CN101264346A - Degradable polymer blood vessel support medicine coating containing anticoagulation phosphorylcholine component - Google Patents
Degradable polymer blood vessel support medicine coating containing anticoagulation phosphorylcholine component Download PDFInfo
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- CN101264346A CN101264346A CNA2007101504123A CN200710150412A CN101264346A CN 101264346 A CN101264346 A CN 101264346A CN A2007101504123 A CNA2007101504123 A CN A2007101504123A CN 200710150412 A CN200710150412 A CN 200710150412A CN 101264346 A CN101264346 A CN 101264346A
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- Prior art keywords
- phosphocholine
- medicine
- blood vessel
- anticoagulation
- degradable polymer
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Landscapes
- Materials For Medical Uses (AREA)
Abstract
The invention relates to the field of medical instruments, in particular to a degradable polymer intravascular stent drug coating containing an anticoagulant phosphorylcholine component. The drug coating is composed of 1% -50% of drugs and 50% -99% of degradable polymers containing anticoagulant phosphorylcholine components as drug carriers, and the drugs can be selected from single antioxidant drugs, mixture of multiple antioxidant drugs, mixture of single or multiple anti-vascular restenosis drugs, and mixture of single or multiple antioxidant drugs and anti-vascular restenosis drugs. The drug carrier is three high molecular copolymers of polylactic acid (PDLLA), polyethylene glycol and phosphorylcholine. And the medicine and the medical biodegradable polymer are uniformly coated on the surface of the blood vessel stent by adopting a mixing or layered coating method, and the occurrence rate of thrombus can be effectively relieved and reduced by local administration so as to finally realize the treatment of coronary restenosis.
Description
Technical field:
The present invention relates to medical instruments field, particularly a kind of degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition.
Background technology:
Atherosclerosis is the important diseases that influences health, and the pathological changes that wherein feeds through to heart coronary artery is called coronary heart disease.Coronary heart disease often causes deficiency myocardial blood supply, and gently then angina pectoris is heavy then cause myocardial infarction, even dead.The U.S. in 2000 ischemic heart desease death accounts for 21.4% of dead sum, and wherein acute myocardial infarction death accounts for 8%.Through the conduit interventional therapy is one of the most frequently used treatment means of vascular obstruction disease, and especially percutaneous transluminal coronary angioplasty (PTCA) is the very effective Therapeutic Method of coronary occlusion disease.The polymer coating of the non-degradable support of present clinical use is a kind of foreign body to human body, can cause the inflammatory reaction of human body, retaining the chronic injury and the advanced thrombus that can cause blood vessel in blood vessel for a long time forms, later stage may cause the atrophy of media, aneurysm to form and reactive neointimal hyperplasia, the immune system of exciting human, immunocyte is piled up in support portions, caused restenosis.Make us that its secular safety is had doubt.Therefore biodegradability support (BDS) coating produces thereupon.
Polylactic acid just began one's study as far back as the beginning of the eighties, was degraded to lactic acid, and further was metabolized to CO
2And H
2O.Polylactic acid has high crystal degree, and its polymeric chain can limit its flowability, and drug release is very slow, hydroxyacetic acid is introduced poly (l-lactic acid) (PLLA) chain can change matrix flow and drug release, and crystallographic weakens the rising that causes the substrate percent hydrolysis.Structure and electric charge are two key factors of the compatibility, and the geometry of support then influences blood vessel injury and neointima hyperplasia.The design that these factors all can be support and coated polymer thereof provides important basis.
Tissue engineering bracket be meant can with organize active somatic cell combine and can implantable bioartificial intravital material, it is the basic boom of engineered tissue.Polyglycolic acid (PGA) and polylactic acid polylactic acid-based materials such as (PLA) are typical synthesized degradable polymer.Because lactic acid and hydroxyacetic acid all are the tricarboxylic acid cycle intermediate metabolitess, and absorption and metabolic mechanism are clear and definite and have a reliable biological safety, thereby polylactic acid and polyglycolic acid be used for by drugs approved by FDA as first degradable absorbing material clinical, be study so far the most extensive, use maximum degradable biomaterials.As tissue engineering bracket material, PLA, PGA and copolymer biomaterial thereof not only have excellent biological compatibility, and have biodegradability and degraded adjustability.At present, polylactic acid-based timbering material has been widely used in the timbering material of tissues such as bone, cartilage, stomach, blood vessel, nerve, skin, and shows its good prospects for application.
Still there is the problem of following several respects in existing simple PLA material:
(1) poly-lactic acid material itself is more crisp, and is hard frangible.Because material self-characteristic, synthetic, processing, shape and human-body biological are different in nature, degradation in vivo time instability may cause the consequence that some are unpredictable.
(2) PLA belongs to the degraded of this build, and the end carboxyl of PLA base polymer plays catalytic action to its hydrolysis.With the carrying out of degraded, end carboxyl amount increases, and degraded is also accelerated.And the catabolite of end carboxyl is stranded in sample interior and has caused inner degraded faster than superficial degradation.When degraded,, acid cause the material internal generation to stride the degraded of collapsing property because of causing the self-catalysis degradation effect, be difficult to control its degraded and absorption rate, half intermediate product of degraded can produce a large amount of acidic materials, these acidic materials can produce bigger stimulation to tissue, seriously some can cause inflammation, local hydrops.
(3) more mainly be, the hydrophobicity of PLA material surface is strong, has influenced the affinity of itself and cell and medicine as the delivery material of tissue engineering bracket material medicine the time.In the adaptability growth that implants and not too be beneficial to tissue in early days.
(4) the degraded mode of this class degradable polymer, body corrode and spread all over whole carrier, and it is loose that the overall structure of carrier can become, water content improves, and carrier begins to disintegrate very soon, and the adhesion of carrier and support itself reduces, carrier is easy to come off, and shortens the useful effect life-span of pharmaceutical film.
(5) material disintegrate front surface is coarse, forms thrombosis easily.
The pliability of Polyethylene Glycol and copolymer of poly lactic acid is better than simple polylactic acid.Regulate easilier according to the soft durometer needs.The biodegradation rate of regulating carrier self can keep the medicine constant release, makes blood drug level maintain a metastable level in a period of time, can improve the inhibition curative effect to vascular endothelial proliferation.And biodegradable polymer self can not cause any toxic and side effects, and this material and human body have excellent biological compatibility metabolizability and absorbability.The degraded end product is nontoxic.
Biomembranous main composition is lipid and protein.The main component of lipid is a phospholipid, and it is a kind of amphiphatic molecule that is arranged in bilayer by hydrophilic segment and hydrophobic part, and hydrophilic segment is on the film surface, and hydrophobic part is towards the centre of film.Double-layer of lipoid constitutes biomembranous skeleton, and protein just is embedded in the double-layer of lipoid, has constituted the microcosmic non-homogeneous structure [1,2] that hydrophilic area, hydrophobic region are inlayed.Biomembranous blood compatibility depends primarily on its double-deck non-homogeneous structure, and phospholipid is this double-deck main structure person.Phospholipid polyalcohol contains negative and positive both sexes end group and alkane nonpolar molecule chain usually, and the both sexes end group is hydrophilic, and the alkane molecule chain is a hydrophobicity.This structure and biomembrane are closely similar, so the blood compatibility of phospholipid polyalcohol and biomembrane are very approaching, and good prospects for application is arranged.It can be used as biomaterial coating [3,4], improves the biocompatibility of medical apparatus, also can be used as ion exchange membrane, ion permeable membrane, makes biosensor [5] and drug controlled release material [6-8] or the like.When common material contacts with biological intravital blood as foreign body, can produce thrombosis at material surface.Thrombosis is relevant with multiple blood constituents such as plasma proteins, coagulation factors, platelet, is a kind of complex reaction.Wherein, hematoblastic activation is the major reason that material surface causes thrombosis.Platelet activation causes hematoblastic adhesion, gathering and distortion, and then forms thrombosis [9].Phosphocholine (PC) can effectively improve the anticoagulant property of its polymeric film.PC content is high more, and hematoblastic adhesive capacity and deformation extent are more little, and the anticoagulant property of its polymeric film is good more.When the mole inventory of PC reaches 35%, almost there is not platelet adhesion on its polymeric film, show good anticoagulant property.Compare with other hydrophilic monomer, the PC of same molar more can effectively improve the anticoagulant property of its polymeric film.The phospholipid polyalcohol that contains PC has good anticoagulant property, and it is having good prospects for application aspect the surface modification of the medical apparatus and instruments that need contact for a long time with blood and artificial organ etc.
Summary of the invention
In sum, with the Biodegradable polymer is carrier, be coated on the intravascular stent surface, it can singly be planted and prepare, again can multiple mixed preparing, with anti-angiogenic restenosis medicaments mixed preparing, pass through local application, can alleviate effectively and can reduce the advanced thrombus incidence rate, and the final treatment coronary restenosis of realizing.
A kind of degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition provided by the invention, it is characterized in that, the blood vessel stent drug coating by the anti-angiogenic restenosis medicaments of the anti-oxidation medicine of 1%-90% or 1%-50% or 1%-99% anti-oxidation medicine and anti-angiogenic restenosis medicaments mix and the anticoagulation composition phosphocholine that contains of 50%-99% connects a degradable polymer and forms as pharmaceutical carrier.
Anti-oxidation medicine of the present invention comprises the product behind superoxide dismutase (SOD), catalase (CAT), coenzyme Q10, glutathion peroxidase (GSH-PX), lycopene, reduced glutathion (GSH), vitamin E, beta-carotene, vitamin C and the process molecular modification thereof, in the said medicine any one or any several drugs all can be prepared with pharmaceutical carrier, wherein, any one content of medicines during several drugs mixes should account for the 1%-99% of the total proportion of medicine; Described anti-angiogenic restenosis class medicine is anticoagulation class medicine, anticancer class medicine, inhibition vascular smooth muscle cell curing class activity inhibitor, anti-inflammatory drug and immunosuppressant, wherein:
Anticoagulation class medicine comprises aspirin, heparin, hirudin, antiplatelet GPllb/IIIa receptor antagonist, clopidogrel; Anticancer class medicine comprises colchicine, paclitaxel;
Suppress vascular smooth muscle cell curing class activity inhibitor and comprise angiogenic peptide, 17-hydroxy-11-dehydrocorticosterone, calcium ion antagonist;
Anti-inflammatory drug comprises dactinomycin, depsidomycin, KanglemycinC, spergualin, cammunomicin, demethomycin, tetranactin, stevastelins, myriocin, gllooxin;
Immunosuppressant comprises rapamycin, the plain A of ring spore enzyme, the plain C of ring spore enzyme, brefeldin A;
Medication coat of the present invention can be made up of the pharmaceutical carrier of any one and 50%-99% in the anti-oxidation medicine superoxide dismutase of 1%-50%, catalase, ubiquinone 1o, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene, the vitamin C.
Medication coat of the present invention can be made up of mixing several arbitrarily in the anti-oxidation medicine superoxide dismutase of 1%-50%, catalase, ubiquinone IO, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene, the vitamin C and the pharmaceutical carrier of 50%-99%; Wherein, the content of any one anti-oxidation medicine in the medicament mixed should account for the 1%-99% of the total proportion of medicine.
Medication coat of the present invention can be by the anti-oxidation medicine superoxide dismutase of 1%-50%, catalase, coenzyme Q10, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene, in the vitamin C any one and aspirin, heparin, hirudin, antiplatelet GPllb/IIfa receptor antagonist, clopidogrel, colchicine, paclitaxel, angiogenic peptide, 17-hydroxy-11-dehydrocorticosterone, calcium ion antagonist, the plain A of ring spore enzyme, dactinomycin, rapamycin, the plain c of ring spore enzyme, brefeldin A, depsidomycin, KanglemycinC, spergualin, cammunomicin, demethomycin, tetranactin, stevastelins, myriocin, the mixing of any one among the gllooxin and the pharmaceutical carrier of 50%-99% are formed; Wherein, the content of any one anti-oxidation medicine in the medicament mixed should account for the 1%-99% of the total proportion of medicine.
Pharmaceutical carrier of the present invention can be three kinds of high-molecular copolymers or a blend between polylactic acid (PDLLA), Polyethylene Glycol and the phosphocholine, wherein polylactic acid (PDLLA) copolymerization or blend ratio are 1%: 99%-99%: in 1% (concentration ratio) scope, and its molecular weight 5000-500000 dalton.
The material of the intravascular stent that the present invention adopts is a rustless steel, Ultimum Ti, the Cobalt evanohm or with the macromolecular material of bio-compatible.
Preparation method provided by the invention comprises two kinds (mainly being the preparations at multicomponent pharmaceutical), and a kind of is with the medicament mixed coating, and another kind is the layering coating.Layering coating should be with anti-angiogenic restenosis class medicine as the intermediate layer, and anti-oxidation medicine is coated in the top layer of intravascular stent, no matter be any, the bottom of every pair of support all has one deck Parylene (Parylene) polymeric film.Coating method can adopt the spraying process of medicine coating method or infusion process any one, no matter take any method, all should reach coating evenly and its medication coat thickness should be between the 1-100 micron, the drug loading of every pair of support is between the 10-1000 microgram.
What the preparation method of the embodiment of the invention adopted is spraying process and infusion process, the rotatable support frame angle repeats spraying several times in spraying process, it is reached evenly, and the medication coat content on the support can be controlled by the concentration of drug solution and the number of times of coating.
Its preparation method is as follows:
1. mix coating: at first xylol is heated to 950 ℃, generate the xylol dimer, then 680 ℃ of following cracking, form monomer vapours, support is placed on the indoor back of room temperature deposition feeds monomer vapours, standby behind the polymeric film of rack surface formation one deck even compact, then pharmaceutical carrier is dissolved in the solvent, adding medicine stirs, after treating fully dissolving and filtering, evenly be coated on the intravascular stent surface that is covered with the parylene polymer film, and in noble gas solvent flashing, descended dry 12 hours in vacuum condition afterwards, again the ethane via epoxyethane sterilization.
2. layering coating: at first xylol is heated to 950 ℃, generate the xylol dimer, then 680 ℃ of following cracking, form monomer vapours, support is placed on the indoor back of room temperature deposition feeds monomer vapours, standby behind the polymeric film of rack surface formation one deck even compact, then pharmaceutical carrier is dissolved in the solvent, adding anti-angiogenic restenosis class medicine stirs, after treating fully dissolving and filtration, evenly be coated on the intravascular stent surface that is covered with the parylene polymer film, and in noble gas solvent flashing; Pharmaceutical carrier is dissolved in the solvent, adding the polyphenoils medicine then stirs, after treating fully dissolving and filtration, evenly be coated on the intravascular stent surface that is covered with anti-angiogenic restenosis class medication coat, and in noble gas solvent flashing, descended dry 12 hours in vacuum condition afterwards, again the ethane via epoxyethane sterilization.
The advantage of layering coating is, both can discharge outer anti-oxidation medicine earlier to reach the purpose of alleviating and reducing because of the damage of radical pair human body cell and tissue behind the myocardial ischemia-reperfusion, the anti-angiogenic restenosis class medicine that can control the intermediate layer again in human body because the too fast danger that causes of release.
The solvent that compounding pharmaceutical coating solution of the present invention uses adopts any one of methanol, ethanol, acetonitrile, isopropyl alcohol, oxolane, acetone, dichloromethane or chloroform.The noble gas that uses in the medication coat preparation process can be any one of other noble gas in nitrogen, helium and the periodic table of chemical element.
The release cycle of anti-oxidation medicine of the present invention is one thoughtful 6 months.
The specific embodiment:
Embodiment one: 0.3g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜50/30/20 (mol/mol/mol)〉be dissolved in 10ml acetone after, adding 0.2g superoxide dismutase (SOD) stirs, after dissolving all even filtration, be sprayed on and be covered with 0.1g ciclosporin A and 0.3g polylactic acid (PDLLA) and ethylene glycol copolymer＜80/20 (mol/mol) on Parylene (Parylene) the polymeric film bottom〉in the middle of the 316L stainless steel stent surface of medication coat, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment two: 0.2g polylactic acid (PDLLA) and phosphocholine blend＜85/15 (mol/mol)〉be dissolved in the 10ml acetonitrile after, add the 0.5g lycopene, 0.01g coenzyme Q10 and 0.01g vitamin E stir, after dissolving all even filtration, be sprayed on and be covered with 0.1g dactinomycin and 0.3g polylactic acid (PDLLA) and ethylene glycol copolymer＜50/50 (mol/mol) on Parylene (Parylene) the polymeric film bottom〉in the middle of the 316L stainless steel stent surface of medication coat, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment three: 0.3g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜30/40/30 (mol/mol/mol)〉be dissolved in 10ml ethanol after, adding 0.3g coenzyme Q10 and 0.01g rapamycin stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment four: 0.5g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine blend＜80/10/10 (mol/mol/mol)〉be dissolved in the 10ml acetonitrile after, adding 0.1g coenzyme Q10 and 0.2g paclitaxel stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment five: 0.2g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜90/5/5 (mol/mol/mol)〉be dissolved in 10ml ethanol after, adding the 0.1g coenzyme Q10 stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment six: after 0.4g polylactic acid (PDLLA) is dissolved in 10ml acetone, adding 0.3g coenzyme Q10 and 0.1g ciclosporin A stirs, after dissolving all even filtration, be sprayed on Parylene (Parylene) the polymeric film bottom and be covered with 316L stainless steel stent surface, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, makes it evenly be coated on rack surface, selects in nitrogen and sends out behind the solvent under vacuum condition in drying at room temperature 12 hours again. the ethane via epoxyethane sterilization.
Embodiment seven: 0.3g polylactic acid (PDLLA) and phosphocholine blend＜30/70 (mol/mol)〉be dissolved in the 10ml oxolane after, (SOD and 0.1g vitamin E stir to add the 0.2g superoxide dismutase, after dissolving all even filtration, be sprayed on and be covered with 0.1g ciclosporin A and 0.3g polylactic acid (PDLLA) and phosphocholine blend＜50/50 (mol/mol) on Parylene (Parylene) the polymeric film bottom〉in the middle of the 316L stainless steel stent surface of medication coat, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment eight: 0.1g polylactic acid (PDLLA) and ethylene glycol copolymer＜65/35 (mol/mol)〉with phosphocholine blend＜75/25 (mol/mol) be dissolved in 10ml acetone after, adding the 0.2g lycopene stirs, after dissolving all even filtration, be sprayed on and be covered with 0.1g dactinomycin and 0.3g polylactic acid (PDLLA) and ethylene glycol copolymer＜70/30 (mol/mol) on Parylene (Parylene) the polymeric film bottom〉in the middle of the 316L stainless steel stent surface of medication coat, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment nine: 0.3g polylactic acid (PDLLA) and Polyethylene Glycol and phosphocholine copolymer＜50/25/25 (mol/mol/mol)〉be dissolved in the I0ml oxolane after, adding 0.2g superoxide dismutase (SOD) and 0.1g vitamin E stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment ten: 0.5g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜35/35/30 (mol/mol/mol)〉be dissolved in 10ml ethanol after, adding the 0.2g rapamycin stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 11: 0.3g polylactic acid (PDLLA) and Polyethylene Glycol and phosphocholine copolymer＜40/30/30 (mol/mol/mol)〉be dissolved in the 10ml isopropyl alcohol after, adding the 0.2g vitamin C stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 12: 0.2g polylactic acid (PDLLA) and Polyethylene Glycol and phosphocholine copolymer＜90/5/5 (mol/mol/mol)〉be dissolved in 10ml ethanol after, add the 0.01g vitamin C, rope E stirs 0.1g coenzyme Q10 and 0.3g support one's family, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 13: 0.5g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymerization mix thing＜75/5/20 (mol/mol/mol)〉be dissolved in the 10ml acetonitrile after, adding 0.02g vitamin C and 0.03g rapamycin stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 14: 0.3g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜45/35/20 (mol/mol/mol)〉be dissolved in the 10ml isopropyl alcohol after, adding 0.1g vitamin C and 0.2g paclitaxel stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 15: 0.4g polylactic acid (PDLLA) and phosphocholine blend＜85/15 (mol/mol)〉be dissolved in 10ml acetone after, adding the plain A of 0.01g vitamin C and 0.01g ring spore enzyme stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Pa rylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 16: 0.3g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜65/25/10 (mol/mol/mol)〉be dissolved in the 10ml acetonitrile after, adding the 0.2g catalase stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Pa rylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 17: 0.2g polylactic acid (PDLLA) and Polyethylene Glycol and phosphocholine copolymer＜80/10/10 (mol/mol/mol)〉be dissolved in 10ml acetone after, adding 0.1g catalase and 0.1g vitamin E stirs, after dissolving all even filtration, dip-coating is to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 18: 0.5g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜35/35/30 (mol/mol/mol)〉be dissolved in the 10ml acetonitrile after, adding 0.1g catalase and 0.2g rapamycin stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 19: 0.3g polylactic acid (PDLLA), Polyethylene Glycol and phosphocholine copolymer＜65/20/15 (mol/mol/mol)〉be dissolved in the 10ml oxolane after, adding 0.1g catalase and 0.2g paclitaxel stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Embodiment 20: 0.4g polylactic acid (PDLLA) and ethylene glycol copolymer＜65/35 (mol/mol/mol)〉with phosphocholine blend＜75/25 (mol/mol/mol) be dissolved in the 10ml acetonitrile after, adding the plain A of 0.01g catalase and 0.1g ring spore enzyme stirs, after dissolving all even filtration, spray to the 316L stainless steel stent surface that is covered with Parylene (Parylene) polymeric film bottom, solvent flashing in nitrogen, and the runing rest angle repeats spraying several times, make it evenly be coated on rack surface, in nitrogen behind the solvent flashing again under vacuum condition in drying at room temperature 12 hours. the ethane via epoxyethane sterilization.
Obviously, the above embodiment of the present invention only is for example clearly is described, and is not to be qualification to embodiment of the present invention.Can also make other changes in different forms on the basis of the above description.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention amplified out and still belong among protection scope of the present invention.
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Claims (11)
1. degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition, it is characterized in that, the blood vessel stent drug coating by the anti-angiogenic restenosis medicaments of the anti-oxidation medicine of 1%-90% or 1%-50% or 1%-99% anti-oxidation medicine and anti-angiogenic restenosis medicaments mix and the anticoagulation composition phosphocholine that contains of 50%-99% connects a degradable polymer and forms as pharmaceutical carrier.
2. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, it is characterized in that described medication coat can be made up of as pharmaceutical carrier the degradable polymer that contains anticoagulation phosphocholine composition of any one and 50%-99% in anti-oxidation medicine superoxide dismutase, catalase, coenzyme Q10, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene and the vitamin C of 1%-50%.
3. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, it is characterized in that, described medication coat can by in the anti-oxidation medicine superoxide dismutase of 1%-50%, catalase, coenzyme Q10, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene, the vitamin C arbitrarily several rods close with the pharmaceutical carrier of 50%-99% and form; Wherein, the content of any one anti-oxidation medicine in the medicament mixed should account for the 1%-99% of the total proportion of medicine.
4. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, it is characterized in that described medication coat can be by the anti-oxidation medicine superoxide dismutase of 1%-50%, catalase, coenzyme Q10, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene, in the vitamin C any one and aspirin, heparin, hirudin, antiplatelet GPllb/IIIa receptor antagonist, clopidogrel, tazettine, paclitaxel, angiogenic peptide, 17-hydroxy-11-dehydrocorticosterone, calcium ion antagonist, the plain A of ring spore enzyme, dactinomycin, rapamycin, the plain C of ring spore enzyme, brefeldin A, depsidomycin, KanglemycinC, spergualin, cammunomicin, demethomycin, tetranactin, stevastelins, myriocin, any one mixing and 50%99% pharmaceutical carrier are formed among the gllooxin; Wherein, the content of any one anti-oxidation medicine should account for the 1%-99% of the total proportion of medicine in the medicament mixed.5. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, it is characterized in that described medication coat can be by the aspirin of 1%-50%, heparin, hirudin, antiplatelet GPllb/IIIa receptor antagonist, clopidogrel, tazettine, paclitaxel, angiogenic peptide, 17-hydroxy-11-dehydrocorticosterone, calcium ion antagonist, the plain A of ring spore enzyme, dactinomycin, rapamycin, the plain C of ring spore enzyme, brefeldin A, depsidomycin, KanglemycinC, spergualin, cammunomicin, demethomycin, tetranactin, stevastelins, myriocin, the pharmaceutical carrier of among the gllooxin any one and 50%-99% is formed.
6. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, described medication coat can be by the anti-oxidation medicine superoxide dismutase of 1%-50%, catalase, coenzyme Q10, glutathion peroxidase, lycopene, reduced glutathion, vitamin E, beta-carotene, any several and aspirin in the vitamin C, heparin, hirudin, antiplatelet GPllb/IIfa receptor antagonist, clopidogrel, tazettine, paclitaxel, angiogenic peptide, 17-hydroxy-11-dehydrocorticosterone, calcium ion antagonist, the plain A of ring spore enzyme, dactinomycin, rapamycin, the plain C of ring spore enzyme, brefeldin A, depsidomycin, KanglemycinC, spergualin, cammunomicin, demethomycin, tetranactin, stevastelins, myriocin, the mixing of any one among the gllooxin and the pharmaceutical carrier of 50%-99% are formed; Wherein, the content of any one anti-oxidation medicine in the medicament mixed should account for the 1%-99% of the total proportion of medicine.
7. as claim 1,2,3,4,5, the 6 described degradable polymer blood vessel stent drug coatings that contain anticoagulation phosphocholine composition, it is characterized in that, described pharmaceutical carrier can be wherein two or three high-molecular copolymer or a blend between polylactic acid (PDLLA), Polyethylene Glycol and the phosphocholine, and wherein polylactic acid (PDLLA) copolymerization or blend ratio are all 1%: 99%-99%: in 1% scope.
8. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, its preparation method is as follows: at first xylol is heated to 950 ℃, generate the xylol dimer, then 680 ℃ of following cracking, form monomer vapours, support is placed on the indoor back of room temperature deposition feeds monomer vapours, standby behind the polymeric film of rack surface formation one deck even compact, then pharmaceutical carrier is dissolved in the solvent, adding medicine stirs, after treating fully dissolving and filtration, evenly be coated on the intravascular stent surface that is covered with the parylene polymer film, and in inert gas solvent flashing, afterwards in vacuum condition dry 12 hours down, ethane via epoxyethane sterilization again.
9. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, another kind of preparation method is as follows: at first xylol is heated to 950 ℃, generate the xylol dimer, then 680 ℃ of following cracking, form monomer vapours, support is placed on the indoor back of room temperature deposition feeds monomer vapours, standby behind the polymeric film of rack surface formation one deck even compact, then pharmaceutical carrier is dissolved in the solvent, adding anti-angiogenic restenosis class medicine stirs, after treating fully dissolving and filtering, evenly be coated on the intravascular stent surface that is covered with the parylene polymer film, and in inert gas solvent flashing; Pharmaceutical carrier is dissolved in the solvent, adding the polyphenoils medicine then stirs, after treating fully dissolving and filtration, evenly be coated on the intravascular stent surface that is covered with anti-angiogenic restenosis class medication coat, and in noble gas solvent flashing, descended dry 12 hours in vacuum condition afterwards, again the ethane via epoxyethane sterilization.
10. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1, another kind of preparation method is as follows: pharmaceutical carrier is dissolved in the solvent, adding anti-angiogenic restenosis class medicine stirs, after treating fully dissolving and filtration, evenly be coated on the intravascular stent surface, and in noble gas solvent flashing; Pharmaceutical carrier is dissolved in the solvent, adding the polyphenoils medicine then stirs, after treating fully dissolving and filtration, evenly be coated on the intravascular stent surface that is covered with anti-angiogenic restenosis class medication coat, and in inert gas solvent flashing, foretell dry 12 hours in vacuum condition afterwards, again the ethane via epoxyethane sterilization.
11. as claim 8, the 9 or 10 described preparation methoies that contain the degradable polymer blood vessel stent drug coating of anticoagulation phosphocholine composition, it is characterized in that described solvent adopts methanol, ethanol, acetonitrile, isopropyl alcohol, tetrahydrochysene to bark and mutters, in acetone, dichloromethane or the chloroform any one; Described noble gas can use any one of other noble gas in nitrogen, helium or the periodic table of chemical element; Described intravascular stent material be rustless steel, nickel admire memorial alloy, bore evanohm or with the high molecule plastic of bio-compatible.
12. the degradable polymer blood vessel stent drug coating that contains anticoagulation phosphocholine composition as claimed in claim 1 is characterized in that described medication coat thickness is between the 1-100 micron, the drug loading of every pair of support is between the 10-1000 microgram; The release cycle of described medicine is one thoughtful 6 months.
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