CN104107459A - Degradable polymer coating support with sequential response function, and making method thereof - Google Patents
Degradable polymer coating support with sequential response function, and making method thereof Download PDFInfo
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- CN104107459A CN104107459A CN201410161182.0A CN201410161182A CN104107459A CN 104107459 A CN104107459 A CN 104107459A CN 201410161182 A CN201410161182 A CN 201410161182A CN 104107459 A CN104107459 A CN 104107459A
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Abstract
A degradable polymer coating support with a sequential response function comprises: an outermost polymer composite material coating, wherein a drug supported on the coating is rapamycin and other drugs with a restenosis inhibition effect; a secondary outer polymer composite material coating, wherein a drug supported on the coating is L-arginine and other drugs with an endothelial cell hyperplasia promotion effect; and an innermost polymer composite material coating, wherein a drug supported on the coating is heparin and other drugs with anticoagulant and antithrombotic effects. The above polymer coating is a polyfatty acid-polyamino acid-polyethylene glycol segmented copolymer. The multi-coating support has a sequential function, inhibits restenosis in the early stage, realizes anticoagulation and endothelialization promotion effects in the middle stage, and inhibits thrombus formation in the later stage. The invention also discloses a making method of the degradable polymer coating support with a sequential response function.
Description
Technical field
The present invention relates to a kind of degradable macromolecule coating bracket with sequential response function, belong to biomedical engineering field.
Background technology
Coronary atherosclerotic heart disease is one of major reason causing mankind's death.Intracoronary stening (percutaneous coronary intervention, PCI) has become the comparatively ideal method of one for the treatment of patients with coronary heart disease at present.In the whole world approximately exceedes 2,000,000 patients with coronary heart disease every year, the 70% row interventional therapy of having an appointment.The interventional therapy of our country is specific to the interventional therapy of coronary heart disease, within 1984, China implements the success of first case intervene operation, according to the statistics of Chinese Medical Association, the interventional therapy of coronary heart disease has exceeded 280,000 examples in the number of cases in the whole nation in 2010, and within 2011, national number of cases reaches 330,000 examples.Coronary Artery Disease Intervention Treatment QCC quality control center of Jilin Province data show, within 2012, Coronary Artery Disease Intervention Treatment reaches 9292 examples.Cardiac intervention treatment is simultaneously also a huge industry, the demonstration of medical industries statistics, and the market total value of global coronary stent in 2010 reaches 2,100,000,000 dollars.Within 2013, global interventional cardiac procedures reaches 5,000,000 examples, wherein 86% uses support.
Since PCI operation success for the first time, cardiac stent has experienced altogether three generations: first generation mounting system: first generation support belongs to bare metal stent (bare metal stent, BMS), adopt the mode of metal machinery to support vascularization, thereby expansion blood vessel, but As time goes on, blood vessel hyperplasia, thereby cause tube chamber restenosis, therapeutic effect is not good enough.Within 2000, be generally suitable in the past this support.Second filial generation bracket for eluting medicament (drug eluting stent, DES): lose for anti-hemostatic tube inner cell hypertrophy causes tube chamber, second filial generation bracket for eluting medicament has been introduced carrier (Polymer) and medicine (Drug) system, be coated on support, medicine can slowly discharge in time, on cell proliferation has good inhibitory action, thereby can effectively prevent vascular restenosis, taking rapamycin and taxol drug FirebirdTM as representative.But paclitaxel can play inhibitory action to all cells, thereby its side effect is also larger, and rapamycin has higher selectivity by contrast, has in actual use acceptance widely.Third generation bracket for eluting medicament: third generation bracket for eluting medicament mainly contains biological absorbable support and carrier-free carried stent two classes.
Biological absorbable support implanted after a period of time, carrier can be decomposed into water and carbon dioxide etc. can absorbed innocuous substance, after being absorbed, support can recover blood vessel normal contraction, stop the generation of vascular restenosis, can repeatedly get involved intervention in same lesion, also can rebuild ordinary stent and insert the blood vessel power of rear disappearance.But current biological absorbable support skeleton is partially thick, be unfavorable for passing through smoothly pathological changes, affecting endothelium reparation covers, the type support need be degraded and disappear between 12-18 month after support is inserted simultaneously, local vascular sections is easily because scaffold degradation loses support force, biological absorbable support structure is different from metal rack simultaneously, poor aspect rigidity and supportive, poor aspect processing calcify lesion.
The functional biological response behavior getting involved mainly for intravascular stent of sequential of intravascular stent.Comprise: the biological behaviour in morning-mid-term that (1) intravascular stent is got involved: the sequential of the biological response behavior after intravascular stent implantation is conventionally: 1) blood vessel injury causes blood coagulation; 2) leukocyte is assembled at damage location; 3) inflammatory reaction; 4) blood vessel wall reconstruct.Said process mainly occurred in 1 month, got involved the proliferation response causing and mainly occurred in 3 months.Therefore bracket for eluting medicament can be given full play to its effect that suppresses restenosis.But medicine and carrier have increased the risk that advanced thrombus forms simultaneously.(2) intravascular stent get involved in-late period biological behaviour: intravascular stent is exposed in blood, needs endotheliocyte to be covered in rack surface.Endothelialization postpones to cause thrombosis.(3) biological behaviour in late period that intravascular stent is got involved: intravascular stent is embedded in blood vessel wall, interface exists and interacts, and the naked metal surface of support has the carrier of not degrading, and continues inflammatory stimulus, can cause endothelialization delay and advanced thrombus to form.
Getting involved position biotic environment is to develop in time to the respondent behavior of intravascular stent, have timing, but current bracket for eluting medicament does not possess the function of timing response.
Summary of the invention
For the problems referred to above, an object of the present invention is to provide a kind of degradable macromolecule coating bracket with sequential response function, according to the needs of support timing function, build needed degradable high polymer material, and with corresponding medicament mixed, adopt the way structure of chemical mixing to support rapamycin, the macromolecular material of heparin and L-arginine, the macromolecular material with different degradation properties is coated on to intravascular stent surface by different level, medicine was played a role in the different time, possesses timing function, commitment suppresses restenosis, realize anticoagulation and short endothelialization effect mid-term, suppress thrombosis late period.
Another object of the present invention is to provide a kind of manufacture method of the degradable macromolecule coating bracket with sequential response function, based on polyglycerol fatty acid, the advantage of the block copolymer of polyamino acid and Polyethylene Glycol, application polymer chemistry synthetic method is manufactured a class and has the Polyethylene Glycol of biological degradability and active group, aliphatic polyester, polyamino acid block copolymer, by adding rapamycin, heparin, the medicines such as L-arginine, rapamycin has the effect of the restenosis of inhibition, and heparin has anticoagulant, anti thrombotic action, the release of L-arginine can discharge nitric oxide (nitric oxide under nitricoxide synthase effect, NO), there is the endotheli ocytosis of promotion effect, give characteristic and function that material is new, as suppress restenosis, anticoagulant property, promote endotheliosis etc., commitment suppresses restenosis, realize anticoagulation and short endothelialization effect mid-term, suppress thrombosis late period, build with the interactional physiology in host position and develop timing, with copolymer degradation, drug release meets support timing biological response.
For realizing first object, technical scheme of the present invention is achieved in that a kind of degradable macromolecule coating bracket with sequential response function, support the polymer composite coating of medicine in the surface coating of existing bare metal stent, it is characterized in that, it comprises: outermost polymer composite coating, and the medicine that this coating supports is rapamycin etc. has the medicine that suppresses restenosis effect; Inferior outer field polymer composite coating, the medicine that this coating supports is L-arginine etc. has the medicine that promotes endotheli ocytosis effect.
For realizing second object, technical scheme of the present invention is achieved in that a kind of manufacture method of the degradable macromolecule coating bracket with sequential response function, comprises the following steps:
Step 1: there is the manufacture of the degradable high polymer material of active group;
Step 2: the chemical surface treatment of metallic blood vessel bracket;
Step 3: the macromolecular material that supports rapamycin, heparin and L-arginine with the way structure of chemical mixing;
Step 4: the macromolecular material with different degradation properties is coated on to intravascular stent surface by different level, medicine was played a role in the different time, possess timing function.
Preferably, also comprise: the polymer composite coating of innermost layer, the medicine that this coating supports is heparin etc. has the medicine of anticoagulant, anti thrombotic action.
Tool of the present invention has the following advantages: the novel degradable polymeric coating layer support of (1) exploitation, possesses timing function: commitment suppresses restenosis, realizes anticoagulation and short endothelialization effect mid-term, suppresses thrombosis late period; (2) degradable polymer, as the platform of medicine combination and long-time eluting, release, has good biocompatibility, avoids occurring anaphylaxis, can ensure lasting balanced release of medicine simultaneously; (3) degradable polymer is by normal organism metabolism approach, and through the regular hour, polymer is finally degraded into small-molecule substance and excretes, and do not have residually, eliminated the untoward reaction of potential polymer to blood vessel.
Brief description of the drawings
Fig. 1 is the cross-sectional structure schematic diagram with the support of two degradable macromolecule coatings.
Fig. 2 is the cross-sectional structure schematic diagram with the support of three degradable macromolecule coatings.
Wherein Reference numeral is expressed as: 1-bare metal stent; The outermost polymer composite coating of 21-; 22-outer field polymer composite coating; The polymer composite coating of 23-innermost layer.
Specific embodiments
Describe specific embodiment of the invention scheme in detail below in conjunction with accompanying drawing.
Embodiment mono-:
As shown in Figure 1, a kind of degradable macromolecule coating bracket with sequential response function, support the polymer composite coating of medicine in the surface coating of existing bare metal stent, it is characterized in that, it comprises: outermost polymer composite coating 21, and the medicine that this coating supports is rapamycin etc. has the medicine that suppresses restenosis effect; Inferior outer field polymer composite coating 22, the medicine that this coating supports is L-arginine etc. has the medicine that promotes endotheli ocytosis effect.
Described polymer composite is the block copolymer of polyglycerol fatty acid, polyamino acid and Polyethylene Glycol, retaining polyglycerol fatty acid, biocompatibility that polyamino acid is good, on the basis of the good carrier such as medicine, gene, give characteristic and function that material is new, as hydrophilic, flexibility, anticoagulant property, anti-macrophage phagocytic etc., increase the active group of copolymer simultaneously, all there is larger advantage and wide application prospect in the many-side such as sustained-release and controlled release, targeting dispenser of medicine, gene, antibody.
Described each coating is single a kind of polymer composite (as the block copolymer of polyglycerol fatty acid, polyamino acid and Polyethylene Glycol), or described each coating assembly that is two or more polymer composites.
According to actual needs, the each coating applying on same support can be same polymer composite.
The medicine that the polymer composite of each coating supports should determine according to actual needs, and ordinary circumstance is the medicine difference that the polymer composite of each coating supports; In some cases, the medicine that the polymer composite of each coating supports is identical, but lasting equilibrium difference release time of the lasting balanced rate of release difference of medicine or medicine.
Embodiment bis-:
As shown in Figure 2, a kind of degradable macromolecule coating bracket with sequential response function, at least apply the two-layer polymer composite coating that supports medicine on existing bare metal stent surface, it is characterized in that, also comprise: the polymer composite coating 23 of innermost layer, the medicine that this coating supports is heparin etc. has the medicine of anticoagulant, anti thrombotic action.
Described polymer composite is the block copolymer of polyglycerol fatty acid, polyamino acid and Polyethylene Glycol, retaining polyglycerol fatty acid, biocompatibility that polyamino acid is good, on the basis of the good carrier such as medicine, gene, give characteristic and function that material is new, as hydrophilic, flexibility, anticoagulant property, anti-macrophage phagocytic etc., increase the active group of copolymer simultaneously, all there is larger advantage and wide application prospect in the many-side such as sustained-release and controlled release, targeting dispenser of medicine, gene, antibody.
Described each coating is single a kind of polymer composite (as the block copolymer of polyglycerol fatty acid, polyamino acid and Polyethylene Glycol), or described each coating assembly that is two or more polymer composites.
According to actual needs, the each coating applying on same support can be same polymer composite.
The medicine that the polymer composite of each coating supports should determine according to actual needs, and ordinary circumstance is the medicine difference that the polymer composite of each coating supports; In some cases, the medicine that the polymer composite of each coating supports is identical, but lasting equilibrium difference release time of the lasting balanced rate of release difference of medicine or medicine.
Embodiment tri-:
A manufacture method with the degradable macromolecule coating bracket of sequential response function, comprises the following steps:
Step 1: there is the manufacture of the degradable high polymer material of active group;
(1) Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester and lactide copolymer (PEG-PLGA): employing has certain molecular weight and makes macromolecular chain initiator with the PEG of one or two section of hydroxyl, with stannous octoate be catalyst, taking toluene as solvent, add a certain proportion of monomer Acetic acid, hydroxy-, bimol. cyclic ester and lactide, under anhydrous and oxygen-free, 130 DEG C of conditions, polyreaction 48h, product is cooling separates out afterwards with ethanol, for subsequent use after dry;
(2) polyethylene glycol-polylactic acid-polyglutamic acid triblock copolymer (PEG-PLA-PGL/RGD):
1. make initiator ring-opening polymerisation lactide with the Polyethylene Glycol of monomethyl ether and obtain the di-block copolymer that end is the polyethylene glycol-polylactic acid of hydroxyl (PEG-PLLA-OH), and then the terminal hydroxy group of di-block copolymer is converted into end amino (PEG-PLLA-NH2);
2. a-amino acid-N-carboxylic acid anhydrides (NCA) that ring-opening polymerisation is made by benzyl glutamate as macromole evocating agent with PEG-PLLA-NH2 has obtained the triblock copolymer (PEG-PLA-PBLG) of polyethylene glycol-polylactic acid-poly benzyl glutamate;
3. hydro-reduction PEG-PLA-PBLG makes polyethylene glycol-polylactic acid-polyglutamic acid (PEG-PLA-PGL).
Step 2: the chemical surface treatment of metallic blood vessel bracket;
The metallic blood vessel bracket of prior art is Ni-Ti alloy normally, with strongly acidic aqueous solution processing make metal surface generate activity hydroxy, utilize this hydroxyl and the lactic acid oligomer graft reaction with isocyanate groups, wash away the polylactic acid not having in grafting, can obtain the metallic blood vessel bracket of surperficial macromolecular grafted modification, this support can increase and apply the intensity between macromolecular material greatly.
Step 3: the macromolecular material that supports rapamycin, heparin and L-arginine with the way structure of chemical mixing;
According to the needs of support timing function, build needed degradable high polymer material, degradation speed difference under constructed macromolecular material biotic environment in vivo, the medicine difference supporting, the medication amount difference supporting, and with corresponding medicament mixed, adopt the way of chemical mixing to build and support the macromolecular material of rapamycin, heparin and L-arginine.
Step 4: the macromolecular material with different degradation properties is coated on to intravascular stent surface by different level, medicine was played a role in the different time, possess timing function;
The main electrostatic spray that adopts of coating, under the very thin condition of coating, can evenly apply, does not stay dead angle yet.
Coating method includes but not limited to electrostatic spray, also can adopt the additive methods such as solution dip coating.In the time adopting solution dip coating, general situation is that the surfaces externally and internally of metal rack is all coated with macromolecule material coating.
The coating order of macromolecule material coating that support outside supports medicine is as follows: 1., in the time having two coatings, first coating time skin, repastes deposited outermost layer.2. in the time having three coatings, first apply innermost layer, then coating time skin, finally apply outermost layer.
Claims (3)
1. one kind has the degradable macromolecule coating bracket of sequential response function, support the polymer composite coating of medicine in the surface coating of existing bare metal stent, it is characterized in that, it comprises: outermost polymer composite coating, and the medicine that this coating supports is rapamycin etc. has the medicine that suppresses restenosis effect; Inferior outer field polymer composite coating, the medicine that this coating supports is L-arginine etc. has the medicine that promotes endotheli ocytosis effect.
2. the degradable macromolecule coating bracket with sequential response function as claimed in claim 1, is characterized in that, also comprises: the polymer composite coating of innermost layer, the medicine that this coating supports is heparin etc. has the medicine of anticoagulant, anti thrombotic action.
3. a manufacture method with the degradable macromolecule coating bracket of sequential response function, comprises the following steps:
Step 1: there is the manufacture of the degradable high polymer material of active group;
(1) Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester and lactide copolymer (PEG-PLGA): employing has certain molecular weight and makes macromolecular chain initiator with the PEG of one or two section of hydroxyl, with stannous octoate be catalyst, taking toluene as solvent, add a certain proportion of monomer Acetic acid, hydroxy-, bimol. cyclic ester and lactide, under anhydrous and oxygen-free, 130 DEG C of conditions, polyreaction 48h, product is cooling separates out afterwards with ethanol, for subsequent use after dry;
(2) polyethylene glycol-polylactic acid-polyglutamic acid triblock copolymer (PEG-PLA-PGL/RGD):
1. make initiator ring-opening polymerisation lactide with the Polyethylene Glycol of monomethyl ether and obtain the di-block copolymer that end is the polyethylene glycol-polylactic acid of hydroxyl (PEG-PLLA-OH), and then the terminal hydroxy group of di-block copolymer is converted into end amino (PEG-PLLA-NH2);
2. a-amino acid-N-carboxylic acid anhydrides (NCA) that ring-opening polymerisation is made by benzyl glutamate as macromole evocating agent with PEG-PLLA-NH2 has obtained the triblock copolymer (PEG-PLA-PBLG) of polyethylene glycol-polylactic acid-poly benzyl glutamate;
3. hydro-reduction PEG-PLA-PBLG makes polyethylene glycol-polylactic acid-polyglutamic acid (PEG-PLA-PGL);
Step 2: the chemical surface treatment of metallic blood vessel bracket;
The metallic blood vessel bracket of prior art is Ni-Ti alloy normally, with strongly acidic aqueous solution processing make metal surface generate activity hydroxy, utilize this hydroxyl and the lactic acid oligomer graft reaction with isocyanate groups, wash away the polylactic acid not having in grafting, can obtain the metallic blood vessel bracket of surperficial macromolecular grafted modification, this support can increase and apply the intensity between macromolecular material greatly;
Step 3: the macromolecular material that supports rapamycin, heparin and L-arginine with the way structure of chemical mixing;
According to the needs of support timing function, build needed degradable high polymer material, degradation speed difference under constructed macromolecular material biotic environment in vivo, the medicine difference supporting, the medication amount difference supporting, and with corresponding medicament mixed, adopt the way of chemical mixing to build and support the macromolecular material of rapamycin, heparin and L-arginine;
Step 4: the macromolecular material with different degradation properties is coated on to intravascular stent surface by different level, medicine was played a role in the different time, possess timing function; The main electrostatic spray that adopts of coating, under the very thin condition of coating, can evenly apply, does not stay dead angle yet.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105797220A (en) * | 2014-12-31 | 2016-07-27 | 先健科技(深圳)有限公司 | Degradable ferrous alloy stent |
| CN105816921A (en) * | 2016-04-20 | 2016-08-03 | 山东百多安医用材料改性工程技术中心 | Bionic vascular stent and preparation method thereof |
| CN105983173A (en) * | 2015-02-10 | 2016-10-05 | 刘雯倩 | Drug controlled-release equipment |
| CN108744071A (en) * | 2018-08-20 | 2018-11-06 | 南京永明医疗器械有限公司 | A kind of multi-functional coatings and preparation method of biodegradable polymer stent |
| CN113750290A (en) * | 2020-06-03 | 2021-12-07 | 深圳先进技术研究院 | Polyether-ether-ketone composite implant and preparation method and application thereof |
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| US5443458A (en) * | 1992-12-22 | 1995-08-22 | Advanced Cardiovascular Systems, Inc. | Multilayered biodegradable stent and method of manufacture |
| CN1806857A (en) * | 2005-01-17 | 2006-07-26 | 李庆范 | Multilayer-coated stent for controlled drug release and manufacturing method thereof |
| CN201179222Y (en) * | 2008-02-03 | 2009-01-14 | 吴昊 | Medicament coating bracket |
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2014
- 2014-04-22 CN CN201410161182.0A patent/CN104107459A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5443458A (en) * | 1992-12-22 | 1995-08-22 | Advanced Cardiovascular Systems, Inc. | Multilayered biodegradable stent and method of manufacture |
| CN1806857A (en) * | 2005-01-17 | 2006-07-26 | 李庆范 | Multilayer-coated stent for controlled drug release and manufacturing method thereof |
| CN201179222Y (en) * | 2008-02-03 | 2009-01-14 | 吴昊 | Medicament coating bracket |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105797220A (en) * | 2014-12-31 | 2016-07-27 | 先健科技(深圳)有限公司 | Degradable ferrous alloy stent |
| CN105983173A (en) * | 2015-02-10 | 2016-10-05 | 刘雯倩 | Drug controlled-release equipment |
| CN105816921A (en) * | 2016-04-20 | 2016-08-03 | 山东百多安医用材料改性工程技术中心 | Bionic vascular stent and preparation method thereof |
| CN108744071A (en) * | 2018-08-20 | 2018-11-06 | 南京永明医疗器械有限公司 | A kind of multi-functional coatings and preparation method of biodegradable polymer stent |
| CN113750290A (en) * | 2020-06-03 | 2021-12-07 | 深圳先进技术研究院 | Polyether-ether-ketone composite implant and preparation method and application thereof |
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Application publication date: 20141022 |