WO1999016416A2 - Coated medical implants, method for producing them, and use of the same for preventing restenosis - Google Patents

Coated medical implants, method for producing them, and use of the same for preventing restenosis Download PDF

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Publication number
WO1999016416A2
WO1999016416A2 PCT/EP1998/006019 EP9806019W WO9916416A2 WO 1999016416 A2 WO1999016416 A2 WO 1999016416A2 EP 9806019 W EP9806019 W EP 9806019W WO 9916416 A2 WO9916416 A2 WO 9916416A2
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WO
WIPO (PCT)
Prior art keywords
polymer
medical implants
stent
epothilone
active ingredient
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PCT/EP1998/006019
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German (de)
French (fr)
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WO1999016416A3 (en
Inventor
Werner Krause
Original Assignee
Schering Ag
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Publication date
Application filed by Schering Ag filed Critical Schering Ag
Priority to JP2000513554A priority Critical patent/JP2001517543A/en
Priority to EP98952617A priority patent/EP1024842A2/en
Priority to AU10251/99A priority patent/AU1025199A/en
Publication of WO1999016416A2 publication Critical patent/WO1999016416A2/en
Publication of WO1999016416A3 publication Critical patent/WO1999016416A3/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D175/00—Coating compositions based on polyureas or polyurethanes; Coating compositions based on derivatives of such polymers
    • C09D175/04—Polyurethanes
    • C09D175/08—Polyurethanes from polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Definitions

  • the invention relates to agents for the production of coated, drug-delivering medical implants, e.g. Stents, the implants prepared in this way, processes for their preparation and their use for restenosis prophylaxis.
  • coated, drug-delivering medical implants e.g. Stents
  • Implants especially stents, are state of the art (Pschyrembel, clinical dictionary 257th edition, publisher W. de Gruyter). Stents are self-expanding endoprostheses that keep the gait open
  • Enable structures in human or animal bodies e.g. vascular, esophageal, tracheal, bile duct stent. They are used as a palliative measure for narrowing due to occlusion (eg atherosclerosis) or external pressure (eg for tumors).
  • Radioactive stents are used, for example, after vascular surgery or interventional radiological interventions (eg balloon angioplasty) for prophylaxis of restenosis.
  • a stent is known from international patent application WO 94/13268, which gradually releases an active substance in the body.
  • a polymer composition is known from US Pat. No. 5,599,552 which can gel in the body. In solid form, it represents an implant that can gradually release an active ingredient.
  • the object of the present invention is therefore to provide medical implants which are better tolerated than conventional medical implants.
  • the surface of the medical implants is coated with a polymer into which at least one active ingredient based on the epothilone base, e.g. Epothilon A or B or a derivative of epothilone, as well as possibly other active substances, e.g. thrombosis-preventing substances and / or estrogens and / or corticosteroids are incorporated.
  • Epothilone and its synthesis are known from the literature (Höfle et al., Angew. Chem. 108: 1 671 -3 (1 996), Schinzer et al., Angew. Chem. 1 09: 543-4 (1997)).
  • the active substance epothilone can also be applied directly to the medical implant without a polymer.
  • the device according to the invention thus consists of the medical implant, possibly of a polymer on the surface of the implant and at least one active ingredient from the class of the epothilones.
  • the invention also relates to devices, substances, solutions and containers for the coating of implants according to the invention, for example in the form of a kit. Such kits can be used by the physician on site for the coating of selected implants.
  • the commercially available implants can be used as the base body, for the stents e.g. a Wiktor stent, a Strecker stent or a Palmaz-Schatz stent.
  • suitable polymers are polyurethanes, polylactides, mixed polylactide glycolides or other polymers described in the literature.
  • the implants according to the invention - described with the aid of stents - can be produced by way of example as follows:
  • An uncoated stent is first coated with a polymer (e.g. a polyurethane, obtainable from the reaction of an amphiphilic polyether, diphenyimethane-4-4'-diisocyanate and butanediol).
  • a polymer e.g. a polyurethane, obtainable from the reaction of an amphiphilic polyether, diphenyimethane-4-4'-diisocyanate and butanediol.
  • a solvent e.g. chloroform
  • Active ingredient epothilone
  • the same solvent for example chloroform or ethyl acetate
  • Another active ingredient can be applied to epothilone derivative.
  • active ingredients are antithrombotic drugs, e.g. Iloprost, estrogens such as ethinyl estradiol or corticoids such as Dexamethasone, Fluocortolon, Difluorcortolon or their esters.
  • An uncoated stent can first be coated with a polymer (e.g. a polyurethane, obtainable from the reaction of an amphiphilic polyether, diphenylmethane-4-4'-diisocyanate and butanediol). This polymer is modified so that it is on the surface
  • Cyclodextrin carries.
  • the polymer is dissolved in a solvent (e.g. chloroform) and the stent is immersed in the polymer solution. After the stent has been removed from the polymer solution, it is dried in a drying chamber at room temperature.
  • the "activation" of the stent now takes place by immersing the modified stent in an aqueous solution of epothilone. The active ingredient is incorporated into the cyclodextrin. The stent is now ready for use.
  • the implants according to the invention achieve the task described in the introduction.
  • the implants according to the invention are physiologically well tolerated.
  • the particular advantage of the implants according to the invention is that the physician can select a stent according to his needs on site and then activate the selected stent by the described method.
  • the few substances and solutions required for this can be delivered prepared accordingly, so that the corresponding medical practitioner only has to immerse the uncoated stent in the given order in the individual solutions.
  • the invention thus also relates to those substances, solutions and preparations (kits) and containers prepared for the method according to the invention.
  • the polymer used is polyurethane, which can be obtained as a chain extender by reacting an amphiphilic polyether, diphenylmethane-4,4'-diisocyanate and butanediol.
  • the stents are coated by immersing them in a 5% chloroform solution of the polymer. Then they are allowed to dry in a clean room drying chamber at room temperature. The average layer thickness is 20 ⁇ m.
  • Epothilon A is coated by immersing the polymer-coated stent in an aqueous solution of Epothilon A (0.5 mg / ml). After drying, the stent is ready for use.
  • the coating of the stent with the polymer and the subsequent coating with epothilone A is carried out as described in Example 1. However, the stent is now alternately immersed in a solution with the polymer and - after drying - in an aqueous solution of Epothilon A. This creates a multi-layer structure. The amount of active ingredient incorporated can be controlled via the number of epothilone-containing layers. The stent is implanted after the last drying cycle.
  • the coating is carried out as described in Example 2. However, the stent is now alternately immersed in a solution with the polymer and - each after drying - in an aqueous solution of epothilone A or lloprost or a solution of an estrogen derivative or corticoid in chloroform.
  • the order of the coating materials can be varied. This creates a multi-layer structure. The amount of active ingredient incorporated can be controlled via the number of the respective layers.
  • the stent is implanted after the last drying cycle.

Abstract

The invention relates to agents for producing coated medical implants which release active substances, e.g., stents, to the implants themselves which are produced in this way, to a method for producing said implants and to the use of the same for preventing restenosis.

Description

Beschichtete medizinische Implantate, Verfahren zu Ihrer Herstellung Coated medical implants, process for their manufacture
und ihre Verwendung zur Restenoseprophylaxeand their use for restenosis prophylaxis
Die Erfindung betrifft Mittel zur Herstellung von beschichteten, wirkstoffabgebenden medizinischen Implantaten, z.B. Stents, die so präpararierten Implantate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Restenoseprophylaxe.The invention relates to agents for the production of coated, drug-delivering medical implants, e.g. Stents, the implants prepared in this way, processes for their preparation and their use for restenosis prophylaxis.
Stand der TechnikState of the art
Implantate, vor allem Stents sind Stand der Technik (Pschyrembel, Klinisches Wörterbuch 257. Auflage, Verlag W. de Gruyter) . Stents sind selbstexpandierende Endoprothesen, die die Offeπhaltung gangartigerImplants, especially stents, are state of the art (Pschyrembel, clinical dictionary 257th edition, publisher W. de Gruyter). Stents are self-expanding endoprostheses that keep the gait open
Strukturen in Körpern von Menschen oder Tieren ermöglichen (z.B. Gefäß-, Ösophagus-, Trachea-, Gallengangstent). Sie werden als palliative Maßnahme bei Verengungen durch Verschluß (z.B. Atherosklerose) oder Druck von außen (z.B. bei Tumoren) verwendet. Radioaktive Stents werden beispielsweise nach gefäßchirurgischen oder interventionell radiologischen Eingriffen (z.B. Ballonangioplastie) zur Restenoseprophylaxe eingesetzt. So ist z.B. aus der Internationalen Patentanmeldung WO 94/13268 ein Stent bekannt, der im Körper nach und nach einen Wirkstoff freisetzt. Aus dem Patent US 5,599,552 ist eine Polymerzusammensetzung bekannt, die im Körper gelieren kann. In fester Form stellt sie ein Implantat dar, das nach und nach einen Wirkstoff freisetzen kann.Enable structures in human or animal bodies (e.g. vascular, esophageal, tracheal, bile duct stent). They are used as a palliative measure for narrowing due to occlusion (eg atherosclerosis) or external pressure (eg for tumors). Radioactive stents are used, for example, after vascular surgery or interventional radiological interventions (eg balloon angioplasty) for prophylaxis of restenosis. For example, a stent is known from international patent application WO 94/13268, which gradually releases an active substance in the body. A polymer composition is known from US Pat. No. 5,599,552 which can gel in the body. In solid form, it represents an implant that can gradually release an active ingredient.
Es besteht nun das Problem, daß das medizinische Implantat für den Organismus einen Fremdkörper darstellt und es zu Unverträglichkeitsreaktionen kommt.There is now the problem that the medical implant represents a foreign body for the organism and there are intolerance reactions.
Aufgabe der vorliegenden Erfindung ist es daher, medizinische Implantate zur Verfügung zu stellen, die besser verträglich sind als herkömmliche medizinische Implantate.The object of the present invention is therefore to provide medical implants which are better tolerated than conventional medical implants.
Diese Aufgabe wird durch die nachfolgend beschriebenen medizinischen Implantate gelöst, wie sie in den Patentansprüchen gekennzeichnet sind .This object is achieved by the medical implants described below, as characterized in the claims.
Beschreibung der ErfindungDescription of the invention
Die oben geschilderte Aufgabe wird erfindungsgemäß dadurch gelöst, daß die Oberfläche der medizinischen Implantate mit einem Polymer beschichtet wird, in das mindestens ein Wirkstoff auf der Bais von Epothilon, z.B. Epothilon A oder B oder ein Derivat von Epothilon, sowie eventuell weitere Wirkstoffe, wie z.B. thromboseverhindernde Substanzen und/oder Ostrogene und/oder Kortikosteroide eingearbeitet sind . Epothilon und seine Synthese sind aus der Literatur bekannt (Höfle et al., Angew. Chem. 108: 1 671 -3 ( 1 996), Schinzer et al., Angew. Chem. 1 09: 543-4 ( 1997)) . In einer besonderen Ausführungsform der Erfindung kann der Wirkstoff Epothilon auch ohne Polymer direkt auf das medizinische Implantat aufgebracht werden.The object described above is achieved according to the invention in that the surface of the medical implants is coated with a polymer into which at least one active ingredient based on the epothilone base, e.g. Epothilon A or B or a derivative of epothilone, as well as possibly other active substances, e.g. thrombosis-preventing substances and / or estrogens and / or corticosteroids are incorporated. Epothilone and its synthesis are known from the literature (Höfle et al., Angew. Chem. 108: 1 671 -3 (1 996), Schinzer et al., Angew. Chem. 1 09: 543-4 (1997)). In a special embodiment of the invention, the active substance epothilone can also be applied directly to the medical implant without a polymer.
Die erfindungsgemäße Vorrichtung besteht somit aus dem medizinischen Implantat, evtl. aus einem Polymer auf der Oberfläche des Implantats und mindestens einem Wirkstoff aus der Klasse der Epothilone. Die Erfindung betrifft aber auch Vorrichtungen, Substanzen, Lösungen und Behältnisse für die erfindungsgemäße Beschichtung von Implantaten, z.B. in Form eines Kits. Derartige Kits können vom Mediziner vor Ort für die Beschichtung von ausgewählten Implantaten verwendet werden.The device according to the invention thus consists of the medical implant, possibly of a polymer on the surface of the implant and at least one active ingredient from the class of the epothilones. However, the invention also relates to devices, substances, solutions and containers for the coating of implants according to the invention, for example in the form of a kit. Such kits can be used by the physician on site for the coating of selected implants.
Als Grundkörper können die handelsüblichen Implantante verwendt werden, bei den Stents z.B. ein Wiktor-Stent, ein Strecker-Stent oder ein Palmaz- Schatz Stent.The commercially available implants can be used as the base body, for the stents e.g. a Wiktor stent, a Strecker stent or a Palmaz-Schatz stent.
Als Polymere kommen beispielsweise Polyurethane, Polylactide, gemischte Polylactid-glycolide oder andere, in der Literatur beschriebene Polymere in Betracht.Examples of suitable polymers are polyurethanes, polylactides, mixed polylactide glycolides or other polymers described in the literature.
Die erfindungsgemäßen Implantate - beschrieben an Hand von Stents - können beispielhaft folgendermaßen hergestellt werden:The implants according to the invention - described with the aid of stents - can be produced by way of example as follows:
1 .1 Ein unbeschichteter Stent wird zunächst mit einem Polymer (z.B. ein Polyurethan, erhältlich aus der Reaktion eines amphiphilen Polyethers, Diphenyimethan-4-4'-diisocyanat und Butandiol) beschichtet. Dazu wird das Polymer in einem Lösemittel (z.B. Chloroform) gelöst und der Stent in die Polymerlösung eingetaucht. Nach Entnahme des Stents aus der Polymeriösung wird er in einer Trockenkammer bei Raumtemperatur getrocknet. Anschließend wird der Stent in eine Lösung von Epothilon A in Ethylacetat getaucht und getrocknet.1 .1 An uncoated stent is first coated with a polymer (e.g. a polyurethane, obtainable from the reaction of an amphiphilic polyether, diphenyimethane-4-4'-diisocyanate and butanediol). To do this, the polymer is dissolved in a solvent (e.g. chloroform) and the stent is immersed in the polymer solution. After the stent has been removed from the polymer solution, it is dried in a drying chamber at room temperature. The stent is then immersed in a solution of Epothilon A in ethyl acetate and dried.
Dieser Prozeß kann - je nach der gewünschten Beladung mit Epothilon - mehrfach wiederholt werden. Der wirkstoffbeladene Stent ist gebrauchsfertig.This process can be repeated several times, depending on the desired loading with epothilone. The active ingredient-loaded stent is ready for use.
1 .2 In einer Variante des Verfahrens nach 1 . 1 wird folgendermaßen vorgegangen: Die Beschichtung mit Polymer und Wirkstoff erfolgt abwechselnd, so daß abwechselnd Schichten mit Polymer und Epothilon entstehen.1 .2 In a variant of the method according to 1. 1 is carried out as follows: The coating with polymer and active ingredient takes place alternately, so that layers with polymer and epothilone alternate.
1 .3. Eine weitere Möglichkeit besteht darin, das Polymer und den1 .3. Another possibility is the polymer and the
Wirkstoff, Epothilon, im selben Lösungsmittel, z.B. Chloroform oder Ethylacetat zu lösen und so in einem Schritt auf den Stent aufzubringen. 1 .4. In einer weiteren Variante kann zusätzlich zu Epothilon oder einemActive ingredient, epothilone, in the same solvent, for example chloroform or ethyl acetate, and thus applied to the stent in one step. 1 .4. In a further variant, in addition to epothilone or a
Epothilon-Derivat ein anderer Wirkstoff aufgebracht werden. Beispiele für andere Wirkstoffe sind thromboseverhindernde Arzneimittel, wie z.B. Iloprost, Ostrogene, wie zum Beispiel Ethinylöstradiol oder Kortikoide, wie z.B. Dexamethason, Fluocortolon, Difluorcortolon oder deren Ester.Another active ingredient can be applied to epothilone derivative. Examples of other active ingredients are antithrombotic drugs, e.g. Iloprost, estrogens such as ethinyl estradiol or corticoids such as Dexamethasone, Fluocortolon, Difluorcortolon or their esters.
2.1 Ein unbeschichteter Stent kann zunächst mit einem Polymer (z.B. ein Polyurethan, erhältlich aus der Reaktion eines amphiphilen Polyethers, Diphenylmethan-4-4'-diisocyanat und Butandiol) beschichtet werden. Dieses Polymer ist derartig modifiziert, daß es an der Oberfläche2.1 An uncoated stent can first be coated with a polymer (e.g. a polyurethane, obtainable from the reaction of an amphiphilic polyether, diphenylmethane-4-4'-diisocyanate and butanediol). This polymer is modified so that it is on the surface
Cyclodextrin trägt. Das Polymer wird in einem Lösemittel (z.B. Chloroform) gelöst und der Stent in die Polymerlösung eingetaucht. Nach Entnahme des Stents aus der Polymerlösung wird er in einer Trockenkammer bei Raumtemperatur getrocknet. Die "Aktivierung" des Stents erfolgt nun dadurch, daß der derartig modifizierte Stent in eine wäßrige Lösung von Epothilon getaucht wird . Dabei wird der Wirkstoff in das Cyclodextrin eingebaut. Der Stent ist nun gebrauchsfertig .Cyclodextrin carries. The polymer is dissolved in a solvent (e.g. chloroform) and the stent is immersed in the polymer solution. After the stent has been removed from the polymer solution, it is dried in a drying chamber at room temperature. The "activation" of the stent now takes place by immersing the modified stent in an aqueous solution of epothilone. The active ingredient is incorporated into the cyclodextrin. The stent is now ready for use.
Die oben beschriebenen Verfahren werden im allgemeinen bei Temperaturen von 0-80°C durchgeführt. Bei der Beschichtung des Stents mit dem Polymer können in Abhängigkeit von dem jeweiligen Polymer Lösemittel eingesetzt werden. Bei Einsatz eines nichtwäßrigen Lösemittels soll dieses vor der Implantation entfernt werden.The processes described above are generally carried out at temperatures of 0-80 ° C. Depending on the polymer, solvents can be used to coat the stent with the polymer. If a non-aqueous solvent is used, it should be removed before implantation.
Die nötigen Arbeitsgänge zur Durchführung der oben prinzipiell beschriebenen Verfahren sind dem Fachmann bekannt. Spezielle Ausführungsformen sind detailliert in den Beispielen beschrieben.The person skilled in the art is familiar with the necessary operations for carrying out the methods described in principle above. Specific embodiments are described in detail in the examples.
Die erfindungsgemäßen Implantate lösen die eingangs beschriebene Aufgabe. Die erfindungsgemäßen Implantate sind physiologisch gut verträglich. Der besondere Vorteil der erfindungsgemäßen Implantate ist, daß der Mediziner vor Ort einen Stent nach seinen Bedürfnissen auswählen und den ausgewählen Stent dann durch das beschriebene Verfahren aktivieren kann. Die wenigen dazu nötigen Stoffe und Lösungen können entsprechend vorbereitet angeliefert werden, so daß der entsprechende Mediziner nur noch den unbeschichteten Stent in der vorgegebenen Reihenfolge in die einzelnen Lösungen tauchen muß. Die Erfindung betrifft somit auch solche für die erfindungsgemäßen Verfahren vorbereiteten Stoffe, Lösungen und Zubereitungen (Kits) und Behältnisse. The implants according to the invention achieve the task described in the introduction. The implants according to the invention are physiologically well tolerated. The particular advantage of the implants according to the invention is that the physician can select a stent according to his needs on site and then activate the selected stent by the described method. The few substances and solutions required for this can be delivered prepared accordingly, so that the corresponding medical practitioner only has to immerse the uncoated stent in the given order in the individual solutions. The invention thus also relates to those substances, solutions and preparations (kits) and containers prepared for the method according to the invention.
Ausführungsbeispiele:EXAMPLES
Die folgenden Beispiele sollen den Erfindungsgegeπstand erläutern, ohne ihn auf diese beschränken zu wollen.The following examples are intended to explain the subject matter of the invention, without wishing to restrict it thereto.
Beispiel 1example 1
Als Polymer wird Polyurethan verwendet, das durch Reaktion eines amphiphilen Polyethers, Diphenylmethan-4,4'-diisocyanat und Butandiol als Kettenverlängerer erhältlich ist. Die Stents werden dadurch beschichtet, daß sie in eine 5 %ige Chloroform-Lösung des Polymers eingetaucht werden. Danach läßt man sie einer Reinraum-Trockenkammer bei Zimmertemperatur trocknen. Die durchschnittliche Schichtdicke beträgt 20 μm. Die Belegung mit Epothilon A erfolgt durch Eintauchen des polymerbeschichteten Stents in eine wäßrige Lösung von Epothilon A (0,5 mg/ml) . Nach dem Trocknen ist der Stent gebrauchsfertig.The polymer used is polyurethane, which can be obtained as a chain extender by reacting an amphiphilic polyether, diphenylmethane-4,4'-diisocyanate and butanediol. The stents are coated by immersing them in a 5% chloroform solution of the polymer. Then they are allowed to dry in a clean room drying chamber at room temperature. The average layer thickness is 20 μm. Epothilon A is coated by immersing the polymer-coated stent in an aqueous solution of Epothilon A (0.5 mg / ml). After drying, the stent is ready for use.
Beispiel 2Example 2
Die Beschichtung des Stents mit dem Polymer und die anschließende Beschichtung mit Epothilon A erfolgt wie unter Beispiel 1 beschrieben. Allerdings wird der Stent jetzt abwechselnd in eine Lösung mit dem Polymer und - nach dem Trocknen - in eine wäßrige Lösung von Epothilon A eingetaucht. Dadurch entsteht ein mehrlagiger Aufbau. Die Menge an inkorporiertem Wirkstoff kann über die Anzahl der Epothilon-haltigen Schichten gesteuert werden. Nach dem letzten Trocknungsgang wird der Stent implantiert. The coating of the stent with the polymer and the subsequent coating with epothilone A is carried out as described in Example 1. However, the stent is now alternately immersed in a solution with the polymer and - after drying - in an aqueous solution of Epothilon A. This creates a multi-layer structure. The amount of active ingredient incorporated can be controlled via the number of epothilone-containing layers. The stent is implanted after the last drying cycle.
Beispiel 3Example 3
Die Beschichtung erfolgt wie unter Beispiel 2 beschrieben. Allerdings wird der Stent jetzt abwechselnd in eine Lösung mit dem Polymer und - jeweils nach dem Trocknen - in eine wäßrige Lösung von Epothilon A oder lloprost oder einer Lösung eines Östrogenderivates oder Kortikoids in Chloroform eingetaucht. Die Reihenfolge der Beschichtungsmaterialien (Polymer bzw. Wirkstoff) kann variiert werden. Dadurch entsteht ein mehrlagiger Aufbau. Die Menge an inkorporiertem Wirkstoff kann über die Anzahl der jeweiligen Schichten gesteuert werden. Nach dem letzten Trocknungsgang wird der Stent implantiert. The coating is carried out as described in Example 2. However, the stent is now alternately immersed in a solution with the polymer and - each after drying - in an aqueous solution of epothilone A or lloprost or a solution of an estrogen derivative or corticoid in chloroform. The order of the coating materials (polymer or active ingredient) can be varied. This creates a multi-layer structure. The amount of active ingredient incorporated can be controlled via the number of the respective layers. The stent is implanted after the last drying cycle.

Claims

Patentansprüche claims
1 . Verwendung von Epothilon oder Epothilonderivaten zur Herstellung eines Implantates zur Verhinderung von Restenose.1 . Use of epothilone or epothilone derivatives to produce an implant to prevent restenosis.
2. Medizinische Implantate, dadurch gekennzeichnet, daß sich auf der Oberfläche des Implantats ein Epothilon-Derivat befindet.2. Medical implants, characterized in that there is an epothilone derivative on the surface of the implant.
3. Medizinische Implantate gemäß Anspruch 2, dadurch gekennzeichnet, daß sich auf der Oberfläche des Implantats weitere Wirkstoffe befinden.3. Medical implants according to claim 2, characterized in that there are further active ingredients on the surface of the implant.
4. Medizinische Implantate gemäß Anspruch 2 oder 3, dadurch gekennzeichnet, daß die Implantate entweder aus einem Polymer bestehen oder auf der Oberfläche ein Polymer enthalten, das Epothilon-Derivate und gegebenfalls weitere Wirkstoffe freisetzen kann.4. Medical implants according to claim 2 or 3, characterized in that the implants either consist of a polymer or contain a polymer on the surface which can release epothilone derivatives and optionally other active ingredients.
5. Medizinische Implantate gemäß Anspruch 3, dadurch gekennzeichnet, daß als weiterer Wirkstoff ein Prostaglandinderivat enthalten ist.5. Medical implants according to claim 3, characterized in that a prostaglandin derivative is contained as a further active ingredient.
6. Medizinische Implantate gemäß Anspruch 3, dadurch gekennzeichnet, daß als weiterer Wirkstoff ein Östrogen enthalten ist.6. Medical implants according to claim 3, characterized in that an estrogen is contained as a further active ingredient.
7. Medizinische Implantate gemäß Anspruch 3, dadurch gekennzeichnet, daß als weiterer Wirkstoff ein Kortikoid enthalten ist.7. Medical implants according to claim 3, characterized in that a corticoid is contained as a further active ingredient.
8. Stents, dadurch gekennzeichnet, daß sich auf der Oberfläche des Stents ein Epothilon-Derivat befindet.8. Stents, characterized in that there is an epothilone derivative on the surface of the stent.
9. Stents gemäß Anspruch 8, dadurch gekennzeichnet, daß sich auf der Oberfläche des Implantats weitere Wirkstoffe befinden.9. Stents according to claim 8, characterized in that there are further active ingredients on the surface of the implant.
10. Vorbereiteter Kit zur Beschichtung medizinischer Implantate, dadurch gekennzeichnet, daß ein Epothilonderivat enthalten ist.10. Prepared kit for coating medical implants, characterized in that an epothilone derivative is included.
1 1 . Kit gemäß Anspruch 10, dadurch gekennzeichnet, daß zusätzlich ein Polymer enthalten ist. 1 1. Kit according to claim 10, characterized in that a polymer is additionally contained.
12. Kit gemäß Anspruch 10, dadurch gekennzeichnet, daß zusätzlich ein Lösungsmittel enthalten ist.12. Kit according to claim 10, characterized in that a solvent is additionally contained.
13. Kit gemäß Anspruch 10, dadurch gekennzeichnet, daß zusätzlich ein weiterer Wirkstoff enthalten ist.13. Kit according to claim 10, characterized in that a further active ingredient is additionally contained.
14. Kit gemäß Anspruch 13, dadurch gekennzeichnet, daß als weiterer Wirkstoff ein Prostaglandinderivat, ein Östrogen oder ein Kortikoid enthalten ist. 14. Kit according to claim 13, characterized in that a prostaglandin derivative, an estrogen or a corticoid is contained as a further active ingredient.
PCT/EP1998/006019 1997-09-29 1998-09-24 Coated medical implants, method for producing them, and use of the same for preventing restenosis WO1999016416A2 (en)

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JP2000513554A JP2001517543A (en) 1997-09-29 1998-09-24 Coated medical implant, method for manufacturing the same and use thereof for preventing restenosis
EP98952617A EP1024842A2 (en) 1997-09-29 1998-09-24 Coated medical implants, method for producing them, and use of the same for preventing restenosis
AU10251/99A AU1025199A (en) 1997-09-29 1998-09-24 Coated medical implants, method for producing them, and use of the same for preventing restenosis

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US7922764B2 (en) 2006-10-10 2011-04-12 Celonova Bioscience, Inc. Bioprosthetic heart valve with polyphosphazene

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WO1999016416A3 (en) 1999-08-05
AU1025199A (en) 1999-04-23
EP1024842A2 (en) 2000-08-09
DE19744135C1 (en) 1999-03-25

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