CN106344595A

CN106344595A - Application of sodium alginate oligose and derivative to treatment of pain

Info

Publication number: CN106344595A
Application number: CN201510424357.7A
Authority: CN
Inventors: 耿美玉; 辛现良; 丁健
Original assignee: Shanghai Green Valley Pharmaceutical Co Ltd
Current assignee: Shanghai Green Valley Pharmaceutical Co Ltd
Priority date: 2015-07-17
Filing date: 2015-07-17
Publication date: 2017-01-25
Anticipated expiration: 2035-07-17
Also published as: CN106344595B

Abstract

The invention relates to application of sodium alginate oligose and a derivative to treatment of pain. The sodium alginate oligose and the derivative of the sodium alginate oligose are particularly mannuronic acid oligose or mannuronic acid oligose with a carboxyl at a 1-position of a reducing end and the derivative or a pharmaceutically acceptable salt, formed by connecting a beta-D-mannuronic acid through a 1,4-glucosidic bond.

Description

The application in treatment pain of algin oligosaccharide and its derivant

Technical field

The present invention relates to algin oligosaccharide and its derivant and its application in terms for the treatment of pain.

Background technology

Pain (pain) is a kind of complicated Physiological Psychology activity, is clinically modal disease One of shape.Acute pain is often a symptom of other diseases, and chronic pain is inherently A kind of disease.At present, the whole world there are about 30% people suffer from chronic pain, China at least 1 More than hundred million pain patients.Migraine is one of clinically common headache type.With recurrent exerbation Property headache be feature, outbreak the intermission normal.Migrainous definite pathogenic factor is unclear, Clinic, based on symptomatic treatment when showing effect and prophylactic treatment, does not also have preferable curative Thing.

Algin is the main constituents of Brown algae cell wall, be by β-carubinose aldehydic acid and α-l- guluronic acid passes through the linear anionic polysaccharide of the bonded formation of Isosorbide-5-Nitrae-glucosides.Algin It is a kind of macromolecular compound, molecular weight is larger, typically between tens of thousands of to millions of dalton. Algin abundance, and it is widely used to food, chemical industry and pharmaceutical sector etc..Algin has There are anticoagulation, antiviral, antibacterial, enhance immunity, antitumor and antiinflammatory etc. multiple biological alive Property.

But due to Algin molecular weight larger so as in terms of medicinal application be subject to certain limiting System.The algin oligosaccharide therefore prepared by various biodegrading process, including mannuronic acid oligosaccharide, Guluronic acid oligosaccharide, sweet Gu oligosaccharide and its derivant, carbohydrate chemistry, glycobiology, The research field such as sugar engineering and Carbohydrate drugs has important researching value.Can be using a lot Method degraded Algin obtains algin oligosaccharide, including enzymatic isolation method, chemical degradation method and physics fall Solution.

Content of the invention

The present invention provides a kind of algin oligosaccharide and its derivant purposes in treatment pain.This Inventing described algin oligosaccharide is Algin hydrolytic degradation products.Preferably, of the present invention brown Algin oligosaccharide be algin oligosaccharide in the range of 300-4500da for the molecular weight and its derivant or The pharmaceutically-acceptable salts of described widow's carbohydrates and their derivative.Algin oligosaccharide of the present invention and its The pharmaceutically-acceptable salts of derivant or described widow's carbohydrates and their derivative are selected from β-carubinose It is carboxylic that aldehydic acid passes through the mannuronic acid oligosaccharide of the bonded formation of Isosorbide-5-Nitrae glucosides or reducing end 1 The mannuronic acid oligosaccharide of base and its derivant or its pharmaceutically acceptable salt.Preferably, The invention still further relates to the algin oligosaccharide of formula (i) or formula (ii) and its derivant or described oligosaccharide And its pharmaceutically-acceptable salts of derivant.The present invention is prepared in the presence of being additionally provided in oxidant Reducing end 1 be the algin oligosaccharide of formula (ii) of carboxyl and its derivant or described oligosaccharide and The pharmaceutically-acceptable salts of its derivant.The present invention provides described various algin oligosaccharides and its spreads out Biological or described widow's carbohydrates and their derivative pharmaceutically-acceptable salts are used for preparation treatment pain Purposes in medicine.The invention still further relates to for the algin oligosaccharide of the present invention treating pain And its pharmaceutically-acceptable salts of derivant or described widow's carbohydrates and their derivative.The invention still further relates to A kind of method treating pain, including the present invention giving bacterium in need for the treatment of Pharmaceutically can the connecing of described algin oligosaccharide and its derivant or described widow's carbohydrates and their derivative By salt.

The present invention be related in one aspect algin oligosaccharide that following structural (i) represents and its Derivant or the pharmaceutically acceptable salt of described widow's carbohydrates and their derivative,

In formula (i), n represents one or more integers of 0-20, such as n be selected from 0,1, 2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、 19th, 20 one or more integers.

The algin oligosaccharide that represented by following structural (ii) and its derivative is further related in the present invention Thing or the pharmaceutically acceptable salt of described widow's carbohydrates and their derivative,

In formula (ii), n represents one or more integers of 0-20, such as n be selected from 0,1, 2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、 19th, 20 one or more integers.

In above-mentioned formula (i) and (ii), preferably n=0-10, more preferably n=2-8, most preferably n=4. The biological effect of the algin oligosaccharide (preferably n=2-8, most preferably n=4) of n=0-10 is preferably Reason is unclear it may be possible to they are easier to be identified and accepted by body cell.In some enforcements In mode, n can also be the one or more integers in the range of described 0-20.

Such as formula (i) of the present invention and (ii) algin oligosaccharide can adopt Patent No. Method in zl200580009396.5 is prepared and is carried out Structural Identification.In the present invention one In better embodiment, the preparation method of the algin oligosaccharide shown in structural formula (i) is: will Containing polymannuronic acid sodium salt, (it is a kind of composition of Algin and commercially can obtain , or be prepared referring for example to Chinese patent zl200580009396.5) solution (excellent Select aqueous solution) it is placed in autoclave, react under conditions of ph2-6, temperature 100-120 DEG C 2-6 hour.Then from autoclave, reacted solution is taken out, and neutralize and (for example use Naoh solution) this reacted solution extremely neutrality.In the case of stirring, by described neutrality Solution is slowly added in ethanol (for example, industrial alcohol, 95% ethanol or dehydrated alcohol), Carry out precipitate with ethanol.Then, filtration separation precipitate with ethanol gained solid matter (such as sucking filtration), preferably exists With ethanol (preferably dehydrated alcohol) washing and filtering gained solid matter during filtration.Obtain separating Solid matter (usually white) be dried, algin oligosaccharide as shown in formula (i) Crude mixture.Preferably, can be by this further wiring solution-forming of algin oligosaccharide crude mixture (preferred aqueous solutions), then add 95% ethanol in this solution, carry out precipitate with ethanol again.Cross Filter separates precipitate with ethanol gained sediment optionally use absolute ethanol washing again.Separate this precipitate And be dried, obtain solid matter.By this solid matter wiring solution-forming (preferred aqueous solutions), use Filter membrane (filter membranes in such as 3 μm of apertures) filters this solution and collects gained filtrate.This is filtered Liquid molecular-exclusion chromatography (bio-gel-p6 or bio-gel-p10 gel column, for example 1.6 × 180cm or other sizes) on carry out eluting and separate, the eluent as mobile phase is permissible It is nh₄hco₃Etc..Collect eluent using multiple containers successively from this chromatograph, and use sulfur Acid-carbazole method detects the sugared content in each container eluent.Sulfate-carbazole detection method is to use Sulphuric acid-carbazole colour developing, with the detection of Conventional UV spectrogrph, result is with optical density value (od value) Represent, different optical density value represents that sugared content is different.For convenience, can be by difference Molecular weight algin oligosaccharide be referred to as successively component 1,2,3...... etc..According to this testing result Collect the eluent containing different molecular weight algin oligosaccharide component respectively.Different molecular will be contained Amount algin oligosaccharide component (for example component 1,2,3...... etc.) eluent each distinguish Concentration, desalination lyophilization, thus the formula (i) obtaining having different molecular weight is shown Algin oligosaccharide.Described have different molecular weight algin oligosaccharide corresponding to brown shown in formula (i) In algin oligosaccharide, n has different values.When target product is algin oligosaccharide mixture, can With by mixing after being separately dried the eluent containing different algin oligosaccharide components or will contain The eluent having different algin oligosaccharide components is dried, thus obtaining target mixture after merging.

The preparation method of the algin oligosaccharide shown in structural formula (ii) is: by above-mentioned without molecule Algin oligosaccharide crude mixture shown in the detached formula (i) of exclusion chromatography or the tool after separation Algin oligosaccharide and the oxidant shown in formula (i) that have different n values react in a heated condition, Thus obtaining the algin oligosaccharide shown in formula (ii).In a detailed embodiment, described Oxidant is that Copper hydrate (is for example existed side by side by adding copper-bath in sodium hydroxide solution Obtained from mixing).By fresh oxidant be added to above-mentioned without molecular-exclusion chromatography separate Algin oligosaccharide crude mixture shown in formula (i) or there are different n values after separating Reacting by heating in the solution (such as aqueous solution) that algin oligosaccharide shown in formula (i) is made, directly Produce to no longer there being brick-red precipitation.By this reaction system carry out centrifugal treating with remove precipitate from And obtain supernatant.For inspection oxidation reaction whether thoroughly purpose, can use a little supernatant Add described oxidant again, check whether that also brick-red precipitation produces.If also brick-red Precipitation produces, then the described oxidant of whole for above-mentioned centrifugation gained supernatant and other part continues Continue and reacted, till no longer having brick-red precipitation to produce when inspection.By finally obtain Reaction system centrifugation obtains supernatant.Ethanol (for example, work is added in gained supernatant Industry ethanol, 95% ethanol or dehydrated alcohol) carry out precipitate with ethanol.Filtration separation precipitate with ethanol gained solidss Matter, and with this solid matter of absolute ethanol washing.Gained solid matter is dried.According to above-mentioned Identical molecular-exclusion chromatography separation side in the preparation method of the algin oligosaccharide of structural formula (i) Method carries out separating.Thus obtaining the algin oligosaccharide shown in formula (ii) with different molecular weight. The described algin oligosaccharide with different molecular weight corresponds in algin oligosaccharide shown in formula (ii) N has different values.When target product is algin oligosaccharide mixture, can be by containing The eluent having different algin oligosaccharide components mixes after being separately dried or will be containing different Brown algae The eluent of glue oligosaccharide compositions is dried after merging, thus obtaining target mixture.

Formula (i) of the present invention or formula (ii) algin oligosaccharide or its pharmaceutically-acceptable salts Derivant comprises one or more hydroxyls by the ester of mineral acid or esterifying organic acid.Energy and the present invention Formula (i) or one or more hydroxyls of formula (ii) algin oligosaccharide or its pharmaceutically-acceptable salts Formed ester described organic acid include but is not limited to: formic acid, acetic acid, oxalic acid, hydroxyacetic acid, third Acid, malonic acid, butanoic acid, succinic acid, valeric acid, acrylic acid, oxalic acid, maleic acid, fumaric acid, Malic acid, succinic acid, citric acid, tartaric acid, lactic acid, methanesulfonic acid, lactic acid, salicylic acid, second Acyl salicylic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, acetone acid, hydroxybutyric acid, adipic acid, adjacent benzene two Formic acid, mandelic acid, benzoic acid, boric acid etc..Can be with formula (i) or formula (ii) Brown algae One or more hydroxyls of glue oligosaccharide or its pharmaceutically-acceptable salts form the described mineral acid bag of ester Include but be not limited to: sulphuric acid, sulfurous acid, phosphoric acid, Metaphosphoric acid, phosphorous acid, hypophosphorous acid, pyrophosphoric acid, Polyphosphoric acids etc..

Formula (i) of the present invention or formula (ii) widow carbohydrates and their derivative pharmaceutically acceptable Salt comprises: inorganic salt, such as lithium salts, sodium salt, potassium salt, beryllium salt, magnesium salt, calcium salt, iron salt, Zinc salt, selenium salt, vanadic salts, pink salt, silicon salt, strontium salt, or with lysine, arginine, bird ammonia The base addition salts that the basic amino acids such as acid are formed, wherein particular certain cancers.Described pharmaceutical salts can use Conventional method is obtained.

Pharmaceutical pack for treating pain of the present invention contains described formula (i) or formula (ii) Brown algae Glue widow's carbohydrates and their derivative or the pharmaceutically acceptable salt of described widow's carbohydrates and their derivative, with And one or more pharmaceutically acceptable carrier.Medicine of the present invention can be tablet, ebonite Capsule, soft capsule, enteric coated capsule, microcapsule, granule, syrup, injection, granule, Emulsion, the form of suspension, solution and the slow releasing preparation for oral or non-oral administration.

Pharmaceutically acceptable carrier of the present invention refers to pharmacy well known to those skilled in the art Upper acceptable carrier, the pharmaceutically acceptable carrier of the present invention includes but is not limited to: filler, Wetting agent, adhesive, disintegrating agent, lubricant, binding agent, fluidizer, odor mask, surface Activating agent, preservative etc..Filler include but is not limited to Lactose, Microcrystalline Cellulose, starch, Icing Sugar, dextrin, Mannitol, calcium sulfate etc..Wetting agent includes but is not limited to carboxylic first with adhesive Base sodium cellulosate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, sucrose, poly- second Alkene pyrrolidone etc..Disintegrating agent includes but is not limited to carboxymethyl starch sodium, crosslinked polyethylene pyrroles Alkanone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose etc..Lubricant include but It is not limited to magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, Polyethylene Glycol, Laurel Alcohol magnesium sulfate etc..Binding agent include but is not limited to arabic gum, alginic acid, carboxymethylcellulose calcium, Sodium carboxymethyl cellulose, dextratess, dextrin, dextrose, ethyl cellulose, gelatin, Liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl are fine Dimension element, Magnesiumaluminumsilicate, maltodextrin, methylcellulose, polymethacrylates, poly- second Alkene pyrrolidone, pre-gelatinized starch, sodium alginate, Sorbitol, starch, syrup and Tragacanth. Fluidizer includes but is not limited to silica sol, Powderd cellulose, magnesium trisilicate, titanium dioxide Silicon and Pulvis Talci.Odor mask include but is not limited to aspartame, stevioside, Fructose, glucose, Syrup, Mel, xylitol, Mannitol, Lactose, Sorbitol, maltose alcohol, glycyrrhizin. Surfactant includes but is not limited to tween 80, poloxamer.Preservative includes but is not limited to Nipagin ester, sodium benzoate, potassium sorbate etc..

The method preparing the various pharmaceutical compositions containing various ratio active component is known, Or be will be readily apparent to one having ordinary skill according to the disclosure.As Remington ' s pharmaceutical sciences, martin, e.w., ed., mack Publishing company, 19th ed. (1995) are described.The side of preparation described pharmaceutical composition Method includes mixing suitable pharmaceutical excipient, carrier, diluent etc..

In a known way manufacture the present invention pharmaceutical preparation, include routine mixing, dissolving or Freeze drying process.

The various approach that the medicine of the present invention is suitable for selected method of application are applied, for example oral Or parenteral (by intravenouss, intramuscular, local or subcutaneous route).

Therefore, medicine of the present invention with suitable pharmaceutically acceptable carrier (as inert diluents Agent or edible carrier) can be administered orally with systemic administration, for example.They can be enclosed in firmly Or in the gelatine capsule of soft shell, can press as tablet.Oral medication is applied, active ingredient Thing can in conjunction with one or more excipient, and with deglutible tablet, buccal tablet agent, buccal tablet, The form of capsule, elixir, suspending agent, syrup, disk etc. uses.This preparation should wrap Containing at least 0.1% reactive compound.In this preparation the ratio of reactive compound it is of course possible to Change, can account for about the 0.01% to about 99% of given unit dosage forms weight.This Treat in useful pharmaceutical preparation, the amount of reactive compound makes it possible to obtain effective dose water Flat.

Tablet, buccal tablet, pill, capsule etc. can also comprise: binding agent, such as Tragacanth, Arabic gum, corn starch or gelatin；Excipient, such as dicalcium phosphate；Disintegrating agent, such as beautiful Rice starch, potato starch, alginic acid etc.；Lubricant, such as magnesium stearate；And sweeting agent, such as Sucrose, Fructose, Lactose or aspartame；Or flavoring agent, such as Herba Menthae, wintergreen oil or Fructus Pruni pseudocerasi perfume Taste.When unit dosage forms are capsule, except above types of material, it can also comprise liquid Carrier, such as vegetable oil or Polyethylene Glycol.Various other materials there may be, as coating, or Otherwise change the physical form of solid unit dosage form.For example, tablet, pill or capsule Agent can be with coatings such as gelatin, wax, Lac or sugar.Syrup or elixir can comprise active ingredient Thing, sucrose or Fructose as sweeting agent, nipagin or propyl parabene conduct Preservative, dyestuff and flavoring agent (as cherry flavor or orange flavor).Certainly, for preparing Any material of any unit dosage forms should be pharmaceutically acceptable and with application amount be Nontoxic.Additionally, reactive compound can mix in slow releasing preparation and delayed release device.

Reactive compound by infusion or can also be expelled to intravenouss or intraperitoneal administration.Permissible Prepare the aqueous solution of reactive compound or its salt, the nontoxic surfactant that optionally can mix. Can also prepare in glycerol, liquid macrogol, glycerol triacetate and its mixture and oil In dispersant.Under common storage and use condition, these preparations comprise preservative in case Only growth of microorganism.

The pharmaceutical dosage form being suitable to inject or be transfused can include comprising being suitable to aseptic injectable or The solution that can be transfused or the active component of the instant preparation of dispersant (are optionally encapsulated in liposome In) aseptic aqueous solution or dispersant or sterilized powder.In all cases, final dosage form Must be aseptic, liquid and stable under production and condition of storage.Liquid-carrier is permissible Solvent or liquid dispersion medium, including, for example water, ethanol, polyhydric alcohol (for example, glycerol, Propylene glycol, liquid macrogol etc.), vegetable oil, nontoxic glyceride and its suitable mix Thing.Suitable mobility can be maintained, for example, by the formation of liposome, by dispersion Required particle size is maintained in the case of agent, or by the use of surfactant.Can lead to Cross various antibacterial agents and antifungal (as metagin, methaform, phenol, Pyrusussuriensiss Acid, thimerosal etc.) produce prophylaxis of microbial effect.In many cases it is preferred to include etc. Penetration enhancer, such as sugar, buffer agent or sodium chloride.By using delayed absorption agent compositionss (for example, Aluminum monostearate and gelatin) can produce injectable compositionss prolongation absorb.

By by the reactive compound of the requirement in suitable solvent with need above enumerate Various other compositions combine, then carry out filtration sterilization, prepare sterile injectable solution.? In the case of preparing the sterilized powder of aseptic injectable solution, preferred preparation method is vacuum It is dried and frozen dry technology, this can produce active component and add any aseptic mistake additionally needing The powder of composition present in filter solution.

Useful solid carrier include pulverize solid (as Talcum, clay, Microcrystalline Cellulose, Silicon dioxide, aluminium oxide etc.).Useful liquid-carrier includes water, ethanol or ethylene glycol or water - ethanol/ethylene glycol mixture, the composition of medicine of the present invention can be optionally in nontoxic surface activity It is dissolved or dispersed in wherein with effective content with the help of agent.Adjuvant (as fragrance) can be added To optimize the property for given purposes with other antimicrobial.

Thickening agent (as synthesis polymer, fatty acid, soap and ester, fatty alcohol, change Property cellulose or modified inorganic material) also can with liquid-carrier be used for being formed paintable paste, Gel, ointment, soap etc., are directly used on the skin of user.

The treatment requirement of compound or its active salt or derivant, depends not only on the spy of selection Fixed salt, and depending on insecticide-applying way, the essence of disease to be treated and patient age and State, ultimately depends on the decision of doctor on the scene or clinician.

Above-mentioned preparation can be existed with unit dosage forms, and this unit dosage forms is the thing containing unit dose Reason dispersal unit, is suitable to human body and other mammalian body administration.Unit dosage forms can be glue Capsule or tablet, or a lot of capsule or tablet.According to involved concrete treatment, active component The amount of unit dose can be become between about 0.01 to about 1000 milligram or more Change or adjust.

In some embodiments, the invention still further relates to for treat pain algin oligosaccharide and Its derivant or described widow carbohydrates and their derivative pharmaceutically-acceptable salts, described for treatment pain The algin oligosaccharide of pain and its derivant or described widow's carbohydrates and their derivative pharmaceutically acceptable Salt is selected from the mannuronic acid oligosaccharide that β-carubinose aldehydic acid passes through the bonded formation of Isosorbide-5-Nitrae glucosides Mannuronic acid oligosaccharide that reducing end 1 is carboxyl and its derivant or its pharmaceutically can connect The salt being subject to.At some preferred aspects, the described algin oligosaccharide for treating pain and its spread out Biological or described widow carbohydrates and their derivative pharmaceutically-acceptable salts be selected from following structural (i) Or the algin oligosaccharide that represents of formula (ii) and its derivant or described widow's carbohydrates and their derivative Pharmaceutically acceptable salt,

Wherein, in formula (i) or formula (ii), respective n is one or more selected from 0-20 Integer.The described algin oligosaccharide for treating pain and its derivant or described oligosaccharide and its spread out Biological pharmaceutically-acceptable salts are also selected from the Algin widow that formula (i) or formula (ii) represent Carbohydrates and their derivative or the pharmaceutically acceptable salt of described widow's carbohydrates and their derivative, and n It is the one or more integers selected from 0-10.The described algin oligosaccharide for treating pain and The pharmaceutically-acceptable salts of its derivant or described widow's carbohydrates and their derivative are also selected from formula (i) Or the algin oligosaccharide that represents of formula (ii) and its derivant or described widow's carbohydrates and their derivative Pharmaceutically acceptable salt, and n is the one or more integers selected from 2-8.Described for The algin oligosaccharide for the treatment of pain and its derivant or described widow's carbohydrates and their derivative are pharmaceutically Acceptable salt is also selected from formula (i) or formula (ii) represents algin oligosaccharide and its derivant, Or the pharmaceutically acceptable salt of described widow's carbohydrates and their derivative, and n is 4.

In some embodiments, the invention still further relates to a kind of method treating pain, including to Give bacterium in need for the treatment of according to algin oligosaccharide of the present invention and its Derivant or the pharmaceutically-acceptable salts of described widow's carbohydrates and their derivative.In some embodiments, Described treatment pain method, include give bacterium in need for the treatment of according to The described algin oligosaccharide of invention and its derivant or described widow's carbohydrates and their derivative are pharmaceutically Acceptable salt, wherein said algin oligosaccharide and its derivant or described widow's carbohydrates and their derivative Pharmaceutically-acceptable salts are selected from β-carubinose aldehydic acid and pass through the sweet of the bonded formation of Isosorbide-5-Nitrae glucosides Dew oligosaccharide or mannuronic acid oligosaccharide that reducing end 1 is carboxyl and its derivant or Its pharmaceutically acceptable salt.In some embodiments, the method for described treatment pain, including Give bacterium in need for the treatment of according to algin oligosaccharide of the present invention and Its derivant or the pharmaceutically-acceptable salts of described widow's carbohydrates and their derivative, wherein said Algin The pharmaceutically-acceptable salts of few carbohydrates and their derivative or described widow's carbohydrates and their derivative are selected from following Algin oligosaccharide that structural formula (i) or formula (ii) represent and its derivant or described oligosaccharide and The pharmaceutically acceptable salt of its derivant,

Wherein, in formula (i) or formula (ii), respective n is one or more selected from 0-20 Integer.In some embodiments, the method for described treatment pain, in need for the treatment of including giving Bacterium according to algin oligosaccharide of the present invention and its derivant or described The pharmaceutically-acceptable salts of few carbohydrates and their derivative, wherein said algin oligosaccharide and its derivant Or the pharmaceutically-acceptable salts of described widow's carbohydrates and their derivative are selected from formula (i) or formula (ii) and represent Algin oligosaccharide and its derivant or described widow carbohydrates and their derivative pharmaceutically acceptable Salt, and n is the one or more integers selected from 0-10.In some embodiments, described Treatment pain method, including give bacterium in need for the treatment of according to the present invention Pharmaceutically can the connecing of described algin oligosaccharide and its derivant or described widow's carbohydrates and their derivative By salt, the pharmacy of wherein said algin oligosaccharide and its derivant or described widow's carbohydrates and their derivative Upper acceptable salt be selected from the algin oligosaccharide that formula (i) or formula (ii) represent and its derivant or The pharmaceutically acceptable salt of described widow's carbohydrates and their derivative, and n is selected from 2-8 Or multiple integer.In some embodiments, the method for described treatment pain, including giving to need Treatment bacterium according to algin oligosaccharide of the present invention and its derivant Or described widow carbohydrates and their derivative pharmaceutically-acceptable salts, wherein said algin oligosaccharide and its The pharmaceutically-acceptable salts of derivant or described widow's carbohydrates and their derivative are selected from formula (i) or formula (ii) The algin oligosaccharide representing and its derivant or described widow's pharmaceutically can the connecing of carbohydrates and their derivative The salt being subject to, and n is 4.

Terms used herein " treatment " generally refers to obtain the pharmacology needing and/or physiology effect Should.This effect, according to completely or partially prevention disease or its symptom, can be preventative； And/or according to partially or completely stable or cure diseases and/or the side effect due to disease generation, Can be curative." treatment " used herein covers any treatment to patient disease, Including: (a) prevents easy infection disease or symptom but is not also diagnosed to be what ill patient was occurred Disease or symptom；B () suppresses the symptom of disease, that is, stop its development；Or (c) alleviation disease Symptom, i.e. lead to disease or symptom to be degenerated.

In the whole embodiment of the present invention, algin oligosaccharide of the present invention and its derivant Also include comprising described one or more algin oligosaccharide and its derivant or described oligosaccharide and its The mixture of the pharmaceutically-acceptable salts of derivant.For example, n can also be selected from each described Multiple integers in numerical range.

On the other hand, in whole embodiments of the present invention, numerical range meaning of the present invention Covering the arbitrary integer in described scope.For example, in whole embodiments of the present invention, Algin oligosaccharide that formula (i) or formula (ii) represent and its derivant or described oligosaccharide and its derivative In the pharmaceutically acceptable salt of thing, n can be the arbitrary integer in the range of 0-20, such as n Can be selected from 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14, 15th, 16,17,18,19 and 20 one or more integers.Unless specified, this Bright described percentage composition refers to weight percentage.

In whole embodiments of the present invention, pain of the present invention includes but is not limited to implement Listed types of pain, for example acute and chronic pain, such as neuropathic pain and art in example Afterwards pain, chronic low back pain, cluster headache, herpes neuralgia, phantom pain, central pain, Toothache, opioid-resistant pain, Encelialgia, operation pain, bone injury pain, tired and point Pain during childbirth, because of the pain leading to including sunburn, puerperal pain, migraine, the heart of burning Angor and the pain (inclusion cystitis) related to urogenital tract, vascular pain, nerve Property pain, migraine, trigeminal neuralgia, intercostal neuralgia, operative incision pain, chronic fascia Scorching pain, talalgia, diabetic peripheral neuropathy pain, phantom pain, myalgia, skeleton Pain, arthralgia, cancerous pain, Non-cancerous pain etc..This term also includes impression injury Property pain or nociception.

Below, the present invention will show beneficial effects of the present invention by embodiment.Art technology Personnel will appreciate that, these embodiments are exemplary, rather than restricted.These embodiments The scope of the present invention will not be limited by any way.

Brief description

Fig. 1: the figure of algin oligosaccharide post separation shown in formula (i).A:p6 post separation figure；B: P10 post separation figure.

Algin oligosaccharide post separation figure shown in Fig. 2: formula (ii).A:p6 post separation figure；B: P10 post separation figure.

Specific embodiment

The preparation of embodiment one algin oligosaccharide

Weigh 1g polymannuronic acid sodium salt (weight average molecular weight 8235da, upper sea green paddy system Medicine company limited provides), add appropriate distilled water to be made into the poly of 1% (percentage by weight) Mannuronic acid sodium water solution.With hydrochloric acid by described 1% polymannuronic acid sodium water solution Ph value be adjusted to 4, then this aqueous solution is placed in autoclave.At a temperature of 110 DEG C Reacting by heating 4 hours.Take out this reacted solution and be allowed to cool from autoclave.Cooling Afterwards, it is worth to neutral liquid with the ph that naoh solution adjusts solution after this reaction.In stirring Under the conditions of, described neutral liquid is slowly added into the ethanol of this 4 times of volume of liquid volume In, carry out precipitate with ethanol and stand overnight.Filtration separation precipitate with ethanol gained solid matter, and divide filtering From when with absolute ethanol washing filtration separation gained solid matter, finally give white filter cake.Will This filter cake is placed in 60 DEG C of baking ovens and is dried, and obtains algin oligosaccharide crude product.

Take above-mentioned algin oligosaccharide crude product 1g, be made into 10% aqueous solution, molten with 95% ethanol Liquid carries out precipitate with ethanol again.Filtration separation again precipitate with ethanol gained sediment with absolute ethanol washing this sink Starch.Separate this precipitate and be dried, obtain solid matter.This solid matter is made into 5% The aqueous solution of (percentage by weight), with 3 μm of this aqueous solutions of aperture membrane filtration and collect filtrate. By this filtrate, in molecular-exclusion chromatography bio-gel-p6 gel column, (1.6 × 180cm is purchased from Bio-rad company) on carry out eluting and separate, the eluent as mobile phase is 0.2mol·l^-1nh₄hco₃.Collect eluting using multiple 5 milliliters of test tubes from this column chromatography successively Liquid, then detects the sugared content of eluent in described each test tube with sulfate-carbazole.According to this Testing result collects the eluent containing different molecular weight algin oligosaccharide component respectively.To contain Each concentrating under reduced pressure the lyophilization respectively of the eluent of different molecular weight algin oligosaccharide component, Discard component 1, obtain the algin oligosaccharide group shown in formula (i) being respectively provided with different molecular weight Divide 2-12 (according to subsequent detection, n is respectively provided with the value of the 0-10) (volume of in figure Represent the effluent volume representing with test tube number) (Fig. 1 a).By bio-gel-p6 gel column (1.6 × 180cm, purchased from bio-rad to be difficult to detached component continuation bio-gel-p10 gel column Company) eluting separation, the eluent as mobile phase is 0.2mol l^-1nh₄hco₃.Make successively Collect eluent with multiple 5 milliliters of test tubes, then detect described each test tube with sulfate-carbazole The sugared content of middle eluent.Collected respectively containing different molecular weight Algin according to this testing result The eluent of oligosaccharide compositions.By the eluent containing different molecular weight algin oligosaccharide component each Concentrating under reduced pressure lyophilization respectively, and obtain formula (i) institute being respectively provided with different molecular weight Show that (according to subsequent detection, n is respectively provided with 11-22's to algin oligosaccharide component 13-24 Value) (volume of in figure represents the effluent volume representing with test tube number) (Fig. 1 b). Described bio-gel-p6 post and p10 post are two kinds has the polypropylene of exclusion different molecular size Amide microsphere, molecular weight can obtain in the algin oligosaccharide of below 3000dalton on p6 post Separate to preferable, molecular weight can be in p10 in the algin oligosaccharide of 3000-6000dalton Preferably separated on post.Through comparing with existing reference substance, ultraviolet spectral analysis, infrared light Analysis of spectrum,¹H-nmr spectrum analyses,¹³Understand after c-nmr spectrum analyses and mass spectral analyses, In p6 post figure (Fig. 1 a) and p10 post figure (Fig. 1 b), respectively obtain component 2-24, It is respectively the algin oligosaccharide compound shown in formula (i) that n is 0-22.According to spectrogram result, Merge the algin oligosaccharide eluent shown in formula (i) of n=2-8 and be dried, then obtain n=2-8 Algin oligosaccharide mixture shown in formula (i).

The preparation of embodiment two algin oligosaccharide oxygen solution product

Take 5g above-mentioned without the molecular-exclusion chromatography detached algin oligosaccharide crude product (weight that is made into 5% Amount percentage ratio) aqueous solution.By 10% (percentage by weight) sodium hydroxide to 50ml Add the copper-bath of 5% (percentage by weight) of 25ml in solution and mix system immediately Standby obtain fresh oxidant Copper hydrate.This fresh oxidant Copper hydrate is added to immediately In the algin oligosaccharide solution of above-mentioned 5% (percentage by weight) of 40ml, pass through boiling water simultaneously Bath is heated, until no longer there being brick-red precipitation to produce.This reaction system is carried out at centrifugation Reason is to remove precipitation thus obtaining supernatant.A little supernatant is taken to add described oxidant again, Check whether that also brick-red precipitation produces.If also brick-red precipitation produce, by above-mentioned from The whole supernatant of heart gained proceeds to react with the described oxidant of other part, until inspection Till no longer having brick-red precipitation to produce.The reaction system finally obtaining centrifugation is obtained Clear liquid.Add 95% ethanol of 4 times of volumes to carry out precipitate with ethanol in supernatant, and stand overnight. Filtration separation precipitate with ethanol gained solid matter, and with this solid matter of absolute ethanol washing.By gained Solid matter is placed in 60 DEG C of baking ovens and dries, and obtains algin oligosaccharide crude product shown in formula (ii).

Take above-mentioned algin oligosaccharide crude product 1g, be made into the aqueous solution of 10% (percentage by weight), Carry out precipitate with ethanol with 95% ethanol solution again, precipitate with ethanol gained sediment is simultaneously optional again for filtration separation Use absolute ethanol washing.Separate this precipitate and be dried, obtain solid matter.By this solid Material is made into the aqueous solution of 5% (percentage by weight), and with 3 μm of aperture membrane filtrations, this is water-soluble Liquid simultaneously collects filtrate.By this filtrate in molecular-exclusion chromatography bio-gel-p6 gel column Eluting is carried out on (1.6 × 180cm, purchased from bio-rad company) separate, washing as mobile phase De- liquid is 0.2mol l^-1nh₄hco₃.Received from this column chromatography using multiple 5 milliliters of test tubes successively Collection eluent, then detects the sugared content of eluent in described each collector tube with sulfate-carbazole. Eluent containing different molecular weight algin oligosaccharide component is collected respectively according to this testing result. Eluent containing different molecular weight algin oligosaccharide component is each distinguished concentrating under reduced pressure cold Lyophilizing is dry, discards component 1, obtains the Brown algae shown in formula (ii) being respectively provided with different molecular weight Glue oligosaccharide compositions 2-12 (according to subsequent detection, n is respectively provided with the value of 0-10) (figure In volume represent the effluent volume representing with test tube number) (Fig. 2 a).Will Bio-gel-p6 gel column is difficult to detached component continuation bio-gel-p10 gel column (1.6 × 180cm, purchased from bio-rad company) eluting separates, and the eluent as mobile phase is 0.2mol·l^-1nh₄hco₃.Collect eluent, Ran Houyong using multiple 5 milliliters of test tubes successively Sulfate-carbazole detects the sugared content of eluent in described each test tube.Divided according to this testing result Do not collect the eluent containing different molecular weight algin oligosaccharide component.Different molecular weight will be contained Each concentrating under reduced pressure the lyophilization respectively of the eluent of algin oligosaccharide component, and distinguished Algin oligosaccharide component 13-23 shown in formula (ii) with different molecular weight (is examined according to follow-up Survey and understand, n is respectively provided with the value of 11-21) (volume of in figure represents with test tube number The effluent volume representing) (Fig. 2 b).Described bio-gel-p6 post and p10 post are two kinds There is the polyacrylamide microsphere of exclusion different molecular size, molecular weight 3000dalton with Under algin oligosaccharide preferably can be separated on p6 post, molecular weight exists The algin oligosaccharide of 3000-6000dalton preferably can be separated on p10 post.Warp Compare with existing reference substance, ultraviolet spectral analysis, infrared spectrum analysiss,¹H-nmr spectrum divides Analysis,¹³Understand after c-nmr spectrum analyses and mass spectral analyses, in p6 post figure (Fig. 2 a) In p10 post figure (Fig. 2 b), respectively obtain component 2-23, it is respectively n is 0-21 Algin oligosaccharide compound shown in formula (ii).According to spectrogram result, collect and merge n=2-8 Algin oligosaccharide eluent shown in formula (ii) and be dried, then obtain the formula (ii) of n=2-8 Shown algin oligosaccharide mixture.

Embodiment three algin oligosaccharide derivant Dichlorodiphenyl Acetate causes the effect of mice pain

1 experiment material

1.1 medicines and reagent

Method according to embodiment two prepares formula (ii) algin oligosaccharide, and (n=2-8 schemes In component 4-10) mixture.This mixture is off-white powder, soluble in water；Acetic acid, Tianjin Kai Tong chemical reagent company limited produces；Aspirin, Shijiazhuang Ou Yi Pharmaceutical is limited Company produces.

1.2 laboratory animal

Kunming mouse, male and female half and half, body weight 18-22g, tested by Shanghai western pul-Bi Kai Company of Animals Ltd. provides.

2 experimental techniques

2.1 animal packet and administration and process

Take mice, be randomly divided into 5 groups, be i.e. blank control group, positive drug aspirin 200mg/kg Group, algin oligosaccharide derivant 25mg/kg, 50mg/kg, 100mg/kg group, every group 10 Animal.From the packet same day, blank control group daily gavage 20ml/kg distilled water, remaining Each group gavage gives relative medicine, is administered once daily, successive administration 7 days.In last dose 1 hour afterwards, the equal lumbar injection of each group mice 0.6% acetum 0.2ml, record injection acetic acid Afterwards in 20 minutes mice writhing incubation period (i.e. from injection acetic acid to writhing response occur when Between) and writhing number of times, it is calculated as follows inhibitory rate and analgesia percentage rate (%).

Inhibitory rate (%)=(the average writhing time of blank control group average writhing number of times-administration group Number)/blank control group average writhing number of times × 100%

Analgesia percentage rate (%)=[(experimental group no writhing number of animals-blank control group no writhing animal Number)/test group of animals number] × 100%

3 statistical procedures

Statistical analysiss are carried out to result, result is with " means standard deviation " (mean ± sd) Represent, be compared using variance analyses (anova).Had significantly with p ＜ 0.05 for difference Meaning, p ＜ 0.01 has extremely notable meaning for difference.

4 experimental results

The effect of 4.1 algin oligosaccharide derivant Dichlorodiphenyl Acetate induced mice writhing responses

The injection of chemicals such as acetum, to mouse peritoneal, can stimulate mouse peritoneum, between causing Have a rest the persistent pain of outbreak, show as that abdominal part receives indent, abdomen antetheca is close to cage bottom, buttocks is askew Turn round and hind leg is upheld, in a kind of specific positions, referred to as writhing response.Writhing incubation period (i.e. from Injection time of occurring to writhing response of acetic acid) and with certain time in writhing number of times, permissible Represent the order of severity of pain.

The experimental result of algin oligosaccharide derivant Dichlorodiphenyl Acetate induced mice writhing response effect is shown in Table 1.Algin oligosaccharide Derivatives In Mice writhing response all has good inhibitory action, and Dose-dependence is assumed, high dose group effect is best between each dosage group.With blank control group Relatively, writhing number of times, inhibitory rate and analgesia percentage difference are all statistically significant (p ＜ 0.01).Show that algin oligosaccharide derivant has the effect for the treatment of pain.

Table 1. algin oligosaccharide derivant Dichlorodiphenyl Acetate induced mice writhing response effect (n=10, mean±sd)

* p ＜ 0.05 * * p ＜ 0.01 vs blank control group

It is the brown of the individual integer selected from 0-20 with n respective in formula (i) or formula (ii) respectively Algin oligosaccharide or its pharmaceutically-acceptable salts carry out above-mentioned test, have also obtained similar result.

Example IV algin oligosaccharide derivant causes the migrainous effect of rat to nitroglycerin

1 experiment material

1.1 medicines and reagent

Method according to embodiment two prepares formula (ii) algin oligosaccharide, and (n=2-8 schemes In component 4-1o) mixture.This mixture is off-white powder, soluble in water.

1.2 laboratory animal

Sd male rat, body weight 180-220g, limited by Shanghai western pul-Bi Kai laboratory animal Company provides.

2 experimental techniques

2.1 animal packets and administration

Take sd rat, be randomly divided into blank control group, model group, algin oligosaccharide derivant 12.5th, 25,50,100,200mg/kg group, every group 8.Started to be administered in the packet same day, Blank control group and model group gavage give distilled water, and remaining each group gives relative medicine, daily It is administered once, successive administration 28 days, 30 minutes after last medicine, except blank control group animal gives Outside normal saline, remaining each group is all in the subcutaneous injection nitroglycerin 10mg/kg modeling of right shoulder.See Examine after rat modeling the red time of occurrence of ear and after persistent period, and modeling 30-45 minute and Number of times difficult to tackle in 60-75 minute two time period；Using fluorescence spectrophotometry cerebral tissue The content of middle 5-ht.Measure at ex356nm/em 483nm wavelength, result is with ng/g Brain represents again.

3 statistical procedures

4 experimental results

It is disorderly with interact a kind of lower blood vessel, neural function of neuromechanism that migraine is blood vessel Random disease.Nitroglycerin can be by expanding meningovascular, forming neurogenic inflammation and activation Hypothalamuses, brain stem and segments of spinal cord neuronal function etc. act on, and cause the super of nervi trigeminus fiber Quick property, causes migraine.Nitroglycerin model is a kind of animal model that nineteen ninety-five sets up, mesh The front animal Nerve in Migraine Model having become classics.According to nitroglycerin pathogenesis, detection model Ear red time that animal is caused due to vasodilation, the number of times difficult to tackle being caused due to pain and brain group Knit cause pain sensitive factor 5-hydroxy tryptamine (5-ht) content it can be estimated that migrainous serious journey Degree.

This result of study finds (table 2-4), 3 minutes about after nitroglycerin subcutaneous injection, Rat occurs that ear is red, and ear is red to continue 2.5 hours about；And 30-45 minute and 60-75 after modeling Number of times difficult to tackle in two time periods of minute is significantly more than blank control group, cerebral tissue 5-ht content It is substantially less than blank control group.Algin oligosaccharide derivant, can under 25-200mg/kg dosage The notable delay red time of occurrence of rat ears, shortens the ear red persistent period, reduces it and divide in 30-45 Number of times difficult to tackle in clock and 60-75 minute two time period, raises the content of 5-ht in cerebral tissue. Show that algin oligosaccharide derivant can substantially suppress rat migraine, also indicate that algin oligosaccharide spreads out Biology has the effect for the treatment of pain.

Table 2. algin oligosaccharide derivant to the nitroglycerin deflection headache red time of occurrence of rat ears and continues The effect (n=8, mean ± sd) of time

##p ＜ 0.01 vs blank control group；* p ＜ 0.05, * * p ＜ 0.01 vs model group

Table 3. algin oligosaccharide derivant to nitroglycerin cause Migraine Rats scratch one's head number of times effect (n=8, mean±sd)

The work to nitroglycerin deflection headache rat cerebral tissue 5-ht content for the table 4. algin oligosaccharide derivant With (n=8, mean ± sd)

##p ＜ 0.01 vs is to white matched group；* p ＜ 0.01 vs model group

The Brown algae being the individual integer selected from 0-20 with n respective in formula (i) or formula (ii) respectively Glue oligosaccharide or its pharmaceutically-acceptable salts carry out above-mentioned test, have also obtained similar result.

Embodiment five algin oligosaccharide derivant is big to the headache of electricity irritation trigeminal ganglion deflection The effect of Mus

1 experiment material

1.1 medicines and reagent

Method according to embodiment two prepares formula (ii) algin oligosaccharide, and (n=2-8 schemes In component 4-10) mixture.This mixture is off-white powder, soluble in water；；Yi Wen Family name is blue, paraformaldehyde, sucrose, glycerol, hydrogen peroxide, and triton x-100, dab all purchase From sigma company；Rabbit anti-Mus c-fos antibody (ab-5), U.S. oncogene research products；The goat-anti rabbit igg serum of biotin labeling, alexis, switzerland；avidin Biotin peroxidase complex, vector laboratories inc., burlingame, ca, usa.

1.2 laboratory animal

Sd rat, 5 monthly ages, male, body weight 200～240g, by Shanghai western pul-Bi Kai Laboratory animal company limited provides.

1.3 experimental apparatus

Lz-6 bench drill car, the emerging medical apparatus and instruments factory of Shanghai Lao Gang；Brain solid positioner, stoelt ing；Md2000 stimulator, Nanjing Medical University.

2 test methods

2.1 animal packets and administration

Take male sd rat, be randomly divided into blank control group, sham operated rats, model group, brown Algin oligosaccharide derivative 12.5,25,50,100,200mg/kg group, every group of 10 animals. Each group is all orally administered to relative medicine, and blank control group, sham operated rats, model group are administered orally distillation Water.After successive administration 10 days, in addition to blank control group, all rats are through chloral hydrate After 350mg/kg intraperitoneal injection of anesthesia, rat is fixed on stereotaxic instrument, the crown hits exactly Otch, successively cuts skin, muscle, exposes cranium in brain sagittal suture intermediate openings.Front 3 millimeters are moved, side is opened at 3 millimeters, uses dental burr jack, then inserts electrodes into three after chimney Fork neuroganglion (depth is counted as 9.5mm with cerebral dura mater), postoperative continuous narcosis.All operations All aseptically carry out.Debug stimulating electrode, parameters of electrical stimulation is cycle 200ms, Amplitude 10v, ripple width 5ms, stimulate 10 minutes.Sham operated rats animal is only inserted electrode, no To stimulation.Stimulate first 7 minutes right femoral vein injection 50mg/kg Azo-Blues, stimulation terminates In 20 minutes, perfusion is fixed.

Stimulate and terminate latter 5 minutes, left ventricle perfusion 2 minutes, open cranium, take full brain, fixing, Pathological section SABC to be done measures c-fos；Another determination electrode position, separates electrode insertion Place and another brain hemisphere correspondence position brain dura mater, are laid in after deionized water wash on microscope slide, 37 degree of dryings 15 minutes, 70% glycerol is fixed.With 647nm excitation wave on Laser Scanning Confocal Microscope Long, 680nm launch wavelength detects the fluorescence intensity of stimulated side and control sides designated area, calculates The ratio of stimulated side/control sides fluorescence intensity, in order to indicate plasma protein leaching rate (plasma Protein extravasation, ppe).Full brain continuously freezes coronal section, thick 10 μm of piece, SABC fluorescent labeling c-fos positive cell.Under Laser Scanning Confocal Microscope, randomly choose 5 The visual field, measures spinal nucleus of trigeminal nerve caudal experimental side and control sides positive cell number, then takes The meansigma methodss in 5 visuals field, then for average positive cell number.

3 statistical procedures

Statistical analysiss are carried out to result, result is with " means standard deviation " (mean ± sd) Represent, be compared using variance analyses (an0va).Had significantly with p ＜ 0.05 for difference Meaning, p ＜ 0.01 has extremely notable meaning for difference.

4 result of the tests

The activation of trigeminal vascular system is the key link that migraineur's pain produces, its The generation of the Neurogenic inflammatory of middle meninges produces in migrainous pain and plays important in maintaining Effect.When being distributed in dural nervi trigeminus and being upset, discharge vaso-active substance, Make meningovascular expansion, plasma fraction extravasation, mast cell degranulation and platelet activation, produce Raw migraine.In addition, the neurotransmitter discharging after pain stimulation and the corresponding receptor on cell membrane In conjunction with, under second message,second messenger's effect, c-fos mrna gene expression, close in nuclear translation Become c-fos albumen, produce the physiological effect to the long time-histories of body.Therefore during migraine, trident god The cell number of the c-fos mrna through nucleus of spinal tract and nucleus raphes magnus and c-fos protein expression increases. Therefore, by measuring migraine animal cerebral dura mater the exudation of serum proteins amount and spinal nucleus of trigeminal nerve Caudal c-fos positive cell quantity can reflect migrainous degree.

Result of study is shown in Table 5, and electricity irritation rat trigeminal ganglion clearly results in cerebral dura mater serum egg Ooze out in vain, algin oligosaccharide derivant 25,50,100,200mg/kg successive administration 10 days, Oozing out of the cerebral dura mater serum albumin that electricity irritation rat trigeminal ganglion leads to can substantially be suppressed, its Suppression ratio is respectively 43.1%, 59.7%, 79.2%, 97.2%；Electricity irritation rat trigeminal After section, spinal nucleus of trigeminal nerve caudal c-fos expression positive cell number substantially increases, Algin Oligosaccharide derivative 25,50,100,200mg/kg successive administration 10 days, can substantially suppress c-fos Expression positive cell number increase, its suppression ratio be respectively 61.1%, 64.6%, 81.7%, 89.3%.Result display algin oligosaccharide derivant can substantially suppress electricity irritation trigeminal ganglion to lead The rat migraine causing.This shows that algin oligosaccharide derivant has the migrainous effect for the treatment of, Also indicate that algin oligosaccharide derivant has the effect for the treatment of pain.

Table 5. algin oligosaccharide derivant is to electricity irritation trigeminal ganglion deflection headache Rat Dura Mater serum egg White leaching rate (ppe leads) and the effect of spinal nucleus of trigeminal nerve caudal c-fos positive cell number (n=10, mean ± sd)

Claims

1. pharmaceutically can the connecing of algin oligosaccharide and its derivant or described widow's carbohydrates and their derivative It is used for the purposes of preparation treatment pain medication by salt.

2. purposes as claimed in claim 1, wherein said pain is acute pain, chronic Pain, neuropathic pain, postoperative pain, chronic low back pain, cluster headache, herpes neuralgia, Phantom pain, central pain, toothache, opioid-resistant pain, Encelialgia, operation pain, Pain in bone injury pain, tired and birth process, because burn including the pain leading to of tanning severely, Puerperal pain, migraine, angina pectoriss and the pain (inclusion cystitis) related to urogenital tract, Vascular pain, trigeminal neuralgia, intercostal neuralgia, operative incision pain, chronic fascitises pain, Talalgia, myalgia, skeleton pain, arthralgia, cancerous pain, Non-cancerous pain.

3. purposes as claimed in claim 1 or 2, wherein said algin oligosaccharide and its derivative Thing is the mannuronic acid widow passing through the bonded formation of Isosorbide-5-Nitrae glucosides selected from β-carubinose aldehydic acid Sugar or mannuronic acid oligosaccharide that reducing end 1 is carboxyl and its derivant or its pharmaceutically may be used The salt accepting.

4. purposes as claimed in claim 3, wherein said algin oligosaccharide and its derivant It is following structural (i) or algin oligosaccharide that formula (ii) represents and its derivant or described widow The pharmaceutically acceptable salt of carbohydrates and their derivative,

Wherein, in formula (i) or formula (ii), respective n is one or more selected from 0-20 Integer.

5. respective n in the purposes described in claim 4, its Chinese style (i) or formula (ii) It is the one or more integers selected from 0-10.

6. in the purposes described in claim 4 or 5, its Chinese style (i) or formula (ii) each N be one or more integers selected from 2-8.

7. in the purposes described in any one of claim 4-6, its Chinese style (i) or formula (ii) Respective n is 4.