CN102309530B - Pharmaceutical composition for treating or slowing inflammatory bowel disease - Google Patents
Pharmaceutical composition for treating or slowing inflammatory bowel disease Download PDFInfo
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- Medicines Containing Plant Substances (AREA)
Abstract
A pharmaceutical composition for treating or alleviating Inflammatory Bowel Disease (IBD) comprises bupleuri radix (Bupleurum) as effective component.
Description
Technical field
The present invention is about the medical composition of one treatment or relieving inflammatory bowel disease (IBD), especially with regard to the medical composition using Radix Bupleuri (Bupleurum) as effective ingredient treatment or relieving inflammatory bowel disease (IBD).
Background technology
Current medical circles are for inflammatory enteropathy (inflammatoryboweldisease；IBD) medicine can be divided into four big classes: (1) immunosuppressant, for instance azathioprine, cyclosporine, steroid etc.；(2) disease therapeuticing medicine, for instance sulfsalazine and 5-aminosalicylic acid (5-aminosalicylicacid；5-ASA)；(3) biological preparation (biologicalagent), to suppress internal specific inflammatory response material to reach therapeutic effect, for instance infliximab and remicade；And (4) diarrhea medication.But, these medicines are neither excellent for the therapeutic effect of inflammatory enteropathy, and have the risk producing other side effect.
Also there is the medicine for treating rheumatoid arthritis of new generation of suppression tumor necrosis factor (TNF-α) at present, be used for treating inflammatory enteropathy, for instance etanercept, adalimumab etc..Though the medicine for treating rheumatoid arthritis of a new generation has the advantage that drug effect is fast, evident in efficacy, immunologic tolerance is good, but factor expensive, that need intravenous injection, be likely to cause the ratio of immunoreation and effective patient low etc., by quite restriction on Clinical practice.
The present inventor is based on above-mentioned problem, from conventional Chinese herbal medicine, actively seeks that side effect is little, can treat or the medicine of relieving inflammatory bowel disease.
Radix Bupleuri (Bupleurum) is namely classified as " Sheng Nong's herbal classic " top grade medicinal plants from ancient times, for the principal agent of " Treatise on Febrile Diseases " Shaoyang disease, can antipyretic, analgesia, removing toxic substances, antiinflammatory, cure mainly feeling of fullness and disecomfort in the chest and hypochondrium, bitter taste in the mouth and dry throat, alternate attacks of chills and fever, jaundice and hepatitis etc..The utilization of known Radix Bupleuri, mainly at root, may separate out containing saponin (saikosaponin), longispinogenin (longispinogenin), sterin, fatty oil, class flavol and saccharide, wherein with saponin for Main Ingredients and Appearance.
Radix Bupleuri is currently in treating hepatitis crude drug the object of active development, but, not yet there is Radix Bupleuri to be applied to the research for the treatment of inflammatory enteropathy or document comes out.The present inventor etc. study specific Radix Bupleuri and extract mode, further confirm that the relation of Radix Bupleuri extract and inflammatory enteropathy, develop medical composition and the method for novel therapeutic or relieving inflammatory bowel disease.
Summary of the invention
The present invention provides the medical composition of a kind for the treatment of or relieving inflammatory bowel disease (IBD), including-Radix Bupleuri (Bupleurum) as effective ingredient.
The present invention also provides for the Radix Bupleuri purposes in preparation treatment or the medicine of relieving inflammatory bowel disease.
Accompanying drawing explanation
Fig. 1 shows the content of TNF-α in mice intestinal leachate, and (A) display is with the control group of the 50% ethanol water injection mice large intestine without TNBS；(B) the vehicle treated group of mice enteritis is brought out in display with TNBS；(C) display is through bringing out the mice for enteritis, the experimental group of the Bupleurum krylovianum extract that oral 100mg/kg embodiment 1 extracts；And (D) shows through bringing out the mice for enteritis, the positive control group of the 5-ASA of oral 200mg/kg.
Fig. 2 shows the content of IL-6 in mice intestinal leachate, and (A) display is with the control group of the 50% ethanol water injection mice large intestine without TNBS；(B) show that the TNBS being dissolved in 50% ethanol brings out the vehicle treated group of mice enteritis；(C) display is through bringing out the mice for enteritis, the experimental group of the Bupleurum krylovianum extract that oral 100mg/kg embodiment 1 extracts；And (D) shows through bringing out the mice for enteritis, the positive control group of the 5-ASA of oral 200mg/kg.
Fig. 3 shows the content of G-CSF in mice intestinal leachate, and (A) display is with the control group of the 50% ethanol water injection mice large intestine without TNBS；(B) show that the TNBS being dissolved in 50% ethanol brings out the vehicle treated group of mice enteritis；(C) display is through bringing out the mice for enteritis, the experimental group of the Bupleurum krylovianum extract that oral 100mg/kg embodiment 1 extracts；And (D) shows through bringing out the mice for enteritis, the positive control group of the 5-ASA of oral 200mg/kg.
Fig. 4 shows the content of IL1-β in mice intestinal leachate, and (A) display is with the control group of the 50% ethanol water injection BABL/c mice large intestine without TNBS；(B) show that the TNBS being dissolved in 50% ethanol brings out the vehicle treated group of mice enteritis；(C) display is through bringing out the mice for enteritis, the experimental group of the Bupleurum krylovianum extract that oral 100mg/kg embodiment 1 extracts；And (D) shows through bringing out the mice for enteritis, the positive control group of the 5-ASA of oral 200mg/kg.
Fig. 5 shows that large intestine diameter is about 1mm, and feces is in granular form with the large intestine kenel of the 50% ethanol water injection mice large intestine without TNBS.
Fig. 6 shows stimulates mice large intestine to form enteritis with TNBS, but does not use the large intestine kenel of any Radix Bupleuri extract, and large intestine enlargement diameter reaches about 3-5mm, and feces is water gruel shape.
Fig. 7 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Bupleurum krylovianum extract with TNBS.
Fig. 8 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 1000mg/kg Bupleurum krylovianum extract with TNBS.
Fig. 9 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Radix Bupleuri extract with TNBS.
Figure 10 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Bupleurum commelynoideum de Boiss. var. flaviflorum Shan et Y.Li extract with TNBS.
Figure 11 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Radix Bupeuri Scorzonerfolii. extract with TNBS.
Figure 12 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Radix Bupleuri triradiati extract with TNBS.
Figure 13 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Bupleurum falcatum extract with TNBS.
Figure 14 shows stimulates mice large intestine to form enteritis, the Orally administered big visible peristalsis visible intestinal peristalsis state of 100mg/kg Bupleurum Kaoi extract with TNBS.
Figure 15 shows stimulates mice large intestine to form enteritis, the big visible peristalsis visible intestinal peristalsis state of 5-ASA of Orally administered 200mg/kg with TNBS.
Detailed description of the invention
The Radix Bupleuri of the present invention can be selected for having the Radix Bupleuri kind of nature and flavor that hardship is put down, is slightly cold.Specifically, it is selected from following constituted group: Bupleurum krylovianum (Bupleurumkrylovianum), Radix Bupleuri (Bupleurumchinense), Bupleurum commelynoideum de Boiss. var. flaviflorum Shan et Y.Li (Bupleurumcommelynoideum), Radix Bupeuri Scorzonerfolii. (Buplcurumscorzonerifolium), Radix Bupleuri triradiati (Bupleurumtriradiatum), Bupleurum falcatum (Bupleurumfalcatum) and Bupleurum Kaoi (Bupleurumkaoi).
Above-mentioned Radix Bupleuri is optional rounds a plant, or preferably adopts root.
The Radix Bupleuri of the present invention can further via solvent extraction.Such as Radix Bupleuri plant is pulverized last, be soaked in alcoholic solution under room temperature, through after a while, at room temperature dry, concentration, it is thus achieved that Radix Bupleuri extract.In the preferred embodiments of the invention, alcoholic solution is preferably ethanol water, and, the concentration of ethanol can be 20%～95% percent by volume, it is advantageous to is 50～95% percents by volume.
The time extracted is generally more than 2 hours, it is advantageous to is 2 hours～24 hours, is more preferred from 4～5 hours.
The temperature extracted is generally room temperature, it is advantageous to for the temperature of room temperature to ethanol water boiling reflux.
Above-mentioned extracting process can include a concentrate drying process again, is concentrated, is dried to solid or crystalline solid by above-mentioned extract after being heated to reflux.Above-mentioned extracting process can repeatable operation for several times, the extract higher to obtain purity.
In the zootype of enteritis, visible peristalsis visible intestinal peristalsis state presents swelling, feces kenel can not be normal granules shape, even in the kenel of rotten shape to water sample.In one embodiment of the invention, the zootype of enteritis is after using Radix Bupleuri, and the phenomenon that phleboedesis is swollen is substantially suppressed, and enteritis position forms the phenomenon of soft stool, and display Radix Bupleuri has the effect of suppression and relieving inflammatory bowel disease.In one embodiment, the zootype of enteritis, after using Radix Bupleuri, also substantially reduces the performance amount of TNF-α, IL-6, G-CSF and IL1-β in the intestinal leachate of inflamed sites, thus it is speculated that these factors are relevant with inflammatory enteropathy.
According to the present invention, Radix Bupleuri may be used to treatment or suppresses the inflammatory enteropathy of individuality, including Crohn disease (Crohn ' sdisease), enteritis or the intestinal diseases with similar inflammation symptom.
Above-mentioned individuality includes mammal, for instance Mus, Canis familiaris L., cat, horse, sheep, pig, monkey, ape, particularly people.
The consumption that effectively makes of Radix Bupleuri by the personage knowing this technical field, can be judged according to conditions such as individual age, physiological situation, inflammation degree, it does not have limit especially, but can be preferably the dosage of 50～1000mg/kg, be more preferred from the dosage of 100mg/kg.
The medical composition of the present invention can farther include pharmaceutically acceptable supporting agent and/or the additive known in this technical field, according to factors such as dosage form, preserving type, methods of application, adds in appropriate proportions.
The medical composition of the present invention can via such as intravenous, intramuscular, oral or subcutaneous administration, it is advantageous to for Orally administered.Patient also can be carried out multiple dose administration by the medical composition of the present invention within suitably period, and this drug delivery regimen is measured according to pharmaceutically Routine methods.
Being embodied as of the present invention describes in detail as follows, but below example is only for disclosing further the technology contents of the present invention, should not use the invention category limiting this case.
The manufacture of [embodiment 1] Radix Bupleuri extract
Choose the plant root of Bupleurum krylovianum (Bupleurumkrylovianum), Radix Bupleuri (Bupleurumchinense), Bupleurum commelynoideum de Boiss. var. flaviflorum Shan et Y.Li (Bupleurumcommelynoideum), Radix Bupeuri Scorzonerfolii. (Buplcurumscorzonerifolium), Radix Bupleuri triradiati (Bupleurumtriradiatum), Bupleurum falcatum (Bupleurumfalcatum), Bupleurum Kaoi (Bupleurumkaoi) respectively, grind to form plant powder.
Take above-mentioned plant powder 0.5g respectively, each with 25ml concentration be 25%, 50%, 75% and 95% percent by volume ethanol water at room temperature shaken overnight after, through super-dry concentrate after, it is thus achieved that each Radix Bupleuri extract.
[embodiment 2] Radix Bupleuri extract is to the inhibitory action of TNF-α, IL-6, G-CSF and IL1-β content in the intestinal leachate of enteritis
The inhibitory action of TNF-α in the intestinal leachate of enteritis, IL-6, G-CSF and IL1-β content is referred to following documents and carries out experiment discussion by the Radix Bupleuri extract of the present invention:
1.CurrentProtocolsinImmunology(2001)15.19.1-15.19.14.
2.LahatG, HalperinD, FabianI, etal.ImmunomodulatoryEffectsofCiprofloxacininTNBS-Induce dColitisinMice.InflammBowelDis2007；13:557-565.
3.tenHoveT, vandenBlinkB, PronkI, etal.Dichotomalroleofinhibitionofp38MAPKwithSB203580inex perimentalcolitis.Gut2002；50:507-512.
4.BoumaG, StroberW.TheImmunologicalandGeneticBasisofInflammatoryBo welDisease.NatureReviewImmunology2003；3:521-533.
Take 6 mices be one group, totally four groups of mices, wherein inject 1.75mg trinitro-benzene-sulfonic acid (trinitrobenzenesulfonicacid from every BABL/c mice anus deeply big enteral 4 centimeters for three groups；TNBS) (Sigma), after 48 hours, formation enteritis is brought out at this position.Another set is with the 50% ethanol water injection BABL/c mice anus deeply big enteral 4 centimeters place without TNBS, as control group (A).Maintain normal visible peristalsis visible intestinal peristalsis state through the position of 50% ethanol water injection, be not induced into enteritis.
Above-mentioned bring out the position for enteritis, take from anus and play 6 centimeters of large intestines, be soaked in PBS2 hour, for (B) vehicle treated group.
Bringing out the mice group for enteritis it addition, above-mentioned, the Bupleurum krylovianum extract 100mg/kg extracted with 50% ethanol water with (C) oral embodiment 1 respectively, as experimental group；And the 5-aminosalicylic acid (5-aminosalicylicacid of (D) oral 200mg/kg；5-ASA) (Sigma), as positive control group.It is taken respectively from anus and plays 6 centimeters of large intestines, be soaked in PBS2 hour.
The mice intestinal leachate that above-mentioned (A), (B), (C), (D) organize is respectively with enzyme immunoassay (ELISA) (R&D), quantitative analysis TNF-α, IL-6, G-CSF and IL1-β content, result is respectively as shown in figures 1-4.
[embodiment 3] Radix Bupleuri extract improves that the phleboedesis of enteritis is big and feces water gruel sample phenomenon
Such as embodiment 2, bring out mice and form enteritis.Respectively to the mice forming enteritis, Orally administered embodiment 1 extracts with 50% ethanol water: Bupleurum krylovianum extract 100mg/kg and 1000mg/kg, Radix Bupleuri extract 100mg/kg, Bupleurum commelynoideum de Boiss. var. flaviflorum Shan et Y.Li extract 100mg/kg, Radix Bupeuri Scorzonerfolii. extract 100mg/kg, Radix Bupleuri triradiati extract 100mg/kg, Bupleurum falcatum extract 100mg/kg and Bupleurum Kaoi extract 100mg/kg.Afterwards, take mice anus respectively and play 6 centimeters of large intestines, observe that phleboedesis is big and feces kenel (such as Fig. 7～14).
On the other hand, by the above-mentioned visible peristalsis visible intestinal peristalsis state using each Radix Bupleuri extract, with above-described embodiment 2 it (1) not contain the visible peristalsis visible intestinal peristalsis state (control group) (such as Fig. 5) of the 50% ethanol water injection mice large intestine of TNBS；(2) TNBS to be dissolved in 50% ethanol stimulates mice large intestine to form enteritis but do not use the visible peristalsis visible intestinal peristalsis state (vehicle treated group) (such as Fig. 6) of Radix Bupleuri extract；And (3) use the visible peristalsis visible intestinal peristalsis state of the 5-ASA of 200mg/kg (Sigma) (positive control group) (such as Figure 15) for the Mouse oral bringing out enteritis, mutually compare.
Not using the enteritis pattern of Radix Bupleuri extract, visible peristalsis visible intestinal peristalsis state presents enlargement and the phenomenon (such as Fig. 6) of feces water gruel sample.But, in the visible peristalsis visible intestinal peristalsis state using above-mentioned Radix Bupleuri extract, the phenomenon that phleboedesis is swollen reduces, and the soft stool even state of normal granules shape occurs, and the phenomenon (Fig. 7～14) taken a turn for the better occurs in the intestines position of display inflammation.5-ASA is the common drug treating inflammatory enteropathy at present, but in using enteritis pattern, the phenomenon of phleboedesis shape does not slow down or disappear (such as Figure 15).
Although the present invention is disclosed above with preferred embodiment; so it is not limited to the present invention, any those who are familiar with this art, without departing from the spirit and scope of the invention; when a little change and retouching can be done, therefore the protection domain of the present invention when depending on after attached the defined person of claim be as the criterion.
Claims (3)
1. a Radix Bupleuri ethanolic extract is in the purposes of preparation treatment or the medicine of relieving inflammatory bowel disease, wherein this Radix Bupleuri system choosing freely following constituted group: Bupleurum krylovianum (Bupleurumkrylovianum), Radix Bupleuri (Bupleurumchinense), Bupleurum commelynoideum de Boiss. var. flaviflorum Shan et Y.Li (Bupleurumcommelynoideum), Radix Bupeuri Scorzonerfolii. (Buplcurumscorzonerifolium), Radix Bupleuri triradiati (Bupleurumtriradiatum), Bupleurum falcatum (Bupleurumfalcatum), and Bupleurum Kaoi (Bupleurumkaoi) or its combination, this Radix Bupleuri is from Radix Bupleuri root,
And this inflammatory enteropathy does not include Crohn disease (Crohn ' sdisease), namely the convection drying concentration after alcohol extraction of wherein said Radix Bupleuri ethanolic extract obtains.
2. purposes according to claim 1, wherein this Radix Bupleuri alcohol extraction system extracts with the ethanol water of concentration 20%～95% percent by volume.
3. the purposes according to any one of claim 1-2, wherein this medicine is Orally administered.
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| Mechanistic Study of Saikosaponin-d (Ssd) on Suppression of Murine T Lymphocyte Activation;Vincent Kam Wai Wong et al.;《Journal of Cellular Biochemistry》;20090319;第107卷;摘要 * |
| 克罗恩病的发病机制和治疗进展;李贞等;《传染病信息》;20091231;第22卷(第3期);p.180左栏第2段 * |
| 抗肿瘤坏死因子治疗在克罗恩病中的应用进展;董向毅等;《国际消化病杂志》;20061231;第26卷(第2期);p.86左栏第4段 * |
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