CN102166141B - Process for preparing drug eluting stent - Google Patents
Process for preparing drug eluting stent Download PDFInfo
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- CN102166141B CN102166141B CN2010102454250A CN201010245425A CN102166141B CN 102166141 B CN102166141 B CN 102166141B CN 2010102454250 A CN2010102454250 A CN 2010102454250A CN 201010245425 A CN201010245425 A CN 201010245425A CN 102166141 B CN102166141 B CN 102166141B
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- eluting medicament
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- sacculus
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Abstract
The invention provides a process for preparing a drug eluting stent, which can effectively increase the stability of a drug eluting stent coating. The process for preparing the drug eluting stent comprises the following steps of: (1) pre-treating a naked stent; (2) coating to form a coating; (3) sterilizing by using ethylene oxide; (4) mounting a balloon; (5) pressing and holding the stent; and (6) internally packaging. After the drug eluting stent is pressed and held on the balloon, the adhesion between the balloon and the coating is avoided; and the coating has a complete surface and adherence tightness after the drug eluting stent is expanded by a balloon expander.
Description
Technical field
The present invention relates to a kind of preparation technology of bracket for eluting medicament, particularly a kind of preparation technology with bracket for eluting medicament of stable coatings.
Background technology
Extensive use along with the intracoronary stent implantation, the development of the increase of clinical case number, the prolongation of following up a case by regular visits to the time and intravascular ultrasound technology, in-stent restenosis (ISR) problem just exposes gradually and more and more comes into one's own, and has become the research emphasis that gets involved the cardiology field.In bare metal stent (BMS) epoch, the incidence rate of in-stent restenosis is up to 20%～30%, and main cause is the endothelium hyperplasia that support is inserted the position.The appearance of bracket for eluting medicament (DES) has solved this problem well, it is by inserting the local medicine that discharges at support, reach inflammation-inhibiting, suppress smooth muscle cell proliferation and effects such as migration, minimizing endotheliocyte hyper-proliferative, thereby reduce narrow generation in the support.
Bracket for eluting medicament is that medicine directly or by appropriate carriers is applied to metal support surface, becomes the local delivery system of medicine, and carrier has two kinds of degradable and non-degradable materials.In bracket for eluting medicament, discharge to suppress in-stent restenosis by drug slow.The preparation technology of bracket for eluting medicament comprises the bare bracket pretreatment, and applying coating is installed sacculus, pressure is held support, sterilization, inner packing etc., traditional preparation technology's flow process are generally bare bracket pretreatment → applying coating → installation sacculus → pressure and hold support → inner packing → sterilization.The degradation material coating bracket finds that drug stent carries out ethylene oxide sterilizing after the foley's tube pressure is held in production process, again through the balloon dilatation catheter expansion, find the coating cracking of support inner surface or come off the integrity of destruction coating.
In order to solve the phenomenon that the DES coating ftractures or comes off after the balloon dilatation catheter expansion, CN1533813A (application number is CN03116063.8) discloses a kind of coating stent of medicine of preventing/treating percutaneous transluminal coronary shaping postoperative restenosis, description is described " for to prevent because of the adhesion between medication coat and the sacculus; can be earlier be coated with last layer Parylene (Parylene) or derivatives thereof in the method for rack surface by vapour deposition, its THICKNESS CONTROL is between the 0.01-10 micron ".Adopt the DES product of the method to have at present, as: the Cypher support that Johnson Co. produces, its drug-loaded layer is PEVA/PBMA non-degradable polymer+Parylene; The BioMatrix support that Singapore Biosensors International company produces, its drug-loaded layer is polylactic acid biodegradable polymers+Parylene; The Axxess support that U.S. DEVAX produces, its drug-loaded layer is polylactic acid biodegradable polymers+Parylene; And the Bobori support produced of Japanese TERUMO company, its drug-loaded layer is polylactic acid biodegradable polymers+Parylene, etc.Parylenes etc. are the non-degradable polymer, yet patient's endothelium healing delay is found in increasing clinical research, chronic inflammatory reaction, adherent bad and late period in late period adverse events such as restenosis, may be because the extended residual of DES drug-carrying polymer causes, therefore, the present invention adopts the totally biodegradable polymer to prepare bracket for eluting medicament as drug-loaded layer.
In order to realize not using nondegradable polymer to do bottom, can guarantee to expand through balloon dilatation catheter behind the drug stent ethylene oxide sterilizing, medication coat and sacculus do not stick together yet again, and outward appearance is complete, the adherent purpose closely of coating needs research and development better medicament FirebirdTM preparation technology.
Summary of the invention
The object of the present invention is to provide a kind of preparation technology of bracket for eluting medicament, this technology can effectively improve the stability of bracket for eluting medicament coating.Avoided the bracket for eluting medicament system that uses ethylene oxide sterilizing to cross, again through balloon dilatation catheter expansion, the possibility that medication coat and sacculus stick together easily; After bracket for eluting medicament is placed in the human vas stenosis, the integrity of coating can guarantee the performance of flushing of anti-blood flow that coating is good, thereby avoided because of coating cracking or blood flow wash away fractionlet in the process come off cause inflammatory reaction may, reduce the generation of untoward reaction such as the interior restenosis of blood vessel in late period, avoided the formation of advanced thrombus.
Purpose of the present invention is achieved through the following technical solutions: a kind of preparation technology of bracket for eluting medicament, bracket for eluting medicament is made of bare bracket and the coating that is coated on the support, it is characterized in that: described preparation technology sterilized before pressure is held for bracket for eluting medicament, and described sterilization is ethylene oxide sterilizing.
The preparation technology of said medicine FirebirdTM carried out ethylene oxide sterilizing for bracket for eluting medicament before sacculus is installed.
The preparation technology of said medicine FirebirdTM carries out ethylene oxide sterilizing for bracket for eluting medicament after applying coating.
The preparation technology of said medicine FirebirdTM is (1) bare bracket pretreatment; (2) applying coating; (3) ethylene oxide sterilizing; (4) sacculus is installed; (5) pressure is held support; (6) inner packing.
The preparation technology of said medicine FirebirdTM is (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: coated carrier is dissolved in the solvent, mix homogeneously, evenly be coated on rack surface, then 25 ℃～50 ℃ dryings 12～72 hours, described solvent is a kind of in acetone, chloroform, oxolane, the dichloromethane, and described coating method of coating is infusion process or spraying process; (3) ethylene oxide sterilizing: bracket for eluting medicament after drying, bracket for eluting medicament, foley's tube and packing inside bag carry out ethylene oxide sterilizing; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: support is implemented to press hold operation; (6) inner packing: the sacculus and the bracket for eluting medicament that are in contraction state are packaged in the packing inside bag under aseptic condition.
Above-mentioned solvent is a kind of in acetone, chloroform, oxolane, the dichloromethane.
Above-mentioned coating method of coating is infusion process or spraying process.
Above-mentioned ethylene oxide sterilizing adopts the air bells laid method.
Above-mentioned sterilization is carried out under specific temperature conditions, preferred 25 ℃-50 ℃.
Above-mentioned coated carrier is Biodegradable material, can be Poly-L-lactic acid (PLLA), polylactic-co-glycolic acid (PLGA), poly-dl-lactide (PDLLA), preferred polylactic-co-glycolic acid (PLGA).
The molecular weight of above-mentioned polylactic-co-glycolic acid (PLGA) is 50,000～250,000, is preferably 50,000～100,000.
Molecule lactic acid and the glycolic proportion of composing of above-mentioned polylactic-co-glycolic acid (PLGA) are, lactic acid (LA): glycolic (GA)=50%～90%: 50%～10%, preferred LA: GA=50%～85%: 50%～15%, wherein lactic acid and glycolic molar percentage meter.
Above-mentioned coating is loaded with the medicine of therapeutic dose, comprises in anti-oxidation medicine, anticoagulation class medicine, anticancer class medicine, inhibition vascular smooth muscle cell curing class medicine, anti-inflammatory drug or the immune suppressant drug one or more.
Above-mentioned anti-oxidation medicine comprises superoxide dismutase, catalase, coenzyme Q10, glutathion peroxidase; Anticoagulation class medicine comprises aspirin, heparin, clopidogrel etc.; Anticancer class medicine comprises colchicine, paclitaxel; Suppress vascular smooth muscle cell curing class medicine and comprise angiogenic peptide, 17-hydroxy-11-dehydrocorticosterone, calcium ion antagonist; Anti-inflammatory drug comprises dactinomycin, Depsidomycin, KanglemycinC, Spergualin, Mytiocin, Gllooxin; Immune suppressant drug comprises rapamycin, Ciclosporin A, ciclosporin C, brefeldin A.
Said medicine and coated carrier mass ratio are 1: 10～2: 1, are preferably 1: 3～1: 1.
The material of above-mentioned bare bracket is any one of rustless steel, Ni-Ti alloy, cochrome or macromolecular material.
The sterilization of support has the air sedimentation usually, radiation sterilization and chemical reagent infusion process etc.Bracket for eluting medicament particularly is loaded with the support of biodegradable coating and medicine, adopt radiation sterilization, regular meeting influences medicament contg because the energy height of radiation electric ion destroys medicines structure, high radiant energy destroys the integrity of coating easily because surpassing the vitrification point of polymer simultaneously; The chemical reagent infusion process also can influence the stable and drug release of coating, and can bring certain dissolvent residual; The sterilization of air bells laid method can be carried out under lower temperature conditions, is particularly suitable for heat-labile material is sterilized, and the sterilization of air bells laid method adopts sterilization material to mainly contain formaldehyde and oxirane etc.Therefore, the present invention adopts and adopt the sterilization of air bells laid method, sterilization material optimization ethylene oxide under 25 ℃ of-50 ℃ of temperature conditions.
Biodegradable material polylactic acid-glycollic acid (PLGA) is synthetic by ring opening copolymer by polylactic acid (PLA) and poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA).Polylactic acid (PLA) and poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA) belong to polylactone family macromolecule material together, nontoxic, good biocompatibility, and hydrolysis can take place after meeting water in the ester bond that exists in their molecular backbones, cause molecular backbone fracture, molecular weight to reduce, and the final degradation product, glycolic acid of poly-Acetic acid, hydroxy-, bimol. cyclic ester and polylactide and lactic acid can be become carbon dioxide and water in vivo and excretes by tricarboxylic acid cycle, so these two kinds of polylactone family macromolecule materials all can finally disappear in body owing to the biodegradation of material after implanting fully.Because PLGA has good biological property, the preferred PLGA of the present invention is as pharmaceutical carrier.
The present invention has following advantage and beneficial effect compared to existing technology:
1, compares with the like product that goes on the market, expand through balloon dilatation catheter again behind the drug stent ethylene oxide sterilizing of the present invention, medication coat does not stick together with sacculus, complete appearance, adherent tight, effectively improved coating abrasion resistance energy, thus the possibility of avoiding coating cracking or washing away the fractionlet that comes off in the process at blood flow, reduce the generation of untoward reaction such as the interior restenosis of blood vessel in late period, avoided the formation of advanced thrombus.
2, avoid using nondegradable polymer to do bottom, reduce the incidence rate that increases thrombosis and in-stent restenosis in the later stage support because of untoward reaction such as endothelium healing delay, chronic inflammatory diseases.
3, preparation technology of the present invention has improved the qualification rate of bracket for eluting medicament system, reduces production costs.
Description of drawings
Fig. 1: preparation technology's flow chart of bracket for eluting medicament of the present invention
Fig. 2: the traditional preparation process process chart of bracket for eluting medicament
Fig. 3: the preparation technology's flow chart that adopts the bracket for eluting medicament of the present invention of electron beam sterilization method
Preparation technology's flow chart of the open bracket for eluting medicament of Fig. 4: CN1533813A
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment and accompanying drawing, but the working of an invention mode is not limited thereto.
Embodiment 1: shown in accompanying drawing 1, (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: with lactic acid---ethanol copolymer (PLGA, lactic acid/glycolic=50/50, molecular weight 100000) is dissolved in and makes 2.0wt% solution in the acetone, and drug rapamycin is dissolved in wherein makes 1.0wt% solution, spray to the cochrome rack surface, make drug loading reach requirement (about 40～200 μ g/mm), the dry drug support is 24 hours again; (3) ethylene oxide sterilizing: bracket for eluting medicament, foley's tube and packing inside bag are extremely aseptic 40 ℃ of following ethane via epoxyethane sterilizations; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: press the merosystolic state of sacculus that bracket for eluting medicament is arranged to foley's tube of holding; (6) inner packing: will press the bracket for eluting medicament system of holding to be packaged in the packing inside bag.
Expand by balloon dilatation catheter, the observation coating is apparent under 40 power microscopes, support inner surface and external surface coating complete appearance.
Embodiment 2: shown in accompanying drawing 2, (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: with lactic acid---ethanol copolymer (PLGA, lactic acid/glycolic=50/50, molecular weight 100000) is dissolved in and makes 2.0wt% solution in the acetone, and drug rapamycin is dissolved in wherein makes 1.0wt% solution, spray to the cochrome rack surface, make drug loading reach requirement (about 40～200 μ g/mm), the dry drug support is 24 hours again; (3) sacculus is installed: bracket for eluting medicament is installed on sacculus; (4) pressure is held support: press the merosystolic state of sacculus that bracket for eluting medicament is arranged to foley's tube of holding; (5) inner packing: will press the bracket for eluting medicament system of holding to be packaged in the packing inside bag; (6) ethylene oxide sterilizing: extremely aseptic 40 ℃ of following ethane via epoxyethane sterilization sterilizations.
Expand by balloon dilatation catheter, the observation coating is apparent under 40 power microscopes, and the inner surface of coating bracket has the small size coating to be glued by sacculus, and the coating at the big ripple of support place has cracking.
Embodiment 3: shown in accompanying drawing 3, (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: with lactic acid---ethanol copolymer (PLGA, lactic acid/glycolic=50/50, molecular weight 100000) is dissolved in and makes 2.0wt% solution in the acetone, and drug rapamycin is dissolved in wherein makes 1.0wt% solution, spray to the cochrome rack surface, make drug loading reach requirement (about 40～200 μ g/mm), the dry drug support is 24 hours again; (3) electron beam sterilization: bracket for eluting medicament, foley's tube and packing inside bag are after electron beam sterilization is extremely aseptic; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: press the merosystolic state of sacculus that bracket for eluting medicament is arranged to foley's tube of holding; (6) inner packing: will press the bracket for eluting medicament system of holding to be packaged in the packing inside bag.
Expand by balloon dilatation catheter, the observation coating is apparent under 40 power microscopes, and the inner surface of coating bracket is kept perfectly, and the coating of outer surface and the big ripple of support all has obvious cracking.
Embodiment 4: shown in accompanying drawing 4, (1) bare bracket pretreatment: bare bracket cleans, drying; (2) apply Parylene and make bottom: utilize vapour deposition process, do bottom at cochrome bare bracket surface-coated Parylene; (3) applying coating: with lactic acid---ethanol copolymer (PLGA, lactic acid/glycolic=50/50, molecular weight 100000) is dissolved in and makes 2.0wt% solution in the acetone, and drug rapamycin is dissolved in wherein makes 1.0wt% solution, spray to the cochrome rack surface, make drug loading reach requirement (about 40～200 μ g/mm), the dry drug support is 24 hours again; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: press the merosystolic state of air bag that bracket for eluting medicament is arranged to balloon catheter of holding; (6) inner packing: will press the bracket for eluting medicament system of holding to be packaged in the packing inside bag; (7) ethylene oxide sterilizing: extremely aseptic 40 ℃ of following ethane via epoxyethane sterilizations.
Expand by balloon expandable, the observation coating is apparent under 40 power microscopes, support inner surface and external surface coating complete appearance.
Embodiment 5: shown in accompanying drawing 1, (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: with lactic acid---ethanol copolymer (PLGA, lactic acid/glycolic=85/15, molecular weight 50000) is dissolved in and makes 3.0wt% solution in the chloroform, and drug rapamycin is dissolved in wherein makes 1.0wt% solution, spray to the cochrome rack surface, make drug loading reach requirement (about 40～200 μ g/mm), the dry drug support is 12 hours again; (3) ethylene oxide sterilizing: bracket for eluting medicament, foley's tube and packing inside bag are extremely aseptic 25 ℃ of following ethane via epoxyethane sterilizations; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: press the merosystolic state of sacculus that bracket for eluting medicament is arranged to foley's tube of holding; (6) inner packing: will press the bracket for eluting medicament system of holding to be packaged in the packing inside bag.
Expand by balloon dilatation catheter, the observation coating is apparent under 40 power microscopes, support inner surface and external surface coating complete appearance.
Embodiment 6: shown in accompanying drawing 1, (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: with lactic acid---ethanol copolymer (PLGA, lactic acid/glycolic=75/25, molecular weight 75000) is dissolved in and makes 1.0wt% solution in the oxolane, and drug rapamycin is dissolved in wherein makes 1.0wt% solution, spray to the cochrome rack surface, make drug loading reach requirement (about 40～200 μ g/mm), the dry drug support is 72 hours again; (3) ethylene oxide sterilizing: bracket for eluting medicament, foley's tube and packing inside bag are extremely aseptic 50 ℃ of following ethane via epoxyethane sterilizations; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: press the merosystolic state of sacculus that bracket for eluting medicament is arranged to foley's tube of holding; (6) inner packing: will press the bracket for eluting medicament system of holding to be packaged in the packing inside bag.
Expand by balloon dilatation catheter, the observation coating is apparent under 40 power microscopes, support inner surface and external surface coating complete appearance.
Above-described embodiment is preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (4)
1. the preparation technology of a bracket for eluting medicament, bracket for eluting medicament is made of bare bracket and the coating that is coated on the support, it is characterized in that: described coated carrier is the Biodegradable material polylactic-co-glycolic acid, the molecular weight of polylactic-co-glycolic acid is 50,000～100,000, the lactic acid of described polylactic-co-glycolic acid and glycolic proportion of composing are, lactic acid: glycolic=50%～85%: 50%～15%, wherein lactic acid and glycolic are in molar percentage, above-mentioned coating is loaded with the medicine of therapeutic dose, and the mass ratio of described medicine and coated carrier is 1: 3～1: 1; The preparation technology of described bracket for eluting medicament is (1) bare bracket pretreatment; (2) applying coating; (3) ethylene oxide sterilizing; (4) sacculus is installed; (5) pressure is held support; (6) inner packing.
2. the preparation technology of a kind of bracket for eluting medicament as claimed in claim 1 is characterized in that: described ethylene oxide sterilizing adopts the air bells laid method, and sterilising temp is 25 ℃-50 ℃.
3. the preparation technology of a kind of bracket for eluting medicament as claimed in claim 1, it is characterized in that: the preparation technology of described bracket for eluting medicament is (1) bare bracket pretreatment: bare bracket cleans, drying; (2) applying coating: coated carrier is dissolved in the solvent, mix homogeneously, evenly be coated on rack surface, then 25 ℃～50 ℃ dryings 12～72 hours, described solvent is a kind of in acetone, chloroform, oxolane, the dichloromethane, and described coating method of coating is infusion process or spraying process; (3) ethylene oxide sterilizing: bracket for eluting medicament after drying, bracket for eluting medicament, foley's tube and packing inside bag carry out ethylene oxide sterilizing; (4) sacculus is installed: bracket for eluting medicament is installed on sacculus; (5) pressure is held support: support is implemented to press hold operation; (6) inner packing: the sacculus and the bracket for eluting medicament that are in contraction state are packaged in the packing inside bag under aseptic condition.
4. the preparation technology of a kind of bracket for eluting medicament as claimed in claim 3 is characterized in that: described ethylene oxide sterilizing adopts the air bells laid method, and sterilising temp is 25 ℃-50 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9364588B2 (en) | 2014-02-04 | 2016-06-14 | Abbott Cardiovascular Systems Inc. | Drug delivery scaffold or stent with a novolimus and lactide based coating such that novolimus has a minimum amount of bonding to the coating |
Families Citing this family (8)
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| WO2013043429A1 (en) * | 2011-09-19 | 2013-03-28 | Abbott Cardiovascular Systems Inc. | Cold ethylene oxide sterilization of a biodegradable polymeric stent |
| CN103656701A (en) * | 2012-09-12 | 2014-03-26 | 上海微创医疗器械（集团）有限公司 | Low-temperature sterilizing method suitable for biodegradable scaffold |
| CN103334070B (en) * | 2013-06-24 | 2016-01-13 | 中国科学院金属研究所 | Improve biological medical degradable magnesium alloy angiocarpy bracket use properties method |
| CN104524646A (en) * | 2014-06-03 | 2015-04-22 | 东莞天天向上医疗科技有限公司 | Biodegradable drug eluting stent and manufacturing method thereof |
| CN104083806B (en) * | 2014-06-13 | 2016-04-27 | 江西中医药大学 | A kind of medication coat for bracket for eluting medicament and its preparation method and application |
| CN107811726B (en) * | 2016-09-13 | 2020-09-25 | 先健科技(深圳)有限公司 | Covered stent |
| CN106474507A (en) * | 2016-10-19 | 2017-03-08 | 深圳市信立泰生物医疗工程有限公司 | A kind of sterilization process improving polymer support medication coat stability |
| CN107158483A (en) * | 2017-07-12 | 2017-09-15 | 上海微特生物技术有限公司 | A kind of sterile working method for improving biodegradable stent systematic function |
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| CN101711710A (en) * | 2009-11-25 | 2010-05-26 | 深圳市信立泰生物医疗工程有限公司 | Medicament eluting stent and preparation method thereof |
| CN101745153A (en) * | 2010-01-21 | 2010-06-23 | 万瑞飞鸿(北京)医疗器材有限公司 | Cobalt-chromium alloy artery stent with full-biodegradation medicine coating, stent system and preparation method thereof |
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| WO2008098418A1 (en) * | 2007-02-14 | 2008-08-21 | Shandong Intech Medical Technology Co., Ltd. | Intracoronary stent with asymmetric drug releasing controlled coating |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101711710A (en) * | 2009-11-25 | 2010-05-26 | 深圳市信立泰生物医疗工程有限公司 | Medicament eluting stent and preparation method thereof |
| CN101745153A (en) * | 2010-01-21 | 2010-06-23 | 万瑞飞鸿(北京)医疗器材有限公司 | Cobalt-chromium alloy artery stent with full-biodegradation medicine coating, stent system and preparation method thereof |
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| US9364588B2 (en) | 2014-02-04 | 2016-06-14 | Abbott Cardiovascular Systems Inc. | Drug delivery scaffold or stent with a novolimus and lactide based coating such that novolimus has a minimum amount of bonding to the coating |
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