CN101766819A - Heparin complex as well as preparation method and application thereof - Google Patents
Heparin complex as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN101766819A CN101766819A CN200910104934A CN200910104934A CN101766819A CN 101766819 A CN101766819 A CN 101766819A CN 200910104934 A CN200910104934 A CN 200910104934A CN 200910104934 A CN200910104934 A CN 200910104934A CN 101766819 A CN101766819 A CN 101766819A
- Authority
- CN
- China
- Prior art keywords
- heparin
- poloxamer
- complex
- low molecular
- heparin complex
- 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.)
- Pending
Links
Abstract
The invention relates to a heparin complex which has the following general formula: Y-X-Y or Y-g-X-g-y or X-Y or X-g-Y, wherein x is poloxamer, g is spacer-arm molecules, Y is heparin, and X, g, Y or X, Y are combined by covalent bonds. The invention also provides a preparation method of the heparin complex. The heparin complex can be applied as pharmaceutical excipients or conveying vectors.
Description
[technical field]
The present invention relates to a kind of heparin complex and preparation method thereof and application, relate in particular to a kind of covalence graft heparin complex and preparation method thereof and application.
[background technology]
Heparin (heparin) is a kind of anion mucopolysaccharide, has anticoagulation antithrombotic acitivity [Kwon OH, NhoYC et al.Biocompatible surfaces by immobilization of heparin on diamond-likecarbon films deposited on various substrates.Surf.Interface Anal.2000,29:386].Low molecular heparin (LMWH) is to obtain the low molecular weight heparin component that low-molecular-weight heparin fragment or classified method obtain by heparin through degraded, and the relative molecular mass scope is mainly used in prevention and treatment thrombotic disease clinically generally 3000～8000.
The complex that the heparin covalence graft forms to the material has plurality of advantages, as reaching the immobilized purpose of heparin, prevents that effectively heparin from being taken away by blood flow at agents area.Simultaneously, complex has biocompatibility and anticoagulant property.
The complex of existing a large amount of covalence graft heparin is synthesized in recent years, and as polyurethanes-PEO-heparin, these materials have shown physicochemical characteristic preferably.The report heparin is arranged along with the increase of the length of the hydrophilic spacerarm of polyethylene oxide (PEO) on macromole surface, its anticoagulating active and increasing.
But heparin complex safety, the stability and still not ideal enough of present preparation to the medicine carrying ability of protein drug.
[summary of the invention]
The technical problem to be solved in the present invention is at the weak point of existing heparin complex, and a kind of heparin complex is provided, and it possesses better stability, safety and medicine carrying ability as pharmaceutical carrier or pharmaceutic adjuvant.
Another technical problem that the present invention will solve is that a kind of preparation method that possesses the heparin complex of better stability, resistance to pressure and medicine carrying ability will be provided.
Another object of the present invention is the application in medical and field of biology of exploitation heparin and the synthetic new complex of poloxamer.
For solving the problems of the technologies described above, the present invention has adopted following technical scheme:
The complex that a kind of heparin and poloxamer form has following general formula:
Y-X-Y or Y-g-X-g-Y or X-Y or X-g-Y
Wherein: X is a poloxamer, g be between the arm molecule, Y is a heparin, X, g, Y or X, Y pass through covalent bonds.
Above-mentioned poloxamer is a polyoxyethylene poly-oxygen propylene aether, be poly-(oxygen ethylene) the c block copolymer of poly-(oxypropylene) b-of poly-(oxygen ethylene) a-of α-hydrogen-ω hydroxyl, structural formula is HO (CH2CH2O) a (OCHCH3CH2) b (CH2CH2O) c, in copolymer, a and c are 2～150, and b is 15～67.
Above-mentioned heparin comprise reorganization heparin, natural heparin, the heparin of deriving, heparinate, low molecular weight heparin and salt thereof, can with chemically modified heparin and the heparinoid molecule and its esters of the functional group reactions of poloxamer and derivant thereof.
Above-mentioned Low molecular heparin is including, but not limited to low molecular sodium heparin, low molecular heparin calcium, Enoxaparin, Fragmin.
Arm molecule g is meant any macromole or small molecule structure that is used for connecting heparin and poloxamer between above-mentioned, wherein macromole is synthetic high polymer or biopolymer, comprise polycaprolactone, Polyethylene Glycol, polysaccharide, protein, micromolecule is meant and contains amino and/or carboxyl functional group, can with the micromolecule of carboxyl in the heparin molecule or amino reaction, comprise ethylenediamine.
A kind of preparation method of heparin complex, utilize the terminal hydroxyl of poloxamer and the active group reaction of intramolecular carboxyl of heparin or amino to obtain described heparin complex, this course of reaction is: poloxamer or be connected with the poloxamer C-terminal carboxylic acidization of an arm molecule, then with the amino reaction of heparin; Perhaps poloxamer or be connected with the poloxamer C-terminal amination of an arm molecule is then with the carboxyl reaction of heparin.
A kind of application of heparin complex, this heparin complex is used as pharmaceutic adjuvant or delivery vector.
This above-mentioned complex is meant as pharmaceutic adjuvant: this above-mentioned complex is used for preparing aqueous dispersion, comprises Emulsion, liposome, micelle, microgranule; Or the drug carrier material of conduct long circulation, temperature or PH sensitivity is used.
This above-mentioned complex is used as delivery vector and is meant: this above-mentioned complex can be used as chemical substance, enzyme or the high molecular weight protein with the heparin blind date, comprises the delivery vector of fibroblast growth factor.
That preparation that above-mentioned this complex forms or material are applied to is oral, in the injection, percutaneous, mucoadhesive delivery system or in the surgery, implant surgery.
[specific embodiment]
Poloxamer (poloxamer), commodity are called pluronic, are white or the translucent waxy solid of little yellow, as surfactant, emulsifying agent, suppository base, excipient etc.Poloxamer can be used for intravenous injection because of preventing haemolysis, can play the hydrotropy effect to some drugs.Utilize poloxamer and heparin covalent bond directly or indirectly, and make corresponding preparation, can reach the purpose of anticoagulation, antithrombotic and slow releasing pharmaceutical as carrier material.
The complex that heparin of the present invention and poloxamer form has following general formula:
Y-X-Y or Y-g-X-g-Y or X-Y or X-g-Y
Wherein: X is a poloxamer, g be between the arm molecule, Y is a heparin, X, g, Y or X, Y pass through covalent bonds.
Above-mentioned poloxamer is a polyoxyethylene poly-oxygen propylene aether, be poly-(oxygen ethylene) the c block copolymer of poly-(oxypropylene) b-of poly-(oxygen ethylene) a-of α-hydrogen-ω hydroxyl, structural formula is HO (CH2CH2O) a (OCHCH3CH2) b (CH2CH2O) c, in copolymer, a and c are 2～150, and b is 15～67.
Above-mentioned heparin comprise reorganization heparin, natural heparin, the heparin of deriving, heparinate, low molecular weight heparin and salt thereof, can with chemically modified heparin and the heparinoid molecule and its esters of the functional group reactions of poloxamer and derivant thereof.
Above-mentioned Low molecular heparin is including, but not limited to low molecular sodium heparin, low molecular heparin calcium, Enoxaparin, Fragmin.
Arm molecule g is meant any macromole or small molecule structure that is used for connecting heparin and poloxamer between above-mentioned, wherein macromole is synthetic high polymer or biopolymer, comprise polycaprolactone, Polyethylene Glycol, polysaccharide, protein, micromolecule is meant and contains amino and/or carboxyl functional group, can with the micromolecule of carboxyl in the heparin molecule or amino reaction, comprise ethylenediamine.
The preparation method that heparin is grafted to poloxamer formation complex is to have utilized terminal hydroxyl and the intramolecular carboxyl of heparin or the amino active group of poloxamer.Can be poloxamer or the poloxamer C-terminal carboxylic acidization that is connected with an arm molecule, then the amino with heparin reacts; Also can be poloxamer or the poloxamer C-terminal amination that is connected with an arm molecule, then with the carboxyl reaction of heparin.Concrete course of reaction is as follows:
A. poloxamer or be connected with the poloxamer C-terminal carboxylic acidization of an arm molecule is then with the amino reaction of heparin
A certain amount of poloxamer or be connected with a poloxamer of arm molecule, succinic anhydride, 4-dimethylaminopyridine, triethylamine places dioxane, and stirring reaction spends the night, and the end of gained reactant is a carboxyl.Utilize the EDC/NHS method, add a certain amount of heparin, stirring reaction 24h dialysed 3 days then, and solution obtains the complex lyophilized solid of heparin and poloxamer formation in the bag filter through lyophilization.
B. poloxamer or be connected with the poloxamer C-terminal amination of an arm molecule is then with the carboxyl reaction of heparin
A certain amount of poloxamer or be connected with a poloxamer of arm molecule under triethylamine catalysis with reacting ethylenediamine, getting terminal is amino product, utilize 1-ethyl-3 then, 3-dimethyl aminopropyl carbodiimide (EDC)/N-hydroxyl reacts in the carboxyl of imidodicarbonic diamide (NHS) method and heparin, can get the complex that heparin and poloxamer form.
This above-mentioned complex is used as pharmaceutic adjuvant or delivery vector, also is being purpose medical science with anticoagulation, antithrombotic and is using in biology.
During as pharmaceutic adjuvant, this above-mentioned complex is used for preparing aqueous dispersion, comprises Emulsion, liposome, micelle, microgranule; Or the drug carrier material of conduct long circulation, temperature or PH sensitivity is used.
The above-mentioned complex combination and chemical substance, enzyme or the high molecular weight protein of heparin blind date, comprise fibroblast growth factor, reach and separate these chemical substances or proteic purpose, can also make slow releasing preparation as transporting carrier and these chemical substances or albumen, reach the purpose of slow release.
This above-mentioned complex is applied to the surface modification of artificial organ or medical apparatus and instruments as coating agent.
That preparation that above-mentioned this complex forms or material are applied to is oral, in injection, percutaneous, mucoadhesive delivery system or surgery, the implant surgery.
Below further specify the present invention from several specific embodiments.
The synthetic external anticoagulation experiment of embodiment one, Low molecular heparin-poloxamer with it
1-1. Low molecular heparin-poloxamer-Low molecular heparin is synthetic
Take by weighing poloxamer 407 (relative molecular weight M=12000, a=c=101 wherein, b=56) 12g, in a round-bottomed flask, add the succinic anhydride of 2mmol, 4-dimethylaminopyridine and the 0.55ml triethylamine of 2mmol, and be dissolved in the 200ml dioxane, stirring reaction 24h gets the terminal poloxamer of carboxyl that is, with it is reactant, utilize 1-ethyl-3,3-dimethyl aminopropyl carbodiimide (EDC)/N-hydroxyl adds the low molecular sodium heparin of 10g, stirring reaction 24h in imidodicarbonic diamide (NHS) method.Product was through bag filter dialysis 3 days, and products therefrom obtains pressed powder by lyophilization, is Low molecular heparin-poloxamer-Low molecular heparin.
1-2. the external anticoagulation experiment of Low molecular heparin-poloxamer-Low molecular heparin
Slide method below the utilization, is respectively positive control and blank with the method operation with 0.1g/ml Low molecular heparin, normal saline at the external anticoagulation time of mensuration variable concentrations Low molecular heparin-poloxamer-Low molecular heparin solution.Low molecular heparin-poloxamer-Low molecular heparin the solution that contains 0.66g/ml, 0.44g/ml, 0.22g/ml is respectively high, medium and low three concentration grouping.
Slide method: with the Low molecular heparin-poloxamer-Low molecular heparin solution that contains high, medium and low concentration and Low molecular heparin and the clean microscope slide of normal saline immersion, taking-up is dried respectively.With the capillary glass-tube Wistar rat is cooked the eye socket endocanthion and get blood, bleed rapidly on microscope slide, the about 5～10mm of drop of blood diameter begins to clock immediately, after this provoke with the dried and clean syringe needle till blood 1 time can provoke fiber protein yarn to syringe needle every 30s, be clotting time.Experimental result is as follows:
Blank group of contrast and positive group result show that Low molecular heparin-poloxamer-Low molecular heparin complex has kept the anticoagulant effect of heparin.
The preparation of embodiment two, Low molecular heparin-poloxamer complexes micelle
Get the Low molecular heparin-poloxamer-Low molecular heparin 50mg of above-mentioned preparation, be scattered in the 20ml distilled water, at 37 ℃ of following supersound process 2min, form the micelle suspension, the solid dried frozen aquatic products is made in lyophilization then, by the external anticoagulation laboratory observation of embodiment one, Low molecular heparin-poloxamer complexes micelle has blood coagulation resisting function, can be singly with or be applied in the thrombolytic preparation as pharmaceutic adjuvant.
Embodiment three: the preparation of synthetic and acid fibroblast growth factor (aFGF) slow release liposome of Enoxaparin-polycaprolactone-poloxamer
3-1. Enoxaparin-polycaprolactone-poloxamer-polycaprolactone-Enoxaparin is synthetic
Poloxamer 188 (M=8350; a=c=80; b=27) 2mmol and 3ml caprolactone are that vacuum state carries out polymerization under catalyst, the Ar gas shiled at Sn-Oct; stopped reaction behind the stirring 24h; product is dissolved with the 10ml chloroform; adding l0 doubly measures the ether sedimentation of volume, filters, and repeats twice with the purification products therefrom.With product at 4mmol succinic anhydride (SA), 2mmol 4-dimethylaminopyridine (DMAP), 0.55ml triethylamine (TEA), the 30ml dioxane is a stirring reaction 24 hours under the solvent, dissolve with the 10ml chloroform, the ether sedimentation that adds 10 times of amount volumes, filter, repeat twice with the purification products therefrom.Utilize 1-ethyl-3,3-dimethyl aminopropyl carbodiimide (EDC)/N-hydroxyl is in imidodicarbonic diamide (NHS) method, products therefrom and Enoxaparin reaction, stirring reaction 24h, the reaction end product was through bag filter dialysis 3 days, solution obtains pressed powder by lyophilization in the last bag filter, i.e. Enoxaparin-polycaprolactone-poloxamer-polycaprolactone-Enoxaparin.
3-2. carry the preparation of aFGF slow release liposome
Get the Enoxaparin-polycaprolactone-poloxamer-polycaprolactone-Enoxaparin of a certain amount of above-mentioned preparation, lecithin, cholesterol were dissolved in the chloroform by 2: 10: 1, stir evenly, vacuum drying, aFGF aqueous solution with gained powder and 10ml left and right sides 80IU/ml, add the 1.2mg polyoxyethylene sorbitan monoleate, 50rmin-1 stirs 2h, makes the liposome that is loaded with aFGF.
The liposome that is loaded with aFGF passes through formula: envelop rate W%=(Ct-CL)/Ct * 100% calculates, the envelop rate meansigma methods reaches 65%, and extracorporeal releasing experiment shows the liposome that is loaded with aFGF, the not prominent phenomenon of releasing, burst size in 12 hours requires to reach 90%, has slow release effect preferably.
Embodiment four, Fragmin-ethylenediamine-poloxamer synthetic and as the application of pharmaceutic adjuvant
1, Fragmin-ethylenediamine-poloxamer is synthetic
(b=44) 15g is a solvent at the 100ml dichloromethane to poloxamer 338 for M=15000, a=c=141, and the 0.6ml triethylamine is done under the catalyst action with 2mmol's
React 4h under the room temperature, then, add the 2.5mmol ethylenediamine, continue reaction 12h, the product of reaction is a terminal amino group, utilize 1-ethyl-3,3-dimethyl aminopropyl carbodiimide (EDC)/N-hydroxyl is in imidodicarbonic diamide (NHS) method, with the carboxyl reaction of itself and 10g Enoxaparin, stirring reaction 24h, the reaction end product was dialysed 3 days through bag filter, lyophilization, and promptly getting and forming new material is Fragmin-ethylenediamine-poloxamer.
2, contain the preparation of the vitamin E emulsifiable paste of Fragmin-ethylenediamine-poloxamer
2.1 prescription:
Vitamin E 20g, octadecanol 6g, monoglyceride 6g, liquid paraffin 3g, glycerol 4g, sodium lauryl sulphate 0.7g, allantoin 0.5g, Low molecular heparin-poloxamer (57IU/mg) 10g, azone 1.0g, Buddhist nun's platinum second fat 0.05g, distilled water 50ml, preparation emulsifiable paste total amount 100g
2.2 preparation method:
Octadecanol, monoglyceride, liquid paraffin, the Buddhist nun's platinum second fat of getting recipe quantity is heated to after 70 ℃ of thawings standby for oil phase; Getting glycerol, sodium lauryl sulphate, allantoin joins in the distilled water, be water after being heated to 70 ℃ of dissolvings, filter, oil phase is joined aqueous phase, mix and stir, when treating that temperature is reduced to below 55 ℃, add Low molecular heparin-poloxamer, azone, vitamin E, continue to be stirred to evenly, obtain containing the vitamin E emulsifiable paste of Low molecular heparin-poloxamer.
In this preparation, Low molecular heparin-poloxamer had both had the effect of surfactant as new type medicinal stuff, played the fixedly effect of slow release heparin again.
In the above-described embodiments, only the present invention has been carried out exemplary description, but those skilled in the art can carry out various modifications to the present invention after reading present patent application under the situation that does not break away from the spirit and scope of the present invention.
Claims (10)
1. heparin complex is characterized in that having following general formula:
Y-X-Y or Y-g-X-g-Y or X-Y or X-g-Y;
Wherein: X is a poloxamer, g be between the arm molecule, Y is a heparin, X, g, Y or X, Y pass through covalent bonds.
2. heparin complex according to claim 1, it is characterized in that: described poloxamer is a polyoxyethylene poly-oxygen propylene aether, it is poly-(oxygen ethylene) the c block copolymer of poly-(oxypropylene) b-of poly-(oxygen ethylene) a-of α-hydrogen-ω hydroxyl, structural formula is HO (CH2CH2O) a (OCHCH3CH2) b (CH2CH2O) c, in copolymer, a and c are 2～150, and b is 15～67.
3. heparin complex according to claim 1 is characterized in that: described heparin comprise reorganization heparin, natural heparin, the heparin of deriving, heparinate, low molecular weight heparin and salt thereof, can with chemically modified heparin and the heparinoid molecule and its esters of the functional group reactions of poloxamer and derivant thereof.
4. heparin complex according to claim 3 is characterized in that: described Low molecular heparin comprises low molecular sodium heparin, low molecular heparin calcium, Enoxaparin, Fragmin.
5. heparin complex according to claim 1, it is characterized in that: described arm molecule g is meant any macromole or small molecule structure that is used for connecting heparin and poloxamer, wherein macromole is synthetic high polymer or biopolymer, comprise polycaprolactone, Polyethylene Glycol, polysaccharide, protein, micromolecule is meant and contains amino and/or carboxyl functional group, can with the micromolecule of carboxyl in the heparin molecule or amino reaction, comprise ethylenediamine.
6. according to the preparation method of each described heparin complex of claim 1 to 5, it is characterized in that: utilize the terminal hydroxyl of poloxamer and the active group reaction of intramolecular carboxyl of heparin or amino to obtain described heparin complex, this course of reaction is: poloxamer or be connected with the poloxamer C-terminal carboxylic acidization of an arm molecule, then with the amino reaction of heparin; Perhaps poloxamer or be connected with the poloxamer C-terminal amination of an arm molecule is then with the carboxyl reaction of heparin.
7. according to the application of each described heparin complex of claim 1 to 5, it is characterized in that: this heparin complex is used as pharmaceutic adjuvant or delivery vector.
8. the application of heparin complex according to claim 7 is characterized in that: this heparin complex comprises as the application of pharmaceutic adjuvant: this complex is used for preparing aqueous dispersion, comprises Emulsion, liposome, micelle, microgranule; Or the drug carrier material of conduct long circulation, temperature or PH sensitivity is used.
9. the application of heparin complex as claimed in claim 7 is characterized in that: this heparin complex can be used as the delivery vector of chemical substance, enzyme or the high molecular weight protein of blindly dating with heparin.
10. the application of described heparin complex according to Claim 8～9 is characterized in that: preparation that this heparin complex forms or material are applied in oral, injection, percutaneous, the mucoadhesive delivery system or surgery, implant surgery in.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910104934A CN101766819A (en) | 2008-12-31 | 2008-12-31 | Heparin complex as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910104934A CN101766819A (en) | 2008-12-31 | 2008-12-31 | Heparin complex as well as preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101766819A true CN101766819A (en) | 2010-07-07 |
Family
ID=42500019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910104934A Pending CN101766819A (en) | 2008-12-31 | 2008-12-31 | Heparin complex as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101766819A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988998A (en) * | 2011-09-10 | 2013-03-27 | 温州医学院 | Poloxamer-adriamycin conjugate with anti-tumor effect and preparation method thereof |
| CN102989036A (en) * | 2011-09-10 | 2013-03-27 | 浙江海正药业股份有限公司 | Hydrogel containing heparin-poloxamer compound for anastomosis of blood vessel and preparation method thereof |
| CN105412941A (en) * | 2015-12-01 | 2016-03-23 | 蚌埠医学院 | PH-sensitive drug-loaded particle as well as preparation method and application thereof |
| CN109464465A (en) * | 2018-10-24 | 2019-03-15 | 温州医科大学 | A kind of islet cell transplantation hydrogel and preparation method thereof |
| CN109529113A (en) * | 2018-10-24 | 2019-03-29 | 温州医科大学 | Low immunogenicity bone defect position packing material and preparation method thereof |
| CN111919835A (en) * | 2020-08-06 | 2020-11-13 | 温州医科大学 | Preservation solution for maintaining activity of red blood cells |
| CN112426414A (en) * | 2020-12-03 | 2021-03-02 | 温州医科大学 | Eye anti-adhesion and blue light damage prevention care solution and preparation method thereof |
| CN113633756A (en) * | 2021-06-17 | 2021-11-12 | 温州医科大学 | FGF21 temperature-sensitive slow-release carrier, gene modification method and preparation method thereof |
-
2008
- 2008-12-31 CN CN200910104934A patent/CN101766819A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988998A (en) * | 2011-09-10 | 2013-03-27 | 温州医学院 | Poloxamer-adriamycin conjugate with anti-tumor effect and preparation method thereof |
| CN102989036A (en) * | 2011-09-10 | 2013-03-27 | 浙江海正药业股份有限公司 | Hydrogel containing heparin-poloxamer compound for anastomosis of blood vessel and preparation method thereof |
| CN102989036B (en) * | 2011-09-10 | 2015-10-21 | 浙江海正药业股份有限公司 | Hydrogel containing heparin-poloxamer complex being applied to angiostomy and preparation method thereof |
| CN102988998B (en) * | 2011-09-10 | 2015-12-02 | 温州医学院 | Poloxamer-amycin conjugate with antitumor action and preparation method thereof |
| CN105412941A (en) * | 2015-12-01 | 2016-03-23 | 蚌埠医学院 | PH-sensitive drug-loaded particle as well as preparation method and application thereof |
| CN109529113A (en) * | 2018-10-24 | 2019-03-29 | 温州医科大学 | Low immunogenicity bone defect position packing material and preparation method thereof |
| CN109464465A (en) * | 2018-10-24 | 2019-03-15 | 温州医科大学 | A kind of islet cell transplantation hydrogel and preparation method thereof |
| CN109464465B (en) * | 2018-10-24 | 2021-08-31 | 温州医科大学 | Hydrogel for islet cell transplantation and preparation method thereof |
| CN111919835A (en) * | 2020-08-06 | 2020-11-13 | 温州医科大学 | Preservation solution for maintaining activity of red blood cells |
| CN111919835B (en) * | 2020-08-06 | 2022-02-08 | 温州医科大学 | Preservation solution for maintaining activity of red blood cells |
| CN112426414A (en) * | 2020-12-03 | 2021-03-02 | 温州医科大学 | Eye anti-adhesion and blue light damage prevention care solution and preparation method thereof |
| CN112426414B (en) * | 2020-12-03 | 2022-02-08 | 温州医科大学 | Eye anti-adhesion and blue light damage prevention care solution and preparation method thereof |
| CN113633756A (en) * | 2021-06-17 | 2021-11-12 | 温州医科大学 | FGF21 temperature-sensitive slow-release carrier, gene modification method and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114585396B (en) | Injectable hydrogel with anti-inflammatory and repair promoting functions, preparation method thereof and application thereof in heart repair | |
| CN101766819A (en) | Heparin complex as well as preparation method and application thereof | |
| TWI306869B (en) | Amphiphilic block copolymers and nano particles comprising the same | |
| Sim et al. | Heparin-based temperature-sensitive injectable hydrogels for protein delivery | |
| CA2653541C (en) | Polymer-based serum albumin substitute | |
| Chen et al. | Saporin-loaded CD44 and EGFR dual-targeted nanogels for potent inhibition of metastatic breast cancer in vivo | |
| CN111423591B (en) | Amphiphilic graft copolymer based on hyaluronic acid and preparation method and application thereof | |
| CN101284885B (en) | Amphipathic cyclodextrin polymers, preparation method and use | |
| CN112933288B (en) | Cross-linked hemostatic sponge with hemostatic and postoperative anti-tumor functions and preparation method thereof | |
| CN102091025B (en) | Anti-tumor injectable hydrogel as well as preparation method and application thereof | |
| JP4262090B2 (en) | Anticancer agent-chitosan complex forming self-aggregate and method for producing the same | |
| CN105963706A (en) | Branched polyHPMA copolymer-DOX conjugate, and preparation method and application thereof | |
| WO2014190849A1 (en) | Doxorubicin prodrug, method of preparing same, and injectable combination | |
| CN105879050A (en) | Self-assembled targeting drug carrier nanoparticle and preparation method thereof | |
| CN105801870B (en) | The preparation method and products obtained therefrom of a kind of poly sialic acid-hyaluronic acid plural gel and application | |
| CN105327362B (en) | A kind of preparation method of the graphene targetable drug carriers of amphipathic nature polyalcohol brush modification | |
| CN108395543B (en) | Modified polyrotaxane, medicine-carrying micelle based on polyrotaxane and preparation method and application of medicine-carrying micelle | |
| CN105482104A (en) | Star-shaped polyglutamic acid as well as injectable hydrogel and preparation method thereof | |
| CN111743861B (en) | Targeted triple-negative breast cancer hypoxia response chiral drug micelle and preparation method thereof | |
| CN111249473B (en) | Delivery system and preparation method of polymerized chloroquine fluorene methyl carbonyl nanogel | |
| CN104371098A (en) | Multi-branched hydrophilic polymer-isocyanate derivative | |
| KR101086055B1 (en) | A thermosensitive pullulan-lactide copolymer, a nanoparticle formed from the same, and a process for the preparation thereof | |
| CN105920614A (en) | Supramolecular hydrogel medicine and gene dual-carrier material and preparation method thereof | |
| EP3219330B1 (en) | Synthesis of nano aggregate of chitosan modified by self-assembling peptide and application thereof to protein delivery | |
| KR20120083701A (en) | Nanoparticles formed by encapsulating an anticancer drug into glycolchitosan-cholanic acid complex and a process for the preparation 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 | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20100707 |