WO2017129050A1 - 一种用于治疗哮喘的药物 - Google Patents

一种用于治疗哮喘的药物 Download PDF

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WO2017129050A1
WO2017129050A1 PCT/CN2017/071815 CN2017071815W WO2017129050A1 WO 2017129050 A1 WO2017129050 A1 WO 2017129050A1 CN 2017071815 W CN2017071815 W CN 2017071815W WO 2017129050 A1 WO2017129050 A1 WO 2017129050A1
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parts
glycoprotein
weight
protein
marine algae
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PCT/CN2017/071815
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English (en)
French (fr)
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程潜
徐宝贞
程龙
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程潜
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • 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
    • A61K36/02—Algae
    • 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)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • 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
    • A61K36/535—Perilla (beefsteak plant)
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin

Definitions

  • the invention relates to a medicine for treating asthma, and belongs to the technical field of medicine.
  • Asthma is a common disease of the respiratory tract and refers to chronic airway inflammation involving a variety of degenerated cells such as eosinophils, mast cells, T cells, airway epithelial cells, and the like.
  • degenerated cells such as eosinophils, mast cells, T cells, airway epithelial cells, and the like.
  • the clinical manifestations of asthma patients are paroxysmal wheezing, shortness of breath, chest tightness or coughing. A few patients may also have chest pain as the main manifestation.
  • the disease has a high incidence worldwide. About 300 million people with asthma worldwide, Chinese asthma The patient is about 30 million.
  • the disease is easy to recurrent, which can lead to chronic obstructive pulmonary disease, emphysema, pulmonary heart disease, heart failure, respiratory failure and other complications, seriously endangering people's health, weakening labor capacity, reducing quality of life, and difficult to get radical cure .
  • antibiotics have no therapeutic effect on asthma, repeated use of antibiotics is likely to cause drug resistance.
  • hormones and theophylline drugs which mainly inhibit inflammation, are commonly used in clinical practice to control asthma symptoms. Although there is a certain effect, long-term use will produce bone. Side effects such as loose, high blood pressure and diabetes.
  • the active ingredients of the Chinese herbal medicines are used to evaluate the airway inflammation and reduce the components of the prescription.
  • the mechanism of action of high reactivity is further studied for its toxicity.
  • the results of the study showed that the group has anti-airway high response, anti-airway inflammation and regulate the type of T helper cells (TH1, TH2) response, which can be used for the treatment of allergic asthma.
  • T helper cells TH1, TH2
  • Patent Polysaccharide prodn. from Gnida kraussiana-for treatment of respiratory infections, asthma, psoriasis, and certain chronic lymphoid leukaemia (s), patent number FR2513518 (A1), discloses: polysaccharides extracted from thymelaeaceous plants of the African savanna Containing arabinose, xylose, rhamnose, fructose, galactose and glucose, the mass ratio is 2:51:6:3:21:15, which has certain effects on asthma, eczema and the like.
  • the present invention provides a medicament for treating asthma to achieve the following objects:
  • the medicament of the present invention effectively reduces airway hyperresponsiveness in a mouse asthma model and relieves tracheal spasm.
  • the medicament of the present invention can effectively treat pulmonary inflammation and reduce inflammatory cell infiltration, and the percentage of eosinophils is 14.6-16.6%.
  • the drug of the present invention increases ⁇ -interferon (IFN- ⁇ ) and antibodies which can inhibit asthma attacks, and reduces interleukin-4 (IL-4), interleukin-5 (IL5), and interleukin- which can induce asthma. 13 (IL-13) content.
  • IFN- ⁇ ⁇ -interferon
  • IL-4 interleukin-4
  • IL5 interleukin-5
  • IL-13 interleukin- 13
  • the present invention adopts the following technical solutions:
  • a medicament for treating asthma characterized in that the medicament is a glycoprotein, or a mixture or polypeptide or protein of a polysaccharide, the glycoprotein comprising 1-99% sugar, 1-99% protein;
  • a mixture of polysaccharides and proteins, by weight, comprises from 1 to 99% polysaccharide and from 1 to 99% protein.
  • the glycoprotein has a molecular weight of 0.2-3000 kDa;
  • the drug is a marine algae glycoprotein.
  • the marine algae glycoprotein comprises, by weight, 1-99% sugar, 1-99% protein; a mixture of the marine algae polysaccharide and protein, including by weight, 1-99%, protein 1- 99%.
  • the marine algae glycoprotein has a molecular weight of 0.2-3000 kDa;
  • the polysaccharide and protein mixture has a molecular weight of 0.2-3000 kDa
  • the protein has a molecular weight of 0.2-3000 kDa.
  • the drug comprises, by weight, 1-99 parts of glycoprotein and 1-25 parts of glucuronic acid.
  • the drug by weight, includes 1-99 parts of marine algae glycoprotein and 1-28 parts of glucuronic acid.
  • the drug in terms of weight content, includes 1-99 parts of marine algae glycoprotein, 1-24 parts of glucuronic acid, and 2-11 parts of green barley.
  • the algae is one or more of cyanobacteria, green algae, red algae, gold algae, and brown algae.
  • the drug by weight, includes 1-99 parts of marine algae glycoprotein, 6-15 parts of medlar, 7-17 parts of perilla, and 1-14 parts of glucuronic acid.
  • the drug by weight, includes 1-99 parts of marine algae glycoprotein, 6-15 parts of medlar, 7-17 parts of perilla, 8-12 parts of rapeseed, and 8-13 parts of bud.
  • the drug by weight, includes 1-99% sugar and 1-99% protein.
  • the marine algae glycoprotein comprises, by weight, 1-99% sugar and 1-99% protein.
  • the medicament of the present invention effectively reduces airway hyperresponsiveness in a mouse asthma model, relieves tracheal fistula, and has an airway pressure-time index (APTI) of 726-880 cm per second.
  • APTI airway pressure-time index
  • the medicament of the present invention can effectively treat pulmonary inflammation and reduce inflammatory cell infiltration, the percentage of eosinophils is 14.66-16.6%, and the model control group contains 43.6% of eosinophils.
  • the drug of the present invention increases ⁇ -interferon (IFN- ⁇ ) and antibodies which can inhibit asthma attacks, and reduces interleukin-4 (IL-4), interleukin-5 (IL 5), and interleukin which can induce asthma.
  • IL-13 interleukin-13
  • interleukin-4 (IL-4) content of 20-48 pg/ml
  • interleukin-5 (IL-5) content of 404-661pg/ml
  • interleukin-13 (IL-13) content It is 289-556 pg/ml
  • the ⁇ -interferon (IFN- ⁇ ) content is 5124-6647 pg/ml.
  • Example 1 A drug for treating asthma
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein in parts by weight, comprises 1% sugar, 99% protein,
  • the molecular weight is 0.2 kDa
  • the marine algae is: cyanobacteria
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein comprises: asparagine, cysteine, lysine, arginine, serine, threonine;
  • Example 2 A drug for treating asthma
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein in parts by weight, comprises 25% sugar, 75% protein,
  • the molecular weight is 55kDa
  • the marine algae is: green algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein in parts by weight, comprises 41% sugar, 59% protein,
  • the molecular weight is 3kDa
  • the marine algae is: cyanobacteria
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein in parts by weight, comprises 99% sugar, 1% protein,
  • the molecular weight is 3000kDa
  • the marine algae is: gold algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein in parts by weight, comprises 26% sugar and 74% protein.
  • the molecular weight is 200kDa
  • the marine algae is: red algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • Example 6 A drug for treating asthma
  • the drug is a marine algae glycoprotein
  • the marine algae glycoprotein in parts by weight, comprises 7% sugar, 85% protein,
  • the molecular weight is 1000kDa;
  • the marine algae is: brown algae;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • the glycoprotein described in the above Examples 1-6 further includes a pigment; the pigment is a natural pigment contained in the algae substance.
  • the drug is a glycoprotein
  • the glycoprotein by weight content, comprises 1-99% sugar, 1-99% protein
  • the molecular weight is 0.2-30000 kDa
  • the sugar is a polysaccharide
  • the drugs include synthetic glycoproteins and synthetic polysaccharides and proteins.
  • the protein comprises 20 amino acids and 8 synthetic amino acids
  • the preparation method of the medicine the glycoprotein is prepared into capsules, tablets and the like according to a conventional process; the mixture of the polysaccharide and the protein is formed into capsules, tablets and the like according to a conventional process.
  • mice The male mice used in this experiment were 6 weeks old;
  • the sensitized mice were divided into 9 groups, the first to sixth groups were treated with the drugs described in Examples 1-6 of the present invention, and the type 25 blunt stainless steel needle was administered intragastrically. Each time 1g, 3 times a day for 17 consecutive days; Group 7 was treated with dexamethasone, 0.5 ml/kg dexamethasone was injected intraperitoneally daily; Group 8 was a model control group, and intraperitoneal saline was administered daily; The group is the 9th group and no treatment is performed.
  • mice APTI Group Number of mice APTI (cm column per second) Example 1 15 880 ⁇ 29 Example 2 15 865 ⁇ 24 Example 3 15 861 ⁇ 25 Example 4 15 800 ⁇ 34 Example 5 15 726 ⁇ 29 Example 6 15 795 ⁇ 42 Dexamethasone treatment group 15 565 ⁇ 31 Model control group 15 1245 ⁇ 110 Blank control group 15 430 ⁇ 26
  • the airway pressure-time index (APTI) level of the drug and dexamethasone treatment groups of Examples 1-6 of the present invention was significantly lower than that of the model control group, and the drug treatment group and the dexamethasone treatment group of the present invention were used. There is no significant difference between the two, and the airway hyperresponsiveness can be completely eliminated.
  • the glycoproteins, airway pressure-time index (APTI) described in Examples 1-6 of the present invention are 726-880 cm per second, Example 5 and Example 6 is a preferred embodiment.
  • mice are killed and the lungs are lavaged with Hewlett-Packard (HBSS) pre-cooled with 1.0 ml of ice-free calcium bath, and the lavage fluid is collected for pre-cooling.
  • HBSS Hewlett-Packard
  • 1000 g was centrifuged at 4 ° C for 10 minutes, and the total number of cells was measured by a hemocytometer. After staining with a Diff-Quik system, each cell was counted under a microscope for 500 cells, and the cells were counted and counted.
  • Histological examination The main organs of the mice after autopsy were fixed with neutral formalin solution, and the 5 micron paraffin sections of the organs were stained with hematoxylin and red periodic acid-Schiff reagent and examined by microscopy.
  • the total number of cells in the tracheal lavage fluid and the percentage of eosinophils were determined, and the total number of cells in the drug treatment group and the dexamethasone treatment group of the present invention was determined.
  • the model control group contained 43.6% of eosinophils, while the eosinophils in the glycoprotein treatment group and the dexamethasone treatment group of the present invention were significantly reduced, indicating that the drug of the present invention was used.
  • Pulmonary inflammation can be treated, and Example 5 and Example 6 are preferred embodiments.
  • Example 7 The experimental method described in Example 7 was used, and the modification was carried out in the treatment group of the present invention, only the glycoprotein described in Example 6 was used, and different feeding concentrations were set, and the experiment was carried out. The results are shown in Table 3 and Table 4.
  • IFN- ⁇ interleukin-4
  • IL-5 interleukin-5
  • IL-13 interleukin-13
  • mice The male mice used in this experiment were 6 weeks old;
  • the sensitized mice were divided into 8 groups, the first to sixth groups were treated with the drugs described in Examples 1-6 of the present invention, and the type 25 blunt stainless steel needle was administered intragastrically. 1 ml each time, twice a day for 17 consecutive days; group 7 was treated with dexamethasone, 0.5 ml/kg dexamethasone was intraperitoneally daily; group 8 was a saline control group, and saline was administered intraperitoneally daily.
  • Example 5 and Example 6 are preferred embodiments.
  • the marine algae glycoprotein in parts by weight, comprises 11% sugar, 85% protein,
  • the molecular weight is 8kDa
  • the marine algae is: spirulina
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • Example 10 A drug for treating asthma
  • Example 11 A drug for treating asthma
  • Example 12 A drug for treating asthma
  • Example 13 A drug for treating asthma
  • the marine algae glycoprotein in parts by weight, comprises 25% sugar, 75% protein,
  • the molecular weight is 20kDa;
  • the marine algae is: chlorella;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • Example 14 A drug for treating asthma
  • weight content it includes 29 parts of marine algae glycoprotein, 8 parts of glucuronic acid, and 5 parts of green barley.
  • Example 15 A drug for treating asthma
  • Example 16 A drug for treating asthma
  • Example 7 According to the test methods described in Example 7 and Example 8, the drugs described in Example 9 to Example 16 were used, and the application effects were as follows:
  • mice APTI Group Number of mice APTI (cm column per second)
  • Example 9 15 700 ⁇ 29
  • Example 10 15 580 ⁇ 24
  • Example 11 15 703 ⁇ 25
  • Example 12 15 699 ⁇ 34
  • Example 13 15 701 ⁇ 29
  • Example 14 15 575 ⁇ 32
  • Example 15 15 705 ⁇ 40
  • Example 16 15 700 ⁇ 41 Dexamethasone treatment group 15 565 ⁇ 31
  • Example 10 is the most preferred embodiment
  • Example 13-16 changed the weight ratio of marine algae glycoprotein, glucuronic acid, and strontium. From the experimental results, Example 14 is the most preferred embodiment.
  • Example 17 A drug for treating asthma
  • the marine algae glycoprotein in parts by weight, comprises 26% sugar and 74% protein.
  • the molecular weight is 8kDa
  • the marine algae is: hair dish;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • Example 18 A drug for treating asthma
  • Example 20 A drug for treating asthma
  • the marine algae glycoprotein in parts by weight, comprises 41% sugar, 59% protein,
  • the molecular weight is 50kDa
  • the marine algae is: seaweed;
  • the sugar is a polysaccharide
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein includes: asparagine, cysteine, lysine, arginine, serine, threonine.
  • Example 21 A drug for treating asthma
  • Example 22 A drug for treating asthma
  • Example 7 According to the test methods described in Example 7 and Example 8, the drugs described in Example 9 to Example 16 were used, and the application effects were as follows:
  • mice APTI Group Number of mice APTI (cm column per second)
  • Example 17 15 670 ⁇ 28
  • Example 18 15 460 ⁇ 23
  • Example 19 15 680 ⁇ 22
  • Example 20 15 675 ⁇ 28
  • Example 21 15 450 ⁇ 27
  • Example 22 15 672 ⁇ 30 Dexamethasone treatment group 15 565 ⁇ 31
  • Example 18 is the most preferred embodiment
  • Example 21 is the most preferred embodiment.
  • the marine algae glycoprotein in parts by weight, comprises 10% sugar, 80% protein,
  • the molecular weight is 8kDa
  • the marine algae is: cyanobacteria
  • the sugar in parts by weight, comprises the following components: xylose 16 parts, fucose 12 parts, arabinose 17 parts;
  • the protein in parts by weight, includes the following components: 10 parts of asparagine, 13 parts of cysteine, and 19 parts of lysine.
  • Example 24 A drug for treating asthma
  • the marine algae glycoprotein in parts by weight, comprises 60% sugar and 29% protein.
  • the molecular weight is 20kDa;
  • the marine algae is: cyanobacteria
  • the sugar in parts by weight, comprises the following components: xylose 16 parts, fucose 12 parts, arabinose 17 parts;
  • the protein in parts by weight, includes the following components: 10 parts of asparagine, 13 parts of cysteine, and 19 parts of lysine.
  • Example 25 A drug for treating asthma
  • marine algae glycoprotein 80 parts of marine algae glycoprotein, 10 parts of Ganoderma lucidum, 8 parts of Ranunculus, 7 parts of medlar, 9 parts of Clematis, 5 parts of bamboo ginseng; said marine algae glycoprotein, in parts by weight, including sugar 15 %, protein 75%,
  • the molecular weight is 35kDa
  • the marine algae is: cyanobacteria
  • the sugar in parts by weight, comprises the following components: xylose 16 parts, fucose 12 parts, arabinose 17 parts;
  • the protein in parts by weight, includes the following components: 10 parts of asparagine, 13 parts of cysteine, and 19 parts of lysine.
  • Example 26 A drug for treating asthma
  • the marine algae glycoprotein in parts by weight, comprises 20% sugar, 70% protein,
  • the molecular weight is 200kDa
  • the marine algae is: cyanobacteria
  • the sugar in parts by weight, comprises the following components: 25 parts of xylose, 22 parts of fucose, and 31 parts of arabinose;
  • the protein in parts by weight, includes the following components: 27 parts of asparagine, 23 parts of cysteine, and 46 parts of lysine.
  • Example 27 A method for preparing a medicament for treating asthma
  • the marine algae glycoprotein powder and the traditional Chinese medicine powder are uniformly mixed to form capsules, tablets, granules and the like.
  • Example 7 According to the test methods described in Example 7 and Example 8, the drugs described in Example 23 to Example 26 were used, and the application effects were as follows:
  • mice APTI Group Number of mice APTI (cm column per second)
  • Example 23 15 470 ⁇ 28
  • Example 24 15 465 ⁇ 23
  • Example 25 15 480 ⁇ 22
  • Example 26 15 475 ⁇ 28
  • Dexamethasone treatment group 15 565 ⁇ 31
  • the medicament of the present invention has a pH of between 5.3 and 9.8, preferably between 6.5 and 7.5.
  • the invention has been subjected to a large number of tests, and the invention has been carried out by performing a plurality of tests on a mixture of marine shells, bones of livestock and poultry, glycoprotein extracted from the skeleton of marine animals, and polysaccharides and proteins.
  • Example 28 A drug for treating asthma
  • the drug is a mixture of polysaccharides and proteins
  • the drug in parts by weight, comprises 1-99% polysaccharide, 1-99% protein;
  • the polysaccharide comprises: xylose, fucose, arabinose, glucose, galactose, mannose, rhamnose;
  • the protein comprises: asparagine, cysteine, lysine, arginine, serine, threonine, alanine, aspartic acid, glutamine, glutamic acid, histidine, Isoleucine, glycine, leucine, methionine, phenylalanine, valine, tyrosine, valine.
  • the polysaccharide and protein mixture has a molecular weight of 0.2-3000 kDa
  • the protein has a molecular weight of 0.2-3000 kDa.
  • the pigment is a natural pigment contained in an algae substance
  • the algal protein may be phycocyanin, phycoerythrin or phycoerythrin.
  • the glycoproteins include synthetic glycoproteins and synthetic polysaccharides and proteins.
  • the drug of the invention has a non-toxic dose of 1.6 g/kg for oral administration for dogs for 12 weeks, which is equivalent to 50 times of the equivalent dose for humans, so the safety of the clinical test can be considered to be guaranteed.
  • the medicament of the present invention may also be a health care product or a food.

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Abstract

本发明提供一种用于治疗哮喘的药物，所述药物为糖蛋白或多糖和蛋白质的混合物或多肽或蛋白。

Description

一种用于治疗哮喘的药物 技术领域
本发明涉及一种用于治疗哮喘的药物，属于医药技术领域。
背景技术
哮喘是呼吸道常见病，是指由多种变性细胞，如嗜酸粒细胞、肥大细胞、T细胞、气道上皮细胞等和细胞组分参与的慢性气道炎症。哮喘患者的临床表现为发作性的喘息、气急、胸闷或咳嗽等症状，少数患者还可能以胸痛为主要表现，该病在世界范围的发病率很高，全球哮喘患者约3亿人，中国哮喘患者约3000万。该病易反复发作，可导致慢性阻塞性肺疾病、肺气肿、肺心病、心功能衰竭、呼吸衰竭等并发症，严重危害人们的身体健康，减弱劳动能力，降低生活质量，且难以得到根治。由于抗生素对哮喘病没有治疗作用，反复使用抗生素容易造成耐药，目前临床上常用以抑制炎症为主的激素、茶碱类药物来控制哮喘症状，虽有一定的疗效，但是长期服用会产生骨质疏松、高血压、糖尿病等副作用。
目前，用于治疗哮喘的西药有很多种，包括糖皮质激素类、β2受体激动剂、茶碱类和部分抗过敏药物，用西药治疗哮喘的不足是疗效欠佳、需联合用药和副作用明显。为此，有关的科研单位和科技工作者研究用中草药治疗哮喘的作用机理和疗效，并取得了一些科研成果。如美国专利申请号为09/800,815、名称为“草药治疗过敏和哮喘”，公开了以中药经验处方“加味三子汤”为基础的技术方案，该技术方案是提取紫苏子、葶苈子、杏仁、黄芩、苦参、当归、白芍、葛根、桔梗、甘草、大枣、生姜和珍珠母十三味中草药的有效成分，用现代医学研究体系评价组方各成分解除气道炎症、降低高反应性的作用机理，进一步研究其毒性反应。研究结果表明，该组方具有抗气道高应答、抗气道炎症和调节T辅助细胞(TH1、TH2)应答类型的作用，可用于过敏性哮喘的治疗。但由于该组方中有十三味中草药，中草药的种类太多，究竟是哪几味中草药在其中承担了主要作用，尚不得知，因此，药品质量难于保证，不便于产业化生产该药物。
专利：Polysaccharide prodn.from Gnida kraussiana-for treatment of respiratory infections，asthma，psoriasis，and certain chronic lymphoid leukaemia(s)、专利号为FR2513518(A1)，公开了：从非洲大草原的thymelaeaceous植物中提取的多糖，含有阿拉伯糖，木糖，鼠李糖，果糖，半乳糖和葡萄糖，质量比例为2∶51∶6∶3∶21∶15，对哮喘、湿疹等有一定效果。
专利：小分子糖蛋白生物制剂及其制备方法CN92114257.9公开了：用于治疗哮喘的小分子糖蛋白生物制剂，最大分子量Mw12551.7，最小分子量Mw1031.82，总的重均分子量 Mw6337.07，紫外光谱：最大吸收峰为236nm，最小吸收峰为320nm，OD260/OD280＝2.7±0.1，每毫升含氮量10±1mg，含有18种氨基酸，其中胱氨酸含量为2.96毫克/100毫升。
发明内容
本发明为解决现有技术中存在的不足，提供一种用于治疗哮喘的药物，以实现以下发明目的：
(1)本发明所述药物，有效降低小鼠哮喘模型的气道高反应性，解除气管痉挛。
(2)本发明所述药物，能够有效治疗肺部炎症，减少炎性细胞浸润，嗜酸性粒细胞的百分比为14.6-16.6％。
(3)本发明所述药物，提高可以抑制哮喘发作的γ-干扰素(IFN-γ)和抗体，降低可以诱发哮喘的白介素-4(IL-4)、白介素-5(IL5)、白介素-13(IL-13)含量。
为解决以上技术问题，本发明采用如下技术方案：
一种用于治疗哮喘的药物，其特征在于：所述药物为糖蛋白，或多糖和蛋白质的混合物或多肽或蛋白，所述糖蛋白包括糖1-99％，蛋白质1-99％；所述多糖和蛋白质的混合物，以重量含量计，包括多糖1-99％，蛋白质1-99％。所述糖蛋白，分子量为0.2-3000kDa；
以下是对上述技术方案的进一步改进：
所述药物为海洋藻类糖蛋白。
所述海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；所述海洋藻类多糖和蛋白质的混合物，以重量含量计，包括多糖1-99％，蛋白质1-99％。
所述海洋藻类糖蛋白，分子量为0.2-3000kDa；
所述多糖和蛋白质的混合物，多糖的分子量为0.2-3000kDa，蛋白质的分子量为0.2-3000kDa。
所述药物，以重量含量计，包括糖蛋白1-99份、葡萄糖醛酸1-25份。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、葡萄糖醛酸1-28份。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、葡萄糖醛酸1-24份、青黛2-11份。
所述藻类为蓝藻、绿藻、红藻、金藻、褐藻中的一种或多种。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、青黛6-15份、紫苏7-17份、葡萄糖醛酸1-14份。
所述药物，以重量含量计，包括海洋藻类糖蛋白1-99份、青黛6-15份、紫苏7-17份、菜菔子8-12份、谷芽8-13份。
所述药物，以重量含量计，包括糖1-99％，蛋白质1-99％。
所述海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％。
相对现有技术，本发明的有益效果为：
(1)本发明所述药物，有效降低小鼠哮喘模型的气道高反应性，解除气管痉挛，气道压力-时间指数(APTI)为726-880每秒厘米水柱。
(2)本发明所述药物，能够有效治疗肺部炎症，减少炎性细胞浸润，嗜酸性粒细胞的百分比为14.6-16.6％，模型对照组中含有43.6％的嗜酸性粒细胞。
(3)本发明所述药物，提高可以抑制哮喘发作的γ-干扰素(IFN-γ)和抗体，降低可以诱发哮喘的白介素-4(IL-4)、白介素-5(IL 5)、白介素-13(IL-13)，白介素-4(IL-4)含量为20-48 pg/ml；白介素-5(IL-5)含量为404-661pg/ml；白介素-13(IL-13)含量为289-556pg/ml；γ-干扰素(IFN-γ)含量为5124-6647pg/ml。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1一种用于治疗哮喘的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量份计，包括糖1％，蛋白质99％，
分子量为0.2kDa；
所述海洋藻类为：蓝藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸；
实施例2一种用于治疗哮喘的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量份计，包括糖25％，蛋白质75％，
分子量为55kDa；
所述海洋藻类为：绿藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例3一种用于治疗哮喘的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量份计，包括糖41％，蛋白质59％，
分子量为3kDa；
所述海洋藻类为：蓝藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例4一种用于治疗哮喘的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量份计，包括糖99％，蛋白质1％，
分子量为3000kDa；
所述海洋藻类为：金藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例5一种用于治疗哮喘的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量份计，包括糖26％，蛋白质74％，
分子量为200kDa；
所述海洋藻类为：红藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例6一种用于治疗哮喘的药物
所述药物为海洋藻类糖蛋白；
所述海洋藻类糖蛋白，以重量份计，包括糖7％，蛋白质85％，
分子量为1000kDa；
所述海洋藻类为：褐藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
上述实施例1-6所述的糖蛋白，还包括色素；所述色素为藻类物质中含有的天然色素。
对上述实施例1-6进行概括为：
一种用于治疗哮喘的药物
所述药物，为糖蛋白；
所述糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；
分子量为0.2-30000kDa；
所述糖为多糖；
所述药物，包括合成糖蛋白及合成多糖和蛋白质。
所述蛋白包括20种氨基酸和8种人工合成氨基酸；
所述药物的制备方法：糖蛋白按照常规工艺制成胶囊、片剂等；多糖和蛋白的混合物按照常规工艺制成胶囊、片剂等。
实施例7所述药物在治疗哮喘中的应用
一、降低气道高反应性，解除气管痉挛，减少炎性细胞浸润
(1)实验用小鼠：本实验所用的雄性小鼠为6周龄；
(2)用药量：每只小鼠给药量为3g/天，每天3次。
(3)抗原致敏、发敏及治疗：将200微克伴清蛋白(CA)和2毫克二硝基苯(DNP)结合的清蛋白溶解在0.3毫升的缓冲液PBS中，给小鼠腹膜内注射致敏，共两次，间隔一周。在第二次致敏7天后，将小鼠麻醉，用含100微克伴清蛋白(CA)的0.05毫升缓冲液PBS气管内用药来发敏，在第20天和第30天时，用相同的方法和两倍剂量继续进行发敏。在初次发敏24小时后，将发敏的小鼠分为9组，第1-6组用本发明实施例1-6所述的药物治疗，用25型计量钝不锈钢针胃内给药，每次1g，每天3次，连续17天；第7组用地塞米松治疗，每天腹膜内注射0.5毫升/公斤的地塞米松；第8组是模型对照组，每天腹膜内给予盐水处理；空白对照组为第9组，不进行任何处理。
(4)迟发相气道反应的测定：最后一次发敏后的第三天，将上述8组的小鼠静脉内注射乙酰胆碱后，连同第9组测定气道压力变化来反映气道应答情况；具体步骤是将小鼠用戊巴比妥麻醉并用18号气管插管保持呼吸道畅通，用RSP1002型压力可控呼吸系统保持每分钟120次呼吸，潮气量恒定在0.2毫升，每只小鼠静脉内注射十烃溴铵25毫克/公斤来诱导肌肉松弛，在气管插管上连接压力转导器来测定气道压力，当气道压力稳定2分钟后，每只小 鼠静脉内注射乙酰胆碱50微克/公斤，用VENTP软件系统观察并记录4分钟的气道压力变化，参照气道压力——时间指数(APTI)(每秒厘米水柱)计算气道压力峰值的时间——组合变化，用来反映气道应答反应。测定的具体数值见表1。
表1
组别 小鼠个数 APTI(每秒厘米水柱)
实施例1 15 880±29
实施例2 15 865±24
实施例3 15 861±25
实施例4 15 800±34
实施例5 15 726±29
实施例6 15 795±42
地塞米松治疗组 15 565±31
模型对照组 15 1245±110
空白对照组 15 430±26
用本发明实施例1-6所述药物和地塞米松治疗组的气道压力——时间指数(APTI)水平显著低于模型对照组，用本发明的药物治疗组与地塞米松治疗组之间没有显著差异性，可以完全消除气道高反应性，本发明实施例1-6所述的糖蛋白，气道压力-时间指数(APTI)为726-880每秒厘米水柱，实施例5和实施例6是优选实施例。
(5)细胞分类计数：上述的气道应答测量结束后，杀死小鼠并用1.0毫升不含钙镁的冰浴预冷后的亨氏液(HBSS)灌洗肺脏，灌洗液收集到预冷的试管中，1000克4℃离心10分钟，细胞总数用血细胞计数器测定，用Diff-Quik系统染色后每张细胞片显微镜下计数500个细胞的方法，进行细胞的分类计数，
组织学检查：尸检后的小鼠主要脏器用中性福尔马林液固定，脏器5微米石蜡切片用苏木素伊红和过碘酸——席夫试剂染色后显微镜检查。
具体数值见下表2：
表2
Figure PCTCN2017071815-appb-000001
为确定在消除气道高反应性后是否伴有炎症减轻，测定了气管灌洗液中的细胞总数和嗜酸性粒细胞的百分比，用本发明的药物治疗组和地塞米松治疗组的细胞总数显著少于模型对照组，模型对照组中含有43.6％的嗜酸性粒细胞，而用本发明的糖蛋白治疗组和地塞米松治疗组的嗜酸性粒细胞均明显减少，说明用本发明的药物能够治疗肺部炎症，实施例5和实施例6是优选实施例。
实施例8所述药物在治疗哮喘中的应用
采用实施例7所述的实验方法，改变之处为，本发明治疗组，只采用实施例6所述的糖蛋白，设置不同的喂食浓度，进行实验，结果如表3、表4。
表3
Figure PCTCN2017071815-appb-000002
表4
Figure PCTCN2017071815-appb-000003
二、提高可以抑制哮喘发作的γ-干扰素(IFN-γ)和抗体，降低可以诱发哮喘的白介素-4(IL-4)、白介素-5(IL 5)、白介素-13(IL-13)，从而起到治疗哮喘的作用。
(1)实验用小鼠：本实验所用的雄性小鼠为6周龄；
(2)用药量：每只小鼠给药3g/天，每天3次。
(3)抗原致敏、发敏及治疗：将200微克伴清蛋白(CA)和2毫克二硝基苯(DNP)结合的清蛋白溶解在0.3毫升的缓冲液PBS中，给小鼠腹膜内注射致敏，共两次，间隔一周。在第二次致敏7天后，将小鼠麻醉，用含100微克伴清蛋白(CA)的0.05毫升缓冲液PBS气管内用药来发敏，在第20天和第30天时，用相同的方法和两倍剂量继续进行发敏。在初次发敏24小时后，将发敏的小鼠分为8组，第1-6组用本发明实施例1-6所述的药物治疗，用25型计量钝不锈钢针胃内给药，每次1毫升，每天两次，连续17天；第7组用地塞米松治疗，每天腹膜内注射0.5毫升/公斤的地塞米松；第8组是盐水对照组，每天腹膜内给予盐水处理。
(4)细胞培养和细胞因子定量：取每小组小鼠的脾细胞，悬于完全培养液中，完全培养液选用RPMI1640，在该完全培养液中加入10％FBS、1％的青霉素、1％的链霉素、1％的谷氨酰胺，还加入2微克/毫升的刀豆素A(ConA)作为阳性对照并设阴性对照，完全培养液中含有50微克/毫升的伴清蛋白(CA)；培养72小时后收集上清；上清中的白介素-4(IL-4)、白介素-5(IL-5)、白介素-13(IL-13)和γ-干扰素(IFN-γ)的水平测定，用ELISA方法，具体数值见表5：
表5
Figure PCTCN2017071815-appb-000004
实施例5和实施例6是优选实施例。
实施例9一种用于治疗哮喘的药物
以重量含量计，包括海洋藻类糖蛋白1份、葡萄糖醛酸1份。
所述海洋藻类糖蛋白，以重量份计，包括糖11％，蛋白质85％，
分子量为8kDa；
所述海洋藻类为：螺旋藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例10一种用于治疗哮喘的药物
同实施例9，只改变海洋藻类糖蛋白和葡萄糖醛酸的重量份配比，改变为：
以重量含量计，包括海洋藻类糖蛋白32份、葡萄糖醛酸9份。
实施例11一种用于治疗哮喘的药物
同实施例9，只改变海洋藻类糖蛋白和葡萄糖醛酸的重量份配比，改变为：
以重量含量计，包括海洋藻类糖蛋白70份、葡萄糖醛酸15份。
实施例12一种用于治疗哮喘的药物
同实施例9，只改变海洋藻类糖蛋白和葡萄糖醛酸的重量份配比，改变为：
以重量含量计，包括海洋藻类糖蛋白99份、葡萄糖醛酸28份。
实施例13一种用于治疗哮喘的药物
以重量含量计，包括海洋藻类糖蛋白1份、葡萄糖醛酸1份、青黛2份。
所述海洋藻类糖蛋白，以重量份计，包括糖25％，蛋白质75％，
分子量为20kDa；
所述海洋藻类为：小球藻；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例14一种用于治疗哮喘的药物
同实施例13，只改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，改变为：
以重量含量计，包括海洋藻类糖蛋白29份、葡萄糖醛酸8份、青黛5份。
实施例15一种用于治疗哮喘的药物
同实施例13，只改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，改变为：
以重量含量计，包括海洋藻类糖蛋白57份、葡萄糖醛酸17份、青黛8份。
实施例16一种用于治疗哮喘的药物
同实施例13，只改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，改变为：
以重量含量计，包括海洋藻类糖蛋白99份、葡萄糖醛酸24份、青黛11份。
上述实施例9-实施例16所述药物在治疗哮喘中的应用：
采用实施例7、实施例8所述的试验方法，采用实施例9-实施例16所述药物，应用效果如下：
表6本发明药物对降低气道高反应性的效果
组别 小鼠个数 APTI(每秒厘米水柱)
实施例9 15 700±29
实施例10 15 580±24
实施例11 15 703±25
实施例12 15 699±34
实施例13 15 701±29
实施例14 15 575±32
实施例15 15 705±40
实施例16 15 700±41
地塞米松治疗组 15 565±31
模型对照组 15 1245±110
空白对照组 15 430±26
表7本发明药物对减少炎性细胞浸润的效果
Figure PCTCN2017071815-appb-000005
表8本发明药物对IL-4、IL-5、IL-13、IFN-γ的影响
Figure PCTCN2017071815-appb-000006
实施例9-12，只改变海洋藻类糖蛋白和葡萄糖醛酸的重量配比，通过实验结果可知，实施例10是最优选的实施例；
实施例13-16改变海洋藻类糖蛋白、葡萄糖醛酸、青黛的重量配比，通过实验结果可知，实施例14是最优选的实施例。
实施例17一种用于治疗哮喘的药物
以重量份计，包括海洋藻类糖蛋白1份、青黛6份、紫苏7份、葡萄糖醛酸1份。
所述海洋藻类糖蛋白，以重量份计，包括糖26％，蛋白质74％，
分子量为8kDa；
所述海洋藻类为：头发菜；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例18一种用于治疗哮喘的药物
同实施例17，只改变海洋藻类糖蛋白、青黛、紫苏、葡萄糖醛酸的重量份配比，改变为：
以重量份计，包括海洋藻类糖蛋白42份、青黛13份、紫苏14份、葡萄糖醛酸11份。
实施例19一种用于治疗哮喘的药物
同实施例17，只改变海洋藻类糖蛋白、青黛、紫苏、葡萄糖醛酸的重量份配比，改变为：
以重量份计，包括海洋藻类糖蛋白99份、青黛15份、紫苏17份、葡萄糖醛酸14份。
实施例20一种用于治疗哮喘的药物
以重量份计，包括海洋藻类糖蛋白1份、青黛6份、紫苏7份、菜菔子8份、谷芽8份。
所述海洋藻类糖蛋白，以重量份计，包括糖41％，蛋白质59％，
分子量为50kDa；
所述海洋藻类为：紫菜；
所述糖为多糖；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸。
实施例21一种用于治疗哮喘的药物
同实施例20，只改变海洋藻类糖蛋白、青黛、紫苏、菜菔子、谷芽的重量份配比，改变为：
以重量份计，包括海洋藻类糖蛋白41份、青黛13份、紫苏9份、菜菔子10份、谷芽12份。
实施例22一种用于治疗哮喘的药物
同实施例20，只改变海洋藻类糖蛋白、青黛、紫苏、菜菔子、谷芽的重量份配比，改变为：
以重量份计，包括海洋藻类糖蛋白99份、青黛15份、紫苏17份、菜菔子12份、谷芽13份。
上述实施例9-实施例16所述药物在治疗哮喘中的应用：
采用实施例7、实施例8所述的试验方法，采用实施例9-实施例16所述药物，应用效果如下：
表9本发明药物对降低气道高反应性的效果
组别 小鼠个数 APTI(每秒厘米水柱)
实施例17 15 670±28
实施例18 15 460±23
实施例19 15 680±22
实施例20 15 675±28
实施例21 15 450±27
实施例22 15 672±30
地塞米松治疗组 15 565±31
模型对照组 15 1245±110
空白对照组 15 430±26
表10本发明药物对减少炎性细胞浸润的效果
Figure PCTCN2017071815-appb-000007
表11本发明药物对IL-4、IL-5、IL-13、IFN-γ的影响
Figure PCTCN2017071815-appb-000008
实施例17-19，只改变海洋藻类糖蛋白、青黛、紫苏、葡萄糖醛酸的重量份配比，通过实验结果可知，实施例18是最优选的实施例；
实施例20-22，只改变海洋藻类糖蛋白、青黛、紫苏、菜菔子、谷芽的重量份配比，通过实验结果可知，实施例21是最优选的实施例。
实施例23一种用于治疗哮喘的药物
以重量份，包括以下组分：
海洋藻类糖蛋白70份、葶苈子5份、天南星9份、柿蒂4份、金铁锁3份、刺五加7份。
所述海洋藻类糖蛋白，以重量份计，包括糖10％，蛋白质80％，
分子量为8kDa；
所述海洋藻类为：蓝藻；
所述糖，以重量份计，包括如下组分：木糖16份，岩藻糖12份，阿拉伯糖17份；
所述蛋白质，以重量份，包括如下组分：天冬酰胺10份、半胱氨酸13份、赖氨酸19份。
实施例24一种用于治疗哮喘的药物
以重量份，包括以下组分：
海洋藻类糖蛋白75份、乌梅8份、华山参4份、枳实7份、川乌9份、山药10份；
所述海洋藻类糖蛋白，以重量份计，包括糖60％，蛋白质29％，
分子量为20kDa；
所述海洋藻类为：蓝藻；
所述糖，以重量份计，包括如下组分：木糖16份，岩藻糖12份，阿拉伯糖17份；
所述蛋白质，以重量份，包括如下组分：天冬酰胺10份、半胱氨酸13份、赖氨酸19份。
实施例25一种用于治疗哮喘的药物
以重量份，包括以下组分：
海洋藻类糖蛋白80份、灵芝10份、猫爪草8份、娑罗子7份、威灵仙9份、竹节参5份；所述海洋藻类糖蛋白，以重量份计，包括糖15％，蛋白质75％，
分子量为35kDa；
所述海洋藻类为：蓝藻；
所述糖，以重量份计，包括如下组分：木糖16份，岩藻糖12份，阿拉伯糖17份；
所述蛋白质，以重量份，包括如下组分：天冬酰胺10份、半胱氨酸13份、赖氨酸19份。
实施例26一种用于治疗哮喘的药物
以重量份，包括以下组分：
海洋藻类糖蛋白78份、苦参12份、金沸草8份、陈皮7份、大风艾9份、旋覆花10份；
所述海洋藻类糖蛋白，以重量份计，包括糖20％，蛋白质70％，
分子量为200kDa；
所述海洋藻类为：蓝藻；
所述糖，以重量份计，包括如下组分：木糖25份，岩藻糖22份，阿拉伯糖31份；
所述蛋白质，以重量份，包括如下组分：天冬酰胺27份、半胱氨酸23份、赖氨酸46份。
实施例27一种用于治疗哮喘的药物的制备方法
包括以下步骤：
(1)称量
按照实施例23-26的配方，称取各组分；
(2)中药的清洗
将配方中除糖蛋白以外的各中药组分进行清洗干净；
(3)中药的浸提
将中药加入12倍体积的清水，在50℃条件下浸泡1h，然后提高温度至60℃，压力20kPa，超声辅助浸提，所述超声，功率为130W，频率为250kHz，处理时间4～5s，间隙时间2～6s，1个小时后，过滤，收集滤液，喷雾干燥，制备中药粉。
(4)加入糖蛋白
将海洋藻类糖蛋白粉末和中药粉混合均匀，制成胶囊、片剂、粒剂等不同剂型。
上述实施例23-实施例26所述药物在治疗哮喘中的应用：
采用实施例7、实施例8所述的试验方法，采用实施例23-实施例26所述药物，应用效果如下：
表12本发明药物对降低气道高反应性的效果
组别 小鼠个数 APTI(每秒厘米水柱)
实施例23 15 470±28
实施例24 15 465±23
实施例25 15 480±22
实施例26 15 475±28
地塞米松治疗组 15 565±31
模型对照组 15 1245±110
空白对照组 15 430±26
表13本发明药物对减少炎性细胞浸润的效果
Figure PCTCN2017071815-appb-000009
表14本发明药物对IL-4、IL-5、IL-13、IFN-γ的影响
Figure PCTCN2017071815-appb-000010
本发明所述药物，pH为5.3-9.8之间，优选为6.5-7.5之间。
本发明经过大量试验，我们采取了海洋贝壳类、畜禽类的骨头、海洋动物的骨架中提取的糖蛋白及多糖、蛋白的混合物进行多次试验，也能实现本发明的发明目的。
实施例28一种用于治疗哮喘的药物
所述药物，为多糖、蛋白质的混合物；
所述药物，以重量份计，包括多糖1-99％、蛋白质1-99％；
所述多糖，包括：木糖、岩藻糖、阿拉伯糖、葡萄糖、半乳糖、甘露糖、鼠李糖；
所述蛋白质，包括：天冬酰胺、半胱氨酸、赖氨酸、精氨酸、丝氨酸、苏氨酸、丙氨酸、天冬氨酸、谷氨酰胺、谷氨酸、组氨酸、异亮氨酸、甘氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、酪氨酸、缬氨酸。
所述多糖和蛋白质的混合物，多糖的分子量为0.2-3000kDa，蛋白质的分子量为0.2-3000kDa。
所述多糖和蛋白的混合物，进一步为藻类多糖和藻类蛋白的混合物；
所述藻类多糖和藻类蛋白的混合物，还包括色素；
所述色素为藻类物质中含有的天然色素；
所述藻类蛋白可以是藻蓝蛋白、藻红蛋白或藻黄色蛋白。
所述糖蛋白包括合成糖蛋白及合成多糖、蛋白。
本发明所述药物对犬经口给药12周无毒性反应剂量为1.6g/kg，相当于人用等效剂量的50倍，故可认为临床试验的安全性可以得到保障。
本发明所述药物，还可以是保健品或食品。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (10)

  1. 一种用于治疗哮喘的药物，其特征在于：所述药物为糖蛋白或多糖和蛋白质的混合物或多肽或蛋白。
  2. 根据权利要求1所述的一种用于治疗哮喘的药物，其特征在于：所述药物为海洋藻类糖蛋白。
  3. 根据权利要求2所述的一种用于治疗哮喘的药物，其特征在于：所述糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；所述海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％；所述多糖和蛋白质的混合物，以重量含量计，包括糖1-99％，蛋白质1-99％。
  4. 根据权利要求2所述的一种用于治疗哮喘的药物，其特征在于：所述糖蛋白，分子量为0.2-3000kDa；所述海洋藻类糖蛋白，分子量为0.2-3000kDa；所述多糖和蛋白质的混合物，多糖的分子量为0.2-3000kDa，蛋白质的分子量为0.2-3000kDa。
  5. 根据权利要求1所述的一种用于治疗哮喘的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、葡萄糖醛酸1-28份。
  6. 根据权利要求1所述的一种用于治疗哮喘的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、葡萄糖醛酸1-24份、青黛2-11份。
  7. 根据权利要求2所述的一种用于治疗哮喘的药物，其特征在于：所述藻类为蓝藻、绿藻、红藻、金藻、褐藻中的一种或多种。
  8. 根据权利要求1所述的一种用于治疗哮喘的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、青黛6-15份、紫苏7-17份、葡萄糖醛酸1-14份。
  9. 根据权利要求1所述的一种用于治疗哮喘的药物，其特征在于：以重量含量计，包括糖蛋白1-99份、青黛6-15份、紫苏7-17份、菜菔子8-12份、谷芽8-13份。
  10. 根据权利要求5-9任一项所述的一种用于治疗糖尿病的药物，其特征在于：所述糖蛋白、海洋藻类糖蛋白，以重量含量计，包括糖1-99％，蛋白质1-99％。
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