EP2125063A2 - Stent métallique biorésorbable à résorption régulée - Google Patents

Stent métallique biorésorbable à résorption régulée

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Publication number
EP2125063A2
EP2125063A2 EP08706827A EP08706827A EP2125063A2 EP 2125063 A2 EP2125063 A2 EP 2125063A2 EP 08706827 A EP08706827 A EP 08706827A EP 08706827 A EP08706827 A EP 08706827A EP 2125063 A2 EP2125063 A2 EP 2125063A2
Authority
EP
European Patent Office
Prior art keywords
acid
weight
resorbable implant
poly
implant according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP08706827A
Other languages
German (de)
English (en)
Inventor
Michael Orlowski
Alexander Rübben
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eurocor GmbH
Original Assignee
Eurocor GmbH
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Filing date
Publication date
Application filed by Eurocor GmbH filed Critical Eurocor GmbH
Publication of EP2125063A2 publication Critical patent/EP2125063A2/fr
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is a special form of bioresorbable metal stent (metallic endoprosthesis) with controlled resorption by a sheath with a special polymer that ensures controlled resorption of the sheathed endoprosthesis after implantation into a blood vessel.
  • the present invention thus relates to resorbable implants containing the metal magnesium and provided with a biodegradable coating.
  • the biodegradable coating preferably consists of biodegradable polymers and may additionally contain at least one pharmacologically active substance such as, for example, an antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic active ingredient, anti-restenosis agents, corticoids, sex hormones, statins, Epothilones, prostacyclins and / or angiogenesis inducers.
  • pharmacologically active substance such as, for example, an antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic active ingredient, anti-restenosis agents, corticoids, sex hormones, statins, Epothilones, prostacyclins and / or angiogenesis inducers.
  • Endoprostheses or stents which, after implantation into lesioned blood vessels, e.g. In Stenoses, dissections, etc. assume a supporting function and keeping the vessels open, have been known for a long time in minimally invasive interventional medicine. They are usually made of metals such as stainless steel or Nitinol. Such metal stents are known in large numbers and have proven themselves in practice. Due to their metal structure and carrying capacity such metal stents should ensure that the vessels remain open after implantation and the blood flow through the vessels is permanently guaranteed.
  • the support effect through the metal structure is often required only for a short time, since the body tissue can recover after implantation of the stent.
  • stents of bioresorbable materials such as e.g. developed from polymers such as polylactide or from metals such as magnesium alloys and used in clinical trials.
  • the degradation of the stent is not defined in time.
  • design and material thickness is the material degradation subjected to strong fluctuations, uncontrollable and generally too fast to ensure a secure ingrowth of the stent into the vessel wall. If absorption is too rapid, the stent can not grow into the vessel wall. Instead, it can detach and cause life-threatening problems for the patient.
  • the object of the present invention is to provide a prosthesis or vascular support which exercises its support function only until the regenerated tissue is again able to perform this function and which is controlled over a period of time during which the vessel regains its supporting function biodegradable.
  • the present invention relates to resorbable implants primarily composed of zinc, calcium and / or magnesium which have a biodegradable coating and may also be capable of corticoids, sex hormones, statins, epothilones, prostacyclins, angiogenesis inducers or one or more antiproliferative, antimigrative, antiangiogenic to release antiinflammatory, antiinflammatory, cytostatic, cytotoxic and / or antithrombotic agents or anti-restenosis agents.
  • the resorbable implant according to the invention consists of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, more preferably at least 70% by weight, even more preferably at least 75% by weight more preferably at least 80 wt .-% and particularly preferably at least 85 wt .-% of the metal magnesium, which is contained in a magnesium alloy with other metals and possibly non-metals, metal salts, metal carbides, metal oxides and / or metal nitrides. That is, the weight percentage refers to magnesium metal atoms and, if present, magnesium ions in the composition (alloy) with the other ingredients.
  • the implant according to the invention additionally contains 0-20% by weight, preferably 0.01-13% by weight, more preferably 0.1-8% by weight, even more preferably 1-7% by weight.
  • Calcium has. Particularly preferably, the mass of calcium is in the range of 1.2 to 6.5% by weight, 1.4 to 6.0% by weight, 1.6 to 5.5% by weight, 1.8%. 5.0 wt .-% and in particular from 2.0 to 4.5 wt .-%.
  • the implant according to the invention additionally contains 0-20% by weight, preferably 0.1-12% by weight, more preferably 0.5-6% by weight, even more preferably 0.8-5% by weight. -% yttrium. More preferably, the mass of yttrium is in the range of 0.9-4.0 wt.%, 1.1-3.5 wt.%, 1.3-3.0 wt.%, 1.5. 2.5 wt .-% and in particular of 1, 7 - 2.3 wt .-%.
  • an implant according to the invention may further comprise at least one metal selected from the group consisting of lithium, beryllium, sodium, aluminum, potassium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, Zinc, gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holium, erbium, Thulium, ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead and / or at least one metal salt having a cation selected from the group consisting of Li + , Be 2
  • metals and metal salts which are present together in masses of less than 10% by weight, preferably less than 6% by weight and more preferably less than 4% by weight, small amounts of non-metals, carbon , Sulfur, nitrogen, oxygen and / or hydrogen.
  • Rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen are in the alloy in unavoidable traces up to a maximum of 10 wt .-%, preferably in amounts of 0.1 to 8 wt .-%, more preferably 0, 5 to 7.0% by weight, more preferably 1 to 0 to 6.0% by weight and most preferably 1 to 5 to 5.0% by weight.
  • a preferred composition of an implant according to the invention comprises, for example
  • rare earths metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.
  • the carbon, sulfur, nitrogen, oxygen, hydrogen or other non-metals or semimetals may be in the form of anions and / or polymers.
  • compositions are: 60% by weight - 70% by weight of magnesium 10.0% by weight - 20% by weight of calcium 5.0% by weight - 15% by weight of yttrium 5.0% by weight -% - 10 wt .-% other metals or metal salts 2.0 wt .-% - 10 wt .-% rare earths, metal carbides, metal oxides, metal nitrides, non-metals, carbon, sulfur, nitrogen, oxygen, hydrogen.
  • rare earths 0.3% by weight - 1% by weight of rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.
  • Metal salts 0.1% by weight - 10% by weight Rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.
  • resorbable in the present invention means that the implant slowly dissolves in the organism over a certain period of time and at some point only its decomposition products are present in dissolved form in the body. At this time, solid components or fragments of the implant are no longer present.
  • the degradation products should be physiologically largely harmless and lead to ions or molecules that can be present in the organism anyway or degraded by the organism to harmless substances or excreted.
  • metals which can be used in combination with the magnesium the following are preferred according to the invention: lithium, beryllium, sodium, zinc, aluminum, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper , Gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holium, erbium, thulium , Ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead.
  • metal salt-containing zinc melts or metal salt-containing zinc alloys Such combinations may be referred to as metal salt-containing zinc melts or metal salt-containing zinc alloys.
  • the metal salt content may only be so high that there is still sufficient flexibility of the material.
  • Suitable metal salts are those mentioned below and in particular salts of magnesium, zinc, calcium, iron and yttrium.
  • absorbable alloys which may contain, for example, the following metals together with magnesium
  • metals lithium, beryllium, sodium, zinc, aluminum, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, Cobalt, nickel, copper, gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, Holium, erbium, thulium, ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead.
  • metals are sometimes contained only in small amounts.
  • magnesium-zinc alloys which contain zinc at from 0.1 to 10% by weight, preferably from 1.0 to 9.5% by weight and more preferably from 4.0 to 9.0% by weight. Further, it is preferable that this magnesium-zinc alloy further contains scandium, titanium, vanadium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver or indium and especially yttrium in an amount of 0.3 to 11 , preferably 0.7 to 10, more preferably 1.1 to 8.5 and particularly preferably 2 to 7 wt .-%.
  • alloys which, in addition to magnesium, predominantly comprise calcium, zinc, iron, tin, zinc or lithium together with up to 10% by weight of scandium, yttrium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, Europium, gadolinium, terbium, dysprosium, holium, erbium, thulium and / or ytterbium.
  • metal salt of the above-mentioned metals are preferable.
  • Such metal salts preferably contain at least one of the following
  • Metal ions Li + , Be 2+ , Na + , Mg 2+ , K + , Ca 2+ , Sc 3+ , Ti 2+ , Ti 4+ , V 2+ , V 3+ , V 4+ , V 5+ , Cr 2+ ,
  • the anions are halogens such as F “ , Cl “ , Br “ , oxides and hydroxides such as OH “ , O 2 " , sulfates, carbonates, oxalates, phosphates such as HSO 4 “ , SO 4 2 “ , HCO 3 “ , CO 3 2 “ , HC 2 O 4 “ , C 2 O 4 2” , H 2 PO 4 “ , HPO 4 2” , PO 4 3 “ , and in particular carboxylates such as HCOO “ , CH 3 COO “ , C 2 H 5 COO “ , C 3 H 7 COO “ , C 4 H 9 COO “ , C 5 HnCOO “ , C 6 H 13 COO “ , C 7 H 15 COO “ , C 8 Hi 7 COO “ , C 9 H 19 COO “ , PhCOO “ , PhCH 2 COO “ .
  • halogens such as F “ , Cl “ , Br “
  • salts of the following acids are preferable: sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, perchloric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, succinic acid, oxalic acid, gluconic acid (glyconic, dextronic acid), lactic acid, malic acid, tartaric acid, Tartronic acid (hydroxymalonic acid, hydroxypropanedioic acid), fumaric acid, citric acid, ascorbic acid, maleic acid, malonic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, (o-, m-, p-) toluic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid , Methanesulfonic acid, ethanesulfonic acid, hydroxyethane
  • salts of amino acids containing, for example, one or more of the following amino acids: glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine , Cysteine, methionine, proline, 4-hydroxyproline, N, N, N-trimethyl-lysine, 3-methyl-histidine, 5-hydroxy-lysine, O-phosphoserine, ⁇ - Carboxyglutamate, ⁇ -N-acetyllysine, ⁇ -N-methylarginine, citrulline, ornithine.
  • the amino acids with L-configuration are used.
  • at least a part of the amino acids used has D configuration.
  • metal salts such as Caclicumchlorid, calcium sulfate, calcium phosphate, calcium citrate, zinc chloride, zinc sulfate, zinc oxide, Zinkeitrat, iron sulfate, iron phosphate, iron chloride, ironocide, zinc, magnesium chloride, magnesium sulfate, magnesium phosphate or magnesium citrate.
  • metal salts are preferably used in masses of 0.01 to 10 wt .-%.
  • the magnesium alloy contains small amounts of a resorbable polymer. These small amounts of resorbable polymer are incorporated into the magnesium alloy, i. mixed with the alloy. Possible suitable resorbable polymers are mentioned below.
  • a stent framework is made of the magnesium alloy which is expandable. This stent framework or this vascular support from the magnesium alloy
  • Magnesium alloy is coated with a biodegradable polymer, i. each stent strut or strut of the vascular support is provided with a biodegradable polymeric layer or biodegradable polymeric coating.
  • Polyvalerolactones poly- ⁇ -decalactones, polylactic acid, polyglycolic acid polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly- ⁇ -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, polymaleic anhydrides,
  • ⁇ -cyclodextrins copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen collagen-N-hydroxysuccinimide, lipids, phospholipids, polyacrylic acid, polyacrylates, polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethyleneamine, polyimides, polycarbonates, Polycarbourethanes, polyvinyl ketones, polyvinyl halides, polyvinylidene halides, polyvinyl ethers, polyisobutylenes, polyvinylaromatics, polyvinyl esters, polyvinyl pyrollidones, polyoxymethylenes, polytetramethylene oxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyether urethanes, silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate
  • Preferred resorbable polymers are polymethylmethacrylates (PMMA), polytetrafluoroethylenes (PTFE), polyurethanes, polyvinylchlorides (PVC), polydimethylsiloxanes (PDMS), polyesters, nylons and polylactides.
  • PMMA polymethylmethacrylates
  • PTFE polytetrafluoroethylenes
  • PVC polyvinylchlorides
  • PDMS polydimethylsiloxanes
  • polyesters nylons and polylactides.
  • Polymer sheaths are also suitable in particular parylene, polyurethanes or amminopump or semipermeable membrane.
  • Parylene is usually the name for completely linear, partially crystalline, uncrosslinked aromatic polymers.
  • the different polymers have different properties and can be divided into four basic types, namely the parylene C, parylene D, parylene N and parylene F, the structure of which is shown below:
  • parylene N poly-para-xylylene
  • parylene C chloropoly-para-xylylene
  • parylene D di-chloro-poly-para-xylylene
  • parylene F poly (tetrafluoro-para-xylylene)
  • the methylene units are fluorinated.
  • Parylene C has the lowest melting point of the aforementioned Parylene of only 290 0 C, is characterized by good mechanical properties and corrosion resistance to corrosive gases and very low permeability to moisture. Parylene C is a biocompatible polymer and therefore suitable for use in a physiological environment.
  • polyesters are particularly preferred.
  • Ethane-1, 2-diol, propane-1, 3-diol or butane-1, 4-diol are used as diols, for example.
  • polyesters for the polymeric layer are used according to the invention. From the group of polyesters, in turn, those polymers are preferred which have the following repeating unit:
  • R, R ', R "and R” 1 is an alkyl radical having 1 to 5 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, DE2008 / 000161
  • Y is an integer from 1 to 9 and X is the degree of polymerization. Particular preference is given to the following polymers having the repeating units shown:
  • Resomer® represents a high-tech product from Boehringer Ingelheim, a medical device made from resorbable polymers that offers an important alternative to conventional medical applications due to its versatility in modern medicine and advances in technology.
  • absorbable polymers are manufactured on the basis of lactic and glycolic acids. Basically, the use of resorbable polymer is particularly preferred in the present invention. Homopolymers of lactic acid (polylactides) are mainly used in the production of resorbable medical implants. Copolymers of lactic and glycolic acids are used as raw materials for the production of active ingredient capsules for the controlled release of pharmaceutical active substances use.
  • lactic acid and glycolic acid based polymers as well as copolymers (alternating or random) and block copolymers (e.g., triblock copolymers) of both acids are preferred.
  • the poly (L-lactide) s having the general formula - (C 6 H 8 O 4) n such as L 210, L 210 S, L 207 S,
  • the poly (L-lactide-co-D, L-lactide) s having the general formula - (C 6 H 8 O 4) n such as LR 706, LR 708, L 214 S, LR 704, the poly (L-lactide -co-trimethyl carbonate) having the general formula - [(C6H8O4) x- (C4H6O3) y] n- such as LT706, the poly (L-lactide-co-glycolide) s having the general formula - [(C6H8O4) x - (C4H4O4) y] n- such as LG 824, LG 857, the poly (L-lactide-co- ⁇ -caprolactone) s with the general formula - [(C6H8O4) x- (C6H10O2) y] n- as LC 703, the poly (D, L-lactide-co-glycolide) s with the general formula - [[(C6
  • a particularly preferred embodiment of the present invention is applicable to implants such as e.g. Stents, which are biodegradable
  • PTFE Polyurethane
  • PVC Polyvinylchloride
  • PDMS Polydimethylsiloxane
  • Nylon or polylactide and in particular a polyester and / or polylactide are provided.
  • the metallic inner part of these implants has the composition of magnesium disclosed herein and optionally calcium or yttrium with the other ingredients mentioned above.
  • the resorbable implants of the present invention have an inner structure of the magnesium alloy encased in the biodegradable polymer, the coating or sheath being only about the individual struts and not having a full-area sheath or coating of the stent structure, i. the spaces between the individual struts are not covered by the biodegradable polymer.
  • a controlled rate of resorption is achieved by enveloping a resorbable stent with a non-soluble or sparingly soluble polymer coating and providing the polymer wrapper, after application to the resorbable stent, with holes to ensure resorption of the internal stent.
  • Such holes may e.g. be produced mechanically, chemically or optically by laser.
  • a continuous semipermeable polymer shell can also be applied to the stent.
  • the metallic stent is provided with a coating which permits a liquid permeation.
  • a bioresorbable magnesium stent with a coating of a polyurethane, a parylene or Ammini-ppx or a mixture of the aforementioned substances, wherein the coating contains holes, which subsequently after the application of the coating on the metal stent in a mechanical or chemical manner or by laser treatment be generated in an optical manner.
  • a preferred embodiment further constitutes a medical implant which contains more than 70% by weight, more preferably more than 80% by weight, even more preferably more than 85% by weight and most preferably more than 90% by weight
  • the magnesium alloy is made and the remaining weight fraction is the biodegradable polymeric coating.
  • resorbable implants which are at least one pharmacologically on the implant and / or in the implant or under the resorbable or biodegradable layer and / or in the biodegradable layer and / or on the biodegradable layer containing active substance.
  • Preferred pharmacologically active substances are antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic agents, anti-restenosis agents, anti-restenosis agents, corticoids, sex hormones, statins, epothilones, prostacyclins, angiogenesis inducers.
  • the antiproliferative, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic and / or antithrombotic agents and anti-restenosis agents are preferred.
  • antiproliferative, antimigrative, antiangiogenic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, antithrombotic and / or anti-restenotic agents are: abciximab, acemetacin, acetylvismion B, aclarubicin, ademetionin, adriamycin, aescin, afromosone, akagerin, aldesleukin, amidorone , Aminoglutethemide, amsacrine, anakinra, anastrozole, anemonin, anopterin, antifungals, antithrombotics, apocymarin, argatroban, aristolactam-all, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzoca
  • Preferred active ingredients are paclitaxel and its derivatives such as 6- ⁇ -hydroxy-paclitaxel or baccatin or other taxotere, sirolimus, tacrolimus, everolimus, gleevec (imatinib), erythromycin, midecamycin, josamycin and triazolopyrimidines.
  • paclitaxel Texol ®
  • all derivatives of paclitaxel such as 6- ⁇ -hydroxy-paclitaxel.
  • the resorbable implants according to the invention are preferably supporting prostheses for canal-like structures and, in particular, vascular supports and stents for blood vessels, urinary tract, respiratory tract, biliary tract or the digestive tract.
  • stents for blood vessels or, more generally, for the cardiovascular system, i. for the cardiovascular area.
  • the biodegradable polymeric layer serves as an active substance carrier for the at least one antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic, antithrombotic active ingredient and / or anti-restenotic active ingredient.
  • the stent allows regeneration of the supported tissue or supported vessel portion. If the tissue has regenerated, it can support the vessel independently and no further support by the stent is required. At this time, the stented in the vessel wall stent has already been significantly reduced.
  • the preferred stents are formed like a lattice, wherein the individual webs of the lattice structure have similar cross-sectional areas.
  • a ratio of the largest to smallest cross-sectional area is less than 2.
  • the similar cross-sectional areas of the webs cause the stent to be degraded evenly.
  • the web rings are connected by connecting webs, wherein the connecting webs preferably have a smaller cross-sectional area or a smaller minimum diameter than the webs which form the web rings. This ensures that the connecting webs are degraded faster in the human or animal body, as the web rings. As a result, the axial flexibility of the stent increases by dismantling the connecting webs faster than the load capacity of the stent decreases as a result of the degradation of the web rings.
  • the medical implant in particular the stent, can be coated by spraying or dipping, whereby a polymer is dissolved in a solvent and this solution is applied to the implant.
  • Suitable solvents are water and preferably organic solvents such as chloroform, methylene chloride (dichloromethane), acetone, tetrahydrofuran (THF), diethyl ether, methanol, ethanol, propanol, isopropanol, diethyl ketone, dimethylformamide (DMF), dimethylacetamide, ethyl acetate, dimethyl sulfoxide (DMSO). , Benzene, toluene, xylene, t-butyl methyl ether (MTBE), petroleum ether (PE), cyclohexane, pentane, hexane, heptane, with chloroform and methylene chloride.
  • organic solvents such as chloroform, methylene chloride (dichloromethane), acetone, tetrahydrofuran (THF), diethyl ether, methanol, ethanol, propanol, isopropanol
  • a suitable solvent or together with the polymer and the at least one applied drug can be dissolved, emulsified, suspended or dispersed.
  • Suitable substances to be applied are the abovementioned pharmacologically active substances and the polymers described above. 2008/000161
  • a stent according to the invention consists of:
  • metals 1% by weight of other metals, metal salts, non-metals, rare earths, metal carbides, metal oxides, metal nitrides, non-metals,
  • the stent according to Example 1 is coated in the dipping process with a solution of a polyglycol and doxorubicin. After drying, the dipping process is repeated two more times.
  • a stent according to the invention consists of: 81% by weight of magnesium
  • the stent according to Example 2 is spray-coated with a solution of a polylactide and the active ingredient paclitaxel in dimethyl sulfoxide or in methanol. The spraying process is repeated several times.
  • a stent according to the invention consists of: 72.0% by weight of magnesium
  • metals 7.8% by weight of other metals, metal salts, nonmetals, rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.
  • the stent according to Example 3 is spray-coated with a solution of a polyester containing the active substance rapamycin in chloroform. The spraying process is repeated several times.
  • a stent according to the invention consists of: 85.0% by weight of magnesium 4.6% by weight of calcium 2.9% by weight of yttrium
  • metals 0.5% by weight of other metals, metal salts, non-metals, rare earths, metal carbides, metal oxides, metal nitrides, non-metals,
  • the stent according to Example 4 is spray-coated with a solution of a polyamide without a pharmacologically active substance in acetone. The spraying process is repeated several times.
  • Stent # 2 CVD-coated with polyamino-p-xylylene-co-poly-p-xylylene (short:
  • Stent no.3 CVD coated with amino-ppx
  • stent no. 4 CVD-coated with amino-ppx, T / DE2008 / 000161
  • Stent time to complete oxidative dissolution: stent no.1 about 7 minutes
  • Stent No. 2 about 12 minutes Stent No. 3 about 15 minutes Stent No. 4 about 30 minutes
  • CVD coating significantly increases the resistance of the metal to the oxidative reagent.
  • the standard coating results in a fourfold increase in the "lifetime" of the stent, and moreover, the experiment shows that the temporal course of the oxidative dissolution can be regulated by the porosity of the coating.
  • FIG. 1 shows the state of dissolution of the stents according to the invention after approx. 9 minutes and FIG. 2 after approx. 16 minutes.

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Abstract

L'invention concerne une forme spéciale de stent métallique biorésorbable à résorption régulée par un enrobage avec un polymère spécial, de sorte à assurer une résorption régulée de l'endoprothèse enrobée après implantation dans un vaisseau sanguin. L'implant résorbable comprend un alliage de magnésium, muni d'un revêtement biodégradable. Le revêtement biodégradable se compose de préférence de polymères biodégradables et peut en outre comprendre au moins une substance à activité pharmacologique comme par exemple un principe actif à effet antiprolifératif, antimigratoire, anti-inflammatoire, antiphlogistique, zytostatique, zytotoxique et/ou antithrombotique, des principes actifs antiresténose, des corticoïdes, des hormones sexuelles, des statines, des épothilones, des prostacyclines et/ou de inducteurs d'angiogenèse.
EP08706827A 2007-01-30 2008-01-30 Stent métallique biorésorbable à résorption régulée Ceased EP2125063A2 (fr)

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DE102007004589A DE102007004589A1 (de) 2007-01-30 2007-01-30 Bioresorbierbarer Metallstent mit kontrollierter Resorption
US89963607P 2007-02-06 2007-02-06
PCT/DE2008/000161 WO2008092436A2 (fr) 2007-01-30 2008-01-30 Stent métallique biorésorbable à résorption régulée

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DE (1) DE102007004589A1 (fr)
RU (1) RU2009132544A (fr)
WO (1) WO2008092436A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110496225A (zh) * 2019-09-28 2019-11-26 广州暨南生物医药研究开发基地有限公司 千金藤碱与自噬抑制剂联用在制备治疗肝癌药物中的应用

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002345328A1 (en) 2001-06-27 2003-03-03 Remon Medical Technologies Ltd. Method and device for electrochemical formation of therapeutic species in vivo
US8840660B2 (en) 2006-01-05 2014-09-23 Boston Scientific Scimed, Inc. Bioerodible endoprostheses and methods of making the same
US8089029B2 (en) 2006-02-01 2012-01-03 Boston Scientific Scimed, Inc. Bioabsorbable metal medical device and method of manufacture
US8048150B2 (en) 2006-04-12 2011-11-01 Boston Scientific Scimed, Inc. Endoprosthesis having a fiber meshwork disposed thereon
JP2010503494A (ja) 2006-09-15 2010-02-04 ボストン サイエンティフィック リミテッド 生分解性内部人工器官およびその製造方法
JP2010503485A (ja) 2006-09-15 2010-02-04 ボストン サイエンティフィック リミテッド 医療用デバイスおよび同デバイスの製造方法
CA2663762A1 (fr) 2006-09-18 2008-03-27 Boston Scientific Limited Endoprothese
CA2674195A1 (fr) 2006-12-28 2008-07-10 Boston Scientific Limited Endoprotheses bio-erodables et procedes de fabrication de celles-ci
DE102007038799A1 (de) * 2007-08-17 2009-02-19 Biotronik Vi Patent Ag Implantat aus einer biokorrodierbaren Magnesiumlegierung und mit einer Beschichtung aus einem biokorrodierbaren Polyphosphazen
US8118857B2 (en) 2007-11-29 2012-02-21 Boston Scientific Corporation Medical articles that stimulate endothelial cell migration
US7998192B2 (en) 2008-05-09 2011-08-16 Boston Scientific Scimed, Inc. Endoprostheses
US8236046B2 (en) 2008-06-10 2012-08-07 Boston Scientific Scimed, Inc. Bioerodible endoprosthesis
DE102008040640A1 (de) 2008-07-23 2010-01-28 Biotronik Vi Patent Ag Endoprothese und Verfahren zur Herstellung derselben
US7985252B2 (en) 2008-07-30 2011-07-26 Boston Scientific Scimed, Inc. Bioerodible endoprosthesis
DE102008038368A1 (de) * 2008-08-19 2010-02-25 Biotronik Vi Patent Ag Verwendung von organischen Gold-Komplexen als bioaktive und radioopaque Stentbeschichtung für permanente und degradierbare vaskuläre Implantate
US8382824B2 (en) 2008-10-03 2013-02-26 Boston Scientific Scimed, Inc. Medical implant having NANO-crystal grains with barrier layers of metal nitrides or fluorides
DE102009002709A1 (de) * 2008-10-06 2010-04-08 Biotronik Vi Patent Ag Implantat und Verfahren zur Herstellung desselben
DE102008042603A1 (de) * 2008-10-06 2010-04-08 Biotronik Vi Patent Ag Implantat sowie Verfahren zur Herstellung einer degradationshemmenden Schicht auf einer Körperoberfläche eines Implantats
DE102008043277A1 (de) * 2008-10-29 2010-05-06 Biotronik Vi Patent Ag Implantat aus einer biokorrodierbaren Eisen- oder Magnesiumlegierung
DE102008054920A1 (de) * 2008-12-18 2010-07-01 Biotronik Vi Patent Ag Implantat sowie Verfahren zur Herstellung einer Schichtstruktur
US8267992B2 (en) 2009-03-02 2012-09-18 Boston Scientific Scimed, Inc. Self-buffering medical implants
JP5463531B2 (ja) * 2009-07-22 2014-04-09 国立大学法人 東京大学 Ｐｈｄ２発現抑制物質搭載ポリイオンコンプレックス
DE102010019365A1 (de) 2009-12-18 2011-06-22 Acoredis GmbH, 07743 Biologisch abbaubares Verschlußimplantate zur Behandlung von Atriumseptumdefekt (ASD) bzw. persistierendem Foramen ovale (PFO) und ihre Herstellung
WO2011119573A1 (fr) 2010-03-23 2011-09-29 Boston Scientific Scimed, Inc. Endoprothèses en métal bioérodable traitées en surface
CA2802753C (fr) 2010-06-21 2018-07-31 Zorion Medical, Inc. Implants bioabsorbables
WO2012003502A2 (fr) 2010-07-02 2012-01-05 University Of Florida Research Foundation, Inc. Alliage de métal bio-résorbable et implants à base de celui-ci
US11491257B2 (en) 2010-07-02 2022-11-08 University Of Florida Research Foundation, Inc. Bioresorbable metal alloy and implants
EP2433660B1 (fr) 2010-09-28 2014-07-30 Biotronik AG Implant revêtu en alliage de magnésium biocorrodable
WO2012075311A2 (fr) 2010-12-01 2012-06-07 Zorion Medical, Inc. Implants absorbables à base de magnésium
US20120150282A1 (en) * 2010-12-10 2012-06-14 Biotronik Ag Implant having a paclitaxel-releasing coating
EP2744532B1 (fr) 2011-08-15 2015-09-16 MeKo Laserstrahl-Materialbearbeitungen e.K. Endoprotheses resorbables contenant un alliage de magnesium
CN102727948A (zh) * 2011-11-14 2012-10-17 上海市第一人民医院 生物可降解镁合金胆管溶石镂刻支架及制备方法
US9333099B2 (en) * 2012-03-30 2016-05-10 Abbott Cardiovascular Systems Inc. Magnesium alloy implants with controlled degradation
US20140088618A1 (en) * 2012-09-21 2014-03-27 Jie Song Elastomeric and degradable high-mineral content polymer composites
US20140180398A1 (en) * 2012-12-20 2014-06-26 Cook Medical Technologies Llc Bioabsorbable Medical Devices and Methods of Use Thereof
EP2767294B1 (fr) 2013-02-13 2018-03-21 Biotronik AG Implant biocorrodable doté d'un revêtement anticorrosion
EP2767295B1 (fr) 2013-02-13 2015-11-04 Biotronik AG Implant biocorrodable doté d'un revêtement anticorrosion
US10266922B2 (en) 2013-07-03 2019-04-23 University Of Florida Research Foundation Inc. Biodegradable magnesium alloys, methods of manufacture thereof and articles comprising the same
DE102013214636A1 (de) 2013-07-26 2015-01-29 Heraeus Medical Gmbh Bioresorbierbare Werkstoffverbunde, enthaltend Magnesium und Magnesiumlegierungen sowie Implantate aus diesen Verbunden
DE102013014821A1 (de) * 2013-09-10 2015-03-12 Alexander Rübben Gefäßendoprothesenbeschichtung
WO2015069724A1 (fr) 2013-11-05 2015-05-14 University Of Florida Research Foundation, Inc. Articles comprenant des vis fixées de façon réversible comprenant une composition biodégradable, leurs procédés de fabrication et leurs utilisations
CN103736152B (zh) * 2013-12-26 2016-12-07 西安爱德万思医疗科技有限公司 一种人体可吸收的耐蚀高强韧锌合金植入材料
JP5955474B2 (ja) * 2013-12-26 2016-07-20 株式会社クレハ 炭化水素資源回収用ボールシーラーならびにその製造方法及びそれを用いる坑井の処理方法
WO2016118444A1 (fr) 2015-01-23 2016-07-28 University Of Florida Research Foundation, Inc. Alliages atténuant et bloquant les rayonnements, procédés de fabrication de ceux-ci et articles les comprenant
WO2017204803A1 (fr) * 2016-05-25 2017-11-30 Q3 Medical Devices Limited Dispositif de support biodégradable
EP3474787A4 (fr) * 2016-06-23 2020-02-19 Poly-Med, Inc. Implants médicaux à biodégradation gérée
CN106236699B (zh) * 2016-08-25 2019-03-29 中国医科大学附属第一医院 一种抗肿瘤缓释植入剂及其制备方法
DE102016119227A1 (de) * 2016-10-10 2018-04-12 Cortronik GmbH Bioresorbierbare Implantate aus extrudiertem Pulver mit variierender chemischer Zusammensetzung
CN108330367B (zh) * 2018-03-02 2020-01-14 北京大学深圳研究院 一种可吸收骨科植入镁合金及其制备方法
CN110680960A (zh) * 2018-07-04 2020-01-14 苏州纳晶医药技术有限公司 一种可控梯度降解螺旋状覆膜支架、其制备方法及其用途
US11931482B2 (en) 2019-03-18 2024-03-19 Brown University Auranofin-releasing antibacterial and antibiofilm polyurethane intravascular catheter coatings
WO2021090177A1 (fr) * 2019-11-04 2021-05-14 Sun Pharmaceutical Industries Limited Composés pour le traitement d'une infection de la dengue
US20220354487A1 (en) 2021-05-10 2022-11-10 Cilag Gmbh International Method for implementing a staple system
CN115569244B (zh) * 2022-09-28 2024-03-12 珠海睿展生物材料有限公司 一种夹心式可降解生物材料及其应用

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8172897B2 (en) * 1997-04-15 2012-05-08 Advanced Cardiovascular Systems, Inc. Polymer and metal composite implantable medical devices
US10028851B2 (en) * 1997-04-15 2018-07-24 Advanced Cardiovascular Systems, Inc. Coatings for controlling erosion of a substrate of an implantable medical device
DE19913978A1 (de) * 1999-03-18 2000-09-28 Schering Ag Asymmetrische Stents, Verfahren zu ihrer Herstellung und ihre Verwendung zur Restenoseprophylaxe
US20040220660A1 (en) * 2001-02-05 2004-11-04 Shanley John F. Bioresorbable stent with beneficial agent reservoirs
DE20204258U1 (de) * 2002-03-16 2003-07-31 Ruebben Alexander Stent mit Beschichtung (Vitastent 2)
ATE318623T1 (de) * 2002-05-14 2006-03-15 Terumo Corp Beschichteter stent für die freisetzung aktiver substanzen
DE10237572A1 (de) * 2002-08-13 2004-02-26 Biotronik Meß- und Therapiegeräte GmbH & Co. Ingenieurbüro Berlin Stent mit polymerer Beschichtung
US20040147999A1 (en) * 2003-01-24 2004-07-29 Kishore Udipi Stent with epoxy primer coating
DE10361941A1 (de) * 2003-12-24 2005-07-28 Restate Patent Ag Magnesiumhaltige Beschichtung
DE102004029611A1 (de) * 2004-02-06 2005-08-25 Restate Patent Ag Implantat zur Freisetzung eines Wirkstoffs in ein von einem Körpermedium durchströmtes Gefäß
US8357391B2 (en) * 2004-07-30 2013-01-22 Advanced Cardiovascular Systems, Inc. Coatings for implantable devices comprising poly (hydroxy-alkanoates) and diacid linkages
US20060083770A1 (en) * 2004-10-15 2006-04-20 Specialty Coating Systems, Inc. Medical devices and methods of preparation and use
EP1842507B1 (fr) * 2005-01-28 2013-04-24 Terumo Kabushiki Kaisha Implant intravasculaire
US20060198869A1 (en) * 2005-03-03 2006-09-07 Icon Medical Corp. Bioabsorable medical devices
WO2006108065A2 (fr) * 2005-04-05 2006-10-12 Elixir Medical Corporation Dispositifs medicaux implantables degradables
DE102005018356B4 (de) * 2005-04-20 2010-02-25 Eurocor Gmbh Resorbierbare Implantate
KR20080008364A (ko) * 2005-05-05 2008-01-23 헤모텍 아게 관 스텐트의 전면 코팅
US20070173923A1 (en) * 2006-01-20 2007-07-26 Savage Douglas R Drug reservoir stent
DE102006038235A1 (de) * 2006-08-07 2008-02-14 Biotronik Vi Patent Ag Verbesserung der Stabilität biodegradierbarer metallischer Stents, Verfahren und Verwendung
DE102006038236A1 (de) * 2006-08-07 2008-02-14 Biotronik Vi Patent Ag Biodegradierbarer Stent mit einer aktiven Beschichtung
DE102006039346A1 (de) * 2006-08-22 2008-03-13 Biotronik Vi Patent Ag Biokorrodierbares metallisches Implantat mit einer Beschichtung oder Kavitätenfüllung aus einem PEG/PLGA-Copolymer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008092436A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110496225A (zh) * 2019-09-28 2019-11-26 广州暨南生物医药研究开发基地有限公司 千金藤碱与自噬抑制剂联用在制备治疗肝癌药物中的应用

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DE102007004589A1 (de) 2008-07-31
US20110076319A1 (en) 2011-03-31
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RU2009132544A (ru) 2011-03-10
BRPI0807827A2 (pt) 2014-08-05

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