CN1735391A - Method of loading beneficial agent to a prosthesis by fluid-jet application - Google Patents

Abstract

An interventional device for delivery of beneficial agent to a lumen and methods of loading and manufacture of the same, which include a prosthesis loaded with beneficial agent to provide a controlled dosage concentration of beneficial agent to the lumen. The beneficial agent is loaded onto the prosthesis by a fluid-dispenser having a dispensing element capable of dispensing the beneficial agent in discrete droplets, each droplet having a controlled trajectory. The method of loading beneficial agent includes dispensing beneficial agent in a raster format and/or an off-axis format along a dispensing path.

Description

Apply method with the method for loading beneficial agent to the prosthese by fluid jet

Background of invention

Invention field

The present invention relates to a kind of fluid distributor that utilizes with the method and system of loading beneficial agent to the prosthese, fluid distributor has the distribution member that can distribute beneficial agent with the form of discontinuous drop, and each drop has in check track.This method relates to especially along dispense path and distributes useful compositions and methods with form (off-axis format) outside raster mode (raster format) and/or the axle.

Description of related art

Percutaneous transluminal coronary angioplasty (PTCA) is the cardiopathic method of a kind of treatment.This method need be incorporated into one group of conduit tube component in patient's the cardiovascular system by the upper arm or femoral artery usually, and the propulsion bulb assembly is by vascular system coronarius, and the air bag on it partly is positioned at the position of passing inaccessible focus.In case be placed in the position of passing focus, then airbag inflation is to predetermined size, to compress the atheromatous plaque of focus radially, to reinvent blood vessel wall.Subsequently, give air bag deflation, conduit tube component is withdrawed from from vascular system.

Though PCTA generally uses, it can be subjected to the puzzlement of two specific questions.The first, behind the several hrs that begins after the process of expansion or within, blood vessel may take place acute closed at once.This obturation is called as " closed suddenly ".Nearly 5 percent closure suddenly takes place in the case of using PTCA.Think that the dominant mechanism of unexpected closure is that elastic resilience, tremulous pulse split and/or thrombosis.Second problem relevant with this process is that after the initial success of angioplasty, it is narrow that tremulous pulse becomes again.This narrow again be called as " restenosis ", it typically occurs within six months in the angioplasty back.It is believed that restenosis be because, in other reason, cellular component is from arterial wall breeding and migration and the change that is called as the arterial wall geometry of " refigure ".

In order to reduce the formation of arterial occlusion and thrombosis and/or restenosis, with a kind of expandable intervention device or prosthese, an one example comprises support, implants in the tube chamber, to keep the opening of blood vessel.In addition, in order to realize the treatment of this angiopathy better, preferably device or prosthese in the tube chamber are loaded for example antiproliferative of one or more beneficial agent, so that it is delivered in the tube chamber.A kind of common application technology that is used for local delivery is to use to be coated with the polymeric carrier that steeps on the rack surface, as disclosed in people's such as Berg U.S. Patent No. 5,464,650, its disclosure is incorporated into herein as a reference.This conventional method and product it has been generally acknowledged that they are gratifying for their intended purpose.Yet some problems relevant with this medicament elution intervention device are that medicine is loaded into the transmutability on the intervention device, and the transmutability of the drug level between device and the device.Other rough sledding comprises: can not strictly control and keep drug level, can not determine any loads for drug distribution or medicine on the device, can not change drug distribution with controlled and predetermined way, to realize that desirable drug loading distributes, can not be with different being loaded on the similar face of device with medicine inconsistent especially or that respond, with the very difficult local surfaces density that is delivered to the beneficial agent in the tube chamber of controlling, especially, if intervention device is a kind of device that scribbles the overlapping or bifurcated of beneficial agent.

Can obviously find out from correlation technique, with beneficial agent for example the medicine conventional method of loading intervention device usually need prosthese all to be coated with stain with the polymer that can discharge medicine, as United States Patent (USP) 5 at Campbell, 649,977 and people's such as Dinh U.S. Patent No. 5, disclosed in 591,227, during its disclosure is incorporated herein as a reference.Because some intervention device may have the surface area of variation along its length direction, this conventional loading technology causes unintentionally or unnecessary DM.In addition, if wish that the prosthese that two or more routines are loaded is overlapping, for example use the nested support or the support of bifurcated, then the accumulated dose of the beneficial agent in the tube chamber will surpass specified or target dose.Another shortcoming with the conventional method of loading beneficial agent intervention device is optionally administration, and for example different positions provides the identical beneficial agent of various beneficial agents or various concentration on prosthese, to be implemented in the treatment at concrete target site place.

Therefore, need a kind of control,, treated with the target location that is implemented in tube chamber so that the intervention device with beneficial agent variable distribution characteristic is provided with the efficient and economic method of loading beneficial agent to the prosthese.In addition, need a kind of intervention device that the associating curative effect of two or more beneficial agents that are carried on the prosthese different surfaces can be provided, to realize general release and to be released on the wall of tube chamber.Further, exist the needs of inconsistent loading beneficial agent on the similar face of prosthese.Advantage of the present invention can satisfy above-mentioned needs.

Summary of the invention

Objects and advantages of the present invention will be listed in the following description, and it is evident that from description subsequently, and will learn by practice of the present invention.

In addition, advantage of the present invention will be by realizing and obtain in written description and claim and from additional accompanying drawing specifically noted method and system.

In order to obtain these and other advantage and according to purpose of the present invention, as imbody with broadly described, the present invention includes the method for a kind of loading beneficial agent that will be used in tube chamber, sending to the prosthese.This method may further comprise the steps: provide a kind of in tube chamber unfolded prosthese; Beneficial agent from prosthesis delivery is provided; A kind of fluid distributor that can be assigned the distribution member of beneficial reagent with discontinuous drop form that has is provided, and each drop has in check trajectory; Between distribution member and prosthese, form relative displacement, to define the dispense path of distributing beneficial agent with raster mode; With optionally distribute beneficial agent to the predetermined portions of prosthese along dispense path from distribution member.

In another aspect of the present invention, a kind of method is provided, wherein the prosthese that provides step to provide by prosthese comprise many interconnective, define its structural elements of opening each other, and allocation step comprises when distribution member and is assigned beneficial reagent when member in the prosthese predetermined portions aligns, and when each other register of distribution member and its, stop beneficial agent being dispensed to prosthese.

Preferably, this method further comprises and detects the step that distribution member when aligns with structural elements in the prosthese predetermined portions.More preferably, detecting step utilizes pick off to carry out.

In another aspect of this invention, provide a kind of method, further comprised the step of the controller that is provided for the operated allocated element.In this aspect of the invention, allocation step is preferably undertaken by with the structural elements position that is positioned at the prosthese predetermined portions controller being programmed.

Aspect another, provide a kind of method of the present invention, wherein the prosthese that provides step to provide by prosthese has a central shaft of determining along its length.Beneficial agent is the surface that is assigned to prosthese from distribution member with discontinuous drop form, along controlled track.The controlled track of beneficial agent is through alignment, in order to avoid crossing with the central axis of prosthese.

In another aspect of the present invention; the prosthese that provides step to provide by prosthese comprises tubular articles; its have many interconnective, limit its structural elements of opening each other, and the controlled track of each drop basically with the predetermined portions of prosthese in structural elements surperficial tangent.More preferably, tangent basically path substantial alignment between the inside of prosthese and outer surface.

Again aspect another, provide a kind of method of the present invention, comprise that further repetition distributes the step of the step of beneficial agent selectively to the predetermined portions of prosthese along dispense path, from distribution member.

A kind of method also is provided, wherein by form dispense path that step determines comprise series of parallel, along the passage of prosthetic surface.Preferably, the prosthese that provides step to provide by prosthese had a kind of tubular body before launching, and tubular body has defined the longitudinal axis by it.More preferably, in this method, be parallel to this longitudinal axis by each parallel channels that forms the definite dispense path of step.

In another aspect of the present invention, distribution member and the relative displacement between the prosthese during the formation step are carried out with constant speed basically.

Of the present invention another aspect, a kind of method is provided, comprise the step that surface charge is applied to the selected drop of the beneficial agent that distributes from distribution member.Preferably, the surface charge that is applied to the selected drop of beneficial agent is a positive charge; And beneficial agent comprises antioxidant.The controlled track of the selected drop by the beneficial agent of electric charge on the applying step band can also change by deflection field.Preferably, distribute the distribution member that provides step to provide to define the width that fluid distributes by fluid.In addition, preferably include the series of parallel passage by forming the definite dispense path of step.The path width of each parallel channels is to select according to the target surface density of prosthese part.A kind of method also is provided, further has been included in the step of using opposite charges in the predetermined portions of prosthese.

Of the present invention again aspect another, allocation step comprise change with loading beneficial agent to relative velocity, to change the local surfaces density of beneficial agent on the prosthese selected location along the selected location of prosthese.Preferably, the step of change relative velocity comprises that change applies the frequency of useful reagent droplet along the unit length of dispense path.The step that changes relative velocity can also comprise the relative displacement that changes between distribution member and the prosthese.The step that changes relative velocity can also comprise the beneficial agent amount of change from each drop of distribution member distribution.

Of the present invention aspect another, this method further comprises the step of a kind of solvent application to the prosthese, makes to be assigned to beneficial agent redistribution on the predetermined portions by allocation step.A kind of method also is provided, has further comprised the following steps: to provide the second kind of beneficial agent that discharges from prosthese; Second kind of distribution member that can distribute second kind of beneficial agent with discontinuous drop form, along controlled track is provided; Along second kind of dispense path, between second kind of distribution member and prosthese, form relative displacement; With along second kind of dispense path, distribute second predetermined portions of second kind of beneficial agent to prosthese from second kind of distribution member.

Again aspect another, this method comprises from support, transplant, support-transplant, filter and other endovascular device selects prosthese of the present invention.

Of the present invention further aspect, the beneficial agent that provides step to provide by beneficial agent is selected from: antithrombotic agent, anticoagulant, antiplatelet reagent, lipotropism class reagent, thrombolytics, antiproliferative, anti-inflammatory agent suppresses hypertrophy reagent, the smooth muscle cell inhibitor, antibiotic, growth factor receptor inhibitors, cell adhesion inhibitors, cell adhesion promoter, antimitotic agent, antifibrin agent (anti fibrin), antioxidant, antineoplastic agent, promote endotheliocyte to recover reagent, anti-allergic material, radiopaque reagent, viral vector, antisense compounds, oligonucleotide (oligionucleotides), cell sees through reinforcing agent, vascularization reagent and their combination.The beneficial agent that provides step to provide by beneficial agent can also be selected from: Paclitaxel, dexamethasone, rapamycin, everolimus, heparin, estradiol, and forms of rapamycin analogs, ABT-578, that is, and 3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS) 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-16 hydrogen-9, the 27-dihydroxy-3-[(1R)-2-[(1S, 3R, 4R)-3-methoxyl group-4-tetrazolium-1-yl) cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy radicals-3H-pyrido [2,1-c] pyridine-1,5 of [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone; 23,27-epoxy radicals-3H-pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-pyridine-1,5,11,28,29 (4H, 6H, 31H)-and pentone, it is at United States Patent (USP) 6,015,815, United States Patent (USP) 6,329,386, made among WO02/123505 and the WO03/129215 open, during its disclosure is incorporated herein separately as a reference.Preferably, when useful reagent is solid, with its dissolving or be dispersed in the solvent.More preferably, solvent is an isobutanol.

Aspect another, allocation step comprises will have the beneficial agent that has bonding agent (binder) to be assigned on the selected portion of prosthese of the present invention.Preferably, bonding agent is biodegradable.More preferably, bonding agent is the polymer that phosphocholine connects.

In another aspect of the present invention, a kind of method that loading beneficial agent is used for sending in the tube chamber to the prosthese is provided, this method comprise the following steps: to provide a kind of will be in tube chamber unfolded prosthese with surface; The beneficial agent that discharges from prosthese is provided; At least one part coated substrates material layer in prosthetic surface; A kind of fluid distributor of distribution member that can distribute the discontinuous drop of beneficial agent along controlled track that has is provided; Between distribution member and prosthese, form relative displacement, to determine to distribute the dispense path of beneficial agent with raster mode; With distribute beneficial agent from distribution member to the predetermined portions of binder layer selectively along dispense path.

Preferably, the binder layer that is provided by applying step comprises the polymer that phosphocholine connects.The prosthese that provides step to provide by prosthese can also comprise many interconnective structural elements.Can be by the dispense path that the formation step defines along a series of above-mentioned interconnective structural elements.This method may further include the step of the controller that is provided for the operated allocated element, and allocation step is undertaken by using along the dispense path of the interconnective structural elements in the prosthese predetermined portions controller to be programmed.The prosthese that provides step to provide by prosthese can also comprise many interconnective structural elements, and allocation step may further include and detects the step that distribution member when aligns with structural elements in the prosthese predetermined portions.

A kind of method also is provided, has wherein determined to load the pattern of beneficial agent by binder layer that applying step is coated with.Applying step can comprise: by fluid distributor base material is applied on the prosthese.

Of the present invention aspect another, allocation step comprises that change is loaded into the relative velocity of selected location with beneficial agent along prosthese, to change the local surfaces density of the beneficial agent that loads on the prosthese selected location.The step that changes relative velocity can comprise that change applies the frequency of useful reagent droplet along the unit length of dispense path.Equally, the step of change relative velocity can also comprise the relative displacement that changes between distribution member and the prosthese.In addition, the step of change relative velocity can also comprise the amount of change from the beneficial agent of every drop of distribution member distribution.

Of the present invention further aspect, the method for measuring the amount that is loaded into the beneficial agent on the prosthese is provided, this method comprises the following steps: to provide with unfolded prosthese in tube chamber; Providing will be from the beneficial agent of prosthesis delivery; The discernible marker that in beneficial agent, adds predetermined ratio; To add the loading beneficial agent of discernible marker to the selected portion of prosthese; Be loaded into the amount of the marker discerned in the prosthese with detection, be loaded into the respective amount of the beneficial agent in the prosthese with mensuration.Comprise radio-opaque material by adding the marker discerned that step adds, and detect step and can comprise step, be loaded into the intensity level of the radio-opaque material on the prosthese with mensuration to the prosthese imaging.Can also comprise fluorescent material by adding the marker discerned that step adds, and detect step and can comprise step, be loaded into the intensity level of the fluorescent material on the prosthese with mensuration to the prosthese imaging.This method may further include the step that the fluid distributor with the distribution member that can distribute useful reagent droplet is provided; Add step and can comprise to the beneficial agent drop that distributes from distribution member and apply surface charge that wherein electric charge is discernible marker; Can comprise the accumulation of mensuration electric charge on prosthese with the detection step, it is loaded in surface charge on the prosthese by the loading step and causes.A kind of method also is provided, and wherein distribution member can distribute the drop of beneficial agent along controlled track, and can change by deflection field by the controlled track that adds the beneficial agent drop of electric charge on the step band.

The present invention also comprises the system of loading beneficial agent to the prosthese that is used for sending in the tube chamber, wherein this system comprise a support will be in tube chamber the bearing of unfolded prosthese; Have the fluid distributor that can distribute the distribution member of beneficial agent with the form of discontinuous drop; Distribution member and bearing are relatively-movable each other; Be used to form the driver of relative displacement between distribution member and the bearing; With the controller that interrelates with driver, to determine to distribute the dispense path of beneficial agent with raster mode, this controller also interrelates with distribution member, with along dispense path, distribute beneficial agent from distribution member selectively to the predetermined portions of the prosthese of bearing support.

Preferably, the system that provides further comprises detector, and when distribution member aligns with the prosthese predetermined portions of bearing support to detect.Detector can be to be selected from following pick off: camera, ultrasonic detector, photodetector, capacitance meter, temperature sensor, electrometer and Hall effect detector.Controller can assign to programme with the prosthese reservations that will distribute beneficial agent.The dispense path of determining by controller can comprise the parallel channels of a series of prosthetic surface of supporting along bearing.Distribution member can determine that fluid distributes width, and dispense path can comprise the series of parallel passage.The path width of each parallel channels is to select according to the target surface density of prosthese part.

System may further include and is used for surface charge is applied to device on the selected drop of the beneficial agent that distributes from distribution member.More preferably, the controlled track of charged beneficial agent drop can change by deflection field.Distribution member can be to be that the relative velocity of variations distributes beneficial agent at the place, selected location along the prosthese of bearing support, to be loaded into the local surfaces density of beneficial agent on the prosthese in the selected location change.In addition, provide a system, wherein, the frequency of using the beneficial agent drop along the unit length of dispense path can change, and is loaded into the local surfaces density of the beneficial agent on the selected location of the prosthese that bearing supports with change.

Preferably, the relative displacement between the prosthese of distribution member and the support of prosthese bearing can change, and is loaded into the local surfaces density of the beneficial agent on the selected location of the prosthese that bearing supports with change.Equally, preferably provide system, wherein the volume of the beneficial agent of the every drop that distributes from distribution member can change, and is loaded into the local surfaces density of the beneficial agent on the prosthese selected location that bearing supports with change.

Be to be understood that above-mentioned general remark and following detailed description are illustrative, and be the further explanation that is used to provide invention required for protection.

Be intended for diagram as the accompanying drawing of incorporating into and constitute a description part, and the further understanding for method and system of the present invention is provided.Accompanying drawing is used for illustrating principle of the present invention with description.

The accompanying drawing summary

Fig. 1 a-1c is the sketch map that has loaded the prosthese of beneficial agent according to of the present invention, and it has the first and the second portion of the beneficial agent of different local surfaces density, and the chart of having described corresponding area density.

Fig. 2 is the sketch map according to first prosthese of the present invention and second prosthese that is configured to define a kind of nested intervention device, and each prosthese has loaded beneficial agent at least in part.

Fig. 3 is first prosthese of Fig. 2 and the sketch map of second prosthese, and it launches with overlapping relation, to provide controlled local surfaces density on the length of crossing over intervention device.

Fig. 4 is the sketch map according to first prosthese of the present invention and second prosthese that is configured to define a kind of intervention device of bifurcated, and each prosthese has loaded beneficial agent at least in part.

Fig. 5 is first prosthese of Fig. 4 and the sketch map of second prosthese, and it launches with overlapping relation, to be provided at the bifurcated intervention device that has controlled local surfaces density on the length of crossing over intervention device.

Fig. 6 is the sketch map of intervention device, and Fig. 6 a is the detailed diagram of having described the raster mode that is used for loading beneficial agent thereon.

Fig. 7 is the sketch map of the embodiment of system of the present invention.

Fig. 8 a-8d is the sketch map of " outside the axle " distribution method of carrying out of the various cross sections at Fig. 6 device.

Fig. 9 is the sketch map of another embodiment of system of the present invention.

Figure 10 is the sketch map with the discontinuous drop of overlap mode loading.

Figure 11 is that the inner surface at intervention device loads useful compositions and methods sketch map.

Figure 12 is the cross section sketch map of structural elements that wherein has the prosthese of cavity.

Figure 13 is the sketch map of the mounting assembly of system of the present invention, and Figure 13 a is the detailed diagram of describing the mounting assembly that comprises spindle.

Detailed description of preferred embodiments

To at length mention now of the present invention with loading beneficial agent to the prosthese method and system and the preferred embodiment of having loaded the intervention device of beneficial agent.As possible, use identical Reference numeral to indicate same or similar part everywhere in all of accompanying drawing.

According to the present invention, provide a kind of intervention device that is used in tube chamber, sending beneficial agent.Specifically, the present invention is suitable provides a kind of intervention device with controlled beneficial agent area density, is used for the treatment of and prevents blood vessel or other intraluminal disease.Usually, " controlled area density " is interpreted as the known or predetermined amount of beneficial agent on the intervention device per surface area, calculates by weight or by volume.

" intervention device " used herein makes a general reference any intraluminal device of sending or implanting that is suitable for.For the purpose of illustration and unrestricted purpose, the example of this intervention device comprises support, graft, and stent-grafts, filter, or the like.As known in the art, this device can comprise one or more prostheses, and each all has first sectional dimension of being used to send purpose or profile and second sectional dimension after expansion or profile.Each prosthese can launch with known mechanical technique, airbag inflation expansion technique for example, or by launching in electricity known in the art or thermal excitation or self-expanding expansion technique equally.This example as illustrations comprises the United States Patent (USP) 4,733,665 of Palmaz; People's such as Roubin United States Patent (USP) 6,106,548; The United States Patent (USP) 4,580,568 of Gianturco; People's such as Penn United States Patent (USP) 5,755,771; With the United States Patent (USP) 6,033,434 of Borghi, this paper introduces all these as a reference.

In order to explain the purpose with illustrations rather than restriction, according to the exemplary embodiment of intervention device of the present invention shown in Fig. 1 a signal.According to one aspect of the present invention, shown in Fig. 1 signal, intervention device generally includes the prosthese 10 that has loaded beneficial agent, so that the local surfaces density of beneficial agent to be provided on the length of crossing over intervention device.Specifically, just as previously pointed out, can be to be used in the blood vessel or support of sending and/or implanting coronarius, graft, stent graft, filter or the like as concrete herein prosthese.Yet prosthese can be tube chamber inner member any kind of, that can load beneficial agent.

At the loading days of beneficial agent, prosthese can be to expand or unexpanded state.The base structure of prosthese almost can be any structure design, and prosthese can be composed of any suitable material, such as, but be not limited to: rustless steel, " MP35N ", " MP20N ", elastinite (nitinol, Nitinol), tantalum, Nitinol, platinumiridio, gold, magnesium, polymer, pottery, tulle or its combination." MP35N " and " MP20N " is derived from StandardPress Steel Co., Jenkintown, the trade name of the cobalt of PA, nickel, chromium and molybdenum alloy." MP35N " by 35% cobalt, 35% nickel, and 20% chromium and 10% molybdenum are formed." MP20N " by 50% cobalt, 20% nickel, and 20% chromium and 10% molybdenum are formed.Prosthese can be made by polymer absorbable by biology or Biostatic.In some embodiments, the surface of prosthese can comprise one or more reservoir or tube chambers that form therein, as following further description.

Prosthese can utilize many methods known in the art to make.For example, prosthese can be made by hollow pipe, or the pipe that forms by utilizing laser, discharge rolling mill, chemical etching or other known technology to carry out machining is made.Perhaps, prosthese can be made by the sheet material that is rolled into tubular articles, or is formed by metal wire known in the art or filament structure.

As mentioned above, prosthese loaded at least in part beneficial agent (10a, 10b, 10c)." beneficial agent " used herein is meant the mixture of any chemical compound that can produce useful or useful effect, chemical compound or the compositions of the material be made up of described chemical compound.Beneficial agent can be but be not limited to polymer, marker, and for example radiopaque dyestuff or microgranule can be medicines maybe, comprise medicament medicinal and treatment usefulness, or comprise the medicament of inorganic or organic drug.Medicament or medicine can be various forms, uncharged molecules for example, the component of molecular complex, the last acceptable salt of pharmacology is hydrochlorate for example, hydrobromate, sulfate, laruate, palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate, and Salicylate.

Water-fast medicament or medicine can use with the form of its soluble derivative, as solute, and when being discharged by device, transform into the biologic activity form by enzyme conversion, the hydrolysis of health pH value or metabolic process with effectively.In addition, medicament or pharmaceutical preparation can have various known form, solution for example, dispersion, slurry grain, microgranule, granule, emulsion, suspension and powder.According to needs, medicine or medicament can with polymer or solvent or not with polymer or solvent.

And unrestricted, medicine or medicament can comprise antithrombotic agent for the purpose of illustration, anticoagulant, anti-platelet agents, thrombolytics, antiproliferative, anti-inflammatory agent suppresses the hypertrophy medicament, smooth muscle breeding inhibitor, antibiotic, growth factor receptor inhibitors, or cell adhesion inhibitors.Other medicines or medicament be including but not limited to antineoplastic agent, antimitotic agent, antifibrin agent, antioxidant, promote endotheliocyte to recover medicament, anti-allergic material, radiopaque medicament, viral vector, antisense compounds, oligonucleotide (oligionucleotides), cell sees through reinforcing agent, vascularization medicament and its combination.

The example of this antithrombotic agent, anticoagulant, antiplatelet medicament and thrombolytics comprises: heparin sodium, low molecular weight heparin, heparinoid, hirudin, argatroban, forskolin, vapriprost, prostacyclin and prostacyclin analog, dextran, D-phe-pro-arg-chloromethyl ketone (synthetic antithrombase), persantin, glycoprotein iib/iiia (platelet membrane receptor antagonist antibody), lepirudin 023 ludon and blood coagulation inhibitor be Angiomax for example ^TM, be obtained from Biogen, Inc., Cambridge, Mass; With the thrombus medicament, urokinase for example, for example, Abbokinase ^TM, be obtained from Abbott Laboratories Inc., NorthChicago, IL, recombinaton urokinase and pro-urokinase are obtained from Abbott LaboratoriesInc., (the Alteplase of tissue plasminogen activator ^TM, be obtained from Genentech, SouthSan Francisco, CA) with for how for general enzyme (TNK-tPA).

This example cytostatic or antiproliferative medicament comprises the analog of rapamycin and it, everolimus for example, and ABT-578, that is, and 3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-16 hydrogen-9, the 27-dihydroxy-3-[(1R)-and 2-[(1S, 3R, 4R)-and 3-methoxyl group-4-tetrazolium-1-yl) cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido [2,1-c] pyridine-1,5 of [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone; 23,27-epoxy 3H pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-pyridine-1,5,11,28,29 (4H, 6H, 31H)-and pentone, it is in U.S. Pat 6,015,815, U.S. Pat 6,329,386, open among the US 2002/123505 of the US 2003/129215 of JIUYUE in 2002 application on the 6th and the application on the 10th of calendar year 2001 JIUYUE, its disclosure is incorporated herein by reference separately in this article, a tacrolimus and a Mei Kemosi, angiogenin (angiopeptin), angiotensin-convertion enzyme inhibitor is captopril for example, for example Capoten  and Capozide , be obtained from Bristol-Myers SquibbCo., Stamford, Conn., cilazapril or lisinopril, for example Prinivil  and Prinzide  are obtained from Merck ﹠amp; Co., Inc., Whitehouse Station, NJ; Calcium channel blocker is nifedipine for example, amlodipine, cilnidipine, lercanidipine, benidipine, trifluoperazine, sulfur nitrogen ketone and verapamil, the fibroblast growth factor antagonist, fish oil (omega 3-fatty acid), histamine antagonist, lovastatin, for example Mevacor  is obtained from Merck ﹠amp; Co., Inc., Whitehouse Station, NJ.In addition, can use topoisomerase enzyme inhibitor for example etoposide and topotecan, and antiestrogen tamoxifen for example.

The example of this antiinflammatory comprises: colchicine and glucocorticoid be betamethasone for example, cortisone, dexamethasone, budesonide, meticortelone, methyl meticortelone and hydrocortisone.The non-steroidal anti-inflammatory medicated bag is drawn together flurbiprofen, ibuprofen, and ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetyl is mute coughs up acid, indometacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamic acid, piroxicam and Phenylbutazone.

The example of this antineoplastic agent comprises: alkylating agent, altretamine for example, bendamucine, carboplatin, carmustine, cisplatin, cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine, prednimustine, and treosulfan (treosulfin), antimitotic agent, vincristin for example, vincaleucoblastine, Paclitaxel, for example, TAXOL , be obtained from Bristol-Myers Squibb Co., Stamford, Conn., Docetaxel (docetaxel), for example, Taxotere  is obtained from Aventis S.A., Frankfort, Germany, metabolic antagonist is methotrexate for example, purinethol, pentostatin, trimetrexate, gemcitabine, imuran, and fluorouracil, with antibiotic doxorubicin hydrochloride for example, for example Adriamycin  is obtained from Pharmacia ﹠amp; Upjohn, Peapack, NJ, and mitomycin, for example Mutamycin  is obtained from Bristol-Myers SquibbCo., Stamford, Conn promotes endotheliocyte to recover for example estradiol of medicament.

The other medicine that can use in this application comprises dexamethasone; Fenofibrate; Tyrosine kinase inhibitor, for example RPR-101511A; The PPAR-alfa agonists is Tricor for example ^TMPreparation is obtained from Abbott Laboratories Inc., North Chicago, IL; Endothelin-receptor antagonists is ABT-627 for example, and it has general formula C ₂₉H ₃₈N ₂O ₆.ClH, and following structural,

Chirality

Be obtained from Abbott Laboratories Inc., North Chicago, IL, open in 144 in U.S. Pat 5,767, during its disclosure is incorporated herein as a reference; Matrix metallo-proteinase inhibitor for example, ABT-518{[S-(R ^*, R ^*)]-N-[1-(2,2-dimethyl-1,3-Dioxol-4-yl)-2-[[4-[4-(three fluoro-methoxyl groups)-phenoxy group] phenyl] sulfonyl] ethyl]-the N-hydroxyformamide }, have general formula C ₂₁H ₂₂F ₃NO ₈S, and have following structural,

Chirality

Be obtained from Abbott Laboratories Inc., North Chicago, IL, it is in U.S. Pat 6,235, and is open in 786, during its disclosure is incorporated herein as a reference; (3,4, the 5-the trimethoxyphenyl)-1H-indole-5-sulfonamide of ABT620{1-methyl-just }, it is in U.S. Pat 6,521, and is open in 658, during its disclosure is incorporated herein as a reference; Antiallergic agent, permirolast potassium nitroprusside for example, phosphodiesterase inhibitor, prostaglandin inhibitor, suramin, serotonin blocker, steroidal, sulfoprotein enzyme (thioprotease) inhibitor, triazolo pyrimidine, and nitric oxide.

Though the prevention of above-mentioned useful medicament and curative properties are well-known, but still, do not represent to be limited to this so that these materials or medicament to be provided for example.Further, existing other the useful medicament that maybe can develop being used is suitable in the present invention equally.

If wish or necessary, beneficial agent can comprise a kind of bonding agent, with carry, loaded reagent, or make reagent continue to discharge, such as, but be not limited to suitable polymers or similar carrier.Term " polymer " " be used for comprising and the product of polyreaction comprise homopolymer, copolymer; terpolymer, or the like, no matter natural or synthetic; comprise random, alternative, block, connect skill, compositions and its variant of side chain, crosslinked, blend, blend.Polymer can exist with true solution, saturated or that suspend as microgranule or oversaturated form in useful medicament.Polymer can be biocompatible, or biodegradable.

For the purpose of illustration and unrestricted; polymeric material comprises the macromole that phosphocholine connects; for example a kind of macromole that contains the phosphocholine side group, for example poly-(MPCw:LMAx:HPMAy:TSMAz), wherein MPC is a 2-methacryloxyethyl PC (methacryoyloxyethylphosphorylcholine); LMA is a lauryl methacrylate; HPMA is a hydroxypropyl methacrylate, and TSMA is methacrylic acid trimethoxy-silylpropyl ester, polycaprolactone; poly--D; L-lactic acid, poly--L-lactic acid, the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester; poly butyric ester; the copolymer of butyric ester and valerate, Ju Dui diethyleno dioxide ketone, poe; polyanhydride; polyglycolic acid, the copolymer of hydroxyacetic acid and carbonic acid trimethylene ester, poly phosphate; the poly phosphate urethane; polyamino acid, cyanoacrylate, poly (trimethylene carbonate); poly-iminocarbonic ester; poly-oxalic acid alkylene ester, polyphosphazene, poly-iminocarbonic ester; and fatty poly-ester carbonate; fibrin, Fibrinogen, cellulose; starch; collagen, Parylene , Parylast ; polyurethane comprises the Merlon urethane; polyethylene, polyethylene terephthalate, vinyl-vinyl acetate copolymer; ethylene-vinyl alcohol copolymer; polysiloxanes comprises the polysiloxanes of polysiloxanes and replacement, polyethylene glycol oxide, mutual-phenenyl two acid bromide two alcohol ester-PEG copolymer; the PCL-PEG copolymer; the PLA-PEG copolymer, polyacrylate, polyvinyl pyrrolidone; polyacrylamide and its combination.The unrestriced example of other suitable polymers comprises: general thermoplastic elastomer (TPE), polyolefin elastomer, EPDM rubber and polyamide elastomer, with the plastic material of Biostatic, for example acrylic polymer and its derivant, polyamide, polyester and epoxy resin.Preferably, polymer contains phosphoryl side group (pendant phosphoryl groups), as the U.S. Pat 5,705 people such as Bowers; 583 and 6,090,901 and people's such as Taylor U.S. Pat 6; disclosed content in 083,257, during it all is incorporated herein as a reference.

Useful reagent can comprise solvent.Solvent can be the combination of any single solvent or solvent.And unrestricted, the example of suitable solvent comprises for the purpose of illustration: water, aliphatic hydrocarbon, aromatic hydrocarbon, alcohols, ketone, dimethyl sulfoxine, oxolane, dihydrofuran, dimethyl acetylamide, acetas and its combination.Preferably, solvent is an ethanol.More preferably, solvent is an isobutanol.In addition, in another aspect of the present invention, with the multiple beneficial agent dissolves or be dispersed in the identical solvent.For the purpose of illustration but not be used for the restriction, dexamethasone, estradiol and Paclitaxel are dissolved in the isobutanol.Perhaps, dexamethasone, estradiol and Paclitaxel are dissolved in the ethanol.In yet another embodiment, with dexamethasone, estradiol and ABT-578, i.e. forms of rapamycin analogs, 3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23-S, 26R, 27R, 34aS) 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-16 hydrogen-9, the 27-dihydroxy-3-[(1R)-and 2-[(1S, 3R, 4R)-and 3-methoxyl group-4-tetrazolium-1-yl) cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23, the pyridine-1,5 of 27-epoxy radicals-3H-pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone; 23, the pyridine-1,5 of 27-epoxy radicals-3H-pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-and pentone, be dissolved in together in a kind of solvent.Preferably, solvent is an ethanol.More preferably, solvent is an isobutanol.

In addition, beneficial agent comprises any said medicine, medicament, polymer and solvent, and they can be used alone or in combination.

Can make in many ways with loading beneficial agent to the surface of prosthese so that the local surfaces density of controlled beneficial agent to be provided, if carry out rightly.For example, prosthese can be built into the structure that comprises with beneficial agent or multiple beneficial reagent-impregnated or pore of filling or reservoir.Can be according to needed local surfaces density mode along the length of intervention device, adjust the size of pore or make pore spaced apart, with corresponding with the beneficial agent amount that is wherein comprised or limit the wherein amount of beneficial agent, wherein will provide bigger pore or closeer space in the part of planning to have bigger local surfaces density.Perhaps, can provide the pore size of homogeneous, but correspondingly limit the amount of the beneficial agent that wherein loads.In addition, if necessary, can on hole or reservoir, use a kind of film of biocompatible material so, to continue or the sustained release beneficial agent from pore or reservoir.

According to some embodiments, beneficial agent directly can be loaded on the prosthese, perhaps, can be to the binder layer that is applied to prosthetic surface with loading beneficial agent.For example and unrestriced, can be with a kind of base coating, for example bonding agent or suitable polymers are applied on the selected surface of prosthese, can form target pattern like this on prosthetic surface.Then beneficial agent is applied directly on the base material pattern.

In one aspect of the invention, target pattern is equivalent to the controlled local area density of target.For example, more substantial binder layer is applied in the part of the intervention device of wishing to have bigger beneficial agent local surfaces density, and will base material in a small amount be applied to and wishes to have in the part of the intervention device that hangs down beneficial agent local surfaces density.

Perhaps, a kind of suitable base coating that beneficial reagent can be retained in wherein can be applied on the surface of prosthese equably according to the present invention, then can be with the selected portion loading beneficial agent of base coating.More substantial loading beneficial agent can be had in the per surface area of base coating of bigger local area density in hope, and will have in the per surface area of low local surfaces density in hope than loading beneficial agent in a small amount.

In yet another embodiment of the present invention, beneficial agent directly can be applied to the surface of prosthese.Usually need a kind of bonding agent or similar component to guarantee to have enough adhesions.For example, this coating technique can comprise: with beneficial agent and suitable bonding agent or polymer mixed, form coating mixture, then it is coated with on the surface of steeping prosthese.According to requiring,, then it is applied to rightly the selected of prosthese part with higher or lower beneficial agent prepared at concentrations coating mixture.

In disclosed in this article each embodiment, if necessary, can on beneficial agent, be used for continuing to discharge with being coated with stain by the porous or biodegradable film of biocompatible material preparation or layer.

Can use conventional coating technique beneficial agent to be coated with on the surface of steeping prosthese, for example utilize spraying, dipping or sputter, and if carry out rightly, Expected Results can also be provided.Utilize this technology, may wish maybe essential use known shielding or extractive technique, with the position and the amount of control loading beneficial agent.Be coated with the stain prosthese with beneficial agent before, preferably use the optical apparatus visual inspection of prosthese, to guarantee not exist mechanical defect.Like this, after defective prosthese eliminating, the beneficial agent that can avoid waste, some of them reagent may be very expensive.

Yet, according to one aspect of the present invention, beneficial agent is to be " printed " on the surface of prosthese by fluid distributor, and fluid distributor has the distribution member that can be assigned beneficial reagent with discontinuous drop form, and wherein each drop has controlled track.If necessary, printing can for example spray or flood and combine with conventional coating technique.

" fluid distributor " used herein general reference has any device of such distribution member, and this distribution member can be with the form distributing fluids of discontinuous drop, and wherein each drop has controlled track.And unrestricted, the example of this fluid distributor comprises for the purpose of illustration: fluid-injection and similar fluid distribution technique device, fluid printer and a kind of electric charge of for example a kind of dropping liquid as required (drop-on-demand) add the deflected stream printing press body.Yet, can form fluid jet, maybe can distribute other fluid distributor of the discontinuous drop with controlled track, also within the scope of the invention.In a preferred embodiment, fluid distributor is a kind of fluid jet print head.This device is obtained from MicroFab Technologiesof Plano, Texas.

The advantage that fluid jet and similar techniques provide many conventional loading technology not possess.For example, can use fluid ejection technique, with controlled volume with raw material for example chemical reagent deposit on the control position of substrate, as disclosed in people's such as Hayes U.S. Pat 4,877,745, in being incorporated herein as a reference.

Can also use fluid jet with reproducible mode deposition materials.Material deposition based on fluid jet is a data-driven, and is contactless, and must instrument." printing " information can directly be produced by CAD information, and digitized be stored in program or the hardware.Therefore, do not need mask or screen cloth.As the interpolation process that does not have chemical waste, fluid jet environmental sound.Other advantage comprises the high efficiency of fluid jet printing technology.For example, on request, for individual drops, fluid jet can be with 1-25, and 000/ second speed is distributed the fluid ball of diameter 15-200 micron, for continuous drop then up to 1MHz.Referring to people such as Cooley, " Applications of Ink-Jet Printing Technology to BioMEMS andMicrofluidic Systems ", Proc.SPIE Conf.on Microfiuidics, (October calendar year 2001), in being incorporated herein as a reference.

According to one aspect of the present invention, disclose a kind of with the method for loading beneficial agent to the prosthese that is used for sending in the tube chamber.This method comprises provides prosthese, from the step of the beneficial agent and the fluid distributor of prosthesis delivery, fluid distributor has the distribution member that can be assigned beneficial reagent with discontinuous drop form, wherein each drop has controlled track.This method further is included between distribution member and the prosthese and forms relative displacement, determining dispense path, and distributes beneficial agent to the predetermined portions of prosthese with raster mode selectively along dispense path.Especially, along dispense path, distribute beneficial agent from distribution member to the predetermined portions of prosthese selectively with raster mode." raster mode " used herein is meant a kind of allocation model of distributing the continuous of useful reagent droplet at a certain distance or being interrupted.Distribution member forms dispense path with the relative motion of the prosthese of adorning beneficial agent, for example comprises, shown in Fig. 6 a, along a certain continuous line style parallel channels series 154 that axially moves around of prosthese.Relative motion depends on reference frame continuing with linear mode from front to back or from right to left and from left to right or from top to bottom.When relative motion turns to, finished one and come and gone mobile or passage 154.That is, relative motion continues to pass prosthese, slows down then, stops, and turns to and accelerate to constant speed.After passing through, distribution member 150 or prosthese 10 change or increase with respect to the optimum seeking site of distribution member at every turn, and like this during passing through subsequently, extra drop can be in identical position collision, although may allow to a certain degree overlapping.For example, when distribution member when prosthese distributes beneficial agent, defined fluid and distributed width " w ".The dispense path that defines by the relative displacement between distribution member and the prosthese can comprise the passage of series of parallel, although if necessary, can determine bigger path width, but wherein the path width that has of each parallel channels is not more than the fluid that distribution member defines and distributes width.

Perhaps, the dispense path that the relative motion by distribution member 150 and prosthese 10 forms can comprise single successive helical, helical along the length of prosthese continuously around the prosthese tubular body.Figure 10 has described this spiral path with diagram method.In such a way, if necessary, the selectivity fluid that carries out with raster mode that can utilize spiral path to be similar to previously described line style path distributes.In a preferred embodiment, the moving direction of relative motion for example is made up of following, rotates the prosthese 10 that will load continuously, little by little axially advances distribution member along prosthese then.Preferably align with distribution member 150 to begin before accepting drop axially and radially these two kinds of motions,, and last till, stop then above these two kinds of positions that motion may be slowed down on the prosthese so that can make two axles accelerate to constant speed at prosthese 10.After each rotation, axially move or increased distribution member 150 or prosthese 10 position with respect to distribution member, preferred so extra beneficial agent drop can be in identical position collision.Can allow the overlapping of any degree, to reach the target surface density of beneficial agent.

This for the purpose of illustration method, shown in Fig. 6 and 7, prosthese 10 comprises many interconnective structural elements 12 of determining opening 14 between it, and has only when the structural elements in distribution member 150 and prosthese 10 predetermined portions is in alignment with each other, and just is assigned beneficial reagent 15.Correspondingly, in this preferred embodiment, when the member 12 of distribution member 150 and prosthese does not line up, stop to distribute beneficial agent 15.For this purpose, this method can comprise the detection step, aligns with the structural elements 12 in the predetermined portions of measuring when distribution member 150 and prosthese 10.Detecting step can realize by pick off 160, photodetector for example, and for example linear array detector or Infrared Detectors, ultrasonic detector, temperature sensor, photographic recorder, capacity measuring set, electroscope, the hall effect sensor detector, or the like.Yet, all within the scope of the present invention at known in the art, any pick off 160 of being used to detect.Perhaps, can provide controller 170, controller 170 usefulness are being adorned structural elements position beneficial agent, the prosthese predetermined portions and are being programmed.In such a way, the distribution member by the cyclelog operation carries out allocation step.These aspects of the present invention can reduce or eliminate reticulate pattern and the bridge joint that occurs when beneficial agent passes interior opening of borrowed structure or gap, and cut the waste.In addition, distribution member 150 can be alignd, the controlled track of each drop directly and the prosthetic surface quadrature or is a certain angle like this.Similarly, trajectory path is alignd, passing the central axis of prosthese, or align at outer shaft with it.

According to another aspect of the present invention, loading beneficial agent is comprised to the method on the prosthese: a prosthese that comprises tubular articles is provided, and tubular articles has the central axis of determining along tubular articles length.This method further comprises from distribution member distributes beneficial agent, distribution member can be dispensed to prosthetic surface with beneficial agent with the form of discontinuous drop and with controlled track, wherein the controlled track of beneficial agent aligns, in order to avoid crossing with the central axis of tubular articles.

For example, for the purpose of illustration and unrestricted purpose, Fig. 8 a-8d has described the different transverse section of the intervention device 10 among Fig. 6.In each cutaway view, the trajectory path 152 of discontinuous drop 155 aligns with " outside axle ", in order to avoid pass the central axis 11 of tubular articles.Specifically, and in Fig. 8 a-8d, described, be for the purpose of illustration and unrestricted purpose, the tangentially alignment between the inner surface of the tubular wall of prosthese 10 and outer surface of the trajectory path 152 of discontinuous drop 155.In such a way, increased the probability on discontinuous drop 155 collision prostheses 10 surfaces of beneficial agent 15.If necessary, yet, another track path alignment outside axle can be used according to the present invention.

With reference to figure 8a-8d, the prosthese that provides step to provide by prosthese comprises tubular articles, it has many interconnective structural elements 12 that limit opening 14 between it, and wherein each drop controlled track 152 basically with the prosthese predetermined portions in the wall or the surface of structural elements 12 tangent.In this respect, make from controlled track 152 alignment of the beneficial agent 15 of distribution member 150 distribution, it can not intersect with the central axis of prosthese like this.This method allows the operating distance of structural elements bigger, does not need the selectivity operation of possible distribution member.That is to say, use " outside axle " method can allow to increase the useful load of beneficial agent on prosthese, do not need Selective Control, perhaps, if necessary, only need limited control distribution member.Yet, in a preferred embodiment,, to control distribution member at least and distribute stopping when the solid (solid) of trajectory path and predetermined area to be loaded when profile does not line up, for example axially surpass any one end 13 of prosthese 10, see Fig. 6.Especially, have only when the trajectory path of useful reagent and prosthese 360 degree rotations inswept solid area when intersecting, distribution member is turned to the position of " opening ".When the trajectory path of useful reagent and prosthese 360 degree rotations inswept solid area non-intersect with volume or when not contacting, distribution member is closed.

Perhaps, and according to a preferred embodiment of the present invention, " outside axle " method utilizes previously described grating technology to carry out.That is to say, use the trajectory path 152 that outside axle, aligns with the central axis of prosthese 10, for example see Fig. 8 a-8d, have only when aliging with the member 12 of prosthese 10 discontinuous drop just from distribution member 150 by the distribution of selectivity.In this embodiment, distribution member 150 has been determined dispense path with the relative motion of prosthese 10, and it comprises sequenced a series of parallel channels that axially moves back and forth along prosthese.Relative motion from right to left, from left to right, or hockets from top to bottom from front to back, and this depends on reference frame.When relative motion changes direction, finished one and come and gone mobile or passage.That is to say that relative motion continues to pass through prosthese, slow down then, stop, turning to and accelerate to constant speed.After passing through, change or increase the position of distribution member 150, during passing through subsequently, extra beneficial agent drop can be at the previous drop that distributes of same position collision so at every turn.Can allow the overlapping of any degree, to reach the target surface density of beneficial agent.

Perhaps, the relative motion of distribution member and prosthese has been determined dispense path, comprises the single continuous helical that twines prosthese along prosthese length.Relative motion composed as follows: rotate for example prosthese continuously, axially advance distribution member 150 gradually then along prosthese.Preferably aliging with the drop of accepting beneficial agent with distribution member before, part (item) begins axially and radially these two kinds of motions, so that can make two axles accelerate to constant speed, and last till above these two kinds of positions that motion may be slowed down on the prosthese, stop then.After each rotation, axially move or increase distribution member or the prosthese position with respect to distribution member, preferred so extra drop can be in identical position collision.Yet, can allow the overlapping of any degree, to reach the area density of the beneficial agent of wanting.

Linear velocity during the beneficial agent liquid droplet distribution can be constant, or can change in a controlled manner.Further, the optimum position of droplet trajectory is, or near the tangent line place of the solid curved surface of prosthese, the structural plane of drop and prosthese interacts.

In a preferred embodiment, dispense path 154 comprises a series of parallel channels along prosthetic surface.For example and unrestricted, the prosthese that provides can have the tubulose body before it launches in tube chamber, and each parallel channels of dispense path 154 is parallel to the longitudinal axis 11 of prosthese 10, shown in Fig. 6 a.After passing through, change or increase the position of distribution member 150 or prosthese 10, so that the discontinuous drop 155 of beneficial agent 15 is assigned on the surface of the prosthese 10 of unloaded still at every turn.Perhaps, as previously noted, parallel channels can be determined a helicon mode around the support longitudinal axis, and wherein each passage is the whole circle of helicon mode.For the purpose of illustration and unrestriced purpose, the relative motion of distribution member and prosthese can comprise rotates prosthese continuously, and axially advances distribution member gradually along prosthese length.Preferably, after each prosthese rotation, the position of distribution member axially changes gradually, so that the extra drop of the beneficial agent that distributes from distribution member is loaded into not on the prosthetic surface of being loaded by previous passage.In another aspect of the present invention, prosthese can have the plane body before loading, so just can load beneficial agent thereon and does not need the Plane of rotation member.Beneficial agent can be repeated along the step that dispense path is assigned on the prosthese, to provide many passages along the prosthese predetermined portions.

As mentioned above, beneficial agent is with raster mode, along dispense path, distribute selectively from distribution member.In such a way, with predetermined space distribution member is opened or closed, can realize raster mode by detector response.Perhaps, by getting in touch with distribution member, programming, can distribute beneficial agent selectively with raster mode to distribute the control device of beneficial agent according to routine data.Various fluid distributors are obtainable and are suitable for providing discontinuous drop along controlled track.For example, can use the injection apparatus of suitable dropping liquid as required, shown in Fig. 9 and 11, wherein distribute discontinuous drop selectively from injector head.In such a way, the injection stream of discontinuous drop can be carried out Kai Heguan on request, and the flow velocity of discontinuous drop can be according to requiring increase and decrease.Perhaps, if use charged arrangement for deflecting, will generate the Continuous Flow of drop, the form deflection that selected drop will be is as known in the art for example seen Fig. 7, as following further described.

In a preferred embodiment of the invention, prosthese is a support, and as mentioned above, fluid distributor is a fluid ejection apparatus.According to this preferred embodiment, driver 120 defines a series of parallel passages 154 usually along its axle, with the longitudinally continuous roof support of constant rate of speed with the longitudinal axis 11 along support 10.Support centers on its axle increment rotation at the end of each passage.Support rotates with the increment of about 1 degree to about 20 degree around its longitudinal axis, and preferably with about 5 degree increment rotations.

Whenever just having detected stent strut or member, or, turn on fluid ejecting head, so that useful reagent droplet to be provided as mentioned above based on the draft procedure pattern predetermined accordingly with support Design in the injector head front.By the controlled flow that distributes from injector head is provided in addition, can provide beneficial agent with raster mode, to give the beneficial agent of support known quantity.If necessary, distribute the known quantity of beneficial agent,, provide consistent local surfaces density based on the change of surface area." local surfaces density " used herein is meant the amount of the beneficial agent of the support of per unit surface area or prosthese.

For example and unrestricted, by correspondingly regulating flow, make the unit length of two different poles, can load the beneficial agent of equivalent with different pole width.Relatively,, can control the flow of injector head,, for example see Fig. 1 with first part 10b that the prosthese 10 with bigger local area density is provided and second part 10a with prosthese of low local surfaces density along the state of progress of support.Similarly, the speed of relative displacement can change between injector head and the prosthese, correspondingly to control local area density.

As mentioned above, determine dispense path 154 by the relative displacement between distribution member and the prosthese.Relative displacement between distribution member and the prosthese can be carried out with constant speed basically, perhaps carries out with the speed that changes, and changing the local surfaces density of beneficial agent, or carries out off and on.Example for pace of change, embodiment referring to Fig. 1 a, for the purpose of illustration and unrestricted purpose, load beneficial agent to the near-end of prosthese body and end portion 10a and the 10c during, the rectilinear motion speed of the prosthese under the fluid distributor should speed 50%, correspondingly to reduce local surfaces density.Perhaps, load beneficial agent to the prosthese body middle section during, the rectilinear motion speed of the prosthese fluid distributor under can slow down 50%, to increase the local surfaces density there.

Perhaps, the unfavorable raster mode of using can use a kind of vectoring technology, and wherein the first with the stent strut of support one end places the injector head front, and turns on injector head.The state that the injector head maintenance is opened distributes useful reagent droplet with constant preset frequency then, is used to provide the reagent of predetermined dispensing rate.With the diaxon control system, following further describing relates to the support that moves continuously, coordinates two axles simultaneously, so that the stent strut of reservation shape is advanced to the front of injector head.This serial movement is placed on beneficial agent on the pole of first, and is in place until the target surface of support, accepting beneficial agent in known surf zone, and distributed the predetermined quantity of beneficial agent.Beneficial agent is provided on the stent strut, does not remove the zone of metal from support thereby injector head can not be assigned to beneficial agent.This method can be recycled and reused for intervention device part subsequently, and the dose known amounts of beneficial agent is provided in each appropriate section of intervention device like this.As raster mode, can control the speed of flow or relative displacement, with according to the local surfaces density that requires to regulate beneficial agent.

In another embodiment, the navigation system of two axles is connected on the charged deflection injector head.Charged deflection injector head can produce the grating mode of drop on the preset width of support.That is to say, also apply surface charge to the selected drop of the beneficial agent that distributes from distribution member according to the present invention.Preferably, if positive surface charge is imposed on beneficial agent, then antioxidant can be included in the beneficial agent.In such a way, antioxidant can help to prevent the oxidation of beneficial agent, when applying positive charge such oxidation may take place.In addition, perhaps can use the oxidation of other known technical prevention or inhibition beneficial agent.The track of charged beneficial agent drop can change by deflection field.For example, can use electrode 144 to make the trajectory deflection of beneficial agent arrive the prosthese predetermined portions, beneficial agent is charged by charger 142, as shown in Figure 7.If necessary, can with the beneficial agent drop on the opposite electric charge that causes be applied to the predetermined portions of prosthese, between beneficial agent drop and prosthese, to provide electrostatic attraction, reach higher precision and efficient.

In order to realize the pre-constant load or the coating layer thickness of beneficial agent, can use that will control fluid distributes and the Several Methods of controlling two axle navigation systems, so that cause the accurate precipitation of beneficial agent on the outer surface of support or prosthese 10.At first, the control prosthese can be opened around the motor 122 of its longitudinal axis rotation, to produce Constant Angular Velocity.Control second motor 124 then, advance the prosthese or the support of distribution member 150 fronts, go out to stride across the spiral or the helical of the support longitudinal axis with approximate with set rate, wherein identical with the raster width of distribution member 150 from the pitch width that rotates to rotation.When using charged deflection distribution member, can be with the surface of prosthese 10 or support, with than the grating mode of single drop faster mode be exposed to distribution member 150, this is in the cards with the system of dropping liquid pattern as required.When detecting first stent strut and be present in the front of shower nozzle 150,, scan and before be kept at the pattern bitmap that is used for describing the pole form in the memorizer 170 by suitable electric charge is provided on selected drop.The second, on each scanning line, have the linear array detector 160 of similar number of drops purpose resolution, can detect the existence of the stent strut of rotating previously by reflection or transillumination at the jet fluid window.The data that will be obtained from this class detector then change the displacement memory over to, and this memory can produce necessary raster data by a disposable byte that migrates out a mould.Method hereto, the bitmap that need be scheduled to not, and can compensate slight change aspect speed, rim detection or location automatically.This method can be recycled and reused for intervention device part subsequently, and the beneficial agent of dose known amounts is provided in each appropriate section of intervention device like this.

In addition according to the present invention, provide the system of loading beneficial agent to the prosthese that is used for sending in the tube chamber.As Fig. 7 and shown in Figure 13, this system comprises bearing 110 and the fluid distributor that is used for supporting prostheses, and fluid distributor has the distribution member 150 that can distribute beneficial agent 15 with the form of discontinuous drop 155, and each drop has controlled track.

Bearing comprises axle or the spindle 112 by any suitable material known in the art.Yet preferred, spindle 112 comprises elastic material, nitinol for example, or have any other material of shape-memory properties.Specifically, handle the support bearing that rustless steel is made, can cause the crooked and distortion of spindle.This distortion causes low running accuracy of the other end from an end of spindle to spindle and high radial beat (run-out), for example 0.25-2.5mm.Can cause so lower loading beneficial agent to the prosthese efficient and lower drop and the interactional efficient of prosthese because the position of shower nozzle lower carriage changes and changes along with circular runout.Superelastic material has the performance of the adaptability to changes that can absorb adaptability to changes and return to many 8% usually.Therefore, preferred, nitinol provides and has had more elastic spindle, and this spindle can bear multiple manual support and install, and does not have the plastic deformation of appearance in the design of rustless steel spindle.

For the purpose of illustration and unrestricted purpose, and as shown in figure 13, can utilize no center grinding technique to make nitinol spindle 112, to obtain high concentricity precision.Although use above-mentioned grinding process, the centrage of the small diameter portion of spindle (for example, 0.5mm diameter) can have difference to a certain degree with the centrage of mid diameter part (for example, 2mm diameter).Can remove this species diversity near the spindle of minor diameter and mid diameter junction partly by heating, and with its bending to remove most of remaining circular runout.Through supercooling, spindle arrangement remains on its reposition, sees Figure 13.After utilizing this technology, the final circular runout on typical spindle is approximately 0.051mm.

This system also comprises: driver is actuator assembly 120 for example, to form the relative displacement between bearing 110 and the distribution member 150, with the controller 170 of getting in touch with driver 120, to determine the dispense path of the relative displacement between distribution member 150 and the bearing 110.Controller is also got in touch with distribution member 150, is used for along dispense path, with selected form, selectively beneficial agent being assigned to the selected portion of the prosthese 10 that supports by bearing 110.In one aspect of the invention, the bearing 110 of supporting prostheses 10 is movably, and distribution member 150 was maintained fixed between the allotment period of beneficial agent 15.Yet in another aspect of the present invention, the bearing 110 of supporting prostheses 10 is maintained fixed, and distribution member 150 moves along dispense path.Perhaps, bearing 110 and distribution member 150 all are movably.Aspect another of embodiment, as described earlier, system comprises detector 160, to detect when distribution member 150 aligns with the predetermined portions of prosthese 10.Various known assemblies can be used for system structure of the present invention with the form of combination.For example, can use to be obtained from MicroFab Technologies of Plano, the jetLab System II of Texas, it can comprise the feature of wanting required for the present invention after improving.

In yet another embodiment of the present invention, can be determined at the beneficial agent quantity of distributing on given or the known surf zone.According to an aspect, the marker discerned of predetermined ratio is joined in the beneficial agent, and beneficial agent and marker all are loaded on the prosthese.Subsequently, detect the marker discerned that is loaded on the prosthese, be loaded into the amount of beneficial agent on the prosthese, corresponding with mensuration.In one aspect of the invention, can discern marker and comprise radio-opaque material.After radio-opaque material and loading beneficial agent are to the prosthese, give the prosthese imaging, and measure intensity level, with the amount of the beneficial agent determining wherein to load and determine local surfaces density thus.Marker can be discerned in this respect and fluorescent dye can also be comprised, for example, coumarine dye.In another aspect of the present invention, can discern marker and comprise charged particle, for example but not be confined to proton or electronics.After marker and loading beneficial agent are to the prosthese, detect step and comprise: be determined at electric charge accumulation on the prosthese or the electric current that causes by charged particle from prosthese.Therefore electric charge accumulation or electric current usually be loaded into prosthese on the amount of beneficial agent corresponding.Perhaps, because fluid ejection technique of the present invention is exactly digital in essence, therefore can determine the quantity of the beneficial agent of distribution by adding up the drop that has sprayed or distributed.

In aspect another is alternative, more generally spray the weight of support before, measure the weight of spraying after-poppet then, can measure the amount of the beneficial agent of loading like this by measuring.Weight difference is corresponding with the medicine that is loaded, and the drug concentrations of being loaded is the function along the effluxvelocity of stent length direction.Another method is when using charged deflection system, to be aggregated in the electric charge accumulation on the prosthese.Because each drop in charged deflection injection apparatus has the surface charge that is injected on it, can make drop deflection in electrostatic field, can add up loss of charge or the savings of the electric charge on the prosthese on the charged electrode in time, to determine to accumulate in the fluidic cumulative volume on the apparatus surface.

Also according to the present invention, can use airborne spectrometer monitor in the ejector reservoir, as the beneficial agent concentration of time function.With fixed concentration load beneficial agent for example medicine be desirable.Yet because the evaporation of solvent during loading process, drug level will increase.Preferably, spectrometer can be disposed,, constant absorbance can be on spectrometer, kept like this in medicine, to add solvent with pump.The constant level of absorbance that presets spectrometer is with the monitoring suitable wavelengths.Maintain the constant absorbance explanation of reading on the spectrometer by the adding solvent and kept presetting drug level.

For the injection apparatus of dropping liquid as required, can make polarity charge on each drop band by adding the constant voltage charged electrode with allotter mouth of pipe adjacency, thereby use identical medicine quantitative analysis design.Coating on support, if insulator, the effect of the charged container that will electrify.If little leakage path is provided, if or provide second plane of reference to gather with electric charge relatively at it, this detection technique can detect electric charge and gather.Can use other alternative technology.For example, if there is internal stent in the metal circular axle, can use its any drop that loses of monitoring or sputter.The electric charge that directly changes this " electrode " over to will form the opposite polarity electric current of the lip-deep electric charge of present support insulation covering.

For every kind of aforesaid these detection techniques, suitable detector can be incorporated in the system of Fig. 7, preferably get in touch with controller 170.

According to another aspect of the present invention, second beneficial agent or multiple beneficial reagent can be loaded on the prosthese as mentioned above.Therefore, further according to the present invention, provide a kind of intervention device that comprises prosthese, this prosthese has loaded the discontinuous drop of many first beneficial agents and the discontinuous drop of many second beneficial agents, for example by utilizing system and method shown in Figure 9.

Specifically, the method for describing in detail above that is used for a beneficial agent can be through improving allowing loading multiple beneficial reagent to prosthese, and when utilizing conventional loading technology, it can cause undesirable result usually.For example and unrestricted purpose, first kind of beneficial agent can have different physics and/or chemical characteristic with second kind of beneficial agent, can be dissolved in the identical solvent to prevent beneficial agent, or under identical pH value or temperature.Especially, first kind of beneficial agent can be dissolved in a kind of solvent, this solvent and the solvent unmixing that dissolves second kind of beneficial agent.Perhaps, first kind of beneficial agent and second kind of beneficial agent can be incompatible each other.Especially, first kind of beneficial agent and second kind of beneficial agent may have undesirable chemical reactivity, maybe may have undesirable different rate of release (otherwise or, have undesirable identical rate of release).In addition, first and second beneficial agents can be disadvantageous mutually only not, and for example, a kind of beneficial agent can reduce the effect of another beneficial agent.Thus, although may wish to load specific multiple beneficial reagent on the similar face of prosthese, when using conventional loading technology, because some incompatibilities and usually going wrong.According to the present invention, provide a kind of intervention device that loads the method for this beneficial agent and be used to send this beneficial agent.

As mentioned above, beneficial agent is that form with many discontinuous drops is loaded into the lip-deep of prosthese.Preferably the discontinuous drop of the multiple beneficial reagent form with non-blended drop is loaded on the prosthese, so that alternative pattern to be provided, perhaps, the non-mixing drop of beneficial agent can be loaded on the prosthese, so that the overlap scheme of first kind of beneficial agent and second kind of beneficial agent to be provided.In such a way, the imbricate of drop, perhaps, the big surface of drop is overlapping with other drop, so that layering effect to be provided, as depicted in figure 10.

Be that the every kind of beneficial agent that wherein is loaded on the prosthese is to be distributed by different distributors according to the preferred many fluid distributors of the present invention.For the purpose of illustration and unrestricted purpose, as shown in Figure 9, first allotter 150 be equipped with first beneficial agent 15 that is dissolved in the solvent ', this solvent is compatible with this first kind of specific beneficial agent.Further, second fluid distributor 150 " is equipped with second kind of beneficial agent 15 ", this beneficial agent 15 " be different from first kind of beneficial agent 15 ', and need the different solvent of the compatibility.For example, first kind of beneficial agent can be water miscible reagent, and second kind of beneficial agent can be water-fast reagent, needs different solvents separately.Correspondingly, two kinds of loading beneficial agents on the similar face of prosthese, and can not occurred because the problem that their not intersolubility produces.

Using two fluid distributors multiple beneficial reagent to be loaded under the situation on the prosthese, can align with the track of each corresponding discontinuous drop of first kind of beneficial agent and second kind of beneficial agent, the drop of every kind of beneficial agent merged before being loaded on the prosthese and mixes like this.In such a way, first and second kinds of beneficial agents can form the third beneficial agent that is loaded on the prosthese.For the purpose of illustration and unrestricted purpose, first kind of beneficial agent can be bisphenol-A-glycidyl ether, and second kind of beneficial agent can be trien.When first kind of beneficial agent and second kind of beneficial agent combination, formed crosslinked coating, the third beneficial agent is provided.In another illustrative example, first kind of beneficial agent can be bisphenol-A-glycidyl ether and Paclitaxel, and second kind of beneficial agent can be trien.When two controlled track combination of beneficial agent, formed the third beneficial agent, a kind of cross-linked coating that is entrained with Paclitaxel is loaded in it on prosthese.Perhaps, the discontinuous drop of first and second kinds of beneficial agents can align along track, to mix on prosthetic surface.

As mentioned above, beneficial agent can comprise medicine and polymeric blends.According to method of the present invention, first and second kinds of beneficial agents can be equivalent to have the drug-polymer mixture of different polymer concentrations, to realize the different rate of release of concrete medicine in each beneficial agent.For example, the drug-polymer mixture with higher concentration polymer has the drug releasing rate slower than the drug-polymer mixture of low concentration in tube chamber.Perhaps, for different rate of release is provided, except the mixture of the pharmaceutical polymer with different polymer concentrations is provided, it also is possible using different polymer or other bonding agent to distribute beneficial agent, wherein specific polymer or bonding agent have different diffusibilitys or affinity, to guarantee sending beneficial agent with different speed.Thus, according to the present invention, can discharge multiple beneficial reagent to be suitable for its active speed, prosthese of the present invention like this contains the multiple beneficial reagent that goes out prosthese with the targeted rate eluting.

For example, the polymer that the cation phosphoric acid choline that has high affinity for anionic therapeutic agent can be connected mixes and is disperseed as first kind of beneficial agent, and the polymer that lipophilic phosphocholine can be connected mixes with the lipophilic drugs as second kind of beneficial agent, to realize different rate of release respectively.

In yet another embodiment of the present invention, being loaded into one of first kind and second kind beneficial agent on the prosthese can have more hydrophobicity or have littler water solublity than another.Thus, according to the present invention, provide a kind of prosthese that comprises first kind and second kind beneficial agent, wherein a kind of of beneficial agent has more hydrophobicity or has littler water solublity than another.In such a way, have more water barrier or hydration inhibitor that hydrophobic beneficial agent can be used as less hydrophobic beneficial agent, thereby reduce the rate of release of less hydrophobic beneficial agent, as the U.S. Provisional Patent Application 60/453 of applying on March 10th, 2003 simultaneously, 555 and PCT/US03/07383 in disclosed, and during wherein each all is incorporated herein as a reference.

Have the multiple prosthese except providing a kind of with unique or the beneficial agent that targeted rate discharges, according to another aspect of the present invention, first kind of beneficial agent can be dissolved in the solvent, wherein second kind of beneficial agent causes first kind of beneficial agent to be precipitated out from solvent in the solvent.For example and unrestricted purpose, first kind of beneficial agent can be the rapamycin that is dissolved in the ethanol, and second kind of beneficial agent can be water.When using method and system of the present invention to carry out the drop combination, rapamycin will be deposited in the drop, and is deposited on the prosthese with the microdeposit thing.

In another aspect of the present invention, at least a can before being loaded on the prosthese, the mixing in first and second kinds of beneficial agents with bonding agent.Further according to this respect, a kind of in the beneficial agent can be firming agent, and the bonding agent that is used for wherein having mixed beneficial agent is solidificated in prosthese.For example, referring to the following examples 4.

As mentioned above, a kind of of beneficial agent can be the solvent of another kind of beneficial agent.Thus, according to the present invention, can be with first kind of beneficial agent, for example medicine, polymer, or its combination is loaded on the prosthese, subsequently can be with second kind of beneficial agent, be a kind of solvent, be loaded on the prosthese, so that redistribute first kind of beneficial agent more equably along prosthese.

As noted above, can comprise at least one reservoir or tube chamber or groove in the prosthese.For the purpose of illustration and unrestricted purpose, can use the side of the laser cut stent of computer control, accurately deposition of benefit agent is gone in the laser cut on the stent strut.For example, pod cut, etching perhaps can be formed pole, for example the bending of pole or bend pipe in addition.According to preferred aspect of the present invention, tube chamber or groove have the transverse section of contour (contoured), are used to keep and eluting beneficial agent wherein.Specifically, illustrated among Figure 12, the transverse section of tube chamber or groove 16 comprises the reduced size with pole surface interface, defines reservoir 18 with mouth 17 and the bigger inner cross-sectional dimension of groove that limits groove 16.Figure 12 has represented a kind of such embodiment, wherein is that the reservoir 18 of groove 16 limits mouth 17.Use fluid injection system of the present invention and method, allow the mouth 17 of beneficial agent input slot 16 thus, and do not have air entrapment in reservoir 18.The deposition of benefit agent of suitable volumes at the cut tangent plane, is filled reservoir 18 at least in part.In this respect, the beneficial agent that is deposited on pod can be included in the compositions of pharmaceutical composition or polymer composition or the medicine and the polymer of different layers.In addition, can have the polymer of different concentration or different pharmaceutical elution speed and/or the different layers of medicine to wherein loading.In addition, the external coating of cambic polymer and/or final polymer can be put on the beneficial agent.This depositional fabric that combines with tube chamber minimizes beneficial especially for the layering with polymer-medicine layer, and is also providing many-sided fitness aspect the drug release pattern of control medicament elution and generation various combination.Also can use the computer formative method medicine and polymeric layer to be coated in the end and the proximal edge of support.

According to another aspect of the present invention, one or more reservoirs or tube chamber or groove load more hydrophilic first kind of beneficial agent, use aforesaid mode with on first kind of beneficial agent of second kind of more hydrophobic loading beneficial agent in tube chamber or the reservoir then.

Further according to the present invention, use aforesaid method and system, the first kind of beneficial agent that is loaded on the prosthese can have first kind of local surfaces density, and the second kind of beneficial agent that is loaded on the prosthese can have second kind of local surfaces density." area density " used herein is meant the amount of beneficial agent on the per unit surface area of selected portion of prosthese." local surfaces density " is meant the long-pending dosage of going up beneficial agent of every local surfaces of prosthese.Crossing over the local surfaces density of each corresponding first kind of beneficial agent partly and the local surfaces density of second kind of beneficial agent can be homogeneous, change with the staged of determining local surfaces density, describe as Fig. 1 b, or the partial face density of crossing over the selected portion of prosthese can change, to determine the gradient of local surfaces density, describe as Fig. 1 c.Correspondingly, provide a kind of intervention device with prosthese, this prosthese has loaded the beneficial agent with the local surfaces density that changes along the selected portion of prosthese body at least in part.

According to a preferred embodiment, when launching in tube chamber, prosthese has the tubulose body.Preferably, the tubulose body comprises first and second parts of having loaded beneficial agent at least in part, and first has first local surfaces density like this, and second portion has second local surfaces density.Each part can be defined as previously selected prosthese length.Perhaps, shown in Fig. 1 b, can determine first, and can determine that second portion is second group of interconnective structural elements by selected one group of interconnective structural elements, for example, connector members or ring element.For example and unrestricted purpose, first and second groups of selected at least one groups of interconnecting in the member can determine that at least one centers on the annular component that Periprosthetic stretches.

In another embodiment of the invention, local surfaces density changes with continuous gradient along the selected portion of prosthese, shown in Fig. 1 c.Correspondingly, in one aspect of the invention, the local surfaces density of beneficial agent changes, and can provide a kind of beneficial agent local surfaces density that has in the prosthese end to be different from the prosthese of the beneficial agent local surfaces density in the middle part of prosthese like this.For the purpose of illustration and unrestricted purpose, can be in the beneficial agent local surfaces density at prosthese middle part greater than beneficial agent local surfaces density, shown in Fig. 1 c at prosthese near-end and far-end.Perhaps, the near-end of prosthese and far-end can have than the bigger beneficial agent local surfaces density in prosthese middle part.In a preferred embodiment of the invention, when prosthese launched in tube chamber, different beneficial agent local surfaces density was corresponding with the position of focus.For example, can load prosthese, make it have bigger beneficial agent local surfaces density along the prosthese predetermined portions, when prosthese was launched in tube chamber, its position with focus was corresponding.Thus, use intervention device of the present invention can realize targeted therapy.

According to the present invention,, can change local surfaces density by changing the relative velocity that loads beneficial agent along the prosthese selected location.For this purpose, applying the frequency of useful reagent droplet along dispense path to the unit length of prosthese can be different.Perhaps, by changing the relative displacement between distribution member and the prosthese, can change the relative velocity that loads beneficial agent.The method that another is alternative to be used for changing the relative velocity that loads beneficial agent is the amount that changes the every drop beneficial agent that is distributed by distribution member.Other method that is used to change the local surfaces density of the beneficial agent that is loaded on the prosthese comprises, beneficial agent is mixed with bonding agent, and change the ratio of beneficial agent for bonding agent.Perhaps, can change the amount of the mixture of the beneficial agent that puts on the prosthese and bonding agent, with the beneficial agent local surfaces density that obtains changing.Can use method known in the art, other change beneficial agent local surfaces density.

As mentioned above, partly be loaded on the surface of prosthese to major general's beneficial agent.Further according to the present invention, prosthese comprises first surface and second surface of having loaded beneficial agent at least in part.In one embodiment of the invention, first surface and second surface are equivalent to the inner surface and the outer surface of prosthese separately.Thus, according to this specific embodiment, with as defined above loading beneficial agent to the inside of prosthese or the surface of tube chamber, and the outer surface of prosthese.Can use aforesaid method for this respect of the present invention, wherein by fluid distributing element being inserted in the internal diameter of prosthese, and with loading beneficial agent on the inner surface of prosthese, or pass prosthese 10 between the member 12 by direct distribution beneficial agent 15, with the inner surface of collision prosthese 10 opposite sides, as shown in figure 11." alignment, " controlled track 152 " runs through the inner surface of the structure member of prosthese 10 best so that the discontinuous drop 155 of beneficial agent, rather than runs through the structure member of prosthese outer surface in this respect, to make distribution member 150.For the purpose of illustration and unrestricted purpose, for comprise the radially multiple prosthese of odd number in the structure member pattern, the alignment thereof of preferred allocation element is vertical mutually with the central axis of prosthese, and in the plane of intersecting with the prosthese central axis.Yet for comprise the radially multiple prosthese of even number in the structure member pattern, the alignment thereof of preferred allocation element is vertical mutually with the central axis of prosthese, but in the plane of not intersecting with the prosthese central axis.As another embodiment, for the prosthese of the tubular element that comprises a plurality of radial and axial multiple structural elements, preferably can by evaluation by prospect or external structure member the projection on background or internal structure member determine the alignment of distribution member.The preferred planar of alignment distribution member can be estimated definite by the plane that the expedite inner surface of maximum is provided when wherein rotate by tubular element.

According to this respect of the present invention, can the coordinated allocation element and the relative motion of prosthese, with " grating " image of the pre-programmed of the location of realizing the inner surface structure member or position.Perhaps, the arrow pattern of structural elements can be carried out pre-programmed, as described earlier.Equally, according to the present invention,, distribute beneficial agent by distribution member, and it is loaded on the inner surface of borrowed structure member along tangent or with the prosthese outer surface basically near the controlled track of prosthese outer surface.

At this respect of the present invention, intervention device can be designed to provide the therapeutic alliance of beneficial agent for target location.For example and unrestricted purpose, the specific beneficial agent that is loaded into the tube chamber of prosthese or inner surface can be carried out whole body and discharge, and the specific beneficial agent that is loaded on the prosthese outer surface is used to be discharged into wall of the lumen.According to one aspect of the present invention, be loaded into the side of prosthese tube chamber or the beneficial agent on the inner surface and include but not limited to: antiplatelet reagent, aspirin, cell adhesion promoter promotes endothelium to recover reagent, promotes transfer agent and estradiol.The beneficial agent that is loaded on the prosthese outer surface includes but not limited to: anti-inflammatory agent, antiproliferative, smooth muscle inhibitor, cell adhesion promoter and forms of rapamycin analogs ABT-578, that is, and 3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-16 hydrogen-9, the 27-dihydroxy-3-[(1R)-and 2-[(1S, 3R, 4R)-and 3-methoxyl group-4-tetrazolium-1-yl) cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy radicals-3H-pyrido [2,1-c] pyridine-1,5 of [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone; 23, the pyridine-1,5 of 27-epoxy radicals-3H-pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone.

According to another embodiment of the invention, determine first surface of prosthese by many interconnective structural elements.Correspondingly, first surface can comprise: selected first group of structural elements, for example, connector members, and second surface can comprise selected second group of structural elements, for example, the annular component that stretches around Periprosthetic.

As mentioned above, with loading beneficial agent to prosthese, to be provided at the controlled local area density on the intervention device length.That is to say that desirable way is, provide the beneficial agent of bigger concentration in a part of prosthese, and provide low concentration in another part of prosthese or perhaps do not have a beneficial agent.For example, in a preferred embodiment, first at support 10, mid portion 10b for example, can provide bigger local surfaces density as shown in Figure 1a, and to the second portion of support 10, for example the one or both ends of this support provide low local surfaces density beneficial agent (10a, 10c).According to the present invention, each part in prosthese first and second parts, each of various patterns that can be by prosthese or selected portion determined.For example, prosthese first can determine by vertical adapter, and the second portion of support is determined by annular ring, or vice versa, as shown in Figure 6.

According to another aspect of the present invention, intervention device comprises with first prosthese of combining form and second prosthese, to define lap and at least one non-overlapping part.For example, and as the content that embodies herein, Fig. 2 or 3 has provided the sketch map of a nested intervention device, comprises first prosthese 20 and second prosthese 30, and it is configured to launch with overlapping relation.Yet if necessary, intervention device can randomly comprise above two prostheses that are combining form.This intervention device 50 is including, but not limited to nested support and modular bifurcated stent.For the purpose of illustration and unrestricted purpose, Fig. 2 represents to have first prosthese 20 of 20a of first and second portion 20b and has the 30a of first and second prosthese 30 of second portion 30b.

As shown in the figure, the beneficial agent scattergram comprises, on the part of first and second parts in one or two in first prosthese and second prosthese, and first local surfaces density of beneficial agent.For example and unrestricted purpose is compared with the second portion 20b of first prosthese 20, the 20a of first of first prosthese 20 has the beneficial agent local surfaces density of half.Similarly, compare with the second portion 30b of second prosthese 30, the 30a of first of second prosthese 30 has the beneficial agent local surfaces density of half.In such a way, overlapping or launch when the end of two supports during technical process with overlapping relation 25, be controlled along the beneficial agent local surfaces density of intervention device 50, thereby make it even.If necessary, partly providing alternative concentration separately, so that the combined effect of expection is provided.

According to the present invention, as shown in Figure 3, when first prosthese with the 20a of first and second portion 20b makes up with second prosthese with the 30a of first and second portion 30b, provide beneficial agent local surfaces density controlled on intervention device 50 length, as shown in Figure 2.Especially, as shown in Figure 3, the overlapping fragments 25 of first prosthese 20 and second prosthese 30 is compared with non-overlapping fragment 20b and 30b, has equal beneficial agent local surfaces density.

Perhaps, can control the beneficial agent scattergram of intervention device, to comprise any different target pattern.For example, as mentioned above, on the far-end and near-end of each prosthese, intervention device can have the beneficial agent local surfaces density of reduction.If with a plurality of prostheses mutually combination lay, but also provide the dosage that reduces of intervention device end generally, be highly ideal in the so this unfavorable dosage that is distributed in the prevention beneficial agent.Perhaps, as imbody herein, along the length of a plurality of prostheses of first prosthese of combining form and second prosthese or combining form, the beneficial agent scattergram can provide local surfaces density controlled, homogeneous.Perhaps, according to the present invention, along the length of the polynary prosthese of first prosthese of combining form and second prosthese or combining form, the beneficial agent scattergram can provide local surfaces density controlled, that change.

The purpose that is used for illustrations, overlapping or nested prosthese, as shown in Figure 3, can have such beneficial agent scattergram, so that the controlled local area density of the segmental beneficial agent of non-overlapping is in fact greater than the controlled local area density of the beneficial agent of overlapping fragments.Similarly, can also be another kind of alternate method: the control overlapping fragments makes it have bigger or different beneficial agent local surfaces density than non-overlapping fragment.Preferably, when a plurality of prostheses that use combining form and when using single prosthese separately, this characteristics can realize the selectivity administration of beneficial agent to target area equally.Beneficial agent is to the selectivity administration of target area, mean the prosthese that beneficial agent can be put on prosthese or combining form, the target beneficial agent can be loaded on the prosthese with pattern optionally like this, so that single beneficial agent or multiple beneficial reagent are discharged by prosthese being in close proximity to the target location place.Especially preferably previously described fluid jet is used for the selectivity administration.

According to the present invention, and as shown in Figure 5, can provide the intervention device of bifurcated equally, it comprise first prosthese 20 of combining form ' with second prosthese 30 ', its determined lap 50 ' with non-overlapping part 20b ', 30b '.For the purpose of illustration and unrestricted purpose, Fig. 4 represent to have first prosthese 20 of the 20a ' of first and second portion 20b ' ' and have second prosthese 30 of the 30a ' of first and second portion 30b ' '.As shown in the figure, for the purpose of illustration and unrestricted purpose, the beneficial agent scattergram comprises, first prosthese 20 ' with second prosthese 30 ' in one or two in a part of first and second parts on, first local surfaces density of beneficial agent.For example and unrestricted purpose is compared with the second portion 20b ' of first prosthese, first prosthese 20 ' the 20a ' of first have half beneficial agent local surfaces density.Second prosthese 30 ' the 30a ' of first have second prosthese 30 ' half the beneficial agent local surfaces density of second portion 30b '.According to the present invention, as shown in Figure 5, by first prosthese with the 20a ' of first and second portion 20b ' and prosthese combination with the 30a ' of first and second portion 30b ', provide the controlled beneficial agent local surfaces density on bifurcated intervention device 50 length, as shown in Figure 4.

Another characteristic of the present invention comprises the selected portion that binder layer is applied to aforesaid prosthese.Beneficial agent is loaded on the binder layer according to method as mentioned above.Binder layer is preferably determined a kind of with the pattern of loading beneficial agent to the prosthese.

For disclosed any embodiment, the present invention also is included in the external coating of application rate control on the prosthese that has loaded beneficial agent, with further control or the lasting beneficial agent that discharges.Can add the rate controlled external coating by on the prosthese that loads beneficial agent, using coating.The thickness of layer is selected so that such control to be provided.Preferably, apply external coating by fluid ejection technique.Preferably, the fluid jet external coating, for example polymer topcoat makes layer thin and more even.Yet can use other conventional method, other fluid distributor for example, vapor deposition, plasma deposition, spraying, or dipping, or any other coating technique known in the art.

The present invention also provides a kind of preparation to send the method for the intervention device of beneficial agent.This method comprise the following steps: to provide a kind of will be in tube chamber unfolded first prosthese; Provide be configured to first prosthese with unfolded second prosthese of overlapping relation, first prosthese of combining form and second prosthese have been determined at least one non-overlapping fragment and an overlapping fragments; With use first prosthese of loading beneficial agent and second prosthese, provide controlled local surfaces density along first prosthese of combining form and the length of second prosthese.The method of describing in detail above is preferred for such loading step.

The present invention also provides a kind of method of sending beneficial agent.According to this method, as describing in detail with the explanation of top intervention device of the present invention, this method comprises the following steps: to provide first prosthese that has the tubulose body in tube chamber when launching; Second prosthese that has the tubulose body in tube chamber when launching is provided; Use beneficial agent to load in first prosthese and second prosthese one at least; First prosthese is launched in tube chamber; Second prosthese launched in tube chamber, to determine at least one non-overlapping fragment and an overlapping fragments with the form of first prosthese combination; Wherein, when launching, on the length of first prosthese and second prosthese, provide controlled beneficial agent local surfaces density with box lunch with at least one in first prosthese and second prosthese of loading beneficial agent.The method of describing in detail above is preferred for such loading step.

Be further understood that the present invention by the embodiment that lists below, provide these embodiment to be for the purpose of illustration and unrestricted purpose.

Embodiment

Embodiment 1: the injection of active substance

By injection method the component of the bi-component epoxy preparation that is purchased is mixed, and put on the surface, form coating.By Buehler, in the preparation of Lake Bluff IL preparation, a part be contain 4,4 '-fluid " epoxy resin " of isopropylidene xenol epichlorohydrin resins and butyl glycidyl ether.Second portion is the fluid " sclerosing agent " that contains diethylenetriamines, trien and polyoxy propane diamine.In this injection method, reagent spraying system (A) is equipped with epoxy resin, and second spraying system (B) is equipped with sclerosing agent.The alignment jet so that the drop that sends from each spout mixes, and moves to the targeting device aloft, after 2-8 hour hardening time, forms crosslinked coating.The droplet size that sends from spout A is bigger 5 times than the droplet size that sends from spout B, and from the total approximately equal of the drop of each spout distribution.

Embodiment 2: the injection of active substance

By injection method the component of the bi-component epoxy preparation that is purchased is mixed, and put on the surface, form coating.By Buehler, in the bi-component commodity preparation of Lake Bluff IL preparation, a part be contain 4,4 '-fluid " epoxy resin " of isopropylidene xenol epichlorohydrin resins and butyl glycidyl ether.Second part is the fluid " sclerosing agent " that contains diethylenetriamines, trien and polyoxy propane diamine.In this injection method, reagent spraying system (A) is equipped with epoxy resin, and second spraying system (B) is equipped with sclerosing agent.The alignment jet so that the drop that sends from each spout mixes, and moves to the targeting device aloft, after 2-8 hour hardening time, forms crosslinked coating.The droplet size that sends from spout A is bigger 4 times than the droplet size that sends from spout B, and from the total approximately equal of the drop of each spout distribution.This coating is faster than embodiment 1 described coating curing rate.

Embodiment 3: the injection of active substance

By injection method the component of the bi-component epoxy preparation that is purchased is mixed, and put on the surface, form coating.By Buehler, in the bi-component commodity preparation of Lake Bluff IL preparation, a part be contain 4,4 '-fluid " epoxy resin " of isopropylidene xenol epichlorohydrin resins and butyl glycidyl ether.Second part is the fluid " sclerosing agent " that contains diethylenetriamines, trien and polyoxy propane diamine.In this injection method, reagent spraying system (A) is equipped with epoxy resin, and second spraying system (B) is equipped with sclerosing agent.The alignment jet so that the drop that sends from each spout mixes, and moves to the targeting device aloft, after 2-8 hour hardening time, forms crosslinked coating.From spout A droplet size that sends and the droplet size approximately equal of sending from spout B, but Duo 4 times than the drop sum that distributes from spout B from the drop sum that spout A distributes.

Embodiment 4: contain the formation of the cross-linked structure of bioactivator

With a reagent spraying system (A) carry fluid epoxy resin and dissolved drug (Paclitaxel) preparation, account for 0 weight % with respect to epoxy resin.Second spraying system (B) be equipped be similar to embodiment 1 described, with etc. the sclerosing agent that combines of the bioavailable polymer of weight or lower weight.This examples of substances is the polymer that phosphocholine connects, general formula is, poly-(MPCw:LMAx:HPMAy:TSMAz), wherein MPC is a 2-methacryloxyethyl phosphocholine, LMA is a lauryl methacrylate, and HPMA is that hydroxypropyl methacrylate and TSMA are methacrylic acid trimethoxy-silylpropyl esters.Polymer is dissolved in solvent for example in the chloroform.The alignment jet aloft mixes so that come from the drop of each spout, and moves to the targeting device, forms the cross-linked coating of carrying medicine and polymer secretly.The droplet size that sends from spout A is bigger 5 times than the droplet size that sends from spout B, and from the total approximately equal of the drop of each spout distribution.Coating 70 ℃ of down heating 4 hours, by means of the trimethoxy silane group, is caused polymer that phosphocholine connects crosslinked with itself mainly, and promoted the curing of epoxy resin and sclerosing agent simultaneously.

Embodiment 5: the formation of medicine microdeposit thing

A medicament ejector system (A) is equipped with the rapamycin that is dissolved in the ethanol.Second spraying system is equipped with water.Sending the volume that a dropping liquid drips from spout A is 50 picoliters (pL), and sending the volume that a dropping liquid drips from spout B is 150 picoliters (pL).The alignment jet aloft mixes so that come from the drop of each spout, and moves to the targeting device.During the drop combination, rapamycin will be deposited in the drop, and is deposited on the target surface with the form of microdeposit thing.

Embodiment 6: medicine is loaded on the coronary stent of polymer base coating

In the demonstration of feasibility, prepared the storage jetting fluid of methacrylate polymers (PC) in isobutanol that the phosphocholine of the ABT-578+4mg/ml of 20mg/ml connects.By MicroFab Technologies of Plano, the fluid injection system that Texas makes is programmed to a kind of, make its equably with 75 microgram chemical spraies on 1.4 * 11mm OCBiodivYsio support, obtain the area density of the every mm length of 5 micrograms.At 278nm punishment light spectrphotometric method for measuring, in the bottle that contains 10 milliliters of isobutanol, spray 21,888 and produced 77 microgram ABT-578.With this understanding, 1 is 170-180 picoliter (pL), and diameter is 67 to 70 microns.Support contains the base coating of the methacrylate polymers (PC) of phosphocholine connection.It is installed on the fixture, and this fixture comprises: provide around carrying out the circular spindle of controlled rotation (θ) with the coaxial central axis of support and providing along the platform of the axle transverse movement (X) of support.Set up motor control, runing rest 720 degree.Observe the orthogonal direction of axle with runing rest, show the outer shaft position of two possible tangent lines, with the outer surface point of contact of support in about 50 microns a bit, all there is one in each side of rotation centerline, it provides situation relatively seldom, wherein sprays track and can not impinge upon on any one supporting structure member.At first select a beginning medicine in these external positions to load.Will install the circular spindle location of support so that the track of liquid droplets will clash into stent strut in " axle is outer " position.Assemble motion controller,, and begin its motion spraying the position that track leaves the support end at X-direction traversing carriage axially.Motion controller is quickened until predetermined speed, in case reach constant speed along moving of X-axis, and the terminal position under shower nozzle fully of stent strut, turn on fluid ejecting head at once.Whenever support X-direction, along described axle outer pathway, under shower nozzle fully by the time, motion controller will make speed fall, stop and with support rotation 5 degree.With the linear direction counter-rotating, and produced next passage.After reaching 360 degree, (72 passage) platform translation approximate the distance of shelf inner diameter (1ID) greatly, arrive another external position, and revolve three-sixth turn again, produced 72 passages again.Each support is injected twice thus, finishes its medicine and loads.

Seven (7) supports are loaded with medicine.Observe the support of drug loading under stereoscopic microscope, showing does not have reticulate pattern to occur between the stent strut, and the surface is as level and smooth as modified.Subsequently support is dipped in the isobutanol, is used to measure the medicine of acquisition, the result is as follows.

Support ABT-578 (microgram)

1 70

2 72

3 69

4 69

5 53

6 61

7 60

The average load that is obtained is 65 micrograms.Based on the medicine drop number of the distribution counted, the capture efficiency of calculating is 84%.

Embodiment 7: spray the peripheral frame of loading the PC coating by reagent

In similar feasibility lecture experiment, to by MicroFab Technologies ofPlano, the fluid injection system that Texas makes is programmed, and distributing 59,904, it is to be used for about 3 times of 11mm OC support.These peripheral blood vessel supports (SFA) are 5 * 30mm, and are installed on the rotary fixing device of large-size.The support matrix more manys opening than having of seeing on OC support coronarius; Yet, obtained good capture efficiency.

Support ABT-578 (microgram)

1 187

2 176

3 185

Meansigma methods 183Avg.

Ejector is distributed to each support 211 microgram medicine, has 86% capture efficiency.

Embodiment 8: use polymer that the medicine loading dock is carried out external coating

The isobutanol solution of the methacrylate polymers (PC) that the phosphocholine of preparation 10mg/ml connects.Be used under the condition of previous embodiment,, preparing external coating with the amount of the every linear millimeter of 5 micrograms along the rotations of 288 passages and 1440 degree altogether of the axial dimension of support.

Embodiment 9: use the polymer with variable surface density that the medicine loading dock is carried out external coating

The isobutanol solution of the methacrylate polymers (PC) that the phosphocholine of preparation 10mg/ml connects.During preceding 25% place and 25% place, back of stent length, the support rectilinear motion speed of setting under the shower nozzle slows down 50%.Jet velocity is constant on the length of support.Produce altogether the rotations of 288 passages and 1440 degree along the axial dimension of support.With this understanding, compare the PC amount that support has obtained to increase at the two ends of support with zone line.

Embodiment 10: the medicine loading dock with variable medical surfaces density

The storage jetting fluid of methacrylate polymers (PC) in isobutanol that the phosphocholine of the ABT-578+4mg/ml of preparation 20mg/ml connects.During preceding 25% place and 25% place, back of stent length, the support rectilinear motion speed of setting under the shower nozzle accelerates 50%.Jet velocity is constant on the length of support.Produce altogether the rotations of 144 passages and 720 degree along the axial dimension of support.With this understanding, compare the amount of the ABT-578 that support has obtained to reduce at the two ends of support with zone line.

Should be appreciated that above-mentioned detailed description and appended examples only are illustrative, rather than as the restriction for the scope of the invention, the scope of the invention only is to be limited by additional claim and their equivalent.Various changes and improvements for disclosed embodiment it will be apparent to those skilled in the art that.For example, charged deflection allotter can be used the fluid ejector replacement of dropping liquid as required, or vice versa.Can under the condition that does not deviate from its spirit and scope, carry out such changes and improvements, include but not limited to, those relevant with chemical constitution, substituent group, derivant, intermediate, synthetic method, preparation and/or using method of the present invention.

Claims (32)

1. the method on the prosthese that loading beneficial agent is sent in the tube chamber, this method comprise the following steps: to provide a kind of will be in tube chamber unfolded prosthese, prosthese comprises the tubular articles with the central shaft that defines along its length; Providing will be from the beneficial agent of prosthesis delivery; A kind of fluid distributor that can distribute the distribution member of beneficial agent with the form of discontinuous drop that has is provided; With the surface that beneficial agent is assigned to prosthese from distribution member along controlled track, wherein the controlled track of beneficial agent aligns, in order to avoid crossing with the central shaft of prosthese.

2. the process of claim 1 wherein that allocation step is with tangent with prosthetic surface basically controlled track distribution beneficial agent.

3. the method for claim 1 further is included in the step that forms relative displacement between distribution member and the prosthese, distributes the dispense path of beneficial agent to the prosthese predetermined portions to define.

4. the method for claim 3, wherein by form dispense path that step defines comprise series of parallel, along the passage of prosthetic surface.

5. the method for claim 3, the distribution member and the relative displacement between the prosthese that wherein form during the step are carried out with constant speed basically.

6. the method for claim 3, wherein prosthese has many interconnective, structural elements of defining opening between it.

7. the method for claim 6, wherein allocation step further comprises and detects the step when distribution member aligns with the structural elements of prosthese.

8. the method for claim 3, wherein allocation step comprise change with loading beneficial agent to relative velocity, to change the local surfaces density of beneficial agent on the prosthese selected location along the prosthese selected location.

9. the method for claim 8, the step that wherein changes relative velocity comprises that change applies the frequency of useful reagent droplet along the unit length of dispense path.

10. the method for claim 8, the step that wherein changes relative velocity comprises the relative displacement that changes between distribution member and the prosthese.

11. the method for claim 3 further comprises the following steps: to provide second kind of beneficial agent with from prosthesis delivery; Second distribution member that can distribute second kind of beneficial agent along controlled track with the form of discontinuous drop is provided; Along the relative displacement between second distribution member of second dispense path formation and the prosthese; With along the second dispense path, distribute second predetermined portions of second kind of beneficial agent to prosthese from second distribution member.

12. the method for claim 1 comprises that further the selected drop to the beneficial agent that distributes from distribution member applies the step of surface charge.

13. the method for claim 12, wherein the controlled track of the selected drop by applying the charged beneficial agent of step changes by means of deflection field.

14. the process of claim 1 wherein that the beneficial agent that provides step to provide by beneficial agent is selected from: antithrombotic agent, anticoagulant, antiplatelet reagent, lipotropism class reagent, thrombolytics, antiproliferative, anti-inflammatory agent suppresses hypertrophy reagent, the smooth muscle cell inhibitor, antibiotic, growth factor receptor inhibitors, cell adhesion inhibitors, cell adhesion promoter, antimitotic agent, the antifibrin agent, antioxidant, antineoplastic agent, promote endotheliocyte to recover reagent, anti-allergic material, radiopaque reagent, viral vector, antisense compounds, oligonucleotide, cell sees through reinforcing agent, vascularization reagent and their combination.

15. the process of claim 1 wherein that the beneficial agent that provides step to provide by beneficial agent is selected from: Paclitaxel, rapamycin, everolimus, heparin, estradiol, dexamethasone, its analog and its combination.

16. the method for claim 15, wherein the analog of rapamycin is 3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-16 hydrogen-9, the 27-dihydroxy-3-[(1R)-and 2-[(1S, 3R, 4R)-and 3-methoxyl group-4-tetrazolium-1-yl) cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23, the pyridine-1,5 of 27-epoxy radicals-3H-pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone; 23, the pyridine-1,5 of 27-epoxy radicals-3H-pyrido [2,1-c] [1,4] oxa-azacyclo-hentriaconta-, 11,28,29 (4H, 6H, 31H)-pentone.

17. the process of claim 1 wherein that the beneficial agent that will provide step to provide by beneficial agent is dispersed in the solvent.

18. the method for claim 17, wherein solvent is an isobutanol.

19. the process of claim 1 wherein that allocation step comprises is assigned to beneficial agent on the selected portion of prosthese with bonding agent.

20. the method for claim 19, wherein bonding agent is biodegradable.

21. the method for claim 1 further is included at least one part of prosthetic surface and applies binder layer; And wherein allocation step includes selectively and distributes the predetermined portions of beneficial agent to binder layer from distribution member.

22. the method for claim 21 be the polymer that phosphocholine connects by the binder layer that applies step and provide wherein, and wherein beneficial agent comprises dexamethasone.

23. the method for claim 1 further comprises the step of measuring the amount that is loaded in the beneficial agent on the prosthese, wherein determination step comprises that detection is loaded into the amount of the marker discerned on the prosthese, is loaded into the corresponding amount of the beneficial agent on the prosthese with mensuration.

24. the method on the prosthese that loading beneficial agent is sent in the tube chamber, this method comprise the following steps: to provide a kind of will be in tube chamber unfolded prosthese; Providing will be from the beneficial agent of prosthesis delivery; A kind of fluid distributor that can be assigned the distribution member of beneficial reagent with discontinuous drop form that has is provided, and each drop has controlled track; Between distribution member and prosthese, form relative displacement, to determine to distribute the dispense path of the discontinuous drop of beneficial agent with raster mode; With optionally distribute beneficial agent to the predetermined portions of prosthese along dispense path from distribution member.

25. the method for claim 24, wherein the prosthese that provides step to provide by prosthese comprises many interconnective, structural elements of defining opening between it, allocation step comprises when distribution member and is assigned beneficial reagent when structural elements in the prosthese predetermined portions aligns, and when the register of distribution member and prosthese, stop beneficial agent being dispensed to prosthese.

26. the method for claim 25, wherein allocation step further comprises and detects the step that distribution member when aligns with structural elements in the prosthese predetermined portions.

27. the method for claim 24 further comprises the step of measuring the amount that is loaded in the beneficial agent on the prosthese, wherein determination step comprises that detection is loaded into the amount of the marker discerned on the prosthese, is loaded into the corresponding amount of the beneficial agent on the prosthese with mensuration.

28. one kind with the system of loading beneficial agent to the prosthese that is used for sending in the tube chamber, this system comprises: be used to support will be in tube chamber the bearing of unfolded prosthese; A kind of fluid distributor that can be assigned the distribution member of beneficial reagent that has with discontinuous drop form, each drop has controlled track, and distribution member and bearing are removable each other; Be used to cause the driver of relative displacement between distribution member and the bearing; With the controller that interrelates with driver, to determine to distribute the dispense path of the discontinuous drop of beneficial agent with raster mode, this controller also interrelates with distribution member, with along dispense path, distribute beneficial agent from distribution member selectively to the predetermined portions of the prosthese of seat supports.

29. the system of claim 28 further comprises detector, aligns with the predetermined portions of prosthese by seat supports to detect distribution member when.

30. the system of claim 28, wherein bearing comprises the spindle of being made by elastic material.

31. the system of claim 28, its middle controller is programmed with the predetermined portions of the prosthese that will be assigned with beneficial agent.

32. the system of claim 28, further comprise the detector that interrelates with controller, be loaded in the amount of the beneficial agent on the prosthese with mensuration, this detector detects the amount that is loaded into the marker discerned on the prosthese, is loaded into the corresponding amount of the beneficial agent on the prosthese with mensuration.

Images