CN101966350A - Anticoagulant treatment method for medical macromolecular material - Google Patents
Anticoagulant treatment method for medical macromolecular material Download PDFInfo
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- CN101966350A CN101966350A CN2009100698864A CN200910069886A CN101966350A CN 101966350 A CN101966350 A CN 101966350A CN 2009100698864 A CN2009100698864 A CN 2009100698864A CN 200910069886 A CN200910069886 A CN 200910069886A CN 101966350 A CN101966350 A CN 101966350A
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Abstract
The invention belongs to biomedical materials. In order to solve the problem on anticoagulation treatment of a medical macromolecular material, the invention provides a scheme, namely an anticoagulant treatment method for a medical macromolecular material. The anticoagulant treatment process comprises the following steps of: firstly, preparing an anticoagulant heparin complex, preparing heparin sodium into a solution, dripping into hyamine, and reacting to obtain the heparin complex; dissolving the complex in an organic solvent to prepare a coating liquid; coating the prepared coating liquid on the surface of the medical macromolecular material twice in a 100-level purified environment; and curing, selecting a difunctional group reagent as a curing agent, soaking the processed material to form a crosslinked heparin polymer coating, and drying to obtain the heparinized medical macromolecular material. The scheme has the advantages of environmental protection, safety and low cost and is easy to operate and suitable for large-scale production; the medical macromolecular material can resist coagulation for more than 6 hours in direct contact with blood in vitro, the biological performance can conform to the requirements of a national standard (GB/T16886-2003/ISO10993:2002), and the anticoagulation treatment method is applicable to various common medical macromolecular materials.
Description
Technical field: the invention belongs to the bio-medical material class.It is specifically related to the method to the processing of medical macromolecular materials anticoagulation.
Background technology: medical material that contacts with blood and device, as artificial blood vessel, artificial heart, artificial lung, guide wire, scaffold tube, intubate, isocon etc., oneself is widely used in the modern medical service.These materials and the device normally make with macromolecular material, itself do not have anticoagulant characteristic or anticoagulation function relatively poor.After blood contacts with it, can produce a series of physiological reaction, the activation of for example hematoblastic absorption and activation, complement, the activation of interior external source coagulation system etc. finally cause the formation of thrombosis.Therefore must make patient's whole body heparinization in use, systemic blood can not be solidified, so just cause the potential danger that reaches postoperative hemorrhage, oozing of blood between art, (bleed and needed the hemostatic patient) in some cases and can't use at all as wound, basis.Therefore to the research of medical macromolecular materials anticoagulation function,, has considerable meaning from the requirement of short-term or life-time service no matter be all to be extremely urgent.Since people such as Gott in 1963 start the surface heparinization method, this research has all been obtained bigger progress both at home and abroad.Just introduced a kind of coating liquid and coating that improves biomedical devices surface anticoagulant performance as patent 03116747.0.This heparinoid formed material is in contact during blood, and heparin discharges and the heparin microenvironment that causes gradually at material surface, and certain heparin rate of release can make macromolecular material possess good resistance blood coagulation character.
Summary of the invention: the objective of the invention is to satisfy an urgent demand in the medical care precess and solve---the method that the medical macromolecular materials anticoagulation is handled to the special this programme that proposes of the anticoagulant function of macromolecule medical material, it has adopted new method to solve the synthetic of heparin complexes, select suitable organic solvent dissolution it and be coated on the medical macromolecular materials surface, can solve the anticoagulant problem of polymer surface well.
By as above design, the method to the processing of medical macromolecular materials anticoagulation that this programme proposed is characterized in that its technical process is as follows:
One. prepare anticoagulant heparin complexes:
1) heparin sodium is dissolved in purified water or the distilled water, being made into concentration is 1%-10% (g/ml) solution;
2) quaternary ammonium salt is progressively splashed in the above-mentioned solution, up to the white precipitate float occurring, continuation reaction 5-30 minute makes it abundant reaction and white precipitate and the quaternary ammonium salt layering is obvious, filters with the G2 funnel, obtains white precipitate;
3) white precipitate fully grinds with purified water or distilled water and washes immersion, is washed till repeatedly that white precipitate begins to unite and the noresidue quaternary ammonium salt, obtains being similar to chewing gum shape white or light yellow heparin complexes;
4) be put in the vacuum desiccator nature or drying under reduced pressure to constant weight.
Two. the preparation coating fluid: selection can be dissolved the organic solvent chloroform of heparin complexes, preparation heparin complexes coating fluid, concentration is 0.1%-10% (g/ml);
Three. coating: in 100 grades of environment purifications, the coating fluid for preparing adopted and flow through the method that formula combines with immersion type and coat the medical macromolecular materials surface, take out after 10 minutes-180 minutes, naturally dry or dry up, used the same method coating later on more once in 1-5 hour;
Four. solidify:
1) selecting bifunctional group reagent is firming agent, and concentration is 0.1%-20% (ml/ml);
2) the above-mentioned medical macromolecular materials of handling well are soaked in the bifunctional group reagent, and solidify down at 30 ℃-60 ℃, be 5-50 minute hardening time, forms crosslinked heparin polymer coating;
3) clean coating surface to remove unreacted bifunctional group reagent with purified water or distilled water, dry naturally or dry up, obtain the medical macromolecular materials of heparinization.
In this programme, the used organic solvent of dissolving heparin complexes also can use two or more in trichloroethane, dichloroethanes, dichloromethane, methanol, ethanol or the above solvent.
Adopt this programme can embody following superiority: 1. heparin is a kind of water miscible sulphuric acid aminoglycan, its molecular weight is about 2000, its chain link unit is by glucamine sulfonic acid, glucuronic acid and Chinese mugwort society sugar sulphur aldehydic acid etc. are formed, it is by combining with Antithrombin III (AT-III), the activity that suppresses serine protease in the blood coagulation alternative pathway stops coagulation process, the effect that has the strong inhibition coagulation activation in vivo, be mainly used in aspects such as anticoagulation therapy clinically, coat apparatus and macromolecule medical material surface energy and show its stable anticoagulant function, no matter still external in vivo heparin is, all has blood coagulation resisting function; 2. the harm that brings for fear of the systemic injection heparin increases the biocompatibility of material simultaneously, by certain method heparin is fixed on polymer surface, can obtain anticoagulant function, heparinization that Here it is.The surface of this heparinization can reduce after the extracorporeal circulation level of complement C3, C4 in the blood, simultaneously can prevent the adhesion of platelet, Fibrinogen, lipoprotein and other macro-molecular protein at material surface, thereby effectively improve the blood compatibility of artificial material, therefore heparin being fixed on the polymer surface to improve its anticoagulant property, is the important channel of improving the anticoagulant property of material; 3. the advantage of this process is: technology operation easily, environmental protection, safety, cost be lower, be suitable for large-scale production, the anticoagulant of external direct contact blood energy is more than 6 hours, and be applicable to multiple macromolecular material commonly used, with not influencing the physicochemical property that is coated with material after the technology coating of the present invention, resulting goods anticoagulation function is good and can keep stable; 4. the biology performance of this programme meets state (GB/T16886-2003/ISO10993:2002) requirement; 5. it comprises polrvinyl chloride, polyethylene, polyoxyethylene, Merlon, polypropylene, polyurethane, polystyrene, politef, cellulose derivative, polysulfones, polyether sulfone, silicone rubber etc. to processed medical macromolecular materials wide adaptability.
The specific embodiment:
Embodiment 1: the preparation of heparin-benzalkonium bromide complex
(1) heparin sodium 1g is dissolved in 10ml purified water or the distilled water;
(2) benzalkonium bromide is made into the concentration of 5% (g/ml) with purified water;
(3) 5% benzalkonium bromide solution progressively is added dropwise in the above-mentioned heparin sodium aqua, till the white precipitate float occurring.Continuation reaction 5-10 minute makes it abundant reaction and white precipitate and the solution layering is obvious.
(4) reuse G2 funnel filters, and obtains white precipitate.White precipitate fully grinds with purified water or distilled water washes immersion, be washed till repeatedly that white precipitate begins to unite and the noresidue quaternary ammonium salt till, obtain being similar to chewing gum shape white or light yellow heparin complexes.Be put in the vacuum desiccator nature or drying under reduced pressure at last to constant weight.
Embodiment 2: the preparation of heparin-benzalkonium chloride complex
(1) heparin sodium 1g is dissolved in 10ml purified water or the distilled water;
(2) benzalkonium chloride is made into the concentration of 5% (g/ml) with purified water;
(3) 5% Benza progressively is added dropwise in the above-mentioned heparin sodium aqua, till the white precipitate float occurring.Continuation reaction 5-10 minute makes it abundant reaction and white precipitate and the solution layering is obvious.
(4) reuse G2 funnel filters, and obtains white precipitate.White precipitate fully grinds with purified water or distilled water washes immersion, be washed till repeatedly that white precipitate begins to unite and the noresidue quaternary ammonium salt till, obtain being similar to chewing gum shape white or light yellow heparin complexes.Be put in the vacuum desiccator nature or drying under reduced pressure at last to constant weight.
Embodiment 3: coating and curing medical polyvinyl (PVC) pipe
(1) application example 1 described heparin quaternary ammonium salt complex 0.3g is dissolved in the 100ml chloroform soln, fully obtains water white coating liquid after the dissolving.
(2) in 100 grades of environment purifications, the coating fluid for preparing adopted and flow through the method that formula combines with immersion type and coat the medical PVC tube-surface, 10-60 takes out after second, naturally dry or dry up, coating oppositely used the same method in 5 hours later on more once, the medical PVC tube-surface forms stable heparin coating, dries naturally or dries up.
(3), be made into the concentration of 0.1%-1% (ml/ml) with purified water with firming agent bifunctional group reagent glutaraldehyde.
(4) above-mentioned coated medical PVC pipe is soaked in the bifunctional group reagent, and solidifies down at 30-60 ℃, be 10-50 minute hardening time, forms crosslinked heparin polymer coating.Clean up unreacted bifunctional group reagent with purified water at last, after drying naturally or drying up, obtain the medical PVC pipe of heparinization.
Embodiment 4: be coated with and solidify medical Merlon (PC) and manage
(1) with application example 1 described heparin quaternary ammonium salt complex 0.5g, is dissolved in 40ml methanol and the 60ml dichloroethane solution, fully obtains water white coating liquid after the dissolving.
(2) at 100 grades of environment the coating liquid for preparing is poured in the medical PC pipe, soaked 1-3 hour, make it the surface and form stable heparin coating, take out, dry naturally or dry up.
(3), be made into the concentration of 0.1%-1% (ml/ml) with purified water with firming agent bifunctional group reagent glutaraldehyde.
(4) above-mentioned coated medical PC pipe is soaked in the bifunctional group reagent, and 30-60 ℃ of curing, be 10-50 minute hardening time, forms crosslinked heparin polymer coating.Clean up unreacted bifunctional group reagent with purified water at last, after drying naturally or drying up, obtain the medical PC pipe of heparinization.
Embodiment 5: coating and curing medical grade silicon rubber (SR) pipe
(1) application example 1 described heparin quaternary ammonium salt complex 0.3g is dissolved in the 100ml chloroform soln, fully obtains water white coating liquid after the dissolving.
(2) in 100 grades of environment purifications, the coating fluid for preparing adopted and flow through the method that formula combines with immersion type and coat medical SR tube-surface, take out after 1 minute, naturally dry or dry up, coating oppositely used the same method in 5 hours later on more once, medical SR tube-surface forms stable heparin coating, dries naturally or dries up.
(3), be made into the concentration of 0.1%-1% (ml/ml) with purified water with firming agent bifunctional group reagent glutaraldehyde.
(4) above-mentioned coated medical SR pipe is soaked in the bifunctional group reagent, and solidifies down at 30-60 ℃, be 10-50 minute hardening time, forms crosslinked heparin polymer coating.Clean up unreacted bifunctional group reagent with purified water at last, after drying naturally or drying up, obtain the medical SR pipe of heparinization.
Embodiment 6: the test of quiescent anticoagulated courageous and upright energy
The main method of estimating at present the medical macromolecular materials anticoagulation function can be divided into external, intravital and half three major types such as intravital.China GB/T16886.1-2001 and GB/T16886.4-2003 have provided the description of some general introduction property to the medical apparatus and instruments biological assessment.We study and select for use the extracorporeal blood contact method to detect the anticoagulation function of the medical macromolecular materials after heparinization is handled at this.
So-called extracorporeal blood contact method is meant to be extracted blood out from the cardiovascular system of laboratory animal, with its with wait that observing material contacts certain hour in some way after, then in of the influence of observation in vitro detected materials to blood coagulation.The concrete operations step is:
(1) selection of rabbit: adult, healthy, 2.5-4.0Kg;
(2) blood collection needles Passivation Treatment;
(3) syringe needle after the Passivation Treatment is accurately inserted the rabbit ventricle, obtain the medical macromolecular materials pipe that fresh Sanguis Leporis seu oryctolagi injects embodiment 3, embodiment 4 and embodiment 5 described processing, put into 37 ± 1 ℃ of water-baths (or incubator), begin immediately to clock, left standstill 15 minutes, respectively get a bit of putting into and see if there is blood point, clot, thrombosis appearance in the clean beaker that fills normal saline, and blank will be arranged.After this per 30 minutes (or 1 hour) is observed once, till little blood point appears in blood.The record final anticoagulation time of this moment.
Claims (2)
1. method that the medical macromolecular materials anticoagulation is handled is characterized in that its technical process is as follows:
One. prepare anticoagulant heparin complexes:
1) heparin sodium is dissolved in purified water or the distilled water, being made into concentration is 1%-10% (g/ml) solution;
2) quaternary ammonium salt is progressively splashed in the above-mentioned solution, up to the white precipitate float occurring, continuation reaction 5-30 minute makes it abundant reaction and white precipitate and the quaternary ammonium salt layering is obvious, filters with the G2 funnel, obtains white precipitate;
3) white precipitate fully grinds with purified water or distilled water and washes immersion, is washed till repeatedly that white precipitate begins to unite and the noresidue quaternary ammonium salt, obtains being similar to chewing gum shape white or light yellow heparin complexes;
4) be put in the vacuum desiccator nature or drying under reduced pressure to constant weight.
Two. the preparation coating fluid: selection can be dissolved the organic solvent chloroform of heparin complexes, preparation heparin complexes coating fluid, concentration is 0.1%-10% (g/ml);
Three. coating: in 100 grades of environment purifications, the coating fluid for preparing adopted and flow through the method that formula combines with immersion type and coat the medical macromolecular materials surface, take out after 10 minutes-180 minutes, naturally dry or dry up, used the same method coating later on more once in 1-5 hour;
Four. solidify:
1) selecting bifunctional group reagent is firming agent, and concentration is 0.1%-20% (ml/ml);
2) the above-mentioned medical macromolecular materials of handling well are soaked in the bifunctional group reagent, and solidify down at 30 ℃-60 ℃, be 5-50 minute hardening time, forms crosslinked heparin polymer coating;
3) clean coating surface to remove unreacted bifunctional group reagent with purified water or distilled water, dry naturally or dry up, obtain the medical macromolecular materials of heparinization.
2. the method that the medical macromolecular materials anticoagulation is handled in accordance with claim is characterized in that the used organic solvent of aforesaid dissolving heparin complexes also can use two or more in trichloroethane, dichloroethanes, dichloromethane, methanol, ethanol or the above solvent.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105194742A (en) * | 2015-09-17 | 2015-12-30 | 协和同仁科技（天津）有限责任公司 | Anticoagulation method for surface of medical high molecular material or product |
| CN105517585A (en) * | 2013-04-26 | 2016-04-20 | 生物相互作用有限公司 | Bioactive coatings |
| CN111356911A (en) * | 2017-11-15 | 2020-06-30 | 雷迪奥米特医学公司 | Platelet activation free heparin-based blood sampler |
| CN113384758A (en) * | 2021-06-18 | 2021-09-14 | 海思盖德(苏州)生物医学科技有限公司 | Anticoagulation coating composition and preparation method and application thereof |
| CN113402704A (en) * | 2021-07-09 | 2021-09-17 | 万华化学集团股份有限公司 | Polycarbonate copolymer and preparation method and application thereof |
| USRE49522E1 (en) | 2013-04-26 | 2023-05-09 | Biointeractions Ltd. | Bioactive coatings |
-
2009
- 2009-07-27 CN CN2009100698864A patent/CN101966350A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105517585A (en) * | 2013-04-26 | 2016-04-20 | 生物相互作用有限公司 | Bioactive coatings |
| CN105517585B (en) * | 2013-04-26 | 2019-11-22 | 生物相互作用有限公司 | Bioactivity coatings |
| USRE49522E1 (en) | 2013-04-26 | 2023-05-09 | Biointeractions Ltd. | Bioactive coatings |
| USRE49528E1 (en) | 2013-04-26 | 2023-05-16 | Biointeractions Ltd. | Bioactive coatings |
| CN105194742A (en) * | 2015-09-17 | 2015-12-30 | 协和同仁科技（天津）有限责任公司 | Anticoagulation method for surface of medical high molecular material or product |
| CN111356911A (en) * | 2017-11-15 | 2020-06-30 | 雷迪奥米特医学公司 | Platelet activation free heparin-based blood sampler |
| CN113384758A (en) * | 2021-06-18 | 2021-09-14 | 海思盖德(苏州)生物医学科技有限公司 | Anticoagulation coating composition and preparation method and application thereof |
| CN113402704A (en) * | 2021-07-09 | 2021-09-17 | 万华化学集团股份有限公司 | Polycarbonate copolymer and preparation method and application thereof |
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Application publication date: 20110209 |