CN108524477A - Treat synephrine composition and its application of gastrointestinal dysfunction or intestinal irritable syndrome - Google Patents

Abstract

The invention discloses a kind of synephrine composition for treating gastrointestinal dysfunction or intestinal irritable syndrome and its applications, the a kind of of the present invention treats gastrointestinal dysfunction or the synephrine composition of intestinal irritable syndrome is made of synephrine and component A, and the component A includes the combination of one or more of aurantiin, aurantiamarin, neohesperidin, isoliquiritin, liquiritin or glycyrrhizic acid.The present invention selectively uses natural component to combine, and has synergistic regulation and control and multiple target point correction effect to 5 HT signal paths, proposes：The fact that " the optimum organization object of natural component, effect will be better than former single component or Chinese medicinal compound extract ".Combination matching has been advanced optimized on this basis, realizes optimum efficiency.

Description

Treat synephrine composition and its application of gastrointestinal dysfunction or intestinal irritable syndrome

Technical field

The present invention relates to a kind of natural drug compositions, and in particular to a kind of to treat gastrointestinal dysfunction or intestines easily swash synthesis The traditional Chinese medicine extraction composition of disease and its application.

Background technology

Gastrointestinal dysfunction is clinical common functional bowel disease, accounts for about the 40~60% of enterogastric diseases.Wherein Intestinal irritable syndrome (irritable bowel Syndrome, IBS) is common alimentary canal non-organic bowel dysfunction disease Disease, the clinical characters with chronic recurrent exerbation.Illness rate in adult is 10%~22%.Its main clinical manifestation is nothing The gastrointestinal symptoms such as abdominal pain, diarrhea, the constipation of organic disease, the cause of disease are functional disturbances of gastrointestinal tract.At present to such disease Disease still lacks effective therapy.

Since its pathology and pathogenesis are still not known in modern medicine, pathogenesis is more complicated, induce because Element is more, and clinical treatment is often difficult to obtain satisfactory effect, and there are anti-IBS to compose the defects of narrow, side effect is big, easy recurrence.In recent years Come, increasingly focuses on conventional medicament in terms of the development and exploitation of anti-IBS medicines both at home and abroad so that treatment of the traditional medicine in this disease In occupy critically important status.In the prior art, according to theory of traditional Chinese medical science and pharmacological effect, it has been disclosed that several treatment intestines are easy Swash the pharmaceutical composition of syndrome.Such as：

With Sini San close tongxieyao formula add Radix Codonopsis, Chinese yam spleen-strengtheningporridge product (Shaanxi Chinese medicine, 1999,20:404)；With Sini San, Sijunzi Tang, tongxieyao formula conjunction side plus-minus (Sichuan Chinese medicine, 2000,18:41)；Using flat stomach Sini San (dried orange peel, Radix Paeoniae Alba, radix bupleuri, Cortex Magnoliae Officinalis, product shell, rhizoma atractylodis, Radix Glycyrrhizae) and plus-minus (traditional Chinese medical science forum, 2002,17:51)；Adding and subtracting treatment IBS with Xiaoyao San, (Hubei Chinese medicine is miscellaneous Will, 2002,24：1)；Dialectical treatment irritable bowel syndrome 120 based on Sini San (traditional Chinese medical science forum, 1999,14：7)；Sini San Treat research (Sichuan Chinese medicine, 2010,28 (8) of the uncomfortable card Model with Irritable Bowel Syndrome of Liver Spleen：10).

Application No. is 201110401688.0 entitled " a kind of new applications and its pharmaceutical composition of total glucoside " Application for a patent for invention in, applicant disclose total glucoside prepare treatment intestinal irritable syndrome drug in purposes and combination Object.

Application No. is the patent disclosures of 201110400856.4 entitled " new applications of the dried immature fruit of citron orange or Bitter Orang P.E " The new application of the dried immature fruit of citron orange or Bitter Orang P.E as unique raw material medicine in the drug for preparing treatment intestinal irritable syndrome.

Although Radix Paeoniae Alba, the medicinal materials such as the dried immature fruit of citron orange, Radix Glycyrrhizae compound or extract have been shown in clinical treatment bowel dysfunction, functional digestive The diseases such as bad, intestinal irritable syndrome, but due to not completely clear, each constituents of the active principle of compound or medicinal substances extract The reasons such as complexity, that there is clinical efficacies in practical applications is unstable, drug quality control difficulty is big, preparation dose is big, The problems such as patient's poor compliance.

General points of view thinks, clinic have the active principle of efficacious prescriptions should include in compound the volatile active of each medicinal material with The summation of water-soluble active ingredient or fat-soluble active ingredient.Traditional view it is even contemplated that, because there is each medicinal material in compound The effect of effect substance is still not clear, therefore the effect of compound decocting liquid or total extract is better than one of which or several ingredients.

Currently, lack a kind of definite ingredients, treatment gastrointestinal dysfunction significant in efficacy or intestinal irritable syndrome Chinese medicine Extract composition and its application.

Invention content

The purpose of the present invention is to provide a kind of specific chemical components, multiple target effect, drug effect is notable, quality controllability is good Treatment gastrointestinal dysfunction or intestinal irritable syndrome traditional Chinese medicine extraction composition and its application.

In order to achieve the above objectives, present invention employs following technical proposals：The a kind of of the present invention treats Functional Gastrointestinal Disease Or the synephrine composition of intestinal irritable syndrome, the synephrine combination of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome Object is made of synephrine and component A, and the component A includes aurantiin, aurantiamarin, neohesperidin, isoliquiritin, liquiritin Or the combination of one or more of glycyrrhizic acid.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, described controls The synephrine composition for treating Functional Gastrointestinal Disease or intestinal irritable syndrome includes that following group counted in parts by weight is grouped as：

1~10 part of synephrine,

1~10 part of aurantiin.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, described controls The synephrine composition for treating Functional Gastrointestinal Disease or intestinal irritable syndrome includes that following group counted in parts by weight is grouped as：

1~10 part of synephrine,

1~10 part of aurantiamarin.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, described controls The synephrine composition for treating Functional Gastrointestinal Disease or intestinal irritable syndrome includes that following group counted in parts by weight is grouped as：

1~10 part of synephrine,

1~10 part of isoliquiritin.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, described controls The synephrine composition for treating Functional Gastrointestinal Disease or intestinal irritable syndrome includes that following group counted in parts by weight is grouped as：

1~10 part of synephrine,

1~10 part of liquiritin.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, it is described The synephrine composition for treating Functional Gastrointestinal Disease or intestinal irritable syndrome includes that following group counted in parts by weight is grouped as：

1~10 part of synephrine,

1~10 part of aurantiin,

1~10 part of glycyrrhizic acid.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, it is described The synephrine composition for treating Functional Gastrointestinal Disease or intestinal irritable syndrome includes that following group counted in parts by weight is grouped as：

1~10 part of synephrine,

1~10 part of aurantiamarin,

1~10 part of glycyrrhizic acid.

Further, the synephrine composition of the treatment Functional Gastrointestinal Disease or intestinal irritable syndrome, described controls The synephrine composition for the treatment of Functional Gastrointestinal Disease or intestinal irritable syndrome further includes the extract and associated extraction object of synephrine, institute The associated extraction object stated be the extract of aurantiin, the extract of aurantiamarin, neohesperidin extract, isoliquiritin extraction The combination of one or more of the extract of object, the extract of liquiritin or glycyrrhizic acid.

Further, all kinds of dosage forms are made using corresponding auxiliary material or technique in the synephrine composition, are used for function The treatment or health care of property gastrointestinal disease or intestinal irritable syndrome.The preparation includes tablet, capsule, pill, granule, dripping pill It is agent, micropill preparation, aerosol, emulsion, gelling agent, microballoon, nanosphere, oral liquid, suspension, injection, mucocutaneous Drug-delivery preparation and suppository.

Application of the synephrine composition of the present invention in Functional Gastrointestinal Disease or intestinal irritable syndrome treatment.

Synephrine of the present invention is natural origin or artificial synthesized compound (Synephrine, C₉H₁₃NO₂, CAS：94-07-5), the synephrine can be containing the extract more than or equal to 10% synephrine..

Glycyrrhizic acid of the present invention be natural origin or artificial synthesized compound (Glycyrrhizic acid, C₄₂H₆₂O₁₆.18α-Glycyrrhizic acid,CAS：83896-44-0；18β-Glycyrrhizic acid,CAS：1405- 86-3), the glycyrrhizic acid can be the amine salt, sylvite or sodium salt of glycyrrhizic acid, and the glycyrrhizic acid can be containing being more than The extract of 20% glycyrrhizic acid.The glycyrrhizic acid can be the hydrolysate enoxolone (Glycyrrhetinic of glycyrrhizic acid Acid, C₃₀H₄₆O₄.18 α-Glycyrrhetinic acid, CAS:1449-05-4；18 β-Glycyrrhetinic acid, CAS：471-53-4).

The aurantiin is natural origin or artificial synthesized compound (Naringin, C₂₇H₃₂O₁₄, CAS：10236- 47-2).The aurantiin can be containing the extract more than 20% aurantiin.The aurantiin includes the water of aurantiin Solve product naringenin (Naringenin, C₁₅H₁₂O₅, CAS:480-41-1).

The aurantiamarin is natural origin or artificial synthesized compound (Hesperidin, C₂₈H₃₄O₁₅, 610.57, CAS：520-26-3), the aurantiamarin can be containing the extract more than 20% aurantiamarin.The aurantiamarin includes orange Hydrolysate hesperetin (Hesperetin, the C of skin glycosides₁₆H₁₄O₆,CAS:520-33-2)。

The neohesperidin is natural origin or artificial synthesized compound (Neohesperidin, C₂₈H₃₄O₁₅, CAS: 13241-33-3), the neohesperidin can be containing the extract more than 20% neohesperidin.The neohesperidin packet Include the new hesperetin of aglycon after neohesperidin hydrolysis.

The liquiritin is natural origin or artificial synthesized compound (Liquiritin, C₂₁H₂₂O₉, CAS：551- 15-5), the liquiritin can be containing the extract more than 10% liquiritin.The liquiritin includes liquiritin hydrolysis Aglycon glycyrrhizin (Liquiritigenin, C afterwards₁₅H₁₂O₄,CAS:578-86-9)。

The isoliquiritin is natural origin or artificial synthesized compound (Isoliquiritin, C₂₁H₂₂O₉, CAS steps on Record 5041-81-6), the isoliquiritin can be containing the extract more than 5% isoliquiritin.The isoliquiritin Aglycon isoliquiritigenin (Isoliquiritigenin, C after being hydrolyzed including isoliquiritin₁₅H₁₂O₄,CAS:961-29-5)。

Advantageous effect：The present invention selectively uses natural component to combine, and proposes：" the optimum organization object of natural component, effect The fact that fruit will be better than former single component or Chinese medicinal compound extract ".Combination matching has been advanced optimized on this basis, has been realized Optimum efficiency.

Compared with prior art, the present invention is the innovative development to Chinese medicine compound prescription, by active ingredient in compound medicinal material Deeply screening and the acquired natural component composition of science combination have qualitative leap, the present invention to have multi-party compared with compound extract Face advantage：(1)：Composition has the characteristics that Chinese medicine compound prescription multiple target point plays drug effect, enhances pharmacological action and clinical efficacy, reduces Toxic side effect.

(2) control of specific chemical components in composition, the formulation and the quality of production that can make drug standard more has Targetedly, drug quality is stably and controllable.Improved simultaneously convenient for the preparation of various dosage forms and preparation level etc..

(3) composition selectively uses the chemical composition of natural traditional Chinese medicine compound, rejecting to abandon a large amount of in Chinese medicine compound prescription Unnecessary ingredient and disturbing factor so that active ingredient is more enriched with, reduce clinical medicine dose, imitated with reaching best technology Fruit.

This is entirely different with traditional scheme.Experimental data proves that composition using the present invention treats gastrointestinal function Disorderly or intestinal irritable syndrome can generate unexpected effect.

Description of the drawings

Fig. 1 is that the multiple target point of fraction compositions of the present invention Sensitive Rats TPH1,5-HT3R, 5-HT4R expression high to internal organ entangles Effect partially.

Normal group,Model group,Synephrine group,Aurantiin group,Glycyrrhizic acid group,Synephrine+aurantiin group, Synephrine+glycyrrhizic acid group,Synephrine+aurantiin+glycyrrhizic acid group,Sini San group,Pinaverium Bromide group

Figure 1A shows, significant difference between model group and normal group.Glycyrrhizic acid and model group difference unobvious, synephrine group Or aurantiin group has different, but rectifying effect unobvious with model group, and group difference is larger.

Figure 1B shows that there are the collection of illustrative plates of notable difference with model group for present composition group.The present composition has aobvious Write multiple target point rectifying effect.Compared with single component group, each point is more concentrated in present composition group, and stayed regional location is bright It is aobvious to tend to normal group.Illustrate of the present invention group be combined group in trend it is apparent, be better than one-component group.

Fig. 1 C show that aurantiin/synephrine/glycyrrhizic acid combination is similar to Sini San, have to 5-HT accesses preferable more Target spot correction acts on.

Specific implementation mode

By following embodiment, present invention be described in more detail, but should be noted that the scope of the present invention is not implemented by these Any restrictions of example.

Preclinical pharmacy, pharmacology and the clinical research that system has been carried out to the composition of the present invention program, according to stomach and intestine work( The clinical symptoms of energy disorder or intestinal irritable syndrome, devise a series of pharmacological evaluations, result of study includes following main contents.

One, the present composition can be obviously improved the high sensitiveness of internal organ, and have apparent gastrointestinal function adjustment effect, stop Bitterly, antifatigue, anti-stress effect.The present composition is better than one-component.

Visceral sensitivity increases the biological marker for being widely used as IBS, and clinical manifestation declines for pain threshold, i.e. pain Feel allergy, this pathological characters can very well be embodied in rat model, by giving post-stimulatory visceral sensitivity in rats Increase, has good similitude with IBS patient.Proctectasia stomach wall is withdrawn reflection (AWR) minimum capacity threshold value and is used extensively In the high sensitive evaluation of internal organ, the evaluation index that general state scores frequently as irritable bowel syndrome drug.

The experimental results showed that " synephrine ingredient related to the present invention (aurantiin, aurantiamarin, new orange peel of the present invention Glycosides, isoliquiritin, liquiritin, glycyrrhizic acid) in one or more of prioritization schemes for constituting compositions " to significantly improve Inner dirty high sensitive Rat general state scores and the minimum capacity threshold value of AWR, can be obviously improved the high sensitiveness of rat model internal organ.Minimum capacity Threshold value factor analysis is the results show that ingredient is there are Synergistic interaction in present composition group, better than single component and other Chinese medical extract has combination synergistic effect.When the component ratio of binary composition is 1~10:When 1~10, present invention combination Object also has antagonism gut function is hyperfunction, improves gut function inhibit, adjust gut function effect, analgesic, antifatigue, anti anoxia, resist and answer Swash effect.The composition of the result of study prompt present invention, which has gastrointestinal dysfunction or intestinal irritable syndrome, significantly improves work With.

It is of the present invention " synephrine ingredient related to the present invention (aurantiin, aurantiamarin, neohesperidin, isoliquiritin, Liquiritin, glycyrrhizic acid) constitute ternary composition " prioritization scheme generate unexpected effect, ternary composition of the present invention It combines synergistic effect and is better than relevant binary composition, be more advantageous to drug effect performance.

The combination being made of the extract of synephrine extract (content is greater than or equal to 10%) ingredient related to the present invention Object also has similar combination synergistic effect, has to gastrointestinal dysfunction or intestinal irritable syndrome and significantly improves effect.The present invention The extract of Related Component includes：Glycyrrhizic acid extract (glycyrrhizic acid content is greater than or equal to 20%), shaddock ped glucoside extract (shaddock ped Glycosides), orange peel glucoside extract (content of hesperidin be greater than or equal to 20%), neohesperidin extract (neohesperidin content be more than or Equal to 20%), Radix Glycyrrhizae glucoside extract (liquiritin content be greater than or equal to 20%), isoliquiritin extract (isoliquiritin content More than or equal to 5%).

Pinaverium Bromide is gastrointestinal tract selectivity calcium-channel antagonists, for treating irritable bowel syndrome, be can significantly reduce straight For intestines to the sensibility of expansion, clinic can lower visceral sensitivity, improve IBS patient's abdominal pain, abdominal distension symptom.This result of study is aobvious Show, Pinaverium Bromide group significantly improves rat model minimum capacity threshold value, the present composition significantly improves rat model minimum appearance Measure threshold value and general state scoring, general state scoring and threshold value improve degree (threshold value deviate normal group 15.08~ 21.12%) aspect is better than Pinaverium Bromide (threshold value deviates normal group 39.54%).

The present composition has similartrend, Sini San the most frequently used as clinical treatment irritable bowel syndrome with Sini San Square foundation, there is safely and effectively advantage, the present composition is prompted to have the potentiality for substituting compound clinical application.

Two, the present composition has synergistic and integral error correcting and position multiple target effect to the regulation and control of 5-HT accesses, to TRPV1 With significantly improving effect.

Further molecular biology research shows that the present composition has association to the 5-HT accesses regulation and control of rat model It is acted on synergy and integral error correcting and position, has to TRPV1 and significantly improve effect.Serotonin (5-HT) signal path has mediated internal organ Sensibility increases and intestinal motive force obstacle.95% 5-HT is originated from gastrointestinal tract in human body, and 5-HT signal paths are in modulation enteron aisle in Pivot nervous system Sensory transmission, maintains intestines peristalsis at the release of regulation and control peripheral neurotransmitter, adjusts and is sent out in intestinal wall secreting function Wave key effect.Serotonin (5-HT) signal path is mainly by the biosynthesis of 5-HT, recycling transhipment, inactivation, receptor activation Etc. important links composition, biosynthesis, reuptake, receptor combine the links such as activation mutually to cooperate in access, mutually restrict, jointly Maintain the normal physiological function of enteron aisle.During 5-HT signal transductions, synthesis rate-limiting enzyme (TPH) catalyzes and synthesizes 5-HT, transports Body (SERT) recycles 5-HT, and monoamine oxidase (MAO) inactivates 5-HT on cell membrane.5-HT3R is body of gland in 5-HT receptor families Anion channel is gated, regulation and control enteron aisle sensory neuron transmits injury signal, the tune with visceral sensitivity to central nervous system It saves closely related.5-HT4R is a kind of G-protein coupling metabotropic receptor, passes through open voltage sensitivity calcium channel, regulation and control drop The release of the important neurotransmitters such as calcium plain gene related peptide (CGRP), Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SP), influences gastrointestinal tract dynamia and visceroceptory sensation. Each performs its own functions for these links in normal state, maintains the normal physiological rhythm and pace of moving things of gastrointestinal function, these links are unbalance or abnormal straight It connects and results in 5-HT signals transmission exception and gastrointestinal function pathological state.Studies have shown that periphery 5-HT levels increase or 5-HT by The factors such as body abnormal expression can cause serotonin signal path abnormal, and 5-HT signal paths regulate and control capsaicin receptor TRPV1 phosphoric acid Change the generation that activation has mediated visceral hypersensitivity, causes IBS patient organ's sensibility to increase disorderly with intestinal motive force, the threshold of pain occur The symptoms such as attenuating, diarrhea, constipation, disclosing 5-HT signal paths and the dirty hypersensitivity IBS occurrence and development of Inner has substantial connection.

Related document report, the threshold of pain of IBS patient lower increase to periphery 5-HT levels it is related.The experimental results showed that this Inventive composition is obviously improved the dirty high sensitive model rat 5-HT levels of Inner, is better than single component.This experimental results showed that, model Group rat colon 5-HT is significantly increased, and TPH1 expression pole dramatically increases, and SERT expresses pole and significantly reduces, the phenomenon and document report As a result it is consistent, in 5-HT signal paths, TPH1 directly affects the biosynthesis of 5-HT, and SERT completes 5-HT transhipment intakes, it Be the important biomolecule molecule for influencing enteron aisle part 5-HT concentration.The experimental results showed that compared with model group, the present composition It TPH1 albumen and significantly improves, prompts at 5-HT synthesis is reduced after subassembly and intake increases with mRNA level in-site in the colonic tissue of group Add may be colonic tissue 5-HT horizontal down-regulations major reason, illustrate the present composition better than any ingredient be used alone Effect.

During the signal transduction of 5-HT accesses, 5-HT receptors have played very important effect.In 5-HT receptors man In race, 5-HT3 receptors and 5-HT4 receptors and IBS pathogenesis relationships are the closest, it has also become important drug target. A series of conduct such as 5-HT3R acceptor inhibitors and 5-HT4R receptor antagonists such as Cisapride, Mosapride, Renzapride The mainstream medicine of irritable bowel syndrome treatment.Rat model colon 5-HT3R expression extremely significantly increases (P ＜ 0.01) in this experiment, 5-HT4R expression significantly reduces (P ＜ 0.05), this result is consistent with IBS clinical study results, illustrates in the 5-HT accesses of periphery Receptor link is to lead to high another the sensitive key factor of internal organ extremely.Present composition group to rat model 5-HT3R and 5-HT4R albumen and the mRNA level in-site effect of being significantly improved (P ＜ 0.05, P ＜ 0.01), explanation consistent with the trend of Sini San group The a variety of receptors for being conducive to regulate and control 5-HT after combination of active principles of the present invention, improve the abnormality of 5-HT signal paths.

Synergistic rule is presented in the regulation and control that 5-HT accesses major protein and mRNA are expressed in present invention combination.For example, pungent Fu Lin+glycyrrhizic acid combination or synephrine+aurantiin combination there is coordinated regulation to make 5-HT3R, 5-HT4R albumen and mRNA expression With (P ＜ 0.01, P ＜ 0.05).Factor analysis show the present composition show Sensitive Rats 5-HT high to internal organ synthesis and The multiple target point synergy regulating and controlling effect of receptor link.In terms of improving TPH1,5-HT3R, 5-HT4RmRNA level, the present invention Combination is better than one-component, has combination synergistic effect.Of the present invention " synephrine ingredient related to the present invention (aurantiin, Aurantiamarin, neohesperidin, isoliquiritin, liquiritin, glycyrrhizic acid) constitute ternary composition prioritization scheme " combination synergy make With better than relevant binary composition.By extract (aurantiin, aurantiamarin, the new orange peel of synephrine extract and Related Component Glycosides, isoliquiritin, liquiritin, glycyrrhizic acid) similar synergistic regulating and controlling effect is also presented in the composition of composition.

Three, present composition enhancing pharmacological action and clinical efficacy, reduce clinical medicine dose, generate unexpected Effect.

We study the various dose of composition and associated sample, the results showed that, binary composition of the present invention It is significantly carried in high dose 50mg/kg (25mg/kg+25mg/kg) or middle dosage 25mg/kg (12.5mg/kg+12.5mg/kg) The minimum capacity threshold value (P ＜ 0.05, P ＜ 0.01) of the high dirty high Sensitive Rats AWR of Inner, hence it is evident that it is high sensitive to improve rat model internal organ State, effective dose 25mg/kg.The binary composition of different component ratio has similar effects.By synephrine extract with The composition of extract (aurantiin, aurantiamarin, neohesperidin, isoliquiritin, the liquiritin, glycyrrhizic acid) composition of Related Component There are similar effects.

Ternary composition of the present invention is in high dose 50mg/kg (16.7mg/kg+16.7mg/kg+16.7mg/kg), middle dosage 25mg/kg (8.3mg/kg+8.3mg/kg+8.3mg/kg), low dosage 12mg/kg (4mg/kg+4mg/kg+4mg/kg) are significantly Improve the minimum capacity threshold value (P ＜ 0.05, P ＜ 0.01) of Inner dirty high Sensitive Rats general state scoring and AWR, hence it is evident that improve mould Type Visceral state.Effective dose is 12mg/kg.The ternary composition of different proportion component of the present invention has similar Effect.By extract (aurantiin, aurantiamarin, the new orange peel of the binary composition and Related Component of synephrine or corresponding extract Glycosides, isoliquiritin, liquiritin, glycyrrhizic acid) composition ternary composition have similar effects：

Sini San compound extract is significantly increased the dirty high sensitivities of Inner greatly in high dose 10g crude drugs/kg, middle dosage 5g/kg Mouse general state scores and the minimum capacity threshold value (P ＜ 0.05, P ＜ 0.01) of AWR, and effective dose is 5g crude drugs/kg.

Compared with compound extract, present composition effective dose significantly reduces the present composition.The present invention combines Object effective dose is substantially reduced.Compared with binary composition, the effective dose of ternary composition of the present invention is substantially reduced.According to dynamic Object effective dose, conversion show that present composition clinical administration dosage is 0.12g~0.24g/ people.

Four, the mechanism of action of the present composition

5-HT signal paths regulation and control capsaicin receptor TRPV1 phosphorylation activations have mediated the generation of visceral hypersensitivity, take off Show the substantial connection of 5-HT signal paths and the dirty hypersensitivities of Inner.A series of 5-HT3R acceptor inhibitors and 5-HT4R receptor antagonists The mainstream medicine that agent such as Cisapride, Mosapride, Renzapride etc. has been treated as irritable bowel syndrome.5-HT receptor antagonists Agent or agonist can improve the symptoms such as abdominal pain, abdominal distension, and clinic is usually used in treating irritable bowel syndrome, but generally existing curative effect is paid no attention to Think, the shortcomings of toxic side effect is big, wherein the mainstream medicines such as tegaserod, Alosetron have dropped out city due to serious toxic side effect .Research in recent years shows that selective receptor agonists or antagonist easily induce 5-HT signal systems and be produced from and bears feedback, to Weaken curative effect of medication；Increase dosage often cause receptor sustained activity or completely block, cause gastrointestinal function be overexcited or Inhibit, is also easy to produce the adverse reactions such as diarrhea or constipation.Biosynthesis, reuptake, receptor combine the links such as activation in 5-HT accesses All linked with one another, mutually collaboration mutually restricts, the common normal physiological function for maintaining enteron aisle.

The present composition shows the multiple target point coordinated regulation of Sensitive Rats 5-HT synthesis high to internal organ and receptor link, High sensitiveness dirty to TRPV1 unconventionality expressions and Inner significantly improves effect." active ingredient is synergistic " → " 5-HT accesses are more Target spot correction regulation and control " → " the high sensitiveness of internal organ improves " is the high sensitiveness of composition for improved rat model internal organ of the present invention Important mechanisms.The present composition is using " mostly because of minor effect " mode to the multiple target points such as 5-HT biosynthesis, receptor synergy Intervene, the chemicals compared with " single target spot block or excited " are more advantageous to and reach 5-HT signal paths balance, restore function of intestinal canal The normal physiological rhythm and pace of moving things.

Experimental example 1

Influence of the composition to Model with Irritable Bowel Syndrome Visceral

1, experimental animal and drug are provided by legitimate channels.Experiment Pinaverium Bromide Tablets 50mg/ pieces (Abbott Products SAS)；Experiment synephrine (98%), glycyrrhizic acid (95%), aurantiin (98%), aurantiamarin (98%) are different sweet Careless glycosides (98%), liquiritin (98%), neohesperidin (98%) are provided by Nantong Fei Yu biotechnologies company.Experiment is carried with correlation Object test sample is taken voluntarily to prepare, synephrine extract (content is greater than or equal to 10%), (content is greater than or equal to glycyrrhizic acid 20%), aurantiin (content is greater than or equal to 20%), aurantiamarin (content is greater than or equal to 20%), neohesperidin extract (contains 20%) amount is greater than or equal to, liquiritin (content is greater than or equal to 10%), isoliquiritin (content is greater than or equal to 5%).Experiment It is purchased from Nanjing first sign Zai Kang pharmacies with the prepared slices of Chinese crude drugs.

2, experimental animal grouping, modeling：Normal group will be randomly divided into after SD rat adaptable feds 7d, model group is natural Recovery group, positive group, sample administration group.All rats for needing modeling carry out the high Sensitive Rats model of internal organ using combined stress method It prepares, randomly selects 2 kinds of Coping styles daily and intervened：Behavior constraint (is placed in self-control fixing pipe 3 hours), forced swimming (20 DEG C, 60 minutes), wet cage raise (12 hours), and food deprivation (24 hours), drinking-water is deprived (12 hours).Adjacent 2 days dry Pre- mode does not repeat, continuous modeling 21 days, each means of intervention averagely uses 2-3 times.

3. each group dosage：Since the 22nd day, in addition to normal group, model group, each group distinguished gastric infusion.Each group is every Day is primary, and continuous gavage is administered 7 days, positive group (Pinaverium Bromide 15mg/kg), and sample sets are administered by various dose.Clear-cutting forestland Group gives equivalent pure water.Sini San group and Pinaverium Bromide group dosage reference standard adult human dose and " experimental animal and people By body surface area equivalent dose conversion ratio table " it determines.

It is prepared by related test sample：Following each sample is made into debita spissitudo with distilled water respectively before use.

Sini San：

According to Sini San prescription (radix bupleuri 9g, Radix Paeoniae Alba 9g, the dried immature fruit of citron orange 9g, Radix Glycyrrhizae 9g), appropriate pharmaceutical decocting piece is weighed, is added 8 times Water impregnates 2h, water boiling and extraction 2 times, each 1h.Merge extracting solution, 60 DEG C are concentrated under reduced pressure into 1.5g crude drugs/ml, before use with steaming Distilled water is made into required concentration.

Synephrine extract：

The dried immature fruit of citron orange or mandarin orange pericarp coarse powder are taken, is extracted 3 times with 50%~80%V/V alcohol refluxs, 10 times of amount extractions 1 are small every time When, merge extracting solution, filtering, recycling design, be concentrated and dried to get.Or, taking the dried immature fruit of citron orange or mandarin orange pericarp coarse powder, 0.01~0.05M dilute Hydrochloric acid water stirring extraction 2 times, 90~100 DEG C of temperature measure extraction 1 hour, filtering for 10 times every time, and Aqueous extracts cross strong-acid type cation Resin is washed with water to neutrality exchanger resin, ammonium hydroxide or carbonic acid hydrogen sodium wet resin, and chloroform, ethyl acetate is used to elute respectively, Collect eluent, recycling design, it is dry to get.

Glycyrrhizic acid extract：

Extracting liquorice coarse powder or licorice piece first use 95%V/V ethyl alcohol to extract, and after extracting solution recycles ethyl alcohol, use oil successively Ether, ethyl acetate, extracting n-butyl alcohol, butanol extraction liquid are spare；The dregs of a decoction use 20%V/V ethyl alcohol to extract again, the extracting solution of gained After recycling ethyl alcohol, with extracting n-butyl alcohol, gained butanol extraction liquid merges, and after recycling n-butanol, is dissolved in water, by supernatant mistake D101 large pore resin absorption columns use 40-70%V/V ethanol elutions after washing, collect eluent, recycling design, it is dry to get. Or, licorice piece water boiling and extraction 3 times, 8~10 times of each amount of water, decoct 2h, extracting solution filtration merges, adjusts extracting solution Concentration is equivalent to primary 0.2~1.0g of dose to every milliliter, and 3000rpm is centrifuged 20 minutes, takes supernatant spare.Supernatant uses Large pore resin absorption column (D101, HPD100, HPD300, AB-8) adsorbs, and after extracting solution crosses column, water rinses decontamination, with 50~ 90% ethanol elution, collects eluent, recycling design, it is dry to get.The analysis result of sample segment：

Shaddock ped glucoside extract：

Dried immature fruit of citron orange coarse powder, 60%~70% alcohol reflux is taken to extract 3 times, every time extraction 1 hour, 6~10 times of amounts, extracting solution filter It crosses, merges, recycle ethyl alcohol.Adjustment extract concentration is equivalent to primary 0.2~1.0g of dose to every milliliter, using macroporous absorption tree Fat column (D101, HPD100, HPD300, AB-8) or polycaprolactam, after extracting solution crosses column, water rinses decontamination, with 50%~ 80%V/V ethanol elutions, collect eluent, recycling design, it is dry to get.Or, taking dried immature fruit of citron orange coarse powder, 60%~70% ethyl alcohol returns Stream extraction 3 times, every time extraction 1 hour, 6~10 times of amounts, extracting solution filtration merge, recycle ethyl alcohol.Extract concentration is adjusted to every Milliliter is equivalent to primary 0.2~1.0g of dose, and 10 times of amount water are added, is sufficiently stirred, staticly settles, filter, and sediment washing is done It is dry to get.

Neohesperidin extract：

Dried immature fruit of citron orange coarse powder, 60%~70% alcohol reflux is taken to extract 3 times, every time extraction 1 hour, 6~10 times of amounts, extracting solution filter It crosses, merges, recycle ethyl alcohol.Adjustment extract concentration is equivalent to primary 0.2~1.0g of dose to every milliliter, using macroporous absorption tree Fat column (D101, HPD100, HPD300, AB-8) or polycaprolactam, after extracting solution crosses column, water rinses decontamination, with 50%~ 80%V/V ethanol elutions, collect eluent, recycling design, it is dry to get.Dried immature fruit of citron orange coarse powder, 60%~70% alcohol reflux is taken to carry It takes 3 times, every time extraction 1 hour, 6~10 times of amounts, extracting solution filtration merges, recycles ethyl alcohol.Extract concentration is adjusted to every milliliter It is equivalent to primary 0.2~1.0g of dose, extract is added 10 times of amount water, is sufficiently stirred, staticly settles, filter, sediment washing, It is dry to get.

Orange peel glucoside extract：

Will 10 times of amount water logging 45rnin of dry dried orange peel coarse powder, wash to colourless, be filtered dry.10~20 times are immersed at room temperature In 10g/L limewash, pH11~12 are adjusted, in ultrasonic extraction 30 minutes, filter to obtain extracting solution.Extracting solution is acidified to HC1 PH4~5,50 DEG C of stirrings, 60 points of kinds, stands overnight, filters, it is dry to get.Or, dry dried orange peel coarse powder is taken, with 60%~70% 20~30 times of V/V ethyl alcohol, 70 DEG C of amount extracts 1 time, every time 2~3h.Extracting solution filters, and merges, and recycling ethyl alcohol is equivalent to every milliliter Primary 0.2~1.0g of dose adjusts pH6.0~6.5,3000rpm to centrifuge 20 minutes, takes supernatant spare.Supernatant uses macropore Adsorption resin column (D101, HPD100, HPD300) adsorbs, and after extracting solution crosses column, water rinses decontamination, with 50~70%V/V second Alcohol elutes, and collects eluent, recycling design, it is dry to get.

Radix Glycyrrhizae glucoside extract or isoliquiritin extract：

Extracting liquorice coarse powder is extracted 2 times, each 2h with 6~8 times of 95%V/V ethyl alcohol, 70 DEG C of amount.Extracting solution filters, and merges, and returns Receive ethyl alcohol, adjustment extract concentration is equivalent to primary 0.1~1.0g of dose to every milliliter, and 3000rpm is centrifuged 20 minutes, takes supernatant Liquid is spare.Supernatant is adsorbed using large pore resin absorption column (D101, HPD100, HPD300, AB-8), after extracting solution crosses column, water Rinse decontamination, with 60%~80%V/V ethanol elutions, collect eluent, recycling design, it is dry to get.

5. the analysis of test sample.

The Paeoniflorin analysis uses high performance liquid chromatography, essential condition：Using octadecylsilane bonded-phase silica For filler, methanol-water-glacial acetic acid (35:65:0.1) it is mobile phase, Detection wavelength：230nm.Or, Kromasil C18 columns (250mm × 4.6mm, 5 μm)；Mobile phase:- 0.02% phosphoric acid water (B) of second eyeball (A), gradient elution；Flow velocity:1.0mL/min；Column Temperature:30℃；Detection wavelength:230nm.Paeoniflorin, albiflorin, albiflorin, oxypaeoniflorin are detected in extract product of paeoniflorin With benzoylpaeoniflorin etc., monoterpene glycosides compound content is measured using benzoic acid as reference substance using spectrophotometry.

The Analysis of Glycyrrhizic Acid using high performance liquid chromatography (chromatographic condition, Kromasil C18 columns (250mm × 4.6mm, 5 μm)；Mobile phase:Methanol:0.2mol/L ammonium acetates:Acetic acid=67:33:1；Flow velocity:1.0mL/min, column temperature:30℃； Detection wavelength:254nm).Essential condition is：Use octadecylsilane bonded-phase silica for filler, methanol -0.2mol/L Ammonium acetate-acetic acid (67：33：1) it is mobile phase, Detection wavelength：250nm.The Radix Glycyrrhizae total saponins assay is using light splitting Photometry, using mono-ammonium glycyrrhizinate as reference substance, using 5% vanillic aldehyde-glacial acetic acid solution and perchloric acid solution as color developing agent.

The analysis of the aurantiamarin, aurantiin and neohesperidin uses high performance liquid chromatography, and essential condition is：Using ten Eight alkyl silane bonded-phase silicas are filler.Chromatographic column HypersilODS2-C18 (4.6mm × 250mm, 5 μm), mobile phase Acetonitrile-water (being adjusted to pH3.0 with phosphoric acid) (17: 83), flow velocity:1.0mL/min, column temperature:25℃；Detection wavelength:283nm.It is described Citrus aurantium total flavone assay use spectrophotometry, with aurantiin be control,

The analysis of the liquiritin, isoliquiritin uses octadecylsilane bonded-phase silica for filler.With second eyeball (A) -0.1% phosphoric acid solution (B) is mobile phase, gradient elution, flow velocity:1.0mL/min, column temperature:30℃；Detection wavelength is 276nm (detection liquiritin), 360nm (detection isoliquiritin), 276nm (detection glycyrrhizin) and 376nm (detection isoliquiritigenin).

Extracting section object experiment test sample analysis result of the present invention is shown in Table 1.

Table 1

5. experimental method

Rat general state evaluation with reference to corresponding standards of grading to the state of mind of rat, by hair color, enliven journey Degree, defecation character, weight etc. score.The fecal character and shape of daily close observation rat change, and camera shooting is used in combination to be subject to Record.Respectively to measure weight primary after modeling is forward and backward and treatment.

Visceral evaluation withdraws reflection (Abdominal Withdrawal using proctectasia stomach wall Reflex, AWR) scoring and cause evaluation index of the minimum capacity threshold value of AWR as Colon and rectum sensibility.Last dose/make For 24 hours, after last dose/modeling after 1h per anums proctectasia (CRD), observation animal abdomen withdraws reflection (AWR) for fasting before mould, Evaluate the visceral sensitivity of animal.Rat 12h is deprived of food but not water before experiment, under etherization, the rubber that vaseline is lubricated Glueballs capsule per anum is inserted into Rat-rectum, and air bag end fixes air bag apart from anus 5cm or so.Under rat waking state, After adapting to 30min, successively according to 20,40,60,80mmHg different stage gas injections, observe and reference standard carry out AWR scorings.It sees When observing rat abdomen and lifting, occur body it is arched when pressure (unit mmHg), as cause the minimum capacity threshold of AWR Value.Every rat measures 3 times, per minor tick 5min, is averaged.

AWR behavior scoring standards：

1. when giving CRD stimulations, rat mood is basicly stable, is chosen as 0 point；

2. rat becomes unstable when giving CRD stimulations, head is twisted once in a while, is chosen as 1 point；

3. rat abdomen muscle of back slight shrinkage but abdomen is not lifted away from ground, is chosen as 2 points；

4. rat abdomen muscle of back shrinks more by force and abdomen is lifted away from ground, it is chosen as 3 points；

5. rat abdomen muscle strong contraction, abdomen, pelvis and perineum are simultaneously lifted away from ground by back archwise, are chosen as 4 Point.

Statistical procedures are handled with SPSS19.0 statistical softwares, and experimental data is indicated with x ± s.Mean compares using t between group It examines, factor analysis is examined using F, and P ＜ 0.05 are statistically significant.

Experimental result

Compared with normal group, model group rats modeling animal initial stage shows as having the fidgets, and moves irritability less, gradually appears hair The dark and gloomy withered unrest of color defecates and gradually softens.Appetite declines, and body becomes thin, and easily wakes up tired sleeping, weight loss, loose stools showed increased, not at Shape in addition it is half congealed rush down, filthy at crissum, root of the tail, dry or wet, hair is withered and yellow and at random, and welt flocks together, slow to the reaction in the external world Slow, when crawl, struggles powerless, and general state scoring is substantially reduced (P ＜ 0.01), and minimum capacity threshold value is remarkably decreased (P ＜ 0.01), meet the high sensitive features of internal organ.Above with normally organize significant difference.After treatment, model group above-mentioned symptom is gradual Improve or disappear, rat spirit improves, and appetite increases, weight gain, and when crawl is quick on the draw, and hair restores gloss, and loose stools subtracts It is few.The symptom of natural recovering group has part improvement.The experimental result of part Experiment group is shown in Table 2.To rat general state and enteron aisle The influence (x ± s, n=6) of pressure minimum capacity threshold value is as shown in table 2：

Table 2

Note：Compared with normal group,^*P<0.05,^**P<0.01；Compared with model group,^#P<0.05,^##P<0.01

Table 3

Adjust the side R=0.852

Part present composition group experimental result and factor analysis the results are shown in Table 2, table 3.Compared with model group, dimension bromine Ammonium group minimum capacity threshold value extremely significantly increases (P ＜ 0.01), general state scoring unknown significance difference.Compared with model group, Synephrine+glycyrrhizic acid group or synephrine+aurantiin group minimum capacity threshold value and general state scoring significantly increase (P ＜ 0.05, P ＜ 0.01).The factor analysis of minimum capacity threshold value shows, ingredient in the group of synephrine+glycyrrhizic acid group or synephrine+aurantiin group There are Synergistic interaction (P ＜ 0.05, P ＜ 0.01), have combination synergistic effect, are better than single component.Synephrine+glycyrrhizic acid Or the composition of synephrine+aurantiin different proportion has similar combination synergistic effect.Further experiment is the results show that this hair The bright composition is " synephrine+aurantiin, synephrine+aurantiamarin, synephrine+neohesperidin, synephrine+isoliquiritin, pungent Fu Lin+liquiritin " has similar combination synergistic effect.

Compared with model group, the minimum capacity threshold value of synephrine+aurantiin+glycyrrhizic acid group and Sini San group significantly increases (P ＜ 0.05, P ＜ 0.01), general state scoring significantly improves (P ＜ 0.05, P ＜ 0.01).The factor analysis of minimum capacity threshold value It shows, there are Synergistic interaction (P ＜ 0.05, P ＜ 0.01) for ingredient in synephrine+aurantiin+glycyrrhizic acid group, and there is combination to increase Effect acts on, and is better than single component.The combination synergistic effect of synephrine+aurantiin+glycyrrhizic acid combination is better than synephrine+aurantiin group It closes or synephrine+glycyrrhizic acid combines.The composition of synephrine+aurantiin+glycyrrhizic acid different proportion has similar combination synergy Effect.

The present invention is investigated synephrine+aurantiamarin+glycyrrhizic acid combination, synephrine+neohesperidin+glycyrrhizic acid combines, is pungent Fu Lin+isoliquiritin+glycyrrhizic acid combination, synephrine+liquiritin+glycyrrhizic acid combination.Compared with model group, the above triple grouping It is combined (dosage：16.7mg/kg+16.7mg/kg+16.7mg/kg) minimum capacity threshold value significantly increases (P ＜ 0.05, P ＜ 0.01), general state scoring significantly improves (P ＜ 0.05, P ＜ 0.01), and the combination synergistic effect of the above ternary composition is better than Relevant binary composition.The composition that three of the above component is formed in varing proportions has similar combination synergistic effect.

Synephrine or synephrine extract and the composition that each component extract is constituted, which have, similar to be combined synergy and makees With.

Experimental example 2

The influence of composition dirty to Inner high Sensitive Rats 5-HT signal paths and TRPV1.

1, prepared by experimental animal, drug, modeling, test sample：With experimental example 1.

2, experimental method

Rat colon tissue samples acquire：After rat last gavage 2h, sacrificed by decapitation takes and is tied at 3cm above rat anus 3 sections, every section of 1-2cm of intestines use physiological saline and PBS buffer solution to rinse (pH7.4) respectively, and filter paper blots, and precise weighing uses liquid nitrogen Quick freeze, -80 DEG C save backup.

Enzyme-linked immunization (ELISA) measures rat colon 5-HT, 5-HT3R, 5-HT4R, TPH1, SERT protein expression level It takes rat colon tissue block PBS buffer solution to clean, physiological saline appropriate is added and carries out tissue homogenate, centrifuging and taking supernatant.Point Do not illustrate to operate according to ELISA kit, its light absorption value at 450nm is surveyed using full-automatic microplate reader, uses CurveExpert1.3 draws mark song, and calculates corresponding concentration.

Fluorescent quantitative PCR (qPCR) measures the mRNA of colonic tissue 5-HT3R, 5-HT4R, TPH1 Expression takes rat colon tissue, and total serum IgE is extracted using Trizol extraction process, is primed reverse transcription into cDNA using OligodT, Reverse transcription condition：37 DEG C of 15min, 85 DEG C of 5s.Fluorescent quantitative PCR, reaction condition are carried out with cDNA samples：95 DEG C of pre-degenerations 30s, 95 DEG C denaturation 5s, 60 DEG C annealing 34s, 95 DEG C extension 15s, 40 cycle, after reaction according to measure sample Ct values and Standard curve finds out the opposite initial concentration of sample to be tested, the opposite starting copy number with target gene divided by corresponding GAPDH The opposite starting copy number of internal reference obtains the relative value of target gene mRNA expression.Primer sequence see the table below.Design of primers sequence As shown in table 4：

Table 4

Statistical procedures are handled with SPSS19.0 statistical softwares, and experimental data is indicated with x ± s.Mean compares using t between group It examines, factor analysis is examined using F, and P ＜ 0.05 are statistically significant.Water is expressed with TPH1,5-HT3R, 5-HT4R mRNA It puts down and carries out three-dimensional clustering for base, compare the comprehensive regulation difference that each group responds 5-HT synthesis and receptor link.

Experimental result

Present composition part Experiment group expresses shadow to GAP-associated protein GAP in the high Sensitive Rats colonic tissue of internal organ and mRNA It rings and the results are shown in Table 5, table 6, it is horizontal that present composition part Experiment group improves TPH1mRNA, 5-HT3RmRNA, 5-HT4RmRNA Factor analysis is shown in Table 7.Compared with normal group, model group rats colonic tissue 5-HT levels extremely significantly increase (P ＜ 0.01). Compared with model group, Pinaverium Bromide group, present composition group and Sini San group colonic tissue 5-HT levels significantly improve (P ＜ 0.05, P ＜ 0.01).

Compared with normal group, model group TPH1,5-HT3R albumen and mRNA level in-site extremely significantly raise (P ＜ 0.01), 5- HT4R albumen and mRNA level in-site significantly reduce (P ＜ 0.05), and SERT protein levels pole significantly reduces (P ＜ 0.01).With model group It compares, Pinaverium Bromide group TPH1 protein levels extremely significantly lower (P ＜ 0.01), and 5-HT4R albumen and mRNA level in-site significantly raise (P ＜ 0.05, P ＜ 0.01).Compared with model group, synephrine+glycyrrhizic acid group or synephrine+aurantiin group TPH1 albumen and mRNA water HUD, which writes, lowers (P ＜ 0.01, P ＜ 0.05), and 5-HT3R albumen and mRNA level in-site significantly lower (P ＜ 0.05, P ＜ 0.01), 5- HT4R albumen and mRNA level in-site significantly raise (P ＜ 0.05, P ＜ 0.01).Improve TPH1mRNA, 5-HT3RmRNA, 5- The horizontal factor analysis of HT4RmRNA shows that there are cooperation interactions for ingredient in synephrine+glycyrrhizic acid group or synephrine+aurantiin group group It acts on (P ＜ 0.05, P ＜ 0.01), there is combination synergistic effect, be better than single component.

Compared with model group, synephrine+aurantiin+glycyrrhizic acid group TPH1 albumen and mRNA level in-site significantly lower (P ＜ 0.01, P ＜ 0.05), 5-HT3R albumen and mRNA level in-site significantly lower (P ＜ 0.05, P ＜ 0.01), 5-HT4R albumen and mRNA Horizontal significantly up-regulation (P ＜ 0.05, P ＜ 0.01).Improve the horizontal factor analysis of TPH1mRNA, 5-HT3RmRNA, 5-HT4RmRNA It shows, there are Synergistic interaction (P ＜ 0.05, P ＜ 0.01) for ingredient in synephrine+aurantiin+glycyrrhizic acid group, and there is combination to increase Effect acts on, and is better than single component, and the combination synergistic effect of synephrine+aurantiin+glycyrrhizic acid combination is better than synephrine+aurantiin group It closes or synephrine+glycyrrhizic acid combines.The composition of synephrine+aurantiin+glycyrrhizic acid different proportion has similar combination synergy Effect.

The present invention is investigated synephrine+aurantiamarin+glycyrrhizic acid combination, synephrine+neohesperidin+glycyrrhizic acid combines, is pungent Fu Lin+isoliquiritin+glycyrrhizic acid combination, synephrine+liquiritin+glycyrrhizic acid combination.Compared with model group, the above triple grouping It is combined (dosage：16.7mg/kg+16.7mg/kg+16.7mg/kg) TPH1 albumen and mRNA level in-site significantly lower (P ＜ 0.01, P ＜ 0.05), 5-HT3R albumen and mRNA level in-site significantly lower (P ＜ 0.05, P ＜ 0.01), 5-HT4R albumen and mRNA Horizontal significantly up-regulation (P ＜ 0.05, P ＜ 0.01).Improve the horizontal factor analysis of TPH1mRNA, 5-HT3RmRNA, 5-HT4RmRNA It has been shown that, the above ternary composition show similar combination synergistic effect, are better than single component, the combination of the above ternary composition Synergistic effect is better than associated binary composition.The ternary composition that three kinds of components of the invention are formed in varing proportions has similar Combination synergistic effect.

Further study showed that the composition that synephrine or synephrine extract are constituted with each component extract generates Similar combination synergistic effect.

Table 5

Note：Compared with normal group,^*P<0.05,^**P<0.01；Compared with model group,^#P<0.05,^##P<0.01

Table 6

Note：Compared with normal group,^*P<0.05,^**P<0.01；Compared with model group,^#P<0.05,^##P<0.01

Table 7

Clustering methodology (ClusterAnalysis) is the group that multivariable research object is divided into opposite homogeneity (clusters) there is statistical analysis technique data processing simply, visual good, energy visual pattern to embody classifying quality etc. Advantage.In order to investigate multiple target point regulating and controlling effect of the related experiment group to 5-HT accesses, the present invention is with TPH1,5-HT3R, 5-HT4R Protein expression level is that base has carried out three-dimensional clustering.Clustering intuitively shows the effect of each group multiple target point coordinated regulation Classification trend prompts the present composition to be better than one-component, the group of ternary component of the present invention in terms of 5-HT multiple target point regulation and control Close object has better multiple target point correction effect to rat model 5-HT signal path abnormalities.

Figure 1A shows, significant difference between model group and normal group.Glycyrrhizic acid and model group difference unobvious, aurantiin group Or synephrine group has different, but rectifying effect unobvious with model group, and group difference is larger.Figure 1B shows, synephrine+ Glycyrrhizic acid group or synephrine+aurantiin group (25+25) or synephrine+aurantiin+glycyrrhizic acid group (dosage：16.7mg/kg+ 16.7mg/kg+16.7mg/kg) there are notable differences with model group, there is notable rectifying effect.Compared with single component group, have It imitates into each point in subassembly group group more to concentrate, stayed regional location obviously tends to normal group.Illustrate that trend is apparent in group, is better than One-component group.Fig. 1 C show that synephrine/aurantiin/glycyrrhizic acid combination is similar to Sini San, have to 5-HT accesses preferable Multiple target point correction acts on.Clustering intuitively show each group multiple target point coordinated regulation effect classification trend, illustrate synephrine/ Aurantiin/glycyrrhizic acid combination has preferable multiple target point correction effect to rat model 5-HT signal path abnormalities, with not The present composition formed in proportion has similar multiple target point correction to act on.

The present invention is investigated synephrine+aurantiamarin+glycyrrhizic acid combination, synephrine+neohesperidin+glycyrrhizic acid combines, is pungent Fu Lin+isoliquiritin+glycyrrhizic acid combination, synephrine+liquiritin+glycyrrhizic acid combination.It was found that ternary composition of the present invention is to mould Type rat 5-HT signal path abnormalities have preferable multiple target point correction effect.

Studies have shown that Related Component is added is (aurantiin, aurantiamarin, neohesperidin, different sweet for synephrine or synephrine extract One or more of careless glycosides, liquiritin, glycyrrhizic acid), generate similar multiple target point correction effect.

Further study showed that associated extraction object (glycyrrhizic acid extract, aurantiin is added in synephrine or synephrine extract Extract, orange peel glucoside extract, neohesperidin extract, Radix Glycyrrhizae glucoside extract, isoliquiritin extract), it generates similar Multiple target point correction acts on.

Adjusting of the experimental example 3 to the gastrointestinal dysfunction rat caused by reserpine

1. animal, reagent are the same as experimental example 1.

2. animal packet and dosage：(1) the capacity physiological saline such as normal group intraperitoneal injection, while gavaging and capacity is waited to steam Distilled water；(2) model group：Reserpine 0.5mg/kg is injected intraperitoneally, while gavaging and waiting capacity distilled water；(3) positive group：Intraperitoneal injection Reserpine 0.5mg/kg, while gavaging Cerekinon 50mg/kg；；(4) sample sets：Reserpine 0.5mg/kg is injected intraperitoneally, simultaneously Gavage test sample respectively (with experimental example one).Each group successive administration two weeks.The excrement of observation rat and sign variation at any time, and Daily weight, the food ration for weighing rat.Following sample is collected by MTL radioimmunoassay kitss：Blood plasma, jejunal tissue storage are standby It surveys.T is examined between carrying out group between each administration group.

3. experimental result model group rats are after injecting reserpine and occur different degrees of diarrhea, loss of appetite successively, Excrement is viscous not well, and constipation, apocleisis are become thin.Compared with model group, the weight of present composition group rat, food ration, thymus gland Index, spleen index, motilin in plasma, jejunum homogenate MTL decline state and significantly improve (P<0.05, P<0.01).Illustrate this hair Bright composition can be obviously improved rat spleen deficiency sign, adjust the function of stomach and intestine.Part present composition group is to gastrointestinal function Disorderly rat MTL's the results are shown in Table 8.Binary composition (synephrine+aurantiin, the synephrine of the further studies have shown that present invention + aurantiamarin, synephrine+neohesperidin, synephrine+isoliquiritin, synephrine+liquiritin, synephrine+glycyrrhizic acid, composition weight Ratio is 10~1:10~1) or multicomponent composite significantly improves rat body weight, food ration, thymus index, spleen index, blood plasma MTL, jejunum homogenate MTL decline state (P<0.05, P<0.01).Synephrine or synephrine extract and Related Component extract institute The composition of composition has similar improvement result.

Table 8

Compared with the control group：△ P ＜ 0.05.Compared with model group：* P ＜ 0.01.

Experimental example 4

To the adjustment effect of intestine movement function

Medicine and reagent is the same as experimental example 1.

Animal and grouping：Kunming mouse, 18~22g of weight is random to be grouped, Normal group：The capacity such as gavage distill Water；(2) model group：The capacity distilled water such as daily gavage；(3) positive group：Cerekinon 100mg/kg；(4) sample sets：It fills respectively Take test sample (with experimental example one).Each group gavage gives corresponding drug, continuous 7d.After the last administration, Normal group is removed Outside, neostigmine 1mg/kg is subcutaneously injected in neostigmine load each group mouse；Atropine load each group mouse is subcutaneously injected Atropine 5mg/kg.After 10min, put to death after Azo-Blue the solution 0.1ml/10g, 15min of the equal gavage of all mouse 5%, it is fast Speed, which is cut open the belly, takes out stomach and intestine section, and record Azo-Blue forward position calculates it and account for the percentage of small intestine overall length to the distance of pylorus.It will respectively give T is examined between carrying out group between medicine group.

Experimental result is shown：Compared with model group, caused by present composition group can obviously inhibit neostigmine load Mouse small intestine hyperfunction (P<0.05), improve the suppressed state (P of mouse small intestine function caused by atropine<0.05) it, is prompted There is dual regulation to gut function.Part present composition group experimental result is shown in Table 9.Further study show that the present invention Binary composition (synephrine+aurantiin, synephrine+aurantiamarin, synephrine+neohesperidin, synephrine+isoliquiritin, Xin Fu Woods+liquiritin, synephrine+glycyrrhizic acid, composition weight ratio 10~1:10~1) or multicomponent composite have to gut function it is two-way Adjustment effect (P<0.05, P<0.01).The composition that synephrine or synephrine extract are constituted with each component extract has Similar dual regulation.

Table 9

Compared with the control group：△ P ＜ 0.05.Compared with model group：* P ＜ 0.01.

Analgesic activity of the experimental example 5 to mouse chemistry induced pain

1. medicine and reagent is the same as experimental example one.

2. animal and grouping：Take Kunming mouse, half male and half female, 18~22g, random grouping.Model group is given in equal volume Distilled water；Each group gavage gives corresponding drug, 20mlkg-1, continuous 5d.Mouse fasting 18h, last dose before experiment Afterwards after 45min, 0.6% acetum 0.2ml/ is injected intraperitoneally only in each mouse, the writhing response occurred in 15min after observation injection Number (abdomen indent, stretching, extension hind leg, buttocks are raised), and calculate analgesia percentage.

Experimental result is shown：Paeoniflorin+synephrine group can substantially reduce the mouse caused by acetic acid and turn round compared with model group Body number (P<0.05), illustrate that the present composition has certain analgesic activity to chemical stimulation.The part present composition Group experimental result is shown in Table 10.Further study showed that binary composition (synephrine+aurantiin, synephrine+orange peel of the invention Glycosides, synephrine+neohesperidin, synephrine+isoliquiritin, synephrine+liquiritin, synephrine+glycyrrhizic acid, composition weight ratio are 10~1:10~1) or multicomponent composite has significant analgesic activity (P to chemical stimulation<0.05, P<0.01).Synephrine Or the composition that synephrine extract is constituted with each component extract has similar analgesic activity to chemical stimulation.

Table 10

Compared with model group：* P ＜ 0.05, * * P ＜ 0.01.

6 antifatigue effect of experimental example

Medicine and reagent is the same as experimental example one.

Animal and grouping：Kunming mouse, half male and half female, 18~22g of weight are random to be grouped.Normal group：It gives Volume of saline；Each group gavage gives corresponding drug, 20mlkg-1, once a day, continuous five days, and after the last administration Be 10% plasticine in mouse tail Shu Tichong after 45min, and it is put into added water termostat water bath (50 × 30 × 20cm) went swimming, depth of water 20cm, water temperature are 25 ± 0.5 DEG C, and timing immediately, when mouse head submerged 10 seconds not Can the person of emerging be muscle power exhaust, timing at once, be mouse swimming time.Experimental result is shown：Compared with model group, Chinese herbaceous peony Medicine glycosides+synephrine composition group can significantly extend the swimming time (P of normal mouse<0.05), show to have apparent antifatigue Effect.Part present composition group experimental result is shown in Table 11.Further study showed that binary composition (Xin Fu of the invention Woods+aurantiin, synephrine+aurantiamarin, synephrine+neohesperidin, synephrine+isoliquiritin, synephrine+liquiritin, synephrine+ Glycyrrhizic acid, composition weight ratio are 10~1:10~1) or multicomponent composite has apparent antifatigue effect (P<0.05, P< 0.01).Synephrine or synephrine extract have similar antifatigue effect with the composition that each component extract is constituted.

Table 11

Compared with the control group：* P ＜ 0.05, * * P ＜ 0.01.

7 anti-stress effect of experimental example is studied

1, medicine and reagent is the same as experimental example one.

2, animal and grouping：Kunming mouse, half male and half female, 18~22g of weight are random to be grouped.Normal group：It gives Isometric(al) physiological saline, each group gavage give corresponding drug, once a day, continuous five days, will after the last administration after 45min Mouse is placed in the closed wide-mouth bottles of 125ml (built-in soda lime 20g).Record the time-to-live of mouse.More than 60min with 60min is counted.

3, experimental result is shown：Compared with model group, present composition group can significantly extend the survival of mouse normobaric hypoxia Time (P<0.05), show that the present composition has apparent anti-stress effect.Part present composition group experimental result It is shown in Table 12.Further study showed that binary composition of the invention (synephrine+aurantiin, synephrine+aurantiamarin, synephrine+ Neohesperidin, synephrine+isoliquiritin, synephrine+liquiritin, synephrine+glycyrrhizic acid, composition weight ratio are 10~1:10~ 1) or multicomponent composite has apparent anti-stress effect (P<0.05, P<0.01).Synephrine or synephrine extract with it is each at The composition that extract is constituted is divided to have similar anti-stress effect.

Table 12

Compared with the control group：* P ＜ 0.05.

Embodiment 1

120 grams of synephrine, 120 grams of aurantiin are taken, crushed 100 sieves respectively, appropriate microcrystalline cellulose is added and is uniformly mixed, Filling 1000 capsules are to get treatment Functional Gastrointestinal Disease or the pharmaceutical composition of intestinal irritable syndrome.Every capsule containing it is pungent not 120 milligrams of woods, 120 milligrams of aurantiin.

Embodiment 2

Embodiment 2 is substantially the same manner as Example 1, but drug prescription is：220 grams of synephrine, 22 grams of glycyrrhizic acid.

Embodiment 3

Embodiment 3 is substantially the same manner as Example 1, but drug prescription is：160 grams of synephrine, 80 grams of aurantiamarin.

Embodiment 4

Embodiment 4 is substantially the same manner as Example 1, but drug prescription is：180 grams of synephrine, 60 grams of liquiritin.

Embodiment 5

40 grams of synephrine, 40 grams of aurantiin, 40 grams of glycyrrhizic acid are taken, 100 sieves is crushed respectively, appropriate microcrystalline cellulose is added Pelletize respectively, three kinds of particles mixed in proportion, filling 1000 capsules to get.Every capsule contains 40 milligrams of synephrine, 40 milligrams of aurantiin, 40 milligrams of glycyrrhizic acid.

Embodiment 6

Embodiment 6 is substantially the same manner as Example 5, but drug prescription is：40 grams of synephrine, 40 grams of glycyrrhizic acid, aurantiamarin 40 Gram.

Embodiment 7

40 grams of synephrine, 40 grams of glycyrrhizic acid, 40 grams of liquiritin are taken, 100 sieves is crushed respectively, appropriate microcrystalline cellulose is added Pelletize respectively with lactose, film coating mixes in proportion three kinds of particles, prepare tablet to get.Every contains synephrine 40 Milligram, 40 milligrams of glycyrrhizic acid, 40 milligrams of liquiritin.

Embodiment 8

40 grams of synephrine, 40 grams of isoliquiritin, 40 grams of aurantiamarin are taken, appropriate poloxamer and water for injection is added, is prepared Injection to get.Every dose of injection contains 40 milligrams of Paeoniflorin, 40 milligrams of isoliquiritin, 40 milligrams of aurantiamarin.

Embodiment 9

It is substantially the same manner as Example 7, but drug prescription is：40 grams of synephrine, 40 grams of liquiritin, 20 grams of aurantiin, new orange 10 grams of skin glycosides, 10 grams of isoliquiritin.

Embodiment 10

40 grams of synephrine, 40 grams of glycyrrhizic acid, 40 grams of neohesperidin are taken, 100 sieves is crushed respectively, appropriate microcrystalline cellulose is added Element and lactose prepare micropill preparation respectively, three kinds of pellets are mixed in proportion, filling capsule to get.Contain Chinese herbaceous peony per agent capsules 40 milligrams of glycosides, 40 milligrams of glycyrrhizic acid, 40 milligrams of neohesperidin.

Embodiment 11

Embodiment 11 is substantially the same manner as Example 10, but drug prescription is：40 grams of synephrine, 40 grams of isoliquiritin, new orange 30 grams of skin glycosides, 10 grams of liquiritin.

Embodiment 12

40 grams of synephrine, 40 grams of aurantiin, 40 grams of isoliquiritin are taken, crushed 100 sieves respectively, appropriate poly- second two is added Alcohol, prepare pill to get.Every dose of pill contains 40 milligrams of synephrine, 40 milligrams of aurantiin, 40 milligrams of isoliquiritin.

Embodiment 13

Embodiment 13 is substantially the same manner as Example 12, but drug prescription is：40 grams of synephrine, 40 grams of glycyrrhizic acid, different Radix Glycyrrhizae 133 grams of the extract of glycosides (extract contains isoliquiritin 30%).

Embodiment 14

Embodiment 14 is substantially the same manner as Example 12, but drug prescription is：40 grams of synephrine, 40 grams of glycyrrhizic acid, liquiritin 73 grams of extract (extract contain liquiritin 55%).

Embodiment 15

Take 40 grams of synephrine, 40 grams of aurantiin, 40 grams of liquiritin, crushed 100 sieves respectively, be added appropriate syrup, glycerine, Sodium carboxymethylcellulose, prepare oral suspensions to get.Contain 40 milligrams of synephrine in every dose of suspension, 40 milligrams of aurantiin is sweet 40 milligrams of careless glycosides.

Embodiment 16

It is substantially the same manner as Example 15, but drug prescription is：The extraction of 40 grams of synephrine, 40 grams of aurantiamarin, isoliquiritin 54 grams of object (extract contains isoliquiritin 74%).

Embodiment 17

It is substantially the same manner as Example 15, but drug prescription is：The extraction of 40 grams of synephrine, 40 grams of isoliquiritin, aurantiin 77 grams of object (extract contains aurantiin 52%).

Embodiment 18

It is substantially the same manner as Example 15, but drug prescription is：The extract of 40 grams of synephrine, 40 grams of glycyrrhizic acid, aurantiamarin 87 grams (extract contains aurantiamarin 46%).

Embodiment 19

It is substantially the same manner as Example 15, but drug prescription is：The extraction of 40 grams of synephrine, 40 grams of glycyrrhizic acid, neohesperidin 45 grams of the extract of 80 grams of object (extract contains neohesperidin 25%), isoliquiritin (extract contains isoliquiritin 45%).

Embodiment 20

40 grams of synephrine, 40 grams of aurantiin, 40 grams of glycyrrhizic acid are taken, 100 sieves is crushed respectively, appropriate dextrin and lactose is added Granulation, prepare granule to get.Every dose of granule contains 40 milligrams of synephrine, 40 milligrams of aurantiin, 40 milligrams of glycyrrhizic acid.

Embodiment 21

It is essentially identical with implementing 20, but drug prescription is：It is 89 grams of synephrine extract (extract contain synephrine 45%), different 115 grams of the extract of 40 grams of liquiritin, liquiritin (extract contains liquiritin 35%).

Embodiment 22

40 grams of synephrine, 40 grams of aurantiin, 40 grams of neohesperidin are taken, 100 sieves is crushed respectively, appropriate microcrystalline cellulose is added Element and lactose pelletize respectively, film coating mixes in proportion three kinds of particles, filling capsule to get.It is pungent not per agent capsules 40 milligrams of woods, 40 milligrams of aurantiin, 40 milligrams of neohesperidin.

Embodiment 23

Embodiment 23 is substantially the same manner as Example 22, but drug prescription is：(extract contains synephrine to 69 grams of synephrine 58%), the extract 14.7 of 40 grams of aurantiamarin, 18.5 grams of the extract (extract contains glycyrrhizic acid 54%) of glycyrrhizic acid, liquiritin Gram (extract contain liquiritin 68%), 20 grams of isoliquiritin.

Embodiment 24

40 grams of synephrine, 40 grams of glycyrrhizic acid, 40 grams of aurantiin are taken, 100 sieves is crushed respectively, appropriate mannitol and breast is added Sugar granulation, prepare buccal tablet to get.Every dose contains 40 milligrams of synephrine, 40 milligrams of glycyrrhizic acid, 40 milligrams of aurantiin.

Embodiment 25

Embodiment 25 is substantially the same manner as Example 1, but drug prescription is：40 grams of synephrine, 200 grams of glycyrrhizic acid.

Embodiment 26

Embodiment 26 is substantially the same manner as Example 1, but drug prescription is：200 grams of synephrine, 40 grams of aurantiin.

Embodiment 27

60 grams of synephrine, 40 grams of aurantiamarin, 20 grams of glycyrrhizic acid are taken, 100 sieves is crushed respectively, prepares capsule respectively, i.e., .Every synephrine capsule contains 60 milligrams of synephrine, and every orange peel glycosides capsule contains 40 milligrams of aurantiamarin, and every glycyrrhizic acid capsule contains 20 milligrams of glycyrrhizic acid.According to conditions of patients situation, three kinds of capsules are taken using different periods.Each capsule takes one in one day Grain.It is taken three times a day, a kind of each capsule.

Embodiment 28

Embodiment 28 is substantially the same manner as Example 27, but drug prescription is：40 grams of synephrine, 40 grams of liquiritin, glycyrrhizic acid 73 grams of extract (extract contain glycyrrhizic acid 55%).

Embodiment 29

60 grams of aurantiamarin, 10 grams of synephrine, 50 grams of glycyrrhizic acid, Paeoniflorin is taken to prepare capsule, every capsule contains Paeoniflorin 60 milligrams；Synephrine prepares aerosol inhalants, and every dose contains 10 milligrams of synephrine；Glycyrrhizic acid prepares oral liquid, and every dose contains 50 milligrams of glycyrrhizic acid.According to conditions of patients situation, three kinds of preparations are taken using different periods.Each preparation takes one in one day Agent.It is taken three times a day, a kind of each preparation.

Embodiment 30

Taking 356 grams of synephrine extract (extract contain synephrine 45%), 267 grams of aurantiin, (extract contains aurantiin 30%).Crushed 100 sieves respectively, prepare respectively granule to get.Every dose of synephrine particle contains 160 milligrams, every dose of synephrine Aurantiin particle contains 80 milligrams of aurantiin.According to conditions of patients situation, two kinds of granules are taken using different periods.It is every in one day Kind particle is taken one.A kind of secondary, each particle is taken daily.

The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, the present invention Claimed range is delineated by the appended claims, the specification and equivalents thereof from the appended claims.

Claims (10)

1. a kind of synephrine composition for treating gastrointestinal dysfunction or intestinal irritable syndrome, it is characterised in that：The treatment The synephrine composition of gastrointestinal dysfunction or intestinal irritable syndrome is made of synephrine and component A, and the component A includes The combination of one or more of aurantiin, aurantiamarin, neohesperidin, isoliquiritin, liquiritin or glycyrrhizic acid.

2. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome include count in parts by weight it is as follows Group is grouped as：

1~10 part of synephrine,

1~10 part of aurantiin.

3. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome include count in parts by weight it is as follows Group is grouped as：

1~10 part of synephrine,

1~10 part of aurantiamarin.

4. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome include count in parts by weight it is as follows Group is grouped as：

1~10 part of synephrine,

1~10 part of isoliquiritin.

5. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome include count in parts by weight it is as follows Group is grouped as：

1~10 part of synephrine,

1~10 part of liquiritin.

6. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome include count in parts by weight it is as follows Group is grouped as：

1~10 part of synephrine,

1~10 part of aurantiin,

1~10 part of glycyrrhizic acid.

7. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome include count in parts by weight it is as follows Group is grouped as：

1~10 part of synephrine,

1~10 part of aurantiamarin,

1~10 part of glycyrrhizic acid.

8. the synephrine composition for the treatment of gastrointestinal dysfunction according to claim 1 or intestinal irritable syndrome, feature It is：The synephrine composition of the treatment gastrointestinal dysfunction or intestinal irritable syndrome further include synephrine extract with Associated extraction object, the associated extraction object be the extract of aurantiin, the extract of aurantiamarin, neohesperidin extract, The extract of isoliquiritin, the extract of liquiritin, glycyrrhizic acid one or more of extract combination.

9. the synephrine composition for the treatment of gastrointestinal dysfunction or intestinal irritable syndrome according to claims 1 to 8, special Sign is：All kinds of dosage forms are made using corresponding auxiliary material or technique in the synephrine composition, for Functional Gastrointestinal Disease or The treatment or health care of intestinal irritable syndrome.

10. synephrine composition the answering in Functional Gastrointestinal Disease or intestinal irritable syndrome treatment described in claim 1~8 With.