CN1488649A - Nano crystal cellulose-heparin complex substance and preparing method thereof - Google Patents
Nano crystal cellulose-heparin complex substance and preparing method thereof Download PDFInfo
- Publication number
- CN1488649A CN1488649A CNA03140166XA CN03140166A CN1488649A CN 1488649 A CN1488649 A CN 1488649A CN A03140166X A CNA03140166X A CN A03140166XA CN 03140166 A CN03140166 A CN 03140166A CN 1488649 A CN1488649 A CN 1488649A
- Authority
- CN
- China
- Prior art keywords
- heparin
- nanocrystal cellulose
- ncc
- highly basic
- cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention refers to cellulose-hamocura compound which is combined by nano crystal cellulose(NCC) and hamocura, and the manufacturing method. The compound structure is shown in the picture, R=CH2, CHCH, OHC-CH, OHCCH2CH2CH2CH, (CH2O)4, (CH2O) 5OHCCH2CH2CH2CH(OH)CH, CH2CH2SO2CH2CH2, CH2CH(OH)CH2, m is 8~25, n is 25~27. The invention also provides a method for producing the compound with NCC and hamocura by cross linking reaction and open loop cross linking reaction of aldehyde, activated ethenyl compound.
Description
Technical field the invention belongs to the cellulose technology field, relates in particular to nanocrystal cellulose (NCC) and heparin and carries out Mierocrystalline cellulose-heparin complex that chemical combination obtains and preparation method thereof.
The technical background cardiovascular disorder is the healthy diseases of a kind of serious harm people.China is the maximum country of world population, also is simultaneously to suffer from the maximum country of cardiovascular disorder.Digital according to statistics, Chinese hyperpietic has surpassed 100,000,000 people, and average annual growth more than 200 ten thousand people.Cardiovascular disorder mostly is chronic disease, and at present, the ideal medicament for the treatment of or control such disease is few, and therefore, it is particularly urgent to develop and develop this type of specific medicament.
Heparin is one of medicine of common treatment cardiovascular disorder.Heparin is a kind of mucopolysaccharide sulfuric acid ester compound that extracts from tissues such as the intestinal mucosa of animals such as pig, ox, sheep or liver, lung, has following general structure:
Heparin can be water-soluble, anticoagulant property is arranged, be used for the treatment of the vascular thrombosis that causes because of a variety of causes clinically and form and embolism, the disseminated inravascular coagulation disease that causes as myocardial infarction, pulmonary infarction, cerebral vessels embolism, peripheral vein embolism, vascular surgery and a variety of causes etc.The blood coagulation resisting function of heparin mainly contains several aspects: 1. the formation of anticoagulant kinase and effect, thus hinder thrombogen to change zymoplasm into; 2. make Fibrinogen can not become scleroproein; 3. the aggegation of energy platelet and destruction etc.Research new discovery to heparin in recent years mainly contains functions such as haemolysis fat.
Heparitin is a kind of material that has with the heparin similar functions, and heparitin is a class synthetic heparin, contains-SO
3 -,-COO
-,-NHSO
3 -Deng functional group, these groups also can dissolve blood fat, also play the effect of Trombin inhibiting, and as poly-dextrose sodium sulfate, polyvinyl sulfuric acid sodium, polyacrylic acid sodium sulfate etc., the heparitin molecular weight is about 7000.Its typical structural formula is:
Heparin content in animal blood is very little.Medically invalid with heparin or heparitin oral liquid, be made generally in injection and be input among the patient blood.The molecular weight heparin that the heparin that is used for the treatment of cardiovascular disorder is, molecular weight about about 6000.But heparin or the heparitin residence time in human body is short, is just excreted by kidney after 1～2 day, does not reach purposes such as dissolving blood ester, dredging vascellum fully.Prolong drug effect, need to connect with carrier.
Japan ゼ オ Application company makes the chain rupture of part Mierocrystalline cellulose with Mierocrystalline cellulose and Periodic acid reaction, be connected with heparin by covalent linkage again, so neither damage high molecular physical strength, can make heparin form firm chemical bond again, be used for intramuscular injection, improve the curative effect of heparin.The Mierocrystalline cellulose here is general Microcrystalline Cellulose, particle diameter 5～50 μ m.Because expensive Periodic acid is used in this reaction, make cost improve.And because used Mierocrystalline cellulose is general Microcrystalline Cellulose, when with after heparin combines, the diameter of considering capillary vessel is 10 μ m, the particle diameter major part of the heparin that the gained chemical bond links to each other is all greater than the diameter of capillary vessel, cause stopping up capillary vessel, make this medicine can not carry out intravascular injection, therefore can not give full play to the effect of heparin.
It is a kind of with nanocrystal cellulose (NCC) and heparin-bounding New-type long-acting medicine that summary of the invention purpose of the present invention provides, it can circulate in blood vessel, improve the residence time of heparin in blood, be used for the treatment of cardiovascular disorder, to improve result of treatment.
Another object of the present invention provides the preparation method of this medicine.
The mixture of nanocrystal cellulose provided by the invention and heparin is:
R＝CH
2，CH
3CH，OHC-CH，OHCCH
2CH
2CH
2CH，(CH
2O)
4，(CH
2O)
5OHCCH
2CH
2CH
2CH(OH)CH，
CH
2CH
2SO
2CH
2CH
2，CH
2CH(OH)CH
2
Wherein m is 8～25, and n is 25～75.
M is preferred 10～14, and n preferred 37～56.
The preparation method of nanocrystal cellulose provided by the invention and heparin-bounding mixture, comprise the steps: earlier to be that the nanocrystal cellulose of 10～80nm adds water to be mixed with weight concentration be 3～10% suspension with particle diameter, add molecular weight again and be 5000～8000 heparin, highly basic, aldehydes or contain epoxy compounds, obtained cross-linking products in 24～72 hours in 20～35 ℃ of following continuously stirring reactions, use sour neutralized reaction product, again through separating, product is collected in washing, wherein nanocrystal cellulose and heparin, highly basic, the mol ratio of aldehydes or epoxy compounds is 100: 1～10: 15～60: 400～1500, preferred 100: 5～8: 30～50: 800～1100.
The another kind of method of nanocrystal cellulose and the preparation of heparin-bounding mixture; comprise the steps: earlier to be that the nanocrystal cellulose of 10～80nm adds water to be mixed with weight concentration be 3～10% suspension with particle diameter; nitrogen protection; under 60～100 ℃; with the peroxide reactions that accounts for nanocrystal cellulose weight 1～3% 10～60 minutes; add molecular weight again and be 5000～8000 heparin; highly basic and activatory vinyl compound obtained cross-linking products in 1～6 hour in 60～100 ℃ of following continuously stirring reactions; use sour neutralized reaction product; again through separating; product is collected in washing; wherein nanocrystal cellulose and heparin; highly basic; the mol ratio of activatory vinyl compound is 100: 1～10: 15～60: 400～800, preferred 100: 5～8: 30～50: 500～600.
Preferred 20～the 50nm of the particle diameter of nanocrystal cellulose wherein, the molecular weight of heparin preferred 5000～7000.
Aldehydes can be selected from formaldehyde, acetaldehyde, oxalic dialdehyde, glutaraldehyde, Alpha-hydroxy hexanedial, four polyoxymethylene, five polyoxymethylene etc.
Contain epoxy compounds and can be selected from epoxy chloropropane, propylene oxide etc.
The activatory vinyl compound can be selected from the thiosulfuric acid sodio-derivative of divinylsulfone, divinylsulfone etc.
Superoxide can be selected from Potassium Persulphate, ammonium persulphate, hydrogen peroxide etc.
Highly basic can be selected from sodium hydroxide, potassium hydroxide etc.
NCC is from the Mierocrystalline cellulose crystal of vegetable fibre as the nanometer particle size that obtains through acid hydrolysis cotton, fiber crops, the wood pulp, its preparation method is that the application for a patent for invention of CN 1405218A, CN 1341663A, CN1267699A all has introduction at Chinese invention patent ZL 94115873.X and publication number, general particle diameter is 3～100nm, the polymerization degree is 37～56, can regulate hydrolysis process according to the experiment situation during use, thereby obtain the NCC of a sizing grain; The unit cell parameters of NCC is as follows: a is 0.835nm, and b is 0.790nm, and c is 0.103nm; The degree of crystallinity of NCC is 60～80%, and it has kept cellulosic structure and Chemical Composition, still belongs to the natural cellulose structure, only the particle metal nano-particle.NCC is water insoluble, but can be scattered in the water; NCC and human compatibility are good, and react with does not influence the human body normal physiological function yet.Need remove impurity as medicinal NCC, and meet medical pharmacopeia index and could use through purifying.
NCC is connected NCC-heparin or the heparitin complex body medicine that makes with heparin or heparitin by chemistry.At first to determine the size of NCC,, generally be about 30nm, and the aperture of kidney be 2～8nm not being principle by kidney chimney filter aperture.In addition, NCC more can not hinder blood circulation to flow, if particle diameter is too big, in the capillary vessel (the about 10 μ m in aperture) that the artery of human body is connected with vein, when carrying out microcirculation, will artery-clogging, directly influence the exchange of the nutrition supply and the oxygen of human body cell, serious meeting makes local tissue necrosis.NCC is with after heparin or heparitin combine by chemical bond, the medicine of making is a nano-grade medicine, behind its input human vas, just in blood vessel, circulate, can also can pass through microcirculqtory system, from the artery to the vein by heart, lung, brain, unblocked, because the medicine of particle diameter tens nanometers just seems quite negligible with respect to the microcirculation capillary vessel of aperture 10 μ m.Therefore, Nano medication just can Long contact time polymerization blood fat and polymeric scleroproein, makes it to dissolve gradually, by excreting behind the body metabolism, reaches dredging vascellum, treatment hypertension purpose.Nano medication is difficult for decomposing in blood, do not play other chemical reaction yet, after through the time more than a year, Nano medication can be decomposed gradually by the enzyme in the blood, heparin or heparitin can come off from NCC, excreted by kidney, NCC also can become low-molecular-weight cellobiose, trisaccharide even glucose and the metabolism that is absorbed by the body, and its metabolite is harmless.
NCC be connected with the chemistry of heparin generally have following several: (a) use the aldehydes crosslinking reaction: as formaldehyde, acetaldehyde, oxalic dialdehyde etc.(b) crosslinking reaction of usefulness activatory vinyl compound: as divinylsulfone.(c) open loop crosslinking reaction: as epoxy chloropropane.
With the formaldehyde crosslinking heparin is example, and formaldehyde is connected to NCC-heparin complex body with the hydroxyl in NCC and the heparin in alkaline aqueous solution.This chemical bond connects than general hybrid medicine carrier difference.Therefore, the heparin difficult drop-off after the connection.Reaction formula is as follows:
The reaction equation of NCC-heparin complex body medicine
Product is analyzed structure and the composition that the complex body Nano medication is determined in test through infrared analysis, nuclear magnetic resonance spectroscopy, X-ray diffraction, ultimate analysis, liquid-phase chromatographic analysis, mass spectroscopy, electronic microscope photos, atomic force microscope analysis etc.
The elimination of NCC-heparin complex body medicine.When human body is subjected to wound maybe to need to have an operation, need to stop the blood coagulation resisting function of heparin, recover the coagulation function of blood, but the poly-hexane dimethylamino-propyl bromide of intravenous injection, at once in and heparin, recover the blood coagulation function, the phenomenon that prevents to lose blood takes place.
Provided by the inventionly be connected by chemical bond with heparin or heparitin with nanocrystal cellulose (NCC), make the Nano medication of anti-cardiovascular disease, it had both kept the anticoagulant property and the haemolysis fat function of heparin, again since diameter of aspirin particle greater than the uriniferous tubules aperture, medicine is not excreted, becomes depot drug product; Nano medication can be circulated among the human body big and small vessel, and in the dissolving blood fat, artery-clogging is not good with human compatibility, can reach and cure the cardiovascular disorder purpose, has a good application prospect.
Embodiment
Embodiment 1
Prepare the NCC-heparin complex with formaldehyde crosslinking:
In the 500ml there-necked flask, with weight percentage be 5%, particle diameter is 20nm, and (± 5nm) NCC suspension (deionized water preparation) 150ml is in reaction flask, the heparin and the 0.66 gram sodium hydroxide that add 10 gram molecular weights about 6000, add concentration 37wt% analytical pure formaldehyde solution 30ml again, treat the heparin dissolving evenly, obtain cross-linking products in 35 ℃ of following continuously stirring reaction 30h.With 1mol/L HCl neutralized reaction product to pH value is 7, separates through ultrafiltration membrance filter, and deionized water wash is removed impurity, NCC-heparin colloidal suspensions, behind sterilization, use after being made into injection.
Embodiment 2
With the crosslinked preparation of acetaldehyde NCC-heparin complex:
In the 500ml there-necked flask, with weight percentage be 7%, (± 5nm) NCC suspension (deionized water preparation) 93ml is in reaction flask for particle diameter 30nm, the heparin and the 0.64 gram sodium hydroxide that add 14.4 gram molecular weights about 7000, add analytical pure acetaldehyde 15.8ml again, treat the heparin dissolving evenly, obtain cross-linking products in 30 ℃ of following continuously stirring reaction 24h.With 1mol/LHCl neutralized reaction product to pH value is 7, separates through ultrafiltration membrance filter, and deionized water wash is removed impurity, NCC-heparin colloidal suspensions, behind sterilization, use after being made into injection.
Embodiment 3
The crosslinked preparation of oxalic dialdehyde NCC-heparin complex:
In the 500ml there-necked flask, with weight percentage be 9%, (± 5nm) NCC suspension (deionized water preparation) 90ml is in reaction flask for particle diameter 50nm, the heparin and the 0.90 gram sodium hydroxide that add 21.0 gram molecular weights about 5500, add analytical pure glyoxal solution 30.5ml again, treat the heparin dissolving evenly, obtain cross-linking products in 25 ℃ of following continuously stirring reaction 60h.Use 1mol/L H
2SO
4Neutralized reaction product to pH value is 7, separates through ultrafiltration membrance filter, and deionized water wash is removed impurity, NCC-heparin colloidal suspensions, behind sterilization, use after being made into injection.
Embodiment 4
With the crosslinked preparation of epoxy chloropropane NCC-heparin complex:
In the 500ml there-necked flask, with weight percentage be 8%, (± 5nm) NCC suspension (deionized water preparation) 90ml is in reaction flask for particle diameter 60nm, the heparin and the 0.90 gram sodium hydroxide that add 21.0 gram molecular weights about 7500, add propylene oxide 30.5ml again, treat the heparin dissolving evenly, obtain cross-linking products in 30 ℃ of following continuously stirring reaction 48h.With 1mol/L HCl neutralized reaction product to pH value is 7, separates through ultrafiltration membrance filter, and deionized water wash is removed impurity, the residual epoxy chloropropane of 50% washing with alcohol, be washed till inclusion-free with deionized water again till, NCC-heparin colloidal suspensions, behind sterilization, use after being made into injection.NCC-heparin colloidal suspensions, behind sterilization, use after being made into injection.
Embodiment 5
With the crosslinked preparation of divinylsulfone NCC-heparin complex:
In the 500ml there-necked flask; with weight percentage is 5%; (± 5nm) NCC suspension (deionized water configuration) adds 150ml in reaction flask to particle diameter 35nm; nitrogen protection; 80 ℃ of reactions; in NCC, cause 20min with the 0.1g Potassium Persulphate; after making NCC produce free radical; the heparin that adds molecular weight about 6000 again; 0.66g sodium hydroxide and 40.0g divinylsulfone, 80 ℃ of following continuously stirring reaction 2h, product is through membrane sepn; use deionized water wash; 50% washing with alcohol, again with deionized water wash till the inclusion-free, weight percentage is 5% the synthetic heparin complex suspension of NCC-; behind sterilization, be made into injection and use.
Claims (10)
1, the mixture of nanocrystal cellulose that structure is following and heparin:
R＝CH
2，CH
3CH，OHC-CH，OHCCH
2CH
2CH
2CH，(CH
2O)
4，(CH
2O)
5OHCCH
2CH
2CH
2CH(OH)CH，
CH
2CH
2SO
2CH
2CH
2，CH
2CH(OH)CH
2
Wherein m is 8～25, and n is 25～75.
2, the mixture of claim 1, wherein m is 10～14, n is 37～56.
3, the preparation method of claim 1 or 2 mixture, comprise the steps: earlier to be that the nanocrystal cellulose of 10～80nm adds water to be mixed with weight concentration be 3～10% suspension with particle diameter, add molecular weight again and be 5000～8000 heparin, highly basic, aldehydes or contain epoxy compounds, obtained cross-linking products in 24～72 hours in 20～35 ℃ of following continuously stirring reactions, use sour neutralized reaction product, again through separating, product, wherein nanocrystal cellulose and heparin are collected in washing, highly basic, the mol ratio of aldehydes or epoxy compounds is 100: 1～10: 15～60: 400～1500.
4, the method for claim 3, wherein the particle diameter of nanocrystal cellulose is 20～50nm, the molecular weight of heparin is 5000～7000, and the mol ratio of nanocrystal cellulose and heparin, highly basic, aldehydes or epoxy compounds is 100: 5～8: 30～50: 800～1100.
5, claim 3 or 4 method, wherein aldehydes be selected from formaldehyde, acetaldehyde, oxalic dialdehyde, glutaraldehyde, Alpha-hydroxy hexanedial, four polyoxymethylene, five polyoxymethylene.
6, claim 3 or 4 method wherein contain epoxy compounds and are selected from epoxy chloropropane, propylene oxide.
7; the preparation method of claim 1 or 2 mixture; comprise the steps: earlier to be that the nanocrystal cellulose of 10～80nm adds water to be mixed with weight concentration be 3～10% suspension with particle diameter; nitrogen protection; under 60～100 ℃; with the peroxide reactions that accounts for nanocrystal cellulose weight 1～3% 10～60 minutes; add molecular weight again and be 5000～8000 heparin; highly basic and activatory vinyl compound obtained cross-linking products in 1～6 hour in 60～100 ℃ of following continuously stirring reactions; use sour neutralized reaction product; again through separating; product, wherein nanocrystal cellulose and heparin are collected in washing; highly basic; the mol ratio of activatory vinyl compound is 100: 1～10: 15～60: 400～800.
8, the method for claim 7, wherein the particle diameter of nanocrystal cellulose is 20～50nm, the molecular weight of heparin is 5000～7000, and the mol ratio of nanocrystal cellulose and heparin, highly basic, activatory vinyl compound is 100: 5～8: 30～50: 500～600.
9, claim 7 or 8 method, wherein the activatory vinyl compound is selected from the thiosulfuric acid sodio-derivative of divinylsulfone, divinylsulfone.
10, claim 7 or 8 method, wherein superoxide is selected from Potassium Persulphate, ammonium persulphate, hydrogen peroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03140166 CN1208351C (en) | 2003-08-15 | 2003-08-15 | Nano crystal cellulose-heparin complex substance and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03140166 CN1208351C (en) | 2003-08-15 | 2003-08-15 | Nano crystal cellulose-heparin complex substance and preparing method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1488649A true CN1488649A (en) | 2004-04-14 |
| CN1208351C CN1208351C (en) | 2005-06-29 |
Family
ID=34155233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03140166 Expired - Fee Related CN1208351C (en) | 2003-08-15 | 2003-08-15 | Nano crystal cellulose-heparin complex substance and preparing method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1208351C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102596800A (en) * | 2009-08-11 | 2012-07-18 | Fp创新研究中心 | Fractionation of a waste liquor stream from nanocrystalline cellulose production |
| CN101461967B (en) * | 2009-01-14 | 2012-08-22 | 天津大学 | Bacteria cellulose and depo-heparin composite material and method for preparing the both |
| CN101128737B (en) * | 2005-01-17 | 2012-11-28 | 新加坡科技研究局 | Novel water-solubility nanometer crystal and its preparing method |
-
2003
- 2003-08-15 CN CN 03140166 patent/CN1208351C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128737B (en) * | 2005-01-17 | 2012-11-28 | 新加坡科技研究局 | Novel water-solubility nanometer crystal and its preparing method |
| CN101461967B (en) * | 2009-01-14 | 2012-08-22 | 天津大学 | Bacteria cellulose and depo-heparin composite material and method for preparing the both |
| CN102596800A (en) * | 2009-08-11 | 2012-07-18 | Fp创新研究中心 | Fractionation of a waste liquor stream from nanocrystalline cellulose production |
| CN102596800B (en) * | 2009-08-11 | 2015-03-04 | Fp创新研究中心 | Fractionation of a waste liquor stream from nanocrystalline cellulose production |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1208351C (en) | 2005-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH05503952A (en) | Method for producing soluble glucans | |
| JP6703806B2 (en) | Low anticoagulant heparin | |
| CN107028896B (en) | A kind of carried medicine sustained-release system and drug | |
| CN1379781A (en) | Novel oligosaccharides, preparation method and pharmaceutical composition containing same | |
| CZ300823B6 (en) | Iron and dextran compound | |
| CN104627958A (en) | Stability-enhanced modified nano particle and preparing method thereof | |
| CN112933286B (en) | Crystal gel for stopping bleeding and bearing anticancer drugs and preparation method thereof | |
| EA020784B1 (en) | Inclusion complexes of pinocembrin with cyclodextrin, process for preparing and use thereof | |
| CN1128167C (en) | Nanometer microball of chitosan-polyacrylic acid composite and its producing method and use | |
| CN1208351C (en) | Nano crystal cellulose-heparin complex substance and preparing method thereof | |
| CN1813684A (en) | Method for preparing 5-fluorouracil/chitosan nano drug-carrying microsphere | |
| CN110876757B (en) | Application of fullerene structure in preparation of medicine for treating atherosclerosis | |
| CN109662956A (en) | A kind of application of the chitosan drug-loading nano particle of oleanolic acid grafting | |
| CN1739531A (en) | Ferric saccharate injection for treating iron-deficiency anemia and its prepn process | |
| CN1208384C (en) | Nano crystal cellulose-heparitin composition and its preparing method | |
| CN115590974A (en) | Functionalized targeting preparation and preparation method and application thereof | |
| JP2010503665A (en) | How to make insulin in the form of an oral preparation | |
| CN114522150A (en) | Preparation method and application of pH-sensitive plant microcapsule nano extruder | |
| FR2458286A1 (en) | PLASMA THINNER, PULLULANE BASED | |
| CN113318241A (en) | Magnolol disulfide bond cyclodextrin inclusion compound for ulcerative colitis and preparation method thereof | |
| CN112876722A (en) | Traditional Chinese medicine coating for improving surface biocompatibility of medical instrument and preparation method thereof | |
| CN113633658A (en) | Application of dextran sulfate galacto-oligosaccharide in preparation of anticoagulant and/or antithrombotic drugs | |
| CH638401A5 (en) | Process for the preparation of haemoglobin preparations having an increased oxygen delivery | |
| CN114619041B (en) | Cerium-modified gold nanocluster and preparation method and application thereof | |
| CN111888334B (en) | Liraglutide microsphere sustained-release agent and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050629 |