CN101600463A - Drug-delivery endovascular stent and using method thereof - Google Patents
Drug-delivery endovascular stent and using method thereof Download PDFInfo
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- CN101600463A CN101600463A CN200780046686.6A CN200780046686A CN101600463A CN 101600463 A CN101600463 A CN 101600463A CN 200780046686 A CN200780046686 A CN 200780046686A CN 101600463 A CN101600463 A CN 101600463A
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Abstract
A kind of improvement to bracket for eluting medicament and preparation method thereof is disclosed.With surface coarsening wiry to having at least about the surface roughness of 20 microinch (0.5 μ m) and the range of surface roughness of about 300-700 microinch (7.5-17.5 μ m).Covered the Li Mosi medication coat have or not polymer by the rack surface of alligatoring, the thickness of this coating is greater than by the scope of the surface roughness of the rack surface of alligatoring.
Description
Technical field
The present invention relates to a kind of endovascular stent and preparation thereof and using method, this support comprises (textured) of upgrading or at least in part by abrasive surface.
Background technology
Complication (for example restenosis) is to accept medical surgery (percutaneous tranluminal coronary angioplasty (percutaneous transluminal coronary angioplasty, PTCA) problem that recurs among the patient to atherosclerosis therapy of form for example.Usually treat restenosis by the method that is called stenting, wherein, medical apparatus and instruments is implanted in the ill tremulous pulse to prevent that it from thromboembolism taking place after surgery by surgical operation.
Support is generally cylindricality, and is usually made by the metal (for example cochrome or medical steel (surgical steel)) of biocompatibility.Support is contractile mostly, and is delivered to the tremulous pulse place that thromboembolism takes place by intraluminal catheter (transluminal catheter).Support is fixed on the conduit, and can self expansion or expand by the expansion of the utricule in this support, removes utricule and conduit after described medical apparatus and instruments has been positioned at suitable position.
The complication that is caused by stent therapy comprises restenosis and thrombosis.In the effort of making in order to overcome these complication, support can contain the medicine layer of anti-restenosis or the medication coat of anti-restenosis, and described anti-narrower medicine is released with controllable mode in the site that support is implanted.Normally, be included in the described medicine in permanent polymer carrier or the biology erosion property polymer support (bioerodable polymercarrier), open in the U.S. Patent No. 5716981 that is entitled as " Anti-angiogenic Compositionsand Methods of Use (angiogenesis inhibitor compoistion and method of use) " of for example Hunte.Can use many other chemistry and biological reagents though also mentioned in the literature record of patent, antiproliferative, anticoagulant, antiinflammatory agents and immunosuppressant are the examples of the typical treatment agent that discharges in this mode.Wherein propose, the polymer support that carries medicine can be coated by porous Biodegradable material, and wherein, described biodegradable layer is used as regulates medicine to intravital release, as, disclosed in U.S. Patent No. 6774278 and 6730064.
Recently, proposed such support, wherein, anti-restenosis medicaments is delivered in the mode in ditch (channels), groove (grooves) or hole, is released in the mode (that is the form of pure medicine) of " no polymer ".As an alternative, in U.S. Patent No. 6805898 and 6918927 for example, thereby also proposed to have the support of rough surface to discharge with the form of pure medicine at rack surface anchoring medicine layer.These supports all do not show or hint out, carry the support of the anti-restenosis compounds of particular types, can strengthen the anti-restenosis activity of chemical compound by selecting surperficial rough features in the scope certain on rack surface.
Be conceived to the complication relevant with stent therapy, need exploitation a kind of have at least one be roughened or by the surface of upgrading to increase the support of surface area, thereby this support can be by the manufactured globality of structure, the load-carrying ability of medicine and the maximized that discharges medicine in the mode that treatment is strengthened to blood vessel of making of this mode, in view of the above, reduced the risk of the degree of the odds of the restenosis that behind blood vessel injury place implant frame, takes place or restenosis.
Summary of the invention
In one embodiment, with respect to by settle viewed the comparing of expansible support of smooth surface at impaired place, the present invention includes and can reduce the restenosis that takes place at patient's blood vessel injury place or the improved method of thrombotic occurrence probability and/or degree, the expandable support of described smooth surface forms by interconnected tinsel and by the outer surface that the polymer support that contains favourable not this medicine (Limus drug) applies described scaffolding thread.With compare by the Li Mosi FirebirdTM (Limus-eluting stent) that is coated with polymer, this improvement is intended to not exist and can keeps under the situation of polymer support or further reduce restenosis and/or thrombotic occurrence probability and/or degree, and method of the present invention may further comprise the steps:
(a) with the outer surface region alligatoring of the scaffolding thread surface roughness at least 20 microinch (μ in) (0.5 μ m), further, the scope of described surface roughness (being up to minimum) is about 300-700 microinch (7.5-17.5 μ m), and
(b) the Li Mosi medication coat by no polymer is to being applied by the alligatoring zone of described scaffolding thread, and greater than by the scope of the surface roughness of the rack surface of alligatoring, that is, the thickness of coating has covered by the surface of alligatoring until the thickness of coating.
Described scaffolding thread can be about 20-40 microinch (0.5-1 μ m) by alligatoring to surface roughness, and/or by the range of surface roughness of alligatoring to about 300-500 microinch (7.5-12.5 μ m).
Described surface coarsening can carry out by the following method: the outer surface region of denuding described scaffolding thread by the abrasive Flow of pressurization; Form the hydrocarbon membranes shelter on the outer surface region of described scaffolding thread, optionally the material of the described support that will be exposed by described shelter is got rid of, and described shelter is got rid of; Outer surface region by the described support of laser-induced thermal etching; Perhaps carry out sandblast, on outer surface region, to form pattern by outer surface region to described scaffolding thread.
Can on the outer surface of described scaffolding thread, carry out described medicine coating with the form of the viscosity solution of medicine, along with drying forms the solid drugs coating on scaffolding thread.Described coating can be so that the final quantity of Li Mosi medicine on the support of every centimeter length be the mode of 25-240 μ g carries out, and to make final applied thickness be 5-15 μ m.A kind of preferred classification of Li Mosi medicine is for being called as the 42-O-ethoxyethyl group chemical compound of Biolimus A9 in this article.
On the other hand, the present invention includes by applying the outer surface of support with the Li Mosi medicine that does not contain polymer, with to carrying out the improvement of the method for administration from the anti-restenosis medicaments of expansible support, described expansible support is formed by the tinsel of interconnection.This improvement is intended to realize the restenosis and thrombotic occurrence probability and/or the degree that reduce by the Li Mosi medicine that coating does not contain polymer, method of the present invention comprises that the outer surface region alligatoring of the scaffolding thread that will be applied by the Li Mosi medicine is to the surface roughness of at least 20 microinch (0.5 μ m) and the range of surface roughness of about 300-700 microinch (7.5-17.5 μ m).
Also disclose a kind of expansible support and reduced the restenosis when support is placed in the blood vessel injury place, take place or the application in thrombotic occurrence probability and/or the degree.Described support comprises: by the expansible support main body that forms of tinsel of interconnection, be formed on described scaffolding thread outer surface region by the surface of alligatoring and load on described scaffolding thread by the Li Mosi medicine coating that does not contain polymer on the zone of alligatoring, the surface roughness of this coating is at least 20 microinch (0.5 μ m), further, described range of surface roughness is about 300-700 microinch (7.5-17.5 μ m); The described applied thickness that does not contain the Li Mosi medicine of polymer is by the scope of the surface roughness of the rack surface of alligatoring greater than described.
Consider detailed description of the present invention and with reference to the following drawings, above-mentioned and others of the present invention and embodiment become apparent.
Description of drawings
Fig. 1 is the scintigram with endovascular stent of tinsel main body;
Fig. 2 A is by the scanning electron micrograph of abrasive rack surface;
Fig. 2 B is the scanning electron micrograph on Fig. 2 A surface, has shown the quantity of the projection that the abrasion back produces on rack surface;
Fig. 2 C is the scanning electron micrograph on Fig. 2 A surface, has shown the quantity of the depression that the abrasion back produces on rack surface;
Fig. 3 A is the diagram that pneumatic press is handled rack surface;
Fig. 3 B is the in-plant front view of the fixing head punch press assembly of Fig. 3 A, has shown that pneumatic press has a plurality of drifts;
Fig. 3 C is the in-plant side view of the fixing head punch press assembly of Fig. 3 B;
Fig. 3 D is the in-plant front view of fixing head adnexa of punch press assembly that is used for the pneumatic press of Fig. 3 A;
Fig. 4 is the scanning electron micrograph that is coated with the support after the processing of medicine;
The medicine Biolimus that Fig. 5 records for the percetage by weight that discharges medicine in the accumulated time by a few hours
Support of the present invention and
Elution curve in the II support;
Fig. 6 is for being illustrated in difference three months and the bimestrial pig transplantation model medicine Biolimus
From support of the present invention and
The figure of the percent that discharges among the II;
Fig. 7 for the expression with mass spectrum record in the pig transplantation model, when from support of the present invention and
During discharging in the II support, medicine Biolimus
Figure along with the maximum concentration (in ng/mL) of time (in hour) in peripheral blood;
Fig. 8 is for representing for not containing medicine and containing Biolimus
The figure of the area percent of the thromboembolism of the support of medicine (occlusion);
Fig. 9 A to Fig. 9 F is for implanting naked metal rack (Fig. 9 A-9B), having the Biolimus of containing
Polymer coating wire rack mount (Fig. 9 C-9D) and have Biolimus
The scintigram of the vascular tissue section that the support of the tinsel micro-fiber structure of coating (Fig. 9 E-9F) is back 28 days; And
Figure 10 A to Figure 10 K is the figure of the tissue morphology measurement (histomorphometry) of containing the grafting vessel of micro structure support.
The specific embodiment
1. definition
Except as otherwise noted, term hereinafter has following meaning.
" surface roughness " or " mean roughness " or " Ra " are meant the arithmetic mean of instantaneous value of the curved surface height that records in the sample length that records from the centrage of image or median plane (line at center or plane) or the deviation range in the area.Usually, as will measuring by contactless talysurf hereinafter with discussing, but also can be by the talysurf of contact or by recording from the height between the surperficial displaing micro picture estimation peak valley.
" range of surface roughness " or " Rt " is the ultimate range between peak-paddy, by calculating with respect to the peak-peak of centrage or median plane with the measurement of the roughness of maximum valley.Usually, measure, but also can record by above-mentioned other method by contactless talysurf.
" Li Mosi medicine " refers to the triolefin immunosuppressive compounds of macro ring, and the general formula that this chemical compound has is in U.S. Patent No. 4650803,5288711,5516781,5665772 and 6153252 for example, PCT open No.WO 97/35575, U.S. Patent No. 6273913B1 and shown in U.S. Patent application No.60/176086,2000/021217A1 and the 2001/002935A1.
" 42-O-alkoxyalkyl chemical compound " refers in laid-open U.S. Patents application 20050101624 on May 12 in 2005 the 42-O-alkoxy-alkyl derivative of the rapamycin of describing (rapamycin), by reference this patent whole and be incorporated into this.Exemplarily, " 42-O-alkoxyalkyl Li Mosi medicine " is " 42-O-ethoxyethyl group rapamycin ", is called as Biolimus A9 in this article.
A kind of like this coating of " coating of no polymer " expression, its structure and caking property are to be provided by medicine itself under the situation that has or do not exist binding agent, rather than are provided by the polymeric matrix (that is polymer support) of the medicine that wherein is embedded with.
II. endovascular stent
Fig. 1 has represented the support that makes up according to the present invention at contraction state.This support comprises having at least one by structural member or main body to small part roughening or abrasive surface, and with the anti-restenosis compounds that is used at least holding and discharging, this will further describe hereinafter.
In illustrated embodiment, the main body of described support is to be formed by a series of tubular element that is called as pole 3 that is connected with each other by the silk that is called connector 4.Each pole 3 has distensible Z-shaped, sawtooth, spiralled wire zone circle or sinusoidal configuration, and with the elasticity that has increased integral support being connected of each connector 4.The diameter of the support of contraction state is about 0.5-2.0mm, preferred 0.71-1.65mm, and length is 5-100mm.The diameter of the support of expansion is at least at least 2 times of this support contraction state, is up to 8-9 doubly, for example says, the contraction state diameter is that the support of 0.7-1.5mm can radial dilatation arrive selected 2.0-8.0mm or bigger expansion state.Have the general rack body structure of this connection, distensible tubular element is known.For example announce that at PCT this paper is incorporated into this with it by reference described in the No.WO 99/07308.
Preferably, supporting structure is made by biocompatible materials, for example rustless steel.The further embodiment that is generally used for the biocompatible materials of supporting structure is cochrome, nickel, magnesium, tantalum, titanium, Nitinol (nitinol), gold, platinum, inconel (inconel), iridium, silver, tungsten or other biocompatible materials, or their alloy arbitrarily; Carbon or carbon fiber; Cellulose acetate, celluloid, silicone, poly-para Toluic Acid's glycol ester (polyethylene teraphthalate), polyurethane, polyamide, polyester, poe (polyorthoester), poly-anhydride (polyanhydride), polyether sulfone, Merlon, polypropylene, High molecular weight polyethylene, politef or other biological compatible copolymer material, or the mixture of their copolymer; Poly--L-lactic acid, poly-DL-lactic acid, polyglycolic acid (polyglycolic acid) or their copolymer, poly-anhydride, polycaprolactone (polycaprolactone), polyhydroxybutyrate valerate (polyhydroxybutyrate valerate) or other biodegradable polymer, or their mixture or copolymer; The suitable mixture of protein, extracellular matrix components (extracellular matrixcomponent), collagen protein, fibrin or its biology preparation (biologic agent) or above-mentioned these materials.Typical stent is existing the description in U.S. Patent No. 6730064.The size of each support will be according to its body cavity that will place (body lumen) and difference.For example say that support can have from about 0.5mm to the diameter of about 25.0mm scope and from about 4mm extremely about 100mm or longer length.The example of the method for measurement bracket is described in U.S. Patent No. 6939376, and this patent is incorporated into this by reference.
Shown in Fig. 2 A, the surperficial at least a portion of at least one of described support has the surface of micro structure roughening or abrasive or upgrading.This micro structure can comprise at least a therapeutic agent that goes out from described micro structure eluting.As from Fig. 2 B-2C visibly, surface described roughening or upgrading provides slit or vertical protrusion surface character and/or has sunk or recessed area.Be understandable that treatment agent solution or the solution that contains therapeutic agent can be inhaled into these recesses by for example capillary force, and convex surfaces is applied.Can increase the surface area that applies in the support in this way.The thickness of these layers refers to the average thickness of layer, for example, and the meansigma methods of the degree of depth of the part injected of layer.Preferably, shown in Fig. 2 A, comprise micro-structure surface to the chamber surfaces (ablumenal surface) (that is the surface that contacts with the blood vessel of treatment behind the placing rack) of the support of small part.
III. the method for preparing textured surface
In one embodiment, this method comprises that the use mask is denuded with the support that prevents at least a portion.Preferably, described mask is the hydro carbons thin film, for example,
Yet, be understandable that the barrier of any suitable anti-grinding all is applicable to these methods.Therefore, in preferred embodiment, do not denuded to the surface of internal cavity of limited bracket.In one embodiment, mask sheet that will about 5mm * 60mm is reeled around the diameter of axle (for example capillary glass tube of 1.4mm).To prop up and be placed on the axle and manual being crimped onto in the hydrocarbon mask.Can use stereomicroscopies 10 times and 40 times to set (stereo microscope set), to guarantee that support does not need to be covered by mask by abrasive part.In preferred embodiment, the cradle wall thickness of at least 80% on all surface is covered by hydrocarbon film layer.
In one embodiment, use micro-spray system (microblasting) subsequently, for example the MICRO that provides of Comco
With
Or analog, rack surface 5 is handled.In one embodiment, use the grinding agent (for example aluminium oxide) of 25 μ m that rack surface 5 is carried out roughening.Pressure is adjusted into 40psi ± 5psi, and nozzle placed apart from rack surface 5 about 2.5cm to 5.0cm locates, on support, to produce a plurality of passages.In another embodiment, remove described mask by any suitable method (for example passing through ultrasonic waves for cleaning).Fill the deionized water that is heated to 45 ℃ in the common ultrasonic washing unit.The chloroform of the HPLC level of sample bottle is heated to 50-60 ℃ on hot plate.The capillary glass tube axle that will have a support of handling hatching 5-10 minute in the vial of chloroform of the HPLC level of 40 ℃ and 50 ℃.The bottle that will contain chloroform and axle subsequently carries out 2 minutes sonicated in 45 ℃ deionized water.
Since to the roughening of rack surface 5, the different member that on the metal surface, exposes, and this can increase corrosive susceptibility.As a result, according to the ASTM standard support of handling is carried out general passivation, and it is cleaned in (for example chloroform, acetone and/or isopropyl alcohol (isopropyl Alcohol)) in a series of solvent.In one embodiment, after mask is removed and the support of handling carried out sonicated, it is taken out from vial of chloroform.With acetone rinsing sample bottle and then fill with acetone.With being placed in this bottle of handling, and in ultrasonic washing unit 2 minutes sonicated.Also recharge with isopropyl alcohol subsequently with the described bottle of isopropyl alcohol.Support surpassed 2 minutes sonicated in the ultrasonic cleaning machine.Subsequently, under 60 ℃ ± 30 ℃, in the nitric acid water-bath of 20 volume %, carried out passivation 30 minutes.Subsequently with support with a large amount of rinsed with deionized water 10 times.To prop up subsequently (for example isopropyl alcohol) in the solvent that is placed on 600ml, and in the ultrasonic cleaning machine, carry out 5 minutes sonicated, allow to carry out air-dry.
In another embodiment, the surface of support is denuded with controllable mode unevenly by sand-blast.The metallic particles (be of a size of about 1-5 μ m, and made by the element that atomic weight is at least 43g/mol) that use is called as bullet carries out roughening to rack surface 5.For example say that bullet can be the form of particulate tantalum, particulate tungsten, particulate platinum, particulate iridium, particulate gold, granule bismuth, granule barium, granule zirconium and their alloy.The example of suitable alloy comprises platinum/nickel alloy and platinum/iridium alloy.
In another embodiment, rack surface 5 can be processed into to produce mechanical syringes (mechanical injector), and its size range is about 3 to about 10 microns.
In another embodiment, rack surface 5 can be by laser-induced thermal etching to produce about 5 to the about 25 microns rule or the pattern of irregular concavo-convex body (asperities)/mechanical syringes.
In another embodiment, rack surface can be processed on nearly surface, chamber (ablumenalsurface) and have and the different roughness of luminal surface (lumen surface).Such as, can handle whole surface by any above-mentioned disclosed method.Subsequently, luminal surface is sheltered, thereby can on nearly surface, chamber, be carried out the surface treatment second time.Ensuing processing can typically utilize more intensive method for modifying.Therefore, the different surface that obtains can be used for giving different useful characteristics for surface, the inside of support (in the tube chamber (lumenal)) to outside (near chamber (ablumenal)) surface.In one embodiment, can the roughness of tube chamber inner surface be optimized, to improve the inside growth and the adhesiveness of cell, disclosed in U.S. Patent application No.2005/0211680 for example, and can be optimized the chamber surfaces roughness, so that the transfer that medicine is organized towards periphery from chamber surfaces to be provided as described herein.
Can place with required pattern by bullet on the predetermined portions of rack surface 5 rack surface 5 is handled aequum.Use plate or roller to execute the granule plus-pressure on rack surface 5, to produce indenture.Can also be by reaching roughness with the speed described granule of jet blasting on rack surface 5 that is enough to produce indenture.The metal surface is carried out example existing description in U.S. Patent No. 6911100 of sand-blast.
In further embodiment, can be by using laser rather than using bullet similarly reach this uniform, controlled surface roughness.Required part to outside or inner rack surface 5 is carried out a series of discharge.The discharge that contacts with the surface has enough energy, so that the evaporation of the lip-deep material of support produces hole (being called as the hole sometimes), this bonded effect is the rough surface with the surface area that has increased.The case description of this method is in U.S. Patent No. 6913617.
In another embodiment, by compression uneven processing is carried out on the surface of support.Described support is attached on the axle, and this axle is inserted the mould that is equipped with preformed projection, to form the indenture of required amount, shape, size and pattern on rack surface 5.Can form indentures with many methods, for example they are welded on the rack surface 5 or by sandblast and form.Subsequently mould is centered around frame peripheral, with the indenture that forms desired depth and cover required surface area.According to the processing of mould and the whole surface of support or part that should the surface are handled.The example of this method is described in U.S. Patent No. 7055237.
In another embodiment, handle rack surface 5 with pneumatic press or hydraulic press.Pneumatic press is well known in the art, described in U.S. Patent No. 4079617.Hydraulic press also is known in the art, as U.S. Patent No. 7033155.As shown in Fig. 3 A-3D, will prop up on the axle 1 that is placed on static or rotation.Preparation will be by computer-controlled pneumatic press or hydraulic press 8, with one of several predetermined ways (for example, at random or with required pattern) rack surface is handled.The punch press assembly 9 of forcing press can be configured to contain one or more drift 10,11 and be defined as the machinery that indenture produces at this.In preferred embodiment, described punch press assembly contains a plurality of drifts.Be understandable that, described drift can for same or different length to form surface micro-structure.Each drift 10,11 remains on retracted position up to computer programming, to handle rack surface 5.According to selected program, drift 10,11 will carry out punching press to rack surface 5 with the power of enough generation indentures.Usually, punch press assembly 9 is set to be no more than the width of required support, and for example, if stent strut 3 is 15 μ m, the overall width of then a plurality of drifts 10,11 also is no more than 15 μ m.The quantity of the drift 10,11 on given punch press assembly 9 can be according to the width of support and difference.Similarly, described punch press assembly 9 can be set to the fixing head on the ready-formed punch press, and these fixing head can be exchanged according to required shape.And described fixing head can be for immobilized and support overturn, perhaps on the contrary, fixing can be for movably, this is embodied in the single drift 10,11 that is fixed to punch press can produce impression at random on rack surface 5.
In another embodiment, with it with before being laser-cut into a plurality of required stent length, the whole length (for example, the length of pipe is 2.5m) of the pipe that is used to make support is handled.Support is by flatly or vertically attached on one or more axles 1, and uses and say among the application that one of disclosed method denudes.In carrying out friction process, support is carried out randomly, equably or with required mode ground support handled.In addition, the length direction and the side of support are carried out vertically, vertically or spirally handled.And by it being moved and the immobilized roughening of process mechanism, or on the contrary, the static and roughening mechanism of entire bracket length of tube can move (for example level low, vertically, spirally) along the length direction of pipe in one of disclosed mode and come rack surface 5 is handled.
The enterprising action potential corrosion test of support after processing is to confirm the satisfaction and the effect thereof of passivation step.The fault electromotive force that data show has a support after handling, passivation is positioned at the voltage levels standards of ASTM regulation satisfactorily.Therefore, after roughening step and passivation, it is more significant similar that the corrosion of support after processing performance and untreated support do not show, and the roughening process can not increase restenosis and thrombotic risk.After passivation, observed micro structure metal surface is suitable with observed biocompatibility in having the support of level and smooth electropolished surfaces.
The thickness of the wall of untreated support is generally about about 0.05mm.As shown in Fig. 2 B-2C, in disclosed mode rack surface 5 to be handled, the average height of the peak of generation (peak) 6 is that the mean depth of about 1.30 μ m and paddy (valley) 7 is the rack surface 5 of 2.08 μ m.Any in order to measure by the (if there is) that influences of roughening process to the supporting structure globality, on the support after the processing, carry out axial fatigue test and auger analysis (auger analysis).Axial fatigue test concentrates on support and is easy to impaired position most, is the connector between stent strut 34.Simulation under the physiological condition surpass 300 ten thousand times circulation after, the support of untreated support contrast and roughening all is kept perfectly.Because the part of processed support is removed in the roughening process, and find that processed support can bear and has the identical fatigue condition that the untreated intact stent in multilist zone more can be born, and should be appreciated that this roughening process has increased the fatigue durability of support really owing to the microstructure of having destroyed rack body.At last, carry out auger analysis on the support of handling, so that surface chemistry is described, this has reflected that identical element has similar amount in the support after the processing of the support of the not alligatoring of passivation and alligatoring.This method that has confirmed the passivation untreated crt bracket carried out in disclosed mode can not produce adverse effect to the rack surface chemistry.
Do not wish this effect limits under special theory, be arranged in the concave-convex surface body of peak-paddy scope of 300-700 microinch or protrusion show be suitable for most with the medicine " injection " of medication coat go into to around blood vessel.Therefore, for instance, when dissolving from coating by medicine or broken when these protrusions are exposed by taking place at placing rack process floating coat, these protrusions can or thrust partial angiosomes by extruding promote the medicine intravasation.The result, with observed the comparing of Li Mosi FirebirdTM that is coated with polymer, the roughness scope of the rack surface that is limited combines with the coating that does not contain polymer, under the situation that does not have polymer support, can keep or reduce restenosis or thrombotic occurrence probability and/or degree further, and the coating of the no polymer that reduces with the surface coarsening degree is compared (promptly, have lower range of surface roughness), further reduced restenosis or thrombotic occurrence probability and/or degree.In addition, that carries out in order to support the present invention studies show that, has the support of surface roughness characteristics, and the scope of peak-valley is that the effect of 800-1000 microinch (20-25 μ m or higher) aspect the minimizing restenosis is relatively poor.
Therefore, on the one hand, the present invention by using bracket for eluting medicament (for example, Li Mosi FirebirdTM) restenosis in the treatment blood vessel injury generation and/or degree aspect have improved effect.Above-mentioned improvement may further comprise the steps: the near at least chamber surface portion of support is carried out alligatoring be at least about 20 microinch (0.5 μ m) until surface roughness, further, alligatoring to the scope of surface roughness is about 300-700 microinch (7.5-17.5 μ m), and apply with the Li Mosi medication coat of no polymer zone by alligatoring to scaffolding thread, the thickness of coating is greater than by the surface roughness of the rack surface of alligatoring, that is, the thickness of coating forms complete basically medication coat.
Preferably, will comprise antiproliferative Biolimus
At least be applied to the nearly cavity segment of support at interior API (that is active pharmaceutical component).Described API can be applied to rack surface in any suitable method, comprises by the rack surface after handling with the API solution spraying.During described API solution also can be immersed in entire bracket behind the required API, or, be coated with API solution by it manually is coated directly onto on the rack surface 5.Biolimus
Have amorphous-hypocrystalline structure, this structure is easy to cracking or fragmentation unlike other crystalline Li Mosi chemical compound.Therefore, Biolimus
Character allowed on its treatment surface attached to the roughening of the support of unexpanded mode and expansion state.
Preferably, described API material is by moving the nearly cavity segment that the liquid method is applied to support automatically, as described in total U.S. Patent No. 6939376.By required API being dissolved in (for example ethyl acetate or acetonitrile) in the appropriate solvent, make the solution of concentration range for about 100-200mg/ml.This solution is placed reservoir, and this reservoir has pump and transports solution with set rate.Control described pump by microcomputer, for example, available from I﹠amp; The 4-Axis Dispensing RobotModel of J Fisnar Inc company.To be used for solvent mixture is transported to the bottom of the solution delivery tube of rack surface 5 attached to reservoir.Described reservoir and delivery tube are assembled into movably supporter, and this supporter can be continuously or mobile solvent delivery tube step by step, for example, and along 0.2mm of per step of the y direction of support.
With the dop (chuck) that inner surface rotation and at least one end support contacts, the support of uncoated is clamped.By rotate continuously or progressively (0.5 per step of degree), realize axial rotation to support.As an alternative, delivery tube is maintained at fixed position, and support also vertically moves along it when rotated, to realize coating process.
Before the use, the pipe of transportation solution is aspirated down and molding at Bunsen burner (Bunsen burner), being formed on the pipe top has the pipe of tapered opening, so that accurately make the mixture of medication/solvent, subsequently, described mixture can be along with the formation at the top of pipe and is applied on needed whole length of support and the side.Below also within the scope of the invention, use more than a kind of operation of dispense tube class to form coating, or use as an alternative more than a kind of movably solution storage tank, this solution storage tank is equipped with different tops, or contains a plurality of different additional medicines in order to the solution that forms coating in the solution of different viscosities or the identical method.
In another embodiment, the non-porous layer of the polymer of the derivant of Parylene, Parylene or other biocompatibility is arranged on the rack surface after the processing, and on this layer, is provided with or forms required api layer.Randomly, the other layer of non-porous polymer is set directly on API, this helps to control the release that takes place in time.According to the present invention, described support comprises at least one deposition api layer thereon, and other surface can not contained API or contain one or more different APIs.In this way, one or more API can be discharged in the blood flow by the luminal surface of support, and the different therapeutic agent that is used for different situations is released to the outer vascular injury position of rack surface.
In another embodiment, described support can be coated by the API molecule under the situation that does not need polymer.As illustrated in fig. 4, more than all or part of method of carrying out roughening in the disclosed method to described support, allow API directly to be attached on the surface of the support 14 after the processing.In common embodiment, API is the Li Mosi medicine, for example in U.S. Patent No. 4650803,5288711,5516781,5665772 and 6153252, announce No.WO 97/35575, U.S. Patent No. 6273913B1 and described in U.S. Patent application No.60/176086,2000/021217A1 and the 2001/002935A1 at PCT.Exemplary Li Mosi medicine is 42-O-alkoxyalkyl medicine, for example Biolimus A9.Other API medicine that can use separately or be used in combination with the Li Mosi medicine comprises: anti-platelet agents or antithrombotic agent, or anti-inflammatory agent (as dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate or other dexamethasone derivant) or anti-inflammatory type sterin.The inner surface of described support and/or outer surface also can be used for transporting the API molecule of other type, for example thrombosis agent, vasodilation, hypotensive agent, antibacterial or antibiotic, antimitotic agent, antiproliferative (antiproliferatives agents), the secretion inhibitor agent, NSAID (non-steroidal anti-inflammatory drug), immunosuppressant, somatomedin and somatomedin antagonistic, tumor inhibitor and/or chemotherapeutics, anti-polymerase, antiviral agent, optical dynamic therapy agent (photodynamic therapy), the antibody target therapeutic agent, prodrug, gonadal hormone, free radical scavenger, antioxidant, biological preparation, X-ray therapy preparation (radiotherapeutic agents), contrast agent and radioactive indicator.
Described support can be included in the assembly that contains rack body, and described rack body is around attached on the flat utricule on the distal end of catheter part, and described conduit is used for support is placed in the position of vascular injury.Utilize described conduit support to be introduced patient's cardiovascular system by brachial artery or femoral artery.Conduit tube component is pushed ahead by the coronary blood guard system, places vascular injury place, angiopathy place or angiostenosis place up to the combination with flat utricule and support.Make utricule expand into preliminary dimension subsequently, support is expanded to enough greatly to contact with tube chamber constantly.Subsequently utricule venting to less shape is fetched from patient's vascular system to allow conduit, and support is stayed the original place.The typical stent implantation process is existing the description in US Patent No 6913617.
IV. using method
This part has been described the performance characteristic of the support that makes up according to vascular treatment method of the present invention and according to the present invention.
Propose method of the present invention so that accepted the patient of local vascular damage, perhaps have risk and/or degree that restenosis takes place among the patient of blood vessel embolism risk and minimize.Normally, blood vessel injury is to produce during for the blood vessel (for example coronary artery or peripheral blood vessel tremulous pulse) of opening the part thromboembolism in angiographic procedure.Optionally, described support be directed into the angiostenosis place, and utilizes utricule to expand with the narrow (that is blood vessel injury disease place) of directly opening blood vessel.First kind mentioned to angiographic process in, at first balloon catheter is placed the thromboembolism place, and, opens with the blood vessel that forces thromboembolism with the utricule of the end inflation one or many of exitting again.This vasodilation (wherein platelet may be removed) that is usually directed to the wound at blood vessel wall place produces a large amount of localized injury usually, make tremulous pulse constantly to because the propagation of cell and again the thromboembolism generation reply.No wonder is that the generation of restenosis or severity are relevant with the blood vessel level of stretch in the angiographic procedure usually.Particularly under excess elongation 10% or more situation, restenosis have a higher probability, and have suitable seriousness usually, that is, blood vessel embolism.In the replaceability process of second kind of mentioned direct placing rack, do not need to carry out angioplasty (promptly in advance, " directly support method "), wherein still can the expansion at vascular injury disease place cause vascular injury owing to support and utricule, this makes the contraction again and the cell proliferation of inserting the place at support, and is observed similar in its order of severity and the aforementioned first kind of process.
Expect that use of the present invention is not subjected to any concrete Therapeutic Method and the restriction of injured blood vessel position, and can use technology described above, perhaps be used for the treatment of the known replacement technology of angiopathy and damage.Carrying out when of the present invention, usually described support is being placed on the far-end of conduit with its contracted state or in the tube chamber of conduit, or be placed on the terminal utricule with contracted state.Subsequently the tip catheter end is imported the position of injury site or potential generation thromboembolism, from conduit, discharge then, for example, sheath to the covered stent of pulling back, so that support is discharged on the described position,, or expands by utricule and to make support expansion on the utricule if described support is a self expansion, in fact when being expanded to support and contacting with blood vessel wall, then in this position with described support implanting tissue wall.
In case in the expansion of described position, the support that is coated with medicine begins the cell release of active compounds (API) in artery position, to suppress cell proliferation and/or to be used for other treatment benefit, for example reduce inflammation, restriction thrombosis, reduce apoptosis etc.Fig. 5 has represented Biolimus
Release dynamics in two kinds of supports, in these two kinds of supports, one is coated with medicine on the surface of its upgrading, and another is
The II support, it has the Biolimus of containing
Polymer coating.
Fig. 6 has represented Biolimus
Drug release percent in the support that is coated with polymer and upgrading.As shown in the figure, only after 2 months, from the support of upgrading, discharged 100% Biolimus
On the contrary, after 3 months, about 30% drug residue is being coated with on the support of polymer.
Fig. 7 has represented with mass spectrograph being coated with polymer
In in the no polymer support of II support and upgrading each, the Biolimus that records
Peaks of blood concentration.As shown in the figure, for the support of upgrading, Biolimus
When peaks of blood concentration appears at about 4 hours.And for being coated with polymer
The II support, Biolimus
When peaks of blood concentration appears at about 2 months.
Fig. 9 A-9F has shown the cross section of angiosomes, described angiosomes have implantation naked metal rack (Fig. 9 A-9B), have the PLA of 225 μ g and the Biolimus of 225 μ g
The metal of polymer coating
II support (Fig. 9 C-9D) and have the Biolimus of 225 μ g
The support (Fig. 9 E-9F) of upgrading, wherein, the silk of coating illustrates in the cross section part.This figure has set forth anti-chemical compound release of vascular wall area towards periphery from each zone of shrinking again.As time passes, the smooth muscle cell that forms blood vessel wall begin to grow into and pass framework or helical opening in the support, finally form successive inner cell layer support wrapped into both sides.If the transplanting of this support is successful, the degree at the blood vessel embolism of this position will reduce by 50% subsequently, that is to say, the diameter that keeps the cross section of mobile passage in the blood vessel be at least the support of expansion when implanting diameter 50%.
Experiment in the restenosis animal model of pig, as people such as Schwartz at (" Restenosis AfterBalloon Angioplasty-A Practical Proliferative Model in Porcine CoronaryArteries ", Circulation 82:(6) 2190-2200, Dec 1990.) described in.Study in the model of pig, these studies confirm that support of the present invention has the ability that can limit extent of restenosis, and have confirmed that support of the present invention has other advantage than the support that proposes at present and tested.This research summary is in embodiment 3.
In brief, the again shrinkage degree of implant frame in animal model (naked metal rack, be coated with the support of polymer and the support of upgrading) after 28 days compared in this research.
Fig. 9 A-9F has shown that the support of the support that is coated with polymer and upgrading has all greatly reduced the level of shrinking again.As a rule, the blood vessel of having accepted to be coated with the support of the support of polymeric drug and upgrading shows and obtains good healing, has formed endodermis preferably.Evidence suggests, after transplanting 28 days, cure fully and blood vessel in stable.
Other experiment confirm support described herein in the trimestral at least duration, have the ability of the degree that can limit restenosis.This research summary is in embodiment 4.
In brief, this research has been compared the bracket for eluting medicament (pfDES) of implanting naked metal rack (BMS) and no polymer the degree of contraction was again taken place after 3 months.Tissue morphology data representation shown in the table 4 is compared with BMS, and pfDES greatly reduces the level of shrinking again.
Following embodiment will set forth the various aspects of making and using support of the present invention.They are not the restrictions to scope of the present invention.
Biolimus
At external drug release from support
Make to be coated with and contain anti-proliferative drugs Biolimus
Polymer
II support and with the Biolimus that contains with nearly chamber micro structure
Support in pH is 7.4/37 ℃ tween medium, carry out vitro drug release.Periodically take a sample, and measure Biolimus by HPLC
Total amount.Fig. 5 has explained
The drug release of II support and micro structure support.
Roughness parameter bench test (bench test)
The outer surface of Bioflex II 6 arch supports (crown stent) is denuded processing, on this rack outer surface, to produce the optionally micro structure of drug load ability, be called as biology-free support (Bio-Freedom Stent, FS).Therapeutic agent can optionally directly be coated in the surface of the micro structure of support.
The roughness parameter of FS is characterised in that Veeco Metrology Group (Tucson, Ariz.) the WYKO NT-2000 system that is available commercially contactless talysurf that used.Have the 32nd edition software the vertical scanning interferometer (vertical scanning interferometer, VSI) model has been removed cylindricality and has been tilted, thereby it is smooth that rack surface is looked like.The low pass filter of the influence of high spatial frequency roughness has been removed in use, and the feature less than 9 pixel forms is carried out smoothing.4 kinds of different supports the results are shown in following table, the surface roughness of these 4 kinds of supports is produced by sandblast, wherein, as defined above, Ra is an average surface roughness, and Rt is a range of surface roughness.
| | Sandblast | 4 | Sandblast | 5 | Sandblast | 6 microinch | |
| Ra | 30.2 | 25.4 | 25.0 | 28.3 | |||
| Rt | 688.8 | 336.8 | 406.9 | 358.9 |
Animal implant tests textured
To have and not have Biolimus
The support from the upgrading of embodiment 2 be implanted in the young pig of outbreed.According to the pig excessively extension model of the standard of excessively extension, use balloon catheter to come placing rack with 10-20%.Before placing rack, the target of young pig is decided blood vessel expand in advance (predilated) by known angiopoiesis technology.
After 28 days, this animal is implemented euthanasia, from this animal, take out heart and perienchyma according to the clause of permission.
Use contains the microscope of digital camera, and with the high-definition picture of the vessel cross-sections that obtains making section, it the results are shown among Fig. 9 A-9F.According to the following steps this image is carried out tissue morphology measurement:
Support and tremulous pulse are dissected, and carry out ultrathin section.Sample to various growth signals, cell proliferation and other cell debris dyes.Tissue morphology measurement is undertaken by following:
With mm
2The tremulous pulse area (Figure 10 A), IEL (Figure 10 B) of meter, with mm
2The meter inner membrance area (Figure 10 C), with mm
2The tube chamber area (Figure 10 D) of meter, in the tube chamber thickness (Figure 10 E) of micron, narrow (Figure 10 F) of area %, based on the histological grade (body 10G) of wound and inflammatory reaction, based on the histological grade (Figure 10 H) of endo cell epimatrix and EB/GC reaction, based on endothelialization and the fibrinous histological grade of inner membrance (Figure 10 I), based on average inflammation, gangrene and Fibrotic histological grade (Figure 10 J), based on outer film inflammation and Fibrotic histological grade (Figure 10 K).
Following table has been represented the therapeutic effect in the time of 28 days.Be entitled as " tube chamber area mm in the following table
2" data reacted the support that from pig, takes out for after 28 days (f/u) and the morphometric Analysis result of blood vessel.
Table 1: the result of tissue morphology measurement
Fig. 8 has shown the support on the surface that each has upgrading and has had the surface of upgrading and the Biolimus of 225 μ g
The area % thromboembolism of support.
3 the monthly age pig implantation research
A. the implantation of support
According to table 3, the Biolimus of 225 μ g will be carried
Carry out the bio-matrix support or the naked BioFlex II support of the no polymer of sandblast by embodiment 2, be implanted in the farm pig model of hybridization.
The zoografting parent (matrix) of the coronary stent of table 3. pig
The naked metal rack of BMS=, pfDES=does not have the bracket for eluting medicament of polymer
*LCX is implant frame not, and this is because the off size of support fitted
CV Path institute limited company obtains the heart from 5 pigs.In 5 pigs, do not carry out multiple support, and in the time of three months implant frame and carry out optical microscope (lightmicroscopic) and analyze.No. 1 animal promptly dead reason before predetermined ensuing period is with to carry out the support implant surgery 2 months the time irrelevant.The LCA of #3 animal (LCX) is implant frame not, and this is because the off size of LCX fitted.
B. material and optical microscope method
For optical microscope, the vessel segment of implant frame is implanted in the methylmethacrylate plastics, cut off proximal stent, mid-stent and rack far end part, be loaded in the section of filling, and with h and E (hematoxylin ﹠amp; Eosin) and Elastic Van Gieson (EVG) dye.The near-end and the distal portions of undyed tremulous pulse are implanted in the paraffin, punish section, and dye with h and E and EVG at the 4-5 micron.Test the formation of inflammation, thrombosis, new intima in all fragments and the existence of vascular damaged by optical microscope.Morphometric analysis: use at the length of all targets is 2.0mm and the diameter micron-sized traceable NIST microscope as the circle of 2.0mm, to somatometry of physique software (IP Lab for Macintosh, Scanalytics, Rockville MD) calibrates.All micron scales authenticate through Klarmann Rulings company.Measured area comprise external elastic membrane (external elastic lamina, EEL), internal elastic membrane (internal elastic lamina, IEL) and intracavity.Between stent strut and stent strut, measure new intima, and each animal is averaged.By deducting IEL from EEL, the average area that obtains.Obtain narrow percentage ratio by equation [1-(tube chamber area/support area)] * 100.Use the Schwartz method (people such as Schwartz RS., J AmColl Cardiol 1992; 19:267-274) determine the score of blood vessel injury.Based on the score that grade analysis obtains each segmental inflammation, fibrin and damages, wherein, 0=does not have inflammation/fibrin/damage, the significant inflammation/fibrin of 3=/damage.The segmental inflammation that two or more granuloma reactions occur is divided into 4 fens.Endothelium is covered as semiquantitative, and is expressed as the percentage ratio of interior cavity perimeter.
C. statistical analysis
The morphometry continuous data is expressed as meansigma methods ± SD.
Use Student t-check (Student ' s t-test) that normal distributed constant is carried out statistical analysis.Parameter or centrifugal pump to improper distribution use the Wilcoxon test to analyze.In the Wilk-Shapiro test, test normal distribution.To think to have significance,statistical less than 0.05 p value.
The D.X actinogram
All supports all show big degree and average expansion and do not have the evidence of fragmentation or bending.
E. observation by light microscope
1. the DES that does not have polymer
In implantation back 3 months, all supports were by the ground expansion of big degree, and obviously there is no evidence thrombosis has taken place.The formation of new intima relaxes, and the average thickness of new intima is 0.16mm and contains smooth muscle cell of loosely being filled and the substrate that is rich in proteoglycan.Blood vessel injury is gentle.Observe the fibrin precipitation of the gentleness around pole.Though found to reply granulomatous in the LCX of No. 5 animals, in other blood vessel, overall inflammation is minimum.Can find and write down giant cell once in a while.Under the situation that does not have intracavity inflammatory cell and/or platelet adhesion, finished endothelialization.Noticeablely be in the new intima of the proximal part of the LCX of No. 2 animals that contain naked metal rack, to have found intensive calcification.
2. naked metal rack
In implantation back 3 months, all supports were by the ground expansion of big degree, and obviously there is no evidence thrombosis has taken place.The formation of new intima relaxes, and the average thickness of new intima is 0..21mm and contains the smooth muscle cell of closely being filled.(LeftAnterior Descending coronary artery LAD) has observed internal break in the anterior descending coronary of No. 2 animals.This blood vessel that has showed serious inflammation around pole may be because the damage that implantation process produces causes.Yet except this animal, blood vessel injury and inflammation are demulcent on the whole.In any support, all do not find fibrin precipitation and adherent bad (malapposition).Under the situation that does not have intracavity inflammatory cell and/or platelet adhesion, finished endothelialization.
F. histomorphometricall
The tissue morphology of the PES of table 4.BMS and no polymer in the time of 3 months relatively
| Handle | The DES of no polymer (n=7) | BMS(n＝4) | The p value |
| EEL area (mm 2) | 9.52±1.27 | 7.32±0.86 | 0.01 |
| IEL area (mm 2) | 8.16±1.09 | 6.15±0.81 | 0.01 |
| Tube chamber area (mm 2) | 6.27±1.59 | 4.17±0.98 | 0.04 |
*The p value is analysed by the credit of Wilcoxon test statistics and is obtained
This zooperal result has confirmed to compare with the implantation of naked metal crt bracket (BMS), and behind the implant frame 3 months the time, the tube chamber area is increased (that is, having reduced restenosis) to the bracket for eluting medicament of no polymer (free DES) significantly in the model of pig.
Description of the invention only is an exemplary illustration, and the change that does not therefore deviate from purport of the present invention comprises within the scope of the invention.This change should not be construed and exceeded the spirit and scope of the invention.
Claims (18)
1, a kind of minimizing because the restenosis that patient's blood vessel injury causes or the occurrence probability and/or the degree methods of thrombosis, with contain viewed the comparing of distensible naked metal rack that the polymer support of favourable not this medicine forms by settling at impaired place by the tinsel of interconnection and by outer surface coating at scaffolding thread, described method has under the situation that does not have polymer support and can keep or further reduced with respect to the restenosis that is reached by the Li Mosi FirebirdTM that has applied polymer or the occurrence probability of thrombosis and/or the improvement of degree, and this method comprises:
The surface roughness (Ra) of at least 20 microinch (0.5 μ m) and the range of surface roughness (Rt) of about 300-700 microinch (7.5-17.5 μ m) are arrived in the outer surface region alligatoring of scaffolding thread, and
Li Mosi medication coat by no polymer applies the alligatoring zone of described scaffolding thread, until the scope of the thickness of coating greater than by the surface roughness of the rack surface of alligatoring.
2, a kind of to carry out the method for administration from the anti-restenosis medicaments of expansible support, described expansible support forms by the tinsel of interconnection and by applying at the outer surface of described support with the Li Mosi medication coat of no polymer, obtained reducing the generation of restenosis or thrombosis and/or the improvement of degree, this method comprises:
The surface roughness of at least 20 microinch (0.5 μ m) and (7.5-17.5 μ m) range of surface roughness of about 300-700 microinch are arrived in the outer surface region alligatoring that applies the scaffolding thread of favourable not this medicine.
3, method according to claim 1 and 2, wherein, with the surface roughness of described scaffolding thread alligatoring to 20-40 microinch (0.5-1 μ m).
4, method according to claim 1 and 2, wherein, described alligatoring is undertaken by the outer surface region of denuding described scaffolding thread with the abrasive Flow of pressurization.
5, method according to claim 1 and 2, wherein, described alligatoring is undertaken by following steps: form the hydrocarbon membranes shelter on the outer surface region of described scaffolding thread, optionally the material of the described support that will be exposed by described shelter is got rid of, and described shelter is got rid of.
6, method according to claim 1 and 2, wherein, described alligatoring is undertaken by the outer surface region of described scaffolding thread is carried out laser-induced thermal etching.
7, method according to claim 1 and 2, wherein, described alligatoring is undertaken by the outer surface region of described scaffolding thread is carried out sandblast, to form pattern on outer surface region.
8, method according to claim 1 and 2, wherein, the heavy-gravity drug solution of coating on the outer surface of described scaffolding thread is passed through in described coating, and the solution that is coated with is carried out drying carry out to form solid medication coat on scaffolding thread.
9, method according to claim 1 and 2, wherein, described coating is undertaken by coating Li Mosi medicine on support, and it is 80-240 μ g that the coating weight of described Li Mosi medicine makes the final quantity of Li Mosi medicine on the support of every centimeter length.
10, method according to claim 10, wherein, described coating is to be that the mode of the final medication coat of 5-15 μ m is carried out to produce thickness.
11, method according to claim 1 and 2, wherein, the described Li Mosi medicine that applies described support is Biolimus A9.
12, a kind ofly be used to reduce the occurrence probability of restenosis or thrombosis and/or the expandable stent of degree, do not produce when being placed on the blood vessel injury place with described support with Li Mosi medicament elution polymer coating and the inflammatory response that produces, this support comprises:
The expansible support main body that forms by interconnected tinsel;
On the outer surface region of described scaffolding thread, form by the surface of alligatoring, this surface by alligatoring has surface roughness and about 300-700 microinch (7.5-17.5 μ m) range of surface roughness of at least 20 microinch (0.5 μ m), and
Load on described scaffolding thread by the Li Mosi medication coat of the no polymer on the zone of alligatoring, the scope of the applied thickness of this coating is greater than by the surface roughness of the rack surface of alligatoring.
13, support according to claim 12, wherein, described scaffolding thread is by the surface roughness of alligatoring to about 20-40 microinch (0.5-1 μ m).
14, support according to claim 12, wherein, described scaffolding thread is by the range of surface roughness of alligatoring to about 300-500 microinch (7.5-12.5 μ m).
15, support according to claim 12, wherein, described Li Mosi medicine is Biolimus A9.
16, support according to claim 12, wherein, the overlay capacity of Li Mosi medication coat on the support of every centimeter length of described no polymer is 80-240 μ g.
17, support according to claim 12, wherein, the thickness of the Li Mosi medication coat of described no polymer is 5-15 μ m.
18, the restenosis or the occurrence probability of thrombosis and/or the application in the degree that cause of the blood vessel injury reducing by the patient of any described support among the claim 12-17.
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| US85307706P | 2006-10-20 | 2006-10-20 | |
| US60/853,077 | 2006-10-20 | ||
| US11/690,768 US8067055B2 (en) | 2006-10-20 | 2007-03-23 | Drug-delivery endovascular stent and method of use |
| US11/690,768 | 2007-03-23 | ||
| US11/751,268 US20080097591A1 (en) | 2006-10-20 | 2007-05-21 | Drug-delivery endovascular stent and method of use |
| US11/751,268 | 2007-05-21 | ||
| PCT/US2007/022284 WO2008051453A2 (en) | 2006-10-20 | 2007-10-19 | Drug-delivery endovascular stent and method of use |
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| CN101600463B CN101600463B (en) | 2015-01-07 |
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| JP5902164B2 (en) * | 2010-08-02 | 2016-04-13 | コーディス・コーポレイションＣｏｒｄｉｓ Ｃｏｒｐｏｒａｔｉｏｎ | Flexible helical stent with intermediate structural features |
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| US6805898B1 (en) * | 2000-09-28 | 2004-10-19 | Advanced Cardiovascular Systems, Inc. | Surface features of an implantable medical device |
| US6764505B1 (en) * | 2001-04-12 | 2004-07-20 | Advanced Cardiovascular Systems, Inc. | Variable surface area stent |
| DK1521603T3 (en) * | 2002-07-12 | 2011-04-18 | Cook Inc | Coated medical device |
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| CN101663054A (en) | 2010-03-03 |
| CN101663054B (en) | 2013-08-07 |
| CN101600463B (en) | 2015-01-07 |
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