CN100366264C - Cornel extract and use thereof - Google Patents
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- CN100366264C CN100366264C CNB031457746A CN03145774A CN100366264C CN 100366264 C CN100366264 C CN 100366264C CN B031457746 A CNB031457746 A CN B031457746A CN 03145774 A CN03145774 A CN 03145774A CN 100366264 C CN100366264 C CN 100366264C
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Abstract
The present invention relates to cornel extract, active components (loganin, morroniside and cornin) thereof and an application of the active components for preparing medicine for curing pain, autoimmune diseases or inflammation.
Description
Technical field
The present invention relates to a kind of plant extract, especially relate to a kind of Fructus Corni extract, its active ingredient and their purposes in the medicine of preparation treatment pain, autoimmune disease or inflammation.
Background technology
In daily life, pain is a kind of common disease.According to statistics, in the 35-50 adult in year, have about 55% can be perplexed by various slight illness, as headache, pain in the shoulder and back, waist leg joint pain, soft tissue pain, sciatica etc., and some disease such as tumor also can be interimly in its course of disease evolution with in various degree pain, its intractable and multiple work and the life that has had a strong impact on the patient.
Studies confirm that the normal immunoloregulation function of healthy individual can be coordinated autoimmune tolerance and autoimmune on a complementary reasonable level.When certain reason makes autoimmune response undue strong, just can cause the damage or the dysfunction of corresponding autologous tissue organ, this pathological state just be called " autoimmune disease " (autoimmune disease, AID).Common " autoimmune disease " by the hyperfunction initiation of immunologic function comprises systemic lupus erythematosus (sle), rheumatoid arthritis, atrophic gastritis, myasthenia gravis etc.In addition, similar pathological change also can take place in body in processes such as organ transplantation, bone marrow transplantation.
Regulate the process of the immunne response of patient's body by immunosuppressant, and then the purpose that reaches treatment is a kind of main treatment means of the hyperfunction disease of immunologic function with the blocking-up disease.Immunosuppressant commonly used comprises alkylating agent (chlormethine, cyclophosphamide), antimetabolite (azathioprine, methotrexate), hormone, fungus metabolite (ciclosporin A) etc.
To be body cause the reaction based on defence that damage took place that inflammatory factor causes to various to inflammation, and the topical manifestations of inflammation is red, swollen, hot, pain and dysfunction.Comparatively obvious when these show acute body surface inflammation, how not obvious the inflammation and the chronic inflammatory disease of internal organs be then.It is local that inflammation not only shows, and often cause general reaction.Common general reaction has the leukocyte number in heating, the blood to increase and degeneration in various degree of parenchymatous organ such as heart, liver, kidney, necrosis etc.
By pathological classification, inflammation can be divided into alterative inflammation, exudative inflammation (comprising serous inflammation, fibrinous inflammation, purulent inflammation, hemorrhagic inflammation and catarrhal inflammation), productive inflammation (general productive inflammation and chronic granuloma inflammation) etc.
Meliatin is the iridoid glycoside compounds, be present in Fructus Corni Cornus officinalicSieb.et Zucc (Li et al., Daozong.Shipin Gongye Keji (2002), 23 (10), 45-47.), Flos Hydrangeae Macrophyllae Hydrangea hortensis (Khalifa et al., Journal ofPharmaceutical Sciences (2001), 28221-229.), Semen Strychni Strychnoscathayensis (Cheng et al., Journal of the Chinese Chemical Society (Taipei, Taiwan) (2001), 48 (2), 235-239) wait in the plant.According to the literature, meliatin has very strong anti-inflammatory activity (Maria del Carmen Recio et al Structural Considerations onthe Iridoids as Anti-inflammatory Agents Planta Med.60 (1994) 232-234).Its structural formula is as follows:
Molecular formula: C
17H
26O
10, molecular weight: 390.39Da, fusing point 221-222 ℃
Morroniside is a kind of iridoid glycoside compounds, is present in Fructus Corni (Endo et al., Yakugaku Zasshi (1973), 93 (1), 30-2.), Radix Ophiopogonis Lonicera morrowii (Ikeshiroet al., Planta Medica (1992), 58 (1), 109.) etc. in the plant.Its structural formula is as follows:
Molecular formula C
17H
26O
11, molecular weight 406.39Da
Cornin is a kind of iridoid glycoside compounds, be present in the plants such as Fructus Corni (Hatano, et al., Phytochemistry (1990), 29 (9), 2975-8.).Its structural formula is as follows:
Molecular formula C
24H
30O
14, molecular weight 542.49Da
Fructus Corni (Cornus Officinalis Sieb et Zu cc) is a kind of Chinese medicine of flat nourishing YIN sun, has liver and kidney tonifying, the astringent or styptic treatment for spontaneous sweating effect of convergence.In recent years, Chinese scholars has been carried out many-sided research to Fructus Corni, because its isolated active ingredient difference, so also different to the pharmacologically active report of Fructus Corni effective ingredient.
Chinese patent Granted publication CN1053371C discloses a kind of Fructus Corni extract, this extract can suppress significantly that mouse lymphocyte transforms, the LAK cell generates and suppress the mouse monokaryon macrophage system to Congo red clean up, suppress rat, mice foot swelling etc. due to the carrageenin, have significant immunosuppressive action and antiinflammatory action.
Above-mentioned Chinese patent also discloses the extracting method of this extract.The inventor is through experiment confirm, and the content of polyphenol is lower than 50% in Zhi Bei the Fructus Corni extract as stated above.In addition, the composition and the proportioning of the unexposed Fructus Corni extract of this patent.
Summary of the invention
The present invention relates to a kind of Fructus Corni extract.This extract comprises meliatin, 5-25% morroniside and the 0.5-5% cornin of 5-20% weight ratio.Particularly, this extract can comprise meliatin, 17.5% morroniside and 2% cornin of 10% weight ratio.This extract comprises the polyphenol of at least 50% weight ratio.
The present invention also provides a kind of pharmaceutical composition that comprises at least two kinds of compositions that are selected from meliatin, morroniside and cornin, and wherein at least a composition is isolating.
The present invention also provides a kind of pharmaceutical composition that contains separative morroniside and pharmaceutically suitable carrier.
The present invention also provides a kind of pharmaceutical composition that contains separative cornin and pharmaceutically suitable carrier.
The invention still further relates to above-mentioned Fructus Corni extract, the purposes of pharmaceutical composition in the medicine of preparation treatment pain, autoimmune disease or inflammation.
The invention still further relates to above-mentioned Fructus Corni extract, preparation of drug combination method.
The details of various aspects of the present invention will be able to detailed description in chapters and sections subsequently.By hereinafter and the description of claim, other characteristics of the present invention, purpose and advantage will be more obvious.
The part of coming out of the present invention is based on so unexpected discovery: meliatin, morroniside, cornin be present in specific proportioning have pain relieving, in the Fructus Corni extract of immunosuppressant and anti-inflammatory activity.Therefore, Fructus Corni extract and active ingredient thereof (separately or with combining form) can be used for treating pain, autoimmune disease or inflammation.
Fructus Corni extract of the present invention contains the meliatin of 5-20% (as 10%) weight ratio, the morroniside of 5-25% (as 17.5%), the cornin of 0.5-5% (as 2%).This extract can also can prepare by other similar approach by the method preparation of embodiment 1.In brief, Fructus Corni is decocted with water, after the filtration with decocting liquid by purification column, the ethanol of water, 10% ethanol and 80-95% eluting resin column is successively collected eluent again, behind the vacuum drying, obtains Fructus Corni extract.The content of polyphenol is measured through hide powder method in this extract, is at least 50% (weight ratio, promptly the arbitrary integer percentage ratio between the 50%-100% comprises 50% and 100%).Hide powder method is the standard method of analysis polyphenol content of " Pharmacopoeia of People's Republic of China version in 2000 " approval, comprises that the material that will contain polyphenol earlier is water-soluble, with measuring polyphenol content in the solution by gravimetry again after the corium farinosum absorbent solution.
In addition, the inventor uses cornin pretreatment human peripheral blood mononuclear cell (PBMC) earlier, and (Calbiochem, San Diego CA) stimulate these cells to use LPS from Salmonella ryphimurium; Use subsequently the TNF-alpha.ELISA test kit (Bender Medsytems, Vienna, Austria) and IL-1beta ELISA test kit (Jingmei Biotech, Shanghai, China). measure the content of TNF-alpha and IL-1beta in the cell respectively; Analyze mRNA or the expressing quantity of TNF-alpha and IL-1beta at last with RT-PCR.The result finds that unexpectedly cornin can significantly suppress the expression of TNF-alpha and two kinds of inflammatory factors of IL-1beta.
Because meliatin, morroniside, cornin three's biological activity difference so can adjust the ratio of three in the Fructus Corni extract as required, adds isolating (comprising chemosynthesis) composition as further purification or in extract.In addition, can also in proportion two or three isolating composition be mixed, be mixed with the pharmaceutical composition of specific proportioning.The proportioning of this extract or compositions has potentiation, thereby makes it have better antiinflammatory, immunosuppressant or analgesic activities than its composition.
Term " isolating " is meant a kind of state, and the chemical compound that is in this state has higher purity than its naturalness (state when being present in nature).Specifically, it (is the arbitrary integer percentage ratio between the 21%-100% that its dry weight purity of isolating meliatin is at least 21%, comprise 21% and 100%), it (is the arbitrary integer percentage ratio between the 26%-100% that its dry weight purity of isolating morroniside is at least 26%, comprise 26% and 100%), its dry weight purity of isolating cornin is at least 6% (be the arbitrary integer percentage ratio between the 6%-100%, comprise 6% and 100%).The purity of chemical compound can detect by some standard methods, analyzes as column chromatography or HPLC.
Particularly, in Fructus Corni extract or its active ingredient, can add pharmaceutically suitable carrier to promote its administration.Preferable, pharmaceutical composition of the present invention contains extract or its active ingredient of 0.1-99.9% weight ratio." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of Fructus Corni extract or its active ingredient, its effective dose simultaneously, and promptly can playing pharmaceutical carrier, to make the consumption of time spent nontoxic to human body.
" pharmaceutically suitable carrier " includes but not limited to: ion exchange material, aluminium oxide, aluminium stearate, lecithin, self-emulsifying drug delivery system (SEDDS) is as d-alpha-vitamin E polyethylene glycol 1000 succinates, the surfactant that pharmaceutical preparatioies such as tween (Tweens) or other similar polymerisation mediums are used, serum albumin such as human serum albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glycerol ester admixture, water, salt, electrolyte such as sulfate protamine, phosphoric acid hydrogen two is received, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate etc.Polyvidon, cellulosic material, polyvinyl alcohol, sodium carboxymethyl cellulose, polypropylene acid esters, ethylene-polyoxyethylene-block polymer and wool grease, cyclodextrin such as alpha-, beta-and gama-cyclodextrin or its drug delivery that all can be used for promoting Fructus Corni extract of the present invention or its active ingredient through derivant such as hydroxyalkyl cyclodextrin such as 2-and 3-hydroxypropyl-beta-cyclodextrin or other soluble derivatives etc. of chemical modification.
Other pharmaceutically acceptable auxiliaries such as filler (as Lactis Anhydrous, starch, lactose beadlet and glucose), binding agent (as microcrystalline Cellulose), disintegrating agent (as crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and cross-linked pvp), lubricant (as magnesium stearate), absorption enhancer, flavouring agent, sweeting agent, diluent, excipient, wetting agent, solvent, solubilizing agent and coloring agent etc. also can add in the pharmaceutical composition of the present invention.
Above-mentioned Fructus Corni extract, its active ingredient and pharmaceutical composition can pass through intestinal or parenteral route administration.The intestinal canal administration preparation comprises pill, granule, capsule, suspension or solution.Non-intestinal drug delivery agent comprises injection, cream, unguentum, patch or spray.That the parenterai administration approach comprises is subcutaneous, in the Intradermal, tremulous pulse, vein, muscle, joint, synovial fluid, breastbone, sheath, intralesional, intracranial injection or instillation.Other route of administration can comprise part, rectum, per nasal, through cheek, vagina, Sublingual, mucosa, trachea or urethra.Fructus Corni extract, its active ingredient and pharmaceutical composition can also suck or implant by aerosol to be accumulated or mode administration such as acupuncture.
The oral formulations of Fructus Corni extract, its active ingredient and pharmaceutical composition includes but not limited to capsule, tablet, Emulsion, aqueous suspension agent, colloidal solution, solution, microcapsule, pill, lozenge, granule, powder.The pharmaceutically suitable carrier that is usually used in tablet comprises lactose and corn starch.Usually also can add lubricants such as magnesium stearate.The pharmaceutically suitable carrier that is usually used in capsule comprises lactose and dried corn starch.When making oral aqueous suspension agent and/or Emulsion, Fructus Corni extract or its active ingredient can suspend or be dissolved in the oil phase and with emulsifying agent or suspending agent and combine.If desired, also can add some sweeting agents and/or flavouring agent and/or toner.
Discover that the acid pH of Fructus Corni extract (pH2-3) can cause gastrointestinal upset (as pain, feel sick, vomiting etc.).If alkaline matter and Fructus Corni extract or its active ingredient administration together then can be alleviated above-mentioned discomfort.Term " administration together " be meant alkaline matter can be before Fructus Corni extract or its active ingredient administration, afterwards or with Fructus Corni extract or the administration simultaneously of its active ingredient; Fructus Corni extract or its active ingredient and alkaline matter can be respectively with the unitary agent administrations or with the mixture form administration.
Need to select suitable alkaline matter to avoid weakening original pharmaceutical active of Fructus Corni extract or its active ingredient because of the adding alkaline matter.Suitable alkaline matter comprises that bicarbonate is (as sodium bicarbonate or potassium bicarbonate, preferred sodium bicarbonate), carbonate is (as sodium carbonate or calcium carbonate, preferred sodium carbonate), hydroxide or basic amino acid (as arginine, lysine or histidine, preferred lysine).The consumption of alkaline matter should be enough to alleviate the gastrointestinal upset that Fructus Corni extract or its active ingredient cause, for example can be according to treatment target stomach discomfort, pain after the medication, feel sick, the variation of symptom such as vomiting adjusts its consumption.When alkaline matter and Fructus Corni extract or its active ingredient during respectively with the unitary agent administration, both usage ratio can according to age of administration object, body weight with and the order of severity of gastrointestinal irritation symptom do corresponding adjustment.When alkaline matter and Fructus Corni extract or its active ingredient during with the mixture form administration, the pH value of mixture can be transferred to 4～10, preferred 6～8, most preferably be 7.The method for preparing mixture is that Fructus Corni extract or its active ingredient and pharmaceutically suitable carrier is water-soluble, adds alkaline matter, and pH value is transferred to 4～10.If desired, also can be with the solution drying.In addition, also Fructus Corni extract or its active ingredient, pharmaceutically suitable carrier and alkaline matter can be pressed the directly mixed pH value appropriate drug compositions that gets of specific consumption proportion.
In addition, Fructus Corni extract or its active ingredient (containing or do not contain alkaline matter) can be wrapped in the enteric layer so that it is insoluble to tart gastric juice and is dissolved in small intestinal, to reduce gastrointestinal irritation.Described enteric layer includes but not limited to enteric hard capsule, enteric coating, enteric microencapsulation or enteric complex capsule.Can be primary raw material with the hydroxy alkyl cellulose phthalate ester, add plasticizer, surfactant and pigment; Or by hydroxypropyl cellulose, polyvinyl ester acid esters, cellulose acetate, phthalic acid ester adding plasticizer and antioxidant; Or make enteric layer by O-phthalic cellulose acetate and acetone material etc.
Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition can be made into aseptic injection, as aseptic water or oil phase suspension.This suspension can promptly use suitable dispersant or wetting agent (as Tween 80) and suspending agent etc. to make by the conventional method of this area.But it can also be at the nontoxic diluent of intestinal external administration or aqueous solution or the suspension in the solvent, as the solution in 1,3 butylene glycol.Relevant available support or solvent comprise mannitol, water, ringer's solution, isotonic sodium chloride etc.In addition, aseptic fixedly oil often is used as the media of solvent or suspending agent, thereby comprises that the multiple soft fixedly oil (bland fixedoil) of synthetic glycerine monoesters or diglyceride all is suitable for.Fatty acid can be used for preparing described injection as octadecenic acid and glyceride ester derivatives thereof (as olive oil or Oleum Ricini, particularly its polyoxyethylene radical derivative) etc.Described oil solution or suspension also can comprise a kind of ethanol dilution agent of long-chain or dispersant or carboxymethyl cellulose or similar other dispersants, and this type of material is usually used in preparing pharmaceutical acceptable emulsion and/or suspending agent.Surfactant that some other preparation is commonly used such as Tweens or Spans and/or other similar emulsifying agents or bioavailability promoter etc. can be used for preparing this preparation too.
Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition can be made into suppository and pass through rectally, method is that Fructus Corni extract or its active ingredient are mixed with the non-irritating excipient that suits, the latter is liquid under rectal temperature for solid at room temperature, thereby this suppository can melt in rectum and discharges active ingredient.This type of excipient includes but not limited to: cupu oil, Cera Flava and polyethylene.The local administration preparation (as ointment) of Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition can be directly used in the affected part.This type of topical formulations contains active ingredient and pharmaceutically suitable carrier, and the latter includes but not limited to mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene or the polyoxy third desaturation compound, emulsifying is cured or water.In addition, pharmaceutical composition of the present invention also can be made into lotion or oil preparation.The carrier that is suitable for includes but not limited to: mineral oil, sorbic alcohol monostearate, polysorbate60, spermaceti ester, hexadecanol, 2-octadecanol, benzyl ethanol or water.Fructus Corni extract of the present invention or its active ingredient also can be made into enema etc. and are used for the rectum topical.The topical transdermal patch is also within protection scope of the present invention.But Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition be per nasal spraying or inhalation also, promptly, use benzyl ethanol or other antiseptic, absorption enhancer, fluorocarbon and/or other solubilizing agents or dispersant to make saline solution by the conventional method of this area.
Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition also can pass through drug delivery implant.Adopt the drug delivery implant mode can reach in the administration subject and continue, regularly discharge the effect of Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition.In addition, drug delivery implant can also be at local organization and organ site-specific delivery of drugs (Negrin et al., Biomaterials 22 (6): 563,2001) regularly release tech also can be used in the administration of Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition, as delayed release capsule, slow release method and the preparation technique for packing (as polymer and liposome) etc. based on the polymer technology.
Patch comprises within the scope of the present invention equally.It comprises basic unit's (as polymer, cloth, yarn and binder) and pharmaceutical composition of the present invention.One side of basic unit can be provided with a protective layer to prevent the outflow of active ingredient.Described patch also can contain a binding agent that is used for fixing, and the latter can be a kind of natural or synthetic material, can temporarily adhere on the skin when it contacts with the administration subject's skin.Binding agent can be a waterproof.
When Fructus Corni extract of the present invention, its active ingredient, pharmaceutical composition and preparation can mix with one or more additional medicines or prophylactic agent.Additional medicaments can be used as independently dosage form and the administration respectively of Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition.Additional medicaments also can with Fructus Corni extract of the present invention, its active ingredient and pharmaceutical composition together with single dosage form administration.
The present invention also provides a kind of method for the treatment of pain, autoimmune disease and inflammation, comprises the Fructus Corni extract of the present invention, its active ingredient and the pharmaceutical composition that give treatment target treatment effective dose.Other Fructus Corni extract also can be used for treating pain.Described treatment target can be those objects that need give pain, autoimmune disease, inflammation treatment.Whether need this treatment can be based on the judgement of this object oneself, also can be based on the judgement of health care professional, described judgement, also can be objectively (as check or check) if can be subjective (as individual viewpoint).Term " treatment " is meant for curing, alleviate, alleviate, remedy, prevent, improve symptom that certain dysfunction, dysfunction show, be secondary to the morbid state of dysfunction or the purpose of the tendency of dysfunction taking place, gives the behavior of a certain material of a certain object." treatment effective dose " is meant that the consumption of described therapeutant is enough to produce the medical effect of above-mentioned expection in being controlled subject.Judgement to this medical effect can be objective (as testing), also can be subjective (as the main suit according to the administration object).
Described pain includes but not limited to: constitutional hyperpathia, Secondary cases hyperpathia, facial muscle pain (myofascial pain), intractable facial muscle pain (intractable myofascial pain), headache, backache, cervicodynia, treatment of traumatic pain, inflammatory pain, ulcer pain, internal organs Crampy Pain, neuropathic pain, susceptibility pain (nociceptive pain), myalgia, bone joint pain or tumprigenicity pain.
Described autoimmune disease includes but not limited to: chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus (IDDM), myasthenia gravis, chronic ulcerative colitis, pernicious anemia companion chronic atrophic gastritis, goodpasture syndrome, it cooks skin ulcer, class sky kitchen skin ulcer, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, systemic lupus erythematosus (sle), mouth xerophthalmia scheorma syndrome, scleroderma, polyarteritis nodosa, the Wegener granulomatosis, rheumatoid arthritis, nephritis, the nephrotic syndrome, organ transplantation, bone marrow transplantation, drug eruption, urticaria, the vegetable solar dermatitis, anaphylactic shock or asthma etc.
Described inflammation includes but not limited to: alterative inflammation, serous inflammation, fibrinous inflammation, purulent inflammation, hemorrhagic inflammation, catarrhal inflammation, productive inflammation or chronic granuloma inflammation.
The Fructus Corni extract of treatment effective dose or its active ingredient are between 1～300mg/kg/d.Any consumption within above-mentioned scope is all effective dose of the present invention, wherein than low dosage between 1mg/kg/d and 299.999mg/kg/d, higher dosage is between 2mg/kg/d and 300mg/kg/d.Described " treatment effective dose " can be used for the single drug or the drug combination treatment of pain, autoimmune disease or inflammation.One of skill in the art is appreciated that the consumption when actual administration can be higher or lower than above-mentioned dosage range.All multifactor impacts be can be subjected at " the treatment effective dose " of a certain object (as mammal-people) and concrete therapeutic scheme, age, body weight, ordinary circumstance, sex, diet, administration time, disease susceptibility, the disease process of drug activity, administration object of used Fructus Corni extract or its active ingredient and the judgement etc. of accepting the doctor for medical treatment comprised.
For the ease of understanding the present invention, the spy enumerates following examples.Its effect should be understood that it is to annotation of the present invention but not to the restriction of any way of the present invention.Each above listed list of references is all introduced the present invention as a reference in full.
Description of drawings
Fig. 1 Fructus Corni extract HPLC of the present invention chromatogram;
The inhibition specific activity that Fig. 2 is of the present invention to have the Fructus Corni extract of specific proportioning components and a cornin pair cell TNF secretion a;
The inhibition specific activity that Fig. 3 is of the present invention to have the Fructus Corni extract of specific proportioning components and a cornin pair cell secretion IL1-beta;
The specific embodiment
Embodiment 1 preparation Fructus Corni extract is also measured wherein polyphenol content with hide powder method
Fructus Corni 500g adds water 5000mL, decocts 3 times, decocts with little degree of being that boils, and each decocting time is 2 hours, and decoction liquor is filtered, and merges stand for standby use; Get the D101 macroporous adsorbent resin, in 1: 2 ratio of crude drug weight ratio dress post, then with above-mentioned decocting liquid with the flow velocity of 20 ml/min by this macroporous adsorptive resins, after passing through fully, water, 10% ethanol and 95% ethanol-eluting resin column again.Collect eluent, behind the vacuum drying, obtain Fructus Corni extract 48g.
Get above-mentioned Fructus Corni extract 2.0076g (W), be dissolved in the 500mL water, get 25mL solution, it is concentrated into dried, then in 105 ℃ of dryings 3 hours, solid product, its weight is T
1=0.0966g.
Other gets above-mentioned solution 100mL, adds 6g corium farinosum (purchasing in Shanghai chemical reagents corporation), vibrates 15 minutes.The elimination corium farinosum is got 25mL filtrate, it is concentrated into dried, then in 105 ℃ of dryings 3 hours, solid product, its weight is T
2=0.0561g.
The 6g corium farinosum is added in the 100mL distilled water, vibrated 15 minutes.The elimination corium farinosum is got 25mL filtrate, it is concentrated into dried, then in 105 ℃ of dryings 3 hours, solid product, its weight is T
0=0.0155g.
(T by formula
1-T
2+ T
0The polyphenol content that) * 20/W * 100% calculates in the Fructus Corni extract to be measured is 55.3%.
The separation and the evaluation of three kinds of active ingredients of embodiment 2 Fructus Corni
The separation of meliatin and evaluation:
Can be with 500mL 95% soak with ethanol three times of 100g Fructus Corni, merge extractive liquid, gets the 10g concentrate.Concentrate is used petroleum ether, chloroform, methanol-eluted fractions successively through the decompression column chromatography.After meoh eluate concentrates, again through silica gel column chromatography (eluant CH
2CL
2/ CH
3OH=6: 4), get meliatin 875mg, its Rf value=0.57 (developing solvent: 0.1M KH
2PO
4: 0.1MH
3PO
4: CH
3CN=7: 7: 4).Its spectroscopic data is:
[α]
D 25＝-81°(c 0.1，H
2O)，UV(λ
max，nm)238(4.0)；IR：(cm
-1，KBr)：3350，3300，1715，1650，1440，1300，1080；
1H NMR(D
2O，300MHz)δppm：7.42(s，H-3)，5.39(d，J＝3.6Hz，H-1)，4.14(m，H-7)，3.73(s，OCH3)，3.05(m，H-5)，2.16(m，H-6a)，2.10(m，H-9)，1.88(m，H-8)，1.73(m，H-6b)，1.06(d，J＝6.9Hz，H-10)，4.78(d，J＝7.8Hz，H-1’)，3.90(d，J＝10.8，H-6a’)，3.50(m，H-6b’)，3.36-3.47(m，H-3-H5’)，3.28(t，J＝8Hz，H-2’).
13C NMR(D
2O，75MHz)δppm：170.3(C-11)，151.2(C-3)，113.3(C-4)，96.9(C-1)，74.6(C-7)，52.0(C-12)，45.2(C-9)，40.6(C-6)，40.4(C-8)，30.1(C-5)，12.3(C-10)，98.9(C-1’)，76.6(C-5’)，76.0(C-3’)，73.0(C-2’)，69.9(C-4’)，61.0(C-6’).
The separation of morroniside and evaluation:
Can be with 500mL 95% soak with ethanol three times of 100g Fructus Corni, merge extractive liquid, gets the 10g concentrate.Concentrate is used petroleum ether, chloroform, methanol-eluted fractions successively through the decompression column chromatography.Meoh eluate is through LH-20 chromatography (eluant CH
3OH/CH
3COCH
3/ H
2O=7: 2: 1), at last again through silica gel column chromatography (eluant CH
2CL
2/ CH
3OH=6: 4), get morroniside 875mg, its Rf value=0.68 (developing solvent is the same).Concentrate is through silica gel column chromatography repeatedly, morroniside 643mg.
Its spectroscopic data is:
[α]
D 25＝-70°(c 1，EtOH)，UV(λ
max，nm)238(4.0)；IR：(cm
-1，KBr)：3350，3300，1710，1650，1080；
1H NMR(D
2O，300MHz)δppm：7.57(s，H-3)，5.90(D，J＝9.3Hz)，H-1)，4.99(d，J＝1.0Hz，H-7)，4.91(d，J＝7.8Hz，H-1’)，4.36(m，H-8)，3.93(dd，J＝2.0，12.4Hz，H-6’a)，3.3-3.8(m，H-2’，3’，4’，5’，6’b)，3.0(dt，J＝12.8，4.6Hz，H-5)，2.05(m，H-6b)，1.90(m，H-6b)，1.85*m，H-9)，1.38(d，J＝3.8Hz，CH3)，3.74(s，OCH3).
The separation of cornin and evaluation:
Can be with 500mL 95% soak with ethanol three times of 100g Fructus Corni, merge extractive liquid, gets the 10g concentrate.Concentrate is used petroleum ether, chloroform, methanol-eluted fractions successively through through the decompression column chromatography.Meoh eluate gets cornin 23mg, its Rf value=0.3 (developing solvent is the same) through reversed-phase silica gel chromatography.Its spectroscopic data is:
[α]
D＝-90°(c 1.0，CH
3OH)；UV(λ
max，nm)275(4.0)；IR(cm
-1，KBr)：3350，2980，1720，1640，1600，1400，1020
1H NMR(acetone-d
6+D
2O，300MHz)δppm：7.43(s，H-3)，7.04(d，J＝2.1Hz，H-2’，H-6’)，5.73(ddd，J＝9.0，11.5，17.7Hz，H-8)，5.40(d，J＝6.6Hz，H-1)，5.25(dd，J＝11.4，17.4Hz，H-10)，4.72(d，J＝7.8Hz，H-1”)，4.12(m，H-7)，3.82(dd，J＝1.8，12.3Hz，H-6”a)，3.61(dd，J＝5.4，12.0，H-6”b)，3.50(s，OCH
3)，3.20-3.42(m，H-2”，3”，4”，5”)，2.86(m，H-5)，2.634(m，H-9)，1.90(m，H-6).
13C NMR(acetone-d
6+D
2O，75MHz)δppm：168.6(C-11)，167.5(C-7’)，153.1(C-8)，145.7(C-3)，134.8(C-2’，6’)，121.0(C-3’，4’，5’)，119.7(C-1’)，110.7(C-4)，109.7(C-10)，99.5(C-1”)，97.2(C-1)，77.3(C-5”)，76.8(C-3”)，73.6(C-2”)，70.5(C-4”)，63.7(C-7)，61.8(C-6”)，51.7(OCH3)，44.3(C-9)，30.7(C-6)，30.4(C-5).
Embodiment 3 Fructus Corni extract HPLC chromatogram and quantitative analyses
With the HPLC system Fructus Corni extract (embodiment 1) is carried out quantitative analysis.Instrument: Agilent 1100, the setting wavelength is 240nm, and analytical column is Zorbax SC184.6*150mm, and flow velocity is 1ml/ minute.Mobile phase is CH
3CN and 0.1% H
3PO
4Solution.The gradient situation is: CH
3CN was incremented to 25% from 0% in 50 minutes.In subsequently 5 minutes, CH
3CN is incremented to 100%.Get HPLC collection of illustrative plates shown in the accompanying drawing 1.
Meliatin, morroniside, all separation and purification in this laboratory of the reference substance of cornin.Analyze through HPLC, purity is all more than 96%.
Record Fructus Corni extract of the present invention (embodiment 1) and contain meliatin 9.7% (retention time 20.4 minutes), morroniside 17.5% (retention time 26.5 minutes), cornin 2.6% (retention time 41.9 minutes).
Embodiment 4 analgesia pharmacodynamic experiments
The acetic acid twisting experiment
Experiment material
1. animal: the NIH mice, female, body weight 18～22g is provided by the Beijing Biological Product Inst., Ministry of Public Health
2. be subjected to the reagent thing: Fructus Corni extract (pressing the preparation of embodiment 1 method), behind dissolved in distilled water, transfer pH7.2 with sodium bicarbonate
3. positive control drug: ibuprofen, tablet, specification 0.1g/ sheet, people's consumption per day are 1.2g, are produced lot number: 9808020 by Dongling Pharmaceutical Co., Ltd., Shenyang
4. reagent: 0.6% acetic acid (HOAc) normal saline solution (100% glacial acetic acid 0.3ml is dissolved among the normal saline solution 50ml of pH7-7.2), normal saline.
Method and result
55 of mices, be divided into normal saline group, ibuprofen group (0.2g/kg), Fructus Corni extract big (0.32g/kg), in (0.16g/kg), little (0.08g/kg) dosage group, every group 11, successive administration 5 days, last 1 day, administration was after 1 hour, immediately lumbar injection 0.6% acetic acid (HOAc) normal saline solution 0.2ml/ only after, observe in 20 minutes mouse writhing number of times and number of elements and write down the result, calculate the analgesia percentage ratio of Fructus Corni extract.The results are shown in Table 1.
Analgesia percentage ratio={ (matched group writhing response number-administration group writhing response number)/matched group writhing response number } * 100%
Table 1 Fructus Corni extract causes the influence (X ± s) of pain to mouse peritoneal injection acetic acid
| Grouping | Number of animals | Dosage (g/kg) | Turn round body number of times (X ± s) | Turn round body mice (only) | Analgesia percentage rate (%) |
| Normal saline ibuprofen Fructus Corni extract Fructus Corni extract Fructus Corni extract | 11 11 11 11 11 | — 0.2 0.08 0.16 0.32 | 24±16.78 1.818±3.46 ** 0.364±0.771 ** 0.818±1.403 ** 1.091±2.58 ** | 11 4 3 3 2 | 0 64 73 73 82 |
Annotate: compare with the normal saline group,
*Be P＜0.01
The hot plate method experiment
Experiment material
1. animal: Kunming mouse, female, body weight 18～20g purchases in China Preventive Medicial Science Institute's epidemic diseases and institute of microbiology
2. be subjected to the reagent thing: Fructus Corni extract (pressing the preparation of embodiment 1 method), use dissolved in distilled water, transfer pH8 with sodium bicarbonate.
3. positive control drug: ibuprofen, tablet, specification 0.1g/ sheet, people's consumption per day are 1.2g, are produced lot number: 9808020 by Dongling Pharmaceutical Co., Ltd., Shenyang
4. adjusting constant water bath box: mayor of Beijing bearing instruments and meters company produces.
Method and result
1. adjusting water bath with thermostatic control: with the water bath topped up with water, make water surface contact hot plate, regulate constant water bath box, make water temperature be controlled at 55 ± 0.5 ℃, hot plate preheating 10 minutes.
2. grouping and experiment: 80 of mices, each one is placed on the hot plate, and mice is from being placed on the hot plate to the pain threshold of metapedes required time (second) as this Mus occurring licking.Allly lick the metapedes time (second) less than 5 seconds or give it up greater than 30 seconds or leaper.With 70 qualified mices be divided at random normal saline group, ibuprofen group, Fructus Corni extract big (0.32g/kg), in (0.16g/kg), little (0.08g/kg) dosage group, every group 14, its normal pain threshold of replication, get two subnormal threshold of pain meansigma methodss, as pain threshold before the administration of this Mus.
3. observe the analgesic activity of Fructus Corni extract: the Fructus Corni extract that each group is given normal saline, ibuprofen and various dose respectively, successive administration 3 days was measured the pain threshold of mice respectively in 30,60,90 minutes after administration in the 4th day, and added up the t check.The results are shown in Table 2.
Table 2 Fructus Corni extract is to the analgesic activity (hot plate method) of mice (X ± s)
| Grouping | Number of animals | Dosage (g/kg) | Pain threshold (S) before the administration | Different time pain threshold (S) after the administration | |
| Time | 30min | 60min | |||
| Normal saline ibuprofen Fructus Corni extract Fructus Corni extract Fructus Corni extract | 11 11 11 11 11 | － 0.2 0.08 0.16 0.32 | 18.04±2.797 18.39±2.795 18.86±2.22 18.72±2.39 18.14±2.57 | 18.61±2.34 32.43±7.197 ** 29.14±7.199 ** 31.07±7.82 ** 33.68±6.41 ** | 18.36±3.39 28.25±7.51 ** 26.43±6.33 ** 27.5±6.297 ** 28.04±6.81 ** |
Annotate: compare with the normal saline group,
*Be P＜0.01
| Different time pain threshold (S) after the administration |
| 90min 18.14±3.18 26.07±8.56 ** 24.29±6.696 ** 25.29±6.91 ** 25.36±7.53 ** |
Above experimental result shows: Fructus Corni extract has significant analgesic activity.The anti-inflammatory activity comparative experiments of embodiment 5 Fructus Corni extracts and cornin
Experiment material:
1. cell: peripheral blood lymphocytes
2. be subjected to the reagent thing: Fructus Corni extract (pressing embodiment 1 preparation), cornin (pressing embodiment 2 preparations).
3. positive control: dexamethasone
4. reagent: Ficoll-Paque Plus (Amersham Bioscience); Endotoxin (LPS) and dexamethasone (CalBiochem.); TNFa ELISA Kit and IL1-beta ELISAKit (brilliant U.S. bio-engineering corporation); DMSO (Sigma).
Method and result:
Fresh blood is anticoagulant with EDTA, and separating periphery blood monocytic cell is suspended in RIMP 1640 culture medium that contain 10%FBS.Adding 100 μ l density in 96 orifice plates is 1 * 10
5The new isolated cells of cell/ml, every porocyte adds up to 10
4Individual, each sample is done 3 holes.
A) in cell, add the Fructus Corni extract of prescribed concentration or cornin (final concentration is respectively 3,10,30,100,300ug/ml, the application of sample amount is 10ul) and positive control (dexamethasone, 10uM).Place 37 ℃ to contain 5%CO
2Incubator in the insulation 15 minutes;
B) adding 10ul concentration is the LPS of 100ug/ml, places 37 ℃ to contain 5%CO
2Incubator in the insulation 16 hours;
C) with centrifugal 15 minutes of 1000rpm, supernatant is transferred in the new plate, measure TNFa and IL1-beta concentration, or cold storage is avoided multigelation in-20 ℃.
Experimental result:
| The inhibition specific activity of Fructus Corni extract and cornin pair cell TNF secretion a | ||
| Be subjected to reagent substrate concentration (ug/ml) | Emiocytosis TNFa concentration (pg/ml) under the extract effect | Emiocytosis TNFa concentration (pg/ml) under the |
| 10 | 118.4±1.6 | 188.6±5.1 |
| 100 | 94.9±11.1 | 163.4±10.7 |
| 300 | 8.1±10.7 | 96.9±7.5 |
| The inhibition specific activity of Fructus Corni extract and cornin pair cell TNF secretion a | ||
| Be subjected to reagent substrate concentration (ug/ml) | Emiocytosis IL1-beta concentration (pg/ml) under the extract effect | Emiocytosis IL1-beta concentration (pg/ml) under the |
| 10 | 89.9±6.8 | 116.2±0.4 |
| 100 | 42.6±4.5 | 61.9±5.6 |
| 300 | 7.9±0.8 | 52.4±1.4 |
More than experiment shows that the anti-inflammatory activity that contains the Fructus Corni extract of specific proportioning of the present invention will obviously be better than the anti-inflammatory activity of its contained monomeric compound cornin, illustrates that specific proportioning of the present invention has synergistic function (referring to accompanying drawing 2,3).
Embodiment 6 Fructus Corni extracts (embodiment 1) tablet can prepare as follows
Fructus Corni extract 30g
Starch 3g
Starch slurry (10%) is an amount of
Citric acid 0.15g
Pulvis Talci 1.5g
Fructus Corni extract is added the starch uniform mixing, add 8% starch slurry and make software, granulate with 14 order nylon mesh, 70～80 ℃ of dryings are through 10～12 order iron wire sieve granulate, with usefulness 12mm punch die tabletting behind the Pulvis Talci mixing.
Embodiment 7 Fructus Corni extracts (embodiment 1) injectable powder can prepare as follows
Fructus Corni extract 20g
NaOH is an amount of
The Fructus Corni extract adding distil water is dissolved, transfer PH to 7.4 with NaOH, with the filtering with microporous membrane of 0.22um, under the aseptic condition, be loaded on respectively in the 10ml cillin bottle, rotating disk, precooling (being lower than 10～20 ℃ of fusing points) is put into and is lower than-45 ℃ household freezer, go out sublimation drying after the crystallization, outlet rolls lid, gets final product.
Embodiment 8 Fructus Corni extracts (embodiment 1) spray can prepare as follows
Fructus Corni extract 21.5g
Vc 1g
Ethanol 296.5g
F
12In right amount
Fructus Corni extract is dissolved in the ethanol, adds propellant F
12(add 50% of cumulative volume earlier, regulate voluntarily according to the injection situation then), add antioxidant Vc at last.
Claims (14)
1. a Fructus Corni plant extract comprises following weight ratio composition: meliatin 5-20%, morroniside 5-25% and cornin 0.5-5%.
2. the extract of claim 1 comprises the polyphenol of at least 50% weight ratio.
3. claim 1 or 2 extract is characterized in that it can be made by following method:
With the Fructus Corni plant contact with water a mixture;
Described mixture heated processing is obtained a solution;
Described solution is passed through macroporous adsorptive resins; With
Water and ethanol water carry out gradient elution and obtain the Fructus Corni plant extract.
4. the extract of claim 3 is characterized in that described heat treated is that solution is heated to little boiling.
5. the extract of claim 3, water, 10% ethanol and the ethanol of 80-95% carry out successively respectively to it is characterized in that described gradient elution.
6. the extract of claim 4, water, 10% ethanol and the ethanol of 80-95% carry out successively respectively to it is characterized in that described gradient elution.
7. claim 1 or 2 extract comprise following weight ratio composition: meliatin 10%, morroniside 17.5% and cornin 2%.
8. the purposes of the Fructus Corni plant extract of claim 1 in the medicine of preparation treatment pain, autoimmune disease or inflammation.
9. the purposes of claim 8, wherein said pain is selected from constitutional hyperpathia, Secondary cases hyperpathia, facial muscle pain, intractable facial muscle pain, bone joint pain, headache, backache, cervicodynia, treatment of traumatic pain, inflammatory pain, ulcer pain, neuropathic pain, susceptibility pain, tumprigenicity pain, internal organs Crampy Pain or myalgia.
10. the purposes of claim 8, wherein said autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus (IDDM), myasthenia gravis, chronic ulcerative colitis, pernicious anemia companion chronic atrophic gastritis, goodpasture syndrome, it cooks skin ulcer, class sky kitchen skin ulcer, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, systemic lupus erythematosus (sle), mouth xerophthalmia scheorma syndrome, scleroderma, polyarteritis nodosa, Wegner granulomatosis, rheumatoid arthritis, nephritis, the nephrotic syndrome, organ transplantation, bone marrow transplantation, drug eruption, urticaria, the vegetable solar dermatitis, anaphylactic shock or asthma.
11. the purposes of claim 8, wherein said inflammation are selected from alterative inflammation, serous inflammation, fibrinous inflammation, purulent inflammation, hemorrhagic inflammation, catarrhal inflammation, productive inflammation or chronic granuloma inflammation.
12. a method for preparing the Fructus Corni plant extract of claim 1 comprises:
With the Fructus Corni plant contact with water a mixture;
Described mixture heated processing is obtained a solution;
Described solution is passed through macroporous adsorptive resins; With
Water and ethanol water carry out gradient elution and obtain the Fructus Corni plant extract.
13. the method for claim 12 is characterized in that described heat treated is that solution is heated to little boiling.
14. the method for claim 12 or 13, water, 10% ethanol and the ethanol of 80-95% carry out successively respectively to it is characterized in that described gradient elution.
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| PCT/CN2004/000715 WO2005003145A1 (en) | 2003-07-03 | 2004-07-01 | Shanzhuyu extract and uses thereof |
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| CNB031457746A CN100366264C (en) | 2003-07-03 | 2003-07-03 | Cornel extract and use thereof |
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| CN103360443A (en) * | 2013-07-30 | 2013-10-23 | 天津科丝美特生物科技有限公司 | Method for extraction and purification of four iridoid glycosides in cornus officinalis |
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| JP2005225763A (en) * | 2004-02-10 | 2005-08-25 | Ichimaru Pharcos Co Ltd | New compound and cosmetic composition or food composition comprising the same |
| CN100435810C (en) * | 2005-08-15 | 2008-11-26 | 江苏吴中苏药医药开发有限责任公司 | Dogwood fruit extract and its preparation process |
| CN102329353A (en) * | 2007-09-13 | 2012-01-25 | 山东绿叶天然药物研究开发有限公司 | Method for preparing morroniside |
| CN101843630B (en) | 2010-06-11 | 2012-07-18 | 首都医科大学宣武医院 | Composite containing iridoid compound and application thereof |
| CN103105408B (en) * | 2013-01-30 | 2016-01-06 | 河南省科高植物天然产物开发工程技术有限公司 | A kind of method differentiating Fructus Corni or spin-off |
| CN105687222A (en) * | 2014-06-06 | 2016-06-22 | 烟台市华文欣欣医药科技有限公司 | Application of pharmaceutical composition in preparing drugs for treating bronchial asthma |
| CN104606216B (en) * | 2015-01-05 | 2017-07-07 | 厦门大学附属中山医院 | Application of the morroniside in treatment medicine for treating arthritis is prepared |
| CN104987354B (en) * | 2015-07-23 | 2017-09-26 | 北京市药品检验所 | The method for preparing morroniside |
| CN105640975B (en) * | 2016-01-11 | 2020-02-28 | 江苏康缘药业股份有限公司 | Medicine for treating asthma |
| CN105902536B (en) * | 2016-06-01 | 2019-05-10 | 北京中医药大学 | Application of the loganin in the drug that preparation improves sleep |
| CN109806271B (en) * | 2019-02-11 | 2020-06-26 | 牡丹江医学院 | Pharmaceutical composition for treating allergic dermatitis and preparation thereof |
| CN110585192A (en) * | 2019-10-12 | 2019-12-20 | 厦门大学 | Application of loganin in preparation of medicine for treating acute enteritis |
| CN110849999B (en) * | 2019-12-05 | 2022-12-06 | 江西永通科技股份有限公司 | Liquid chromatography method for separating 8-epiloganin and loganin |
| CN111423475A (en) * | 2020-03-17 | 2020-07-17 | 连江仁泽生物科技有限公司 | Method for extracting verbena glycoside from verbena and medicine for treating dysmenorrhea |
| CN113480585B (en) * | 2021-08-10 | 2023-10-10 | 北京中医药大学 | Preparation method of cornus officinalis new glycoside bulk drug |
| CN115957227A (en) * | 2022-12-07 | 2023-04-14 | 安徽中医药大学第一附属医院(安徽省中医院) | Application of morroniside in preparation of health care products and/or medicines for increasing muscle, preventing skeletal muscle atrophy and/or preventing muscle injury |
| CN116510023A (en) * | 2022-12-14 | 2023-08-01 | 上海交通大学医学院附属第九人民医院 | Application of chemical in preparation of product for preventing and/or treating chronic wound |
| CN116889572A (en) * | 2023-06-06 | 2023-10-17 | 中山大学附属第八医院（深圳福田） | Use of iridoid compounds in preparation of medicines for preventing and/or treating multiple sclerosis |
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