CN106924272A - Purposes of the salicylic acid glucosides methyl in prevention and/or systemic lupus erythematosus and its complication medicine is prepared - Google Patents

Purposes of the salicylic acid glucosides methyl in prevention and/or systemic lupus erythematosus and its complication medicine is prepared Download PDF

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CN106924272A
CN106924272A CN201611259895.6A CN201611259895A CN106924272A CN 106924272 A CN106924272 A CN 106924272A CN 201611259895 A CN201611259895 A CN 201611259895A CN 106924272 A CN106924272 A CN 106924272A
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lupus
complication
lupus erythematosus
systemic lupus
salicylic acid
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CN106924272B (en
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杜冠华
方莲花
张东明
何阳阳
阎雨
林溢煌
吴平
张慧芳
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Institute of Materia Medica of CAMS
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

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  • Molecular Biology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Salicylic acid glucosides methyl compound and its pharmaceutically acceptable salt the invention discloses a class as shown in formula (1) are preparing the medicinal usage of prevention and/or systemic lupus erythematosus and its complication.In the present invention, the pharmacological action that salicylic acid glucosides methyl has to be reduced the expression of autoantibody and inflammatory factor in lupus mice body, improve immunologic function;With the effect for slowing down lupus arthritis sample pathogenesis;Pharmacological action with immune complex deposit, improvement lupus mice renal function in reduction lupus mice renal tissue;Effect with protection lupus mice spleen function.Salicylic acid glucosides methyl compound is to extract the monomeric compound of separation in folks of china Chinese traditional herbs Caulis et folium gaultheriae yunnanensis, has the advantages that toxicity is low, extraction process is simple, synthetic route is ripe;Its raw material resources is wide, and easily a large amount of preparations, it is a kind of traditional Chinese medicine monomer of the complication such as more satisfactory new systemic lupus erythematosus and its immune dysfunction, lupus arthritis, LN, systemic lupus erythematosus splenic injury with good applicating and exploitation prospect.

Description

Salicylic acid glucosides methyl prepare prevention and/or systemic lupus erythematosus and its Purposes in complication medicine
Technical field
The present invention relates to the new pharmacological action of salicylic acid glucosides methyl compound and its pharmaceutically acceptable salt, and Salicylic acid glucosides methyl compound and its pharmaceutically acceptable salt prepare prevention and treatment systemic loupus erythematosus and its Application in complication disease medicament;Category pharmaceutical technology field.
Technical background
Systemic loupus erythematosus (systemic lupus erythematosus, SLE) is a kind of product with autoantibody The autoimmune connective tissue disease for being deposited as major pathologic features of raw and immune complex, be it is a kind of be difficult to cure it is slow The health of the mankind in property disease, serious harm.Clinical characteristics are the tissue damage of general, most significantly I.e. so-called facial rash (butterfly macules).Except skin, systemic loupus erythematosus generally has an effect on nearly all important group (such as joint) and organ (such as heart, liver, brain, kidney and lung) are knitted, hematological system and central nervous system are also often that body is mainly received Tired part.Estimate according to U.S.'s lupus foundation, patient of the whole America with systemic loupus erythematosus is not less than 1,500,000, it is annual new Increase case up to 1.6 ten thousand.In China and world wide, also about 100 and 5,000,000 people endure systemic loupus erythematosus to the fullest extent Torment.Systemic loupus erythematosus is a kind of chronic disease for expending a large amount of medical resources.In the U.S., Patients with SLE Year per capita treatment total cost (in hospital, outpatient service and pharmacy) be up to 29,232 dollars, significantly larger than other non-systemics are red Expense produced by the patients with chronic diseases of yabbi sore.
Clinically systemic loupus erythematosus common drug mainly includes NSAIDs, antimalarial, glucocorticoid, exempts from Epidemic disease inhibitor and biological agent.These medicines only being capable of relief of symptoms to a certain extent, it is impossible to thorough cure diseases, while again Have the shortcomings that toxic and side effect is big, adverse reaction is more.
Therefore, the research for Therapy for Systemic Lupus Erythematosus medicine not only has huge social benefit, and can be with Substantially mitigate the financial burden of state's family and home, be very urgent and necessary.
In Chinese invention patent application (denomination of invention:" salicylic acid glucosides methyl compound, its synthetic method and use On the way ", application number:200910082224.0;Publication number CN101863934A;Publication date 2010-10-20) in disclose a class water Poplar acid glucosides methyl compound, discloses application of this kind of compound in antipyretic, anti-inflammatory and analgesic is prepared.Without public affairs Open its application in prevention and/or systemic lupus erythematosus and its complication product is prepared.
The content of the invention
The technical problem to be solved in the present invention is to provide salicylic acid glucosides methyl compound and its pharmaceutically acceptable Application of the salt in prevention and/or systemic lupus erythematosus and its complication product is prepared.
To solve above technical problem, the invention provides following technical scheme:
The first aspect of technical solution of the present invention there is provided the salicylic acid glucosides methyl compound as shown in formula (1) And its application of the pharmaceutically acceptable salt in prevention and/or systemic lupus erythematosus and its complication product is prepared;
R is selected from the disaccharides or trisaccharide that monose, monose are constituted, wherein described monose includes glucose, fructose, galactolipin; Further, described disaccharides includes lactose, maltose, sucrose.
Wherein, described prevention and/or systemic lupus erythematosus and its complication is selected from immune dysfunction, lupus Arthritis, LN, systemic lupus erythematosus splenic injury;Described product includes medicine, food, health products.
Technical solution of the present invention second aspect there is provided a kind of pharmaceutical composition and prepare prevention and/or treatment system Application in lupus erythematosus and its complication product, it is characterised in that the chemical combination shown in the logical formula (I) containing treatment effective dose Thing and pharmaceutically acceptable carrier or auxiliary material,
R is selected from the disaccharides or trisaccharide that monose, monose are constituted, wherein described monose includes glucose, fructose, galactolipin; Further, described disaccharides includes lactose, maltose, sucrose.
Wherein, described prevention and/or systemic lupus erythematosus and its complication is selected from immune dysfunction, lupus Arthritis, LN, systemic lupus erythematosus splenic injury;Described product includes medicine, food, health products.
Further, the pharmaceutical composition described in technical solution of the present invention second aspect also include with other active materials with Any ratio shares the pharmaceutical composition being made.
Further, above-described pharmaceutical composition is selected from following formulation:Solution, suspension, freeze-dried powder, breast Agent, pill, capsule, powder, sustained release preparation, control release preparation, extended release preparation and microsome delivery system.
Pharmaceutical composition described in second aspect present invention, prepares, using several approach to tested with known method Person applies, including but not limited to parenteral, oral, part, intracutaneous, intramuscular, intraperitoneal, subcutaneous, vein, intra-nasal route.
Salicylic acid glucosides methyl compound can be prepared by known methods and obtain in the present invention.
The pharmaceutical composition of salicylic acid glucosides methyl compound of the invention it is optional can be by any conventional method Prepared with one or more pharmaceutically acceptable carrier and/or excipient.Therefore, salicylic acid glucosides methyl compound and it Pharmaceutically acceptable salt can especially be formulated as example sucking or be blown into (by mouth or nose) or oral, containing changing, parenteral or rectum Administration.
The pharmaceutical composition of salicylic acid glucosides methyl compound can also use solution, suspension, emulsion, pill, glue Capsule, powder, control release or extended release preparation.These preparations are by the salicylic acid glucosides methyl class chemical combination containing therapeutically effective amount Thing, preferably purified form, and appropriate carrier, in the form of providing to the appropriate administration of patient.
Advantageous Effects:
The present invention sets up mouse system lupus erythematosus model by intraperitoneal injection norphytane (pristane), after modeling 1st month to carrying out examination into mould mouse, the failed mouse of deleting madel, and model success mouse is grouped at random, Proceed by pharmaceutical intervention within the 45th day after model is prepared.During whole experiment, every other month to lupus mice serum The expression of the autoantibodies such as middle DNA is dynamically determined, while also being carried out to lupus mice arthritis sample pathogenesis Effective monitoring.6th month after model is prepared, mice serum and main internal organs are collected, from splenic injury and kidney The aspects such as function damage assess effective alleviations and therapeutic action of the DL0309 to lupus mice pathogenesis.Tested more than, Present invention firstly discovers that salicylic acid glucosides methyl compound has reduces autoantibody and inflammatory factor in lupus mice body Expression, the effect for improving immunologic function;With the effect for slowing down lupus arthritis sample pathogenesis;With reducing, lupus is small Immune complex deposit, the effect of improvement lupus mice renal function in mouse renal tissue;With protection lupus mice spleen function Effect, can be applied to prepare prevention, alleviate and/or systemic lupus erythematosus and its immune dysfunction, lupus joint The product of the complication such as inflammation, LN, systemic lupus erythematosus splenic injury.
And medicine salicylic acid glucosides methyl compound of the invention be folks of china Chinese traditional herbs Caulis et folium gaultheriae yunnanensis in carry The monomeric compound of separation is taken, has the advantages that toxicity is low, extraction process is simple, synthetic route is ripe;Its raw material resources is wide It is wealthy, and easily a large amount of preparations, with application and DEVELOPMENT PROSPECT well.
Brief description of the drawings
Influence (the A of itself DNA antibody expression in the lupus mice body that Fig. 1 .DL0309 are induced pristane:IgG types DNA autoantibodies;B:IgM type DNA autoantibodies).
Influence (the A of itself Sm antibody expression in the lupus mice body that Fig. 2 .DL0309 are induced pristane:IgG types Sm Autoantibody;B:IgM type Sm autoantibodies).
Influence (the A of itself HAB expression in the lupus mice body that Fig. 3 .DL0309 are induced pristane:IgG Type histone autoantibody;B:IgM type histones autoantibody).
The influence of IL-6 (A) and total IgG (B) expression in the lupus mice body that Fig. 4 .DL0309 are induced pristane.
The influence of the lupus mice metapedes volume that Fig. 5 .DL0309 are induced pristane.
DL0309 is observed under Fig. 6 .X- light radiographies effect is effectively improved to lupus mice hindlimb joints deformity and swelling.
Improvement result (the A of the lupus mice renal function that Fig. 7 .DL0309 are induced pristane:Creatinine in serum contains Amount;B:The ratio of total protein and creatinine in urine specimen).
Fig. 8 renal histopathologies detect (H&E dyeing) (a- control groups;B- model groups;C- model groups;D- aspirin Group;E- metacortandracin groups;F- low dose groups;G- middle dose groups;H- high doses group).
Fig. 9 renal histopathologies detect (PAS dyeing) (a- control groups;B- model groups;C- model groups;D- aspirin Group;E- metacortandracin groups;F- low dose groups;G- middle dose groups;H- high doses group).
The deposition of total IgG compound in Figure 10 renal tissues.
The deposition of C3 complement complex in Figure 11 renal tissues.
Influences of Figure 12 .DL0309 to lupus mice spleen index.
Figure 13 spleen tissues pathology detect (H&E dyeing) (a- control groups;B- model groups;C- model groups;d-DL0309 Low dose group;E-DL0309 middle dose groups;F-DL0309 high dose groups;G- aspirin groups;H- metacortandracins group)
Specific embodiment
Salicylic acid glucosides methyl compound is further illustrated with reference to the present invention to prevent in vivo, alleviate and/or control Treat pharmacological action and the medicinal usage of systemic loupus erythematosus and its complication.
Following embodiments illustrate the present invention in more detail, are not any limitation of the invention.
Experimental example 1:The systemic loupus erythematosus mouse model induced by norphytane (pristane) is a kind of classical, wide It is the mouse model of accreditation, is commonly used to assess the pharmacological action of anti-lupus medicine.The raising of mouse, packet and administrations are such as Under:Inbred strais BALB/c female mices (SPF grades, 7~8 week old) are purchased from Beijing Vital River Experimental Animals Technology Co., Ltd. (quality certification number:SCXK (capital) 2012-0001;Sequence number:11400700048526).BALB/c mouse since before modeling 1 week, extremely Before experiment terminates (after modeling 6 months), raise always in institute of Materia Medica,Chinese Academy of Medical Sciences Experimental Animal Center barrier system System, 5~7/cage.Rearing conditions are:25 DEG C of constant temperature, 50% relative humidity, conventional feed and free waters and 12h illumination/ Dark alternate cycles.
1st month after modeling, according to the expression of internal autoantibody to carrying out examination into mould mouse, and will be into Mouse is grouped mould at random, 12/group.Respectively control group, model group, DL0309 low dose groups (200mg/kg body weight), DL0309 middle dose groups (400mg/kg body weight), DL0309 high doses group (800mg/kg body weight), positive drug aspirin group (303mg/kg body weight) and positive drug metacortandracin group (5mg/kg body weight).The 45th day after modeling starts, according to above-mentioned dosage It is administered orally, 1 times/day.Administered volume is 0.2mL/10g body weight.Wherein control group and model group synchronously give The CMC-Na solution of volume.
(1) influence that itself DNA antibody is expressed in the lupus mice body that detection DL0309 is induced pristane.
After modeling the 1st, 2 ... 6 months, blood is taken by cutting tail, and serum and haemocyte are separated.Using ELISA method is measured to DNA, Sm, HAB level in serum sample.Draw each group serum sample in itself DNA, Sm, HAB relative expression levels with the time performance graph (see Fig. 1, Fig. 2 and Fig. 3), lupus model mice serum The expression of the above-mentioned autoantibody of two kinds of forms of middle IgG and IgM significantly raises (* P<0.05 or * * P<0.01);It is middle and high The DL0309 of dosage, positive drug aspirin can reduce DNA-IgG/IgM, Sm-IgG/ in lupus mice body with metacortandracin The rising of the autoantibodies level such as IgM and histone-IgG/IgM, with the difference of model group have statistical significance (#P< 0.05,##P<0.01 or###P<0.001), illustrate that Oral administration of compounds DL0309 can effectively suppress in lupus mice body itself The generation of antibody.
(2) shadow of inflammatory cytokine IL-6 levels in the lupus mice serum that DL0309 is induced pristane is detected Ring.
2nd month (namely carrying out the 15th day after pharmaceutical intervention) after modeling, determines IL-6 in each group mice serum Expression (see Fig. 4 A).IL-6 this important inflammatory mediator is detected obvious height in lupus model mice serum Expression (* * P<0.01);The DL0309 of high dose, positive drug aspirin can significantly reduce lupus mice serum with metacortandracin Middle IL-6 expression (#P<0.05 or##P<0.01), illustrate that Oral administration of compounds DL0309 can effectively suppress lupus small The expression of inflammatory cytokine in mouse body.
(3) influence of total IgG level in the lupus mice serum that DL0309 is induced pristane is detected.
After modeling the 1st, 2 ... 6 months, the content of total IgG in each group mice serum is determined (see figure by ELISA 4B).The content of total IgG rising over time progressively in lupus mice serum, 2nd month after modeling start with Control group is compared and shows significant difference (* * P<0.01);The DL0309 of middle and high dosage, positive drug aspirin and metacortandracin Can significantly reduce total IgG in lupus mice serum expression (#P<0.05 or##P<0.01)。
(4) influence of the lupus mice foot swelling degree that detection DL0309 is induced pristane.
6th month after modeling, mouse metapedes same position is rule by independent experiment personnel, mouse metapedes is dipped in In measuring cup liquid, and line position and liquid level is set to maintain an equal level, after measuring and record mouse using toy toes volume measuring apparatus Sufficient volume (see Fig. 5).The average external volume of lupus mice metapedes significantly raises (* * P relative to control group<0.01);Middle and high dosage DL0309, positive drug aspirin and metacortandracin can significantly reduce lupus mice metapedes volume (#P<0.05 or##P< 0.01), illustrate that Oral administration of compounds DL0309 can effectively suppress foot swelling degree after lupus mice.
(5) influence of the lupus mice arthritis sample pathogenesis that detection DL0309 is induced pristane.
6th month after modeling, mouse hind leg is placed under X- light and is observed.Lupus model mouse metapedes is in X- light Under visible obvious deformity, while also observing that obvious swelling at ankle;And the DL0309 groups of middle and high dosage, positive drug Aspirin does not observe obvious such phenomenon (see Fig. 6) with metacortandracin group, illustrates Oral administration of compounds DL0309 energy It is enough effectively to alleviate lupus mice arthritis sample pathogenesis.
(6) influence of the lupus mice creatinine in serum content that detection DL0309 is induced pristane.
6th month after modeling, mice serum is collected, with SOD enzymatic assays creatinine in serum content (see Fig. 7 A).Wolf Sore model mice creatinine in serum content is significantly raised;The DL0309 of high dose, positive drug aspirin can have with metacortandracin Effect reduces creatinine in serum content.
(7) influence of total protein content in the lupus mice urine that DL0309 is induced pristane is detected.
6th month after modeling, mouse urine is collected, with creatinine content in SOD enzymatic assays urines, surveyed with BCA methods Determine total protein content in urine.By calculating the two ratio (see Fig. 7 B), it is seen that in lupus model mouse urine in unit creatinine The content of total protein is significantly raised;The DL0309 of high dose, positive drug aspirin can effectively reduce unit flesh with metacortandracin The content of total protein in acid anhydride.
(8) influence that the lupus mice Pathological that detection DL0309 is induced pristane changes.
6th month after modeling, each group mouse kidney is collected, carry out pathologic finding.Through H&E dyeing (see Fig. 8), under mirror Observing in visible lupus model mouse kidney tissue has massive inflammatory cells infiltrated, and glomerular mesangium broadens, and capillary wall increases Thickness, shows typical glomerulonephritis feature;The DL0309 of high dose, positive drug aspirin and metacortandracin can be obvious Improve lupus mice this pathological change.Through PAS dyeing (see Fig. 9), blood capillary in the visible normal murine glomerular of Microscopic observation Pipe loop is thin and clear, and capillary loops is substantially thickened in the glomerulus of lupus lesion, and glomerulus swelling causes capsula glomeruli narrow, together Shi Kejian basilar memebranes are disorderly, the pathological change such as renal tubule is thickened;The DL0309 of high dose, positive drug aspirin and metacortandracin energy Enough obvious this pathological changes of improvement lupus mice.Above-mentioned experiment confirms DL0309 to lupus mice kidney from pathologic angle The protective effect of dirty damage.
(9) influence of immune complex deposit in the lupus mice nephridial tissue that DL0309 is induced pristane is detected.
6th month after modeling, each group mouse kidney is collected, carry out indirect IF staining.It is aobvious in 200 times of fluorescence Micro- Microscopic observation (see Figure 10), lupus model mouse kidney tissue especially glomerulus position can be inspired it is strong red glimmering Light, illustrates the substantial amounts of total IgG compound of glomerulus site deposition;The DL0309 of high dose, positive drug aspirin and Po Ni Pine can significantly reduce the deposition of total IgG compound in lupus mice nephridial tissue.Seen under 400 times of laser confocal microscopes Examine (see Figure 11), lupus model murine glomerular can be inspired strong green fluorescence, illustrate that glomerulus site deposition is big The C3 complement complex of amount;The DL0309 of high dose, positive drug aspirin and metacortandracin can significantly reduce lupus mice The deposition of C3 complement complex in nephridial tissue.Above-mentioned experiment confirms that DL0309 is immunized again in can reducing lupus mice nephridial tissue The deposition of compound, also further illustrates the mechanism that DL0309 protects lupus mice renal function.
(10) influence of lupus mice spleen index, spleen pathological change that detection DL0309 is induced pristane.
6th month after modeling, mouse spleen is collected, calculate the spleen index of each group mouse than body weight with spleen weight (see Figure 12).Lupus model mouse spleen index is increased (* * P by about one time compared to control group<0.01);High dose DL0309, positive drug aspirin and metacortandracin can significantly reduce lupus mice spleen index rising (#P<0.05 or##P< 0.01), illustrate that DL0309 can play significant protective effect to the spleen of lupus mice.Also entered by histopathological examination One step confirms above-mentioned conclusion.Microscopic observation is visible (Figure 13), and cell paraplasm in lupus model mouse boosting tissue, spleen is white Pith knot structure is in multinodular and expansion;Positive drug aspirin and metacortandracin and DL0309 can significantly improve this pathology Change.
Integral animal experiment result shows that lupus mice body is interior itself to be resisted salicylic acid glucosides methyl compound with reducing The expression of body and inflammatory factor, the effect for improving immunologic function;With the effect for slowing down lupus arthritis sample pathogenesis; Effect with immune complex deposit, improvement lupus mice renal function in reduction lupus mice renal tissue;With protection wolf The effect of sore mouse spleen function.
In sum, salicylic acid glucosides methyl compound have prevention, alleviate and/or systemic lupus erythematosus and The effect of its complication, salicylic acid glucosides methyl compound is to extract the list of separation in folks of china Chinese traditional herbs Caulis et folium gaultheriae yunnanensis Body compound, has the advantages that toxicity is low, extraction process is simple, synthetic route is ripe;Its raw material resources is wide, and easily big Prepared by amount, with application and DEVELOPMENT PROSPECT well, can be applied to prepare prevention, alleviate and/or systemic lupus erythematosus And its product of the complication such as immune dysfunction, lupus arthritis, LN, systemic lupus erythematosus splenic injury.

Claims (10)

1. as lead to formula (I) shown in salicylic acid glucosides methyl compound and its pharmaceutically acceptable salt prepare prevention and/ Or the application in systemic lupus erythematosus and its complication product;
R is selected from monose, disaccharides, the trisaccharide of monose composition, wherein described monose includes glucose, fructose, galactolipin, it is described Disaccharides includes lactose, maltose, sucrose.
2. application according to claim 1, it is characterised in that described prevention and/or systemic lupus erythematosus and its simultaneously Hair disease is selected from immune dysfunction.
3. application according to claim 1, it is characterised in that described systemic loupus erythematosus and its complication is closed selected from lupus Section is scorching.
4. application according to claim 1, it is characterised in that described systemic loupus erythematosus and its complication are selected from systemic lupus erythematosus Ephritis.
5. application according to claim 1, it is characterised in that described systemic loupus erythematosus and its complication are selected from systemic lupus erythematosus Splenic injury.
6. application according to claim 1, it is characterised in that described product includes medicine, food, health products.
7. application of a kind of pharmaceutical composition in prevention and/or systemic lupus erythematosus and its complication product is prepared, Characterized in that, compound and pharmaceutically acceptable carrier or auxiliary material shown in the logical formula (I) containing treatment effective dose,
R is selected from monose, disaccharides, the trisaccharide of monose composition, wherein described monose includes glucose, fructose, galactolipin, it is described Disaccharides includes lactose, maltose, sucrose.
8. application according to claim 7, it is characterised in that described pharmaceutical composition also includes with other materials with any ratio Example shares the pharmaceutical composition being made.
9. according to the application of claim any one of 7-8, it is characterised in that described prevention and/or treatment system erythema wolf Sore and its complication are selected from immune dysfunction, lupus arthritis, LN, systemic lupus erythematosus splenic injury;Described product Including medicine, food, health products.
10. pharmaceutical composition according to claim 7, it is characterised in that described pharmaceutical composition is selected from following formulation:It is molten Liquid, suspension, freeze-dried powder, emulsion, pill, capsule, powder, sustained release preparation, control release preparation, extended release preparation and micro- Plastochondria delivery system.
CN201611259895.6A 2015-12-31 2016-12-31 Application of methyl salicylate glucoside in preparation of medicines for preventing and/or treating systemic lupus erythematosus and complications thereof Active CN106924272B (en)

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