CN1970579A - High substitution degree carboxymethyl indianbread polysaccharide and its preparation method and uses - Google Patents

High substitution degree carboxymethyl indianbread polysaccharide and its preparation method and uses Download PDF

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CN1970579A
CN1970579A CN 200610163425 CN200610163425A CN1970579A CN 1970579 A CN1970579 A CN 1970579A CN 200610163425 CN200610163425 CN 200610163425 CN 200610163425 A CN200610163425 A CN 200610163425A CN 1970579 A CN1970579 A CN 1970579A
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cmp
solution
pachymose
reaction
substitution value
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CN100509857C (en
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陈春霞
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Hunan Busky Pharmaceutical Co ltd
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戴甲木
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Abstract

The invention discloses a carboxymethyl pachyman (CMP) with high-degree of substitution and making method and application, which is characterized by the following: adopting water or water alcohol solution as dielectric; proceeding substitution reaction for pachyman, chloroacetic acid and fitful excessive sodium hydroxide to obtain CMP without vibrating technique and equipment; improving CMP D/S and solubility to reach injection need.

Description

High-substitution carboxymethyl Pachymose and preparation method thereof and its application
Technical field
The invention belongs to antitumor macromolecule polysaccharide field, (Carboxymethylpachymaran is CMP) and preparation method thereof with its application to relate in particular to carboxymethylpachymaran as the high degree of substitution by carboxymethyl of biological response modifier.
Background technology
Poria cocos is the dry sclerotia of polyporaceae plant Poria cocos [Poria cocos (Schw.) Wolf], it is one of traditional Chinese medicine " four monarch's eight delicacies " from ancient times, effect with " promoting diuresis to eliminate damp pathogen, the peaceful heart of invigorating the spleen ", ingredient Pachymose have the structure of β (1 → 3) bonded glucose linear structure and β (1 → 6) bonded glucosyl group side chain.Test shows, do not have anti-tumor activity without the Pachymose of chemical modification, and the decoction yield of Poria cocos in boiling water is no more than 1%.Carboxymethylpachymaran (CMP) through chemical modification obviously improves the water-soluble of Pachymose, be beneficial to absorption by human body, and CMP can induce and short people's blood lymphocyte generation interferon-' alpha ' (IFN-α) that induces, interferon-(IFN-γ), interleukin II (IL-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor various kinds of cell active factores such as (GM-CSF), has enhancing immunity, antitumor (mainly bringing into play anti-tumor activity) by raise immunity and activate immunity system of supervision, antiviral, anti-radiation, protect the liver, antibiotic, diuresis, improve sleep, hypoglycemic, reducing blood-fat, pharmacological activities such as anti-ageing or antifatigue, can be widely used in the assisting therapy of tumor chemoradiotherapy, significantly strengthen immunologic function in patients with malignant tumor, reduce and eliminate the side reaction of chemicotherapy, strengthen patient's physique, promote patient's appetite, improve patient's sleep, improve patient's life quality and prolongation life.CMP is a kind of novel biological response modifier (BRM).
Existing evidence: CMP presses 13.2g/kg dosage and irritates stomach mouse, no acute toxic reaction; CMP presses 0.22-1.73g/kg dosage (used dosage behaviour clinical dosage 180 times) and irritates stomach 12 weeks of rat, no toxic side effects, 3 months safety of continuous use; Toxicological test proves that also CMP does not have the result of mutagenesis, teratogenesis tire.
It is medium that people such as Hamuro (1971) adopt Virahol and water, the synthetic CMP that produces under the liquid-solid phase oscillating condition, because of need Large Oscillating equipment, be difficult to carry out suitability for industrialized production, and need a large amount of organic solvents (as ether, methyl alcohol, acetone, acetic acid and ethanol) that CMP is carried out aftertreatment and purifying, not only production cost is higher, also causes environmental pollution.
People such as Shi Qingdong (1996) are medium with ethanol and water, adopt to replace under the liquid-solid phase agitation condition and produce CMP, and the degree of substitution by carboxymethyl of gained CMP (DS) is 0.92, the solubleness that shows as product is less, foreign matter content is higher, in NaCl, and chloride %<3.0%; With P bMeter, heavy metal %<0.002%, and remove impurities difficult the separation, and having limited the clinical application range of CMP greatly, the CMP that makes as this method can not be used to prepare injection.
Therefore, the CMP of preparation high substitution value to improve its solubleness and to widen its clinical application range, becomes the technical problem that people press for solution.
Summary of the invention
Purpose one of the present invention provides a kind of method for preparing high substitution value CMP, comprising the steps: 1) Pachymose joins in water or the water alcohol mixed solution, after stirring, the basic solution that adds Pachymose quality 1-8% or 2-6% or 3-5%, be stirred to dissolving fully, get the Pachymose alkaline solution; 2) after the 1.0-10mol/L Mono Chloro Acetic Acid fully reacts with suitably excessive 2.0-10mol/L basic solution, join 1) in the Pachymose alkaline solution of step gained, carry out substitution reaction, the CMP that separation and purification generates, promptly.
Further, the molecular formula of described Pachymose is (C 6H 10O 5) n, can be made by method well known in the art, the Pachymose alkalization extracting solution as the alkalization extraction method makes is equivalent to 1) the Pachymose alkaline solution that makes of step; Or the Pachymose crude product that makes of alkaline extraction acid precipitation method.
Described alkalization extraction method is meant: it is extractions of alkalizing of the basic solution of 1.0-4.0mol/L or 2.0-3.0mol/L that Poria powder adds concentration, and supernatant liquor is got in centrifugation, promptly gets the Pachymose extracting solution that alkalizes.
Described alkaline extraction acid precipitation method is meant: Poria powder concentration is that the basic solution of 1.0-4.0mol/L or 2.0-3.0mol/L stirs extraction, and supernatant liquor is got in centrifugation; Supernatant liquor adds acid (as acetic acid, hydrochloric acid, sulfuric acid or nitric acid), gets acid deposit; Throw out promptly gets the Pachymose crude product through centrifugal, washing.
Further, described water-alcohol solution is that alcoholic solvent well known in the art adds the solution that water makes, and described alcoholic solvent is selected from any or its combination of methyl alcohol, ethanol, propylene glycol, ethyl acetate, acetone, dimethyl sulfoxide (DMSO), ether, Virahol, dimethyl formamide.
Basic solution of the present invention is dissolved in water by alkaline matter well known in the art and makes, and described alkaline matter is selected from any or its combination of sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, is preferably sodium hydroxide or potassium hydroxide.
Further, the concentration of chloroacetic acid solution is 2.0-9.0mol/L, is preferably 3.0-8.0mol/L, and more preferably 4.0-7.0mol/L most preferably is 4.5-6.0mol/L.
Further, 2) concentration of step basic solution is 3.0-9.0mol/L, is preferably 4.0-8.0mol/L, and more preferably 5.0-7.0mol/L most preferably is 5.5-6.5mol/L.
Further, the described suitably excessive actual amount that is meant basic solution neutral and alkali material is than itself and the excessive 0.5-40% of the required theoretical consumption of Mono Chloro Acetic Acid generation neutralization reaction, preferred excessive 5-30%, more preferably excessive 10-25%, most preferably excessive 15-20%.
Further, 2) reaction solution carries out substitution reaction 1-5h the step under 30-100 ℃ of condition, and preferable reaction temperature is 40-90 ℃, and other is preferably 50-85 ℃, more preferably 60-82 ℃, most preferably is 75-80 ℃; The preferred reaction time is 2-4h, more preferably 2.5-3.5h.
Further, described separation is meant 2) add the acidic solution of 1.0-10mol/L in the step reaction solution, transfer its pH value 5.0-7.0 after, the alcoholic solvent of 3-5 times of volume of adding is separated out the CMP crude product; Described alcoholic solvent is selected from any or its combination of methyl alcohol, ethanol, propylene glycol, ethyl acetate, Virahol, ether, acetone.
Acidic solution of the present invention is dissolved in water by acidic substance well known in the art and makes, and preferred described acidic substance are selected from any or its combination of acetic acid, hydrochloric acid, sulfuric acid or nitric acid, are preferably hydrochloric acid or nitric acid.
The principle of substitution reaction of the present invention is: (C 6H 10O 5) n+nClCH 2COOH+nNaOH → (C 8H 12O 7) n+nNaCl+nH 2O, (C 6H 10O 5) n+nClCH 2COOH+nKOH → (C 8H 12O 7) n+nKCl+nH 2O.
Because the concentration of Mono Chloro Acetic Acid and basic solution is higher in the substitution reaction, has other reactions of Mono Chloro Acetic Acid and alkaline matter, generates small molecular weight impurities such as a spot of sodium-chlor, sodium chloroacetate, hydroxyethanoic acid sodium, Repone K, potassium chloroacetate, hydroxyethanoic acid potassium.
Further, described purifying is meant that the CMP crude product adds the aqueous solution that water is made into 1.0-6.0% or 2.0-5.0% or 3-4%, adds the basic solution adjust pH 9.0-12.0 of 1.0-10mol/L, is stirred to the CMP crude product and dissolves fully; Add 30%H 2O 2Solution, its consumption are lysate cubic capacity 0.1 ‰-2.0 ‰ or 0.5 ‰-1.0 ‰, carry out decoloring reaction; The acidic solution adjust pH 5.0-7.0 that adds 1.0-10mol/L, ultrafiltration is removed molecular weight less than 0.7 * 10 4Daltonian CMP and other small molecular weight impurities.
Further, the concentration of basic solution is 2.0-9.0mol/L, is preferably 3.0-8.0mol/L, and more preferably 4.0-7.0mol/L most preferably is 5.0-6.0mol/L.
Further, the temperature of decoloring reaction is 10 ℃-70 ℃, is preferably 15 ℃-60 ℃, more preferably 20 ℃-50 ℃.The time of decoloring reaction decides according to the performance level of decoloring reaction, is generally 2-48h, is preferably 5-40h, and more preferably 10-30h most preferably is 15-25h.
Further, the concentration of acidic solution is 1.0-9.0mol/L, is preferably 2.0-8.0mol/L, and more preferably 3.0-7.0mol/L most preferably is 4.0-6.0mol/L.
Further, described ultrafiltration is to carry out ultrafiltration with the DH-UF hollow fiber membrane ultrafiltration device.
According to actual needs, can carry out the separating for several times purifying to the high substitution value CMP that reaction is produced, to improve its purity.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the molecular weight of high substitution value CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 6.0 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
The present invention to increase the effective collision frequency of alkalization Pachymose with sodium chloroacetate or potassium chloroacetate, accelerates carboxymethylation reaction speed, and improves the degree of substitution by carboxymethyl (DS) of CMP by improving the reaction density of Mono Chloro Acetic Acid and basic solution.The degree of substitution by carboxymethyl of the CMP that preparation method of the present invention obtains (DS) is not less than 1.0; obviously improve the solubleness of CMP; also shorten the reaction times; dwindle the cubic capacity of reaction system; reduce the consumption and the alcoholic solvent amount that remains in the waste water of alcoholic solvent in the purge process; reduce production costs greatly, be beneficial to environment protection.
The preparation method of CMP of the present invention is a liquid phase nonoscillatory technology, need not oscillator device, the convenient suitability for industrialized production that realizes, have characteristics such as easy, material-saving, energy-saving and environmental protection, improve degree of substitution by carboxymethyl (DS) and its solubleness of CMP simultaneously, quality product can reach the requirement of injecting drug use, obviously widens the clinical application range of CMP.
In addition, alcoholic solvent capable of circulation being used for of reclaiming waste reaction solution and ultrafiltration waste liquid produces.The liming that adds an amount of new preparation is in the waste liquid that reclaims behind the alcoholic solvent, and wherein molecular weight is less than 0.7 * 10 4Daltonian CMP, sodium chloroacetate, hydroxyethanoic acid sodium, potassium chloroacetate, hydroxyethanoic acid potassium and liming generate calcium precipitation, filtered and recycled or remove calcium precipitation, and contained small amount of sodium chloride, Repone K in the electrolysis treatment waste liquid, make it reach emission request, to reduce environmental pollution and to reduce production costs.
The present invention adopts calibration curve method to measure the average molecular weight range of carboxymethylpachymaran, adopts acid wash or acidization to measure its substitution value.The concrete mensuration process of acid wash is referring to Bolhuis Gerad K, Arends-Scholte Anna W, Stuut Gerrit J, etal Disintegration Efficiency of Sodium Starchglycolates Prepared fromDifferent Native Starchs[J] .Eur J Pharm Bio Pharm, 1994,40 (5): 317-320.
Another object of the present invention provides a kind of CMP of high substitution value, made by following method: 1) Pachymose joins in water or the water alcohol mixed solution, after stirring, adds the basic solution of Pachymose quality 1-8% or 2-6% or 3-5%, be stirred to dissolving fully, get the Pachymose alkaline solution; 2) after the 1.0-10mol/L Mono Chloro Acetic Acid fully reacts with suitably excessive 2.0-10mol/L basic solution, join 1) in the Pachymose alkaline solution of step gained, carry out substitution reaction, the CMP that separation and purification generates, promptly.
Further, the molecular formula of described Pachymose is (C 6H 10O 5) n, can be made by method well known in the art, the Pachymose alkalization extracting solution as the alkalization extraction method makes is equivalent to 1) the Pachymose alkaline solution that makes of step; Or the Pachymose crude product that makes of alkaline extraction acid precipitation method.
Described alkalization extraction method is meant: it is extractions of alkalizing of the basic solution of 1.0-4.0mol/L or 2.0-3.0mol/L that Poria powder adds concentration, and supernatant liquor is got in centrifugation, promptly gets the Pachymose extracting solution that alkalizes.
Described alkaline extraction acid precipitation method is meant: Poria powder concentration is that the basic solution of 1.0-4.0mol/L or 2.0-3.0mol/L stirs extraction, and supernatant liquor is got in centrifugation; Supernatant liquor adds acid (as acetic acid, hydrochloric acid, sulfuric acid or nitric acid), gets acid deposit; Throw out promptly gets the Pachymose crude product through centrifugal, washing.
Further, described water-alcohol solution is that alcoholic solvent well known in the art adds the solution that water makes, and described alcoholic solvent is selected from any or its combination of methyl alcohol, ethanol, propylene glycol, ethyl acetate, acetone, Virahol, ether, dimethyl sulfoxide (DMSO), dimethyl formamide.
Basic solution of the present invention is dissolved in water by alkaline matter well known in the art and makes, and described alkaline matter is selected from any or its combination of sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, is preferably sodium hydroxide or potassium hydroxide.
Further, the concentration of chloroacetic acid solution is 2.0-9.0mol/L, is preferably 3.0-8.0mol/L, and more preferably 4.0-7.0mol/L most preferably is 4.5-6.0mol/L.
Further, 2) concentration of step basic solution is 3.0-9.0mol/L, is preferably 4.0-8.0mol/L, and more preferably 5.0-7.0mol/L most preferably is 5.5-6.5mol/L.
Further, the described suitably excessive actual amount that is meant basic solution neutral and alkali material is than itself and the excessive 0.5-40% of the required theoretical consumption of Mono Chloro Acetic Acid generation neutralization reaction, preferred excessive 5-30%, more preferably excessive 10-25%, most preferably excessive 15-20%.
Further, 2) reaction solution carries out substitution reaction 1-5h the step under 30-100 ℃ of condition, and preferable reaction temperature is 40-90 ℃, and other is preferably 50-85 ℃, more preferably 60-82 ℃, most preferably is 75-80 ℃; The preferred reaction time is 2-4h, more preferably 2.5-3.5h.
Further, described separation is meant 2) add the acidic solution of 1.0-10mol/L in the step reaction solution, transfer its pH value 5.0-7.0 after, the alcoholic solvent of 3-5 times of volume of adding is separated out the CMP crude product; Described alcoholic solvent is selected from any or its combination of methyl alcohol, ethanol, propylene glycol, ethyl acetate, ether, Virahol, acetone.
Acidic solution of the present invention is dissolved in water by acidic substance well known in the art and makes, and preferred described acidic substance are selected from any or its combination of acetic acid, hydrochloric acid, sulfuric acid or nitric acid, are preferably hydrochloric acid or nitric acid.
Further, described purifying is meant that the CMP crude product adds the aqueous solution that water is made into 1.0-6.0% or 2.0-5.0% or 3-4%, adds the basic solution adjust pH 9.0-12.0 of 1.0-10mol/L, is stirred to the CMP crude product and dissolves fully; Add 30%H 2O 2Solution, its consumption are lysate cubic capacity 0.1 ‰-2.0 ‰ or 0.5 ‰-1.0 ‰, carry out decoloring reaction; The acidic solution adjust pH 5.0-7.0 that adds 1.0-10mol/L, ultrafiltration is removed molecular weight less than 0.7 * 10 4Daltonian CMP and other small molecular weight impurities.
Further, the concentration of basic solution is 2.0-9.0mol/L, is preferably 3.0-8.0mol/L, and more preferably 4.0-7.0mol/L most preferably is 5.0-6.0mol/L.
Further, the temperature of decoloring reaction is 10 ℃-70 ℃, is preferably 15 ℃-60 ℃, more preferably 20 ℃-50 ℃.The time of decoloring reaction decides according to the performance level of decoloring reaction, is generally 2h-48h, is preferably 5h-40h, and more preferably 10h-30h most preferably is 15h-25h.
Further, the concentration of acidic solution is 1.0-9.0mol/L, is preferably 2.0-8.0mol/L, and more preferably 3.0-7.0mol/L most preferably is 4.0-6.0mol/L.
Further, described ultrafiltration is to carry out ultrafiltration with the DH-UF hollow fiber membrane ultrafiltration device.
According to actual needs, can carry out the separating for several times purifying to the high substitution value CMP that reaction is produced, to improve its purity.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the molecular weight of high substitution value CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 60 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
Another object of the present invention is to provide a kind of pharmaceutical composition with enhancing immunity effect, described composition is made up of the CMP and the pharmaceutically acceptable carrier of high substitution value.
Composition of the present invention can be various formulation well known in the art.Be suitable for formulation of the present invention and can be oral preparations, external preparation or injection, be preferably oral preparations or injection.Described oral preparations is selected from oral liquid, tablet, capsule, granule, pill, powder, syrup, mixture, distillate medicinal water, suspension agent, emulsion or medicinal tea, and preferred described suspension agent is selected from does outstanding agent or suspension; Described external preparation is selected from gelifying agent, paste, liniment, lotion, basting agent etc., and preferred described paste is selected from emplastrum, coagulates paste or ointment; Described injection is selected from injection (injection liquid), transfusion or freeze-dried powder etc.Can adopt preparation technique means well known in the art to prepare composition of the present invention.
Described pharmaceutically acceptable carrier is usual excipients or the auxiliary material that is used to prepare described preparation well known in the art.Vehicle or auxiliary material that oral preparations or external preparation are commonly used include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent etc.Tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, Mierocrystalline cellulose and derivative thereof, gelatine size, syrup, starch slurry or polyvinylpyrrolidone, the preferred cellulose derivative is Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose or HPMC; Weighting agent, for example lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, inorganic calcium salt, sorbyl alcohol or glycine, preferred inorganic calcium salt is calcium sulfate, calcium phosphate, secondary calcium phosphate, precipitated calcium carbonate; Lubricant, for example micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyoxyethylene glycol; Disintegrating agent, for example starch and derivative thereof, polyvinylpyrrolidone or Microcrystalline Cellulose, preferred starch derivative is sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Vehicle or auxiliary material that described injection is commonly used include but are not limited to: oxidation inhibitor, for example S-WAT, sodium bisulfite and Sodium Pyrosulfite; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; Conditioning agent, for example hydrochloric acid, Citric Acid, potassium hydroxide, sodium hydroxide, Sodium Citrate and buffer reagent phosphoric acid dioxy sodium and Sodium phosphate dibasic; Emulsifying agent, for example Tween-80, do not have that sour sorb is smooth, Pu Luonike F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween-80, bile, glycerine etc.
In addition, also activeconstituents can be mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier, again according to the preparation method of sustained-release preparation well known in the art, as adding the retarding agent dressing or with making micropill after the active principle microcapsulesization again, as sustained release pellet or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the dressing retarding agent etc. of mixing, and described oil to mix agent be glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane, dimethyl siloxane; Described hydrophilic colloid is derivatived celluloses such as Xylo-Mucine, hydroxypropylcellulose, Vltra tears, or PVP, gum arabic, tragcanth or carbopol etc.; Described dressing retarding agent is ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic acid resinoid etc.
Further, the weight percentage of the CMP of contained high substitution value is 0.1-99% in the composition, is preferably 0.5-90%, and more preferably 5-80% most preferably is 10-65%.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the molecular weight of high substitution value CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 6.0 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
Another object of the present invention is to provide a kind of CMP oral liquid, form by the CMP and the pharmaceutically acceptable carrier of high substitution value with enhancing immunity effect.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the weight percentage of contained high substitution value CMP is 0.1-30% in the oral liquid, is preferably 0.5-25%, and more preferably 1.0-20% most preferably is 2-15%.
Further, the molecular weight of high substitution value CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 6.0 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
Another object of the present invention is to provide a kind of CMP freeze-dried powder, form by the CMP and the pharmaceutically acceptable carrier of high substitution value with enhancing immunity effect.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the weight percentage of contained high substitution value CMP is 0.1-10% in the freeze-dried powder, is preferably 0.5-8%, and more preferably 1.0-6% most preferably is 1.5-5%.
Further, described pharmaceutically acceptable carrier is selected from any or its combination of freeze-dried excipient or osmotic pressure regulator.
Further, described freeze-dried excipient is selected from any or its combination of N.F,USP MANNITOL, dextran (dextran), amino acid, glucose, sucrose, lactose, sorbyl alcohol, trehalose, gelatin hydrolysate or sodium-chlor, and described amino acid is preferably any or its combination of arginine or Methionin; Preferred freeze-dried excipient is any or its combination of N.F,USP MANNITOL, glucose, sucrose, lactose, arginine, Methionin or sodium-chlor, more preferably any or its combination of N.F,USP MANNITOL, glucose, sucrose or sodium-chlor.
Further, described osmotic pressure regulator is selected from any or its combination of glucose, sucrose or sodium-chlor.
Further, the molecular weight of CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 6.0 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
Except as otherwise noted, percentage composition of the present invention is weight percentage, and described molecular weight is relative molecular weight, and its unit is dalton.
The daily dosage of CMP of the present invention or its composition, day is taken number of times and the cycle of taking can decide according to patient's composite factors such as the state of an illness, age, sex, physique and other medicining conditions.Common daily dosage is 5mg-1000mg/ day, is preferably 10mg-800mg/ day, more preferably 20mg-600mg/ day, also is preferably 25mg-400mg/ day, most preferably is 50mg-300mg/ day.Take number of times and be 1-4 time/day or 2-3 time/day or 1 time/day or 1 time/next day.Usually 4 weeks of continuous use are 1 course of treatment, can significantly improve the T of tumour patient 4/ T 8Ratio and natural killer (NK) cell activity, work in coordination with and kill, kill and wound malignant cell, suppress the development and the transfer of malignant tumour, also can improve various patients' appetite and digestion, improve and eliminate patient's clinical symptom such as poor appetite, stomach discomfort, abdominal distension, diarrhoea, dry mouth and tougue, and the clinical symptom such as stomach abdominal pain, hepatalgia, constipation of alleviating and overcome the patient.Take the CMP or 3~6 courses of treatment of its composition, remarkable to the prognosis of malignant tumor patient, and do not see tangible toxic side effects.
Another object of the present invention is to provide high substitution value CMP to be used for preparing and have enhancing immunity, antitumor, antiviral, anti-ly radiate, protect the liver, antibiotic, diuresis, improvement are slept, the application of the medicine of hypoglycemic, reducing blood-fat, anti-ageing or anti-fatigue effect.
Further, described enhancing immunity is used and is meant the various hypoimmunity crowds that are applicable to, as middle-aged and old immunocompromised persons, chronic bronchitis, chronic hepatitis, chronic nephritis, malignant tumour or AIDS patient's control or assisting therapy.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the molecular weight of CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 6.0 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
Another object of the present invention is to provide high substitution value CMP to be used for preparing the application of excipient substance, preferred described excipient substance is disintegrating agent or tackiness agent.
Pachymose has the polysaccharide poly-hydroxy structure that is similar to chitosan, is easy to carry out number of chemical and modifies or high molecular polymerization.High substitution value CMP after carboxymethyl is modified not only itself has multiple pharmacologically active and (as has enhancing immunity, antitumor, antiviral, anti-radiation, protect the liver, antibiotic, diuresis, improve sleep, hypoglycemic, reducing blood-fat, multiple efficacies such as anti-ageing or antifatigue), good biocompatibility, biodegradability, and has a good water absorption and swelling, can water-swelling generate gel, water-swelling at normal temperatures and not gelatinization, can quicken and control the disintegration and the stripping of preparation of traditional Chinese medicine composition, has good disintegrating property, cohesiveness, swelling property, compatibility, compressibility, mobile, and have bigger surface-area and a porosity, improve moisture absorption speed and water regain, increase swelling capacity, make effective constituent in the preparation in disintegrating procedue, be Powdered evenly collapse diffusing, strengthen the disintegration ability of preparation, improve bioavailability of medicament, have good disintegrating property.In addition, high substitution value CMP has coarse structure and (has tangible land waste rock shape structure through the visible CMP particle surface of electron-microscope scanning, particle surface is uneven), and has bigger tessellation between pharmaceutical cpd and other auxiliary materials, strengthen cohesive strength, be beneficial to preparations shaping, can be used as the disintegrating agent or the tackiness agent of preparation, to improve the hardness and the glossiness of preparation.
Further, the degree of substitution by carboxymethyl of described CMP is not less than 1.0, preferably is not less than 1.05, more preferably is not less than 1.10, most preferably is not less than 1.2.
Further, the molecular weight of CMP is 0.7 * 10 4-1.0 * 10 6Dalton is preferably 3.0 * 10 4-8 * 10 5Dalton, more preferably 6.0 * 10 4-5.0 * 10 5Dalton most preferably is 8.0 * 10 4-3.0 * 10 5Dalton.
Further, the polymerization degree of high substitution value CMP is 32<n<4545, is preferably 136<n<3636, and more preferably 272<n<2272 most preferably are 363<n<1363.
Description of drawings
The standard polysaccharide Dexfran of Fig. 1 known molecular amount presses the molecular weight standard curve of Ka.v logarithm Log Mw mapping;
The elution curve of the carboxymethylpachymaran that Fig. 2 the present invention makes on the SephadexG-200 chromatography column, according to the Ka.v value that records, trying to achieve its molecular weight is 0.7 * 10 4-1.0 * 10 6Dalton.
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment 1The preparation of high substitution value CMP
High substitution value CMP is made by following method:
1) dried Poria cocos 75kg is ground into fine powder, puts in the steeping tank, pumps into 400L water, stirs, and soaks 12h;
2) be that the sodium hydroxide solution of 2.25mol/L slowly pumps in the steeping tank with 400L concentration, stirring reaction 1h filters, and gets filtrate;
3) in neutralization tank, drop into after 300L concentration is the chloroacetic acid solution of 5.3mol/L, slowly add the sodium hydroxide solution that 300L concentration is 6.25mol/L again, be stirred to sufficient reacting, be cooled to room temperature;
4) with 3) the step reaction solution pumps into 2) in the step gained filtrate, fully behind the mixing, slowly be warming up to 75 ℃, isothermal reaction 2.5h;
5) transfer 4 with the hydrochloric acid soln of 6mol/L) the pH value 5.0-7.0 of step gained reaction solution, add 95% ethanol that is equivalent to 3 times of volumes of reaction solution, stir, filter, wash, get CMP alcohol and analyse thing;
9) CMP alcohol is analysed thing behind 60 ℃ of dry 4h, and 105 ℃ of dry 2h get CMP raw product 37.5kg.
10) the 7.5kgCMP raw product is scattered in the 250L distilled water, the sodium hydroxide solution that adds 6mol/L is transferred pH to 10.0-13.0; Adding 1.25L concentration is 30% H 2O 2Solution, 15 ℃ of decoloring reaction 36h remove foreign pigment; Add 6.0,3000 rev/mins of centrifugation 30min of hydrochloric acid soln adjust pH of 6mol/L, get filtrate, filtrate is used DH-UF hollow fiber membrane ultrafiltration device filtering molecular weight 0.7 * 10 4Following CMP, and behind the impurity such as sodium-chlor, sodium chloroacetate and hydroxyethanoic acid sodium of trace, 95% ethanol that adds 3 times of filtrate volumes in the filtrate, carry out alcohol and analyse, filtration or centrifugal is got CMP alcohol and is analysed thing behind 60 ℃ of dry 4h, 105 ℃ of dry 2h, pulverize, get the pure product of CMP of 6.0kg degree of substitution by carboxymethyl 1.0, it has following physico-chemical property:
Proterties: white powder, odorless slightly draws moist.
Molecular formula: (C 8H 12O 7) the n polymerization degree (n): 32<n<4545
Molecular weight: 0.7 * 10 4-1.0 * 10 6Dalton
IR[KBr](cm -1):3700-3000,2900,1600.7,1425.2,1324.9,1078.0,891.0。
UV (0.1mol/L HCl solution, H 2O, 0.1mol/LNaOH solution): no absorption peak.
13C-NMP[H 2D](ppm):180.078,104.870,87.697,86.667,84.935,83.145,77.851,76.490,75.669,73.273,72.296,70.345,62.975。
[a] 20D:-1.70-1.90(C=5,H 2O)
1% pH value of aqueous solution 5.0-7.0
Moisture content percentage composition<8.0%
In sodium-chlor, muriate %<0.01%; With P bMeter, heavy metal %<0.001%, in As, arsenic %<0.0001%.
Embodiment 2The mensuration of carboxymethylpachymaran molecular weight
Condition determination: instrument is a LKB column chromatography system, the SephadexG-200 post.Mobile phase is NaCl solution (the pH value 7.0) buffered soln of 0.2mol/L, flow velocity 0.5ml/min, sample size (W/V) 1mg/ml, 10 ℃ of constant temperature.The differential refraction detects automatically, registering instrument record peak position.
Typical curve: with standard polysaccharide Dexfran T2000 (Mw2000000), T500 (Mw500000), T40 (Mw40000), T20 (Mw20000), T10 (Mw10000), T5 (Mw5000) the production standard curve of known molecular amount, press Ka.v logarithm Log Mw mapping, typical curve is seen Fig. 1.
The elution curve of the carboxymethylpachymaran that the present invention makes on the SephadexG-200 chromatography column is referring to Fig. 2, and according to the Ka.v value that records, trying to achieve its molecular weight (Mw) is 0.7 * 10 4-1.0 * 10 6Dalton.
Molecular formula according to carboxymethylpachymaran is (C 8H 12O 7) n, its molecule measuring definite value is 0.7 * 10 4-1.0 * 10 6, the polymerization degree (n) 0.7 * 10 4/ Mw C8H12O7<n<1.0 * 10 6/ Mw C8H12O7, promptly the polymerization degree of carboxymethylpachymaran of the present invention (n) is 32<n<4545.
Embodiment 3Acidization is measured the degree of substitution by carboxymethyl (DS) of carboxymethylpachymaran
Precision takes by weighing carboxymethylpachymaran sample 0.4041g, place the beaker of 150ml, 80 ℃ of heating in water bath stir and make dissolving, after the cooling, hydrochloric acid soln with 2mol/L is transferred pH to 4.0, adds dehydrated alcohol 100ml, stirs, standing over night, centrifugation alcohol is analysed thing, and alcohol is analysed thing with 95% ethanol repetitive scrubbing, chloride ion-containing not to the washings.Clean alcohol is analysed the NaoH standardized solution 40.00ml dissolving of thing with 0.1000mol/L, after treating that solution is transparence, use the standard salt acid solution back titration of 0.1000mol/L immediately, redness to phenolphthalein indicator is just decorporated, and the volume of the hydrochloric acid standard solution of record 0.1000mol/L that back titration consumes is 2 1.60ml.
Calculate the substitution value (DS) of carboxymethylpachymaran according to following formula:
D · S = 0.162 A 1 - 0.058 A A = C NaOH V NaOH - C HCl V HCl m
In the formula: A be in and the mmol number of the NaOH that consumed of 1g acid carboxymethylpachymaran sample;
C NaOHConcentration (0.1000mol/L) for the NaOH standardized solution;
V NaOHVolume number (40.00ml) for the NaOH standardized solution that adds 0.1000mol/L;
C HClThe concentration (0.1000mol/L) of the hydrochloric acid standard solution of using for back titration;
V HClVolume number (21.60ml) for the hydrochloric acid standard solution of 0.1000mol/L that back titration consumes;
M is the quality (g) of sample;
0.162 be the mmol quality of the dehydration glucose unit of Pachymose;
0.058 after a hydroxyl is replaced by carboxymethyl in the dehydration glucose unit, the net added value of dehydration glucose unit mmol quality.
The degree of substitution by carboxymethyl of gained carboxymethylpachymaran of the present invention (D.S) is 1.0, and computation process is as follows:
A = 0.1000 × 40.00 - 0.1000 × 21.60 0.4041 = 4.5533 ( m mol )
D · S = 0.162 × 4.5533 1 - 0.058 × 4.5533 = 1.0
Embodiment 4The preparation of high substitution value CMP
High substitution value CMP is made by following method:
1) the dried Poria cocos fine powder of 75kg pumps into 400L water, stirs, and soaks 14h;
2) be that the sodium hydroxide solution of 3mol/L slowly pumps in the steeping tank with 400L concentration, stirring reaction 1h filters, and gets filtrate;
3) in neutralization tank, drop into after 300L concentration is the chloroacetic acid solution of 5.5mol/L, slowly add the sodium hydroxide solution that 300L concentration is 6.5mol/L again, be stirred to sufficient reacting, be cooled to room temperature;
4) with 3) the step reaction solution pumps into 2) in the step gained filtrate, fully behind the mixing, slowly be warming up to 78 ℃, isothermal reaction 2h;
5) transfer 4 with the hydrochloric acid soln of 6mol/L) the pH value 6.0 of step gained reaction solution, add 95% ethanol that is equivalent to 3 times of volumes of reaction solution, stir, filter, wash, get CMP alcohol and analyse thing;
9) CMP alcohol is analysed thing behind 60 ℃ of dry 4h, and 105 ℃ of dry 2h get CMP raw product 37.8kg.
10) the 7.5kgCMP raw product is scattered in the 250L distilled water, the sodium hydroxide solution that adds 6.5mol/L is transferred pH to 10.0-13.0; Adding 1.5L concentration is 30% H 2O 2Solution, 25 ℃ of decoloring reaction 20h remove foreign pigment; Add 6.0,3000 rev/mins of centrifugation 30min of hydrochloric acid soln adjust pH of 6.5mol/L, get filtrate, filtrate is used DH-UF hollow fiber membrane ultrafiltration device filtering molecular weight 0.7 * 10 4Following CMP and other small molecular weight impurities, 95% ethanol that adds 3.2 times of filtrate volumes in the filtrate, carrying out alcohol analyses, filtration or centrifugal, get CMP alcohol and analyse thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, pulverize, get the pure product of CMP of 6.1kg degree of substitution by carboxymethyl 1.05, its relative molecular weight is 0.7 * 10 4-1.0 * 10 6Dalton.
Embodiment 5The preparation of high substitution value CMP
High substitution value CMP is made by following method:
1) the dried Poria cocos fine powder of 75kg pumps into 400L water, stirs, and soaks 16h;
2) be that the sodium hydroxide solution of 4mol/L slowly pumps in the steeping tank with 400L concentration, stirring reaction 1h filters, and gets filtrate;
3) in neutralization tank, drop into after 300L concentration is the chloroacetic acid solution of 6.0mol/L, slowly add the sodium hydroxide solution that 300L concentration is 6.8mol/L again, be stirred to sufficient reacting, be cooled to room temperature;
4) with 3) the step reaction solution pumps into 2) in the step gained filtrate, fully behind the mixing, slowly be warming up to 82 ℃, isothermal reaction 1.5h;
5) transfer 4 with the hydrochloric acid soln of 6mol/L) the pH value 6.0 of step gained reaction solution, add 95% ethanol that is equivalent to 3 times of volumes of reaction solution, stir, filter, wash, get CMP alcohol and analyse thing;
9) CMP alcohol is analysed thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, gets CMP raw product 37.9kg.
10) the 7.5kgCMP raw product is scattered in the 250L distilled water, the sodium hydroxide solution that adds 6.5mol/L is transferred pH to 10.0-13.0; Adding 1.6L concentration is 30% H 2O 2Solution, 30 ℃ of decoloring reaction 18h remove foreign pigment; Add 6.0,3000 rev/mins of centrifugation 30min of hydrochloric acid soln adjust pH of 6.5mol/L, get filtrate, filtrate is used DH-UF hollow fiber membrane ultrafiltration device filtering molecular weight 0.7 * 10 4Following CMP and other small molecular weight impurities, 95% ethanol that adds 3.2 times of filtrate volumes in the filtrate, carrying out alcohol analyses, filtration or centrifugal, get CMP alcohol and analyse thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, pulverize, get the pure product of CMP of 6.15kg degree of substitution by carboxymethyl 1.10, its relative molecular weight is 0.7 * 10 4-1.0 * 10 6Dalton.
Embodiment 6The preparation of high substitution value CMP
High substitution value CMP is made by following method:
1) the dried Poria cocos fine powder of 75kg pumps into 400L water, stirs, and soaks 16h;
2) be that the sodium hydroxide solution of 4mol/L slowly pumps in the steeping tank with 400L concentration, stirring reaction 1h filters, and gets filtrate;
3) in neutralization tank, drop into after 300L concentration is the chloroacetic acid solution of 5.8mol/L, slowly add the sodium hydroxide solution that 300L concentration is 7.0mol/L again, be stirred to sufficient reacting, be cooled to room temperature;
4) with 3) the step reaction solution pumps into 2) in the step gained filtrate, fully behind the mixing, slowly be warming up to 82 ℃, isothermal reaction 1h;
5) transfer 4 with the hydrochloric acid soln of 6mol/L) the pH value 6.0 of step gained reaction solution, add 95% ethanol that is equivalent to 3 times of volumes of reaction solution, stir, filter, wash, get CMP alcohol and analyse thing;
9) CMP alcohol is analysed thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, gets CMP raw product 38.1kg.
10) the 7.5kgCMP raw product is scattered in the 250L distilled water, the sodium hydroxide solution that adds 6.5mol/L is transferred pH to 10.0-13.0; Adding 1.6L concentration is 30% H 2O 2Solution, 30 ℃ of decoloring reaction 18h remove foreign pigment; Add 6.0,3000 rev/mins of centrifugation 30min of hydrochloric acid soln adjust pH of 6.5mol/L, get filtrate, filtrate is used DH-UF hollow fiber membrane ultrafiltration device filtering molecular weight 0.7 * 10 4Following CMP and other small molecular weight impurities, 95% ethanol that adds 3.2 times of filtrate volumes in the filtrate, carrying out alcohol analyses, filtration or centrifugal, get CMP alcohol and analyse thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, pulverize, get the pure product of CMP of 6.18kg degree of substitution by carboxymethyl 1.15, its relative molecular weight is 0.7 * 10 4-1.0 * 10 6Dalton.
Embodiment 7The preparation of high substitution value CMP
High substitution value CMP is made by following method:
1) the dried Poria cocos fine powder of 75kg pumps into 400L water, stirs, and soaks 16h;
2) be that the sodium hydroxide solution of 5mol/L slowly pumps in the steeping tank with 400L concentration, stirring reaction 1h filters, and gets filtrate;
3) in neutralization tank, drop into after 300L concentration is the chloroacetic acid solution of 6.0mol/L, slowly add the sodium hydroxide solution that 300L concentration is 7.2mol/L again, be stirred to sufficient reacting, be cooled to room temperature;
4) with 3) the step reaction solution pumps into 2) in the step gained filtrate, fully behind the mixing, slowly be warming up to 85 ℃, isothermal reaction 1h;
5) transfer 4 with the hydrochloric acid soln of 6mol/L) the pH value 6.0 of step gained reaction solution, add 95% ethanol that is equivalent to 3 times of volumes of reaction solution, stir, filter, wash, get CMP alcohol and analyse thing;
9) CMP alcohol is analysed thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, gets CMP raw product 40.0kg.
10) the 7.5kgCMP raw product is scattered in the 250L distilled water, the sodium hydroxide solution that adds 6.5mol/L is transferred pH to 10.0-13.0; Adding 1.6L concentration is 30% H 2O 2Solution, 30 ℃ of decoloring reaction 15h remove foreign pigment; Add 6.0,3000 rev/mins of centrifugation 30min of hydrochloric acid soln adjust pH of 6.5mol/L, get filtrate, filtrate is used DH-UF hollow fiber membrane ultrafiltration device filtering molecular weight 0.7 * 10 4Following CMP and other small molecular weight impurities, 95% ethanol that adds 3.2 times of filtrate volumes in the filtrate, carrying out alcohol analyses, filtration or centrifugal, get CMP alcohol and analyse thing successively at 60 ℃ of dry 4h and 105 ℃ of dry 2h, pulverize, get the pure product of CMP of 6.2kg degree of substitution by carboxymethyl 1.20, its relative molecular weight is 0.7 * 10 4-1.0 * 10 6Dalton.
Embodiment 8The preparation of high substitution value CMP oral liquid
In the clean area proportioning room, the 100L deionized water is pumped in the clean lass lining material-compound tank, drop into the pure product of GMP of 20kg, the molecular weight of the pure product of CMP (Mw) is 0.7 * 10 4-1.0 * 10 6, the substitution value of carboxymethyl is 1.05; The interlayer input steam of material-compound tank, 100 ℃ of heating for dissolving, cooling, press filtration, filtrate pump in another glass-lined reactor of cleaning, add Sodium Cyclamate 1.5kg, Sorbic Acid 1.5kg, stir, molten dosing is carried out auto-filling at clean area, the 10ml/ bottle, can is finished, and seals, put 115 ℃ of sterilization 30min in the steam sterilization cabinet, promptly.
Embodiment 9The preparation of high substitution value CMP freeze-dried powder
In the clean area proportioning room, the 100L bi-distilled water is pumped in the clean lass lining material-compound tank, drop into pure product of CMP and the 1200g sodium chloride for injection of 656g, the molecular weight of the pure product of CMP (Mw) is 0.7 * 10 4-1.0 * 10 6, the substitution value of carboxymethyl is 1.10; The interlayer input steam of material-compound tank is heated to 80 ℃, and insulation 30min stirs and makes dissolving.Be cooled to room temperature, carry out coarse filtration with the ceramic filter stick of aperture<1 μ m, coarse filtration liquid uses the glass filter bulb of aperture<0.5 μ m to carry out the essence filter again.Smart filtrate is carried out auto-filling by the 5ml/ bottle at aseptic area, and can is finished, and places sterilisable chamber, successively carries out vacuum freezedrying under-25 ℃ and-70 ℃ of conditions, sterile seal, promptly.
High substitution value CMP freeze-dried powder is after high temperature (40 ℃, 60 ℃, 80 ℃), high humidity (RH92.5%, RH75%, 25 ℃) and the test of illumination influence factors such as (4000Lx), and appearance character, clarity, pH value, content and sterility test all meet the requirements.Through the trimestral investigation result of accelerated test (40 ℃, RH75%), appearance character, clarity, pH value, content and sterility test all meet the requirements.Keep sample through room temperature and to investigate 1,3,5,12,18,24 month, through regularly taking a sample to check, every index all meets the requirements.
Below by testing the multiple pharmacological effect of the high substitution value CMP that example checking the present invention makes.Except as otherwise noted, the present invention tests the dosage standard of example all in the pure product of CMP.
Test example 1The enhancing immunity effect of high substitution value CMP
Carboxymethylpachymaran is pressed 50mg/kg dosage subcutaneous injection every day Kunming mouse 1 time, logotype 10 days, compare with the control group cortisone acetate, the phagocytic rate of Turnover of Mouse Peritoneal Macrophages increases by 84.57% (P<0.01), and phagocytic index increases by 110.0% (P<0.05).
Carboxymethylpachymaran is pressed the Switzerland mouse 1 time of 50mg/kg dosage subcutaneous injection every day lotus S180 sarcoma, logotype 10 days, compare with control group physiological saline, can make that the abdominal cavity of mouse is huge bites thin phagocytic rate and phagocytic index increases by 70.83% (P<0.01) and 112.0% (P<0.01) respectively.
Carboxymethylpachymaran is pressed the C57 mouse inbred lines 1 time of 50mg/kg dosage subcutaneous injection every day band Lewis lung cancer, logotype 10 days, compare with control group physiological saline, can make the phagocytic rate and the phagocytic index branch of the peritoneal macrophage of mouse add 142.47% (P<0.01) and 136.36% (P<0.05) in the side of increasing in addition.
The NIH mouse is irritated stomach by (120~480) mg/kg dosage give CMP, the immunosuppression that can cause antineoplastic chemotherapy medicine endoxan (Cy), the thymus gland of NIH mouse, the weight of spleen are increased, the content of hemolytic antibody raises, improvement and elimination endoxan are to its restraining effect, strengthen phagocytosis of macrophages, improve the NK cell activity, promote interleukin II (IL-2) to normal level, the content of tumour necrosis factor (TNF) of the NIH mouse of lotus knurl is obviously increased.
Carboxymethylpachymaran is pressed (25~200) mg/kg dosage intraperitoneal injection of mice every day 1 time, and logotype 4 days is compared with control group physiological saline, and the PFC and the SRFC of mouse boosting cell obviously increases (P<0.01).
Carboxymethylpachymaran is pressed 100mg/kg dosage abdominal injection every day 1 time, and logotype 4 days is compared with control group physiological saline, and mouse strengthens (P<0.01) to the DTH significant reaction that BSA brings out.
Carboxymethylpachymaran (0.05~500) μ g/ml concentration has obvious facilitation to the propagation of C57BL/6J and the two-way mixing splenic lymphocyte cultivation of BALB/C mice, with two-way splenic lymphocyte nutrient solution ratio, P<0.05 of mixing that does not add carboxymethylpachymaran.
The peritoneal macrophage of carboxymethylpachymaran (5~100) μ g/ml concentration and Kunming mouse is cultivated altogether, supernatant liquor tumor necrosis factor-alpha (TNF-α) secretion increasing, with the control group ratio of the common nutrient solution of the peritoneal macrophage that does not add carboxymethylpachymaran, P<0.05.
Test example 2The antitumor action of high substitution value CMP
Carboxymethylpachymaran (100~300) mg/kg dosage is irritated stomach, be 47.76%~61.94% to the inhibiting rate of the S180 sarcoma of NIH mouse, and the 5-Fu inhibiting rate of 20mg/kg dosage is 59.70%, and both contrast P<0.05.
Carboxymethylpachymaran (150~300) mg/kg dosage is irritated stomach, is 39.22%~59.80% to the inhibiting rate of the EAC knurl strain of NIH mouse, with control group physiological saline ratio, P value<0.05.
Carboxymethylpachymaran (25~500) mg/kg dosage abdominal injection every day 1 time, logotype 10 days is 75.5%~92.7% to the inhibiting rate of ICR/JCL mouse tumor U-14, with control group physiological saline ratio, P<0.01.
Irritate stomach next day of carboxymethylpachymaran (50~200) mg/kg dosage, the inhibiting rate to Kunming mouse liver cancer H22 after 12 days is 39.03%~62.24%, with control group physiological saline ratio, P<0.05.
Carboxymethylpachymaran 25mg/kg dosage abdominal injection every day 1 time, logotype 10 days is 32.0% to the inhibiting rate of C57 mouse inbred lines Lewis lung cancer, with control group physiological saline ratio, P<0.01.
Carboxymethylpachymaran (0.1~50) μ g/ml concentration all has the obvious suppression effect to the S180 sarcoma of the Kunming mouse of vitro culture and the growth of liver cancer H22 cell, S180 sarcoma and liver cancer H22 cell control group ratio, P<0.05 with the vitro culture that does not add carboxymethylpachymaran.
Test example 3The antivirus action of high substitution value CMP
With the carboxymethylpachymaran pre-treatment human embryonic lung cell of (0.1~1.0) mg/ml concentration 24 hours, abandon supernatant liquor, the folliculus stomatitis virus (VSV-Indiana strain) that adds different concns again, hatched 24 hours in 37 ℃, the CPE situation that VSV-Indiana is presented on the human embryonic lung cell, with the control group ratio that does not add carboxymethylpachymaran, significant difference is arranged, 0.1mg/ml be effective indirect antiviral concentration, 1.0mg/ml the concentration antiviral effect is more remarkable, on people's embryo myocyte with the human embryonic lung cell on presented ask that it is consistent connecing antivirus action.
Carboxymethylpachymaran has provide protection to the pig kidney passage cell pathology that causes because of infection herpes simplex virus I-type (HSV-I), is infecting (10~100) TCID 50Under the situation of the HSV-I of (half cell cultures infective dose), the carboxymethylpachymaran of 2.0mg/ml concentration has direct restraining effect to the cytopathy (CPE) that HSV-I causes pig kidney passage cell, is infecting HSV-I100TCID 50Situation under, the ID of carboxymethylpachymaran 50Be 0.5mg/ml.
Test example 4The anti-radiation function of high substitution value CMP
Carboxymethylpachymaran can resist 60The leukocytic inhibition of Co-r ray induced mice tip, the mouse of test group is pressed 100mg/kg dosage abdominal injection every day 1 time, logotype 7 days, then 60Co-r radiation exposure 14.9min (50.4 roentgens/min), total exit dose 750 roentgens continued administration 5 again, and the not leukocyte count and physiological saline control group ratio slightly of the mouse of test group increase by 69.41%, P<0.05.
Test example 5The hepatoprotective effect of high substitution value CMP
Carboxymethylpachymaran has provide protection to the liver of carbon tetrachloride poisoning mouse; the test group mouse is pressed (100,200) mg/kg dosage abdominal injection every day 1 time with carboxymethylpachymaran; logotype 5 days; the isometric physiological saline of control group mice abdominal injection every day; logotype 5 days; afternoon on the 5th, each organizes mouse by subcutaneous injection 0.15% tetracol phenixin peanut oil solution 0.2ml.Put to death mouse after 16 hours, get the hematometry serum glutamic pyruvic transaminase, test group mice serum glutamate pyruvate transaminase reduces by 27.32% and 41.03% respectively, with physiological saline control group ratio, P<0.01.
Press 100mg/kg dosage abdominal injection every day 1 time before the rat liver partial excision operation, logotype 4 days, part is excised the left lobe of liver of rat and middle period (account for full liver 65%~75%) then, successive administration 3 days again after the operation, drug withdrawal was put to death rat after 2 days, got liver and weighed, and liver regeneration degree and the Liver Regeneration of rat be heavy/and body weight increases by 73.29% and 18.95% respectively, with physiological saline control group ratio, P<0.01 and P<0.001.
Test example 6High substitution value CMP is to the improvement effect of sleep
Test group Switzerland mouse is pressed 100mg/kg dosage abdominal injection every day carboxymethylpachymaran 1 time, logotype 7 days, the isometric physiological saline of control group Switzerland mouse abdominal injection every day, logotype 7 days, each group was all by 50mg/kg dosage abdominal injection Thiopental Sodium injection liquid on 1, observe the time that the mouse righting reflex loss continues of respectively organizing then, the result of test proves, carboxymethylpachymaran can strengthen the inhibition of Thiopental Sodium to the mouse maincenter, the time that the mouse righting reflex loss of carboxymethylpachymaran test group continues is 4.69 times of Thiopental Sodium control group, with Thiopental Sodium control group ratio, P<0.05.
Test example 5High substitution value CMP induces and urgees to induce the effect of the human blood lymphocyte activity factor
Carboxymethylpachymaran with different concns (1.25~100) μ g/ml induces and urgees to induce people quasi-lymphocyte interferon-α (Interferon-α, IFN-α), and inducing tires improves 6 times, and the short potency ratio routine that induces induces 10~20 times of raisings.
Carboxymethylpachymaran with 100 μ g/ml concentration induces and the short human peripheral lymphocyte interferon-r (Interferon-r that induces, 1FN-r), interleukin II (Interleukin-2, IL-2), interleukin-6 (Interleukin-6, IL-6) with tumor necrosis factor-alpha (Tumor necrosis factor-α, TNF-α), inducing tires improves 10.9,0.8,0.5,4.0 times respectively, urgees to induce to tire to induce raising (0.4~0.6), (1.2~2.8), (0.5~0.8), (0.5~1.1) doubly than routine respectively.
Induce with short with the carboxymethylpachymaran of 100 μ g/ml concentration and to induce the human peripheral lymphocyte granulocyte-macrophage colony-stimulating factor (Granulocyte-macrophage colony-stimulating factor, GM-CSF), tiring to reach 8 * 10 4More than the U/ml.
In sum, carboxymethylpachymaran is mainly brought into play its multiple good pharmacological action by the following mechanism of action:
1) dependence host's immunity system, enhancing body immunizing power (specificity and non-specific) suppresses and killing tumor cell.By activating complement, induce the multiple lymphocyte activity factor, strengthen the activity of scavenger cell, NK cell, T lymphocyte and bone-marrow-derived lymphocyte, antitumor, the antivirus action of multipath synergy performance.
2) suppress tumour cell DNA, RNA and synthesize, directly kill killing tumor cell.
3) sialic acid (SA) content, the inhibition PI that improves on the tumor cell membrane changes, reduces arachidonic acid (C 20) content that waits, multipath suppresses the division and the propagation of tumour cell.
4) strengthen the liver SOD activity, remove oxyradical, dissolve carcinogenic substance, prevent normal cell DNA variation.

Claims (10)

1, a kind of method for preparing high substitution value CMP, comprising the steps: 1) Pachymose joins in water or the water alcohol mixed solution, after stirring, adds the basic solution of Pachymose quality 1-8% or 2-6% or 3-5%, be stirred to dissolving fully, get the Pachymose alkaline solution; 2) after the 1.0-10mol/L Mono Chloro Acetic Acid fully reacts with suitably excessive 2.0-10mol/L basic solution, join 1) in the Pachymose alkaline solution of step gained, carry out substitution reaction, the CMP that separation and purification generates, promptly.
2, method according to claim 1, described water-alcohol solution is that alcoholic solvent well known in the art adds the solution that water makes, and described alcoholic solvent is selected from any or its combination of methyl alcohol, ethanol, propylene glycol, ethyl acetate, acetone, ether, dimethyl sulfoxide (DMSO), dimethyl formamide.
3, method according to claim 1, the described suitably excessive actual amount that is meant basic solution neutral and alkali material is than itself and the excessive 0.5-40% of the required theoretical consumption of Mono Chloro Acetic Acid generation neutralization reaction, preferred excessive 5-30%, more preferably excessive 10-25%, most preferably excessive 15-20%.
4, method according to claim 1,2) reaction solution carries out substitution reaction 1-5h the step under 30-100 ℃ of condition, and preferable reaction temperature is 40-90 ℃, and other is preferably 50-85 ℃, more preferably 60-82 ℃, most preferably is 75-80 ℃; The preferred reaction time is 2-4h, more preferably 2.5-3.5h.
5, a kind of CMP of high substitution value, made by following method: 1) Pachymose joins in water or the water alcohol mixed solution, after stirring, adds the basic solution of Pachymose quality 1-8% or 2-6% or 3-5%, be stirred to dissolving fully, get the Pachymose alkaline solution; 2) after the 1.0-10mol/L Mono Chloro Acetic Acid fully reacts with suitably excessive 2.0-10mol/L basic solution, join 1) in the Pachymose alkaline solution of step gained, carry out substitution reaction, the CMP that separation and purification generates, promptly.
6, a kind of pharmaceutical composition with enhancing immunity effect, described composition is made up of the CMP and the pharmaceutically acceptable carrier of high substitution value.
7, a kind of CMP oral liquid with enhancing immunity effect is made up of high substitution value CMP and pharmaceutically acceptable carrier.
8, a kind of CMP freeze-dried powder with enhancing immunity effect is made up of high substitution value CMP and pharmaceutically acceptable carrier.
9, described high substitution value CMP of claim 5 or the described pharmaceutical composition of claim 6 or the described oral liquid of claim 7 or the described freeze-dried powder of claim 8 be used for preparing have enhancing immunity, antitumor, antiviral, anti-ly radiate, protect the liver, antibiotic, diuresis, improvement are slept, the application of the medicine of hypoglycemic, reducing blood-fat, anti-ageing or anti-fatigue effect.
10, high substitution value CMP is used for preparing the application of excipient substance, and preferred described excipient substance is disintegrating agent or tackiness agent.
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