CN101600463B - Drug-delivery endovascular stent and method of use - Google Patents

Abstract

An improvement in drug-eluting stents, and method of their making are disclosed. The surface of a metal stent is roughened to have a surface roughness of at least about 20 muin (0.5 mum) and a surface roughness range of between about 300-700 muin (7.5-17.5 mum). The roughened stent surface is covered with a polymer-free coating of a limus drug, to a coating thickness greater than the range of surface roughness of the roughened stent surface.

Description

Drug-delivery endovascular stent and using method thereof

Technical field

The present invention relates to a kind of endovascular stent and preparation and application thereof, (textured) that this support comprises upgrading at least in part or the surface be abraded.

Background technology

Complication (such as restenosis) is receiving the medical surgery (problem recurred in the patient to atherosclerotic treatment of such as percutaneous tranluminal coronary angioplasty (percutaneous transluminal coronary angioplasty, PTCA) form.Usually by being called that the method for stenting treats restenosis, wherein, by surgical operation, medical apparatus and instruments is implanted in ill tremulous pulse to prevent it from after surgery thromboembolism occurring.

Support is generally cylindricality, and is usually obtained by the metal (such as cobalt chromium closes 1 gold medal or medical steel (surgical steel)) of biocompatibility.Most support is contractile, and is delivered to the tremulous pulse place that thromboembolism occurs by intraluminal catheter (transluminal catheter).Support is fixed on conduit, and can self expansion or expanded 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 caused by stent therapy comprises restenosis and thrombosis.In order to overcome in effort that these complication make, support can contain the medicine layer of anti-restenosis or the medication coat of anti-restenosis, and described anti-restenosis drug is again released in a controlled manner in the site of stenter to implant.Normally, be included in the described medicine in permanent polymer carrier or bioerodable polymers carrier (bioerodable polymercarrier), open in being entitled as in the U.S. Patent No. 5716981 of " Anti-angiogenic Compositionsand Methods of Use (angiogenesis inhibitor compoistion and method of use) " of such as Hunte.Although also refer in the literature record of patent can use many other chemistry and biological reagent, antiproliferative, anticoagulant, antiinflammatory agents and immunosuppressant are the examples of the typical treatment agent discharged in like fashion.Wherein propose, the polymer support carrying medicine can be coated by the Biodegradable material of porous institute, and wherein, described biodegradable layer is used as regulating drug to the release in body, e.g., disclosed in U.S. Patent No. 6774278 and 6730064.

Recently, proposed such support, wherein, anti-restenosis drugs is delivered in the mode in ditch (channels), groove (grooves) or hole, is released in the mode of " non-polymer " (that is, the form of pure medicine).Alternately, in such as U.S. Patent No. 6805898 and 6918927, it is also proposed and there is rough surface to carry out at rack surface anchoring medicine layer the support that discharges with the form of pure medicine.These supports all do not show or suggest, carry the support of the anti-restenosis compound of particular types, can by the anti-restenosis activity selecting surperficial rough features to strengthen compound in scope certain on rack surface.

Be conceived to the complication relevant to 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, this support can by this mode manufactured thus make the globality of structure, the load-carrying ability of medicine and with treat strengthening mode to blood vessel release medicine maximized, accordingly, the risk of the odds of restenosis or the degree of restenosis occurred after blood vessel injury place implant frame is reduced.

Summary of the invention

In one embodiment, with respect to settling at impaired place, the expansible support of smooth surface is viewed to be compared, the present invention includes the method for the improvement that can reduce restenosis or thrombotic occurrence probability and/or the degree occurred at the blood vessel injury place of patient, the expandable support of described smooth surface is by the tinsel be connected to each other and by being formed containing the polymer support of favourable not this medicine (Limus drug) applies the outer surface of described scaffolding thread.Compared with the Li Mosi FirebirdTM (Limus-eluting stent) by being coated with polymer, this improvement can keep when being intended to there is not polymer support or reduce restenosis and/or thrombotic occurrence probability and/or degree further, and method of the present invention comprises the following steps:

A () is by the surface roughness of the exterior surface area alligatoring of scaffolding thread at least 20 microinch (μ in) (0.5 μm), further, the scope (being up to minimum) of described surface roughness is about 300-700 microinch (7.5-17.5 μm), and

B () is applied by the region that is roughened of Li Mosi medication coat to described scaffolding thread of non-polymer, until the thickness of coating is greater than the scope of the surface roughness of the rack surface be roughened, that is, the thickness of coating covers the surface be roughened.

It is about 20-40 microinch (0.5-1 μm) that described scaffolding thread can be roughened to surface roughness, and/or is roughened the range of surface roughness to about 300-500 microinch (7.5-12.5 μm).

Described surface coarsening can carry out by the following method: the exterior surface area of being denuded described scaffolding thread by the abrasive Flow of pressurization; The exterior surface area of described scaffolding thread forms hydrocarbon-film mask, optionally the material of the described support exposed by described shelter is got rid of, and described shelter is got rid of; By the exterior surface area of support described in laser-induced thermal etching; Or by carrying out sandblasting, to form pattern in exterior surface area to the exterior surface area of described scaffolding thread.

Described medicine coating can be carried out on the outer surface of described scaffolding thread, along with drying forms solid drugs coating on scaffolding thread with the form of the viscosity solution of medicine.Described coating can be carried out for the mode of 25-240 μ g to make the final quantity of Li Mosi medicine on the support of every centimeter length, and makes final applied thickness be 5-15 μm.A kind of preferred classification of Li Mosi medicine is the 42-O-ethoxyethyl group compound being called as Biolimus A9 in this article.

On the other hand, the present invention includes the outer surface by applying support with the Li Mosi medicine not containing polymer, to carry out the improvement of the method for administration to the anti-restenosis drugs from expansible support, described expansible support is formed by the tinsel interconnected.This improvement is intended to not realize the restenosis that reduces and thrombotic occurrence probability and/or degree containing the Li Mosi medicine of polymer by coating, method of the present invention comprises the exterior surface area alligatoring of scaffolding thread that applied by the Li Mosi medicine surface roughness at least 20 microinch (0.5 μm), and the range of surface roughness of about 300-700 microinch (7.5-17.5 μm).

Also disclose a kind of expansible support and reduce the application in the restenosis or thrombotic occurrence probability and/or degree occurred when support is placed in blood vessel injury place.Described support comprises: the expansible support main body formed by the tinsel interconnected, the surface be roughened of exterior surface area being formed in described scaffolding thread and load on the region be roughened of described scaffolding thread not containing the Li Mosi medicine coating of polymer, the surface roughness of this coating is at least 20 microinch (0.5 μm), further, described range of surface roughness is about 300-700 microinch (7.5-17.5 μm); Described not containing the scope of the surface roughness of rack surface of applied thickness for being roughened described in being greater than of the Li Mosi medicine of polymer.

Consider detailed description of the present invention with reference to the following drawings, above-mentioned and other side of the present invention and embodiment become apparent.

Accompanying drawing explanation

Fig. 1 is the scintigram of the endovascular stent with tinsel main body;

Fig. 2 A is the scanning electron micrograph of the rack surface be abraded;

Fig. 2 B is the scanning electron micrograph on Fig. 2 A surface, the quantity of the projection produced on rack surface after showing abrasion;

Fig. 2 C is the scanning electron micrograph on Fig. 2 A surface, the quantity of the depression produced on rack surface after showing abrasion;

Fig. 3 A is the diagram that pneumatic press processes rack surface;

Fig. 3 B is the in-plant front view of the fixing head punch press assembly of Fig. 3 A, shows pneumatic press and has multiple drift;

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 the fixing head adnexa of the punch press assembly of pneumatic press for Fig. 3 A;

Fig. 4 is the scanning electron micrograph of the support after the process being coated with medicine;

Fig. 5 is the medicine Biolimus that the percetage by weight discharging medicine in the accumulated time by a few hours records at support of the present invention and elution curve in II support;

Fig. 6 represents in difference three months and bimestrial pig transplantation model, medicine Biolimus from support of the present invention and the figure of the percent discharged in II;

Fig. 7 be expression mass spectrum record in pig transplantation model, when from support of the present invention and during discharging in II support, medicine Biolimus along with the figure of the maximum concentration (in ng/mL) of time (in hour) in peripheral blood;

Fig. 8 is for representing for not drug containing with containing Biolimus the figure of the area percent of the thromboembolism (occlusion) of the support of medicine;

Fig. 9 A to Fig. 9 F is for implanting bare mental stents (Fig. 9 A-9B), having containing Biolimus polymer coating wire rack mount (Fig. 9 C-9D) and there is Biolimus the scintigram of support (Fig. 9 E-9F) vascular tissue section of latter 28 days of the tinsel micro-fiber structure of coating; And

Figure 10 A to Figure 10 K is the figure of the tissue morphology measurement (histomorphometry) of grafting vessel containing microstructure stent.

Detailed description of the invention

1. define

Except as otherwise noted, term hereinafter has following meaning.

" surface roughness " or " mean roughness " or " Ra " refer to the arithmetic mean of instantaneous value of the curved surface height recorded in the deviation range in the sample length or area that record from centrage or the median plane (line at center or plane) of image.Usually, as hereafter measured by contactless talysurf with discussing, but also can by the talysurf of contact or by estimating that the height between peak valley records from surperficial displaing micro picture.

" range of surface roughness " or " Rt " is the ultimate range between peak-paddy, by the peak-peak relative to centrage or median plane with calculate with the measurement of the roughness of maximum valley.Usually, measured by contactless talysurf, but also can be recorded by other method above-mentioned.

" Li Mosi medicine " refers to the triolefin immunosuppressive compounds of macro ring, and the general formula that this compound has is at such as U.S. Patent No. 4650803,5288711,5516781,5665772 and 6153252, PCT open No.WO 97/35575, U.S. Patent No. 6273913B1 and shown in U.S. Patent application No.60/176086,2000/021217A1 and 2001/002935A1.

" 42-O-alkoxyalkyl compound " refers to the 42-O-alkoxy-alkyl derivative of rapamycin (rapamycin) described in U.S. Patent application 20050101624 disclosed in 12 days Mays in 2005, 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.

" coating of non-polymer " represents so a kind of coating, its structure and caking property are provided by medicine itself when presence or absence binding agent, instead of provided by the polymeric matrix (that is, polymer support) of the medicine be wherein embedded with.

II. endovascular stent

Fig. 1 illustrates the support built according to the present invention at contraction state.This support comprises and has at least one by the structural member on the surface of at least part of roughening or abrasion or main body, and to be at least used for holding and the anti-restenosis compound discharged, this will hereafter conduct further description.

In the illustrated embodiment, the main body of described support is by by being called that a series of tubular element being called as pole 3 that the silk of connector 4 is connected with each other is formed.Each pole 3 has distensible Z-shaped, sawtooth, spiralled wire zone circle or sinusoidal configuration, and adds the elasticity of integral support with the connection 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 support of expansion is at least at least 2 times of this stent collapses state, is up to 8-9 doubly, such as, says, contraction state diameter is the expansion state that the support of 0.7-1.5mm can be radially expanded into selected 2.0-8.0mm or larger.Have the general rack body structure of this connection, distensible tubular element is known.Such as announcing described in No.WO 99/07308 at PCT, being incorporated into this herein by quoting.

Preferably, supporting structure is obtained by biocompatible materials, such as rustless steel.The further embodiment being 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 arbitrary alloy; Carbon or carbon fiber; Cellulose acetate, celluloid, silicone, poly-para Toluic Acid's glycol ester (polyethylene teraphthalate), polyurethane, polyamide, polyester, poe (polyorthoester), condensing model (polyanhydride), polyether sulfone, Merlon, polypropylene, High molecular weight polyethylene, politef or the compatible copolymer material of other biology, or the mixture of their copolymer; Poly-L-lactide, poly-DL-lactic acid, polyglycolic acid (polyglycolic acid) or their copolymer, condensing model, 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 these materials above-mentioned.Typical support is existing in U.S. Patent No. 6730064 to be described.The size of each support is different from the body cavity (body lumen) that will place according to it.Such as say, support can have the scope from about 0.5mm to about 25.0mm diameter and from about 4mm to the length of about 100mm or longer.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.

As shown in Figure 2 A, described support at least one surface there is roughening at least partially or the micro structure of abrasion or the surface of upgrading.This micro structure can comprise the therapeutic agent that at least one elutes from described micro structure.As from Fig. 2 B-2C visibly, described roughening or the surface of upgrading provide gap or vertical protrusion surface character and/or sink or recessed area.Be understandable that, treatment agent solution or the solution containing therapeutic agent can be inhaled into these recesses by such as capillary force, and apply convex surfaces.The surface area applied in support can be increased in this way.The thickness of these layers refers to the average thickness of layer, such as, and the meansigma methods of the degree of depth of the part injected of layer.Preferably, as shown in Figure 2 A, the chamber surfaces (ablumenal surface) of at least part of support (that is, after placing rack with the surface of the contacts blood for the treatment of) comprises micro-structure surface.

III. the method for textured surface is prepared

In one embodiment, the method comprise use mask be abraded to prevent support at least partially.Preferably, described mask is hydro carbons thin film, such as, but be understandable that, the barrier of any applicable abrasive resistant is all applicable to these methods.Therefore, in a preferred embodiment, the surface of internal cavity to limited bracket is not abraded.In one embodiment, the diameter of the mask sheet of about 5mm × 60mm around axle (capillary glass tube of such as 1.4mm) is reeled.To prop up and be placed in axle and be crimped onto in hydrocarbon mask by hand.Can use 10 times with the stereomicroscopy of 40 times setting (stereo microscope set), with guarantee part that support do not need to be abraded cover by mask.In a preferred embodiment, the stent wall thickness of at least 80% on all surface cover by hydrocarbon film layer.

In one embodiment, micro-spray system (microblasting) is used subsequently, the MICRO that such as Comco provides with or analog, rack surface 5 is processed.In one embodiment, the grinding agent (such as aluminium oxide) of 25 μm is used to carry out roughening to rack surface 5.Be 40psi ± 5psi by pressure adjusting, and nozzle is placed in locates, to produce multiple passage on support apart from rack surface 5 about 2.5cm to 5.0cm.In another embodiment, described mask is removed by any suitable method (such as passing through ultrasonic waves for cleaning).The deionized water being heated to 45 DEG C is filled in common ultrasonic washing unit.The chloroform of the HPLC level of sample bottle is heated to 50-60 DEG C on hot plate.The glass capillary tube mandrel with the support processed is hatched 5-10 minute in the vial of chloroform of the HPLC level of 40 DEG C and 50 DEG C.Subsequently the bottle containing chloroform and axle is carried out in the deionized water of 45 DEG C the sonicated of 2 minutes.

Due to the roughening to rack surface 5, the different component exposed on the metal surface, this can increase the susceptibility to corrosion.As a result, carry out general passivation according to the support of ASTM standard to process, and it is cleaned in (such as chloroform, acetone and/or isopropyl alcohol (isopropyl Alcohol)) in a series of solvent.In one embodiment, be removed when mask and after the support of process is carried out sonicated, it taken out from vial of chloroform.With Acetone rinse sample bottle and then fill with acetone.By being placed in this bottle of process, and in ultrasonic washing unit the sonicated of 2 minutes.Also recharge subsequently with isopropyl alcohol with bottle described in isopropyl alcohol.Support is performed for more than in supersonic cleaning machine the sonicated of 2 minutes.Subsequently, at 60 DEG C ± 30 DEG C, in the nitric acid water-bath of 20 volume %, carry out passivation 30 minutes.Subsequently by support a large amount of rinsed with deionized water 10 times.Will be placed on (such as isopropyl alcohol) in the solvent of 600ml subsequently, and in supersonic cleaning machine, carry out the sonicated of 5 minutes, allow to carry out air-dry.

In another embodiment, the surface of support is uniformly abraded in a controlled manner by sand-blast.The metallic particles (be of a size of about 1-5 μm, and the element being at least 43g/mol by atomic weight obtaining) being called as bullet is used to carry out roughening to rack surface 5.Such as say, 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 produce mechanical syringes (mechanical injector), and its size range is about 3 to about 10 microns.

In another embodiment, rack surface 5 can by laser-induced thermal etching to produce the rule of about 5 to about 25 microns or the pattern of irregular Asperity model (asperities)/mechanical syringes.

In another embodiment, rack surface can be processed into, on surface, nearly chamber (ablumenalsurface), there is the roughness different from luminal surface (lumen surface).Such as, whole surface can be processed by any above-mentioned disclosed method.Subsequently, luminal surface is sheltered, thus second time surface treatment can be carried out on the surface in nearly chamber.Ensuing process can typically utilize stronger method for modifying.Therefore, the different surface obtained can be used for as different useful characteristics is given to outside (nearly chamber (ablumenal)) surface in inside (in tube chamber (the lumenal)) surface of support.In one embodiment, can be optimized the roughness of tube chamber inner surface, to improve inside growth and the adhesiveness of cell, disclosed in such as U.S. Patent application No.2005/0211680, and can be optimized chamber surfaces roughness, to provide the transfer organized towards periphery from chamber surfaces by medicine as described herein.

Can process rack surface 5 by the predetermined portions that the bullet of aequum is placed in rack surface 5 with required pattern.Plate or roller is used to execute granule plus-pressure to produce indenture on rack surface 5.Can also by reaching roughness with the speed granule described in jet blasting on rack surface 5 being enough to produce indenture.Metal surface is carried out to example existing description in U.S. Patent No. 6911100 of sand-blast.

In further embodiment, can by using laser instead of using bullet similarly to reach this uniform, controlled surface roughness.Partly a series of electric discharge is carried out needed for the rack surface 5 of outside or inside.Have enough energy with the electric discharge of surface contact, to make the material on the surface of support evaporate, produce hole (sometimes referred to as hole), the effect of this combination is the rough surface with the surface area added.The example of the method is described in U.S. Patent No. 6913617.

In another embodiment, by compression, uneven process is carried out to the surface of support.Described support is attached in axle, this axle is inserted the mould being equipped with preformed projection, with the indenture of amount, shape, size and the pattern on rack surface 5 needed for formation.Indenture can be formed in many ways, such as, they are welded on rack surface 5 or by sandblasting and be formed.Subsequently mould is centered around a frame peripheral, the surface area needed for also covering with the indenture forming desired depth.According to the processing of mould, the whole surface of support or the part on this surface are processed.The example of the method is described in U.S. Patent No. 7055237.

In another embodiment, with pneumatic press or hydraulic press process rack surface 5.Pneumatic press is well known in the art, as described in U.S. Patent No. 4079617.Hydraulic press is also known in the art, as U.S. Patent No. 7033155.As seen in figs. 3 a-3d, be placed on propping up in axle 1 that is static or that rotate.Preparation will by computer-controlled pneumatic press or hydraulic press 8, processes rack surface with one of several predetermined ways (such as, random or with required pattern).The punch press assembly 9 of forcing press can be configured to the machinery being defined as indenture generation containing one or more drifts 10,11 at this.In a preferred embodiment, described punch press assembly contains multiple drift.Be understandable that, described drift can be that same or different length is to form surface micro-structure.Each drift 10,11 remains on retracted position until computer programming, to process rack surface 5.According to selected program, drift 10,11 carries out punching press by with the power enough producing indenture to rack surface 5.Usually, punch press assembly 9 is set to the width being no more than required support, and such as, if stent strut 3 is 15 μm, then the overall width of multiple drift 10,11 is also no more than 15 μm.The quantity of the drift 10,11 on given punch press assembly 9 can be different according to the width of support.Similarly, described punch press assembly 9 can be set to the fixing head on prefabricated punch press, and these fixing head can be exchanged according to required shape.And described fixing head can for static and overturn support, or on the contrary, fixing can be moveable, this be embodied in single drift 10,11 energy that is fixed to punch press random on rack surface 5, produce impression.

In another embodiment, by it with before being laser-cut into multiple required stent length, the whole length (such as, the length of pipe is 2.5m) of the pipe for the manufacture of support is processed.Support flatly or is vertically attached in one or more axle 1, and uses in the application and say that one of disclosed method is denuded.Carrying out in friction process, carrying out processing support randomly, equably or with required mode to support.In addition, the length direction of support and side are carried out longitudinally, vertically or spirally processed.And by be moved and through static roughening mechanism, or on the contrary, the static and roughening mechanism of whole stent tube length can move (such as level low, vertically, spirally) and processes rack surface 5 by the length direction one of in the manner disclosed along pipe.

The enterprising action potential corrosion test of support after treatment, to confirm satisfaction and the effect thereof of passivation step.The breakdown potential of support after data demonstrate process, passivation is positioned at the voltage levels standards that ASTM specifies satisfactorily.Therefore, after the roughening process and passivation, the corrosion of the support performance after process does not show similar more significantly to untreated support, and roughening process can not increase restenosis and thrombotic risk.After passivation, the micro-structure metal surface observed with to have the biocompatibility observed in the support of level and smooth electropolished surfaces suitable.

The thickness of the wall of untreated support is generally about about 0.05mm.As shown in Fig. 2 B-2C, process in the manner disclosed to rack surface 5, the average height at the peak (peak) 6 of generation is about 1.30 μm and the mean depth of paddy (valley) 7 is the rack surface 5 of 2.08 μm.Anyly by roughening process (if there is) being affected on supporting structure globality to measure, support after treatment carrying out axial fatigue test and auger analysis (auger analysis).Axial fatigue test concentrates on the position that support is easy to impaired most, is the connector 4 between stent strut 3.After the circulation more than 300 ten thousand times under simulation physiological condition, the support of untreated scaffold control and roughening all keeps complete.Because a part for processed support is removed in roughening process, and find that processed support can bear the identical fatigue condition that can bear with the untreated intact stent with more multilist region, should be appreciated that this roughening process adds the fatigue durability of support owing to destroying the microstructure of rack body really.Finally, the support of process carries out auger analysis, is described with effects on surface chemistry, which reflects identical element in the support after the support of non-alligatoring and the process of alligatoring of passivation and there is similar amount.Which demonstrate and can not produce adverse effect to rack surface chemistry to the method for the passivation that untreated crt bracket carries out in the manner disclosed.

Embodiment 2 provides the surface roughness Ra measured by 4 supports such as prepared above by carrying out surface abrasion with the particle jetting of pressurization and coarse parameter Rt.Can find out, the value of surface roughness is all at least 20 microinch (0.5 μm), and be generally about 20-40 microinch (μ inch) (0.5 μm-1.0 μm), further, for 300-700 microinch (7.5 μm-17.5 μm), and be generally at 300-5000.5 microinch (7.5 μm-12.5 μm).According to an aspect of the present invention, find these roughness values, the numerical value particularly in these roughness range, be best for the anti-restenosis effect obtaining the best in patient body.

Under not wishing that this effect is limited to special theory, the concave-convex surface body or the protrusion that are arranged in the peak-paddy scope of 300-700 microinch show the blood vessel being most suitable for being entered by the medicine of medication coat " injection " to surrounding.Therefore, for example, when dissolving from coating by medicine or by fragmentation occurring at placing rack process floating coat and makes these protrusions expose, these protrusions can promote medicine intravasation by extruding or thrust the angiosomes of local.Result, compared with observing with the Li Mosi FirebirdTM being coated with polymer, the roughness range of the rack surface limited is combined with the coating not containing polymer, when there is not polymer support, can keep or reduce restenosis or thrombotic occurrence probability and/or degree further, and compared with the coating of the non-polymer reduced with surface coarsening degree (namely, there is lower range of surface roughness), reduce further restenosis or thrombotic occurrence probability and/or degree.In addition, in order to support that the research that the present invention carries out shows, have the support of surface roughness characteristics, the scope of peak-valley is that the effect of 800-1000 microinch (20-25 μm or higher) in minimizing restenosis is poor.

Therefore, on the one hand, the present invention is by using the effect in the generation of bracket for eluting medicament (such as, Li Mosi FirebirdTM) restenosis in treatment blood vessel injury and/or degree with improvement.Above-mentioned improvement comprises the following steps: carry out alligatoring until surface roughness is at least about 20 microinch (0.5 μm) at least near chamber surface portion of support, further, alligatoring is about 300-700 microinch (7.5-17.5 μm) to the scope of surface roughness, and apply with the region be roughened of Li Mosi medication coat to scaffolding thread of non-polymer, the thickness of coating is greater than the surface roughness of the rack surface be roughened, that is, the thickness of coating forms substantially complete medication coat.

Preferably, antiproliferative Biolimus will be comprised the nearly cavity segment of support is at least applied at interior API (that is, active pharmaceutical component).Described API can be applied to rack surface in any suitable method, comprises by with the rack surface after the process of API solution spraying.Whole support also can be immersed in after required API by described API solution, or by being manually coated directly onto on rack surface 5 by it, is coated with API solution.Biolimus have amorphous-semicrystalline structure, this structure is easy to cracking or fragmentation unlike the Li Mosi compound of other crystallization.Therefore, Biolimus character allow in its treatment surface being attached to the roughening of the support of unexpanded mode and expansion state.

Preferably, described API material by automatically moving the nearly cavity segment that liquid method is applied to support, as described in the total U.S. Patent No. 6939376.By required API being dissolved in (such as ethyl acetate or acetonitrile) in suitable solvent, obtained concentration range is the solution of about 100-200mg/ml.This solution is placed in reservoir, and this reservoir has pump and transports solution with set rate.Such as, by pump described in Microcomputer control, purchased from the 4-Axis Dispensing RobotModel of I & J Fisnar Inc company.The solution delivery tube being used for solvent mixture to be transported to rack surface 5 is attached to the bottom of reservoir.Described reservoir and delivery tube are assembled into moveable supporter, and this supporter can continuously or step by step mobile solvent delivery tube, and such as, the y direction along support often walks 0.2mm.

With the dop (chuck) contacted with the inner surface of at least one end of support rotated, the support of uncoated is clamped.By (0.5 degree often walks) rotating continuously or progressively, realize the axial-rotation to support.Alternately, delivery tube is maintained at fixing position, and support also vertically moves along it when rotated, to realize coating process.

Before use, the pipe of transport solution is aspirated and molding under Bunsen burner (Bunsen burner), be formed in the pipe that there is tapered opening on pipe top, so that accurately make the mixture of medication/solvent, subsequently, on the described mixture whole length that can be applied to required for support along with the formation at the top of pipe and side.Below also within the scope of the invention, use more than a kind of operation of dispense tube class to form coating, or alternately use more than a kind of moveable solution storage tank, this solution storage tank is equipped with different top, or the different supplementary medicine containing the multiple solution in order to form coating in the solution of different viscosities or identical method.

In another embodiment, the non-porous layer of the polymer of the derivant of Parylene, Parylene or other biocompatibility is arranged on rack surface after treatment, and the api layer needed for arranging on this layer or being formed.Optionally, API directly arranges the other layer of non-porous polymer, this contributes to the release controlling to occur in time.According to the present invention, described support comprises at least one api layer be deposited thereon, and other surface can not containing API or containing one or more different APIs.In this way, one or more API can be discharged in blood flow by the luminal surface of support, and are released to the vascular injury site outside rack surface for the different therapeutic agent of different situations.

In another embodiment, described support can when not needing polymer coated by API molecule.As illustrated in fig. 4, all or part of method of carrying out roughening to described support in above disclosed method, permission API is directly attached on the surface of the support 14 after process.In common embodiment, API is Li Mosi medicine, such as 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 2001/002935A1 at PCT.Exemplary Li Mosi medicine is 42-O-alkoxyalkyl medicine, such as Biolimus A9.Other API medicine that can be used alone or be combined with Li Mosi medicine comprises: anti-platelet agents or antithrombotic agent, or anti-inflammatory agent (as dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate or other dexamethasone derivative) or anti-inflammation steroids.The inner surface of described support and/or outer surface also can be used for transporting the API molecule of other type, such as thrombosis agent, vasodilation, hypotensive agent, antibacterial or antibiotic, antimitotic agent, antiproliferative (antiproliferatives agents), 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), antibody-targeted therapy agent, prodrug, gonadal hormone, free radical scavenger, antioxidant, biological preparation, radiotherapeutic agents (radiotherapeutic agents), contrast agent and radioactive indicator.

Described support can be included in the assembly containing rack body, and described rack body is around on the flat utricule be attached on distal catheter portion, and described conduit is used for the position of Stent Implantation in vascular injury.Described conduit is utilized by brachial artery or femoral artery, support to be introduced the cardiovascular system of patient.Conduit tube component is pushed ahead by coronary vessel system, until the combination of flat utricule and support is placed in vascular injury place, angiopathy place or angiostenosis place.Make balloon inflation arrive preliminary dimension subsequently, with by stent-expansion to enough large to contact with tube chamber constantly.Subsequently utricule venting is fetched to allow conduit to less shape from the vascular system of patient, and support is stayed original place.Typical stent implantation procedure is existing in US Patent No 6913617 to be described.

IV. using method

This section describes the performance characteristic according to vascular treatment methods of the present invention and the support according to the present invention's structure.

Propose method of the present invention to make to receive the patient of localized vascular injury, or the risk of restenosis occurs in the patient with blood vessel embolism risk and/or degree minimizes.Normally, blood vessel injury is to produce when opening blood vessel (the such as coronary artery or peripheral blood vessel tremulous pulse) of part thromboembolism in angiographic procedure.Optionally, described support be directed into angiostenosis place, and the narrow (that is, blood vessel injury disease place) utilizing utricule to carry out expanding directly to open blood vessel.Mentioned by the first to angiographic process in, first balloon catheter is placed in thromboembolism place, and the inflation of the utricule of end is exitted one or many again, open to force the blood vessel of thromboembolism.This vasodilation (wherein platelet may be removed) being usually directed to the wound at blood vessel wall place produces a large amount of localized injury usually, make tremulous pulse constantly to due to cell propagation and again thromboembolism produce and reply.No wonder, the generation of restenosis or severity are usually relevant with the blood vessel level of stretch in angiographic procedure.Particularly when excess elongation 10% or more, restenosis there is higher probability, and there is suitable seriousness usually, that is, blood vessel embolism.In the replaceability process of the direct placing rack mentioned by the second, do not need to carry out angioplasty (namely in advance, " Direct stenting method "), wherein still can cause vascular injury due to the expansion at vascular injury disease place of support and utricule, this makes contraction again and the cell proliferation of inserting place at support, and that observes in its order of severity and the first process aforementioned is similar.

Expect that use of the present invention is not subject to the restriction of any concrete Therapeutic Method and injured blood vessel position, and technology described above can be used, or be used for the treatment of the known replacement technology of angiopathy and damage.When carrying out of the present invention, usually by described support with its contracted state be placed on conduit far-end or in the tube chamber of conduit, or to be placed on the utricule of end with contracted state.Subsequently tip catheter end is imported the position of injury site or potential generation thromboembolism, then discharge from conduit, such as, to the sheath of covered stent of pulling back, to be discharged on described position by support, if described support is self expansion, or make stent-expansion on utricule by balloon inflation, in fact when being expanded to support and vessel wall contact, then in this position by described stenter to implant tissue wall.

Once expand in described position, the support being coated with medicine starts to the cell release of active compounds (API) in artery position, with antiproliferative effect and/or for other treatment benefit, such as, reduce inflammation, restriction thrombosis, reduce apoptosis etc.Fig. 5 illustrates 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 iI support, it has containing Biolimus polymer coating.

Fig. 6 illustrates Biolimus drug release percent in the support being coated with polymer and upgrading.As shown in the figure, only after 2 months, from the support of upgrading, release the Biolimus of 100% on the contrary, after 3 months, the drug residue of about 30% is on the support being coated with polymer.

Fig. 7 illustrates with mass spectrograph being coated with polymer in each in the non-polymer support of II support and upgrading, the Biolimus recorded peaks of blood concentration.As shown in the figure, for the support of upgrading, Biolimus time peaks of blood concentration appears at about 4 hours.And for being coated with polymer iI support, Biolimus peaks of blood concentration appear at about 2 months time.

Fig. 9 A-9F shows the cross section of angiosomes, described angiosomes have implantation bare mental stents (Fig. 9 A-9B), there is 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 there is the Biolimus of 225 μ g the support (Fig. 9 E-9F) of upgrading, wherein, the silk of coating illustrates in section.The figure illustrates the release of the anti-compound shunk again vascular wall area towards periphery from each region.Along with passage of time, the smooth muscle cell forming blood vessel wall starts to grow and pass the framework in support or helical opening, and support is wrapped into both sides by the final continuous print inner cell layer that formed.If the transplanting of this support is successful, the degree of the blood vessel embolism subsequently in this position will reduce by 50%, and that is, Ink vessel transfusing keeps the diameter of cross section of the passage of flowing to be at least 50% of the diameter of the support of expansion when implanting.

Experiment in the restenosis animal model of pig, if the people such as Schwartz are at (" Restenosis AfterBalloon Angioplasty-A Practical Proliferative Model in Porcine CoronaryArteries ", Circulation 82:(6) 2190-2200, Dec 1990.) described in.Be studied in the model of pig, these researchs confirm that support of the present invention has the ability that can limit extent of restenosis, and confirm that support of the present invention has other advantage than the support proposed at present and test.This research summary in embodiment 3.

In brief, this research compares the again shrinkage degree of in animal model implant frame (bare mental stents, be coated with the support of polymer and the support of upgrading) after 28 days.

The support that Fig. 9 A-9F shows support and the upgrading being coated with polymer all significantly reduces the level of shrinking again.As a rule, receive the vascular manifestations being coated with the support of polymeric drug and the support of upgrading and go out to obtain good healing, define good endodermis.Evidence suggests, cure completely and vessel homeostasis after 28 days in transplanting.

Other experiment confirms that support described herein is at least trimestral duration, has the ability of the degree that can limit restenosis.This research summary is in embodiment 4.

In brief, this research compares the degree that the bracket for eluting medicament (pfDES) implanting bare mental stents (BMS) and non-polymer occurs after 3 months to shrink again.Tissue morphology data representation shown in table 4, compared with BMS, pfDES greatly reduces the level of shrinking again.

Following embodiment manufactures setting forth and uses the various aspects of support of the present invention.They are not the restrictions to scope of the present invention.

Embodiment 1

Biolimus in vitro from the drug release of support

Make to be coated with containing anti-proliferative drugs Biolimus polymer iI support and with have nearly chamber micro structure containing Biolimus support be carry out vitro drug release in the Tween medium of 7.4/37 DEG C at pH.Periodically sample, and measure Biolimus by HPLC total amount.Fig. 5 illustrates the drug release of II support and microstructure stent.

Embodiment 2

Roughness parameter bench test (bench test)

The outer surface of Bioflex II 6 arch support (crown stent) is carried out abrasion process, to produce the optionally micro structure of drug loading capacity on this rack outer surface, be called as biology-free support (Bio-Freedom Stent, FS).Therapeutic agent optionally can be applied directly the surface of the micro structure at support.

The feature of the roughness parameter of FS is to employ Veeco Metrology Group (Tucson, Ariz.) the WYKO NT-2000 system being available commercially non-contact surface photometer.Model eliminates cylindricality and inclination item to have the vertical scanning interferometer (vertical scanning interferometer, VSI) of the 32nd edition software, thus it is smooth that rack surface is looked like.Use the low pass filter eliminating the impact of high spatial frequency roughness, smoothing is carried out to the feature being less than 9 pixel forms.The result of 4 kinds of different supports is shown in following table, and the surface roughness of these 4 kinds of supports is produced by sandblasting, and wherein, as defined above, Ra is average surface roughness, and Rt is range of surface roughness.

	Sandblasting 3 microinch	Sandblasting 4 microinch	Sandblasting 5 microinch	Sandblasting 6 microinch
					Ra	30.2	25.4	25.0	28.3
Rt	688.8	336.8	406.9	358.9

Embodiment 3

Animal implant tests textured

To have and not there is Biolimus the stenter to implant of the upgrading from embodiment 2 in the young pig of outbreed.According to the pig overstretch model of standard of excessively extension with 10-20%, balloon catheter is used to carry out placing rack.Before placing rack, determine blood vessel by the target of known angioplasty techniques to young pig and carry out preexpanding (predilated).

After 28 days, according to the clause of permitting to this euthanizing animals, from this animal, take out heart and perienchyma.

Use the microscope containing digital camera, to obtain the high-definition picture of the vessel cross-sections making section, the results are shown in Fig. 9 A-9F.According to the following steps tissue morphology measurement is carried out to this image:

Support and tremulous pulse are dissected, and carries out ultrathin section.The sample of various growth signals, cell proliferation and other cell debris is dyeed.Tissue morphology measurement is carried out as follows:

With mm ²meter tremulous pulse area (Figure 10 A), IEL (Figure 10 B), with mm ²meter Intimal area (Figure 10 C), with mm ²meter Lumen Area (Figure 10 D), in the tube chamber thickness of micron (Figure 10 E), 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 intimal extracellular matrix 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 adventitia removal and Fibrotic histological grade (Figure 10 K).

Following table illustrates the therapeutic effect 28 days time." Lumen Area mm is entitled as in following table ²" data reacted the morphometric Analysis result of support and the blood vessel that (f/u) is after 28 days taken out from pig.

Table 1: tissue morphology measurement's result

Fig. 8 shows each support with the surface of upgrading and has the surface of upgrading and the Biolimus of 225 μ g the area % thromboembolism of support.

Embodiment 4

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 biomatrix scaffold of the non-polymer of sandblasting or naked BioFlex II support by embodiment 2, be implanted in the farm pig model of hybridization.

The zoografting parent (matrix) of the coronary stent of table 3. pig

BMS=bare mental stents, the bracket for eluting medicament of pfDES=non-polymer

^*the non-implant frame of LCX, this is because the off size of support is fitted

CV Path institute limited company obtains the heart from 5 pigs.In 5 pigs, do not carry out the support of repetition, and three months time implant frame and carry out optical microscope (lightmicroscopic) analyze.The reason that No. 1 animal is namely dead before predetermined ensuing period, and carries out stenter to implant 2 months time and perform the operation and have nothing to do.LCA (LCX) the non-implant frame of #3 animal, this is because the off size of LCX is fitted.

B. material and light microscope methods

For optical microscope, the vessel segment of implant frame is implanted in methylmethacrylate plastics, cut off proximal stent, mid-stent and holder end portion distal end, be loaded in the section of filling, and dye with h and E (hematoxylin & eosin) and Elastic Van Gieson (EVG).The near-end of undyed tremulous pulse and distal portions are implanted in paraffin, in 4-5 micron punishment section, and dye with h and E and EVG.The formation of inflammation, thrombosis, new intima and the existence of vascular damaged in all fragments is tested by optical microscope.Morphometric analysis: use for the length of all targets for 2.0mm and the micron-sized traceable NIST microscope of the diameter circle that is 2.0mm, to somatometry of physique software (IP Lab for Macintosh, Scanalytics, Rockville, MD) calibrate.All micron scale are through the certification of Klarmann Rulings company.Measured area comprises 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 obtained.Narrow percentage ratio is obtained by equation [1-(Lumen Area/support area)] × 100.Use Schwartz method (people such as Schwartz RS., J AmColl Cardiol 1992; 19:267-274) determine the score of blood vessel injury.Obtain the score of the inflammation of each fragment, fibrin and damage based on grade analysis, wherein, 0=does not have inflammation/fibrin/damage, the significant inflammation/fibrin/damage of 3=.To occurring that the inflammation of the fragment that two or more granuloma is reacted is to being divided into 4 points.Endothelium is covered as semiquantitative, and is expressed as the percentage ratio of interior cavity perimeter.

C. statistical analysis

Morphometry continuous data is expressed as meansigma methods ± SD.

Student t-inspection (Student ' s t-test) is used to carry out statistical analysis to normal distributed constant.Wilcoxon test is used to analyze to the parameter of improper distribution or centrifugal pump.Normal distribution is tested in Wilk-Shapiro test.The p value being less than 0.05 is thought to have significance,statistical.

D.X actinogram

All supports all show large degree and average expansion and do not have the evidence of fragmentation or bending.

E. observation by light microscope

1. the DES of non-polymer

3 months after the implantation, all supports were expanded by large degree, and obviously there is no evidence and there occurs thrombosis.The formation of new intima comparatively relaxes, and the average thickness of new intima is 0.16mm and contains by the smooth muscle cell of loosely filling and the substrate being rich in proteoglycan.Blood vessel injury is gentleer.Observe the fibrine precipitation of the gentleness around pole.Although found in the LCX of No. 5 animals granulomatous response, in other blood vessel, overall inflammation has been minimum.Occasional finds and have recorded giant cell.Endothelialization is completed when there is no intracavity inflammatory cell and/or platelet adhesion.Strikingly, in the new intima of the proximal part of the LCX of No. 2 animals containing bare mental stents, find intensive calcification.

2. bare mental stents

3 months after the implantation, all supports were expanded by large degree, and obviously there is no evidence and there occurs thrombosis.The formation of new intima comparatively relaxes, and the average thickness of new intima is 0..21mm and containing the smooth muscle cell be closely packed.Internal break is observed in the anterior descending coronary (LeftAnterior Descending coronary artery, LAD) of No. 2 animals.This blood vessel having showed extensive inflammation around pole may be that the damage produced due to implantation process causes.But except this animal, blood vessel injury and inflammation are what relax on the whole.All in any support and do not find fibrine precipitation and adherent bad (malapposition).Endothelialization is completed when there is not intracavity inflammatory cell and/or platelet adhesion.

F. histomorphometricall

The tissue morphology of PES 3 months time of table 4.BMS and non-polymer compares

Process	The DES (n=7) of non-polymer	BMS(n＝4)	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
				Lumen Area (mm 2)	6.27±1.59	4.17±0.98	0.04

^*p value is obtained by Wilcoxon test statistics Epidemiological Analysis

This zooperal result confirms compared with the implantation of naked metal crt bracket (BMS), the bracket for eluting medicament (free DES) of non-polymer is in the model of pig after implant frame when 3 months, Lumen Area is increased significantly (that is, decreasing restenosis).

Description of the invention is only exemplary illustration, and the change therefore not deviating from purport of the present invention comprises within the scope of the invention.This change should not be construed beyond the spirit and scope of the invention.

Claims (17)

1. prepare the method for support for one kind, with by settles at impaired place formed by the tinsel interconnected and apply on the outer surface of scaffolding thread the distensible bare mental stents of polymer support containing favourable not this medicine viewed compared with, described support reduces the restenosis caused by blood vessel injury of patient or the occurrence probability of thrombosis and/or degree, and the method comprises:

By the surface roughness (Ra) of the exterior surface area alligatoring of scaffolding thread at least 20 microinch (0.5 μm), and the range of surface roughness (Rt) of 300-700 microinch (7.5-17.5 μm), and

Apply, until the thickness of coating is greater than the range of surface roughness of the rack surface be roughened with the alligatoring region of Li Mosi medication coat to described scaffolding thread of non-polymer.

2. prepare a method for expansible support, described expansible support is formed by the tinsel interconnected and is applied at the outer surface of described support by the Li Mosi medication coat of non-polymer, and for anti-restenosis drugs administration, the method comprises:

By the surface roughness of the exterior surface area alligatoring of the scaffolding thread of favourable not this medicine of coating at least 20 microinch (0.5 μm), and the range of surface roughness of 300-700 microinch (7.5-17.5 μm).

3. method according to claim 1 and 2, wherein, by described scaffolding thread alligatoring to the surface roughness of 20-40 microinch (0.5-1 μm).

4. method according to claim 1 and 2, wherein, described alligatoring is undertaken by denuding the exterior surface area of described scaffolding thread by the abrasive Flow of pressurization.

5. method according to claim 1 and 2, wherein, described alligatoring is undertaken by following steps: in the exterior surface area of described scaffolding thread, form hydrocarbon-film mask, is optionally got rid of by the material of the described support exposed by described shelter, and is got rid of by described shelter.

6. method according to claim 1 and 2, wherein, described alligatoring is undertaken by carrying out laser-induced thermal etching to the exterior surface area of described scaffolding thread.

7. method according to claim 1 and 2, wherein, described alligatoring is undertaken by carrying out sandblasting to the exterior surface area of described scaffolding thread, to form pattern in exterior surface area.

8. method according to claim 1 and 2, wherein, described coating by being coated with the drug solution of thickness on the outer surface of described scaffolding thread, and is carried out dry carrying out to form the medication coat of solid on scaffolding thread to the solution of coating.

9. method according to claim 1 and 2, wherein, described coating is undertaken by being coated with Li Mosi medicine on support, and the coating weight of described Li Mosi medicine makes the final quantity of Li Mosi medicine on the support of every centimeter length be 80-240 μ g.

10. method according to claim 1, wherein, described coating is that the mode producing the final medication coat that thickness is 5-15 μm is carried out.

11. methods according to claim 1 and 2, wherein, the described Li Mosi medicine applying described support is Biolimus A9.

12. 1 kinds of expandable stents for the occurrence probability and/or degree that reduce restenosis or thrombosis, do not produce when described being placed on blood vessel injury place having the support of Li Mosi drug eluting polymer coatings and the inflammatory response produced, this support comprises:

The expansible support main body formed by the tinsel be connected to each other;

The surface be roughened that the exterior surface area of described scaffolding thread is formed, this surface be roughened has the surface roughness of at least 20 microinch (0.5 μm), with 300-700 microinch (7.5-17.5 μm) range of surface roughness, and

The Li Mosi medication coat of the non-polymer of load on the region be roughened of described scaffolding thread, the thickness of this coating is greater than the range of surface roughness of the rack surface be roughened.

13. supports according to claim 12, wherein, described scaffolding thread is roughened the surface roughness to 20-40 microinch (0.5-1 μm).

14. supports according to claim 12, wherein, described scaffolding thread is roughened the range of surface roughness to 300-500 microinch (7.5-12.5 μm).

15. supports according to claim 12, wherein, described Li Mosi medicine is Biolimus A9.

16. supports according to claim 12, wherein, the overlay capacity of Li Mosi medication coat on the support of every centimeter length of described non-polymer is 80-240 μ g.

17. supports according to claim 12, wherein, the thickness of the Li Mosi medication coat of described non-polymer is 5-15 μm.