DE102008040143A1 - Magnesium stent with a complete or partial coating comprising or consisting of dipyridamole - Google Patents

Abstract

Degradable magnesium stent with a complete or partial coating comprising or consisting of dipyridamole, is claimed. Independent claims are included for: (1) a medicine product comprising a balloon catheter, which is completely or partially coated with the coating, and the degradable magnesium stent, which is crimped on the surface of the balloon catheter; (2) a process for the preparation of the magnesium stent comprising providing a magnesium stent base body, providing a preparation comprising or consisting of dipyridamole and one or more solvents, and coating the magnesium stent base body with the preparation; (3) the preparation of the medicine product comprising providing the balloon catheter, providing a preparation comprising or consisting of dipyridamole and one or more solvents, coating the balloon catheter with the preparation, folding the coated balloon catheter, providing the magnesium stent and crimping the stent on the folded, coated balloon catheter; and (4) a process for improving the integrity of the implanted magnesium stent comprising either providing the magnesium sent and implanting the magnesium stents into a human or animal body, or providing the medicine product and implanting the magnesium stent into a human or animal body. ACTIVITY : Vasotropic; Vasodilator; Anticoagulant; Thrombolytic; Cytostatic. MECHANISM OF ACTION : None given.

Description

Technical area:

The The present invention relates to a degradable magnesium stent or a medical device with coating comprising or consisting of Dipyridamole, uses and method of improving integrity of degradable magnesium stents and methods of manufacture of degradable magnesium stents according to the invention and medical devices according to the invention.

Background of the invention:

balloon angioplasty, d. H. Dilation of a vasoconstriction with a Inflatable angioplasty balloon (catheter) leads to one due to an elastic closure of the vessel (so-called "recoil") and / or for another reason (Including trauma-initiated) restenosis to a high rate of revascularizing Interventions.

Around To circumvent these disadvantages, on the one hand active ingredients be administered systemically. In the case of systemic use of Dipyridamole as a vasodilator (coronary use) was called the "coronary Steal "phenomenon observed. "Coronary steal "means that blood within the coronary circulation from an area that already has reduced blood perfusion (ischemic area) in favor of an area that is normal perfused, redistributed, d. H. that another disadvantage the already damaged vessel section towards the non-stenotic vascular sections is present.

According to one Another alternative is in coronary angioplasty In particular, stents used as support structures to the above to avoid mentioned disadvantages.

stents in general, endovascular prostheses or implants, which are used for example for the treatment of stenoses. Stents are also known for their treatment of aneurysms.

stents basically have a support structure suitable is the wall of a vessel in a suitable way support so as to dilate the vessel or to bridge an aneurysm. Be stents to be introduced into the vessel in a compressed state and then expanded at the site to be treated and against the vessel wall pressed. This expansion can, for example, help a balloon catheter. Alternatively, self-expanding Stents known. These are for example made of a super-elastic Metal, such as nitinol, built up.

stents are currently divided into two basic types, the permanent stents and the degradable stents. Durable stents are designed that they are in the vessel for an indefinite Period may remain. Degradable stents, however be in a for a predetermined period of time Dismantled vessel. Preferably, degradable Stents only degraded when the traumatized tissue of the vessel healed and thus the stent does not continue in the vessel lumen must remain.

When degradable stent materials are degradable, for example Metal alloys, polymers or composites that have a sufficient structural Carrying capacity to the vessel lumen over to support a predetermined period, known.

stents however, generally cause a mechanical failure in itself Stimulus on the vessel walls, so that for example, form restenoses by neointimal formation (permanent stents, foreign body effect). To avoid this Stents with long-acting, antiproliferative active ingredients be coated to suppress the neointimal formation. However, one could accumulate in such a medication observe late thrombotic events.

Moreover, in degradable magnesium stents in animal experiments within the first two weeks after implantation a significant loss of diameter of the stent and thus a reduced blood flow has been observed. It is believed that this loss of lumen results in the degradable magnesium stent releasing Mg ²⁺ and OH ^- ions during degradation in the vessel. This peculiarity, which was observed during magnesium degradation in vessels, can be summarized under the keyword "alkalosis". This leads to an increase in the pH and thus to an ion migration. Due to the imbalance in the charge distribution in the cells, it is assumed that the muscle tone and thus the radial pressure on the magnesium stent is increased, leading to premature loss of stent integrity (significant diameter loss).

• Togni M., Windecker St., Cocchia R., Wenaweser P., Cook St., Billinger M., Meier B., Hess O.: Sirolimus-Elutiong Stent Associatet With Paradoxic Coronary Vasoconstriction; J. Am. College Cardiology; Vol. 46; 2; 2005 .

Apart from magnesium-based stents, vasoconstrictions have also been observed with drug-eluting stents.

• Togni M., Windecker St., Cocchia R., Wenaweser P., Cook St., Billinger M., Meier B., Hess O .: Sirolimus Elutiong Stent Associatet With Paradoxic Coronary Vasoconstriction; J. Am. College Cardiology; Vol. 46; 2; 2005 ,

• – der implantierte Magnesium-Stent seine Integrität nicht verliert, bevor die Funktion des Stents nicht mehr physiologisch sinnvoll ist, d. h. bis das traumatisierte Gefäßgewebe (im wesentlichen) verheilt ist,
• – erneute Gefäßverengungen (Restenosen) im Bereich des eingesetzten Stents reduziert werden und/oder
• – die Rate an Spätkomplikationen, insbesondere Spätthrombosen, reduziert wird.

In order for the dilation of the vessels by implants of magnesium stents, so-called stenting, to be successful (long-term), it is an object of the present invention to provide a magnesium stent which should be chosen such that

• The implanted magnesium stent does not lose its integrity until the function of the stent is no longer physiologically meaningful, ie until the traumatized vascular tissue has healed (essentially),
• - Re-vasoconstriction (restenosis) in the area of the inserted stent are reduced and / or
• - The rate of late complications, especially late thrombosis, is reduced.

Summary of the invention:

The This object is achieved by the objects of the independent Claims solved.

Therefore The invention relates to a degradable magnesium stent with comprising a complete or partial coating or consisting of dipyridamole.

• i) der Ballonkatheter ganz oder teilweise mit einer Beschichtung umfassend oder bestehend aus Dipyridamol beschichtet ist und
• ii) der Magnesium-Stent auf Oberfläche des Ballonkatheters, die mit dem Dipyridamol beschichtet ist, gecrimpt ist.

The invention further relates to a medical device comprising an i) balloon catheter and ii) a degradable magnesium stent crimped on it, characterized in that

• i) the balloon catheter is wholly or partially coated with a coating comprising or consisting of dipyridamole, and
• ii) the magnesium stent is crimped on the surface of the balloon catheter coated with the dipyridamole.

As well The invention relates to a use of dipyridamole as a coating on a degradable magnesium stent and / or as a coating a balloon to transport a degradable magnesium stent to improve the integrity of the degradable magnesium stent in the implanted state.

• a) Bereitstellung eines Magnesium-Stent Grundkörpers,
• b) Bereitstellung einer Zubereitung umfassend oder bestehend aus Dipyridamol und einem oder mehreren Lösungsmitteln und
• c) Beschichtung des Magnesium-Stents Grundkörpers aus Schritt a) mit der einer wirksamen Menge der Zubereitung aus Schritt b).

The invention also relates to a method for producing a magnesium stent according to the invention, characterized in that the method comprises or consists of the following steps:

• a) provision of a magnesium stent basic body,
• b) providing a preparation comprising or consisting of dipyridamole and one or more solvents and
• c) coating of the magnesium stent base body from step a) with that of an effective amount of the preparation from step b).

• a) Bereitstellung eines Ballonkatheters,
• b) Bereitstellung einer Zubereitung umfassend oder bestehend aus Dipyridamol und einem oder mehreren Lösungsmitteln,
• c) Beschichtung des Ballonkatheters aus Schritt a) mit der einer wirksamen Menge der Zubereitung aus Schritt b),
• d) Faltung des in Schritt c) beschichteten Ballonkatheters,
• e) Bereitstellung eines Magnesium-Stents und
• f) Crimpen des Magnesium-Stents aus Schritt e) auf den aus Schritt d) gefalteten, beschichteten Ballonkatheter.

Furthermore, the invention relates to a method for producing a medical device according to the invention, characterized in that the method comprises or consists of the following steps:

• a) provision of a balloon catheter,
• b) providing a preparation comprising or consisting of dipyridamole and one or more solvents,
• c) coating the balloon catheter from step a) with an effective amount of the preparation from step b),
• d) folding of the balloon catheter coated in step c),
• e) providing a magnesium stent and
• f) crimping the magnesium stent from step e) onto the coated balloon catheter folded from step d).

• a') Bereitstellung und Falten eines Ballonkatheters,
• b') Bereitstellung einer Zubereitung umfassend oder bestehend aus Dipyridamol und einem oder mehreren Lösungsmitteln,
• c') Beschichtung des gefalteten Ballonkatheters aus Schritt d') mit der einer wirksamen Menge der Zubereitung aus Schritt c'),
• d') Bereitstellung eines Magnesium-Stents und
• e') Crimpen des Magnesium-Stents aus Schritt e) auf den aus Schritt d) gefalteten, beschichteten Ballonkatheter.

An alternative method for producing a medical device according to the invention is characterized in that the method comprises or consists of the following steps:

• a ') providing and folding a balloon catheter,
• b ') providing a preparation comprising or consisting of dipyridamole and one or more solvents,
• c ') coating the folded balloon catheter from step d') with an effective amount of the preparation from step c '),
• d ') providing a magnesium stent and
• e ') crimping the magnesium stent from step e) onto the coated balloon catheter folded from step d).

• a) Bereitstellung eines erfindungsgemäßen degradierbaren Magnesium-Stents und
• b) Implantierung des Magnesium-Stents in einen menschlichen oder tierischen Körper.

Another method for improving the integrity of an implanted magnesium stent is characterized in that the method comprises or consists of the following steps:

• a) providing a degradable magnesium stent according to the invention and
• b) implantation of the magnesium stent in a human or animal body.

• a) Bereitstellung eines erfindungsgemäßen Medizinproduktes und
• b) Implantierung des degradierbaren Magnesium-Stents umfasst in dem Medzinprodukt aus Schritt a) einen menschlichen oder tierischen Körper.

An alternative method for improving the integrity of an implanted magnesium stent is characterized in that the method comprises or consists of the following steps:

• a) providing a medical device according to the invention and
• b) Implantation of the degradable magnesium stent comprises in the medine product of step a) a human or animal body.

preferred Embodiments of the subject invention be in the dependent claims as well as the are presented in the following detailed description and are, if useful, combinable with each other.

Detailed description of the invention:

The present invention is based on the surprising finding that a degradable magnesium stent according to the invention or one with a medical device according to the invention implantable (inventive) degradable Magnesium stent has improved integrity in the implanted State, d. H. in the physiologically relevant time until the healing of the traumatized vascular tissue no significant Diameter loss after implantation, at the same time reduced Has late thrombosis rate and thus the risk of renewed Vascular constriction is also reduced.

Dipyridamole is believed to be responsible for its vasodilating and antivasoconstrictive properties (see Sky color et. al., "Dipyridamole Inhibits PDGF and bFGF-induced Vascular Smooth Muscle Cell Proliferation", Kidney International, Vol. 52 (1997), p. 1671-1677 ) counteracts the vascular spasm in the region of the implanted degradable magnesium stents and thus improves the integrity of the degradable magnesium stent. Since dipyridamole is administered spatially limited on the magnesium stent or on the angioplasty balloon of the medical device, surprisingly no coronary steal phenomenon was observed.

It is further assumed that dipyridamole is also known for its platelet aggregation-inhibiting and antiproliferative properties (see Sky color et. al., ibid. ) on smooth muscle cells causes the reduction of late thrombosis rate and the positive effect on the remodeling of the vessel wall after angioplasty. In terms of remodeling, the difference with the use of drugs that over-emphasize the antiproliferative effect is that it minimizes vascular damage during and after revascularization, especially by sparing the endothelium.

With In other words, there is the advantage of revascularization a dipyridamole-coated according to the invention degradable magnesium stent or medical device in the non-cell damaging Vasodilation, by eliminating vasoconstrictive signal cascades (Countering vasospasm), in combination with Inhibition of platelet aggregation and accompanied by an inhibitory Effect on the neointimal formation without damaging the Endothelium.

vessels, which are suitable for such stent implantations are human or animal blood vessels, in particular Arteries and veins, of which arteries are particularly preferred, Stent implants in coronary arteries are particularly preferred.

in the For purposes of this invention, "vessel lumen" means the Cavity of a suitable blood vessel.

For the purposes of this invention, "elution" or "elution" means that dipyridamole is released from the stent coating (carrier matrix). In a preferred embodiment, the elution time of dipyridamole from the carrier matrix [T _e (D)] corresponds to the degradation time of the magnesium stent according to the invention [T _d (S)]. A corresponding embodiment can be realized in that the magnesium stent according to the invention is partially coated with the polymer matrix. Preferably, dipyridamole elutes over a four month period, more preferably over a period of at least three to eight weeks beginning with the stenting implants.

in the For the purposes of the present invention, the term "degradable Magnesium stent "that the basic body of the magnesium stent in a physiological environment, especially in the vascular system degrades a human or animal body, d. H. Degraded so that the stent is its integrity loses. According to the invention, the magnesium stent degrades only when the function of the stent is no longer physiological makes sense, or is necessary, d. H. if the traumatized tissue the vessel has healed and the stent is no longer must remain in the vessel lumen.

According to the comprises or consists of the degradable magnesium stent or Magnesium stent body made of a biocorrodible Alloy. Under alloy in the present case is a metallic structure understood, whose main components magnesium, iron, zinc or tungsten are. The main component is the alloy component, its weight fraction highest on the alloy. A share of the main component is preferably more than 50% by weight, more preferably more than 70% by weight. Preferred is a magnesium alloy, wherein Magnesium is the main component.

The Alloy comprising magnesium and iron, zinc and / or tungsten is so in their composition to choose that they are biocorrodible is. Being biocorrodible in the sense of the present invention Alloys referred to where in a physiological environment Degradation takes place, which ultimately leads to the Entire stent or formed from the material part of the stent loses its mechanical integrity.

A magnesium alloy which is preferred according to the invention preferably contains yttrium and other rare earth metals, since such an alloy, in particular also due to its physicochemical properties and its high biocompatibility their degradation products, distinguishes.

Especially preferred are magnesium alloys of the WE series, in particular WE43 and magnesium alloys of the composition rare earth metals 5.5-9.9% by weight, of which yttrium 0.9-5.5% by weight and Balance <1% by weight, the remainder may contain zirconium and / or silicon and wherein Magnesium occupies the 100% by weight missing proportion of the alloy, used. These magnesium alloys already confirmed experimental and in first clinical trials their special Suitability, d. H. they show a high biocompatibility, favorable Processing properties, good mechanical properties and a for the purposes of adequate corrosion behavior. Under the collective term "rare earth metals" present scandium (21), yttrium (39), lanthanum (57) and the 14 at Lanthanum (57) the following elements, namely cerium (58), neodymium (60), promethium (61), samarium (62), europium (63), gadolinium (64), Therbium (65), Dysprosium (66), Holmium (67), Erbium (68), Thulium (69), ytterbium (70) and glutecium (71).

For the purposes of the present invention, all conventional stent geometries can be used as the degradable magnesium stent according to the invention. Particular preference is given to stent geometries which are known in US 6,896,695 . US 2006/241742 . US 5,968,083 (Tenax) EP 1 430 854 (Helix design) US 6,197,047 and EP 0 884 985 to be discribed.

The complete or partial coating comprising or consisting of dipyridamole of an inventive Demodulating magnesium stents is usually considered to be continuous Coating or designed as a point load at discrete locations. Preferably, the abluminal surface, i. H. typically cylindrical stent, the outer cylindrical surface, that is, the tissue facing the tissue and not the vessel lumen Surface, coated. The abluminal dipyridamole coating On the one hand has the advantage that dipyridamole directly to the destination of the tissue can be delivered and no or irrelevant systemic Side effect unfolded. On the other hand has a corresponding preferred dipyridamole coating over a coating additionally on the luminal side a reduced risk Thromboembolie, since at the same time containing active ingredient Coating on both the luminal and the abluminal Side of stents was observed that endothelialization of a stent coated in this way (growth of the stent with vascular cells) slows down until it is prevented and thus increase the risk of thromboembolism. The amount of dipyridamole (TDL) is for a 10 mm long magnesium stent 1-10 mg with 2-3 mg being preferred.

In In another preferred embodiment, the mechanical on Coated most heavily loaded areas. Mechanically loaded Areas are particularly deformed during dilatation. The is mainly on bends and less on longitudinal connectors the case. Alternatively, according to the invention Dipyridamole coating in cavities and holes a designed in a corresponding type stent basic body can be filled or there are dipyridamole depots attached to the magnesium stent body.

Provided Dipyridamole as a pure substance on the magnesium stent body is applied, is first a preparation in one suitable solvents selected from the group consisting of methanol, ethanol, chloroform or dimethyl sulfoxide (DMSO) and then the magnesium stent body coated with this preparation. The coating can according to conventional methods be accomplished. The preparation is preferably spray-coated, by means of single or multi-fluid nozzles, rotary atomization and pressure nozzles, dip-coating, applied by brush, printing etc. If necessary, one can or several coating steps, a conventional drying step or other common physical or chemical post-processing steps, z. As vacuum or plasma treatments, follow before the coated Angioplastieballon is treated further.

• a) schnell resorbierbaren und degradierbaren Materialien: Fette; Lipide, bevorzugt Cholesterin, Cholesterinesther; Saccharide, bevorzugt Alginat, Chitosan, Levan, Hyaluronsäure, Heparin, Dextran, Nitrocellulose bzw. Derivate der Cellulose, Chondroitinsulfat und Carragenan; Fibrin; Albumin; und/oder Polypeptide und deren Derivaten,
• b) langsam resorbierbaren und degradierbaren Polymeren: Polydioxanon; Polyglycolid; Polylactide, bevorzugt Poly-L-Lactid, Poly D,L Lactid, und Copolymere sowie Blends wie Poly(L-Lactid-co-glycolid), Poly(D,L-lactid-co-glycolid), Poly(L-Lactid-co-D,L-Lactid), Poly(L-Lactid-co-trimethylen carbonat)], Poly-E-caprolacton; Di- und Triblockcopolymere der vorstehend genannten Polylactide mit Polyethylenglycol, Polyhydroxyvalerat, Ethylvinylacetat, Polyethylenoxid, Polyphosphorylcholin und Polyhydroxybuttersaure (ataktisch, isotaktisch, syndiotaktisch sowie deren Blends); und/oder Polyorthoesther,
• c) nicht resorbierbaren und dauerhaften Polymeren: Polypropylen; Polyethylen; Polyvinylchlorid; Polyacrylate, bevorzugt Polyetyl- und Polymethylacrylate, Polymethylmetacrylat, Polymethyl-co-ethyl-acrylat und EthylenlEthylacrylat; Polytetrafluorethylen, bevorzugt Ethylen/Chlortrifluorethylen-Copolymere und Ethylen/Tretrafluorethylen-Copolymere; Polyamide, bevorzugt Polyamidimid, Polyamid 11 (PA-11), Polyamid 12 (PA-12), Polyamid 46 (PA-46) und Polyamid (PA-66), wobei sich die Polyamide in Shore-Härten, E-Modul und weiteren mechanischen Kennzahlen unterscheiden; Polyetherimid; Polyethersulfon und Blends hiervon; Polyphenylsulfone und Blends hiervon; Poly(iso)butylen; Polyether-etherketon (PEEK) und Blends hiervon, bevorzugt mit Polyethersulfon (PES); Polyvinylchlorid; Polyvinylfluorid; Polyvinylalkohol; Polyvinylacetat; Polyurethan; Polybuthylenterephthalat; Silikone; Polyphosphazen; Polymerschäume, bevorzugt aus Carbonaten und Styrolen; Copolymere oder Blends der vorstehend genannten Polymerklassen und/oder Polymere aus der Klasse der Thermoplaste und Elastomere.

According to a further preferred embodiment, the coating of the magnesium stent according to the invention additionally comprises one or more polymers selected from the group consisting of:

• a) rapidly absorbable and degradable materials: fats; Lipids, preferably cholesterol, cholesterol esters; Saccharides, preferably alginate, chitosan, levan, hyaluronic acid, heparin, dextran, nitrocellulose or derivatives of cellulose, chondroitin sulfate and carragenan; Fibrin; Albumin; and / or polypeptides and their derivatives,
• b) slowly resorbable and degradable polymers: polydioxanone; polyglycolide; Polylactides, preferably poly-L-lactide, poly D, L lactide, and copolymers and blends such as poly (L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (L-lactide) co-D, L-lactide), poly (L-lactide-co-trimethylene carbonate)], poly-E-caprolactone; Di- and triblock copolymers of the abovementioned polylactides with polyethylene glycol, polyhydroxyvalerate, ethylvinyl acetate, polyethylene oxide, polyphosphorylcholine and polyhydroxybutyric acid (atactic, isotactic, syndiotactic and their blends); and / or polyorthoesther,
• c) non-resorbable and durable polymers: polypropylene; polyethylene; polyvinyl chloride; Polyacrylates, preferably polyethyl and polymethyl acrylates, polymethyl methacrylate, polymethyl co-ethyl acrylate and ethylene-ethyl acrylate; Polytetrafluoroethylene, preferably ethylene / chlorotrifluoroethylene copolymers and ethylene / tetrafluoroethylene copolymers; Polyamides, preferably polyamide-imide, polyamide 11 (PA-11), polyamide 12 (PA-12), polyamide 46 (PA-46) and polyamide (PA-66), where the polyamides in Shore hardness, modulus of elasticity and others distinguish mechanical characteristics; polyetherimide; Polyethersulfone and blends thereof; Polyphenylsulfones and blends thereof; butylene poly (iso); Polyether ether ketone (PEEK) and blends thereof, preferably with polyethersulfone (PES); polyvinyl chloride; polyvinyl fluoride; polyvinyl alcohol; polyvinyl acetate; polyurethane; polybutylene terephthalate; silicones; polyphosphazene; Polymer foams, preferably from carbonates and styrenes; Copolymers or blends of the abovementioned classes of polymers and / or polymers of the class of thermoplastics and elastomers.

Advantageous on the polymer coating of the invention Magnesium stents is that by the selection of polymers the absorption or Degradationgeschwindigkeit of the coating can be controlled.

Provided alternatively dipyridamole as a pure substance on the inventive Magnesium stent present, so the invention Magnesium stent preferably additionally comprising a topcoat or consisting of one or more poly-para-xylylenes (parylenes) on. In a particularly preferred embodiment, the or Pairs of topcoats selected from the group from Parylene N, Parylene C and / or Parylene D, very particularly preferred Parylene C is used as topcoat. By the deposition of the parylene From the gas phase, even geometrically demanding forms can be coated. In addition, it can be over the duration Adjust the tightness of the top coat of the coating. The material is thermally split and at room temperature under especially deposited magnesium suitable conditions. First at longer coating time, the layer becomes impermeable. Short coating times cause pinholes (leaks) on, which allow the diffusion of water or gases.

For the medical device according to the invention will be suitable Balloon catheter used to make magnesium stents in a human or to implant animal body.

Of the degradable magnesium stent, for the inventive Medical device has a magnesium stent body as described above. Preference is given to an inventive Magnesium stent also for the invention Medical device used.

In a preferred embodiment, an inventive Medical device additionally a protector tube, around the dipyridamole coating on the balloon catheter and if necessary on the magnesium stent before and during implantation to protect.

Prefers is used to produce a medical device according to the invention first a suitable, possibly pre-dilated Balloon catheter provided (step a). The balloon catheter is common in the range of 1.5-5 bar, preferably in the range of 3 up to 4 bar predilated. The pre-dilation makes it possible evenly coat the balloon catheter. The coating with the active ingredient is carried out by dissolving of the active ingredient in methanol or ethanol (and others) (step b). Dry and balloon fold after venting (step c). After balloon folding, large areas are prone to abrasion protected.

Of Further, a preparation comprising or consisting of dipyridamole and one or more suitable solvents (Step b). Suitable solvents are preferably selected from the group consisting of methanol, ethanol, chloroform and / or Dimethyl sulfoxide (DMSO).

In Another preferred embodiment comprises the dipyridamole preparation additionally selected one or more carrier substances from the group consisting of maltodextrin, gelatin, trimethyl citrate and / or hyaluronic acid. The vehicles have doing different tasks like: delay and extension the release, reduction of the loss by abrasion or improvement the drug intake or transport to the vessel wall.

Subsequently becomes the balloon catheter of step a) with an effective amount the dipyridamole preparation from step b) coated. The coating The surface of the balloon may become normal Procedure be accomplished. The preparation is preferred by means of spray coating, by means of single or multi-fluid nozzles, Rotary atomization and pressure nozzles, dipping method ("Dip-coating"), by brush, printing etc. applied.

Possibly may be a common one or more coating steps Drying step or other usual physical or chemical post-processing steps, eg. B. vacuum or plasma treatments, before continuing to treat the coated balloon catheter.

Optionally, after drying, the coated balloon catheter is literally folded (Step d) and a provided magnesium stent (Step e) is crimped onto the coated balloon catheter, ie, placed on the balloon catheter in a non-displaced manner (Step f).

In Another preferred embodiment of the protector tube to protect the dipyridamole coating over the with the Crimped (inventive) magnesium stent coated balloon catheter coated.

The Drug loading of the balloon catheter with dipyridamole is usually in the range of 10-60% by weight, preferably in the range of 20-30% by weight each based on the total weight of the coated balloon catheter.

The Active substance amount of dipyridamole (TDL) is usually for a 13 mm long balloon catheter in the range of 1-10 mg, preferably in the range of 2-3 mg.

Here may also be the preferred embodiments of the invention Magnesium stents and / or of the invention Medical device can be applied.

In A preferred embodiment is the balloon catheter first folded before using the dipyridamole preparation usually is coated. Preferably, the dipyridamole solution applied by dip-coating on the folded balloon catheter. Advantageous to this embodiment of the invention is that in this case the fact is exploited that the coating material, So dipyridamole, also penetrates into the balloon folds and thus the Amount of dipyridamole can be increased.

In Another preferred embodiment comprises the dipyridamole preparation one or more in addition to the solvents Carrier substances selected from the group consisting from maltodextrin, gelatin, trimethyl citrate and / or hyaluronic acid.

Here may also be the preferred embodiments of the invention Magnesium stents and / or of the invention Medical device can be applied.

For the use according to the invention of dipyridamole as coating can also the inventive preferred embodiments of the magnesium stent and / or the inventive Medical device used. The same applies to the Method for improving the integrity of an implanted Magnesium stents.

embodiments

The The present invention will hereinafter be described by way of example described, however, the scope of the invention Do not limit the item.

1. Degradable magnesium stent on a balloon catheter coated with dipyridamole as a pure substance:

dipyridamole is in methanol (alternatively ethanol, dimethyl sulfoxide (DMSO) and / or Chloroform) and to a 3-4 bar predilated balloon coated. After drying, the balloon is folded properly and after crimping, d. H. safe placement of a Magnesium stents on the balloon catheter, with a protector tube Mistake.

Of the Balloon is pre-dilated with 3 bar and into a saturated one Solution of dipyridamole dipped in ethanol. After drying The balloon is vented and folded back. The fallen balloon is again, with a short residence time (<1 sec), in the Coating solution dipped and dried again.

alternative The already folded balloon can also be determined by suitable methods coated with the dipyridamole preparation. Preferably For this the dipyridamole preparation is coated by means of dip-coating. Advantageous to this embodiment of the invention is that in this case the fact is exploited that the coating material also penetrates into the balloon folds and thus the concentration Dipyridamole is increased.

2. Degradable magnesium stent on a balloon catheter coated with a dipyridamole preparation:

dipyridamole is methanol with a suitable solvent (alternatively Ethanol, dimethyl sulfoxide (DMSO) and / or chloroform) and preferably with one or more carrier substances selected from the group consisting of maltodextrin, gelatin, Trimethyl citrate and / or hyaluronic acid mixed. These Preparation is done on the 3-4 bar pre-dilated balloon applied. After drying, the balloon is folded and with provided a protector tube.

With Hyaluronic acid as auxiliary substance becomes a 2% hyaluron solution submitted and as long a saturated dipyridamole-methanol solution added until just precipitation begins. This coating solution can be folded over the dip well or unfolded balloon.

Advantageous to this invention Embodiment is that in this case the fact is exploited that the coating material also penetrates into the balloon folds and thus the concentration of dipyridamole is increased. After this treatment, the assembly of the degradable magnesium stent follows.

3. Degradable magnesium stent on one coated with dipyridamole as a pure substance and parylene Balloon:

at This variant is in addition to other parylenes in particular Parylene C is preferred as (i) opaque layer or as (ii) layer with Pinholes.

Of the Active substance is applied to the magnesium stent. Very much now vulnerable surface (active ingredient can easily be rubbed off will be brought into the recipient. Here are small metal rakes, which allow an almost non-contact coating. Of the Parylene coating process is started. The duration must be like that that the topcoat is not opaque (pinholes) is present and the active ingredient can diffuse. This should be the parylene layer be thinner than 1.4 microns.

4. Degradable magnesium stent coated with a dipyridamole preparation:

These Coating is analogous to Example 2. The magnesium stent gets involved with the hyaluronic acid dipyridamole solution coated, dried and mounted on the balloon. alternative Also, the finished assembled stent can be complete with balloon over be coated a dip coating.

QUOTES INCLUDE IN THE DESCRIPTION

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Cited patent literature

• US 6896695 [0035]
• US 2006/241742 [0035]
• US 5968083 [0035]
• - EP 1430854 [0035]
• US 6197047 [0035]
• EP 0884985 [0035]

Cited non-patent literature

• - Togni M., Windecker St., Cocchia R., Wenaweser P., Cook St., Billinger M., Meier B., Hess O .: Sirolimus Elutiong Stent Associatet With Paradoxic Coronary Vasoconstriction; J. Am. College Cardiology; Vol. 46; 2; 2005 [0011]
• - Sky color et. al., "Dipyridamole Inhibits PDGF and bFGF-induced Vascular Smooth Muscle Cell Proliferation", Kidney International, Vol. 52 (1997), p. 1671-1677 [0024]
• - Sky color et. al., ibid. [0025]

Claims (15)

Degradable magnesium stent with a complete or partial coating comprising or consisting of dipyridamole. Magnesium stent according to claim 1, characterized in that the coating in addition one or more polymers comprises or consists of selected from the group consisting of: a) rapidly absorbable and degradable materials: fats; Lipids, preferably cholesterol, Esther cholesterol; Saccharides, preferably alginate, chitosan, levan, Hyaluronic acid, heparin, dextran, nitrocellulose or derivatives cellulose, chondroitin sulfate and carragenan; Fibrin; Albumin; and / or polypeptides and their derivatives, b) slowly absorbable and degradable polymers: polydioxanone; polyglycolide; polylactides, preferably poly-L-lactide, poly D, L lactide, and copolymers and blends such as poly (L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (L-lactide-co-D, L-lactide), Poly (L-lactide-co-trimethylene carbonate)], poly-E-caprolactone; di- and triblock copolymers of the aforementioned polylactides Polyethylene glycol, polyhydroxyvalerate, ethylvinylacetate, polyethyleneoxide, Polyphosphorylcholine and polyhydroxybutyric acid (atactic, isotactic, syndiotactic and their blends); and / or polyorthoesther, c) non-resorbable and durable polymers: polypropylene; polyethylene; polyvinyl chloride; Polyacrylates, preferably polyethyl and polymethyl acrylates, polymethyl methacrylate, Polymethyl co-ethyl acrylate and ethylene ethyl acrylate; polytetrafluoroethylene, preferably ethylene / chlorotrifluoroethylene copolymers and ethylene / tetrafluoroethylene copolymers; Polyamides, preferably polyamide-imide, polyamide 11 (PA-11), polyamide 12 (PA-12), polyamide 46 (PA-46) and polyamide (PA-66); polyetherimide; Polyethersulfone and blends thereof; Polyphenyl sulfones and blends thereof; butylene poly (iso); Polyether ether ketone (PEEK) and blends thereof, preferably with polyethersulfone (PES); polyvinyl chloride; polyvinyl fluoride; polyvinyl alcohol; polyvinyl acetate; polyurethane; polybutylene terephthalate; silicones; polyphosphazene; Polymer foams, preferred from carbonates and styrenes; Copolymers or blends of the above mentioned polymer classes and / or polymers from the class of thermoplastics and elastomers. Magnesium stent according to claim 1, characterized in that the wholly or partly with dipyridamole as a pure substance coated magnesium stent comprising a top coat or consisting of one or more poly-para-xylylenes (parylenes) includes or consists of. Magnesium stent according to claim 3, characterized in that the one or more parylene of Topcoats be selected from the group consisting of Parylene N, Parylene C and / or Parylene D. Magnesium stent according to claim 3 or 4, characterized in that the topcoat comprises Parylene C. or consists of. Magnesium stent according to one of preceding claims, characterized in that the Coating comprising or consisting of dipyridamole on the abluminal Surface of the stent is applied. Medical device comprising an i) balloon catheter and ii) a degradable magnesium stent crimped thereon, characterized in that i) the balloon catheter whole or partially with a coating comprising or consisting of dipyridamole is coated and ii) the magnesium stent on the surface of the balloon catheter coated with the dipyridamole, crimped is. Medical device according to claim 7, characterized in that as magnesium stent ii) of the magnesium stent used according to one of claims 1 to 6 becomes. Medical device according to claim 7 or 8, characterized in that the medical device additionally iii) comprises a protector tube. Use of dipyridamole as a coating on a degradable magnesium stent and / or as a coating of a Balloon catheter for transporting a degradable magnesium stent to improve the integrity of the degradable magnesium stent in the implanted state. Method for producing a magnesium stent according to one of claims 1 to 6, characterized characterized in that the method comprises the following steps or it consists of: a) provision of a magnesium stent basic body, b) Providing a preparation comprising or consisting of dipyridamole and one or more solvents and c) coating of the magnesium stent body of step a) with the an effective amount of the preparation of step b). Method for producing a medical device according to one of Claims 7 to 9, characterized in that the method comprises or comprises the following steps: a) provision of a balloon catheter, b) providing a preparation comprising or consisting of dipyridamole and one or more solvents, c) coating the balloon catheter from step a) with an effective amount of the dipyridamole preparation from step b), d) folding the balloon catheter coated in step c), e) providing a magnesium stent and f) crimping the magnesium stent from step e) onto the coated balloon catheter folded from step d). Process for the preparation of a medical device according to one of claims 7 to 9, characterized that the method comprises or consists of the following steps: a ') Providing and folding a balloon catheter, b ') provision a preparation comprising or consisting of dipyridamole and a or more solvents, c ') coating the folded balloon catheter from step a ') with that of an effective Amount of the preparation from step b '), d ') providing a Magnesium and e ') crimping the magnesium from step e') the coated balloon catheter folded from step d '). Process for improving integrity an implanted magnesium stent, characterized in that the method comprises or consists of the following steps: a) Providing a degradable magnesium stent according to a of claims 1 to 6 and b) Implantation of the magnesium stent into a human or animal body. Process for improving integrity an implanted magnesium stent, characterized in that the method comprises or consists of the following steps: a) Provision of a medical device according to a of claims 7 to 9 and b) implantation of the degradable Magnesium stents in the medical device of step a) in a human or animal body.