金胶囊，从长期、大量的产品中随机选取多个批次的产品，并对各批次的妇科千金胶囊产品参照实施例1中的HPLC检测方法进行检测。
从实施例1检测的多个批次样品中随机挑选6个批次和实施例2中随机挑选6个批次，进行HPLC检测，检测结果见表1所示。
表1实施例1、实施例2制备的妇科千金胶囊中八种成分含量(μg/粒)
Figure PCTCN2020072103-appb-000001
Figure PCTCN2020072103-appb-000002
对比例1妇科千金胶囊
选取实施例1中Z-藁本内酯、Z-3-丁烯基苯酞、染料木苷、药根碱、巴马汀和小檗碱的含量均不符合实施例1要求的清膏，直接进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊，2015版《中华人民共和国药典》的规定，每粒妇科千金胶囊的内容物为0.4g。并对各批次的妇科千金胶囊产品采用相同的方法进行HPLC检测。
检测条件和方法同实施例1，检测结果如表2所示。
表2对比例1制备的妇科千金胶囊中八种成分含量(μg/粒)
  批次1 批次2 批次3 批次4
染料木苷/mg 24.35±0.46 21.33±0.25 24.21±0.23 18.08±1.11
药根碱/mg 71.56±0.16 76.35±1.68 67.84±1.22 58.26±2.63
巴马汀/mg 55.33±1.23 51.32±0.26 48.76±0.25 59.03±1.07
小檗碱/mg 75.10±0.22 54.10±0.42 73.26±0.32 69.16±0.56
穿心莲内酯/mg 1380.26±10.38 1131.26±7.18 1065.56±5.62 1166.61±14.02
脱水穿心莲内酯/mg 568.72±8.85 651.04±0.54 718.24±0.32 562.58±10.22
Z-藁本内酯/mg 1684.02±2.35 1700.34±2.05 1573.36±5.16 1710.25±1.68
Z-3-丁烯基苯酞/mg 23.31±0.24 18.35±1.20 28.15±1.16 25.21±1.67
从表2中可知，按照现有的方法制备的妇科千金胶囊中，除了穿心莲内酯和脱水穿心莲内酯的含量符合药典上的规定外，其他有效成分的含量在批次之间存在较大的差异，容易导致药效的不稳定。
实施例3体外药效试验
采用的药品或材料：巴豆油，由南京皮肤病研究所提供；角叉菜胶，日本和光纯药工业株式会社生产；营养肉汤培养基，广东环凯微生物科技有限公司产品；霉菌培养基，由中国药品生物制品检定所提供。
分别采用实施例1(批次1和批次6)和对比例1(批次1)制备的千金胶囊作为样品。所采用的清洁级昆明种小鼠，SD大鼠均由湖南省药品检验所提供；大肠杆菌ATCC25922，金黄色葡萄球菌ATCC25923，乙型溶血性链菌ATCC32172，均由湖南省卫生防疫站提供，白色念珠菌，由临床分离，由湖南医科大学附三院临床检验科细菌室提供。
1)对标准菌的体外抑菌试验
结果如表3至表5所示。
表3实施例1的批次1妇科千金胶囊抑菌试验结果(液体试管法)
Figure PCTCN2020072103-appb-000003
表4实施例1的批次6妇科千金胶囊抑菌试验结果(液体试管法)
Figure PCTCN2020072103-appb-000004
表5对比例1批次1妇科千金胶囊抑菌试验结果(液体试管法)
Figure PCTCN2020072103-appb-000005
＝＝表示两组重复试验均无细菌生长，+、++、+++分别表示细胞的增长程度
表3至表5实验结果表明：实施例1和对比例1的妇科千金胶囊对大肠杆菌、金黄色葡萄球菌、乙型溶血性链球菌和白色念珠菌的最小抑菌浓度分别为12.5、6.25、12.5、12.5，两者抑菌浓度一致。
2)对临床分离致病菌的体外抑菌实验
大肠杆菌、金黄色葡萄球菌、乙型溶血性链球菌、白色念珠菌均由临床病人分离获得，并经细菌学鉴别，由湖南医科大学附院三院临床检验科细菌室提供。
结果如表6至表8所示。
表6实施例1的批次1妇科千金胶囊对临床分离的抑菌实验结果(液体试管法)
菌株 株数(株) 细菌浓度(GFu/mL) 最小抑菌浓度(％)
大肠杆菌 32 10 5～10 6 50.0～25.0
金黄色葡萄球菌 23 10 5～10 6 12.5～3.13
乙型溶血性链球菌 20 10 5～10 6 50.0～25.0
白色念珠菌 27 10 5～10 6 12.5～3.13
表7实施例1的批次6妇科千金胶囊对临床分离的抑菌实验结果(液体试管法)
菌株 株数(株) 细菌浓度(GFu/mL) 最小抑菌浓度(％)
大肠杆菌 32 10 5～10 6 50.0～25.0
金黄色葡萄球菌 23 10 5～10 6 12.5～3.13
乙型溶血性链球菌 20 10 5～10 6 50.0～25.0
白色念珠菌 27 10 5～10 6 12.5～3.13
表8对比例1批次1妇科千金胶囊对临床分离的抑菌实验结果(液体试管法)
菌株 株数(株) 细菌浓度(GFu/mL) 最小抑菌浓度(％)
大肠杆菌 32 10 5～10 6 50.0～25.0
金黄色葡萄球菌 23 10 5～10 6 12.5～3.13
乙型溶血性链球菌 20 10 5～10 6 50.0～25.0
白色念珠菌 27 10 5～10 6 12.5～3.13
表6至表8实验结果表明：实施例1和对比例1制备的妇科千金胶囊对临床分离的四种细菌有相同的抑制作用，效果一致。
3)体内抑菌实验
对小鼠感染大肠杆菌的保护作用：取昆明种小鼠150只，雌雄兼用，体重20～22g，均分成15组(n＝10)，五组用于实施例1批次1的妇科千金胶囊，五组用于实施例1批次6的妇科千金胶囊，五组用于对比例1批次1的妇科千金胶囊，其剂量分别为17.3、24.7、35.3、50.4和72.0g生药/kg。
灌胃给体积均为0.5mL/20g，各组均在给药后一小时，每只小鼠注射0.5mL大肠杆菌(10 6FGu/mL)容汤培养液，在小鼠感染细菌后12小时和24小时，再给药二次，然后观察七天，记录动物死亡数。动物死亡高峰在24小时后至48小时之间。
表9妇科千金胶囊对大肠杆菌感染小鼠的保护作用
Figure PCTCN2020072103-appb-000006
表9实验结果表明：实施例1和对比例1制备的妇科千金胶囊对大肠杆菌感染小鼠高剂量组均具有一定的保护作用。
4)抗炎作用(对巴豆油所致小鼠肿胀的影响)
待用药物配置：取待用妇科千金胶囊的内容物，分别用蒸馏水配成不同浓度的悬浮液，供小鼠用，每日进行灌胃给药一次，灌胃用药液现配现用。
小鼠100只，雄性，体重24～26g，均分为10组(n＝10)，分别灌胃给予不同浓度的药液，对照组灌胃等体积的蒸馏水，每天一次，共7天，末次给药1小时，每鼠右耳涂2％巴豆油(2％巴豆油、20％无水乙醇、5％蒸馏水和73％乙 醚)0.1mL，所有小鼠左耳不做任何处理；共给药7天，末次给药4小时后颈椎脱臼处死小鼠，剪下双耳，打孔称重，计算每组小鼠肿胀度。
表10妇科千金胶囊对巴豆油所致小鼠耳肿胀的影响(X±SD，n＝10)
Figure PCTCN2020072103-appb-000007
与对照组比较，*P＞0.05，**P＜0.05，***P＜0.01
表10结果表明：实施例1和对比例1制备的妇科千金胶囊与对照组比较，均能明显抑制巴豆油所致小鼠耳肿胀；但实施例1中2个批次的抑制效果明显优于对比例1的妇科千金胶囊。
5)对角叉菜所致大鼠足跖肿胀的影响
SD大鼠70只，雄性，均分为七组(n＝10)，分别灌胃给予不同浓度的药液，对照组灌胃等体积的蒸馏水，每天一次，共七天，末次给药1小时，于大鼠右足跖底部注射角叉菜0.1mL/只致炎。致炎后2小时再给药一次，除测量致炎前正常足跖大小外，致炎后每隔1小时测足跖大小，共6次，计算肿胀度。
表11妇科千金胶囊对大鼠角叉菜所致足跖肿用的影响(X±cm，n＝10)
Figure PCTCN2020072103-appb-000008
与对照组比较，*P＞0.05，**P＜0.05，***P＜0.01
表11结果表明：实施例1和对比例1制备的妇科千金胶囊与对照组比较，均能明显抑制角叉菜所致大鼠足肿胀；但实施例1中2个批次的妇科千金胶囊对于角叉菜所致大鼠足肿胀的抑制作用优于对比例1的妇科千金胶囊，特别是在用药后的3～4h时间段内。
6)对醋酸致痛小鼠的影响
取小鼠100只，雌雄各半，体重20～22g，随机分成10组(n＝10)，分别灌胃给予不同浓度的药液，对照组灌胃等体积的蒸馏水，于给药后一小时，每只小鼠注射0.6％醋酸0.2mL/只。注射5min后开始记录，记录10分钟内小鼠扭体次数。
表12妇科千金胶囊对醋酸致痛小鼠的影响(X±SD，n＝10)
Figure PCTCN2020072103-appb-000009
与对照组比较，**P＜0.05，***P＜0.01
表12结果表明：实施例1和对比例1制备的妇科千金胶囊与对照组比较，均可显著减少醋酸致痛小鼠扭体次数；但实施例1中2个批次的妇科千金胶囊对于醋酸致痛的效果明显优于对比例1的妇科千金胶囊。
7)对热板法致痛小鼠痛阈的影响
小鼠痛阈按照如下方法进行测定：在20±1℃室温条件下，将小鼠置于55±0.5℃热板上，以接触热板至舔后足所经历的时间为痛阈值。
然后取痛阈小于30秒的雌性小鼠100只，体重20-22g，均分成10组(n＝10)，按醋酸致痛小鼠中的剂量一次性灌胃给药，按上述测定方法，在55±0.5℃下测定给药前和给药后30、60和90分钟痛阈值，结果见表13。
表13妇科千金胶囊对热板法致痛小鼠痛阈的影响(X±SD，n＝10)
Figure PCTCN2020072103-appb-000010
Figure PCTCN2020072103-appb-000011
对照组比较，**P＜0.05，***P＜0.01
表13结果表明，实施例1和对比例1制备的妇科千金胶囊与对照组比较，均可明显提高热板激动致痛小鼠的痛阈；但实施例1中2个批次的妇科千金胶囊对热板激动致痛小鼠的痛阈的提高百分率明显高于对比例1的妇科千金胶囊。
8)对失血型血虚小鼠的影响
小鼠110只，雌雄兼用，体重20～22g，均分成11组(n＝10)，首先取血测小鼠RBC和HB的正常值，然后除正常对照组外，其它组每只小鼠从眼眶静脉丛放血0.5mL，24小时后再取血测小鼠RBC和HB的值，然后按灌胃给不同剂量的药，每天一次，共七天，末次给药后24小时，小鼠眼眶静脉丛取血测RBC和HB值，结果见表14。
表14妇科千金胶囊对失血型血虚小鼠的影响(X±SD，n＝10)
Figure PCTCN2020072103-appb-000012
与模型组经比较，*P＜0.05，**P＜0.01
表14结果表明，实施例1和对比例1制备的妇科千金胶囊与对照组比较，均对失血性血虚小鼠具有明显的补血作用；但实施例1中2个批次的妇科千金胶囊对失血性血虚小鼠的补血效果明显高于对比例1的妇科千金胶囊。
综观上述实验结果可见，实施例1和对比例1的千金胶囊对大肠杆菌、黄色葡萄菌、乙型溶血性链球菌和白色念珠菌体外最小抑菌浓度，以及对临床分离的上述四种细菌最小抑菌浓度相同。
但在小鼠体内试验中，实施例1中2个批次、对比例1的妇科千金胶囊能明显抑制巴豆油所致小鼠耳肿胀和角叉菜所致大鼠足肿胀；减少醋酸所致小鼠扭体次数，提高热板法致痛小鼠的痛阈；还能对失血性血虚小鼠具有明显的补血作用；但实施例1中2个批次制备的妇科千金胶囊的上述功效相对于对比例1的妇科千金胶囊具有一定程度的提升，效果优于对比例1的妇科千金胶囊。
实施例4临床使用结果：
为了比较本发明控制了多种有效成分含量的妇科千金胶囊与原有方法制备妇科千金胶囊(即对比例1)的药效是否存在差异，进行了临床试验。各试验点集中统一按照有关新药研究的要求，拟定了临床研究原则、确立了诊断标准、纳入标准、排弃标准，并以此为准则，收集观察病例。同时在使用中遵药品所附说明书的服药方法，就诊时开始服药，7天为一疗程，连续用药二个疗程，并按拟定的临床观察表格收集临床症状和体症变化。
表15为湖南中医学院第二附属医院、湖南省中医研究院、湖南医科大学第一附属医院等应用该药品，对240例患慢性盆腔炎患者服用千金胶囊两个疗程后的临床变化，分为3组，每组80例患者。具体结果见表15。
表15慢性盆腔炎患者治疗好转及所占比例表
Figure PCTCN2020072103-appb-000013
表16～表18列出240例患附件炎病人服用妇科千金胶囊的效果统计，其中表16是240例附件炎患者妇科检查情况、表17疗效统计，表18是服用妇科千金胶囊前后症状的改变情况。
表16附件炎患者妇科检查情况
部位 例数 明显压痛 一般压痛 轻压痛
一侧附件炎 99 30 53 16
双侧附件炎 141 63 60 18
合计 240 93 113 34
表17附件炎患者服用妇科千金胶囊疗效
Figure PCTCN2020072103-appb-000014
表18附件炎患者服用妇科千金胶囊前后症状的改变
Figure PCTCN2020072103-appb-000015
从表15～18中可知，本发明所述妇科千金胶囊在治疗慢性盆腔炎和附件炎方面的效果均优于对比例的妇科千金胶囊，其中实施例批次6的效果优于批次1，实施例批次1的效果由于略优于对比例1批次1。反映除了控制Z-藁本内酯、 Z-3-丁烯基苯酞、穿心莲内酯和脱水穿心莲内酯的含量外，同时还控制染料木苷、药根碱、巴马汀、小檗碱在标准范围内，治疗效果能进一步提升。
实施例5子宫内膜炎临床使用结果
依照治疗慢性盆腔炎展示出来的良好效果，我们还针对治疗子宫内膜炎的疗效进行对比。具体是选取608例子宫内膜炎患者作为研究对象，年龄在30～40岁之间，治疗方案是给与抗生素联合孕激素进行治疗。将0.5g甲硝唑加入到0.9％氯化钠溶液250mL中，静脉滴注，每8小时1次，在月经结束后3日服用甲孕酮，5mg/次，每天2次，服用14日，并以此作为空白对照组。观察组在空白对照组的基础上给予实施例1(3个批次)和实施例2(3个批次)的妇科千金胶囊，对照组在空白对照组的基础上给予对比例1(3个批次)制备的妇科千金胶囊。治疗结果详见表19～21。
评价标准：
显效：临床症状消失，月经恢复正常，超声检查炎症消失；
有效：临床症状好转，超声检查炎症好转，子宫内膜增厚；
无效：未有上述改善。
表19临床疗效比较
Figure PCTCN2020072103-appb-000016
表20月经恢复情况比较
Figure PCTCN2020072103-appb-000017
Figure PCTCN2020072103-appb-000018
表21B超检查恢复比较
Figure PCTCN2020072103-appb-000019
从表19～21的数据可以看出，相较于原来仅控制穿心莲有效成分的妇科千金胶囊，本发明同时控制染料木苷、和/或药根碱、和/或巴马汀、和/或小檗碱含量的妇科千金胶囊，提升了妇科千金胶囊治疗子宫内膜炎的效果，具体表现为有效率及显效率得到提升，说明在控制染料木苷、和/或药根碱、和/或巴马汀、和/或小檗碱含量时，妇科千金胶囊能与抗生素和孕激素有更好的相互配合作用。
从上述实施例和对比例的一致性实验可以看出，在生产过程中，增加对混合清膏试样成分的检测，并控制在合理的范围内，可以使获得的妇科千金胶囊中的8种有效成分的含量控制在合理某一范围内，这样制得的产品批次之间一致性更好，并且临床治疗效果得到提升。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，对于本领域的普通技术人员来说，在上述说明及思路的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (20)

  1. 一种妇科千金胶囊的质量控制方法，其特征在于，包括如下步骤：
    以千斤拔、金樱根、穿心莲、当归、功劳木、单面针、鸡血藤和党参为原料；
    S1.首先将当归用乙醇渗漉法提取制成清膏；
    S2.将穿心莲用乙醇回流法提取制成清膏；
    S3.将功劳木、单面针水煮提取两次，经过滤后将两者滤液合并制成清膏；
    S4.将千斤拔、金樱根、鸡血藤、党参水煮提取一次后过滤，将过滤后的药渣与步骤S1产生的当归药渣、步骤S2产生的穿心莲药渣以及步骤S3产生的功劳木和单面针药渣一起水煮，过滤，合并滤液并制成清膏；
    S5.合并上述S1、S2、S3、S4四种清膏，混匀，控制清膏中Z-藁本内酯和Z-3-丁烯基苯酞中至少一种的含量、以及穿心莲内酯与脱水穿心莲内酯的总量均达到标准含量，进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊。
  2. 根据权利要求1所述方法，其特征在于，步骤S5中每毫克清膏中Z-藁本内酯的含量不少于0.01mg和/或Z-3-丁烯基苯酞的含量不少于0.00017mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.01mg；
    优选地，步骤S5中每毫克清膏中Z-藁本内酯的含量不少于0.015mg和/或Z-3-丁烯基苯酞的含量不少于0.00025mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.015mg。
  3. 根据权利要求2所述方法，其特征在于，步骤S5中每毫克清膏中Z-藁本内酯的含量为0.0165～0.022mg和/或Z-3-丁烯基苯酞的含量为0.00036～0.0006mg、以及穿心莲内酯与脱水穿心莲内酯的总量不少于0.02mg。
  4. 一种妇科千金胶囊的质量控制方法，其特征在于，包括如下步骤：
    以千斤拔、金樱根、穿心莲、当归、功劳木、单面针、鸡血藤和党参为原料；
    S1.首先将当归用乙醇渗漉法提取制成清膏；
    S2.将穿心莲用乙醇回流法提取制成清膏；
    S3.将功劳木、单面针水煮提取两次，经过滤后将两者滤液合并制成清膏；
    S4.将千斤拔、金樱根、鸡血藤、党参水煮提取一次后过滤，将过滤后的药渣与步骤S1产生的当归药渣、步骤S2产生的穿心莲药渣以及步骤S3产生的功劳木和单面针药渣一起水煮，过滤，合并滤液并制成清膏；
    S5.合并上述S1、S2、S3、S4四种清膏，混匀，控制清膏中Z-藁本内酯的含量、和/或Z-3-丁烯基苯酞的含量、和/或染料木苷的含量、和/或药根碱的含量、和/或巴马汀的含量、和/或小檗碱的含量、以及穿心莲内酯与脱水穿心莲内酯的总量均达到标准含量，进行喷雾干燥，然后制粒、罐装，得到所述妇科千金胶囊。
  5. 根据权利要求4所述妇科千金胶囊的质量控制方法，其特征在于，步骤S5中每毫克清膏中染料木苷的含量不少于0.00015mg、药根碱的含量不少于0.0004mg、巴马汀的含量不少于0.00038mg、小檗碱的含量不少于0.0004mg、Z-藁本内酯的含量不少于0.01mg、Z-3-丁烯基苯酞的含量不少于0.00017mg、穿心莲内酯与脱水穿心莲内酯的总量不少于0.01mg；
    优选地，步骤S5中每毫克清膏中染料木苷的含量不少于0.0002mg、药根碱的含量不少于0.0006mg、巴马汀的含量不少于0.0006mg、小檗碱的含量不少于0.0006mg、Z-藁本内酯的含量不少于0.015mg、Z-3-丁烯基苯酞的含量不少于0.00025mg、穿心莲内酯与脱水穿心莲内酯的总量不少于0.015mg。
  6. 根据权利要求5所述妇科千金胶囊的质量控制方法，其特征在于，S5中控制每毫克清膏中所述染料木苷的含量为0.0025～0.0035mg、药根碱的含量为0.009～0.015mg、巴马汀的含量为0.007～0.01mg、小檗碱的含量为0.0085～0.01mg、Z-藁本内酯的含量为0.0165～0.022mg、Z-3-丁烯基苯酞的含量为0.00036～0.0006mg、穿心莲内酯与脱水穿心莲内酯的总量不少于0.02mg。
  7. 根据权利要求5所述妇科千金胶囊的质量控制方法，其特征在于，由所述方法制备的每粒所述妇科千金胶囊，含有的染料木苷不少于0.025mg、药根碱不少于0.08mg、巴马汀不少于0.06mg、小檗碱不少于0.08mg、Z-藁本内酯不少于2.0mg、Z-3-丁烯基苯酞不少于0.03mg、穿心莲内酯与脱水穿心莲内酯的总量不少于1.6mg。
  8. 根据权利要求5所述妇科千金胶囊的质量控制方法，其特征在于，由所述方法制备的每粒所述妇科千金胶囊，含有的染料木苷不少于0.025mg、药根碱不少于0.08mg、巴马汀不少于0.060mg、小檗碱不少于0.08mg、Z-藁本内酯 不少于2.0mg、Z-3-丁烯基苯酞不少于0.03mg、穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；
    优选地，由所述方法制备的每粒所述妇科千金胶囊，含有的染料木苷不少于0.032mg、药根碱不少于0.12mg、巴马汀不少于0.075mg、小檗碱不少于0.12mg、Z-藁本内酯不少于2.6mg、Z-3-丁烯基苯酞不少于0.04mg、穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg。
  9. 根据权利要求6所述妇科千金胶囊的质量控制方法，其特征在于，由所述方法制备的每粒所述妇科千金胶囊中含有0.04～0.06mg的染料木苷、0.165～0.20mg的药根碱、0.090～0.130mg的巴马汀、0.13～0.18mg的小檗碱、3.0～3.65mg的Z-藁本内酯、0.065～0.105mg的Z-3-丁烯基苯酞、穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
  10. 根据权利要求1至9所述妇科千金胶囊的质量控制方法，其特征在于，步骤S5中采用的检测方法为HPLC检测；
    优选地，步骤S5中所述检测步骤为：取1g清膏加200mL 75％甲醇水溶液溶解，再取2mL溶解液用75％甲醇水溶液，超声提取(30±5)min，待降至常温后，用75％甲醇水溶液补足减失质量，过0.45μm微孔滤膜，取滤液作为待测溶液；
    优选地，步骤S5中HPLC检测条件为：采用Kromasil 100-5-C18色谱柱(250mm×4.6mm，5μm)，流动相以乙腈作为A相和0.1％磷酸水溶液作为B相，梯度洗脱，流速为1.0mL·min，检测波长为254nm，柱温为(30±0.5)℃，进样量为10μL；
    优选地，在S5中，所述控制为通过调整S1、S2、S3、S4的提取工艺或原料来源，使得S1～S4的四种清膏混合后的染料木苷、药根碱、巴马汀、小檗碱、Z-藁本内酯和Z-3-丁烯基苯酞的含量达到需要的范围。
  11. 一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，其特征在于，每粒所述妇科千金胶囊含有不少于2.0mg的Z-藁本内酯；优选含有不少于2.6mg的Z-藁本内酯；更优选含有3.0～3.65mg的Z-藁本内酯；
    以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；优选地，穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg；更优选穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
  12. 一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，其特征在于，每粒所述妇科千金胶囊含有不少于0.03mg的Z-3-丁烯基苯酞；优选含有不少于0.04mg的Z-3-丁烯基苯酞；优选含有0.065～0.105mg的Z-3-丁烯基苯酞；
    以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；优选穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg；更优选穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
  13. 一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，其特征在于，每粒所述妇科千金胶囊含有不少于2.0mg的Z-藁本内酯，含有不少于0.03mg的Z-3-丁烯基苯酞；以及穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg；
    优选地，每粒所述妇科千金胶囊含有不少于2.6mg的Z-藁本内酯，含有不少于0.04mg的Z-3-丁烯基苯酞，以及穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg；
    更优选地，每粒所述妇科千金胶囊含有3.0～3.65mg的Z-藁本内酯，含有0.065～0.105mg的Z-3-丁烯基苯酞，以及穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
  14. 一种妇科千金胶囊，以千斤拔、功劳木、穿心莲、单面针、鸡血藤、当归、党参、金樱根为原料制成，其特征在于，每粒所述妇科千金胶囊，含有的染料木苷不少于0.025mg、药根碱不少于0.08mg、巴马汀不少于0.060mg、小檗碱不少于0.08mg、Z-藁本内酯不少于2.0mg、Z-3-丁烯基苯酞不少于0.03mg、穿心莲内酯与脱水穿心莲内酯的总量不少于1.9mg。
  15. 根据权利要求14所述妇科千金胶囊，其特征在于，每粒所述妇科千金胶囊，含有的染料木苷不少于0.032mg、药根碱不少于0.12mg、巴马汀不少于0.075mg、小檗碱不少于0.12mg、Z-藁本内酯不少于2.6mg、Z-3-丁烯基苯酞不少于0.04mg、穿心莲内酯与脱水穿心莲内酯的总量不少于2.5mg。
  16. 根据权利要求15所述妇科千金胶囊，其特征在于，每粒所述妇科千金胶囊，含有0.04～0.06mg的染料木苷、0.165～0.20mg的药根碱、0.090～0.130mg的巴马汀、0.13～0.18mg的小檗碱、3.0～3.65mg的Z-藁本内酯、0.065～0.105mg的Z-3-丁烯基苯酞、穿心莲内酯与脱水穿心莲内酯的总量不少于3.5mg。
  17. 根据权利要求11～16任一项所述妇科千金胶囊，其特征在于，所述染料木苷、药根碱、巴马汀、小檗碱、Z-藁本内酯、Z-3-丁烯基苯酞的含量、穿心莲内酯与脱水穿心莲内酯的总量通过HPLC检测确定。
  18. 根据权利要求17所述妇科千金胶囊，其特征在于，所述HPLC检测的样品经如下方法制备：取出妇科千金胶囊内容物1.00g，置于三角瓶中，精密加入20mL的75％甲醇水溶液，超声提取(30±5)min，待降至常温后，用75％甲醇水溶液补足减失质量，过0.45μm微孔滤膜，取滤液作为待测溶液；
    优选地所述HPLC检测依照如下条件进行：采用Kromasil 100-5-C18色谱柱(250mm×4.6mm，5μm)，流动相以乙腈作为A相和0.1％磷酸水溶液作为B相，梯度洗脱，流速为1.0mL·min-1，检测波长为254nm，柱温为(30±0.5)℃，进样量为10μL。
  19. 根据权利要求11至16任一所述所述妇科千金胶囊，其特征在于，所述当归、党参、穿心莲和单面针的用量各为妇科千金胶囊药材总量的9％；金樱根、鸡血藤、功劳木和千斤拔的用量各为妇科千金胶囊药材总量的16％。
  20. 权利要求11至16任一所述妇科千金胶囊在制备治疗妇科疾病中的应用。
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