CN108853026A - A kind of andrographolide for animals is scattered - Google Patents

A kind of andrographolide for animals is scattered Download PDF

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Publication number
CN108853026A
CN108853026A CN201810952728.2A CN201810952728A CN108853026A CN 108853026 A CN108853026 A CN 108853026A CN 201810952728 A CN201810952728 A CN 201810952728A CN 108853026 A CN108853026 A CN 108853026A
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andrographolide
dissipates
sodium
test
sodium hydrogensulfite
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冯静波
叶峰先
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Wuxi Zhengda Biology Co Ltd
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Wuxi Zhengda Biology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Abstract

The invention discloses a kind of andrographolides for animals to dissipate, and the scattered raw material of the andrographolide includes：3wt% andrographolide, 0.9wt% sodium hydrogensulfite, surplus are starch supplementary material；Andrographolide is reacted with sodium hydrogensulfite, the mixture of Andrographolidi Natrii Bisulfis and andrographolide is formed, is equipped with starch supplementary material, the andrographolide is made and dissipates.Product of the present invention has the function of antibacterial, anti-inflammatory, has special efficacy to bacillary dysentery, can effectively solve the problems, such as livestock intestinal tract.

Description

A kind of andrographolide for animals is scattered
Technical field
The present invention relates to novel chiral synthon technical fields more particularly to a kind of animal compound for treating livestock intestinal tract disease to wear Heart lotus lactone dissipates.
Background technique
Piglet since autodigestion ability and anti-adversity ability are poor, wean when easily cause weaning stress, cause appetite it is poor, Phenomena such as disorders of digestion, diarrhea, slow growth, efficiency of feed utilization be low, the state of mind and appearance are performed poor, to production Cause very big loss.Nutrition can have a adverse impact to intestine of young pigs health, be mainly shown as primary stressor： Diarrhea rate increases, and intestinal permeability increases；Digestion and absorbability are low, and intestinal villus is impaired, and digestive enzyme activity reduces；Immune function It can decline；Intestinal microflora changes, the decline of beneficial bacterium flora ratio, and harmful bacteria flora ratio rises etc..Wean is young Pig can be such that the expression quantity of tight junction protein lowers due to the appearance of weaning stress, and intercellular Occludin albumen divides again Match；Goblet cell quantity increases, and the decline of mucilage secretion amount is more conducive to sticking for harmful bacteria；Mucosa-immune proinflammatory cytokines Expression quantity up-regulation, causes inflammatory reaction, damages Mucosa Barrier；Mucous membrane microbiota can also change correspondingly.Due to weaned piglet When alimentary canal subject bigger pressure, diarrhea becomes the most important performance of early weaning syndrome, and also therefore such illness is normal Often along with damage intestinal health, efficiency of feed utilization is influenced.
It is mainly pre- by route of nutrition and drug other than controlling environmental condition in production to alleviate weaning stress Prevent to realize.As antibiotic, Gao Xin, probiotics, oligosaccharide, enzyme preparation, antibacterial peptide, acidulant, Chinese herbal feed additive Deng they activate endogenous enzymes by improving intestine of young pigs pH value, transfer, excitation and strengthen the modes such as self immune system, reach The purpose for improving piglet growth performance, grice diarrhoea being effectively reduced.
Antibiotic is used as the drug for treating and preventing bacteriosis since last century in large quantities, is passed to control livestock and poultry Extremely important contribution has been made in the sound development of infectious diseases and maintenance modern farming.On the one hand antibiotic can pass through mind Promote the growth and development of animal through endocrine system, on the other hand can also be by inhibiting or killing pathogenic bacteria, reducing body has Evil infection, to safeguard animal health growth.In addition it has been reported that, antibiotic can change animal intestine wall thickness, increase film Permeability, is more conducive to the absorption of nutriment, so that body growth be promoted to develop.But long-time service antibiotic will cause anti- Pharmacological property the pathogenic bacteria even appearance of superbacteria can also remain in livestock products and environment, human body caused to generate a large amount of drug-fast bacterias Strain and lose the resistance to certain diseases.
High dose zinc oxide is as effective means prevention and treatment grice diarrhoea, piglet is promoted to grow, in production practices and research In show in weanling pig daily ration add pharmacological dose high zinc to piglet have growth enhancing effect.Meanwhile Gao Xinke with Activity of Digestive Enzymes in Intestine is improved, the institutional framework of piglet digestive is improved, adjusts intestinal microflora, increases small intestine antibacterial peptide Gene expression, reduce histamine release and promote intestinal tract injury repair the effects of, be prevention and control grice diarrhoea, promote animal The universal measure of growth.But after high dose zinc oxide in domestic animal body by digesting and assimilating, after excrement is discharged into environment, make soil Zinc accumulates and pollutes environment in earth, seriously endangers the sound development of livestock and poultry individual and ecological environment.
Probiotics refers to that having for the interior participation intestinal microbial balance of intake animal body is direct by enhancing animal to enteral The inhibiting effect of harmful microorganism group, or disease is prevented by enhancing non-specific immune function, and rush is played indirectly Precession object production function and the active microorganism culture improved food conversion ratio.The mechanism of action of probiotics is to form advantage to have Bacteria group competitively inhibits pernicious bacteria to expand, and metabolite contains with harmful bacteria contention attachment point, nutrition and oxygen Machine acid and lysozyme etc. make the reduction of alimentary canal pH value, are unfavorable for pernicious bacteria growth, to play the effect of disease resistance.But When pathogen has comparative advantage, probiotics cannot reach the using effect of antibiotics.Most probiotics are with viable bacteria Body Direct-fed, the easy in inactivation in production, transport, storage.Flora is selective to host, to low-level daily ration animal and comes into being Animal is obvious, general to high-level daily ration animal effect.
Oligosaccharide refers to that 2~10 monosaccharide form a kind of low molecular sugar of linear chain or branched chain by glucosides key connection, few Sugar is widely present in nature, can be used for the few of feed, mainly be included：Manna oligosacchride, fructooligosaccharide, isomaltulose, cream Oligosaccharides, wood oligose etc., do not have to hydrolyze the enzyme system of oligosaccharide in animal stomach, but the oligosaccharides property of can choose promote it is beneficial The proliferation of bacterium (mainly Bifidobacterium) reduces the chance that animal diseases occur to inhibit the growth of harmful bacteria in enteron aisle.It is low The receptor of poly oligosaccharide and pathogen on enteron aisle is closely similar, competitively in conjunction with cause of disease can be allowed to that intestines cannot be grown into Wall loses pathogenecity.But oligosaccharide is a kind of substance for improving immunity indirectly, itself does not have bactericidal effect, is only Beneficial bacterium provides nutrient or provides target for pathogen, can only assist disease-resistant, diseases prevention；The easy moisture absorption of oligosaccharides substance simultaneously, no Conducive to storage or uniformly addition, and higher operating costs.
Enzyme preparation is a kind of protein with biocatalysis.Cub enteron aisle is in the stage of development in wean fashion, disappears Change system is not developed also completely, and digestive ferment hyposecretion, vigor are low, require supplementation with exogenous enzymes assist digestion vegetable protein and Polysaccharide.Fodder enzyme preparation has the function of that improving nutrition digestion absorbs, eliminates anti-nutritional factors and promote intestinal health.With it is oligomeric Oligosaccharides is similar, and enzyme preparation does not also participate in attack pathogen directly, and most of effects are the growth substrates for reducing pathogen；High-quality In the case of daily ration, Production of Livestock and Poultry rate or disease resisting effect are whether improved, it is all unobvious.
Antibacterial peptide is a kind of peptides active material for fighting extraneous pathogenic bacterial infection that host defense system generates, and is that it is exempted from The chief component of epidemic disease system.The mechanism of action of antibacterial peptide is it is believed that be that perforation forms ion on the cell membrane of pathogen Channel causes membrane structure to destroy, and ion intracellular is caused to be largely lost, and cell is not able to maintain normal osmotic pressure and dead； Also it has been reported that antibacterial peptide can inhibit the respiration of bacterium, and lead to its death.Wide spectrum and not generate drug resistance be it Main feature does not act on eukaryocyte.Since antibacterial peptide molecular weight is small, separating-purifying is difficult, and natural resources are limited, chemistry Synthesis and genetic engineering are main acquisition means, but antibacterial peptide gene is directly expressed in microorganism, may be generated to host Poison and cannot synthesize the expression product of sufficient amount.Other than bacitracin, it is in the laboratory research stage mostly, is converted to life Force of labor it is less,
Chinese herbal medicine category pure natural substance, there is promotion growth of animal, enhances its constitution, boosts metabolism, improves productivity The effects of energy, resisting stress and disease preventing and treating.Discovery has more than 200 kinds of Chinese herbal medicines to contain various immunologic active materials, energy so far Enhance the immune function of animal body；More than 400 kinds of Chinese herbal medicines have sterilization, bacteriostasis；More than 50 kinds of Chinese herbal medicines have inactivation to virus Inhibiting effect.But Chinese herbal feed additive novelty is not high, and kind is reused or combines more, some raw materials deposit cub In inadaptability, skill upgrading is needed in terms of processing and refining.The effect of due to compound Chinese herb, ingredient was extremely complex, Mou Xiecheng Side effect may be occurred to other feed addictives by dividing, and additive amount is larger, be worked slow.Due to Chinese herbal feed additive formula It is indefinite, technique is coarse, quality testing is without foundation, cause product curative effect irregular.And plant extracts is with medicinal plant Separation process is extracted by physical chemistry, orientation obtains and richness according to the needs of the purposes of the final products to extraction for raw material Collect a certain kind or plurality of active ingredients in medicinal plant, the product formed without changing its effective component main structure.Mesh Preceding plant extracts is mainly used for improving immunity of organisms, antibacterial, anti-inflammatory, improves livestock and poultry production performance.Such as saccharicter-penin, folium cortex eucommiae Extract, macleaya cordata extracts and mountain flower Baical Skullcap root P.E dissipate etc..
Herba Andrographitis is the dry ground of acanthaceous plant Herba Andrographitis Andrographis paniculata (Burm.f.) Nees Upper part.Cauline leaf at the beginning of autumn is tapped when luxuriant, is dried.Alias Euphorbia, Banlangen, four fragrant grass, circular cone palpus medicinal herbs etc..Its bitter, It is cold in nature, return lung, stomach, large intestine, small intestinl channel.Have the effects that antibacterial, anti-inflammatory, antiviral, antipyretic, enhancing is immune.Clinical application in Treat the infection of the upper respiratory tract, acute bronchitis, pneumonia, bacillary dysentery etc..It is known as " Chinese medicine antibacterial element ".
The chemical component of Herba Andrographitis is mainly lactone and flavonoids.Lactone is mainly contained in Folium Andrographis, ingredient master There are andrographolide, desoxyandrographolide, neoandrographolide, Dehydro and drographolide, dexyandrographolide Glucoside, 14- deoxidation -12- methoxyl group andrographolide, 14- deoxidation -11- oxidation andrographolide and Herba Andrographitis are peaceful.Flavonoid Object is mainly contained in andrographis root, is polymethoxyflavone.Herb lactone content is 2%~5%.
Summary of the invention
In view of the above-mentioned problems existing in the prior art, the applicant provides a kind of andrographolides for animals to dissipate.This Invention product has the function of antibacterial, anti-inflammatory, has special efficacy to bacillary dysentery, can effectively solve the problems, such as livestock intestinal tract.
Technical scheme is as follows：
A kind of andrographolide for animals is scattered, and the scattered raw material of the andrographolide includes：3wt% andrographolide, 0.9wt% sodium hydrogensulfite, surplus are starch supplementary material；Andrographolide is reacted with sodium hydrogensulfite, forms sulfurous acid The mixture of hydrogen andrographolide sodium and andrographolide, is equipped with starch supplementary material, and the andrographolide is made and dissipates.
The andrographolide is calculated by dry product, is 95.0%~101.0% containing andrographolide；In the Herba Andrographitis The content that ester dissipates sulfite hydrogen andrographolide sodium is no less than 2.5wt%, and the content of andrographolide is no less than 0.2%.
The sodium hydrogensulfite is the mixture of sodium hydrogensulfite and sodium pyrosulfite, calculates by sulfur dioxide, is 61.5%~67.4%.The starch supplementary material is cornstarch.
A kind of preparation method that andrographolide is scattered, the preparation method include the following steps：
(1) andrographolide 30g is taken, 20 times of 70% ethyl alcohol of amount are added and dissolve by heating, obtained solution A is spare；
(2) 9g sodium hydrogensulfite is added into solution A, is heated to reflux 30 minutes, filters, collects filtrate；
(3) filtrate is carried out that ethyl alcohol is recovered under reduced pressure, is concentrated to get the clear cream that relative density is 1.20~1.25 (room temperatures)；
(4) clear cream is spray-dried, starch supplementary material is added, mixed, 1000g andrographolide is made and dissipates.
The present invention is beneficial to be had technical effect that：
The application of the Herba Andrographitis that the present invention uses in livestock and poultry breeding is mainly reflected in the following aspects：1, as feed Additive uses, and the nutritional ingredient of feed can be improved, and increases broiler weight, reduces the death rate in raising, has certain Health-care effect.It can be improved the price of deed and the speed of growth of livestock and poultry using compound andrographis paniculata, and plant the hatching rate of fowl, lay eggs Rate and incubation rate, and then improve productivity effect.2, enhance immunity of organisms, the newcastle disease HI that Herba Andrographitis can significantly improve broiler chicken is anti- Body titre levels, and have certain dose dependent.Herba Andrographitis can improve body antibody titer, have and delay atrophy of immune organ Effect, can influence the development of the bursa of farbricius, promote the growth of bone-marrow-derived lymphocyte, have the function of promoting thymus development in various degree, maintain Body specificity and non-specific immune function.3, in prevention and treatment livestock and poultry, andrographis paniculata injection is to piglet yellow-white dysentery, pneumonia And enteritis has preferable therapeutic effect.It is the compound preparation of ingredient to chicken colibacillosis, infectiousness larynx gas using Herba Andrographitis Guan Yan, white diarrhea etc. all have good curative effect.
Andrographolide is diterpene ginkgolide, is one of principle active component of Herba Andrographitis, have it is clearing heat and detoxicating, The function of cool blood detumescence.Andrographolide is esters structure, is dissolved in boiling ethyl alcohol, slightly molten in methanol or ethyl alcohol, atomic molten It is almost insoluble in water or ether in chloroform.
Andrographolide has multiple pharmacological effect, but its water solubility is poor, and taste is extremely bitter, and adding can reduce in pig starter feed Palatability, and oral bioavailable is lower, clinically adds higher operating costs for a long time, is unfavorable for product promotion.Therefore it studies Develop that a kind of water solubility is higher, the stronger andrographolide medicament of bioactivity is to solving the problems, such as that livestock intestinal tract is very necessary 's.By the modification to its structure, enhance its activity, to improve the specificity of its treatment.The present invention is by andrographolide and sub- Sodium bisulfate addition adds a hydrophilic radical at salt, to andrographolide, improves its water solubility, can enhance bioactivity, drops Low bitter taste improves its palatability.It is reported according to pertinent literature, andrographolide and sodium hydrogensulfite carry out addition reaction, mainly It is the Δ in andrographolide structure12Carbon double bond on carry out 1:1 addition.
Herba Andrographitis is known as " Chinese medicine antibiotic ", main active substances --- and-andrographolide has antibacterial, anti-inflammatory, resists The effects of virus, immunological regulation, Hepatoprotective cholagogue.Show andrographolide for after weaned piglet by preliminary experiment result of study The child care stage can reduce grice diarrhoea disease incidence, promote piglet growth.Consider its additive amount and raw material in pig starter feed Cost is configured in terms of andrographolide, the traditional Chinese powder medicine that content is 3%.
Modern pharmacological studies have shown that andrographolide is made with antibacterial anti-inflammatory, antiviral, immunological regulation, Hepatoprotective cholagogue etc. With.1, antibacterial action, andrographolide is to Escherichia coli, staphylococcus aureus, bacillus subtilis, streptococcus and white yeast Deng have stronger bacteriostatic activity, it is excellent compared with chloramphenicol to the curative effect of bacillary dysentery.Research finds the punching of subinhibitory concentration Lotus lactone can significantly affect the polymerization of the release of lactic dehydrogenase, actin cytoskeleton, and then reduce big by poultry diease originality Enterobacteria (APEC-O78) induction II type pneumonocyte degree of adhesion of chicken, and significantly affect APEC-O78 virulence factor expression and From the activity for luring substance.2, anti-inflammatory effect, andrographolide play anti-inflammatory effect by inhibiting NF-kB to connect with DNA, in turn Reduce the expression of proinflammatory albumen such as COX-2.Animal experiments show that subcutaneous or potassium dehydroandrographolide succinate is injected intraperitoneally or gavages in Herba Andrographitis Ester, to caused by dimethylbenzene, acetic acid, histamine mouse skin or abdominal cavity capillary permeability increase, rat egg white foot Swollen and crotons oiliness granulation capsule sepage all has significant inhibiting effect.3, immunoregulation effect, andrographolide can promote The proliferation of immunocompetent cell enhances the phagocytosis and wandering index of macrophage, improves the ratio of CD3, CD4, cd8 cell Example enhances immune function.Andrographolide can improve cavy mononuclear macrophage to the phagocytic rate of chicken red blood cell and improve outside people The activity of natural kill (NK) cell killing K562 cell in all blood promotes the growth of killing (LAK) cell, increases cell table Type extends the lethal effect time of LAK cell, moreover it is possible to human peripheral blood mononuclear cell be induced to generate interferon (IFN)-α, IFN- The biology of γ, tumor necrosis factor α (TNF-α), pharmacological action and the cell factors such as class interleukins (rIL2), IFN-α is imitated There should be similarity, and have synergistic effect therewith.These effectors act synergistically to form one with cells such as macrophage, NK in vivo A network, to improve the immune function of body.4, hepatoprotective and cholagogic effects, intraperitoneal injection andrographolide can make rat bile stream Amount obviously increases.Andrographolide can fight carbon tetrachloride, tetrabutyl peroxide, galactosamine and Paracetamol and cause Liver toxicity, significantly reduce the level of lipid peroxidation enzyme, alanine aminotransferase, alkaline phosphatase etc..
Detailed description of the invention
Fig. 1 is starch flame assay；
Fig. 2 is that andrographolide dissipates flame assay；
Fig. 3 is Andrographolidi Natrii Bisulfis thin layer figure；
In figure：G dissipates for andrographolide；S is Andrographolidi Natrii Bisulfis；Left figure point sample amount is respectively 10 μ l, 5 μ L, right figure point sample amount are respectively 1 μ l；
Fig. 4 is Andrographolidi Natrii Bisulfis thin layer figure；
In figure：G dissipates for andrographolide；S is Andrographolidi Natrii Bisulfis；Point sample amount is respectively 2 μ l, 4 μ l；
Fig. 5 is andrographolide thin layer figure；
In figure：G dissipates for andrographolide；S is andrographolide；Point sample amount is respectively 4 μ l, 6 μ l；
Fig. 6 is that andrographolide dissipates thin layer figure；
In figure：G1 dissipates for andrographolide；S1 is Andrographolidi Natrii Bisulfis；S2 is andrographolide；Point sample amount It is divided into 2 μ L, 4 μ L；
Fig. 7 is andrographolide thin layer figure；
In figure：G dissipates for andrographolide；S1 is Andrographolidi Natrii Bisulfis；S2 is andrographolide；Point sample amount point It Wei not 4 μ L, 6 μ L；
Specific embodiment
With reference to the accompanying drawings and examples, the present invention is specifically described.
Andrographolide, content：98.19%, lot number：1603141, the limited public affairs of biotechnology are reached purchased from Sichuan perseverance Easthome Department；Sodium hydrogensulfite, lot number：1601041, it is purchased from Distributions in Liaocheng of Shandong Province An Xin pharmaceutic adjuvant Co., Ltd；DEXTROSE ANHYDROUS, lot number： 201603151, it is purchased from Shandong Xiwang Pharmaceutical Co., Ltd.；Lactose, lot number：20160102, have purchased from Zhejiang Gao Mao biotechnology Limit company；Cornstarch, lot number：20160412, purchased from Shandong large biology exploitation limited liability company.
Embodiment 1
Andrographolide 30g is taken, adds 20 times of 70% ethyl alcohol of amount to dissolve by heating, adds 9g sodium hydrogensulfite and be heated to reflux 30 Minute, filtration, decompression filtrate recycling ethanol is concentrated into the clear cream that relative density is 1.20 (room temperatures), and adjustment inlet air temperature is 170 DEG C, sample rate 5L/h is spray-dried, and cornstarch is added, and mixes, 1000g is made to get the Herba Andrographitis for animals Lactones dissipates.
It is using Herba Andrographitis effective component that andrographolide, which dissipates, ----andrographolide and its addition product are auxiliary as main component The traditional Chinese powder medicine mixed with cornstarch.Mainly according in Andrographolidi Natrii Bisulfis and Herba Andrographitis in identifying item The physicochemical property of ester is formulated, and is identified (Fig. 1) to Andrographolidi Natrii Bisulfis using sodium ion flame reaction, is used Thin-layered chromatography identifies Andrographolidi Natrii Bisulfis and andrographolide respectively, by preparation method of test article, expansion The research of the conditions such as system, coloration method, the clear spot that the thin-layer identification method finally obtained identifies, favorable reproducibility.
Using the content of high effective liquid chromatography for measuring Andrographolidi Natrii Bisulfis and andrographolide.Containing measurement Determine in method, Andrographolidi Natrii Bisulfis has good linear relationship, linear equation within the scope of 5.34~171 μ g/ml For：Y=0.1077x-0.0368, r=1, average recovery rate 98.05%；Andrographolide is in 9.85~157.53 μ g/ml models There is good linear relationship in enclosing, linear equation is：Y=0.0658x+0.057, r=0.9999, average recovery rate are 98.24%.
Embodiment 2
Andrographolide 30g is taken, adds 20 times of 70% ethyl alcohol of amount to dissolve by heating, adds 9g sodium hydrogensulfite and be heated to reflux 30 Minute, filtration, decompression filtrate recycling ethanol is concentrated into the clear cream that relative density is 1.25 (room temperatures), and adjustment inlet air temperature is 170 DEG C, sample rate 5L/h is spray-dried, and cornstarch is added, and mixes, 1000g is made to get the Herba Andrographitis for animals Lactones dissipates.
Embodiment 3
Andrographolide 30g is taken, adds 20 times of 70% ethyl alcohol of amount to dissolve by heating, adds 9g sodium hydrogensulfite and be heated to reflux 30 Minute, filtration, decompression filtrate recycling ethanol is concentrated into the clear cream that relative density is 1.24 (room temperatures), and adjustment inlet air temperature is 170 DEG C, sample rate 5L/h is spray-dried, and cornstarch is added, and mixes, 1000g is made to get the Herba Andrographitis for animals Lactones dissipates.
Test case：
1 stability of test case
With andrographolide dissipate character, identification, appearance uniform degree, moisture, granularity, Andrographolidi Natrii Bisulfis and Determination of Andrographolide is inspection target, and andrographolide obtained by Examples 1 to 3 dissipates has carried out accelerated test, acceleration by light respectively Test and long term test observe index of correlation situation of change；Test result is respectively as shown in table 1~9.
1 embodiment of table, 1 andrographolide dissipates accelerated test result
Note：Identifying 1. "+" indicates that test solution shows sodium ion flame reaction；Identifying 2. "+" indicates test solution institute The position of aobvious principal spot and color are identical as the principal spot of reference substance solution；Identifying 3. "+" indicates that test solution shows main spot The position and color of point are identical as the principal spot of reference substance solution；Appearance uniform degree requires test sample that uniform color, nothing is presented Decorative pattern and color spot are judged to meet regulation.On the same below.
2 embodiment of table, 2 andrographolide dissipates accelerated test result
3 embodiment of table, 3 andrographolide dissipates accelerated test result
4 embodiment andrographolide of table dissipates highlight test result
5 embodiment of table, 2 andrographolide dissipates highlight test result
6 embodiment of table, 3 andrographolide dissipates highlight test result
7 embodiment of table, 1 andrographolide dissipates long-term test results
8 embodiment of table, 2 andrographolide dissipates long-term test results
9 embodiment of table, 3 andrographolide dissipates long-term test results
As a result result of study shows that andrographolide is dispersed under commercially available back respectively, accelerates to put under hot and humid environment It sets 6 months, significant change does not occur for the scattered character of andrographolide, and identification can detect corresponding spot, and appearance uniform degree meets Regulation, moisture rise to 6.4 by 5.8, and granularity can be sieved by No. 4, and Andrographolidi Natrii Bisulfis content is by under 2.75% 2.70% is dropped to, Determination of Andrographolide drops to 0.21% by 0.24%.The accelerated test in hot and humid environment, effectively at Content is divided to reduce, it is proposed that dissipate andrographolide and be stored in " sealing, set shady place ".
Intense light irradiation test in, by andrographolide it is in bulk enter colorless and transparent container in, be placed on intensity of illumination be 4500 10 days in the environment of ± 500Lx, the scattered character of andrographolide does not change, and identification can detect corresponding spot, and appearance is equal Evenness meets regulation, and moisture variation is unobvious, and granularity can be sieved by No. 4, Andrographolidi Natrii Bisulfis content by 2.75% drops to 2.74%, and Determination of Andrographolide drops to 0.23% by 0.24%, illustrates short-term intense light irradiation to punching Lotus lactone dissipates physicochemical property and influences less.
Andrographolide is dispersed under commercially available back, is 25 DEG C ± 2 DEG C in temperature, the environment that relative humidity is 60% ± 10% Interior carry out long-term stable experiment, after placing 12 months, the scattered character of andrographolide does not change, and identification can detect phase Spot is answered, appearance uniform degree meets regulation, and moisture rises to 6.3 by 5.8, and granularity can pass through No. 4 sieves, sodium hydrogensulfite punching Lotus lactone content drops to 2.72% by 2.75%, and Determination of Andrographolide drops to 0.22% by 0.24%, indices Variation is not significant, in controlled range, therefore continues long-term stable experiment.It is studied by stability test, punching Lotus lactone is dispersed in the case of commercially available back, and storage condition is that " sealing, set shady place " saves.
2 quality determination of test case
(1) character
Three batch Examples 1 to 3 andrographolides are weighed respectively and dissipate each 1g, are placed on smooth glass paper, tile about 5cm2, Its surface is flattened, in bright place's observation, this product is white powder, and nose hears tasteless, and mouth, which is tasted, slightly bitter taste.According to more lot samples The actual conditions of product be described as " this product be white powder；It is odorless, slight bitter."
(2) identify
(2.1) sodium ion flame reaction
Referring to 2015 editions《Chinese Pharmacopoeia》Four 0301 sodium salt discrimination tests.This product 1g is taken, is placed in 25ml measuring bottle, adds water Dissolution is ultrasonically treated 5min, lets cool, scale is settled to water, as test solution；Extracting corn starch 1g again, according to confession The identical method processing of test product, as negative control solution.Platinum filament is taken, after being moistened with hydrochloric acid, test sample is dipped, in colourless flame Middle burning.Test sample flame color shows foresythia, and negative controls flame is colourless, the method can to andrographolide dissipate in Andrographolidi Natrii Bisulfis carries out the identification of sodium ion specificity, sees Fig. 1~2.
(2.2) Andrographolidi Natrii Bisulfis TLC identifies
Referring to the thin-layer identification method of LIANBIZHI ZHUSHEYE sulfite hydrogen andrographolide sodium, this product 1g is taken, is placed in In 50ml measuring bottle, add methanol 40ml, be ultrasonically treated 20min, let cool, with methanol constant volume to scale, shake up, filter, precision measures Subsequent filtrate 20ml, is concentrated into 1ml, as test solution.It separately takes Andrographolidi Natrii Bisulfis reference substance appropriate, adds methanol Solution of every 1ml containing 10mg is made, as reference substance solution.It is tested according to thin-layered chromatography, draws above two solution each 5~10 μ l is put respectively on same silica gel g thin-layer plate, with chloroform-acetone-ethanol-water (5:5:5:It 1) is solvent, expansion takes Out, it dries, spray (faces use with the equivalent mixed liquor of -5% potassium hydroxide-ethanol solution of 2%3,5- dinitrobenzoic acid ethanol solution Prepare), it is clear that hot wind is blown to spot development, inspects in the sunlight immediately.Spot hangover is tight when point sample amount is 10 μ l as the result is shown Weight, spot is larger on chromatogram when point sample amount is 5 μ l, illustrates that point sample amount is excessive, sees Fig. 3.Point sample amount is reduced to 1 μ l, by same The method of sample carries out thin-layered chromatography test, and final chromatogram display dot is still larger, sees Fig. 3, illustrates the test sample of preparation It is intended to reduce with reference substance solution concentration.
Test sample and reference substance solution concentration are reduced simultaneously, the specific method is as follows：This product 1g is taken, is placed in 25ml measuring bottle, Add methanol 20ml, be ultrasonically treated 20min, put to room temperature, with methanol constant volume to scale, shake up, filters, as test solution； It separately takes Andrographolidi Natrii Bisulfis reference substance appropriate, adds methanol that solution of every 1ml containing 1mg is made, as reference substance solution. It is tested according to thin-layered chromatography, draws each 2~4 μ l of above two solution, put respectively on same silica gel g thin-layer plate, with three chloromethanes Alkane-acetone-ethanol-water (5:5:5:1) it is solvent, is unfolded, take out, dry, sprays molten with 2%3,5- dinitrobenzoic acid ethyl alcohol The equivalent mixed liquor (facing with preparation) of -5% potassium hydroxide-ethanol solution of liquid, it is clear that hot wind is blown to spot development.As a result in chromatography Test sample and Andrographolidi Natrii Bisulfis be on corresponding position in figure, there is a spot of same color, and the method can be to wearing Heart lotus lactone dissipates sulfite hydrogen andrographolide sodium and carries out specificity identification, therefore is included in standard, sees Fig. 4.
(2.3) andrographolide TLC identifies
Referring to version in 2015《Chinese Pharmacopoeia》The thin-layer identification method of " Herba Andrographitis " in one, takes this product 1g, is placed in 50ml In measuring bottle, methanol is added to dissolve, be ultrasonically treated 20min, put to room temperature, with methanol constant volume to scale, shake up, filtered, precision measures Subsequent filtrate 20ml is concentrated into 1ml as test solution.It takes andrographolide reference substance appropriate, adds methanol that every lml is made and contain The solution of lmg, as reference substance solution.It is tested according to thin-layered chromatography, draws test solution and each 4~6 μ l of reference substance solution, It is put respectively on same silica GF254 lamellae, with chloroform-acetate-methanol (4:3:0.4) it is solvent, is unfolded, Take out, dry, set and inspected under ultraviolet lamp (254nm), as a result in chromatogram test sample and andrographolide in corresponding position On, there is the spot of same color；Spray is with the equivalent of -5% potassium hydroxide-ethanol solution of 2%3,5- dinitrobenzoic acid ethanol solution Mixed liquor (face with prepare), hot wind are blown to that spot development is clear, and as a result the spot of test sample is not clear enough, illustrates that test sample needs to increase It adds some points sample amount.Therefore, sample solution preparation method is adjusted to：This product 1g is taken, is placed in 25ml measuring bottle, methanol 20ml is added, It is ultrasonically treated 20min, is put to room temperature, with methanol constant volume to scale, filtration, filtrate is concentrated into 2ml as test solution.By phase With method re-start the TLC test of andrographolide, as a result in chromatogram test sample with andrographolide in phase It answers on position, there is the spot of same color；Spray is with -5% potassium hydroxide-ethanol solution of 2%3,5- dinitrobenzoic acid ethanol solution Equivalent mixed liquor (face with prepare), it is clear that hot wind is blown to spot development, inspects in the sunlight.As a result the test sample in chromatogram With andrographolide on corresponding position, there is the spot of same color, but spot is unstable, to be observed immediately after colour developing.This side Method can dissipate middle andrographolide to andrographolide and carry out specificity identification, therefore be included in standard, see Fig. 5.
By above-mentioned experiment it is recognised that Andrographolidi Natrii Bisulfis and andrographolide are in thin layer discrimination process The color developing agent sprayed is all the equivalent mixed liquor of -5% potassium hydroxide-ethanol solution of 2%3,5- dinitrobenzoic acid ethanol solution, We attempt to verify whether that on one block of lamellae while the Andrographolidi Natrii Bisulfis in sample and punching can be identified Lotus lactone, follows the steps below：Take this product 1g, be placed in 25ml measuring bottle, add methanol 20ml, be ultrasonically treated 20min, put to Room temperature is shaken up with methanol constant volume to scale, filtration, as test solution.Separately take Andrographolidi Natrii Bisulfis reference substance Appropriate with andrographolide reference substance, respectively plus solution of every 1ml containing 1mg is made in methanol, as reference substance solution.According to thin layer color Spectrometry test, draws above-mentioned each 2~4 μ l of three kinds of solution, is put respectively on same silica gel g thin-layer plate, with chloroform-acetone- Alcohol-water (5:5:5:1) it is solvent, is unfolded, take out, dry, sprays with -5% hydrogen of 2%3,5- dinitrobenzoic acid ethanol solution The equivalent mixed liquor (face with prepare) of potassium oxide ethanol solution, it is clear that hot wind is blown to spot development, inspects in the sunlight.As a result exist Test sample and Andrographolidi Natrii Bisulfis have the spot of same color on corresponding position in chromatogram；Andrographolide Reference substance is corresponding with purple dot in higher height, but test sample immaculate in the position, sees Fig. 6 (left figure), thus it is speculated that be due to supplying Caused by Determination of Andrographolide is lower in test sample solution.Test sample is concentrated 20 times on this basis, repeats above-mentioned experiment, knot Fruit test sample and Andrographolidi Natrii Bisulfis and andrographolide in chromatogram have same color on corresponding position Spot, but the hangover of sample chromatogram sulfite hydrogen andrographolide sodium spot is serious, sees Fig. 6 (right figure).It can by experiment To find out, since test sample sulfite hydrogen andrographolide sodium differs more with Determination of Andrographolide, thin layer mirror is being carried out When other, the point sample concentration that cannot control the two simultaneously is optium concentration, therefore cannot identify test sample simultaneously with this method In Andrographolidi Natrii Bisulfis and andrographolide.
Re-selection method follows the steps below：1 product 1g of Example, is placed in 25ml measuring bottle, adds methanol 20ml is ultrasonically treated 20min, puts to room temperature, and with methanol constant volume to scale, filtration, it is molten as test sample that filtrate is concentrated into 2ml Liquid.Separately take Andrographolidi Natrii Bisulfis reference substance and andrographolide reference substance appropriate, respectively plus methanol is made every lml and contains The solution of lmg, as reference substance solution.It is tested according to thin-layered chromatography, draws each 4~6 μ l of standard solution, test solution 6 ~8 μ l are put respectively on same silica GF254 lamellae, with chloroform-acetate-methanol (4:3:It 0.4) is expansion Agent is unfolded, and takes out, dries, set and inspect under ultraviolet lamp (254nm), as a result test sample and andrographolide exist in chromatogram On corresponding position, there is a spot of same color, and Andrographolidi Natrii Bisulfis immaculate, see Fig. 7 (left figure)；Spray is with 2% The equivalent mixed liquor (facing with preparation) of -5% potassium hydroxide-ethanol solution of 3,5- dinitrobenzoic acid ethanol solution, hot wind is blown to spot Point colour developing is clear, inspects in the sunlight immediately.As a result test sample and andrographolide have phase on corresponding position in chromatogram With the spot of color, and clear spot, and Andrographolidi Natrii Bisulfis immaculate, see Fig. 7 (right figure).It can be with by experiment Find out, Andrographolidi Natrii Bisulfis cannot be unfolded under this condition, therefore can not identify simultaneously with the method for examination Product sulfite hydrogen andrographolide sodium and andrographolide.It is final to determine, sulfite hydrogen sodium punching is dissipated to andrographolide Lotus lactone and andrographolide carry out specificity identification according to the method obtained is initially tested respectively, and are included in standard.
The research of 3 pharmacological toxicology of test case
(1) the scattered Pharmacodynamics research of andrographolide
It weighs andrographolide and dissipates 50.33g, purified water 100ml is added to dissolve, 11000r/min is centrifuged 10min, takes supernatant It is concentrated under reduced pressure into 10ml, up to the medical fluid of (in terms of Andrographolidi Natrii Bisulfis) 137.4mg/ml after aseptic filtration.It weighs Colistine sulfate 0.01024g is configured to the medical fluid of 71.21 μ g/ml with sterile saline, spare after aseptic filtration.Take Yin Pungent of diindyl U.S., the medical fluid of 2.5mg/ml is made of sterile saline.It is placed in 4 DEG C and saves.
(1.1) for the preparation of examination bacterium solution
Strain is chosen single bacterium colony and be inoculated into 10ml nutrient broth medium, be placed in 37 through culture, rejuvenation before test 10~12h in DEG C constant incubator.By original bacteria liquid with 10-1It dilutes again, is diluted to 10 respectively-8, each bacterium solution takes 10 respectively-6、10-7、 10-8Concentration take 100 μ l to be added on nutrient agar panel with micro sample adding appliance, uniformly pushed away with bacteria stick is applied and be dispersed in media surface, Each concentration applies 3 plates, plate is placed in 37 DEG C of constant incubators, Escherichia coli and salmonella are after culture It 12h and observes for 24 hours, calculates clump count, original bacteria liquid concentration is calculated according to diluted concentration, concentration needed for being diluted to test is standby With.
(1.2) measurement of MIC
12, middle test tube of no cingula silica gel plug are taken, add 2ml nutrient broth medium in every test tube, in the 1st test tube It is middle addition for reagent liquid 2ml, after mixing, be sucked out 2ml be added in the 2nd test tube, be uniformly mixed, and so on be diluted to 10th test tube is drawn 2ml and is discarded.Then taking concentration with micro sample adding appliance is 1 × 105Cfu/ml's adds for examination 100 μ l of bacterium solution Into the 1st~11 test tube, the 12nd test tube is as negative control.Test tube is placed in 37 DEG C of constant incubators, Escherichia coli It 12h and is for 24 hours observed after culture with salmonella, takes out test tube and be placed in observed under daylight.It is sought in the test tube for thering is bacterium to grow It is muddy to support broth bouillon, nutrient broth medium clarification in the test tube of asepsis growth.Andrographolide made from embodiment 1 dissipates It is as shown in table 10 to the MIC value of pig common pathogen.
Table 10
Note："+" indicates muddy, and "-" indicates clarification.
As shown in Table 10, andrographolide, which is dissipated, has different degrees of inhibiting effect to 2 boar pathogenic bacteria, to hog cholera Detection of Salmonella bacteriostasis is stronger, MIC 8.59mg/ml, slightly weak to Radix Polygalae Crotalarioidis Escherichia bacteriostasis, and MIC is 17.17mg/ml。
(1.3) anti-inflammation test, is randomly divided into 5 groups, every group 10, half male and half female is respectively implemented by Kunming mouse 50 1 gained andrographolide of example dissipates (high, medium and low) dosage group, drug (Indomethacin) control group and positive controls.In Herba Andrographitis Ester dissipates (high, medium and low) dosage group and presses 137.4mg/kg, 68.7mg/kg, 34.35mg/kg gastric infusion, drug control group respectively Indomethacin is gavaged by 12.5mg/kg, positive controls gavage isometric(al) clear water, and each group mouse is administered once daily, successive administration 3 days.After last dose 1h, every group of mouse right ear be two-sided to be coated with 30 μ l of dimethylbenzene, and left ear does not apply as own control, after 30min Mouse is carried out to pluck eyeball blood sampling, serum is separated, for measuring the TNF-α in serum.Then mouse cervical dislocation is put to death, is stood Ears are cut along auricle base line, auricle is laid respectively at two ear same areas of left and right with diameter 6mm punch, uses electronics immediately Balance two auricle weight of weighing.Calculate ear swelling and swelling inhibiting rate.Test result is as shown in table 11,12.
Swelling=auris dextra tablet quality-left auricle quality
Swelling inhibiting rate=(positive controls be averaged swelling-administration group be averaged swelling)/positive controls are averagely swollen Expansibility × 100%
Serum TNF-α content is measured according to kit specification.
10 andrographolide of table dissipates the influence that paraxylene causes mouse ear swelling
Note：Capitalization difference indicates the extremely significant P of difference<0.01；Lowercase difference indicates significant difference P<0.05.
11 andrographolide of table dissipates the influence to inflammatory factor level in mice serum
Note：Capitalization difference indicates the extremely significant P of difference<0.01；Lowercase difference indicates significant difference P<0.05.
By table 10 and table 11 it is found that compared with positive controls, andrographolide dissipates each dosage group and Indomethacin group is equal It can the extremely significant reduction cause inflammation ear swelling of mouse and the level (P of serum levels of inflammatory cytokines TNF-α<0.01).
(2) the scattered studies on acute toxicity of andrographolide
Using the andrographolide addition product that rat oral gavages 5000mg/kg is given, (andrographolide dissipates original to preliminary experiment Material) rat bad reaction is not observed.20 rats are selected in formal test, and the andrographolide of administered by oral gavage 5000mg/kg adds It at object, is observed 14 days after single administration, observes the Clinical signs and death condition of rat, cut open kill after the test, carry out eye sight Pathological examination.Result of study shows：Andrographolide is scattered actually nontoxic to rat, and use is safe.
(2) long term toxicity is studied
4 week old cleaning grade Wistar rat 80, half male and half female are selected, weight is 100 ± 20g.4 groups are randomly divided into, i.e., Andrographolide addition product high dose group (2000mg/kgbw), middle dose group (1000mg/kgbw) and low dose group (500mg/kgbw) separately sets a control group.Continuous gavage is administered 30 days.Clinical manifestation is observed, weight and feed benefit are calculated With rate, blood routine and blood parameters are analyzed, carry out histopathologic examination, acquired results and control group are subjected to otherness Compare.Result of study shows：Andrographolide be dispersed in clinically application be it is safe, the safe range of clinical application is larger.

Claims (5)

1. a kind of andrographolide for animals dissipates, which is characterized in that the scattered raw material of the andrographolide includes：3wt% Herba Andrographitis Lactone, 0.9wt% sodium hydrogensulfite, surplus are starch supplementary material；Andrographolide is reacted with sodium hydrogensulfite, is formed sub- The mixture of sodium bisulfate andrographolide and andrographolide, is equipped with starch supplementary material, and the andrographolide is made and dissipates.
2. andrographolide according to claim 1 dissipates, which is characterized in that the andrographolide is calculated by dry product, It is 95.0%~101.0% containing andrographolide；The andrographolide dissipates the content of sulfite hydrogen andrographolide sodium not Less than 2.5wt%, the content of andrographolide is no less than 0.2%.
3. andrographolide according to claim 1 dissipate, which is characterized in that the sodium hydrogensulfite be sodium hydrogensulfite with The mixture of sodium pyrosulfite is calculated by sulfur dioxide, is 61.5%~67.4%.
4. andrographolide according to claim 1 dissipates, which is characterized in that the starch supplementary material is cornstarch.
5. a kind of scattered preparation method of andrographolide described in claim 1, which is characterized in that the preparation method includes as follows Step：
(1) andrographolide 30g is taken, 20 times of 70% ethyl alcohol of amount are added and dissolve by heating, obtained solution A is spare；
(2) 9g sodium hydrogensulfite is added into solution A, is heated to reflux 30 minutes, filters, collects filtrate；
(3) filtrate is carried out that ethyl alcohol is recovered under reduced pressure, is concentrated to get the clear cream that relative density is 1.20~1.25 (room temperatures)；
(4) clear cream is spray-dried, starch supplementary material is added, mixed, 1000g andrographolide is made and dissipates.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942520A (en) * 2019-04-10 2019-06-28 大理金明动物药业有限公司 Andrographolide sulfonate and the preparation method and application thereof
CN111189944A (en) * 2020-03-11 2020-05-22 济南广盛源生物科技有限公司 Method for simultaneously identifying radix sophorae flavescentis and common andrographis herb in three-flavor bistort rhizome oral liquid

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CN101362740A (en) * 2007-08-08 2009-02-11 李宏 Method for synthesizing andrographolide sodium bisulfite
WO2011048479A2 (en) * 2009-10-21 2011-04-28 Maqui New Life S.A. Compositions that include anthocyanidins and methods of use
CN103622960A (en) * 2013-12-11 2014-03-12 胡少平 Compound andrographolidume preparation for veterinary use
CN103622951A (en) * 2012-08-27 2014-03-12 康阳润和（北京）医药科技有限公司 Preparation method of Andrographolidi Natrii Bisulfis oral liquid

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Publication number Priority date Publication date Assignee Title
CN101148441A (en) * 2007-06-12 2008-03-26 孙克 Andrographolidi natrii bisulfis and preparation method thereof
CN101362740A (en) * 2007-08-08 2009-02-11 李宏 Method for synthesizing andrographolide sodium bisulfite
WO2011048479A2 (en) * 2009-10-21 2011-04-28 Maqui New Life S.A. Compositions that include anthocyanidins and methods of use
CN103622951A (en) * 2012-08-27 2014-03-12 康阳润和（北京）医药科技有限公司 Preparation method of Andrographolidi Natrii Bisulfis oral liquid
CN103622960A (en) * 2013-12-11 2014-03-12 胡少平 Compound andrographolidume preparation for veterinary use

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942520A (en) * 2019-04-10 2019-06-28 大理金明动物药业有限公司 Andrographolide sulfonate and the preparation method and application thereof
CN109942520B (en) * 2019-04-10 2023-08-01 大理金明动物药业有限公司 Andrographolide sulfonate and preparation method and application thereof
CN111189944A (en) * 2020-03-11 2020-05-22 济南广盛源生物科技有限公司 Method for simultaneously identifying radix sophorae flavescentis and common andrographis herb in three-flavor bistort rhizome oral liquid

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