CN109364206B - Preparation method and application of active part of apricot and shellfish cough relieving granule - Google Patents

Preparation method and application of active part of apricot and shellfish cough relieving granule Download PDF

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CN109364206B
CN109364206B CN201811203453.9A CN201811203453A CN109364206B CN 109364206 B CN109364206 B CN 109364206B CN 201811203453 A CN201811203453 A CN 201811203453A CN 109364206 B CN109364206 B CN 109364206B
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ethanol
parts
filtering
cough
root
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CN109364206A (en
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肖伟
胡玉梅
杨彪
周宇
黄文哲
曹泽彧
曹亮
柴尧
王振中
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Jiangsu Kanion Pharmaceutical Co Ltd
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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
    • A61K36/17—Gnetophyta, e.g. Ephedraceae (Mormon-tea 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)
    • 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
    • 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)
    • A61K36/34—Campanulaceae (Bellflower family)
    • A61K36/346—Platycodon
    • 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
    • A61K36/484—Glycyrrhiza (licorice)
    • 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
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8966—Fritillaria, e.g. checker lily or mission bells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/904—Stemonaceae (Stemona family), e.g. croomia
    • 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
    • A61P11/10—Expectorants
    • 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
    • A61P11/14—Antitussive agents
    • 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
    • A61K2236/39—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
    • A61K2236/55—Liquid-liquid separation; Phase separation

Abstract

The invention discloses a preparation method of an active site of a granule containing apricot shells and fritillary bulbs for relieving cough, which comprises the following steps: weighing the following raw material medicines according to the compound weight ratio: taking four raw materials of mix-fried ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 4-8 times of 50-80% ethanol for refluxing for 1-3 hours, filtering, and concentrating the filtrate under reduced pressure to obtain clear paste; boiling radix Platycodi, radix Glehniae, semen Oroxyli, Glycyrrhrizae radix and semen Armeniacae amarum for 1-3 hr, filtering, and concentrating the filtrate under reduced pressure to obtain fluid extract; mixing the above two fluid extracts, mixing, purifying with nonpolar macroporous resin chromatography column, eluting with water, 20-35% ethanol solution, and 60-95% ethanol solution as eluent, and collecting 60-95% ethanol eluate. The method provided by the invention can solve the technical problems of single dosage form, large dosage, low content of effective components, inconvenience in clinical administration and the like of the cough-relieving granules containing the apricot seeds and the fritillary, can reduce the production cost and improve the transfer rate of the effective components, and is more suitable for industrial production.

Description

Preparation method and application of active part of apricot and shellfish cough relieving granule
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to an extraction method of an active part of an apricot shell cough relieving granule and application of the active part in preparation of a cough treating medicine, belonging to the technical field of extraction methods of active parts of a traditional Chinese medicine compound.
Background
Cough refers to a disease characterized clinically by the failure of the lung to disperse and descend, the adverse ascending of lung qi, and the impact of the lung on the airways to produce cough with phlegm or expectoration due to external or internal cold. The cause of cough due to exogenous pathogenic factors is the six exogenous pathogenic factors; the cause of internal injury cough is dysfunction of viscera due to internal injury factors such as diet and emotion, and endogenous pathogenic factors. Cough due to exogenous pathogenic factors and cough due to internal injury are both caused by the pathogenic factors obstructing the dispersing and descending of lung qi and forcing the qi to go upwards and downwards. Exogenous cough and endogenous cough can be affected into diseases, and pathogenic excess changes into healthy qi deficiency after long-term treatment. Cough caused by external contraction is often caused by frequent attack of pathogenic factors, such as delayed treatment and pathogenic factor injury to lung qi, and is converted into internal injury cough; the lung is diseased, the wei-defensive aspect is insecure, and the lung is easily triggered or aggravated by exogenous pathogenic factors, especially when the climate changes. Cough is one of the most common diseases in internal medicine, the incidence rate is very high, the incidence rate of chronic cough is counted to be 3% -5%, the incidence rate in the old can reach 10% -15%, and the incidence rate in cold regions is higher. The traditional Chinese medicine has great advantages in treating cough, and accumulates abundant treatment experience.
The cough-relieving granule of the apricot and the shellfish is prepared by taking the local prescription of a Sanao decoction and a Ganju decoction of golden lack as the basis and adding flavor, and is a Chinese medicinal compound preparation which is independently researched and developed by the company and is marketed. Has definite clinical curative effect for more than ten years on the market, and has the efficacies of clearing lung qi, relieving cough and reducing sputum.
The granule is prepared by adding a large amount of diluents and flavoring agents after being extracted by a solvent, has single dosage form, large dosage, easy moisture absorption, low content of effective components and large dosage, and is inconvenient for patients to take. Therefore, it is necessary to extract and refine the original prescription to obtain a compound preparation with high content of effective components and remarkable pharmacodynamic activity, so as to facilitate clinical use.
Disclosure of Invention
Aiming at the technical problems of single dosage form, large dosage of granules, easy moisture absorption, low content of effective components, inconvenient clinical administration and the like of the cough-relieving granules of the apricot and the shellfish in the prior art, the invention aims to provide the cough-relieving granules of the apricot and the shellfish which have low cost and high transfer rate and are suitable for industrial production.
The preparation method of the active site provided by the invention comprises the following steps:
step 1: weighing the following raw material medicines according to the compound weight ratio: 1-3 parts of mix-fried ephedra herb, 1-10 parts of bitter almond, 1-6 parts of platycodon grandiflorum, 1-6 parts of whiteflower hogfennel root, 1-6 parts of thunberg fritillary bulb, 1-6 parts of radix stemonae, 1-3 parts of oroxylum indicum and 1-10 parts of radix glehniae; 1-3 parts of liquorice;
step 2: taking four raw materials of mix-fried ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 4-8 times of 50-80% ethanol for refluxing for 1-3 hours, filtering, and concentrating the filtrate under reduced pressure to obtain clear paste; boiling radix Platycodi, radix Glehniae, semen Oroxyli and Glycyrrhrizae radix, adding semen Armeniacae amarum, boiling, filtering, and concentrating the filtrate under reduced pressure to obtain fluid extract;
and step 3: mixing the two fluid extracts obtained in step 2, mixing, purifying with nonpolar macroporous resin chromatography column, eluting with water, 20-35% ethanol solution, and 60-95% ethanol solution as eluent, and collecting 60-95% ethanol eluate.
Further, the method also comprises the step of drying the eluent obtained in the step 3 to obtain the dried paste of the active parts of the cough relieving granule of the apricot shells.
Preferably, the compound of step 1 is preferably: 1-1.5 parts of honey-fried ephedra herb, 2-4 parts of bitter almond, 1-3 parts of platycodon grandiflorum, 1-3 parts of whiteflower hogfennel root, 1-3 parts of thunberg fritillary bulb, 1-3 parts of sessile stemona root, 1-1.5 parts of oroxylum indicum, 2-4 parts of coastal glehnia root and 1-1.5 parts of liquoric root. More preferably, 1 part of honey-fried ephedra herb, 3.33 parts of bitter apricot seed, 2 parts of platycodon root, 2 parts of whiteflower hogfennel root, 2 parts of thunberg fritillary bulb, 2 parts of sessile stemona root, 1 part of Indian trum etflower seed, 3.33 parts of coastal glehnia root and 1 part of liquoric root.
Specifically, the nonpolar macroporous resin in the step 3 is preferably macroporous resin D101.
Preferably, the reflux extraction of 50-80% ethanol in step 2 is performed 2 times. Among them, the ethanol concentration is more preferably 65 to 75%.
Specifically, the preparation method of the active site of the apricot and shellfish cough relieving granule comprises the following steps:
reflux extraction: weighing the apricot shell cough relieving granule medicinal materials according to the prescription amount, taking 4 raw material medicaments of mix-fried ephedra herb (preferably mix-fried ephedra herb with honey), whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 6 times of 70% ethanol, refluxing for 2 hours, filtering, adding 4 times of 70% ethanol into dregs of a decoction, refluxing for 2 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.07 for later use; adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 1.5 hours, filtering, adding 8 times of water into medicine residues, boiling for 1.5 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.09;
separation and refining: mixing the two fluid extracts, mixing, separating with macroporous resin D101 with the weight of 1:1, eluting the adsorption column with water until the water eluate is colorless, eluting with 30% ethanol solution to remove impurities, and eluting with 95% ethanol solution;
concentrating and drying: concentrating under reduced pressure, recovering 95% ethanol, and spray drying to obtain the active fraction of the granule.
Specifically, the preparation method of the active site of the apricot and shellfish cough relieving granule comprises the following steps:
reflux extraction: weighing the apricot shell cough relieving granule medicinal materials according to the prescription amount, taking 4 raw material medicaments of mix-fried ephedra herb (preferably mix-fried ephedra herb with honey), whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 8 times of 70% ethanol, refluxing for 2 hours, filtering, adding 4 times of 70% ethanol into dregs of a decoction, refluxing for 2 hours, filtering, combining filtrates, and concentrating under reduced pressure at 60 ℃ to obtain clear paste with the relative density of 1.06 for later use; adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 2 hours, filtering, adding 10 times of water into the medicine residues, boiling for 2 hours, filtering, combining the filtrates, and concentrating under reduced pressure at 60 ℃ to obtain clear paste with the relative density of 1.08;
separation and refining: mixing the two fluid extracts obtained in step 1, mixing well, separating with macroporous resin D101, wherein the weight of the resin is 0.8:1, eluting the adsorption column with water until the water eluate is colorless, eluting with 20% ethanol solution to remove impurities, and eluting with 60% ethanol solution;
concentrating and drying: concentrating under reduced pressure, recovering 60% ethanol, and spray drying to obtain the active fraction of the granule.
The invention also provides an active site of the apricot and shellfish cough relieving granule, which is characterized by being prepared by a preparation method of any one of the apricot and shellfish cough relieving granule active sites.
The invention also provides application of any one of the apricot shell cough relieving granule active parts in preparation of cough relieving or phlegm eliminating medicines.
The invention also provides a cough-relieving or phlegm-eliminating medicine which is characterized by being prepared from any one of the apricot shell cough-relieving granule active parts and one or more pharmaceutically acceptable carriers or excipients.
Specifically, the medicament comprises an oral preparation or a dosage form for parenteral administration. The oral preparation is selected from one of tablets, capsules, pills, granules, suspensions, dripping pills and oral liquid preparations; the parenteral administration dosage form is selected from one of injection, aerosol, suppository or subcutaneous administration dosage form. The medicine of the present invention may have conventional medicine excipient, such as solvent, disintegrant, corrective, preservative, coloring agent, etc.
The invention has the following beneficial effects:
the active part of the original formula is prepared by a macroporous resin method, and pharmacodynamic evaluation shows that under the condition of the same crude drug amount, the part can replace the original formula and is convenient to prepare various dosage forms.
The active site of the cough-relieving granule containing the apricot shells and the shellfish is prepared by a macroporous resin method, has low cost and low toxicity, and is suitable for industrial mass production.
The preparation method of the original prescription has the final paste yield of 20.1 percent according to YBZ23862005 standard, and the active part dry paste prepared by the method has the paste yield of about 1.5 percent.
The method of the invention has low paste yield, so the method is convenient for preparing modern medicament forms such as tablets, pills, capsules, sustained-release agents and the like, has small clinical dose of the product, and improves the compliance of patients.
Detailed Description
As described above, the present invention aims to provide a preparation method and an application of an active site of an aibei cough-relieving granule. The following will specifically describe the contents of the experimental examples.
It is specifically noted that similar alternatives and modifications will be apparent to those skilled in the art, which are also intended to be included within the present invention. It will be apparent to those skilled in the art that the techniques of the present invention may be implemented and applied by modifying or appropriately combining the methods and applications described herein without departing from the spirit, scope, and content of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention.
If the specific conditions are not indicated, the method is carried out according to the conventional conditions or the conditions suggested by manufacturers, and the used raw material medicines or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.
Example 1 preparation of an active site of an aiben cough suppressing granule
Prescription: 100g of honey-fried ephedra herb, 333g of bitter almond, 200g of platycodon grandiflorum, 200g of whiteflower hogfennel root, 200g of thunberg fritillary bulb, 200g of radix stemonae, 333g of radix glehniae, 100g of semen oroxyli and 100g of liquorice.
Step one, reflux extraction: weighing the apricot and fritillary cough relieving granule medicinal materials according to the prescription amount, taking 4 kinds of raw material medicines of ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 6 times of 70% ethanol for reflux extraction for 2 times, 2 hours each time, filtering, adding 4 times of 70% ethanol into medicine dregs, refluxing for 2 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.07(60 ℃) for later use. Adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 1.5 hours, filtering, adding 8 times of water into medicine dregs, boiling for 1.5 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.09(60 ℃).
Step two, separation and refining: combining the two clear pastes obtained in the step one, mixing uniformly, and separating by adopting macroporous resin D101, wherein the weight of the resin is as follows: the weight of the medicinal materials is 1:1, the adsorption column is firstly eluted by water until water eluent is colorless, then, 4 column volumes are eluted by 20 percent ethanol solution for removing impurities, and then, 6 column volumes are eluted by 60 percent ethanol solution.
Step three, concentrating and drying: concentrating under reduced pressure, recovering 60% ethanol, and spray drying at inlet temperature of 80 deg.C and outlet temperature of 150 deg.C to obtain active components of the granule with a paste yield of 1.53%.
Example 2 preparation of an active site of an aiben cough suppressing granule
Prescription: 100g of honey-fried ephedra herb, 333g of bitter almond, 200g of platycodon grandiflorum, 200g of whiteflower hogfennel root, 200g of thunberg fritillary bulb, 200g of radix stemonae, 333g of radix glehniae, 100g of semen oroxyli and 100g of liquorice.
Step one, reflux extraction: weighing the apricot and fritillary cough relieving granule medicinal materials according to the prescription amount, taking 4 kinds of raw material medicines of ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 8 times of 70% ethanol for reflux extraction for 2 times, 2 hours each time, filtering, adding 4 times of 70% ethanol into medicine dregs, refluxing for 2 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.06(60 ℃) for later use. Adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 2 hours, filtering, adding 10 times of water into the medicine residues, boiling for 2 hours, filtering, combining the filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.08(60 ℃).
Step two, separation and refining: combining the two clear pastes obtained in the step one, mixing uniformly, and separating by adopting macroporous resin D101, wherein the weight of the resin is as follows: the weight of the medicinal materials is 0.8:1, the adsorption column is firstly eluted by water until water eluent is colorless, then, ethanol solution with the concentration of 30% is adopted for eluting 8 column volumes for removing impurities, and then ethanol solution with the concentration of 95% is adopted for eluting 4 column volumes.
Step three, concentrating and drying: concentrating under reduced pressure, recovering 95% ethanol, and spray drying at inlet temperature of 85 deg.C and outlet temperature of 150 deg.C to obtain active components of the granule with a paste rate of 1.48%. Comparative example preparation method of 150% ethanol elution site
Prescription: 100g of honey-fried ephedra herb, 333g of bitter almond, 200g of platycodon grandiflorum, 200g of whiteflower hogfennel root, 200g of thunberg fritillary bulb, 200g of radix stemonae, 333g of radix glehniae, 100g of semen oroxyli and 100g of liquorice.
Step one, reflux extraction: weighing the apricot and fritillary cough relieving granule medicinal materials according to the prescription amount, taking 4 kinds of raw material medicines of ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 6 times of 70% ethanol for reflux extraction for 2 times, 2 hours each time, filtering, adding 4 times of 70% ethanol into medicine dregs, refluxing for 2 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.07(60 ℃) for later use. Adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 1.5 hours, filtering, adding 8 times of water into medicine dregs, boiling for 1.5 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.09(60 ℃).
Step two, separation and refining: combining the two clear pastes obtained in the step one, mixing uniformly, and separating by adopting macroporous resin D101, wherein the weight of the resin is as follows: the weight of the medicinal materials is 1:1, the adsorption column is firstly eluted by water until water eluent is colorless, then 20% ethanol solution is adopted for eluting 4 column volumes to remove impurities, and then 50% ethanol is adopted for eluting 6 column volumes.
Step three, concentrating and drying: concentrating under reduced pressure, recovering ethanol, and spray drying at inlet temperature of 80 deg.C and outlet temperature of 150 deg.C to obtain dried extract of 50% ethanol elution part.
Experimental example 1 cough-relieving experiment of each extracted part
Mouse ammonia cough-inducing method: taking SPF grade ICR healthy mice, weighing 18-22 g, randomly dividing the mice into 8 groups, each group containing 10 mice and each half of the mice. Namely, a model group (0.5% of CMC-Na), a positive control group (pentoxyverine tablets), a apricot seed cough relieving granule group (commercial apricot seed cough relieving granules), a water washing group (dry paste obtained by treating the water eluent in the second step of the example 2), a 30% ethanol elution group (dry paste obtained by treating the 30% ethanol eluent in the second step of the example 2), a 50% ethanol elution group (dry paste of the 50% ethanol elution part in the comparative example 1), an active part group in the example 1 and an active part group in the example 2. Wherein the dosage of the group of the granule comprises semen Armeniacae amarum, water washing group, 30% ethanol eluting group, 50% ethanol eluting group, example 1 active group, and example 2 active groupAll are 16g crude drug/kg-1The administration is continued for 3 days, and the administration is carried out 1 time per day at a ratio of 8:00-10:00 per day. Fasting is carried out for 12h before the last administration, the mice are placed in a self-made closed glass container after the last administration for 1h, and the cough latency time of the mice and the cough frequency within 3min from the spraying are recorded after concentrated ammonia water is sprayed into the mice by an ultrasonic atomizer for 20 s. The results are shown in Table 1.
The calculation formula is as follows:
Figure BDA0001830604770000071
Figure BDA0001830604770000072
TABLE 1 medicinal effect test result of cough relieving medicine for each part of the granule (n is 10)
Figure BDA0001830604770000073
Figure BDA0001830604770000081
Note: p <0.05 compared to model group; p <0.01 compared to model group;
as can be seen from table 1, the active sites of the cough-relieving granules of apricots and fritillary in examples 1 and 2 are very different from those of the model group, the cough latency is significantly prolonged, the number of coughs within 3min is significantly reduced, and the cough prolonging rate and the cough suppressing rate are significantly increased, which indicates that the active sites of the cough-relieving granules of apricots and fritillary have significant cough-relieving effect, the cough prolonging rate is substantially equivalent to that of the cough-relieving granules of apricots and fritillary, and the cough suppressing rate is significantly better than that of the other groups.
Experimental example 2 phlegm eliminating experiment of each extracted part
Taking SPF grade ICR healthy mice, weighing 20-22g, randomly dividing into 8 groups, each group comprises 10 mice, and each group is male and female. Namely a model group (0.5 percent of CMC-Na), a positive control group (ambroxol hydrochloride) and apricot shell cough relieving granulesGranule group (commercial granule of Aibei cough relieving granule), water washing group (dry extract obtained after water eluent treatment in the second step of example 2), 30% ethanol elution group (dry extract obtained after 30% ethanol eluent treatment in the second step of example 2), 50% ethanol elution group (dry extract of 50% ethanol elution part in the second step of comparative example), example 1 active part group, and example 2 active part group. Wherein the dosage of the granule, water washing fraction, 30% ethanol eluting fraction, 50% ethanol eluting fraction, the active fraction of example 1, and the active fraction of example 2 is 12g crude drug/kg-1The administration is continued for 3 days, and the administration is carried out 1 time per day at a ratio of 8:00-10:00 per day. Fasting is not prohibited for 12 hours before the last administration, after the last administration for 30min, 2.5% phenol red physiological saline solution is injected into the abdominal cavity of each mouse for 0.1mL/10g, after 30min, cervical vertebra is removed to kill the mouse, the mouse is fixed at the back, the trachea is separated, a No. 7 needle with a tip cut off is inserted into the trachea for about 0.4cm under the larynx, the needle is ligated and fixed by a No. 4 silk thread, 1mL of 5% sodium bicarbonate solution is absorbed by a 5mL syringe, the respiratory tract is washed back and forth for 3 times, the lavage fluid is injected into the test tube, the respiratory tract is sequentially lavaged by 2mL of 5% sodium bicarbonate solution for 3 times, the lavage fluid is merged for 3 times, after the test tube is kept still for 30min, the supernatant is absorbed, and the absorbance is measured at the position of 545nm by. The standard curve range of the prepared phenol red is 50.00-1.25 mu g/mL-1And (3) according to a standard curve equation, calculating the respiratory phenol red output of each mouse, comparing the phenol red output of each group of mice, namely the sputum output, and calculating the sputum elimination index.
Figure BDA0001830604770000091
TABLE 2 phlegm eliminating effect experiment results of each part of the Xingbei cough relieving granule (n is 10)
Figure BDA0001830604770000092
Note: p <0.05 compared to model group; comparison with model group P <0.01
As can be seen from Table 2, the comparison between the active site of the cough-relieving granule of apricot and shellfish and the model group shows that the active site of the cough-relieving granule of apricot and shellfish has very significant difference, the excretion amount of phenol red and the expectoration index are both significantly improved, and the effect is superior to that of other groups, which shows that the active site of the cough-relieving granule of apricot and shellfish has better expectoration effect.
Experimental example 3 method for preparing different dosage forms from active parts of cough-relieving granules of apricot shells and shellfish
The active site of the cough-relieving granule containing the apricot shells and the shellfish can be added with various conventional auxiliary materials for preparing different dosage forms so as to prepare any clinically acceptable dosage form prepared by one or more pharmaceutically acceptable carriers or excipients, including oral preparations or parenteral administration dosage forms. Such as tablet, capsule, injection, aerosol, dripping pill, etc.
1) Preparation of capsules: taking 100g of the active part extract, adding 180g of starch and 60g of dextrin, adding 1g of magnesium stearate, uniformly mixing, adding a proper amount of 75% ethanol, fully and uniformly stirring, preparing into a soft material, sieving through a 20-30-mesh sieve, preparing into granules, drying at low temperature, grading, and quantitatively transferring into hard capsules.
2) Preparation of tablets: taking 100g of the active part extract, adding 80g of starch, 50g of dextrin and 50g of microcrystalline cellulose, adding a proper amount of starch slurry to prepare a soft material, granulating, drying, sieving, adding 1g of superfine silica gel powder, and tabletting to obtain the traditional Chinese medicine composition.
3) Preparation of injection: dissolving the active part extract with 25 times of water for injection, adjusting pH to 7, adsorbing with activated carbon, filtering with 0.22um filter membrane, bottling, and sterilizing at high temperature.
4) Preparing the dripping pill: adding 100g of active site extract into 250g of octadecanol, placing in an evaporating dish, heating in water bath until the active site extract is completely melted, adding borneol, stirring until the borneol is melted, and keeping the temperature of the liquid medicine at 80-85 ℃; adding appropriate amount of cooling agent PEG6000 into the cooling column, cooling the outer wall with cold water, adjusting the distance between the outlet of the dropper and the cooling agent, and controlling the dropping speed to be 30-35 drops per minute, and the weight of each granule is 50 mg. Cooling and drying to obtain the product.
5) Preparation of the powder: 100g of active part extract, 200g of dextrin and 50g of microcrystalline cellulose are added, the mixture is crushed into fine powder by a crusher, the fine powder is sieved, a proper amount of magnesium stearate is added, and the mixture is packaged according to the dosage to obtain the oral liquid.

Claims (10)

1. A preparation method of an active site of an apricot and shellfish cough relieving granule comprises the following steps:
step 1: weighing the following raw material medicines according to the compound weight ratio: 1-3 parts of mix-fried ephedra herb, 1-10 parts of bitter almond, 1-6 parts of platycodon grandiflorum, 1-6 parts of whiteflower hogfennel root, 1-6 parts of thunberg fritillary bulb, 1-6 parts of radix stemonae, 1-3 parts of oroxylum indicum and 1-10 parts of radix glehniae; 1-3 parts of liquorice;
step 2: taking four raw materials of mix-fried ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 4-8 times of 50-80% ethanol for refluxing for 1-3 hours, filtering, and concentrating the filtrate under reduced pressure to obtain clear paste; boiling radix Platycodi, radix Glehniae, semen Oroxyli and Glycyrrhrizae radix, adding semen Armeniacae amarum, boiling, filtering, and concentrating the filtrate under reduced pressure to obtain fluid extract;
and step 3: mixing the two fluid extracts obtained in step 2, mixing, purifying with nonpolar macroporous resin chromatography column, eluting with water, 20-35% ethanol solution, and 60-95% ethanol solution as eluent, and collecting 60-95% ethanol eluate.
2. The method for preparing a compound of claim 1, wherein the compound of step 1 is: 1 part of honey-fried ephedra herb, 3.33 parts of bitter almond, 2 parts of platycodon root, 2 parts of whiteflower hogfennel root, 2 parts of thunberg fritillary bulb, 2 parts of sessile stemona root, 1 part of Indian trum etflower seed, 3.33 parts of coastal glehnia root and 1 part of liquoric root.
3. The method according to claim 1, further comprising drying the eluate obtained in step 3.
4. The method according to claim 1, wherein the 50-80% ethanol reflux extraction in step 2 is performed 2 times; and 3, selecting the nonpolar macroporous resin D101 from the macroporous resin.
5. The production method according to any one of claims 1 to 4, characterized by comprising:
reflux extraction: weighing the apricot shell cough relieving granule medicinal materials according to the prescription amount, taking 4 raw material medicaments of mix-fried ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 70% ethanol of 6 times of the amount of the raw material medicaments, refluxing for 2 hours, filtering, adding 70% ethanol of 4 times of the amount of the medicinal residues, refluxing for 2 hours, filtering, combining the filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.07 for later use; adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 1.5 hours, filtering, adding 8 times of water into medicine residues, boiling for 1.5 hours, filtering, combining filtrates, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.09;
separation and refining: mixing the two fluid extracts, mixing, separating with macroporous resin D101 with the weight of 1:1, eluting the adsorption column with water until the water eluate is colorless, eluting with 30% ethanol solution to remove impurities, and eluting with 95% ethanol solution;
concentrating and drying: concentrating under reduced pressure, recovering 95% ethanol, and spray drying to obtain the active fraction of the granule.
6. The production method according to any one of claims 1 to 4, characterized by comprising:
reflux extraction: weighing the apricot shell cough relieving granule medicinal materials according to the prescription amount, taking 4 raw material medicaments of mix-fried ephedra herb, whiteflower hogfennel root, thunberg fritillary bulb and sessile stemona root, adding 70 percent ethanol with the amount of 8 times, refluxing for 2 hours, filtering, adding 70 percent ethanol with the amount of 4 times of the medicinal residues, refluxing for 2 hours, filtering, combining the filtrates, and concentrating under reduced pressure at 60 ℃ to obtain clear paste with the relative density of 1.06 for later use; adding 10 times of water into the four raw material medicines of platycodon grandiflorum, radix glehniae, semen oroxyli and liquorice, boiling, adding bitter apricot seeds, boiling for 2 hours, filtering, adding 10 times of water into the medicine residues, boiling for 2 hours, filtering, combining the filtrates, and concentrating under reduced pressure at 60 ℃ to obtain clear paste with the relative density of 1.08;
separation and refining: mixing the two fluid extracts obtained in step 1, mixing well, separating with macroporous resin D101, wherein the weight of the resin is 0.8:1, eluting the adsorption column with water until the water eluate is colorless, eluting with 20% ethanol solution to remove impurities, and eluting with 60% ethanol solution;
concentrating and drying: concentrating under reduced pressure, recovering 60% ethanol, and spray drying to obtain the active fraction of the granule.
7. An active site of an aigbei cough relieving granule prepared by the preparation method of any one of claims 1 to 6.
8. Use of the active site of claim 7 in the manufacture of a medicament for the treatment of cough or expectoration.
9. A cough suppressing or expectorant medicament made from the active site of claim 7 together with one or more pharmaceutically acceptable carriers or excipients.
10. The medicament of claim 9, wherein the medicament comprises an oral formulation or a parenteral dosage form.
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