DE20200220U1 - stent - Google Patents

Description

08.01.2002 00032-02 He/nm

translumina GmbH D-72379 Hechingen

Stents

The present invention relates to a stent with a wall having struts, wherein areas for receiving one or more medications are provided in the wall and/or in the struts. Stents are known in numerous different embodiments and serve to keep pre-dilated blood vessels wide and to prevent or at least significantly delay restenosis.

A common procedure for treating vascular stenosis is to first dilate the vessel with a catheter. A disadvantage of this type of percutaneous transluminal coronary angioplasty (PTCA) is that the vessel can become narrower again, i.e. restenosis. To prevent this, the stent is shrunk onto a balloon catheter in a further step and inserted into the pre-dilated vessel. The stent is then expanded by increasing the pressure in the balloon catheter, which causes the stent to press against the vessel wall.

Conventional stents usually have the shape of a hollow cylinder, the wall of which is formed by a large number of longitudinal and transverse

The struts are arranged in such a way that the stent can be shrunk onto a balloon catheter and also expand when pressure is applied to the balloon catheter. This special structure of the stent means that the stent expanded in this way retains its expanded structure and thus ensures that the vessel remains wide. Stents are known whose surface is largely smooth. Stents are also known that have a surface structure that is usually applied to the surface using an etching technique. It is also known to use roughness in the surface or depressions in the surface as drug depots.

EP 0 950 386 A2 describes a stent in which channels are incorporated into the struts, the open side of which is located on the outer circumference of the stent. These channels contain medications, such as rapamycin, which largely prevent the proliferation of the endothelium and thus effectively prevent restenosis. Other antibiotics, cytostatics or heparin can also be used as medications.

The creation of channels produced by etching techniques has the disadvantage that the amount of medication cannot be known precisely due to the irregular etching, i.e. it is difficult to dose the medication precisely. Another disadvantage is that due to the arrangement of the channels, the medication is located on the outside of the stent and thus on the side facing away from the blood flow, so that it is not possible to influence the flow conditions on the distribution and absorption of the medication.

It is therefore the object of the present invention to further develop a stent of the type mentioned at the outset in such a way that an exact drug dosage is possible and, moreover, influences of the blood flow on the release kinetics of the drug can be realized.

This object is achieved by a stent with the features of patent claim 1. According to this, the areas are designed in the form of pores penetrating the wall or the struts. Such a design has the advantage that the medication is now also available on the side facing the blood flow, so that effects of the flow properties of the blood can be used to control the kinetics of the medication dissolution and distribution in the blood. The blood absorbs the medication and distributes it in a flushing radius that depends on the blood velocity, the pore geometry and the vessel diameter. Another advantage is that the precise dosing of the medication is possible due to the specifically predeterminable pore structure. This depends on the number of pores in the struts and the pore volume.

In a further embodiment of the present invention, the stent is essentially cylindrical and the longitudinal axis of the pores runs vertically or obliquely relative to the longitudinal axis of the stent. The obliquely running pores can be designed antegrade or retrograde. Such a design influences how quickly the medication is dissolved by the blood flowing to the pores or is absorbed into the blood.

The pores can be produced, for example, by laser applications, etching, forming processes or removal processes or by combinations of these processes. The etching technology, which can be used in addition to laser technology, can have a significant influence on the pore geometry. For example, it can be provided that the pores are produced by an initial laser application and then by etching.

The walls can have a convex or concave shape in longitudinal section and/or be straight or conical. While straight designs are preferably produced using laser technology,

Etching techniques or removal processes can be used to round off edges or hollow out flat areas, so that the aforementioned structure of a convex or concave shape can be realized by this combination.

The pores can be created or changed in shape using strong acids, for example. One of the forming processes is shot blasting, which creates pores in the wall of the stent. Removal processes include sandblasting, which essentially removes surface material and can therefore change the pore geometry. Any combination of these processes is possible. In addition to the aforementioned shot blasting and sandblasting processes, blasting with other blasting materials is also possible.

During etching, it is possible to protect areas of the stent from the etchant by means of masking, so that only the exposed areas are etched. The mask can, for example, be a polymer mask that is glued to the stent.

Alternatively or in addition to the convex and/or concave shape of the walls, the pores can have straight or conical walls. Combinations of these are also possible. For example, pores can be provided with one wall being straight and the other wall being slanted towards it. Combinations of differently designed pores within a stent are also conceivable.

In a further embodiment of the present invention, one or more drugs are accommodated in the pores and the openings of the pores are closed by a polymer. This has the advantage that the drug is not released immediately, but only after the polymer has dissolved or separated. The type and thickness of the polymer can be used to vary its dissolution rate or the diffusion rate of the drug and thus the kinetics of drug release.

-5-

Of course, it is also conceivable that the drugs are absorbed into the pores without the use of polymers.

In a further embodiment of the present invention, a layer structure can be provided in the pores, the individual layers of which alternately consist of one or more drugs and polymer. In this case, a drug can be applied directly to the pore wall, the polymer as the next layer, another drug as the next layer, etc. Such a structure can be used to determine which drug should be made available at what point in time.

It is conceivable that the pore cross-section is completely filled by the layer structure. Here too, the end areas of the pores are preferably closed by means of a polymer.

According to a particularly preferred embodiment of the present invention, channels are provided which connect the pores to one another. This creates a structure which is not only formed by the pores located in the struts, but which also has channels connecting the pores, which brings further advantages with regard to dosing accuracy and drug release kinetics.

The channels can be filled with one or more drugs and the end areas of the channels that open into the pores can be closed by means of a polymer. In this way, a macro- and a micropore structure is provided, which allows further variations in terms of the kinetics of drug release as well as the drug type and composition. For example, it can be provided that both the pores and the channels contain different drugs, each enclosed by polymers. In this case, the drugs contained in the pores are released first and then, after the

Polymer caps that close the channels absorb the medication contained in the channels. This not only enables precise dosing, but also an accurate prediction of the timing of the medication release. It is also possible for medication to only be present in the channels and for the pores to remain open or be filled with polymer.

The polymer is preferably a biocompatible, biodegradable polymer, in particular a polylactide.

In a further embodiment of the present invention, it is provided that at least some of the pores have a bulbous shape in their longitudinal section, which is characterized by an opening region of smaller diameter and a bulging region of larger diameter.

Such pores preferably contain particles containing polymer and medication, the outer layer of which consists of a polymer, preferably of a polymer according to claim 10, and in the interior of which one or more medications are contained, the smallest diameter of the particles being greater than the diameter of the mouth area. A superstructure is thus formed, which is formed on the one hand by the arrangement of the pores in the stent and on the other hand by the structure of the particles. Such particles can be produced with great precision, so that the amount of medication contained in them is generally known very precisely. The special design of the pores means that exactly one, preferably spherical, particle is contained in each of the pores, so that the dosage of the medication on the stent is known very precisely from the number of pores. The particles are contained in the pores at a specific location. The particles can penetrate into the pores mechanically or electrostatically, for example. It is also conceivable that the medication is evenly distributed in a polymer matrix. It is also possible that only drugs without polymers are used in the pores.

-7-

Several consecutive layers of polymer and drug can be arranged inside the spherical structures. This also results in the advantage already mentioned above that the kinetics of drug release, even of different drugs, can be determined very precisely using such a structure.

According to a preferred embodiment of the present invention, the pores are accommodated in the areas of the struts that extend in the longitudinal direction of the stent. These areas of the stent are not greatly deformed when shrinking onto the catheter or during dilation in the vessel, so that the pore geometry is essentially retained. This has the advantage that no excessive deformation occurs, which would result in the pore geometry being changed and thus an undesirable influence on the flow behavior of the blood and on the amount of medication and thus on the release kinetics of the medication.

Alternatively or additionally, it can be provided that the pores are accommodated in the areas of the struts that extend in the circumferential direction of the stent. These are the areas that are subject to the greatest deformations both during shrinkage and especially during dilation. An arrangement of the pores in these areas can be aimed for, for example, in order to remove a pre-stressed polymer plug on the pores by mechanical effects during expansion, so that the medication is immediately available.

The present invention further relates to a stent with a wall having struts, wherein areas for receiving medication are provided in the wall and/or in the struts. The areas are designed as recesses which have an opening area of smaller diameter and a bulging area of larger diameter. The

-8th-

Recesses are preferably used to accommodate particles containing medication, i.e. particulate medication depots, and enable particularly precise dosing, which can be precisely specified by the number of recesses and the medication content of the medication depots.

The recesses can be produced by a combination of laser application and etching, with the mouth area having rounded edges. Other geometries are also conceivable, for example with mouth areas that run at an angle to the longitudinal axis of the stent. In addition to or in addition to these processes, forming processes such as shot blasting or removal processes such as sandblasting are also conceivable. Any combination of the processes mentioned can be used to achieve the desired geometry of the recesses.

In a preferred embodiment, particles containing polymer and medication are accommodated in the recesses, the outer layer of which consists of a polymer, preferably of a polymer according to claim 10, and in the interior of which one or more medications are accommodated, the smallest diameter of the particles being greater than the largest diameter of the openings of the recesses. This ensures that the particles are fixed in the recesses and do not move out of the recesses when the stent is shrunk onto the catheter or when the stent is expanded. The kinetics of medication release can be influenced by the polymer layer. This can be influenced by the type of polymer used as well as by the thickness of the polymer layer.

In a further embodiment of the invention, particles containing polymer and medication are accommodated in the recesses, the polymer preferably consisting of a polymer according to claim 10, the medication being distributed in a polymer matrix and the smallest diameter of the particles being above the largest diameter of the mouths of the recesses. The structure of the particles can thus be achieved by a shell-shaped structure with

·

-9-

an outer polymer layer or by a uniform distribution of the drug in a polymer matrix of the particle.

Further details and advantages of the present invention are explained in more detail using an embodiment. Shown are:

Fig. 1: Different geometries of the pores penetrating the struts of the stent in schematic longitudinal sections,

Fig. 2: a schematic longitudinal sectional view of two pores in the struts of the stent with a channel connecting them,

Fig. 3: a schematic longitudinal sectional view of a pore in the strut of the stent with a bulbous shape and

Fig. 4: a schematic longitudinal sectional view of a recess in the strut of the stent with a bulbous shape.

Fig. 1 shows schematic longitudinal sectional views of different geometries of the pores 10 penetrating the struts 20 of a stent. Below the struts 20 shown is the side of the stent through which blood flows. Fig. 1 a) shows a pore design with straight pore walls and a longitudinal axis that is perpendicular to the longitudinal axis of the stent. Such a pore design can preferably be produced by lasering.

Fig. 1 b) and 1 c) show retrograde (b)) and antegrade pore designs (c)), assuming that the flow direction of the blood runs from left to right as shown in Fig. 1. Fig. 1 d) shows a pore geometry with conical walls. Fig. 1 e) and 1 f) show pore designs with concave (e)) and convex (f)) walls. The curves of the walls are produced by etching techniques. Fig. 1 g) shows a

-10-

Pore geometry according to Fig. 1 a), in which, however, after the production of the pore 10 by means of a laser, the edges of the mouth area were rounded off by etching.

Such pore designs influence the flow pattern in the opening area of the pore 10 and thus on the flushing radius and the vortex formation in the area of the pore openings or the pores 10. These factors determine the distribution of the drug in the vessel as well as the temporal course of the drug release, i.e. the release kinetics.

Fig. 2 shows two pores 10 connected by a channel 30. The pores 10 correspond to those shown in Fig. 1 a) and are cut into the struts 20 of the stent by laser application. The channel 30 connecting the pores 10 is then produced by targeted application of an etching agent in the area of the pore walls. Such geometries allow, for example, the use of different medications in the pores 10 and in the channel 30. In addition, it is possible to ensure that the medication absorbed in the channel 30 is released after the medication in the pores 10, so that medication can be provided over longer periods of use.

Fig. 3 shows a pore 10 with a substantially bulbous shape. This is characterized by an opening region 12 of smaller diameter and a bulging region 14 of larger diameter. Such a pore geometry enables the introduction of preferably spherical elastic drug depots whose diameter is larger than that of the opening region 12.

Fig. 4 shows a further embodiment of the present invention. In this case, recesses 40 are provided in the struts 20 of the stent, which are not designed as pores penetrating the struts. The recess 40

• t

··

- 11 -

otherwise corresponds essentially to the pore 10 shown in Fig. 3 and also has an opening area 42 of smaller diameter and a bulging area 44 of larger diameter. They also serve to introduce preferably spherical drug depots whose diameter is larger than that of the opening area 42. Both structures according to Fig. 3 and Fig. 4 allow particularly precise drug dosing.

The use of a stent is illustrated using a stent as shown in Fig. 2:

In preparation for the insertion of a stent, the stenosis is removed by inserting a catheter and the vessel is pre-dilated. The stent is then shrunk onto a balloon catheter, which means that the diameter of the stent decreases from approximately 1.8 mm to 1 mm. After the stent has been inserted into the pre-dilated vessel, the balloon catheter is activated and the stent is expanded to a diameter that is larger than the initial diameter of 1.8 mm. The stent now lies firmly against the vessel wall.

The stent is designed as a hollow cylinder. The wall of the hollow cylinder is formed by a large number of struts, some of which extend longitudinally and some of which extend transversely. The stent according to Fig. 2 has pores 10, which are located in the longitudinally extending areas of the struts. In this embodiment, these are essentially cylindrical pores 10, which are connected to one another by means of fine channels 30. The pores 10 are filled with a multilayer structure consisting of alternating layers of rapamycin and polylactide. The openings of the pores 10 are closed by a polylactide cover. This applies accordingly to the openings of the fine channels 30 into the pores 10. The channels 30 also contain rapamycin or another medication, such as another antibiotic or a cytostatic agent.

The pores 10 are manufactured by laser application and can have bevelled edges in both end areas, which are obtained by an etching technique.

I ss":' ·

-12-

Pores with diameters of up to approx. 5 μηι can be created using laser technology.

After this stent is introduced into the vessel, the polylactide caps covering the pores are biologically decomposed and the medication absorbed in the pores 10 is gradually released. Due to the shape of the pores 10, it is now possible for inner or outer layers of the layer structure absorbed in the pores 10 to be dissolved preferentially. If the inner layers are dissolved first, the medication absorbed in them is released accordingly during this time, with the time offset being controllable by the number and thickness of the polylactide layers. As soon as the multi-layer structure in the pore 10 is dissolved, the polylactide caps closing the channels 30 are biologically decomposed. At a time offset from this, the medication absorbed in the channels 30 is flushed out and is released accordingly at a time offset from the medication absorbed in the multi-layer structure of the pores 10. The precisely predictable structure of the pores 10 and channels 30 not only enables an exact dosage of the medication, but also an exact determination of the temporal sequence of the

Release of medication. The release of medication on the side facing the bloodstream occurs when the blood flows towards the pore openings, absorbs the medication and distributes it in a flushing radius that depends on blood velocity, pore geometry and vessel diameter. ;

Of course, in addition to the introduction of the drug(s) into the pores or recesses, it can be provided that the drug(s) are applied to the surface of the wall and/or the struts on the inside and/or outside of the stent.

Claims (19)

1. Stent with a wall having struts, wherein in the wall and/or in the struts there are provided regions for receiving one or more medicaments, characterized in that the regions are designed in the form of pores penetrating the wall or the struts. 2. Stent according to claim 1, characterized in that the stent is essentially cylindrical and the longitudinal axis of the pores runs vertically or obliquely with respect to the longitudinal axis of the stent. 3. Stent according to claim 1 or 2, characterized in that the pores are manufactured by laser application, by etching, by forming processes or by removal processes or by combinations of these processes. 4. Stent according to one of claims 1 to 3, characterized in that the walls of the pores assume a convex or concave shape in longitudinal section and/or that the pores have straight or conical walls. 5. Stent according to one of claims 1 to 4, characterized in that one or more medicaments are accommodated in the pores and the mouths of the pores are closed by means of a polymer. 6. Stent according to one of claims 1 to 5, characterized in that a layer structure is provided in the pores, the individual layers of which consist alternately of one or more medicaments and of polymer. 7. Stent according to claim 6, characterized in that the pore cross-section is completely filled by the layer structure. 8. Stent according to one of claims 1 to 7, characterized in that channels are provided which connect the pores with one another. 9. Stent according to claim 8, characterized in that the channels are filled with one or more medicaments and that the end regions of the channels opening into the pores are closed by means of a polymer. 10. Stent according to one of claims 5 to 9, characterized in that the polymers are a biocompatible, biodegradable polymer, in particular a polylactide. 11. Stent according to one of claims 1 to 10, characterized in that at least some of the pores have a bulbous shape in their longitudinal section, which is characterized by an opening region of smaller diameter and a bulging region of larger diameter. 12. Stent according to claim 11, characterized in that particles containing polymer and medicament are accommodated in the pores, the outer layer of which consists of a polymer, preferably of a polymer according to claim 10, and in the interior of which one or more medicaments are accommodated, the smallest diameter of the particles being greater than the diameter of the mouth region. 13. Stent according to claim 12, characterized in that several successive layers of polymer and drug are arranged in the interior of the particles. 14. Stent according to one of claims 1 to 13, characterized in that the pores are accommodated in the regions of the struts which extend in the longitudinal direction of the stent. 15. Stent according to one of claims 1 to 14, characterized in that the pores are accommodated in the regions of the struts which extend in the circumferential direction of the stent. 16. Stent with a wall having struts, wherein regions for receiving medication are provided in the wall and/or in the struts, characterized in that the regions are designed as recesses which have an opening region of smaller diameter and a bulging region of larger diameter. 17. Stent according to claim 16, characterized in that the recesses are produced by a combination of laser application and etching and the mouth region has rounded edges. 18. Stent according to claim 16 or 17, characterized in that particles containing polymer and medicament are accommodated in the recesses, the outer layer of which consists of a polymer, preferably of a polymer according to claim 10, and in the interior of which one or more medicaments are accommodated, the smallest diameter of the particles being above the largest diameter of the mouths of the recesses. 19. Stent according to claim 16 or 17, characterized in that particles containing polymer and medicament are accommodated in the recesses, wherein the polymer preferably consists of a polymer according to claim 10, wherein the medicament is distributed in a polymer matrix and wherein the smallest diameter of the particles is above the largest diameter of the mouth region of the recesses.