CN101641059B - Intracoronary stent with asymmetric drug releasing controlled coating - Google Patents
Intracoronary stent with asymmetric drug releasing controlled coating Download PDFInfo
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Abstract
An intracoronary stent with an asymmetric drug releasing controlled coating includes a naked stent and a coating consisting of a drug and a carrier. The coating is coated over the surface of the outer wall of the naked stent. The coating is divided into several layers, and the concentrations in the coating increase from the outer layer to the inner layer stepwise.
Description
Technical field:
The present invention relates to medical instruments field, but be specifically related to used a kind of support in the coronary heart disease interventional therapy with asymmetric medication coat and controlled release drug coating.
Background technology:
Coronary heart disease is the principal disease that threatens human health, and global number in 2005 surpasses 2,400,000 people and accepts heart intervention treating.China is the district occurred frequently of global coronary heart disease, and annual coronary disease patient surpasses 1,000,000 examples, but accepts about 100,000 examples of patient of interventional therapy owing to the reason China of economy and technology.Coating stent of medicine is reduced to 5～10% with long-term restenosis rate by 20～50%, becomes the revolutionary therapeutic advance of modern medicine, and the utilization rate of coating stent of medicine surpasses 80% of interventional therapy.Disclose a kind of coronary artery skeleton medicinal coating of preventing restenosis of blood vessel as Chinese patent ZL 02100011.5, applied processing on the coronary artery bracket surface with spraying process or infusion process after drug taxol is added the pharmaceutical carrier solution that aliphatic poly lactone and copolymer thereof form.This support that has medication coat provides a kind of simple and feasible solution for preventing vascular restenosis.But JIUYUE in 2006 2～6 days has reported but that in world heart disease association (WCC) that Barcelona, ESP is held and ESC (ESC) meeting block incidence rate the late period of coating stent of medicine is a little more than bare bracket, and this statistical result makes coating stent of medicine run into new challenge again.Therefore, for satisfying the requirements at the higher level of early stage restenosis of clinical solution and late period infraction, must further consider: 1, the release dosage of medicine and time need to regulate control according to clinical needs; 2, the bracket coating as pharmaceutical carrier can disappear as early as possible after drug release finishes; 3, adopt the medicine of high-drug-effect, be beneficial to reduce the thickness of amount of drug and coating; 4, the medication coat of support should not influence the reparation of blood vessel endothelium, in case the formation of tampon.
Summary of the invention:
The object of the present invention is to provide a kind of asymmetric drug releasing controlled coating intracoronary stent that satisfies clinical requirements at the higher level with and processing method.
Asymmetric drug releasing controlled coating intracoronary stent provided by the invention, comprise bare bracket and the coating of forming by medicine and carrier, described coating is coated in described bare bracket outer wall surface, and described coating is multilamellar, and coating Chinese medicine concentration increases from the skin to the internal layer successively.
In the described support, carrier is that molecular weight is (lactide-Acetic acid, hydroxy-, bimol. cyclic ester) random copolymer of 5～200,000 in the described coating, and wherein the content of polylactide is 25～80mol%.
In the described support, described coating Chinese medicine is one or more in paclitaxel, rapamycin, heparin and the Docetaxel.
In the described support, described coating Chinese medicine is one or more combination in Docetaxel or Docetaxel and paclitaxel, rapamycin and the heparin.
In the described support, described coating internal layer Chinese medicine concentration is 1～50%, and outer Chinese medicine concentration is 0～50%.
In the described support, strengthen gradually to internal layer active medicine concentration from skin in the described coating.
In the described support, described rack body material is the metal rack that rustless steel, Ni-Ti alloy or surface are coated with titanium.
In the described support, the medicine in the described different coating can be identical or different.
The present invention also provides a kind of processing method of asymmetric drug releasing controlled coating intracoronary stent, is the coating that contains medicine and carrier at described bare bracket outer wall surface coated with multiple layer.
Described method concrete steps are: pharmaceutical carrier is dissolved in solvent evenly, add medicine after being divided into many parts respectively, the stirring and dissolving after-filtration, again the layering of different pharmaceutical solution is coated in described support outer wall surface, solvent flashing in air, room temperature desolventizing 48 hours under vacuum then, ethane via epoxyethane sterilization again.
In the described method, described solvent is oxolane, acetone, dichloromethane or chloroform.Adopt above design, the asymmetric medication coat structure of support of the present invention helps the growth of endotheliocyte and the reparation of blood vessel endothelium; Pharmaceutical carrier constantly is degraded in drug release process and absorbs, rapidly disappears after drug release is intact, can avoid the bracket coating middle and advanced stage to the caused stimulation of blood vessel; Adopt the medicine of high-drug-effect, can reduce the thickness of amount of drug and coating, with of the stimulation of minimizing initial stage to blood vessel; Adopt the medication coat technology of bilayer or multilamellar and different rate of releasing drug coatings, to regulate the release dosage and the time of control medicine.
The specific embodiment:
Comprehensive, asymmetric drug releasing controlled coating intracoronary stent provided by the present invention comprises bare bracket, medicine and pharmaceutical carrier three parts, and medicine and pharmaceutical carrier are fitted in the coating that is formed for being coated on bare bracket together.For satisfying the requirements at the higher level that propose in the clinical practice, the present invention is with regard to the employed ingredient of medication coat and medicament contg, concentration, carrier component and content, and the coating method of coating is furtherd investigate.Among the present invention, with regard to medication coat, wherein:
Ingredient:
Reported that the medicine that can be used for bracket coating has paclitaxel (as patent CN02100011.5), rapamycin, heparin etc., these medicines itself all can suppress the restenosis of blood vessel; But after existing these medicines combined with carrier material in the coating and coat support, amount of drug and release time and speed can't meet clinical needs fully.Therefore, the present invention needs further its occupation mode of research when using these known drugs, comprise the selection of carrier material and the coating form of medication coat, to satisfy higher clinical needs;
On the other hand, the present invention also adopts new bracket coating medicine Docetaxel, it is semisynthetic paclitaxel derivant, can accelerate tubulin polymerization become the speed of microtubule and delay microtubule depolymerisation, cause forming the microtubule fasolculus of stable non-functional, thereby destroy mitosis and cell proliferation.Docetaxel is used for bracket coating, has that consumption is little, the tangible characteristics of curative effect.Thus, both can reduce dosage when adopting Docetaxel, also can reduce the consumption of carrier, side effect is reduced greatly.Use Docetaxel drug concentrations can be at 0.01～1 μ g/mm in the stent drug coating
2In the scope.
Also have, the present invention has also studied share of Docetaxel and other known drugs in conjunction with the coating method of coating, has also obtained good test effect.
Pharmaceutical carrier:
1, the material as carrier should be the macromolecular material that can comparatively fast disappear after drug release is intact; 2, carrier material is answered good biocompatibility, little to the stimulation of blood vessel; 3, carrier material should have control action to the release time and the rate of release of medicine; 4, the catabolite of pharmaceutical carrier reply human body has no side effect.
The pharmaceutical carrier of bracket coating of the present invention is selected the biodegradable fatty polylactone.Because polylactide (PLA), poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA), polycaprolactone (PCL) all are to have gone through can be used for intravital biodegradated polymer materal, they are nontoxic, have excellent biological compatibility and physicochemical property; Can carry out copolymerization, regulate degradation speed, the physicochemical property of copolymer, thereby control release rate of drugs by component, composition, molecular weight and the molecular weight distribution etc. of regulating copolymer.
According to clinical research, support is implanted back 7 hours～1 week and 2,3 months～6 months was the high-incidence season that the early stage restenosis of blood vessel takes place, medicine in the bracket coating is released near this period the time, and the release of medicine is directly related with the composition of carrier material.The present invention is according to the influence to drug release of the physicochemical property of different aliphatic poly lactones and degradation rate, selecting to use molecular weight is that (Acetic acid, hydroxy-, bimol. cyclic ester one lactide) random copolymer (PLGA) of 5～200,000 is carrier material, and wherein the content of lactide is 25～80mol%.
The coating method of coating:
The present invention is configured to medication coat solution with medicine and drug carrier material, is worked into the outer wall surface of support then with spraying process or cladding process.
Among the present invention, what adopt is asymmetric coating way, the rack inner wall that is characterized in the support outer wall that contacts with blood vessel wall to have coating and contacts with blood does not have coating, thereby can reach the minimizing medicine endotheliocyte is suppressed, helps the regenerated purpose of blood vessel endothelium.
The another important feature of coated designs of the present invention is, adopts the mode of bilayer or multiple coating, by drug level, the medicament categories that changes each coating, and in conjunction with the kind and the performance of carrier material, reaches the purpose to pharmaceutical release time and rate of release control.
Specifically: the outermost layer coating Chinese medicine concentration of multiple coating is lower or do not contain medicine, to postpone and to reduce the release of medicine; And internal layer coating Chinese medicine concentration is higher, makes after the outer coating Chinese medicine discharges substantially, carrier material has been degraded, and the medicine in the internal layer coating can discharge in a large number.By to different coating Chinese medicine concentration, coating layer thickness, and the regulation and control of carrier material kind and performance, but reach coating Chinese medicine controlled release of the present invention, pharmaceutically active scalable, to satisfy the clinical requirement that prevents vascular restenosis.
The concrete coating in the operation, the present invention all adopts the technology of primary coating high-activity drug thin layer to each coating, can satisfy like this and reduce coated carrier to the stimulation of blood vessel, reduce the carrier use amount as far as possible, reaches the purpose that prevents early stage vascular restenosis.
Below will further describe technology contents of the present invention with specific embodiment.
Embodiment 1:
(2.10g glycolide-lactide copolymer) random copolymer (PLGA, molecular weight 100,000, after lactide/glycolides=70/30 (mol%) is dissolved in 0.5L acetone, getting wherein, 2/3rds solution add the 0.46g Docetaxel, after adding the 0.12g Docetaxel in 1/3rd solution in addition, after stirring, dissolve all even filtration respectively, form a solution and No. two solution;
A solution spraying is once arrived 316L (3.0 * 20mm) stainless steel stent outer wall surface, solvent flashing in air; Then again with No. two solution sprayings in the support outer wall surface, in air behind the solvent flashing again under vacuum condition in room temperature desolventizing 48 hours, form the support of this routine band coating.
This example support uses 180 μ g carrier materials, and Docetaxel content is 10 μ g in the outer coating; Docetaxel content is 40 μ g in the internal layer coating.
Embodiment 2:
The support of the method preparation band medication coat identical with embodiment 1, wherein, used 137 μ g carrier materials (PLGA, molecular weight 120,000, lactide/glycolides=60/40 (mol/mol), Docetaxel content is 8 μ g in the outer coating; Docetaxel content is 30 μ g in the internal layer coating.
Embodiment 3:
The support of the method preparation band medication coat identical with embodiment 1, wherein, (lactide/glycolides=80/20mol%), Docetaxel content is 15 μ g in the outer coating for PLGA, molecular weight 50,000 to have used 193 μ g carrier materials; Docetaxel content is 45 μ g in the internal layer coating.
Embodiment 4:
The support of the method preparation band medication coat identical with embodiment 1, wherein, (polylactide/poly-Acetic acid, hydroxy-, bimol. cyclic ester=50/50 (mol/mol) uses taxol drug in the outer coating for PLGA, molecular weight 200,000, and content is 25 μ g to have used 234 μ g carrier materials; Docetaxel content is 40 μ g in the internal layer coating.
Embodiment 5:
The support of the method preparation band medication coat identical with embodiment 1 wherein, has used 283 μ g carrier material (PLGA, molecular weight 80,000, lactide/glycolides=75/25 (mol%), coating is divided into three layers, use Docetaxel in the outer coating, content is 15 μ g; Use medicine to be rapamycin in the coating of intermediate layer, content is 50 μ g; Docetaxel content is 20 μ g in the internal layer coating.
Embodiment 6:
The support of the method preparation band medication coat identical with embodiment 1 wherein, has used 212 μ g carrier material (PLGA, molecular weight 200,000, lactide/glycolides=25/75mol%, coating is divided into two-layer, use taxol drug in the outer coating, content is 25 μ g; Content of taxol is 85 μ g in the internal layer coating.
Embodiment 7:
The support of the method preparation band medication coat identical with embodiment 1, but outer coating is the PLGA (lactide/glycolides=50/50mol%, molecular weight 150,000) of not pastille; The intermediate layer is the PLGA (lactide/glycolides=70/30mol%, molecular weight 100,000) that contains Docetaxel 55 μ g; Internal layer is the PLGA (lactide/glycolides=80/20mol%, molecular weight 200,000) that contains paclitaxel 25 μ g.
Embodiment 8:
(2.10g glycolide-lactide copolymer) random copolymer (PLGA, molecular weight 100,000, after lactide/glycolides=70/30 (mol%) is dissolved in 0.5L acetone, getting wherein, 2/3rds solution add the 0.46g paclitaxel, after adding the 0.12g paclitaxel in 1/3rd solution in addition, after stirring, dissolve all even filtration respectively, form a solution and No. two solution;
A solution spraying is once arrived 316L (3.0 * 20mm) stainless steel stent outer wall surface, solvent flashing in air; Then again with No. two solution sprayings in the support outer wall surface, in air behind the solvent flashing again under vacuum condition in room temperature desolventizing 48 hours, form the support of this routine band coating.
Used 393 μ g carrier materials (PLGA, molecular weight 100,000, lactide/glycolides=70/30 (mol%), using the paclitaxel amount in the outer coating is 31 μ g; Content of taxol is 70 μ g in the internal layer coating.
Compliance test result:
1, support is implanted: laboratory animal is miniature pig, and is male, body weight 20～30kg.Operational approach and human body operation process are in full accord.Row femoral artery otomy behind the general anesthesia, insert the 7Fr catheter sheath in the femoral artery, send into the guide wire branch ostium place of circling round to a left side along femoral artery, sending into seal wire enters a left side and circles round, to be loaded on the foley's tube behind the support of each embodiment preparation among the present invention and the crt bracket ethane via epoxyethane sterilization, send into a stage casing of circling round, a left side along seal wire.Crt bracket is the support (carrier material PLGA, lactide/glycolides=50/50 (mol/mol) 2500 μ g, content of taxol 50 μ g) of embodiment one preparation among the patent ZL 02100011.5.
2, minimum cavity footpath
Support implant 4 weeks of back, 8 weeks and 12 Wednesdays a time point respectively to each group test pig implant frame position enforcement radiography.Concrete operations: partly sterilised, cut to expose femoral artery, insert the arterial sheath disconnected conduit of pulse-taking of coming of age, to coronary ostium, directly be recorded as the minimum cavity footpath through aorta at DSA machine descending coronary artery radiography and the lumen of vessels of measuring stenosis.
3, drug release rate
Detect sampling: after support being put into the buffer of 5ml pH7.2, under 37 ℃, carry out drug release test.At each time point taking-up support of 1 week, 2 weeks, 4 weeks and 12 weeks, contain 10 milliliters of color comparison tubes of 40% methanol with putting into behind the distilled water flushing, concussion (120 times/minute) lixiviate 5 minutes.With high-performance liquid chromatogram determination solution Chinese medicine content, as residual drug.Be calculated as follows:
Drug release rate=(coating dose-residual drug)/coating dose
4, depolymerization weight-loss ratio
With weighing after the drying is M
0Bare bracket coat the not polymer solution of pastille, treat that weighing is M after solvent evaporates and the constant weight
1, support is put into the buffer of 5ml pH7.2 after, the test of under 37 ℃, degrading.4 weeks, 8 the week and 12 Wednesdays a time point, the taking-up support, with distilled water flushing and after being dried to constant weight, weighing is M again
2
Polymer weight-loss ratio (%)=(M
1-M
2)/(M
1-M
0) * 100
5. the average neointimal hyperplasia area of blood vessel
Implant 4 weeks of back, 8 weeks and put to death animal behind the time point radiography 12 Wednesdays at support, get the coronary artery of holder part, do sclerous tissues's embedding pathological section after the formalin fixed, carry out computer image analysis under the common light microscopic, calculate the average neointimal hyperplasia area of blood vessel.
The result is referring to table 1 in checking:
Can see from above confirmatory experiment result:
Compare with crt bracket, the drug release of the support that the embodiment of the invention provides is to discharge the peak first time in the 1st～2 week, forms in the 2nd～4 week to discharge the peak for the second time, and the 4th all medicines afterwards will steadily discharge; Can see by design of the present invention with this, can effectively regulate and control the deenergized period of stent drug, match with clinical needs.
Data to example 1 and example 8 compare, can also see, use Docetaxel can reduce the drug dose and the carrier consumption of support, use taxol drug, minimum cavity directly becomes big and average neointimal hyperplasia area reduction, illustrating that the Docetaxel coating stent of medicine is little to blood vessel irritation, is than the more efficiently stent drug of paclitaxel.
Can also recognize that the present invention is by the number of plies of coating and every layer the different burst sizes that can regulate medicine with consumption of medicament categories, to meet clinical requirement.Support as example 7, it applies three layers of coating, be under zero the situation at outer drug level, can effectively control the release at medicine initial stage, the intermediate layer adds the effective medicine Docetaxel of high concentration, its drug release was peaked in the 2nd week, and the taxol drug of internal layer is peak release when the 4th week then, then steadily discharges.
Comprehensive, medicine can controlled release after support of the present invention was implanted, the carrier absorption of can degrading well, minimum cavity footpath and the average endometrial hyperplasia area data of blood vessel show that also support of the present invention can prevent better that ISR and advanced thrombus from forming, and safe and effectively can satisfy clinical requirement. The support of band medication coat of the present invention has following outstanding advantage:
1, adopts asymmetric coating, make the easy Regeneration and Repair of blood vessel endothelium;
2, adopt multiple coating, and each layer drug concentration difference, it is controlled that medicine is discharged, to satisfy clinical requirement.
3, once finish the coating of coating, and coating is thin, can reduces the use amount of carrier, and alleviate carrier material to the excitant of vascular tissue;
4, adopt the much higher alkene taxol of curative effect, can reduce drug dose, reduce coating layer thickness, to reduce side effect;
5, pharmaceutical carrier is Biodegradable material, can adjust degradation cycle and the drug release rate of carrier material by regulating ratio of components and the molecular weight of carrier copolymer, thus the release that control coating Chinese traditional medicine discharges.
Industrial applicability:
The support of band medication coat of the present invention is further developing on existing coating technology:
1, uses efficient medicine, particularly used Docetaxel, made coating the thinnest, alleviated the stimulation to blood vessel;
2, employed carrier material is that approved can be used for the biodegradation material in the body, can be after medicine discharges rapidly complete obiteration in the body;
3, by changing the coating method of coating, clinical requirement to medicine controlled releasing is satisfied in the release of regulating medicine;
4, adopt asymmetric coating technology, be conducive to the Regeneration and Repair of blood vessel endothelium;
5, can effectively prevent the ISR of hemostatic tube, reduce the possibility that advanced thrombus takes place;
6, be to design comparatively reasonably arteria coronaria coating stent of medicine.
Claims (9)
1. asymmetric drug releasing controlled coating intracoronary stent, comprise bare bracket and the coating of forming by medicine and carrier, it is characterized in that described coating is coated in described bare bracket outer wall surface, and described coating is a multilamellar, and coating Chinese medicine concentration increases from the skin to the internal layer successively;
Carrier is that molecular weight is lactide-Acetic acid, hydroxy-, bimol. cyclic ester random copolymer of 5～200,000 in the described coating, and wherein the content of polylactide is 25～80mol%.
2. according to the described support of claim 1, it is characterized in that described coating Chinese medicine is one or more in paclitaxel, rapamycin, heparin and the Docetaxel.
3. according to the described support of claim 2, it is characterized in that described coating Chinese medicine is one or more combination in Docetaxel and paclitaxel, rapamycin and the heparin.
4. according to the described support of arbitrary aforementioned claim, it is characterized in that in the described coating, internal layer Chinese medicine concentration is 1～50%, outer Chinese medicine concentration is 0～50%.
5. according to the described support of claim 4, it is characterized in that described rack body material is the metal rack that rustless steel, Ni-Ti alloy or surface are coated with titanium.
6. according to claim 2 or 3 described supports, it is characterized in that the medicine in the described different coating can be identical or different.
7. the processing method to the described asymmetric drug releasing controlled coating intracoronary stent of 6 arbitrary claim is characterized in that, is the coating that contains medicine and carrier at described bare bracket outer wall surface coated with multiple layer.
8. according to the described method of claim 7, it is characterized in that, concrete steps are that pharmaceutical carrier is dissolved in solvent evenly, add medicine after being divided into many parts respectively, the stirring and dissolving after-filtration is coated in described support outer wall surface, solvent flashing in air with the layering of different pharmaceutical solution again, room temperature desolventizing 48 hours under vacuum then, ethane via epoxyethane sterilization again.
9. described according to Claim 8 method is characterized in that described solvent is oxolane, acetone, dichloromethane or chloroform.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007800508483A CN101641059B (en) | 2007-02-14 | 2007-02-14 | Intracoronary stent with asymmetric drug releasing controlled coating |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007800508483A CN101641059B (en) | 2007-02-14 | 2007-02-14 | Intracoronary stent with asymmetric drug releasing controlled coating |
| PCT/CN2007/000542 WO2008098418A1 (en) | 2007-02-14 | 2007-02-14 | Intracoronary stent with asymmetric drug releasing controlled coating |
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| Publication Number | Publication Date |
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| CN101641059A CN101641059A (en) | 2010-02-03 |
| CN101641059B true CN101641059B (en) | 2011-10-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020134542A1 (en) * | 2018-12-25 | 2020-07-02 | 先健科技(深圳)有限公司 | Drug eluting device and manufacturing method thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI794616B (en) * | 2019-07-09 | 2023-03-01 | 日商大塚醫療器材股份有限公司 | Drug-eluting stent |
| CN117298358A (en) * | 2023-04-27 | 2023-12-29 | 雅伦生物科技(北京)有限公司 | Drug coating, drug eluting stent containing same and preparation method thereof |
| CN116712619B (en) * | 2023-04-27 | 2024-01-19 | 北京信立泰医疗器械有限公司 | Drug coating for medical devices |
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| US5824048A (en) * | 1993-04-26 | 1998-10-20 | Medtronic, Inc. | Method for delivering a therapeutic substance to a body lumen |
| CN2315919Y (en) * | 1997-03-07 | 1999-04-28 | 吴雄 | Internal supporter for curve esophagus (blood vessel) |
| CN1355005A (en) * | 2001-12-13 | 2002-06-26 | 华东理工大学 | Medicine eluted cardiovascular frame and its preparing process |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5824048A (en) * | 1993-04-26 | 1998-10-20 | Medtronic, Inc. | Method for delivering a therapeutic substance to a body lumen |
| CN2315919Y (en) * | 1997-03-07 | 1999-04-28 | 吴雄 | Internal supporter for curve esophagus (blood vessel) |
| CN1355005A (en) * | 2001-12-13 | 2002-06-26 | 华东理工大学 | Medicine eluted cardiovascular frame and its preparing process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020134542A1 (en) * | 2018-12-25 | 2020-07-02 | 先健科技(深圳)有限公司 | Drug eluting device and manufacturing method thereof |
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