US20040234575A1 - Medical products comprising a haemocompatible coating, production and use thereof - Google Patents

Medical products comprising a haemocompatible coating, production and use thereof Download PDF

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US20040234575A1
US20040234575A1 US10/483,545 US48354504A US2004234575A1 US 20040234575 A1 US20040234575 A1 US 20040234575A1 US 48354504 A US48354504 A US 48354504A US 2004234575 A1 US2004234575 A1 US 2004234575A1
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layer
poly
hemocompatible
medical device
biostable
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Roland Horres
Marita Linssen
Michael Hoffmann
Erika Hoffmann
Donato Di Biase
Volker Faust
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Hemoteq AG
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Publication of US20040234575A1 publication Critical patent/US20040234575A1/en
Assigned to HEMOTEQ GMBH reassignment HEMOTEQ GMBH CORRECTIVE ASSIGNMENT TO CORRECT THE DOCUMENT DATES SPELLING OF INVENTOR NAMES TITLE OF INVENTION PREVIOUSLY RECORDED ON REEL 015531 FRAME 0263. ASSIGNOR(S) HEREBY CONFIRMS THE CORRECTIVE ASSIGNMENT. Assignors: FAUST, VOLKER, LINSSEN, MARITA KATARINA, DI BIASE, DONATO, HOFFMANN, ERIKA, HOFFMANN, MICHAEL, HORRES, ROLAND
Assigned to HEMOTEQ AG reassignment HEMOTEQ AG CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: FAUST, VOLKER, LINSSEN, MARITA KATARINA, DI BIASE, DONATO, HOFFMANN, ERIKA, HOFFMAN, MICHAEL, HORRES, ROLAND
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/10—Heparin; Derivatives thereof
    • 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
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C09D105/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention concerns the utilisation of polysaccharides containing the sugar building block N-acylglucosamine for the preparation of hemocompatible surfaces of medical devices, methods for the hemocompatible coating of surfaces with said polysaccharides as well as medical devices with these hemocompatible surfaces.
  • stents Whilst the usage of vessel supports, so-called stents, the described risk of thrombosis also occurs as one of the risk factors in blood bearing vessels.
  • the stent In cases of vessel strictures and sealings due to e.g. arteriosclerotic changes especially of the coronary arteries the stent is used for the expansion of the vessel walls. It fixes lime fragments in the vessels and improves the flow properties of the blood inside the vessel as it smoothens the surface of the interior space of the vessel. Additionally a stent leads to a resistance against elastic restoring forces of the expanded vessel part.
  • the utilised material is mostly medicinal stainless steel.
  • the stent thrombosis occurs in less than one percent of the cases already in the cardio catheter laboratory as early thrombosis or in two to five percent of the cases during the hospital recreation. In about five percent of the cases vessel injuries due to the intervention are caused because of the arterial lock and the possibility of causing pseudo-aneurysms by the expansion of vessels exists, too. Additionally the continuous application of heparin as anticoagulant increases the risk of bleeding.
  • the vessel injuries caused during the implantation of the stents arise inflammation reactions, which play an important role for the healing process during the first seven days.
  • the herein concurrent processes are among others connected with the release of growth factors, which initiate an increased proliferation of the smooth muscle cells and lead with this to a rapid restenosis, a renewed sealing of the vessel because of uncontrolled growth.
  • cicatrisations can be too distinctive (neointima hyperplasia) and lead to not only a coverage of the stent surface but to the sealing of the total interior space of the stent.
  • the undertakings are enormous on this area of producing a stent which can reduce the restenosis in this manner or eliminate totally.
  • the most common construction type consists of a stent, which is coated with a suitable matrix, usually a biostable polymer.
  • the matrix includes an antiproliferative or antiphlogistic agent, which is released in temporally controlled steps and shall suppress the inflammation reactions and the excessive cell division.
  • U.S. Pat. No. 5,891,108 reveals for example a hollow moulded stent, which can contain pharmaceutical active agents in its interior, that can be released throughout a various number of outlets in the stent.
  • EP-A-1 127 582 describes a stent that shows on its surface ditches of 0.1-1 mm depth and 7-15 mm length, which are suitable for the implementation of an active agent. These active agent reservoirs release, similarly to the outlets in the hollow stent, the contained pharmaceutical active agent in a punctually high concentration and over a relatively long period of time, which leads to the fact, that the smooth muscle cells are not anymore or only very delayed capable of enclosing the stent.
  • phosphorylcholine a component of the erythrocytic cell membrane, shall create a non thrombogeneous surface as ingredient of the coated non biodegredable polymer layer on the stent.
  • the active agent is absorbed by the polymer containing phosphorylcholine layer or adsorbed on the surface.
  • Object of the present invention is to provide hemocompatibly coated medical devices as well as methods of hemocompatible coating and the use of hemocompatibly coated medical devices, especially stents, to prevent or reduce undesired reactions as for example restenosis.
  • Especially object of the present invention is to provide stents which permit a continuous controlled ingrowth of the stent—on the one side by suppression of the cellular reactions in the primal days and weeks after implantation by the support of the selected agents and agent combinations and on the other side by providing an athrombogeneous resp. inert resp. biocompatible surface, which guarantees that with the decrease of the agent's influence no reactions to the existing foreign surface take place which also can lead to complications in a long term.
  • EP-B-0 333 730 describes a process to produce hemocompatible substrates by recess, adhesion and/or modification and anchorage of non thrombogeneous endothelic cell surface polysaccharide (HS I).
  • HS I non thrombogeneous endothelic cell surface polysaccharide
  • the present invention solves the object by providing medical devices that show properties of a surface coating of determined polysaccharides and paclitaxel. Instead of or together with paclitaxel determined other antiphlogistic as well as anti-inflammatory drugs resp. agent combinations of simvastatine, 2-methylthiazolidine-2,4-dicarboxylic acid and the correspondent sodium salt), macrocyclic suboxide (MCS) and its derivatives, tyrphostines, D24851, thymosin a-1, interleucine-1 ⁇ inhibitors, activated protein C (aPC), MSH, fumaric acid and fumaric acid ester, PETN (pentaerythritol tetranitrate), PI88, dermicidin, baccatin and its derivatives, docetaxel and further derivatives of paclitaxel, tacrolimus, pimecrolimus, trapidil, a- and ⁇ -estradiol, sirolimus, colchicin, and melan
  • the subject matter of the present invention are medical devices the surface of which is at least partially covered with a hemocompatible layer, wherein the hemocompatible layer comprises at least one compound of the formula 1:
  • n is an integer between 4 and 1050 and
  • Y represents the residues —CHO, —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , —COC 4 H 9 , —COC 5 H 11 , —COCH(CH 3 ) 2 , —COCH 2 CH(CH 3 ) 2 , —COCH(CH 3 )C 2 H 5 , —COC(CH 3 ) 3 , —CH 2 COO ⁇ , —C 2 H 4 COO ⁇ , —C 3 H 6 COO ⁇ , —C 4 H 8 COO ⁇ .
  • the hemocompatible layer can be added directly onto the surface of a preferably non hemocompatible medical device or deposited onto other biostable and/or biodegradable layers. Further on additional biostable and/or biodegradable and/or hemocompatible layers can be localised on the hemocompatible layer.
  • the active agent paclitaxel is present on, in and/or under the hemocompatible layer or the hemocompatible layers, respectively.
  • the active agent can form herein an own active agent layer on or under the hemocompatible layer and/or can be incorporated in at least one of the biostable, biodegradable and/or hemocompatible layers.
  • the compounds of the general formula 1 are used, wherein Y is one of the following groups: —CHO, —COCH 3 , —COC 2 H 5 or —COC 3 H 7 . Further on preferred are the groups —CHO, —COCH 3 , —COC 2 H 5 and especially preferred is the group —COCH 3 .
  • the compounds of the general formula 1 contain only a small amount of free amino groups. Because of the fact that with the ninhydrine reaction free amino groups could not be detected anymore, due to the sensitivity of this test it can be implied that less than 2%, preferred less than 1% and especially preferred less than 0.5% of all —NH—Y groups are present as free amino groups, i.e. within this low percentage of the —NH—Y groups Y represents hydrogen.
  • polysaccharides of the general formula 1 contain carboxylate groups and amino groups
  • the general formula covers alkali as well as alkaline earth metal salts of the corresponding polysaccharides.
  • Alkali metal salts like the sodium salt, the potassium salt, the lithium salt or alkaline earth metal salts like the magnesium salt or the calcium salt can be mentioned.
  • ammonia primary, secondary, tertiary and quaternary amines, pyridine and pyridine derivatives ammonium salts, preferably alkylammonium salts and pyridinium salts can be formed.
  • bases which form salts with the polysaccharides
  • bases are inorganic and organic bases as for example NaOH, KOH, LiOH, CaCO 3 , Fe(OH) 3 , NH 4 OH, tetraalkylammonium hydroxide and similar compounds.
  • the polysaccharides according to formula 1 possess molecular weights from 2 kD to 15 kD, preferred from 4 kD to 13 kD, more preferred from 6 kD to 12 kD and especially preferred from 8 kD to 11 kD.
  • the variable n is an integer in the range of 4 to 1050. Preferred n is an integer from 9 to 400, more preferred an integer from 14 to 260 and especially preferred an integer between 19 and 210.
  • the general formula 1 shows a disaccharide, which has to be viewed as the basic module for the used polysaccharides and that formes the polysaccharide by the n-fold (multiple) sequencing of the basic module.
  • This basic module which is built of two sugar molecules shall not be interpreted in the manner, that the general formula 1 only includes polysaccharides with an even number of sugar molecules.
  • the formula implements of course also polysaccharides with an odd number of sugar building units.
  • the end groups of the polysaccharides are represented by hydroxyl groups.
  • paclitaxel layer can diffuse partially into the hemocompatible layer or get taken up totally by the hemocompatible layer.
  • biostable layer is present under the hemocompatible layer.
  • the hemocompatible layer can be coated totally and/or partially with at least one more, above lying biostable and/or biodegradable layer. Preferred is an external biodegradable or hemocompatible layer.
  • a further preferred embodiment contains a layer of paclitaxel under the hemocompatible layer or between the biostable and the hemocompatible layer, so that paclitaxel is released slowly through the hemocompatible layer.
  • Paclitaxel can be bound covalently and/or adhesively in and/or on the hemocompatible layer and/or the biostable and/or the biodegradable layer, in which the adhesive bonding is preferred.
  • biodegradable substances for the biodegradable layer(s) can be used: polyvalerolactones, poly- ⁇ -decalactones, polylactonic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of the polylactides and polyglycolides, poly- ⁇ -caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly(1,4-dioxane-2,3-diones), poly(1,3-dioxane-2-one), poly-para-dioxanones, polyanhydrides such as polymaleic anhydrides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactonedimethylacrylates, poly-b-maleic acid, polycaprolactonebutyl-acrylates, multiblock polymers such as e.g.
  • polyether ester multiblock polymers such as e.g. PEG and poly(butyleneterephtalates), polypivotolactones, polyglycolic acid trimethyl-carbonates, polycaprolactone-glycolides, poly(g-ethylglutamate), poly(DTH-iminocarbonate), poly(DTE-co-DT-carbonate), poly(bisphenol-A-iminocarbonate), polyorthoesters, polyglycolic acid trimethyl-carbonates, polytrimethylcarbonates, polyiminocarbonates, poly(N-vinyl)-pyrrolidone, polyvinylalcoholes, polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly[p-carboxyphenoxy)propane], polyhydroxypentanoic acid, polyanhydrides, polyethyleneoxide-propyleneoxide,
  • biostable substances for the biostable layer(s) can be used: polyacrylic acid and polyacrylates as polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethylenamine, polyimides, polycarbonates, polycarbourethanes, polyvinylketones, polyvinylhalogenides, polyvinylidenhalogenides, polyvinylethers, polyisobutylenes, polyvinylaromates, polyvinylesters, polyvinylpyrollidones, polyoxymethylenes, polytetramethyleneoxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyetherurethanes, silicone-polyetherurethanes, silicone-polyurethanes, silicone-polycarbonate-urethanes, polyolefine elastomeres, polyisobutylenes, EPDM gums, fluoride, poly
  • any medical devices with the herein disclosed hemocompatible surfaces especially those, which shall be suitable for the short- or the longterm contact with blood or blood products.
  • Such medical devices are for example prostheses, organs, vessels, aortas, heart valves, tubes, organ spareparts, implants, fibers, hollow fibers, stents, hollow needles, syringes, membranes, tinned goods, blood containers, titrimetric plates, pacemakers, adsorbing media, chromatography media, chromatography columns, dialyzers, connexion parts, sensors, valves, centrifugal chambers, recuperators, endoscopes, filters, pump chambers.
  • the present invention is especially related to stents.
  • the polysaccharides of formula 1 can be formed from heparin and/or heparansulphates. These materials are in structurally view quite similar compounds. Heparansulphates occur ubiquitously on cell surfaces of mammals. In dependence from the cell type they differ strongly in molecular weight, degree of acetylation and degree of sulphation. Heparansulphate from liver shows for example an acetylation coefficient of about 50%, whereas the heparansulphate of the glycocalix from endothelic cells can exhibit an acetylation coefficient from about 90% and higher. Heparin shows only a quite low degree of acetylation from about up to 5%.
  • the sulphation coefficient of the heparansulphate from liver and of heparin is ⁇ 2 per disaccharide unit, in case of heparansulphate from endothelial cells close to 0 and in heparansulphates from other cell types between 0 and 2 per disaccharide unit.
  • the compounds of the general formula 1 are characterized by an amount of sulphate groups per disaccharide unit of less than 0.05. Further on the amount of free amino groups in these compounds is less than 1% based on all —NH—Y groups.
  • All heparansulphates have with heparin a common sequence in biosynthesis.
  • First of all the core protein with the xylose-containing bonding region is formed. It consists of the xylose and two galactose residues connected to it.
  • To the last of the two galactose units a glucuronic acid and a galactosamine is connected alternately until the adequate chain length is reached.
  • Finally, a several step enzymatic modification of this common polysaccharide precursor of all heparansulphates and of heparin follows by means of sulphotransferases and epimerases which generate by their varying completeness of transformation the broad spectra of different heparansulphates up to heparin.
  • Heparin is alternately build of D-glucosamine and D-glucuronic acid resp. L-iduronic acid, in which the amount of L-iduronic acid is up to 75%.
  • D-glucosamine and D-glucuronic acid are connected in a ⁇ -1,4-glycosidic resp.
  • L-iduronic acid in an a-1,4-glycosidic bonding to the disaccharide, that forms the heparin subunits.
  • These subunits are again connected to each other in a ⁇ -1,4-glycosidic way and lead to heparin.
  • the position of the sulphonyl groups is variable.
  • Heparansulphate also named as heparitinsulphate, contains with exception of the heparansulphate from liver less N- and O-bound sulphonyl goups as heparin but in exchange more N-acetyl goups. The amount of L-iduronic acid compared to heparin is also lower.
  • a special pentasaccharide unit is made responsible, which can be found in commercial heparin preparatives in about every 3 rd molecule.
  • Heparin preparations of different antithrombotic activity can be produced by special separation techniques.
  • highly active for example by antithrombin-III-affinitychromatography obtained preparations (“High-affinity”-heparin) this active sequence is found in every heparin molecule, while in “No-affinity”-preparations no characteristical pentasaccharide sequences and thus no active inhibition of coagulation can be detected.
  • the amino groups of the heparin are mostly N-sulphated or N-acetylated.
  • the most important O-sulphation positions are the C2 in the iduronic acid as well as the C6 and the C3 in the glucosamine.
  • the sulphate group on C6 is made responsible, in smaller proportion also the other functional groups.
  • the compounds of the general formula 1 despite of the structural differences to the heparin resp. heparansulphate, still show the hemocompatible properties of heparin and additionally after the immobilisation of the compounds no noteworthy depositions of plasma proteins, which represent an initial step in the activation of the coagulation cascade, could be observed.
  • the hemocopatible properties of the compounds according to invention still remain also after their immobilisation on artificial surfaces.
  • the sulphate groups of the heparin resp. the heparansulphates are necessary for the interaction with antithrombin III and impart thereby the heparin resp. the heparansulphate the anticoagulatory effect.
  • the inventive compounds are not actively coagulation suppressive, i.e. anticoagulative, due to an almost complete desulphation the sulphate groups of the compounds are removed up to a low amount of below 0.2 sulphate groups per disaccharide unit.
  • the inventive compounds of the general formula 1 can be generated from heparin or heparansulphates by first substantially complete desulphation of the polysaccharide and subsequently substantially complete N-acylation.
  • substantially completely desulphated refers to a desulphation degree of above 90%, preferred above 95% und especially preferred above 98%.
  • the desulphation coefficient can be determined according to the so-called ninhydrin test which indicates free amino groups. The desulphation takes place in the way as with DMMB (dimethylmethylene blue) no colour reaction is obtained. This colour test is suitable for the indication of sulphated polysaccharides but its detection limit is not known in technical literature.
  • the desulphation can be carried out for example by pyrolysis of the pyridinium salt in a solvent mixture. Especially a mixture of DMSO, 1,4-dioxane and methanol has proven of value.
  • Substantially completely N-acylated refers to a degree of N-acylation of above 94%, preferred above 97% and especially preferred above 98%.
  • the acylation runs in such a way completely that with the ninhydrin reaction for detection of free amino groups no colour reaction is obtained anymore.
  • acylation agents are preferably used carboxylic acid chlorides, -bromides or -anhydrides.
  • Acetic anhydride, propionic anhydride, butyric anhydride, acetic acid chloride, propionic acid chloride or butyric acid chloride are for example suitable for the synthesis of the compounds according to invention.
  • carboxylic anhydrides as acylation agents.
  • solvent especially for carboxylic acid anhydrides deionised water is used, especially together with a cosolvent which is added in an amount from 10 to 30 volume percent.
  • cosolvents are suitable methanol, ethanol, DMSO, DMF, acetone, dioxane, THF, ethyl acetate and other polar solvents.
  • carboxylic acid halogenides preferably polar water free solvents such as DMSO or DMF are used.
  • inventive compounds of the general formula comprise in the half of the sugar molecules a carboxylate group and in the other half a N-acyl group.
  • the present invention describes the use of the compounds with the general formula 1 as well as salts of these compounds for the coating, especially a hemocompatible coating of natural and/or artificial surfaces.
  • hemocompatible the characteristic of the compounds according to invention is meant, not to interact with the compounds of the blood coagulation system or the platelets and so not to initiate the blood coagulation cascade.
  • the invention reveals polysaccharides for the hemocompatible coating of surfaces.
  • Preferred are polysaccharides in the range of the above mentioned molecular weight limits.
  • the used polysaccharides are characterised in that they contain the sugar building unit N-acylglucosamine in a great amount. This means that 40 to 60% of the sugar building units are N-acylglucosamine and substantially the remaining sugar building units bear each a carboxyl group.
  • the polysaccharides consist generally in more than 95%, preferred in more than 98%, of only two sugar building units, whereas one sugar building unit bears a carboxyl group and the other one a N-acyl group.
  • One sugar building unit of the polysaccharides is N-acylglucosamine preferred N-acetylglucosamine and in case of the other one it is the uronic acids glucuronic acid and iduronic acid.
  • Preferred are polysaccharides, which conspire substantially the sugar glucosamine, whereas substantially the half of the sugar building units bears a N-acyl group, preferred a N-acetyl group, and the other half of the glucosamine building units bears one carboxyl group which is bond directly by the amino group or by one or more methylenyl groups. In the case of these carboxylic acid groups bound to the amino group it is concerned to be preferred the carboxymethyl- or carboxyethyl groups.
  • polysaccharides are preferred which substantially conspire in one half of N-acylglucosamine, preferred of N-acetylglucosamine and substantially conspire in the other half of the uronic acids glucuronic acid and iduronic acid.
  • polysaccharides that show a substantially alternating sequence of N-acylglucosamine and one of the both uronic acids.
  • substantially shall make clear, that statistical variations are to be taken into account.
  • One substantially alternating sequence of the sugar building units implies, that generally no two equal sugar building units are bound to each other but does not exclude totally such a defect connection.
  • substantially the half means almost 50% but allows small variations, because especially in the case of biosynthetically synthesised macromolecules the ideal case is never reached and some variations are always to be taken into account, because enzymes do not work perfectly and in catalysis always some error rate has to be anticipated.
  • heparin a strongly alternating sequence of N-acetylglucosamine and the uronic acid units is existing.
  • the immobilisation of the polysaccharides on these surfaces can be achieved via hydrophobic interactions, van der Waals forces, electrostatic interactions, hydrogen bonds, ionic interactions, cross-linking of the polysaccharides and/or by covalent bonding onto the surface.
  • Preferred is the covalent linkage of the polysaccharides (side-on bonding), more preferred the covalent single-point linkage (side-on bonding) and especially preferred the covalent end-point linkage (end-on bonding).
  • Biological and/or artificial surfaces of medical devices can be provided with a hemocompatible coating by means of the following method:
  • b′ deposition of a biostable and/or biodegradable layer onto the surface of the medical device or the hemocompatible layer.
  • Deposition shall refer to at least partial coating of a surface with the adequate compounds, wherein the compounds are positioned and/or immobilised or anyhow anchored on and/or in the subjacent surface.
  • Non hemocompatible surfaces shall refer to such surfaces that can activate the blood coagulatory system, thus are more or less thrombogeneous.
  • An alternative embodiment comprises the steps:
  • the last-mentioned embodiment makes sure, even in the case of e.g. mechanical damage of the polymeric layer and therewith also of the exterior hemocompatible layer, that the surface coating does not lose its characteristic of being blood compatible.
  • biological or artificial surface is the combination of an artificial medical device with an artificial part to be understood, e.g. pork heart with an artificial heart valve.
  • the single layers are deposited preferably by dipping or spraying methods, whereas one can deposit also paclitaxel at the same time with the deposition of one layer onto the medical device surface, which is then implemented in the respective layer covalently and/or adhesively bound. In this way it is possible at the same time with the deposition of a hemocompatible layer onto the medical device to deposit the active agent paclitaxel.
  • the substances for the biostable or biodegradable layers were itemised already above.
  • paclitaxel is bound covalently on the subjacent layer. Also paclitaxel is preferably deposited by dipping or spraying methods on and/or in the hemocompatible layer or the biostable layer.
  • step d) implements the deposition of at least one biodegradable layer and/or at least one biostable layer onto the hemocompatible layer resp. the layer of paclitaxel.
  • step d′) implements the deposition of at least one compound of the general formula 1 as hemocompatible layer onto the biostable and/or biodegradable layer resp. the layer of paclitaxel.
  • step d′) follows.
  • step d) resp. d′) the deposition of paclitaxel can take place into and/or onto the at least one biodegradable and/or biostable layer or the hemocompatible layer.
  • the single layers as well as paclitaxel are preferably deposited and/or implemented by dipping or spraying methods onto and/or into the subjacent layer.
  • the biostable layer is deposited on the surface of the medical device and completely or incompletely covered with a hemocompatible layer which (preferably covalently) is bound to the biostable layer.
  • the hemocompatible layer comprises heparin of native origin of regioselectively synthesised derivatives of different sulphation coefficients (sulphation degrees) and acylation coefficients (acylation degrees) in the molecular weight range of the pentasaccharide, which is responsible for the antithrombotic activity, up to the standard molecular weight of the purchasable heparin of 13 kD, heparansulphate and its derivatives, oligo- and polysaccharides of the erythrocytic glycocalix, desulphated and N-reacetylated heparin, N-carboxymethylated and/or partially N-acetylated chitosan as well as mixtures of these substances.
  • sulphation degrees sulphation coefficients
  • acylation degrees acylation degrees
  • Subject of the invention are also medical devices which are hemocompatibly coated according to one of the herein mentioned methods.
  • the medical devices it is preferably a matter of stents.
  • the conventional stents which can be coated according to the inventive methods, consist of stainless steel, nitinol or other metals and alloys or of synthetic polymers.
  • the stents according to invention are coated with an according to the general formula 1 preferred covalently bound hemocompatible layer.
  • a second layer covers this first hemocompatible layer completely or also incompletely.
  • This second layer conspires preferably paclitaxel.
  • the hemocompatible coating of a stent provides on the one hand the necessary blood compatibility and reduces so the risk of thrombosis and also the containment of inflammation reactions due to the intrusion and the absence of a non-endogenous surface, and paclitaxel, which is preferred to be distributed homogeneously over the total surface of the stent provides that the covering of the stent surface with cells, especially smooth muscle and endothelial cells, takes place in a controlled way, so that the interplay of thrombosis reactions and inflammation reactions, the release of growth factors, proliferation and migration of cells during the recovery process provides the generation of a novel “repaired” cell layer, which is referred to as neointima.
  • the use of paclitaxel, covalently or/and adhesively bound to the subjacent layer or/and covalently or/and adhesively implemented in at least one layer ensures, that this active agent is set free continuously and in small doses, so that the population of the stent surface by cells is not inhibited, however an excessive population and the ingrowth of cells into the vessel lumen is prevented.
  • This combination of both effects awards the ability to the stent according to invention, to grow rapidly into the vessel wall and reduces both the risk of restenosis and the risk of thrombosis.
  • the release of paclitaxel spans about a period from 1 to 12 months, preferably 1 to 3 months after implantation.
  • Paclitaxel is preferred contained in a pharmaceutical active concentration from 0.001-10 mg per cm 2 stent surface, preferred 0.01-5 mg and especially preferred 0.1-1.0 mg per cm 2 stent surface. Additional active agents can be contained in similar concentration in the same or in the hemocompatible layer.
  • the applied amounts of polymer are per layer between 0.01 mg to 3 mg, preferred 0.20 mg to 1 mg and especially preferred between 0.2 mg to 0.5 mg.
  • Suchlike coated stents release the active agent paclitaxel controlled and continuously and hence are excellently suitable for the prevention and reduction of restenosis.
  • the preferred embodiment of the stents according to invention shows a coating, which consists of at least two layers.
  • second layer is that layer, which is deposited on the first layer.
  • the first layer conspires the hemocompatible layer, which is substantially completely covered by a second layer, which consists of paclitaxel, that is covalently and/or adhesively bound to the first layer.
  • the paclitaxel layer is dissolved slowly, so that the active agent is released according to the velocity of the solution process.
  • the first hemocompatible layer guarantees the necessary blood compatibility of the stent in the degree as the active agent is removed.
  • the adhesion of cells is strongly reduced only for a certain period of time and an aimed controlled adhesion is enabled, where the external layer had been already widely degradated.
  • the hemocompatible layer remains as athrombogeneous surface and masks the foreign surface in such a way, that no life-threatening reaction can occur anymore.
  • Suchlike stents can be generated by a method of the hemocompatible coating of stents, to which the following principle underlies:
  • the stents according to invention solve both the problem of acute thrombosis and the problem of neointima hyperplasia after a stent implantation.
  • inventive stents are especially well suited, because of their coating for the continuous release of one or more antiproliferative, immuno-suppressive active agents. Due to this capability of the aimed continuous active agent release in a required amount the inventively coated stents prevent the danger of restenosis almost completely.
  • the natural and/or artificial surfaces which had been coated according to the above described method with a hemocompatible layer of aforesaid polysaccharides, are suitable especially as implants resp. organ replacement parts, that are in direct contact with the blood circuit and blood, preferably in the form of stents in combination with an antiproliferative active agent, preferably paclitaxel, for the prevention of restenosis.
  • inventively coated medical devices are suited especially but not only for the direct and permanent blood contact, but show surprisingly also the characteristic to reduce or even to prevent the adhesion of proteins onto suchlike coated surfaces.
  • the adhesion of plasma proteins on foreign surfaces which come in contact with blood is an essential and initial step for the further events concerning the recognition and the implementing action of the blood system.
  • the deposition of the inventive coating prevents or at least reduces for example the unspecific adhesion of proteins on micro-titer plates or other support mediums which are used for diagnostic detection methods, that disturb the generally sensitive test reactions and can lead to a falsification of the analysis result.
  • FIG. 1 shows a tetrasaccharide unit of a heparin or heparansulphate with statistic distribution of the sulphate groups and a sulphation coefficient of 2 per disaccharide unit as it is typical for heparin (FIG. 1 a ).
  • FIG. 1 b shows an example of a compound according to the general formula in the description.
  • FIG. 2 shows the influence of an into a PVC-tube expanded, surface modified stainless steel coronary stent on the platelet loss (PLT-loss).
  • SH1 is a with heparin covalently coated stent
  • SH2 is a with chondroitinsulphate coated stent
  • SH3 is a stent coated with polysaccharides gained from the erythrocytic glycocalix
  • SH4 is a with Ac-heparin covalently coated stainless steel coronary stent.
  • FIG. 3 shows a schematic presentation of the restenosis rate of with completely desulphated and N-reacetylated heparin (Ac-heparin) covalently coated stents and with oligo- and polysaccharides of the erythrocytic glycocalix (polysacch. of erythro. glycoc.) coated stents in comparison to the uncoated stent and with polyacrylic acid (PAS) coated stents after 4 weeks of implantation time in pork.
  • Ac-heparin N-reacetylated heparin
  • FIG. 4 quantitative coronary angiography
  • FIG. 5 elution plot of paclitaxel from the stent (without support medium).
  • heparin-pyridinium-salt were added in a round flask with a reflux condenser with 90 ml of a 6/3/1 mixture of DMSO/1,4-dioxan/methanol (v/v/v) and heated for 24 hours to 90° C. Then 823 mg pyridinium chloride were added and heated additional 70 hours to 90° C. Afterwards it was diluted with 100 ml of water and titrated with dilute sodium hyrdoxide to pH 9. The desulphated heparin was dialyzed contra water and freeze-dried.
  • heparin-pyridinium-salt were added in a round flask with a reflux condenser with 90 ml of a 6/3/1 mixture of DMSO/1,4-dioxan/methanol (v/v/v) and heated for 24 hours to 90° C. Then 823 mg pyridiniumchloride were added and heated additional 70 hours to 90° C. Afterwards it was diluted with 100 ml of water and titrated with dilute sodium hydroxide to pH 9. The desulphated heparin was dialyzed contra water and freeze-dried.
  • the membranes are extracted and after fixation of the adherent platelets the platelet occupancy is measured.
  • the respective results are set into relation to the highly thrombogeneous subendothelial matrix as negative standard with a 100% platelet occupancy.
  • the adhesion of the platelets takes place secondary before the formation of the plasma protein layer on the foreign material.
  • the plasma protein fibrinogen acts as cofactor of the platelet aggregation.
  • the such induced activation of the platelets results in the bonding of several coagulation associated plasma proteins, as e.g. vitronectin, fibronectin and von Willebrand-factor on the platelet surface. By their influence finally the irreversible aggregation of the platelets occurs.
  • the platelet occupancy presents because of the described interactions an accepted quantum for the thrombogenity of surfaces in case of the foreign surface contact of blood. From this fact the consequence arises: the lower the platelet occupancy is on the perfunded surface the higher is the hemocompatibility of the examined surface to be judged.
  • the blood was pumped for 10 minutes with a flow rate of 150 ml/min.
  • the platelet content of the blood was measured before and after the perfusion with a coulter counter.
  • the platelet loss was of 10%.
  • the analysis of the polished, chemically not surface coated stent yields an additional average platelet loss of 22.7%. Therewith causes this compared to the PVC empty tube less than 1% measurable foreign surface an approximately comparable platelet loss.
  • a direct result is that the medicinal stainless steel 316 LVM used as stent material induces an about 100 times stronger platelet damage compared to a medical grade PVC surface, although this test surface only accounts for 0.84% of the total surface.
  • Not expanded stents of medicinal stainless steel LVM 316 were degreased in the ultrasonic bath for 15 minutes with acetone and ethanol and dried at 100° C. in the drying closet. Then they were dipped for 5 minutes into a 2% solution of 3-aminopropyltriethoxysilane in a mixture of ethanol/water (50/50: (v/v)) and then dried for 5 minutes at 100° C. Afterwards the stents were washed with demineralised water over night.
  • the target of the experiments was primarily to evaluate the influence of the Ac-heparin coating on the stent induced vessel reaction. Besides the registration of possible thrombotic events the relevant parameters for restenotic processes like neointima area, vessel lumen and stenosis degree were recorded. For the examinations 6-9 month old domestic porks were used, one for the validation of stents for a long time established and approved animal model.
  • the stents are fixed in that way, that the inside of the stents does not touch the bar.
  • a feeding amplitude of 2.2 cm and a feeding velocity of 4 cm/s and a distance of 6 cm between stent and spray valve the stent is sprayed with the particular spray solution. After the drying (about 15 minutes) at room temperature and proximate in the fume hood over night it is balanced again.

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