CN101485902A - Biological degradable metal stent coated with rapamycin-probucol composite medicament - Google Patents
Biological degradable metal stent coated with rapamycin-probucol composite medicament Download PDFInfo
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- CN101485902A CN101485902A CNA2009100774548A CN200910077454A CN101485902A CN 101485902 A CN101485902 A CN 101485902A CN A2009100774548 A CNA2009100774548 A CN A2009100774548A CN 200910077454 A CN200910077454 A CN 200910077454A CN 101485902 A CN101485902 A CN 101485902A
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- probucol
- rapamycin
- stent
- metal stent
- combination drug
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Abstract
The invention provides a biodegradable rapamycin-probucol composite medicine coated metal stent, which comprises a metal stent, active ingredients which coat on the surface of the metal stent, and a slow release vector, wherein the active ingredients are rapamycin and probucol; and the slow release vector is in vivo degradable fatty cluster polymers. The coated metal stent not only maintains the advantage of preventing restenosis of the medicine coated stent but also solves the problem of late stent thrombus along with complete release of a slow release coating; and the probucol in the coating has the function of inhibiting local inflammatory reaction caused by the vector and a medicine. The coated metal stent is mainly used for interventional therapy of coronary heart disease, prevention of restenosis, and reduction of formation of late thrombus after the stent is implanted.
Description
Technical field
The present invention relates to a kind of metal rack that is provided with the slow releasing pharmaceutical coating, the slow releasing pharmaceutical coating refers to contain the combination drug coating of rapamycin and probucol, and this coating has slow release effect.Be mainly used in interventional therapy of coronary heart disease, prevention of restenosis reduces the formation that support is inserted the back advanced thrombus.
Background technology
Along with the change of life style, atherosclerotic incidence rate continues to increase.Coronary atherosclerosis becomes present threat human life's primary factor.This type of patient that develops into of coronary heart disease interventional therapy has brought Gospel.Scientific progress has promoted the development of arteria coronaria interventional therapy, yet the postoperative restenosis problem is still perplexing clinical treatment.No matter be that simple balloon expandable or naked metal rack are inserted, the endothelium that causes in the art is torn, and further on this basis platelet deposition, thrombosis, smooth muscle cell proliferation and a series of pathological processes such as migration, extracellular matrix formation, causing new intima to form is the main cause of restenosis.
This puzzlement has been removed in the appearance of coating stent of medicine to a certain extent.Rack surface coating immunosuppressant, anti-inflammatory agent, antiproliferative agents, anti-migration medicine etc., make medicine be directly released into the vascular lesion position, both improved the targeting of medicine, avoided the whole body toxic and side effects of oral medication again, particularly greatly reduce the postoperative restenosis rate, restenosis rate is reduced to below 10%.
Coronary restenosis has obtained control to a certain degree, but the thrombosis problem highlights in the support, no matter is acute thrombus, subacute stent thrombosis, or advanced thrombus forms.Wherein advanced thrombus forms and more becomes the focus that people pay close attention to.
After coating stent of medicine implanted one month, drug effect had discharged basically, and pharmaceutical carrier generally to be polylactic acid etc. retain in the body with support, the local inflammation reaction that it caused, and then the blood vessel endothelium delay that causes is the main cause of stent thrombosis in late period.
Therefore, need further study, easily produce local inflammation to solve support to coating stent of medicine, and late period stent thrombosis problem.
Summary of the invention
The purpose of this invention is to provide and a kind ofly have anti-restenosis performance, and behind the support blood vessel endothelialization is good again, help reducing thrombotic newtype drug support in the support in late period.
In order to realize the object of the invention, a kind of Biodegradable rapamycin of the present invention-probucol composite medicament coat metal stent, it comprises metal rack, coats the active component and the slow-released carrier of described metal support surface, described active component is rapamycin and probucol, and described slow-released carrier is a kind of degradable in vivo adip cluster polymer.
The weight ratio of described rapamycin, probucol and slow-released carrier is 10～40:5～30:30～85.
Rapamycin of the present invention is a kind of natural Macrocyclolactone lactone kind medicine.Be effective immunosuppressant, can prolong the transplanting survival rate, to tissue transplantation, bone marrow transplantation and islet cell transplantation are all effective.Rapamycin combines with a kind of special transducin that is called TOR (rapamycin target), acts on the cell mitogen G1 phase, and suppresses its activity, makes cell turn back to resting stage, thus cell growth inhibiting.Because the mechanism of action of its uniqueness, rapamycin is compared with other immunosuppressant, and toxicity is very low.Rapamycin can suppress the hyperplasia of arterial injury and support implantation back inflammatory reaction and smooth muscle cell.The content of dispersion of rapamycin of the present invention is 1.20～2.0ug/mm
2, expected drug discharged more than 80% at 28 days.
Because the anti-proliferative effect of rapamycin lacks selectivity; medicine has also suppressed the normal recovery of endotheliocyte when suppressing smooth muscle cell proliferation; make damage location endothelialization time lengthening; damage location is difficult to healing; there is the later stage inflammatory reaction, thereby easily causes thrombosis in the tardy property support.At the deficiency and the shortcoming of this kind bracket for eluting medicament, the present invention has designed two kinds of medication combined being coated on the support, i.e. probucol and rapamycin remedy the deficiency of single medicine effect.From postoperative blood vessel injury mechanism, get involved damage and make blood vessel Topically active oxygen generate (superoxide anion and hydrogen peroxide) in a large number, directly stimulated vascular smooth muscle cell propagation mediates lipid peroxidation, vascular endothelial cell injury simultaneously.The endotheliocyte and the activatory macrophage of damage discharge multiple somatomedin, cytokine and other vaso-active substances, stimulate the secretion of tunica intima hyperplasia and extracellular matrix, finally make vascular restenosis.Probucol is to have the powerful antioxidant of transferring the fat effect concurrently, can remove oxygen-derived free radicals, reduces the nitric oxide deactivation, prevents the LDL oxidation, generates by suppressing oxLDL, promotes endothelial regeneration, reduces the synthetic and secretion Endothelin (ET) of endotheliocyte.Research is also found, probucol can strengthen the biological activity (comprising erythrocuprein, catalase and glutathion peroxidase) of multiple antioxidant enzyme, reduce the intracellular reactive oxygen concentration, suppress the signals-modulating effect of active oxygen, prevent vascular smooth muscle cell hyper-proliferative or apoptosis.Recently studies show that probucol can obviously suppress the gene expression of platelet-derived growth factor A, blood vessel adhesion molecule 1 and mononuclear cell chemistry chemotactic protein 1, thereby suppresses vascular smooth muscle cell proliferation and local inflammatory reaction.In view of probucol has above-mentioned advantage, use is united in it and rapamycin, remedy independent use rapamycin and suppress the shortcoming that blood vessel endothelium is repaired, thereby reduce the inflammation of blood vessel injury, promote endothelial regeneration, and suppress smooth muscle cell proliferation, effectively prevent postoperative restenosis.
The content of dispersion of probucol of the present invention is 0.5～3.0ug/mm
2, expected drug discharged more than 80% at 28 days.
The present invention adopts combination drug to combine with slow-released carrier, and the control medicine is with the release of a definite form.The medical degradable macromolecular material that described adip cluster polymer is chemosynthesis has excellent biological compatibility and biodegradability.It can be by the simple ester linkage hydrolyzing of chemical degradation-be or enzymatic degradation and chain rupture generates hydroxy fatty acid in environment that water is arranged or body fluid, and participates in tricarboxylic acid cycle in vivo and resolve into CO
2And H
2O excretes by metabolism, especially poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA), polylactide (PLA), polycaprolactone (PCL) and their copolymer, and slow-released carrier is safe and reliable, have the controllability of excellent biological compatibility and degradation speed.Slow-released carrier of the present invention was degraded in the time of 2 months and is reached more than 90%.
Metal rack of the present invention is the hollow out arbitrary shape, timbering material is a kind of in L605 cochrome, 316L rustless steel, Nitinol or the magnesium alloy, this material has the ability and the tensile strength of higher fatigue crack-resistant than rustless steel, and pliability is better, is suitable for supporting for a long time narrow blood vessel.This material has good anti-corrosion, can withstand the immersion corrosion of human body fluid, and has excellent biocompatibility; This support has less external diameter and good pliability, is convenient to arrive the target lesion point by blood vessel, and enough support strengths are arranged after opening again.
Support of the present invention is made up of naked metal rack and medication coat, and medication coat evenly is coated on rack surface.Its preparation method comprises the steps:
The polymer that will contain rapamycin and probucol is dissolved in the solvent, be coated on metal support surface by methods such as spraying, dip-coating or brushings, metal rack with coating is positioned in the vacuum drying oven then, solidifies in dry 0.5～72 hour under 20～100 ℃ of environment; Metal rack can repeatedly repeat said process to reach expection coating layer thickness (1mm～10mm) and drug loading.
Described solvent is a kind of in trichloroethane, oxolane, methanol, acetonitrile, the chloroform.
Combination drug coat metal stent of the present invention had both kept the advantage of coating stent of medicine prevention of restenosis, along with the release fully of controlled-release coating, had solved the problem of stent thrombosis in late period again.Probucol in its coating has the effect that suppresses carrier and the reaction of drug-induced local inflammation again.This support has the following advantages:
1, suppresses smooth muscle cell proliferation, reduce the generation of restenosis then; 2, inflammation-inhibiting reaction promotes blood vessel endothelialization again; 3, significantly reduce postoperative complication.4, be mainly used in interventional therapy of coronary heart disease, prevention of restenosis reduces support and inserts back advanced thrombus formation.
Description of drawings
Fig. 1 is a coating stent of medicine sem photograph of the present invention;
Fig. 2 is the profile scanning Electronic Speculum figure of coating stent of medicine of the present invention;
Fig. 3 is the burst size effect relationship figure of medicament controlled-release coating of the present invention.
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
The described metal rack body portion of present embodiment is the open-loop design shape with L605 cochrome laser engraving.
The mixture that elder generation gets rapamycin, probucol and poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA) respectively by the weight ratio of 1:1:3 is dissolved in the trichloroethane, and total concentration by weight is 1.5%, mixes being uniformly dispersed the ultrasonic then metal support surface that is sprayed at ambient temperature.Air set 30min.Repeat the aforesaid operations process, reach requirement (rapamycin 1.6ug/cm up to the support drug loading
2, probucol 2.0ug/cm
2, coating layer thickness 5mm).To prop up at last and be placed in the vacuum drying oven dry 0.5 hour.Fig. 1 is the coating stent of medicine sem photograph that completes, and Fig. 2 is the support profile of band coating.
Wherein poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA) can be by polylactide (PLA) or polycaprolactone (PCL), or two or three copolymer replaces in three kinds of polymer.
Fig. 3 is the burst size effect relationship figure of medicament controlled-release coating of the present invention.Adopt high-efficient liquid phase technique to measure the release performance curve of medicine in 4% bovine serum albumin solution of pH=7.4, two kinds of medicines discharged comparatively fast at the release initial stage, and at middle and late stage, drug release is mild gradually, and medicine can discharge more than 28 days.
Embodiment 2
The described metal rack body portion of present embodiment is the hollow out diamond structure with 316L stainless steel laser engraving.
The mixture that elder generation gets rapamycin, probucol and polylactide (PLA) respectively by the weight ratio of 20:5:60 is dissolved in the methanol, and total concentration by weight is 2.0%, mixes being uniformly dispersed the ultrasonic then metal support surface that is sprayed at down at 40 ℃.Air set 50min.Repeat the aforesaid operations process, reach requirement (rapamycin 1.2ug/cm up to the support drug loading
2, probucol 2.0ug/cm
2, coating layer thickness 3mm).To prop up again and be placed in the vacuum drying oven dry 16 hours.
Embodiment 3
The described metal rack body portion of present embodiment is " Z " shape bellows-shaped with the Nitinol laser engraving.
The mixture that elder generation gets rapamycin, probucol and polycaprolactone (PCL) respectively by the weight ratio of 40:30:50 is dissolved in the oxolane, and total concentration by weight is 3.0%, mixes being uniformly dispersed the ultrasonic then metal support surface that is sprayed at down at 60 ℃.Air set 30min.Repeat the aforesaid operations process, reach requirement (rapamycin 2.0ug/cm up to the support drug loading
2, probucol 1.0ug/cm
2, coating layer thickness 1mm).To prop up again and be placed in the vacuum drying oven dry 32 hours.
Embodiment 4
The described metal rack body portion of present embodiment is the open-loop design shape with the magnesium alloy laser engraving.
The mixture that elder generation gets the copolymer of rapamycin, probucol and PGA and PCL respectively by the weight ratio of 30:30:85 is dissolved in the trichloroethane, and total concentration by weight is 1.5%, mixes being uniformly dispersed the ultrasonic then metal support surface that is sprayed at down at 100 ℃.Air set 30min.Repeat the aforesaid operations process, reach requirement (rapamycin 1.8ug/cm up to the support drug loading
2, probucol 1.5ug/cm
2, coating layer thickness 10mm).To prop up again and be placed in the vacuum drying oven dry 72 hours.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (8)
1. combination drug coat metal stent, it is characterized in that, it comprises metal rack, coats the active component and the slow-released carrier of described metal support surface, and described active component is rapamycin and probucol, and described slow-released carrier is a kind of adip cluster polymer.
2. according to the described combination drug coat metal stent of claim 1, it is characterized in that the weight ratio of described rapamycin, probucol and slow-released carrier is 10～40:5～30:30～85.
3. according to claim 1 or 2 described combination drug coat metal stents, it is characterized in that the content of dispersion of described rapamycin is 1.20～2.0ug/mm
2
4. according to any described combination drug coat metal stent of claim 1～3, it is characterized in that the content of dispersion of described probucol is 0.5～3.0ug/mm
2
5. according to any described combination drug coat metal stent of claim 1～4, it is characterized in that described adip cluster polymer is poly-Acetic acid, hydroxy-, bimol. cyclic ester, polylactide, polycaprolactone and their copolymer.
6. according to any described combination drug coat metal stent of claim 1～5, it is characterized in that described metallic stent material is a kind of in L605 cochrome, 316L rustless steel, Nitinol or the magnesium alloy.
7. method for preparing any described combination drug coat metal stent of claim 1～6, it is characterized in that, comprise the steps: that the polymer and the slow-released carrier that will contain rapamycin and probucol earlier are dissolved in the solvent, be coated on metal support surface by spraying, dip-coating or brushing method, then metal rack is positioned in the vacuum drying oven, solidified in dry 0.5～72 hour down at 20～100 ℃, repeatedly repeat to reach required drug loading.
8. according to the preparation method of the described combination drug coat metal stent of claim 7, it is characterized in that described solvent is a kind of in trichloroethane, oxolane, acetone, methanol, acetonitrile, the chloroform.
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| CN2009100774548A CN101485902B (en) | 2009-02-11 | 2009-02-11 | Biological degradable metal stent coated with rapamycin-probucol composite medicament |
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| CN101485902B CN101485902B (en) | 2012-10-31 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784418A (en) * | 2012-08-10 | 2012-11-21 | 中国医学科学院生物医学工程研究所 | Procedurally-released biological drug nanoporous intravascular stent and preparation method thereof |
| CN104644297A (en) * | 2015-02-16 | 2015-05-27 | 上海微创医疗器械（集团）有限公司 | Bioabsorbable stent and preparation method thereof |
| CN106310395A (en) * | 2015-06-30 | 2017-01-11 | 上海微创医疗器械（集团）有限公司 | Composite drug-loading stent and preparation method thereof |
| CN107158486A (en) * | 2017-03-24 | 2017-09-15 | 陈绍良 | Jamaicin FirebirdTM |
| CN108187151A (en) * | 2018-01-23 | 2018-06-22 | 南京鼓楼医院 | A kind of stent of medication coat |
| CN111132638A (en) * | 2017-07-27 | 2020-05-08 | 波士顿科学国际有限公司 | Adjustable mandrel for forming stents with anti-migration features |
| CN117281959A (en) * | 2023-11-22 | 2023-12-26 | 北京久事神康医疗科技有限公司 | Drug stent and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101327343B (en) * | 2007-06-20 | 2012-05-23 | 乐普（北京）医疗器械股份有限公司 | Compound medicament intravascular stent and preparation method thereof |
-
2009
- 2009-02-11 CN CN2009100774548A patent/CN101485902B/en active Active
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784418A (en) * | 2012-08-10 | 2012-11-21 | 中国医学科学院生物医学工程研究所 | Procedurally-released biological drug nanoporous intravascular stent and preparation method thereof |
| CN102784418B (en) * | 2012-08-10 | 2014-04-16 | 中国医学科学院生物医学工程研究所 | Procedurally-released biological drug nanoporous intravascular stent, preparation method and application thereof |
| CN104644297A (en) * | 2015-02-16 | 2015-05-27 | 上海微创医疗器械（集团）有限公司 | Bioabsorbable stent and preparation method thereof |
| CN106310395A (en) * | 2015-06-30 | 2017-01-11 | 上海微创医疗器械（集团）有限公司 | Composite drug-loading stent and preparation method thereof |
| CN107158486A (en) * | 2017-03-24 | 2017-09-15 | 陈绍良 | Jamaicin FirebirdTM |
| CN111132638A (en) * | 2017-07-27 | 2020-05-08 | 波士顿科学国际有限公司 | Adjustable mandrel for forming stents with anti-migration features |
| CN111132638B (en) * | 2017-07-27 | 2022-03-29 | 波士顿科学国际有限公司 | Adjustable mandrel for forming stents with anti-migration features |
| CN108187151A (en) * | 2018-01-23 | 2018-06-22 | 南京鼓楼医院 | A kind of stent of medication coat |
| CN117281959A (en) * | 2023-11-22 | 2023-12-26 | 北京久事神康医疗科技有限公司 | Drug stent and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN101485902B (en) | 2012-10-31 |
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Effective date of registration: 20171107 Address after: 102200 Beijing, Changping District super Road, building No. 37, No. 7 Patentee after: Lepu (Beijing) Medical Equipment Co.,Ltd. Address before: 518054 Guangdong city of Shenzhen province Nanshan District Guangdong streets Changhong Technology Park Building Room 503 Patentee before: (Shenzhen) International Development Centre Limited |