CN114177220A - Composition of human and forsythia fruit and its antiviral medicine - Google Patents
Composition of human and forsythia fruit and its antiviral medicine Download PDFInfo
- Publication number
- CN114177220A CN114177220A CN202010959266.4A CN202010959266A CN114177220A CN 114177220 A CN114177220 A CN 114177220A CN 202010959266 A CN202010959266 A CN 202010959266A CN 114177220 A CN114177220 A CN 114177220A
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- Prior art keywords
- ginseng
- composition
- forsythia
- extract
- cyclodextrin
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Abstract
The invention discloses a composition containing ginseng component and forsythia suspense component, a preparation method and application of the composition in resisting virus, relieving fever, resisting inflammation and improving immunity. The composition has the advantages of quick response and small toxic and side effects, is an antiviral drug and health food with safety, high efficiency, stability and simple preparation process, is suitable for industrial production, and is easy to popularize. The invention provides a new medicine, health food and raw materials for preventing and treating various viral diseases, relieving fever, resisting inflammation and improving immunity.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a composition of ginseng and forsythia suspense extracts, a preparation method and application of the composition in resisting virus, relieving fever, resisting inflammation and improving immunity.
Background
Ginseng, a plant belonging to the genus panax of the family araliaceae, has been widely used in china, korea, and japan for over 2000 years, and has been mainly used for the purpose of preventing diseases and prolonging life. According to records of Shen nong Ben Cao Jing, there are the following ginseng: the functions of nourishing the five internal organs, calming nerves, calming soul, stopping palpitation, removing pathogenic qi, improving eyesight and intelligence, losing weight and prolonging life are achieved. Modern medical research shows that the main effects and actions of ginseng are as follows: has effects in resisting cancer and tumor, regulating immunity, resisting diabetes, improving liver function, relieving cardiovascular and cerebrovascular disorders, resisting arteriosclerosis, regulating blood pressure, relieving climacteric disorder and osteoporosis, relieving fatigue, resisting oxidation, and inhibiting aging.
Ginsenoside has been widely studied and used as a main active ingredient of ginseng, and among them, 20(R) -ginsenoside Rg3 is most spotlighted, and it has good safety as a main active ingredient of ginseng, has been prepared into an anti-tumor oral preparation for clinical use, and has been intensively studied as an injection.
Fructus forsythiae is the dry fruit of Forsythia Suspensa (Thunb.) Vahl, which is a plant of Forsythia of Oleaceae, and is mainly distributed in Henan, Shanxi, Shaanxi, Shandong, etc., and also in Hubei, Hebei, Sichuan and Gansu of China. It is commonly used to treat acute wind-heat type common cold, carbuncle, sore, tuberculous lymphadenitis, urinary tract infection, etc. [1 ]. The main components of fructus forsythiae are phillyrin and phillygenin, which is also called ginsenoside Rg3((+) -phillygenin), and the structural formulas of the two components are shown as follows.
The fructus forsythiae contains phillyrin as main ingredient, and has pharmacological effects of resisting virus, bacteria and oxidation, scavenging free radicals, etc. Phillygenin, also one of the main active ingredients of forsythia, has the effects of resisting oxidation, reducing blood fat, scavenging free radicals, inhibiting bacteria, resisting tumors, resisting inflammation and the like.
In the existing research, the pharmacological actions of single components such as ginseng medicinal materials or ginseng total saponins, forsythia medicinal materials or forsythiaside are mostly researched, but the pharmacological action research of resisting virus, relieving heat, resisting inflammation and improving immunity by using ginseng and forsythia as a medicine pair is not found. The inventor extracts the effective components of the ginseng and the forsythia suspense from the ginseng and the forsythia suspense medicinal materials by a large amount of modern scientific research and adopting an advanced separation and purification technology, and performs application research on antivirus, antipyretic, anti-inflammatory and immunity improvement on the human ginseng and the forsythia suspense and corresponding medicinal preparations thereof, and the application of the ginseng and the forsythia suspense in medicinal preparations and health-care foods has wide market prospect.
Disclosure of Invention
The invention aims to provide a novel composition of ginseng and forsythia, a preparation method and application thereof in resisting virus, relieving fever, resisting inflammation and improving immunity, aiming at the defects in the prior art. The composition of ginseng and forsythia has strong performance and efficacy in resisting virus, relieving fever, resisting inflammation and improving immunity, and provides a new way for developing new medicines for the diseases, namely a new idea for new application in medicines or health-care foods for treating, conditioning and relieving the diseases.
In order to achieve the above objects, the present invention provides a composition of ginseng and forsythia suspensa, a preparation method and applications thereof.
The weight ratio of the ginseng component to the forsythia suspensa component in the human-participated forsythia suspensa composition is 2-98: 2-98, preferably 80:20 or 20:80, more preferably 90:,6 or 6:90, and even more preferably 98:2 or 2: 98.
In particular, in the ginseng-forsythia suspense composition, the content of ginsenoside Rg3 in the ginseng component is more than or equal to 0.03%, preferably more than or equal to 10%, more preferably more than or equal to 50%, more preferably more than or equal to 80%, more preferably more than or equal to 90%, and more preferably more than or equal to 99%; the content of phillyrin in the forsythia suspensa component is not less than 0.15%, preferably not less than 15%, more preferably not less than 60%, even more preferably not less than 80%, even more preferably not less than 90%, even more preferably not less than 99%.
Preferably the composition of the first aspect of the invention is a composition for anti-viral, antipyretic, anti-inflammatory and/or immune enhancement comprising ginsenoside and phillyrin. More preferably, the ginsenoside is total ginsenoside, panaxadiol saponins, ginsenoside Rg3 or 20(R) -ginsenoside Rg 3.
Further, the composition preferably further comprises forsythin.
Preferably the composition of the first aspect of the invention consists of ginseng extract and forsythia extract. Preferably wherein the extract is an alcoholic extract or an aqueous extract, for example, the composition of the first aspect of the invention may consist of an alcoholic extract of ginseng and an alcoholic extract of forsythia suspensa, or the composition of the first aspect of the invention may consist of an aqueous extract of ginseng and an aqueous extract of forsythia suspensa. The alcohol may be methanol or ethanol or an aqueous solution thereof, preferably ethanol or an aqueous solution thereof. In the alcohol aqueous solution, the concentration of the alcohol may be 50 to 100% (V/V), preferably 60 to 95% (V/V), such as 70 to 90% (V/V). Preferably, the weight ratio of the ginseng used for extraction to the forsythia suspense used for extraction is 2-50: 50-98. In a specific embodiment of the present invention, the step of extracting may include: soaking Ginseng radix and/or fructus forsythiae in alcohol or water, heating, retaining filtrate, optionally adding alcohol or water into the residue, heating, retaining filtrate, and drying the filtrate.
It is also preferred that the composition of the first aspect of the invention further comprises one or more of notoginseng, aloe, licorice, fleece-flower root, ginkgo biloba, black sesame extract, ginger extract, grape seed extract, pomegranate seed extract, plant essential oils, arbutin, vitamin C and derivatives thereof or vitamin E and derivatives thereof.
In a second aspect, the present invention provides an antiviral, antipyretic, anti-inflammatory and/or immunostimulant formulation comprising a composition according to the first aspect of the invention and a pharmaceutically or nutraceutically acceptable carrier. Preferably, the present invention provides an antiviral, antipyretic, anti-inflammatory and/or immunity-enhancing drug or health product comprising a ginseng component and a forsythia fruit component. Preferably, the weight ratio of the ginseng component to the forsythia suspense component is 2-98: 2-98, preferably 80:20 or 20:80, more preferably 90:6 or 6:90, and even more preferably 98:2 or 2: 98. Particularly, the medicine or the health care product consists of the composition components of ginseng and forsythia and a pharmaceutically acceptable carrier.
Wherein the weight ratio of the total weight of the ginseng component and the forsythia suspensa component in the composition of the human and the forsythia suspensa to the pharmaceutically acceptable carrier is 1: 1-1: 100, preferably 1:10, more preferably 1:5, even more preferably 1:2, even more preferably 1: 1.
Particularly, the weight ratio of the composition of the human and the forsythia suspensa to the total weight of the medicine or the health care product is 0.01-50: 100, preferably 0.1 to 50: 100, more preferably 1 to 50: 100.
particularly, the ginseng component and the forsythia suspensa component can be added with pharmaceutically acceptable carriers and food additives.
Pharmaceutically acceptable carriers are generally accepted by health care professionals for this purpose and as inactive ingredients of medicaments. A compilation of pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical excipients (Handbook of Pharmaceutical excipients, 2 nd edition, edited by A.Wade and P.J.Weller; published by American Phar-Pharmaceutical Association, Washington and The Pharmaceutical Press, London,1994), among other tools. Food additives are non-nutritive substances that are intentionally added to food, typically in small amounts, to improve the appearance, flavor, texture, or storage properties of the food. The related food additives can be found in the national food safety standard 'food additive use standard'. Food additives are non-nutritive substances that are intentionally added to food, typically in small amounts, to improve the appearance, flavor, texture, or storage properties of the food. The related food additives can be found in the national food safety standard 'food additive use standard'.
In particular, the carrier includes excipients such as starch, water, and the like; lubricants, such as magnesium stearate and the like; disintegrants, such as microcrystalline cellulose and the like; fillers, such as lactose and the like; binders such as pregelatinized starch, dextrin, and the like; a sweetener; an antioxidant; preservatives, flavoring agents, coloring agents, fragrances, and the like.
In particular, the medicament is in the form of tablets, capsules, pills, powders, granules, syrups, solutions, emulsions, injections, sprays, aerosols, gels, creams, cataplasms, rubber patches or plasters.
In particular, the health food is in the form of tablets, capsules, pills, powders, granules, syrups, solutions, emulsions, sprays, aerosols, gels, creams, cataplasms, rubber plasters or emplastrums, or in the form of food such as dairy products, candies, beverages, biscuits, tea leaves and related products, wines and the like.
In particular, the medicine or health product also comprises one or more of pseudo-ginseng, aloe, liquorice, fleece-flower root, ginkgo, black sesame extract, ginger extract, grape seed extract, pomegranate seed extract, plant essential oil, arbutin, vitamin C and derivatives thereof or vitamin E and derivatives thereof.
In the ginseng-forsythia suspense composition, the ginseng component and the forsythia suspense component exist in the form of traditional Chinese medicinal materials, or a ginseng-forsythia suspense extraction composition prepared by a solvent heating extraction method, or a ginseng-forsythia suspense-cyclodextrin composition formed by combining the ginseng-forsythia suspense extraction composition with cyclodextrin or derivatives thereof, or a ginsenoside-phillyrin composition formed by combining ginsenoside, phillyrin and cyclodextrin or derivatives thereof.
In particular, the ginseng-fructus forsythiae extract composition selects ginseng-fructus forsythiae alcohol extract and ginseng-fructus forsythiae water extract; the ginsenoside is total ginsenoside, panaxadiol saponins, and 20(R) -ginsenoside Rg 3; the forsythin is forsythin-forsythiaside composition or forsythin.
In particular, the ginseng-forsythia-cyclodextrin composition is characterized in that a mixture formed by mixing a ginseng-forsythia extract composition and alpha-, beta-or gamma-cyclodextrin or derivatives thereof is selected, or a compound formed by processing the ginseng-forsythia extract composition and the alpha-, beta-or gamma-cyclodextrin or derivatives thereof by a physical and chemical method is selected.
In particular, the ginsenoside-phillyrin-cyclodextrin composition is characterized in that a mixture formed by mixing ginsenoside-phillyrin and alpha-, beta-or gamma-cyclodextrin or derivatives thereof is selected, or a compound formed by processing ginsenoside-phillyrin and alpha-, beta-or gamma-cyclodextrin or derivatives thereof by a physical and chemical method is selected.
Wherein, the weight ratio of the traditional Chinese medicine components to the cyclodextrin or the cyclodextrin derivative in the compound is 1: 1-100.
In particular, the cyclodextrin is alpha-or beta-, gamma-cyclodextrin; the cyclodextrin derivative is hydroxyethyl beta-cyclodextrin, 2, 6-dimethyl beta-cyclodextrin, 2,3, 6-trimethyl beta-cyclodextrin, 2, 6-diethyl beta-cyclodextrin, 2,3, 6-triethyl beta-cyclodextrin, maltosyl beta-cyclodextrin or sulfobutyl ether beta-cyclodextrin, p-methylbenzenesulfonyl chloride (p-TsCl) -substituted beta-cyclodextrin, 6-substituted beta-CD p-methylbenzenesulfonate (beta-cyclodextrin-6-OTs), 2-oxyhydroxypropyl-beta-cyclodextrin, 2-mono-substituted p-methylbenzenesulfonate (beta-cyclodextrin-2-OTs), beta-cyclodextrin p-methylbenzenesulfonate (Tosyl-beta-CD), Beta-cyclodextrin star-shaped macromolecule PCL- (Tos) 7-beta-CD.
In a third aspect, the present invention provides a process for the preparation of a composition according to the first aspect of the invention, comprising the steps of mixing ginsenoside and phillyrin, and optionally phillyrin; or, it comprises the step of heating and extracting the human participation forsythia and optional Chinese medicinal materials by adopting a solvent. The former may be a method of mixing substantially pure compounds.
In a specific embodiment of the invention, the ginseng-forsythia suspense alcohol extract is prepared by the following steps:
1) respectively mixing the ginseng and the forsythia suspense with an extraction solvent uniformly, and then soaking;
2) respectively heating and extracting the soaked ginseng, fructus forsythiae and the extraction solvent mixture, filtering and collecting the extracting solution;
3) collecting the extractive solutions, concentrating, making into extract, and drying.
Particularly, the soaking treatment time in the step 1) is 30-60min, preferably 30 min.
Particularly, the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1: 10.
In particular, the extraction solvent is ethanol solution with volume percentage concentration of more than or equal to 50 percent, preferably 50-75 percent.
Wherein, the heating extraction times in the step 2) are 2-3 times, and preferably 3 times.
Particularly, in each heating extraction process, the weight ratio of the ginseng and the forsythia suspense medicinal materials to the extraction solvent is 1:8-12, preferably 1: 8; the temperature of each heating extraction is 60-80 deg.C, preferably 70 deg.C; the heating extraction time is 0.5-2h, preferably 1 h.
Wherein, the concentration temperature in the concentration treatment process in the step 3) is 65-85 ℃, and preferably 80 ℃; the relative density of the concentrated extract is 1.05-1.15, preferably 1.1; the temperature during the drying treatment is 70-90 ℃, preferably 85 ℃.
Wherein the ginseng-fructus forsythiae water extract is prepared by the following steps:
1) respectively mixing Ginseng radix and fructus forsythiae with water, and soaking;
2) respectively decocting the soaked mixture of ginseng, forsythia and water, filtering and collecting the extract;
3) collecting the extractive solutions, concentrating, making into extract, and drying.
Particularly, the soaking treatment time in the step 1) is 30-60min, preferably 30 min.
Particularly, the weight ratio of the ginseng and the forsythia suspensa medicinal materials to water is 1:8-12, preferably 1: 10.
Wherein, the decocting and extracting times in the step 2) are 2-3 times, preferably 3 times.
Particularly, in each decocting and extracting process, the weight ratio of the ginseng medicinal material to water is 1:8-12, preferably 1: 8; the temperature for each decocting extraction is 90-100 deg.C, preferably 90-95 deg.C; the heating extraction time is 0.5-2h, preferably 1 h.
Wherein, the concentration temperature in the concentration treatment process in the step 3) is 70-95 ℃, and preferably 80 ℃; the relative density of the concentrated extract is 1.05-1.15, preferably 1.1; the temperature during the drying treatment is 70-95 ℃, and preferably 85 ℃.
The total ginsenoside is prepared by the following steps:
1) uniformly mixing the medicinal material human participation extraction solvent, and then carrying out soaking treatment;
2) heating and extracting the mixture of the soaked ginseng and the extraction solvent, filtering and collecting the extracting solution;
3) separating the collected ginseng extract by adopting a macroporous resin column, collecting and combining the eluent to obtain ginseng resin column eluent;
4) concentrating and drying the ginseng resin column eluent to obtain the ginseng resin eluent.
Particularly, the soaking treatment time in the step 1) is 30-60min, preferably 30 min.
Particularly, the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1: 10.
In particular, the extraction solvent is ethanol solution with volume percentage concentration of more than or equal to 50 percent, preferably 50-75 percent.
Wherein, the heating extraction times in the step 2) are 2-3 times, and preferably 3 times.
Particularly, in each heating extraction process, the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1: 8; the temperature of each heating extraction is 60-80 deg.C, preferably 70 deg.C; the heating extraction time is 0.5-2h, preferably 1 h.
Particularly, the method also comprises the step of concentrating the ginseng extract collected in the step 2) to prepare a ginseng concentrated solution and then carrying out the macroporous resin column separation treatment.
In particular, the concentrated ginseng solution obtained after the concentration treatment contains 1 to 3.5g of crude ginseng per ml, i.e., 1 to 3.5g of crude drug/ml, preferably 2.5g of crude drug/ml.
Wherein, the macroporous resin column chromatography treatment in the step 3) comprises the following steps in sequence: 3A) injecting the ginseng extract into a macroporous resin column, and then eluting by using water as an eluent; 3B) eluting with 30-50 vol% ethanol solution as eluent, and collecting the ethanol eluate to obtain ginseng resin eluate.
Particularly, in the macroporous resin column chromatography process, the ratio of the weight of the ginseng in the ginseng extract to the volume of the macroporous resin is 1: 0.8 to 2.5, preferably 1: 1.
particularly, in the process of separating and treating the macroporous resin column, the ratio of the column diameter of the macroporous resin column to the column height of the resin is 1: 5-10, preferably 1:5 to 7, more preferably 1: 5.5-5.9.
Wherein, the macroporous absorption resin in the step 3) selects one of X-5, AB-8, NK-2, NKA-2, NK-9, D3520, D101 and WLD, and is preferably D101.
In particular, the ratio of the amount of water used in step 3A) to the column volume of the macroporous resin column is 2-4: 1, preferably 4: 1; the ratio of the dosage of the ethanol solution with the volume percentage concentration of 30-50% in the step 3B) to the column volume of the macroporous resin column is 2-8: 1, preferably 4 to 8: 1, more preferably 8: 1.
in particular, the eluent ethanol solution in step 3B) has a concentration of 50% by volume.
Wherein, the concentration temperature in the concentration treatment process in the step 4) is 65-90 ℃, and preferably 80 ℃; the temperature during the drying treatment is 75-95 ℃, and preferably 85 ℃.
Particularly, the content of the total saponins of the ginseng is 20-50% (the detection method is carried out according to the method of the national standard GB/T19506-2009 appendix B).
Wherein the panaxadiol saponins are prepared by the following steps:
1) uniformly mixing the medicinal material human participation extraction solvent, and then carrying out soaking treatment;
2) heating and extracting the mixture of the soaked ginseng and the extraction solvent, filtering and collecting the extracting solution;
3) subjecting the collected Ginseng radix extractive solution to macroporous resin chromatography for the first time, collecting and mixing eluates to obtain Ginseng radix resin column first eluate;
4) subjecting the first eluate to macroporous resin column chromatography for the second time, collecting and mixing the eluates to obtain second eluate;
5) and concentrating and drying the second ginseng resin eluent to obtain the ginseng resin.
Particularly, the soaking treatment time in the step 1) is 30-60min, preferably 30 min.
Particularly, the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1: 10.
In particular, the extraction solvent is ethanol solution with volume percentage concentration of more than or equal to 50 percent, preferably 50-75 percent.
Wherein, the heating extraction times in the step 2) are 2-3 times, and preferably 3 times.
Particularly, in each heating extraction process, the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1: 8; the temperature of each heating extraction is 60-80 deg.C, preferably 70 deg.C; the heating extraction time is 0.5-2h, preferably 1 h.
Particularly, the method also comprises a step 2A) of concentrating the ginseng extract collected in the step 2) to prepare a ginseng concentrated solution and then carrying out the first macroporous resin column chromatography separation treatment.
In particular, the concentrated ginseng solution obtained after the concentration treatment contains 1 to 3.5g of crude ginseng per ml, i.e., 1 to 3.5g of crude drug/ml, preferably 2.5g of crude drug/ml.
Wherein the first macroporous resin column chromatography treatment in the step 3) comprises the following steps in sequence: 3A) injecting the ginseng extract into a macroporous resin column, and then eluting by using water as an eluent; 3B) eluting with 30-50 vol% ethanol solution as eluent, and collecting ethanol eluate to obtain Ginseng radix-macroporous resin first eluate.
Particularly, in the macroporous resin column chromatography process, the ratio of the weight of the ginseng in the ginseng extract to the volume of the macroporous resin is 1: 0.8 to 2.5, preferably 1: 1.
particularly, in the process of separating and treating the macroporous resin column, the ratio of the column diameter of the macroporous resin column to the column height of the resin is 1: 5-10, preferably 1:5 to 7, more preferably 1: 5.5-5.9.
Wherein, the macroporous absorption resin in the step 3) selects one of X-5, AB-8, NK-2, NKA-2, NK-9, D3520, D101 and WLD, and is preferably D101.
In particular, the ratio of the amount of water used in step 3A) to the column volume of the macroporous resin column is 2-4: 1, preferably 4: 1; 3B) the ratio of the dosage of the ethanol solution with the medium volume percentage concentration of 30-50 percent to the column volume of the macroporous resin column is 2-8: 1, preferably 4 to 8: 1, more preferably 8: 1.
in particular, the eluent ethanol solution in step 3B) has a concentration of 50% by volume.
Particularly, the method also comprises the step of concentrating the ginseng resin first eluent collected in the step 3) to prepare a ginseng resin first concentrated solution, and then carrying out the second macroporous resin column chromatography separation treatment.
In particular, the concentrated ginseng solution obtained after the concentration treatment contains 3.5 to 6g of crude ginseng per ml, i.e., 3.5 to 6g of crude drug/ml, preferably 5.0g of crude drug/ml.
Particularly, the second macroporous resin column chromatography treatment in the step 4) comprises the following steps of: 4A) injecting the first eluent of the ginseng resin column into a macroporous resin column, and then eluting by adopting an ethanol solution with the volume percentage concentration of 50-60% as an eluent; 4B) and eluting by using an ethanol solution with the volume percentage concentration of 70-80% as an eluent, and collecting ethanol eluent to obtain a second ginseng resin eluent.
Particularly, in the second macroporous resin column chromatography process in the step 4), the ratio of the weight of ginseng in the first eluent of the ginseng resin column to the volume of the macroporous resin is 1: 0.8 to 2.5, preferably 1: 1.
particularly, in the process of separating and treating the macroporous resin column, the ratio of the column diameter of the macroporous resin column to the column height of the resin is 1: 5-10, preferably 1:5 to 7, more preferably 1: 5.5-5.9.
Wherein, the macroporous absorbent resin in the step 4) is one of HPD-200, D203, XAD-4 and HPD-100, preferably HPD-100.
Particularly, the ratio of the using amount of the ethanol solution with the volume percentage concentration of 50-60% in the step 4A) to the column volume of the macroporous resin column is 2-4: 1, preferably 4: 1; the ratio of the amount of the ethanol solution with the mass percentage concentration of 70-80% in the step 4B) to the column volume of the macroporous resin column is 2-8: 1, preferably 4 to 8: 1, more preferably 8: 1.
wherein, the concentration temperature in the concentration treatment process in the step 5) is 65-95 ℃, and preferably 80 ℃; the temperature during the drying treatment is 70-95 ℃, and preferably 85 ℃.
Particularly, the detection method for the panaxadiol saponins with the content of 30-70 percent is according to the national standard: the method of GB/T19506-2009 appendix B).
Wherein, the content of the 20(R) -ginsenoside Rg3 is 1 to 98 percent; preferably 30 to 80%, and more preferably 60%.
In particular, the content of the 20(R) -ginsenoside Rg3 is more than or equal to 1 percent, preferably more than or equal to 30 percent, more preferably more than or equal to 60 percent, even more preferably more than or equal to 80 percent, and even more preferably more than or equal to 98 percent.
Wherein, the content of the 20(R) -ginsenoside Rg3 derivatives is 1 to 98 percent; preferably 30 to 80%, and more preferably 60%.
In particular, the content of the 20(R) -ginsenoside Rg3 derivative is more than or equal to 1 percent, preferably more than or equal to 30 percent, more preferably more than or equal to 60 percent, even more preferably more than or equal to 80 percent, and even more preferably more than or equal to 98 percent.
Wherein the forsythin is prepared by extracting according to the following method:
1) heating and refluxing the forsythia suspense leaves or forsythia suspense by using a solvent for 2-3 times, wherein each time lasts for 2-4 hours;
2) concentrating the extracting solution, standing, and separating out precipitate to obtain a mixture crude product of forsythiaside and phillyrin;
3) dissolving the mixture crude product of forsythiaside and phillyrin by using a solvent, standing, and separating out crystals to obtain a phillyrin mixture;
4) recrystallizing the mixture of forsythin and phillyrin with solvent to obtain phillyrin extract.
In particular, the solvent in the steps 1), 3) and 4) is methanol, ethanol, acetone, aqueous methanol or aqueous ethanol.
Particularly, the mass percentage concentration of the water-containing methanol is 70-95%; the mass percentage concentration of the hydrous ethanol is 70-95%.
Wherein, the temperature of standing in the step 2) is room temperature, preferably 10-35 ℃, and more preferably 20-25 ℃; standing for 1-48 h; the ratio of the concentrated volume of the extracting solution in the step 2) to the volume of the original extracting solution is 0.1-0.5: 1.
in particular, the temperature of the recrystallization treatment in step 4) is room temperature, preferably 10 to 35 ℃, and more preferably 20 to 25 ℃.
In a fourth aspect, the present invention provides a process for the preparation of a formulation according to the third aspect of the present invention, comprising the step of admixing a composition according to the first aspect of the present invention and a pharmaceutically or nutraceutically acceptable carrier.
Preferably the method of the fourth aspect of the invention comprises the step of mixing the composition of the first aspect of the invention with a cyclodextrin or a derivative thereof (e.g. an alpha-, beta-or gamma-cyclodextrin or a derivative thereof). It is also preferred that the method of the fourth aspect of the invention comprises the step of physically and chemically treating the composition of the first aspect of the invention with a cyclodextrin or a derivative thereof (e.g. an alpha-, beta-or gamma-cyclodextrin or a derivative thereof) to form a complex.
In a fifth aspect, the invention provides the use of a composition according to the first aspect of the invention in the manufacture of a medicament or health food for anti-viral, antipyretic, anti-inflammatory and/or immune enhancement. Accordingly, the present invention provides a method for anti-viral, antipyretic, anti-inflammatory and/or enhancing immunity comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the first aspect of the invention. Preferably, the individual may be a mammal, preferably a human.
As used herein, unless otherwise indicated, the term "therapeutically effective amount" is the amount of a drug required to produce an effective effect; the "therapeutically effective amount" is adjustable and variable and ultimately determined by the medical practitioner, taking into account factors including the route of administration and the nature of the formulation, the general condition of the recipient's weight, age, etc., and the nature and severity of the condition being treated.
Compared with the prior art, the invention has the following obvious advantages:
the preparation method of the composition of the forsythia suspensa participated by the inventor is simple and convenient, is suitable for industrial production, has obvious functions of resisting virus, relieving fever, resisting inflammation and improving immunity, has the effect remarkably superior to that of singly using ginseng and forsythia suspensa, and develops a new field for the application of the medicinal materials of the forsythia suspensa participated by the inventor.
1. The composition of the forsythia suspense participated by the inventor has scientific formula compatibility, unique formula, exact efficacy, high safety and controllable quality;
2. the composition provided by the invention develops a new medicinal value, and series of experimental researches prove that the composition has the effects of resisting virus, relieving heat, resisting inflammation and improving immunity, the action effect of the composition is obviously superior to that of the effect of single medication of ginseng and fructus forsythiae, and the ginseng and the fructus forsythiae are combined according to a specific proportion and have a synergistic effect;
3. the composition has the advantages of simple preparation method, mild process conditions, low cost and low cost;
4. the composition has the advantages of obvious effect, quick response, small toxic and side effect, good safety, long-term use and good medicinal prospect;
5. the product of the invention has rich raw material sources, low price, safe clinical use, simple preparation process, small dosage and convenient use, can be prepared into various dosage forms, and is easy to popularize.
6. The composition of the fructus forsythiae, which is participated by the inventor, can be prepared by adopting monomer components quantitatively, or can be prepared into a composition of the fructus forsythiae for adults by extraction, or the composition of the fructus forsythiae for adults is combined with alpha-or beta-, gamma-cyclodextrin or cyclodextrin derivatives to form a formula composition, or the composition of the fructus forsythiae for humans can be prepared into a formula composition together with other active components (such as one or more of dandelion extract, isatis root extract, honeysuckle extract, rhizoma anemarrhenae extract, radix scrophulariae extract, selfheal extract, rhizoma phragmitis extract, lophatherum gracile extract, gardenia extract, bulbus fritillariae cirrhosae extract, ilex latifolia thunb extract and houttuynia cordata extract) to prepare a compound medicine with antiviral, antipyretic, anti-inflammatory and immunity improving functions.
Detailed Description
The benefits of the formulations of the present invention are further described below in the detailed description. These examples are merely illustrative and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Examples 1-4 preparation of a composition of Ginseng-Forsythia suspensa (crude drug powder)
The two medicinal powders of ginseng and forsythia are respectively taken and can be mixed according to the weight ratio of table 1 to prepare the composition of adult and forsythia. The ginseng and the forsythia are qualified medicinal materials which meet the standard of Chinese pharmacopoeia.
TABLE 1 raw material proportioning Table of the composition of ginseng and forsythia suspensa of examples 1-4
EXAMPLE 5 preparation of alcoholic extract of Ginseng-Forsythia suspensa composition
1. First extraction treatment
Adding pulverized Ginseng radix (300g) and fructus forsythiae (300g) into a multifunctional Chinese medicinal extraction tank, respectively mixing with 70 vol% ethanol solution (3000g), soaking for 30min, turning on the power supply of the multifunctional extraction tank, heating, respectively performing first heating extraction treatment on Ginseng radix and fructus forsythiae, extracting at 70 deg.C for 1 hr, and filtering to obtain first extractive solution and first residue; wherein the weight ratio of the ginseng and the forsythia suspense to the extraction solvent (ethanol solution) is 1: 10.
The weight ratio of the ginseng and the forsythia suspense to the extraction solvent is 1:10, and the other ratios are 1:8-12 are suitable for use in the present invention; the soaking time is 30min, and other soaking times are more than or equal to 30min and are suitable for the invention, preferably 30-60 min; the extraction solvent is not only ethanol solution with 70 percent of volume concentration, but also other ethanol solution with more than or equal to 50 percent of volume concentration is applicable to the invention, and ethanol solution with 50-75 percent of volume concentration and absolute ethanol are preferred; the extraction temperature is 60-80 ℃, and the heating extraction time is 0.5-2 h.
2. Second extraction treatment
Adding 70% ethanol solution into the first residue, heating, performing second heating extraction treatment on Ginseng radix and fructus forsythiae respectively, extracting at 70 deg.C for 1 hr, and filtering to obtain second extractive solution and second residue; wherein the weight ratio of the ginseng and the forsythia suspense to the extraction solvent is 1: 10.
3. Extracting for the third time
Adding 70% ethanol solution into the second residue, heating, performing third heating extraction treatment on Ginseng radix and fructus forsythiae respectively, extracting at 70 deg.C for 1 hr, and filtering to obtain third extractive solution; wherein the weight ratio of the ginseng and the forsythia suspense to the extraction solvent is 1: 10.
In the embodiment of the invention, except for 70% ethanol solution by volume percentage concentration, other ethanol solutions with the volume percentage concentration of more than or equal to 50% are all suitable for the invention in the extraction solvent used in the second and third extraction processes of the alcohol extracts of ginseng and forsythia suspensa, and the ethanol solution with the concentration of 50-75% and absolute ethanol are preferably selected; the extraction temperature is 60-80 ℃ and is suitable for the invention; the heating extraction time of 0.5-2h is suitable for the invention.
In the embodiment of the invention, the heating extraction times are 3 times in the preparation process of the alcohol extracts of ginseng and forsythia, and the extraction times are 2-3 times, so that the invention is suitable for the preparation of the alcohol extracts of ginseng and forsythia.
4. Concentrating and drying
Mixing the first, second and third extractive solutions obtained by filtering for 3 times at a weight ratio of 2:98, evaporating and concentrating in a rotary evaporator at 80 deg.C to obtain extract with relative density of 1.1, and drying in an oven at 85 deg.C to constant weight to obtain the final product.
The alcoholic extract of the composition of human and forsythia is light brown yellow powder, has special smell and is dissolved in ethanol.
In the concentration treatment process of the alcohol extract of the composition of ginseng and forsythia suspense, the concentration temperature is 65-85 ℃, and the relative density of the concentrated extract is 1.05-1.15, so that the invention is suitable for the composition of ginseng and forsythia suspense; the temperature of 70-90 ℃ in the drying process is suitable for the invention. The content of the total ginsenoside in the panaxynol extract prepared by the method is 2-5%.
Example 6 preparation of aqueous extract of Ginseng-Forsythia suspensa composition
1. Soaking treatment
Respectively placing pulverized Ginseng radix (300g), fructus forsythiae (300g), and tap water (3000g) as extraction solvent in a multifunctional Chinese medicinal extraction tank, mixing, and soaking for 30 min; the weight ratio of ginseng and forsythia suspense to the extraction solvent water is 1: 10.
In the preparation process of the water extracts of ginseng and forsythia suspense, the soaking time is more than or equal to 30min, and is preferably 30-60 min; the weight ratio of the human participation extraction solvent water is 1:10, and the other ratios are 1:8-12 are all suitable for use in the present invention.
2. First extraction treatment
Soaking for 30min, turning on a power supply of a multifunctional extraction tank, heating, decocting and extracting Ginseng radix and fructus forsythiae respectively for the first time, extracting at 95 deg.C for 1 hr, and filtering to obtain a first extractive solution and a first residue;
3. second extraction treatment
Adding tap water into the first residue, heating, decocting Ginseng radix and fructus forsythiae respectively for the second time, extracting at 90 deg.C for 1 hr, and filtering to obtain second extractive solution and second residue; wherein the weight ratio of the ginseng to the extraction solvent is 1: 10.
4. Extracting for the third time
Adding tap water into the second medicinal residue, heating, respectively carrying out third decoction and extraction treatment on the ginseng and the fructus forsythiae, extracting at the constant temperature of 90 ℃ for 1 hour, and filtering to obtain a third extracting solution; wherein the weight ratio of the ginseng and the forsythia suspense to the extraction solvent is 1: 10.
In the embodiment of the invention, the weight ratio of the ginseng medicinal material to the extraction solvent water in the first, second and third extraction processes of the water extracts of ginseng and forsythia is 1:10, and the other ratios are 1:8-12 are suitable for use in the present invention; the extraction temperature is 90-100 ℃, and is preferably 90-95 ℃; the heating extraction time is 0.5-2h, preferably 1 h.
In the embodiment of the invention, the heating extraction times are 3 times in the preparation process of the water extracts of ginseng and forsythia, and the extraction times are 2-3 times, which are all suitable for the invention.
5. Concentrating and drying
Mixing the first, second and third extractive solutions obtained by filtering for 3 times at a weight ratio of 2:98, evaporating and concentrating in a rotary evaporator at 80 deg.C to obtain extract with relative density of 1.1, and drying in oven at 85 deg.C to constant weight to obtain Ginseng radix water extract.
The water extract of the composition of the human and the forsythia is light brown yellow powder, has special smell and good water solubility.
In the concentration treatment process of the ginseng and forsythia suspense composition water extract, the concentration temperature is 70-95 ℃, and the relative density of the concentrated extract is 1.05-1.15, so that the ginseng and forsythia suspense composition water extract is suitable for the invention; drying temperatures of 70-95 ℃ are suitable for the present invention.
Example 7 preparation of Total saponins of Panax ginseng
1. First extraction treatment: same as in example 5.
2. And (3) second extraction treatment: same as in example 5.
3. And (3) extracting for the third time: same as in example 5.
4. Concentration treatment
Mixing the first, second and third extractive solutions obtained by 3 times filtering, and concentrating in rotary evaporator at 80 deg.C to obtain Ginseng radix concentrated solution (120ml) corresponding to 2.5g crude drug/ml Ginseng radix solution.
The concentration of the ginseng concentrated solution in the concentration treatment process of the invention is equivalent to 1-3.5g crude drug per ml of concentrated solution (namely 1-3.5g crude drug/ml) besides 2.5g crude drug per ml of concentrated solution, and the invention is also applicable to the ginseng concentrated solution.
5. Macroporous resin column chromatography
Loading the ginseng concentrated solution on a macroporous resin column, and carrying out macroporous resin column separation treatment, wherein D101 type macroporous adsorption resin is selected as the macroporous adsorption resin, and the ratio of the volume (300ml) of the resin in the resin column to the weight (dry weight) of ginseng is 1:1 (namely if the dry weight of the ginseng is 1 kilogram, the volume of the macroporous resin is 1L; if the dry weight of the medicinal materials is 1g, the volume of the macroporous resin is 1ml), after the concentrated supernatant completely flows into a resin column, washing with water with 4 times of the column volume, and discarding the eluent; eluting with ethanol solution with volume percentage concentration of 50% and 8 times of column volume, and collecting eluate to obtain Ginseng radix-macroporous resin eluate;
the ratio of the weight of ginseng in the ginseng extract to the volume of macroporous resin in the process of carrying out macroporous resin column chromatography on the ginseng concentrated solution is 1: 0.8 to 2.5 are suitable for the present invention; except D101, other macroporous adsorption resins such as X-5, AB-8, NK-2, NKA-2, NK-9, D3520, D101 and WLD are suitable for the invention; in the water elution process, the ratio of the water consumption to the column volume of the macroporous resin column is 2-4: 1 is suitable for use in the present invention; when the eluent is an ethanol solution, the volume percentage concentration of the ethanol solution is 30-50% except 50%; the ratio of the dosage of the ethanol solution to the column volume of the macroporous resin column is 2-4: 1 are suitable for use in the present invention.
6. Concentrating and drying
Placing the Ginseng radix-macroporous resin eluate in a rotary evaporator, concentrating at 80 deg.C under reduced pressure, recovering solvent, and drying the concentrated residue in a drying oven at 85 deg.C to obtain 2.6g of total ginsenoside.
The total saponins of Ginseng radix are light brown yellow powder with special odor. The content of the obtained total ginsenoside is measured by a GB/T19506-2009 appendix B method, and the total ginsenoside content is 32%.
In the concentration treatment process of the ginseng-macroporous resin eluent, the concentration temperature is 65-90 ℃ and the invention is applicable; drying temperatures of 75-95 ℃ are suitable for the invention. The content of the total ginsenoside prepared by the method is 20-50%.
EXAMPLE 8 preparation of Panaxadiol saponins
1. First extraction treatment: same as in example 5.
2. And (3) second extraction treatment: same as in example 5.
3. And (3) extracting for the third time: same as in example 5.
4. Concentration treatment: same as in example 5.
5. First macroporous resin column chromatography
A ginseng-macroporous resin first eluate was obtained as in example 5.
6. Second macroporous resin column chromatography
Concentrating the first Ginseng radix-macroporous resin eluate in a rotary evaporator at 80 deg.C to obtain first Ginseng radix-macroporous resin concentrated solution (60ml), which is equivalent to Ginseng radix solution of 5.0g crude drug/ml;
loading the ginseng-macroporous resin first concentrated solution on a macroporous resin column, and carrying out macroporous resin column separation treatment, wherein the macroporous resin is HPD-100 type macroporous resin, and the ratio of the volume (300ml) of the resin in the resin column to the weight (dry weight) of ginseng is 1:1 (namely if the dry weight of the ginseng is 1 kilogram, the volume of the macroporous resin is 1L; if the dry weight of the medicinal materials is 1g, the volume of the macroporous resin is 1ml), after the concentrated supernatant completely flows into a resin column, washing the resin column by using ethanol solution with the volume percentage concentration of 60 percent which is 4 times of the volume of the column, and discarding the eluent; then eluting with 80% ethanol solution with volume percentage concentration 8 times of column volume, and collecting eluate to obtain Ginseng radix-macroporous resin second eluate.
The concentration of the ginseng concentrated solution in the concentration treatment process of the invention is equal to 3.5-6g crude drug per ml of concentrated solution (namely 3.5-6g crude drug/ml) besides 5.0g crude drug per ml of concentrated solution, and the invention is also applicable to the ginseng concentrated solution.
The ratio of the weight of the ginseng in the first concentrated solution of the ginseng-macroporous resin to the volume of the macroporous resin in the process of carrying out macroporous resin column chromatography on the first concentrated solution of the ginseng-macroporous resin is 1: 0.8 to 2.5 are suitable for the present invention; except HPD-100, other HPD-200, D203 and XAD-4 are suitable for the invention; in the elution process of the 60% ethanol solution, the ratio of the dosage of the 60% ethanol solution to the column volume of the macroporous resin column is 2-4: 1 is suitable for use in the present invention; in the elution process of the 80% ethanol solution, the ratio of the dosage of the 80% ethanol solution to the column volume of the macroporous resin column is 2-4: 1 are suitable for use in the present invention.
7. Concentrating and drying
And (3) placing the second ginseng-macroporous resin eluent in a rotary evaporator, carrying out reduced pressure concentration treatment at the temperature of 80 ℃, recovering the solvent, and placing the concentrated residue in a drying oven, and drying at the temperature of 85 ℃ to obtain 0.7g of the panaxadiol total saponins.
The panaxadiol saponins is light yellow powder and has special odor. The water solubility is good. The content of the obtained panaxadiol saponins is 59% by high performance liquid chromatography which is determined by adopting an appendix VI of the first part of the 2010 edition Chinese pharmacopoeia.
In the concentration treatment process of the ginseng-macroporous resin eluent, the concentration temperature is 65-95 ℃ and the invention is applicable; drying temperatures of 70-95 ℃ are suitable for the present invention. The panaxadiol saponins prepared by the method have the content of 30-70 percent.
EXAMPLE 9 preparation of phillyrin and phillygenin compositions
Adding 10kg of 95% (m/m) ethanol into 1kg of dried folium forsythiae, heating and reflux-extracting for 2 times, each time for 2 hours, filtering, concentrating the filtrate under reduced pressure to 1/2 of the original volume, standing at 25 deg.C for 1h, and separating out precipitate; dissolving with methanol, recrystallizing, and separating out precipitate; repeating the above method, recrystallizing with methanol to obtain phillyrin/phillygenin composition amorphous powder, and measuring phillyrin and phillygenin contents by HPLC to respectively reach 98% and 2%.
EXAMPLE 10 preparation of phillyrin and phillygenin composition
Adding 10kg of methanol into 1kg of dried fructus forsythiae, heating and refluxing for extraction for 3 times, each time for 4 hours, filtering, concentrating the filtrate under reduced pressure to 1/10 of the original volume, standing at 20 ℃ for 48 hours, and separating out a precipitate; dissolving with ethanol, recrystallizing, and separating out precipitate; repeating the above method, and recrystallizing with ethanol to obtain phillyrin/phillygenin composition amorphous powder with phillyrin and phillygenin content of 95% and 4%, respectively.
EXAMPLE 11 preparation of phillyrin and phillygenin compositions
Adding 70% (m/m) methanol 10kg into dried folium forsythiae 1kg, heating and reflux extracting for 3 times, each for 3 hr, filtering, concentrating the filtrate under reduced pressure to 1/3 of original volume, standing at room temperature for 2 hr, and separating out precipitate; dissolving with 90% methanol, recrystallizing, and separating out precipitate; repeating the above method, and recrystallizing with methanol to obtain phillyrin/phillygenin composition amorphous powder with phillyrin and phillygenin contents of 88% and 2%, respectively.
EXAMPLE 12 preparation of phillyrin and phillygenin compositions
Adding 10kg of anhydrous ethanol into 1kg of dried fructus forsythiae, heating and refluxing for extraction for 2 times, each time for 4 hours, filtering, concentrating the filtrate under reduced pressure to 1/4 of the original volume, standing at room temperature for 24 hours, and separating out a precipitate; dissolving the precipitate with acetone, recrystallizing to obtain precipitate; repeating the above method, and recrystallizing with acetone to obtain phillyrin/phillygenin composition amorphous powder containing phillyrin and phillygenin 90% and 6%, respectively.
EXAMPLE 13 preparation of a combination of Forsythiaside and Forsythiagenin
Adding 10kg of acetone into 1kg of dried weeping forsythia leaves, heating and refluxing for extraction for 3 times, extracting for 3 hours each time, filtering, concentrating the filtrate under reduced pressure to 1/5 of the original volume, standing for 10 hours at room temperature, and separating out a precipitate; dissolving with 70% ethanol, recrystallizing, and separating out precipitate; repeating the above method, and recrystallizing with 70% ethanol to obtain phillyrin/phillygenin composition amorphous powder containing phillyrin and phillygenin 80% and 5%, respectively.
Examples 14-18 preparation of Total Saponin-Forsythiaside and Forsythiaside compositions
The total ginsenosides prepared in example 7 and the phillyrin and phillygenin compositions of examples 9-13 are mixed according to the weight ratio of 2:98 respectively to obtain the total ginsenosides and phillyrin compositions.
Examples 19-23 preparation of Panaxadiol saponins-Forsythiaside and Forsythiaside compositions
The panaxadiol saponins prepared in example 8 and the phillyrin and phillygenin compositions of examples 9-13 are mixed according to the weight ratio of 2:98 respectively to obtain the composition of total ginsenosides and phillyrin.
EXAMPLE 24 preparation of Total Saponin-Forsythiaside composition
The total ginsenoside prepared in example 7 and phillyrin are mixed according to the weight ratio of 2:98 to obtain the total ginsenoside-phillyrin composition.
EXAMPLE 25 preparation of Panaxadiol saponin-Forsythiaside composition
The panaxadiol saponins prepared in example 7 and forsythin were mixed at a weight ratio of 2:98 to obtain a panaxadiol saponins-forsythin composition.
Example 2620 preparation of (R) -ginsenoside Rg 3-Forsythiaside composition
Mixing 20(R) -ginsenoside Rg3 and phillyrin at a weight ratio of 2:98 to obtain a composition of 20(R) -ginsenoside Rg3 and phillyrin.
EXAMPLES 27-40 preparation of a composition of Ginseng-Forsythia suspensa composition with Cyclodextrin
The compositions of ginseng and forsythia suspense prepared in examples 5, 6, 14-26 were prepared in the weight ratios described in table 2, according to the following method: (1) directly adding into cyclodextrin solution, or (2) directly adding into cyclodextrin solution and fully stirring for 1-24h, (3) directly adding into cyclodextrin solution and heating for 10-120 min, (4) directly adding into cyclodextrin solution and ultrasonic processing for 10-120 min, (5) directly grinding with cyclodextrin powder for 10-120 min, and (6) mixing Ginseng radix and fructus forsythiae composition with cyclodextrin powder uniformly and sieving; (7) directly adding the mixture into a cyclodextrin derivative solution, or (8) directly adding the mixture into the cyclodextrin derivative solution and fully stirring for 1-24h, (9) directly adding the mixture into the cyclodextrin derivative solution and heating for 10-120 min, (10) directly adding the mixture into the cyclodextrin derivative solution and carrying out ultrasonic treatment for 10-120 min, (11) directly grinding the mixture with cyclodextrin derivative powder for 10-120 min, and (12) uniformly mixing the mixture with the cyclodextrin derivative powder and sieving.
TABLE 2 raw material ratios and preparation methods of examples 5, 6, 14-24
The adjuvants of examples 27-40 are exemplified by the use of beta-cyclodextrin, and other cyclodextrins, cyclodextrin derivatives are suitable for use in the present invention, such as 1) beta-hydroxypropyl cyclodextrin, 2) hydroxyethyl-beta-cyclodextrin, 3)2, 6-dimethyl-beta-cyclodextrin, 4)2,3, 6-trimethyl-beta-cyclodextrin, 5)2, 6-diethyl-beta-cyclodextrin, 6)2,3, 6-triethyl-beta-cyclodextrin, 7) maltosyl-beta-cyclodextrin, 8) sulfobutylether-beta-cyclodextrin, 9) p-methylbenzenesulfonyl chloride (p-TsCl) -substituted beta-cyclodextrin, 10) 6-substituted beta-CD p-methylbenzenesulfonate (beta-cyclodextrin-6-OTs), 11) 2-oxopropyl-beta-cyclodextrin, 12) 2-monosubstituted p-methylbenzenesulfonate (. beta. -cyclodextrin-2-OTs), 13) beta-cyclodextrin p-methylbenzenesulfonate (. beta. -CD) j, and 14) the star macromolecule of beta-cyclodextrin PCL- (Tos) 7-beta-CD.
EXAMPLE 41 preparation of tablets of the composition Ginseng-Forsythia suspensa
The tablets of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
according to the proportion, the ginseng and forsythia suspensa composition prepared in the examples 5, 6 and 14-40 is uniformly mixed with starch, then the mixture is prepared into granules, and the talcum powder and the magnesium stearate are added, uniformly mixed and pressed into 10000 tablets.
EXAMPLE 42 preparation of Ginseng-Forsythia Capsule composition granules
The granules of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
100g of a composition of human and forsythia suspensa (the weight ratio of the two is 2:98)
Microcrystalline cellulose 10000g
According to the proportion, the ginseng and forsythia suspensa composition prepared in the examples 5, 6 and 14-40 is uniformly mixed with microcrystalline cellulose, and then the mixture is prepared into granules which are packaged into 10000 bags.
EXAMPLE 43 preparation of a Capsule composition of Ginseng and Forsythia suspensa
Capsules of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
250g of human and forsythia suspensa composition (the weight ratio of the two is 2:98)
2500g of starch
According to the proportion, the ginseng and forsythia suspensa composition prepared in the examples 5, 6 and 14-40 is uniformly mixed with starch and then encapsulated to prepare 10000 granules.
EXAMPLE 44-47 preparation of Capsule of composition of Ginseng-Forsythia
The composition components of the human and the forsythia suspensa are uniformly mixed with starch according to the weight ratio in the table 3 and then encapsulated, and 10000 capsules are prepared respectively.
TABLE 3
The raw materials in the table can be the ginseng-fructus forsythiae composition in examples 5, 6 and 14-40 and a compound consisting of ginseng component, fructus forsythiae component and cyclodextrin.
EXAMPLE 48-51 preparation of Ginseng-Forsythia Capsule composition granules
The components of the composition of the human and the forsythia suspensa are uniformly mixed with microcrystalline cellulose according to the weight ratio in the table 4, and then the mixture is prepared into granules and bagged into 10000 bags.
TABLE 4
The raw materials in the table can be replaced by the composition of the ginseng and the forsythia suspensa in examples 5, 6 and 14-40 and a compound consisting of the ginseng component, the forsythia suspensa component and cyclodextrin.
EXAMPLE 52 preparation of a tablet of the Ginseng-Forsythia composition
The tablets of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
according to the proportion, the composition of ginseng and forsythia is uniformly mixed with the extract powder, then the mixture is uniformly mixed with starch to prepare granules, and the granules are added with talcum powder and magnesium stearate to be uniformly mixed and then pressed into 10000 tablets. The composition of ginseng and forsythia suspensa in this example can be replaced with the composition of ginseng and forsythia suspensa in examples 5, 6 and 14-40, and a composite comprising a ginseng component, a forsythia suspensa component and cyclodextrin.
EXAMPLE 53 preparation of Ginseng-Forsythia Capsule composition granules
The granules of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
250g of human and forsythia suspensa composition (the weight ratio of the two is 2:98)
Glycyrrhiza extract 250g
2455 g of microcrystalline cellulose
Mixing the above extract powder with Ginseng radix and fructus forsythiae composition, mixing with microcrystalline cellulose, granulating, and packaging into 10000 bags. The composition of ginseng and forsythia suspensa in this example can be replaced with the composition of ginseng and forsythia suspensa in examples 5, 6 and 14-40, and a composite comprising a ginseng component, a forsythia suspensa component and cyclodextrin.
EXAMPLE 54 preparation of a Capsule of the composition Ginseng-Forsythia
Capsules of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
according to the proportion, the composition of ginseng and forsythia is uniformly mixed with the extract powder, and then the mixture is uniformly mixed with starch and encapsulated to prepare 10000 granules. The composition of ginseng and forsythia suspensa in this example can be replaced with the composition of ginseng and forsythia suspensa in examples 5, 6 and 14-40, and a composite comprising a ginseng component, a forsythia suspensa component and cyclodextrin.
EXAMPLE 54 tablet preparation of the Ginseng-Forsythia Capsule composition
The tablets of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
mixing the above extract powder with Ginseng radix and fructus forsythiae composition, mixing with starch, granulating, adding pulvis Talci and magnesium stearate, mixing, and tabletting to obtain 10000 tablets. Wherein, the composition of ginseng and forsythia suspensa in this example can be replaced with the composition of ginseng and forsythia suspensa prepared in examples 5, 6, and 14-40.
EXAMPLE 55 preparation of Ginseng-Forsythia Capsule composition granules
The granules of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
mixing the above extract powder with Ginseng radix and fructus forsythiae composition, mixing with microcrystalline cellulose, granulating, and packaging into 10000 bags. Wherein, the composition of ginseng and forsythia suspensa in this example can be replaced with the composition of ginseng and forsythia suspensa prepared in examples 5, 6, and 14-40.
EXAMPLE 56 Capsule preparation of Ginseng-Forsythia composition
Capsules of the composition of the human and the forsythia suspensa are prepared according to the following mixture ratio:
according to the proportion, the composition of ginseng and forsythia is uniformly mixed with the extract powder, and then the mixture is uniformly mixed with starch and encapsulated to prepare 10000 granules. Wherein, the composition of ginseng and forsythia suspensa in this example can be replaced with the composition of ginseng and forsythia suspensa prepared in examples 5, 6, and 14-40.
Test example 1 antiviral test of Ginseng-Forsythia suspensa composition
1 in vitro antiviral assay
1.1 test materials
(1) Medicine
Phillyrin (content > 98%), white powder, produced by Dalian Fusheng Natural drug development Limited, has a purity of 99.5% as determined by two detectors of high performance liquid chromatography, ultraviolet detector and evaporative light scattering detector area normalization, and is calibrated and confirmed to have a content of 99.5% by using a phillyrin reference substance for Chinese drug biological product content determination.
20(R) -ginsenoside Rg3 (content > 98%), white powder, and high purity of 99.0% by high performance liquid chromatography with ultraviolet detector and evaporative light scattering detector area normalization method; and the content of the ginsenoside Rg3 reference substance is calibrated and confirmed to be 99.1 percent by using the content measurement of Chinese medicinal biological products.
Composition of human and forsythia suspensa: the product of Dalian Fusheng natural medicine development Co., Ltd is respectively calibrated by a reference substance for measuring the content of Chinese medicine biological products, and the content of ginsenoside Rg3 and phillyrin in the product is determined.
Ginseng radix-fructus forsythiae composition alcoholic extract (A; example 5), ginsenoside Rg3 and phillyrin content are 0.15%, 18.6% respectively;
the content of ginsenoside Rg3 and phillyrin in the water extract of Ginseng radix-fructus forsythiae composition (B; example 6) is 0.17% and 17.7%, respectively;
the total ginsenoside-phillyrin and phillygenin composition (C; example 14) has ginsenoside Rg3 and phillyrin contents of 0.04% and 95.6%, respectively;
the panaxadiol saponins-phillyrin and phillygenin composition (D; example 19) contains ginsenoside Rg3 and phillyrin 0.12% and 96.6%, respectively;
20(R) -ginsenoside Rg 3-phillyrin composition (E; example 26), the contents of ginsenoside Rg3 and phillyrin are 2.0% and 96.6%, respectively.
Ribavirin injection is colorless transparent liquid, is produced by Henan Runzhong GmbH, and has a product batch number: 1206261, national drug standards: h19993553, 100mg/ml, as a positive control drug for this experiment.
Oseltamivir phosphate, china institute for drug and biological products. Product batch number: 101096-200901, 100 mg/count is used as the positive control drug in this test.
The medicines are dissolved by corresponding reagents, filtered, sterilized and subpackaged at 4 ℃ for later use, and are the medicines to be tested in the test.
(2) Cell lines: vero (Vero cells) cell lines were maintained by the basic medical college of Jilin university.
(3) Virus strain: influenza virus strains, parainfluenza virus strains, Respiratory Syncytial Virus (RSV) strains: purchased at the institute of viral research of the academy of preventive medicine sciences of China; ② Coxsackie virus B3(CVB3) Strain: from the United states, preserved for the present teaching and research laboratory; ③ coxsackievirus A16(CoxA16) strain, enterovirus EV71 strain: presented by national hospital of Japan and stored in the teaching and research room; fourthly, adenovirus (AdV) is from the pediatric research room of the university of Bai Qien medical college; fifthly, the herpes simplex virus I (HSV-1) is purchased from the institute for testing the biological products of the medicines of the Ministry of health.
(4) Main equipment and reagents:
the biological safety cabinet: BHC-1300 IIA/B3, AIRTECH; CO 22An incubator: MCO-18AIC, SANYO; and (3) inverting the microscope: CKX41, OLYMPUS; electronic analytical balance: AR1140/C, DHAUS; culture medium: DMEM, HyClone; fetal bovine serum: hyclone; trypsin: gibco; MTT: sigma; DMSO, DMSO: tianjin, North-Union Fine chemical development, Inc.
1.2 test methods
(1) Cell preparation
Subculturing Vero cells for 1-2 days to obtain slices, clear boundary, strong stereoscopic impression and refractivity, digesting with pancreatin until the cell surface has needle-point-like small hole, completely sucking out digestive juice, taking several ml of culture solution to blow off cells, counting, diluting with culture solution (DMEM containing 10% fetal calf serum) to about 5 × 107After one/L, the cells are inoculated into a 96-well culture plate, and the cells grow into a monolayer.
(2) Drug toxicity assay
Cytotoxicity test: the drugs were diluted at the concentrations shown in Table 1-1 for cytotoxicity assay.
TABLE 1-1 drug dilution reference Table (unit: g/L)
Dropping the above diluted medicines with different concentrations in maintenance solution (DMEM containing 2% fetal calf serum) on Vero single layer cells at a volume of 0.2ml per wellThe concentration of 9 multiple wells were filled with 9-well normal control (normal control without drug) and 9-well blank control (culture medium), and the mixture was incubated at 37 deg.C with 5% CO2Incubate in incubator, place inverted microscope every day to observe CPE and record. After 72h, 20. mu.L (5 mg. multidot.mL) of MTT solution was added to each well-1) And continuing to incubate for 4h, removing culture solution from each well, adding 100 mu L DMSO into each well, oscillating for 5min, measuring OD value at 492nm, and calculating the cell survival rate. In SPSS 18.0 statistical software, Probit regression analysis is carried out on the cell survival rate, and the maximum nontoxic concentration (TC) of the drug to Vero cells is calculated0) And half the Toxic Concentration (TC)50)。
(3) TCID for various viruses50Measurement of (2)
Each virus was diluted 10-fold down to 10-1,10-2,10-3,10-4,10-5,10-6Different dilutions were sequentially inoculated on a single layer of Vero cell 96-well culture plate, 100. mu.L per well, 10 wells per dilution, and a normal cell control group was set. Standing at 37 deg.C for 5% CO2Incubating for 2 hr, discarding virus solution, adding cell maintenance solution 100 μ L per well, standing at 37 deg.C and 5% CO2Culturing in medium. The cytopathic effect was observed under a microscope starting on day 3, and the results were judged and recorded on days 7-8, and the virus titer was calculated by the karber method using the highest dilution that resulted in 50% of the wells being positive for the lesions as the endpoint.
Formula (II)(TCID50: 50% of the infected amount of the tissue cells; XM: the logarithm of the highest concentration dilution of the virus;
d: logarithm of dilution factor (fold); Σ pi: sum of the percentage of lesions at each dilution. )
(4) Effect of drugs on cytopathic Effect of viruses
Taking a culture plate full of monolayer cells, removing culture solution by aspiration, and adding 100TCID50Corresponding amounts of virus challenge cells were inoculated at 37 ℃ with 5% CO2Adsorbing in incubator for 2 hr, adding medicinal liquid with specific concentration (maximum nontoxic concentration) of 10 per concentrationMultiple wells were cultured, 200. mu.L/well. The ribavirin injection and oseltamivir phosphate are set as positive drug control groups, and a normal control group (without adding viruses or drugs) and a virus control group (with viruses but without adding drugs) are set at the same time, so that the influence of the drugs on the virus-induced CPE is observed. After 72h, the OD value is measured at 492nm by using an MTT colorimetric method, and the antiviral effective rate (ER%) of the medicine is calculated. The significant differences between the antiviral efficacy of each drug were compared in the SPSS 18.0 statistical software using ANOVA.
ER% (mean OD value in drug-treated group-mean OD value in virus-control group)/(mean OD value in cell-control group-mean OD value in virus-control group) × 100%
1.3 test results
(1) TCID of various viruses50
(2) drug toxicity assay
1) Determination of drug cytotoxicity
Maximum non-Toxic Concentration (TC) of each drug to Vero cells0) Half maximal Toxic Concentration (TC)50) And the concentrations for the drug antiviral experiments are shown in tables 1-2.
TABLE 1-2 drug cytotoxicity test results (unit: g/L)
2) The protective effect of the medicine on the cytopathic effect of the virus
The effective rate of the medicine against various viruses and the result of ANOVA method one-factor variance analysis are shown in tables 1-3 and 1-4.
Tables 1-3 drug antiviral effective Rate (ER%) statistics Table 1
Tables 1-4 statistics of effective antiviral (ER%) of drugs table 2
Note: p compared to the viral control group<0.05,**P<0.01; compared with phillyrin, the ginseng-forsythia suspense composition has the advantages that in each group,#P<0.05,##P<0.01; compared with the ginsenoside Rg3, the ginseng-forsythia composition has the advantages that,▲P<0.05,▲▲P<0.01; the ginseng-forsythia suspense composition compared with ribavirin for each group,△P<0.05,△△P<0.01,△△△P<0.001; compared with oseltamivir phosphate, the ginseng-forsythia composition has the advantages that in each group,●P<0.05,●●P<0.01,●●●P<0.001。
the results in tables 1-3 and 1-4 show that each group of the ginseng-fructus forsythiae composition has obvious inhibition effect on 8 viruses (P)<0.01 or P<0.001) and has the antiviral effective rate of 100 percent on influenza virus, parainfluenza virus, herpes simplex virus type I (HSV-I), enterovirus EV71 and Adenovirus (ADV), and the curative effect is obviously superior to that of phillyrin and ginsenoside Rg3, which shows that each group of the ginseng-forsythia composition has synergistic effect. In addition, the Ginseng-fructus forsythiae composition can inhibit influenza, Coxsackie virus A16(CoxA16), Respiratory Syncytial Virus (RSV), herpes simplex virus type I (HSV-I), Adenovirus (ADV), enterovirus EV71 and Coxsackie virus B3(CVB3) The curative effect is obviously better than that of a positive medicine ribavirin (P)<0.01 or P<0.001) inhibiting influenza, coxsackievirus A16(CoxA16), Respiratory Syncytial Virus (RSV), herpes simplex virus type I (HSV-I), Adenovirus (ADV), enterovirus EV71 and coxsackievirus B3(CVB3) The curative effect is obviously better than that of oseltamivir phosphate (P)<0.05, or P<0.01、P<0.001)。
2. In vivo antiviral assay
2.1 materials of the experiment
(1) Laboratory animal
Kunming mouse is provided by Experimental animals center of Bai Qien medical department of Jilin university, and the medical letter is No. 10-5219.
(2) Detection instrument and reagent
2.2 Experimental methods
(1) Determination of half lethal dose of influenza virus and parainfluenza virus in mice
Influenza virus and parainfluenza virus (cell lysate) were diluted 10-fold to 10-fold delivery ratio-1、10-2、10-3、10-4、10-5Virus solution at concentration. 120 Kunming mice, 60 influenza virus groups and parainfluenza virus groups are respectively taken and randomly divided into 6 groups, the mice are lightly anaesthetized by ether, and 0.03mL of virus solution with different dilutions is infected by nasal drops. Meanwhile, a blank control is set, and the virus suspension is replaced by physiological saline. Death and survival were observed daily until 14 days post infection. Death within 24h of infection was non-specific and not counted, and viral fluid LD50 was calculated by Karber method. Calculating the formula:[ wherein: LD50: half lethal dose; XM: the logarithm of the highest concentration dilution of the virus; d: logarithm of dilution factor (fold); Σ pi: sum of the percentage of lesions at each dilution]。
(2) Research on anti-influenza virus and anti-pneumonia caused by parainfluenza virus infection by ginseng-fructus forsythiae composition
1) Test animals and groups
540 four-week-old Kunming mice were taken and subjected to 2 experiments.
270 mice are taken firstly, are randomly divided into 27 groups, and each group comprises 10 mice, and the ginseng-fructus forsythiae composition is used for a test for determining the lung index and the lung index inhibition rate of mice infected by influenza and parainfluenza viruses; for each experiment, 90 mice were taken and the experiment was repeated 3 times. Taking 270 mice, randomly dividing the mice into 27 groups of 10 mice, and using the mice in each group of the ginseng-fructus forsythiae composition for the determination test of the hemagglutination titer of the lung suspension virus; for each experiment, 90 mice were taken and the experiment was repeated 3 times.
2) Infection method
Putting a ball of absorbent cotton into a beaker with the size of 200-300 mL, then pouring a proper amount of diethyl ether (only the absorbent cotton is wet), turning over the beaker filled with the absorbent cotton, putting the mouse into the beaker for anesthesia, and when the mouse is extremely excited and is obviously weak, putting the mouse on the back and dripping the nose into the beakerInfection with 15LD50Influenza virus and parainfluenza virus 0.03 ml/nostril, and normal control group replaced virus suspension with physiological saline.
3) Method and dosage of administration
The groups of the ginseng-fructus forsythiae composition, the ginsenoside Rg3 group, the phillyrin group, the ribavirin and the oseltamivir phosphate control group are respectively subjected to conventional intragastric administration one day before infection, the groups of the ginseng-fructus forsythiae composition are respectively divided into high, medium and low dose groups, the administration doses are respectively 13.0, 6.5 and 3.25mg/kg, the phillyrin group is 13mg/kg, the ginsenoside Rg3 group is 13mg/kg, the ribavirin positive drug is 58.5mg/kg, the oseltamivir phosphate is 19.5mg/kg, the administration is carried out once a day for 5 days, and the normal control group and the virus control group are subjected to normal infusion of physiological saline with the same volume.
4) Observation index
Measurement of pulmonary index
On the 5 th day after the administration of the drug, the mice are forbidden to eat water for 8 hours, the animals are killed by picking eyeballs and bleeding after weighing, the whole lung is picked out by opening the chest cavity, the mice are washed twice by normal saline, the surface water is sucked dry by filter paper, the lung weight is weighed by an electronic balance, and the lung index and the inhibition rate of the lung index are calculated according to the following formulas:
lung index ═ (mouse lung weight/mouse body weight) × 100%
Lung index inhibition rate ═ (mean lung index in infection model group-mean lung index in experimental group)/mean lung index in infection model group × 100%
② determination of hemagglutination titer of lung suspension virus
Respectively taking the lungs of each group of mice on the 5 th day after treatment, placing a homogenizer at low temperature, grinding the lungs into homogenate, diluting the lung tissue suspension into 10% by normal saline, centrifuging the lung tissue suspension, taking the supernatant, diluting the supernatant in a multiple ratio, dripping the diluted lung tissue suspension onto a titration plate according to 0.2 ml/hole, adding 0.2ml of 1% chicken erythrocyte suspension into each hole, uniformly mixing the suspension, placing the mixture at room temperature for 30min, and observing and recording the hemagglutination titer. The titer was expressed as the dilution factor of the suspension, as the point when the erythrocytes were agglutinated (++).
2.3 test results and analysis
(1) Measurement of half lethal dose of influenza virus and parainfluenza virus in mice
Test group Kunming mice were infected with 30 μ L influenza virus and parainfluenza virus solution by nasal drip, and 3 groups before 3 days (virus concentration is 10)-1Group 10-2Group 10-3Groups) mice all developed varying degrees of morbidity symptoms: shrugging, trembling, reduced diet, etc.; the mice appeared walking and swaying on day 5; mice in the highest virus concentration group began to die on day 6, and the remaining groups continued to die on day 7 post-infection. After the observation for 14 days, the death number of the mice in each group is counted, and the results are shown in tables 1-4 and 1-5 below. Calculating the LD of the influenza virus50Is a dilution of 10-2.9LD of parainfluenza Virus50Is a dilution of 10-2.5。
TABLE 1-4 statistics of median lethal dose test results for influenza viruses
Calculation of viral LD by Karber method50. LogLD of influenza Virus50The following were used:
TABLE 1-5 Parainfluenza Virus median lethal dose test results statistics
Calculation of viral LD by Karber method50. LogLD of parainfluenza Virus50The following were used:
(2) the composition of human and fructus forsythiae has effects in resisting pneumonia caused by influenza virus and parainfluenza virus infection
Measurement of pulmonary index
After infection of mice with influenza and parainfluenza viruses, the mean pulmonary index results show: compared with the infection model group, the lung indexes of 3 dose groups of a normal control group, a phillyrin group of 13.0mg/kg/d, a ginsenoside Rg3 group of 16.0mg/kg/d and a ginseng-forsythia composition group (a low dose group of 3.25mg/kg/d, a medium dose group of 6.5mg/kg/d and a high dose group of 13.0mg/kg/d), a ribavirin group and an oseltamivir phosphate group are obviously reduced (P <0.05 or P < 0.01); wherein, each group of the ginseng-forsythia suspense composition has obvious protective action within the concentration range of 3.25-13.0 mg/kg/d, the lung indexes are all obviously reduced, the inhibition rate on the lung tissue lesion index is obviously reduced, the curative effect is obviously superior to that of the forsythin group and the ginsenoside Rg3 group (P <0.01 or P <0.05), and the results are shown in tables 1-6 and 1-7.
Table 1-6 inhibition of lung index in mice infected with influenza virus by the composition of ginseng-forsythia (n ═ 3)
Comparison of virus control groups in each test group<0.05,**P<0.01; compared with the phillyrin, the composition of the human and the forsythia,#P<0.05,##P<0.01; compared with the ginsenoside Rg3,▲P<0.05,▲▲P<0.01。
TABLE 1-7 inhibition of parainfluenza virus infection in mice with the composition of Ginseng-Forsythia suspensa (n ═ 3)
Comparison of virus control groups in each test group<0.05,**P<0.01; compared with the phillyrin, the composition of the human and the forsythia,#P<0.05,##P<0.01; human participationCompared with the ginsenoside Rg3,▲P<0.05。
② determination of hemagglutination titer of lung suspension virus
After the influenza virus and the parainfluenza virus infect the mouse, the hemagglutination titer (InX) of the lung tissue virus of the infection model group is respectively 32.40 and 33.11, the hemagglutination titer of the lung tissue virus is reduced after the composition of the ginseng-forsythia with different concentrations is used for treating for 5 days, compared with an infection model group, the difference is significant (P is less than 0.01), and the hemagglutination titer of different dosage groups of the composition to influenza and parainfluenza virus is obviously lower than that of a forsythin group and a ginsenoside Rg3 group (P is less than 0.05-P is less than 0.001), which shows that the composition has synergistic effect, the inhibition rate of the compound on virus propagation is obviously higher than that of phillyrin group and ginsenoside Rg3 group (P is less than 0.05-P is less than 0.001), the inhibition rate of high, medium and low dose groups of the ginseng-fructus forsythiae composition on the hemagglutination titer of the lung suspension of the mice infected by the influenza virus is obviously higher than that of phillyrin groups and ginsenoside Rg3 groups (P is less than 0.01-P is less than 0.001). The above test results are shown in tables 1 to 8 and 1 to 9.
Table 1-8 effect of ginseng-forsythia composition on hemagglutination titer of influenza virus infected mouse lung suspension (n ═ 3)
TABLE 1-9 Effect of Ginseng and Forsythia suspensa combinations on the hemagglutination titer of parainfluenza Virus infected mouse lung suspensions (n ═ 3)
In tables 1-8 and 1-9, the virus control groups of each test group were compared with P<0.05,**P<0.01; the ginseng-forsythia suspense composition is compared with phillyrin in each group,#P<0.05,##P<0.01,###P<0.001; comparing each group of the ginseng-forsythia suspense composition with ginsenoside Rg3,▲P<0.05,▲▲P<0.01,▲▲▲P<0.001。
test example 2 antipyretic and anti-inflammatory test of composition of ginseng and forsythia suspensa
1.1 test materials
(1) The Wistar rat test animal has the weight of 120-250 g, male and female functions and a qualification number: the 13 th to 1225 th medical characters; japanese white rabbit, male, weighing 1.5-2.0 kg. Certificate number: the 10 th-5115 th part of the medical letters are all supplied by the Changchun high-tech animal experiment center, and the animal feed is supplied by the Jilin university laboratory animal department.
(2) Test drug
Phillyrin (content > 98%), white powder, produced by Dalian Fusheng Natural drug development Limited, has a purity of 99.5% as determined by two detectors of high performance liquid chromatography, ultraviolet detector and evaporative light scattering detector area normalization, and is calibrated and confirmed to have a content of 99.5% by using a phillyrin reference substance for Chinese drug biological product content determination.
20(R) -ginsenoside Rg3 (content > 98%), white powder, and high purity of 99.0% by high performance liquid chromatography with ultraviolet detector and evaporative light scattering detector area normalization method; and the content of the ginsenoside Rg3 reference substance is calibrated and confirmed to be 99.1 percent by using the content measurement of Chinese medicinal biological products.
Composition of human and forsythia suspensa: the product of Dalian Fusheng natural medicine development Co., Ltd is respectively calibrated by a reference substance for measuring the content of Chinese medicine biological products, and the content of ginsenoside Rg3 and phillyrin in the product is determined.
Ginseng radix-fructus forsythiae composition alcoholic extract (A; example 5), ginsenoside Rg3 and phillyrin content are 0.15%, 18.6% respectively;
the content of ginsenoside Rg3 and phillyrin in the water extract of Ginseng radix-fructus forsythiae composition (B; example 6) is 0.17% and 17.7%, respectively;
the total ginsenoside-phillyrin and phillygenin composition (C; example 14) has ginsenoside Rg3 and phillyrin contents of 0.04% and 95.6%, respectively;
the panaxadiol saponins-phillyrin and phillygenin composition (D; example 19) contains ginsenoside Rg3 and phillyrin 0.12% and 96.6%, respectively;
20(R) -ginsenoside Rg 3-phillyrin composition (E; example 26), the contents of ginsenoside Rg3 and phillyrin are 2.0% and 96.6%, respectively.
1.2 Main instruments and reagents
YLS-7A rat toe swelling measuring instrument: a Shandong province medical science institute equipment station; 722 visible spectrophotometer: manufactured by Shanghai spectrometer instruments Inc.; portable digital thermoscope: model number WSC-411P, Pudong, Shanghai; pilocarpine: tianjin City people pharmaceutical factory, batch number 20130112; histamine: shanghai Biochemical institute, batch number: 20130115, respectively; 5-hydroxytryptamine: shanghai Biochemical institute, lot number 20130623; evans blue: shanghai chemical reagent procurement supply station, batch number: 20130217, respectively; chlorpheniramine maleate tablets: pharmaceutical industry ltd, batch number, in vinpocetine, research area: 20130801, respectively; carrageenan: jilin province pharmaceutical research institute, lot number: 20130502, respectively; paracetamol tablets: baikang pharmaceutical industry, Limited liability company, Liaoyuan city, lot number: 20130512, respectively; an aspirin tablet: white city vanca pharmaceutical industry ltd, lot number: 20130305, respectively; beer yeast: beijing Oobo Star Biotechnology responsibility Co., Ltd, lot number: 2013020, respectively; typhoid and paratyphoid vaccines: institute for vinca biologicals, lot number: 20130216.
1.3 statistical processing
Statistical analysis Using rank sum test, X, of two sample comparisons2And (5) checking and t-checking.
2.1 Effect of the combination of Ginseng and Forsythia suspensa on sweat secretion from rat plantar region (coloring method)
(1) Materials and methods
The experiment observes the sweat secretion change according to the mechanism that sweat glands are distributed on the flesh cushion at the plantar part of the foot of the rat and the sweat secretion amount of the rat can generate purple reaction when meeting the sweat by using iodine and starch.
500 Wistar rats with half male and half female bodies and 120-150 g of body weight are taken in the test. The weight and sex were randomly divided into 50 groups, namely: the control (0.5% carboxymethyl cellulose) group, the phillyrin group, the ginsenoside Rg3 group, the ginseng-forsythia composition low, medium and high dose groups (2.5, 5 and 10mg/kg respectively) and the positive drug pilocarpine (35mg/kg) group are respectively selected from 10 groups, 10 groups are tested each time, and the test time periods are 5 (1, 5, 10, 15 and 20 min). Rats were placed in home-made rat fixation bags, exposing both hind limbs. The right foot sole dirt is lightly scrubbed and cleaned by dipping a cotton swab in absolute ethyl alcohol. Except for the subcutaneous injection of pilocarpine, the other groups are administrated by gastric lavage. 1h after administration (30 min after administration of pilocarpine group), firstly, lightly wiping sweat originally existing in the right foot sole and caused by struggling of each group of rats with a dry cotton swab, coating a Tian-Gao-Yuan reagent A liquid (2 g of iodine is dissolved in 100ml of absolute ethyl alcohol), and after full drying, thinly coating a Tian-Gao-Yuan reagent B liquid (50 g of soluble starch and 100ml of castor oil are uniformly mixed). The color and the amount of the dark purple colored spots (i.e. sweat spots) appeared after applying the B liquid for 1, 5, 10, 15 and 20min respectively, and were carefully observed with a magnifying glass. After the test is finished, the difference between the groups is compared according to the statistical treatment of the rank sum test of the comparison of the two samples.
(2) Results
Compared with a control group, the middle and high dose groups (5, 10mg/kg) of each group of the ginseng-fructus forsythiae composition have obvious promotion effects (p is less than 0.05) on sweat secretion of rat foot soles 10, 15 and 20min after the application of the liquid B, the 2.5mg/kg group of each group of the ginseng-fructus forsythiae composition have obvious promotion effects (p is less than 0.05) on sweat secretion of rat foot soles 15 and 20min after the application of the liquid B, the sweating effects of the groups are equivalent to that of the positive drug pilocarpine, and the group of the ginseng-fructus forsythiae composition has the effect of slowly promoting sweat secretion of rat foot soles. The promotion effect of the high-dose composition of the ginseng and forsythia suspensa on sweat secretion of rat plantar areas after 10, 15 and 20min after B liquid application is obviously superior to that of forsythin and ginsenoside Rg3(p is less than 0.05), the promotion effect of the high-dose composition of the ginseng and forsythia suspensa on sweat secretion of rat plantar areas after 10 and 15min after B liquid application is obviously superior to that of forsythin and ginsenoside Rg3(p is less than 0.05), and the promotion effect of the low-dose composition of the ginseng and forsythia suspensa on sweat secretion of rat plantar areas after 15min after B liquid application is obviously superior to that of forsythin and ginsenoside Rg3(p is less than 0.05). The test results show that the effect of each group of the ginseng-fructus forsythiae composition on promoting sweat secretion of rat foot metatarsus is obviously superior to that of phillyrin and ginsenoside Rg3, and the specific details are 2-1, 2-2, 2-3, 2-4 and 2-5.
TABLE 2-1 Effect of composition of Ginseng and Forsythia suspensa on sweat secretion from plantar region of normal rat foot (coloring method)
TABLE 2-2 Effect of composition of Ginseng and Forsythia suspensa on sweat secretion from plantar region of normal rat foot (coloring method)
TABLE 2-3 Effect of composition of Ginseng and Forsythia suspensa on sweat secretion from plantar region of normal rat foot (coloring method)
TABLE 2-4 Effect of Ginseng and Forsythia suspensa combinations on sweat secretion from the plantar aspect of the foot in normal rats (coloring method)
TABLE 2-5 Effect of composition of Ginseng radix and forsythiae fructus on sweat secretion from plantar region of normal rat foot (coloring method)
Sweat point rating criteria: "-" no sweat spots on the surface of the rat plantar flesh pad; the surface of the rat plantar meat pad shows occasionally sweat spots, and the area of the sweat spots accounts for less than 10% of the surface of the plantar; the surface of the rat plantar meat pad is scattered with sweat points, and the area of the sweat points is about 11 to 40 percent of the surface of the plantar; the sweat points are distributed on a plurality of positions on the surface of the rat plantar meat pad, and the area of the sweat points accounts for about 41-70% of the surface of the plantar; the surface of the flesh pad of the rat foot is evenly distributed with sweat spots, and the area of the sweat spots is about 71 percent of the surface of the foot.
Comparison of virus control groups in each test group<0.05; compared with the phillyrin, the composition of the human and the forsythia,#P<0.05; compared with the ginsenoside Rg3,▲P<0.05。
2.2 Effect of the combination of Ginseng and Forsythia suspensa on sweat secretion from rat plantar region (histomorphism observation)
(1) Materials and methods
This test is based on the fact that when the sweat glands of rats are excited, the morphology of the sweat glands in the epithelial cells is altered in addition to the increase in sweat secretion. The increase and enlargement of the number of the vacuoles of the sweat gland epithelial cells can be seen under an optical microscope. The enlarged vacuole is the swelling, the rupture, the fusion and the enlargement of secretory vesicles of mitochondria in sweat gland epithelial cells under an electron microscope, and the secretory activity of sweat glands can be known through observing the morphology of sweat gland epithelial tissues of plantar parts of feet of rats.
The test takes 300 Wistar rats with half male and female, and the weight of 120-160 g. The weight and sex of the animals are randomly divided into 30 groups, namely: the control group (0.5% carboxymethyl cellulose) ginsenoside Rg3, phillyrin and ginseng-forsythia composition are respectively divided into a low, medium and high (2.5, 5 and 10mg/kg) dose group and a positive drug pilocarpine (35mg/kg) group, 10 of the groups are respectively tested for 3 times. Except for the subcutaneous injection of pilocarpine, the other groups are administrated by a gastric lavage way. Control group was given 0.5% carboxymethylcellulose 1After the administration of pilocarpine 30min, and the administration of phillyrin, ginsenoside Rg3, ginseng and fructus forsythiae for 1h, cutting off right hind limb at ankle joint, taking off right plantar meat pad, placing in 10% formaldehyde solution, fixing, dehydrating, embedding, slicing, HE staining, observing the change in sweat gland epithelial cells of plantar region of each group of rats under optical microscope, mainly observing vacuole incidence, and passing through X2The test was statistically processed and the differences between groups were compared. The above experiment was repeated 3 times.
Percent vacuole generation is vacuole sweat gland number/observed sweat gland number multiplied by 100%
(2) Results
Compared with a control group, 2.5, 5 and 10mg/kg groups of the ginseng-fructus forsythiae composition have extremely remarkable promoting effects on sweat secretion of rat foot soles (p is less than 0.001); wherein, the curative effect of the low, medium and high dose groups (2.5, 5, 10mg/kg) is obviously better than that of phillyrin and ginsenoside Rg3(p is less than 0.001 or less than 0.01), which indicates that the composition of ginseng and forsythia has synergistic effect. The test results are detailed in tables 2-6;
TABLE 2-6 Effect of Ginseng and forsythiae fructus composition on sweat secretion from rat plantar region (histomorphometry, n-3)
P compared to control group<0.01,***p<0.001; the ginseng-forsythia suspense composition is compared with phillyrin in each group,##p<0.01,###p<0.001; comparing each group of the ginseng-forsythia suspense composition with ginsenoside Rg3,▲▲p<0.01,▲▲▲p<0.001;
2.3 Effect of composition of Ginseng and Forsythia suspensa on fever of beer yeast-induced rats
(1) Materials and methods
Male Wistar rats weighing 180-200 g. Before the test, the normal anal temperature is measured for 2 times (each time interval is certain time) by a WSC-411P type portable digital thermometer respectively, and the average value of the two measurements is taken as the normal body temperature of the rat. Then selecting 300 rats with the body temperature of 36.5-38 ℃, and randomly dividing the rats into 30 groups according to the body weight: the model group (0.5% carboxymethyl cellulose), the ginseng-fructus forsythiae composition groups were divided into low, medium and high (2.5, 5, 10mg/kg) dose groups, phillyrin group (13mg/kg), ginsenoside Rg3 group (13mg/kg) and positive drug paracetamol (100mg/kg) groups, 10 per group, and the test was repeated 3 times per group. Each group of rats was back-injected subcutaneously with 10mL/kg of 10% lager brewing yeast suspension to cause fever. After 10% beer yeast suspension is given for 6.0h, the composition of the ginsenoside Rg3 and the phillyrin and the paracetamol are both administered by intragastric administration, and the model group is intragastric administration with equal volume of 0.5% carboxymethyl cellulose. Anal temperature was measured 1, 2,3 and 4h after administration, respectively. Changes in body temperature were observed and the differences between groups were compared by t-test treatment of percent fever. The above experiment was repeated 3 times in total.
(2) Results
After 10% of fresh beer yeast suspension is injected into rats in each group subcutaneously for 6h, the body temperature rise is about 1.5 ℃, and the difference with that before pyrogenicity is obvious (p is less than 0.001), which indicates that the establishment of a beer yeast induced rat fever model is successful. Compared with the model group, the middle and high dose groups and the low dose groups of the ginseng-fructus forsythiae composition have obvious cooling effect on rat fever caused by beer yeast suspension in 1, 2,3 and 4 hours after the drug administration and 2,3 and 4 hours after the drug administration (p is less than 0.05-p is less than 0.001); meanwhile, the cooling curative effect of different dosage groups of the ginseng-forsythia suspensa composition is remarkably superior to that of a forsythin group and a ginsenoside Rg3 group (p is less than 0.001 or less than 0.01), which shows that the composition has obvious synergistic effect. The results of the above tests are shown in tables 2 to 7.
2.4 Effect of combination of Ginseng and Forsythia suspensa on Carrageenan swelling of rat foot
(1) Materials and methods
Taking 220 male Wistar rats with the weight of 120-150 g, and randomly dividing the rats into 22 groups according to the weight, namely: blank control (0.5% sodium carboxymethylcellulose) group, Ginseng radix-fructus forsythiae composition comprises low, medium and high (2.5, 5 and 10mg/kg) dose groups, phillyrin group, 20(R) -ginsenoside Rg3 group and positive medicine aspirin (200mg/kg) group, and each group contains 10 patients. Each group of experiment was administered by sublingual intravenous injection. The normal volume of the right hind paw of each group of rats was determined by capillary amplification before the experiment. To avoid errors, the measurement position should be fixed, and 1 person operates before and after administration. The average of the two measurements was taken as the normal volume of the right hind paw of the rat before dosing. Immediately after administration, rats were inflamed by subcutaneous injection of 0.1ml of 1% carrageenan into the plantar aspect of the right hind limb. The right hind plantar volume was measured 15, 30, 60, 120, 180, 240, 300 and 360min after the onset of inflammation. And the differences between groups were compared by t-test treatment between groups by percentage difference in plantar volume (swelling rate) before and after rat inflammation.
Results
Compared with a blank control group, after administration, the high dose group (10mg/kg), the medium dose group (5mg/kg) and the low dose group (2.5mg/kg) of each group of the ginseng-fructus forsythiae composition have obvious inhibition effects on rat foot sole swelling caused by carrageenan within 15min to 360min after administration (p is less than 0.05 or p is less than 0.01), the curative effect of the composition is obviously superior to that of a forsythin 10mg/kg group and a 20(R) -ginsenoside Rg310mg/kg group (p is less than 0.05 or p is less than 0.01), and the curative effects of each dose group of the composition at 60min and 240min after administration are all obviously superior to that of a 20(R) -ginsenoside Rg3 group (p is less than 0.01). The above test results show that the combination of phillyrin and 20(R) -ginsenoside Rg3 in each group of the ginseng-forsythia suspense composition has an obvious synergistic effect, and the details are shown in tables 2-8.
Test example 3 discussion of the effect of the composition of ginseng and forsythia suspensa on the improvement of immune function in mice
1 materials of the experiment
1.1 drugs and reagents
Phillyrin (content > 98%), white powder, produced by Dalian Fusheng Natural drug development Limited, has a purity of 99.5% as determined by two detectors of high performance liquid chromatography, ultraviolet detector and evaporative light scattering detector area normalization, and is calibrated and confirmed to have a content of 99.5% by using a phillyrin reference substance for Chinese drug biological product content determination.
20(R) -ginsenoside Rg3 (content > 98%), white powder, and high purity of 99.0% by high performance liquid chromatography with ultraviolet detector and evaporative light scattering detector area normalization method; and the content of the ginsenoside Rg3 reference substance is calibrated and confirmed to be 99.1 percent by using the content measurement of Chinese medicinal biological products.
Composition of human and forsythia suspensa: the product of Dalian Fusheng natural medicine development Co., Ltd is respectively calibrated by a reference substance for measuring the content of Chinese medicine biological products, and the content of ginsenoside Rg3 and phillyrin in the product is determined.
Ginseng radix-fructus forsythiae composition alcoholic extract (A; example 5), ginsenoside Rg3 and phillyrin content are 0.15%, 18.6% respectively;
the content of ginsenoside Rg3 and phillyrin in the water extract of Ginseng radix-fructus forsythiae composition (B; example 6) is 0.17% and 17.7%, respectively;
the total ginsenoside-phillyrin and phillygenin composition (C; example 14) has ginsenoside Rg3 and phillyrin contents of 0.04% and 95.6%, respectively;
the panaxadiol saponins-phillyrin and phillygenin composition (D; example 19) contains ginsenoside Rg3 and phillyrin 0.12% and 96.6%, respectively;
20(R) -ginsenoside Rg 3-phillyrin composition (E; example 26), the contents of ginsenoside Rg3 and phillyrin are 2.0% and 96.6%, respectively.
Positive control drug: pidotimod oral solution (Jiangsu Wuzhong pharmaceutical Co., Ltd., Suzhou pharmaceutical factory, 10 ml: 400mg, lot number 2014091211);
1.2 Experimental animals
Kunming mouse, age 6-8W, weight 18-22g, purchased from the university of Dalian medical laboratory animal center, quality certification number: SCXK (13) 2013-.
2 method of experiment
2.1 grouping and administration
152 healthy male mice were selected, acclimatized for 4 days, and randomly divided into 19 groups by weight: negative control group, positive drug control group, phillyrin group, 20(R) -ginsenoside Rg3 group, and Ginseng-fructus forsythiae composition comprises high, medium and low dosage groups. The positive control group is administered with pidotimod (50mg/kg), phillyrin (144mg/kg), 20(R) -ginsenoside Rg3(144mg/kg), and the composition of ginseng and forsythia is administered to each group of low dose group (36mg/kg), medium dose group (72mg/kg), high dose group (144mg/kg), and the group is administered with gastric lavage for 1 time per day and 30 days continuously, and the negative control group is administered with the same volume of water.
2.2 experiment and results
2.2.1 ConA-induced splenic lymphocyte transformation assay in mice
1h after the last administration, spleens were aseptically harvested from each group of animals to prepare spleen cell suspensions. Spleen cell suspension was diluted to 3X 106After the concentration of each individual/mL, the spleen cell suspension was divided into 2 portions, and each portion was placed in two 24-well culture plates, 1mL per well, and 75. mu.L of ConA solution (a) was added to one well and the other well was used as a control (b) and incubated at 37 ℃ for 72 hours. Thiazole blue (MTT) was added 4h before the end of the culture. After the incubation, acid isopropanol was added, mixed well and the absorbance value (ABS) of each solution was measured at 570 nm. Computing gainFertility (proliferative ability abra-ABSb). Each dose group of test samples was compared to a negative control group. The results are shown in Table 1.
2.2.2 NK cell Activity assay
1h after the last administration, spleens were aseptically harvested from each group of animals to prepare spleen cell suspensions. After lysing erythrocytes with sterile water for injection, the cell suspension was diluted with 1% glacial acetic acid. Adjusting the concentration of the spleen cell suspension to 2X 107After one/mL, the cells were added to a 96-well plate and cultured. Each animal was divided into: reaction wells (spleen cell suspension and YAC-1 cell suspension 100. mu.L, effective target ratio 50: 1); natural release pores (YAC-1 cell suspension and culture medium each 100. mu.L); maximum release pore (YAC-1 cell suspension and 100. mu.L each of 1% NP 40). All the above steps are made into 3 parallel tubes. 96 well plates at 37 ℃ 5% CO2After 4h incubation in an incubator, LDH matrix solution and 1moL/LHCl were added, the solutions from each parallel well were combined and Absorbance (ABS) was measured at 490 nm. Calculating the activity of NK cells. NK cell activity (%) ═ ABSReaction well-ABSNatural release hole)/(ABSMaximum release hole-ABSNatural release hole). The results are shown in Table 1.
TABLE 1 Effect of the combination of Ginseng and Forsythia suspensa on NK cell Activity and on ConA ability to induce lymphocyte proliferation (x. + -. s)
3 results of the test
After the T lymphocytes are stimulated by ConA, the blast cells have proliferation reaction, and after MTT is decomposed into blue-purple crystals by living cells, particularly by mitochondrial hydrolases in the proliferation cells, the increase of the optical density value indicates the cell enhancement effect. As can be seen from Table 1, the difference in optical density between the high, medium and low dose groups of the ginseng-forsythia suspensa composition was higher than that of the negative control group, indicating that the sample had the effect of promoting the proliferation of spleen cells.
After NK cells kill cells, when LDH in cytoplasm of the living cells is released to the outside of the cells, the LDH can dehydrogenate lithium lactate, NAD is reduced into NADH, the NADH is reduced into iodonitro-tetrazolium chloride (INT) through reduction of dehydrogen phenazine dimethyl sulfate (PMS), the INT is reduced into a purple formazan compound after receiving H +, and the optical density value is measured through an enzyme-labeling instrument. As can be seen from Table 1, the NK cell activities of the high, medium and low dose groups of the ginseng-forsythia suspensa composition are all significantly higher than those of the negative control group, indicating that the sample has the effect of improving the NK cell activity.
The above test results show that: the ginseng-fructus forsythiae composition has the effects of promoting splenocyte proliferation and improving NK cell activity in different dosages in each group; and the combined use of ginseng and forsythia has a synergistic effect, has the effects of remarkably promoting the proliferation of spleen cells and remarkably improving the activity of NK cells, and can remarkably improve the immunologic function.
Claims (10)
1. A composition for anti-viral, antipyretic, anti-inflammatory and/or immune enhancement comprises a ginseng component and a forsythia fruit component.
2. The composition of claim 1, wherein the ginseng component comprises ginseng, ginseng extract, total saponins of ginseng, panaxadiol saponins, ginsenoside Rg3 or 20(R) -ginsenoside Rg 3; the fructus forsythiae component comprises fructus forsythiae (leaf), fructus forsythiae (leaf) extract, phillyrin, and optionally phillygenin.
3. The composition of claim 1 or 2, wherein the extract is an alcoholic extract or an aqueous extract.
4. The composition of claim 1, wherein the weight ratio of the ginseng component to the forsythia suspense component is 2-98: 98-2.
5. The composition of claim 1, further comprising one or more of notoginseng, aloe, licorice, fleece-flower root, ginkgo biloba, black sesame extract, ginger extract, grape seed extract, pomegranate seed extract, plant essential oils, arbutin, vitamin C and derivatives thereof, or vitamin E and derivatives thereof.
6. An antiviral, antipyretic, anti-inflammatory and/or immunity enhancing formulation comprising the composition of any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
7. The preparation of claim 6, wherein the weight ratio of the composition of any one of claims 1 to 5 to the pharmaceutically or nutraceutically acceptable carrier is 1:1 to 1: 100; alternatively, the pharmaceutically or nutraceutically acceptable carrier is a cyclodextrin, such as α -, β -or γ -cyclodextrin or a derivative thereof; alternatively, the formulation is a pharmaceutical formulation, preferably it is in the form of a tablet, capsule, pill, powder, granule, syrup, solution, emulsion, injection, spray, aerosol, gel, cream, cataplasma, rubber patch or plaster; or the preparation is health food, preferably in the form of tablet, capsule, pill, powder, granule, syrup, solution, emulsion, spray, aerosol, gel, cream, cataplasma, rubber patch or emplastrum, or in the form of food such as dairy product, candy, beverage, biscuit, tea and related products or wine.
8. A method of preparing a composition as claimed in any one of claims 1 to 5, which includes the steps of mixing a ginseng component and a forsythia fruit component; or, it comprises the step of heating and extracting the human participation forsythia and optional Chinese medicinal materials by adopting a solvent.
9. A process for the preparation of a formulation according to claim 6 or 7, comprising the step of mixing a composition according to any one of claims 1 to 5 with a pharmaceutically or nutraceutically acceptable carrier; preferably, it comprises a step of mixing the composition of any one of claims 1 to 5 with cyclodextrin or a derivative thereof (e.g., α -, β -or γ -cyclodextrin or a derivative thereof), or it comprises a step of physically and chemically treating the composition of any one of claims 1 to 5 with cyclodextrin or a derivative thereof (e.g., α -, β -or γ -cyclodextrin or a derivative thereof) to form a complex.
10. Use of a composition according to any one of claims 1 to 5 for the preparation of a medicament or health food for antiviral, antipyretic, anti-inflammatory and/or immune enhancement.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010959266.4A CN114177220A (en) | 2020-09-14 | 2020-09-14 | Composition of human and forsythia fruit and its antiviral medicine |
KR1020237011165A KR20230061471A (en) | 2020-09-04 | 2021-08-31 | Forsythia fructus ingredients and optional Panax ginseng ingredients and uses thereof |
CN202180050269.9A CN115955975A (en) | 2020-09-04 | 2021-08-31 | Forsythia suspensa component and optional ginseng component and uses thereof |
BR112023003935A BR112023003935A2 (en) | 2020-09-04 | 2021-08-31 | COMPOSITIONS WITH FORSYTHIA SUSPENSA EXTRACT, FORSITIN AND FORSITIN DERIVATIVES, PHYLIGENIN AND OPTIONAL COMPONENT PANAX GINSENG AND APPLICATIONS |
EP21863593.6A EP4209225A4 (en) | 2020-09-04 | 2021-08-31 | Forsythiae fructus component and optional ginseng component, and use thereof |
CA3190270A CA3190270A1 (en) | 2020-09-04 | 2021-08-31 | Forsythia suspensa component and optional panax ginseng component and the application |
PCT/CN2021/115584 WO2022048529A1 (en) | 2020-09-04 | 2021-08-31 | Forsythiae fructus component and optional ginseng component, and use thereof |
JP2023514428A JP2023539681A (en) | 2020-09-04 | 2021-08-31 | Forsythia ingredients and optional ginseng ingredients and applications thereof |
US18/024,173 US20230338454A1 (en) | 2020-09-04 | 2021-08-31 | Forsythia suspensa component and optional panax ginseng component and the application |
ZA2023/03671A ZA202303671B (en) | 2020-09-04 | 2023-03-17 | Forsythiae fructus component and optional ginseng component, and use thereof |
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CN202010959266.4A CN114177220A (en) | 2020-09-14 | 2020-09-14 | Composition of human and forsythia fruit and its antiviral medicine |
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