DE102004020856A1 - Medical product coated with biostable layer of polysulfone, useful particularly as stent for preventing restenosis, controls kinetics of release of incorporated active agents, e.g. antiproliferative agents - Google Patents

Medical product coated with biostable layer of polysulfone, useful particularly as stent for preventing restenosis, controls kinetics of release of incorporated active agents, e.g. antiproliferative agents

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Publication number
DE102004020856A1
DE102004020856A1 DE200410020856 DE102004020856A DE102004020856A1 DE 102004020856 A1 DE102004020856 A1 DE 102004020856A1 DE 200410020856 DE200410020856 DE 200410020856 DE 102004020856 A DE102004020856 A DE 102004020856A DE 102004020856 A1 DE102004020856 A1 DE 102004020856A1
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Germany
Prior art keywords
polysulfone
layer
acid
characterized
medical device
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DE200410020856
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German (de)
Inventor
Volker Dr. Faust
Erika Hoffmann
Michael Dr. Hoffmann
Roland Horres
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HEMOTEQ AG, 52146 WüRSELEN, DE
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Hemoteq GmbH
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Priority to DE10345132 priority Critical
Priority to DE10345132.3 priority
Application filed by Hemoteq GmbH filed Critical Hemoteq GmbH
Priority to DE200410020856 priority patent/DE102004020856A1/en
Priority claimed from DE502004005857T external-priority patent/DE502004005857D1/en
Priority claimed from AP200603570A external-priority patent/AP200603570A0/en
Publication of DE102004020856A1 publication Critical patent/DE102004020856A1/en
Priority claimed from ZA2006/02180A external-priority patent/ZA200602180B/en
Application status is Withdrawn legal-status Critical

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    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09DCOATING 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
    • C09D181/00Coating compositions based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing sulfur, with or without nitrogen, oxygen, or carbon only; Coating compositions based on polysulfones; Coating compositions based on derivatives of such polymers
    • C09D181/06Polysulfones; Polyethersulfones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L33/00Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06Use of macromolecular materials
    • A61L33/068Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body

Abstract

The invention relates to medical devices with at least one biocompatible biostable coating of polysulfone, with which the addition of at least one hydrophilic polymer in a suitable amount, the elution kinetics of the applied and / or applied at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombogenic drug controllable and also a spatial separation of various active substances or active substance concentrations with the aid of the layer system of biostable polymers can be achieved, methods for producing these medical devices and their use especially in the form of stents to prevent restenosis.

Description

  • The This invention relates to medical surfaces having a biocompatible, biostable coating of polysulfones and / or polysulfone derivatives or copolymers with polysulfone which contain at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic Contains active substance and / or covered by active substance, process for producing these surfaces as well their use in the form of long-term implants, especially stents for the prevention of restenosis.
  • In Recent years have seen the use of stents in balloon dilatation from closed blood vessels always further spread found. Although stents the risk of a renewed Shrink vessel occlusion, So far, they have not been able to completely complete such restenoses prevent.
  • A exact conceptual description of restenosis is in the literature not to be found. The most common used morphological definition of restenosis is the one after successful PTA (percutaneous transluminal angioplasty) restenosis as a reduction of vessel diameter to less than 50% of the normal one. This is an empirical one fixed value, its hemodynamic Significance and relationship to the clinical symptoms of a solid scientific basis is lacking. In practice, the clinical worsening of a patient as a sign of restenosis of the patient previously treated vessel section considered.
  • There are two different causes for the restenosis caused by the stent:
    • a.) In the first time after implantation, the surface of the stent is directly exposed to the blood and it may come to an acute thrombosis due to the now existing foreign surface, which closes the blood vessel again.
    • b.) Implantation of the stent causes vascular injuries which, in addition to the thrombosis mentioned above, also cause inflammatory reactions that play a decisive role in the healing process in the first seven days. Among other things, the processes involved in this process are associated with the release of growth factors, thus initiating an increased proliferation of smooth muscle cells, thus resulting in a short-term reocclusion of the vessel due to uncontrolled growth.
    • c.) After a few weeks, the stent begins to grow into the tissue of the blood vessel. This means that the stent is completely surrounded by smooth muscle cells and no longer has any contact with the blood. This scarring can be too pronounced (neointimal hyperplasia) and result in not only covering the stent surface, but closing the entire interior of the stent.
  • you has tried in vain to solve the problem of restenosis by coating to dissolve the stents with heparin (J. Whörle et al, European Heart Journal (2001) 22 1808-1816). Heparin addressed as an anticoagulant, however, only the former cause and beyond only in solution to unfold its full effect. This first problem can be solved now medicinal almost completely avoided by the administration of anticoagulants. The second and third problem one tries to solve at the moment, by the growth smooth muscle cells local to the stent. This is e.g. With radioactive stents or stents trying which pharmaceutical Contain active ingredients.
  • So revealed US-A-5,891,108 for example, a hollow shaped stent which may contain in its interior pharmaceutical agents which are released through a plurality of openings in the stent. EP-A-1 127 582 on the other hand, describes a stent which has indentations of 0.1-1 mm depth and 7-15 mm length on its surface, which are suitable for receiving an active substance. These drug reservoirs, similar to the openings in the hollow stent, selectively release the contained pharmaceutical agent in high concentration and over a relatively long period of time, but with the result that the smooth muscle cells are no longer or only very able to retard the stent to envelop. Therefore, the stent is exposed to the blood for much longer, which again leads to increased vascular occlusion by thrombosis (Liistro F., Colombo A., Late acute thrombosis after paclitaxel eluting stent implantation, Heart (2001) 86 262-4).
  • One solution to this problem is the phosphorylcholine coating of Biocompatibles (WO 0101957), in which phosphorylcholine, a cell membrane component of erythrocytes, is said to produce a non-thrombogenic surface on the stent as part of the applied non-biodegradable polymer layer. In this case, the active ingredient depends on the molecular weight of this polymer-containing Phosphorylcholine layer absorbed or adsorbed on the surface.
  • task The present invention is a medical device with a hemocompatible Surface as well a manufacturing process for this medical device with the hemocompatible surface provide.
  • Especially should the hemocompatible surface of the medical device a continuous and controlled ingrowth allow the medical device into the vessel wall.
  • These The object is achieved by the technical teaching of the independent claims of solved present invention. Further advantageous embodiments of the invention will become apparent from the dependent ones claims, the description, the figures and the examples.
  • The The present invention relates to medical devices whose surface (s) at least partially with at least one biostable layer of polysulfone is coated (are).
  • It has been surprising proved that the coating of medical surfaces in Constant blood contact, with polysulfone, polyethersulfone and / or polyphenylsulfone and its derivatives are extremely good suitable biocompatible carrier for active ingredients represents. By admixture of hydrophilic biocompatible polymers let yourself the pore size of the polysulfone matrix vary so that over this one Variety of possibilities in terms of the active ingredients used, their usable amount as well as the desired Release rate allows become. In particular, the elution kinetics of the at least one Active ingredient over the pore size in the biostable layer is regulated. The pore size is again determined by Art and amount of the hydrophilic polymer used.
  • About the Formation of copolymers can be also vary the hydrophilicity or hydrophobicity of the polysulfone. For example, polysulfone copolymers with 4,4'-bis (hydroxylphenyl) pentanoic acid (BPA) synthesize, so that carboxyl side groups are introduced in this way, which lower the hydrophobicity of the polysulfone skeleton. There is also now the possibility introduced functional groups, for example, to derivatize the carboxyl group (Macrom Chem Phys 195 (1994), 1709, Coll Polym Sci 279 (2001), 727).
  • About the possibility the construction of at least two layers of variable in its composition Polymer can be also a layer-dependent Differentiation with respect to the active ingredients used as well as in terms of concentration. This adaptability draws the polysulfone matrix as a universally applicable biostable Coating material for the prevention of restenosis.
  • A thermoplastic polysulfone is prepared from bisphenol A and 4,4'-dichlorophenylsulfone via polycondensation reactions.
    Figure 00040001
    Poly [oxy-1,4-phenylene-sulfonyl-1,4-phenylene-oxy (4,4'-isopropylidene-diphenylene)]
  • The polysulfones which can be used for the coating according to the invention have the following general structure:
    Figure 00040002
    wherein
    x means the degree of polymerization which is in the range of x = 10 to x = 10,000, preferably in the range of x = 20 to x = 3,000, more preferably in the range of x = 40 to x = 1,000, more preferably in the range of x = 60 to x = 500, more preferably in the range of x = 80 to x = 250 and particularly preferably in the range of x = 100 to x = 200.
  • Further is preferred if x lies in such a range, so that a weight average polymer of 60,000-120,000 g / mol, preferably from 70,000 to 99,000 g / mol, more preferably 80,000 to 97,000, even more preferably from 84,000 to 95,000 and especially preferred from 86,000 to 93,000 g / mol results.
  • moreover is preferred when x is in such a range that for the Number average of the polymer is a range of 20,000-70,000 g / mol, preferably from 30,000-65,000 g / mol, more preferably from 32,000-60,000, even more preferred from 35,000 to 59,000, particularly preferably gives a range of 45,000-58,000 g / mol.
  • y and z are integers ranging from 1 to 10, and R and R 'are independently one Alkylene group having 1 to 12 carbon atoms, an aromatic group having 6 to 20 carbon atoms, a heteroaromatic group having 2 to 10 carbon atoms, a cycloalkylene group having 3 to 15 Carbon atoms, an alkylene arylene group having 6 to 20 carbon atoms, an arylenealkylene group having 6 to 20 carbon atoms, an alkyleneoxy group having 1 to 12 carbon atoms, an aryleneoxy group having 6 to 20 carbon atoms, a heteroarylenoxy group having 6 to 20 carbon atoms, a Cycloalkylenoxygruppe having 3 to 15 carbon atoms, a Alkylenarylenoxygruppe having 6 to 20 carbon atoms or an arylenealkyleneoxy group with 6 to 20 carbon atoms. The aforementioned groups can further Wear substituents, in particular those described below under "substituted" polysulfones are.
  • Examples of the groups R and R 'are -R 1 -, -R 2 -, -R 3 -, -R 4 -, -R 5 -, -R 6 -, -R 1 -R 2 -, -R 3 R 4 , R 5 R 6 , R 1 R 2 R 3 , R 4 R 5 R 6 , R 1 R 2 R 3 R 4 , R 1 -R 2 -R 3 -R 4 -R 5 - as well as -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -;
    where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently of one another are the following groups:
    -CH 2 -, -C 2 H 4 -, -CH (OH) -, -CH (SH) -, -CH (NH 2 ) -, -CH (OCH 3 ) -, -C (OCH 3 ) 2 - , -CH (SCH 3 ) -, -C (SCH 3 ) 2 -, -CH (NH (CH 3 )) -, -C (N (CH 3 ) 2 ) -, -CH (OC 2 H 5 ) - , -C (OC 2 H 5 ) 2 -, -CHF-, -CHCl-, -CHBr-, -CF 2 -, -CCl 2 -, -CBr 2 -, -CH (COOH) -, -CH (COOCH 3 ) -, -CH (COOC 2 H 5 ) -, -CH (COCH 3 ) -, -CH (COC 2 H 5 ) -, -CH (CH 3 ) -, -C (CH 3 ) 2 -, - CH (C 2 H 5 ) -, -C (C 2 H 5 ) 2 -, -CH (CONH 2 ) -, -CH (CONH (CH 3 )) -, -CH (CON (CH 3 ) 2 ) - .
    -C 3 H 6 -, -C 4 H 8 -, -C 5 H 9 -, -C 6 H 10 -, cyclo-C 3 H 4 -, cyclo-C 3 H 4 -, cyclO-C 4 H 6 -, cyclO-C 5 H 8 -, -OCH 2 -, -OC 2 H 4 -, -OC 3 H 6 -, -OC 4 H 8 -, -OC 5 H 9 -, -OC 6 H 10 -, -CH 2 O-, -C 2 H 4 O-, -C 3 H 6 O-, -C 4 H 8 O-, -C 5 H 9 O-, -C 6 H 10 O-, -NHCH 2 - , -NHC 2 H 4 -, -NHC 3 H 6 -, -NHC 4 H 8 -, -NHC 5 H 9 -, -NHC 6 H 10 -, -CH 2 NH-, -C 2 H 4 NH-, -C 3 H 6 NH-, -C 4 H 8 NH-, -C 5 H 9 NH-, -C 6 H 10 NH-, -SCH 2 -, -SC 2 H 4 -, -SC 3 H 6 - , -SC 4 H 8 -, -SC 5 H 9 -, -SC 6 H 10 -, -CH 2 S-, -C 2 H 4 S-, -C 3 H 6 S-, -C 4 H 8 S -C 5 H 9 S-, -C 6 H 10 S-,
    -C 6 H 4 -, -C 6 H 3 (CH 3 ) -, -C 6 H 3 (C 2 H 5 ) -, -C 6 H 3 (OH) -, -C 6 H 3 (NH 2 ) -, -C 6 H 3 (Cl) -, -C 6 H 3 (F) -, -C 6 H 3 (Br) -, -C 6 H 3 (OCH 3 ) -, -C 6 H 3 (SCH 3 ) -, -C 6 H 3 (COCH 3 ) -, -C 6 H 3 (COC 2 H 5 ) -, -C 6 H 3 (COOH) -, -C 6 H 3 (COOCH 3 ) -, - C 6 H 3 (COOC 2 H 5 ) -, -C 6 H 3 (NH (CH 3 )) -, -C 6 H 3 (N (CH 3 ) 2 ) -, -C 6 H 3 (CONH 2 ) -, -C 6 H 3 (CONH (CH 3 )) -, -C 6 H 3 (CON (CH 3 ) 2 ) -,
    -OC 6 H 4 -, -OC 6 H 3 (CH 3 ) -, -OC 6 H 3 (C 2 H 5 ) -, -OC 6 H 3 (OH) -, -OC 6 H 3 (NH 2 ) -, -OC 6 H 3 (Cl) -, -OC 6 H 3 (F) -, -OC 6 H 3 (Br) -, -OC 6 H 3 (OCH 3 ) -, -OC 6 H 3 (SCH 3 ) -, -OC 6 H 3 (COCH 3 ) -, -OC 6 H 3 (COC 2 H 5 ) -, -OC 6 H 3 (COOH) -, -OC 6 H 3 (COOCH 3 ) -, - OC 6 H 3 (COOC 2 H 5 ) -, -OC 6 H 3 (NH (CH 3 )) -, -OC 6 H 3 (N (CH 3 ) 2 ) -, -OC 6 H 3 (CONH 2 ) -, -OC 6 H 3 (CONH (CH 3 )) -, -OC 6 H 3 (CON (CH 3 ) 2 ) -,
    -C 6 H 4 O-, -C 6 H 3 (CH 3 ) O-, -C 6 H 3 (C 2 H 5 ) O-, -C 6 H 3 (OH) O-, -C 6 H 3 (NH 2 ) O-, -C 6 H 3 (Cl) O-, -C 6 H 3 (F) O-, -C 6 H 3 (Br) O-, -C 6 H 3 (OCH 3 ) O -, -C 6 H 3 (SCH 3 ) O-, -C 6 H 3 (COCH 3 ) O-, -C 6 H 3 (COC 2 H 5 ) O-, -C 6 H 3 (COOH) O- , -C 6 H 3 (COOCH 3 ) O-, -C 6 H 3 (COOC 2 H 5 ) O-, -C 6 H 3 (NH (CH 3 )) O-, -C 6 H 3 (N ( CH 3 ) 2 ) O-, -C 6 H 3 (CONH 2 ) O-, -C 6 H 3 (CONH (CH 3 )) O-, -C 6 H 3 (CON (CH 3 ) 2 ) O- .
    -SC 6 H 4 -, -SC 6 H 3 (CH 3 ) -, -SC 6 H 3 (C 2 H 5 ) -, -SC 6 H 3 (OH) -, -SC 6 H 3 (NH 2 ) -, -SC 6 H 3 (Cl) -, -SC 6 H 3 (F) -, -SC 6 H 3 (Br) -, -SC 6 H 3 (OCH 3 ) -, -SC 6 H 3 (SCH 3 ) -, -SC 6 H 3 (COCH 3 ) -, -SC 6 H 3 (COC 2 H 5 ) -, -SC 6 H 3 (COOH) -, -SC 6 H 3 (COOCH 3 ) -, - SC 6 H 3 (COOC 2 H 5 ) -, -SC 6 H 3 (NH (CH 3 )) -, -SC 6 H 3 (N (CH 3 ) 2 ) -, -SC 6 H 3 (CONH 2 ) -, -SC 6 H 3 (CONH (CH 3 )) -, -SC 6 H 3 (CON (CH 3 ) 2 ) -,
    -C 6 H 4 S-, -C 6 H 3 (CH 3 ) S-, -C 6 H 3 (C 2 H 5 ) S-, -C 6 H 3 (OH) S-, -C 6 H 3 (NH 2 ) S-, -C 6 H 3 (Cl) S-, -C 6 H 3 (F) S-, -C 6 H 3 (Br) S-, -C 6 H 3 (OCH 3 ) S -, -C 6 H 3 (SCH 3 ) S-, -C 6 H 3 (COCH 3 ) S-, -C 6 H 3 (COC 2 H 5 ) S-, -C 6 H 3 (COOH) S- , -C 6 H 3 (COOCH 3 ) S-, -C 6 H 3 (COOC 2 H 5 ) S-, -C 6 H 3 (NH (CH 3 )) S-, -C 6 H 3 (N ( CH 3 ) 2 ) S-, -C 6 H 3 (CONH 2 ) S-, -C 6 H 3 (CONH (CH 3 )) S-, -C 6 H 3 (CON (CH 3 ) 2 ) S- .
    -NH-C 6 H 4 -, -NH-C 6 H 3 (CH 3 ) -, -NH-C 6 H 3 (C 2 H 5 ) -, -NH-C 6 H 3 (OH) -, - NH-C 6 H 3 (NH 2) -, -NH-C 6 H 3 (Cl) -, -NH-C 6 H 3 (F) -, -NH-C 6 H 3 (Br) -, -NH -C 6 H 3 (OCH 3 ) -, -NH-C 6 H 3 (SCH 3 ) -, -NH-C 6 H 3 (COCH 3 ) -, -NH-C 6 H 3 (COC 2 H 5 ) , -NH-C 6 H 3 (COOH) -, -NH-C 6 H 3 (COOCH 3 ) -, -NH-C 6 H 3 (COOC 2 H 5 ) -, -NH-C 6 H 3 ( NH (CH 3 )) -, -NH-C 6 H 3 (N (CH 3 ) 2 ) -, -NH-C 6 H 3 (CONH 2 ) -, -NH-C 6 H 3 (CONH (CH 3 )) -, -NH-C 6 H 3 (CON (CH 3 ) 2 ) -,
    -C 6 H 4 -NH-, -C 6 H 3 (CH 3 ) -NH-, -C 6 H 3 (C 2 H 5 ) -NH-, -C 6 H 3 (OH) -NH-, C 6 H 3 (NH 2 ) -NH-, -C 6 H 3 (Cl) -NH-, -C 6 H 3 (F) -NH-, -C 6 H 3 (Br) -NH-, -C 6 H 3 (OCH 3 ) -NH-, -C 6 H 3 (SCH 3 ) -NH-, -C 6 H 3 (COCH 3 ) -NH-, -C 6 H 3 (COC 2 H 5 ) -NH -, -C 6 H 3 (CO OH) -NH-, -C 6 H 3 (COOCH 3 ) -NH-, -C 6 H 3 (COOC 2 H 5 ) -NH-, -C 6 H 3 (NH (CH 3 )) - NH-, -C 6 H 3 (N (CH 3 ) 2 ) -NH-, -C 6 H 3 (CONH 2 ) -NH-, -C 6 H 3 (CONH (CH 3 )) - NH-, -C 6 H 3 (CON (CH 3 ) 2 ) -NH-.
  • Particular preference is given to polysulfones in which the groups -R 1 -, -R 2 -, -R 3 -, -R 1 -R 2 -, -R 1 -R 2 -R 3 - independently of one another have the following meanings: -C 6 H 4 O-, -C (CH 3 ) 2 -, -C 6 H 4 -, -C 6 H 4 SO 2 -, -SO 2 C 6 H 4 -, -OC 6 H 4 -, and -C 6 H 4 OC (CH 3 ) 2 -C 6 H 4 -.
  • According to the invention Polysulfone or are the polysulfones for the biostable layer or the biostable layers selected from the group comprising: polyethersulfone, substituted polyethersulfone, polyphenylsulfone, substituted polyphenylsulfone, Polysulfone block copolymers, perfluorinated polysulfone block copolymers, semifluorinated polysulfone block copolymers, substituted polysulfone block copolymers and / or mixtures of the aforementioned polymers.
  • The term "substituted" polysulfones is understood to mean polysulfones which have functional groups. In particular, the methylene units may have one or two substituents and the phenylene units may have one, two, three or four substituents. Examples of these substituents are: -OH, -OCH 3 , -OC 2 H 5 , -SH, -SCH 3 , -SC 2 H 5 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -SOCH 3 , -SOC 2 H 5 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -OCF 3 , -O-COOCH 3 , -O-COOC 2 N 5 , -NH-CO-NH 2 , -NH-CS-NH 2 , -NH-C (= NH) -NH 2 , - O-CO-NH 2 , -NH-CO-OCH 3 , -NH-CO-OC 2 H 5 , -CH 2 F -CHF 2 , -CF 3 , -CH 2 Cl -CHCl 2 , -CCl 3 , - CH 2 Br -CHBr 2 , -CBr 3 , -CH 2 I -CHI 2 , -Cl 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 .
  • polysulfones are characterized by their high resistance to aggressive chemicals from, they are resistant to hydrolysis and heat resistant and have very good mechanical and tribological (no surface abrasion) Properties. As material for The use in the living organism can be considered as more special Features high dimensional stability and multiple sterilizability highlight. Polysulfones have been around as medical polymers ever since long time in use. The main use concentrated on hollow fibers e.g. in blood dialysers, where the polysulfone fiber Fresenius due to its good hemocompatibility and membrane-forming properties prevailed in the global market as a leader Has. The problem of dialysis consists mainly of the Need that during the hemodialysis an anticoagulant, usually heparin, must be added its side effects get out of hand after a few years. During one five-hour treatment flow about 75 liters of blood - this corresponds to about 15 times the amount of blood present in the patient - by the dialyzer. This makes it clear that the membrane is a very high hemocompatibility requirement is placed.
  • One another big one The field is the application of polysulfone capillaries in ophthalmology and in the form of flat membranes in various medical devices.
  • Prefers if that is for the biostable layer used polysulfone at least one hydrophilic polymer is added. It can in the respective polysulfone the relationship from polysulfone to hydrophilic polymer 50 wt% to 50 wt% to 99.999 wt .-% to 0.001 wt .-% amount.
  • Suitable hydrophilic polymers are polyvinylpyrrolidone, glycerol, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylates, polyacrylamide, polyvalerolactones, poly-ε-decalactones, polylactic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly-ε-caprolactone, polyhydroxybutyric acid , Polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly (1,4-dioxane-2,3-diones), poly (1,3-dioxan-2-ones), poly-para-dioxanones, polyanhydrides such as polymaleic anhydrides, fibrin , Polycyanoacrylates, polycaprolactone dimethyl acrylates, poly-b-maleic acid, polycaprolactone butyl acrylates, multiblock polymers such as from oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers such as PEG and poly (butylene terephthalate), polypivotolactones, polyglycolic acid trimethylcarbonates, polycaprolactone glycolides, poly (g-ethylglutamate), poly ( DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminoc arbonate), polyorthoesters, polyglycol-acid trimethyl-carbonates, polytrimethylcarbonates, polyiminocarbonates, poly (N-vinyl) -pyrrolidone, polyvinyl alcohols, polyester amides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxide-propylene oxide, soft polyurethanes, polyurethanes with amino acid residues in the backbone, polyether esters such as polyethylene oxide, polyalkene oxalates, polyorthoesters and their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, modified zein, polyhydroxyalkanoates, pectinic acid, actinic acid, modified and unmodified fibrin and casein, carboxymethylsulfate, albumin, hyaluronic acid, Chitosan and its derivatives, chondroitin sulfate, dextrans, b-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen, collagen N-hydroxysuccinimide, lipids, phospholipids, modifications and copolymers and / or mixtures of the abovementioned substances, wherein polyvinylpyrrolidone, polyethylene glycol and glycerol are preferably used.
  • For example is used to increase the viscosity in the production of the polysulfone solution polyvinylpyrrolidone (PVP) added that while the hollow fiber production in the precipitant soluble is and is removed again. The finished porous hollow fiber contains average still a percentage of 1-2% PVP. The addition of polyvinylpyrrolidone is not just the viscosity while beneficial to production, i.e. acts to increase viscosity, but also the pore size of the polysulfone co-determining factor and thus for the permeability properties of the final product, because this depends on the pore size and particle size. Consequently can be over the Amount and molecular weight of the added polyvinylpyrrolidone the Pore size and thus the permeability regulate the produced polysulfone.
  • The biocompatible and good mechanical properties of polysulfone and the possibility to regulate the pore size by the addition of polyvinylpyrrolidone and / or another hydrophilic Polymer makes this polymer the ideal carrier for all drugs. the to targeted local application, e.g. in cardiology for prevention of vascular restraints, can be used are.
  • The preferred amount of the added polymer is in the range of 0.5-50 % By weight, more preferred are 1-20 Wt .-%, more preferably 2-10% wt .-%. The added Amount depends essentially on the desired elution rate of the active ingredient used.
  • The inventive medical devices have a surface, which can be made of any material. This surface is preferably not hemocompatible. Furthermore, this surface is preferably not coated, in particular not with polymers and / or organic Macromolecules.
  • At this surface The biostable layer of polysulfone can be adhesive or covalent as well partially adhesive and partially covalently bound. The covalent is preferred Connectivity. The layer of polysulfone covers the surface of the Medical device at least partially, but preferably completely. These it is at the medical device to a stent, so at least the surface exposed to the blood the polysulfone coated.
  • On this first biostable layer of polysulfone and / or in this first layer of polysulfone may preferably at least one, at least an antiproliferative, antiinflammatory, antiinflammatory and / or applied antithrombotic drug-containing layer and / or be introduced. The at least one layer containing at least an antiproliferative, antiinflammatory, antiinflammatory and / or antithrombotic drug may be completely off one or more active substances or another layer from biostable polysulfone, wherein the active ingredient or the Agents or, may be a hemocompatible layer, wherein the active ingredient or agents are located.
  • While hydrophobic Active substances in and / or on and / or under a biostable layer can be applied, hydrophilic agents are preferably on and / or applied under a biostable layer.
  • The inventive medical devices can thus surfaces having one, two, three or more layers coated wherein one, two or three layers are preferred and in particular two layers are preferred.
  • Of the or the antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agents may be adhesive or covalent or Part adhesive and partly covalently bound to the respective layer, being the adhesive Binding is preferred.
  • has the surface coating several biostable layers of polysulfone and / or hemocompatible Layers and / or drug layers, these layers can each from different polysulfones with different hydrophilic ones Polymers and different amounts of hydrophilic polymers as well as different hemocompatible compounds or different Active ingredients exist.
  • It is further preferred if the medical device has a surface which comprises a hemocompatible layer which is used up and / or introduced onto or into the lowermost first biostable layer of polysulfone. This hemocompatible layer can also form a second or third layer bil which lies directly or indirectly on the lowest biostable layer and / or on or under an active substance layer or a second biostable polysulfone layer. In addition, it is preferred if the hemocompatible layer forms the lowermost layer and an active substance layer is again covered by a biostable layer of polysulfone or a biostable layer of polysulfone with active ingredient or combination of active substances is applied directly to the lowermost hemocompatible layer.
  • These Hemocompatible layer preferably consists of completely desulfated and N-reacetylated heparin, desulfated and N-reacetylated Heparin, N-carboxymethylated, partially N-acetylated chitosan and / or mixtures of these substances. The hemocompatible layer can in addition to the aforementioned substances also more hemocompatible organic substances, but preferably consists only of the aforementioned substances.
  • Prefers is in the medical devices according to the invention, if a single hemocompatible layer is present. Further is preferred if these a hemocompatible layer the outer or forms the lowest layer.
  • Further it is preferred that a layer be the underlying surface or the underlying layer completely covered, but also a only partial coverage possible is.
  • Further is particularly preferred when it is in the medical device of the invention is about a stent. This stent can be made of any material and material mixtures exist. Preference is given to metals and plastics such as medical grade stainless steel, titanium, chromium, vanadium, Tungsten, molybdenum, Gold and nitinol. Preferably, the stent is uncoated and / or not or only partially hemocompatible. In particular, the stent no coating of organic material. Medical wires can as Medical devices are excluded.
  • These stents according to the invention are preferred with at least one biocompatible complete or incomplete covering the stent Layer of biostable polysulfone with or without a defined Proportion of a hydrophilic polymer and with at least one antiproliferative, anti-inflammatory, provided anti-inflammatory and / or antithrombotic drug. In this case, the active ingredient in the matrix and / or the matrix as the second Layer covering present. The second layer is the one Layer, which is applied to the first layer, etc.
  • A further preferred embodiment the stents according to the invention has a coating consisting of at least two layers Polysulfone exists. According to this Two layer design the first layer consists of a layer which essentially Completely by another biostable layer of the same or different Pore size covered is. One or both layers contains at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agent. As well will also be drug combinations used, which support each other in their effect and / or complete.
  • It exists from this two-layer design the possibility various types Active ingredients separated from each other in each case for the respective active ingredient accommodate suitable layer, so for example, a hydrophobic active substance in the one more hydrophilic layer and holds a has different elution kinetics than that of another hydrophobic one Active substance which is present in the more hydrophobic polymer layer or vice versa. This offers a wide field of possibilities availability to bring the active ingredients into a specific meaningful sequence than also to control the elution time and concentration.
  • A further preferred embodiment the stents according to the invention has a coating consisting of at least three layers consists. According to this Three layer design the first layer consists of a layer which essentially Completely by another second layer of pure active ingredient or drug combinations Completely or incompletely covered is, in turn, by a third biostable polysulfone layer same or different pore size is covered. The polysulfone layers contain either no active ingredient or one or both Matrices for at least one anti-proliferative, anti-inflammatory and / or Antithrombotic drug. Likewise, drug combinations used, which support each other in their effect and / or complete.
  • This embodiment is particularly suitable for the application of hydrophilic active ingredients or drug combinations in the form of a pure drug layer. The overlying biostable polymer layer with a defined content of hydrophilic polymer serves for the controlled elution of the active ingredient. Wirkstoffkom combinations with at least one hydrophilic active ingredient give different elution kinetics.
  • When Topcoat can be also use the hydrophilic polymer, the underlying also Polysulfone may be added.
  • The biocompatible coating of a stent ensures the necessary blood compatibility and the active ingredient (or drug combination) that exceeds the total surface of the stent evenly distributed is, causes the fouling of the stent surface with cells, in particular smooth muscle and endothelial cells, in a controlled manner expires. Thus, there is no rapid colonization and overgrowth of the stent surface Cells that could lead to restenosis, but the growth the stent surface with cells but not by a high drug concentration is completely prevented what the risk of thrombosis with brings.
  • Consequently guaranteed the use of polysulfone, that the active substance or combination of active substances, adhesively bound to the underlying layer and / or adhesive in the Layer stored, continuously and released in small doses so that does not involve the colonization of the stent surface Cells prevented, but over-colonization is prevented. This combination of both effects gives the stent according to the invention the ability, to grow into the vessel wall quickly and reduces both the risk of restenosis and the risk a thrombosis. The release of the active substance (s) extends about one Period from 1 to 24 months, preferably over 1-12 months after implantation, particularly preferred 1-3 Months after implantation.
  • The Release of the active ingredient can be over the Regulation of pore size with the Addition of the polyvinylpyrrolidone or a similar hydrophilic polymer adapting to the individual characteristics of the active substance, the elution rate as well as its pharmacokinetics and more than a drug also the elution order the required requirements can be met.
  • The active substances used are antiproliferative substances, antiphlogistic substances and antithrombotic substances. As antiproliferative agents, cytostatic agents, macrolide antibiotics, and / or statins are preferably used. Applicable antiproliferative agents are sirolimus (rapamycin), everolimus, pimecrolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin , Pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoboside, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxyoxycyclophosphamide estramustine, melphalan, betulinic acid, camptothecin, lapachol, beta-lapachone, podophyllotoxin, betulin, tropfosfamide, podophyllic acid 2-ethylhydrazide, ifosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, tremozolomide, thiotepa, daunorubicin, doxorubicin, aclubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine 5'-dihydrogenphosphate , Mofebutazone, acemetacin, diclofenac, lonazolac dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, β-sitosterol, ademetionin, myrtaincine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, cladribine, mercaptopurine, Thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegasparase, anastrozole, exemestane, letrozole, formestan, aminoglutethemide, adriamycin, Azithromycin, spiramycin, cepharantin, SMC proliferation inhibitor 2w, epothilones A and B, mitoxanthrones, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc antisense selectin (cytokine antagonist) CETP inhibitor, cadherins, cytokine inhibitors, COX 2-inhibitor, NFkB, angiopeptin, ciprofloxacin, camptothecin, fluroblastin, monoclonal antibodies that inhibit muscle z inhibiting proliferation, bFGF antagonists, probucol, prostaglandins, folic acid and derivatives, B-series vitamins, vitamin D derivatives such as calcipotriol and tacalcitol, thymosin α-1, fumaric acid and its derivatives such as dimethyl fumarate, IL-1β inhibitor, Colchicine, NO donors such as pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estrone, estriol, ethinyl estradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, camebakaurin and other terpenoids found in the Verapamil, tyrosine kinase inhibitors (tyrphostins), cyclosporin A, paclitaxel and its derivatives (6-α-hydroxy-paclitaxel, baccatin, taxotere, etc.), synthetically prepared and naturally derived macrocyclic oligomers of carbon dioxide ( MCS) and its derivatives, Molgramostim (rhuGM-CSF), peginterferon α-2b, Lanograstim (r -HuG-CSF), Filgrastim, Macrogol, Dacarbazine, Basiliximab, D aclizumab, ellipticin, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanocine, nocadazole, S100 protein, PI-88, melanocyte stimulating hormone (α-MSH), bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulator, Tissue inhibitor of metal proteinase-1 and 2, free nucleic acids, nucleic acids incorporated in virus carriers, DNA and RNA fragments, plaminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, called IGF-1. Cefadroxil, cefazolin, cefaclor, cefotixine, tobramycin, gentamycin are also used in the group of antibiotics. Penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxoparin, hemoparin ® (desulphated and N-reacetylated heparin), tissue plasminogen, also have a positive influence on the postoperative period. Activator, GpIIb / IIIa platelet membrane receptor, Factor X a inhibitor, activated protein C, antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyramidol, trapidil, nitroprussides, PDGF- Antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, caspase inhibitors, apoptosis inhibitors, apoptosis regulators such as p65, NF-kB and Bcl-xL antisense oligonucleotides and prostacyclin, vapiprost, α, β- and γ-interferon, histamine antagonists, serotonin blockers, halofuginone, nifedipine, tocopherol, tranirast, molsidom in, tea polyphenols, epicatechingallate, epigallocatechin gallate, boswellic acids and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotolol, amidorone. Other drugs include steroids (hydrocortisone, betamethasone, dexamethasone), non-steroidal drugs (NSAIDS) such as fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone and others. Antiviral agents such as acyclovir, ganciclovir and zidovudine are also useful. Various antimycotics find application in this area. Examples are clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine. Antiprozoal agents such as chloroquine, mefloquine, quinine are equally effective agents, as well as natural terpenoids such as hippocaesculin, barringtogenol C21-angelate, 14-dehydroagrostistachine, agroscerin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolides, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2 , B3, Tubeimoside, Bruceanole A, B, C, Bruceantinoside C, Yadanzioside N, and P, Isodeoxyelephantopin, Tomenphantopin A and B, Coronarin A, B, C and D, Ursolic acid, Hyptate A, Zeorin, Iso-Iridogermanal, Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrine, 1,11-Dimethoxycanthin-6-one, 1-Hydroxy-11-Methoxycanthin -6-one, scopolectin, taxamairin A and B, rainilol, triptolide, further cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburine chloride, cictoxin, sinococulin, bastbrestatin A and B, cudraisoflavone A, Cu rcumin, dihydronitidine, nitidinium chloride, 12-beta-hydroxypregnadiene-4,16-diene 3,20-dione, bilobol, ginkgol, ginkgolic acid, helenaline, indicine, indicin-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, Larreatin, Malloterine, Mallotochromanol, Isobutyrylmallotochromanol, Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Oxoushinsunin, Aristolactam-All, Bis-Parthenolidine, Periplocoside A, Ghalacinoside, Ursolic Acid, Deoxypso Sorsmin, Psycorubin, Ricin A, Sanguinarine , Manwuweizsäure, Methylsorbifolin, Sphatheliachromen, Stizophyllin, Mansonin, Streblosid, Akagerin, Dihydrousambaraensin, Hydroxyusambarin, Strychno-pentamin, Strychnophyllin, Usambarin, Usambarensin, Berberine, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol, Umbelliferone, Afromoson, Acetylvismion B, Desacetylvismion A, Vismion A and B, other natural terpenoids such as Hippocaesculin, 14-Dehydroagrostistachin, C-Ty pe Natriuretic Peptide (CNP), Agroscerin, Agrostistachin, 17-Hydroxyagrostistachin, Ovatodiolide, 4,7-Oxycycloanisomic Acid, Yadanziosides N and P, Isodeoxyelephantopin, Tomenphantopin A and B, Coronarin A, B, C and D, Ursolic Acid, Hyptate Acid A , Zeorin, Iso-Iridogermanal, Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin.
  • The Active substances are used singly or in combination in the same or different Concentration used. Particularly preferred are active ingredients which in addition to its antiproliferative effect also immunosuppressive properties exhibit. Such agents include erythromycin, midecamycin, Tacrolimus, sirolimus, paclitaxel and its derivatives, and josamycin. and Trapidil, D-24851, α- and β-estradiol, macrocyclic Carbon suboxide (MCS) and its derivatives, PI-88, sodium salt of 2-methylthiazolidine-1,4-dicarboxylic acid and derivatives, and sirolimus. Also preferred is a combination of several antiproliferative acting Substances or antiproliferative agents with immunosuppressive Agents.
  • The active ingredients are particularly preferably selected from the group comprising: paclitaxel and derivatives thereof, β-estradiol, simvastatin, PI 88 (sulphated oligosaccharide; Progen Ind.), Macrocyclic Kohlensuboxide (MCS) and derivatives thereof, trapidil ®, N- (pyridine- 4-yl) - [1-4- (4-chlorobenzyl) -indol-3-yl] -glyoxylamide (D-24851), tacrolimus.
  • The active ingredient is preferably present at a pharmaceutically active concentration of 0.001-20 mg per cm 2 stent surface, more preferably 0.005-15, and most preferably 0.01-10 mg per cm 2 stent surface. Other active ingredients may be contained in similar concentration in the same or in further layers. Also preferred is an embodiment which comprises two different active ingredients in contains the same layer or in different layers. Furthermore, an embodiment is preferred which has a pure active substance layer as the uppermost layer.
  • The amounts of polymer applied are per medicine product and in particular per stent per layer preferably between 0.01 mg / cm 2 to 3 mg / cm 2 surface, more preferably 0.20 mg to 1 mg and most preferably 0.2 mg to 0.5 mg / cm 2 surface.
  • Prefers are also embodiments, which contain an active ingredient in two layers. You can too be two different agents. Is the same active ingredient in contain two layers, so is preferred if the two layers have a different concentration of active ingredient. Of Another is preferred if the lower layer has a lower active substance concentration as the upper layer.
  • The stents according to the invention can be produced by a method for the biocompatible coating of stents, which is based on the following principle:
    • a. Providing a stent, and
    • b. Applying at least one biostable layer of polysulfone with or without at least one hydrophilic polymer, and
    • c. Applying and / or introducing at least one antiproliferative, antiinflammatory, antiinflammatory and / or antithrombotic active substance onto and / or into the biostable layer, or
    • b '. Applying at least one biostable layer of polysulfone with or without the at least one hydrophilic polymer together with at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agent.
  • After step b 'may preferably still step c' follow:
    • c '. Applying at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agent to the biostable polymer layer.
  • After the steps a, b and c or the steps a, b 'or the steps a, b' and c ', a further step d may follow:
    • d. Applying at least a second biostable layer of polysulfone.
  • These second biostable layer of polysulfone can on the one hand from a consist of polysulfone other than the first underlying layer and on the other hand, another amount of the same or another hydrophilic Contain polymers. It is preferred if this second biostable Layer of polysulfone contains at least one active ingredient. Especially preferred embodiments are with a biostable layer of polysulfone with or without hydrophilic Polymers as external Layer.
  • Of the antiproliferative, antiinflammatory, antiinflammatory and / or Antithrombotic drug is preferred from the group listed above selected.
  • Further are embodiments preferred which have a hemocompatible layer. These hemocompatible Layer consists of the above-mentioned hemocompatible substances, especially from completely Desulfated and N-reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated, partially N-acetylated Chitosan and / or mixtures of these substances and becomes immediate or indirectly applied to the lower biostable layer. These hemocompatible layer can be between two other layers as well as forming the top layer. embodiments with two hemocompatible layers are also possible, but only one hemocompatible layer is preferred. The hemocompatible layer can be adhesive as well as covalent or partly adhesive and partly covalent to the underlying layer are bound.
  • The respective layers are preferably in the dipping or spraying process applied. In addition, the individual layers are preferred only then applied to the underlying layer when dry is.
  • Prefers is a method consisting of the two steps a) and b ').
  • The Coating principle offers a wide variation in terms of requirements on the active substance and also on the properties of the polysulfone used, so that different coating variants resulting, which can also be combined with each other.
  • The possibility the properties of polysulfone over the amount and molecular weight of the added hydrophilic polymer such as PVP in terms of the active ingredients used a wide field of adaptability components to a coordinated system.
  • Further Layers of polysulfone without the addition of PVP and / or the same or differing PVP content with and without active ingredients possible. Likewise leaves a covalently bonded directly to the stent surface preferably Layer off completely N-deacetylated and reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan and / or mixtures of these substances whose athrombogenic properties in violation of the overlying biostable layer or layers, as for example in advance or even while implantation by mechanical destruction of the coating arise can for the Masking the underlying foreign surface care. This inert layer let yourself if required, either covalently or adhesively also between two Layers and / or use as a top layer.
  • Option A:
    • a.) Providing an uncoated stent
    • b.) applying a biostable polysulfone layer with or without hydrophilic polymer
    • c.) application of an active substance or combination of active ingredients in and / or on the polysulfone layer in the dipping or spraying process
    • d.) substantially complete and / or incomplete coating the biostable drug-containing polysulfone layer with at least another biostable polysulfone layer corresponding to the first layer or from this first layer in their content of hydrophilic Polymer and thus different in pore size
    • e.) applying the same or another active substance or a drug combination in and / or on the outer biostable layer, so that targeted different active ingredients and / or drug combinations with Help the two layers placed separately on the stent can be as well as with different pore size of the polymer a different Loading with active ingredient is feasible as well as a different one Elution rate of the same and / or another active ingredient allows becomes.
  • Especially the term "applying" in step c) and / or Step e) "diffusion" of the drug in the respective layer.
  • Prefers are medical devices with two biostable layers of polysulfone, which different hydrophilic polymers in different Concentrations may contain.
  • Also feasible is the application of all intended polymer layers before diffusion of the active substance in these layers, if the same active substance or Combination of active ingredients should be found in both layers.
  • In addition, can be another layer of a suitable polysulfone or the pure hydrophilic polymers as diffusion barrier and topcoat muster.
  • Variant B
    • a.) Providing an uncoated stent
    • b.) applying a biostable polysulfone layer with or without hydrophilic polymer
    • c.) is substantially complete and / or incomplete coating the biostable polymer layer with at least one antiproliferative, anti-inflammatory and / or antithrombotic drug and / or drug combination in the spray process
    • d.) substantially complete and / or incomplete coating the active substance layer with at least one further biostable polysulfone layer, the first layer corresponds to or differs from this first layer their content of hydrophilic polymer and thus in the pore size with or without active ingredient and / or active ingredient combination and / or
    • d '.) essentially complete and / or incomplete coating the drug layer with a hydrophilic polymer as a topcoat with or without active ingredient and / or combination of active ingredients
  • With These variants can be applied, the coating material to the active ingredients and also the time-released amount of active ingredient to the requirements to adapt to the affected segment.
  • at Multilayer systems covered the newly applied layer essentially covers the underlying layer Completely. "Essentially" means to 50 to 100%, preferably 70-100%, more preferably 80-100%, more preferably 90-100% and especially preferred over 96% and more preferably more than 98%.
  • object The invention can also be produced by the aforementioned method Medical devices and in particular stents.
  • The stents according to the invention solve both the problem of acute thrombosis as well as the problem of neointimal hyperplasia after a stent implantation. In addition, the stents according to the invention are suitable due to their coating, whether as a single layer or as a multilayer system, especially good for the continuous release of one or more antiproliferative, antiinflammatory, antiphlogistic, antithrombotic and / or immunosuppressive agents. Because of this ability the targeted continuous drug release in required Amount prevent the inventively coated stents the danger restenosis almost completely.
  • The Prevention or reduction of restenosis on the one hand by suppression the cellular Reactions in the first days and weeks after implantation with Help of the selected Active ingredients and drug combinations and on the other hand by the Providing a biocompatible surface, so with decay of the active ingredient influence no more reactions to the existing foreign surface use, which would also lead in the long term to a reclosure of the blood vessel.
  • figure description
  • 1 : Elimination diagram of macrocyclic carbon suboxide (MCS) in a three-layer system with polysulfone as a base coat, the active agent as the middle layer and a coating of polysulfone completely covering the middle active layer in a proportion of 0.04% polyvinylpyrrolidone.
  • 2 : Elution diagram of paclitaxel from a polysulfone matrix containing 9.1% polyvinylpyrrolidone
  • 3 : Elution diagram of simvastatin from pure polysulfone matrix without proportion of hydrophilic polymer
  • 4 : Elution diagram of β-estradiol with proportionally 15 wt .-% of the pure polysulfone matrix without proportion of hydrophilic polymer
  • 5 Elution diagram of Trapidil from a polysulfone matrix containing 4.5% polyvinylpyrrolidone
  • 6 : Elution diagram of Trapidil with a 50% content of pure polysulfone matrix
  • 7 : Photomicrography of the vascular segments after 4 weeks implantation in the pig.
  • 7A shows the cross section through the segment of a matrix stent without drug.
  • 7B shows a cross section through the vessel segment with the loaded in higher concentration with MCS polysulfone-coated stent.
  • example 1
  • Coating of stents with polyethersulfone
  • spray solution:
    • a. PS solution: 176 mg of PS (polyethersulfone, Odel ®, available from Solvay) are balanced and replenished with chloroform to g 20th → 0.88% horsepower
      Figure 00220001
  • Example 2
  • Coating of stents with polyethersulfone (basecoat) and polyethersulfone with 0.04% PVP or 0.08% PVP as topcoat
  • Spray solutions:
    • a. Polysulfone solution: 17.6 mg PS will be weighed and made up to 2 g with chloroform. → 0.88% horsepower
    • b. Polysulfone / PVP solution: 25.2 mg PS and 1.2 mg PVP are weighed and adjusted to 3 with chloroform g filled. → 0.84% horsepower, 0.04% PVP
    • b '. Polysulfone / PVP solution: 24 mg PS and 2.4 mg PVP are weighed and adjusted to 3 with chloroform g filled. → 0.80% horsepower, 0.08% PVP
  • spray:
  • The weighed stents are mixed with the spray solutions in the order given with a.) 0.5 ml and b.) 0.85 ml spray-coated. It is after every spraying process Waiting at least 6 hours before applying the next coat. After drying at room temperature overnight in the clean room is repeated weighed.
  • Figure 00230001
  • Example 3
  • Production of stents with MCS and polyethersulfone in the 3-layer system according to variant B
  • Spray solutions:
    • a) Polyethersulfone solution: (first layer: basecoat, Basic coat): 70.4 mg of PS are weighed in and with chloroform filled to 8 g. → 0.88% horsepower
    • b) MCS solution (2. Layer: Middlecoat): 39.6 mg of MCS are weighed in and washed with 20% ethanol in water to 18 g. → 0.22% MCS
    • c) polyethersulfone / PVP solution (3rd layer: topcoat): 100.8 mg PS and 4.8 mg polyvinylpyrrolidone are weighed and made up to 12 g with chloroform. → 0.84% horsepower, 0.04% PVP
  • spray:
  • Not Expanded stainless steel stents are weighed after being cleaned and spray-coated. The stents are with the appropriate amount of each spray solution with a) 0.5 ml; b.) 1.5 ml and c.) 0.85 ml in the order given sprayed. It waits at least 6 hours after each shift, before the next Sprayed layer becomes. After drying at room temperature overnight, weigh again. The mean value of the active substance content on the stents is 153 ± 9 μg.
  • Figure 00240001
  • Example 4
  • Determination of the elution kinetics: MCS polyethersulfone with 4.5% PVP
  • ever A stent is placed in a snap-top vial with 2 ml of PBS buffer offset, closed with parafilm and for a given times in a drying oven at 37 ° C incubated. After expiration of the selected Time will be the supernatant pipetted off and its UV absorbance measured at 207 nm. The respective Stent is again mixed with 2 ml of PBS and incubated again at 37 ° C. This process is repeated several times.
  • Example 5
  • Coating of stents with simvastatin-loaded polysulfone matrix
  • Spray solutions:
    • a. PS / simvastatin solution: 26.4 mg PS and 8.8 Simvastatin mg are weighed and made up to 4 g with chloroform. → 0.66% horsepower, 0.22% simvastatin
    • b. PS / Simvastatin / PVP solution: 24.8 mg PS, 8.8 mg simvastatin and 1.6 mg PVP are weighed and made up to 4 g with chloroform. → 0.62% PS, 0.22% simvastatin, 0.04% PVP
      Figure 00250001
  • Example 6
  • Coating of stents with simvastatin-loaded polysulfone matrix with high PVP content
  • spray solution:
    • a. PS / Simvastatin / PVP Solution: Weigh out 23.2 mg PS, 8.8 mg simvastatin and 3.2 mg PVP and make up to 4 g with chloroform. → 0.58% PS, 0.22% simvastatin, 0.08% PVP
      Figure 00250002
  • Example 7
  • Coating of stents with paclitaxel loaded polysulfone matrix matrix
  • Spray solutions:
    • a. PS / paclitaxel solution: 13.2 mg PS and 4.4 mg paclitaxel are weighed in and made up to 2 g with chloroform. → 0.66% horsepower, 0.22% paclitaxel
    • b. PS / PVP / paclitaxel solution: 11.6 mg PS, 1.6 mg PVP and 4.4 mg paclitaxel are weighed and made up to 2 g with chloroform. → 0.58% PS, 0.08% PVP, 0.22% paclitaxel
      Figure 00260001
  • Example 8
  • Coating of stents with 17-β-estradiol in polysulfone matrix
  • Spray solutions:
    • a. PS / 25% 17-β-estradiol - solution: 46.2 mg PS and 15.4 mg 17-β-estradiol are weighed and made up to 7 g with chloroform. → 0.66% horsepower, 0.22% 17-β-estradiol
    • b. PS / 20% 17-β-estradiol solution: 28.2 mg PS and 7 mg 17-β-estradiol are weighed and made up to 4 g with chloroform. → 0.704% PS, 0.176% 17-β-estradiol
    • c. PS / 15% 17-β-estradiol solution: 29.9 mg of PS and 5.3 mg of 17-β-estradiol are weighed out and made up to 4 g with chloroform. → 0.748 hp, 0.132% 17-β-estradiol
      Figure 00260002
  • Example 9
  • Coating of stents with a polyphenol-containing polysulfone matrix
  • spray solution
    • PS / Trapidil solution: 19.8 mg PS and 6.6 mg Trapidil are weighed and made up to 3 g with chloroform. → 0.66% PS, 0.22% Trapidil
      Figure 00270001
  • Example 10
  • in vivo studies stents with polyethersulfone as matrix with and without macrocyclic suboxide
  • In 13 domestic pigs of different sex with 20-25 g weight were in the coronary arteries with polyethersulfone coated stents implanted. A distinction was made between three groups of stents. One group contained a high dose paclitaxel, the second contained a low dosage paclitaxel and the last group was the pure matrix stent without added drugs. After four weeks the stents were removed and for inflammatory reactions (peri-strut) and neointima formation.
  • Figure 00270002
  • All examined stents independently of the coating showed only minimal inflammation around the stent struts and at the Adventitia. The higher one average intimal thickness of stents with low drug loading let themselves on the during the implantation stronger overstretching of the vessel traced. Of the pure matrix stent shows no abnormalities attributable to the polymer in the vascular reactions, what its hemocompatibility and fitness as a drug carrier underlines.
  • Example 11
  • in vivo studies stents with polyethersulfone as a matrix with and without paclitaxel
  • Similar to the previous Example 10, polyethersulfone coated stents were compared to paclitaxel loaded polyethersulfone coated stents:
    Figure 00280001
  • Also The results of this study show the success of polysulfone coating.

Claims (23)

  1. Medical device, characterized in that its surface is at least partially coated with at least one biostable layer of polysulfone.
  2. Medical device according to claim 1, characterized that this Polysulfone selected from the group is comprised of: polyethersulfone, substituted polyethersulfone, Polyphenylsulfone, substituted polyphenylsulfone, polysulfone block copolymers, perfluorinated polysulfone block copolymers, semifluorinated polysulfone block copolymers, substituted Polysulfonblockcopolymere and / or mixtures of aforementioned polymers.
  3. Medical device according to claim 1 or 2, characterized that the at least one biostable layer of polysulfone at least contains a hydrophilic polymer.
  4. Medical device according to claim 3, characterized that the polysulfone with the at least one hydrophilic polymer in a mixing ratio from 50% by weight: 50% by weight to 99.999% by weight: 0.001% by weight.
  5. Medical device according to claim 3 or 4, characterized that the hydrophilic polymer is selected from the group comprising: polyvinylpyrrolidone, glycerol, polyethylene glycol, polypropylene glycol, Polyvinyl alcohol, polyhydroxyethyl methacrylates, polyacrylamide, Polyvalerolactones, poly-ε-decalactones, polylactic acid, polyglycolic acid Polylactides, polyglycolides, copolymers of polylactides and polyglycolides, Poly-ε-caprolactone, polyhydroxybutyric, Polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, Poly (1,4-dioxane-2,3-dione), Poly (1,3-dioxan-2-ones), poly-para-dioxanones, polyanhydrides such as polymaleic anhydrides, Fibrin, polycyanoacrylate, polycaprolactone dimethylacrylate, poly-b-maleic acid, polycaprolactonebutylacrylate, Multiblock polymers of oligocaprolactone diols and oligodioxanonediols, Polyetherester multiblock polymers of PEG and poly (butylene terephthalate), Polypivotolactone, polyglycolic acid trimethyl carbonate, Polycaprolactone-glycolides, poly (g-ethylglutamate), poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminocarbonate), polyorthoesters, polyglycol-acid trimethyl-carbonates, polytrimethylcarbonates, Polyiminocarbonates, poly (N-vinyl) pyrrolidone, polyvinyl alcohols, Polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphazenes, Poly [p-carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydrides, Polyethylene oxide-propylene oxide, soft polyurethanes, polyurethanes with amino acid residues in the backbone, polyether esters, polyethylene oxide, polyalkenoxalates, Polyorthoesters and their copolymers, lipids, carrageenans, fibrinogen, Strength, Collagen, protein-based polymers, polyamino acids, synthetic polyaminoacids, Zein, modified zein, polyhydroxyalkanoates, pectinic acid, actinic acid, modified and unmodified fibrin and casein, carboxymethylsulfate, albumin, hyaluronic acid, Chitosan and its derivatives, chondroitin sulfate, dextrans, b-cyclodextrins, and Copolymers with PEG and polypropylene glycol, gum arabic, guar, Gelatin, collagen collagen N-hydroxysuccinimide, lipids, phospholipids, Modifications and copolymers and / or mixtures of the aforementioned Substances.
  6. Medical device according to claim 5, characterized that the hydrophilic polymer is selected from the group comprising: polyvinyl pyrrolidone, polyethylene glycol, polypropylene glycol and / or glycerin.
  7. Medical device according to one of the preceding claims, characterized characterized in that the pore size of the Polysulfone coating by the mixing ratio of polysulfone with the at least one hydrophilic polymer is determined.
  8. Medical device according to one of the preceding claims, characterized characterized in that in, under and / or on the at least a biostable layer of polysulfone with or without the at least a hydrophilic polymer at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic drug.
  9. Medical device according to one of the preceding claims, characterized characterized in that the biostable layer is adhesively or covalently attached to the surface of the Medical device is bound.
  10. Medical device according to one of the preceding claims, characterized characterized in that the coating of the surface of the medical device one, two, three or more layers.
  11. Medical device according to one of the preceding claims, characterized characterized in that below and / or on the at least one biostable layer of polysulfone with or without the at least a hydrophilic polymer at least one completely desulfated layer and N-reacetylated heparin, desulfated and N-reacetylated Heparin, N-carboxymethylated and / or partially N-acetylated Chitosan and / or mixtures of these substances.
  12. Medical device according to one of the preceding claims, characterized in that the at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agents are selected from the group comprising: sirolimus (rapamycin), everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, Erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoboside, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, C-Type Natriuretic Peptides (CNP), 4-Hydroxyoxycyclophosphamide, Estramustine, Melphalan, Ifosfamide, Tropfosfamide, Chlorambucil, Bendamustine, Dacarbazine, Busulfan, Procarbazine, Treosulfan, Tremozolomide, Thiotepa, Daunorubicin, Doxorubicin, Aclarubicin, Epirubicin, Mitoxantrone, Idarubicin, Bleomycin , Mitomycin, dactinomycin, methot rexate, fludarabine, fludarabine 5'-dihydrogen phosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase , Pegasparase, anastrozole, exemestane, letrozole, formestane, aminoglutethemide, adriamycin, azithromycin, spiramycin, cepharantin, SMC proliferation inhibitor-2w, epothilones A and B, mitoxanthrone, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc Antisense, betulinic acid, camptothecin, lapachol, β-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon α-2b, lanograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab , Daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherins, cytokine inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin, camptothecin, fluroblastin, monoclonal antibodies that are the muscle inhibit cell proliferation, bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, colchicine, NO donors such as pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen , Staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, camebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), Cyclosporin A, paclitaxel and its derivatives such as 6-α-hydroxy-paclitaxel, baccatin, taxotere and others, synthetically prepared and naturally derived macrocyclic oligomers of carbon suboxide (MCS) and its derivatives, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothioma alat, oxaceprol, celecoxib, β-sitosterol, ademetionin, myrtainaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticin, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanocine, nocadazole, S 100 protein, bacitracin, vitronectin Receptor antagonists, azelastine, guanidyl cyclase stimulator, metalloproteinase 1 and 2 tissue inhibitor, free nucleic acids, nucleic acids incorporated in virus carriers, DNA and RNA fragments, plamogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF- Inhibitors, IGF-1, drugs from the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotixine tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxoparin , desulphated and N-reacetylated heparin (hemoparin ®), tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, Fak tor X a -Inhibitor antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as Dipyramidole, trapidil, nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators such as p65 , NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol tranilast, molsidomine, tea polyphenols, epicatechingallate, epigallocatechin gallate, boswellic acids and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin , Procainimide, Retinoic Acid, Quinidine, Disopyrimide, Flecainide, Propafenone, Sotolol, Amidoron., Natural and Synthetically Generated Steroids such as Bryophyllin A, Inotodiol, Maquiroside A, Ghalakinoside, Mansonin, Strebloside, Hydrocortisone, Betamethasone, Dexamethasone, Nonsteroidal Substances (NSAIDS) Fenoporfen, ibuprofen, indomethacin, naproxen, phe nylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, antifungal agents such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, and natural terpenoids such as hippocaelculin, barringtogenol C21-angelate, 14-dehydroagrostistachine, agroscerin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolides, 4,7-oxycycloanisomelic acid, bacchinoids B1, B2, B3 and B7, tubeimoside, bruceanols A, B and C, bruceantinosides C, yadanziosides N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronarine A, B, C and D, ursolic acid, hyptate acid A, zeorine, iso-iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Apocymarin, Aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburine chloride, cictoxin, sinococulin, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidinium chloride, 12-beta-hydroxypregnadiene 3,20-dione, bilobol, ginkgol, ginkgolic acid, helenaline , Indicin, Indicin N-oxide, Lasiocarpine, Inotodiol, Glycoside 1a, Podophyllotoxin, Justicidin A and B, Larreatin, Malloterine, Mallotochromanol, Isobutyrylmallotochromanol, Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin , Aristolactam-All, bis-parthenolidine, periplocoside A, ghalacinoside, ursolic acid, deoxypypsorospermine, psycorubin, ricin A, sanguinarine, manuwuic acid, methylsorbifolin, sphatheliachromes, Stizo phyllin, mansonine, strebloside, akagerin, dihydrousambaraensin, hydroxyusambarin, strychnopentamine, strychnophyllin, usambarin, usambarensin, berberine, liriodenin, oxoushinsunin, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromosone, acetylvismion B, deacetylvismion A, vismions A and B.
  13. A medical device according to claim 11, characterized in that the at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agents are selected from the group comprising: paclitaxel and its derivatives, β-estradiol, simvastatin, PI 88 sulphated oligosaccharide; Progen Ind) Macrocyclic Kohlensuboxide (MCS) and derivatives thereof, trapidil ®, N- (pyridin-4-yl) -. [1-4- (4-chlorobenzyl) indol-3-yl] -glyoxylamid (D-24851) , Tacrolimus acts.
  14. Medical device according to one of the preceding claims, characterized in that the at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic active ingredient in a pharmaceutically active concentration of 0.001-20 mg per cm 2 surface is included.
  15. Medical device according to one of the preceding claims, characterized characterized in that in multilayer systems, the last layer a pure drug layer is.
  16. Method for biocompatible coating of medical devices characterized by the steps: a. Providing a stent, and b. Applying at least one biostable layer Polysulfone with or without at least one hydrophilic polymer, and c. Applying and / or introducing at least one antiproliferative, antiinflammatory, antiinflammatory and / or antithrombotic Drug on and / or in the biostable layer, or b '. Apply at least a biostable layer of polysulfone with or without the at least a hydrophilic polymer together with at least one antiproliferative, antiinflammatory, antiinflammatory and / or antithrombotic Active ingredient.
  17. The method of claim 16, comprising the step b 'and the others step c '. Applying at least one antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic agent on the biostable Polymer layer.
  18. A method according to claim 16 or 17, comprising another step d. Applying at least one second biostable Layer of polysulfone.
  19. Method according to one of claims 16-18, characterized that on and / or under the at least one biostable layer from polysulfone at least one layer of fully desulfated and N-reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan and / or mixtures of these substances is applied.
  20. Medical devices available by a method according to one the claims 16-19.
  21. Medical devices according to one of claims 1-15 or 20, characterized in that the at least one antiproliferative, antiinflammatory, antiinflammatory and / or antithrombotic Active ingredient released by the surface coating released becomes.
  22. Medical devices according to one of claims 1-15, 20 or 21, characterized in that the respective antiproliferative, anti-inflammatory, anti-inflammatory and / or antithrombotic active ingredient in a pharmaceutically active concentration of 0.001-10 mg per cm 2 surface of the medical device and per drug-carrying layer is.
  23. Medical devices according to one of claims 1-15 or 20-22 characterized in that the medical device is a Stent acts.
DE200410020856 2003-09-29 2004-04-28 Medical product coated with biostable layer of polysulfone, useful particularly as stent for preventing restenosis, controls kinetics of release of incorporated active agents, e.g. antiproliferative agents Withdrawn DE102004020856A1 (en)

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DE200410020856 DE102004020856A1 (en) 2003-09-29 2004-04-28 Medical product coated with biostable layer of polysulfone, useful particularly as stent for preventing restenosis, controls kinetics of release of incorporated active agents, e.g. antiproliferative agents
DE502004005857T DE502004005857D1 (en) 2003-09-29 2004-09-29 Biokompatible, biostabile coating of medical surfaces
PL04786896T PL1667743T3 (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
NZ546068A NZ546068A (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
EA200600470A EA011822B1 (en) 2003-09-29 2004-09-29 A medical product comprising a biocompatible biostable polysulfone coating, and method for applying said coating
CNA2004800281495A CN101094698A (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
PCT/DE2004/002184 WO2005032611A2 (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
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JP2006527276A JP4861178B2 (en) 2003-09-29 2004-09-29 Medical article surface coating with biocompatibility and biological stability
DE112004002385T DE112004002385D2 (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
AU2004277302A AU2004277302B2 (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
ES04786896T ES2304626T3 (en) 2003-09-29 2004-09-29 Hemocompatible medical surfaces that have a biocompatible, bostable coating.
AP200603570A AP200603570A0 (en) 2003-09-29 2004-09-29 Biocompatible, Biostable coating of medical surfaces.
KR1020067005938A KR100983440B1 (en) 2003-09-29 2004-09-29 Biocompatibility and biostable coating on the surface of medical products
CA2540382A CA2540382C (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
EP04786896A EP1667743B1 (en) 2003-09-29 2004-09-29 Biocompatible, biostable coating of medical surfaces
AT04786896T AT382377T (en) 2003-09-29 2004-09-29 Biokompatible, biostabile coating of medical surfaces
ZA2006/02180A ZA200602180B (en) 2003-09-29 2006-03-15 Biocompatible, biostable coating of medical surfaces
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