STENT MADE FROM BIOLOGICALLY DEGRADABLE MAGNESIUM ALLOY

专利摘要:
Stent made from biologically degradable magnesium alloy The present invention relates to stents produced from a degradable magnesium alloy under physiological conditions and a polymer outer coating. The stents according to the invention may therefore be coated with at least one antiinflammatory, antiproliferative, antiangiogenic, antirestenotic and / or antithrombogenic active substance.
公开号:BR112014003125B1
申请号:R112014003125-8
申请日:2012-08-15
公开日:2019-07-09
发明作者:Michael Stekker；Nobert Hort；Frank Feyerabend；Erika Hoffmann；Michael Hoffmann；Roland Horres
申请人:Hemoteq Ag；Meko Laserstrahl-Materialbearbeitungen E.K；
IPC主号:

专利说明:

STENT MADE FROM A BIOLOGICALLY DEGRADABLE MAGNESIUM ALLOY [001] The present invention relates to stents produced from a magnesium alloy degradable under physiological conditions and an external polymer coating. The stents according to the invention can therefore be additionally coated with at least one active anti-inflammatory, antiproliferative, anti-angiogenic, anti-restenotic and / or anti-thrombogenic active substance.
[002] The implantation of vessel supports, such as, for example, stents, is currently a conventional surgical approach for the treatment of strictures. They are usually produced from metal alloys such as stainless steel that is not subject to corrosion or nitinol. Metal stents of this nature are known on a large scale and have proven to be good in practice. Depending on their metal structure and their carrying capacity, metal stents of this nature must ensure that the vessels remain open after implantation and blood flow is continuously guaranteed through the vessels.
[003] New research, however, has shown that stenosis of vessels should not be permanently widened by means of an endoprosthesis, especially in the form of a stent. It has been absolutely sufficient to support the blood vessel for a limited period of time, as the traumatized tissue of the vessel heals and the smooth muscle cells of the vessels regenerate and take over the task of keeping the blood vessel open, therefore, the stent need not stay longer than necessary in the vascular lumen.
[004] Currently, stents are divided into two basic types: permanent and degradable or resorbable stents. Permanent stents are configured in such a way that they can remain in the vessel for an indefinite period of time. Resorbable stents, in turn, are degraded over a predetermined period of time in the vessel.
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2/73 [005] Currently, there is an attempt to solve the problem of restenosis after stent implantation, in which an attempt is made to locally prevent the growth of smooth muscle cells. This is attempted, for example, with stents, which release active pharmaceutical substances, which preferentially act in an antiproliferative manner. These active substances are released predominantly from a coating containing the active substance, which can be applied to both permanent stents and resorbable stents.
[006] The support effect through the metal structure is currently only necessary for a short period, since after implantation of the stent the body tissue can recover and the support function is no longer needed. Degradable and resorbable stents are preferably removed only if the traumatized tissue of the vessel is healed and the vessel stabilizes, so that the stent should not continue to remain in the vascular lumen. Especially in the case of stents that come into contact with blood, they cause, as materials with foreign bodies, the formation of restenosis. Efforts to improve the stents for better biocompatibility of the stent material, for greater flexibility when material orifices become narrower and the reduction of the surface of foreign bodies must continually minimize the risk of the stent-induced restenosis index. Resorbable stents have the advantage here that the foreign body material does not remain continuously in the vessel and that the danger of restenosis is, as a result, temporally limited. An application of resorbable stents is also advantageous in children, since the growth of the vessel is not negatively influenced here, or the stent, after a certain period in which the child has grown, does not need to be removed again.
[007] For this reason, stents are currently being developed in progressive quantities from materials
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3/73 bioresorbables, such as, for example, from polymers such as polyhydroxybutyrate, or from metals such as magnesium or iron, and have been used in clinical procedures.
[008] The great resilience of the vessels after a dilation is a major factor for restenosis. For this reason, resorbable vessel supports must consist of a material that can be well removed from the body, but which also has a sufficiently high holding force to prevent re-closure of the vessel.
[009] A stent, once used, must retain its size and shape, despite the different forces on it, such as, for example, the pulsating load due to the heartbeat. In addition, the stent must be flexible enough to be driven into a balloon and later expand into the vessel.
[0010] Resorbable polymers, which are used for the production of stents, have lower mechanical strength values than non-resorbable metal alloys used until then. Compensation for this disadvantage can occur due to greater stent width struts. However, this increases the mechanical irritation of the vessel wall during stent implantation and, thus, also increases the risk of restenosis. Resorbable stents made of iron or an iron-based alloy have the disadvantage that the length of stay in the vessel until complete removal is longer than necessary and desired. For resorbable stents, the desired period of time for resorption is between 3 and 12 months, in which the mechanical load capacity must be assured in advance. Magnesium is present in the body as an trace element and is therefore suitable as a base for a resorbable stent. In addition, alloy components from metals in the group of rare earths were selected, since they do not occur naturally in the body. This makes it possible to detect degradation products in the tissue and organs.
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4/73 [0011] Magnesium and magnesium alloys have surprising physical and mechanical characteristics for a variety of applications. Its low weight, combined with its high strength, makes magnesium and magnesium alloys suitable materials for endoprostheses as well. Magnesium and magnesium alloys are very reactive and therefore subject to corrosion. However, for resorbable implants these characteristics are desirable. Despite this, the following problems arise in the state of the art: although at first the desired goal of resorption of the implanted stent is achieved, the problem of an undefined temporal removal of the stent arises. Depending on the choice of material, the removal of the material is subject to several uncontrollable and, in general, very rapid variations to ensure safe internal growth of the stent in the vessel walls. In the case of very rapid resorption, the resorbable stent is unable to grow internally in the vessel wall and assume the support function until the vessel segment regenerates. On the contrary, it can come loose or pieces of the stent can come off and be swept into the blood flow and cause problems that threaten the patient's life.
[0012] A bioresorbable metal stent from magnesium and yttrium is published in European patent EP 1 419 793 B1. A magnesium alloy with yttrium, neodymium and other optional components suitable for the manufacture of stents is described in European patent EP 2 169 090. These stents have the disadvantage that they dissolve very quickly and, therefore, in an uncontrolled manner. Since the dissolution process starts predominantly before the stent has grown into the vessel wall, fragments can come off, be transported through the bloodstream and cause a heart attack. In addition, these stents made of a magnesium and yttrium alloy were found to promote the deposition of calcium phosphate on the luminal surface of the stent
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5/73 and thus lead to a new closure of the stent (restenosis in the stent) and, therefore, also of the vessel, which must be prevented.
[0013] European patent applications EP 2 213 314 A1 and EP 1 842 507 A1 also disclose stents from a magnesium alloy containing gadolinium. In order to obtain the desired mechanical properties, such as, for example, strength, tensile strength or ductility, require gadolinium in amounts greater than 5% by weight. In the case of quantities greater than 5% by weight, however, gadolinium faces the problem that the processability and homogeneity of the alloy are no longer guaranteed. Worsened processability would lead to thicker stent struts, which pose a problem, given that the bloodstream would be impaired, which results in thrombi. With that, it can be established that until August 2012 there was no metal alloy in the state of the art, which would be suitable as material for the production of bioresorbable stents.
[0014] For this reason the need arises to develop an active substance suitable for resorbable stents and to combine this with a polymeric coating that allows to control the degradation of the stent. The aim of the present invention is to provide a vessel support which provides its support function only long enough until the regenerated tissue itself is able to assume the function and which avoids the disadvantages of the prior art.
[0015] Summing up the concrete objective, the objective of the present invention is to provide a stent made of a magnesium alloy and a polymeric coating adapted to the alloy, whose kinetic dissolution is delayed or significantly slowed compared to the known stents.
[0016] Said objective is solved through the technical teaching of the independent claims of the present invention. Additional advantages of the invention result from the dependent claims, the description and the examples.
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6/73 [0017] It has been found that magnesium alloys with a relatively high content of dysprosium, which is still preferably mixed with neodymium and / or europium and, optionally, zirconium and / or zinc, are characterized by an advantageous behavior corrosion, kinetics of desired absorption and mechanical properties suitable for the production of stents.
[0018] The present invention therefore relates to stents consisting of a biologically degradable magnesium alloy, which contains the following components based on the total weight of the alloy:
5.0% by weight to 25.5% by weight of dysprosium
0.01% by weight to 5.0% by weight of neodymium and / or europium
0.1% by weight to 3.0% by weight of zinc
0.1% by weight to 2.0% by weight of zirconium remaining to 100% by weight of magnesium, in which the stent has a polymeric coating.
[0019] The polymeric coating of the stents of the invention is limited to the stent struts of the basic structure itself or can involve the entire hollow body, such as a sock, optionally on both sides, in the abluminal as well as in the luminal side of the stent body , or fill the free interstices of the stent body in such a way that the wrap is on a plane with the stent struts also covered. The coating variants can be reasonably combined.
[0020] According to the invention, the internal structure of the vessel support or stent of the invention consists of a magnesium alloy. This alloy consists of 5.0 to 25.5% by weight of Di and 0.01 to 5.0% by weight of Nd or 0.01 to 5.0% by weight of Eu or 0.01 to 5.0% by weight of Nd and Eu together, 0.0% by weight - 3.0% by weight of zinc and 0.0% by weight of - 1.5% by weight of zirconium, the remainder up to 100% by weight being Mg.
[0021] In addition, the internal structure of the vessel support is preferably made of magnesium alloys containing 5.0 to 25.5% by weight of
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Di is 0.01 to 5.0% by weight of Nd or 0.01, to 5.0% by weight of Eu or 0.01 to 5.0% by weight of Nd and Eu together, 0.1% in weight at 2.0% by weight of zirconium, further comprising 0.1% by weight at 2.0% by weight of zinc.
[0022] Furthermore, the internal structure of the vessel support is preferably made of magnesium alloys containing 5.0 to 25.5% by weight of Di and 0.01 to 5.0% by weight of Nd or 0.01 to 5.0% by weight of Eu or 0.01 to 5.0 % by weight of Nd and Eu together, 0.1% by weight to 3.0, preferably up to 2.0% by weight of zinc, additionally comprising 0.1% by weight to 0.3% by weight of zirconium. Therefore, these alloys can even contain unavoidable impurities.
[0023] It is especially preferable if the internal structure of a stent of the invention consists of a magnesium alloy that contains the following components based on the total weight of the alloy (given in% by weight):
81.5% by weight to 91.9% by weight of magnesium
7.0% by weight to 15.0% by weight of dysprosium
0.5% by weight to 1.5% by weight of neodymium and / or europium
0.5% by weight to 1.5% by weight of zinc
0.1% by weight to 0.5% by weight of zirconium in which the stent has a polymeric coating.
[0024] Magnesium (Mg) as the main component of the alloy was chosen because Mg is biologically degradable and a necessary element for the body, which does not accumulate in the body in a way that is harmful. Excess magnesium is usually produced naturally.
[0025] Dysprosium, together with precipitated forms of intermetallic magnesium. The high solubility of magnesium dysprosium also ensures that the necessary heat treatments for the production of stent prostheses can be successfully carried out, which precipitates to dissolve and, specifically, reprecipitate and can thus adjust the properties, such as the strength, ductility and corrosion resistance within large limits. High strength and high ductility
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8/73 delay the biological degradation of the alloy which is especially desired for a stent made of a magnesium alloy. As used herein, the terms ductility and elongation at break are used interchangeably. Deformation resistance as a measure of strength should be in the range of 80 MPa - 180 MPa.
[0026] Dysprosium further increases the strength of the alloy, because it is dissolved in the mixed crystal and precipitates can form. Europium forms only precipitates similar to neodymium. In the individual grain of the alloys described here, which contain dysprosium, as well as europium and / or solid neodymium hardening solution and precipitation hardening can be combined. By heat treatment it can dissolve and specifically reprecipitate the magnesium precipitates with dysprosium. In this way resistance and ductility can be adjusted within a wide range by the composition of the alloy. However, as soon as all the precipitates in the grain contours have disappeared, grains can start to grow (OstwaldRipening). However, coarse grains have a negative effect on strength and ductility and therefore should be avoided. The magnesium with europium or magnesium - neodymium precipitated at the grain boundaries stabilize the grain boundaries during a heat treatment, which is always necessary during the production of stents. Therefore, the grain size is not changed due to the stabilizing effect of europium and / or neodymium. In any case, it is desirable to stabilize an existing fine particle size because, according to Hall-Petch, a refined microstructure positively affects strength and ductility. This stabilization within an Mg - Di alloy is achieved by adding europium and / or neodymium.
[0027] For the production of prostheses, especially the resistance characteristics and the corrosion behavior have been taken into account to make it possible for an alloy to be so strong and resistant to corrosion.
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9/73 [0028] It has been found that the minimum corrosion of the magnesium alloys described here occurs at a content of 10% by weight of Di. Therefore, it is especially preferred if the content of dysprosium in the respective alloys is approximately 10% by weight ± 2% by weight. Figure 7 shows, with respect to corrosion, that a binary magnesium alloy containing dysprosium with an amount between 7 to 15% by weight, even better than 8 to 12% by weight of dysprosium, has a preferentially minimal corrosion behavior. Corrosion is the crucial property for the rate of degradation of the stent in the vessel. It is important that a biodegradable alloy does not lose its stability too early, so that no fragments are released and that the stability is guaranteed by the stent until it can be re-attached to the vessel alone and until the stent has grown inside the vessel wall.
[0029] Neodymium and europium also show no negative effects on cells in vitro. Europio, compared to neodymium, was tolerated even a little better. Both elements are virtually insoluble in magnesium and form intermetallic phases with magnesium, which are also not dissolved by heat treatments essential for the production of stents. These precipitations are located at the grain boundaries and stabilize them, so that the fine grain of the metal formation is maintained. According to the invention, it has been shown that 1% by weight of neodymium or 1% by weight of europium or 1% by weight of europium and neodymium together is sufficient. With amounts of europium and / or neodymium of more than 1% by weight, the ductility of the alloy begins to decrease, which is undesirable for the production of stents, and amounts of europium and / or neodymium of more than 2% by weight reduces the alloy's ductility in such a way that the minimum essential ductility of 15% is no longer guaranteed. Amounts of Eu and / or Nd of more than 2% by weight lead to an increase in the fragility of the alloy and a decrease in ductility with further increase in the weight ratio.
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10/73 [0030] But, in particular, the ductility of alloys is essential for the suitability of a construction material for the production of stents. After the manufacture of the stent, most of a catheter balloon is inserted into a carrier, and thus plastically deformed for the first time. Subsequently, in situ in the blood vessel, the stent is expanded and is plastically deformed once again. A high elongation at break and, consequently, a high ductility is necessary to be able to perform these quite drastically deformations without damage. At the same time, a high strength, it is also necessary to avoid the rupture of the stent supports during these two deformations and to avoid compression of the stent and, thus, the occlusion of the vessel by the recovery forces of the vessel wall. Among the possible strengthening mechanisms of the Hall-Petch-Mechanism (grain-bound reinforcement) it is suitable to achieve high strength and, simultaneously, increase ductility. All the alloying elements, the resulting intermetallic phases and also the cold deformation created by the deformation of the stent increase the strength, but decrease the ductility at the same time. To compensate, a fine grain is indispensable.
[0031] Zinc improves the casting characteristics of the magnesium alloy and has a reinforcing effect. Thus, the fatigue and tensile strength can be increased by adding zinc up to 3% by weight. The tensile strength should be, preferably as high as possible and preferably more than 180 MPa (> 180 MPa), even more preferred than 200 MPa (> 200 MPa). However, the tendency for hot crack formation increases with more than 1% by weight of Zn (see Figure 8). In this way, micropores are formed, which negatively affects the tensile strength and ductility of an alloy. They act as interior notches, so that, in stress tests of a construction material, they are generally not clearly below the maximum force attainable in a fractional amount of theoretical ductility. In general, an effect
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11/73 disadvantageous on the processing behavior and the mechanical properties of the alloys described here shows with more than 2% by weight of zinc. Zinc is an essential element for humans, which is part of many enzymes and has many functions. Among others, zinc has an anti - inflammatory effect. However, with high doses acute intoxication can occur and a long-term supply causes disorders, mainly of iron and copper metabolism (cf. Guidelines for drinking water quality, the World Health Organization, 1996). Therefore, toxic side effects cannot be excluded, with a content of 4% by weight of zinc and more. The amount of zinc should therefore be less than 2.0% by weight, preferably below 1.8% by weight, more preferably less than 1.6% by weight, even more preferably less than 1.4% by weight and especially preferred below 1.2% by weight. It should not fall below 0.1% by weight of Zn, preferably 0.3% by weight of Zn and especially 0.5% by weight of Zn, as a lower limit.
[0032] Zirconium (Zr) may be present in the magnesium alloy in addition to zinc or also, instead of zinc. Here, Zr is used as a grain refiner. In addition, the Zr can bind Fe and thus reduce its content further. It has been found that elemental iron increases corrosion, which must be avoided according to the invention. This could be explained by the fact that iron together with magnesium forms a galvanic element, while other reasons are also conceivable. For a magnesium alloy for the production of stents of the invention, a Zr alloy in a range up to about 0.4% by weight. Also greater amounts of Zr of 2% by weight, or even 3% by weight as a result of a very similar grain refinement, but increase the price of the alloy remarkably and, in addition, lead to a weakening of the alloy, which in turn leads to a decrease in ductility. Zr and Mg show an expert reaction in the Mg-rich corner of their phase diagram. This means that during pure primary solidification Zr precipitates. Due to the crystalline structure
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12/73 and hexagonal lattice parameters that are very similar to that of Mg, Zr functions as a grain refiner. In this way, the Zr - nucleation sites must first reach a diameter of about 2 mm or more. However, Zr has a substantially higher density than Mg. Therefore, the ZR- particles in a molten Mg - fall comparatively fast to the ground. Thus, only half the amount of 1% Zr by weight is used effectively exploitable as a grain refiner. In general, the remaining part precipitates at the bottom of the crucible. Stirring during solidification can be used successfully to suppress this sedimentation. However, this is expensive and is not suitable in all conditions. As a rule, therefore, about half of the used Zr is lost. This is, among others, an essential expenditure issue. Since, with regard to grain refinement, the results achieved with clearly smaller amounts of Zr from 0.05% by weight to 0.50% by weight, were as good as with 1% by weight, 2% by weight, or 3% by weight and, in addition, with an amount of Zr below 0.50% by weight, there is no embrittlement, 0.05% by weight to 0.50% by weight, and even more preferably 0.08 wt% to 0.40 wt% zirconium are used according to the invention.
[0033] The influence of Zr was exemplarily examined with the magnesium alloy, containing 10% by weight, Di and 1% by weight of Nd. Permanent direct molten molting (TütenguBverfahren) has been used as a production process. For construction materials produced by permanent casting changes direct cold, it can be assumed that a cast part shows a homogeneous microstructure and that the alloying elements are homogeneously distributed, too. However, the structure is relatively rough and the grain size is on the order of several millimeters (Fig. 1). The inventors were able to demonstrate that the addition of only 0.6 wt% of Zr led to a clear reduction in grain size (figure 2). Therefore, unlike three major proportions of Zr (0.2, 0.4, 0.6% by weight) and their influence on the training structure were
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13/73 examined. To determine the grain size of the linear interception method was applied. Surprisingly, a small proportion of 0.2% by weight results in a clear grain refinement (fig. 2) and the grain size is around 102 mM. The addition of 0.4 or 0.6% by weight results in grain sizes of about 68 mM, respectively 64 mM (Fig. 4 and 5). We can therefore conclude that an increase of 0.2% by weight of Zr already results in an effective grain refinement and that, surprisingly, the total amount of Zr can be activated for grain refining. This reduces costs for Zr alone by around 50%.
Therefore, it is preferred that an alloy according to the invention has additionally 0.02 to 0.80% by weight, preferably 0.04 to 0.60% by weight, preferably 0.05 to 0.55% by weight. weight, additionally preferred 0.06 to 0.50% by weight, even more preferred 0.07 to 0.45% by weight, even more preferred 0.08 to 0.40% by weight, even more preferred 0.09 to 0.35% by weight, even more preferred 0.10 to 0.30% by weight, even more preferred 0.12 to 0.28% by weight and especially preferred 0.15 to 0.25% by weight of zirconium.
[0035] The size of the granules was determined according to the known method of linear interception. During the linear granule interception method, the granule size is counted in an ocular way, on a focusing screen or on photographic images. Intersecting lines can be either linear or circular. Granules that are only cut in half at the end of the line are counted as half granules. The magnification is chosen in such a way that at least 50 granules are cut per grid. At least five sites with a total number of at least 250 interception points in the sample are examined.
[0036] Additionally, the present invention relates preferably to stents made of biologically magnesium alloys
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14/73 degradable, which contain the following components based on the total weight of the alloy (given in% by weight):
80.7% by weight to 94.7% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of zirconium in which the stent has a polymeric coating.
[0037] Optionally, the amount of neodymium in this alloy can be replaced by europium, or an additional 0.1% by weight to 2.0% by weight can be added by europium.
[0038] It goes without saying that all the components of an alloy must add up to 100% by weight. If the above alloy contains 15.0% by weight. Dysprosium (Di), and 5.0% by weight. Neodymium (Nd), therefore, the magnesium content may not exceed 80% by weight. If alloyed above contains 76.0% by weight of magnesium (Mg), then other components apart from dysprosium and neodymium are obligatorily present between 4.0% by weight. and 18.9% by weight. The other components are, for example, the impurities described herein, such as, for example, other metals, metallic, non-metallic salts, carbon, sulfur, nitrogen, oxygen, silicon and / or hydrogen.
[0039] Unless specifically listed, the alloys described herein may contain unavoidable impurities, which are in the range of the lower limit of detection or in the range of 1 ppm to 0.4% by weight, preferably up to 0.3% by weight, even more preferably up to 0.2% by weight and, in particular, preferably up to 0.1% by weight. Silicon as the main ingredient in impurities can already reach 0.3% by weight. It is therefore particularly preferable that the unavoidable impurities, with the exception of silicon, represent a total of less than 0.3% by weight, preferably less than 0.2% by weight, even more preferably less than 0.1 % by weight, even more preferably less than 0.05% by weight,
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15/73 even more preferred less than 0.01% by weight, even more preferred less than 0.001% by weight, even more preferred less than 500 ppm and especially preferred less than 300 ppm. The percentages mentioned above refer to the sum of all impurities, except for silicon and not for the individual impurity. These impurities (including silicon) can also be present in the alloy in an amount from 1 ppm to 0.4% by weight. or 0.3% by weight. or 0.2% by weight. or 0.1% by weight, if not explicitly listed as an alloying element, and, if not mentioned, they are added in the weight ratio of said alloying component, over which they enter the alloy. However, it is preferable, when impurities, with the exception of silicon, must not exceed each quantity of 500 ppm, preferably 300 ppm, even more preferably 200 ppm and 150 ppm, especially preferred. Silicon can be an important component of impurities and exist in the alloy up to 0.3% by weight, preferably up to 0.2% by weight. and more preferably up to 0.1% by weight. Depending on how magnesium is extracted, magnesium may contain a high content ranging from silicon. If very pure magnesium is used, the Si content in the alloy may also be less than 400 ppm, preferably below 300 ppm, even more preferably below 250 ppm, and especially preferred below 200 ppm.
[0040] The invention further comprises stents consisting of magnesium alloys composed of the following components, based on the total weight of the alloy:
76.0% by weight to 95.0% by weight of magnesium
5.0% by weight to 25.5% by weight of dysprosium
0.0% by weight to 5.0% by weight of neodymium
0.0% by weight to 5.0% by weight of europium
0.0% by weight to 3.0% by weight of zinc
0.0% by weight to 1.5% by weight of zirconium
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0.0% by weight to 1.0% by weight of other metals, metal salts and non-metals, which are generally referred to as impurities, in which the stent has a polymeric coating.
[0041] It is preferred when the alloy of the invention comprises 5.0 to 25.5% by weight, preferably 5.2 to 22.0% by weight, more preferably 5.4 to 20.0% by weight, more preferably 5.5 to 19.0% by weight, more preferably 5.6 to 18.0% by weight, more preferably 5.7 to 17.0% by weight, more preferably 7.0 to 17.0% by weight, more preferably 7.5 to 16.5% by weight, more preferably 5.8 to 16.0% by weight, more preferably 8.0 to 16.0% by weight, most preferably 5.9 to 15.0% by weight, more preferably 8.3 to 15.8% by weight, more preferably 8.5 to 15.5% by weight, more preferably 8.7 to 15.0% by weight, more preferably 6.0 to 14.0% by weight, most preferably 8.8 to 14.8% by weight. weight, more preferably 8.9 to 14.5% by weight, more preferably 9.0 to 14.0% by weight, more preferably 6.1 to 13.0% by weight, more preferably 9.1 to 13.5% by weight, more preferably 9.2 to 13.0% by weight, most preferably 6.2 to 12.5% by weight, but is preferably 9.3 to 12.7% by weight, more preferably 9.4 to 12.4% by weight, more preferably 6.3 to 12.0% by weight, more preferably 9.5 to 12.2% by weight, more preferably 9.5 to 12.0% by weight, most preferably 6.4 to 11.5 % by weight, more preferably 9.5 to 11.5% by weight, more preferably 6.5 to 11.0% by weight and most preferably 9.5 to 11.0% by weight of dysprosium.
[0042] Preferably, the amount of neodymium is in the range of 0.0 to 8.0% by weight, more preferably from 0.1 to 5.0% by weight, even more preferably from 0.2 to 4.0% by weight and even more preferably 0.3 to 3.0% by weight, even more preferably 0.4 to 2.0% by weight and especially preferred from 0.5 to 1.5% by weight.
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17/73 [0043] Together with neodymium (Nd), or instead of Nd also europium (Eu) can be included in the alloy, in proportions 0.0-8.0% by weight, more preferably 0.1 to 5, 0% by weight, even more preferably 0.2 to 4.0% by weight, even more preferably 0.3 to 3.0% by weight, even more preferably 0.4 to 2.0% by weight, and especially , preferably 0.5 to 1.5% by weight.
[0044] It is further preferred that the proportion of shared Nd and Eu in the alloy is 0.01 to 8.0% by weight, more preferably from 0.1 to 5.0% by weight, even more preferably 0.2 to 4.0% by weight, even more preferably. 0.3 to 3.0% by weight, even more preferably 0.4 to 2.0% by weight. and, especially, preferably 0.5-1.5% by weight.
[0045] The sum of the proportions by weight of dysprosium and neodymium, preferably in the range of 5.1 to 23.0% by weight, more preferably between 6.6 to 15.5% by weight, even more preferably, and in particularly preferably 8.4-13.0% by weight.
[0046] It is further preferred that the alloy further comprises 0.2 to 4.0% by weight, more preferably 0.3-3.0% by weight, even more preferably 0.4 to 2.0% by weight, even more preferably 0.5 to 1.5% by weight and, especially, preferably 0.7-1.3% by weight of zinc (Zn).
[0047] In addition to the aforementioned components of a magnesium alloy, from which the base structure of the prosthesis of the invention was made, it can also contain 0.0% by weight to 1.0% by weight, preferably 0.1 % by weight to 0.6% by weight, more preferably 0.2% by weight to 0.4% by weight and it is especially preferred in total no more than 0.3% by weight. Other metals, metal salts, non-metals, carbon, sulfur, silicon, nitrogen, oxygen and / or hydrogen. These other components are impurities that are in the small amounts mentioned above, harmless to the properties of the product or the properties of the alloy. It is essentially Fe and Si, which can enter
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18/73 during the production of primary magnesium by the necessary application of ferrosilicon during Pidgeon - Process or by the general use of steel tools, during the processing and handling of magnesium and its alloys. It is preferred, however, that the metals Cu, Ni, Fe are each present below 300 ppm, preferably below 200 ppm and more preferably below 150 ppm. Heavy metals, in particular Fe, Cu and Ni as nobler components, form a galvanic element with magnesium and thus increase corrosion, especially in contact with a corrosive agent, such as blood, in which the presence of chloride ions. Hydrogen is formed in the aqueous medium, so that cracking and corrosion occurs, which should be avoided with implants and especially vascular implants such as stents. Therefore Cu, Ni, Fe extremely deteriorate the corrosion behavior, if more than the mentioned quantities are present. Commonly Cu and Ni enter magnesium alloys through recycling processes and can be avoided if pure primary magnesium is used.
[0048] Silicon (Si) should not be present in amounts greater than 0.4% by weight, preferably above 0.3% by weight and more preferably above 0.2% by weight. because Si affects the properties of the alloy and the properties of the product in a negative way, then the addition of silicon deteriorates the modality. Stable silicides (Mg2Si) can be formed. Materials with an increase in the amount of Mg2Si precipitate and additionally form needles and therefore result in a great notch effect and an elongation at low break. However, high elongation at break is necessary for stents.
[0049] Furthermore, it is preferable that the elements of beryllium, aluminum and manganese are present below 300 ppm, preferably below 200 ppm and more preferably below 150 ppm in the magnesium alloys from which the base structure of the prosthesis of the invention was made. Beryllium salts, beryllium oxide and beryllium are toxic to human beings
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19/73 humans and are classified as carcinogenic. Beryllium can cause skin, lung, spleen and liver damage. Beryllium accumulates preferentially in bones, the kidney and cells of the reticulum endothelial system of the liver, spleen and lymph nodes and induces the formation of tumors after latency lasts for years. Therefore, if possible, beryllium should be avoided entirely in a degradable vascular implant. Therefore, it is preferable that the alloy does not contain beryllium. Manganese as an essential trace element for humans and an important part of enzymes. But in addition to that, manganese is also neurotoxic and damages the central nervous system. For chronic long-term exposure, an excessive dementia disease with symptoms similar to Parkinson's disease, such as motor impairments, can occur. A role for aluminum in Alzheimer's disease is discussed repeatedly, too, and aluminum is believed to accelerate, if not even causing the onset of Alzheimer's disease. At least, aluminum has been detected in plaques in patients' brains. Therefore, as a precaution, manganese and aluminum should be avoided, as components of a degradable vascular prosthesis that slowly degrades over a longer period of time, also from the point of view of marketing.
[0050] La, Ce, Pr and Sm belong to other metals or non-metals, which can be packed individually or together in the alloy in a maximum amount of 0.3% by weight, preferably 0.2% by weight. and more preferably 0.1% by weight. Whereas the following elements must be avoided or be contained in the alloy together in a maximum amount of 0.1% by weight, preferably 0.05% by weight, more preferably 0.01% by weight of Tb, Ho, Er, Tm, Yb and Lu. Thus, it is preferred that the magnesium alloys from which the base structure of the prosthesis of the invention was made in total contain no more than 0.1% by weight, preferably 0.05% by weight and, more preferably, 0.01% by weight of the elements terbium, holmium, erbium, thulium, ytterbium and lutetium, in which, still
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Preferred 20/73 of these elements should be avoided entirely, which means being present as impurities in the ppm range below 150 ppm, and especially preferential below 100 ppm.
[0051] The maximum amount of 1.0% by weight. impurities include other metals or non-metals, such as, for example, silicon, carbon, oxygen, nitrogen, hydrogen or sulfur, also when those are additionally explicitly indicated.
[0052] Surprisingly, it was found that, despite the relatively high amount of dysprosium, the alloys disclosed here and, respectively, stents are made of the same non-radio - opaque. The angiography performed in the animal study showed that the stents were not opaque, which means that they were not visible on the X-ray images during coronary angiography (see Figures 6A - AD). This allows you to see the vase light clearly. Thus, one can non-invasively follow the healing and control process with regard to possible in-stent - restenosis in patients, which means by imaging procedures such as MRT or CT. Therefore, it is preferable that the alloys from which the base structure of the prosthesis of the invention was made are not radio - opaque. If the stents should still be visible on the X-ray image so that the correct positioning can be verified one can attach radiopaque markers to specific locations of the stent or the balloon catheter used for stent implantation which, which is done regularly in practice .
[0053] A preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy or consisting of the following components:
77.0% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.2% by weight to 4.0% by weight of neodymium
0.2% by weight to 4.0% by weight of zinc in which the stent has a polymeric coating.
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21/73 [0054] A preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy or consisting of the following components:
88% by weight of magnesium
10% by weight of dysprosium
1% by weight of neodymium
1% by weight of zinc in which the stent has a polymeric coating.
[0055] A preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy or consisting of the following components:
79.0% by weight to 94.75% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.2% by weight to 4.0% by weight of neodymium
0.05% by weight to 2.0% by weight of zirconium in which the stent has a polymeric coating.
[0056] An additional and preferred embodiment of the invention relates to stents comprising or consisting of the following components:
88% by weight of magnesium
10% by weight of dysprosium
1% by weight of neodymium
1% by weight of zirconium, in which the stent has a polymeric coating.
[0057] A preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
75.0% by weight to 94.55% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.2% by weight to 4.0% by weight neodymium
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0.2% by weight to 4.0% by weight of zinc
0.05% by weight to 2.0% by weight of zirconium in which the stent has a polymeric coating.
[0058] An especially preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
87% by weight of magnesium
10% by weight of dysprosium
1% by weight of neodymium
1% by weight of zinc
1% by weight of zirconium in which the stent has a polymeric coating.
[0059] A preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
76.0% by weight to 94.5% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.2% by weight to 4.0% by weight of neodymium
0.2% by weight to 4.0% by weight of zinc
0.1% by weight to 1.0% by weight of impurities such as, for example, other metals, metal salts and non-metals in which the stent has a polymeric coating.
[0060] A preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
80.0% by weight to 94.7% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 2.0% by weight of zinc
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0.1% by weight to 1.0% by weight of impurities such as, for example, other metals, metal salts and non-metals in which the stent has a polymeric coating.
[0061] An additional and preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
81.7% by weight to 94.7% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 0.3% by weight of zinc
0.1% by weight to 1.0% by weight of impurities such as, for example, other metals, metal salts and non-metals in which the stent has a polymeric coating.
[0062] An additional and preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
79.7% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 0.3% by weight of zinc
0.1% by weight to 1.0% by weight of impurities such as, for example, other metals, metal salts and non-metals in which the stent has a polymeric coating.
[0063] An additional and preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
79.7% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of europium
0.1% by weight to 2.0% by weight of zinc
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0.1% by weight to 0.3% by weight of zirconium
0.1% by weight to 1.0% by weight of impurities such as, for example, other metals, metal salts and non-metals in which the stent has a polymeric coating.
[0064] An additional and preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
77.7% by weight to 94.5% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of europium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of zirconium
0.1% by weight to 1.0% by weight of impurities such as, for example, other metals, metal salts and non-metals in which the stent has a polymeric coating.
[0065] A further preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
79.0% by weight to 94.75% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.2% by weight to 4.0% by weight of europium
0.05% by weight to 2.0% by weight of zirconium in which the stent has a polymeric coating.
[0066] A further preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
88% by weight of magnesium
10% by weight of dysprosium
1% by weight of europium
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1% by weight of zirconium in which the absorbable stent is surrounded by a biologically degradable polymeric coating.
[0067] A further preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
77.0% by weight to 94.75% by weight of magnesium
5.0% by weight to 15.0% by weight dysprosium
0.2% by weight to 4.0% by weight of europium
0.05% by weight to 4.0% by weight of zinc in which the stent has a polymeric coating.
[0068] A further preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
88% by weight of magnesium
10% by weight of dysprosium
1% by weight of europium
1% by weight of zinc in which the stent has a polymeric coating.
[0069] A further preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
75.0% by weight to 94.7% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.2% by weight to 4.0% by weight of europium
0.05% by weight to 4.0% by weight of zinc
0.05% by weight to 2.0% by weight of zirconium in which the stent has a polymeric coating.
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26/73 [0070] A further preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
87% by weight of magnesium
10% by weight of dysprosium
1% by weight of europium
1% by weight of zinc
1% by weight of zirconium in which the stent has a polymeric coating.
[0071] An especially preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
87.8% by weight of magnesium
10.0% by weight of dysprosium
1.0% by weight of neodymium
1.0% by weight of zinc
0.2% by weight of zirconium in which the stent has a polymeric coating.
[0072] An especially preferred additional embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
86.8% by weight of magnesium
10.0% by weight of dysprosium
1.0% by weight of europium
1.0% by weight of zinc
0.2% by weight of zirconium in which the stent has a polymeric coating.
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27/73 [0073] An additional especially preferred embodiment of the invention relates to stents consisting of a biologically degradable magnesium alloy comprising or consisting of the following components:
87.8% by weight of magnesium
10.0% by weight of dysprosium
1.0% by weight of neodymium
1.0% by weight of europium
1.0% by weight of zinc
0.2% by weight of zirconium in which the stent has a polymeric coating.
[0074] All weight percentages specified in this specification refer to the total weight of the corresponding alloy. Therefore, it applies to all compositions, mentioned here, that the sum of all components in total must be added to 100.00% by weight. This means that, after adding all the components listed in the magnesium alloy, the difference to 100% by weight. is magnesium as the main component. In addition, these compositions may contain a very low amount of partially unavoidable production-related impurities. It is preferred that these impurities are each <0.2% by weight, preferably <0.02% by weight, and especially preferably <250 ppm by weight. and the sum of all impurities <0.4% by weight, preferably <0.05% by weight and especially preferred <150 ppm. It is particularly preferred if the unavoidable impurities represent less than 0.1% by weight, preferably 0.05% by weight, and even more preferable by 0.01% by weight. Even more preferred below 150 ppm, and especially preferred below 100 ppm. If the impurities are metals, metal salts or metal carbides, metal nitrates, metal oxides, metal silicates or metal silicides, it is preferred that the related impurities are each present in quantities less than 300
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28/73 ppm, preferably 200 ppm and even more preferably below 150 ppm.
[0075] The term impurities, as used herein, indicates that all components of the alloy, with the exception of magnesium, dysprosium, neodymium, europium, zinc and zirconium, regardless of whether or not they are explicitly listed.
[0076] Furthermore, the present invention preferably comprises stents whose basic structure consists of biologically degradable magnesium alloys, which do not contain additional components, in addition to magnesium, dysprosium, neodymium, europium, zinc, zirconium and inevitable impurities related to production . That is, it is preferable if the components of the alloy, next to the magnesium base, are selected from the following group consisting or comprising: dysprosium, neodymium, europium, zinc, zirconium and inevitable production-related impurities. It is particularly preferred that the alloys contain no yttrium. In vitro, yttrium is less acceptable for cells from other rare earths, such as dysprosium. In addition, the effectiveness of yttrium to improve resistance by solid solution, and precipitation hardening, respectively, is clearly less than that of other rare earths, such as dysprosium, because yttrium has a magnesium solubility clearly lower than dysprosium ( solubility in Y magnesium: 12.47% by weight, Di: 25.34% by weight). Free gadolinium ions are highly toxic. Due to the high toxicity of free gadolinium ions these are used in contrast agents only with chelating agents having high stability constants (for example, the chelating agent DTPA). But today it is assumed that the release of highly toxic free gadolinium ions from contrast agents causes the development of systemic nephrogenic fibrosis (NSF) in patients with severe renal failure, patients on dialysis and liver transplant patients. Lithium is used in the form of specific salts as a medicine for mental illness, especially for affective disorders. At the
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29/73 However, lithium has a narrow therapeutic index and even serum levels of 1.5 mmo / l can cause side effects. Within long-term treatment with water and loss of sodium and lithium (diabetes insipidus), hyperacidity of the blood (acidosis) and lithium - nephropathy with a decrease in kidney function can occur. One of the problems here is that the Li + plasma level and thus the lithium effect is influenced by all substances and external circumstances, with an effect on Na + excretion. Therefore, a potential risk of undesirable side effects results from the release of lithium ions.
[0077] Furthermore, it is therefore preferable if the composition of the magnesium alloy does not contain lithium and / or non-gadolinium. These metals are preferably not included or only in small amounts from a total of 0.01% by weight to 1.0% by weight, preferably in amounts of, in total from 0.001% by weight to 0.01% by weight . Still preferably, Li and Gd are contained only as impurities in the ppm range of less than 150 ppm, especially preferably less than 100 ppm.
[0078] If the additional components, in addition to magnesium, dysprosium, neodymium, europium, zinc and / or zirconium are contained in the alloy, these additional components are impurities such as other metals, metallic, non-metallic salts, carbon, sulfur, nitrogen , oxygen, silicon and / or hydrogen, which are combined present in small amounts of <0.6% by weight, preferably <0.5% by weight, more preferably <0.4% by weight, more preferably <0, 3% by weight, more preferably <0.2% by weight, and especially preferably <0.1% by weight.
[0079] Like other metals, which may be present in the composition of the inventive magnesium alloy, the following are to be mentioned: sodium, potassium, calcium, scandium, titanium, vanadium, chromium, iron, cobalt, nickel, copper, gallium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, promethium, tantalum, tungsten, rhenium, platinum,
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30/73 gold and lead. Except lanthanum, cerium, praseodymium and samarium which may be present in the alloy of each one up to a maximum of 0.3% by weight, Preferred 0.2% by weight and even more preferred up to a maximum of 0.1% by weight , and the elements of strontium, sodium, potassium, calcium, scandium, titanium, vanadium, chromium, cobalt, gallium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, promethium, tantalum, tungsten, rhenium , platinum, gold and lead, which are preferably present only as impurities in the ppm range and should not exceed each amount of 500 ppm, 400 ppm preferentially, preferred an additional 300 ppm, even an additional preferred 200 ppm and, in particular, an 150 ppm.
[0080] In addition, metal salts can be present in very small amounts in the alloy. Fe, Cu, Ni or Co salts can only be present in quantities up to 100 ppm, preferably only up to 50 ppm. The elements terbium, holmium, erbium, thulium, ytterbium, lutetium, beryllium, aluminum, manganese, copper, nickel, iron, lithium and gadolinium should preferably be contained in the alloy each in quantities of less than 300 ppm, preferably 200 ppm, even more preferred 150 ppm and particularly preferred every 100 ppm and combined does not exceed an amount of 3000 ppm, preferably 2000 ppm, even more preferred 1500 ppm and especially preferred every 1000 ppm.
[0081] Metal salts preferably comprise at least one of the following metal ions: Na +, Mg2 +, K +, Ca2 +, Sc3 +, Ti2 +, Ti4 +, V2 +, V3 +, V4 +, V5 +, Cr2 +, Cr3 +, Cr4 +, Cr6 +, Fe2 +, Fe3 +, Co2 +, Co3 +, Ni2 +, Cu +, Cu2 +, Zn2 +, Zr2 +, Zr4 +, Nb2 +, Nb4 +, Nb5 +, Mo4 +, Mo6 +, Tc2 +, Tc3 +, Tc4 +, Tc5 +, Tc6 +, Tc7 +, Ru3 +, Ru4 +, Ru5 +, Ru4 +, Ru5 Rh3 +, Rh4 +, Pd2 +, Pd3 +, Ag +, In +, In3 +, Ta4 +, Ta5 +, W4 +, W6 +, Pt2 +, Pt3 +, Pt4 +, Pt5 +, Pt6 +, Au +, Au3 +, Au5 +, Sn2 +, Sn4 +, Pb2 +, Pb2, Ce4 +, Gd3 +, Nd3 +, Pr3 +, Pr3 +, Pm3 +, Sm3 +, Eu2 +, Di3 +.
[0082] As anions are used halogens, such as F-, Cl, Br-, oxides and hydroxides such as OH-, O2-, sulfates, carbonates, oxalates,
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31/73 phosphates, such as HSO4 ·, SOH4 ² -, HCO3 ·, CO3 ² · HC2O4, C2O4 ² ·, H2PO4 ·, HPO4 ² ·, PO4 ^3- [0083] The magnesium alloys described here are chosen so that they are, in particular, suitable for the production of absorbable or degradable prostheses and especially vascular implants or stents, respectively.
[0084] Furthermore, the present invention, therefore, relates to an absorbable prosthesis or an absorbable, vascular implant consists of any of the magnesium alloys described herein, in which the stent has a polymeric coating. The absorbable stent according to the invention is preferably a stent for blood vessels, urine, respiratory tract, biliary tract or digestive tract. In turn, among these stents are vascular implants or stents for blood vessels or in general, for the cardiovascular system are preferred.
[0085] The term absorbable, as used here, means that the implant slowly dissolves in the body of a human or animal over a certain period of time and, at some point only its degradation products are present in the body in dissolved form. At this point in time, solid components or fragments of the implant no longer exist. Degradation products must be substantially physiologically harmless and lead to ions or molecules that occur in the body in any way, or can be degraded by the body to harmless substances, or can be excreted.
[0086] Vascular stents or implants are preferably laser cut from a tube that consists of a revealed magnesium alloy. The biologically degradable magnesium alloy stents disclosed herein are absorbed under physiological conditions over a period of 8 to 50 weeks, preferably 10 to 30 weeks.
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32/73 [0087] The terms absorbable or degradable or biodegradable, or biodegradable, therefore, refer to the fact that the human or animal body is able to decompose the stent or vascular implants within a certain period of time, from so that atoms, ions or molecules are present, which can be present in the dissolved state in blood or other body fluids.
[0088] Stents as used here are endoprostheses in the form of liquid that are implanted in a hollow organ or a body cavity, to keep it open in the form of a grid or. The basic structure of a stent refers here to uncoated metal supports, it is not a solid tube, but in a network. If you consider, for example, the base skeleton of a vascular stent, it is cut, for example, using a laser, from a massive tube, so that individual struts as thin as possible are the result, which are connected to each other . The arrangement and formation of nodes and supports is called stent design. In accordance with the present invention, all geometries of the common stent can be used as the inventive magnesium stent.
[0089] When cutting a stent, areas between the individual supports are cut. A stent or a vascular implant, therefore, has a plurality of solid components (for example, structure struts, in the form of rings, spirals, waves and wires), which together form the stent or stent, as well as a plurality of interstices between these solid components. Within the common incarnation of endoprostheses or stents, the supports merge into us. However, there are also ways of carrying out endoprostheses, where no or almost no nodes are present and the supports, for example, have the shape of rings or spirals. preferably, the extensors are self-expanding or balloon-expanding stents, which are pushed by a catheter into the diseased area or the area to be treated, in which the stents are expanded to their defined nominal diameter.
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33Γ73 [0090] Vascular implants or stents are cut, using lasers, from tubes that consist of one of the alloys described here. The tubes are obtained by processing wires from the respective alloys. The alloys are preferably produced in the so-called permanent mold with direct cold fusion (TütenguBverfahren). In this method, the components of the biologically degradable magnesium alloys are melted in a smoothed steel crucible under an atmosphere of inert gas, at a melting bath temperature of 660-740 ° C. The molten product is stirred until complete mixing has occurred and then transferred to a thin-walled coquille, which has been preheated to a temperature of 600 ° C and maintained for one hour at a temperature of about 700 ° C. After that, the coquille is cooled in a water bath to a temperature of 1520 ° C. The pins are then obtained heated before extrusion to a temperature of 250-500 ° C and maintained at this temperature for 3-6 hours. Extrusion and cooling of the extruded billet to monitor the ambient temperature.
[0091] Therefore, the present invention relates to stents made from the alloys of the invention obtained by permanent molding with direct cold fusion (TütenguBverfahren), in which the stent has a polymeric coating. Particularly preferable is a magnesium alloy stent obtained when using permanent cold melt molding containing the following components, based on the total weight of the alloy:
80.4% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium and / or europium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of zirconium and impurities such as other metals, salts of metals and non-metals in the amounts disclosed in this report, where the alloy does not
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34/73 contains yttrium and does not contain gadolinium, and the stent has a polymeric coating.
[0092] The present invention also relates to stents made from all magnesium alloys with one of the compositions disclosed in this report and obtained by using permanent molding with direct fusion, in which the stent has a polymeric coating . Therefore, the preferred ranges disclosed for the individual alloy components are also valid in the context of the magnesium alloys obtained after permanent casting with direct melting.
[0093] In addition, the present invention relates to stents made of metal wires, which are preferably produced by extrusion of alloys according to the invention obtained after permanent molding with direct melting of the individual alloy components disclosed in this report , which are also valid in the context of magnesium alloy wires obtained when using permanent casting with direct melting. Thus, the present invention comprises, in particular, stents made of magnesium alloy wire obtained after permanent casting with direct melting containing the following components, based on the total weight of the alloy:
80.4% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium and / or europium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of zirconium and impurities such as other metals, metal and non-metal salts in the quantities disclosed in this report, in which the alloy does not contain yttrium and does not contain gadolinium, and in which the stent has a polymeric coating.
[0094] In addition, the present invention relates to stents made of tubes that are preferably produced with metallic wire obtained by
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35/73 extrusions, which consist of alloys according to the invention obtained after permanent molding with direct fusion, in which the stent has a polymeric coating.
[0095] The preferential ranges of quantity of the individual alloy components disclosed in this report are also valid in the context of tubes produced from metal wires of magnesium alloys obtained when using permanent casting with direct melting. Therefore, the present invention particularly comprises stents made from tubes that can be obtained from magnesium alloy obtained after permanent molding with direct melting containing the following components, based on the total weight of the alloy:
80.4% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium and / or europium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of zirconium and impurities such as other metals, metal and non-metal salts in the quantities disclosed in this report, in which the alloy does not contain yttrium and does not contain gadolinium, and where tubes can be obtained from metal wires that are obtained by extrusion, and in which the stent has a polymeric coating.
[0096] In addition, the present invention relates to stents, which are cut from the tubes, in which the tubes are made of wire preferably obtained by extrusion, in which the wire consists of the alloys according to the invention obtained after casting changes permanent cold direct, in which the stent has a polymeric coating. The preferred quantity ranges of the individual alloy components disclosed herein are also valid in the context of the stent made of tubes, which were again formed of wires made up of magnesium alloys obtained after direct cold molten casting.
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36/73 [0097] The present invention also relates to a method for the production of absorbable prostheses, which comprises the following steps:
a) To provide an alloy according to the invention obtained after permanent molding with direct cold fusion,
b) Production of a wire made from the alloy obtained after step a), by extrusion,
c) Production of a tube made from the wire obtained after step b), and
d) cutting of tube stents obtained after step c).
[0098] The invention also comprises absorbable stents obtained according to the method above. In step d), a laser is preferably used to cut the stents from the tube obtained according to step c). In order to obtain a magnesium alloy according to the invention after direct permanent cold casting changes more steps can be carried out before step a). In these steps, the components of the magnesium alloys are melted in a smoothed steel crucible by the sequential addition of elements in pure form or like the alloys at a melting bath temperature of 660-740 ° C in a smoothed steel crucible. Virtually any nickel-free steel can be used as a material for the crucible. Graffiti would be another possibility. All fusion operations are carried out under inert gas. After adding the alloying elements, the melt is mechanically stirred. In a next step, the molten material is transferred to a thin-walled coquille, which has been preheated to a temperature of 600 ° C. In a last step, the coquille is immersed in a water bath that has a temperature of 15-20 ° C.
[0099] In an animal testing study (see example 7) on the efficacy and safety of stents made of magnesium alloys according to the invention, it can be demonstrated that the vascular or implant stents according to the invention from the magnesium alloys described here can be driven into a balloon without any problems. Stent implantation was performed without known complications, such as a poorly positioned stent, thrombosis or dissection. After 4 weeks, it was observed
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37/73 a complete reendothelization of the stent vessel segments. This indicates that no excessive inflammation reactions have occurred and the magnesium alloys according to the invention have not caused intolerance reactions in the vessel tissue. The rate of restenosis was in the range of common Bare Metal (BMS) stents in the prior art, respectively in the range of drug-eluting stents (DES) (cf. figures for the RA Costa conversation; given within the Euro -PCR, Paris, May 2011).
[00100] Furthermore, the interior metallic structure of the inventive stent made of a biologically degradable magnesium alloy described here preferably has the characteristic that dissolves more quickly than the polymer coating, that is, the internal structure of the vessel support is degraded faster under physiological conditions than the polymeric coating. Preferably, the magnesium alloy is converted within the polymeric shell to the corresponding metal salts, which can escape through the polymeric coating. When using different polymers in a stent, there is also the possibility of using polymers that differ in the degradation time.
[00101] The present invention also relates to stents made of a biologically degradable magnesium alloy, whose polymeric coating comprising or consisting of one or more substances is selected from the group consisting of or comprising: polyvinylpyrrolidone, glycerin, polyhydroxyethyl methacrylate, glycol polyethylene, polypropylene glycol, polyvinyl alcohol, polydioxanone, polycaprolactone, polygluconate, poly (lactic acid) - polyethylene - copolymer oxide, modified cellulose, polyhydroxybutyrate, polyamino acids, polyphosphate esters, polyvalerolactones, poly- polyglycolic, polylactides, preferably poly (L - lactide), poly (D, Lltido), and copolymers, as well as mixtures such as poly (L - lactide - co-glycolide), poly (D, L - lactide - co-glycolide) , poly (L-lactide - co - D, L - lactide), poly (L - lactide carbonate - co - trimethylene), polyglycolides, copolymer eros of
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38/73 polylactides and polyglycolides, poly-and-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate - co-valerates, poly (1,4-dioxane - 2, 3 - dione), poly (1,3-dioxane - 2-one), poly - paradioxanones, polyanhydrides, polymalleic acid anhydrides, polyhydroxy methacrylates, fibrin, polycyanoacrylates, polyethylacrylates, polycaprolactone, poly
- b - maleic acid, butyl acrylate, oligocaprolactonediols and oligodioxanonediols multiblock polycaprolactone polymers, PEG multiblock polyether esters polymers and polybutylene terephthalate, polyvinyl acetate, polyglycol polyethylene glycol (polyololol, polyololol and polyololol). ), poly (DTH - iminocarbonate), poly (DTE
- co - DT - carbonate), poly (bisphenol A - iminocarbonate), polyorthoesters, trimethyl polyglycolic acid carbonates, carbonates, polyitrimethyl polyiminocarbonates, poly (N-vinyl) - pyrrolidone, polyvinyl alcohols, polyester amides, polyesters, glycolized polyphosphoestenes, polyphenols , poly [ carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydrides, propylene oxide, polyethylene oxide, soft polyurethanes, polyurethanes with the amino acid residues in the backbone, polyetheresters such as polyethylene oxide, polyalene oxalates, polyesters , as well as its copolymers, lipids, waxes, oils, polyunsaturated fatty acids, eicosapentaenoic acid, timnodonic acid, docosahexaenoic acid, arachidonic acid, linoleic acid, linolenic acid - α, γ - linolenic acid, carrageenans, fibrinogen, agar - agar, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, ze na, polyhydroxyalkanoates, pectic acid, actinic acid, carboxymethyl cellulose sulfate, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfates and their derivatives, heparin, chondroitin sulfate, dextran, beta-cyclodextrins, copolymers with PEG and polypropylene glycol. arabic, guar, gelatin, collagen, collagen N hydroxysuccinimide, lipids, phospholipids, polyacrylic acid, polyacrylates, polymethyl methacrylate, polybutyl methacrylate, polyacrylamide, polyacrylonitrile,
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39/73 polyamides, polyetheramides, polyethylene amine, polyimides, polycarbonates, polycarbourethanes ketones, polyvinyl halides, polyvinyl, polyvinylidene halides, polyvinyl ethers, polyisobutylene, polyvinyl aromatic compounds, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters, polyvinyl esters and polyvinyl esters. , polytetramethylene oxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyether urethanes, silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate polyurethanes, polyolefin elastomers, polyisketutilenes, fluorosethylethylethylones, chitosanethylethylones, chitosanethylethylones, chitosanethylethylones , polyethylene terephthalate, polyvalerates, carboxymethylcellulose, cellulose, rayon, rayon triacetates, cellulose nitrates, cellulose acetates, hydroxyethyl cellulose, cellulose butyrate, cellulose acetate butyrate, acetate vinyl acetate copolymers, polysulfones, resins resins A BS, EPDM gums, silicones such as polysiloxanes, polydimethylsiloxanes, polyvinyl halogens, cellulose ethers, cellulose triacetates, shellac, polyparaments - xylilenes (Parilenes) such as Parilene N, Parilene C and / or D Parilene, and copolymers of the polymers mentioned above.
[00102] It is advantageous that the abluminal lining (directed towards the vessel wall) dissolves more slowly than the luminal stent lining (directed towards the vessel lumen). In addition, a stent is preferable as it has micropores, holes, openings or channels in only the luminal, polymeric, biodegradable coating. For example, the degradation of the stent from the blood flow side is thus accelerated. Large amounts of hydrogen gas are formed during the degradation of magnesium alloys. This is another reason that it is preferable that micropores, holes, openings, channels or other structures that allow gas to escape are present on the polymer side, a biodegradable coating that is directed towards the lumen and blood flow but not on the abluminal side. of the lining, since in this way the gas is removed and dispersed with the bloodstream and cannot accumulate between the stems and the vessel wall.
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40/73 [00103] These micropores, holes, openings and / or channels can be incorporated mechanically, chemically, thermally or optically into the polymer after the coating has been applied. This can, for example, occur through mechanical treatment such as sandblasting, by chemical methods, such as engraving, or oxidation, by mechanical - chemical methods, such as polishing methods, by thermal methods such as melting or brand, or through optical methods such as laser treatment.
[00104] It is preferable, according to the invention, if the polymeric coating is designed in such a way that the inner metal structure can dissolve in the coating and both hydrogen gas and metal ions are predominantly released into the blood in the luminal side of the lining, but do not leak directly into the surrounding tissue.
[00105] However, a stent made from one of the biodegradable magnesium alloys, described herein, in which the polymeric coating has no micropores, holes, openings or channels are particularly preferred. This is especially true for polymeric coatings without an active agent.
[00106] It is preferable, when the interior base structure of the biologically degradable magnesium alloy is degraded under physiological conditions, before the outer polymeric coating, so that an empty polymer coating grown on the vessel wall remains after the degradation of the skeleton of interior base, which is, however, flexible and does not exert considerable pressure on the vessel wall and further adapts well to the new shape of the vessel. After all the interior metallic base structure has dissolved, the polymeric coating can also be degraded biologically, so that, after a few months, the stent has completely dissolved. Thus, the degradation of the polymeric coating must proceed constantly and without the occurrence of the danger of detaching fragments. Thus, it is preferred in accordance with
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41/73 the invention, that the polymeric coating dissolves more slowly than the internal structure of the magnesium alloys, described herein, and selectively allows the leakage of salts and ions so that the interior structure can dissolve.
[00107] In general, the polymeric coating serves to regulate the rate of degradation of the metallic stent structure. By choosing the substance or the mixture of substances that form the polymeric coating from the period until the dissolution of the base structure can be influenced. In addition, the polymeric coating can serve as a protective coating against base skeleton fragments and the surface of the stent may be configured to be more biocompatible or more hemocompatible. This means that the polymeric coating of a stent of the invention improves hemocompatibility. This can be a better and uniform colonization of the surface, with smooth muscle cells or especially endothelial cells. But the surface of the stent may also initiate less blood clotting due to the polymer coating and thus lead to a reduced risk of thrombosis.
[00108] According to other preferred modalities, at least one anti-inflammatory, anti-proliferative, anti-angiogenic, antirestenotic (anti-restenosis), antineoplastic, antimigrative and / or antithrombogenic active agent is present inside or on the outer polymeric coating . This active agent can be contained in the polymeric coating in a covalently bonded form or in the form of an adhesive or ionically bonded or be applied as an additional layer. In this way, coated endoprostheses or stents are obtained, which have at least one active agent in the polymeric coating or which have an additional layer containing the active agent in the polymeric coating. Preferably, at least one anti-inflammatory, anti-proliferative, anti-angiogenic, anti-restenotic (anti-restenosis), antineoplastic,
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42/73 antimigrative and / or antithrombogenic is applied in the form of an active release layer of the additional agent (drug delivery system) on the surface of the polymeric stent lining.
[00109] The at least one anti-inflammatory used, antiproliferative, anti-angiogenic, antirestenotic (anti-restenosis), antineoplastic, an antimigrative and / or antithrombogenic active agent is preferably selected from the group comprising or consisting of: abciximab, acemetacin , acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics, antithrombotics, apocimarin, arginine, asthma, arythema, arthromycin, arginine , aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, bombrestatin, Boswellic acids and their derivatives, Brucinol and bruceanol A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, S - phenoxyacetic carbamoyl, acid, carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamicin, coumadin, type natur, peptide cudraisoflavone A, curcumin, cyclophosphamide, cyclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1.11 dimethoxicanthin-6-one, docetaxel, doxorinicine, epinephrine, and , etoboside, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine phosphate, 5 '- dihydrogen, fluorouracil, folimicin, phosphestrol, gemcitabine, ghalakinoside, ginkgol, ginkgic acid, hydroxygamide, glycoside , lapachol, lomustine, lovastatin, melphalan, midecamicin, mitoxantrone, nimustine,
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43Γ73 pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formylate, moxylone, micholone -ethyl, molgramostim (GM-CSF), peginterferon α -2b, lanograstim (r- HuG -CSF), macrogol, selectin (cytokine antagonist), cytokinin, COX - 2 inhibitor inhibitor, angiopeptine, monoclonal antibodies that inhibit muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1 - hydroxy 11 - methoxicanthin - 6-one, scopolectin, NO donors, pentaerythritol tetranitrate and sidnonimines, S-nitrous derivatives, tamoxifen, staurosporine, β - estradiol, α - estradiol, estriol, estrone, ethinylestradiol, medroxyprogesterone, estradiol cipionates, estradiol benzoate, tranilast, kamebakaurin and other useful terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tirfostins), paclitaxel and its derivatives, 6 - α - hydroxy - paclitaxel, taxoteres, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β sitosterol, mirtecaine, polidocanol, nonivamide, levomentol, elipticin, D 24851 (Calbiochem), colcemide, cytoclassasin AE, indanocine, nocodazole, bacitracin, azitronin receptor antagonist, antagonist antagonists proteinase metal tissue cyclase - 1 and -2, free nucleic acids, nucleic acids incorporated in virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, inhibitors of VEGF, IGF 1, the active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, pen iciline, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipiramidole, trapidil, nitroprussides
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44/73 PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, α, β and γ interferons, histamine antagonists, seroton blockers, seroton blockers apoptosis, apoptosis regulators, halofuginone, nifedipine, paracetamol, dexpanthenol, clopidogrel, acetylsalicylic acid derivatives, streptomycin, neomycin, framicetin, paromomycin, ribostamycin, kanamycin, amikacin, arbecin, bimechancin, bekanicin, bekanicin, bekanicin, bekanicin, bekanicin, bekanicin, bekanicin, beechin, beechin netilmycin, sisomycin, isepamycin, verdamicin, astromicin, apramicin, geneticin, amoxicillin, ampicillin, bacampicillin, pivmecillinam, flucloxacillin, mezlocillin, piperacillin, azlocillin, temocillin, ticarcilin, toxicillin, sulicyillin, toxicillin, sulcus , cefotiam, cefuroxime, cefmenoxim, cefodizim, cefoperazon, cefotaxim, ce ftazidime, cefsulodine, ceftriaxone, cefepim, cefpirom, cefoxitin, cefotetan, cefalexin, axetil cefuroxime, Cefixim, cefpodoxim, ceftibuten, imipenem, meropenem, ertapen, doripenin, tyrone, azimethamine, dyrene , minocycline, trimethoprim, sulfamethoxazole, sulfametrol, nitrofurantoin, lomefloxacin, norfloxacin, ciprofloxacin, ofloxacin, fleroxacin, levofloxacin, spparfloxacin, moxifloxacin, vancomycin, teicoplanin, chloroform, trichloromethamol, tridolinone , mupirocin, bacitracin, neomycin, fluconazole, itraconazole, voriconazole, posaconazole, amphotericin B, 5 - flucitosin, caspofungin, anidulafungin, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, ethanate; , dicloxacilline, tetracycline, triamcinolone, Mi tocin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotolol, natural and synthetically produced steroids, inotodiol, maquiroside A, ghalakinoside, mansonine,
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45/73 strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDs), fenprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir, zidovudine, clotrimazole, flucyzine, flucyzine, flucyzine, fluke antiprozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol - C21- angelato, 14dehydroagrostistachach, agroskerin, agrostistachin, 17- hydroxygrostistachin, ovatodiolids, 4,7-oxy-cycloanisomide, Bicarbonate, and B2, baccharin bruceantinoside C, iadanziosides N and P, isodeoxielephantopin, tomenphantopin A and B, coronarin A, BC and D, ursolic acid, hyptatic acid A, iso-iridogermanal, maitenfoliol, effusantin A, excisanin A and B, longikaurin B, C sculptponeatinin, k , leukamenin A and B, 13,18 - dehydro - 6 - alpha senecioiloxichaparrin, taxamairin A and B, regenilol, triptolide, cimarin, hydroxianopterine, protoan emonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12 - beta - hydroxypregnadien - 3, 20 - dione, helenaline, indicine, indicine - N - oxide, lasiocarpine, inotodiol, podophylloxin, justicidin A and B, larificin and A, B , malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansin, licoridicin, margetine, pancratistatin, lyriodenine, bisparthenolidine, oxoushinsunine, periplocoside A, ursolic acid, deoxipsorosine, wheat, cholinergine, rhodin, psichor spathelia, stizophillin, mansonine, strebloside, dihidrousambaraensine, hydroxiusambarine, strichnopentamine, strichnophilline, usambarine, usambarensine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxilaricininolin, molinxinicinolaminicolin, pimecrolimus, ridaforolimus, deoxorapamycin, tacrolimus FK 506, temsirolimus ez otarolimus, somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trophosphamide, treosulfan, tremozolomide,
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46/73 thiotepa, tretinoin, spiramycin, umbeliferone, deacetylvismione A, vismione A and B, zeorin. and amino acids, such as cystine, as well as sulfur-containing salts, hydrates, solvates, enantiomers, racemates, mixtures of enantiomers, mixtures of diastereomers, metabolites, prodrugs and mixtures of the aforementioned active agents. The concentration per unit of active agent is preferably in the range of 0.001-500 mg per cm of the coated surface of the stent. Especially preferred are the active agents according to the present invention are paclitaxel, rapamycin and its derivatives, such as 6 - α - hydroxy - paclitaxel, baccatin and other taxoteres, biolimus A9, miolimus, novolimus, pimecrolimus, tacroliums, temsirolimus, zotarolimus , everolimus, ridaforolimus or even limous derivatives, erythromycin, midecamicin, josamycin and triazolopyrimidines.
[00110] An additional preferred embodiment of the inventive stents thus has a coating, which consists of at least two layers. In two similar systems, the layer that is applied directly on the stent is called the first layer. The layer that is applied on this first layer is called the second layer.
[00111] According to a preferred two-layer modality, the first layer consists of a pure polymeric coating, which is covered with a second layer that contains at least one antiproliferative, an anti-inflammatory and / or antithrombotic active agent, or that it consists only of this active agent.
[00112] Between the first layer of polymeric coating and the second layer containing the active agent, an additional mediator adhesion layer can be applied. Alternatively, a compound to support adhesion can be contained in the second layer containing the active agent.
[00113] A preferred embodiment of the invention is thus related to a stent consisting of a base skeleton from
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47/73 a biodegradable magnesium alloy, disclosed herein, and a polymeric coating, optionally with at least one active agent.
[00114] It is also possible that the active agent is applied on the stent after the polymeric coating is already applied on the metallic base structure and the active agent does not form its own layer, but penetrates this already existing polymeric layer. It is, therefore, preferable that the active agent does not absorb the entire layer, but remains in an external part and builds a concentration gradient, which decreases towards the basic scaffold.
[00115] If the at least one active agent or combination of active agents is applied over the polymeric coating of the stent, additional substances can be applied as pharmacologically acceptable carriers or as a matrix in combination with at least one active agent or combination of agents active.
[00116] As pharmacologically acceptable vehicles, the polymers already mentioned above can serve as well as low molecular weight substances, such as, for example, lactose, starch, sodium carboxymethyl starch, sorbitol, sucrose, magnesium stearate , dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol, polyvinyl alcohols, polyvinylpyrrolidone, gelatin, naturally occurring sugars, naturally occurring, as well as synthetic gums such as acacia or guar gum, alginate sodium, sodium benzoate, sodium acetate, glycerides, isopropyl myristates and palmitates, citrates, such as tributyl- and triethyl citrates and their acetylated derivatives, phthalates, such as dimethyl phthalate or dibutyl phthalate, benzoic acid benzyl ester etc. , triacetin, 2 - pyrrolidone, boric acid, aluminum and magnesium silicates, natural locust bean gum, karaya gum, guar, tragacanth, agar, celluloses and, cellulose derivatives such as methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, as well as alginates, alumines and bentonites, polyethylene glycol and also waxes such
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48/73 such as, for example, beeswax, carnauba wax, candelilla wax and the like can be used. Here, the substance of the second layer matrix can be identical to that of the polymer of the first layer. The additional support substances or matrix can be used in a weight ratio of up to 70% by weight, preferably to 50% by weight. based on which active agent used (s).
[00117] The polymeric coating is applied by means of known methods, such as the spray method, the immersion method, the plasma method, the brush method, the injection method, electrospinning or pipetting method for the magnesium alloy of the base structure and preferably also firmly adheres to it. The stent of the invention can thus be coated by spraying, pipetting, brushing, squirting, plasma deposition or the immersion method, electrospinning, in which the polymeric substance, or mixtures of the substances are dissolved in a solvent and this solution is applied over the implant. Subsequently, the solvent or mixture of solvents is removed by evaporation at room temperature. The coating of stents according to the invention can be carried out either before or after being driven into a catheter balloon. In the case where the coating is applied not until the stent is mounted in a catheter balloon, an immersion or spray method is preferred. Here, the catheter balloon can also be coated, perhaps extending beyond the ends of the stent. The polymer can also be preformed in a tube form, and applied to the external or internal surface of the base structure of the inventive stents. In case a tube is applied or the polymeric coating is applied as a complete coating, that is, a coating that completely covers the interstices, it is preferable, if this polymeric coating exceeds the length of the stent or the vessel support and does not end at ends of the vessel support. In another step, the protruding ends of the coating are placed around the edges of the support of the
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49/73 vessel to the outside and the resulting edges are integrated under pressure and high temperature into the base polymer layer. With this, a strengthened coating on the ends of the stent is guaranteed and the risk of detachment for these weak points is reduced.
[00118] The polymeric coating must be relatively uniform, and has a layer thickness of 0.01 to 100 µm. The thickness of the desired layer also depends on the respective polymer and can be carried out in several coating steps interrupted by drying phases. The tightness of the polymeric coating can be regulated through the thickness of the coating. Especially in the case of deposition of the polymer from a gaseous phase, the layer becomes impermeable, with a longer coating life. In periods of short coating leaking spots occur that allow the diffusion of water or gases.
[00119] As solvents are water and suitable solvents, preferably organic, such as chloroform, methylene chloride (dichloromethane), acetone, tetrahydrofuran (THF), diethyl ether, methanol, ethanol, propanol, isopropanol, diethyl ketone , dimethylformamide (DMF), dimethylacetamide, acetic ethyl ester, dimethyl sulfoxide (DMSO), benzene, toluene, xylene, t-butyl methyl ether (MTBE), petroleum ether (PE), cyclohexane, pentane, hexane, heptane , in chloroform and methylene chloride, are particularly preferred.
[00120] In addition, at least one anti-inflammatory, antiproliferative, anti-angiogenic, anti-restenosis (anti-restenosis), antineoplastic, an anti-migratory and / or anti-thrombogenic active agent to be applied can be dissolved, emulsified, suspended or dispersed in one suitable solvent or also in conjunction with the polymer. If a polymer as a matrix substance is contained in the second layer, this polymer can be dissolved and applied together with the active agent, or applied
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50/73 separately, preferably before, in a spray, pipetting or diving method.
[00121] In a preferred embodiment, firstly the polymeric coating is applied over the stent, dried and after an active agent is applied over this coating. For this, preferably a solution of at least one active agent and, potentially, a carrier substance, in a highly volatile solvent is applied over the polymeric coating of the stent. Subsequently, the solvent or mixture of solvents is removed by evaporation at room temperature.
DESCRIPTION OF THE FIGURES [00122] Figure 1: shows a photo for determining the grain size of a magnesium alloy with 10% by weight of dysprosium and 1% by weight of neodymium.
[00123] Figure 2: shows a photo for determining the grain size of a magnesium alloy with 10% by weight of dysprosium, 1% by weight of neodymium and 0.6% of zirconium.
[00124] Figure 3: shows a photo for determining the grain size of a magnesium alloy with 10% by weight of dysprosium, 1% by weight of neodymium and 0.2% of zirconium. The grain size is at 102 pm.
[00125] Figure 4: shows a photo for determining the grain size of a magnesium alloy with 10% by weight of dysprosium, 1% by weight of neodymium and 0.4% of zirconium. The grain size is 68 pm.
[00126] Figure 5: shows a photo to determine the grain size of a magnesium alloy with 10% by weight of dysprosium, 1% by weight of neodymium and 0.6% of zirconium. The grain size is at 64 pm.
[00127] Figure 6: shows 4 photos of the moment during balloon angioplasty for implantation of an uncoated stent in a pig
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51/73 (see Example 8). Figure 6A was taken without an X-ray contrast agent, after the catheter was moved to the corresponding coronary artery. Both arrows indicate the distal and proximal radiopaque markings of the still-folded catheter balloon in which the stent is placed. Figure 6B was taken with an X-ray contrast agent during catheter balloon dilation for expansion and positioning. Both arrows mark the ends of the catheter balloon. The catheter balloon closes the vessel, so that the X-ray contrast agent cannot penetrate the underlying portion of the vessel. The stent / balloon and artery ratio was 1.2 to 1. Figure 6C was taken without X-ray contrast agent after the balloon catheter was removed from the vessel again. The stent remains in the vessel, however, it cannot be seen in the photo, since the magnesium alloy according to the invention is not opaque. Figure 6D was taken with an X-ray contrast agent after the balloon catheter was removed from the vessel again. The stent remains in the vessel. The arrows indicate the ends of the stent. A little more contrast agent builds up in the stent region. However, the stent itself cannot be seen.
[00128] Figure 7: shows a graphical representation of the results of the corrosion tests with binary magnesium alloys containing between 5% and 20% of dysprosium and the rest of magnesium. Corrosion was measured in 0.9% saline in an eudiometer. The results in% refer to the fraction of dysprosium in percentage by weight.
[00129] Figure 8: shows a graphical representation of the trend's dependence on the formation of hot crack together with the amounts of zinc in the alloy. Magnesium alloys containing 10% dysprosium, 1.0% neodymium, zinc with increasing weight percent, 0.2% zirconium weight and the rest of magnesium were tested. The results in% refer to the fraction of zinc in percentage by weight.
EXAMPLES
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Example 1: Production of the Alloys [00130] The alloys were produced in the so-called “permanent mold with direct cold fusion” (Tütenguβverfahren). This method serves for the production of pre-materials for subsequent extrusion and is characterized by the fact that the material with a homogeneous microstructure and a homogeneous distribution of binding elements in the ingot can be produced. In addition, it is exceptionally suitable for producing smaller quantities of high quality pins for forming the metal.
[00131] With this method, the magnesium alloys (L1, L2, .. L34) are cast in a smoothed steel crucible. Any nickel-free steel can be used as a crucible material. Graffiti could be another possibility. All smelting operations are carried out under inert gas. Melting bath temperatures are in the range of 660 to 740 ° C. Upon reaching the temperature of the melting bath, the alloying elements in the form of pure elements or master alloys were added. After adding the alloying elements the melt was mechanically stirred. The stirring time depends on how long it takes for the master elements or alloys to completely dissolve in the melt. After this preparation, the fusion was transferred to a thin-walled coquille, which was preheated to a temperature of 600 ° C. After a period of about 60 minutes, the coquille was immersed in a water bath with a temperature of 15-20 ° C. Due to the immersion, the coquille solidified completely.
[00132] Before extrusion the surface of part of the mold was adjusted to the diameter of the extrusion press container. In addition, prior to extrusion, the molding pin was heated to a temperature of 250-500 ° C and maintained for 3-6 hours at that temperature to dissolve intermetallic phases or to homogenize segregations. Subsequently, extrusion was performed and the billet produced in this way was cooled
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[00133] The following alloys have been prepared:
League L1:
87.8% by weight magnesium
10.0% by weight dysprosium
1.0% by weight neodymium
1.0% by weight zinc
0.2% by weight impurities comprising Si, Ni, Faith, Cu and others metals and non-metals.League L2:86.6% by weight magnesium 10.0% by weight dysprosium 1.0% by weight neodymium 0.2% by weight zirconium 0.2% by weight impurities comprising Si, Ni, Faith, Ass and others metals and non-metals.League L3:87.6% by weight magnesium 10.0% by weight dysprosium 1.0% by weight neodymium 0.2% by weight zinc 0.2% by weight zirconium 0.2% by weight impurities comprising Si, Ni, Faith, Ass and others
metals and non-metals.
League L4:
89.7% by weight magnesium
6.0% by weight dysprosium
2.0% by weight neodymium
2.0% by weight zinc
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0.3% by weight impurities comprising Si, Ni, Faith, Cu and others metals and non-metals. League L5: 90.7% by weight magnesium 5.5% by weight dysprosium 3.0% by weight neodymium 0.5% by weight zirconium 0.3% by weight impurities comprising Si, Ni, Faith, Cu and others metals and non-metals. League L6: 87.4% by weight magnesium 8.0% by weight dysprosium 2.2% by weight neodymium 1.8% by weight zinc 0.3% by weight zirconium 0.3% by weight impurities comprising Si, Ni, Faith, Cu and others metals and non-metals. League L7: 82.7% by weight magnesium 12.0% by weight dysprosium 2.5% by weight neodymium 2.5% by weight zinc 0.3% by weight Impurities including Si, Ni, Faith, Cu and others
metals and non-metals.
League L8:
74.2% by weight magnesium
22.5% by weight dysprosium
2.6% by weight neodymium
0.4% by weight zirconium
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0.3% by weight Impurities comprising Si, Ni, Faith, Cu and others metals and non-metals. League L9: 83.1% by weight magnesium 15.2% by weight dysprosium 1.2% by weight neodymium 0.2% by weight zirconium 0.3% by weight Impurities comprising Si, Ni, Faith, Cu and others metals and non-metals. League L10: 88.9% by weight magnesium 8.0% by weight dysprosium 1.4% by weight neodymium 1.2% by weight zinc 0.2% by weight zirconium 0.3% by weight Impurities comprising Si, Ni, Faith, Cu and others
metals and non-metals.
League L11:90.6% by weight magnesium 8.0% by weight dysprosium 1.0% by weight neodymium 0.2% by weight zinc 0.2% by weight zirconium League L12:89.3% by weight magnesium 8.0% by weight dysprosium 1.0% by weight neodymium 1.0% by weight europium 0.5% by weight zinc 0.2% by weight zirconium
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Liga L1386.0% by weight magnesium 12.0% by weight dysprosium 1.0% by weight neodymium 0.8% by weight zinc 0.2% by weight zirconium League L14:90.1% by weight magnesium 6.0% by weight dysprosium 1.0% by weight neodymium 1.0% by weight europium 1.5% by weight zinc 0.4% by weight zirconium League L15:86.8% by weight magnesium 10.0% by weight dysprosium 1.0% by weight neodymium 1.0% by weight europium 1.0% by weight zinc 0.2% by weight zirconium League L16:82.8% by weight magnesium 14.0% by weight dysprosium 0.5% by weight neodymium 0.5% by weight europium 2.0% by weight zinc 0.2% by weight zirconium League L17:87.3% by weight magnesium 10.0% by weight dysprosium
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1.5% by weight neodymium 1.0% by weight zinc 0.2% by weight zirconium League L18:87.45% by weight magnesium 10.0% by weight dysprosium 1.5% by weight neodymium 1.0% by weight zinc 0.05% by weight iron League L19:83.1% by weight magnesium 15.0% by weight dysprosium 0.9% by weight neodymium 1.0% by weight zirconium League L20:95.0% by weight magnesium 4.5% by weight dysprosium 0.5% by weight neodymium League L21:73.7% by weight magnesium 20.0% by weight dysprosium 5.0% by weight neodymium 1.0% by weight zinc 0.3% by weight zirconium League L22:87.25% by weight magnesium 10.0% by weight dysprosium 1.5% by weight neodymium 1.0% by weight zinc 0.05% by weight iron
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0.2% by weight zirconium League L23:85.8% by weight magnesium 12.0% by weight dysprosium 1.0% by weight neodymium 1.0% by weight zinc 0.2% by weight zirconium League L24:82.1% by weight magnesium 15.0% by weight dysprosium 0.9% by weight neodymium 1.0% by weight zinc 1.0% by weight zirconium League L25:79.1% by weight magnesium 20.0% by weight yttrium 0.9% by weight europium League L26:92.5% by weight magnesium 5.0% by weight dysprosium 2.5% by weight europium League L27:82.1% by weight magnesium 15.5% by weight dysprosium 1.2% by weight neodymium 1.0% by weight zinc 0.2% by weight zirconium 0.001% by weight Impurities including Si, Ni, Fe, Cu and others metals and non-metals.League L28:
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72.0% by weight magnesium 20.0% by weight gadolinium 5.0% by weight neodymium 1.0% by weight zinc 2.0% by weight zirconium League L29:88.8% by weight magnesium 6.0% by weight dysprosium 4.0% by weight europium 1.0% by weight zinc 0.2% by weight zirconium Alloy L30:89.8% by weight magnesium 8.0% by weight dysprosium 1.0% by weight europium 1.0% by weight zinc 0.2% by weight zirconium League L31:73.2% by weight magnesium 25.0% by weight dysprosium 0.4% by weight neodymium 1.4% by weight europium League L32:87.4% by weight magnesium 10.0% by weight dysprosium 1.0% by weight europium 0.5% by weight neodymium 1.0% by weight zinc 0.1% by weight zirconium League L33:
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87.0% by weight magnesium 10.0% by weight dysprosium 0.3% by weight europium 1.5% by weight neodymium 1.0% by weight zinc 0.2% by weight zirconium League L34:86.0% by weight magnesium 12.0% by weight dysprosium 1.0% by weight europium 0.8% by weight zinc 0.2% by weight zirconium
Example 2: Tube Production [00134] From the L1 to L10 alloys, extruded wires were prepared according to Example 1. In these extruded wires, a precision drill hole is introduced in the longitudinal direction, which already determines the thickness of the stent wall. Through several formation steps, a tube of predetermined diameter and the right wall thickness is made. Between the individual stages of formation there is repeated heat treatment.
Example 3: Stent Production [00135] A tube produced according to Example 2 is attached inside an adapter to the laser machine. A pulsed solid state laser (FKL) cuts the contours of the outer tube design. Laser cutting is performed under an inert gas atmosphere.
[00136] The stent design is stored in an NC program (numerical control). This provides the laser with a transverse path (cutting pattern), according to which the tube is structured. Through laser beam cutting, burr formation occurs, especially on the inside of the tube, along the entire cutting contour. This can cause burrs and cutouts to remain in the contour after the cutting process has ended. At
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61/73 burrs and cutouts will be removed mechanically and the stent is cleaned of manufacturing waste. In a first optical visual control, an inspection of the cutting contour is performed.
[00137] Subsequently, the stent is electronically polished. The stent is connected anodically and immersed in an acid bath. By means of a cathode fixed in the bath, an electrical circuit is closed. The electrical circuit is maintained for several minutes. Electrical polishing is an inverted galvanic process where material is removed in a controlled manner from the surface of the anodically connected component. Due to the method, removal occurs preferably in sharp corners and edges. The stent has a smooth surface and rounded edges along the outline. After polishing, the stent is cleaned and free of acidic residues. During the final cleaning all remaining manufacturing residues are removed from the surface of the stent. In a final optical visual control, the geometry of the stent is measured and the surface is tested for cleanliness.
Example 4: Determination of grain size [00138] The counting of the grain size was done using the linear intercept method. Grains that are only cut in half at the end of the line have been counted here as grains in half. The amplification was selected in such a way that at least 50 grains are cut through the grid. At least 5 sites with a total of at least 250 points of intersection were assessed in the sample.
Example 5: Determination of the corrosion rate [00139] At room temperature, the corrosion rates of various alloys were determined for a period of 3 days in a physiological saline solution (see Table 1). An alloy was tested containing 90.8% by weight of magnesium, 8% by weight of Dysprosium, 1% by weight of neodymium, 0.2% by weight of zirconium, an alloy containing 89.8% by weight of magnesium, 8% by weight of dysprosium , 1% by weight of neodymium, 1% by weight of Eu and 0.2% by weight Zr, an alloy containing 86.8% by weight Mg, 12% by weight Dysprosium 1%
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62/73 by weight Nd, and 0.2% by weight Zr, and an alloy containing 87.8% by weight Mg, 10% by weight Dysprosium 1% by weight Nd, 1% by weight Europium and 0.2% by weight zirconium. Additionally, alloys containing 1.0 wt% neodymium, 1.0 wt% zinc, 0.2 wt% zirconium, between 5 and 20 wt% dysprosium and the magnesium balance (see Figure 7) were tested. Corrosion products were removed by immersing the samples in chromic acid (180 g / L) for 20 minutes at room temperature. The average corrosion rate was calculated in millimeters per year using the following equation:
8.76xΙΟ ⁴ χΔ g
Λ-r -p
At the. Composition Rate ofcorrosion (mm / year) L11 Mg8Di1NdO.2ZnO.2Zr 9.25 ± 0.38 L15 Mg10Di1 Nd1 Eu1ZnO.2Zr 0.81 ± 0.06 L23 Mg12Di1 Nd1ZnO.2Zr 2.94 ± 1.88 L16 Mg8Di1 Nd1 Eu1Zn0.1Zr 4.9 ± 1.62 L14 Mg6Di1Nd1Eu1.5ZnO.4Zr 9.56 ± 0.29 L16 Mg14DiO.5NdO.5Eu2ZnO.2Zr 1.25 ± 0.12 L18 Mg10Di1.5Nd1Zn0.05Fe 12.41 ± 2.16 L20 Mg4.5DiO.5Nd 25.56 ± 2.34 L24 Mg15DiO.9Nd1Zr1Zn 2.98 ± 1.78 L25 Mg20Y0.9Eu 44.71 ± 3.22 L28 Mg20Gd5Nd1Zn2Zr 38.96 ± 1.34 L30 Mg8Di1Eu1ZnO.2Zr 3.88 ± 1.87 L22 Mg1 ODi 1.5Nd1Zn0.2Zr0.05Fe 4.47 ± 2.11 L34 Mg12Di1EuO.8ZnO.2Zr 5.46 ± 1.22 L29 Mg6Di4Eu1ZnO.2Zr 12.20 ± 1.36 L33 Mg10Di0.3Eu1.5Nd1 ZnO.2Zr 1.25 ± 0.67 L26 Mg5Di2.5Eu 23.56 ± 1.56 L31 Mg25DiO.4Nd1.4Eu 48.71 ± 1.87
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63/73 [00140] Table 1: Corrosion rate of the alloys of the invention, measured over 3 days at room temperature and in 0.9% NaCl; the specification of the components of the alloys is given in percentages by weight and milligram, since the main component always adds up to 100% of the alloy. The alloys were tested after molding, without hot treatment, the average values and standard deviations of the various alloys are listed.
Example 6: Mechanical characteristics of alloys [00141] Alloys and mold parts were produced according to Example 1 and extruded. The T4 hot treatment was carried out at 510 ° C over 8 hours and eventually after the T6 hot treatment at 200 ° C over a 72 hour period. After the T4 hot treatment the samples were immediately cooled in water. All samples were taken from the same position as the blocks.
[00142] Tensile tests were carried out at room temperature according to DIN EM 10002-1 (corresponding to ISO 6892 and ASTM E8), and pressure tests were carried out at room temperature according to DIN 50106 (corresponding to ISO 604 and ASTM D695). At least 3 samples were tested for each value. The tensile strength was calculated in terms of the maximum tensile strength achieved in the tensile test in relation to the original cross section of the sample.
[00143] Table 2: mechanical characteristics of the alloys of the invention. Alloys were tested as a sample after extrusion (ST, without hot treatment), and after different hot treatments, T4 (tempered solution), and T6 (an additional hot treatment after T4, also known as "aging"). The information on the components of the alloys is given in percentage by weight and in milligrams, since the main component always complements the quantitative data up to 100% of the alloy. SD means standard deviation of the mean values, which are indicated in the left column (n = 3).
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Composition Yield strength (MPa) SD Tensile strength(MPa) SD Elongation at break (%) SD ST Mg8Di1Nd0.2Zn0.2Zr 107.33 1.8 208.5 0.85 28.12 3.41 T487.54 0.46 176.84 2.03 18.83 1.79 T697.95 1.67 194.11 1.1 19.33 0.68 ST Mg10Di1Nd1Eu1Zn0.2Zr 169.30 0.74 283.89 0.68 16.96 1 T4151.97 1.77 259.50 2.57 18.02 0.29 T6159.23 2.23 275.55 1.78 18.15 2.77 ST Mg12Di1Nd1Zn0.2Zr 126.07 1.8 226.04 0.35 28.55 0.08 T498.38 0.43 188.45 0.5 20.47 0.91 T6114.6 1.69 205.2 1.25 17.99 0.79 ST Mg8Di1Nd1Eu1Zn0.1Zr 132.24 1.1 227.21 0.59 19.75 1.11 T4114.93 1.25 210.73 1.51 20.89 1.01 T6136.77 1.77 223.28 0.67 23.64 2.01 ST Mg6Di1Nd1Eu1.5Zn0.4Zr 128.14 8.02 202.74 2.91 24.62 2.09 T480.97 2.27 173.47 2.02 23.78 3.52 T684.26 2.57 178.26 1.35 26.32 2.5 ST Mg14Di0.5Nd0.5Eu2Zn0.2Zr 165.64 4.95 218.17 3.07 18.9 1.14 T4110.78 1.87 201.28 1.19 21.62 1.07 T6153.15 3.55 264.09 0.71 17.66 1.33 ST Mg10Di1.5Nd1Zn0.05Fe 145.46 3.55 237.21 0.75 28.9 1.73 T4102.78 4.38 193.36 5.84 27.57 0.88 T6108.84 1.68 200.16 2.97 25.56 1.66 ST Mg4.5Di0.5Nd 68.39 7.9 208.48 2.03 28.4 0.72 T460.31 1.71 179.04 0.83 23.17 0.38 T675.13 1.32 250.34 1.42 13.34 0.74 ST Mg15Di0.9Nd1Zr1Zn 136.93 1.6 227.07 0.42 22.9 3.03 T495.79 1.94 200.59 2.59 21.57 0.34 T6112.09 0.41 206.11 0.19 19.56 0.66 ST Mg20Y0.9Eu 159.75 1.99 238.55 0.76 11.57 0.58 T4123.19 4.83 214 1.42 19.62 2.74
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T6144.08 4.37 220.2 2.58 15.58 0.94 ST Mg20Gd5Nd1Zn2Zr 297.75 8.12 338.53 5.67 1.53 0.27 T4195.82 15.6 276.89 0.91 6.58 0.95 T6327.07 17.5 378.45 14.94 0.76 0.32 ST Mg8Di1Eu1Zn0.2Zr 112.85 1.15 198.9 0.43 24.07 1.05 T493.5 1.01 182.38 0.91 24.02 0.81 T699 0.99 185.7 0.4 25.9 1.16 ST Mg10Di1.5Nd1Zn0.2Zr0.05Fe 127.8 4.62 215.84 1 19.39 1.4 T496.72 4.02 192.99 2.87 25.92 0.98 T6112.34 3.1 201.35 2.18 24.44 1.91 ST Mg12Di1Eu0.8Zn0.2Zr 182.30 1.52 293.62 1.37 22.39 2.06 T4164.48 1.44 268.66 0.45 23.70 1.63 T6172.34 2.12 271.35 1.82 23.34 1.79 ST Mg6Di4Eu1Zn0.2Zr 115.09 1.39 208.3 1.68 2.30 0.51 T497.55 0.74 189.39 0.84 4.78 1.71 T6112.58 1.59 196.71 2.31 3.41 0.69 ST Mg10Di0.3Eu1.5Nd1Zn0.2Zr 168.54 6.15 277.11 2.09 16.46 2.33 T4136.36 5.11 244.89 2.37 20.67 3.15 T6152.22 2.42 253.91 2.33 18.56 1.87 ST Mg5Di2.5Eu 74.25 1.63 283.50 1.44 21.60 1.27 T460.19 1.69 264.46 0.91 23.16 1.43 T665.38 1.83 266.64 1.36 22.85 1.64 ST Mg25Di0.4Nd1.4Eu 106.34 2.98 211.15 1.65 18.90 1.55 T488.74 1.69 178.56 2.03 20.03 2.31 T694.21 1.34 191.25 1.67 19.54 1.99
Example 7: Stent coating according to the invention [00144] Stents of a magnesium alloy consisting of 87.8% by weight of magnesium, 10.0% by weight of dysprosium, 1.0% by weight of neodymium, 1 , 0% by weight of zinc and 0.2% by weight of zirconium, which were laser cut, heat treated and polished, were coated. Coating by
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66/73 spraying was performed using one of the following two spray solutions:
Spray solution composition 1:
4.25 mg rapamycin
5.65 mg of RG 858S resomer (poly (DL-lactide-co-glycolide), 85:15) ml of ethyl acetate
0.05 mg alpha tocopherol
0.05 mg ascorbic palmitate
Sprinkler solution 2 composition:
0.97688 mg paclitaxel
8.79113 mg RG 858S, poly (DL-lactide-co-glycolide), 85:15 ml chloroform [00145] The unclean expanded stents were hung horizontally on a thin metal rod (d = 0.2 mm) , which is mounted on the rotational axis of the rotation and advance device and which rotates at 28 rpm. The stents were placed in such a way that the internal side of the stents has no contact with the nail and is sprayed with one of the rapamycin spray solutions mentioned above. After that, the stents were dried over the night under a hood. If necessary, the coating procedure can be repeated until the desired active agent load is on the stent. The active coating agent applied in the present case contained about 1.4 pg of rapamycin / mm ² and 0.25 pg of paclitaxel / mm ² on the surface of the stent.
Example 8: Animal study [00146] 16 stents produced according to Examples 2, 3 and 7 were implanted in the coronary arteries of 8 domestic pigs. The stents had a diameter of 3.0 mm and a length of 14 ° mm (catheter balloon length 15 mm) and were made of an alloy of the following composition:
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87.8% by weight of magnesium
10.0% by weight of dysprosium
1.0% by weight of neodymium
1.0% by weight of zinc
0.2% by weight of zirconium [00147] The “continuity” period was chosen for all 8 animals within 4 weeks after implantation. Two groups were tested in total. The first group comprises uncoated stents (BMS), the second group comprises stents coated with the poly (lactideoco-glycolide) polymer (PLGA) and the active agent Paclitaxel.
[00148] One day before stent implantation, a single dose of clopidrogel (300 mg) and aspirin (250 mg) was administered orally to the pigs. Under general anesthesia, access to the femoral artery was obtained through surgical exposure and a large pill of sodium heparin (10,000 IU) was administered. A 6F coronary guide catheter was inserted through the femoral artery into the descendants of the aorta. Coronary angiography was performed when using manual injection of a nonionic contrast agent to obtain the anatomical conditions for the procedure.
[00149] Stents were implanted in the anterior interventricular branch (RIVA or LAD) and circumflex branch (RCX or LCx). Balloon dilation pressure for stent implantation was chosen to reach a stent balloon at an arterial rate of 1.2 to 1. The pigs were then allowed to recover. During all 4 weeks to “continue” the animals received orally a daily dose of 100 mg of aspirin and 75 mg of clopidogrel per 30 g of body weight.
[00150] After 4 weeks to "continue", control angiography and optical coherence tomography (OCT) were performed. In the OCT procedure, a 0.014 inch guide wire was inserted into the LAD and LCx and pulled through the stents implanted inside the distal part of the vessel. An OCT intravascular catheter was subsequently advanced
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68/73 distally from the stent along the guide wire. The injection pump was turned over to inject contrast agents at a rate of 3.0 ml / s in order to transiently displace blood. The entire length of the lesion was photographed with an automatic pullback device at 100 mm / s. After shooting, the OCT catheter was removed and the images were saved. The animals were then sacrificed and the coronary arteries were explanted.
[00151] The explanted arteries were fixed by perfusion with a pressure of 100 mmHg for 1 hour using 7% formalin. The stents were processed for light microscopy. For light microscopy, the arteries were cut into 3 sections: proximal, medial and distal stent segments. These segments were embedded in methyl methacrylate (Technovit 9100).
[00152] The stent artery segments were cut into 4-6 pm slices using a rotating microtome and were stained with hematoxylin and eosin.
[00153] As part of the analysis details of the study, both stent position, dilation pressure and dilation time, as well as any complications during implantation, were listed.
Quantitative Coronary Angioplasty (CSF) [00154] A CSF was performed to analyze restenoses in the stent. Thus, the following parameters were determined: vessel diameter before after stent implantation, minimum lumen diameter (MLD) after stent implantation and in continuity and the diameter is the smallest absolute diameter of the internal vessel in the segment region dilated, estimated from two planes of orthogonal projection LLL (loss of late lumen) is a measurement of narrowing of the lumen due to neointimal hyperplasia. The lumen diameter is measured directly after the intervention and 4 weeks after the intervention, the difference between the two is given as LLL. The length of the dilated segment or as a stenosis was checked and the stenosis was calculated as a percentage.
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Optical Coherence Tomography (OCT) [00155] The images from optical coherence tomography were analyzed according to the relevant guideline (JACC, 2012). The following parameters were obtained: stent apposition, stent arm coverage, tissue protrusion, arterial dissection, thrombosis. Quantitative analysis of OCT images includes the minimum and maximum diameter of the stent and the lumen area. The following parameters were calculated: maximum area stenosis and stent symmetry. For the quantitative analysis, the “worst” cross section per test group was determined.
[00156] Calculation of area stenosis (% AS):
% AS = intimate area / stent area = (stent area the lumen area) / stent area.
[00157] Stent symmetry calculation:
stent symmetry = (maximum stent diameter to minimum stent diameter) / maximum stent diameter.
[00158] Fibrin deposition, degree of inflammation (intimate and adventitia), hemorrhage and necrosis were analyzed according to published guidelines.
Histomorphometry [00159] Histomorphometry was performed using computer-assisted planimetry. The lumen, the area of the internal elastic lamina and the external elastic lamina and the maximum neointimal thickness were measured. The extent of neointima and mean, as well as that of stenosis, was calculated as a percentage.
Results [00160] The expansion pressure used was between 12 and 18 atm. The balloon inflated took 30 seconds. In general, stent and balloon manipulation was excellent; very good pushing ability and very fast deflating time were recorded.
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Group Pre-MLD(mm) Post-MLD(mm) FUP-MLD(mm) FUP-RD(mm) FUP-% DS (%) LLL(mm) Uncoated stents (BMS) 2.68 2.93 2.08 2.92 28.75 0.85 SD 0.11 0.07 0.53 0.20 16.79 0.47 PLGA-Paclitaxel 2.65 2.97 2.43 3.01 19.50 0.53 SD 0.11 0.10 0.27 0.16 6.26 0.27
[00161] Table 3: results of quantitative coronary angioplasty (QCA), the mean values and standard deviations (SD) of both test groups are listed; MLD = minimum lumen diameter, RD = diameter of a reference segment,% DS = percentage diameter stenosis, FUP = follow up, LLL = late lumen loss.
animalAt the. Artery Group Stent placement Protru are made of fabric Thrombus in the stent Stent dissection Edge dissection endothelization MEKO-1 LAD BMS 0 0 0 0 0 complete MEKO-1 LCx BMS 0 0 0 0 0 incomplete MEKO-2 LAD BMS 0 0 0 0 0 complete MEKO-2 LCx BMS 0 0 0 0 0 complete MEKO-3 LAD BMS 0 0 0 0 0 complete MEKO-3 LCx BMS 0 0 0 0 0 complete MEKO-4 LAD BMS 0 0 0 0 0 complete MEKO-4 LCx BMS 0 0 0 0 0 complete MEKO-5 LAD PLGA-Paclitaxel 0 0 0 0 0 incomplete MEKO-5 LCx PLGA-Paclitaxel 0 0 0 0 0 incomplete MEKO-6 LAD PLGA-Paclitaxel 1 0 0 0 0 incomplete MEKO-6 LCx PLGA-Paclitaxel 1 0 0 0 0 incomplete MEKO-7 LAD PLGA-Paclitaxel 1 0 0 0 0 complete MEKO-7 LCx PLGA-Paclitaxel 0 0 0 0 0 incomplete
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MEKO-8 LAD PLGA-Paclitaxel 1 0 0 0 0 incomplete MEKO-8 LCx PLGA-Paclitaxel 1 0 0 0 0 incomplete
[00162] Table 4: qualitative analysis of optical coherence tomography (OCT) by implanted stent.
[00163] From tables 3 and 4 it can be concluded that first none of the tested complications occurred when using a stent according to the invention and, secondly, that an endothelization was almost always complete after 4 weeks, which meant that the increased risk of thrombosis in the stent due to complete endothelization or inflammation reactions was no longer present. Comparable results have also been obtained with stents from a magnesium alloy containing europium instead of neodymium.
Type Minimum stent diameter (mm) Maximum stent diameter (mm) Stent area (mm ² ) Lumen area (mm ² ) %AT(%) Stent symmetry Uncoated stents (BMS) 2.54 2.72 7.58 5.08 34.0 0.07 SD 0.34 0.35 1.80 1.69 13.2 0.02 PLGA-Paclitaxel 2.46 2.97 9.16 7.10 22.4 0.17 SD 0.59 0.29 1.39 1.77 13.8 0.18
[00164] Table 5: additional results from the qualitative analysis of optical coherence tomography (OCT); mean values and standard deviations (SD) and mean values of both test groups are listed.
Example 9: coating of stents according to the invention [00165] Stents of a magnesium alloy consisting of 87.8% by weight of magnesium, 10.0% by weight of dysprosium, 1.0% by weight of europium, 1 , 0% by weight of zinc and 0.2% by weight of zirconium, which were laser cut, heat treated and polished, were coated. The spray coating was carried out using the following spray solution:
[00166] Composition of the spray solution:
Petition 870190042409, of 05/06/2019, p. 80/97
72Γ73
0.97688 mg paclitaxel
8.79113 mg of Resomer RG 858S, poly (DL-lactide-co-glycolide), 85:15 1 ml chloroform [00167] The clean unexpanded stents were hung horizontally on a thin metal rod (d = 0.2 mm) , which is mounted on the rotational axis of the rotation and advance device and rotated at 28 rpm. The stents were placed in such a way that the internal side of the stent does not come into contact with the stem and sprayed with the aforementioned spray solution. Subsequently the stents were dried over the night under a hood. The applied active agent coating had about 0.3 pg paclitaxel Γ mm ² from the surface of the stent.
Example 10: coating a stent according to the invention with a double layer system [00168] Coating solution 1: 176 mg of polyethersulfone were weighed and filled to 20 g with chloroform (0.88% solution).
[00169] Coating solution 2: a 35% solution of rapamycin and PLGA (0.8%) in chloroform.
[00170] Here, the stent consisting of the magnesium alloy L22 (Example 1) is coated. The clean unexpanded stents were hung horizontally on a thin metal rod, which is mounted on the rotating axis of the rotation and advance device and rotated at 28 rpm. The stents were placed in such a way that the internal side of the stent does not come into contact with the rod and sprayed with the coating solution 1. Subsequently, drying occurs overnight at room temperature.
[00171] After drying the first layer, a second layer is applied by dripping in coating solution 2. The stent is thereafter dried in the compartment dryer for 4 hours at 30 ° C.
Example 11:
[00172] A stent according to the invention, consisting of:
Petition 870190042409, of 05/06/2019, p. 81/97
73/73
88.9% by weight of magnesium
8.0% by weight of dysprosium
1.4% by weight of neodymium
1.2% by weight of zinc
0.2% by weight of zirconium was cleaned and mounted on a sprinkler device as already explained. The stent is then coated with a solution of poly-D-caprolactone in methylene chloride using the interval spray method.
Example 12: coating a stent of the invention on the luminal and abluminal side with two polyactides (PLGA 75/25 and PLGA 50/50) which degrades at a different speed [00173] A stent according to example 11 is hung horizontally on a thin metal rod (d = 0.2 mm), which is mounted on the rotating axis of the rotation and advancement device, so that the internal wall of the stent does not have contact with the rod. On the abluminal surface of the stent the smallest degradable polylactides (PLGA 75/25) dissolved in chloroform is applied to the stent struts using the continuous pipetting method while the stent slowly rotates around its longitudinal axis. Drying takes place under a gentle air flow at room temperature.
[00174] The abluminal coated stent is now coated from the luminal side with the fastest degrading polymer (PLGA 50/50 / solution is from 145.2 mg of polylactide in 20 g of chloroform). In order to do this, stents are brushed along the struts with the polymeric solution using a brush. After that, drying occurs again under a gentle air flow at room temperature.
Petition 870190042409, of 05/06/2019, p. 82/97

权利要求:
Claims (15)
[1]
1. Stent made from biologically degradable magnesium alloy, characterized by the fact that the alloy contains, in relation to the total weight of the alloy, the following components:
5.0% by weight to 25.5% by weight of dysprosium
0.01% by weight to 5.0% by weight of neodymium and / or europium
0.1% by weight to 3.0% by weight of zinc
0.1% by weight to 2.0% by weight of zirconium and unavoidable impurities, rest at 100% by weight of magnesium in which the stent has a polymeric coating.
[2]
2. Stent according to claim 1, characterized by the fact that the alloy contains 0.1% by weight to 2.0% by weight of zinc.
[3]
3. Stent according to claim 1 or 2, characterized by the fact that the alloy contains 0.1% by weight to 0.3% by weight of zirconium.
[4]
Stent according to any one of claims 1 to 3, characterized in that the alloy contains impurities.
[5]
Stent according to any one of claims 1 to 4, characterized in that the alloy additionally comprises:
1ppm to 0.3% by weight of impurities, such as, for example, other metals, salts of metals and non-metals.
[6]
6. Stent according to any one of claims 1 to 5, characterized in that the alloy does not contain yttrium and does not contain gadolinium.
[7]
7. Stent according to any one of claims 1 to 6, characterized by the fact that the alloy does not contain, in total, more than 0.1% by weight of the elements terbium, holmium, erbium, thulium, ytterbium and lutetium .
[8]
8. Stent according to any one of claims 1 to 5 or
7, characterized by the fact that the alloy consists of:
80.7% by weight to 94.7% by weight of magnesium
Petition 870190042409, of 05/06/2019, p. 83/97
2/5
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of impurities, such as, for example, other metals, salts of metals and non-metals and in which the alloy does not contain yttrium and does not contain gadolinium.
[9]
9. Stent according to one of claims 1 to 5 or 7, characterized by the fact that the alloy consists of:
82.4% by weight to 94.7% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 0.3% by weight of zirconium
0.1% by weight to 0.3% by weight of other metals, salts of metals and non-metals and in which the alloy does not contain yttrium and does not contain gadolinium.
[10]
10. Stent according to any one of claims 1 to 7, characterized by the fact that the alloy consists of:
80.4% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium and / or europium
0.1% by weight to 2.0% by weight of zinc
0.1% by weight to 0.3% by weight of zirconium
0.1% by weight to 0.3% by weight of impurities, such as, for example, other metals, salts of metals and non-metals and in which the alloy does not contain yttrium and does not contain gadolinium.
[11]
11. Stent according to claim 10, characterized by the fact that the alloy consists of:
79.7% by weight to 94.6% by weight of magnesium
5.0% by weight to 15.0% by weight of dysprosium
0.1% by weight to 2.0% by weight of neodymium
0.1% by weight to 2.0% by weight of zinc
Petition 870190042409, of 05/06/2019, p. 84/97
3/5
0.1% by weight to 0.3% by weight of zirconium
0.1% by weight to 1.0% by weight of impurities, such as, for example, other metals, salts of metals and non-metals and in which the alloy does not contain yttrium and does not contain gadolinium.
[12]
12. Stent according to any one of claims 1 to 11, characterized in that the polymeric coating comprises one or more substances from the following group: polyvinylpyrrolidone, glycerin, polyhydroxyethyl methacrylates, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polydioxanone, polycaprolactone , polygluconate, polyethylene oxide (lactic acid) copolymer, modified cellulose, polyhydroxybutyrate, polyamino acids, polyphosphate esters, polyvalerolactones, polyedecalactones, polylactonic acid, polyglycolic acid polylactides, polyglycolides, pololactides, pololactides and polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly (1,4-dioxane-2,3dione), poly (1,3-dioxane-2-one), poly-to-dioxanones, polyanhydrides, acid anhydrides polymaleal, polyhydroxy methacrylates, fibrin, polycyanoacrylates, policapr dimethylacrylates olactone, butyl polycaprolactone acrylates of poly-b-maleic acid, multiblock polymers from oligocaprolactonediois and oligodioxanonediois, polyether ester multiblock polymers from PEG and polybutylene terephthalate, polyvinyl acetate, polyvinyl glycates, polyethylene glycolates, trimethyl acetate poly (ethyl g-glutamate), poly (DTH-iminocarbonate), poly (DTE-co-DTcarbonate), poly (bisphenol A-iminocarbonate), poly-esters, polyglycolic acid trimethyl carbonates, poly-polymethylcarbonate poly-carbonates, poly (N-vinyl ) -pyrrolidone, polyvinyl alcohols, polyester amides, glycolized polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propane], polyhydroxy pentanoic acid, polyanhydrides, polyethylene oxide propylene oxide, soft polyurethanes, polyurethanes amino acid residues in the column, polyetheresters, such as polyethylene oxide,
Petition 870190042409, of 05/06/2019, p. 85/97
4/5 polyalkene oxalates, polyiortoesters, as well as their copolymers, lipids, waxes, oils, polyunsaturated fatty acids, eicosapentaenoic acid, tymnodonic acid, docosahexaenoic acid, arachidonic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, carrageenanine , fibrinogen, agar-agar, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, polyhydroxyalkanoates, pectic acid, actinic acid, carboxymethylcellulose sulfate, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfate and its derivatives, heparin, chondroitin sulfate, dextran, beta-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen, collagen hydroxysuccinimide, lipids, phospholipids, polyacrylic acid, polyacrylamide, polyacrylate, methacrylate, methacrylate, methacrylate , polyacrylonitriles, polyamides, polyetheramides, amine polyethylene, polyimides, polycarbonates, polycarbourethanes, polyvinyl ketones, polyvinyl halides, polyvinylidene halides, polyvinyl ethers, polyisobutylene, polyvinyl aromatic compounds, polyvinyl esters, polyvinylpyrethylene, polyethylene, polyethylene, polyoxymethylene, polyoxymethylene, polyoxymethylene , polyurethanes, polyether urethanes, silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, polyisobutylene, fluorosilicones, carboxymethyl, polyaryletherethercetones, polyethylmethylketones, polyethylmethylketones, polyetherethylene, tether , rayon, rayon triacetates, cellulose nitrates, cellulose acetates, hydroxyethyl cellulose, cellulose butyrate, cellulose acetate butyrate, ethyl vinyl acetate copolymers, polysulfones, epoxy resins, ABS resins, EPDM gums, silicones, such such as polysiloxanes, pol idimethylsiloxanes, polyvinyl halogens, cellulose ethers, cellulose triacetates, shellac, poly-para-xylene and copolymers of the polymers mentioned above.
Petition 870190042409, of 05/06/2019, p. 86/97
5/5
[13]
13. Stent according to any one of claims 1 to 12, characterized in that the polymeric coating has no micropores, holes, openings or channels.
[14]
14. Stent according to any one of claims 1 to 13, characterized by the fact that at least one active anti-inflammatory, antiproliferative, anti-angiogenic, anti-restenotic (anti-restenosis), antineoplastic substance is found in or on the polymeric coating. antimigrative and / or antithrombogenic.
[15]
15. Stent according to any one of claims 1 to 14, characterized in that, in the case of the stent, it is a stent for blood vessels, for the urinary tract, respiratory tract, biliary tract or for the digestive tract .

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DE102020115605A1|2020-06-12|2021-12-16|Phenox Gmbh|Implant for the treatment of aneurysms|

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DE102020115600A1|2020-06-12|2021-12-16|Phenox Gmbh|Implant for the treatment of aneurysms|

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DE102020115614A1|2020-06-12|2021-12-16|Phenox Gmbh|Delivery system for implants for the treatment of bifurcation aneurysms|

法律状态:
2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-02-05| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2019-05-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2019-07-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/08/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/08/2012, OBSERVADAS AS CONDICOES LEGAIS |

优先权:

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申请号 | 申请日 | 专利标题

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DE102011110114|2011-08-15|

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DE102011110114.8|2011-08-15|

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US201161573114P| true| 2011-09-06|2011-09-06|

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US61/573,114|2011-09-06|

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PCT/EP2012/065975|WO2013024125A1|2011-08-15|2012-08-15|Resorbable stents which contain a magnesium alloy|

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