CN102755670B - Preparation method of traceable biodegradable polymer bracket - Google Patents
Preparation method of traceable biodegradable polymer bracket Download PDFInfo
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- CN102755670B CN102755670B CN201110113145.9A CN201110113145A CN102755670B CN 102755670 B CN102755670 B CN 102755670B CN 201110113145 A CN201110113145 A CN 201110113145A CN 102755670 B CN102755670 B CN 102755670B
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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 preparation method of traceable biological degradation polyalcohol support.
Background technology
In 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 clinical trial.The application that 3 milestones are respectively Balloon Angioplasty, 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, within postoperative 6 months, restenosis incidence rate is below 9%, bare metal stent restenosis rate is 20%～30%, the simple postoperative restenosis rate of balloon expandable is up to 30%～50%, comparatively speaking, coating stent of medicine has been a large breakthrough.
Upper in the sick academic year meeting (ESC) of heart of Europe in 2006 and World Heart sick conference (WCC), the safety of DES has been subject to querying and again becoming academia bone of contention.DES postpone again local vascular allergy that endothelialization, polymer coating cause and inflammatory reaction and support late period adherent bad etc., all may increase advanced thrombus event, the late mortality rate of DES and incidence rate of myocardial infarction increase compared with common metal support.Studies have found 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.
Conventionally, drug-loaded biological degradable blood vessel bracket (BDS) is comprised of degradable polymer material and medicine two parts; With DES, compare, take degradable polymer as main body, larger drug load can be provided within the longer time; Can throw in multi-medicament; 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 good biocompatibility, particularly blood compatibility; (2) by biodegradation, become nontoxic product and without immunogenicity; (3) to narrow tube chamber, provide temporary supporting role, and without long-term complication; (4) can be used as the medicine that carrier carries antithrombotic and anti-neointimal hyperplasia, and without carrying out long-term whole body anticoagulant.
Although the current obtained progress of biologically absorbable polymer support research is encouraging, but it still can not adapt to clinical needs completely at aspects such as mechanical strength, volume, X ray spike, support imbedding systems, wherein existing topmost problem has 2 points: radiation tensile strength and the persistent period of (1) bioabsorbable stent, because the inherent strength of polymer is low, as reached certain mechanical support power, BDS volume will be larger, and its application in little tube chamber is restricted; (2) x-ray imaging is poor, is difficult to accurate location,
In document US5670161A, disclose a kind of preparation method of polymer blood vessel stent of medicine carrying, raw material used is polylactic acid and polycaprolactone, and adopting anti-restenosis medicaments arsenic trioxide is medicine, melt extrude and prepare tubing, laser cutting machine is etched into network structure by tubing.Similar with it, in document CN1367023, a kind of preparation method of biodegradable medicine composite macromolecular scaffold material is disclosed, it is characterized in that polyphosphazene polymer lactic acid, polycaprolactone and anti-restenosis medicaments to be dissolved in solvent; Pour film forming in container into, make filament; Filament is dipped and dried in the mixed solution of being prepared by Pfansteihl and glycolide copolymer, solvent and anti-restenosis medicaments, or lyophilization; Then in anticoagulation solution, soak, dry; Filament is wound on mould, and thermoset forming, obtains macromolecular scaffold material.The subject matter that above-mentioned two technical schemes exist is: the inherent strength of the polymeric materials such as the polylactic acid of employing, polycaprolactone is low, and as reached certain mechanical support power, BDS volume will be larger, and its application in little tube chamber is restricted; In addition, polylactic acid and polycaprolactone all belong to body degradation-type polymer, and after degraded starts, its semiconductors and mechanical strength occur sharply to change, and easily cause the forfeiture of rack mechanical performance.
Summary of the invention
The object of the invention is, for overcoming defect and the deficiency of prior art, provides a kind of preparation method of traceable biological degradation polyalcohol support; The light-solidifying poly-anhydride drug-loading polymer rack that described biological degradation polyalcohol support adopts nanoparticle to strengthen is a kind of traceable biodegradable polymer intravascular stent.
The present invention is that contrast agent is distributed in degradable polymer PLLA as " core " material using organic iodine, using the poly-anhydride that comprises anti-restenosis medicaments as " shell " material, adopt coaxial electrostatic spinning technique, tracer and anti-restenosis medicaments three to combine, by Polymer Processing technology, prepare traceable biological degradation polyalcohol support, the zero level that realizes 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 preparation method of traceable biological degradation polyalcohol support of the present invention, is characterized in that, it comprises the following steps:
Using in the ultrasonic dichloromethane solution that is distributed to polylactic acid PLLA of organic iodine contrast medium as " core " material, ultrasonic being scattered in the dichloromethane solution that gathers anhydride of nucleophic NO donor is " shell " material, by coaxial electrostatic spinning technique, make the polymer nanofiber composite film material of medicine carrying; By icroextrusion machine, obtain tubular material, 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 the 1-10% of poly-anhydride quality;
The dichloromethane solution mass concentration of described poly-anhydride is 10-30%;
Described polymer nanofiber composite film material contains organic iodine contrast medium and anti-restenosis medicaments.
In the present invention, the organic iodine contrast medium that described tracer is wide clinical application, contrast agent (claiming again contrast medium) is to inject (or taking) to the chemicals of tissue or organ for strengthening observing effect; The density of described chemicals is higher or lower than surrounding tissue, some instrument display image of the contrast of formation; Operand as conventional in x-ray observation, barium sulfate etc.;
Described organic iodine contrast medium is one of medicine the most often using in interventional radiology operation, is mainly used in the demonstration of blood vessel, body cavity; Contrast agent kind is various, contrast agent for interventional radiology mostly is second filial generation nonionic monomers contrast agent at present, mainly comprise iopamidol, iohexol, iopromide, iomeprol, iopentol, ioversol etc., above-mentioned organic iodine contrast medium has the features such as infiltration is forced down, toxic and side effects is little, better tolerance, stable performance, can high-temperature sterilization, be widely used; In the present invention, the addition of organic iodine contrast medium is the 10-30% of PLLA quality.
In the present invention, described polylactic acid is high molecular can spinning poly lactate material, and its molecular weight is 20-50 ten thousand; At present in Tissue Engineering Study, polylactic acid biodegradation material is one of timbering material of the most frequently used transplanted cells; Compare as collagen and proteoglycan etc. with natural extracellular matrix, described PLA material not only has good physical and mechanical properties, can, by the adjusting of molecular weight and molecular weight distribution, to adapt 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 high molecular (molecular weight 20-50 ten thousand) can spinning poly lactate material;
Described poly-anhydride is to be novel synthesising biological degradable high polymer materials of a class that the beginning of the eighties, the Langer of Massachusetts Institute Technology etc. found in 20th century, because it has the good easy modification of surface erosion degradability, biocompatibility, structure, degradation speed is adjustable and the excellent properties such as workability, at medical science Disciplinary Frontiers, be applied; Up to the present, synthetic poly-anhydride kind is existing a lot of, as aliphatic poly anhydride, fragrant adoption anhydride, unsaturated polyester anhydride, the poly-anhydride of crosslinkable etc., yet in medicine sustained and controlled release field, apply maximum various polyanhydride copolymers that are polymerized according to a certain percentage by different monomers that are actually; Because poly-anhydride has unique surface erosion, it can avoid material in use, because a large amount of degraded causes the sharply decline of mechanical property; Poly-anhydride material its mechanical strength when mass loss reaches 50% still can keep 70%～80%;
In the present invention, described poly-anhydride is by polymerization single polymerization monomer decanedioic acid (SA) and two-to carboxyphenoxy-hexane (CPH), copolymerization forms, wherein decanedioic acid (SA) with two-to carboxyphenoxy-hexane (CPH) mass ratio, be 1: 1, those skilled in the art can prepare by prior art (wherein, comprising the synthetic method in list of references).
In the present invention, described nucleophilic NO donor medicine, refers to and contains [N (O) NO]
-the compound of functional group, is the compound of the secondary amine group NH that contains nucleophilic, reacts generation [N (O) NO] with NO
-group; In one embodiment of the present of invention, adopt diethylenetriamine/nitric oxide addition compound product (DETA/NO), it is a kind of nucleophic NO donor of half-life the longest (20h) of finding so far, its preparation method is: diethylenetriamine (DETA) is joined in the autoclave that solvent is acetonitrile to logical N
2bubbling 10min, passes into NO gas again after evacuation, maintaining pressure is 5atm; React after 3 days, product is filtered, successively with acetonitrile and absolute ether, repeatedly wash, put into vacuum drying oven normal temperature drying 24h, obtain puffy white powder, product is put into exsiccator-20 ℃ cryopreservation.
In the present invention, described cutting tubular material method is according to setting pattern, tubing to be etched into network structure by laser cutting machine, has Z-type, ripple type and honeycomb type.
In the present invention, described coaxial electrostatic spinning technique, that polymer solution or solution spray stretching and the spinning process of acquisition nano-scale fiber under electrostatic interaction, particularly, in advance without mixing by two kinds of different polymer solutions, but coaxial injection under the driving of each comfortable electric field force obtains the method for continuous composite fibre; At present, this technology is mainly for the preparation of nanofiber and hollow Nano fiber in use or the nanotube of 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 Materials, can form multiple composite construction, and core material and Shell Materials can be performance complements, the performance of bi-material organically can be combined, the polymer nanocomposites that makes to obtain has good biocompatibility and has again excellent mechanical performance;
(2) preparation technology is simple; In 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 flat receiver can obtain the nano-composite fiber film of different-thickness.
Therefore, the composite nano fiber pipe and the membrane material that for preparation, comprise medicine, coaxial electrostatic spinning technique is a kind of simple effective method, in the every field of biomedical research (comprising tissue engineering bracket, surperficial dressing, drug release, medical bandage), has broad application prospects.
The present invention combines described coaxial electrostatic spinning technique, tracer and anti-restenosis medicaments three, by Polymer Processing technology, prepare traceable drug-carrying polymer intravascular stent, current biological degradation polyalcohol support mechanical property and the poor subject matter of x-ray imaging have been overcome, solved a targeting NO release difficult problem for nucleophic NO donor, for capturing the clinical medicine difficult problems such as in-stent restenosis, provide new approach, there is important learning value and wide potential applicability in clinical practice.
For the ease of understanding, below by specific embodiment, the preparation method of traceable biological degradation polyalcohol support of the present invention is described in detail.It needs to be noted, specific embodiment is only in order to illustrate, obviously those skilled in the art can carry out various corrections or change to the present invention according to explanation herein, within these corrections and change also will be included the scope of the invention in.
The specific embodiment
Embodiment 1
In reaction bulb, add dichloromethane 54g, polylactic acid PLLA 6g and ioversol 0.3g, stirring and dissolving, ultrasonic dispersion 0.5h, conduct " core " material in the solution obtaining, in an other reaction bulb, add dichloromethane 54g, poly-anhydride 6g, nucleophic NO donor 0.06g, conduct " shell " material in solution after ultrasonic dispersion, by 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, the injection speed of two kinds of polymer is all 10ml/h, by icroextrusion machine, obtain tubular material, laser cutting machine is etched into network structure support by tubing.Be 5 months the nucleophilic NO donor medicine deenergized period in PBS solution, and the degradable time of support is 12 months, observes its CT value for 20HU under CT.
Embodiment 2
In reaction bulb, add dichloromethane 57g, polylactic acid PLLA 3g and iohexol 0.9g, stirring and dissolving, ultrasonic dispersion 0.5h, conduct " core " material in the solution obtaining, in an other reaction bulb, add dichloromethane 42g, poly-anhydride 18g, nucleophic NO donor 1.8g, conduct " shell " material in solution after ultrasonic dispersion, by 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, the injection speed of two kinds of polymer is all 10ml/h, by icroextrusion machine, obtain tubular material, laser cutting machine is etched into network structure support by tubing.Be 2 months the nucleophilic NO donor medicine deenergized period in PBS solution, and the degradable time of support is 6 months, observes its CT value for 35HU under CT.
Embodiment 3
In reaction bulb, add dichloromethane 55g, polylactic acid PLLA 5g and Iopromide 1.5g, stirring and dissolving, ultrasonic dispersion 0.5h, conduct " core " material in the solution obtaining, in an other reaction bulb, add dichloromethane 48g, poly-anhydride 12g, nucleophic NO donor 0.6g, conduct " shell " material in solution after ultrasonic dispersion, by 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, the injection speed of two kinds of polymer is all 10ml/h, by icroextrusion machine, obtain tubular material, laser cutting machine is etched into network structure support by tubing.Be 3 months the nucleophilic NO donor medicine deenergized period in PBS solution, and the degradable time of support is 8 months, observes its CT value for 60HU under CT.
Claims (10)
1. a preparation method for traceable biological degradation polyalcohol support, is characterized in that, it comprises the following steps:
Using in the ultrasonic dichloromethane solution that is distributed to polylactic acid of organic iodine contrast medium as " core " material, ultrasonic being scattered in the dichloromethane solution that gathers anhydride of nucleophic NO donor is " shell " material, by coaxial electrostatic spinning technique, obtain the polymer nanofiber composite film material of medicine carrying, by icroextrusion machine, obtain tubular material, tubing is etched into network structure support, makes traceable biological degradation polyalcohol support;
Wherein, described organic iodine contrast medium 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 the 1-10% of poly-anhydride quality, and the dichloromethane solution mass concentration of described poly-anhydride is 10-30%.
2. by preparation method claimed in claim 1, it is characterized in that, described organic iodine contrast medium is selected from iohexol, Iopromide or ioversol.
3. by preparation method claimed in claim 1, it is characterized in that, described nucleophilic NO donor medicine is for containing [N (O) NO]
-the compound of functional group.
4. according to the preparation method described in claim 1 or 3, it is characterized in that, described nucleophilic NO donor medicine, is diethylenetriamine/nitric oxide addition compound product, by following method, makes: diethylenetriamine is joined in the autoclave that solvent is acetonitrile to logical N
2bubbling 10min, passes into NO gas again after evacuation, maintaining pressure is 5atm; React after 3 days, product is filtered, successively with acetonitrile and absolute ether, repeatedly wash, put into vacuum drying oven normal temperature drying 24h, obtain puffy white powder, product is put into exsiccator-20 ℃ cryopreservation.
5. preparation method according to claim 1, is characterized in that, described polymer nanofiber composite film material contains organic iodine contrast medium and anti-restenosis medicaments.
6. preparation method according to claim 1, is characterized in that, described network structure support, comprises Z-type, ripple type and honeycomb type.
7. preparation method according to claim 1, is characterized in that, described organic iodine contrast medium is selected from iopamidol, iohexol, iopromide, iomeprol, iopentol or ioversol.
8. preparation method according to claim 1, is characterized in that, the addition of described organic iodine contrast medium is the 10-30% of PLLA quality.
9. preparation method according to claim 1, is characterized in that, described polylactic acid is high molecular can spinning poly lactate material, and its molecular weight is 20-50 ten thousand.
10. preparation method according to claim 1, is characterized in that, described poly-anhydride is by polymerization single polymerization monomer decanedioic acid and two-to carboxyphenoxy-hexane, copolymerization forms, wherein, described decanedioic acid with two-to the mass ratio of carboxyphenoxy-hexane, be 1:1.
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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 |
| CN109338485B (en) * | 2018-12-05 | 2021-04-06 | 东华大学 | Visual tracing method for nanofiber in nanofiber/short fiber blending 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 |
| CN111494778B (en) * | 2020-04-23 | 2022-05-03 | 深圳市儿童医院 | Ureteral stent tube capable of developing |
| 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 | Self-anticoagulation developable 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5670161A (en) * | 1996-05-28 | 1997-09-23 | Healy; Kevin E. | Biodegradable stent |
| WO2001049340A1 (en) * | 1999-12-30 | 2001-07-12 | Advanced Cardiovascular Systems, Inc. | Stent with radiopaque coating consisting of particles in a binder |
| CN101011578A (en) * | 2007-02-15 | 2007-08-08 | 河北科技大学 | Antimicrobial medicament preparation with polyanhydrides as vector and its preparing process |
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2011
- 2011-04-29 CN CN201110113145.9A patent/CN102755670B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5670161A (en) * | 1996-05-28 | 1997-09-23 | Healy; Kevin E. | Biodegradable stent |
| WO2001049340A1 (en) * | 1999-12-30 | 2001-07-12 | Advanced Cardiovascular Systems, Inc. | Stent with radiopaque coating consisting of particles in a binder |
| CN101011578A (en) * | 2007-02-15 | 2007-08-08 | 河北科技大学 | Antimicrobial medicament preparation with polyanhydrides as vector and its preparing process |
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