CN116492355B - Use of a composition for the preparation of a medicament for alleviating pain - Google Patents
Use of a composition for the preparation of a medicament for alleviating pain Download PDFInfo
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- CN116492355B CN116492355B CN202310758382.3A CN202310758382A CN116492355B CN 116492355 B CN116492355 B CN 116492355B CN 202310758382 A CN202310758382 A CN 202310758382A CN 116492355 B CN116492355 B CN 116492355B
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- Prior art keywords
- pain
- notoginseng
- ginsenoside
- composition
- enzyme
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Abstract
The invention relates to the field of pain relief, and discloses application of a composition in preparation of a medicament for relieving pain. The composition comprises ginsenoside F2, ginsenoside Rd and ginsenoside Rh1. The composition used in the invention has analgesic activity, can be used for relieving pain, especially pain caused by non-infectious inflammation, and has lower required dosage.
Description
Technical Field
The invention relates to the field of pain relief, in particular to application of a composition in preparation of a medicament for relieving pain.
Background
The international society of pain research (International Association for the Study of Pain) defines pain as "unpleasant sensory and emotional experiences caused by actual or potential tissue damage, or a description of such damage". Pain is a complex physiological and psychological activity consisting of both the sensation of pain in the body caused by noxious stimuli and the pain response of the body to noxious stimuli. Wherein pain due to biogenic or chemogenic inflammation, i.e. inflammatory pain, is pain associated with various disease processes, such as rheumatoid arthritis, rheumatoid arthritis and ankylosing spondylitis, fibromyalgia syndrome, etc.; still other mild to moderate pain lasting more than 3 months are clinically multiple disorders (Liu Yanqing, cui Jianjun. Practical pain science [ M. ] Beijing. People health Press. 2019).
Current methods of pain relief include removal of the cause of pain while simultaneously treating the symptoms of pain, with drug application being the first treatment for pain relief, commonly used pain relief drugs are salicylic acid and opioids, which are used when good pain relief effects are available for most patients, but care should be taken during such drug application that the individual differences in the effective pain relief amounts of the patients are large, and compliance with the guidelines for individualization of the medication is to be followed. The phenomenon of drug resistance or aging shortening easily occurs in the pain relieving treatment applied in the treatment process.
The commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) for inflammatory pain have the effects of relieving fever, easing pain, resisting inflammation and resisting rheumatism, act by reducing the biosynthesis of prostaglandin in vivo, have moderate analgesic effect, have side effects of common gastrointestinal reaction, can cause gastric ulcer and painless gastrorrhagia after long-term administration, and also pay attention to coagulation function change and salicylic acid reaction.
Ginsenoside as active ingredient of Panax plant of Araliaceae (such as Notoginseng radix, ginseng radix and radix Panacis Quinquefolii) has also been reported in relieving pain. For example, CN107441105a discloses the use of a panaxadiol saponin Rb component in the preparation of a medicament for preventing and treating pain, the Rb components 40mg/kg and 30mg/kg being intragastrically effective for preventing paclitaxel-induced neuralgia in mice and rats, respectively. CN103845348A discloses the use of 20 (R) -ginsenoside Rg3 in the preparation of a medicament for dysmenorrhea, the therapeutically effective amount of 20 (R) -ginsenoside Rg3 administered to a subject is 0.6-12mg/kg·d. CN105358168A discloses a composition for alleviating premenstrual syndrome and dysmenorrhea, which contains ginseng fruit extract, and can be administered to a subject per day by 240mg of ginsenoside Re and 1400mg of ginseng fruit extract (containing 33.42% of total ginsenoside) respectively, to alleviate or improve premenstrual syndrome. The ginsenoside in the above documents has high dosage and limited therapeutic effect.
Disclosure of Invention
The present invention aims to overcome the above problems of the prior art and to provide the use of a composition for the preparation of a medicament for alleviating pain.
In order to achieve the above object, the present invention provides the use of a composition comprising ginsenoside F2, ginsenoside Rd and ginsenoside Rh1 for the preparation of a medicament for alleviating pain.
The inventor of the present invention found that a composition containing ginsenoside F2, ginsenoside Rd and ginsenoside Rh1 has analgesic activity, and the composition can be used for relieving pain, especially pain caused by non-infectious inflammation, and has obvious relieving effect and lower required dosage. The method of the invention is used for transforming the composition of the fibrous roots, stems, leaves and flowers of the pseudo-ginseng, not only can obtain the composition of the rare saponins F2, rd and Rh1, but also has higher content, and can reach 40-80 weight percent of the total extract, and the proportion of each rare ginsenoside in the obtained product is more beneficial to relieving pain.
Drawings
FIG. 1 shows the HPLC detection result of the Notoginseng radix enzymolysis product obtained in example 1.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The invention provides application of a composition in preparing a medicament for relieving pain, wherein the composition comprises ginsenoside F2, ginsenoside Rd and ginsenoside Rh1.
In the present invention, in order to obtain a better pain relieving effect, the weight ratio of ginsenoside F2 to ginsenoside Rd is 1:0.1-8, and may be 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, or any two values thereof, which form a range, and preferably 1:0.2-5.
In the present invention, in order to obtain a better pain relieving effect, the weight ratio of the ginsenoside F2 to the ginsenoside Rh1 is 1:0.1-8, and may be 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, or any two values thereof form a range and a range, and preferably 1:0.2-5.
In the present invention, the total content of ginsenoside F2, ginsenoside Rd and ginsenoside Rh1 in the composition is 40 to 80 wt%, may be 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt% or any two or more of the values in the range and the range, and the content of total ginsenoside is 70 wt% or more, may be 70 wt%, 78 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt% or any two or more of the values in the range and the range. The composition may also contain other unavoidable impurities.
The composition of the present invention may be obtained by directly mixing the above components, or may be obtained by extracting from a raw material containing ginsenoside, and according to a specific embodiment of the present invention, the preparation method of the composition includes:
(1) Extracting Notoginseng radix with alcohol to obtain extractive solution;
(2) Concentrating the extractive solution, and contacting with hydrolase.
In the invention, the alcohol extraction method is not limited, and ginsenoside in the pseudo-ginseng raw material can be extracted, and preferably, the alcohol extraction mode is as follows: the method for extracting the alcohol comprises the following steps: firstly, mixing the pseudo-ginseng raw material with an alcohol solution or water for first extraction, and then carrying out first solid-liquid separation; mixing the liquid obtained by the first solid-liquid separation with alcohol for second extraction, and then carrying out second solid-liquid separation; more preferably, the weight ratio of the notoginseng raw material to the alcohol solution or the water is 1:8-15, and the weight ratio can be 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15 or any two values of the above ranges and values in the ranges. Further preferably, the conditions of the first extraction include: the temperature is 80-100deg.C, and the time is 1-3h. In the invention, the weight of the pseudo-ginseng raw material is calculated on a dry basis.
In the present invention, when the pseudo-ginseng raw material is mixed with the alcohol solution, the conditions for the first extraction include: the temperature is 80-100deg.C, and the time is 1-3h.
In the present invention, when the notoginseng raw material is mixed with water, the conditions for the first extraction include: the temperature is 90-100 ℃ and the time is 1-3h.
Preferably, the alcohol solution has a concentration of 50 to 80% by volume.
More preferably, the concentration of alcohol in the second extraction system is 60-80% by volume.
In the present invention, when the raw material of pseudo-ginseng is mixed with the alcohol solution in the first extraction, the concentration of alcohol in the second extraction system is 65 to 80% by volume.
In the present invention, when the raw material of notoginseng in the first extraction is mixed with the aqueous solution, the concentration of alcohol in the second extraction system is 50 to 65% by volume.
Preferably, the conditions of the second extraction include: the temperature is 20-40 ℃ and the time is 8-15h.
In the present invention, in order to obtain more ginsenoside from the raw material of notoginseng, the first extraction and the first solid-liquid separation may be performed multiple times, preferably 2-3 times, i.e. the solid obtained by the first solid-liquid separation is re-extracted to obtain multiple times of liquid of the first solid-liquid separation. Mixing the obtained liquids, and mixing with alcohol for second extraction.
In the invention, the liquid obtained by the first solid-liquid separation can be concentrated before being mixed with alcohol, and the weight ratio of the pseudo-ginseng raw material to the concentrated product is 1:0.5-1.5.
In the present invention, the mode of solid-liquid separation is not particularly limited, and filtration may be employed.
In the invention, the alcohol used in the alcohol extraction is not limited, and ginsenoside in the pseudo-ginseng raw material can be extracted. The alcohols used in the first and second extractions may be the same or different, and may be C1-C4 lower alcohols, preferably ethanol.
In the invention, in order to enable the ginsenoside composition in the obtained composition to be more capable of relieving pain, the dosage of the pseudo-ginseng root is A, the dosage of the pseudo-ginseng stem and leaf is B, and the dosage of the pseudo-ginseng stem and leaf is A: b is 1:0.3-7, and can be 1:0.3, 1:0.5, 1:0.7, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, or any two or more values thereof. The stem and leaf of Notoginseng radix refers to stem and leaf of Notoginseng radix.
In the invention, in order to enable the ginsenoside composition in the obtained composition to be more capable of relieving pain, the dosage of the pseudo-ginseng flower is C, A: c is 1:0.1-4, and can be 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or any two values above.
In the present invention, in order to allow more conversion of ginsenoside in the extract into ginsenoside F2, ginsenoside Rd and ginsenoside Rh1 to obtain a composition having pain relief, the hydrolase is an enzyme capable of hydrolyzing sugar chains, particularly an enzyme capable of acting O-glycosidic bond, preferably at least one of cellulase, hemicellulase and pectinase; more preferably, the hydrolytic enzymes are cellulases, hemicellulases and pectinases.
In the present invention, in order to make the composition of ginsenoside F2, ginsenoside Rd and ginsenoside Rh1 obtain better pain relief effect, the enzyme activity ratio of the cellulase to the hemicellulase is 1:100-1000, and the enzyme activity ratio may be 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, 1:1000 or any two values above.
Preferably, the ratio of the enzyme activities of the cellulase and the pectase is 1:10-100, and can be 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100 or any two values of the above ranges and values in the ranges.
In the present invention, in order to make the hydrolase have a better living environment, a buffer solution can be used to maintain the pH of the contact system at 5-6 during the contact.
In the invention, the weight ratio of the notoginseng raw material to the concentrated product of the extracting solution is 1:0.5-1.5; preferably, the total enzyme activity of the hydrolase is 100 to 300U, and may be 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, U or any two values thereof, or a value within a range formed by any two values thereof, relative to 1g of the concentrated product of the extract; more preferably, the contacting conditions include: the temperature is 45-60 ℃, can be 45 ℃,50 ℃,55 ℃, 60 ℃ or more, and the time is 30-48h, and can be 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, 48h or more; further preferably, the contacting is by stirring; more preferably, the stirring is at a rate of 100-200rpm.
In the invention, the cellulase enzyme activity is as follows: the amount of enzyme that produced 1 microgram of glucose per minute by decomposing a 1% sodium hydroxymethyl cellulose solution at 50℃and pH4.8 was one enzyme activity unit (U).
In the invention, the enzyme activity of the hemicellulase is as follows: the amount of enzyme that produced 1 microgram of glucose per minute by decomposing a 1% xylan solution at 50℃and pH4.8 was one enzyme activity unit (U).
In the invention, the pectase activity is as follows: at 50℃and pH3.5, 1h of decomposition produced 1mg of galacturonic acid as an enzyme activity unit (U).
In the invention, the method further comprises the following steps: enzyme inactivating the contact product in the step (2); preferably, the enzyme inactivation is performed by heating; more preferably, the conditions for enzyme inactivation include: boiling (normal pressure) for 6-15min.
In the present invention, the source of the hydrolase may be commercially available, or the hydrolase-producing bacteria may be inoculated into the concentrated extract.
In the invention, the method further comprises the following steps: the enzyme-inactivated product was concentrated and dried in vacuo.
Preferably, the pain is pain caused by non-infectious inflammation; more preferably, the pain includes at least one of muscle pain, joint pain and dysmenorrhea.
In the present invention, the composition can relieve pain by reducing the expression level of COX-2 in an organism, reducing the content of tumor necrosis factor (TNF-alpha), interleukin (IL-1 beta, IL-6) and prostaglandin 2 (PGE 2).
In the invention, the composition is prepared into medicines, and can be prepared into different dosage forms through different medicinal auxiliary materials, and can be at least one of oral liquid, granules, capsules, tablets, wine, syrup, gel, cream and ointment, and the effect is not weakened.
In practice, the composition of the present invention may exert a better pain-relieving effect at a lower dose, for example, in mice, and may be used in an amount of 0.5-5mg/kg body weight.
In the invention, if the oral liquid is prepared, the components and the dosage are as follows: the weight ratio of the composition to the red date extract to the polyoxyethylene hydrogenated castor oil to the propylene glycol to the sodium benzoate to the stevioside to the ethanol to the purified water is 1:2-8:0.5-4:0.2-3:0.1-1:0.1-1:0.1-1:60-99. The preparation method comprises the following steps: weighing materials according to the proportion, and dissolving the composition in propylene glycol for standby; dissolving antiseptic in ethanol for use; mixing the rest materials except purified water, adding 20-40 wt% of purified water, dissolving completely, adding the above two solutions, mixing, homogenizing, adding rest purified water, mixing, homogenizing, and filtering.
In the invention, if the composition is prepared into granules, the components and the dosage are as follows: the weight ratio of the composition to the sucrose powder to the dextrin to the starch to the lactose is 1:15-30:10-30:0.5-4:2-8. The preparation method comprises the following steps: weighing materials according to the proportion, adding starch into boiling water (normal pressure) for pulp flushing for standby; mixing the composition with sucrose powder by equivalent incremental method, adding dextrin, mixing, adding starch slurry, granulating, drying, grading, and mixing.
In the invention, if the composition is prepared into capsules, the composition and the dosage are as follows: the weight ratio of the composition to the starch to the dextrin to the microcrystalline cellulose to the talcum powder is 1:10-30:5-15:0.5-5:0.1-0.6. The preparation method comprises the following steps: weighing the materials according to the proportion, adding a proper amount of boiling water (normal pressure) into 0.5-1.5 weight percent of starch for flushing for later use; mixing the composition with starch by equivalent progressive method, adding dextrin and microcrystalline cellulose, mixing, adding starch slurry, granulating, drying, grading, adding pulvis Talci, mixing, and encapsulating.
In the present invention, if prepared as a tablet, the ingredients and amounts are: the weight ratio of the composition to the starch to the hydroxypropyl cellulose sodium to the dextrin to the microcrystalline cellulose to the polyvinylpyrrolidone to the silicon dioxide to the magnesium stearate is 1:5-10:0.1-1:3-10:1-2:1-2:0.05-0.15:0.1-0.5. The preparation method comprises the following steps: weighing materials according to the proportion, adding purified water into sodium hydroxypropyl cellulose to prepare a solution with the concentration of 0.5-1.5 weight percent, and uniformly mixing starch, dextrin, polyvinylpyrrolidone and 40-60 weight percent of microcrystalline cellulose for later use; mixing the composition with the above adjuvant mixture by equivalent incremental method, granulating with sodium hydroxypropyl cellulose solution, drying, grading, adding silicon dioxide, magnesium stearate, and microcrystalline cellulose, mixing, and tabletting.
In the invention, if the wine is prepared, the components and the dosage are as follows: the weight ratio of the composition, the red jujube water extract, the stevioside, the edible ethanol and the purified water is 1:1-10:0.1-1:40-70:20-60. The preparation method comprises the following steps: weighing the materials according to the proportion, and dissolving the composition and stevioside in edible ethanol for standby; dissolving fructus Jujubae water extract in purified water, adding the above prepared solution, mixing, homogenizing, adding the rest purified water, mixing, homogenizing, and filtering.
In the invention, if syrup is prepared, the components and the amounts are as follows: the weight ratio of the composition to the red jujube water extract to the sucrose to the polyethylene glycol to the purified water is 1:1-10:30-70:5-15:20-50. The preparation method comprises the following steps: weighing the materials according to the proportion, and dissolving the composition and the water extract of the red dates in polyethylene glycol for standby; dissolving sucrose in purified water, adding the above prepared solution, mixing, and filtering.
In the invention, if the gel is prepared, the components and the amounts are as follows: the weight ratio of the composition to carbomer C940 to the polyethylene glycol to the propylene glycol to the triethanolamine to the ethylparaben to the purified water is 1:0.5-1.5:0.5-1.5:10-20:0.5-1.5:0.05-0.2:70-90. The preparation method comprises the following steps: weighing the materials according to the proportion, adding the composition into 20-30 wt% of propylene glycol, and stirring and dissolving completely to obtain a composition concentrate for later use; adding carbomer C940, adding 30-40 wt% of propylene glycol, stirring, dispersing uniformly, adding 50-70 wt% of purified water, starting a stirrer, and stirring for 20-40min to uniformly mix for later use; placing polyethylene glycol, ethylparaben and the rest propylene glycol into the solution, and heating in water bath at 50-60deg.C for dissolving. The concentrate of the composition and the carbomer solution are added to triethanolamine and purified water is added to the full. Starting a stirrer of the preparation pot, stirring for 20-40min, and fully and uniformly mixing to obtain the final product.
In the invention, if the cream is prepared, the components and the dosage are as follows: the weight ratio of the composition to stearic acid to white vaseline to glyceryl monostearate to liquid paraffin to triethanolamine to propylene glycol to purified water is 1:5-15:1-10:2-15:1-10:0.1-1:0.5-4:60-80. The preparation method comprises the following steps: weighing materials according to the proportion, and dissolving the composition in propylene glycol for standby; adding stearic acid, white vaseline, glyceryl monostearate and liquid paraffin into a stirring pot for preparing an oil phase, heating to 75-85deg.C, melting, stirring for dissolving, and mixing uniformly to obtain an oil phase with particle diameter smaller than 75 μm; dissolving triethanolamine in purified water, and adding the composition solution into triethanolamine water solution to obtain water phase; adding the filtered oil phase into the water phase, stirring for emulsification, moisturizing for 20-40min, stirring, homogenizing, and filtering.
In the invention, if the ointment is prepared, the components and the dosage are as follows: the weight ratio of the composition to the liquid paraffin to the yellow vaseline is 1:1-5:30-60. The preparation method comprises the following steps: weighing materials according to the proportion, heating and melting 15-25 wt% of Huang Shilin and liquid paraffin, cooling to 70-80 ℃, adding the composition, stirring to fully infiltrate and uniformly disperse the composition to obtain a concentrated composition liquid for later use; heating and melting residual yellow vaseline, cooling to 40-45deg.C, continuously stirring, adding concentrated solution of the composition, stirring, homogenizing, and filtering.
The present invention also relates to the composition and the preparation method thereof, and the details are not described herein.
The present invention also relates to a method of alleviating pain comprising administering said composition to an individual in need thereof.
The present invention will be described in detail by examples. In the following examples, the sources of cellulases: noveven Viscozyme L, specific activity of enzyme 100U/g;
source of hemicellulase: ningxia Hospital industries, inc., FDG-2255, enzyme specific activity 50000U/g;
sources of pectinase: FFY-0654, the specific activity of enzyme is 10000U/g.
HPLC detection is as follows:
chromatographic conditions and system suitability test: octadecylsilane chemically bonded silica is used as a filler; the mobile phase was water (A) -acetonitrile (B) gradient eluted (elution conditions: 69% water by volume, 31% acetonitrile by volume, 0 min; 69% water by volume, 31% acetonitrile by volume, 15 min; 35% water by volume, 65% acetonitrile by volume, 48min; 69% water by volume, 31% acetonitrile by volume, 49 min; 69% water by volume, 31% acetonitrile by volume, 50 min), elution conditions are shown in the following table; the volume flow is 1 mL/min; the sample injection amount is 10 mu L; the detection wavelength is 203 nm; column temperature was 30 ℃. The theoretical plate number of ginsenoside F2 is not lower than 6000.
Preparation of a control solution: taking appropriate amounts of ginsenoside F2, ginsenoside Rd and ginsenoside Rh1 reference substances, precisely weighing, and adding methanol to obtain 1mL solutions each containing 0.1 mg.
Preparation of test solution: taking 0.1g of notoginseng enzymolysis product, precisely weighing, adding a proper amount of methanol, carrying out ultrasonic treatment for 10min, cooling, fixing the volume to 10 mL, shaking uniformly, taking supernatant, passing through a microporous filter membrane of 0.22 mu m, and taking subsequent filtrate.
Assay: precisely sucking 20 μl of each of the control solution and the sample solution, and measuring with a liquid chromatograph.
Example 1
Weighing Notoginseng radix fibrous root, notoginseng radix stem and leaf, notoginseng radix flower=4:3:3, mixing, pulverizing into 150-220 μm coarse powder 1kg (total ginsenoside content 19 wt%) with high speed pulverizer, reflux extracting in 12kg 70 vol% ethanol extraction concentrating tank (temperature 90 deg.C for 1.5 hr), and filtering; extracting the filter residue again: reflux-extracting with 12kg of 70 vol.% ethanol at 90deg.C for 1.5 hr, and filtering; combining the two filtrates, concentrating to 1.5kg, cooling, adding ethanol under stirring to ethanol volume concentration of 70 vol%, standing at room temperature for 12 hr, filtering, and concentrating the filtrate under reduced pressure to 1kg for use.
Placing the pseudo-ginseng extract in an enzyme reactor, adding 3kg of disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with the pH value of 5.5 for dissolution, adding 0.01kg of compound enzyme composed of cellulase, hemicellulase and pectase according to the enzyme activity ratio of 1:500:50, carrying out enzymolysis reaction for 30 hours at the temperature of 45 ℃ under the stirring of 200rpm, boiling in a boiling water bath (normal pressure) for 10 minutes to inactivate the enzyme, concentrating and drying in vacuum to obtain pseudo-ginseng enzymolysis product (95 g), detecting by adopting HPLC (high performance liquid chromatography), and detecting the content of the product as shown in figure 1:
the total ginsenoside content in the Notoginseng radix enzymolysis product is 96 wt%, and the total ginsenoside content of F2, rd and Rh1 in the Notoginseng radix enzymolysis product is 80 wt%, wherein the ginsenoside content of F2 is 50 wt%, the ginsenoside Rd content is 24 wt%, and the ginsenoside Rh1 content is 6 wt%.
Example 2
The preparation method comprises the steps of weighing fibrous roots of pseudo-ginseng, stems and leaves of pseudo-ginseng and flowers of pseudo-ginseng=4:3:3 according to the weight ratio, mixing, crushing by a high-speed crusher to obtain 1kg of 150-220-micrometer coarse powder (the total ginsenoside content is 19% by weight), adding 12kg of purified water into an extraction concentration tank, boiling (normal pressure), keeping micro-boiling for 2 hours, filtering, extracting filter residues again, filtering again, combining the two filtrates, concentrating to 1.5kg, cooling, adding ethanol until the volume concentration of the ethanol reaches 60% by volume under stirring, standing for 12 hours at room temperature, filtering, and concentrating the filtrate to 1kg under reduced pressure for later use.
Placing the pseudo-ginseng extract in an enzyme reactor, adding 3kg of disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with the pH value of 5.5 for dissolution, adding 0.01kg of compound enzyme composed of cellulase, hemicellulase and pectase according to the enzyme activity ratio of 1:600:40, carrying out enzymolysis reaction for 36 hours at 50 ℃ under 200rpm stirring, boiling in a boiling water bath (normal pressure) for 10 minutes to inactivate the enzyme, concentrating and drying in vacuum to obtain pseudo-ginseng enzymolysis product (112 g), detecting by HPLC, and detecting the content:
the total ginsenoside content in the Notoginseng radix enzymolysis product is 85 wt%, and the total ginsenoside content of F2, rd and Rh1 in the Notoginseng radix enzymolysis product is 40 wt%, wherein the ginsenoside content of F2 is 12 wt%, the ginsenoside Rd content is 15 wt%, and the ginsenoside Rh1 content is 13 wt%.
Example 3
The procedure of example 1 was followed except that the enzyme was inactivated by stirring at 100rpm at 60℃for 48 hours, boiling in a boiling water bath (normal pressure) for 15 minutes, and the fibrous root of Notoginseng, stem and leaf of Notoginseng, and flower of Notoginseng=6:3:1 (total ginsenoside amount: 16% by weight). The enzymolysis product of pseudo-ginseng (80 g) is obtained.
The total ginsenoside content in the Notoginseng radix enzymolysis product is 86 wt%, and the total ginsenoside F2, rd and Rh1 content in the Notoginseng radix enzymolysis product is 72 wt%, wherein the ginsenoside F2 content is 36 wt%, the ginsenoside Rd content is 21 wt%, and the ginsenoside Rh1 content is 15 wt%.
Example 4
The procedure of example 2 was followed except that the fibrous root of notoginseng, stem and leaf of notoginseng, and flower of notoginseng=1:6:3 (total ginsenoside amount: 18% by weight), ethanol was added to a concentration of 80% by volume of ethanol with stirring. The enzymolysis product of pseudo-ginseng (106 g) is obtained.
The total ginsenoside content in the Notoginseng radix enzymolysis product is 81 wt%, and the total ginsenoside content of F2, rd and Rh1 in the Notoginseng radix enzymolysis product is 53 wt%, wherein the ginsenoside content of F2 is 19 wt%, the ginsenoside Rd content is 26 wt%, and the ginsenoside Rh1 content is 8 wt%.
Example 5
The procedure of example 1 was followed except that the enzyme activity ratio of cellulase to hemicellulase to pectinase was changed to 1:50:200. The enzymolysis product of pseudo-ginseng (120 g) is obtained.
The total ginsenoside content in the Notoginseng radix enzymolysis product is 43 wt%, and the total ginsenoside content of F2, rd and Rh1 in the Notoginseng radix enzymolysis product is 34 wt%, wherein the ginsenoside content of F2 is 3 wt%, the ginsenoside Rd content is 27 wt%, and the ginsenoside Rh1 content is 4 wt%.
Test case
Notoginseng radix enzymolysis product gel prescription: 1 weight percent of notoginseng enzymolysis products; carbomer C940 1 wt%; polyethylene glycol 1 wt%; propylene glycol 15 wt%; 1% by weight of triethanolamine; 0.1% by weight of ethylparaben; purified water 80.9 wt%. The notoginseng enzymolysis product was obtained in example 1 above.
The preparation method of the pseudo-ginseng enzymolysis product gel comprises the following steps: weighing materials according to a prescription, adding the notoginseng enzymolysis product into propylene glycol with the dosage of 1/4 of the prescription, and stirring and dissolving completely to obtain a notoginseng enzymolysis product concentrate for later use; adding carbomer C940 with the prescription amount, adding propylene glycol with the prescription amount of 1/3, stirring, dispersing uniformly, adding purified water with the preparation amount of 60%, starting a stirrer, and stirring for 30 minutes sufficiently to uniformly mix for later use; the prescribed amounts of polyethylene glycol, ethylparaben and another 3/4 of propylene glycol were placed therein and dissolved by heating in a water bath at 55 ℃. Adding triethanolamine into the concentrated solution of the enzymolysis product of radix Notoginseng and carbomer solution, and adding purified water to full amount. Starting a stirrer of the preparation pot, stirring for 30min, and fully and uniformly mixing to obtain the product.
Notoginseng radix total saponin gel: the recipe and the preparation method of the notoginseng enzymolysis product gel are the same, except that the notoginseng enzymolysis product is replaced by the notoginseng total saponins.
The enzyme-linked immunosorbent assay (ELISA) method uses the following kit sources: jiangsu enzyme exempts from the Utility company.
Notoginseng radix total saponin is purchased from Chuxiong cloud plant pharmaceutical industry Co., ltd, and comprises the following main components: 10.59 wt% of ginsenoside R1, 31.22 wt% of ginsenoside Rg1, 3.66 wt% of ginsenoside Re, 33.89 wt% of ginsenoside Rb1 and 7.97 wt% of ginsenoside Rd.
1. Pain relief effect of different notoginseng enzymolysis products is compared
In vitro inflammation model of RAW264.7 cells induced with LPS (lipopolysaccharide), RAW264.7 cells induced with LPS were individually interfered (RAW 264.7 cells in logarithmic growth phase were treated with 5×10) 4 The culture was performed in 96-well plates (200 uL/well), and the culture was performed for 24 hours, and then, in addition to the negative control group (medium only), the total saponins of Notoginseng (20. Mu.g/mL), the enzymolysis products of Notoginseng (8. Mu.g/mL) of example 1, the enzymolysis products of Notoginseng (16. Mu.g/mL) of example 2, the enzymolysis products of Notoginseng (9. Mu.g/mL) of example 3, the enzymolysis products of Notoginseng (12. Mu.g/mL) of example 4, and the enzymolysis products of Notoginseng (19. Mu.g/mL) of example 5 were added, followed by incubation for 1 hour, and then LPS induction (LPS only was added to the model group) at a final level of 1. Mu.g/mL, and 3 wells were used. After 24, 48 and 72 hours of drug action), notoginseng enzymolysis products are obtained from the example 1, the cell activity is measured by an MTT method, and inflammatory mediators tumor necrosis factor (TNF-alpha) and interleukins (IL-1 beta and IL-6) are measured by an enzyme-linked immunosorbent assay (ELISA method), and the results are shown in table 1; prostaglandin 2 (PGE 2) and COX-2 were assayed by enzyme-linked immunosorbent assay (ELISA) and the results are shown in Table 2.
TABLE 1
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 2
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
The natural medicine disclosed by the invention is applied to RAW264.7 cells induced by Lipopolysaccharide (LPS), and examples 1, 2, 3 and 4 can reduce the expression level of COX-2 protein, effectively inhibit the production of PGE2, IL-1 beta, IL-6 and TNF-alpha, realize effective relief of inflammatory pain and have better effect than that of total arasaponin; example 5 can reduce COX-2 protein expression level to some extent, inhibit PGE2, IL-1 beta, IL-6 and TNF-alpha production, and has some effect of relieving inflammatory pain, but the effect is not significantly different from that of total saponins of Notoginseng radix.
The enzymolysis product of pseudo-ginseng prepared in the example 1 which can effectively relieve inflammatory pain and has better effect than the total saponins of pseudo-ginseng is selected for pain relieving action mechanism and drug effect evaluation.
2. Pain relieving mechanism of notoginseng enzymolysis product
In vitro inflammation model of RAW264.7 cells induced with LPS (lipopolysaccharide), RAW264.7 cells induced with LPS were individually interfered (RAW 264.7 cells in logarithmic growth phase were treated with 5×10) 4 The concentration of/mL is inoculated on a 96-well plate (200 uL/well), cultured for 24 hours, and the total saponins of pseudo-ginseng (20 mu g/mL), the low-dose group of the enzymolysis product of pseudo-ginseng (2 mu g/mL), the medium-dose group of the enzymolysis product of pseudo-ginseng (4 mu g/mL) and the high-dose group of the enzymolysis product of pseudo-ginseng (8 mu g/mL) are respectively added except for a negative control group (only added with culture medium), incubated for 1 hour, then LPS induction is added (only added into a model group), the final level is 1ug/mL, and 3 compound wells are formed in each group. After 24, 48 and 72 hours of drug action), notoginseng enzymolysis products are obtained from the example 1, the cell activity is measured by an MTT method, and inflammatory mediators tumor necrosis factor (TNF-alpha) and interleukins (IL-1 beta and IL-6) are measured by an enzyme-linked immunosorbent assay (ELISA method), and the results are shown in Table 3; enzyme-linked immunosorbent assay (ELISA) for measuring prostaglandin 2 (PGE 2)And COX-2, the results are shown in Table 4.
TABLE 3 Table 3
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 4 Table 4
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
The natural medicine provided by the invention is applied to RAW264.7 cells induced by Lipopolysaccharide (LPS), can reduce the expression level of COX-2 protein, effectively inhibit the production of PGE2, IL-1 beta, IL-6 and TNF-alpha, realize effective relief of inflammatory pain, and has an effect superior to that of total arasaponin.
3. Evaluation of muscle pain relieving effect of Notoginseng radix enzymolysis product
120 rats were randomly divided into 6 groups, namely, a negative control group, a model group, a positive drug group (24 mg/kg of total saponins of panax notoginseng), a low-dose group (1 mg/kg) of panax notoginseng enzymolysis products, a medium-dose group (2 mg/kg) of panax notoginseng enzymolysis products, and a high-dose group (4 mg/kg) of panax notoginseng enzymolysis products, each group of 20 rats. The physiological saline of pH4 was injected 2 times into the right gastrocnemius muscle of each group of rats except the negative control group, and 1 time of injections was performed at intervals of 2, 5, and 10 days, and as a result, the notoginseng enzymolysis product was obtained from the above example 1, and it was found that after 4 hours of injection of the physiological saline at the 1 st time, the mechanical pain threshold of the hind paw on the same side of the rat injection site was lowered, and was restored to the baseline level after 24 hours, and after 2 nd injection of the acidic physiological saline, the mechanical threshold of the hind paw on the same side and on the opposite side was significantly lowered, and continued for 4 weeks, and the establishment of the persistent muscle pain model due to the persistent inflammatory reaction was successful. Each test group was orally administered by gastric lavage for 7 days and 2 times a day on rats with a model of persistent muscle pain of rats injected with an acidic physiological saline into gastrocnemius muscle, and spontaneous behavioral manifestations of the rats were observed daily, and the results are shown in table 5; the mechanical pain threshold and thermal pain threshold were evaluated by the hot plate method on day 8 (ref: jinyu Chen, min Sl,. Ginsenoside metabolite compound K exerts anti-inflammatory and analgesic effects via downregulating COX2, informammophilogy, 2018, (26)), and the results are shown in Table 6; after the observation is finished, the right feet of 10 rats are peeled and cut randomly, soaked in 5ml of physiological saline for 1 hour, centrifuged to obtain supernatant, and the inflammatory mediators prostaglandin 2 (PGE 2) and cyclooxygenase (COX-2) are measured by an enzyme-linked immunosorbent assay (ELISA) method, and the results are shown in Table 7; the remaining rats were anesthetized, the abdominal aorta was bled, anticoagulated, serum was taken and stored at-20℃for later use, and tumor necrosis factor (TNF- α) and interleukins (IL-1. Beta., IL-6) were measured by enzyme-linked immunosorbent assay (ELISA), the results of which are shown in Table 8.
TABLE 5
TABLE 6
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 7
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 8
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
4. Evaluation of joint pain relieving effect of notoginseng enzymolysis product
(1) 120 rats were randomly divided into 6 groups, namely, a negative control group, a model group, a positive drug group (24 mg/kg of total saponins of panax notoginseng), a low dose group (1 mg/kg) of panax notoginseng enzymolysis products, a medium dose group (2 mg/kg) of panax notoginseng enzymolysis products, and a high dose group (4 mg/kg) of panax notoginseng enzymolysis products, each group of 20 rats, and the panax notoginseng enzymolysis products were obtained in example 1 above. The right hind foot bottoms of rats in each group except the negative control group were subcutaneously injected with Complete Freund's Adjuvant (CFA), inducing the generation of peripheral inflammation. The injection site has no liquid exudation, and the foot is obviously red and swelling and the pain threshold is obviously reduced the next day, thus the molding is successful. Each test group was orally administered by gastric lavage for 7 days and 2 times daily on joint pain model rats with joint inflammation, and spontaneous behavioral manifestations of the rats were observed daily, and the results are shown in table 9; the mechanical pain threshold and thermal pain threshold were evaluated by hot plate method on day 8 (reference: jinyu Chen, min Sl,. Ginsenoside metabolite compound K exerts anti-inflammatory and analgesic effects via downregulating COX2, informammobarology, 2018, (26)), and the results are shown in Table 10; after the observation, 10 rats were peeled and cut at random from the swollen right feet, soaked in 5ml physiological saline for 1h, centrifuged to obtain supernatant, and the inflammatory mediators prostaglandin 2 (PGE 2) and cyclooxygenase (COX-2) were measured by enzyme-linked immunosorbent assay (ELISA), the results of which are shown in Table 11; the remaining rats were anesthetized, the abdominal aorta was bled, anticoagulated, serum was taken and stored at-20℃for later use, and tumor necrosis factor (TNF- α) and interleukins (IL-1. Beta., IL-6) were measured by enzyme-linked immunosorbent assay (ELISA), the results of which are shown in Table 12.
TABLE 9
Table 10
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 11
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
Table 12
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
(2) 140 rats were randomly divided into 7 groups, namely, a negative control group, a model group, a blank gel group, a positive drug group (24 mg/kg of total saponins of panax notoginseng), a low-dose group (1 mg/kg) of panax notoginseng enzymolysis product gel, a medium-dose group (2 mg/kg) of panax notoginseng enzymolysis product gel, and a high-dose group (4 mg/kg) of panax notoginseng enzymolysis product gel, wherein the dosage of each group is 20 rats based on the amount of the panax notoginseng enzymolysis product. The right hind foot bottoms of rats in each group except the negative control group were subcutaneously injected with Complete Freund's Adjuvant (CFA), inducing the generation of peripheral inflammation. The injection site has no liquid exudation, and the foot is obviously red and swelling and the pain threshold is obviously reduced the next day, thus the molding is successful. Each test group was applied to the joint pain model rats with joint inflammation for 7 days on the right hind feet, 3 times daily, and the spontaneous behavioral manifestations of the rats were observed daily, and the results are shown in table 13; the mechanical pain threshold and thermal pain threshold were evaluated by hot plate method on day 8 (reference: jinyu Chen, min Sl,. Ginsenoside metabolite compound K exerts anti-inflammatory and analgesic effects via downregulating COX2, informammobarology, 2018, (26)), and the results are shown in Table 14; after the observation, 10 rats were peeled and cut at random from the swollen right feet, soaked in 5ml physiological saline for 1h, centrifuged to obtain supernatant, and the inflammatory mediators prostaglandin 2 (PGE 2) and cyclooxygenase (COX-2) were measured by enzyme-linked immunosorbent assay (ELISA), the results of which are shown in Table 15; the remaining rats were anesthetized, the abdominal aorta was bled, anticoagulated, serum was taken and stored at-20℃for later use, and tumor necrosis factor (TNF- α) and interleukins (IL-1. Beta., IL-6) were measured by enzyme-linked immunosorbent assay (ELISA), the results of which are shown in Table 16.
TABLE 13
TABLE 14
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 15
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
Table 16
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
5. Evaluation of dysmenorrhea relieving effect of Notoginseng radix enzymolysis product
The 60 female rats were randomly divided into 6 groups, namely, a negative control group, a model group, a positive drug group (24 mg/kg of Panax notoginsenosides), a Notoginseng radix enzymatic hydrolysate-low dose group (1 mg/kg), a Notoginseng radix enzymatic hydrolysate-medium dose group (2 mg/kg), and a Notoginseng radix enzymatic hydrolysate-high dose group (4 mg/kg), each group of 10 rats, and Notoginseng radix enzymatic hydrolysate was obtained in the above example 1. Rats in each group except the negative control group were given gavage with Bujiale (estradiol valerate tablet) 1 time daily (0.2 mg/day 1, 0.1 mg/day 2-9, 0.2 mg/day 10). Starting on day 5, the same amount of soybean oil was administered by the dose intragastric administration, the negative control group and the model group, 24 hours after the last administration of Bujiale, the last administration was performed, after 1 hour of the last administration, 2U/mouse oxytocin was intraperitoneally injected into each group of rats, the pain response of the rats within 30 minutes was observed, the number of times of twisting of the animals (abdominal indent, trunk and hindlimb extension, hip and side limb internal rotation of the rats) was observed as an index of strong uterine contraction (dysmenorrhea) by the torsion response, and the results are shown in Table 17. After the observation is finished, the rat is anesthetized, the abdominal aorta is subjected to blood collection, anticoagulation, serum is taken and stored at-20 ℃ for standby, and tumor necrosis factors (TNF-alpha) and interleukins (IL-1 beta and IL-6) are measured by an enzyme-linked immunosorbent assay (ELISA) method, and the results are shown in Table 18; the rats were dissected to obtain uterus, homogenized, centrifuged to obtain supernatant, and the inflammatory mediators prostaglandin 2 (PGE 2) and cyclooxygenase (COX-2) were measured by enzyme-linked immunosorbent assay (ELISA), the results of which are shown in Table 19.
TABLE 17
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 18
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
TABLE 19
Note that: * For comparison with the negative control groupp< 0.01; # is compared with the model groupp< 0.01; compared with the total saponins of Notoginseng radixp＜0.01。
Chemical mediators such as Prostaglandins (PG), TNF-alpha, histamine, bradykinin and protons, which are produced during inflammation, stimulate nociceptors responsible for peripheral pain, which in turn produces a painful sensation. PG is a lipid mediator synthesized from arachidonic acid by Cyclooxygenase (COX), and is a pro-inflammatory lipid mediator of inflammation, in which prostaglandin PGE2, which is mainly produced during inflammatory reaction, is involved in the initiation of inflammation and the appearance of signs of inflammation, so that inflammatory pain can be effectively relieved by down-regulating COX2 and thus inhibiting PGE2 synthesis.
In the examples of the present invention, it is understood from the above table that PGE2, COX-2 and IL-1 beta, IL-6 and TNF-alpha levels in serum were elevated in rat tissues in model group of muscular soreness, joint pain and dysmenorrhea as compared with negative control groupp< 0.01); compared with model group, each dosage of Notoginseng radix enzymolysis product can reduce PGE2, COX-2 in tissue and IL-1β, IL-6 and TNF- α levels in serump< 0.01); compared with the positive pharmaceutical group, each dosage of the notoginseng enzymolysis product can reduce PGE2, COX-2 in tissues and IL-1 beta, IL-6 and TNF-alpha levels in serumpThe natural medicine has the effect of relieving muscle pain, joint pain and dysmenorrhea, the effect is better than that of the total saponins of panax notoginseng, and the panax notoginseng extract can be prepared into oral liquid or gel with good effect and simple operation.
The compositions prepared in the examples of the present invention can reduce COX-2 expression levels in organisms, reduce levels of tumor necrosis factor (TNF-alpha), interleukins (IL-1 beta, IL-6), prostaglandin 2 (PGE 2), and relieve pain, and have better effects within the preferred scope of the present invention.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (4)
1. Use of a composition for the preparation of a medicament for alleviating pain, characterized in that,
the preparation method of the composition comprises the following steps:
weighing Notoginseng radix fibrous root, notoginseng stem and leaf and Notoginseng flower=4:3:3 according to weight ratio, mixing, pulverizing into 150-220 μm coarse powder 1kg by high speed pulverizer, reflux extracting in a 12kg 70 vol% ethanol extraction concentration tank at 90deg.C for 1.5 hr, and filtering; extracting the filter residue again: reflux-extracting in a 70 vol% ethanol extraction concentration tank at 90deg.C for 1.5 hr, and filtering; mixing the two filtrates, concentrating to 1.5kg, cooling, adding ethanol under stirring to ethanol volume concentration of 70 vol%, standing at room temperature for 12 hr, filtering, and concentrating the filtrate under reduced pressure to 1kg for use;
placing the pseudo-ginseng extract into an enzyme reactor, adding 3kg of disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with the pH value of 5.5 for dissolution, adding 0.01kg of compound enzyme composed of cellulase, hemicellulase and pectase according to the enzyme activity ratio of 1:500:50, stirring at 45 ℃ for enzymolysis reaction for 30 hours at 200rpm, boiling for 10min under normal pressure, inactivating the enzyme, and concentrating and drying in vacuum.
2. The use of claim 1, wherein the pain is pain caused by non-infectious inflammation.
3. The use of claim 2, wherein the pain comprises at least one of muscle pain, joint pain, and dysmenorrhea.
4. The use according to claim 1, wherein the medicament is in the form of at least one of an oral liquid, a granule, a capsule, a tablet, a wine, a syrup, a gel, a cream and an ointment.
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| CN1771977A (en) * | 2004-11-09 | 2006-05-17 | 成都华神集团股份有限公司制药厂 | Notoginseng glycol-saponin composition and its prepn and use |
| CN103845348A (en) * | 2012-11-30 | 2014-06-11 | 富力 | Application of 20(R)-ginsenoside Rg3 in preparation of medicines for treating dysmenorrhea |
| CN104434676A (en) * | 2014-12-04 | 2015-03-25 | 文山学院文山三七研究院 | Extraction process of pseudo-ginseng extract powder |
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| CN1771977A (en) * | 2004-11-09 | 2006-05-17 | 成都华神集团股份有限公司制药厂 | Notoginseng glycol-saponin composition and its prepn and use |
| CN103845348A (en) * | 2012-11-30 | 2014-06-11 | 富力 | Application of 20(R)-ginsenoside Rg3 in preparation of medicines for treating dysmenorrhea |
| CN104434676A (en) * | 2014-12-04 | 2015-03-25 | 文山学院文山三七研究院 | Extraction process of pseudo-ginseng extract powder |
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