CN100435756C - Arsenic trioxide control release elution stent - Google Patents
Arsenic trioxide control release elution stent Download PDFInfo
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- CN100435756C CN100435756C CNB2005100237145A CN200510023714A CN100435756C CN 100435756 C CN100435756 C CN 100435756C CN B2005100237145 A CNB2005100237145 A CN B2005100237145A CN 200510023714 A CN200510023714 A CN 200510023714A CN 100435756 C CN100435756 C CN 100435756C
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- bracket
- medicament
- arsenic trioxide
- coating
- elution
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Abstract
The present invention relates to a medicament elution bracket for preventing and curing coronary disease, which belongs to the fields of a medicament and a medical appliance. The present invention aims at a cell apoptosis mechanism to select a coating medicament for the medicament elution bracket. The arsenic trioxide of the effective component of traditional Chinese medicine of arsenic (Arsenicum) is adopted as a bracket medicament. The apoptosis of smooth muscle cells in a second stage after a blood vessel is damaged is induced by the controlled release of the composite coating of polymethacrylic acid butyl ester/nanometer silicon dioxide and double PLGA coatings. The functions of different dosages of arsenic trioxide to endometrial hyperplasia after a bracket operation of a dog by controlling the medicament elution bracket are measured by pharmacokinetics in vitro and are tested by animal experiments. A result proves that the double-coating controlled release of the present invention can cause a medicament to start to be released within several hours after the medicament is implanted from the bracket and to act for a long time. Compared with the organic crosslinking agent of the prior art, the nanometer silicon dioxide in the composite coating in the bracket is safe and nontoxic to use. The controlled release elution bracket of the arsenic trioxide has the therapeutic effect of preventing and curing restenosis after the bracket operation, and has high safety.
Description
Technical field
The invention belongs to medicine and medical instruments field, relate to a kind of bracket for eluting medicament that coronary stent is implanted the back restenosis of preventing and treating, be specifically related to a kind of arsenic trioxide control release elution stent.
Background technology
One of the main difficult problem in the cardiology of arteria coronaria intervention at present field is a restenosis behind the Stent, and great deal of research results shows that systemic administration can not obtain satisfied effect.With the support is delivery vector, makes medicine have advantages such as local drug concentration height, systemic side effects are little at the bracket for eluting medicament of impaired coronary artery local action, is expected to become the effective way that solves post stent implantation restenosis.The propagation of vascular smooth muscle cell (SMC) and migration are the main causes that causes vascellum endometrial hyperplasia, causes restenosis, and the selection great majority of medicine are to suppress SMC propagation and migration, as paclitaxel and rapamycin FirebirdTM at present.But, keeping relative balance between normal vascular SMC propagation and the apoptosis, the degree of cell proliferation surpasses apoptosis will cause neointimal hyperplasia.Studies confirm that the SMC apoptosis that blood vessel injury causes mainly appears at two stages, the phase I is that this process may stimulate the SMC hypertrophy in the several hrs of damage back, helps new intima and forms; In several days to several months, apoptotic relative deficiency of this phase may be the major reason that restenosis forms after second stage appeared at and damages, so regulate the New Policy that apoptosis can be used as the treatment restenosis.
Arsenicum is the white crystals that the Chinese medicine arsenicum sablimatum gets through distillation, and chemical constituent is arsenic trioxide (As
2O
3), though toxic, toxic and side effects was also low when clinical using dosage was low.China is used for the treatment of the significant curative effect of acute promyelocytic leukemia the earliest and is generally acknowledged by the many scholars in the world.Now be widely used in lymphoma clinically, leukemia, hepatocarcinoma, gastric cancer and other tumor.Result of study shows that the mechanism of action of its treatment tumor is obvious inducing tumor cell generation apoptosis.Preliminary study shows, at external As
2O
3Can be by induction of vascular SMC apoptotic effect to reduce SMC quantity; Peritoneal injection As
2O
3, can and raise bax mechanism cell death inducing, the restenosis that control rabbit injury of carotid artery causes by downward modulation bcl-2.But whether can be used for in-stent restenosis, prevent that the new intima hypertrophy from not appearing in the newspapers as yet.In view of As
2O
3Whole body administration toxicity is very big, is carrier with the support, according to vascular SMC hypertrophy and apoptosis rule, and research As
2O
3Bracket for controlling releasing and elution prevents that the support postoperative restenosis from being to get involved the clinical exigence of heart disease.
Summary of the invention
The purpose of this invention is to provide a kind of bracket for eluting medicament that coronary artery bracket is implanted the back restenosis of preventing and treating, be specifically related to a kind of arsenic trioxide control release elution stent.
Technical scheme of the present invention is: design As
2O
3The sustained release coating is implanted the back at support and was discharged medicine and localized sustained effect in several hours, induces the SMC apoptosis, prevents restenosis.
It is support that drug stent of the present invention adopts stainless steel material, and medicine is As
2O
3Powder or solution (commercially available), controlled releasing coating divides two-layer, and internal layer is polybutyl methacrylate/nanometer silicon dioxide composite material, wherein every mm
2Support contains As
2O
31.6-3.2 μ g.Skin is polymer (PLGA) coating of degradable polylactic acid and glycolic, and two coating layer thicknesses are 10-25 μ m.
The present invention is directed to Apoptosis Mechanism and select the bracket coating medicine, adopt Chinese medicine arsenicum sablimatum effective constituents A s
2O
3As stent drug, utilize the two coating sustained release of polybutyl methacrylate/nano silicon composite coating and PLGA, the SMC apoptosis of induction of vascular damage back second stage is measured and zoopery test various dose As through external pharmacokinetics
2O
3Bracket for controlling releasing and elution to the dog stenting after the effect of neointimal hyperplasia, the result confirms, the two coating sustained release of the present invention can make medicine implant back beginning in several hours and long-term release from support, cell death inducing suppresses neointimal hyperplasia, prevents restenosis.
This As
2O
3The advantage of sustained release coating bracket is after support is implanted, in the SMC apoptosis phase I that blood vessel injury causes mainly is the degraded of PLGA external coating, the medicine of internal layer is inoperative, and therefore do not induce to transfer and die, after support is implanted several hours, be second stage, the external coating degraded is finished, undercoating exposes, and medicine begins by polybutyl methacrylate/nano silicon sustained release, the effect of performance cell death inducing, suppress neointimal hyperplasia, prevent restenosis.Nano silicon is more safer, nontoxic than using the said organic crosslinking agent of prior art in this support undercoating.This As
2O
3Bracket for controlling releasing and elution has the curative effect of control support postoperative restenosis and safe.
Description of drawings
Fig. 1 is that 4w damage arteria coronaria histopathology variation (HE * 14) inner membrance obviously thickened after the coating pack support was implanted.
Fig. 2 is 1.6 μ g/mm
2As
2O
3Bracket for controlling releasing and elution is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner film thickness and is reduced than the coating group.
Fig. 3 is 2.4 μ g/mm
2As
2O
3Bracket for controlling releasing and elution is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner film thickness and is significantly reduced than the coating group.
Fig. 4 is 3.2 μ g/mm
2As
2O
3Bracket for controlling releasing and elution is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner film thickness and is significantly reduced than the coating group.
The specific embodiment
Embodiment 1
Preparation As
2O
3Bracket for controlling releasing and elution
Adopt compound sustained release material of polybutyl methacrylate/silicon dioxide (nanometer) and medicament mixed to be applied to the surface of stainless steel stent, the two coatings of described polybutyl methacrylate/nanometer silicon dioxide composite material coating and PLGA are medicine sustained release coating.At first prepare the tetrahydrofuran solution of 1% polybutyl methacrylate, wherein contain the nano silicon of amount of polymers 25-30%, as the sustained release coating, with As
2O
3Powder adds 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, as undercoating, accurately to weigh, the medicament contg that makes every square millimeter of rack surface is 1.6-3.2 μ g.The chloroformic solution of the PLGA of configuration 1% is sprayed at outer surface equably, and 40 ℃ of oven dry are as external coating.Two coating layer thicknesses are 10-25 μ m.Support is compressed on the sacculus, the plastic bag encapsulation, the ethylene oxide sterilizing sterilization is standby, makes 1.6 μ g/mm
2, 2.4 μ g/mm
2, 3.2 μ g/mm
2The As of three kinds of concentration
2O
3Bracket for controlling releasing and elution.The preparation of simple coating bracket is not except adding the medicine, and all the other processes are identical with bracket for eluting medicament.
External pharmacokinetics is measured:
To above-mentioned As
2O
3The external sustained release test that bracket for controlling releasing and elution carries out, the result shows: medicine does not almost discharge in initial 3 hours, discharge rapidly then, arrive the peak during 1 week, rate of release eases up gradually afterwards, after 3 months, still have the medicine that surpasses half not discharge, the two coatings of polybutyl methacrylate/nano silicon are than significantly slowing down the release time of simple polymer of the same race, if adjust the ratio of medicine and coating, and the ratio of polybutyl methacrylate/nano silicon can obviously be adjusted the shape of release profiles in the coating, shows that the nano silicon in the composite coating has the effect that prolongs release time.
To above-mentioned As
2O
3Bracket for controlling releasing and elution carries out zoopery,
Healthy hybrid adult dogs is divided into 4 groups at random: coating bracket group, 1.6 μ g/mm
2, 2.4 μ g/mm
2, 3.2 μ g/mm
2As
2O
3The As of three kinds of dosage
2O
3Each 12 of bracket for controlling releasing and elution groups, in the ratio of stent diameter, arteria coronaria diameter 1.2～1.3: 1 support being implanted circling round of experimental dog at random props up and the suitable vessel segment of anterior descending branch, art began to take aspirin 250mg in preceding 1 day, put to death until 30 days, each group is got support and is implanted the section blood vessel, 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 detects α-smooth muscle actin (α-SM actin) and expresses and the image semi-quantitative analysis, the analysis of TUNEL method combining image, low cytometric analysis, transmission electron microscope observing and detection apoptosis.
The result shows:
(1) coating bracket and AS
2O
3After bracket for controlling releasing and elution is implanted the dog arteria coronaria, 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 no pathologic infringement of tissue such as the heart, liver, spleen, lung, kidney, brain shows coating bracket and AS
2O
3Bracket for controlling releasing and elution has the favorable tissue compatibility and safety;
(2) support is implanted back 4w, and the bracket for eluting medicament group of 3 kinds of dose concentrations obviously reduces than coating group new intima degree, and tube chamber enlarges markedly.
(3) transmission electron microscope morphologic detection result shows that the bracket for eluting medicament group apoptotic cell quantity of 3 kinds of dosage is obviously more than all the other each groups.
The flow cytometer quantitative analysis results shows that the bracket for eluting medicament group percentage of cell apoptosis of 3 kinds of dosage is significantly higher than the coating group, with 2.4 μ g/mm
2, 3.2 μ g/mm
2The group effect is obvious.
The bracket for eluting medicament group apoptotic index of 3 kinds of dosage is significantly higher than the coating group, with 2.4 μ g/mm
2, 3.2 μ g/mm
2The group effect is obvious.
(4) SABC method detection of drugs FirebirdTM is to the influence of dog arteria coronaria α-SM actin, and the result shows that the bracket for eluting medicament group positive expression of 3 kinds of dosage significantly is less than the coating group, with 2.4 μ g/mm
2, 3.2 μ g/mm
2The group effect is obvious.
Experiment confirm, controlled releasing coating support of the present invention has following advantage: 1. formation interpenetrating networks or inorganic particulate 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. the existence of silicon dioxide provides and the stainless steel base good bonding force, outer PLGA implants back degraded after several hours at support, can guarantee that medicine can not discharge in several hours of initial stage, drug release is afterwards controlled by internally coated polybutyl methacrylate/silicon dioxide (nanometer);
4. the compound controlled releasing coating support of polybutyl methacrylate/silicon dioxide (nanometer)-PLGA has excellent biological compatibility; 5. the compound controlled releasing coating support of polybutyl methacrylate/silicon dioxide (nanometer)-PLGA is implanted dog coronary artery safety, feasible; 6; As
2O
3The compound controlled releasing coating support of polybutyl methacrylate/silicon dioxide (nanometer)-PLGA can effectively be prevented and treated restenosis in the dog coronary artery bracket; 7.As
2O
3The compound controlled releasing coating support of polybutyl methacrylate/silicon dioxide (nanometer)-PLGA is one of its feature by the SMC apoptosis control in-stent restenosis of inducing damage back second stage.
Claims (5)
1, a kind of arsenic trioxide control release elution stent, it is characterized in that adopting stainless steel material is support, controlled releasing coating divides two-layer, internal layer is polybutyl methacrylate/nanometer silicon dioxide composite material, wherein every square millimeter of rack surface medicament contg is 1.6-3.2 μ g, skin is the polymer coating of degradable polylactic acid and glycolic, and two coating layer thicknesses are 10-25 μ m, and described medicine is an arsenic trioxide.
2, by the described arsenic trioxide control release elution stent of claim 1, the weight ratio that it is characterized in that described medicine arsenic trioxide and polybutyl methacrylate is 1: 1.
3, by the described arsenic trioxide control release elution stent of claim 1, it is characterized in that every square millimeter of rack surface medicament contg is 1.6 micrograms.
4, by the described arsenic trioxide control release elution stent of claim 1, it is characterized in that every square millimeter of rack surface medicament contg is 2.4 micrograms.
5, by the described arsenic trioxide control release elution stent of claim 1, it is characterized in that every square millimeter of rack surface medicament contg is 3.2 micrograms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100237145A CN100435756C (en) | 2005-01-31 | 2005-01-31 | Arsenic trioxide control release elution stent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100237145A CN100435756C (en) | 2005-01-31 | 2005-01-31 | Arsenic trioxide control release elution stent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1657023A CN1657023A (en) | 2005-08-24 |
| CN100435756C true CN100435756C (en) | 2008-11-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100237145A Expired - Fee Related CN100435756C (en) | 2005-01-31 | 2005-01-31 | Arsenic trioxide control release elution stent |
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| CN (1) | CN100435756C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3639830A4 (en) * | 2017-08-08 | 2021-03-24 | Xinxin Medical Technology (Shanghai) Co. Ltd | Composite anti-restenosis drug for coronary drug-eluting stent, and controlled release system thereof |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360094C (en) * | 2005-10-21 | 2008-01-09 | 哈尔滨工程大学 | Blood stent covered with arsenic oxide(s) film and preparing method thereof |
| CN100464789C (en) * | 2005-12-22 | 2009-03-04 | 上海交通大学 | Digestive tract stent with anti-cancer medicinal particles |
| CN1799650B (en) * | 2005-12-30 | 2010-07-14 | 李文涛 | Method for preparing biodegradable drug-carried high molecular material stent |
| 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 |
| CN101161300B (en) * | 2007-11-27 | 2011-03-16 | 北京美中双和医疗器械有限公司 | Arsenic trioxide medicament elution bracket and its preparation method |
| CN106063751A (en) * | 2016-05-20 | 2016-11-02 | 陈鹏 | A kind of Multifunctional intelligent bed |
| CN116099058A (en) * | 2022-10-26 | 2023-05-12 | 北京美中双和医疗器械股份有限公司 | Medicine coating and preparation method thereof |
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|---|---|---|---|---|
| CN1391886A (en) * | 2002-08-01 | 2003-01-22 | 复旦大学 | Medicine releasing control method for implanting type medical equipment |
| CN2561433Y (en) * | 2002-08-07 | 2003-07-23 | 杨巍 | Blood vessel stent with medicinal coating |
| 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 |
| WO2004087234A1 (en) * | 2003-04-04 | 2004-10-14 | Bayco Tech Limited | Vascular stent |
| CN1557507A (en) * | 2004-01-16 | 2004-12-29 | 东南大学 | Re-stricture preventing medicinal sustained releasing bracket and its preparation |
-
2005
- 2005-01-31 CN CNB2005100237145A patent/CN100435756C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391886A (en) * | 2002-08-01 | 2003-01-22 | 复旦大学 | Medicine releasing control method for implanting type medical equipment |
| CN2561433Y (en) * | 2002-08-07 | 2003-07-23 | 杨巍 | Blood vessel stent with medicinal coating |
| 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 |
| WO2004087234A1 (en) * | 2003-04-04 | 2004-10-14 | Bayco Tech Limited | Vascular stent |
| CN1557507A (en) * | 2004-01-16 | 2004-12-29 | 东南大学 | Re-stricture preventing medicinal sustained releasing bracket and its preparation |
Non-Patent Citations (2)
| Title |
|---|
| 医用生物降解材料－聚乳酸及其共聚物. 胡培战，吴兰亭，杨士林.生物医学工程学杂志，第10卷第2期. 1993 |
| 医用生物降解材料－聚乳酸及其共聚物. 胡培战，吴兰亭，杨士林.生物医学工程学杂志，第10卷第2期. 1993 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3639830A4 (en) * | 2017-08-08 | 2021-03-24 | Xinxin Medical Technology (Shanghai) Co. Ltd | Composite anti-restenosis drug for coronary drug-eluting stent, and controlled release system thereof |
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| Publication number | Publication date |
|---|---|
| CN1657023A (en) | 2005-08-24 |
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