CN102755670A - Preparation method of traceable biodegradable polymer bracket - Google Patents
Preparation method of traceable biodegradable polymer bracket Download PDFInfo
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- CN102755670A CN102755670A CN2011101131459A CN201110113145A CN102755670A CN 102755670 A CN102755670 A CN 102755670A CN 2011101131459 A CN2011101131459 A CN 2011101131459A CN 201110113145 A CN201110113145 A CN 201110113145A CN 102755670 A CN102755670 A CN 102755670A
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- 238000002360 preparation method Methods 0.000 title abstract description 10
- 229920002988 biodegradable polymer Polymers 0.000 title abstract description 7
- 239000004621 biodegradable polymer Substances 0.000 title abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000002840 nitric oxide donor Substances 0.000 claims abstract description 16
- 208000037803 restenosis Diseases 0.000 claims abstract description 16
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims abstract description 14
- 229920001432 poly(L-lactide) Polymers 0.000 claims abstract description 13
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
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- 150000008064 anhydrides Chemical class 0.000 claims description 20
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- 238000001132 ultrasonic dispersion Methods 0.000 claims description 10
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- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000006116 polymerization reaction Methods 0.000 claims description 5
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- AMDBBAQNWSUWGN-UHFFFAOYSA-N Ioversol Chemical compound OCCN(C(=O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I AMDBBAQNWSUWGN-UHFFFAOYSA-N 0.000 claims description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 4
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- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
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- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical group C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 claims description 2
- 229960000824 iopentol Drugs 0.000 claims description 2
- IUNJANQVIJDFTQ-UHFFFAOYSA-N iopentol Chemical compound COCC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I IUNJANQVIJDFTQ-UHFFFAOYSA-N 0.000 claims description 2
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- Materials For Medical Uses (AREA)
Abstract
The invention belongs to the technical field of bioengineering, and relates to a preparation method of a traceable biodegradable polymer bracket. The method comprises the following steps of: dispersing an organic iodine-series contrast agent into a degradable polymer PLLA (Poly L Lactic Acid) to obtain a 'core' material; combining polyanhydride which contains an anti-restenosis medicament and serves as a 'shell' material with a tracer and an anti-restenosis medicament by adopting a coaxial static spinning technology; and preparing a traceable biodegradable polymer bracket through a polymer processing technology to realize zero grade release of a medicament. Due to the adoption of the traceable biodegradable polymer bracket disclosed by the invention, the problems of poor physical property and poor X-ray imaging property of the conventional biodegradable polymer bracket are solved, the problem of targeted release of a nucleophilic NO donor is solved, and a novel way is provided for restenosis in the bracket; and the traceable biodegradable polymer bracket has important learning value and wide clinical application prospect.
Description
Technical field
The invention belongs to technical field of bioengineering, relate to a kind of method for preparing of traceable biological degradation polyalcohol support.
Background technology
In the clinical treatment, percutaneous coronary intervention (pci) (PCI) has become the important method of coronary heart disease reconstructing blood vessel at present, and its curative effect is confirmed by extensive clinical trial.The application that 3 milestones are respectively sacculus plasty, coronary stent in the process of interventional therapy and the popularization of bracket for eluting medicament (DES); Wherein, The clinical trial of bracket for eluting medicament has obtained remarkable effect; 6 months restenosis incidence rates of postoperative are below 9%; The bare metal stent restenosis rate is 20%～30%, balloon expandable postoperative restenosis rate is then up to 30%～50% merely, and comparatively speaking, coating stent of medicine has been a big breakthrough.
In European cardiology annual meeting (ESC) in 2006 and world's cardiology conference (WCC), the safety of DES has received querying also becomes the academia bone of contention once more.It is adherent bad etc. that DES postpones local vascular allergy that endothelialization, polymer coating cause and inflammatory reaction and support late period again, all may increase the advanced thrombus incident, and the late mortality rate of DES and incidence rate of myocardial infarction increase than the common metal support.Discovering that drug-loaded biological degradation polymer support is an important development of medicament elution metal rack, is an effective solution that solves DES restenosis in late period problem, has important Research Significance and potential applicability in clinical practice.
Usually, drug-loaded biological degradable blood vessel bracket (BDS) is made up of degradable polymer material and medicine two parts; Comparing with DES, is main body with the degradable polymer, and bigger drug load can be provided in the longer time; Can throw in multiple medicine; Mechanicals efforts to blood vessel wall reduces along with the degraded of support, suppresses vascellum endometrial hyperplasia.
Than metal rack, the superiority of BDS is: (1) has excellent biological compatibility, particularly blood compatibility; (2) become nontoxic product and do not have immunogenicity through biodegradation; (3) to narrow tube chamber temporary supporting role is provided, and does not have secular complication; (4) can be used as the medicine that carrier carries antithrombotic and anti-neointimal hyperplasia, and need not to carry out secular whole body anticoagulant.
Although the present progress that obtains of biologically absorbable polymer support research is encouraging; But it still can not adapt to clinical needs fully at aspects such as mechanical strength, volume, X ray spike property, support imbedding systems; Wherein existing topmost problem has 2 points: (1) can absorb the radiation tensile strength and the persistent period of support, because the inherent strength of polymer is low, as reaching certain mechanical support power; The BDS volume will be bigger, and its application in little tube chamber is restricted; (2) x-ray imaging is poor, is difficult to accurate location,
In document US 5670161A; Disclose a kind of method for preparing of polymer blood vessel stent of medicine carrying, used raw material is polylactic acid and polycaprolactone, and adopting anti-restenosis medicaments arsenic trioxide is medicine; Melt extrude preparation tubing, laser cutting machine is etched into RF with tubing.Similar with it, in document CN1367023, a kind of method for preparing of biodegradable medicine composite macromolecular scaffold material is disclosed, it is characterized in that polyphosphazene polymer lactic acid, polycaprolactone and anti-restenosis medicaments are dissolved in the solvent; Pour film forming in the container into, process filament; Filament dipped in the mixed solution by L-lactic acid and glycolide copolymer, solvent and the preparation of anti-restenosis medicaments dry, or lyophilization; In anticoagulation solution, soak then, dry; Filament is wound on the mould, and thermoset forming obtains macromolecular scaffold material.The subject matter that above-mentioned two technical schemes exist is: the inherent strength of polymeric materials such as the polylactic acid of employing, polycaprolactone is low, and as reaching certain mechanical support power, the BDS volume will be bigger, and its application in little tube chamber is restricted; In addition, polylactic acid and polycaprolactone all belong to body degradation-type polymer, and degraded beginning its semiconductors of back and mechanical strength take place sharply to change, and are prone to cause the forfeiture of rack mechanical performance.
Summary of the invention
The objective of the invention is defective and deficiency, a kind of method for preparing of traceable biological degradation polyalcohol support is provided for overcoming prior art; Described biological degradation polyalcohol support adopts the enhanced light-solidifying poly-anhydride drug-loading polymer rack of nanoparticle, is a kind of traceable biodegradable polymer intravascular stent.
The present invention is that contrast agent is distributed among the degradable polymer PLLA as " core " material with organic iodine; What will comprise anti-restenosis medicaments gathers anhydride as " shell " material; Adopt coaxial electrostatic spinning technique, tracer and anti-restenosis medicaments three to combine; Through the traceable biological degradation polyalcohol support of Polymer Processing technology preparation, realize that the zero level of medicine discharges; Wherein, described " core " material can strengthen the mechanical strength of support and imaging capability is provided, and described " shell " material can provide stable medicine-releasing performance.
Particularly, the method for preparing of traceable biological degradation polyalcohol support of the present invention is characterized in that it may further comprise the steps:
With the organic iodine contrast medium ultra-sonic dispersion in the dichloromethane solution of polylactic acid PLLA as " core " material; The nucleophic NO donor ultra-sonic dispersion is " shell " material in the dichloromethane solution that gathers anhydride; Through coaxial electrostatic spinning technique, make the polymer nanofiber composite film material of medicine carrying; Obtain tubular material through miniature extruder, adopt cutting tubular material method, make traceable biological degradation polyalcohol support;
Wherein, described organic iodine tracer addition is the 10-30% of polylactic acid PLLA quality;
The dichloromethane mass concentration of described polylactic acid PLLA is 5-10%;
Described nucleophic NO donor addition is to gather the 1-10% of anhydride quality;
Said dichloromethane solution mass concentration of gathering anhydride is 10-30%;
Described polymer nanofiber composite film material contains organic iodine contrast medium and anti-restenosis medicaments.
Among the present invention, described tracer is the organic iodine contrast medium of wide clinical application, and contrast agent (claiming contrast medium again) is to inject (or taking) chemicals to tissue or organ for strengthening observing effect; The density of said chemicals is higher or lower than surrounding tissue, and the contrast of formation is with some instrument display image; Like x-ray observation Operand commonly used, Barium Sulfate etc.;
Described organic iodine contrast medium is one of medicine that the most often uses in the interventional radiology operation, is mainly used in the demonstration of blood vessel, body cavity; The contrast agent kind is various; Mostly the contrast agent that is used for interventional radiology at present is second filial generation nonionic monomers contrast agent; Mainly comprise iopamidol, iohexol, iopromide, iomeprol, iopentol, ioversol etc., above-mentioned organic iodine contrast medium have the infiltration force down, characteristics such as toxic and side effects is little, better tolerance, stable performance; But high-temperature sterilization is widely used; The addition of organic iodine contrast medium is the 10-30% of PLLA quality among the present invention.
Among the present invention, but described polylactic acid is high-molecular weight spinning poly lactate material, and its molecular weight is 20-50 ten thousand; At present in the Tissue Engineering Study, the polylactic acid biodegradation material is one of timbering material of the most frequently used transplanted cells; Compare with natural extracellular matrix such as collagen and proteoglycan etc., described PLA material not only has good physical and mechanical properties, can be through the adjusting of molecular weight and molecular weight distribution, adapting to different needs, and have abundant manufacturing process; In the present invention in order to improve the mechanical strength of polymer support, radial support intensity particularly, the polylactic acid of employing be HMW (molecular weight 20-50 ten thousand) but the spinning poly lactate material;
The described anhydride that gathers is to be one type of novel synthesising biological degradable high polymer material that the beginning of the eighties, the Langer of Massachusetts Institute Technology etc. found in 20th century; Because it has that surface of good corrosion degradability, biocompatibility, structure are prone to modification, degradation speed is adjustable and excellent properties such as workability, has been applied in field, medical science forward position; Up to the present; The synthetic anhydride kind of gathering is existing a lot; Gather anhydride etc. like aliphatic poly anhydride, fragrant adoption anhydride, unsaturated polyester anhydride, crosslinkable, yet use maximum various polyanhydride copolymers that are polymerized according to a certain percentage by different monomers that are actually in the medicine sustained and controlled release field; Have unique surface erosion property owing to gather anhydride, it can avoid material in use, causes the rapid decline of mechanical property owing to a large amount of degradeds; Gathering the anhydride material reaches 50% o'clock its mechanical strength in mass loss and still can keep 70%～80%;
Among the present invention; The described anhydride that gathers is by polymerization single polymerization monomer decanedioic acid (SA) and two-copolymerization forms to carboxyl phenoxy group-hexane (CPH); Wherein decanedioic acid (SA) with two-be 1: 1 to carboxyl phenoxy group-hexane (CPH) mass ratio; Those skilled in the art can be by prior art for preparing (wherein, comprise in the list of references synthetic method).
Among the present invention, described nucleophilic NO donor medicine is meant and contains [N (O) NO]
-The chemical compound of functional group is the chemical compound that contains nucleophilic secondary amine group NH, generates [N (O) NO] with the NO reaction
-Group; Adopt diethylenetriamine/nitric oxide addition compound product (DETA/NO) in one embodiment of the present of invention; It is a kind of nucleophic NO donor of growing half-life of finding so far (20h) most; Its preparation method is: diethylenetriamine (DETA) is joined in the autoclave that solvent is an acetonitrile logical N
2Bubbling 10min feeds NO gas again behind the evacuation, keeping pressure is 5atm; React after 3 days, product is filtered, successively repeatedly wash, put into vacuum drying oven normal temperature drying 24h, obtain the puffy white powder, product is put into exsiccator-20 ℃ cryopreservation with acetonitrile and absolute ether.
Among the present invention, described cutting tubular material method is according to setting pattern tubing to be etched into RF through laser cutting machine, the Z type is arranged, ripple type and honeycomb type.
Among the present invention; Described coaxial electrostatic spinning technique; Being that polymer solution or solution spray under electrostatic interaction and stretch and obtain the spinning process of nano-scale fiber, particularly, is in advance without mixing with two kinds of various polymerization thing solution; But coaxial injection under the driving of each comfortable electric field force obtains the method for successive composite fibre; At present, this technology is mainly used in nanofiber and the hollow nanofiber or the nanotube of preparation nano/micron encapsulation, shell-cored structure;
Described coaxial electrostatic spinning technique has following outstanding feature:
(1) designability is strong.Utilize the various combination of core material and shell material; Can form multiple composite construction; And core material and shell material can be performance complements; Can the performance of two kinds of materials organically be combined, make the polymer nanocomposites that obtains promptly have excellent biological compatibility and have excellent mechanical performance again;
(2) preparation technology is simple; In the preparation process; Adopt the receptor of different shape can obtain difform nanometer composite fiber material; As adopt different cylinder receiving systems can obtain the nano-composite fiber pipe of different-diameter, adopt dull and stereotyped receptor can obtain the nano-composite fiber film of different-thickness.
Therefore; The medicine of composite nano fiber pipe and membrane material comprise to(for) preparation; Coaxial electrostatic spinning technique is a kind of simple effective method, has broad application prospects in the every field of biomedical research (comprising tissue engineering bracket, surperficial dressing, drug release, medical bandage).
The present invention combines described coaxial electrostatic spinning technique, tracer and anti-restenosis medicaments three; Prepare traceable drug-carrying polymer intravascular stent through the Polymer Processing technology; Overcome the subject matter of present biological degradation polyalcohol support mechanical property and x-ray imaging difference; Solved the targeting property release difficult problem of nucleophic NO donor, new approach is provided, had important academic values and broad clinical application prospect for capturing clinical medicine difficult problems such as in-stent restenosis.
For the ease of understanding, through specific embodiment the method for preparing of traceable biological degradation polyalcohol support of the present invention is carried out detailed description below.What need particularly point out is, specific embodiment only is in order to explain that obviously those skilled in the art can explain according to this paper, and the present invention is carried out various corrections or change, and these corrections and changing also will be included within the scope of the invention.
The specific embodiment
Embodiment 1
In reaction bulb, add dichloromethane 54g, polylactic acid PLLA 6g and ioversol 0.3g, stirring and dissolving, ultra-sonic dispersion 0.5h; As " core " material, add dichloromethane 54g in the other reaction bulb, gather anhydride 6g, nucleophic NO donor 0.06g in the solution that obtains, conduct " shell " material in the solution behind the ultra-sonic dispersion; Through double-channel trace syringe, high-voltage electrostatic spinning apparatus and dual pathways spinneret; Obtain the polymer nanofiber composite film material of medicine carrying, concrete device parameter is voltage 15KV, and the injection speed of two kinds of polymer all is 10ml/h; Obtain tubular material through miniature extruder, laser cutting machine is etched into the RF support with tubing.Be 5 months the nucleophilic NO donor medicine deenergized period in PBS solution, and the complete degradation time of support is 12 months, and under CT, observing its CT value is 20HU.
Embodiment 2
In reaction bulb, add dichloromethane 57g, polylactic acid PLLA 3g and iohexol 0.9g; Stirring and dissolving, ultra-sonic dispersion 0.5h, conduct " core " material in the solution that obtains; Add dichloromethane 42g in the other reaction bulb, gather anhydride 18g, nucleophic NO donor 1.8g; As " shell " material,, obtain the polymer nanofiber composite film material of medicine carrying in the solution behind the ultra-sonic dispersion through double-channel trace syringe, high-voltage electrostatic spinning apparatus and dual pathways spinneret; Concrete device parameter is voltage 15KV; The injection speed of two kinds of polymer all is 10ml/h, obtains tubular material through miniature extruder, and laser cutting machine is etched into the RF support with tubing.Be 2 months the nucleophilic NO donor medicine deenergized period in PBS solution, and the complete degradation time of support is 6 months, and under CT, observing its CT value is 35HU.
Embodiment 3
In reaction bulb, add dichloromethane 55g, polylactic acid PLLA 5g and Iopromide 1.5g; Stirring and dissolving, ultra-sonic dispersion 0.5h, conduct " core " material in the solution that obtains; Add dichloromethane 48g in the other reaction bulb, gather anhydride 12g, nucleophic NO donor 0.6g; As " shell " material,, obtain the polymer nanofiber composite film material of medicine carrying in the solution behind the ultra-sonic dispersion through double-channel trace syringe, high-voltage electrostatic spinning apparatus and dual pathways spinneret; Concrete device parameter is voltage 15KV; The injection speed of two kinds of polymer all is 10ml/h, obtains tubular material through miniature extruder, and laser cutting machine is etched into the RF support with tubing.Be 3 months the nucleophilic NO donor medicine deenergized period in PBS solution, and the complete degradation time of support is 8 months, and under CT, observing its CT value is 60HU.
Claims (10)
1. the method for preparing of a traceable biological degradation polyalcohol support is characterized in that it may further comprise the steps:
With the organic iodine contrast medium ultra-sonic dispersion in the dichloromethane solution of polylactic acid as " core " material; The nucleophic NO donor ultra-sonic dispersion is " shell " material in the dichloromethane solution that gathers anhydride; Obtain the polymer nanofiber composite film material of medicine carrying through coaxial electrostatic spinning technique; Obtain tubular material through miniature extruder, tubing is etched into the RF support, make traceable biological degradation polyalcohol support;
Wherein, Described organic iodine tracer addition is the 10-30% of polylactic acid PLLA quality; The dichloromethane mass concentration of described polylactic acid PLLA is 5-10%; Described nucleophic NO donor addition is to gather the 1-10% of anhydride quality, and said dichloromethane solution mass concentration of gathering anhydride is 10-30%.
2. by the described method for preparing of claim 1, it is characterized in that described tracer material is selected from iohexol, Iopromide or ioversol.
3. by the described method for preparing of claim 1, it is characterized in that described nucleophilic NO donor medicine is for containing the chemical compound of [N (O) NO]-functional group.
4. according to claim 1 or 3 described method for preparinies, it is characterized in that described nucleophilic NO donor medicine is diethylenetriamine/nitric oxide addition compound product, makes through following method: diethylenetriamine is joined in the autoclave that solvent is an acetonitrile logical N
2Bubbling 10min feeds NO gas again behind the evacuation, keeping pressure is 5atm; React after 3 days, product is filtered, successively repeatedly wash, put into vacuum drying oven normal temperature drying 24h, obtain the puffy white powder, product is put into exsiccator-20 ℃ cryopreservation with acetonitrile and absolute ether.
5. method for preparing according to claim 1 is characterized in that, described polymer nanofiber composite film material contains organic iodine contrast medium and anti-restenosis medicaments.
6. method for preparing according to claim 1 is characterized in that, described RF support comprises the Z type, ripple type and honeycomb type.
7. method for preparing according to claim 1 is characterized in that described organic iodine contrast medium is selected from iopamidol, iohexol, iopromide, iomeprol, iopentol or ioversol.
8. method for preparing according to claim 1 is characterized in that, the addition of described organic iodine contrast medium is the 10-30% of PLLA quality.
9. method for preparing according to claim 1 is characterized in that, but described polylactic acid is high-molecular weight spinning poly lactate material, and its molecular weight is 20-50 ten thousand.
10. method for preparing according to claim 1 is characterized in that, described gather anhydride be by the polymerization single polymerization monomer decanedioic acid with two-carboxyl phenoxy group-hexane copolymerization is formed, wherein, described decanedioic acid with two-be 1: 1 to the mass ratio of carboxyl phenoxy group-hexane.
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| CN109338485A (en) * | 2018-12-05 | 2019-02-15 | 东华大学 | Visual tracking method of nanofibers in nanofiber/staple fiber blend system |
| CN110042490A (en) * | 2019-05-15 | 2019-07-23 | 赛得利(九江)纤维有限公司 | A kind of viscose rayon and preparation method thereof containing tracer label |
| CN111494778A (en) * | 2020-04-23 | 2020-08-07 | 深圳市儿童医院 | Visualized ureteral stent |
| CN111632206A (en) * | 2020-05-29 | 2020-09-08 | 四川大学 | A self-anticoagulated and visualized small-caliber artificial blood vessel stent and preparation method thereof |
| CN113622053A (en) * | 2020-05-08 | 2021-11-09 | 上海微创医疗器械（集团）有限公司 | Fiber and preparation method thereof, film, covered stent and preparation method thereof |
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Cited By (8)
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| CN105126162A (en) * | 2014-06-05 | 2015-12-09 | 北京化工大学 | Fluorescent biodegradable scaffold material and preparation method thereof |
| CN109338485A (en) * | 2018-12-05 | 2019-02-15 | 东华大学 | Visual tracking method of nanofibers in nanofiber/staple fiber blend system |
| CN109338485B (en) * | 2018-12-05 | 2021-04-06 | 东华大学 | Visual tracking method of nanofibers in nanofiber/staple fiber blend system |
| CN110042490A (en) * | 2019-05-15 | 2019-07-23 | 赛得利(九江)纤维有限公司 | A kind of viscose rayon and preparation method thereof containing tracer label |
| CN111494778A (en) * | 2020-04-23 | 2020-08-07 | 深圳市儿童医院 | Visualized ureteral stent |
| CN113622053A (en) * | 2020-05-08 | 2021-11-09 | 上海微创医疗器械（集团）有限公司 | Fiber and preparation method thereof, film, covered stent and preparation method thereof |
| CN111632206A (en) * | 2020-05-29 | 2020-09-08 | 四川大学 | A self-anticoagulated and visualized small-caliber artificial blood vessel stent and preparation method thereof |
| CN117599261A (en) * | 2024-01-23 | 2024-02-27 | 柔脉医疗(深圳)有限公司 | Visual artificial vascular stent and preparation method and application thereof |
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