WO2022134245A1 - 一种清热解表中药组合物及其制备方法 - Google Patents

一种清热解表中药组合物及其制备方法 Download PDF

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WO2022134245A1
WO2022134245A1 PCT/CN2021/072050 CN2021072050W WO2022134245A1 WO 2022134245 A1 WO2022134245 A1 WO 2022134245A1 CN 2021072050 W CN2021072050 W CN 2021072050W WO 2022134245 A1 WO2022134245 A1 WO 2022134245A1
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volatile oil
preparation
chinese medicine
traditional chinese
parts
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French (fr)
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刘景萍
刘全国
陈克领
吴育强
郑国菊
王家
李党
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海南葫芦娃药业集团股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/532—Agastache, e.g. giant hyssop
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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)
    • A61K36/195—Strobilanthes
    • 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)
    • A61K36/27—Asclepiadaceae (Milkweed family), e.g. hoya
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/287—Chrysanthemum, e.g. daisy
    • 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)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A61K36/315—Isatis, e.g. Dyer's woad
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/534—Mentha (mint)
    • 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)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A61K36/634—Forsythia
    • 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)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • 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)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • 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)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A61K36/815—Lycium (desert-thorn)
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/85—Verbenaceae (Verbena family)
    • A61K36/855—Clerodendrum, e.g. glorybower
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps

Definitions

  • the invention relates to the technical field of traditional Chinese medicine preparations, in particular to a traditional Chinese medicine composition for clearing away heat and relieving external appearance and a preparation method thereof.
  • Xiaoer Ganmao Granules The prescription of Xiaoer Ganmao Granules is included in the 2020 edition of the "Chinese Pharmacopoeia”. It is a traditional Chinese medicine preparation, containing ten kinds of patchouli, forsythia, isatidis, chrysanthemum, Daqingye, rehmannia, Digupi, Baiwei, mint, gypsum, etc.
  • Traditional Chinese medicine has the functions of dispelling wind and relieving the surface, clearing heat and detoxifying, mainly in the treatment of children with wind-heat cold, symptoms of fever, headache, cough with sticky phlegm, sore throat, flu and other aspects.
  • the preparation process is as follows: take 25 g of gypsum and Radix Isatidis and pulverize them into fine powder; 100 g of Rehmannia glutinosa, Baiwei, Digupi and gypsum are boiled twice with water for 3 hours for the first time and 1 hour for the second time, combined with decoction, filtered ; Chrysanthemum, Daqingye hot soaked twice, the first time for 2 hours, the second time for 1 hour, combined the leaching solution, filtered; Patchouli, peppermint, Forsythia extract volatile oil, its aqueous solution was filtered, the filtrate and the above two liquids Combine and concentrate to a clear paste with a relative density of 1.30-1.35 (50°C); take 1 part of the clear paste, 2 parts of sucrose powder, and 1 part of dextrin, mix with the above fine powders to make granules, dry, add volatile oil, Mix well and get it.
  • Forsythia suspensa and chrysanthemum are the ministerial medicines in the prescription.
  • Forsythin extracted from forsythia is the main active ingredient
  • flavonoids and volatile oil extracted from chrysanthemum are the main active ingredients.
  • the content is closely related to the efficacy.
  • forsythia distillates and extracts volatile oil
  • chrysanthemum is mostly extracted by water.
  • the content of forsythin and chrysanthemum flavonoids in the product is generally low, resulting in slow efficacy. The treatment effect is not good enough.
  • the present invention aims at the shortcomings of the original Xiaoer Ganmao Granules, and carries out reasonable reforms to provide Xiaoerganmao Granules with good medicinal effect and a preparation method thereof.
  • a preparation method of a traditional Chinese medicine composition for clearing away heat and detoxifying the skin includes the following components: patchouli, chrysanthemum, forsythia, Daqingye, Ban GmbH, Rehmannia glutinosa, Digupi, Baiwei, mint and Gypsum, is characterized in that, comprises the following steps:
  • R2 weigh the components according to the prescription: Patchouli, Chrysanthemum, Forsythia, Daqingye, Ban GmbH, Rehmannia glutinosa, Digupi, Baiwei, Mint, Gypsum;
  • R4 take chrysanthemum and forsythia and soak in ethanol aqueous solution, ultrasonically extract, filter, keep the medicinal residues for use, and recover ethanol from the filtrate to obtain clear paste;
  • step R5 take Daqingye, Rehmannia glutinosa, Baiwei, Digupi, 75-85% gypsum of the recipe and the medicinal residues of step R4, add ethanol aqueous solution for heating and reflux extraction, combine the extracts, filter, after the filtrate is recovered with ethanol, mix with The aqueous solution in step R3 and the clear paste in step R4 are combined, and concentrated to a thick paste with a relative density of 1.25-1.30 at 60°C;
  • step R6 get the volatile oil obtained in step R3 to prepare volatile oil inclusion compound
  • step R8 Take the medicinal material fine powder in step R7 and mix with the auxiliary materials, add the thick paste in step R5, mix well, make granules, and add the volatile oil inclusion compound obtained in step R6 after drying, and mix well to obtain the target product.
  • step R3 the volatile oil extraction method is to add 5 to 8 times of water to extract the volatile oil for 1 to 3 hours.
  • the volume concentration of the ethanol aqueous solution is 55-65%, the addition amount is 10-20 times, the soaking time is 0.5-1 hour, and the ultrasonic extraction time is 1-2 hours. More preferably, the volume concentration of the ethanol aqueous solution is 60%.
  • the reflux extraction is to add 10-15 times the amount of 15-25% v/v ethanol aqueous solution for heating and reflux extraction for more than 2 times, each time for 1-2 hours. More preferably, the volume concentration of the ethanol aqueous solution is 20%.
  • step R6 the method for preparing the volatile oil inclusion compound is as follows: take 8-10 times the weight of volatile oil with hydroxypropyl- ⁇ -cyclodextrin, add water to make a saturated solution, and keep it at a constant temperature of 40°C to 50°C. Under stirring, add volatile oil, continue stirring at constant temperature for 1 to 2 hours, suction filtration, and vacuum dry the clathrate at 35 to 40°C to obtain volatile oil clathrate.
  • the auxiliary materials include sucrose, dextrin and magnesium stearate.
  • the recipe quantities of the raw materials of the traditional Chinese medicine composition are: 75 parts of patchouli, 75 parts of chrysanthemum, 75 parts of forsythia, 125 parts of Daqingye, 75 parts of Ban GmbH, 75 parts of Rehmannia glutinosa parts, 75 parts of Digupi, 75 parts of Baiwei, 50 parts of mint, and 125 parts of gypsum.
  • a traditional Chinese medicine composition for clearing away heat and dispelling skin is prepared by the preparation method of the traditional Chinese medicinal composition for clearing heat and dispelling skin according to any one of the present invention.
  • the present invention improves the content of main components such as forsythin and total chrysanthemum flavonoids in the product, improves the curative effect of the product, shows through the clinical test results, the product of the present invention shows that it is effective in relieving cough, expectorating phlegm and inhibiting the The bacteria and other aspects are slightly better than the products prepared by the traditional method.
  • the clinical test results show that the total effective rate in treating children's colds is over 93%, which is significantly higher than that of the products produced by the traditional preparation method.
  • the volatile oils of Patchouli and Peppermint are made into inclusion products, which can effectively reduce the loss of the volatile oil in the process of storage and transportation of the finished product, improve the stability of the product, and thereby ensure the efficacy. Moreover, using the hydroxypropyl- ⁇ -cyclodextrin inclusion process, the volatile oil inclusion compound has an excellent effect.
  • the present invention utilizes part of the gypsum medicinal material fine powder as the excipient of the granulation process, reduces the addition of raw and auxiliary materials, and saves the production cost.
  • Method 1 Take 50 g of forsythia and chrysanthemum, add 10 times the amount of 60% (v/v) ethanol aqueous solution, soak for 1 h, ultrasonicate for 1 h, filter, recover ethanol from the filtrate, and concentrate to a thick paste.
  • Method 2 take 50 g of forsythia and chrysanthemum, add 10 times the amount of water to soak for 1 h, add ultrasound for 1 h, filter, recover ethanol from the filtrate, and concentrate to a thick paste.
  • Method 3 Take 50 g of forsythia and chrysanthemum, add 10 times the amount of 60% (v/v) ethanol aqueous solution, soak for 1 h, heat under reflux for 1 h, filter, recover ethanol from the filtrate, and concentrate to thick paste.
  • Method 4 take 50 g of forsythia and chrysanthemum, add 10 times the amount of water to soak for 1 h, then heat and reflux for 1 h, filter, recover ethanol from the filtrate, and concentrate to a thick paste.
  • the extracting rates of methods 2 and 4 are all higher, but the contents of total flavonoids and forsythia are all lower, the method 3 is higher, the total flavonoids content and the content of forsythin are lower, and method 1
  • the yield of the paste is low, but the content of total flavonoids and forsythin is relatively high, and the ultrasonic extraction of ethanol solution is safer. Considering comprehensively, ultrasonic extraction is preferred in the present invention.
  • the present invention compares water, 20% (v/v) ethanol aqueous solution, 40% ( v/v) Extraction effect when aqueous ethanol solution is the extraction solvent.
  • Method 1 Take 10g of Daqingye, 10g of Rehmannia glutinosa, 10g of Baiwei, 10g of Digupi and 13g of gypsum, add 10 times the amount of water, heat and reflux for extraction twice, 1 hour each time, filter, centrifuge the filtrate, and take the supernatant liquid.
  • Method 2 Take 10g of Daqingye, 10g of Rehmannia glutinosa, 10g of Baiwei, 10g of Digupi and 13g of gypsum respectively, add 10 times the amount of 20% (v/v) ethanol, heat and reflux for 2 times, 1 hour each time, filter , the filtrate was centrifuged, and the supernatant was taken.
  • Method 3 Take 10g of Daqingye, 10g of Rehmannia glutinosa, 10g of Baiwei, 10g of Digupi and 13g of gypsum respectively, add 10 times the amount of 40% (v/v) ethanol, heat and reflux for extraction twice, 1 hour each time, filter , the filtrate was centrifuged, and the supernatant was taken.
  • the extracts of the three methods all have a certain inhibitory effect on Staphylococcus aureus, Streptococcus pneumoniae, and wherein the bacteriostatic effect of the extract of method 2 is the strongest, therefore, the present invention is preferably 20% (v/v) ) aqueous ethanol solution as the extraction solvent.
  • R2 take by weighing the components according to the following parts by weight: Patchouli 75g, Forsythia 75g, Ban GmbH 75g, Chrysanthemum 75g, Daqingye 125g, Rehmannia glutinosa 75g, Digupi 75g, Baiwei 75g, Peppermint 50g, Gypsum 125g;
  • R4 take chrysanthemum and forsythia and add 10 times the amount of 60% (v/v) ethanol aqueous solution to soak for 0.5 hours, ultrasonically extract for 2 hours, filter, keep the medicinal residues for use, and recover ethanol from the filtrate to obtain clear paste;
  • step R5 take Daqingye, Rehmannia glutinosa, Baiwei, Digupi, 100g of gypsum and the medicinal residues of step R4, add 10 times the amount of 20% (v/v) ethanol aqueous solution, heat and reflux for extraction 2 times, each time for 2 hours, The extracts were combined, filtered, and the filtrate was combined with the aqueous solution of step R3 and the clear paste of step R4 after the ethanol was recovered, and concentrated to a thick paste with a relative density of 1.25 at 60°C;
  • step R6 take the hydroxypropyl- ⁇ -cyclodextrin of 8 times the weight of the volatile oil obtained in step R3, add water to make a saturated solution, under constant temperature stirring at 40 ° C, add the volatile oil, continue stirring at constant temperature for 2 hours, suction filtration, and encapsulation The material was dried under vacuum at 35°C to obtain volatile oil inclusions;
  • step R8 Take the medicinal material fine powder in step R7 and mix it with sucrose, dextrin and magnesium stearate auxiliary materials, add the thick paste in step R5, mix well, make granules, add the volatile oil inclusion compound obtained in step R6 after drying, and mix well , subpackage, and get it.
  • R4 take chrysanthemum and forsythia and add 20 times the amount of 60% (v/v) ethanol aqueous solution to soak for 1 hour, ultrasonically extract for 1 hour, filter, keep the medicinal residues for use, and recover ethanol from the filtrate to obtain clear paste;
  • step R5 take Daqingye, Rehmannia glutinosa, Baiwei, Digupi, 100g of gypsum and the medicinal residues of step R4, add 15 times the amount of 20% (v/v) ethanol aqueous solution and heat and reflux for extraction twice, 1 hour each time, The extracts were combined, filtered, and the filtrate was combined with the aqueous solution of step R3 and the clear paste of step R4 after the ethanol was recovered, and concentrated to a thick paste with a relative density of 1.30 at 60°C;
  • step R6 take the hydroxypropyl- ⁇ -cyclodextrin of 10 times the weight of the volatile oil obtained in step R3, add water to make a saturated solution, under constant temperature stirring at 50 ° C, add volatile oil, continue stirring at constant temperature for 1 hour, suction filtration, and encapsulation The material was dried under vacuum at 40°C to obtain volatile oil inclusions;
  • step R8 Take the medicinal material fine powder in step R7 and mix it with sucrose, dextrin and magnesium stearate auxiliary materials, add the thick paste in step R5, mix well, make granules, add the volatile oil inclusion compound obtained in step R6 after drying, and mix well , subpackage, and get it.
  • R4 take chrysanthemum and forsythia and add 15 times the amount of 60% (v/v) ethanol aqueous solution to soak for 0.5 hours, ultrasonically extract for 1.5 hours, filter, keep the medicinal residues for use, and recover ethanol from the filtrate to obtain clear paste;
  • step R5 take Daqingye, Rehmannia glutinosa, Baiwei, Digupi, 100 g of gypsum and the medicinal residues of step R4, add 12 times the amount of 20% (v/v) ethanol aqueous solution, heat and reflux for extraction twice, the first time is 1.5 hours , the second time for 1 hour, the extracts were combined, filtered, and the filtrate was combined with the water solution of step R3 and the clear paste of step R4 after the ethanol was recovered, and concentrated to a thick paste with a relative density of 1.28 at 60 ° C;
  • step R6 take the hydroxypropyl- ⁇ -cyclodextrin of 9 times the weight of the volatile oil obtained in step R3, add water to make a saturated solution, under constant temperature stirring at 45 ° C, add the volatile oil, continue stirring at constant temperature for 1.5 hours, suction filtration, and encapsulation The material was dried under vacuum at 38°C to obtain volatile oil inclusions;
  • step R8 Take the medicinal material fine powder in step R7 and mix it with sucrose, dextrin and magnesium stearate auxiliary materials, add the thick paste in step R5, mix well, make granules, add the volatile oil inclusion compound obtained in step R6 after drying, and mix well , subpackage, and get it.
  • R3 take 25g of gypsum, isatis root and pulverize it into fine powder
  • mice Kunming mice, clean grade, male and female, body weight 20 ⁇ 2g, provided by the animal room of Guangxi Medical University.
  • mice in each group showed coughing phenomena such as mouth opening and abdominal muscle contraction to varying degrees.
  • the incubation period of cough in mice was significantly prolonged (P ⁇ 0.01 or P ⁇ 0.05), and the number of coughs was reduced (P ⁇ 0.01 or P ⁇ 0.05).
  • the results showed that with the increase of the sample dose of Example 3 of the present invention, the incubation period of coughing in each group of mice was prolonged, and the number of coughs was reduced.
  • the sample of Example 3 of the present invention had a certain antitussive effect, and the effect was better than that of the comparative example. 1 (prepared by traditional method) sample. See Table 4 for details.
  • Fifty Kunming mice were randomly divided into 5 groups: high (12g/kg), medium (6g/kg), and low (3g/kg) three-dose groups, blank control group (with the same volume of 0.9% normal saline) ), the sample of Comparative Example 1 (6g/kg). Oral administration, 1 time/d, for 7 days. 30min after the last administration, each mouse was intraperitoneally injected with 0.02ml/g body weight of 2.5% phenol red NaHCO 3 solution. After 30min, the mice were sacrificed, the trachea was dissected and separated, and each tracheal segment was placed in a pre-filled 1.5ml 5% NaHCO solution. 3.
  • Example 3 of the present invention Compared with the blank control group, the amount of phenol red secretion in the high and medium dose groups of the samples of Example 3 of the present invention and the sample group of Comparative Example 1 (prepared by the traditional method) increased significantly (P ⁇ 0.05 or P ⁇ 0.01).
  • Example 3 of the present invention Although the secretion of phenol red in the sample low-dose group increased to a certain extent, the difference was not statistically significant (P>0.05).
  • the results show that the high and medium dose groups of the samples of Example 3 of the present invention have a certain expectorant effect. See Table 5 for details.
  • a certain number of small test tubes were taken and divided into 10 groups, 10 tubes in each group, and 1 ml of nutrient broth medium was added to each tube of each group.
  • the bacterial suspension diluted to 10 -3 (the number of bacteria per 1mL is about 100 million cfu), each group is added 0.1mL from the first tube to the eighth tube, and 0.1mL of bacterial solution is also added to the tenth tube, and the ninth tube is added.
  • the tube with drug and no bacteria was used as a negative control, and the tenth tube with bacteria solution and no drug was used as a positive control.
  • the small test tubes prepared above were placed in an incubator at 36° C. for 24 to 48 hours, and the presence or absence of bacterial growth in each tube was observed with the naked eye. The results are shown in Table 6.
  • Example 3 of the present invention has inhibitory effects on Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa in vitro, and the antibacterial results of the samples of Example 3 are better than Comparative Example 1 sample. It is shown that the sample of Example 3 of the present invention has a strong bacteriostatic effect on common pathogenic bacteria in the respiratory tract.
  • Example 3 of the present invention after oral administration, can significantly reduce the number of coughs in mice caused by ammonia water, indicating that it has a certain antitussive effect; it has an effect on increasing the phenol red excretion in the lungs of mice , indicating that it has a certain expectorant effect; in vitro antibacterial experiments prove that the sample of Example 3 of the present invention has a certain inhibitory effect on Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa.
  • Example 3 of the present invention has antitussive, expectorant and bacteriostatic effects, and the effect is better than the Xiaoerganmao Granules (Comparative Example 1 sample) produced by the traditional method, indicating that the product preparation method of the present invention effectively improves the effective sex.
  • a total of 120 children with cold and wind-heat syndrome were selected and randomly divided into 2 groups, namely the experimental group and the control group, with 60 cases in each group. Among them, there were 33 males and 27 females in the experimental group, aged 17 months to 8 years, with an average of (5.2 ⁇ 0.8) years, and the course of disease was 1 to 2 days; the control group had 31 males and 29 females, aged 18 months to 8 years, with an average of ( 5.5 ⁇ 0.6) years old, the course of disease is 1-2 days. There was no significant difference in general data between the two groups (P>0.5), which was comparable.
  • test group was treated with the sample of Example 1 of the present invention, orally, 6-12g once for one to three years old, 12-18g once for seven-year-old, and 24g once for eight-year-old, twice a day for 5 consecutive days.
  • control group was treated with the sample of Comparative Example 1 of the present invention, orally, 6-12 g once for one to three years old, 12-18 g once for seven years old, and 24 g once for eight years old, twice a day for 5 consecutive days.
  • SPSS 22.0 statistical software was used for data processing and analysis, and t-test was used at the same time. When P ⁇ 0.05, the difference was statistically significant.
  • Example 1 produced by the preparation method of the present invention is superior to the Xiaoergan Granules (Comparative Example 1 sample) produced by the traditional method in the effect of the preparation method of the present invention on children's cold, indicating that it improves the effectiveness, and is safe and reliable to take, No adverse reactions or side effects.

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Abstract

一种清热解表中药组合物及其制备方法，包括以下步骤：取广藿香、薄荷提取挥发油，得挥发油，蒸馏后的水溶液留用；取菊花、连翘加乙醇水溶液浸泡，超声提取，滤过，药渣留用，滤液回收乙醇，得清膏；取大青叶、地黄、白薇、地骨皮、处方量75～85％的石膏以及上述的药渣，加乙醇水溶液加热回流提取，合并提取液，滤过，滤液回收乙醇后与上述水溶液和清膏合并，浓缩为稠膏；取上述的挥发油制备挥发油包合物；取余量石膏、板蓝根粉碎成细粉，得药材细粉，灭菌后备用；取上述药材细粉与辅料混匀，加入稠膏，混匀，制颗粒，干燥后加入挥发油包合物，混匀，即得。本发明提高了产品中连翘苷、菊花总黄酮含量，提高了产品的疗效。

Description

一种清热解表中药组合物及其制备方法 技术领域
本发明涉及中药制剂技术领域，特别涉及一种清热解表中药组合物及其制备方法。
背景技术
小儿感冒颗粒处方收载于《中国药典》2020年版一部，是中药制剂，含有广藿香、连翘、板蓝根、菊花、大青叶、地黄、地骨皮、白薇、薄荷、石膏等十味中药，具有疏风解表，清热解毒的作用，主要治疗小儿风热感冒，症见发热，头胀痛，咳嗽痰粘，咽喉肿痛，流感等方面疗效显著。其制备工艺为：取石膏25g、板蓝根粉碎成细粉；地黄、白薇、地骨皮、石膏100g加水煎煮二次，第一次3小时，第二次1小时，合并煎液，滤过；菊花、大青叶热浸二次，第一次2小时，第二次1小时，合并浸出液，滤过；广藿香、薄荷、连翘提取挥发油，其水溶液滤过，滤液与以上二液合并，浓缩至相对密度为1.30～1.35(50℃)的清膏；取清膏1份、蔗糖粉2份、糊精1份，与上述细粉混匀，制成颗粒，干燥，加入挥发油，混匀，即得。
方中连翘、菊花为臣药，从连翘中提取的连翘苷为其主要活性成份，从菊花中提取的黄酮类、挥发油为其主要活性成分，连翘苷、菊花黄酮类、挥发油的含量多少与药效密切相关，目前市面上的产品的制备方法中连翘蒸馏提取挥发油、菊花多为水提，产品中的连翘苷、菊花黄酮类的含量普遍较低，导致药效慢，治疗效果不够好。
发明内容
鉴于此，本发明针对原小儿感冒颗粒的不足，进行合理的改革，提供一种药效好的小儿感冒颗粒及其制备方法。
本发明的技术方案是这样实现的：
一种清热解表中药组合物的制备方法，所述中药组合物的原料包括以下组分：广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷和石膏，其特征在于，包括以下步骤：
R1、分别取广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷，净选，干燥；
R2、按处方量称取组分：广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷、石膏；
R3、取广藿香、薄荷提取挥发油，得挥发油，蒸馏后的水溶液留用；
R4、取菊花、连翘加乙醇水溶液浸泡，超声提取，滤过，药渣留用，滤液回收乙醇，得清膏；
R5、取大青叶、地黄、白薇、地骨皮、处方量75～85％的石膏以及步骤R4的药渣，加乙醇水溶液加热回流提取，合并提取液，滤过，滤液回收乙醇后与步骤R3的水溶液、步骤R4的清膏合并，浓缩至60℃相对密度为1.25～1.30的稠膏；
R6、取步骤R3所得的挥发油制备挥发油包合物；
R7、取处方余量石膏、板蓝根粉碎成细粉，灭菌后备用；
R8、取步骤R7的药材细粉与辅料混匀，加入步骤R5的稠膏，混匀，制颗粒，干燥后加入步骤R6得到的挥发油包合物，混匀，制得目标产品。
进一步的，步骤R3中，所述挥发油提取方法为加5～8倍量水提取挥发油1～3小时。
进一步的，步骤R4中，所述乙醇水溶液的体积浓度为55～65％，加入量为10～20倍量，浸泡时间为0.5～1小时，超声提取时间为1～2小时。更优选地，所述乙醇水溶液的体积浓度为60％。
进一步的，步骤R5中，所述回流提取为加10～15倍量15-25％v/v乙醇水溶液加热回流提取2次以上，每次1～2小时。更优选地，所述乙醇水溶液的体积浓度为20％。
进一步的，步骤R6中，所述制备挥发油包合物的方法为：取挥发油重量8～10倍量的羟丙基-β-环糊精，加水制成饱和溶液，在40℃～50℃恒温搅拌下，加入挥发油，继续恒温搅拌1～2小时，抽滤，包结物置35～40℃真空干燥，制得挥发油包结物。
进一步的，步骤R8中，所述辅料包括蔗糖、糊精和硬脂酸镁。
进一步的，按重量份计，所述中药组合物的原料各组分的处方量为：广藿香75份、菊花75份、连翘75份、大青叶125份、板蓝根75份、地黄75份、地骨皮75份、白薇75份、薄荷50份、石膏125份。
一种清热解表中药组合物，由本发明任一项所述的清热解表中药组合物的制备方法制得。
与现有技术相比，本发明的有益效果是：
(1)本发明提高了产品中连翘苷、菊花总黄酮等主要成分的含量，提高了产品的疗效，经临床试验结果表明，本发明产品经药理实验结果表明其在止咳、祛痰和抑菌等方面均略优 于传统方法制备的产品，经临床试验结果表明，其在治疗儿童感冒的总有效率在93％以上，明显高于传统制备方法生产的产品。
(2)本发明将广藿香和薄荷挥发油制成包结物，可有效减少成品在储存、运输等过程中挥发油的损失，提高了产品的稳定性，从而保证了药效。而且，利用羟丙基-β-环糊精包结工艺，制得挥发油包结物效果优。
(3)本发明利用部分石膏药材细粉作为制粒工艺的赋形剂，减少原辅料的加入，节约了生产成本。
具体实施方式
为了更好理解本发明技术内容，下面提供具体实施例，对本发明做进一步的说明。
本发明实施例所用的实验方法如无特殊说明，均为常规方法。
本发明实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
一、提取工艺的研究
主要对菊花、连翘、大青叶、地黄、白薇、地骨皮、石膏(4/5量)等药材的提取工艺进行了筛选。
1.连翘、菊花的提取工艺
本发明曾考察了乙醇浓度、提取方式、提取时间对菊花总黄酮提取率、连翘苷的影响。
1.1提取方式
(1)方法1：取连翘、菊花各50g，加10倍量60％(v/v)乙醇水溶液浸泡1h后超声1h，滤过，滤液回收乙醇，浓缩至稠膏。
(2)方法2：取连翘、菊花各50g，加10倍量水浸泡1h后加超声1h，滤过，滤液回收乙醇，浓缩至稠膏。
(3)方法3：取连翘、菊花各50g，加10倍量60％(v/v)乙醇水溶液浸泡1h后加热回流提取1h，滤过，滤液回收乙醇，浓缩至稠膏。
(4)方法4：取连翘、菊花各50g，加10倍量水浸泡1h后加热回流提取1h，滤过，滤液回收乙醇，浓缩至稠膏。
分别取以上方法所得稠膏，测定其得膏率及总黄酮、连翘苷的含量，结果见表1。
表1不同提取方法对连翘、菊花提取结果
Figure PCTCN2021072050-appb-000001
Figure PCTCN2021072050-appb-000002
由表1可知，方法2、4的提膏率均较高，但是总黄酮、连翘的含量均较低，方法3得膏率较高，总黄酮含量、连翘苷含量较低，方法1得膏率低，但总黄酮含量、连翘苷含量较高，而且乙醇溶液超声提取更为安全，综合考虑，本发明优选超声提取。
1.2乙醇浓度
在以上对比实验结果的基础上，还对乙醇浓度进行了筛选试验，利用方法1，对比了50％(v/v)乙醇、60％(v/v)乙醇、70％(v/v)乙醇，分别测定所得稠膏总黄酮、连翘苷的含量，结果见表2。
表2不同浓度乙醇水溶液对连翘、菊花提取结果
Figure PCTCN2021072050-appb-000003
由表2可知，60％(v/v)乙醇作为提取溶媒时，总黄酮、连翘苷的含量均较高，因此，本发明优选60％(v/v)乙醇作为提取溶媒。
2.大青叶、地黄、白薇、地骨皮、石膏(4/5量)的提取工艺
传统工艺中，大青叶、地黄、白薇、地骨皮、石膏(4/5量)为水提，因此，本发明对比了以水、20％(v/v)乙醇水溶液、40％(v/v)乙醇水溶液为提取溶媒时的提取效果。
方法1：分别取大青叶10g、地黄10g、白薇10g、地骨皮10g、石膏13g，加10倍量水加热回流提取2次，每次1小时，滤过，滤液离心，取上清液。
方法2：分别取大青叶10g、地黄10g、白薇10g、地骨皮10g、石膏13g，加10倍量20％(v/v)乙醇加热回流提取2次，每次1小时，滤过，滤液离心，取上清液。
方法3：分别取大青叶10g、地黄10g、白薇10g、地骨皮10g、石膏13g，加10倍量40％(v/v)乙醇加热回流提取2次，每次1小时，滤过，滤液离心，取上清液。
分别取以上方法所得提取液100μl，进行金黄色葡萄球菌、肺炎球菌的抑菌圈试验，结果见表3。
表3不同提取溶媒提取物对金黄色葡萄球菌、肺炎球菌的抑菌效果
Figure PCTCN2021072050-appb-000004
Figure PCTCN2021072050-appb-000005
由表3可知，三种方法的提取液均对金黄色葡萄球菌、肺炎球菌有一定的抑制作用，其中方法2的提取液的抑菌作用最强，因此，本发明优选20％(v/v)乙醇水溶液作为提取溶媒。
二、清热解表中药组合物的制备方法
实施例1
R1、分别取广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷，净选，干燥；
R2、按以下重量份称取组分：广藿香75g、连翘75g、板蓝根75g、菊花75g、大青叶125g、地黄75g、地骨皮75g、白薇75g、薄荷50g、石膏125g；
R3、取广藿香、薄荷加5倍量水提取挥发油3小时提取挥发油，得挥发油，蒸馏后的水溶液留用；
R4、取菊花、连翘加10倍量60％(v/v)乙醇水溶液浸泡0.5小时，超声提取2小时，滤过，药渣留用，滤液回收乙醇，得清膏；
R5、取大青叶、地黄、白薇、地骨皮、100g的石膏以及步骤R4的药渣，加10倍量20％(v/v)乙醇水溶液加热回流提取2次，每次2小时，合并提取液，滤过，滤液回收乙醇后与步骤R3的水液、步骤R4的清膏合并，浓缩至60℃相对密度为1.25的稠膏；
R6、取步骤R3所得的挥发油重量8倍量的羟丙基-β-环糊精，加水制成饱和溶液，在40℃恒温搅拌下，加入挥发油，继续恒温搅拌2小时，抽滤，包结物置35℃真空干燥，即得挥发油包结物；
R7、取石膏25g、板蓝根粉碎成细粉，灭菌后备用；
R8、取步骤R7的药材细粉与蔗糖、糊精、硬脂酸镁辅料混匀，加入步骤R5的稠膏，混匀，制颗粒，干燥后加入步骤R6得到的挥发油包合物，混匀，分装，即得。
实施例2
R1.分别取广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷，净选，干燥；
R2.按以下重量份称取组分：广藿香75g、连翘75g、板蓝根75g、菊花75g、大青叶125g、地黄75g、地骨皮75g、白薇75g、薄荷50g、石膏125g；
R3、取广藿香、薄荷加8倍量水提取挥发油1小时提取挥发油，得挥发油，蒸馏后的水溶液留用；
R4、取菊花、连翘加20倍量60％(v/v)乙醇水溶液浸泡1小时，超声提取1小时，滤过，药渣留用，滤液回收乙醇，得清膏；
R5、取大青叶、地黄、白薇、地骨皮、100g的石膏以及步骤R4的药渣，加15倍量20％(v/v)乙醇水溶液加热回流提取2次，每次1小时，合并提取液，滤过，滤液回收乙醇后与步骤R3的水液、步骤R4的清膏合并，浓缩至60℃相对密度为1.30的稠膏；
R6、取步骤R3所得的挥发油重量10倍量的羟丙基-β-环糊精，加水制成饱和溶液，在50℃恒温搅拌下，加入挥发油，继续恒温搅拌1小时，抽滤，包结物置40℃真空干燥，即得挥发油包结物；
R7、取石膏25g、板蓝根粉碎成细粉，灭菌后备用；
R8、取步骤R7的药材细粉与蔗糖、糊精、硬脂酸镁辅料混匀，加入步骤R5的稠膏，混匀，制颗粒，干燥后加入步骤R6得到的挥发油包合物，混匀，分装，即得。
实施例3
R1.分别取广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷，净选，干燥；
R2.按以下重量份称取组分：广藿香75g、连翘75g、板蓝根75g、菊花75g、大青叶125g、地黄75g、地骨皮75g、白薇75g、薄荷50g、石膏125g；
R3、取广藿香、薄荷加6倍量水提取挥发油2小时提取挥发油，得挥发油，蒸馏后的水溶液留用；
R4、取菊花、连翘加15倍量60％(v/v)乙醇水溶液浸泡0.5小时，超声提取1.5小时，滤过，药渣留用，滤液回收乙醇，得清膏；
R5、取大青叶、地黄、白薇、地骨皮、100g的石膏以及步骤R4的药渣，加12倍量20％(v/v)乙醇水溶液加热回流提取2次，第一次1.5小时，第二次1小时，合并提取液，滤过，滤液回收乙醇后与步骤R3的水液、步骤R4的清膏合并，浓缩至60℃相对密度为1.28的稠膏；
R6、取步骤R3所得的挥发油重量9倍量的羟丙基-β-环糊精，加水制成饱和溶液，在45℃恒温搅拌下，加入挥发油，继续恒温搅拌1.5小时，抽滤，包结物置38℃真空干燥，即得挥发油包结物；
R7、取石膏25g、板蓝根粉碎成细粉，灭菌后备用；
R8、取步骤R7的药材细粉与蔗糖、糊精、硬脂酸镁辅料混匀，加入步骤R5的稠膏，混匀，制颗粒，干燥后加入步骤R6得到的挥发油包合物，混匀，分装，即得。
对比例1(传统方法)
R1.分别取广藿香、连翘、板蓝根、菊花、大青叶、地黄、地骨皮、白薇、薄荷，净选， 干燥；
R2.按以下重量份称取组分：广藿香75g、连翘75g、板蓝根75g、菊花75g、大青叶125g、地黄75g、地骨皮75g、白薇75g、薄荷50g、石膏125g；
R3、取石膏25g、板蓝根粉碎成细粉；
R4、地黄、白薇、地骨皮、石膏100g加水煎煮二次，第一次3小时，第二次1小时，合并煎液，滤过；
R5、菊花、大青叶热浸二次，第一次2小时，第二次1小时，合并浸出液，滤过；
R6、广藿香、薄荷、连翘提取挥发油，其水溶液滤过，滤液与以上二液合并，浓缩至相对密度为1.30～1.35(50℃)的清膏；
R7、取清膏1份、蔗糖粉2份、糊精1份，与上述细粉混匀，制成颗粒，干燥，加入挥发油，混匀，即得。
四、药理试验
目的：通过考察本发明产品的止咳、祛痰及抑菌作用，为临床用药提供实验依据。
1试验材料
样品：本发明实施例3、对比例1样品。
实验动物：昆明种小鼠，清洁级，雌雄兼用，体质量20±2g，由广西医科大学动物室提供。
2方法与结果
2.1小鼠浓氨水致咳实验
取昆明种小鼠50只，随机分成5组：实施例3样品高(12g/kg)、中(6g/kg)、低(3g/kg)三个剂量组，空白对照组(给同体积0.9％生理盐水)，对比例1样品(6g/kg)。灌胃给药，1次/d，连续7d。末次给药后lh，将小鼠逐一放入4L密闭干燥容器内，恒压喷入25％浓氨水气雾，喷雾5s引咳，观察其咳嗽潜伏期及咳嗽次数(每2min)。
致咳后各组小鼠均出现不同程度的嘴巴张开，腹肌收缩等咳嗽现象，与空白对照组相比，本发明实施例3样品高剂、中、低量组和对比例1样品能显著延长小鼠咳嗽的潜伏期(P＜0.01或P＜0.05)，并减少咳嗽次数(P＜0.01或P＜0.05)。结果表明，随着本发明实施例3样品剂量的增加，各组小鼠咳嗽的潜伏期有所延长，咳嗽次数有所减少，本发明实施例3样品具有一定的止咳作用，且作用优于对比例1(传统方法制备)样品。具体见表4。
表4对浓氨水致小鼠咳嗽反应
Figure PCTCN2021072050-appb-000006
Figure PCTCN2021072050-appb-000007
注：与空白对照组比： *P＜0.05， **P＜0.01
2.3小鼠气管段酚红排泌实验
取昆明种小鼠50只，随机分成5组：样品高(12g/kg)、中(6g/kg)、低(3g/kg)三个剂量组，空白对照组(给同体积0.9％生理盐水)，对比例1样品(6g/kg)。灌胃给药，1次/d，连续7d。末次给药后30min，每只小鼠腹腔注射2.5％酚红NaHCO 3溶液0.02ml/g体质量，30min后处死小鼠，解剖分离气管，将各气管段放入预先盛有1.5ml 5％NaHCO 3溶液的试管中，超声波清洗，使气管段中的酚红完全释放，清洗液离心，取上清液于全波长酶标仪546nm处比色，测定吸光度(A)值，代入酚红标准曲线，计算酚红含量。
与空白对照组比较，本发明实施例3样品高、中剂量组和对比例1(传统方法制备)样品组的酚红分泌量显著增加(P＜0.05或P＜0.01)，本发明实施例3样品低剂量组酚红分泌量虽然有一定程度地增加，但差异无统计学意义(P＞0.05)。结果表明，本发明实施例3样品高、中剂量组有一定的祛痰作用。具体见表5。
表5对小鼠气管段酚红排泄量的影响
Figure PCTCN2021072050-appb-000008
注：与空白对照组比： *P＜0.05， **P＜0.01
2.4抑菌作用
取一定数量的小试管，分为10组，每组10支，分别于各组各管分别加入营养肉汤培养基1ml。1～5组第一个小试管加入本发明实施例3样品溶液(1.0g/ml)1mL，6～10组第一个试管加入对比例1样品(1.0g/ml)1mL，各组混匀后各吸出1mL加入各自第二个小试管中，依次重复进行递减稀释到第九管，第九管混匀后，吸出1mL混合液弃去，第十管不加药液，然后吸取培养24小时稀释至10 -3的菌悬液(每1mL含菌数约为1亿cfu)，各组从第一管到第八管分加紧加入0.1mL，第十管亦加入菌液0.1mL，第九管加药不加菌作为阴性对照，第 十管加菌液不加药作为阳性对照。将上述制备好的小试管置培养箱中36℃培养24～48小时，用肉眼观察各管有无细菌生长，结果详见表6。
表6对实验菌株的抑菌效价
Figure PCTCN2021072050-appb-000009
表6结果表明，本发明实施例3样品和对比例1样品体外对金色葡萄球菌、感冒嗜血杆菌、肺炎球菌和铜绿假单胞菌均有抑制作用，实施例3样品的抑菌结果优于对比例1样品。表明本发明实施例3样品对呼吸道常见致病菌有较强的抑菌作用。
以上药效学试验结果表明，本发明实施例3样品经口服给药，对氨水引起的小鼠咳嗽次数明显减少，表明有一定的止咳作用；对小鼠肺内酚红排出量有增加的作用，表明有一定的祛痰作用；体外抑菌实验证明，本发明实施例3样品对金色葡萄球菌、感冒嗜血杆菌、肺炎球菌和铜绿假单胞菌均有一定的抑制作用。综合上述结果认为，本发明实施例3样品具有止咳、祛痰和抑菌作用，且作用效果优于传统方法生产的小儿感冒颗粒(对比例1样品)，说明本发明产品制备方法有效提高了有效性。
五、临床试验
1.资料与方法
1.1一般资料
选取120例感冒风热证儿童患者，随机分成2组，即试验组与对照组，每组60例。其中试验组男33例，女27例，年龄17月～8岁，平均(5.2±0.8)岁，病程1～2d；对照组男31例，女29例，年龄18月～8岁，平均(5.5±0.6)岁，病程1～2d。两组患者一般资料比较，差异无统计学意义(P＞0.5)，具有可比性。
1.2病例选择
上述病例均符合《中医儿科学(2007年第2版)》中小儿感冒风热证的相关标准。临床症状为：高热，恶寒，少汗，鼻塞或流浊涕，喷嚏，咳嗽痰黄，咽喉红肿，燥热口干，舌质红，苔薄黄，脉浮数或指纹浮紫。血常规检查：外周血细胞正常或减少，中性粒细胞减少，淋巴细胞相对增加；排除肺炎、支气管炎。
1.3.治疗方法
试验组采用本发明实施例1样品治疗，口服，一至三岁一次6～12g，四于七岁一次12～18g，八岁一次24g，一日2次，连续服用5日。对照组采用本发明对比例1样品治疗，口服，一 至三岁一次6～12g，四于七岁一次12～18g，八岁一次24g，一日2次，连续服用5日。
1.4疗效评价
观察两组治疗效果以及不良反应情况。疗效评价标准为：
(1)痊愈：体温恢复正常，感冒症状全部消除；
(2)显效：体温恢复正常，感冒症状基本消除；
(3)有效：体温有所下降，但未恢复正常，感冒症状大部分消除；
(3)无效：体温未恢复或升高，感冒症状无改善。
1.5统计学处理
采用SPSS 22.0统计软件进行数据处理和分析，同时采用t检验，当P<0.05时，表明差异有统计学意义。
2.结果
2.1不良反应和安全性评价
治疗过程中，两组患者均未出现不良反应。
2.2临床疗效比较
见表7。
表7两组临床疗效比较(例)
Figure PCTCN2021072050-appb-000010
3.结论
以上临床试验结果表明，经本发明制备方法生产的实施例1样品在儿童感冒效果上优于传统方法生产的小儿感冒颗粒(对比例1样品)，说明其提高了有效性，且服用安全可靠，无不良反应副作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种清热解表中药组合物的制备方法，其特征在于，包括以下步骤：
    R1、分别取广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷，净选，干燥；
    R2、按处方量称取组分：广藿香、菊花、连翘、大青叶、板蓝根、地黄、地骨皮、白薇、薄荷、石膏；
    R3、取广藿香、薄荷提取挥发油，得挥发油，蒸馏后的水溶液留用；
    R4、取菊花、连翘加乙醇水溶液浸泡，超声提取，滤过，药渣留用，滤液回收乙醇，得清膏；
    R5、取大青叶、地黄、白薇、地骨皮、处方量75～85％的石膏以及步骤R4的药渣，加乙醇水溶液加热回流提取，合并提取液，滤过，滤液回收乙醇后与步骤R3的水溶液、步骤R4的清膏合并，浓缩至60℃相对密度为1.25～1.30的稠膏；
    R6、取步骤R3所得的挥发油制备挥发油包合物；
    R7、取处方余量石膏、板蓝根粉碎成细粉，灭菌后备用；
    R8、取步骤R7的药材细粉与辅料混匀，加入步骤R5的稠膏，混匀，制颗粒，干燥后加入步骤R6得到的挥发油包合物，混匀，制得目标产品。
  2. 根据权利要求1所述的清热解表中药组合物的制备方法，其特征在于，步骤R3中，所述挥发油提取方法为加5～8倍量水提取挥发油1～3小时。
  3. 根据权利要求1所述的清热解表中药组合物的制备方法，其特征在于，步骤R4中，所述乙醇水溶液的体积浓度为55～65％，加入量为10～20倍量，浸泡时间为0.5～1小时，超声提取时间为1～2小时。
  4. 根据权利要求1所述的清热解表中药组合物的制备方法，其特征在于，步骤R5中，所述回流提取为加10～15倍量15-25％v/v乙醇水溶液加热回流提取2次以上，每次1～2小时。
  5. 根据权利要求1所述的清热解表中药组合物的制备方法，其特征在于，步骤R6中，所述制备挥发油包合物的方法为：取挥发油重量8～10倍量的羟丙基-β-环糊精，加水制成饱和溶液，在40℃～50℃恒温搅拌下，加入挥发油，继续恒温搅拌1～2小时，抽滤，包结物置35～40℃真空干燥，制得挥发油包结物。
  6. 根据权利要求3所述的清热解表中药组合物的制备方法，其特征在于，步骤R4中，所述乙醇水溶液的体积浓度为60％。
  7. 根据权利要求4所述的清热解表中药组合物的制备方法，其特征在于，步骤R5中，所述乙醇水溶液的体积浓度为20％。
  8. 根据权利要求1所述的清热解表中药组合物的制备方法，其特征在于，步骤R8中，所述辅料包括蔗糖、糊精和硬脂酸镁。
  9. 根据权利要求1所述的清热解表中药组合物的制备方法，其特征在于，按重量份计，各组分处方量为：广藿香75份、菊花75份、连翘75份、大青叶125份、板蓝根75份、地黄75份、地骨皮75份、白薇75份、薄荷50份、石膏125份。
  10. 一种清热解表中药组合物，其特征在于，由权利要求1-9任一项所述的清热解表中药组合物的制备方法制得。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115040628A (zh) * 2022-07-21 2022-09-13 李庆梅 一种清热解毒的中药组合物及其制备方法
CN116509980A (zh) * 2023-07-03 2023-08-01 北京盛际中医药研究院 一种宣肺理气的中药组合物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102935143A (zh) * 2012-08-06 2013-02-20 江西普正制药有限公司 一种中药复方制剂小儿感冒颗粒的制备方法
CN102961427A (zh) * 2012-12-14 2013-03-13 安徽老炊食品有限公司 野菊花提取工艺、野菊花总黄酮测定方法
CN104383117A (zh) * 2014-12-05 2015-03-04 海南葫芦娃制药有限公司 小儿感冒颗粒及其制备方法
CN105770189A (zh) * 2016-05-10 2016-07-20 葵花药业集团(冀州)有限公司 一种水果味小儿感冒泡腾颗粒及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1762462A (zh) * 2004-09-24 2006-04-26 贵阳云岩西创药物科技开发有限公司 一种治疗小儿感冒的中药制剂及其制备方法
CN1887305A (zh) * 2005-06-28 2007-01-03 安徽省安泰医药生物技术有限责任公司 菊蓝抗流感颗粒的制备方法及质量控制技术
CN101274034B (zh) * 2007-03-27 2011-03-30 北京亚东生物制药有限公司 一种具有疏风解表、清热解毒作用的中药组合物
CN102119978B (zh) * 2007-03-27 2012-10-31 北京亚东生物制药有限公司 具有解表、清热解毒的组合物及其制备、检测方法
CN102133301A (zh) * 2011-03-24 2011-07-27 江苏苏南药业实业有限公司 一种小儿感冒颗粒的制备方法
CN111905024A (zh) * 2020-08-27 2020-11-10 三金集团湖南三金制药有限责任公司 一种小儿感冒颗粒及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102935143A (zh) * 2012-08-06 2013-02-20 江西普正制药有限公司 一种中药复方制剂小儿感冒颗粒的制备方法
CN102961427A (zh) * 2012-12-14 2013-03-13 安徽老炊食品有限公司 野菊花提取工艺、野菊花总黄酮测定方法
CN104383117A (zh) * 2014-12-05 2015-03-04 海南葫芦娃制药有限公司 小儿感冒颗粒及其制备方法
CN105770189A (zh) * 2016-05-10 2016-07-20 葵花药业集团(冀州)有限公司 一种水果味小儿感冒泡腾颗粒及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PENG XIAOXIA, ET AL.: "Process Improvement of Manufacturing Xiao’er Ganmao Granules", CLINICAL JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 17, no. 2, 28 April 2005 (2005-04-28), pages 139 - 140, XP055946286, DOI: 10.16448/j.cjtcm.2005.02.035 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115040628A (zh) * 2022-07-21 2022-09-13 李庆梅 一种清热解毒的中药组合物及其制备方法
CN116509980A (zh) * 2023-07-03 2023-08-01 北京盛际中医药研究院 一种宣肺理气的中药组合物及其制备方法和应用
CN116509980B (zh) * 2023-07-03 2023-10-10 北京盛际中医药研究院 一种宣肺理气的中药组合物及其制备方法和应用

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