CN100441155C - Curcuma zedoary oil controlled release elution rack for preventing and curing re-stenosis in coronary artery rack - Google Patents
Curcuma zedoary oil controlled release elution rack for preventing and curing re-stenosis in coronary artery rack Download PDFInfo
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- CN100441155C CN100441155C CNB2005100237130A CN200510023713A CN100441155C CN 100441155 C CN100441155 C CN 100441155C CN B2005100237130 A CNB2005100237130 A CN B2005100237130A CN 200510023713 A CN200510023713 A CN 200510023713A CN 100441155 C CN100441155 C CN 100441155C
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- restenosis
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Abstract
The present invention belongs to the fields of a medicament and a medical appliance, which relates to a medicament elution bracket for preventing and curing restenosis in a bracket, particularly to a zedoary turmeric oil controlled release elution bracket for preventing and curing restenosis in a coronary artery bracket. The bracket uses zedoary turmeric oil liquid as a medicament effective component, and uses a stainless steel material as a bracket. A controlled release coating layer is a composite material of polymethacrylic acid butyl ester/nanometer silicon dioxide. The bracket of the present invention has the functions of inhibiting cell growth, inducing cell apoptosis, resisting inflammation, resisting thrombosis, inhibiting collagen synthesis and continuously resisting hyperplasy for a long time. After the bracket is embedded into a coronary artery, the compatibility and the safety of tissues are favorable. A neogenesis inner membrane degree in the coronary artery is obviously reduced. A tube cavity is obviously increased, and the number of apoptosis cells is obviously increased. The present invention can prevent and cure restenosis after a bracket operation.
Description
Technical field
The invention belongs to medicine and medical instruments field, relate to the bracket for eluting medicament of preventing and treating in-stent restenosis, be specifically related to a kind of Oleum Curcumae bracket for controlling releasing and elution of preventing and treating restenosis in the coronary artery bracket.
Background technology
Percutaneous coronary intervention (PCI) is the critical treatment method of coronary heart disease.At present stent endoprosthesis has been substituted the main means that balloon dilatation becomes PCI.According to statistics, the annual nearly needs of patients 1500000 or more in the whole world is PCI and is treated, but behind the support restenosis rate up to 15～30%.Therefore preventing and treating restenosis behind the support becomes the emphasis and the focus of PCI research field.It is reported that treatment such as clinical cutting balloon expandable commonly used, directed rotary-cut, laser forming, gene therapy, whole body administration restenosis curative effect is all not satisfied.Though intravascular radiotherapy has been obtained curative effect preferably, easily cause " edge effect " and thrombosis.Prevent and treat the issue of restenosis clinical test results in recent years along with carried stent, make people see the rosy prospect of this technology, speaking highly of this technology and indicate that PCI has entered " bracket for eluting medicament epoch ", is " revolution for the third time " that the cardiovascular diseases gets involved.Wherein restenosis is the difficult problem of this technical development of puzzlement behind the coronary intervention, and bracket for eluting medicament is expected to become the effective way that solves post stent implantation restenosis.
At present the most noticeable in the world paclitaxel and the large-scale clinical trial of rapamycins coating support are also in further studying.The bracket for eluting medicament that China does not still have independent intellectual property right enters clinical research.
Oleum Curcumae is the volatile oil that extracts from the Chinese medicine Rhizoma Curcumae, contains various active compositions such as curzerenone, curcumenol, beta-elemene, curcumin, curdione.Studies show that, Oleum Curcumae has the growth of tumour cell of inhibition and inducing apoptosis of tumour cell, anticoagulant, antiplatelet adhere to, improve effects such as hemorheology, antithrombotic formation, antiinflammatory, anti peroxidation of lipid, but still useless in the report of bracket coating.
Summary of the invention
The purpose of this invention is to provide a kind of bracket for eluting medicament of preventing and treating in-stent restenosis, be specifically related to a kind of Oleum Curcumae bracket for controlling releasing and elution that prevents restenosis in the coronary artery bracket.
The present invention adopts Oleum Curcumae material liquid (Ruian, Zhejiang pharmaceutical factory, lot number 980908), is sprayed at the surface of polybutyl methacrylate/nanometer titanium dioxide silicon coating stainless steel stent, coating layer thickness 12～30um, rack surface medicament contg 1.8-3.6 μ g/mm
2
The present invention adopts polybutyl methacrylate/nanometer silicon dioxide composite material as medicine sustained release coating (CN 02136332.3).Its preparation method is, the tetrahydrofuran solution of the polybutyl methacrylate of preparation 1% wherein contains the nano silicon of amount of polymers 25-30%, as the sustained release coating.The Oleum Curcumae medicine is added above-mentioned solution, the weight ratio that makes medicine and polybutyl methacrylate is 1: 1, stirring is suspended in the solution medicine, be sprayed on above-mentioned suspension on the support equably with spray gun, 40 ℃ of oven dry, accurately weigh, the medicament contg that makes every square millimeter of rack surface is 1.8-3.6 μ g, coating layer thickness 12～30um.Bracket for eluting medicament is installed on the sacculus, standby behind the oxirane disinfection.The preparation of simple coating bracket then directly with the sustained release coating spraying on support, all the other processes are identical with bracket for eluting medicament.
Support of the present invention Rhizoma Curcumae fluid wherein, have cell growth inhibiting and cell death inducing, antiinflammatory, antithrombotic forms, suppress the collagen anabolic effect, and Oleum Curcumae is a fat-soluble medicine, easily pass through cell membrane, continuingly act on the pathological changes part, even it is of short duration, minimum dosage also can produce the permanent anti-proliferative effect that continues, characteristics in conjunction with polybutyl methacrylate/nanometer titanium dioxide silicon coating sustained release, histocompatibility and safety behind the implantation arteria coronaria are good, the new intima degree obviously reduces in the arteria coronaria, tube chamber enlarges markedly and apoptotic cell quantity showed increased, act on a certain link and have a clear superiority in than paclitaxel and rapamycins coating support are single, can prevent and treat the support postoperative restenosis.
The compound sustained release material of coating polybutyl methacrylate/silicon dioxide (nanometer) that the present invention adopts mixes the surface that is applied to stainless steel stent with medicine Rhizoma Curcumae fluid, have following advantage: 1. formation interpenetrating networks or silicon dioxide granule are evenly dispersed among the polybutyl methacrylate between polybutyl methacrylate and the silicon dioxide, so coating possesses the good pliability of macromolecular material; 2. exist covalency to connect between silicon dioxide and the polybutyl methacrylate, make polybutyl methacrylate finer and close, help the long-term release of medicine, and more safer, nontoxic than using organic crosslinking agent, 3. adopt medicine Rhizoma Curcumae fluid, have the permanent anti-proliferative effect that continues.
Description of drawings
Fig. 1 is the external sustained release test result of Oleum Curcumae bracket for controlling releasing and elution.
Fig. 2 coating group: support is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner membrance and is obviously thickened.
Fig. 3 Rhizoma Curcumae line of oils: support is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner film thickness and is reduced than the coating group.
The specific embodiment
Embodiment 1
Preparation Oleum Curcumae bracket for controlling releasing and elution
Adopt the stainless steel material support, polybutyl methacrylate/nanometer silicon dioxide composite material is as medicine sustained release coating.At first prepare the tetrahydrofuran solution of 1% polybutyl methacrylate, the nano silicon that wherein contains amount of polymers 25-30%, described Oleum Curcumae medicine is added solution, the weight ratio that makes medicine and polybutyl methacrylate is 1: 1, stirring is suspended in the solution medicine, above-mentioned suspension is sprayed on the support equably 40 ℃ of oven dry with spray gun, accurately weigh, calculate the medicament contg of every square millimeter of rack surface.Coating layer thickness 12～30 μ m, rack surface medicament contg 1.8-3.6 μ g/mm
2Bracket for eluting medicament is installed on the sacculus, standby behind the oxirane disinfection.
The curcuma zedoary oil bracket for controlling releasing and elution carries out external sustained release test, the result shows: medicine is rapid release in initial about 2 weeks, rate of release eases up gradually then, after 4 months, still have the medicine that surpasses half not discharge, compare significantly with the release time of simple polymer of the same race and to slow down, guaranteed the continuous action of medicine.Simultaneously, by the ratio of simple adjustment medicine and coating, and the ratio of polybutyl methacrylate/nano silicon in the coating, can adjust the shape of release profiles to a great extent.Show that the nano silicon in the composite coating has the effect that prolongs release time.
Embodiment 2
Zoopery test Oleum Curcumae bracket for controlling releasing and elution to laboratory animal dog stenting after the effect of neointimal hyperplasia, estimate the safety and the curative effect of Oleum Curcumae bracket for controlling releasing and elution control support postoperative restenosis.
Healthy hybrid adult dogs is divided into 2 groups at random: in the ratio of stent diameter, arteria coronaria diameter 1.2～1.3: 1 respectively with the Oleum Curcumae bracket for controlling releasing and elution of simple coating bracket, embodiment 1, its coating layer thickness 12 μ m, rack surface medicament contg 1.8 μ g/mm
2Implanting at random circles round props up and the suitable vessel segment of anterior descending branch, be coating group, Rhizoma Curcumae line of oils, every group 10, art began to take aspirin 250mg in preceding 1 day, put to death until 30 days, get support and implant a section blood vessel, coating group and medication group are respectively got vitals such as the heart, liver, spleen, lung, kidney, stomach, brain, skeletal muscle, testis of 2 animals wherein again, and be fixing.
Each pack support vessel segment of optical microscope and scanning electron microscopic observation and vitals histopathology change.Computer picture quantitative analysis support vessel segment new intima area, cavity area and average inner film thickness.The SABC method is measured support vessel segment α-smooth muscle actin (α-SM actin), proliferating cell nuclear antigen (PCNA) is expressed and the image semi-quantitative analysis, the analysis of TUNEL method combining image, low cytometric analysis, transmission electron microscope observing and detection apoptosis.
Result's demonstration,
1. light microscopic and scanning electron microscopic observation brace sections blood vessel NIP, no thrombosis forms, no arterial wall attenuation, no aneurysm forms, film, adventitia necrosis in the nothing, the heart, liver, spleen, lung, kidney, brain etc. organize no pathologic to damage.Show that histocompatibility and safety behind the Oleum Curcumae bracket for controlling releasing and elution implantation dog arteria coronaria are good.
2. 4w Rhizoma Curcumae line of oils obviously reduced than coating group new intima degree after support was implanted, and tube chamber enlarges markedly.Show that the Oleum Curcumae bracket for controlling releasing and elution can prevent and treat restenosis in the dog coronary artery bracket.
3. transmission electron microscope morphologic detection: find that Rhizoma Curcumae line of oils apoptosis cell amount is obviously more than all the other each groups.
The flow cytometer quantitative analysis finds that Rhizoma Curcumae line of oils percentage of cell apoptosis is apparently higher than the coating group.
Rhizoma Curcumae line of oils apoptotic index is apparently higher than the coating group, and the Rhizoma Curcumae line of oils is the most remarkable.
4. the SABC method detects PCNA, and Rhizoma Curcumae line of oils positive expression obviously is less than the coating group, shows that the Oleum Curcumae bracket for controlling releasing and elution is influential to dog arteria coronaria PCNA.
5. the SABC method detects α-SM actin, and Rhizoma Curcumae line of oils positive expression obviously is less than the coating group, shows that the Oleum Curcumae bracket for controlling releasing and elution is influential to dog arteria coronaria α-SM actin.
The result confirms:
1. the compound controlled releasing coating support of polybutyl methacrylate/silicon dioxide of the present invention (nanometer) has good biocompatibility.
2. the compound controlled releasing coating support of polybutyl methacrylate/silicon dioxide of the present invention (nanometer) is implanted dog coronary artery safety, feasible.
3. the compound controlled releasing coating support of Oleum Curcumae polybutyl methacrylate/silicon dioxide of the present invention (nanometer) can effectively be prevented and treated restenosis in the dog coronary artery bracket.
4. the mechanism of action of the compound controlled releasing coating support control of Oleum Curcumae polybutyl methacrylate/silicon dioxide of the present invention (nanometer) in-stent restenosis mainly is to induce new intima and middle film smooth muscle cell apoptosis, and suppresses smooth muscle cell proliferation.
Embodiment 3
Healthy hybrid adult dogs is divided into 2 groups at random: in the ratio of stent diameter, arteria coronaria diameter 1.2～1.3: 1 respectively with the Oleum Curcumae bracket for controlling releasing and elution of simple coating bracket, embodiment 1, its coating layer thickness 30 μ m, rack surface medicament contg 3.6 μ g/mm
2Implanting at random circles round props up and the suitable vessel segment of anterior descending branch, be coating group, Rhizoma Curcumae line of oils, every group 10, art began to take aspirin 250mg in preceding 1 day, put to death until 30 days, got support and implanted the section blood vessel, respectively get the vitals such as the heart, liver, spleen, lung, kidney, stomach, brain, skeletal muscle, testis of 2 animals wherein again, fixing.
Each pack support vessel segment of optical microscope and scanning electron microscopic observation and vitals histopathology change.Computer picture quantitative analysis support vessel segment new intima area, cavity area and average inner film thickness.The SABC method is measured support vessel segment α-smooth muscle actin (α-SM actin), proliferating cell nuclear antigen (PCNA) is expressed and the image semi-quantitative analysis, the analysis of TUNEL method combining image, low cytometric analysis, transmission electron microscope observing and detection apoptosis.
Experimental result is with embodiment 2.
Claims (3)
1, the Oleum Curcumae bracket for controlling releasing and elution of restenosis in the control coronary artery bracket, it is characterized in that with Oleum Curcumae liquid be effective ingredient, with the stainless steel material that scribbles the compound sustained release material of polybutyl methacrylate/nano silicon is support, the compound sustained release material of described polybutyl methacrylate/nano silicon mixes the surface that is applied to stainless steel stent with medicine Rhizoma Curcumae fluid, described bracket coating thickness 12～30 μ m, rack surface medicament contg 1.8-3.6 μ g/mm
2
2, by the Oleum Curcumae bracket for controlling releasing and elution of restenosis in the described control coronary artery bracket of claim 1, it is characterized in that described coating layer thickness is 12 μ m, rack surface medicament contg 1.8 μ g/mm
2
3, by the Oleum Curcumae bracket for controlling releasing and elution of restenosis in the described control coronary artery bracket of claim 1, it is characterized in that described coating layer thickness is 30 μ m, rack surface medicament contg 3.6 μ g/mm
2
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100237130A CN100441155C (en) | 2005-01-31 | 2005-01-31 | Curcuma zedoary oil controlled release elution rack for preventing and curing re-stenosis in coronary artery rack |
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| CNB2005100237130A CN100441155C (en) | 2005-01-31 | 2005-01-31 | Curcuma zedoary oil controlled release elution rack for preventing and curing re-stenosis in coronary artery rack |
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| CN1647776A CN1647776A (en) | 2005-08-03 |
| CN100441155C true CN100441155C (en) | 2008-12-10 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170216497A1 (en) * | 2014-05-28 | 2017-08-03 | Xiyuan Hospital Of China Academy Of Chinese Medical Sciences | Scaffold with drug coating for preventing and treating restenosis and preparation method thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181650B (en) * | 2006-08-02 | 2010-06-16 | 上海市普陀区中心医院 | Bracket for controlling releasing and elution of tranilast medicament coating |
| WO2011089618A2 (en) * | 2010-01-22 | 2011-07-28 | Concept Medical Research Private Limited | Drug-eluting insert able medical device for treating acute myocardial infarction, thrombus containing lesions and saphenous- vein graft lesions |
| CN106237492A (en) * | 2015-06-14 | 2016-12-21 | 上海市第人民医院 | The beta-elemene bracket for controlling releasing and elution of preventing and treating Coronary Artery In-Stent Restenosis |
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| US4886062A (en) * | 1987-10-19 | 1989-12-12 | Medtronic, Inc. | Intravascular radially expandable stent and method of implant |
| US5464650A (en) * | 1993-04-26 | 1995-11-07 | Medtronic, Inc. | Intravascular stent and method |
| CN1391886A (en) * | 2002-08-01 | 2003-01-22 | 复旦大学 | Medicine releasing control method for implanting type medical equipment |
| CN1513567A (en) * | 2002-12-31 | 2004-07-21 | 中国科学院金属研究所 | Cardiovascular support having control releasing therapeutic medicine |
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2005
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4886062A (en) * | 1987-10-19 | 1989-12-12 | Medtronic, Inc. | Intravascular radially expandable stent and method of implant |
| US5464650A (en) * | 1993-04-26 | 1995-11-07 | Medtronic, Inc. | Intravascular stent and method |
| CN1391886A (en) * | 2002-08-01 | 2003-01-22 | 复旦大学 | Medicine releasing control method for implanting type medical equipment |
| CN1513567A (en) * | 2002-12-31 | 2004-07-21 | 中国科学院金属研究所 | Cardiovascular support having control releasing therapeutic medicine |
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| 莪术油抑制大鼠血管成形术后胶原积聚作用的研究. 翁书和，赵军礼，陈镜合，罗小星，吴思慧.中医药学刊，第21卷第8期. 2003 |
| 莪术油抑制大鼠血管成形术后胶原积聚作用的研究. 翁书和，赵军礼，陈镜合，罗小星，吴思慧.中医药学刊，第21卷第8期. 2003 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170216497A1 (en) * | 2014-05-28 | 2017-08-03 | Xiyuan Hospital Of China Academy Of Chinese Medical Sciences | Scaffold with drug coating for preventing and treating restenosis and preparation method thereof |
| US9968717B2 (en) * | 2014-05-28 | 2018-05-15 | Xiyuan Hospital Of China Academy Of Chinese Medical Sciences | Scaffold with drug coating for treating restenosis and preparation method thereof |
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| CN1647776A (en) | 2005-08-03 |
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