CN102861364A - Preparation method and application of dexamethasone sodium phosphate-sodium alga acid composite slow-release coating - Google Patents
Preparation method and application of dexamethasone sodium phosphate-sodium alga acid composite slow-release coating Download PDFInfo
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Abstract
The invention discloses a preparation method and application of a dexamethasone sodium phosphate-sodium alga acid composite slow-release coating. A high polymer material is soaked in a sulfuric acid solution of potassium permanganate to conduct acidizing; then the high polymer material is placed in a polymine solution to obtain an amination embellished surface; and oxidation treatment is carried out on the sodium alga acid by using periodic acid or sodium periodate to enable aldehyde groups to be exposed at the tail end of an alginic acid segment to obtain multi-aldehyde group oxidation sodium alga acid, the dexamethasone sodium phosphate solution is soluble in deionized water, and finally materials of the amination embellished surface is placed in a reaction liquid to obtain the composite coating. The technical scheme is that the dexamethasone sodium phosphate and the sodium alga acid can be fixed on the surface of an extracorporeal circulation pipeline in a surface coating mode and has anti-freezing and anti-inflammatory double activity, external medicines are durable and stable in slow-release performance, the dexamethasone sodium phosphate-sodium alga acid composite slow-release coating can replace vein heparinization in a short period, systemic inflammatory response can be lightened through slow release, and short-period operation requirements in department of cardiac surgery can be met.
Description
Technical field
The present invention relates to polymer surface coating technology field, more particularly, relate to a kind of dexamethasone sodium phosphate and many aldehyde sodium alginates of utilizing polymer surface is carried out coating modified preparation method.
Background technology
Biomedical material is used and is faced biocompatibility and blood compatibility two large problems.Coating technology is passed through the pre-modification to material surface, thereby has improved biocompatibility and the anticoagulating active on biomedical material surface.Wherein an example is heparin, heparin belongs to mucopolysaccharide, molecular weight 5000-40000, it is the mixture that is consisted of by electronegative linear polysaccharide, the most important character of heparin is its anticoagulation characteristic, the anticoagulating active of heparin come from it can with organism in multiple coagulation inhibitor interact, reach anticoagulant purpose by the anticoagulating active that accelerates or improve these inhibitive factor, but be stained with defective for Profilin.Wherein heparin is most important to the effect of antithrombin Ⅲ (AT-III).Biomedical material surface heparin fixation principle (being face coat) can be summarized as Physical and chemical method at present.Physical is namely by the winding between mechanical embedding, the strand and infiltration, be fixed to biomaterial surface by modes such as porose material absorption with heparin, thereby reaches the purpose with Immobilized Heparin.Chemical method is namely by reactive functional group abundant on the heparin molecule chain, but reacts such as corresponding reactive group on sulfonic group, amino, carboxyl etc. and the target material surface, with ionic bond or in the mode of covalent bond it is fixed to biomaterial surface.Patient is prone to systemic inflammatory response behind the cardiopulmonary bypass surgery, this mainly is because the defective of material itself, when treating often by intravenous injection and intramuscular injection anti-inflammation drugs, by alleviating and preventing from organizing reaction to inflammation, thereby the clinical manifestation that reduces inflammation, but can have side effects owing to blood drug level is excessive.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, overcome extracorporeal circulation with macromolecular material easily inspire systemic inflammatory response, the shortcoming such as biocompatibility is poor and anticoagulating active is poor, utilize ionic bond and space winding, periodate oxidation and terminal point technique for fixing, a kind of dexamethasone sodium phosphate-many aldehyde sodium alginates composite coating and preparation method thereof is provided.
Technical purpose of the present invention is achieved by following technical proposals:
The preparation method of a kind of dexamethasone sodium phosphate-sodium alginate composite slow release coating, carry out according to following step:
At first, namely step (1) is immersed in macromolecular material in the sulfuric acid solution of potassium permanganate, carries out acidification, wherein:
Described macromolecular material can be selected polyethylene, polrvinyl chloride, polypropylene, polyester, silicone rubber, nylon, Merlon or the politef of medical grade, these materials can be used for the structure of extracorporeal circulation of blood pipeline, need to be to its modifying surface to improve the compatibility of itself and blood.
The sulfuric acid solution of described potassium permanganate is adopted and is utilized following mode to be prepared: first potassium permanganate is dissolved in mix homogeneously in the deionized water, then slowly be reached for 10%-70% to the mass percent of sulphuric acid and get final product to wherein adding concentrated sulphuric acid (mass percent is 95-98% concentrated sulphuric acid), mixing.
Macromolecular material being immersed in the sulfuric acid solution of potassium permanganate, carrying out acidification, mainly is for material modified surface nature, and can select the acid treatment time is 1min-10min, and room temperature is processed, and temperature is 20-25 ℃; The intensity that can adopt the mode of machinery or ultrasonic agitation to strengthen reacting in the acidification process can use deionized water that material is cleaned after acidification.
Step (2) places polymine (PEI) aqueous solution with the material of acidified processing, the surface that reaction is modified to obtain amination, wherein:
The mass percentage concentration of described polymine (PEI) solution is 0.005%-0.5%, and the response time is 10min-60min, and room temperature is processed, and temperature is 20-25 ℃.
Step (3) uses periodic acid or sodium periodate oxidation to process sodium alginate, so that alginic acid fragment ends exposed aldehyde radical obtains many aldehyde radicals oxidized sodium alginate (OSA), wherein:
The mol ratio of the repetitive of periodic acid or sodium metaperiodate and sodium alginate is (1-3): 10, and oxidation reaction stirring reaction at least 24 hours under the lucifuge condition, preferred 24-40 hours, temperature was 20-25 ℃; Adopt the ethylene glycol cessation reaction, the aqueous solution of 96wt% ethanol precipitates, sucking filtration, dialysis after the precipitation, and-80 ℃ of lyophilizations obtain many aldehyde radicals oxidized sodium alginate.
Step (4), the reaction solution of configuration coated substance dexamethasone sodium phosphate (DSP) and many aldehyde radicals oxidized sodium alginate (OSA), in the wherein said reaction solution, coating substance DSP concentration is 0.01-0.5mg/mL, coating substance OSA concentration is 0.05-2mg/mL, NaCl concentration is 0.15-0.55mol/L, sodium cyanoborohydride concentration is 0.01-0.1mg/mL, solvent is deionized water, can select at normal temperatures (temperature is 20-25 ℃) mix homogeneously dissolving, the pH value of adjusting reaction solution is 3.0-6.0; When adjusting pH, can adopt the aqueous hydrochloric acid solution of 0.1mmol/L.
Step (5) places the reaction solution of step (4) configuration with the material of amination modification of surfaces, obtains the DSP/OSA composite coating by space physics winding, ionic bond and terminal point fixation, and wherein reaction temperature is 30 ℃-60 ℃, preferred 40-50 ℃; At least 2 hours response time, preferred 2-6 hour.
The terminal point fixation that the present invention adopts, belong to special covalent coupling method, it at first introduces active ammonia basic unit by pre-functionalization on the artificial material surface, secondly by periodic acid or sodium periodate oxidation sodium alginate, produce terminal polysaccharide molecule fragment with active aldehyde radical, the aldehyde radical of polysaccharide fragment does not participate in hemiacetal and forms, and is combined into Schiff's base with the active amino on artificial material surface, is reduced to subsequently stable covalency body.Single and be in end because of OSA fragment active aldehydes radix amount, end points adheres to, Cheng Jianliang is single, so the functional activity of OSA molecule part can be stretched out from the artificial material surface and the free combination of blood molecule, brings into play the advantage of good biocompatibility, anticoagulating active.Simultaneously the present invention adopts space physics to twine and the ionic bond combined techniques, and DSP is combined with the PEI of precoating by ionic bond on the one hand, and long-chain polysaccharide macro-molecular OSA carries out the space physics winding to DSP on the other hand.
The sodium alginate that the present invention uses is a kind of natural linear polysaccharide, has the characteristics such as good biocompatibility, bio-adhesiveness, safety, water solublity, slow release and polyelectrolyte, is widely used in medicine, food, drug release and field of tissue engineering technology.Many aldehyde radicals alginic acid is by periodic acid the suitable diol structure of sodium alginate to be oxidized to two aldehyde structures, thereby in the sodium alginate molecule, introduce new activity functional groups, can with the macromolecular substances generation cross-linking reaction with free amine group, improved simultaneously its degradation property (as shown in Figure 1).The dexamethasone sodium phosphate that the present invention uses is a kind of of Aeroseb-Dex, belongs to biological micromolecule, has very strong antiinflammatory, antiviral, Antishock function is widely used in clinical practice, by alleviating and prevent from organizing reaction to inflammation, thus the clinical manifestation that reduces inflammation.
DSP/OSA composite coating provided by the present invention, formed by polymine, sodium alginate, dexamethasone sodium phosphate, it is low that native toxicity is low, cost is enriched in the source, but at room temperature long term storage, and sodium alginate and dexamethasone sodium phosphate group are fixed on the surface of material in the coating, increase the area contact with blood with or chance, effectively bring into play its character; Physics twines and the dexamethasone sodium phosphate of ionic bond combination had both reached effectively fixing, can slowly discharge along with the extracorporeal circulation blood flow again, has effectively brought into play the anti-inflammatory activity of dexamethasone sodium phosphate; The terminal point fixation is implemented convenient, and many aldehyde sodium alginates that terminal point is fixed are in conjunction with firm, and space conformation is good, can effectively increase biocompatibility and the anticoagulating active of polymer surface, can effectively twine dexamethasone sodium phosphate (as shown in Figure 2) again.
With undressed PVC, with the PVC of PEI coating, carry out examination of infrared spectrum (infrared spectrum manufacturer and model Thermo NICOLET 6700, detector are that DTGs KBr, beam splitter are that KBr, wave-length coverage are 650-4000nm) with the PVC of DSP/OSA coating, from shown in the accompanying drawing 3-5 as can be known, 1550cm
-1The place is NH
2Characteristic absorption peak, 3400cm
-1About the characteristic absorption peak of visible sodium alginate, illustrate that many aldehyde sodium alginates pass through NH
2Be fixed on the surface of material, 2500-4000cm
-1The characteristic absorption peak of the visible dexamethasone sodium phosphate of scope illustrates that DSP is fixed on the surface of material by physics winding and ionic bond.
The dexamethasone sodium phosphate route of administration mostly is intravenous injection and intramuscular injection at present, technical scheme of the present invention can be in the face coat mode at the surperficial fixedly dexamethasone sodium phosphate of extracorporeal circulation pipeline, can play constantly antiinflammatory action by slow release, be unlikely to again to have side effects owing to blood drug level is excessive, just can bring into play to greatest extent the antiinflammatory action of dexamethasone sodium phosphate.The DSP/OSA composite coating possesses anticoagulant and antiinflammatory double activity, external medicine sustained release performance lasting stability, in extracorporeal circulation, can short-term substitute the vein heparinization, can alleviate systemic inflammatory response by slow release DSP again, can satisfy the requirement of department of cardiac surgery operation a middle or short term.In field of biomedical materials, have broad application prospects and higher practical value such as extracorporeal circulation pipeline, artery filter, venous incubation etc.
Description of drawings
The preparation principle sketch map of many aldehyde radicals of Fig. 1 oxidized sodium alginate.
Fig. 2 coating substance DSP fixation principle sketch map.
Blank polrvinyl chloride (PVC) infrared spectrogram of Fig. 3.
The PVC infrared spectrogram of Fig. 4 band PEI coating.
The PVC infrared spectrogram of Fig. 5 band DSP/OSA coating.
Fig. 6 composite coating pipeline DSP dynamic release curve.
The specific embodiment
Further specify technical scheme of the present invention below in conjunction with specific embodiment.The extracorporeal circulation pipeline that the macromolecular material that uses provides as Dongguan Kewei Medical Instrument Co., Ltd, material are polrvinyl chloride; Dexamethasone sodium phosphate CAS:2392-39-4, the large magnificent great achievement medication chemistry company limited in Wuhan, molecular formula C
22H
28FNa
2O
8P, molecular weight are 516.41; Sodium alginate: CAS:9005-38-3, SIGMA-ALDRICH, molecular formula (C
6H
7NaO
6) n, n=80～750, M
W32000 ~ 200000.
The first step is dissolved in 0.344 gram potassium permanganate in 162 ml deionized water, slowly adds 95wt% concentrated sulphuric acid 10ml, makes very mix homogeneously of concentrated sulphuric acid and potassium permanganate.
Second step, the middle macromolecular material PVC that adds in step 1 gained solution, mechanical agitation is fully reacted 10min, and temperature is 20 ℃; Adopt deionized water that material is cleaned after the reaction.
The 3rd step, immerse in the 0.01wt% polyethyleneimine: amine aqueous solution through the pretreated macromolecular material of step 2,20 ℃ of reactions of room temperature 60min obtains the surface that amination is modified.
The 4th step, press sodium metaperiodate and sodium alginate unit mol ratio 1:10, the oxidation processes alginic acid, make alginic acid fragment ends exposed aldehyde radical, ethylene glycol cessation reaction, 96wt% ethanol water precipitation, sucking filtration, dialysis after the precipitation,-80 ℃ of lyophilizations obtain many aldehyde sodium alginates, i.e. coating substance OSA.Oxidation reaction stirring reaction 24 hours under the lucifuge condition, temperature is 20 ℃.
In the 5th step, at first the 10mg dexamethasone sodium phosphate is dissolved in the 200ml deionized water, and 20 ℃ of abundant mixings of room temperature obtain coating substance DSP; Then take this solution as the configurations reaction solution, coating substance DSP 0.05mg/mL wherein, OSA concentration 0.1mg/ml, NaCl 0.15mol/L, sodium cyanoborohydride 0.1mg/mL, and regulate pH value as 3.0 take the aqueous hydrochloric acid solution of 0.1mmol/L.
In the 6th step, the macromolecular material that amination is modified places reactant liquor, 40 ℃ of reaction temperatures, 2 hours response time.
The first step is dissolved in 0.328 gram potassium permanganate in 144 ml deionized water, slowly adds 95% concentrated sulphuric acid 20ml, makes very mix homogeneously of concentrated sulphuric acid and potassium permanganate.
Second step adds macromolecular material in step 1 gained solution, ultrasonic agitation is fully reacted 1min, and temperature is 25 ℃; Adopt deionized water that material is cleaned after the reaction.
The 3rd step, immerse in the 0.5wt% polyethyleneimine: amine aqueous solution through the pretreated macromolecular material of step 2,25 ℃ of reactions of room temperature 10min obtains the surface that amination is modified.
The 4th step, press sodium metaperiodate and sodium alginate unit mol ratio 3:10, the oxidation processes alginic acid, make alginic acid fragment ends exposed aldehyde radical, ethylene glycol cessation reaction, 96wt% ethanol water precipitation, sucking filtration, dialysis after the precipitation,-80 ℃ of lyophilizations obtain many aldehyde sodium alginates, i.e. coating substance OSA.Oxidation reaction stirring reaction 40 hours under the lucifuge condition, temperature is 25 ℃.
In the 5th step, at first the 20mg dexamethasone sodium phosphate is dissolved in the 200ml deionized water, and 25 ℃ of abundant mixings of room temperature obtain coating substance DSP; Then take this solution as the configurations reaction solution, coating substance DSP 0.1mg/mL wherein, OSA concentration 2mg/ml, NaCl 0.15mol/L, sodium cyanoborohydride 0.1mg/mL, and regulate pH value as 4.0 take the aqueous hydrochloric acid solution of 0.1mmol/L.
In the 6th step, the macromolecular material that amination is modified places reactant liquor, 50 ℃ of reaction temperatures, 6 hours response time.
The first step is dissolved in 0.328 gram potassium permanganate in 144 ml deionized water, slowly adds 95% concentrated sulphuric acid 20ml, makes very mix homogeneously of concentrated sulphuric acid and potassium permanganate.
Second step adds macromolecular material in step 1 gained solution, ultrasonic agitation is fully reacted 8min, and temperature is 25 ℃; Adopt deionized water that material is cleaned after the reaction.
The 3rd step, immerse in the 0.05wt% polyethyleneimine: amine aqueous solution through the pretreated macromolecular material of step 2,25 ℃ of reactions of room temperature 30min obtains the surface that amination is modified.
The 4th step, press sodium metaperiodate and sodium alginate unit mol ratio 1:10, the oxidation processes alginic acid, make alginic acid fragment ends exposed aldehyde radical, ethylene glycol cessation reaction, 96wt% ethanol water precipitation, sucking filtration, dialysis after the precipitation,-80 ℃ of lyophilizations obtain many aldehyde sodium alginates, i.e. coating substance OSA.Oxidation reaction stirring reaction 30 hours under the lucifuge condition, temperature is 20 ℃.
In the 5th step, at first the 40mg dexamethasone sodium phosphate is dissolved in the 200ml deionized water, and 20 ℃ of abundant mixings of room temperature obtain coating substance DSP; Then take this solution as the configurations reaction solution, coating substance DSP 0.2mg/mL wherein, OSA concentration 0.05mg/mL, NaCl 0.35mol/L, sodium cyanoborohydride 0.01mg/mL, and regulate pH value as 6 take the aqueous hydrochloric acid solution of 0.1mmol/L.
In the 6th step, the macromolecular material that amination is modified places reactant liquor, 60 ℃ of reaction temperatures, 4 hours response time.
The first step is dissolved in 0.328 gram potassium permanganate in 144 ml deionized water, slowly adds 95% concentrated sulphuric acid 20ml, makes very mix homogeneously of concentrated sulphuric acid and potassium permanganate.
Second step adds macromolecular material in step 1 gained solution, mechanical agitation is fully reacted 5min, and temperature is 25 ℃; Adopt deionized water that material is cleaned after the reaction.
The 3rd step, immerse in the 0.005wt% polyethyleneimine: amine aqueous solution through the pretreated macromolecular material of step 2,25 ℃ of reactions of room temperature 50min obtains the surface that amination is modified.
The 4th step, press sodium metaperiodate and sodium alginate unit mol ratio 2:10, the oxidation processes alginic acid, make alginic acid fragment ends exposed aldehyde radical, ethylene glycol cessation reaction, 96wt% ethanol water precipitation, sucking filtration, dialysis after the precipitation,-80 ℃ of lyophilizations obtain many aldehyde sodium alginates, i.e. coating substance OSA.Oxidation reaction stirring reaction 35 hours under the lucifuge condition, temperature is 25 ℃.
In the 5th step, at first the 80mg dexamethasone sodium phosphate is dissolved in the 200ml deionized water, and 25 ℃ of abundant mixings of room temperature obtain coating substance DSP; Then take this solution as the configurations reaction solution, coating substance DSP 0.4mg/mL wherein, OSA concentration 0.5mg/mL, NaCl 0.25mol/L, sodium cyanoborohydride 0.05mg/mL, and regulate pH value as 5 take the aqueous hydrochloric acid solution of 0.1mmol/L.
In the 6th step, the macromolecular material that amination is modified places reactant liquor, 30 ℃ of reaction temperatures, 4 hours response time.
The first step is dissolved in 0.328 gram potassium permanganate in 144 ml deionized water, slowly adds 95% concentrated sulphuric acid 20ml, makes very mix homogeneously of concentrated sulphuric acid and potassium permanganate.
Second step adds macromolecular material in step 1 gained solution, mechanical agitation is fully reacted 5min, and temperature is 25 ℃; Adopt deionized water that material is cleaned after the reaction.
The 3rd step, immerse in the 0.005wt% polyethyleneimine: amine aqueous solution through the pretreated macromolecular material of step 2,25 ℃ of reactions of room temperature 50min obtains the surface that amination is modified.
The 4th step, press sodium metaperiodate and sodium alginate unit mol ratio 2:10, the oxidation processes alginic acid, make alginic acid fragment ends exposed aldehyde radical, ethylene glycol cessation reaction, 96wt% ethanol water precipitation, sucking filtration, dialysis after the precipitation,-80 ℃ of lyophilizations obtain many aldehyde sodium alginates, i.e. coating substance OSA.Oxidation reaction stirring reaction 35 hours under the lucifuge condition, temperature is 25 ℃.
In the 5th step, at first the 100mg dexamethasone sodium phosphate is dissolved in the 200ml deionized water, and 20 ℃ of abundant mixings of room temperature obtain coating substance DSP; Then take this solution as the configurations reaction solution, coating substance DSP 0.5mg/mL wherein, OSA concentration 1mg/mL, NaCl 0.25mol/L, sodium cyanoborohydride 0.05mg/mL, and regulate pH value as 5 take the aqueous hydrochloric acid solution of 0.1mmol/L.
In the 6th step, the macromolecular material that amination is modified places reactant liquor, 30 ℃ of reaction temperatures, 4 hours response time.
The first step is dissolved in 0.328 gram potassium permanganate in 144 ml deionized water, slowly adds 95% concentrated sulphuric acid 20ml, makes very mix homogeneously of concentrated sulphuric acid and potassium permanganate.
The 3rd step, immerse in the 0.5wt% polyethyleneimine: amine aqueous solution through the pretreated macromolecular material of step 2,25 ℃ of reactions of room temperature 40min obtains the surface that amination is modified.
The 4th step, press sodium metaperiodate and sodium alginate unit mol ratio 2:10, the oxidation processes alginic acid, make alginic acid fragment ends exposed aldehyde radical, ethylene glycol cessation reaction, 96wt% ethanol water precipitation, sucking filtration, dialysis after the precipitation,-80 ℃ of lyophilizations obtain many aldehyde sodium alginates, i.e. coating substance OSA.Oxidation reaction stirring reaction 30 hours under the lucifuge condition, temperature is 25 ℃.
In the 5th step, at first the 2mg dexamethasone sodium phosphate is dissolved in the 200ml deionized water, and 20 ℃ of abundant mixings of room temperature obtain coating substance DSP; Then take this solution as the configurations reaction solution, coating substance DSP 0.01mg/mL wherein, OSA concentration 1mg/mL, NaCl 0.55mol/L, sodium cyanoborohydride 0.05mg/mL, and regulate pH value as 4 take the aqueous hydrochloric acid solution of 0.1mmol/L.
In the 6th step, the macromolecular material that amination is modified places reactant liquor, 50 ℃ of reaction temperatures, 2 hours response time.
Utilize phenolsulfuric acid method (Dubois M, Gilles K A, Hamilton JK, et al.Colorimetric method for determination of sugars and related substances[J] .Analytical Chemistry, 1956,28 (3): 350-356.), change by sodium alginate (OSA) reactant liquor absorbance before and after calculating reaction, indirectly obtain the fixed amount of OSA, prove that simultaneously OSA is really fixing, sodium alginate is successfully fixing among the visible embodiment 1-5.
| Abs before the reaction | Abs after the reaction | Fixed amount μ g/cm 2 | |
| Embodiment 1 | 0.126 | 0.109 | 0.79 |
| |
0.394 | 0.328 | 7.78 |
| |
0.153 | 0.127 | 5.03 |
| |
0.235 | 0.224 | 0.49 |
| |
0.292 | 0.268 | 3.62 |
| |
0.258 | 0.236 | 4.58 |
Utilize high performance liquid chromatography (Chen Yongpeng, Wang Guixue, Chen Yan, Jin Xianchun, Hou Yanbin, Luo Lailong, Sun Dagui. coating preparation and the external slow release experimentation [J] of dexamethasone endovascular stent, Third Military Medical University's journal, 2008,5 (10): 935-937.), the liquid chromatograph model is Agilent 1100 Series, USA, the peak area value after mensuration DSP liquid and the PVC material effects, the DSP that is fixed by standard curve method measures.
| Peak area value | DSP density μ g/cm 2 | |
| Embodiment 1 | 683.33 | 4.35 |
| |
936.12 | 2.74 |
| |
786.26 | 3.71 |
| |
732.15 | 3.92 |
| |
755.29 | 3.16 |
| |
712.64 | 4.14 |
Macromolecular material PVC to coating tests, and respectively the sample of embodiment 1-6 is carried out the test (getting the test result meansigma methods of 6 embodiment) of four of coagulation functions and Profilin absorption; Wherein the test of four of coagulation functions adopts application of automated coagulation analyzer to measure the (STA-R of Diagnostica Stago
Application of automated coagulation analyzer); Protein adsorption adopts BCA method (Ishihara K, Fukumoto K, Iwasaki Y, Nakabayashi N.Modification of polysulfone with phospholipid polymer for improvement of the bloodcompatibility.Part 1.Surface characterization.Biomaterials 1999,20 (17): 1545-1551.).
Profilin absorption (having improved biocompatibility)
| Types of coatings | HAS adsorbs (μ g/cm 2) | HPF adsorbs (μ g/cm 2) |
| The blank group | 270.7 | 544.3 |
| The composite coating group | 108.5 | 157.9 |
* adhesion protein adopts the BCA standard measure
* HAS: human serum albumin HPF: human fibrinogen
Utilize preparation method of the present invention to form the DSP-OSA composite coating on the medical polyvinyl surface, and the DSP dynamic release of this composite coating pipeline tested (Chen Yongpeng, Wang Guixue, Chen Yan, Jin Xianchun, Hou Yanbin, Luo Lailong, Sun Dagui. coating preparation and the external slow release experimentation [J] of dexamethasone endovascular stent, Third Military Medical University's journal, 2008,5 (10): 935-937.).Composite coating pipeline DSP dynamic release curve, as shown in Figure 6 (release profiles of embodiment presents consistent form substantially); Data are as shown in the table:
From above-mentioned experiment, can find out, the macromolecular material of process OSA and DSP composite coating is in four of coagulation functions of test, protein adsorption performance, compare with the blank group, obviously anticoagulant and protein adsorption are effectively improved biocompatibility and anticoagulant functions.DSP has reached dynamic release, and slow release effect is obvious, and this composite coating can use at the medical tubing material surface, to reach slow release DSP, brings into play to greatest extent the antiinflammatory action of dexamethasone sodium phosphate.
More than the present invention has been done exemplary description; should be noted that; in the situation that does not break away from core of the present invention, the replacement that is equal to that any simple distortion, modification or other those skilled in the art can not spend creative work all falls into protection scope of the present invention.
Claims (10)
1. the preparation method of dexamethasone sodium phosphate-sodium alginate composite slow release coating is characterized in that, carries out according to following step:
Step (1) is immersed in macromolecular material in the sulfuric acid solution of potassium permanganate, carries out acidification
Step (2) places the polyethyleneimine: amine aqueous solution with the material of acidified processing, the surface that reaction is modified to obtain amination
Step (3) uses periodic acid or sodium periodate oxidation to process sodium alginate, so that alginic acid fragment ends exposed aldehyde radical obtains many aldehyde radicals oxidized sodium alginate
Step (4), the reaction solution of configuration coated substance dexamethasone sodium phosphate and many aldehyde radicals oxidized sodium alginate, in the wherein said reaction solution, coating substance dexamethasone sodium phosphate concentration is 0.01-0.5mg/mL, many aldehyde radicals of coating substance oxidized sodium alginate concentration is 0.05-2mg/mL, and NaCl concentration is 0.15-0.55mol/L, and sodium cyanoborohydride concentration is 0.01-0.1mg/mL, solvent is deionized water, and the pH value of adjusting reaction solution is 3.0-6.0
Step (5) places the reaction solution of step (4) configuration with the material of amination modification of surfaces, obtains composite coating by space physics winding, ionic bond and terminal point fixation, and wherein reaction temperature is 30 ℃-60 ℃, at least 2 hours response time.
2. the preparation method of dexamethasone sodium phosphate according to claim 1-sodium alginate composite slow release coating, it is characterized in that, in the described step (1), described macromolecular material can be selected polyethylene, polrvinyl chloride, polypropylene, polyester, silicone rubber, nylon, Merlon or the politef of medical grade; The sulfuric acid solution of described potassium permanganate is adopted and is utilized following mode to be prepared: first potassium permanganate is dissolved in mix homogeneously in the deionized water, then slowly to wherein adding the concentrated sulphuric acid that mass percent is 95-98%, mix to the mass percent of sulphuric acid and be reached for 10%-70%.
3. the preparation method of dexamethasone sodium phosphate according to claim 1-sodium alginate composite slow release coating, it is characterized in that, in the described step (1), macromolecular material is immersed in the sulfuric acid solution of potassium permanganate, carrying out acidification, mainly is for material modified surface nature, and can select the acid treatment time is 1min-10min, room temperature is processed, and temperature is 20-25 ℃; The intensity that can adopt the mode of machinery or ultrasonic agitation to strengthen reacting in the acidification process can use deionized water that material is cleaned after acidification.
4. the preparation method of dexamethasone sodium phosphate according to claim 1-sodium alginate composite slow release coating, it is characterized in that, in the described step (2), the mass percentage concentration of described polyethyleneimine: amine aqueous solution is 0.005%-0.5%, response time is 10min-60min, room temperature is processed, and temperature is 20-25 ℃.
5. the preparation method of dexamethasone sodium phosphate according to claim 1-sodium alginate composite slow release coating, it is characterized in that, in the described step (3), the mol ratio of the repetitive of periodic acid or sodium metaperiodate and sodium alginate is (1-3): 10, oxidation reaction stirring reaction at least 24 hours under the lucifuge condition, temperature is 20-25 ℃; Adopt the ethylene glycol cessation reaction, the aqueous solution of 96wt% ethanol precipitates, sucking filtration, dialysis after the precipitation, and-80 ℃ of lyophilizations obtain many aldehyde radicals oxidized sodium alginate.
6. the preparation method of dexamethasone sodium phosphate according to claim 5-sodium alginate composite slow release coating is characterized in that, in the described step (3), the time of oxidation reaction is 24-40 hour.
7. the preparation method of dexamethasone sodium phosphate according to claim 1-sodium alginate composite slow release coating is characterized in that, in the described step (4), when adjusting pH, adopts the aqueous hydrochloric acid solution of 0.1mmol/L.
8. the preparation method of dexamethasone sodium phosphate according to claim 1-sodium alginate composite slow release coating is characterized in that, in the described step (5), reaction temperature is 40-50 ℃; Response time is 2-6 hours.
9. the application of preparation method in biomedical material of dexamethasone sodium phosphate as claimed in claim 1-sodium alginate composite slow release coating, it is characterized in that, described composite slow release coating possesses anticoagulant and antiinflammatory double activity, and can realize the slow release of dexamethasone sodium phosphate.
10. the application of preparation method in field of biomedical materials of dexamethasone sodium phosphate according to claim 9-sodium alginate composite slow release coating, it is characterized in that described biomedical material refers to extracorporeal circulation pipeline, artery filter, venous incubation.
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| CN103554300A (en) * | 2013-11-20 | 2014-02-05 | 青岛明月海藻集团有限公司 | Method for preparing high-viscosity oxidized sodium alginate |
| CN105078918A (en) * | 2015-01-09 | 2015-11-25 | 田曼霖 | Dexamethasone acetate slow-release preparation and preparation method thereof |
| CN112190772A (en) * | 2020-10-12 | 2021-01-08 | 淮阴工学院 | Anastomosis nail with anti-inflammation function and preparation method thereof |
| CN113975463A (en) * | 2021-11-22 | 2022-01-28 | 湖南普林特医疗器械有限公司 | Porous tantalum implant with bioactive coating and preparation method thereof |
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| CN105078918A (en) * | 2015-01-09 | 2015-11-25 | 田曼霖 | Dexamethasone acetate slow-release preparation and preparation method thereof |
| CN105078918B (en) * | 2015-01-09 | 2018-04-17 | 田曼霖 | A kind of dexamethasone acetate sustained release preparation and preparation method thereof |
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