CN103271956A - Garcinia mangostana extractive, as well as preparation method and application thereof - Google Patents
Garcinia mangostana extractive, as well as preparation method and application thereof Download PDFInfo
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- CN103271956A CN103271956A CN2013102400786A CN201310240078A CN103271956A CN 103271956 A CN103271956 A CN 103271956A CN 2013102400786 A CN2013102400786 A CN 2013102400786A CN 201310240078 A CN201310240078 A CN 201310240078A CN 103271956 A CN103271956 A CN 103271956A
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Abstract
The invention relates to a garcinia mangostana extractive and an application thereof in immunosuppressant and medicine; the garcinia mangostana extractive provided by the invention is applied to immunosuppressant, and is an immunosuppressant with natural activity, the immunosuppressant effect of the garcinia mangostana extractive is slightly weaker than that of cyclosporin A, and is an immunosuppressant widely used at present, but the garcinia mangostana extractive has poisonousness which is lower than that of cyclosporin A in animal level, namely, the effect level of the garcinia mangostana extractive is far less than toxic level, and the garcinia mangostana extractive is an efficient and harmfulless immunosuppressant; and meanwhile, the molecular weight is small, the structure is simple, transformation and decoration are easy, and the garcinia mangostana extractive can be prepared to be different pharmaceutic preparations.
Description
Technical field
The present invention relates to a kind of Chinese medicine extract and in the application of immunosuppressant formulation art, particularly relate to a kind of Cortex Garciniae extract and preparation method thereof and the application in immunosuppressant and medicine.
Background technology
Cortex Garciniae is Guttiferae Garcinia plant, is used as medicine with bark (endothelium).Cortex Garciniae is a kind of as this local medicine of Southeast Asia, early be widely used in treating diarrhoea, malaria, antiinflammatory, antiulcer and leukemia and septicemia etc. in the traditional medicine of the countries such as Thailand, India, Burma, the multiple use such as also have obvious antiallergic and relieving asthma.But the effect of Cortex Garciniae extract aspect immunosuppressant rarely has report.
Immunosuppressant is the medicine that a class has immunosuppressive action, major function is applied to the treatment of the rear rejection of autoimmune disease and anaphylaxis and organ transplantation (after one's own heart, liver, kidney, lung and bone marrow transplantation etc.) for suppressing the abnormal immunoreation of body.Autoimmune disease is to cross strong or the persistent period is long so that the corresponding clinical symptoms of destroying self normal structure structure and causing due to autoimmune response; Anaphylaxis is that body antigen continue to stimulate or same antigen stimulates rear generation again, and a kind of disorderly and tissue injury is the pathologic immunoreation of main manifestations take physiological function; After clinical organ transfer operation, receptor's immune system can be identified graft antigen and produce and reply, and in graft, immunocyte also can be identified donee's tissue antigen and produce immunne response, and this is graft-rejection.These symptoms are all that the immunne response of body " inappropriate " causes, and immunosuppressant can play the effect for the treatment of to a certain extent, especially played pivotal role in the prevention of organ transplant rejection and treatment, be widely used clinically.
All immunosuppressant can be divided into following several at present: (1) anti-metabolism: azathioprine (Aza), methotrexate, mycophenolate (MMF) etc.; (2) alkylating agent: cyclophosphamide etc.; (3) Corticosterone class: prednisone, dexamethasone etc.; (4) antibiotics: CsA, FK506, rapamycin etc.; (5) antibody class: antilymphocyte globulin (ALG), monoclonal T lymphocyte antibody (OKT3) etc.; (6) Chinese herbal medicine: tripterygium glycosides, Cordyceps preparation etc.First three is planted as the immunosuppressant of having used clinically, though the curative effect of these medicines has been proved, can only improve symptom, can not effectively fundamentally control generation and the development of disease, and toxic and side effects is large, can not continue for a long time to use.The antibody class immunosuppressant can single-mindedly act on lymphocyte, but the while is expensive and bring serious untoward reaction, requires further improvement.Extract and seek the focus that cheap effectively immunosuppressant becomes transplanting educational circles and pharmaceutical industry from natural drug, this is mainly because compare with the chemical medicine immunosuppressant, the Chinese medicine immunosuppressant has following characteristics: (1) composition variation, pharmacological action is extensive and compound, except immunosuppressive action, also have the effects such as antiinflammatory, antiallergic and immune two-ways regulation; (2) little, the few side effects of toxicity, though the toxic side effect that has, decrement or drug withdrawal namely disappear; (3) share with other immunosuppressant, can improve curative effect, reduce latter's toxic and side effects.Therefore, use Chinese medicine immunosuppressant treatment immune disease, more and more be subjected to pharmacy work favor all.The present invention aims to provide a kind of Cortex Garciniae extract as the immunosuppressant of high-efficiency low-toxicity.
Summary of the invention
The objective of the invention is to propose neotype immunosuppressant---the Cortex Garciniae extract of the treatment of autoimmune diseases such as a kind of organ-graft refection of can be used for, rheumatoid arthritis, systemic lupus erythematosus (sle).
For achieving the above object, the invention provides a kind of preparation method of Cortex Garciniae extract, described preparation method comprises the following steps: pulverize (1): get the Cortex Garciniae bark, drying is pulverized; (2) percolation extracts: in the Cortex Garciniae of described pulverizing, adding weight portion is Cortex Garciniae consumption 10-20 65～85% ethanol doubly, carries out percolation and extracts; (3) extraction: with the ethanol extraction water dissolution in step (2), use successively respectively petroleum ether, ethyl acetate, n-butanol extraction; (4) silica gel column chromatography separates: the ethyl acetate in step (3) is partly gone up silica gel column chromatography, use petroleum ether: the acetone gradient elution, collect eluent; (5) recrystallization: with the eluent in step (4) with 85～98% ethyl alcohol recrystallization; (6) drying under reduced pressure: the crystal to step (5) carries out sucking filtration, and drying under reduced pressure namely obtains white Cortex Garciniae extract.
Preferably, in step (1), described Cortex Garciniae bark is crushed to 50～100 orders.
Further preferably, in step (6), the temperature of drying under reduced pressure is 50～80 ℃.
The second purpose of the present invention is for providing a kind of Cortex Garciniae extract, and described Cortex Garciniae extract is to extract via above-mentioned preparation method preparation to obtain.
The 3rd purpose of the present invention wherein contains above-mentioned Cortex Garciniae extract for a kind of immunosuppressant is provided.
The 4th purpose of the present invention is for providing a kind of pharmaceutical composition, and it contains pharmaceutically acceptable carrier, additive and/or excipient, and above-mentioned immunosuppressant.
The 5th purpose of the present invention is the above-mentioned application of Cortex Garciniae extract in the preparation immunosuppressant.
The 6th purpose of the present invention is the Cortex Garciniae extract for the preparation of the application in treatment autoimmunity medicine.
The 7th purpose of the present invention is the application in the rejection medicine after for the preparation for the treatment of anaphylaxis and organ transplantation of Cortex Garciniae extract.
The 8th purpose of the present invention is the Cortex Garciniae extract for the preparation of the application in treatment body function of immune system and the abnormal relevant disease medicament of reactive state.
Based on technique scheme, advantage of the present invention is:
The present invention adopts the percolation technology, make that in raw material, effective ingredient more fully and more easily is extracted, the silica gel column chromatography and the recrystallization that adopt of the present invention in addition, can access highly purified extract, whole technique has that product purity is high, yield is high, easy and simple to handle, for large-scale production provides the technique thinking.In addition, Cortex Garciniae extract of the present invention is a kind of immunosuppressant with natural activity, its immunosuppressive action and current widely used immunosuppressant---cyclosporin A slightly a little less than, but its toxicity on the animal level is lower than cyclosporin A, be its Dosages well below toxicity dose, be a kind of immunosuppressant of efficient, low toxicity; Its molecular weight is little, simple in structure simultaneously, is easy to transformation and modifies, and can make different pharmaceutical preparation.
Description of drawings
Accompanying drawing described herein is used to provide a further understanding of the present invention, consists of the application's a part, and illustrative examples of the present invention and explanation thereof are used for explaining the present invention, do not consist of improper restriction of the present invention.In the accompanying drawings:
Fig. 1 is non-specific lymphocytotoxicity test (LCT) data;
Fig. 2 is the T cell inhibitory effect effect that the Cortex Garciniae extract is induced Con A;
Fig. 3 is the proliferation function that the Cortex Garciniae extract suppresses unidirectional mixed lymphocytes;
Fig. 4 is the effect that the Cortex Garciniae extract suppresses the mice ear that DNFB brings out.
The specific embodiment
Below by drawings and Examples, technical scheme of the present invention is described in further detail.
Embodiment 1: the extraction purification of Cortex Garciniae extract
Take the Cortex Garciniae bark that dries, be crushed to the 50-100 order, with 75% ethanol percolation, obtain the Cortex Garciniae ethanol extract after concentrating under reduced pressure after pulverizing; The Cortex Garciniae ethanol extract is used petroleum ether, ethyl acetate, n-butanol extraction after with aqueous suspension successively, obtain respectively petroleum ether extractum, ethanol ethyl ester extractum, n-butyl alcohol extractum and aqueous extract.on ethyl acetate extract, silicagel column carries out chromatography, through petroleum ether: acetone (3: 1～1: 1) gradient elution, for example: 3: 1, 2: 1, 1: 1, petroleum ether wherein: the crystallization of separating out in acetone=1: 1 stream part, also use 95% alcohol flushing through sucking filtration, collect, 95% ethyl alcohol recrystallization, sucking filtration, 55 ℃ of drying under reduced pressure, the white powder that obtains is the Cortex Garciniae extract, the Cortex Garciniae extract of this white powder can directly be prepared into novel immunosuppressant, certainly, also can be according to the situation of materia medica and actual preparation, suitably add various existing auxiliary agents.
Cortex Garciniae extract of the present invention is asked for an interview following embodiment at the pharmacodynamics test of preparation neotype immunosuppressant and relative medicine application:
Embodiment 2: non-specific lymphocytotoxicity test (LCT)
The Balb/c mice is plucked the disconnected neck execution of eyeball blood-letting bacterium get spleen, make cell suspension with the RPMI1640 culture fluid.Then the medicine with each concentration of 100 μ l cell suspension, 100 μ l adds 96 orifice plates; Matched group adds the culture fluid that 100 μ l contain 15% serum, in 37 ℃, cultivates 68 hours under 5% carbon dioxide conditions.When finishing Deng cultivation, every hole adds 20 μ l CCK-8, continues to put into incubator and hatches.After 4 hours, microplate reader reads OD450.
Analyze experimental data as can be known: Cortex Garciniae extract of the present invention lymphocyte to normal mouse when high concentration has certain toxicity, just very weak to lymphocytic toxicity below the concentration of 20.76 μ M, and CsA has a strong impact on lymphocytic survival rate in concentration range, has very strong cytotoxicity (seeing Fig. 1), so Cortex Garciniae extract of the present invention is very low to lymphocytic toxicity in the finite concentration scope.
Embodiment 3: the Cortex Garciniae extract is to the lymphopoietic inhibitory action of Con A inducing mouse T
The Balb/c mice is plucked the disconnected neck execution of eyeball blood-letting bacterium and gets spleen, makes cell suspension with the RPMI1640 culture fluid.
Then the medicine of each concentration of 90 μ l cell suspension, 100 μ l and the ConA of 10 μ l are added 96 orifice plates; Matched group adds the culture fluid that 100 μ l contain 15% serum, in 37 ℃, cultivates under 5% carbon dioxide conditions 20,44 and 68 hours.When finishing Deng cultivation, every hole adds 20 μ lCCK-8, continues to put into incubator and hatches.After 4 hours, microplate reader reads OD450.
Analyze experimental data as can be known: the T cell proliferation that Cortex Garciniae extract of the present invention is induced Con A can play obvious inhibitory action (seeing Fig. 2), and inhibitory action and dosage have dependency relationships in time, be that dosage is higher, the time is longer, and inhibitory action is more obvious.
Embodiment 4: the inhibitory action of Cortex Garciniae extract subtend mixed lymphocyte reaction (MLR)
The Balb/c mice is plucked the disconnected neck execution of eyeball blood-letting bacterium and gets spleen, makes cell suspension with the RPMI1640 culture fluid.
Wherein inbred line C57BL mouse splenocyte organizine splits mould C processing, and as reacting cells, inbred line Balb/c mouse boosting cell is as irritation cell, and two kinds of cell suspension equal-volumes mix.Then add 100 μ l mixed cell suspensions in 96 well culture plates, drug solution 100 μ l, matched group adds 100 μ l and contains the culture fluid of 15% serum, and the single culture of establishing two kinds of cells is in contrast.In 37 ℃, cultivated under 5% carbon dioxide conditions 44,68 and 92 hours.When finishing Deng cultivation, every hole adds 20 μ l CCK-8, continues to put into incubator and hatches.After 4 hours, microplate reader reads OD450.
Analyze experimental data as can be known: Cortex Garciniae extract of the present invention can obviously suppress the proliferation function of unidirectional mixed lymphocytes, and inhibitory action and dosage has dependency relationships (seeing Fig. 3) in time, and namely dosage is higher, and the time is longer, and inhibitory action is more obvious.
Embodiment 5: the acute toxicity testing of Cortex Garciniae extract to mice
Mensuration with fixative.At first carry out prerun with 500mg/kg as predose, non-toxic reaction occurs.Formally test minutes 500, two groups of 2000mg/kg test.Each dosage is with 8 animals, male and female half and half.
Experimental result shows: at once observe after oral administration, having no mice has central excitation or suppresses symptom, having no muscular tension changes or the amyostasia symptom, the white mice activity freely, gait is normal, defecation is normal, hair color gloss, nose, eye, oral cavity are without abnormal secretions, and appetite is normal, none death of animal in 14 days.This explanation Cortex Garciniae extract of the present invention is without the poisoning danger of serious acute, and its toxicity on the animal level is low.
Embodiment 6: the inhibition of the delayed hypersensitive reaction that the Cortex Garciniae extract is induced DNFB (DTH)
Blab/c, cleaning level mice, adaptability was fed 3 days, test and scraped approximately 2 * 2cm2 of hair in mouse web portion on 1st, to be coated with mass concentration be 2%DNFB acetone soln 50ul sensitization in scraping a mao position for the 2nd day and the 3rd day, the 2nd day beginning oral administration, and matched group gives the CsA solution of equivalent.The 7th is that 2%DNFB acetone soln 10ul coats left ear and attacks with mass concentration, and auris dextra applied with acetone solution in contrast.Attacked 24h on 8th, and laid two ears with card punch after administration 1h, weigh.Calculate the ear swelling degree, i.e. the weight difference of left auricle and auris dextra sheet.
Analyze experimental data as can be known: Cortex Garciniae extract of the present invention can suppress the mice ear that DNFB brings out effectively.Along with the dosage raising of Cortex Garciniae extract of the present invention, suppress the effect better (seeing Fig. 4) of ear swelling.Inhibition when Cortex Garciniae extract of the present invention is 100mg/kg is suitable with CsA 40mg/kg effect.This explanation Cortex Garciniae extract of the present invention has certain inhibitory action to the mice delayed hypersensitive reaction that DNFB brings out.
Embodiment 7: the effect of Cortex Garciniae extract in the skin transplantation of mice allotype
Mouse skin transplantation experiments Blab/c cleaning level mice, adaptability was fed after seven days, lost hair or feathers at the back with sodium sulfide.After 2 days, for Mus intraperitoneal injection pentobarbital sodium 50mg/kg anesthesia, remove one of holostrome skin in its trunk with the clamp method, make the approximately skin graft of 1cm * 1cm.After being subjected to the anesthesia of Mus C57BL same method, back breast abdomen intersection, skin degerming cuts off one of holostrome skin with eye scissors with the clamp method, forms the approximately wound surface of 1cm * 1cm.The donor skin graft is affixed on is subjected to Mus wound surface place, after sewing up, wrap up with aseptic dressing in the art district, observes the survival of grafted skin situation.After skin graft operation finished 24 hours, successive administration was divided into Cortex Garciniae extract of the present invention, CsA positive controls and blank group.With skin grafts area 80% occur downright bad, turn black or time of turning white is repelled standard as skin graft, record the survival of grafted skin time.
Observe mice skin grafts growing state, and record experimental group and control group mice allograft survival of grafted skin time, preliminary experimental results such as table 1.
Table 1: the retarding action of Cortex Garciniae extract to allogeneic skin graft
Experimental result shows: Cortex Garciniae extract of the present invention can delay the Blab/c mice to the dermatoplastic rejection of allogeneic C57BL mouse, and this has shown that Cortex Garciniae extract of the present invention is hopeful to be applied to the clinical prevention organ transplant rejection.
Embodiment 8: the improvement effect of the mice rheumatoid joint that the Cortex Garciniae extract is induced the II Collagen Type VI
With the II Collagen Type VI of 2mg/ml acetate dissolution, not formula Freund's complete adjuvant, Freunds incomplete adjuvant be in the abundant mixing emulsifying of ratio of 2: 1: 1.Be to accelerate the collagen emulsifying rate and keep active, the solution that proportioning is good is placed in the eppendorf pipe, puts into the pin of twice of a doubling, and the eppendorf pipe is placed on magnetic stirring apparatus, stirs 20-30min in freezer.Pressing 0.1ml/ dosage only injects in DBA/1 mouse tail root.After initial immunity the 21st day, II Collagen Type VI and Freunds incomplete adjuvant in the emulsifying of 1: 1 ratio mixing, are carried out immunity again by 0.1ml/ dosage only to injected in mice, note avoiding the initial immunity position.Blank group injection equivalent normal saline.
After the immunity, second day begins to occur inflammation for the second time, the beginning administration.Be divided into Cortex Garciniae extract, CsA positive controls and blank group, successive administration 14 days.Self administration of medication begins, every scoring in 3-4 days once.By 5 grades of point system marking [8]." 0: without red and swollen; " 1 ": the red pneumonedema in joint; " 2 ": the joint is slightly red and swollen; " 3 ": the joint moderate is red and swollen; " 4 ": the red and swollen companion of joint severe dysfunction.The arthritis mark of every mice is the summation of 4 joint marks, and best result is 16 minutes.Each summation of organizing all mouse arthritis marks is the average arthritis mark of this group divided by this group mice number of elements.
Experimental result shows: Cortex Garciniae extract of the present invention can significantly reduce mice rheumatoid joint sickness rate and the clinical integration of arthritis that the II Collagen Type VI is induced, to the most significant inhibitory action that has of mice rheumatoid arthritis.This has shown that Cortex Garciniae extract of the present invention is hopeful to be applied to clinical prevention and treatment autoimmune disease.
Should be noted that at last: above embodiment is only in order to illustrate that technical scheme of the present invention is not intended to limit; Although with reference to preferred embodiment, the present invention is had been described in detail, those of ordinary skill in the field are to be understood that: still can modify or the part technical characterictic is equal to replacement the specific embodiment of the present invention; And not breaking away from the spirit of technical solution of the present invention, it all should be encompassed in the middle of the technical scheme scope that the present invention asks for protection.
Claims (10)
1. the preparation method of a Cortex Garciniae extract, it is characterized in that: described preparation method comprises the following steps:
(1) pulverize: get the Cortex Garciniae bark, drying is pulverized;
(2) percolation extracts: in the Cortex Garciniae of described pulverizing, adding weight portion is Cortex Garciniae consumption 10-20 65～85% ethanol doubly, carries out percolation and extracts;
(3) extraction: with the ethanol extraction water dissolution in step (2), use successively respectively petroleum ether, ethyl acetate, n-butanol extraction;
(4) silica gel column chromatography separates: the ethyl acetate in step (3) is partly gone up silica gel column chromatography, use petroleum ether: the acetone gradient elution, collect eluent;
(5) recrystallization: with the eluent in step (4) with 85～98% ethyl alcohol recrystallization;
(6) drying under reduced pressure: the crystal to step (5) carries out sucking filtration, and drying under reduced pressure namely obtains white Cortex Garciniae extract.
2. preparation method according to claim 1, is characterized in that: in described step (1), described Cortex Garciniae bark is crushed to 50～100 orders.
3. preparation method according to claim 1, it is characterized in that: in described step (6), the temperature of drying under reduced pressure is 50～80 ℃.
4. Cortex Garciniae extract is characterized in that: described Cortex Garciniae extract is to extract via the described preparation method preparation of above-mentioned any one claim to obtain.
5. an immunosuppressant, wherein contain Cortex Garciniae extract claimed in claim 4.
6. pharmaceutical composition, it is characterized in that: it contains pharmaceutically acceptable carrier, additive and/or excipient, and immunosuppressant claimed in claim 4.
7. the application of Cortex Garciniae extract claimed in claim 4 in the preparation immunosuppressant.
8. the Cortex Garciniae extract is for the preparation of the application in treatment autoimmunity medicine.
9. Cortex Garciniae extract application in the rejection medicine after for the preparation for the treatment of anaphylaxis and organ transplantation.
10. the application of Cortex Garciniae extract in the abnormal relevant disease medicament for the preparation for the treatment of body function of immune system and reactive state.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017016428A1 (en) * | 2015-07-24 | 2017-02-02 | 山酮新药开发股份有限公司 | Use of mangosteen rind extract in preparation of medicine for treating skin diseases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011106417A2 (en) * | 2010-02-23 | 2011-09-01 | Tahitian Noni International, Inc. | Garcinia mangostana l. and iridoid based formulations |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011106417A2 (en) * | 2010-02-23 | 2011-09-01 | Tahitian Noni International, Inc. | Garcinia mangostana l. and iridoid based formulations |
Non-Patent Citations (1)
| Title |
|---|
| JUREN CEN ET AL.: "Isogarcinol Is a New Immunosuppressant", 《PLOS ONE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017016428A1 (en) * | 2015-07-24 | 2017-02-02 | 山酮新药开发股份有限公司 | Use of mangosteen rind extract in preparation of medicine for treating skin diseases |
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Application publication date: 20130904 |