WO2017032285A1 - 一种参苓白术颗粒及其制备方法 - Google Patents

一种参苓白术颗粒及其制备方法 Download PDF

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WO2017032285A1
WO2017032285A1 PCT/CN2016/096158 CN2016096158W WO2017032285A1 WO 2017032285 A1 WO2017032285 A1 WO 2017032285A1 CN 2016096158 W CN2016096158 W CN 2016096158W WO 2017032285 A1 WO2017032285 A1 WO 2017032285A1
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weight
parts
granules
ethanol
hours
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PCT/CN2016/096158
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English (en)
French (fr)
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林德良
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北京汉典制药有限公司
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Priority to US15/744,679 priority Critical patent/US10813964B2/en
Priority to RU2018108853A priority patent/RU2722015C1/ru
Priority to JP2018528373A priority patent/JP6797202B2/ja
Priority to AU2016312007A priority patent/AU2016312007B2/en
Priority to PL16838544.1T priority patent/PL3338786T3/pl
Priority to EP16838544.1A priority patent/EP3338786B1/en
Publication of WO2017032285A1 publication Critical patent/WO2017032285A1/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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/284—Atractylodes
    • 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)
    • 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
    • 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)
    • A61K36/62—Nymphaeaceae (Water-lily family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/894—Dioscoreaceae (Yam family)
    • A61K36/8945—Dioscorea, e.g. yam, Chinese yam or water yam
    • 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)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8994—Coix (Job's tears)
    • 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)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9064—Amomum, e.g. round cardamom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the invention belongs to the field of traditional Chinese medicine preparations, and particularly relates to a new ginseng Baizhu granule for treating spleen and stomach, benefiting lung qi, especially for treating spleen and stomach weakness, eating less stool, shortness of breath cough and limb fatigue, and preparation method thereof .
  • Shenqi Baizhu granules derived from the "Chinese Pharmacopoeia" have the effect of replenishing the spleen and stomach, benefiting the lungs, and are used for spleen and stomach weakness, eating less stools, shortness of breath, coughing, and fatigue.
  • the prescription consists of:
  • the preparation process of Shenqi Baizhu Granules which is included in the prescriptions for the preparation of traditional Chinese medicines (20th volume), is as follows: extracting volatile oil from Amomum villosum L. and Atractylodes macrocephala L., and extracting the aqueous solution after distillation; collecting the medicinal residue and other ginseng, etc. The mixture was boiled, filtered, and the filtrate was combined with the above aqueous solution and concentrated to a paste.
  • CN1788783A discloses a preparation method of Shenqi Baizhu Granules.
  • the specific process is: the above ten flavors, yam crushed into fine powder, spare; extract the volatile oil from the amomum, the distilled aqueous solution is collected separately; the dregs and ginseng, bran fried atractylodes plus 95% ethanol 4 times soak for 24 hours, The mixture was heated under reflux for 3 hours, filtered, and the filtrate was recovered to ethanol, and concentrated to a clear paste having a relative density of 1.0 (65 ° C); the dregs were further added with 50% ethanol 4 times, heated under reflux for 3 hours, filtered, and the filtrate was recovered for ethanol.
  • the ginseng Baizhu granules prepared by the above method have a packing size of 3 g/bag, three times a day, 2 to 3 g each time.
  • Shenqi Baizhu Granule has a good effect on the treatment of spleen and stomach weakness syndrome in children.
  • Shenqi Baizhu granules are added to water, the liquid medicine is turbid, the sensory impression is not good, and the mouthfeel is not good; the child patient is unwilling to take it, and the medication is poorly compliant.
  • Shenqi Baizhu granules have no single-dose packaging for children.
  • no usage or dosage of the child is mentioned, which makes the preparation of the preparation non-standard and easy in children.
  • the dose is not accurate; if the dose is insufficient, it will not produce the desired effect and prolong the cycle of treatment and rehabilitation. Therefore, it is necessary to provide Shenqi Baizhu Granules which are specially suitable for children, and improve the preparation method of Shenqi Baizhu Granules, on the one hand to improve the curative effect, on the other hand to improve the compliance of children to meet the needs of clinical children.
  • the present invention provides a novel ginseng atractylodes granule and a preparation method thereof.
  • the new Shenqi Baizhu granules after adding an appropriate amount of water to disperse, obtain a clear solution, and the mouthfeel is good; thereby improving the compliance of the child taking the medicine.
  • the new ginseng atractylodes granules of the present invention have comparable clinical total efficacy compared with prior art granules, but have a significantly stronger effect on improving spleen and stomach weakness in children than prior art granules; Usage and dosage of children.
  • a ginseng atractylodes granule comprising a raw material medicine extract and an auxiliary material;
  • the raw material medicine composition is: ginseng 400 parts by weight, ⁇ 400 parts by weight, bran atractylodes 400 parts by weight, yam 400 parts by weight, fried white lentils 300 parts by weight 200 parts by weight of lotus seeds, 200 parts by weight of braised coix seed, 200 parts by weight of Amomum vulgaris, 200 parts by weight of platycodon, 400 parts by weight of licorice;
  • the auxiliary materials include citric acid, stevioside and lactose; A clear solution was obtained after water dispersion.
  • the ginseng atractylodes granules are administered to a child in need of 3-5 years old, 1 g per time, 3 times a day; the ginseng atractylodes granules are administered to a child 5-14 years old, 2 g per day, daily 3 times.
  • Another object of the present invention is to provide a method for preparing the above-mentioned Shenqi Baizhu Granules, wherein the raw material composition of the Shenqi Baizhu Granules is:
  • ginseng 400 parts by weight of ginseng, 400 parts by weight of glutinous rice, 400 parts by weight of bran atractylodes, and 400 weight of yam 300 parts by weight of fried white lentils, 200 parts by weight of lotus seeds, 200 parts by weight of bran fried coix seed, 200 parts by weight of Amomum villosum, 200 parts by weight of Campanulaceae, 400 parts by weight of licorice;
  • the preparation method comprises the following steps:
  • step 2 The drug residue obtained in step 2 is soaked with ginseng, atractylodes, and platycodon grandiflorum for 80 hours with 80% to 95% ethanol.
  • the volume of ethanol is 8 to 12 times the weight of the medicinal material, heated under reflux for 2 to 3 hours, filtered, and the filtrate is filtered.
  • the ethanol is recovered and concentrated to a clear paste having a relative density of 1.10 to 1.20 at 65 ° C; the dregs are further added with 30% to 60% ethanol for 2 to 3 hours, and the volume of the ethanol is 8 to 10 times the weight of the medicinal material, filtered, and the filtrate is filtered.
  • the ethanol is recovered and concentrated to a clear paste having a relative density of 1.10 to 1.20 at 80 ° C, and the dregs are reserved;
  • the dregs obtained in step 3 are decoctioned with medlar, yam, fried white lentils, lotus seeds, bran fried coix seed, licorice and six flavors of water, the first time 1 to 3 hours, the second time 1 to 2 hours, each The volume of the sub-added water is 8 to 12 times the weight of the medicinal material, and the two decoctions are combined, filtered, and the filtrate is combined with the distilled aqueous solution obtained in the step 2, allowed to stand, filtered, and the filtrate is concentrated to a relative density of 80 ° C. When it is 1.15 ⁇ 1.30, the two kinds of clear paste obtained in step 3 are added, and further concentrated to a clear paste having a relative density of 1.10 to 1.25 at 80 ° C, and spray-dried to obtain a spray-dried powder;
  • the amomum is firstly added to the sand kernel by 8 to 12 times the weight of the amomum for 1 hour, and then the volatile oil of the amomum is extracted.
  • the amomum is firstly immersed in the water of 10 times the weight of the sand kernel for 1 hour, and the volatile oil of the amomum villosum is extracted.
  • the Amomum villosum is extracted by the steam distillation method for 4 to 8 hours; more preferably 6 hours.
  • the drug residue obtained in the step 2 is extracted with ginseng, atractylodes, and platycodon first with 95% ethanol, and then extracted with 50% ethanol.
  • the volume of the 95% ethanol is 8 to 10 times the weight of the extracted medicinal material, and the volume of the 50% ethanol is 8 times the weight of the extracted medicinal material.
  • the present invention provides a preparation method of Shenqi Baizhu Granule, and the raw material composition of the Shenqi Baizhu Granule is:
  • ginseng 400 parts by weight of ginseng, 400 parts by weight of glutinous rice, 400 parts by weight of bran atractylodes, 400 parts by weight of yam, 300 parts by weight of fried white lentils, 200 parts by weight of lotus seeds, 200 parts by weight of bran fried coix seed, 200 parts by weight of Amomum villosum L., Campanulaceae 200 Parts by weight, licorice 400 parts by weight;
  • the preparation method comprises the following steps:
  • the dregs obtained in step 3 are decocted with medlar, yam, fried white lentils, lotus seeds, bran fried coix seed, licorice and six flavors of water, the first time for 2 hours, the second time for 1.5 hours, the volume of water added each time. It is 10 times the weight of the medicinal material, two decoctions are combined, filtered, and the filtrate is combined with the distilled aqueous solution obtained in step 2, allowed to stand, filtered, and the filtrate is concentrated to 80 ° C and the relative density is 1.15 to 1.30.
  • the two kinds of clear paste obtained in step 3 are further concentrated to a clear paste having a relative density of 1.15 to 1.20 at 80 ° C, and spray-dried to obtain a spray-dried powder;
  • step 2 taking the spray-dried powder obtained in the step 4, adding 1% by weight of the spray-dried powder of citric acid, 0.01% to 0.05% of stevioside, and a proper amount of lactose, mixing, dry-forming into granules, and spraying
  • the volatile oil of Amomum villosum obtained in step 2 is mixed to prepare 1000 parts by weight of particles;
  • Another object of the present invention is to provide a ginseng atractylodes granule prepared by the above preparation method, which is obtained by adding an appropriate amount of water to obtain a clear solution.
  • composition of 1000 parts by weight of Shenqi Baizhu Granules obtained by the preparation method of the present invention is:
  • the spray-dried powder the volatile oil of Amomum villosum L.
  • the spray-dried powder has a weight of 0.5% to 1% of citric acid
  • the spray-dried powder has a weight of 0.01% to 0.05% of stevioside, and the balance is lactose.
  • the amount of the spray-dried powder and the volatile oil of Amomum villosum L. prepared by the preparation method of the present invention is also not fixed, and the corresponding amount of lactose is also used. It will be adjusted according to the actual conditions so that the total amount of the granules is 1000 parts by weight.
  • Still another object of the present invention is to provide a method for using the above-mentioned Astragalus membranaceus granules.
  • the ginseng atractylodes granules are prepared by the above preparation method; the methods of use include weak spleen and stomach, less food and stool, shortness of breath and cough, Children with weak limbs, 1g every 3-5 years, 3 times a day; 2g every 5-14 years, 3 times a day.
  • another object of the present invention is to provide the above-mentioned Shenqi Baizhu Granules, or the Shenqi Baizhu Granules prepared by the above preparation method for preparing a medicine for treating children with spleen and stomach weakness, eating less stool, shortness of breath cough, and limb fatigue. use.
  • Shenqi Baizhu granule provided by the invention can be used not only for children's disease, but also for spleen and stomach weakness, eating less stool, shortness of breath, cough, limb fatigue, and can also be used for adults to see the above symptoms. When used in adults, the amount can be increased accordingly. In general, the adult dose is 3g each time, 3 times a day.
  • the "parts by weight” as used in the present invention means the proportional relationship of the weight of each of the medicinal herbs and the finally prepared ginseng atractylodes granules. According to the actual situation, 1 part by weight may be 1 g, 1 kg, 100 g, or any other mass (e.g., 20 g, 50 g, etc.). When 1 part by weight is 1 g, 1000 g of ginseng atractylodes granules were prepared according to the above preparation method, and 1 g per bag was dispensed into 1000 bags.
  • concentration of ethanol described in the specification of the present invention refers to a volume percent concentration.
  • the granule prepared by the invention has high content of active ingredients, indicating high extraction efficiency and better ensuring the efficacy.
  • the determination of the polysaccharide and ginsenoside Rg1 content of Experiment 2 and Experimental Example 3 showed that the granules prepared by the present invention and Comparative Example 3 (Shenzhen Baizhu granules disclosed in Publication No. CN1788783A) were higher than Comparative Example 1 in the above-mentioned index components. 2, and the content of Example 1 is the highest, which is a preferred embodiment.
  • the commercially available Shenqi Atractylodes preparation has only the usage and packaging specifications of adults.
  • the invention determines the usage and dosage of different children's age groups and special packaging specifications, which makes children's medication more convenient and accurate.
  • the origin, manufacturer and supply batch number of the above raw materials are as follows:
  • the preparation method comprises the following steps:
  • the dregs obtained in the step 2 are soaked with ginseng, atractylodes, and platycodon grandiflorum plus 95% ethanol for 10 times (volume/weight multiple) for 24 hours, heated under reflux for 3 hours, filtered, and the filtrate is recovered to ethanol, and concentrated to a relative density of 1.15 ⁇ 1.20 (65°C) clearing paste; the dregs are further added with 50% ethanol 8 times (volume/weight multiple) for 3 hours, filtered, and the filtrate is recovered and concentrated to a relative density of 1.12 ⁇ 1.13 (80 °C). Clearing paste, dregs spare;
  • the above-mentioned preparation method of Shenqi Baizhu granules the main functions are: spleen and stomach, benefiting lung; for children with spleen and stomach weakness, eating less stool, shortness of breath cough, limb fatigue. Dosage usage is: children 3-5 years old each time 1g, 3 times a day; 5 years old - 4 years old each time 2g, 3 times a day.
  • the preparation method comprises the following steps:
  • the dregs obtained in the step 2 are soaked with ginseng, atractylodes and platycodon grandiflorum plus 12 times ethanol (volume/weight multiple) for 12 hours, heated under reflux for 3 hours, filtered, and the filtrate is recovered to ethanol and concentrated to relative density. It is a clear paste of 1.10 ⁇ 1.15 (65 °C); the dregs are further added with 30 times of 30% ethanol (volume/weight multiple) for 2 hours, filtered, and the filtrate is recovered and concentrated to a relative density of 1.12 to 1.13 (80). °C) clearing paste, dregs spare;
  • the above-mentioned preparation method of Shenqi Baizhu granules the main functions are: spleen and stomach, benefiting lung; for children with spleen and stomach weakness, eating less stool, shortness of breath cough, limb fatigue. Dosage usage is: Children 3-5 Each year 1g, 3 times a day; 5 years old - 14 years old each time 2g, 3 times a day.
  • the preparation method comprises the following steps:
  • the slag obtained in the step 3 is decocted with the remaining scorpion and the like, and the water is decocted twice, the first time for 1 hour, the second time for 1 hour, and the water is added 8 times each time, filtered, and the filtrate is obtained in step 2.
  • the distilled aqueous solution is combined, allowed to stand, filtered, and the filtrate is concentrated to a relative density of 1.25 to 1.30 (80 ° C), and the two kinds of clearing pastes obtained in the step 3 are added to continue to be concentrated to a relative density of 1.15 to 1.20 (80).
  • the above-mentioned preparation method of Shenqi Baizhu granules the main functions are: spleen and stomach, benefiting lung; for children with spleen and stomach weakness, eating less stool, shortness of breath cough, limb fatigue. Dosage usage is: children 3-5 years old each time 1g, 3 times a day; 5 years old - 4 years old each time 2g, 3 times a day.
  • the Shenqi Baizhu oral liquid is prepared by the following method:
  • the ginseng is pulverized into fine powder, and 1400ml and 1000ml of 50% ethanol are added respectively, and the mixture is heated and refluxed for secondary extraction (the reflux temperature and the reflux speed are appropriately adjusted), the first time is 1.5 hours, the second time is 1 hour, and the filter is filtered and refluxed.
  • the extracts were combined, and the ethanol was recovered under reduced pressure to a syrup to obtain a concentrated liquid, which was stored in a refrigerator.
  • step 4 Mix the concentrated liquid obtained in step 1 and step 3, add appropriate amount of water, stir, statically filter, add the volatile oil and distillate obtained in step 2 to the filtrate, add appropriate amount of Tween-80 and sorbitol, and add water. The total amount is adjusted to 3300 ml, and the solution is prepared, filtered, filtrated, autoclaved, packaged, and obtained.
  • the ginseng atractylodes granules are prepared by the following method:
  • step 2 The dregs of step 2 and the rest of the ginseng and other eight flavors, boiled three times with water, the first 1.5 hours, the second and third times each for 1 hour, each time adding 10 times, the combined decoction, filtered, filtrate and The above aqueous solutions are combined and concentrated to a clear paste having a relative density of 1.20 to 1.25 (55 ° C);
  • step 3 The dregs obtained in step 3 are soaked with ginseng, atractylodes and 95% ethanol for 4 hours, heated under reflux for 3 hours, filtered, and the filtrate is recovered to ethanol and concentrated to a clear density of 1.0 (65 ° C).
  • the dregs are further added with 50% ethanol in 4 times, heat refluxed for 3 hours, filtered, and the filtrate is recovered into ethanol, and concentrated to a clear paste having a relative density of 1.12 to 1.13 (80 ° C), and the dregs are reserved;
  • step 5 The thick paste obtained in step 5 is added to the yam fine powder of 100 mesh sieve, mixed, dried at 60 ° C, and pulverized; 1 part of dry paste and 0.4 parts of lactose powder are mixed, and granules are prepared by using 70% ethanol. Spray the volatile oil of Amomum villosum L., mix well, and make 1000g of granules, and dispense, 3g/bag.
  • the ginseng Baizhu granules prepared in Examples 1-3 of the present invention have significantly better solubility than the comparative example 3, and the taste is sweet and sour, and the acceptance of children is significantly higher than that of the respective 1-3.
  • the medicinal solution of the granules of Comparative Example 3 was precipitated in a large amount, and the mouthfeel was poor for children, dysphagia was difficult, and the degree of acceptance was the lowest.
  • a variety of medicinal materials such as medlar and ginseng in the prescription of Atractylodes sinensis contain polysaccharides that can improve the immunity of the human body.
  • the content of polysaccharides can be used as one of the indicators of the efficacy of the preparation. Therefore, the polysaccharide content of the preparations prepared in the respective examples and comparative examples was determined by the following method.
  • the glucose reference solution 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1.0 mL were accurately aspirated in turn, placed in a 50 ml volumetric flask, and water was added to the mark and shaken.
  • Accurately measure 2ml of each solution place it in a test tube, add 1ml of 4% phenol solution, mix well, quickly add 7.0ml of sulfuric acid, shake well, keep in 40 ° C water bath for 30 minutes, take out, set in ice water bath 5 Minutes, take out, take the first part as a blank, according to the spectrophotometry (2015 edition of the Chinese Pharmacopoeia General Principles 0401), measure the absorbance at the wavelength of 490nm, take the absorption as the ordinate, the concentration as the abscissa, draw the standard curve .
  • the polysaccharides prepared in the oral solution prepared in Comparative Example 1 and the granules prepared in Comparative Example 2 have significantly lower polysaccharide content than other samples, indicating that the extraction method of Comparative Example 1 and Comparative Example 2 is insufficient for the extraction of polysaccharides, which is not conducive to drug efficacy. fully use.
  • the content of the polysaccharide in each of the granules of Examples 1-3 and Comparative Example 3 was substantially the same, and the content of Example 1 was the highest, indicating that the preparation method of Example 1 is a more preferable aspect in terms of extraction of the polysaccharide.
  • test solution is taken from granules, finely ground, accurately weighed 10.0g, precision added to 100ml of methanol, weighed, heated and refluxed for 1 hour, allowed to cool, then weighed, and the weight of the lost weight was compensated with methanol. , filtered. Precisely take 50ml of the filtrate and evaporate it in an evaporating dish. Add 50ml of water to the residue to dissolve. Add petroleum ether (60 ⁇ 90°C) twice, 30ml each time, discard the ether solution, and water the water is saturated with n-butanol.
  • the measurement method accurately absorbs 10 ⁇ l of each of the reference solution and the test solution, and injects into a high-performance liquid chromatograph, and measures, that is, it is obtained.
  • the specific results are shown in Table 3.
  • the ginsenoside content of Examples 1-3 and Comparative Example 1 and Comparative Example 3 of the present invention is higher than that of Comparative Example 2, and the contents of Examples 1-3 and Comparative Example 3 are substantially equivalent, both higher than Comparative Examples 1 and 2 . Therefore, the preparation method of the present invention and the preparation method of Comparative Example 3 are more reasonable from the extraction effect of the ginsenoside component represented by ginsenoside Rg1. Among them, the ginsenoside Rg1 content of Example 1 is the highest, which is a more preferable scheme.
  • Example 1 To observe the effects of Example 1 and Comparative Examples 1-3 on intestinal mucosal barrier function in young rats with chronic diarrhea.
  • Test drugs Example 1, Comparative Example 2, Comparative Example 3 prepared Shenqi Baizhu Granules and Comparative Example 1 prepared Shenqi Baizhu oral liquid
  • the rats in each group were given the corresponding drugs once a day, and the blank control group and the natural recovery group were given an equal volume of sterile distilled water for 2 weeks.
  • urine was collected to detect the ratio of lactulose/mannitol (L/M) in the urine, and femoral blood was collected to detect plasma endotoxin.
  • Test group 40 cases, the Shenqi Baizhu granules prepared in Example 1 of the present invention were administered: children 3-5 years old, 1 g each time, 3 times a day; 5 years old - 14 years old, 2 g each time, 3 times a day.
  • Control group 40 cases, given the preparation of Comparative Example 3, Shenqi Baizhu granules: children 3-5 years old each time 1g, 3 times a day; 5 years old - 14 years old each time 2g, 3 times a day.
  • the course of treatment is 3 weeks.
  • the total effective rate of the test group was 100%, and the cure rate was 82.5%; the total effective rate of the control group was 90%, and the cure rate was 65%.
  • the test group was superior to the control group in terms of the improvement of the specific stool frequency.
  • the specific results are shown in Table 6.
  • the test group was also superior to the control group in terms of compliance and ease of administration.
  • Shenqi Baizhu Granule prepared by the preparation method of the present invention has certain advantages in treating children with spleen and stomach weakness syndrome, and has good safety and is suitable for children's application.

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Abstract

一种参苓白术颗粒及其制备方法，所述颗粒包括原料药提取物和辅料，所述原料药为：人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份，所述辅料包括柠檬酸、甜菊苷及乳糖，所述颗粒加适量水分散后得到澄清溶液。

Description

一种参苓白术颗粒及其制备方法
相关申请的交叉引用
本申请要求2015年8月21日递交的中国专利申请号为201510520582.0的专利申请的权益，在此将其全部内容引入作为参考。
技术领域
本发明属于中药制剂领域，具体涉及一种用于补脾胃、益肺气，特别用于治疗儿童脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力的新的参苓白术颗粒及其制备方法。
背景技术
参苓白术颗粒，来源于《中国药典》，具有补脾胃，益肺气的功效，用于脾胃虚弱，食少便溏，气短咳嗽，肢倦乏力。处方组成为：
人参400g、茯苓400g、麸炒白术400g、山药400g、炒白扁豆300g、莲子200g、麸炒薏苡仁200g、砂仁200g、桔梗200g、甘草400g。
现有技术中对于参苓白术颗粒的制备方法有多处记载。如部颁中药成药制剂(第二十册)收录的参苓白术颗粒的制备工艺为：取砂仁、白术提取挥发油，蒸馏后的水溶液另器收集；药渣与其余人参等八味，加水煎煮，煎液滤过，滤液与上述水溶液合并，浓缩至膏。取清膏1份、蔗糖2份、糊精2.5份及乙醇适量制成颗粒，干燥，加入上述白术、砂仁挥发油，混匀，既得。该工艺不尽合理，原因在于山药、人参、桔梗等药材含有的皂苷类成分用水不能被充分提取出来。
又如公开号为CN1788783A(公开日2006年6月21日)的中国发明专利申请公开了一种参苓白术颗粒的制备方法。具体工艺过程为：以上十味，山药粉碎成细粉，备用；取砂仁提取挥发油，蒸馏后的水溶液另器收集；药渣与人参、麸炒白术加95％乙醇4倍量浸泡24小时，加热回流3小时，滤过，滤液回收乙醇，并浓缩至相对密度为1.0(65℃)的清膏；药渣再加50％的乙醇4倍量，热回流3小时，滤过，滤液回收乙醇，并浓缩至相对密度为1.12～1.13(80℃)的清膏，药渣备用；其余茯苓等六味加8倍量水煎煮2小时，滤过，药渣与上述醇提后备用渣再加8倍量水共同煮1.5小时，滤过，合并 两次滤液及上述蒸馏后水溶液，滤过，滤液浓缩至相对密度为1.2(80℃)时，加入上述两种清膏，继续浓缩至相对密度为1.30～1.34(80℃)的稠膏。加入过100目筛的山药细粉，混匀，60℃低温干燥，粉碎。取干膏1份、乳糖粉0.4份混匀，以70％乙醇制成颗粒，喷入砂仁挥发油，混匀，共制得1000g颗粒，即得。
上述方法制备得到的参苓白术颗粒分装规格为3g/包，每日三次，每次2～3g。临床实践中，参苓白术颗粒对治疗儿童脾胃虚弱证有很好的疗效。但是上述现有技术的参苓白术颗粒加入水后，药液浑浊，感官印象不好，且口感不好；造成儿童患者不愿服用，服药的顺应性差。
另外，现有技术中的参苓白术颗粒都没有针对儿童的单剂量包装，在成人用参苓白术制剂中，均未提及儿童的用法用量，从而造成该制剂在儿童应用的不规范，容易造成剂量不准确；如剂量不足，则不能产生应有的疗效，延长治疗和康复的周期。因此，有必要提供专门适合儿童服用的参苓白术颗粒，并改进参苓白术颗粒的制备方法，一方面提高疗效，另一方面提高患儿的顺应性，以满足临床儿童用药的需求。
发明内容
针对现有技术存在的问题，本发明提供一种新的参苓白术颗粒及其制备方法。所述新的参苓白术颗粒，加适量水分散后得到澄清的溶液，而且口感好；从而可以提高儿童服药的顺应性。另外，本发明的新的参苓白术颗粒，与现有技术的颗粒剂比较，临床总疗效相当，但是在改善儿童脾胃虚弱方面的作用显著强于现有技术的颗粒剂；并且确定了专门针对儿童的用法用量。
为实现上述发明目的，本发明采取如下的技术方案：
一种参苓白术颗粒，包括原料药提取物和辅料；所述原料药组成为：人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份；所述辅料包括柠檬酸、甜菊苷及乳糖；所述参苓白术颗粒加适量水分散后得到澄清的溶液。
优选的，所述参苓白术颗粒给予需要的3-5岁的儿童，每次1g，每日3次；所述参苓白术颗粒给予需要的5-14岁的儿童，每次2g，每日3次。
本发明的另一个目的在于提供上述参苓白术颗粒的制备方法，所述参苓白术颗粒的原料药组成为：
人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重 量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份；
所述制备方法包括如下步骤：
(1)按照上述组成准备各味药材；
(2)取砂仁用水蒸气蒸馏法提取得到砂仁挥发油，蒸馏后的水溶液另器收集，药渣备用；
(3)将步骤2得到的药渣同人参、白术、桔梗加80％～95％乙醇浸泡24小时，乙醇的体积是药材重量的8～12倍，加热回流2～3小时，滤过，滤液回收乙醇，并浓缩至65℃相对密度为1.10～1.20的清膏；药渣再加30％～60％乙醇回流2～3小时，乙醇的体积是药材重量的8～10倍，滤过，滤液回收乙醇，并浓缩至80℃相对密度为1.10～1.20的清膏，药渣备用；
(4)步骤3得到的药渣与茯苓、山药、炒白扁豆、莲子、麸炒薏苡仁、甘草六味加水煎煮二次，第一次1～3小时，第二次1～2小时，每次加水的体积是药材重量的8～12倍量，合并两次煎液，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至80℃相对密度为1.15～1.30时，加入步骤3得到的两种清膏，继续浓缩成80℃相对密度为1.10～1.25的清膏，喷雾干燥，得喷雾干燥粉；
(5)取步骤4得到的所述喷雾干燥粉，加入所述喷雾干燥粉重量0.5％～1％的柠檬酸、0.01％～0.05％的甜菊苷以及适量乳糖，混匀，干法制成颗粒，喷入步骤2得到的所述砂仁挥发油，混匀，制成1000重量份颗粒；
(6)取步骤5得到的所述颗粒，分装，每袋1g。
优选的，所述步骤2中，将所述砂仁先加入所述砂仁重量8～12倍的水浸泡1小时，再提取所述砂仁挥发油。
更优选的，所述步骤2中，将所述砂仁先入所述加砂仁重量10倍的水浸泡1小时，再提取所述砂仁挥发油。
还优选的，所述砂仁经所述水蒸气蒸馏法提取所述砂仁挥发油的时间为4～8小时；更优选为6小时。
优选的，所述步骤3中，所述步骤2得到的药渣同人参、白术、桔梗先用95％乙醇提取，再用50％乙醇提取。
进一步优选的，所述步骤3中，95％乙醇的体积是提取药材重量的8～10倍，50％乙醇的体积是提取药材重量的8倍。
作为一个优选的实施方式，本发明提供一种参苓白术颗粒的制备方法，所述参苓白术颗粒的原料药组成为：
人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份；
所述制备方法包括如下步骤：
(1)按照上述组成准备各味药材；
(2)取砂仁，加所述砂仁重量10倍量的水，浸泡1小时，水蒸气蒸馏法提取挥发油6小时，收集砂仁挥发油，备用；蒸馏后的水溶液另器收集，备用；药渣备用；
(3)将步骤2得到的药渣同人参、白术、桔梗加95％乙醇浸泡24小时，95％乙醇的体积是药材重量的8～10倍，加热回流3小时，滤过，滤液回收乙醇，并浓缩至65℃相对密度为1.10～1.20的清膏；药渣再加50％乙醇回流3小时，50％乙醇的体积是药材重量的8倍，滤过，滤液回收乙醇，并浓缩至80℃相对密度为1.10～1.20的清膏，药渣备用；
(4)步骤3得到的药渣与茯苓、山药、炒白扁豆、莲子、麸炒薏苡仁、甘草六味加水煎煮二次，第一次2小时，第二次1.5小时，每次加水的体积是药材重量的10倍，合并两次煎液，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至80℃相对密度为1.15～1.30时，加入步骤3得到的两种清膏，继续浓缩成80℃相对密度为1.15～1.20的清膏，喷雾干燥，得喷雾干燥粉；
(5)取步骤4得到的所述喷雾干燥粉，加入所述喷雾干燥粉重量1％的柠檬酸、0.01％～0.05％的甜菊苷以及适量乳糖，混匀，干法制成颗粒，喷入步骤2得到的所述砂仁挥发油，混匀，制成1000重量份颗粒；
(6)取步骤5得到的所述颗粒，分装，每袋1g。
本发明的另一个目的在于提供一种通过上述制备方法制备得到的参苓白术颗粒，所述参苓白术颗粒加适量水分散后得到澄清的溶液。
显然，利用本发明所述制备方法得到的1000重量份的参苓白术颗粒的组成为：
所述喷雾干燥粉，所述砂仁挥发油，所述喷雾干燥粉重量0.5％～1％的柠檬酸，所述喷雾干燥粉重量0.01％～0.05％的甜菊苷，余量为乳糖。
由于不同批次的药材之间不可避免地存在差异，因此通过本发明所述制备方法制备得到的所述喷雾干燥粉和砂仁挥发油的量也是不固定的，相应的各批次乳糖的用量也将根据实际情况调整，从而使颗粒剂的总量为1000重量份。
本发明还有一个目的在于提供上述参苓白术颗粒的使用方法，优选的，所述参苓白术颗粒采用上述制备方法制备得到；所述使用方法包括对于脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力的儿童，3-5岁每次1g，每日3次；5-14岁每次2g，每日3次。
此外，本发明的另一个目的在于提供上述参苓白术颗粒，或采用上述制备方法制备得到的参苓白术颗粒用于制备治疗儿童脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力的药物的用途。
当然，本发明提供的所述参苓白术颗粒不仅可以用于儿童症见脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力，也可以用于成人见上述症状者。用于成人时，用量相应增加即可。一般的，成人剂量为每次3g，每日3次。
本发明所述的“重量份”，表示的是各味药材以及最终制备的参苓白术颗粒的重量的比例关系。根据实际情况，1重量份可以是1g，1kg，100g，或者其他任意的质量(如20g，50g等)。当1重量份是1g时，按照上述制备方法制备得到1000g参苓白术颗粒，每袋1g，分装成1000袋。
本发明说明书中所述的乙醇浓度，如80％～95％乙醇、30％～60％乙醇、95％乙醇、50％乙醇等，都是指的体积百分比浓度。
本发明的有益技术效果是：
1.儿童服药顺应性高于现有技术的制剂。实验例1的测定结果显示本发明的颗粒剂溶化性和口感均好于各对比例，儿童的接受度也明显高于各对比例。
2.本发明制备的颗粒剂，有效成分含量高，说明提取效率高，能够更好的保证药效。实验2和实验例3的多糖及人参皂苷Rg1含量测定显示，本发明制备的颗粒剂与对比例3(公开号CN1788783A公开的参苓白术颗粒)在上述指标成分含量上均高于对比例1和2，且实施例1的含量最高，是优选的实施方案。
3.临床应用结果显示，本发明的参苓白术颗粒对于脾胃虚弱儿童的总有效率、治愈率均高于对比例3的颗粒剂，且对患儿大便次数改善方面好于对比例3，患儿倦怠、气短症状明显好转。说明本发明制备的参苓白术颗粒疗效更好。
4.现市售参苓白术制剂只有成人的用法用量及包装规格，本发明确定了不同儿童年龄段的用法用量及专门的包装规格，使儿童用药更方便和准确。
实施发明的最佳方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的原料、试剂，包括药材等，如无特殊说明，均购自公开的商业渠道。下述实施例和试验例所用的试验方法，如果没有特别说明，均采用本领域的常规方法。
下述实施例和对比例的参苓白术颗粒的原料药组成相同，即：
人参400g，茯苓400g，白术(麦麸炒)400g，山药400g，白扁豆(炒)300g，桔梗200g，莲子200g，薏苡仁(炒)200g，砂仁200g，甘草400g。
上述原料的产地、厂家和供货批号见下表：
原料药名称 产地(中国) 供应商名称
人参 吉林 北京华邈中药工程技术开发中心
砂仁 海南 亳州市宏宇中药饮片有限公司
桔梗 内蒙 亳州市宏宇中药饮片有限公司
茯苓 安徽 亳州市宏宇中药饮片有限公司
白术(炒) 浙江 亳州市宏宇中药饮片有限公司
山药 河北 亳州市宏宇中药饮片有限公司
白扁豆(炒) 广西 亳州市宏宇中药饮片有限公司
莲子 湖南 亳州市宏宇中药饮片有限公司
麸炒薏苡仁 贵州 亳州市宏宇中药饮片有限公司
甘草 甘肃 亳州市宏宇中药饮片有限公司
实施例1一种参苓白术颗粒的制备方法及其制备的参苓白术颗粒
所述制备方法包括如下步骤：
(1)按照处方准备各味药材；
(2)取砂仁，加10倍量水，浸泡1小时，水蒸气蒸馏法提取挥发油6小时，收集砂仁挥发油，备用；蒸馏后的水溶液另器收集，备用；药渣备用；
(3)将步骤2得到的药渣同人参、白术、桔梗加95％乙醇10倍量(体积/重量倍数)浸泡24小时，加热回流3小时，滤过，滤液回收乙醇，浓缩至相对密度为1.15～1.20(65℃)的清膏；药渣再加50％乙醇8倍量(体积/重量倍数)回流3小时，滤过，滤液回收乙醇，浓缩至相对密度为1.12～1.13(80℃)的清膏，药渣备用；
(4)将步骤3得到的药渣与剩余的茯苓等六味加水煎煮二次，第一次2 小时，第二次1.5小时，每次加水10倍量(体积/重量倍数)，合并两次煎液，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至相对密度为1.20～1.25(80℃)时，加入步骤3得到的两种清膏，继续浓缩成相对密度为1.15～1.20(80℃)的清膏，喷雾干燥，得喷雾干燥粉850g；
(5)取步骤4得到的所述喷雾干燥粉，加入8.5g柠檬酸、0.09g甜菊苷及114.43g乳糖，混匀，干法制成颗粒，喷入所述砂仁挥发油，混匀，共制得1000g颗粒；
(6)取步骤5得到的所述颗粒，分装，1g/袋。
上述制备方法得到的参苓白术颗粒，功能主治为：补脾胃、益肺气；用于儿童脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力。用量用法为：儿童3-5岁每次1g，每日3次；5岁-14岁每次2g，每日3次。
实施例2一种参苓白术颗粒的制备方法及其制备的参苓白术颗粒
所述制备方法包括如下步骤：
(1)按照处方准备各味药材；
(2)取砂仁，加8倍量水，浸泡1小时，水蒸气蒸馏法提取挥发油8小时，收集砂仁挥发油，备用；蒸馏后的水溶液另器收集，备用；药渣备用；
(3)将步骤2得到的药渣同人参、白术、桔梗加90％乙醇12倍量(体积/重量倍数)浸泡24小时，加热回流3小时，滤过，滤液回收乙醇，并浓缩至相对密度为1.10～1.15(65℃)的清膏；药渣再加30％乙醇10倍量(体积/重量倍数)回流2小时，滤过，滤液回收乙醇，并浓缩至相对密度为1.12～1.13(80℃)的清膏，药渣备用；
(4)将步骤3得到的药渣与剩余的茯苓等六味加水煎煮二次，第一次3小时，第二次2小时，每次加水12倍量(体积/重量倍数)，合并两次煎液，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至相对密度为1.15～1.20(80℃)时，加入步骤3得到的两种清膏，继续浓缩成相对密度为1.15～1.20(80℃)的清膏，喷雾干燥，得喷雾干燥粉870g；
(5)取步骤4得到的所述喷雾干燥粉，加入8.7g柠檬酸、0.09g甜菊苷及120.4g乳糖，混匀，干法制成颗粒，喷入所述砂仁挥发油，混匀，共制得1000g颗粒；
(6)取步骤5得到的所述颗粒，分装，1g/袋。
上述制备方法得到的参苓白术颗粒，功能主治为：补脾胃、益肺气；用于儿童脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力。用量用法为：儿童3-5 岁每次1g，每日3次；5岁-14岁每次2g，每日3次。
实施例3一种参苓白术颗粒的制备方法及其制备的参苓白术颗粒
所述制备方法包括如下步骤：
(1)按照处方准备各味药材；
(2)取砂仁，加12倍量水，浸泡1小时，水蒸气蒸馏法提取挥发油4小时，收集砂仁挥发油，备用；蒸馏后的水溶液另器收集，备用；药渣备用；
(3)将步骤2得到的药渣同人参、白术、桔梗加85％乙醇8倍量(体积/重量倍数)浸泡24小时，加热回流2,5小时，滤过，滤液回收乙醇，浓缩至相对密度为1.10～1.15(65℃)的清膏；药渣再加60％乙醇回流3小时，滤过，滤液回收乙醇，浓缩至相对密度为1.12～1.13(80℃)的清膏，药渣备用；
(4)将步骤3得到的药渣与剩余的茯苓等六味加水煎煮二次，第一次1小时，第二次1小时，每次加水8倍量，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至相对密度为1.25～1.30(80℃)时，加入步骤3得到的两种清膏，继续浓缩成相对密度为1.15～1.20(80℃)的清膏，喷雾干燥，得喷雾干燥粉840g；
(5)取步骤4得到的所述喷雾干燥粉，加入8.4g柠檬酸、0.08g甜菊苷及151.52g乳糖，混匀，干法制成颗粒，喷入所述砂仁挥发油，混匀，共制得1000g颗粒；
(6)取步骤5得到的所述颗粒，分装，1g/袋。
上述制备方法得到的参苓白术颗粒，功能主治为：补脾胃、益肺气；用于儿童脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力。用量用法为：儿童3-5岁每次1g，每日3次；5岁-14岁每次2g，每日3次。
对比例1一种参苓白术口服液
所述参苓白术口服液通过如下方法制备：
(1)将人参粉碎成细粉，分别加50％乙醇1400ml、1000ml，加热回流提取二次(适当调节回流温度和回流速度)，第一次1.5小时，第二次1小时，用滤器过滤回流提取液，合并，减压回收乙醇至糖浆状，制得浓缩液，冷藏备用。
(2)将白术和砂仁置水蒸气中蒸馏收集挥发油馏出液。
(3)将人参经回流提取后的药渣及白术和砂仁经蒸馏后的药渣同其他七味药共置煎煮锅中，分别加水1800ml煎煮二次，煮沸时间分别为1.5小时 和1小时，收集两次煎煮液，滤过，滤液浓缩至糖浆状，加乙醇适量，使含醇达65％，冷藏，放置，上清液过滤，滤液减压回收乙醇至糖浆状得浓缩液。
(4)将步骤1和步骤3得到的浓缩液混匀加水适量，搅拌、静置过滤，滤液中加入步骤2得到的挥发油及馏出液，再加入适量吐温-80及山梨醇，再加水使总量至3300ml，制得配液，滤过，滤液灌装，热压灭菌，包装，既得。
对比例2一种参苓白术颗粒
所述参苓白术颗粒通过如下方法制备：
(1)按照处方准备各原料药；
(2)取砂仁、白术加10倍水提取挥发油，提取时间6小时，蒸馏后的水溶液另器收集；
(3)步骤2的药渣与其余人参等八味，加水煎煮三次，第一次1.5小时，第二、三次各1小时，每次加10倍量，合并煎液，滤过，滤液与上述水溶液合并，浓缩至相对密度1.20～1.25(55℃)的清膏；
(4)取清膏1份、蔗糖2份、糊精2.5份及乙醇适量制成颗粒，干燥，加入上述白术、砂仁的挥发油，混匀，分装，6g/袋。
【功能与主治】补脾胃，益肺气。用于脾胃虚弱，食少便溏，气短咳嗽，肢倦乏力。
【用法与用量】开水冲服，一次6g，一日3次。
对比例3一种参苓白术颗粒
(1)按照处方准备各味药材；
(2)山药粉碎成细粉，备用；
(3)取砂仁，加10倍量水提取挥发油，蒸馏后的水溶液另器收集；
(4)步骤3得到的药渣与人参、白术加95％乙醇4倍量浸泡24小时，加热回流3小时，滤过，滤液回收乙醇，并浓缩至相对密度为1.0(65℃)的清膏；药渣再加50％的乙醇4倍量，热回流3小时，滤过，滤液回收乙醇，并浓缩至相对密度为1.12～1.13(80℃)的清膏，药渣备用；
(5)其余茯苓等六味加8倍量水煎煮2小时，滤过，药渣与步骤4得到的醇提后备用药渣合并，再加8倍量水共同煮1.5小时，滤过，合并两次滤液及上述蒸馏后水溶液，滤过，滤液浓缩至相对密度为1.2(80℃)时，加入步骤4得到的两种清膏，继续浓缩至相对密度为1.30～1.34(80℃)的稠膏；
(6)步骤5得到的稠膏加入过100目筛的山药细粉，混匀，60℃低温干燥，粉碎；取干膏1份、乳糖粉0.4份混匀，以70％乙醇制成颗粒，喷入砂仁挥发油，混匀，共制得1000g颗粒，分装，3g/袋，即得。
【功能与主治】补脾胃，益肺气。用于脾胃虚弱，食少便溏，气短咳嗽，肢倦乏力。
【用法与用量】开水冲服，一次2～3g，一日3次。
效果实施例1实施例1-3和对比例1-3制备的参苓白术颗粒的溶化性及口感测定
按2015版《中国药典》通则0104“颗粒剂”项下的测定方法对实施例1-3及对比例2-3制备的参苓白术颗粒样品进行溶化性的测定(每袋颗粒剂加入200ml水)。
另外选择5名儿童对实施例1-3和对比例1-3制备的样品进行口感的测定，并按照愿意接受程度对各样品进行评分，其中5分为完全接受，4分、3分、2分的接受程度依次递减，1分为不能接受；取评分的均值为各组样品的接受度评分。
结果见表1。
表1溶化性及口感测定结果
Figure PCTCN2016096158-appb-000001
结论：本发明实施例1-3制备的参苓白术颗粒，溶化性显著好于对比例3，口感味道酸甜，儿童接受度明显高于各对比例1～3。对比例3的颗粒剂加水后的药液有大量沉淀，对于儿童来说口感差，吞咽困难，接受度最低。
因此，上述实验结果表明本发明的参苓白术颗粒更适合儿童。
效果实施例2实施例1-3和对比例1-3制剂中多糖含量的测定
参苓白术处方中的茯苓、人参等多种药材都含有能够提高人体免疫力的多糖，多糖含量的高低可以作为制剂药效强度的指标之一。因此，通过下述方法测定各实施例和对比例制备的制剂的多糖含量。
试验方法：
对照品溶液的制备
精密称取105℃干燥至恒重的无水葡萄糖对照品50mg，加超纯水溶解、定容于50mL量瓶中，摇匀，精密吸取5mL上述溶液于50mL容量瓶中，定容至刻度，得到0.1mg/mL的葡萄糖对照品溶液。
绘制标准曲线
依次精密吸取上述葡萄糖对照品溶液0、0.1、0.2、0.4、0.6、0.8、l.0mL，分别置于50ml量瓶中，加水至刻度，摇匀。精密量取上述各溶液2ml，置具塞试管中，分别加4％苯酚溶液1ml，混匀，迅速加入硫酸7.0ml，摇匀，于40℃水浴中保温30分钟，取出，置冰水浴中5分钟，取出，以第一份为空白，照分光光度法(2015版《中国药典》通则0401)，在490nm的波长处测定吸收度，以吸收度为纵坐标，浓度为横坐标，绘制标准曲线。
测定法
取样品1g(或1ml)〔同时对于实施例1-3和对比例2-3，另取样品粉末测定水分(依照2015版《中国药典》通则0832)〕，精密称定。置100ml量瓶中，加水使溶解并定容至刻度，摇匀。精密量取2ml，加乙醇10ml，搅拌，离心，取沉淀加水溶解，置50ml量瓶中，并稀释至刻度，精密量取2ml,照标准曲线的制备项下的方法，自“加4％苯酚溶液1ml线起，依法测定吸收度，从标准曲线上读出供试品溶液中多糖含量。
结果：见表2。
表2多糖含量测定结果
组别 多糖含量(mg/g或mg/ml)
实施例1 768.39
实施例2 742.05
实施例3 747.63
对比例1 56.8
对比例2 371.76
对比例3 743.18
结论：对比例1制备的口服液和对比例2制备的颗粒剂的多糖含量明显低于其它样品，说明利用对比例1和对比例2的制备方法对多糖的提取不充分，不利于药效的充分发挥。实施例1-3和对比例3每克颗粒剂中多糖含量基本相同，其中实施例1的含量最高，说明在多糖的提取方面，实施例1的制备方法是更优选的方案。
效果实施例3各实施例和对比例制备的制剂中人参皂苷Rg1的含量测定
照高效液相色谱法(2015版《中国药典》通则0512)测定。
色谱条件与***适用性试验用十八烷基硅烷键合硅胶为填料，乙腈－0.1％磷酸(18:82)为流动相，检测波长203nm，理论板数按人参皂苷Rg1峰计算应不低于2500。
对照品溶液的制备精密称取人参皂苷Rg1对照品适量，加甲醇制成每1ml含0.3mg的溶液，即得。
供试品溶液的制备取颗粒，研细，精密称定10.0g，精密加入甲醇100ml，称定重量，加热回流1小时，放冷，再称定重量，用甲醇补足减失的重量，摇匀，滤过。精密量取续滤液50ml，至蒸发皿中蒸干，残渣加水50ml使溶解，加石油醚(60～90℃)提取2次，每次30ml，弃去醚液，水液用水饱和的正丁醇振摇提取5次(30ml、25ml、25ml、20ml、20ml)，合并正丁醇提取液，用1％NaOH溶液提取2次，每次20ml，弃去碱液，再用正丁醇饱和的水洗涤2次，每次20ml，正丁醇液蒸干，残渣加甲醇使溶解并转移至5ml量瓶中，加甲醇至刻度，摇匀，用微孔滤膜(0.45μ)滤过，即得。
取口服液10ml，加水至50ml，自“加石油醚(60～90℃)提取2次……”开始与颗粒剂供试品溶液的制备相同。
测定法分别精密吸取对照品溶液与供试品溶液各10μl，注入高效液相色谱仪，测定，即得。具体结果见表3。
表3人参皂苷Rg1含量测定结果
供试品 人参皂苷Rg1含量(mg/g或mg/ml)
实施例1 1.39
实施例2 1.35
实施例3 1.36
对比例1 1.23
对比例2 0.68
对比例3 1.34
结论：本发明的实施例1-3及对比例1和对比例3人参皂苷含量高于对比例2，且实施例1-3和对比例3的含量基本相当，都高于对比例1和2。因此，从以人参皂苷Rg1为代表的人参皂苷类成分的提取效果看，本发明的制备方法和对比例3的制备方法更合理。其中，实施例1的人参皂苷Rg1含量最高，是更优选的方案。
效果实施例4参苓白术颗粒对慢性腹泻幼年大鼠肠黏膜屏障影响的研究
目的：观察实施例1、对比例1-3对慢性腹泻幼鼠肠黏膜屏障功能的影响。
受试药品：实施例1、对比例2、对比例3制备的参苓白术颗粒和对比例1制备的参苓白术口服液
方法：4周龄Wistar大鼠随机分为空白对照组、自然恢复组(不予药物治疗)、谷氨酰胺组和实施例1(0.9g/kg)、对比例1(3ml/kg)、对比例2(1.8g/kg)、对比例3(0.9g/kg)组(均为各制剂临床等效剂量折算成大鼠的剂量)，除空白对照组与自然恢复组以外，其余各组幼鼠予生大黄水煎剂灌胃，造成慢性腹泻模型。造模成功后各组幼鼠每日灌胃给予相应药物1次，空白对照组与自然恢复组灌胃等体积无菌蒸馏水，共给药2周。治疗后收集尿液检测尿液中乳果糖/甘露醇(L/M)比值，股动脉采血检测血浆内毒素。
结果：各组的尿液中乳果糖/甘露醇(L/M)比值和血浆内毒素测定结果分别见表4和表5。
表4和表5的数据显示，给药2周后，与空白对照组比较，自然恢复组幼鼠尿液中L/M比值、血浆内毒素水平明显升高(P＜0.01)；与自然恢复组比较，实施例1、对比例1、对比例2、对比例3和谷氨酰胺组幼鼠尿液中L/M比值、血浆内毒素水平明显降低(P＜0.05，P＜0.01)，但实施例1对幼鼠尿液中L/M比值、血浆内毒素水平降低明显优于对比例1、对比例2和对比例3。
表4各组幼鼠尿液中乳果糖和甘露醇比值的比较
Figure PCTCN2016096158-appb-000002
组别 动物数(只) 给药剂量 尿量(mL) 乳果糖/甘露醇(L/M)
空白对照组 10 － 8.5±1.4 0.20±0.06
自然恢复组 10 － 8.0±1.8 0.29±0.06**
谷氨酰胺组 10 6.0g/kg 8.3±1.7 0.21±0.05#
实施例1 10 0.9g/kg 8.0±1.3 0.20±0.04#
对比例1 10 3ml/kg 8.1±1.2 0.23±0.05#
对比例2 10 1.8g/kg 8.2±1.6 0.25±0.04
对比例3 10 0.9g/kg 8.2±1.4 0.24±0.04
与空白对照组比较，**P＜0.01；与自然恢复组比较，#P＜0.05。
表5各组幼鼠血浆内毒素水平比较
Figure PCTCN2016096158-appb-000003
组别 动物数(只) 给药剂量(g/kg) 内毒素(U/L)
空白对照组 10 － 8.3±1.7
自然恢复组 10 － 14.4±2.9**
谷氨酰胺组 10 6.0 11.4±1.9#
实施例1 10 0.9g/kg 11.1±1.7##
对比例1 10 3ml/kg 11.6±1.8#
对比例2 10 1.8g/kg 12.9.0±1.6
对比例3 10 0.9g/kg 11.5±1.5#
与空白对照组比较，**P＜0.01；与自然恢复组比较，#P＜0.05，##P＜0.01。
效果实施例5(临床观察例)实施例1和对比例3的参苓白术颗粒临床应用观察比较
试验目的
通过临床验证，考察本发明制备的参苓白术颗粒治疗儿童脾胃虚弱的疗效及对儿童的安全性。
1.病例选择
①年龄3-14岁之间；性别不限；②符合中医辨证：脾胃虚弱证(大便时溏时泻，饮食减少，食后腹胀，舌体胖淡，或有齿痕，苔薄白，脉细弱)且或西医符合慢性腹泻诊断标准(疗程在半个月以上的迁延性腹泻，2个月以上的慢性腹泻；大便次数增多，每日在3次及其以上，伴有大便量和性状的改变。)；③病程在半个月及其以上的非感染性腹泻者；④大便每天大于等于3次且小于等于7次。
2.试验方法
随机分组，单盲对照试验。
试验组：40例，给予本发明实施例1制备的参苓白术颗粒：儿童3-5岁每次1g，每日3次；5岁-14岁每次2g，每日3次。
对照组：40例，给予对比例3制备的参苓白术颗粒：儿童3-5岁每次1g，每日3次；5岁-14岁每次2g，每日3次。
疗程为3周。
3.疗效评价标准
临床痊愈:全部脾胃虚弱症状消失,脾胃参考指标明显改善。
显效:脾胃虚弱症状明显改善,改善在2级以上,脾胃参考指标有好转。
有效:脾胃虚弱症状有所改善,改善在1级以上,所患客观指标稳定。
无效:脾胃虚弱症状及观察诊断指标无改善或加重。
2.1.4实验结果
试验组总有效率100％，治愈率达82.5％；对照组的总有效率为90％，治愈率为65％。两组相较，虽无显著性意义(p＞0.05)；但在具体大便次数改善方面，试验组优于对照组，具体结果见表6。另外，在依从性及服用的方便性上，试验组也优于对照组。
表6临床观察结果
组别 治疗前大便次数 治疗后大便次数 治疗前大便异常人数 治疗后大便异常人数
试验组 平均6.8次/d 平均1.4次/d 40 5
对照组 平均6.6次/d 平均1.8次/d 40 8
试验组40例患儿均未发现任何不良反应及肝肾功能损害，说明本颗粒具有很好的安全性。
总之，通过上述临床实验证明，本发明所述制备方法制备的参苓白术颗粒，在对儿童脾胃虚弱证的治疗相较对比例3具有一定的优势，且安全性好，适合儿童的应用。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明做出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

Claims (12)

  1. 一种参苓白术颗粒，包括原料药提取物和辅料；所述原料药组成为：人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份；所述辅料包括柠檬酸、甜菊苷及乳糖；所述参苓白术颗粒加适量水分散后得到澄清的溶液。
  2. 根据权利要求1所述的参苓白术颗粒，其特征在于，所述参苓白术颗粒给予需要的3-5岁的儿童，每次1g，每日3次；所述参苓白术颗粒给予需要的5-14岁的儿童，每次2g，每日3次。
  3. 一种参苓白术颗粒的制备方法，所述参苓白术颗粒的原料药组成为：
    人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份；
    所述制备方法包括如下步骤：
    (1)按照上述组成准备各味药材；
    (2)取砂仁用水蒸气蒸馏法提取得到砂仁挥发油，蒸馏后的水溶液另器收集，药渣备用；
    (3)将步骤2得到的药渣同人参、白术、桔梗加80％～95％乙醇浸泡24小时，乙醇的体积是药材重量的8～12倍，加热回流2～3小时，滤过，滤液回收乙醇，并浓缩至65℃相对密度为1.10～1.20的清膏；药渣再加30％～60％乙醇回流2～3小时，乙醇的体积是药材重量的8～10倍，滤过，滤液回收乙醇，并浓缩至80℃相对密度为1.10～1.20的清膏，药渣备用；
    (4)步骤3得到的药渣与茯苓、山药、炒白扁豆、莲子、麸炒薏苡仁、甘草六味加水煎煮二次，第一次1～3小时，第二次1～2小时，每次加水的体积是药材重量的8～12倍，合并两次煎液，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至80℃相对密度为1.15～1.30时，加入步骤3得到的两种清膏，继续浓缩成80℃相对密度为1.10～1.25的清膏，喷雾干燥，得喷雾干燥粉；
    (5)取步骤4得到的所述喷雾干燥粉，加入所述喷雾干燥粉重量0.5％～1％的柠檬酸、0.01％～0.05％的甜菊苷以及适量乳糖，混匀，干法制成颗粒，喷入步骤2得到的所述砂仁挥发油，混匀，制成1000重量份颗粒；
    (6)取步骤5得到的所述颗粒，分装，每袋1g。
  4. 根据权利要求3所述的制备方法，其特征在于，所述步骤2中，将所述砂仁先加入所述砂仁重量8～12倍的水浸泡1小时，再提取所述砂仁挥发油。
  5. 根据权利要求4所述的制备方法，其特征在于，所述步骤2中，将所述砂仁先加入所述砂仁重量10倍的水浸泡1小时，再提取所述砂仁挥发油。
  6. 根据权利要求2至5中任一项所述的制备方法，其特征在于，所述砂仁经所述水蒸气蒸馏法提取出所述砂仁挥发油的时间为4～8小时；更优选为6小时。
  7. 根据权利要求2至6中任一项所述的制备方法，其特征在于，所述步骤3中，所述步骤2得到的药渣同人参、白术、桔梗先用95％乙醇提取，再用50％乙醇提取。
  8. 根据权利要求7所述的制备方法，其特征在于，所述步骤3中，95％乙醇的体积是提取药材重量的8～10倍，50％乙醇的体积是提取药材重量的8倍。
  9. 一种参苓白术颗粒的制备方法，所述参苓白术颗粒的原料药组成为：
    人参400重量份、茯苓400重量份、麸炒白术400重量份、山药400重量份、炒白扁豆300重量份、莲子200重量份、麸炒薏苡仁200重量份、砂仁200重量份、桔梗200重量份、甘草400重量份；
    所述制备方法包括如下步骤：
    (1)按照上述组成准备各味药材；
    (2)取砂仁，加所述砂仁重量10倍量的水，浸泡1小时，用水蒸气蒸馏法提取6小时，收集砂仁挥发油，备用；蒸馏后的水溶液另器收集，备用；药渣备用
    (3)将步骤2得到的药渣同人参、白术、桔梗加95％乙醇浸泡24小时，95％乙醇的体积是药材重量的8～10倍，加热回流3小时，滤过，滤液回收乙醇，并浓缩至65℃相对密度为1.10～1.20的清膏；药渣再加50％乙醇回流3小时，50％乙醇的体积是药材重量的8倍，滤过，滤液回收乙醇，并浓缩至80℃相对密度为1.10～1.20的清膏，药渣备用；
    (4)步骤3得到的药渣与茯苓、山药、炒白扁豆、莲子、麸炒薏苡仁、甘草六味加水煎煮二次，第一次2小时，第二次1.5小时，每次加水的体积是药材重量的10倍，合并两次煎液，滤过，滤液与步骤2得到的所述蒸馏后的水溶液合并，静置，滤过，滤液浓缩至80℃相对密度为1.15～1.30时， 加入步骤3得到的两种清膏，继续浓缩成80℃相对密度为1.15～1.20的清膏，喷雾干燥，得喷雾干燥粉；
    (5)取步骤4得到的所述喷雾干燥粉，加入所述喷雾干燥粉重量1％的柠檬酸、0.01％～0.05％的甜菊苷以及适量乳糖，混匀，干法制成颗粒，喷入步骤2得到的所述砂仁挥发油，混匀，制成1000重量份颗粒；
    (6)取步骤5得到的所述颗粒，分装，每袋1g。
  10. 权利要求3至9中任一项所述的制备方法制备得到的参苓白术颗粒；所述参苓白术颗粒加适量水分散后得到澄清的溶液。
  11. 权利要求1、2或10所述的参苓白术颗粒的使用方法，所述使用方法包括：对于脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力的儿童，3-5岁每次1g，每日3次；5-14岁每次2g，每日3次。
  12. 权利要求1、2或10所述的参苓白术颗粒用于制备治疗儿童脾胃虚弱、食少便溏、气短咳嗽、肢倦乏力的药物的用途。
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CN105056092A (zh) 2015-11-18
US20180207215A1 (en) 2018-07-26
AU2016312007B2 (en) 2021-09-30
US10813964B2 (en) 2020-10-27
JP6797202B2 (ja) 2020-12-09
PL3338786T3 (pl) 2024-04-22
JP2018523713A (ja) 2018-08-23
CN105056092B (zh) 2019-05-03
EP3338786A4 (en) 2019-05-01
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