CN113332318B - Pharmaceutical composition with effect of improving depression symptoms and preparation method thereof - Google Patents

Pharmaceutical composition with effect of improving depression symptoms and preparation method thereof Download PDF

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Publication number
CN113332318B
CN113332318B CN202110524134.3A CN202110524134A CN113332318B CN 113332318 B CN113332318 B CN 113332318B CN 202110524134 A CN202110524134 A CN 202110524134A CN 113332318 B CN113332318 B CN 113332318B
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composition
combination
needle mushroom
water
sodium
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CN113332318A (en
Inventor
许瀛引
谢丽源
张志远
周洁
唐杰
何晓兰
陈影
彭卫红
王勇
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Sichuan Edible Fungi Research Institute
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Sichuan Edible Fungi Research Institute
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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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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Abstract

The invention relates to a pharmaceutical composition for improving depression symptoms, which comprises 50-80% of needle mushroom enzyme-deactivating water extract, 1-3% of theanine, 1-10% of probiotics, 5-30% of prebiotics, 5-10% of sugar substitute and a pharmaceutically acceptable carrier. The composition has the beneficial effects of improving depression symptoms, improving sleep, improving anxiety, improving memory, enhancing immunity and the like.

Description

Pharmaceutical composition with effect of improving depression symptoms and preparation method thereof
Technical Field
The invention relates to the field of medicines, and relates to a pharmaceutical composition with an effect of improving depression symptoms, and a preparation method and application thereof.
Background
In order to better retain the color, aroma, taste and nutrient components of the flammulina velutipes, the flammulina velutipes is often placed in boiling water for instant heating to be de-enzymed in industrial production so as to destroy and inhibit the enzyme activity in the flammulina velutipes, prevent the nutrient components in the flammulina velutipes from oxidative degradation and discoloration and off-taste, reduce the total number of bacteria and avoid bacterial pollution. The needle mushroom water-removing water contains rich nutrient components and high-content gamma-aminobutyric acid (GABA). Gamma-aminobutyric acid is an inhibitory neurotransmitter within the brain. Research shows that the GABA neuron activity of a depression model mouse is improved to promote the release of GABA neurotransmitter, and gamma-aminobutyric acid (GABA) has an antidepressant effect.
Many marketed products containing GABA, such as Alpinia oxyphylla extract, gamma-aminobutyric acid, phosphatidylserine, ginkgo (ginkgo) extract, cinnamon extract, earthworm protein powder and other plant extracts are refined to obtain the GABA. But has the defects of higher cost, poor treatment effect and the like.
Chinese patent application (CN202110400700. X) discloses a needle mushroom water extract with high gamma-aminobutyric acid content and a preparation method thereof, and all technical contents of the application are indispensable components of the application.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition with an effect of improving depression symptoms, which comprises 50-80% of needle mushroom enzyme-deactivated water extract, 1-3% of theanine, 1-10% of probiotics, 5-30% of prebiotics, 5-10% of sugar substitute and a pharmaceutically acceptable carrier.
In the preferred technical scheme of the invention, the content of the water extract of the needle mushroom in the composition after enzyme deactivation is 55-75%, preferably 60-70%.
In the preferable technical scheme of the invention, the content of gamma-aminobutyric acid in the water extract of needle mushroom after enzyme deactivation is 0.15-1%, preferably 0.3-0.8%, and more preferably 0.5-0.6%.
In the preferable technical scheme of the invention, the total amount of amino acids in the needle mushroom water extract after de-enzyming is 2-10%, preferably 3-8%, and more preferably 5-6%.
In a preferred embodiment of the present invention, the amino acid is selected from any one of aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, γ -aminobutyric acid, histidine, tryptophan, lysine, arginine, and proline, or a combination thereof.
In the preferred technical scheme of the invention, the content of protein in the needle mushroom water extract after enzyme deactivation is 2-10%, preferably 3-8%, and more preferably 5-6%.
In the preferred technical scheme of the invention, the preparation of the water extract of needle mushroom comprises the following steps: filtering needle mushroom water, adding 1-10% (w/v) dispersant into the filtrate, stirring, mixing, and spray drying the obtained dispersion.
In a preferred embodiment of the present invention, the filtration is selected from any one or a combination of centrifugal filtration, vacuum filtration, and vacuum filtration.
In the preferable technical scheme of the invention, the viscosity of the needle mushroom enzyme deactivating water is not lower than 1500CP.
In a preferred embodiment of the present invention, the dispersant is selected from any one of lactose, maltodextrin, mannitol, glucose, D-trehalose, lactose, maltodextrin, dextrin, hydroxypropyl- β -cyclodextrin, sucrose, or a combination thereof.
In the preferable technical scheme of the invention, the addition amount of the dispersing agent is 2-8%, and preferably 5-6%.
In the preferable technical scheme of the invention, the stirring time is 1-20min, and preferably 5-10min.
In the preferred technical scheme of the invention, the air inlet speed of the spray drying is 20-50m 3 H, preferably from 30 to 40m 3 /h。
In the preferred technical scheme of the invention, the inlet temperature of the spray drying nozzle is 80-120 ℃, and preferably 90-100 ℃.
In the preferable technical scheme of the invention, the gas flow rate of the spray drying is 400-800L/h, preferably 500-600L/h.
In the preferred technical scheme of the invention, the sample injection rate of the spray drying is 5-10ml/min, and preferably 7-8ml/min.
In the preferable technical scheme of the invention, the content of theanine in the composition is 1.5-2.5%, and is preferably 1.8-2%.
In a preferred technical scheme of the invention, the content of the probiotics in the composition is 2-8%, and preferably 4-6%.
In a preferred technical scheme of the invention, the probiotics are selected from any one or combination of lactobacillus casei, yeast, probiotic bacillus, clostridium butyricum, lactobacillus, bifidobacterium lactis, streptococcus thermophilus and actinomycetes.
In a preferred technical scheme of the invention, the addition amount of the probiotics in the composition is more than 1.5 hundred million/g of the composition.
In a preferred technical scheme of the invention, the content of the prebiotics in the composition is 10-25%, preferably 15-20%.
In a preferred technical scheme of the invention, the prebiotics are selected from any one of orange powder, inulin, fructo-oligosaccharide, galacto-oligosaccharide, manno-oligosaccharide, xylo-oligosaccharide, trehalose, L-arabinose and resistant dextrin or a combination thereof.
In a preferred technical scheme of the invention, any one or combination of curcumin, rhodiola rosea extract, broccoli extract, forsythia suspensa extract, saffron extract and 5-hydroxytryptophan is optionally added into the composition.
In a preferred embodiment of the present invention, the sugar substitute content of the composition is 6 to 9%, preferably 7 to 8%.
In a preferred technical scheme of the invention, the sugar substitute is selected from any one of or a combination of mogroside, erythritol, stevioside, xylitol, sorbitol and palatinit.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or a combination of a filler (also called diluent), a lubricant (also called glidant or antiadherent), a dispersant, a wetting agent, a binder, a regulator, a solubilizer (also called stabilizer), an antioxidant, an emulsifier, a flavoring agent and an aromatizing agent.
In a preferred technical scheme of the invention, the binder is selected from any one of syrup, acacia, gelatin, sorbitol, tragacanth, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, gelatin slurry, syrup, starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, starch slurry and polyvinylpyrrolidone or a combination thereof.
In a preferred technical scheme of the invention, the filler is selected from any one of lactose, powdered sugar, dextrin, starch or derivatives thereof, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, glycine, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch and corn starch or a combination thereof.
In a preferred technical scheme of the invention, the lubricant is selected from any one of or a combination of superfine silica powder, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil and polyethylene glycol.
In a preferred technical scheme of the invention, the disintegrating agent is selected from any one of starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and microcrystalline cellulose or a combination thereof.
In a preferred embodiment of the present invention, the wetting agent is selected from any one of sodium lauryl sulfate, water, alcohol, or a combination thereof.
In a preferred technical scheme of the invention, the emulsifier is selected from any one of polysorbate-80, sorbitan fatty acid, pluronic F-68, lecithin and soybean lecithin or a combination thereof.
In a preferred embodiment of the present invention, the acid-base regulator is selected from any one of inorganic acids and organic acids or a combination thereof, and preferably is any one of or a combination of citric acid, sodium citrate, malic acid, sodium malate, hydrochloric acid, acetic acid, sodium acetate, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, carbonic acid, sodium carbonate, sulfonic acid, sodium sulfonate, glutamic acid, tartaric acid, sodium tartrate, lactic acid, sodium lactate, fumaric acid, sodium fumarate, itaconic acid, ascorbic acid, sodium ascorbate, nicotinic acid, sodium nicotinate, fumaric acid, α -ketoglutaric acid, tartaric acid, sodium formate, acetic acid, oxalic acid, succinic acid, carbon dioxide, citric acid, and sodium citrate.
In the preferable technical scheme of the invention, the concentration of the pH regulator is 0.5-8mol/L, preferably 0.8-6mol/L, more preferably 1-5mol/L, and further preferably 2-4mol/L.
In a preferred embodiment of the present invention, the stabilizer (solubilizer) is selected from any one of glycerol, tween-80, or a combination thereof.
In a preferred technical scheme of the invention, the antioxidant is selected from any one of potassium sorbate, sodium sulfite, sodium bisulfite, sodium metabisulfite and dibutylbenzoic acid or a combination thereof.
In a preferred technical scheme of the invention, the aromatizer is selected from any one of spice, edible spice and flavoring essence or the combination thereof.
In a preferred embodiment of the present invention, the composition of the present invention may be in various dosage forms well known in the art, and may be prepared by using conventional formulation techniques in the art.
In a preferred technical scheme of the invention, the composition is an oral preparation.
In a preferred technical scheme of the invention, the oral preparation is selected from any one of oral liquid (liquid preparation), syrup, suspension, tablets, capsules, granules, pills, powder, dripping pills, mixture, distillate, effervescent, paste, emulsion and tea.
In a preferred technical scheme of the invention, the pharmaceutical composition of the invention and a pharmaceutically acceptable sustained-release carrier are mixed according to the preparation requirements, and then are prepared into pellets, such as sustained-release pellets or controlled-release pellets, according to the preparation method of the sustained-release preparation well known in the art, such as adding a retardant coating or microencapsulating an active ingredient; the sustained and controlled release carrier comprises but is not limited to an oil-fat doping agent, a hydrophilic colloid, a coating retarder and the like, wherein the oil-fat doping agent is selected from any one or the combination of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane and dimethyl siloxane; the hydrophilic colloid is selected from any one or combination of sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, PVP, acacia, tragacanth and carbopol; the coating retarder is selected from any one of Ethyl Cellulose (EC), hydroxypropyl methyl cellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose Acetate Phthalate (CAP), acrylic resin or their combination.
In the preferred technical scheme of the invention, the composition contains 50-80% of the water extract of needle mushroom and 1-3% of theanine1-10% of probiotics, 5-30% of prebiotics, 5-10% of sugar substitute, caCl 2 0.1-2% and sodium alginate 0.1-2%.
In the preferred technical scheme of the invention, the composition contains 55-75% of the water extract of needle mushroom after enzyme deactivation, 1.5-2.5% of theanine, 2-8% of probiotics, 10-25% of prebiotics, 6-9% of sugar substitute, caCl 2 0.1-2% and sodium alginate 0.1-2%.
In the preferred technical scheme of the invention, the composition contains 60-70% of needle mushroom water extract after enzyme deactivation, 1.8-2% of theanine, 4-6% of probiotics, 15-20% of prebiotics, 7-8% of sugar substitute, caCl 2 0.1-2% and sodium alginate 0.1-2%.
The invention also aims to provide a preparation method of a pharmaceutical composition with the efficacy of improving depression symptoms, the composition contains 50-80% of needle mushroom water-removing extract, 1-3% of theanine, 1-10% of probiotics, 5-30% of prebiotics, 5-10% of sugar substitutes and a pharmaceutically acceptable carrier, and the preparation method comprises the following steps: weighing required amount of water extract and probiotics of needle mushroom, preparing microcapsule colloidal particles by a microcapsule granulation method, and fully mixing the freeze-dried microcapsule colloidal particles with the rest components after freeze-drying to obtain the needle mushroom water extract and probiotics.
In the preferable technical scheme of the invention, 0.1-2% of sodium alginate and 0.1-2% of CaCl are added in the microcapsule granulation 2 And (3) solution.
In the preferable technical scheme of the invention, the diameter of the microcapsule colloidal particle is 0.15-2mm.
In the preferred technical scheme of the invention, after the freeze-dried microcapsule colloidal particles are fully mixed with the rest components, the mixture is granulated and tabletted.
In the preferred technical scheme of the invention, the content of the water extract of the needle mushroom in the composition after enzyme deactivation is 55-75%, preferably 60-70%.
In the preferred technical scheme of the invention, the total amount of amino acids in the needle mushroom water extract is 2-10%, the content of protein is 2-10%, and the content of gamma-aminobutyric acid is 0.15-1%.
In the preferred technical scheme of the invention, the total amount of amino acids in the needle mushroom water extract after enzyme deactivation is 3-8%, preferably 5-6%.
In a preferred embodiment of the present invention, the amino acid is selected from any one of aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, γ -aminobutyric acid, histidine, tryptophan, lysine, arginine, proline, or a combination thereof.
In the preferred technical scheme of the invention, the protein content of the water extract of needle mushroom is 3-8%, preferably 5-6%.
In the preferable technical scheme of the invention, the content of gamma-aminobutyric acid in the water extract of needle mushroom after enzyme deactivation is 0.3-0.8%, preferably 0.5-0.6%.
In the preferred technical scheme of the invention, the preparation of the water extract of the needle mushroom after enzyme deactivation comprises the following steps: filtering needle mushroom de-enzyming water, adding 1-10% (w/v) dispersant into the collected filtrate, stirring, mixing, and spray drying the prepared dispersion to obtain the final product.
In a preferred embodiment of the present invention, the filtration is selected from any one or a combination of centrifugal filtration, vacuum filtration, and vacuum filtration.
In the preferable technical scheme of the invention, the viscosity of the needle mushroom water-removing water is not lower than 1500CP.
In a preferred embodiment of the present invention, the dispersant is selected from any one of lactose, maltodextrin, mannitol, glucose, D-trehalose, lactose, maltodextrin, dextrin, hydroxypropyl- β -cyclodextrin, sucrose, or a combination thereof.
In the preferable technical scheme of the invention, the addition amount of the dispersing agent is 2-8%, and preferably 5-6%.
In the preferred technical scheme of the invention, the stirring time is 1-20min, preferably 5-10min.
In the preferred technical scheme of the invention, the air inlet speed of the spray drying is 20-50m 3 H, preferably from 30 to 40m 3 /h。
In the preferred technical scheme of the invention, the inlet temperature of the spray drying nozzle is 80-120 ℃, and preferably 90-100 ℃.
In the preferable technical scheme of the invention, the gas flow rate of the spray drying is 400-800L/h, preferably 500-600L/h.
In the preferable technical scheme of the invention, the sample injection rate of the spray drying is 5-10ml/min, and the preferable sample injection rate is 7-8ml/min.
In a preferred technical scheme of the invention, the content of theanine in the composition is 1.5-2.5%, preferably 1.8-2%.
In a preferred technical scheme of the invention, the content of the probiotics in the composition is 2-8%, and preferably 4-6%.
In a preferred technical scheme of the invention, the probiotics are selected from any one or combination of lactobacillus casei, yeast, probiotic bacillus, clostridium butyricum, lactobacillus, bifidobacterium lactis, streptococcus thermophilus and actinomycetes.
In a preferred technical scheme of the invention, the addition amount of the probiotics in the composition is more than 1.5 hundred million/g of the composition.
In a preferred technical scheme of the invention, the content of the prebiotics in the composition is 10-25%, preferably 15-20%.
In a preferred technical scheme of the invention, the prebiotics are selected from any one of orange powder, inulin, fructo-oligosaccharide, galacto-oligosaccharide, manno-oligosaccharide, xylo-oligosaccharide, trehalose, L-arabinose and resistant dextrin or a combination thereof.
In a preferred technical scheme of the invention, any one or combination of curcumin, rhodiola rosea extract, broccoli extract, forsythia suspensa extract, saffron extract and 5-hydroxytryptophan is optionally added into the composition.
In a preferred embodiment of the present invention, the sugar substitute content of the composition is 6 to 9%, preferably 7 to 8%.
In a preferred technical scheme of the invention, the sugar substitute is selected from any one of or a combination of mogroside, erythritol, stevioside, xylitol, sorbitol and palatinit.
In a preferred embodiment of the invention, the compositionComprises water extract of needle mushroom (50-80%), theanine (1-3%), probiotics (1-10%), prebiotics (5-30%), sugar substitute (5-10%), caCl 2 0.1-2% and sodium alginate 0.1-2%.
In the preferred technical scheme of the invention, the composition contains 55-75% of needle mushroom enzyme-deactivating water extract, 1.5-2.5% of theanine, 2-8% of probiotics, 10-25% of prebiotics, 6-9% of sugar substitute, caCl 2 0.1-2% and sodium alginate 0.1-2%.
In the preferred technical scheme of the invention, the composition contains 60-70% of needle mushroom water extract after enzyme deactivation, 1.8-2% of theanine, 4-6% of probiotics, 15-20% of prebiotics, 7-8% of sugar substitute, caCl 2 0.1-2% and sodium alginate 0.1-2%.
Another object of the present invention is to provide use of a pharmaceutical composition having efficacy of improving depression symptoms for the preparation of a medicament for improving depression symptoms.
In a preferred embodiment of the present invention, the depression symptom includes any one of anxiety, sleep deficiency, and memory deterioration, or a complication thereof.
The invention also aims to provide a pharmaceutical composition with the efficacy of improving depression symptoms, which consists of either needle mushroom water-removing water extract or a pharmaceutical composition containing needle mushroom water-removing water and an antidepressant.
In a preferred technical scheme of the invention, the antidepressant is selected from any one of fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram and escitalopram or a combination thereof.
In a preferred embodiment of the present invention, the dosage of the composition of the present invention is related to the age, sex, health condition, current treatment status, concomitant medication, etc. of the patient, and the recommended dosage is 10 to 20 g/day.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Unless otherwise stated, the invention adopts GB 5009.124-2016 national food safety standard for determination of amino acid in food to detect the content of amino acid, and GB 5009.5-2016 national food safety standard for determination of protein in food to detect the content of protein.
Compared with the prior art, the beneficial technical effects of the invention comprise:
1. the needle mushroom enzyme-deactivating water extract and theanine with high gamma-aminobutyric acid content and rich nutrition (including essential and nonessential amino acids, proteins, dietary fibers, trace elements and the like of a human body) are scientifically screened, and the composition is matched with probiotics and prebiotics, so that the composition has the beneficial effects of well improving depression symptoms, improving sleep, improving anxiety, improving memory, enhancing immunity and the like.
2. The pharmaceutical composition can be used together with other medicines, and has the advantages of flexible use mode, capability of being taken by tube feeding or oral administration, no side effect, wide applicable population and the like.
3. The method realizes the cyclic utilization of the needle mushroom enzyme deactivating water, improves the resource utilization rate, reduces the production cost, has the advantages of simple and convenient preparation, contribution to industrial production and the like.
Detailed Description
The present invention is described below with reference to examples. The invention is not limited to the examples.
Reference example 1 preparation of enzyme-deactivated Water extract of Flammulina velutipes
The preparation method of the needle mushroom water-removing agent comprises the following steps:
putting 0.3 ton of needle mushroom into 1 ton of boiling water at 100 ℃ for de-enzyming for 3 minutes, taking out the needle mushroom, and then putting 0.3 ton of needle mushroom for de-enzyming. Repeating the above operations until completing the enzyme deactivation of 3 tons of needle mushrooms, filtering under reduced pressure, collecting the water, and detecting the viscosity of the water to be 1500cp by using a texture analyzer (brand SMS, UK, productivity, model TA.XT PLUS).
The preparation method of the water extract of needle mushroom comprises the following steps:
(1) Filtering 1000ml of needle mushroom enzyme deactivation water by using two layers of gauze, and collecting filter residues and filtrate;
(2) Adding 5% maltodextrin into the filtrate, and stirring for 10min to obtain dispersion;
(3) The power supply of the spray dryer is turned on, and the drying air inlet speed is set to be 35m 3 And h, the inlet temperature is 100 ℃, the flow rate of atomizing gas is 600L/h, the sample injection rate of a peristaltic pump is 8ml/min, the dispersion liquid prepared in the step (2) is sprayed into spray drying, and spray drying extract is collected. The content of the nutrient components in the extract is shown in table 1.
TABLE 1
Detecting item, unit Example 1
Aspartic acid,% 0.32
Threonine, by% 0.17
Serine, l% 0.16
Glutamic acid% 1.25
Glycine% 0.26
Alanine% 0.59
Valine% 0.17
Methionine, is% 0.022
Isoleucine% 0.12
Leucine,% of 0.21
Tyrosine% 0.22
Phenylalanine,% of 0.33
Gamma-aminobutyric acid% 0.65
Histidine% 0.34
Tryptophan% 0.74
Lysine% 0.25
Arginine content% 0.10
Proline% 0.13
Amino acidsTotal amount of% 6.04
Protein g/100g 6.83
EXAMPLE 1 preparation of a pharmaceutical composition of the invention
The composition of the pharmaceutical composition is as follows:
Figure BDA0003065167010000141
the preparation method of the composition comprises the following steps:
weighing required amount of needle mushroom water extract for deactivating enzymes, dissolving in 0.1-2% sodium alginate solution to obtain mixed solution as wall material. The prepared wall material is added into an injector, is arranged on a microcapsule granulator, and is filled with probiotic bacillus serving as a core material by using another high-temperature sterilized pressure bottle. A concentric nozzle (0.50 mm) of suitable diameter is selected according to the requirements of the granulation size. The bottom of the instrument is provided with a magnetic stirrer and 0.1-2% of CaCl 2 Glass of solution. Turning on the power supply of the microcapsule granulating apparatus, gradually increasing the vibration frequency and the electrostatic device voltage to high-frequency vibration to form discontinuous bundles of the sprayed liquid, wherein the microcapsule particles carry the same charges about 1cm below the nozzle, and the microcapsules cannot be adhered together under the mutual repulsion action of the same charges. The particles enter CaCl 2 The absorption liquid is quickly solidified for 40min to form a film and is hardened to form a microcapsule glue solution coated by calcium alginate. Freeze drying the microcapsule solution at-50 deg.C to obtain microcapsule powder with particle diameter of less than or equal to 600 μm, mixing the microcapsule powder with other components of the composition, and wet granulating and tabletting.
EXAMPLE 2 preparation of pharmaceutical compositions of the invention
The composition of the pharmaceutical composition is as follows:
Figure BDA0003065167010000151
the preparation method of the composition comprises the following steps:
weighing required amount of needle mushroom water extract for deactivating enzymes, dissolving in 0.1-2% sodium alginate solution to obtain mixed solution as wall material. The prepared wall material is added into a syringe, is arranged on a microcapsule granulator, and is filled with lactobacillus casei as a core material by using another high-temperature sterilized pressure bottle. A concentric nozzle (0.50 mm) of suitable diameter is selected according to the requirements of the granulation size. The bottom of the instrument is provided with a magnetic stirrer and 0.1-2% of CaCl 2 Glass of solution. Turning on the power supply of the microcapsule granulating apparatus, gradually increasing the vibration frequency and the electrostatic device voltage to high-frequency vibration to form discontinuous bundles of the sprayed liquid, wherein the microcapsule particles carry the same charges about 1cm below the nozzle, and the microcapsules cannot be adhered together under the mutual repulsion action of the same charges. The particles enter CaCl 2 The absorption liquid is quickly solidified for 40min to form a film and is hardened to form a microcapsule glue solution coated by calcium alginate. Freeze drying the microcapsule solution at-50 deg.C to obtain microcapsule powder with particle diameter of less than or equal to 600 μm, mixing the microcapsule powder with other components of the composition, and wet granulating and tabletting.
EXAMPLE 3 preparation of a pharmaceutical composition of the invention
The composition of the pharmaceutical composition is as follows:
Figure BDA0003065167010000161
the preparation method of the composition comprises the following steps:
weighing required amount of needle mushroom water extract for deactivating enzymes, dissolving in 0.1-2% sodium alginate solution to obtain mixed solution as wall material. Adding the prepared wall material into injectionIn the apparatus, the apparatus was mounted on a microcapsule granulator, and another autoclave sterilized at high temperature was filled with bifidobacterium lactis as a core material. A concentric nozzle (0.50 mm) of suitable diameter is selected according to the requirements of the granulation size. The bottom of the instrument is provided with a magnetic stirrer and 0.1-2% of CaCl 2 Glass of solution. Turning on the power supply of the microcapsule granulating apparatus, gradually increasing the vibration frequency and the electrostatic device voltage to high-frequency vibration to form discontinuous bundles of the sprayed liquid, wherein the microcapsule particles carry the same charges about 1cm below the nozzle, and the microcapsules cannot be adhered together under the mutual repulsion action of the same charges. The particles enter CaCl 2 The absorption liquid is quickly solidified for 40min to form a film and is hardened to form a microcapsule glue solution coated by the calcium alginate. Freeze drying the microcapsule solution at-50 deg.C to obtain microcapsule powder with particle diameter of less than or equal to 600 μm, mixing the microcapsule powder with other components of the composition, and wet granulating and tabletting.
Test example 1Research on antidepressant action of pharmaceutical composition
Mirtazapine was used as a positive control in this study. 10 sleep disorder volunteers are selected and divided into a control group and a test group according to a random number table method, wherein each group comprises 5 patients. Inclusion criteria were: the Chinese medicinal composition meets the relevant diagnosis standard in Chinese depressive disorder prevention and treatment guideline revision and depressive disorder standard treatment, and has Hamilton Depression Scale (HAMD) score higher than 17 points and Pittsburgh Sleep Quality Index (PSQI) score higher than 8 points. The control group was administered mirtazapine once a day at 20 mg/day; the test group was administered the composition of example 1 once a day, 2 tablets each time (1 g/tablet). Both groups were taken for 4 weeks. The results are shown in tables 2 to 4.
TABLE 2 comparison of Hamilton Depression Scale (HAMD) scores in two groups of patients
Group of Number of examples Before treatment After treatment
Control group 5 28.57±2.91 13.16±2.86**
Test group 5 25.73±3.35 11.24±1.74**
Note: * P < 0.05; * Denotes p < 0.01. The same applies below.
TABLE 3 Hamilton anxiety Scale (HAMA)
Group of Number of examples Before treatment After treatment
Control group 5 18.87±2.04 10.14±2.25**
Test group 5 19.02±2.84 8.82±1.73**
Note: * P < 0.05; * Denotes p < 0.01. The same applies below.
TABLE 4 Pittsburgh Sleep Quality Index (PSQI)
Group of Number of examples Before treatment After treatment
Control group 5 12.87±1.59 8.71±1.26**
Test group 5 12.53±1.85 7.06±1.18**
Note: * P < 0.05; * Denotes p < 0.01. The same applies below.
HAMA score of 56 total, higher score more severe anxiety; HAMD score 54 total, higher score depression more severe; PSQI score was 21, with higher scores being worse sleep treatment.
The research result shows that after the mirtazapine or the composition of the embodiment of the invention is continuously taken, the depression and anxiety degree of a patient is reduced, the sleep quality is improved, and the sleep improving effect of the composition of the embodiment 1 is better than that of the mirtazapine.
Test example 2The research on the function of improving memory of the pharmaceutical composition of the invention
80 male ICR mice (body weight 20 + -2 g) were selected and randomized into 4 groups of 20 mice each. Normal group: intragastric administering 200 μ L of distilled water every day; building a module: intragastric administration of 200 μ L distilled water every day; positive control group: the gavage mice take 300mg/kg oxiracetam every day; test groups: mice were gavaged daily at 400mg/kg of the composition of example 1. Each group was gavaged for 2 weeks. The mice in the model group, the positive control group and the test group are injected with 1mg/kg of scopolamine before the experiment. Mice were recorded for 5 consecutive days escape latency by the Morris water maze experiment. The results are shown in Table 5.
TABLE 5 incubation period of escape(s) for mice
Group of Day 1 Day 2 Day 3 Day 4 Day 5
Normal group 35.48±5.15 30.47±3.79 27.16±3.75 25.48±2.46 22.45±2.48
Module group 58.48±5.77# 51.38±4.69## 48.07±4.57## 44.14±3.52## 40.21±3.03##
Positive control group 44.48±5.76* 39.17±4.08* 36.25±2.93** 33.42±3.45** 30.41±3.27**
Test group 43.78±5.14* 38.44±4.84* 34.94±5.60** 32.83±3.49** 29.12±4.25**
Compared with the normal group, # means p < 0.05, # # means p < 0.01; and comparing with the modeling group, wherein p is less than 0.05 and p is less than 0.01.
Scopolamine can effectively inhibit the central nervous system, and the memory of the test animal is obviously reduced. Compared with the normal group, the escape latency of mice injected with scopolamine intraperitoneally is obviously increased, which indicates that the memory of the test mice is obviously declined. After the oxiracetam and the composition disclosed by the invention are used for intragastric administration, the escape latency of a mouse is gradually shortened, and the composition disclosed by the invention is more effective in improving the memory of a test mouse than the oxiracetam.
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined in the appended claims.

Claims (62)

1. The pharmaceutical composition for improving the depressive symptom is characterized by comprising 50-80% of needle mushroom water-removing water extract, 1-3% of theanine, 1-10% of probiotics, 5-30% of prebiotics, 5-10% of sugar substitute and a pharmaceutically acceptable carrier in percentage by weight, wherein the total amount of amino acids in the needle mushroom water-removing water extract is 2-10%, the content of gamma-aminobutyric acid is 0.15-1%, and the content of protein is 2-10%;
the preparation method of the water extract of needle mushroom comprises the following steps: water for removing water from needle mushroom
Filtering, adding 1-10% dispersant by weight volume ratio into the collected filtrate, stirring, uniformly mixing, and spray drying the prepared dispersion to obtain the final product; the dispersing agent is selected from any one of lactose, maltodextrin, mannitol, glucose, D-trehalose, hydroxypropyl-beta-cyclodextrin and sucrose or the combination thereof.
2. The composition of claim 1, wherein the water extract of needle mushroom in the composition comprises 55-75% of the water extract.
3. The composition of claim 1, wherein the water extract of needle mushroom in the composition has a water-removed content of 60-70%.
4. The composition as claimed in claim 1, wherein the total amount of amino acids in the water-removed extract of needle mushroom is 3-8%.
5. The composition of claim 4, wherein the total amount of amino acids in the water extract of needle mushroom is 5-6%.
6. The composition of claim 1, wherein the amino acid is selected from any one of aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, gamma-aminobutyric acid, histidine, tryptophan, lysine, arginine, proline or a combination thereof.
7. The composition as claimed in claim 1, wherein the water extract of needle mushroom with water removed contains 3-8% of protein.
8. The composition of claim 7, wherein said water extract of needle mushroom with water removed has a protein content of 5-6%.
9. The composition of claim 1, wherein the water extract of needle mushroom with green removed contains 0.3-0.8% of gamma-aminobutyric acid.
10. The composition of claim 9, wherein the water extract of needle mushroom with green removed contains 0.5-0.6% of gamma-aminobutyric acid.
11. The composition of claim 1, wherein the filtration is selected from any one or a combination of centrifugal filtration, reduced pressure filtration, or vacuum filtration.
12. The composition of claim 1, wherein the needle mushroom de-enzyming water has a viscosity of not less than 1500CP.
13. The composition of claim 1 wherein the dispersant is added in an amount of 2 to 8%.
14. The composition of claim 13 wherein the dispersant is added in an amount of 5 to 6%.
15. The composition of claim 1, wherein the stirring time is from 1 to 20min.
16. The composition of claim 15, wherein the stirring time is from 5 to 10min.
17. The composition of claim 1, wherein the spray drying has an air intake rate of 20 to 50m 3 /h。
18. The composition of claim 17, wherein the spray-drying has an air intake rate of 30 to 40m 3 /h。
19. The composition of claim 1, wherein the spray drying nozzle has an inlet temperature of from 80 ℃ to 120 ℃.
20. The composition of claim 19, wherein the spray drying nozzle has an inlet temperature of from 90 ℃ to 100 ℃.
21. The composition of claim 1, wherein the spray-dried gas flow rate is from 400 to 800L/h.
22. The composition of claim 20, wherein the spray-dried gas flow rate is from 500 to 600L/h.
23. The composition of claim 1, wherein the spray drying is carried out at a sample rate of 5 to 10ml/min.
24. The composition of claim 23, wherein the spray drying is performed at a sample rate of 7 to 8ml/min.
25. The composition of claim 1, wherein the theanine content of the composition is 1.5% to 2.5%.
26. The composition of claim 25, wherein the theanine content of the composition is 1.8% to 2%.
27. The composition of claim 1, wherein the probiotic content of the composition is 2-8%.
28. The composition of claim 27, wherein the probiotic content of the composition is 4-6%.
29. The composition of claim 1, wherein the probiotic bacteria are selected from any one of yeast, probiotic bacillus bacteria, clostridium butyricum, lactobacillus, bifidobacterium lactis, streptococcus thermophilus, actinomycetes or a combination thereof.
30. The composition of claim 1, wherein the probiotic is added in an amount greater than 1.5 hundred million per gram of composition.
31. The composition of claim 1, wherein the prebiotic content of the composition is from 10% to 25%.
32. The composition of claim 31, wherein the prebiotic content of the composition is from 15% to 20%.
33. The composition of claim 1, wherein the prebiotic is selected from any one of orange powder, inulin, fructo-oligosaccharide, galacto-oligosaccharide, manno-oligosaccharide, xylo-oligosaccharide, trehalose, L-arabinose, resistant dextrin or a combination thereof.
34. The composition of claim 1, wherein any one or a combination of curcumin, rhodiola rosea extract, broccoli extract, forsythia suspensa extract, saffron extract, 5-hydroxytryptophan is added to the composition.
35. The composition of claim 1, wherein the sugar substitute is present in the composition in an amount of 6% to 9%.
36. The composition of claim 35, wherein the sugar substitute is present in the composition in an amount of 7% to 8%.
37. The composition of claim 1, wherein the sugar substitute is selected from any one of mogrosides, erythritol, steviol glycosides, xylitol, sorbitol, palatinitol or a combination thereof.
38. The composition according to any one of claims 1 to 37, wherein the pharmaceutically acceptable carrier is selected from any one of or a combination of fillers, lubricants, dispersants, wetting agents, binders, pH modifiers, solubilizers, antioxidants, emulsifiers, flavoring agents, perfuming agents, disintegrants, stabilizers.
39. The composition of claim 38, wherein the binder is selected from any one of syrup, acacia, gelatin, sorbitol, tragacanth, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, starch, sodium carboxymethylstarch, sodium starch glycolate, polyvinylpyrrolidone, or a combination thereof.
40. The composition of claim 38, wherein the filler is selected from the group consisting of lactose, powdered sugar, dextrin, starch or derivatives thereof, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, calcium sulfate, calcium phosphate, dibasic calcium phosphate, precipitated calcium carbonate, sorbitol, glycine, sodium starch glycolate, or any combination thereof.
41. The composition of claim 38, wherein the lubricant is selected from any one of silica gel micropowder, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, or a combination thereof.
42. The composition of claim 38, wherein the disintegrant is selected from any one of starch, sodium carboxymethyl starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, or a combination thereof.
43. The composition of claim 38, wherein the wetting agent is selected from any one of sodium lauryl sulfate, water, an alcohol, or a combination thereof.
44. The composition of claim 38, wherein the emulsifier is selected from any one of polysorbate-80, sorbitan elaeate, pluronic F-68, lecithin, soy lecithin, or a combination thereof.
45. The composition of claim 38, wherein the pH modifying agent is selected from any one of inorganic acids, organic acids, or combinations thereof.
46. The composition of claim 45, wherein the concentration of the pH modifying agent is 0.5 to 8mol/L.
47. The composition of claim 46, wherein the concentration of the pH modifying agent is 0.8 to 6mol/L.
48. The composition of claim 47, wherein the concentration of the pH modifying agent is 1 to 5mol/L.
49. The composition of claim 48, wherein the concentration of the pH modifying agent is 2 to 4mol/L.
50. The composition of claim 38, wherein the stabilizer is selected from any one of glycerol, tween-80, or a combination thereof.
51. The composition of claim 38, wherein the antioxidant is selected from any one or a combination of potassium sorbate, sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutylbenzoic acid.
52. The composition of claim 38, wherein said flavor vehicle is selected from any one of a flavor, a flavorant, a fragrance, or a combination thereof.
53. The composition of claim 1, wherein the composition is an oral formulation.
54. The composition of claim 53, wherein the oral formulation is selected from any one of oral liquid, syrup, suspension, tablet, capsule, granule, pill, powder, drop pill, mixture, lotion, effervescent, paste, emulsion, tea.
55. The composition of claim 1, wherein the composition comprises the water extract of needle mushroom (Flammulina velutipes Fr.) Sing 50-80%, theanine 1-3%, probiotic bacteria 1-10%, prebiotics 5-30%, sugar substitute 5-10%, caCl 2 0.1-2% and sodium alginate 0.1-2%.
56. The composition of claim 55, wherein the composition comprises the killed aqueous extract of Flammulina velutipes (Fr.) Sing 55-75%, theanine 1.5-2.5%, probiotic 2-8%, prebiotics 10-25%, sugar substitute 6-9%, caCl 2 0.1-2% and sodium alginate 0.1-2%.
57. The composition of claim 56, wherein the composition comprises gold needles60-70% of water extract of mushroom enzyme deactivation, 1.8-2% of theanine, 4-6% of probiotics, 15-20% of prebiotics, 7-8% of sugar substitute, caCl 2 0.1-2% and sodium alginate 0.1-2%.
58. A method for preparing a pharmaceutical composition for improving depressive symptoms according to claim 1, wherein the composition comprises the water extract of needle mushroom 50-80%, theanine 1-3%, probiotics 1-10%, prebiotics 5-30%, sugar substitute 5-10% and pharmaceutically acceptable carrier, comprising the following steps: weighing required amount of water extract and probiotics of needle mushroom, preparing microcapsule colloidal particles by a microcapsule granulation method, freeze-drying, and fully mixing the freeze-dried microcapsule colloidal particles with the rest components to obtain the product, wherein the microcapsule granulation is added with 0.1-2% of sodium alginate and 0.1-2% of CaCl 2 Solution, the diameter of the microcapsule colloidal particle is 0.15-2mm, and the freeze-dried microcapsule colloidal particle is fully mixed with the rest components, granulated and tabletted.
59. Use of a pharmaceutical composition according to any one of claims 1-57 or a pharmaceutical composition prepared by a method according to claim 58 for the manufacture of a medicament for ameliorating the symptoms of depression.
60. The use of claim 59, wherein the depressive symptom comprises any one of anxiety, sleep deficit, memory decline, or complications thereof.
61. A pharmaceutical composition with efficacy of improving depression symptoms, which consists of the pharmaceutical composition as claimed in any one of claims 1 to 57 or the pharmaceutical composition prepared by the method as claimed in claim 58 and an antidepressant.
62. The pharmaceutical composition of claim 61, wherein said antidepressant is selected from any one of fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram or a combination thereof.
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