EP3648806A1 - Revêtement de surface biorésorbable pour le retardement de dégradation - Google Patents

Revêtement de surface biorésorbable pour le retardement de dégradation

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Publication number
EP3648806A1
EP3648806A1 EP18738314.6A EP18738314A EP3648806A1 EP 3648806 A1 EP3648806 A1 EP 3648806A1 EP 18738314 A EP18738314 A EP 18738314A EP 3648806 A1 EP3648806 A1 EP 3648806A1
Authority
EP
European Patent Office
Prior art keywords
hydrophobic
hydrophobic cationic
acid
electrolyte
surface coating
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.)
Withdrawn
Application number
EP18738314.6A
Other languages
German (de)
English (en)
Inventor
Max DIETZ
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.)
Drei Lilien Pvg & Co KG GmbH
Original Assignee
Drei Lilien Pvg & Co KG GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Drei Lilien Pvg & Co KG GmbH filed Critical Drei Lilien Pvg & Co KG GmbH
Publication of EP3648806A1 publication Critical patent/EP3648806A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/34Macromolecular 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • 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
    • 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
    • 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings
    • 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
    • A61L2420/00Materials or methods for coatings medical devices
    • A61L2420/02Methods for coating medical devices

Definitions

  • the present invention relates to a biodegradable surface coating for inhibiting arrosion / corrosion or degradation of solid materials for medical applications and their integration into cell assemblies.
  • the anti-proliferative substances used for this purpose are cytotoxic and may themselves cause unwanted tissue reactions, such as neoartheriosclerosis.
  • Another disadvantage of the known polymer coatings is that in order to maintain the full area of the coating and its integrity, a layer structure is required which has a certain minimum thickness, which is between 5 and 150 ⁇ . It also leads to surface irregularities, which in turn can lead to an increased adhesion of platelets and to a proliferation increase of adherent cells. It has been shown that with thin polymer coatings coating gaps remain, so that coating thicknesses must be selected, which are generally more than 10 ⁇ . Together with the resulting surface roughness this in turn leads to a deterioration of the applicability of vascular implants.
  • Medical implants are also made of metal alloys or polymers that are partially or completely degraded at the site of implantation over time. It has been found that a delay of the degradation is advantageous in a large number of applications. This applies, for example, to magnesium-based stents in which, without inhibition of degradation, after only a few days loss of support function occurs due to fractures of individual arroded struts. Therefore, hydrophobic alloys as well as degradable polymer coatings have been proposed, thereby extending the time to instability of such a stent. However, it has been shown that the achievable time delay of the degradation is not sufficient and such coated stents are very difficult to demonstrate in a vessel. Furthermore, an increased frequency of thrombosis formation has been reported. Therefore, there is a great need for a surface coating with improved corrosion protection at the same time low layer thickness, which does not require activation of inflammatory processes.
  • a surface coating of medical implants may be desirable if, for example, improved wound healing can be achieved or the biocompatibility can be improved or the implant can or must also be protected against degradation and corrosive changes. Furthermore, surface coatings are used to release drugs locally. According to the state of the art, different coating systems for medical technology are used for these different tasks
  • hydrophilic degradation products can be layers containing water by diffusive Processes that are driven by an electrical gradient or a diffusion gradient penetrate, thereby entering an adjacent water phase.
  • water permeability is or can be reduced to a relevant extent.
  • hydrophilic compounds are used to ensure high biocompatibility and degradability of the coating substances.
  • polymeric coatings are therefore predominantly hydrophilic and absorb water.
  • Another problem is to prevent passage of water and degradation products through surface coating without causing activation of clotting factors or adherent cells and / or having high long-term stability and / or eliminated by a diffusive dissolution and dissolution process ie without a monocytic degradation, can be metabolized by attaching cells or eliminated via a lymphatic transport system.
  • the object of the invention is to provide a surface coating which on the one hand is biocompatible, biodegradable and flexible, and on the other hand impermeable to water.
  • another object is to provide a surface coating with which medical products can be provided with very low layer thicknesses and is also biocompatible, biodegradable, flexible and impermeable to water.
  • the object of such a coating is that it delays or prevents arrosion / corrosion and / or degradation of the coated material.
  • the present object is achieved by providing a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • the present invention relates to the provision of a surface coating for medical devices, in particular blood-contacting medical devices, comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • One embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is anhydrous.
  • Another aspect of the present invention is a medical product coated with a surface coating according to the invention.
  • An embodiment of the invention is directed to a medical product having a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is applied anhydrous. It has been shown that an effective delay or inhibition of corrosion / corrosion or degradation processes of the coated materials, in particular by efficient isolation of the material against penetration of water molecules and / or ions, is determined. It was found that, especially in an aqueous medium with dissolved electrolytes, such an efficient insulation, which also requires electrical insulation and is characterized by the electrical surface resistance, is suitable for this purpose.
  • Isolating or “isolation” as used herein means that mass transfer in both directions is not possible for a given time interval.
  • the term “insulating” or “isolation” includes the penetration of water molecules and / or ions, i. the reduction of the permeability of water molecules and / or ions or the complete impermeability of water molecules and / or ions.
  • the term may include electrical isolation.
  • a reduction or complete elimination of water permeability may be recognized by a delay / inhibition of corrosion / corrosion of water-erodible or corrodible materials such as iron or magnesium. Therefore, the extent of the corrosion / corrosion delay can be used to quantify the water impermeability.
  • the reduction in water impermeability as referred to herein is at least> 90%, more preferably> 95%, and more preferably> 98 ° to an uncoated surface upon incorporation of the material in an aqueous medium such as physiological solutions such as PBS or NaCl the duration of at least 4 weeks.
  • Electrode isolation means the reduction or complete elimination of galvanic voltage or current flow.
  • Reduction is when the galvanic voltage or current flow is at least 95%, more preferably 98% - calculated the difference between coated and uncoated metallic surface - is reduced.
  • the electrical insulation can be characterized by the surface electrical resistance.
  • the contact of cells with a foreign material causes an immunological reaction that has a proinflammatory effect.
  • an immunological reaction that has a proinflammatory effect.
  • a tissue trauma As a tissue trauma was triggered, there is a synergistic amplification of the immunological reaction.
  • a pH shift or a high ion concentration or a shift in the osmolality of the tissue fluid surrounding the implant cause a potentiation of the immunological reaction.
  • compounds are released that cause one or more of the aforementioned local effects, eg. By the release of hydrogen ions or lactic acid.
  • Such an immunological reaction does not occur, or only to a minor extent, if there is no inflammatory reaction in the tissue section in which the foreign material decomposes.
  • the electrostatically bound nitrile fatty acids due to their strong hydrophobicity, exhibit a significantly lower detachment behavior of surfaces when stored in an aqueous medium compared to the non-nitrated corresponding fatty acids, there is no long-term stability in an aqueous medium. This can lead, in particular in the case of degradable materials, in which coating with nitrofatty acids is not sufficiently long, to the fact that proinflammatory processes occur due to an already occurring degradation, which then nevertheless leads to undesired tissue reactions.
  • a biocompatible and biodegradable surface coating for medical or medical grade solid materials can be provided to reduce or inhibit the immunostimulatory / proinflammatory and / or proliferative stimulus of the material surface of the solid material over a period of time that is physiologic healing / healing of concomitant / underlying injury / trauma to the tissue association in which the solid material resides goes beyond.
  • an immunological reaction of the tissue or body fluid adjacent to a medical or medical material coated according to the present invention which exceeds a physiological response can be prevented.
  • Another embodiment of the present invention is a surface coating for corrosion and / or degradation delay, comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • the surface coating is biodegradable and insulating and / or self-healing.
  • the surface coatings of the invention preferably have a water contact angle of> 80 ° or> 80 °, more preferably> 90 ° or> 90 °, more preferably> 100 ° or> 100 °, more preferably> 1 10 ° or> 1 10 °, more preferably > 120 ° or> 120 °, more preferably> 130 ° or> 130 °, more preferably> 140 ° or> 140 °, even more preferably> 150 ° or> 150 °,> 160 ° or> 160 ° and most preferably> 170 ° or> 170 °.
  • Water contact angle is usually measured at a standard pressure of 1, 013 bar and standard temperature of 25 ° C.
  • Another aspect of the present invention is an anhydrous composition for corrosion and / or degradation retardation comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte for use in medicine in the form of a coating.
  • anhydrous corrosion and / or degradation retardant composition comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte for use in the treatment of arteries, in particular arterial stenoses, in the form of a coating.
  • One measure of the permeability of a barrier layer by water molecules is, inter alia, the ion conductivity / electron conductivity, or the electrical resistance of such a coating, which is also referred to below as insulation resistance or surface resistance. Therefore, the completeness of the insulation achieved by a coating was determined by determining the ionic conductivity of a coated metallic substrate in an electrolyte bath (0.9% NaCl and 0.5% NaSO 4 ).
  • An indirect indication of penetration of water molecules through a barrier, or corrosion / erosion may be leakage of ions or degradation products (eg, hydrogen ions) from the coated material into an aqueous medium into which the coated materials to verify long-term stability be inserted.
  • the change in the electrical conductivity of the aqueous medium in which the substrates are inserted can be used as a summation measurement parameter.
  • polyelectrolytes are suitable for surface coating since, when dissolved in an aqueous medium, they can be applied very easily to surfaces having an opposite charge with a high resistance when used together with them Be brought in contact.
  • the aqueous polyelectrolyte systems known from the prior art are of low or medium viscosity, so that they can nevertheless be detached from surfaces in an aqueous medium by a shear flow. Therefore, according to the prior art, multiple layers of coating are applied with polyelectrolytes which are applied in alternating sequence with opposite signs of their charge groups. Such coatings can not be prepared anhydrous, so they do not prevent degradation of the substrate they cover.
  • the substances previously used for the coating have a high water solubility and at the same time are not soluble in organic solvents, at least alone. Furthermore, the said substances already contain water because of their high water affinity. Furthermore, the said substances are viscous in pure form and therefore unsuitable for a thin application.
  • biocompatible compounds known for a prior art surface coating are applied in the form of aqueous solutions.
  • coating substances that were dissolved in an aqueous system it has been shown that even a short water exposure is sufficient to initiate superficial degradation in degradable materials / implants.
  • the z. B. leads to the formation of free ions or hydroxides, even after drying, with production of an anhydrous surface, corrosion / degradation even after application of a largely water-impermeable layer, it comes in these areas significantly earlier and faster to further corrosion / erosion, as is the case with coated surfaces where there is no such surface activation by water contact.
  • nitro group-bearing carboxylic acids can be used for the surface coating of medical materials / implants.
  • nitro-group-bearing fatty acids nitrofatty acids
  • fatty acids can be deposited from an organic solvent phase on surfaces.
  • very thin layers e.g. in the form of monolayers. In this case, closed layers which have a marked surface hydrophobicity with a water contact angle of 60 ° to 90 ° can be produced.
  • single- or multi-layer coatings with fatty acids are not sufficient to prevent the passage of water molecules through such a coating with fatty acids.
  • the surface coating according to the invention is therefore preferably biodegradable.
  • a preferred embodiment of the present invention is therefore directed to a surface coating comprising at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is prepared anhydrous and bioresorbable.
  • Another aspect of the present invention is directed to a method of making surface coatings comprising the following steps:
  • Preference is given to a method for suppressing the release of proinflammatory and proliferation-promoting corrosion / corrosion products from medical implants.
  • Preferred is a method of providing reservoir formation in a coating composition with carboxylic acids / nitrocarboxylic acids which enable cell homing to surfaces of medical implants and wound care materials coated therewith.
  • Preferred is a method in which by a degradation delay of a medical device, which is surrounded by a body fluid or at least in an area adjacent to such and / or by a Degradation delay of the coating with carboxylic acids / nitrocarboxylic acids, a proliferation of fibroblasts, endothelial cells, epithelial cells or leukocytes is reduced or prevented.
  • a surface coating is preferred for reducing or avoiding restenosis and / or thrombosis after implantation of a vascular implant.
  • a preferred embodiment is directed to a surface coating according to the invention, wherein the surface coating comprises a carboxylic acid layer comprising the at least one carboxylic acid and an electrolyte layer comprising the at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising the at least one hydrophobic cationic electrolyte and / or the at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • a further preferred embodiment is directed to a surface coating according to the invention, the surface coating comprising a carboxylic acid layer comprising the at least one carboxylic acid and an electrolyte layer comprising the at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising the at least one hydrophobic cationic electrolyte and / or or the at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous, wherein the carboxylic acid layer is on the electrolyte layer.
  • the surface of the solid material from step a) is preferably wetted with at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte ,
  • a process according to the invention with a step c) drying of the surface after step b) is preferred.
  • Preference is furthermore given to a process according to the invention comprising a step d) water-free wetting of the surface from step c) with at least one carboxylic acid.
  • a method according to the invention preferably contains step e) rinsing and drying of the surface from step d). In order to remove solvents, they are dried in step c). In particular, it is meant that an organic solvent is completely removed from the coating. Drying may be at elevated or reduced temperatures.
  • Another aspect of the present invention is directed to a method of making surface coatings, comprising the following steps:
  • step b) waterless wetting of the surface of the solid material from step a) with at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte,
  • step d) waterless wetting of the surface from step c) with at least one carboxylic acid
  • a preferred embodiment of the present invention relates to a process for producing a surface coating, comprising the following steps: a) providing a solid material having a cleaned and / or hydrophobicized material surface,
  • step b) waterless wetting of the surface of the solid material from step a) with at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte,
  • step d) waterless wetting of the surface from step c) with at least one carboxylic acid
  • a preferred embodiment of the present invention relates to a process for producing a surface coating comprising the following steps: a) providing a solid material having a cleaned and / or hydrophobicized material surface, b) waterless wetting of the surface of the solid material with at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte,
  • the processes according to the invention are preferably directed to processes for producing a hydrophobic, biodegradable, biocompatible and insulating surface coating, in particular preferably for corrosion and / or degradation delay of solid materials. It is therefore preferred if in step f) a biodegradable, biocompatible surface coating with hydrophobic surface properties is obtained.
  • Another aspect of the present invention is directed to a process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials.
  • Another aspect of the present invention is directed to a process for producing surface coating for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps:
  • a layer comprising at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least A hydrophobic cationic polyelectrolyte will hereinafter be referred to as "electrolyte layer.”
  • electrolyte layer A layer comprising at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least A hydrophobic cationic polyelectrolyte will hereinafter be referred to as "electrolyte layer.”
  • Polyelectrolytelayer refers to a layer comprising at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic polyelectrolyte.
  • Another aspect of the present invention is directed to a surface coating obtainable or obtained by a process according to the invention.
  • a hydrophobic, biocompatible, biodegradable and / or insulating surface coating is preferred.
  • One embodiment of the present invention is directed to a surface coating obtainable or obtained by a process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps:
  • step a) a solid material comprising a cleaned and / or hydrophobized material surface is preferably provided.
  • Another aspect of the present invention is a medical product having a surface coating obtainable or obtained by a method of the invention. It is preferably a hydrophobic, biodegradable, biocompatible and insulating surface coating.
  • Hydrophilic cationic polyelectrolytes are widely used in the prior art, for example as flocculants in water treatment or as stabilizers in suspensions of aqueous media.
  • hydrophobic cationic electrolytes are less common. They are for example in Building material systems, such as used in cement. Positive charge groups are provided predominantly by quaternized nitrogen compounds. But other charge carriers are suitable, such as imines, azanes, triazanes, tetrazanes, nitrones.
  • DE10124387A1 discloses methods with which hydrophilic cationic polyelectrolytes can be hydrophobically functionalized.
  • a prerequisite for achieving an anti-erosion / corrosion-resistant coating and insulating the coated material according to the coating methods of the present invention is that a cationic electrolyte or polyelectrolyte of an anhydrous phase and high adhesion force is deposited on a material surface. Since a covalent combination of the compounds to be used for the surface coating is not desired in order to allow good biodegradability and to ensure the lowest possible requirement for the involvement of cellular degradation processes, it is also the object of the invention to provide an insulating layer structure by hydrophobic attraction forces this stability offers.
  • hydrophobic cationic polyelectrolytes can be applied anhydrously on surfaces of different materials to a closed film.
  • the preferably physiosorptively applied hydrophobic cationic polyelectrolytes have a high binding stability and virtually do not dissolve in an aqueous medium.
  • a multilayer structure of hydrophobic cationic polyelectrolytes also failed to achieve electrical isolation of the coated material so that water molecules could pass through a coating of hydrophobic cationic polyelectrolytes and result in corrosion / corrosion of the coated material. Therefore, hydrophobic cationic polyelectrolytes having different ratios of charge-carrying linkage moieties and carbon chain lengths were investigated. It was found that as the charge groups decreased and / or the carbon chain lengths increased, as well as the degree of branching, although hydrophobicity increased, isolation of a surface coated therewith could not be ensured.
  • an electrical insulation could be achieved by applying a self-assembling layer of fatty acids from an anhydrous mixed solution to an electrolyte layer applied anhydrous. It has also been found that electrical insulation is not achieved when coating with the same or similar compounds, but using a mixed solution containing water. This applies to both the application of the electrolyte layer (hydrophobic cationic electrolytes and / or hydrophobic cationic polyelectrolytes), as well as for the application of the carboxylic acids.
  • Preferred is a method according to the invention described herein for producing a biodegradable surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials comprising a single- or multi-layered construction comprising at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and a carboxylic acid, carried out by means of an anhydrous application.
  • the surface layer preferably consists of a layer containing at least one hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and also at least one carboxylic acid.
  • a preferred embodiment of the present invention is a process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps:
  • a single-layer or multi-layered layer structure consists of at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and the at least one carboxylic acid, and wherein the layer application takes place in each case anhydrous.
  • a surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials is obtainable or obtained by a method of the invention described herein, wherein a single or multi-layered layer structure of at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and a carboxylic acid by means of an anhydrous application, preferably.
  • the surface coating comprises or consists of at least one carboxylic acid for the corrosion and / or degradation delay of solid materials; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein a single- or multi-layered layer structure consists of a layer comprising or consisting of the at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and a layer comprising or consisting of the at least one carboxylic acid, and wherein the layer application is carried out in each case anhydrous.
  • liquid carboxylic acids of different chain lengths could be applied directly by known methods, such as the micropipetting method or a spray-coating, which also has a surface hydrophobicity with water contact angles of>of> 80 ° or> 80 °, more preferably> 90 ° or> 90 °, more preferably> 100 ° or> 100 °, more preferably> 1 10 ° or> 1 10 °, more preferably> 120 ° or> 120 °, further preferably> 130 ° or> 130 °, more preferably> 140 ° or> 140 °, even more preferably> 150 ° or> 150 °,> 160 ° or> 160 ° and most preferably> 170 ° or> 170 ° , Even such applied carboxylic acid compounds could be removed in part by rinsing with an ethanolic solution again.
  • a high occupancy rate (per unit area) and occupancy stability of carboxylic acids could be achieved by depositing fatty acids having a chain length of> 5 onto anhydrous hydrophobic cationic polyelectrolyte layers using organic solvents using an anhydrous surface coating process become.
  • Occupancy stability is reported as a time-dependent release of carboxylic acids when placed in an aqueous medium at a temperature of 37 ° C. Those skilled in the art will appreciate that occupancy stability is considered relative to other coatings.
  • the process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprises the following steps:
  • the completeness of the coverage could be determined by an increase in the surface hydrophobicity, which was determined, for example, by water contact angle measurements and the electrical resistance of the surface coating.
  • the measurable surface hydrophobicity did not increase further from a chain length of saturated and unbranched carboxylic acids of 14, at the same time the achievable surface resistance increased with increasing chain length and degree of branching and the proportion of unsaturated carboxylic acids with unsaturated double bond in ice. Configuration.
  • Surface coatings prepared according to the invention have water contact angles of> 80 ° or> 80 °, more preferably> 90 ° or> 90 °, more preferably> 100 ° or> 100 °, more preferably> 1 10 ° or> 1 10 °, more preferably> 120 ° or> 120 °, more preferably> 130 ° or> 130 °, more preferably> 140 ° or> 140 °, even more preferably> 150 ° or> 150 °,> 160 ° or> 160 ° and most preferably> 170 ° or> 170 °.
  • a 3-layer construction more preferably a 2-layer structure and more preferably a l-layer structure. If the most complete and long-lasting degradation delay and electrical insulation are in the foreground of the application, it may be advantageous to ensure the highest possible layer structure, which is achieved by a multi-layer coating order. Therefore, in such an application, preferably a 4-ply, more preferably a 6-ply, more preferably an 8-ply, and still further preferably to form a 10-layer layer structure.
  • the number of layers is not limited, so even more layers can be applied.
  • a coating according to the invention improves the degradation stability in several respects: on the one hand, the binding of carboxylic acids and in particular of nitro fatty acids to the surface of the coating is markedly increased, and thus the time to detachment, which leads to a change in physics chemical (loss of hydrophobicity) and biological properties leads to significantly prolonged occupancy of the carboxylic acid on a native material surface.
  • the coating accomplishes a significant delay in exposing the native material surface to an aqueous medium or biological system / organism. Consequently, this also significantly delays potential corrosion / corrosion of the material surface. However, the biological reaction to the material surface and / or the corrosion / corrosion product is also delayed.
  • the degradation processes which are usually initiated or maintained by contact with water, are delayed and the function of the coated material, which as a rule has mechanical tasks, is maintained over a relatively long period of time. Therefore, a degradation stability increase in various fields is desired and usable.
  • Preferred is a process for producing a biodegradable surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials, wherein a single or multi-layered layer structure of a hydrophobic cationic polyelectrolyte and a carboxylic acid preferably contains at least one nitrofatty acid or a mixture comprising or consisting of at least nitrofatty acids and at least one non-nitrated fatty acids by means of an anhydrous application takes place.
  • the at least one carboxylic acid is preferably a fatty acid, more preferably a nitrated carboxylic acid, and most preferably a nitrated carboxylic acid wherein the carboxylic acids have a carbon chain length of 6 to 24 from 8 to 22, more preferably from 10 to 20, more preferably from 12 to 20, and most preferably from 14 to 18.
  • the process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprises the following steps:
  • the process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation delay of solid materials comprises the following steps:
  • the method for producing a hydrophobic, biodegradable and insulating surface coating for the corrosion and / or degradation delay of solid materials comprises the following steps:
  • step d) water-free wetting of the surface with at least one carboxylic acid, wherein the carboxylic acids in step d) are mixtures of nitrated and non-nitrated fatty acids having a carbon chain length of 6 to 24,
  • the method for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprises the following steps:
  • carboxylic acid is a nitrofatty acid or a mixture comprising or consisting of at least one nitrofatty acid and at least one non-nitrated fatty acid, wherein the fatty acid has a carbon chain length of 6 to 24 having,
  • the prevention / delaying of erosion / corrosion or degradation of solid materials according to the invention can be produced by a respective simple and preferably monolayer coating with a hydrophobic cationic electrolyte layer and a fatty acid according to the invention, which have each been applied anhydrous.
  • a layer structure has a layer thickness which is ⁇ 50 ⁇ m, more preferably ⁇ 10 ⁇ m, more preferably ⁇ 1 ⁇ m, even more preferably ⁇ 50 nm and most preferably ⁇ 20 nm is.
  • a multi-layered layer structure with a hydrophobic cationic electrolyte in combination with one of the fatty acids according to the invention further increases the insulation resistance. Therefore, a multi-layered layer structure with a hydrophobic cationic polyelectrolyte is a preferred method.
  • a final coating with at least one nitrofatty acid or a mixture comprising or consisting of at least one nitrofatty acid and at least one non-nitrated fatty acid which has been applied anhydrous is particularly preferred.
  • the final coating comprises or consists of at least one nitrofatty acid which has been applied anhydrous.
  • the finished surface coating according to the invention preferably has a total height of its layer structure, which is between 5 nm and 50 ⁇ , more preferably between 10nm and 45 ⁇ , more preferably between 10nm and 40 ⁇ , 10nm and 35 ⁇ , more preferably between 10nm and 30 ⁇ , more preferably between 10nm and 25 ⁇ , more preferably between 15nm and 20 ⁇ , even more preferably between 15nm and 15 ⁇ and more preferably between 20nm and 10 ⁇ .
  • Cationic polyelectrolytes have extensive documentation on cytotoxic effects (Kafil V, Omidi Y. Cytotoxic Impacts of Linear and Branched Polyethyleneimines Nanostructures in A431 Cells Biolmpacts: Bl. 201 1; 1 (1): 23-30).
  • the cytotoxicity increases, for example, with the degree of branching of polyethyleneimine.
  • a surface coating according to the invention described herein is also obtainable or obtainable by a process according to the invention described here which prevents or delays the erosion / corrosion or degradation of solid materials and is also suitable for preventing cytotoxic effects in the event of a degradation of the coating.
  • templates which had been stored in an aqueous medium over the same period of time and had no coating were completely or partially dissolved, and those which had been coated only with a hydrophobic cationic polyelectrolyte showed significant substance defects or had a partial dissolution (magnesium alloy). on.
  • the surfaces coated according to the invention retained their hydrophobic surface properties unchanged over a period of at least 3 weeks during which they were placed in an aqueous solution at 37 ° C., recognizable by the fact that the water contact angle did not fall more than 10 ° with respect to the initial measurement.
  • a preferred embodiment of the underlying invention is directed to a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps:
  • a single- or multi-layered layer structure of at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and a final coating with nitrofatty acid or a mixture of nitrofatty acids and non-nitrated fatty acids by means a water-free application takes place, whereby a water-resistant heatnhydrophobleiter with a water contact angle of> 80 ° or> 80 °, more preferably> 90 ° or> 90 °, more preferably> 100 ° or> 100 °, more preferably> 1 10 ° or> 1 10 °, more preferably> 120 ° or> 120 °, more preferably> 130 ° or> 130 °, more preferably> 140 ° or> 140 °, even more preferably> 150 ° or> 150 °,> 160 ° or> 160 ° and most preferably> 1
  • a preferred embodiment of the present invention is a surface coating for corrosion and / or degradation retardation of solid materials comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein a single or multilayered layer structure of at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and a final coating with nitrofatty acid or a mixture of nitrofatty acids and non-nitrated fatty acids by means of an anhydrous application, wherein the surface coating is water resistant and a water contact angle of> 80 ° or> 80 °, more preferably > 90 ° or> 90 °, more
  • coatings prepared according to the invention anhydrous it was found that degradation starts at the earliest after 4 weeks under the selected experimental conditions.
  • surface hydrophobicity achieved was comparable (water contact angle> 90 °)
  • the electrical isolation achieved was 2-3 orders of magnitude less when the coatings were coated with hydrophilic cationic polyelectrolytes and under non-anhydrous conditions.
  • the solid materials provided in step a) preferably have a purified or hydrophobized or a cleaned and hydrophobized material surface.
  • a preferred embodiment of the present invention is a process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps:
  • the result summary showed that achieving a surface hydrophobicity with a water contact angle of> 80 ° or> 80 °, more preferably> 90 ° or> 90 °, more preferably> 100 ° or> 100 °, more preferably> 1 10 ° or> 1 10 °, more preferably> 120 ° or> 120 °, more preferably> 130 ° or> 130 °, more preferably> 140 ° or> 140 °, even more preferably> 150 ° or> 150 °,> 160 ° or> 160 ° and most preferably> 170 ° or> 170 ° and an electrical insulation resistance of> 200 ohms / cm 2 , preferably of> 300 ohms / cm 2 , more preferably of> 400 ohms / cm 2 , more preferably of> 500 ohms / cm 2, and most preferably> 1, 000 ohms / cm 2. by the coating structure according to the invention reliably prevents corrosion / erosion of the coated material.
  • surface coating for corrosion and / or degradation delay of solid materials comprising or consisting of at least one carboxylic acid and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is prepared anhydrous, and wherein a surface hydrophobicity with a water contact angle of> 90 ° and electrical insulation resistance of 500 ohms / cm 2 is achieved.
  • nitrated fatty acids by means of an anhydrous application, whereby a surface hydrophobicity with a water contact angle of> 80, more preferably of> 90 °, preferably of> 100 °, more preferably of> 1 10 ° C and most preferably of> 120 ° and electrical insulation resistance > 200 ohms / cm 2 , preferably> 300 ohms / cm 2 , more preferably> 400 ohms / cm 2 , more preferably> 500 ohms / cm 2 and most preferably> 1000 ohms / cm 2 .
  • a surface coating for corrosion and degradation delay of solid materials available or obtained by the just mentioned method.
  • a surface coating for corrosion and / or degradation delay of solid materials comprising or consisting of at least one carboxylic acid and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein a single-layer or multi-layer layer construction of a hydrophobic cationic polyelectrolyte and a final coating with nitrofatty acid or a mixture of nitrofatty acids and non-nitrated fatty acids by means of an anhydrous application, wherein the surface coating is prepared anhydrous, and wherein the surface coating has a surface hydrophobicity with a water contact angle of > 80 °, more preferably> 90 °, more preferably> 100 °, even more preferably> 10 ° and most preferably> 120 ° and an electrical insulation resistance of> 200 ohms / cm 2 , preferably of> 300
  • the surface coatings according to the invention are further distinguished, on account of the physiosorptive assembly, by a degradation occurring spontaneously under physiological conditions.
  • a physiologically degradable / resorbable surface coating for corrosion / degradation delay can be provided by the methods of the invention.
  • nitrofatty acids cause a significant increase in the coherence of a coating with fatty acids.
  • the highest long-term stability which ensured freedom from degradation over a period of 8 weeks, was when anhydrous deposition of nitro fatty acids (C 18: 1) on a hydrophobic cationic polyelectrolyte anhydrously applied to a degradable material.
  • a surface coating is available or preferred by the method just described.
  • a surface coating according to the invention described herein is preferred if it has a degradation of at least 8 weeks.
  • scaffolds made of a magnesium alloy with a coating system of dopamine, hydrophobicized polyethyleneimine (25 kDa) and nitroolic acid in which anhydrous deposition of the compounds was carried out, fixed in a vessel model using a balloon catheter and the degradation under flow conditions by sequential image analysis and the determination determined by magnesium in the flow medium.
  • the duration of detectable corrosion onset was increased by 560% or by 250%.
  • the duration until the complete release of the scaffold was extended by 840% and 510%, respectively.
  • a similar delay in onset and complete resolution could also be demonstrated for scaffolds from PLLA when using a coating system hydrophobized PEI (5kDa, highly branched) and nitrooleic acid (C18: 1, also called nitrooleic acid).
  • the resistance to degradation in an aqueous medium and the electrical insulation achieved could also be documented, for example, in metal surfaces coated according to the invention, such as, for example, steel alloys. In this case, the detection was carried out by means of a continuous determination of the electrical insulation resistance of the coating in an electrolyte bath and the measurement of the conductivity of the solution.
  • the aqueous media contained, among other things, acids or bases, enzymes or proteins in various concentrations, at room temperature and temperatures of up to 45 ° C.
  • an alkyl silane followed by an anhydrous application of hydrophobic (K ow 1, 3) polyalkylene polyamine (MW 8,000 Da) followed by anhydrous deposition of non-nitrated or nitrated fatty acids ( C14 - C20).
  • a sole coating with the alkylsilane, followed by the hydrophobic cationic polyelectrolyte achieved only a small increase in the electrical insulation resistance (0.8 ohms). Furthermore, there was an increase in the conductivity of the storage solutions after 3 + 1-2 days.
  • the high and stable insulation resistance is also explained by a complete or almost complete freedom from defects of inventively coated material surfaces. Since even with a high-resistance insulation resistance small insulation gaps can exist, which cause a leakage current and thus can be the starting point of erosive / corrosive processes, a test for a flawlessness is also required. This takes place, for example, in an electrolyte bath with the application of a DC voltage between the aqueous medium and the electrical connection to the test specimen. The metallic test materials were bonded by solder to a platinum wire provided with an insulating resin coating to the junction. During the test, a 40V DC voltage was applied between the electrolyte bath and the electrical material connection.
  • stainless steel platelets (10 cm 2 ) were coated by means of spay-coating with a polyurethane and a PLLA polymer, with a layer height of 20 and ⁇ ⁇ .
  • stainless steel platelets with the inventive method for example compound 1, 3 and 7 according to Example 2, by 1 to 3 times application and coating with nitrool or Nitrolinolenic acid and the native fatty acids coated.
  • defect sites existed at a frequency of 5 +/- 3 per cm 2 with a small layer thickness, and at a high layer thickness, this was 3 +/- 2 per cm 2 .
  • defect sites were after a single-layer coating with a hydrophobic cationic polyelectrolyte and a fatty acid with a C chain length of> 5, as well as a surface water contact angle of> 80 ° or. > 80 ° at a frequency between 1 and 2 +/- 1 per cm 2 before and when using a multi-layered layer structure of the hydrophobic cationic polyelectrolytes virtually no defect sites were present.
  • a surface coating is preferably preferably biodegradable obtainable by a method according to the invention with defect-free insulation of a material surface. Accordingly, a particularly preferred
  • a surface coating according to the invention described herein which is free or nearly free of insulation defects and has a surface contact angle of> 80 ° or> 80 ° is preferred.
  • a surface coating according to the invention described herein wherein a single or multilayer coating of a hydrophobic cationic polyelectrolyte and a final coating with at least one nitrofatty acid or a mixture of at least one nitrofatty acids and at least one non-nitrated fatty acids, wherein the surface coating is free or is approximately free of insulation defects and a surface water contact angle of> 80 ° or> 80 °, more preferably from> 90 ° or> 90 °, preferably from> 100 ° or> 100 °, more preferably from> 1 10 ° or> 1 10 ° and most preferably from> 120 ° or> 120 °.
  • a preferred embodiment of the present invention is a surface coating for corrosion and / or degradation retardation of solid materials comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is prepared anhydrous, and wherein the surface coating is free or nearly free of insulation defects and has a surface contact angle of> 80 °.
  • a method described herein for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation of solid materials wherein the surface coating is free or nearly free of insulation defects and has a surface contact angle of> 80 °.
  • a surface coating is preferably obtainable or obtained by the process just described.
  • a preferred embodiment of the present invention is a process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps:
  • the surface coating is free or nearly free of insulation defects and has a surface contact angle of> 80 ° or> 80 °.
  • a process according to the invention for producing a biodegradable surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials comprising a single or multi-layered layer of a hydrophobic cationic polyelectrolyte and a final coating with nitrofatty acid or a mixture of nitrofatty acids and Non-nitrated fatty acids by means of a water-free application, which is free or nearly free of insulation defects and a surface water contact angle of> 80 ° or> 80 °.
  • a surface coating is available or obtained by the method just described. Nearly free of insulation defects means that there are ⁇ 2 +/- 1 defects per cm 2 .
  • a coating composition according to the invention consisting of anhydrous hydrophobic polyelectrolytes and fatty acids, compared to a coating which was carried out only with non-nitrated or nitrated fatty acids, glass slides were coated accordingly and then fibroblasts for 12 weeks cultured. Cultures were analyzed at intervals of 14 days for the vitality and structural changes of adherent cells. It was found that in a coating which was done only with non-nitrated fatty acids, there was a strong proliferation of adherent cells, which made it impossible to continue the cultivation after 4 weeks. When coated with nitrooleic acid, there was a low proliferation rate of adherent cells within the first 4 weeks.
  • the proliferation rate increased and cell multilayers formed.
  • nitroolic acid as the final carboxylic acid layer
  • the long-term course there was only a sporadic formation, with a completely closed cell occupancy.
  • the cells also differed morphologically: While the cells were predominantly configured in cell cultures in which there was a polygonal / dendritic proliferation tendency, cells adhering to / proliferating on a surface according to the invention had a spindle-shaped to rounded morphology. At the respective times of investigation, the cells were detached from the overlay by the addition of trypsin and the surface properties of the exposed coating areas were investigated.
  • a confocal laser microscopy was carried out after staining with a hydrophobic chromophore. It was found that the hydrophobic surface properties that were present after all coatings were no longer present, this being the case with a coating with non-nitrated fatty acids after 2 weeks, with coatings with nitrated fatty acids after 4 weeks and with a layer structure according to the invention Use of nitrofatty acid as outer boundary layer after 10 weeks was the case. In cells grown on a coating of non-nitrated fatty acids, intracellular vacuoles and structural features of proliferating cells were found. In cells grown on a coating with nitrooleic acid, such structural features did not exist until week 4 and were significantly weaker pronounced.
  • a layer structure according to the invention has a considerably longer deposit on a surface to which cells adhere than is the case with a coating with carboxylic acids and is degraded in the course of time without triggering a recognizable tissue reaction.
  • a method according to the invention described herein for producing a hydrophobic, biodegradable and insulating surface coating for the corrosion and / or degradation delay of solid materials is preferred, wherein a delayed biodegradation of the layer structure takes place without cell activation.
  • fatty acids are also completely metabolized by cells, which likewise does not increase inflammatory processes.
  • the layer structure according to the invention for preventing / delaying the erosion / corrosion or degradation of materials which come into contact with living cells or physiological media is thus biodegradable and biocompatible, with simultaneous absence of pro-inflammatory effects during biodegradation.
  • a layer structure according to the invention may contain substances which reduce or prevent inflammatory processes or cell proliferation.
  • the biodegradable layer structure according to the invention also ensures the release of biologically active compounds for immunomodulation in adjacent cells / tissues.
  • hydrophilic and lipophilic compounds which had been incorporated into a layer structure of hydrophobic cationic polyelectrolytes, could diffuse out of it and be detected in adjacent cell layers.
  • the release kinetics in particular by the number of charge groups of the hydrophobic cationic polyelectrolytes, and their molecular weight and degree of branching, as well as a multi-layer layer structure can be controlled with a hydrophobic anionic polyelectrolyte. It could be shown that releasability of compounds which have been incorporated into a hydrophobic polyelectrolytic layer structure is possible without a degradation of the layer structure. At the same time, the insulating properties of the coating according to the invention can be maintained. Thus, by the purely electrostatic cohesion of the coating components, a release of compounds and a degradation of the coating structure can run independently of each other in time.
  • step b) at least one supportive compound, at least one active compound or a mixture containing at least one supportive compound and at least one active compound is used for wetting the surface of step a), the at least one supportive compound, at least one active compound or the mixture containing at least one supportive compound and at least one active compound being introduced into the hydrophobic electrolyte layer in such a way These are diffused before the biodegradation of the layer structure, from this or released.
  • a surface coating is available or obtained by the method just described.
  • At least one supportive and / or at least one active compound can be admixed with the at least one hydrophobic cationic electrolyte and / or at least one hydrophobic cationic polyelectrolyte and applied together with them.
  • the at least one hydrophobic cationic electrolyte and / or at least one hydrophobic cationic polyelectrolyte and / or at least one anionic electrolyte and / or anionic polyelectrolyte may be admixed with at least one supportive and / or at least one active compound and applied together with them.
  • a preferred embodiment is therefore a process for producing a hydrophobic, biodegradable and insulating surface coating for the corrosion and / or degradation delay of solid materials comprising the following steps:
  • the surface coating further contains at least one supportive compound, at least one active compound or a mixture containing at least one supportive compound and at least one active compound, preferably the at least one supportive compound, at least one active compound or the mixture containing at least one supportive compound and at least one active compound introduced into the hydrophobic electrolyte layer such that they are diffused or released from the layer structure before the biodegradation of the layer structure.
  • the coating according to the invention is characterized by its low construction height. With imaging analytical methods, such as scanning electron microscopy, these are not displayed. By means of spectral analytical methods a proof can be led. Thus, a layer structure of the coating according to the invention between 5 and 15 nm could be found by means of EDX.
  • An indirect detection method is confocal laser microscopy, in which the adherence of chromophores to a substrate can be determined at a lateral resolution of 200 nm. As a result, completeness of a flat coating can be determined. It was found that the surfaces produced according to the invention were coated defect-free. There was also freedom from defects in anhydrous coatings with non-nitrated fatty acids after being placed in an aqueous medium after 4 weeks. Nonetheless, the absence of defects in coatings made with nitrated fatty acids was significantly prolonged at 8 weeks.
  • an anhydrous nitro-fatty acid coating on anhydrous hydrophobic cationic polyelectrolytes is a particularly preferred method for obtaining biocompatible degradable material / implant surfaces having hydrophobic surface properties.
  • the influence of the C chain length of the fatty acids was moderate. Proliferation of the cells corresponded to that achieved with the hydrophobic cationic polyelectrolyte surface coatings, with a significantly lower rate of cell death. In contrast, the adhesion of cells to surfaces produced according to the invention was in which nitrofatty acids were used, significantly increased. However, the proliferation rate was significantly lower compared to a coating with non-nitrated fatty acids. Also lower was the number of dead cells.
  • a coating composition consisting of an anhydrous applied layer of hydrophobic cationic polyelectrolytes, followed by an anhydrous application of fatty acids, is a particularly preferred embodiment for obtaining a biocompatible surface for adherence of cells.
  • Particularly preferred is the use of nitrofatty acids for the production of a biocompatible surface for adherence and for a controlled growth of cells on foreign surfaces.
  • Preferred is a process for producing a biodegradable surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials, comprising a single or multi-layered sandwich of hydrophobic cationic polyelectrolyte and a final coating of nitrofatty acid or a mixture of nitrofatty acids and non-nitrated ones Fatty acids by means of an anhydrous application takes place, whereby an adherence of cells is made possible with a confluent planar tissue finish.
  • a clear difference in cell growth on such coated surfaces was when a non-nitrated or a nitrated fatty acid was used.
  • nitrofatty acids were used, stimulation with cytokines resulted in a closed single-layered cell structure, which did not proliferate any further.
  • non-nitrated fatty acids were used, multilayer formation and uncontrolled cell proliferation occurred. Therefore, a coating according to the invention using nitrofatty acids is a particularly preferred application for the formation of a monolayer flat cell combination.
  • the surface properties of materials coated according to the invention enable a good cell adhesion, but only with the use of nitrofatty acids does a closed and no proliferating cell combination occur.
  • Such a coating also allows the formation of an extracellular matrix, in the context of which there is also a degradation of the coating compounds.
  • a significantly delayed degradation of degradable materials can be established by a coating method according to the invention. If a closed cell layer has already formed, a degradation of metal alloys or organic polymers proceeds without a relevant activation of the cells covering the degradation process and at a low rate of progress. It has been found that the beneficial biological effects, both on the degradation / corrosion delay, and on the stability of the hydrophobic surface in an aqueous medium, as well as the electrical insulation achieved with the coating, are determined.
  • a surface coating according to the invention described herein for the corrosion and / or degradation delay of solid materials is preferred, whereby complete or approximately complete adhesion / aggregation of coagulation factors and / or thrombocytes is achieved.
  • a process for producing a biodegradable surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials wherein a single or multi-layered layer structure of a hydrophobic cationic polyelectrolyte and a final coating with nitrofatty acid or a mixture of nitrofatty acids and not Nitrated fatty acids by means of a water-free application, whereby a complete or almost complete adhesion / aggregation of coagulation factors and / or platelets is achieved.
  • an electrical insulation and hydrophobing (water contact angle> 90 °) of a copper and a zinc element in which an inventive application of an alkylsilane, followed by a coating with a hydrophobic cationic polyelectrolyte and a subsequent deposition of nitroerucic acid was carried out, can be achieved (> 1, 000 ohms / cm 2 ).
  • the elements were connected to a voltmeter via a port external to the water bath and were stored in an electrolytic bath for 4 weeks. In the course there was no formation of a tension between the metal elements.
  • Preferred is a process for producing a biodegradable surface coating to prevent / delay arrosion / corrosion or degradation of solid materials, thereby achieving electrical insulation.
  • Preference is furthermore given to a process for producing a biodegradable surface coating for preventing / delaying erosion / corrosion or degradation of solid materials, in which a single-layer or multi-layer layer structure consisting of a hydrophobic cationic polyelectrolyte and a final coating with nitrofatty acid or a mixture of nitrofatty acids and non-fatty acids. nitrated fatty acids by means of a water-free application takes place, whereby an electrical insulation is achieved.
  • the surface to be coated is first rendered hydrophobic in order, in particular in the case of strongly hydrophilic surfaces, such as glass, to increase the bonding stability to the hydrophobic cationic polyelectrolytes to be applied subsequently.
  • this is done by methods of the prior art, such as by covalently or adsorptively bound, mostly amphiphilic compounds.
  • a silanization, z. B. with an alkyl silane take place.
  • biogenic compounds such as dopamine may be physiosorptively adhered to a surface.
  • the compounds used for the initial hydrophobization are preferably dissolved in an organic solvent and separated from the solvent phase on the surface to be coated.
  • the loading layer is applied directly to the hydrophobing layer.
  • This is likewise preferably anhydrous, for example from a solvent phase.
  • a hydrophobing is particularly preferred when the material surface is hydrophilic. Therefore, it is preferable to perform surface hydrophobing of a material surface when the water contact angle at the material surface is ⁇ 40 °, more preferably ⁇ 30 °, and more preferably ⁇ 20 °.
  • Preferred is a process for producing a biodegradable surface coating for inhibiting / delaying erosion / corrosion or degradation of solid materials, comprising a single or multi-layered sandwich of hydrophobic cationic polyelectrolyte and a final coating of nitrofatty acid or a mixture of nitrofatty acids and non-nitrated ones Fatty acids by means of a water-free application takes place, the material surface is first rendered hydrophobic.
  • step a) preferably the processes according to the invention described herein after step a) comprise a step a2) cleaning, hydrophobing or cleaning and hydrophobicizing the surface of the solid material.
  • the process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprises the following steps:
  • inventive processes described herein preferably comprise after step a) a step a2) cleaning, hydrophobing or cleaning and hydrophobing the surface of the solid material when the water contact angle at the material surface ⁇ 40 °, more preferably ⁇ 30 ° and more preferably ⁇ 20 ° is.
  • the application of one or more loading layer (s) with supportive and / or active compounds by firstly an anhydrous surface coating is carried out with hydrophobic cationic polyelectrolytes and then one or more compounds are applied thereto.
  • An application of a mixture of one or more hydrophobic cationic polyelectrolytes together with an active and / or supportive compound can also be configured in a preferred embodiment.
  • a layer structure which contains compounds to be released can also be effected by means of an alternating layer-wise deposition of hydrophobic cationic polyelectrolytes and release compounds. In one embodiment, such a layered construction is effected by an alternating application of hydrophobic cationic and hydrophobic anionic polyelectrolytes.
  • hydrophobic compounds are used for this purpose, either directly or after applying a hydrophobing (for example with dopamine or an alkylsilane) on a surface to be coated and / or after application of a hydrophobic cationic or anionic polyelectrolyte and alternately with a hydrophobic cationic and / or anionic polyelectrolytes, followed by deposition of fatty acids.
  • a hydrophobing for example with dopamine or an alkylsilane
  • a hydrophobic cationic or anionic polyelectrolyte alternately with a hydrophobic cationic and / or anionic polyelectrolytes
  • the deposition of nitrofatty acids is preferred.
  • the compounds to be introduced into the layer structure are preferably hydrophobic and can be dissolved in an organic solvent and applied to the substrate surface from the solvent phase using known techniques, such as dip-coating or spray-coating.
  • the compounds to be delivered are dissolved or suspended in one of the hydrophobic cationic or anionic polyelectrolytes and applied together with these on the surface by one of the methods described herein.
  • the coating takes place according to the layer-by-layer process technology.
  • free fatty acids which are present dissolved in an anhydrous medium are used for solubilizing compounds to be applied. This is particularly preferred if a controlled release of supportive and / or active compounds is to take place with the layer structure according to the invention.
  • biodegradable surface coating according to the invention obtainable or obtained according to one described herein Controllable release method of supportive compounds and / or active compounds.
  • the last coating layer which prior to a deposition of fatty acids on a compound-loaded surface, completely or predominantly consists of a hydrophobic cationic electrolyte and / or hydrophobic cationic polyelectrolyte.
  • Particularly preferred is the deposition of nitrofatty acids as the final layer of an inventive layer structure for the release of compounds.
  • the surface is wetted anhydrously with at least one hydrophobic anionic electrolyte and / or at least one hydrophobic anionic polyelectrolyte or a mixture comprising at least one hydrophobic anionic electrolyte and at least one hydrophobic anionic polyelectrolyte.
  • this wetting can take place directly or indirectly on the surface of the solid material. Indirect means that the wetting is carried out on an already applied layer.
  • the steps b) to c) between the steps c) and d) can be performed twice or more times.
  • the steps b2) to c2) between the steps c) and d) can be performed twice or more times.
  • a preferred embodiment of the present invention is a process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprising the following steps: a) providing a solid material,
  • steps b) to c2) are carried out twice or more times.
  • step b2) at least one supportive, at least one active compound or a mixture containing at least one supportive and at least one active compound is further used for wetting the surface.
  • an inventive layer structure with supportive and / or active compounds causes in particular hydrophobic compounds to be dissolved out of the layer structure and released into a surrounding medium. It was particularly surprising that many of the hydrophobic but also hydrophilic compounds could be very well dissolved and formulated in an anhydrous solution of hydrophobic polyelectrolytes, so that in this way a well-adhering application of the compounds was made possible. Surprisingly, it has been found that the solubility of many supportive and active compounds can be significantly improved by the addition of nitro fatty acids in organic solvents. This has been true, for example, of active compounds such as paclitaxel and everolimus, as well as supportive compounds such as cholesterol or carotenoids.
  • nitrofatty acids were also superior to non-nitrated fatty acid in a complete solution of compounds, when the melting point of the corresponding nitrated fatty acid was significantly higher than that of the non-nitrated fatty acid.
  • the formulations prepared with nitrofatty acids could be Apply very evenly in ultra-thin layers and were then no longer removed by aqueous or alcoholic solutions.
  • the compounds / active substances included herein which have been formulated with nitro fatty acids correlated the release kinetics of the compounds / active ingredients with the used concentration of the nitrofatty acid.
  • a coating method of uptake of compounds / actives with adjustable and controllable diffusive release of these compounds / agents can be provided.
  • a preferred embodiment of the underlying invention therefore comprises methods for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation delay of solid materials comprising the following steps:
  • d1) dissolving at least one supportive and / or at least one active compound in at least one carboxylic acid, preferably in at least one nitrofatty acid or a mixture comprising or consisting of at least one nitrofatty acid and / or at least one non-nitrated fatty acid,
  • a release system of a surface coating for supportive and / or active compounds is preferred, in which the diffusive release kinetics is set by a quantitative ratio between the compound to be liberated and a nitrofatty acid used for solution / solubilization.
  • the period of electrical insulation and / or prevention or delay of an erosion / degradation of a According to the invention coated material surface can be further extended by nitrofatty acids in one or more layers, consisting of hydrophobic cationic polyelectrolytes, simultaneously with these or separately from each other in / on a layer or layers in the layer structure on / be applied.
  • hydrophobic cationic polyelectrolytes are mixed with nitrofatty acids. This is anhydrous and preferably in an organic solvent such as dichloromethane or pentane. The compound mixture is then applied in the solvent phase. After drying, the process can be repeated as often as desired.
  • the last application layer is made with a hydrophobic cationic polyelectrolyte in which no nitrofatty acids are present.
  • the final (outermost) layer is then applied by deposition of nitrated and / or non-nitrated fatty acids.
  • the “final layer” or outermost layer refers to the layer last applied, starting from the surface to be coated thus being the outermost layer or last layer
  • the surface coating as the outermost layer comprises carboxylic acid, preferably fatty acids, more preferably nitrated Fatty acids and further preferably a mixture comprising or consisting of nitrated fatty acids and carboxylic acids.
  • nitrofatty acids which had been used together with one of the compounds and the hydrophobic cationic polyelectrolyte for layer buildup, diffuse and adhere to the surface of the layer system, as nitrofatty acids subsequently form on the surfaces of a corresponding coating structure the final external surface covering was done exclusively with non-nitrated fatty acids could be detected.
  • a method can be provided wherein diffusion of the incorporated nitro fatty acids to the coating surface occurs by incorporation of nitrofatty acids into a layered structure with a hydrophobic cationic polyelectrolyte.
  • a reservoir for mobile or mobilizable nitrofatty acids can be prepared by introducing them alone or together with hydrophobic cationic polyelectrolytes in a coating composition, so that a redistribution of the nitrofatty acids can take place via diffusive processes or concentration gradients.
  • This is particularly advantageous since it allows defects in the outer layer, consisting of fatty acids, to be compensated for by nitrofatty acids diffusing to the surface.
  • This can be a quasi self-healing hydrophobic surface coating can be provided.
  • the fatty acids used for reservoir formation may also contain non-nitrated carboxylic acids.
  • self-healing or "quasi-self-healing” as used herein means the ability of a coating comprising a plurality of layers to re-balance defects in the outermost layer by compounds from an inner layer by diffusion.
  • a preferred embodiment of the present invention is directed to a surface coating wherein the surface coating is self-healing. Therefore, the object of the invention is also directed to processes for the prolonation of the provision of carboxylic acids / nitrocarboxylic acids on the coated material surface. As a result, both the degradation of the coating itself, as well as the degradation / erosion of the coated material can be further delayed. In addition, this also results in a facilitated transport of compounds from the coating structure to the coating surface and their delivery to a surrounding medium, as well as a provision of supportive compounds that counteract or prevent Biofilmentstehung. Thus, the methods are also directed to a reservoir formation, in particular for carboxylic acids and nitrocarboxylic acids, within the coating structure according to the invention.
  • a mixture containing at least one carboxylic acid is preferably at least one fatty acid which is nitrated and / or non-nitrated and at least one hydrophobic cationic electrolyte, at least one hydrophobic cationic polyelectrolyte or a mixture of at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte is used.
  • the process for producing a hydrophobic, biodegradable and insulating surface coating for corrosion and / or degradation retardation of solid materials comprises the following steps:
  • step b) fatty acids are mixed with the hydrophobic cationic electrolytes and / or hydrophobic cationic polyelectrolytes and applied and / or applied separately in sequential order to produce a reservoir formation for fatty acids and / or to solve supportive and / or active connections and to integrate them into the layer structure.
  • step b) fatty acids are mixed with the hydrophobic cationic electrolytes and / or hydrophobic cationic polyelectrolytes and applied and / or applied separately in sequential order to produce a reservoir formation for fatty acids and / or supportive and / or active compounds to solve and integrate into the layer structure and this process step 2 or more times repeated and / or combined with other process steps.
  • a process for producing a biodegradable surface coating for preventing / delaying erosion / corrosion or degradation of solid materials in which a single-layer or multi-layer layer construction consists of a hydrophobic cationic and / or hydrophobic cationic polyelectrolyte and a final coating with carboxylic acid, preferably with at least a nitrofatty acid or a mixture of at least one nitrofatty acid and at least one non-nitrated fatty acid, by means of a water-free application and a reservoir formation for carboxylic acids in the layer structure is obtained by the one or more carboxylic acids together with and / or on a layer of a hydrophobic cationic polyelectrolyte is / are introduced.
  • Particularly preferred for a reservoir formation is the use of at least one nitrofatty acid.
  • the coating steps are chosen such that a reservoir formation of the carboxylic acids used is accomplished.
  • a further layer sequence of the said layers can take place.
  • a fatty acid to be applied together with the at least one hydrophobic cationic electrolyte and / or hydrophobic cationic polyelectrolyte and above this to comprise a further layer comprising the at least one carboxylic acid or at least one further carboxylic acid.
  • nitroolic acid which has been mixed anhydrously with a low molecular weight polyelectrolyte and dissolved in polyethylene glycol for better spreadability, can be incorporated homogeneously into the melt of polypropylene during an extrusion process and subsequently dried in the extruded product (eg thread material). is present. After the extrusion nitrofatty acids were detected at the surface. After intensive cleaning of the surfaces with organic solvents and no longer possible detection of nitrofatty acids on the cleaned surfaces, nitrofatty acids could be detected again on the surface after 2 days.
  • a reservoir for mobile nitrofatty acids can be prepared which can be incorporated onto and / or into organic polymers and allows diffusion of the nitro fatty acids from the organic polymers. It has also been shown that this reservoir formation can be used for carboxylic acids in order to prevent biofilm formation since the carboxylic acids present on the material surface and in particular the nitrocarboxylic acids have an antibacterial effect.
  • carboxylic acids and in particular nitrofatty acids
  • a hydrophobic cationic polyelectrolyte into / onto a starting material, such as PP or PU, which is subsequently formed by forming (thermally or mechanically) into a solid material , continue to remain mobile / diffusible and reach the surface of the material by means of diffusion, where they arrange themselves.
  • incorporation of a hydrophobic cationic electrolyte and / or hydrophobic cationic polyelectrolyte or a mixture thereof containing a carboxylic acid into / on a / is effected
  • Starting material / starting compound which are transformed / formed by forming and / or polymerizing to a solid piece of material, wherein the introduced carboxylic acids / nitrocarboxylic acids remain mobile / diffusible within the solid material.
  • a surface coating having a multilayered layer structure of a hydrophobic cationic electrolyte and / or hydrophobic cationic polyelectrolyte and a final layer comprising or consisting of at least one carboxylic acid, preferably at least one nitrofatty acid or a mixture of at least one nitrofatty acid and / or at least one non-nitrated Fatty acid, wherein the application or layer formation takes place in each case anhydrous.
  • Carboxylic acids which have been applied as a surface coating on a medical device may diffuse into a body fluid or e.g. in vascular grafts or ingested or metabolized by cells, decreasing the number of carboxylic acids over time.
  • a surface coating containing a carboxylic acid reservoir the carboxylic acids herein contained can be replenished to / have been minimized on the outermost layer.
  • the amount of carboxylic acids on the surface of a coating can be controlled or metered.
  • hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte alternating with a mixture of a hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte and at least one carboxylic acid.
  • the hydrophobic cationic electrolyte or hydrophobic cationic Polyelectrolyte and the mixture of a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte and the at least one carboxylic acid each in a solvent having different polarity, such as. As methanol and pentane, dissolved.
  • hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or the mixture of a hydrophobic cationic electrolyte or alternatively a hydrophobic cationic polyelectrolyte and the at least one carboxylic acid can be deposited as a first layer on a surface to be coated.
  • another layer structure is carried out in an alternating manner, but it is also possible a layer structure in which first several layers of a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte or a mixture of a hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte and the at least one carboxylic acid are applied , This may be advantageous in particular when introducing active or supportive compounds.
  • the carboxylic acid can in principle be applied in concentrated form, but for a single-layer layer structure a solution in an organic solvent is preferred.
  • Preferred organic solvents which are used in process step b3) are alcohols.
  • drying takes place. If a further coating is desired, a further coating cycle is carried out with a mixture of a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte and at least one carboxylic acid, the mixture preferably being present in an apolar solvent.
  • a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte or a mixture of a hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte is used for wetting the surface of the solid material and then in step c) Drying takes place and subsequently, in step b3), a wetting of the surface, obtainable after step c), takes place with a nitrated and / or non-nitrated carboxylic acid.
  • carboxylic acids including nitrofatty acids, which have been introduced for the purpose of reservoir formation as an intermediate layer alone or together with an active or supportive compound, over time, very likely due to a diffusion gradient, to the surface of the Coating
  • a fatty acid has been applied either in the form of one of the aforementioned mixtures or as a single layer, that over time these fatty acids are present on the coating surface.
  • a final coating of a coating which is carried out with a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte, with the at least one carboxylic acid according to step d) can be dispensed with, provided that at least one carboxylic acid has been introduced in the course of the coating structure is.
  • the embodiment of step d) according to the invention is advantageous.
  • step d) is a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte and a mixture of a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte without the addition of a carboxylic acid.
  • hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte and mixtures of these tend to form clusters on surfaces. This tendency is more pronounced on hydrophilic surfaces.
  • the clustering can lead to map-like configured shrinkage phenomena of the coating, which can cause defects in the coating. This is the case in particular when using high molecular weight polyelectrolytes and high concentrations of these. It has been found that such cluster formation can be counteracted by various measures.
  • the surface to be coated can first be rendered hydrophobic. Further, a low concentration and a multi-layer deposition of a hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte may be made.
  • An alternating coating with a hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte with a mixture of a hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte and at least one carboxylic acid also requires a more uniform surface distribution. Furthermore, however, a subsequent spreading of clustered compounds can also be effected. For this purpose, methods of the prior art can be used. It could be shown that spreading is possible by treatment with an oxygen or argon plasma. An improvement of the spread can i.a. be recognized that the scattering is significantly reduced in a repeated water contact angle measurement. But also by means of an electro-chemical determination of defects whose number is reduced. However, spreading can also be carried out by a thermal treatment which takes place after drying and by an ultrasound treatment which takes place after application.
  • a surface coating according to the invention has an antimicrobial effect. So it was found that bacteria are very common The cause of an infectious deposit of implants (biofilm) are, despite direct exposure to the coated material surfaces, neither adhering nor growing thereupon, as long as there were no indications of an incipient degradation of the coating. Long-term repeat studies have found that nitrofatty acid coatings provide significantly longer freedom from bacterial colonization than coatings that use the corresponding native fatty acid.
  • a surface coating with a long-term antimicrobial effect is preferred.
  • Preferred is a surface coating in which a long-term anti-microbial effect is achieved by carboxylic acids / nitrocarboxylic acids within the coating that can diffuse to the material surface.
  • the embodiments of the method according to the invention make it possible to shield a material from an aqueous medium in a very simple and cost-effective manner.
  • an initialization of corrosive processes by a water contact can be completely prevented even during the application.
  • With the insertable connections can be a long lasting Sealing of surfaces that is biodegradable, can be ensured, and by selecting suitable and biodegradable compounds of hydrophobic cationic polyelectrolytes and carboxylic acids, the time of dissolution of the surface coating can be controlled. This degradation does not lead to unwanted cell / tissue reactions.
  • the non-covalent layer structure allows the greatest possible flexibility between the connections or the layers with each other, so that it is possible even with a geometric change of the coated material or its areal extent that the compounds used for the coating of the changed shape or the changed dimensions of space defect-free to adjust.
  • the surfaces coated according to the invention allow a very good adherence of cells and are therefore suitable for cell homing.
  • the use of nitrofatty acids causes a controlled growth of adherent cells and allows the formation of a flat confluent cell / tissue network.
  • surface coatings according to the invention using nitrofatty acids are also very suitable for applications such.
  • a multilayered layer structure with hydrophobic polyelectrolytes is also possible which involves the introduction of further compounds such as, for example, hormones, antioxidants or medicaments
  • water-free mixtures of hydrophobic cationic polyelectrolytes and nitrofatty acids can be used to produce reservoir systems which enable a diffusive distribution and release of nitrofatty acids, and which can be prepared by the choice of suitable hydrophobic cationic and / or anionic polyelectrolytes Both in a superficial layer structure or in polymer structures can thus, with the inventive method also a controllable release system for Verbindun gen / agents / nitrofatty acids are provided from surface coatings.
  • This reservoir formation can be used, in particular, for loading with antimicrobially active carboxylic acids / nitrocarboxylic acids in order to ensure a long-lasting replenishment of carboxylic acids / nitrocarboxylic acids diffused out of the surface layer, thereby enabling long-lasting protection against biofilm formation.
  • a surface coating of the invention described herein is obtainable or obtained by a method of the invention for use in cell homing and for confluent cell growth.
  • “Anhydrous” means that the applied at least one hydrophobic cationic electrolyte and / or at least one hydrophobic cationic polyelectrolyte or at least one nitrofatty acid or at least one non-nitrated fatty acid or a mixture of the at least one nitrofatty acid or at least one non-nitrated fatty acid and their If, for example, a solution of the hydrophobic cationic polyelectrolyte is prepared with a solvent, the solution is anhydrous if at most 1000 ppm of water is present in the solution.
  • corrosion refers to one or more subsequent and / or parallel processes in which, due to hydrolysis and / or oxidation, they increase a dissolution of atoms / ions and / or molecules and / or particles from a composite material comes and / or atoms / ions and / or compounds are changed by a physico-chemical / chemical reaction as a result of contact with an aqueous medium Reaction and / or degradation products which are present in the form of a loose composite and / or diffuse into a surrounding medium, for example the oxidation of iron with the formation of iron ions and iron oxides or the hydrolytic cleavage of lactic acid polymer chains to release lactic acid molecules or the hydrolytic release of magnesium ions from a metal lattice structure with liberation of
  • the corrosion, corrosion and degradation products are those elements, ions or Compounds that are formed or released during an erosion, corrosion or degradation process.
  • K ow as used herein is meant the distribution quotient of a compound between an octanol and a water phase in a non-ionized state.
  • the ow or P value refers only to one species of a substance:
  • e o l is the concentration of the species / substance in the octanol-rich
  • s-c TM is the concentration of the species / substance in the water-rich phase.
  • resorbable or “degradable” or “biodegradable” or “biodegradable” or biodegradable” or biodegradable refer to the fact that the human or an animal organism is able to dissolve the surface coating or the solid material within a certain period of time, so that Atoms, ions or molecules are present, which are dissolved in the blood or other body fluids and can be metabolized and / or excreted.
  • Degradation stability can be arbitrarily designed by the methods disclosed herein. In the absolute sense, a Degardations practic is achieved over a set period.
  • the term "freedom from degradation” as defined herein means that there is no change in at least 2 of the following properties over a defined period of time: surface hydrophobicity, adhesion behavior of living cells, adhesion behavior of plasmatic blood components, leaching of corrosion / corrosion products of the coated material a surrounding aqueous medium, electrical insulation, mechanical integrity / stability of the coated material.
  • the properties are tested by placing the coated material in a suitable aqueous medium for the period to be tested.
  • An electrical insulation is present at an electrical resistance of> 200 ohm / cm 2 , preferably of> 300 ohm / cm 2 , more preferably of> 400 ohm / cm 2 , more preferably > 500 ohms / cm 2 , even more preferably> 1000 ohms / cm 2 , even more preferably> 1100 ohms / cm 2 , even more preferably> 1200 ohms / cm 2 , even more preferably> 1300 ohms / cm 2 , even more preferably> 1400 ohms / cm 2 , even more preferably> 1500 ohms / cm 2 , even more preferably> 1600 ohms / cm 2 , even more preferably> 1 800 ohms / cm 2 more preferably> 1900 ohms / cm 2 , even more
  • the change in the abovementioned properties is preferably ⁇ 10%, more preferably ⁇ 5%, more preferably ⁇ 3% and more preferably ⁇ 1%, based on the starting state before application or the test investigation.
  • a freedom of degradation preferably exists over a period of 4 weeks, more preferably 8 weeks, and even more preferably 12 weeks.
  • the degradation stability also causes a degradation delay, which can be quantified using the aforementioned parameters.
  • a delay of the surface coating itself is meant. This refers to the loss / release of carboxylic acids / nitrocarboxylic acids as compared to a single surface coverage on a material.
  • the term “retardation delay” also refers to the corrosion / corrosion of the coated material which occurs with a time delay over a sole coating with a carboxylic acid / nitrocarboxylic acid., A time delay of more than 14 days, more preferably> 30 days, more preferably > 45 days, and even more preferably> 60 days, compared to a sole surface coating with the corresponding fatty acid / nitric acid.
  • the terms “medical device” or “medical device” are used herein as generic terms that include any implants, natural and artificial grafts, suture and bandage materials, as well as parts of medical devices such as catheters.
  • the medical products which also include cosmetic or partially cosmetic and partially medical implants, are preferably medical devices, more preferably implants that are temporarily or permanently introduced into the organism and medical articles that come into contact with cells / tissues, such as Wound materials, suture materials, wound and body cavity closure systems, biological grafts, artificial grafts, biological implants, artificial implants, artificial blood vessels, natural blood vessels, blood conductors, blood pumps, dialyzers, dialysis machines, vascular prostheses, vascular supports, heart valves, artificial hearts, vascular clamps, autologous implants, Bone implants, intraocular lenses, shunts, dental implants, infusion tubes, medical cuffs, bandages, medical clamps, pumps, pacemakers, laboratory gloves, medical scissors, medical cutlery, needles, cannulas, endoprostheses
  • the surface coatings according to the invention are thus suitable for all medical devices or medical devices that come into contact with cells / tissues / organs temporarily or permanently and that this contact can lead to irritation of the coming in contact cells / tissues / organs that are undesirable Reaction (as described below or on page 8 above) of said structures leads. This includes medical or cosmetic procedures that have similar properties.
  • the medical instruments, implant and wound materials referred to herein are all made of solid materials whose surfaces are in at least part of a temporary and / or permanent contact with cells / tissues / fluids of a human or animal body / organism or also with ex vivo tissue associations or contact individual cells or can contact.
  • the solid materials are preferably a medical device, particularly a medical device that may come into contact with cells, tissues, biological fluids, or a combination of at least two of them.
  • another aspect of the present invention is a medical product having a coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the coating is prepared anhydrous.
  • another aspect of the underlying invention is a medical product having a hydrophobic, biodegradable, and insulating surface coating obtainable by a method of the invention described herein.
  • the medical products can be implants, in particular long-term or short-term implants. It is also possible to equip permanent long-term implants with a surface coating according to the invention.
  • Co / Ni Stainless steel alloys are provided with a surface coating according to the invention. This avoids the diffusion of allergenic components, especially nickel, and thus an allergic reaction. Even in the case of permanent long-term implants in which a bioresorbable surface coating does not last the entire life of said implant, it is important to prevent additional exposure to allergy-causing substances in the first weeks after implantation in addition to the inflammatory influences.
  • the solid materials herein may be hard or soft, solid or flexible and deformable. This does not include materials that are liquid, gelatinous or pasty. These include, but are not limited to:
  • Soft tissue implants such as silicone implants, joint implants, cartilage implants, natural or artificial (eg Dacron) tissue implants and grafts, autogenous tissue implants, intraocular lenses, surgical adhesion barriers, nerve regeneration channels, birth control devices, shunts, tissue scaffolds such as pericardial tissue, tissue-based matrices, dental devices and dental implants, drug infusion tubes, Cuffs, drainage devices (eg for eye, lung, abdominal, urinary, oral) tubes (endotracheal, tracheostomy) and tubes (also for extracorporeal circulation), surgical nets, ligatures, sutures, staples, Wires, pins, nails and screws, masking material, foams, pedicles, films, implantable electrical stimulators, pumps, ports, reservoirs, injection catheters or stimulation or sensing electrodes / probes, wound coatings, sutures, membranes, rings or sleeves, surgical instruments such as scalpels , Lancets , Scissors, tweezers or hooks, clinical gloves, hypodermic needle
  • Vascular implants including scaffolds, stents and flow diverts, as well as coils.
  • osteosynthetic materials materials for osteosynthesis
  • catheters including infusion cannulas
  • wound dressings or wound dressings foams, absorbers, gauze, bandages.
  • Sutures such as sutures, filaments, clips, wires and the like.
  • orthopedic prostheses dental implants, fixators and drains.
  • a particularly preferred embodiment of the present invention relates to a method according to the invention, wherein the solid material is preferably arterial stents, in particular stents.
  • a further embodiment of the present invention is thus an arterial stent with a surface coating according to the invention, which is preferably biodegradable, obtainable by a method according to the invention described herein.
  • a further embodiment of the present invention is thus an arterial stent with a hydrophobic, biodegradable and insulating surface coating, obtainable by a method according to the invention described herein.
  • a further embodiment of the present invention is thus a stent having a surface coating according to the invention preferably biodegradable obtainable by a method according to the invention described herein.
  • a further embodiment of the present invention is thus a stent with a hydrophobic, biodegradable and insulating surface coating obtainable by a method according to the invention described herein.
  • a further preferred embodiment is directed to an arterial stent having a surface coating comprising at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • a further preferred embodiment is directed to a stent having a surface coating comprising at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or a hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous.
  • one embodiment of the underlying invention is directed to a medical product having a coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the coating is prepared anhydrous, wherein the medical product is a soft tissue implant, such as silicone implants, joint implants, cartilage implants, natural or artificial (eg Dacron) tissue implants and grafts and vascular prostheses, autogenous tissue implants, intraocular lenses, surgical adhesion barriers, nerve regeneration channels, birth control devices, shunts, tissue scaffolds such as pericardial tissue, tissue-based matrices, dental devices and dental implants, Drug infusion tubes, cuffs, drainage devices (eg for eye, lung, abdominal, urinary, jaw) tubes (endotracheal, tracheostomy) and tubes
  • Sutures such as sutures, filaments, clips, wires and the like or orthopedic prostheses, dental implants, fixators and drains.
  • vascular implants in particular a stent in the sense of a vascular support and a so-called scaffold, which is generally bioresorbable.
  • this also includes so-called flow diverter and implantable sleeves.
  • substrate materials are used interchangeably herein and refer to the material / material that is to be surface-coated.
  • the materials are materials used in medical products, most preferably materials used for medical instruments, implant and wound materials. These may be inorganic or organic as well as composite materials.
  • the inorganic materials may be, for example, metals or metal alloys, sintered silicon, zirconium, aluminum compounds, as well as light metals such as aluminum, including their oxide forms.
  • a further development of stent materials are cobalt-chromium alloys, such as L605.
  • This alloy consists of cobalt (base), chromium (19-21%), tungsten (14- 16%), nickel (9-1%), iron (max 3%) and manganese (1-2%) , and too small proportions of silicon (max 0.4%), carbon (0.05-0.15%) and sulfur (max 0.03%).
  • the DIN designation of the alloy is CoCr20W15Ni, and Co-20Cr-15W-10NL
  • magnesium alloys Such an alloy is known, for example, under the name Resoloy.
  • the inorganic compounds include silicon-based materials, such as silicone.
  • the organic materials are carbon-based compounds which are in the form of natural polymers such as cellulose or latex or in the form of synthetic polymers such as polyurethane, polypropylene, acrylates, polyamides or polyesters.
  • the preferred materials can be durable and non-susceptible to corrosion, easily degradable and self-dissolving.
  • the solid material is a corrodible and / or degradable material.
  • a medical product according to the invention with a coating according to the invention, wherein the medical product consists of a corrodible and / or degradable material.
  • the corrodible and / or degradable materials include, but are not limited to, polymers such as PLLA (poly-L-lactide) and polycarbonates of iodinated desaminotyrosyl tyrosine ethyl ester units.
  • Biodegradable polymers can be classified in
  • natural polysaccharides eg starch, cellulose, chitin, chitosan, hyaluronone, pectin
  • naturally occurring proteins eg fibrin, gelatin, collagen, laminin and fibronectin
  • synthetic polymers eg Poly (vinyl alcohol), poly (ethylene oxide), poly (vinyl pyrrolidone)
  • semisynthetic e.g., chemically modified natural polymers such as chitosan
  • the materials may be solid or flexible or soft as long as it is a solid material. The outer shape is irrelevant, as long as it is possible to ensure a coating that is closed on all sides using one of the disclosed coating methods. The materials can not be soaked or absorbent. Absorbent tissues and membranes can also be used.
  • Polyelectrolytes are polymers which carry many ionic or ionizable groups. Depending on the nature of the ionizable groups, they may be present as polybase or polycation and as polyacid or polyanion. Cationic polyelectrolytes are thus polymers which carry ionic or ionizable groups, ie be present either as polybase or polycation.
  • electrolytes are compounds which carry one or more ionic or ionizable groups and, depending on the nature of the ionizable groups, are present as base or cation.
  • the hydrophobic cationic electrolytes and polyelectrolytes according to the invention are characterized by one or more cationic charge groups which are ionizable or by one or more basic groups which are ionizable, a carbon compound which contains no or only a very small proportion ( ⁇ 2% by weight). has hydrophilic groups (eg, OH groups) and has a Kow of> 0.3 or> 0.3.
  • a polyelectrolyte carries at least two cationic charge groups or at least two basic groups which are ionizable and preferably a carbon-containing quaternary nitrogen compound.
  • At most 90% of the nitrogens are quaternary nitrogens, more preferably at most 80% of the nitrogens, further preferably at most 70%, further preferably at most 60%, further preferably at most 50%, even more preferably at most 40%, even more preferably at most 30%, even more preferably at most 20%, even more preferably at most 10%, and most preferably at most 5%.
  • a Kow of> 0.4 or> 0.4 more preferably a Kow of> 0.5 or> 0.5, more preferably of> 0.5 or> 0.5, more preferably of> 0.6 or> 0.5, more preferably> 0.7 or> 0.7, more preferably> 0.8 or> 0.8, even more preferably> 0.9 or> 0.9, even more preferably 1 , 0 or> 1, 0, even more preferably> 1, 5 or> 1, 5, even more preferably> 2.0 or or> 2.0, even more preferably> 2.5 or> 2.5 even more preferably> 3.0 or> 3.0, even more preferably> 3.5 or> 3.5, even more preferably> 4.0 or> 4.0, even more preferably> 5, 0 or> 5.0, even more preferably> 6.0 or>, 6.0 even more preferably from 7.0 or> 7.0, even more preferably from 8.0 or> 8.0 and most preferably from > 9.0 or> 9.0.
  • a further embodiment of the present invention directed to a process for producing surface coating, comprising the following steps:
  • One embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is anhydrous wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte bears at least two cationic charge groups or at least two basic groups and is a carbon-containing quaternary nitrogen compound, wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte has been rendered hydrophobic by addition of a carboxylic acid / nitrocarboxylic acid.
  • the at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte is rendered hydrophobic by adding a carboxylic acid / nitrocarboxylic acid.
  • One embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is prepared anhydrous, wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte at least two cationic charge groups or at least two carries basic groups and is a carbon-containing quaternary nitrogen compound.
  • hydrocarbon compounds which have an unbranched or branched carbon chain. It is also possible that there is more than one branch.
  • the molecular weight may be between 200 and 500,000 Da, more preferably between 1,000 and 250,000 Da, and more preferably between 5,000 and 125,000 Da.
  • the consistency can be firm to liquid.
  • solid or highly viscous cationic polyelectrolytes they can be dissolved in an organic solvent.
  • the cationic groups may be present on one or more nitrogen atoms which are terminal or linkage of a compound. It is also possible for 2 or more nitrogen atoms together or else together with other elements to provide positive charge groups.
  • the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte is a carbon-containing compound having a molecular weight between 200 and 500,000 Da, which is at least two carries cationic charge groups or at least two basic groups which are ionizable and which has a Kow of> 0.3.
  • hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte comprises a carbon-containing compound having a molecular weight of between 200 and 500,000 Da which carries at least two cationic charge groups or at least two basic groups which are ionizable and which has a Kow of> 0.3
  • another embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is made anhydrous, wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte comprises a carbon-containing compound having a molecular weight between 200 and 500,000 Da which carries at least two cationic charge groups or at least two basic groups which are ionizable and which has a Kow of> 0.3.
  • Nitrogen compounds which provide a cationic charge group or can be converted into cationic charge groups can be, for example, the following groups: amines, amides, ammonium, imines, azanes, triazines, tetrazanes, nitrones, guanidine, amidine, pyrrolidine, piperidine, piperazine, morpholine , N-heteroaromatics, such as imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, Isoquinoline, quinoline, benzimidazole, purine, thiazole or oxazole.
  • groups such as imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, Isoquinoline, quinoline, benzimidazole, purine, thiazole or oxazole.
  • the cationic charge group consists of a quaternized nitrogen compound.
  • the organic polycation furthermore preferably has quaternary cationic groups, preferably quaternary amines selected from the group consisting of or consisting of ammonium, guanidinium, amidinium, imidazolium, pyrrolidinium, pyrazinium, piperidinium, pyrimidinium, pyridazinium pyrazolium , Isoquinolinium, quinolinium, purinium, benzimidazolium, thiazolinium, oxazolinium, phosphonium and sulfonium ions.
  • heterocyclic aromatics or aliphatic heterocycles may also carry additional amine groups.
  • hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte carries at least two cationic charge groups or at least two basic groups selected from the list consisting of or ammonium, guanidinium, amidinium, imidazolium, pyrrolidinium, pyrazinium, piperidinium, pyrimidinium, pyridazinium, pyrazolium, isoquinolinium , Quinolinium, purinium, benzimidazolium, thiazolinium, oxazolinium, phosphonium and sulfonium.
  • One embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte bearing at least two cationic charge groups or at least two basic groups selected from the list comprising or consisting of ammonium, guanidinium, amidinium, imidazolium, pyrrolidinium, pyrazinium, piperidinium, pyrimidinium, pyridazinium, Pyrazolium, isoquinolinium, quinolinium, purinium, benzimidazolium, thiazolinium, oxazolinium, phosphonium and sulfonium.
  • hydrophobic cationic electrolytes and polyelectrolytes may also be condensation or polymerization products of hydrophobic carbon compounds and compounds having cationic charge groups or hydrophilic cationic electrolytes which are covalently linked to hydrophobic carbon compounds or covalently bonded to each other and to one another by polymerization. Furthermore, they may be hydrophilic cationic polyelectrolytes, which are rendered hydrophobic with hydrophobic compounds (see also the procedures hereafter).
  • the cationic groups are very well suited to bind to hydrophobic groups. As a result, the number of charge carriers decreases and the hydrophobicity is increased. It has been found that the saturation of the cationic groups, respectively the increase of the hydrophobicity, are accompanied by an increase of the degradation stability. This also applies to a saturation of the cationic groups by carboxylic acids which are bound electrostatically. It is believed that cationic groups that do not have hydrophobic shielding promote water ingress / penetration that occurs during degardation.
  • cationic electrolytes and polyelectrolytes are preferred in which there is a hydrophobic shielding of the cationic groups by means of electrostatically bonded carboxylic acids and / or covalently bonded hydrophobic radicals, preferably> 50%, more preferably> 75%, more preferably> 90% and most preferably> 98% of the cationic groups.
  • the hydrophobic cationic polyelectrolytes may be composed of amino acids. Suitable are homologous organic polycations, such as polylysine, polyarginine, polyornithine, polyhistidine or heterologous polycations with two or more different amino acids, wherein at least one amino acid into a positively charged charge group, preferably via a nitrogen unit.
  • the polyamino acids are rendered hydrophobic.
  • an amino acid is copolymerized with an amino acid selected from the group consisting of phenylalanine, lysine, arginine, histidine, ornithine or a mixture of at least two of these amino acids.
  • the said amino acids can be previously hydrophobed or the resulting copolymer is rendered hydrophobic.
  • the monomeric amino acids can be protected from polymerization.
  • a protective group for the functionality to be protected preference is given to using fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz, Z) or acetyl groups, more preferably triphenylmethyl (Trt), benzyloxymethyl (Born), benzyl -, phenyl, dinitrophenyl (Dnp), toluenesulfony-1 (Tos), mesitylenesulfonyl (Mts), acetamidomethyl (Acm), tert-Butylmercapto phenomenon (tBum) used.
  • the protecting groups can also be used frequently to produce the desired hydrophobic character of the polyelectrolytes. It has been found that arginine in its protected form already has the desired hydrophobic character of the hydrophobic cationic electrolyte. Particularly preferred is e.g. an arylsulfonyl protecting group. It is also possible via the protecting groups to introduce the desired carbon chain lengths as disclosed herein prior to polymerization. It would also be conceivable to polymerize monomeric amino acid with protective groups having different carbon chain lengths. Alternatively, it would also be possible to deprotect the protected polyamino acid only partially.
  • One embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating anhydrous, wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte comprises a polymer and / or copolymer comprising or consisting of at least one amino acid phenylalanine, lysine, arginine, histidine and / or ornithine.
  • One embodiment of the present invention relates to a surface coating comprising or consisting of at least one carboxylic acid; and at least one hydrophobic cationic electrolyte or hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte, wherein the surface coating is prepared anhydrous, wherein the hydrophobic cationic electrolyte or the hydrophobic cationic polyelectrolyte polyphenylalanine, polylysine, polyarginine, polyornithine , Polyhistidine or a compound containing or consisting of the amino acids lysine, arginine, histidine, phenylalanine and / or ornithine.
  • one embodiment of the present invention is directed to a method of making surface coatings comprising the following steps:
  • polymers are obtained by first functionalizing the monomers with a reactive group which preferably reacts with the carboxyl group, such as N-carboxyanhydrides (NCA).
  • NCA N-carboxyanhydrides
  • further functional groups of the compounds which interfere with a polymerization reaction are to be protected by known processes.
  • these Compounds becomes a suitable concentration ratio in a solvent phase, such as. B. THF, prepared and initiated a reaction activation, for example by adding a reaction-promoting solvent or a nucleophile such as an amine.
  • reaction activation is understood to mean the initiation of the reaction or the initiation of the polymerization.
  • the polymerization reaction can be terminated by known processes.
  • the polymerization products can be fractionated according to their molecular weight, as required.For compounds containing protective groups of cationic functional groups, these are If, therefore, functional groups which can be converted into a cationic group should carry a protective group, these are removed in a further step If the obtainable hydrophobic cationic polypeptides have the specification according to the invention, they can be prepared analogously to the described surface deposition methods native or hydrophobized material surfaces are deposited.
  • Prior art polycationic compounds that do not have the requisite hydrophobicity can be made by coupling them with non-polar and / or poorly polar compounds. Such methods are known in the art.
  • a hydrophobic modification of cationic electrolytes takes place according to one of the following methods or according to a method of the prior art.
  • the hydrogen atoms of primary and secondary amino groups be in part by linear or branched alkyl, alkenyl, alkynyl, hydroxyalkyl or alkylcarboxyl radicals having from 6 to 24 carbon atoms, preferably from 8 to 24 carbon atoms, preferably from 10 to 22 carbon atoms, preferably with 12 to 20 carbon atoms, even more preferably with 14 to 18 carbon atoms in the alkyl radical, which may carry further substituents such as alkyl, alkene, alkyne, hydroxy groups, amino groups, halogens, sulfide groups or carboxyl groups.
  • the reaction is carried out with linear or branched carboxylic acids having 10 to 22 carbon atoms, preferably having 14 to 20 carbon atoms, more preferably 12 to 20 carbon atoms, even more preferably having 14 to 18 carbon atoms in the alkyl or alkylene radical, such as Capric, undecanoic, lauric, tridecanoic, myristic, pentadecanoic, palmitic, margaric, stearic, nonadecanoic, arachidic, behenic, palmitoleic, oleic, linoleic, linolenic, arachidonic and mixtures thereof, preferably stearic, palmitic and oleic acids, or Anhydrides of said carboxylic acids and / or linear or branched Alkyl halides having 10 to 22 carbon atoms, preferably having 12 to 20 carbon atoms, even more preferably having 14 to 18 carbon atoms, such as tetradecyl chloride,
  • the degree of hydrophobing (the degree of modification) is preferably 0.1 wt .-% to 100 wt .-%, more preferably 0.2 wt .-% to 80 wt .-%, more preferably 0.3 wt .-% to 60 wt .-%, further preferably 0.4 to 50% by weight, more preferably 0.5 to 40% by weight, more preferably 0.6 to 30% by weight, further preferably 0.7 to 20% by weight, further preferably 0 , 9 to 10 wt .-% and particularly preferably 1 to 7 wt .-% of the above hydrophobing units, based on the weight of the finished product.
  • the at least one hydrophobic cationic electrolyte and / or hydrophobic cationic polyelectrolyte is hydrophobicized.
  • hydrophobing are compounds having epoxy groups.
  • epoxy groups e.g. Epoxyethane, epoxypropane, epoxybutane, epoxypentane, epoxyhexane, epoxyheptane, epoxyoctane, epoxynonane or epoxydecane
  • the H atom of the amino group is replaced by the carbon of the epoxide building block.
  • lipophilic polyalkylenepolyamines are also preferred. These compounds can be obtained according to the prior art, for example by alcohol amination, in the aliphatic amino alcohols with one another or aliphatic diamines or polyamines with aliphatic diols or polyols with elimination of water in the presence of a homogeneous catalyst. At least one of the starting materials is an alkyl or alkylene group containing five or more carbon atoms.
  • the hydrophobicity achievable therewith can be established, whereby a different dissolution behavior in organic solvents having a different polarity can be produced.
  • This can be used in a particularly advantageous manner to allow a multiple application of hydrophobic cationic electrolytes and polyelectrolytes, which are dissolved in organic solvents of different polarity, thereby avoiding an arrival and / or replacement of an already made order of the compounds.
  • a carboxylic acid / nitrocarboxylic acid can be applied to a coating with a hydrophobic cationic electrolyte or polyelectrolyte, without a relevant dissolution of the order by dissolving them in methanol or acetone and applying the solution to the material surface (eg by spray coating or micropippetting method ) or the material is introduced into an appropriate solution (eg dipp-coating). Therefore, in a preferred embodiment of the coating according to the invention, an application of hydrophobic cationic electrolytes or polyelectrolytes takes place have different hydrophobicity or solution behavior in organic solvents wherein the order of these compounds is carried out alternately on a material surface.
  • hydrophobic cationic electrolyte or polyelectrolyte it is preferable to first carry out a deposition of a hydrophobic cationic electrolyte or polyelectrolyte and, after drying, to deposit a deposition of a hydrophobic cationic electrolyte or polyelectrolyte with a lower or higher hydrophobicity and using a different organic solvent on the material surface.
  • the one and / or both of the hydrophobic cationic electrolytes or polyelectrolytes may be present in the form of a mixture with one or more carboxylic acids / nitrocarboxylic acids. It is further preferred according to the invention and preferred to carry out a separation of carboxylic acids / nitrocarboxylic acids between the abovementioned coating steps, which is preferably present dissolved in a polar organic solvent.
  • Suitable quaternizing agents are alkylating agents such as alkyl halides, methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propylidoid, butyl chloride, butyl bromide, butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, hexyl chloride, hexyl bromide, hexyl iodide, heptyl chloride, heptyl bromide, heptyl iodide, octyl chloride , octyl bromide, octyl chloride , octyl bromide, octyl chloride , octyl bromide, o
  • hydrophobic polyalkyleneimines are understood as meaning polymers of homologs of ethyleneimine (aziridine) or of a 2-substituted-2-oxazoline monomer, such as propylene imine (2-methylaziridine), 1- or 2-butyleneimine (2-ethylaziridine or 2,3-dimethylaziridine) ,
  • polystyrene resin may be homopolymers of the abovementioned alkyleneimines or a said oxazoline monomer or its higher homologs and the graft polymers of polyamidoamines or polyvinylamines with ethyleneimine or a 2-substituted-2-oxazoline monomer or its higher homologs.
  • Polyalkylenenimines may be modified by reaction with alkylene oxides such as ethylene oxide, propylene oxide or butylene oxide, dialkyl carbonates such as dimethyl carbonate and diethyl carbonate, alkylene carbonates such as ethylene carbonate or propylene carbonate, or C 1 -C 6 carboxylic acids.
  • hydrophobic polyethyleneimines are particularly preferred. These may be homopolymers of ethyleneimine (aziridine) or a 2-substituted 2-oxazoline monomer or its higher homologs, as well as the graft polymers of polyamidoamines or polyvinylamines with ethyleneimine or a 2-substituted 2-oxazoline monomer or its higher homologues.
  • the polyethyleneimines can be uncrosslinked or crosslinked, quaternized and / or modified by reaction with alkylene oxides, dialkyl or alkylene carbonates or C 1 - to C 6 -carboxylic acids.
  • the amines are only partially modified with the dialkyl or Alkylencarbonaten or d- to Ce carboxylic acids.
  • diisocyanates such as hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane-4,4'-diisocyanate and
  • Diphenylmethane diisocyanate dihaloalkanes such as 1, 2-dichloroethane, 1, 3-trichloropropane, 1, 4-dichlorobutane and 1, 6-dichlorohexane, diepoxides such as oligo- and Polyethylenglycolbisepoxide, epihalohydrins such as epichlorohydrin, bischlorohydrin ethers of alkylene glycols and polyalkylene glycols with 2 bis 100 ethylene oxide and / or propylene oxide units, alkylene carbonates such as ethylene carbonate and propylene carbonate and bischloroformates such as 2,2-Dimethylpropylenbischloroformiat.
  • dihaloalkanes such as 1, 2-dichloroethane, 1, 3-trichloropropane, 1, 4-dichlorobutane and 1, 6-dichlorohexane
  • diepoxides such as oligo- and Poly
  • Hydrophobic polyethyleneimines can also consist of polymers which have been prepared from ethyleneimine units and polyamidoamines by grafting. Grafted polyamidoamines are known, for example, from US Pat. No. 4,144,123 or DE-B-2,434,816.
  • Hydrophobic polyalkylenepolyamines are compounds containing at least 3 basic nitrogen atoms in the molecule, for example diethylenetriamine, dipropylenetriamine, triethylenetetramine, tripropylenetetramine, tetraethylenepentamine, pentaethylenehexamine, N- (2-aminoethyl) -1, 3-propanediamine and N, N'-bis (3 - aminopropyl) ethylenediamine. These compounds can also be adjusted by copolymerization or grafting to the hydrophobicity of the invention.
  • hydrophobic polyvinylamines which are homopolymers or copolymers of N-vinylcarboxamides which are at least partially saponified.
  • the polyvinylamines can be present in uncrosslinked or crosslinked form, quaternized and / or modified by reaction with alkylene oxides, dialkyl or alkylene carbonates or C 1 - to C 6 -carboxylic acids.
  • hydrophobic cationic polyelectrolytes may be compounds prepared from the following monomer subunits: 2-aminoethyl acrylate, 2-aminoethyl methacrylate, dimethylaminoethyl acrylate (DMAEA), dimethylaminopropyl acrylate, propenoic acid 2- (dimethylamino) propyl ester, dimethylaminobutyl acrylate, diethylaminoethyl acrylate, diethylaminopropyl acrylate Propenoic acid 2- (diethylamino) propyl ester, diethylaminobutyl acrylate, dipropylaminoethyl acrylate, dipropylaminopropyl acrylate, 2-propenoic acid 2- (dipropylamino) propyl ester, dipropylaminobutyl acrylate, 2- (morpholin-4-yl) ethyl acrylate, 2- (di
  • DMAEM Dimethylaminoethyl methacrylate
  • 2- (dimethylamino) propyl methacrylate dimethylaminobutyl methacrylate, diethylaminoethyl methacrylate, diethylaminopropyl methacrylate, 2- (diethylamino) propyl methacrylate, diethylaminobutyl methacrylate, dipropylaminoethyl methacrylate, dipropylaminopropyl methacrylate, 2- (dipropylamino) propyl methacrylate, dipropylaminobutyl methacrylate, methacrylic acid.
  • cetylacetyl (imidazol-4-ylmethyl) polyethyleneimine is preferred.
  • Other compounds which are suitable for the preparation of hydrophobic cationic polyelectrolytes are, for example, compounds with primary, secondary and tertiary amines, such as.
  • hydrophobic compounds of polyamidoamine PAMAM
  • polyethylenimine PEI
  • polypropylenimine PPI
  • hydrophobized polyamidoamine PAMAM
  • hydrophobized polyethylenimine PEI
  • hydrophobized polypropylenimine PEI
  • hydrophobized polymers and / or copolymers containing or consisting of arginine Particularly preferred are hydrophobic compounds of polyamidoamine (PAMAM), polyethylenimine (PEI) and polypropylenimine (PPI), which are preferably modified as described herein.
  • hydrophobic cationic polyelectrolyte such as from polyamines, for example.
  • Polyethyleneimine (PEI) or polyamino acids are preferably at least 25%, more preferably at least 30%, even more preferably at least 40% of the aminoprotons of the starting material by linear or branched alkyl alkenyl, alkynyl , Hydroxyalkyl or alkylcarboxyl radicals preferably having at least 6 carbon atoms, preferably having at least 8 carbon atoms, more preferably having at least 10 carbon atoms, even more preferably having at least 12 carbon atoms, even more preferably having at least 14 carbon atoms and even more preferably having at least 16 carbon atoms.
  • PEI Polyethyleneimine
  • polyamino acids are preferably at least 25%, more preferably at least 30%, even more preferably at least 40% of the aminoprotons of the starting material by linear or branched alkyl alkenyl, alkynyl , Hydroxyalkyl or alkylcar
  • hydrophobization is preferably understood as meaning the degree of alkylation.
  • the degree of alkylation is preferably the ratio of the alkylating reagent used to the number of primary amines and / or secondary and / or tertiary amines more preferably the ratio of the alkylating reagent used to the number of primary amines and / or secondary and most preferably the ratio of alkylating reagent used Number of primary amines.
  • An alkylation level is particularly preferably 1-100%, preferably 10-100%, more preferably 20-100%, more preferably 30-100%, more preferably 40-100%, still more preferably 50-100%, even more preferably from 60 to 100%, more preferably from 70 to 100%, even more preferably from 80 to 100%, and still more preferably from 90 to 100%.
  • the at least one polyelectrolyte is particularly preferably selected from the group consisting of polybenzylamine, polyvinylpyrrolidine, polyvinylpiperidine, polyvinylimidazole, polyvinylpyridine, polyvinylamine, polyvinylguanidine, polyvinylamidine, polyallylamine, polyallylguanidine, diallyl, polydiallyldimethylammonium salt (PDADMA salt), hexadimethrine bromide (polybrene), poly [bis (2-chloroethyl) ether-a / M, 3-bis [3- (dimethylamino) propyl] urea] and copolymers of the aforementioned polymers, wherein the polyelectrolytes are preferably hydrophobicized.
  • active compound or “supportive compound” is meant molecular compounds having a known effect in biological Have systems or can cause an effect on biological systems.
  • the active compounds meant herein are preferably molecular compounds known as medicinal agents.
  • the preferred supportive compounds are, for example, those compounds which regulate a release of the active compounds and / or have an influence on their stability or exert an influence on the degradation of the coating and / or have biological effects.
  • a formulation can also be carried out with a carboxylic acid and a suitable substance, such as an active ingredient or a supportive compound, admixed to one of the hydrophobic cationic polyelectrolytes or deposited on a coating carried out.
  • a suitable substance such as an active ingredient or a supportive compound
  • such compounds can also be electrostatically bound to hydrophobic anionic electrolytes / polyelectrolytes and deposited together with them on a layer of a hydrophobic cationic polyelectrolyte or deposited together with them during the deposition process.
  • the active compound is preferably an antiproliferative, antiinflammatory, antimigrative, antiinflammatory, antiangiogenic, cytostatic, cytotoxic, antirestenotic, antineoplastic, antibacterial and / or antimycotic active ingredient.
  • sulfur-containing amino acids such as cystine and salts, hydrates, solvates, enantiomers, racemates, enantiomer mixtures, diastereomer mixtures; Metabolites, prodrugs and mixtures of the aforementioned active ingredients.
  • Preferred active compounds are, for example, heparin, aspirin, ramipril, trapidil, batroxobin, corticoids, such as dexamethasone or 17-.beta.-estradiol, m-TOR inhibitors, such as rapamycin (sirolimus, everolimus, tarcolimus, zotarolimus, biolimus), taxols, such as paclitaxel ,
  • Preferred supportive compounds are, for example, cholesterol, angiopeptin, VEGF, PEG, collagen, hyaluronic acid and its derivatives, antioxidants, vitamins, such as calciferol or carotenoids.
  • nitrofatty acids as described herein.
  • Carboxylic acids are organic compounds that carry one or more carboxyl groups. A distinction is made between aliphatic, aromatic and heterocyclic carboxylic acids. Aliphatic forms of carboxylic acids, also called alkanoic acids, are fatty acids and are further listed in the following paragraph.
  • fatty acids are aliphatic carbon chains having a carboxylic acid group.
  • the carbon atoms can be linked with single bonds (saturated fatty acids) or with double bond bridges (unsaturated fatty acids), these double bonds may be in an egg or trans configuration.
  • saturated fatty acids saturated fatty acids
  • double bond bridges unsaturated fatty acids
  • fatty acids such compounds having more than 4 consecutive carbon atoms adjacent to the carboxyl group are referred to as fatty acids.
  • linear saturated fatty acids examples include nonanecarboxylic acid (capric acid), dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), n-eicosanoic acid (arachidic acid) and n-docosanoic acid (behenic acid).
  • Examples of mono-olefin fatty acids are myristoleic acid, palmetoleic acid, petroselinic acid, oleic acid, elaidic acid, dicelic acid and erucic acid.
  • Examples of polyolefin fatty acids are linoleic acid, linolenic acid, punicic acid, arachidonic acid and nervonic acid.
  • Fatty acids may also carry functional groups, such as. As the vernolic acid, ricinoleic acid and lactobacillic acid.
  • the functional groups herein also include terminal carbon cyclic radicals.
  • fatty acids used herein, the following compounds are exemplified: hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, cis-9-tetradecenoic acid, cis-9-hexadecenoic acid cis-6-octadecenoic acid, cis-9-octadecenoic acid, cis-1-octadecenoic acid, cis-9-eicosenoic acid, cis-1-eicosenoic acid, cis-13-docosenoic acid, cis-15-tetracenoic acid, t9-octadecenoi
  • Eicosatrienoic acid 9c1 1t13t-eleostearic acid, 8t10t12c-calendulic acid, 9c1 1t13c-catalpinic acid, 4,7,9,1,1,13,16,19-docosaheptadecanoic acid, taxoleinic acid, pinolenic acid, sciadonic acid, 6-octadecanoic acid, tl 1 -ctadecene-9- acid, 9-octadecanoic acid, 6-octadecene-9-enoic acid, t10-heptadecene-8-acetic acid, 9-octadecene-12-acetic acid, t7, t1 1-octadecadiene-9-amino acid, t8, t10-octadecadiene-12-acetic acid , 5,8,1 1, 14-eicosatetraic acid, retinoic acid, isopalmitic acid
  • nitrocarboxylic acids which can be used according to the invention, which are also referred to herein synonymously as nitro-fatty acids or "nitrated fatty acids", contain at least one carboxylic acid unit and one C-NO 2 unit (bond between carbon and nitrogen), and preferably correspond to the general formula X:
  • the compound contains at least one nitro (-NO 2) group attached to one of the carbon atoms of the carbon chain.
  • the nitro group represented by the general formula (X) has no specific position and may be bonded to any of the carbon atoms (a to co) of the alkyl chain, ie, the carbon atom chain. Most preferred is when the nitro group or groups are / is attached to a vinyl unit of the unsaturated alkyl chain of an unsaturated carboxylic acid. That is, the nitro group (s) is most preferably attached to a double bond in the unsaturated alkyl chain of the unsaturated carboxylic acid.
  • the carbon atom chain which may be referred to as an alkyl chain, may contain more than one nitro group.
  • the carbon atom chain may also contain double bonds and / or triple bonds and may be linear or branched and contain further substituents defined as substituents S1 to S20.
  • the term "alkyl chain” not only refers to linear and saturated alkyl groups, but also refers to mono-unsaturated, polyunsaturated, branched and further substituted alkyl groups or alkenyl groups or alkynyl groups. Preferred are the mono-, di- and poly-unsaturated carbon atom chains of the unsaturated carboxylic acids (including unsaturated carboxylic acid esters).
  • the carbon atom chain refers to an alkyl chain to which is bonded at least one nitro group consisting of 1 to 40 carbon atoms, which alkyl chain may contain one or more double and / or one or more triple bonds and may be cydic and / or by one or more nitro groups and / or one or more substituents S1 - S20 may be substituted.
  • alkyl is unclear, due to the fact that an alkyl group is saturated and contains no double or triple bonds, the following definition is provided: the term
  • Carbon atom chain refers to an alkyl chain or alkenyl chain or alkynyl chain to which is bonded at least one nitro group consisting of 1 to 40 carbon atoms, which alkyl chain may be cydic and may be substituted by one or more nitro groups and / or one or more substituents S1 - S20, the alkenyl chain contains one or more double bonds and may be cydic and substituted by one or more nitro groups and / or one or more substituents S1 - S20 and the alkynyl chain contains one or more triple bonds and may be cydic and one or more nitro groups and / or one or more substituents S1 - S20.
  • the term "may be substituted by one or more nitro groups” is understood to mean that one or more nitro groups may be present on the carbon atom chain in addition to the one nitro group necessarily required and explicitly mentioned and designated in the general formula (X ).
  • the term "carbon atom chain” refers to an alkyl chain which is saturated or which may contain one or more double bonds and / or triple bonds or refers to an alkyl chain (only saturated carbon atom chains are meant), alkenyl chain or alkynyl chain having at least one nitro group which is the nitro group which is explicitly drawn and mentioned in the general formula (X).
  • the carbon atom chain preferably contains 1 to 10, more preferably 1 to 5 double bonds or vinyl radicals.
  • the carbon atom chain consists of 1 to 40 carbon atoms, preferably 2 to 30 carbon atoms and more preferably 4 to 24 carbon atoms, which alkyl chain may contain one or more double and / or one or more triple bonds and / or may be substituted by one or more nitro groups and / or one or more substituents S1-S20.
  • nitrocarboxylic acids are unsaturated nitrocarboxylic acids. According to the invention, it is possible to use both cis and trans isomers and (depending on the substituents which can produce chiral centers) enantiomers, diastereomers and their racemates.
  • the nitro group can be attached to any position of the carbon chain.
  • Preferred unsaturated nitrocarboxylic acids are: nitro-cis-9-tetradecenoic acid (nitromyristoleic acid), nitro-cis-9-hexadecenoic acid (nitropalmitoleic acid), nitro-cis-6-hexadecenoic acid (nitrosalpenoic acid), nitro-cis-6 (nitropetrosuloic acid), nitro-cis -9- octadecenoic acid (nitrooleic acid), nitro-trans-9-octadecenoic acid, trans-9-nitro-9-octadecenoic acid, trans-10-nitro-9-octadecenoic acid, cis-9-nitro-9-octadecenoic acid, cis-10 Nitro-9-octadecenoyl, trans -10-nitro-8-octadecenoic acid, trans-9-nitro-10-octadecenoic acid, cis-10-nitro-8-octade
  • nitrofatty acids of oleic acid Particularly preferred are the nitrofatty acids of oleic acid. Particular preference is given to nitro-cis-9-octadecenoic acid, nitro-trans-9-octadecenoic acid or a mixture of these or trans-9-nitro-9-octadecenoic acid, cis-9-nitro-9-octadecenoic acid, cis-9-nitro -10-octadecenoic acid, and trans-9-nitro-10-octadecenoic acid or mixtures of these.
  • nitrocarboxylic acids with saturated alkyl chains are: nitrocarboxylic acid (nitrocapric acid), nitrodecanoic acid (nitromyrinic acid), nitrotetradecanoic acid (nitromycetic acid), nitrohexadecenoic acid (nitropalmitic acid), nitroheptadecanoic acid (nitromargaric acid), nitrooctadecanoic acid (nitrostearic acid), nitroic acid (nitroreacylic acid), nitrotocosenoic acid ( Nitrobesterklare), Nitrotetracosanklare (Nitrolignocerklare).
  • saturated nitrocarboxylic acids can contain 1, 2, 3, 4, 5 or 6 further nitro groups and can contain one or more of the abovementioned substituents S1-S20.
  • unsaturated nitrocarboxylic acids are preferred and, furthermore, unsaturated nitrocarboxylic acids containing one or two nitro groups are preferred.
  • the concentration of the at least one nitro carboxylic acid and other active ingredients, if present, is preferably in the range from 0001 to 500 mg per cm 2, preferably from 0:01 - 500 mg per cm 2, preferably 0.1 - 500 mg per cm 2, preferably 1 - 500 mg per cm 2, more preferably from 0001 to 450 mg per cm 2, more preferably 0:01 - 450 mg per cm 2, more preferably 0.1 - 450 mg per cm 2, more preferably 1 - 450 mg per cm 2, more preferably from 0001 to 400 mg per cm 2, more preferably 0:01 - 400 mg per cm 2, more preferably 0.1 - 400 mg per cm 2, more preferably 1 - 400 mg per cm 2, more preferably from 0001 to 300 mg per cm 2, more preferably 0:01 - 300 mg per cm 2, more preferably 0.1 - 300 mg per cm 2, more preferably 1 - 300 mg per cm 2, more preferably from 0001 to 200 mg per cm 2, more preferably 0:01 - 200 mg per cm 2, more preferably 0.1
  • the object of this method step is to provide a material surface in a form in which it can be coated with the method according to the invention.
  • the material may be metal or a metal alloy, a plastic, an inorganic compound such as ceramic or porcelain or an enamel, or a synthetic polymer such as PLA or a biopolymer such as cellulose. These can be resistant to completely dissolvable materials.
  • the material can be closed or open-pored or textured, with a smooth to rough surface. Also composites are suitable.
  • the surfaces may be absorbent or not soakable. There may be surface properties that vary between hydrophilic oleophobic to lipophilic oleophilic. Preference is given to metals and metal alloys and polymers. Particularly preferred are materials that are easily corrodible and / or biodegradable. Also preferred are smooth surfaces that are hydrophobic and / or lipophilic.
  • cleaning agents are, for example, organic solvents, such as alcohols, acetone or chloroform, furthermore acids, such as, for example, H 2 SO 4 , and also alkalis, such as NaOH or oxidizing agents, such as H 2 O 2 .
  • the duration of the exposure and the cleaning process are material-dependent and can be determined by a person skilled in the art.
  • the cleaning result can be checked by analytical methods such as electron microscopy.
  • hydrophobing is known to the person skilled in the art and generally refers to the change of the interaction of a substance or material with water, whereby the affinity of the substance or of the material for water is lowered
  • the surface of the material is preferably carried out until a water contact angle of> 40 °, preferably of> 60 °, more preferably of> 70 ° and most preferably> 85 °.
  • a surface hydrophobicization according to the invention is achieved when a water contact angle of> 60 ° is present. According to the invention, the hydrophobization takes place in that the surfaces do not come into contact with water.
  • a covalent surface hydrophobing can be carried out, for example, by silicon compounds which carry, for example, alkane or alkyl compounds, and can condense with OH groups done. This can be anhydrous from a solvent phase, for. As t-butanol or diacetone alcohol, take place.
  • organosilanes such as n-octadecyltrimethoxysilane C21 H52O3S1 (ODTMS) or - n-octadecyltriethoxysilane C2 4 H 6 O3Si (ODTES), and bivalent silanes, such as bis [3- (triethoxysilyl) propyl] tetrasulfide (BTES) and bis (trimethoxysilylpropyl) or aminosilanes such as 3-aminopropyltriethoxysilane (APTES), but also halogenated silanes such as perfluorodecyltrichlorosilanes.
  • BTES bis [3- (triethoxysilyl) propyl] tetrasulfide
  • APTES 3-aminopropyltriethoxysilane
  • halogenated silanes such as perfluorodecyltrichlorosilanes
  • the silanization solution for example, 2-10% of the silane with 5% triethylamine in dried toluene.
  • the incubation of the samples takes place, for example, for 2.5 hours in pre-silanized glass vessels at 75.degree.
  • the vessels are kept in motion with a sample shaker at a low number of revolutions.
  • the samples are removed and rinsed several times with toluene to remove only weakly adhering silane molecules. Thereafter, the samples are dried with compressed air or in a stream of nitrogen and stored for 1.5 hours at 135 ° C in an oven.
  • hydrophobing compounds which have an affinity for OH groups. Further preferred are compounds that are metabolized and / or excreted from the human organism and have low toxicity. Dopamine and polydopamine are preferred.
  • the application may be anhydrous, e.g. from a solution in methanol.
  • parylene C, D, N or F which is preferably applied over the entire surface by means of a gas deposition process.
  • hydrophobing consists of a coating with halogenated organic or inorganic compounds, wherein the preferred halogens are fluorine, chlorine and bromine. Examples are PTFE or chlorinated paraffins. Such coatings can also be deposited via a gas phase or applied in the form of a melt.
  • the order of the compounds for hydrophobing is preferably carried out under protective gas conditions and under the respectively suitable and adapted to the material to be coated temperatures.
  • Deposition of hydrophobing compounds can also be accomplished by physico-chemical deposition techniques. Known methods are an ALD, PVD or CVD method.
  • the processes for hydrophobization are carried out monolayer coatings.
  • the successful hydrophobing can be carried out by known analytical methods, such as the water contact angle measurement. Preference is given to a hydrophobing which requires a water contact angle of> 60 °, more preferably of> 70 ° and particularly preferably of> 85 °.
  • the hydrophobic cationic electrolytes and polyelectrolytes of the invention are carbon-based compounds having one or more positive charge groups. Preferred are compounds having a molecular weight between 200 and 500,000, more preferred are those having a molecular weight of between 1,000 and 100,000 Da, and more preferably between 2,000 and 50,000 Da. According to the invention, both unbranched and singly or multiply branched hydrophobic cationic electrolytes and polyelectrolytes. Branched and multi-branched hydrophobic cationic polyelectrolytes are preferred. Mixtures of hydrophobic cationic electrolytes and polyelectrolytes with different C chain length and / or degree of branching can also be used.
  • a hydrophobic property of the hydrophobic cationic electrolytes and polyelectrolytes to be used according to the invention is preferred. This can be recognized, for example, from the fact that after application to a surface, the hydrophobic cationic electrolytes or polyelectrolytes can not be redissolved with an aqueous medium. Furthermore, they impart hydrophobic properties after drying the material surface, which can be determined by means of water contact angle measurements. The hydrophobicity produced thereby causes a water contact angle when measured at 20 ° C.
  • hydrophobic cationic electrolytes and polyelectrolytes have a K ow of> 0.3, more preferably of> 0.8 and even more preferably of> 1. Hydrophobic does not mean that the hydrophobic cationic electrolytes and polyelectrolytes can not be dissolved in one part in an aqueous medium.
  • the mixed solution may consist of one or more organic solvents.
  • Preferred solvents are: volatile alcohols, such as ethanol, methanol, isopropyl alcohol, but also low-volatility alcohols, such as polyethylene glycol or wax alcohols or polyethers, furthermore chlorinated hydrocarbons, such as dichloromethane, volatile alkane, alkene or alkyne compounds in aliphatic or cyclic form , as Heptane or cyclohexane or benzenes.
  • apolar organic solvents such as toluene or THF. In principle, all nonpolar solvents are suitable.
  • alkanes including their constitutional isomers and their cyclic form pentane, hexane, heptane, octane, nonane, decane, undecane, or dodecane, benzene, toluene, xylenes, trimethylbenzene, ethers, halogenated solvents or alcohols.
  • cyclopentane n-pentane, cyclohexane, n-hexane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, cycloheptane, n-heptane, 2- Methylhexane, 3-methylhexane, 2,2-dimethylpentane, 2,3-dimethylpentane, 3,3-dimethylpentane, 2,4-dimethylpentane, 3-ethylpentane, 2,3,3-trimethylbutane, cyclooctane, cyclooctene, such as trans- Cyclooctene or cis-cycloctene, n-octane, 2-methylheptane, 3-methylheptane, 4-methylheptane, 2,2-dimethylhexane, 2,3-dimethyl
  • the solvents are volatile solvents.
  • Volatile solvents are solvents having a boiling point of at most 200 ° C, preferably at most 190 ° C, more preferably at most 180 ° C, more preferably at most 170 ° C, more preferably at most 160 ° C, more preferably at most 150 ° C, more preferably at most 140 ° C, more preferably at most 130 ° C, more preferably at most 120 ° C, more preferably at most 1 10 ° C, more preferably at most 100 ° C, more preferably at most 90 ° C, more preferably at most 80 ° C, more preferably at most 70 ° C, more preferably at most 60 ° C, and most preferably at most 50 ° C at room temperature and normal pressure.
  • solvents are n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, n-octane, isooctane (2,2,4-trimethylpentane), ethanol, propane-1-ol, propan-2-ol , Butane-1 -ol, butan-2-ol, tert-butanol, pentane-1-ol, pentan-2-ol, pentan-3-ol, 2-methyl-2-butanol, hexane-1-ol, toluene , 1, 2-dimethylbenzene, 1, 3-dimethylbenzene, 1, 4-dimethylbenzene, THF (tetrahydrofuran), 2-methyltetrahydrofuran, MTBE (2-mehoxy-2-methylpropane) or TBME (tert-butylmethyl ether), tert-amyl ether ,
  • the most preferred solvents are pentane, iso-octane (2,2,4-trimethylpentane), toluene, THF (tetrahydrofuran), MTBE (2-methoxy-2-methylpropane) and TBME (tert-butyl methyl ether), ethanol, propane-1 -ol, propan-2-ol, DMSO, DCM (dichloromethane) or chloroform (trichloromethane).
  • the usable solvents can also be combined with each other.
  • the surface coating according to the invention preferably has a (generally) homogeneous layer thickness of 5 nm to 50 ⁇ m, more preferably of 10 nm and 25 ⁇ m and more preferably from 20 nm to 10 ⁇ m, and most preferably from 30 nm to 1 ⁇ m.
  • 2- or multi-layer coatings are carried out with hydrophobic cationic electrolytes and polyelectrolytes.
  • drying is carried out as described above.
  • the coating process is then carried out with the identical hydrophobic cationic electrolyte and polyelectrolyte as before and / or with another hydrophobic cationic electrolyte and polyelectrolyte under the same or changed process conditions.
  • hydrophobic cationic electrolytes and polyelectrolytes are multi-layered, comprising a hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture comprising at least one hydrophobic cationic electrolyte and at least one hydrophobic cationic polyelectrolyte and in an alternative coating step Mixture of a carboxylic acid and a hydrophobic cationic electrolyte or at least one hydrophobic cationic polyelectrolyte or a mixture of the like consecutively or alternately applied to the material surface.
  • the material surfaces are subjected to drying after each coating application.
  • steps b) and c) can be repeated two or more times consecutively after step c) and before step d).
  • the method according to the invention for producing a surface coating comprises the following steps:
  • a two-layered or multi-layered layer structure with hydrophobic cationic electrolytes and polyelectrolytes is prepared by alternately coating with hydrophobic cationic electrolytes and / or polyelectrolytes and hydrophobic anionic electrolytes and / or polyelectrolytes. It is preferred if the last layer of a hydrophobic electrolyte and / or polyelectrolyte is a hydrophobic cationic electrolyte and / or polyelectrolyte.
  • one or more hydrophobic cationic electrolytes and / or polyelectrolytes are mixed with one or more carboxylic acids, including nitrofatty acids. This is preferably carried out in a solvent phase in which the compounds are dissolved anhydrous. After complete mixing and preferably under clear solution, the mixture containing one or more hydrophobic cationic electrolytes and / or polyelectrolyte (s) and carboxylic acids may be applied. In principle, all nonpolar solvents are suitable.
  • alkanes including their constitutional isomers and their cyclic form pentane, hexane, heptane, octane, nonane, decane, undecane, or dodecane, benzene, toluene, xylenes, trimethylbenzene, ethers, halogenated solvents or alcohols.
  • cyclopentane n-pentane, cyclohexane, n-hexane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, cycloheptane, n-heptane, 2 Methylhexane, 3-methylhexane, 2,2-dimethylpentane, 2,3-dimethylpentane, 3,3-dimethylpentane, 2,4-dimethylpentane, 3-ethylpentane, 2,3,3-trimethylbutane, cyclooctane, cyclooctene, such as trans Cyclooctene or cis -cycloctene, n-octane, 2-methylheptane, 3-methylheptane, 4-methylheptane, 2,2-dimethylhexane, 2,3-dimethyl
  • Thymethylheptane 2,2,5-trimethylheptane, 2,2,6-trimethylheptane, 2,3,3-
  • Thymethylheptane 2,3,4-trimethylheptane, 2,3,5-trimethylheptane, 2,3,6-
  • Thymethylheptane 3,4,4-trimethylheptane, 3,4,5-trimethylheptane, 2,2,3,3-
  • the solvents are volatile solvents.
  • Volatile solvents are solvents having a boiling point of preferably at most 140 ° C, more preferably at most 130 ° C, further preferably at most 120 ° C, more preferably at most 1 10 ° C, more preferably at most 100 ° C, more preferably at most 90 ° C, more preferably at most 80 ° C, more preferably at most 70 ° C, more preferably at most 60 ° C, and most preferably at most 50 ° C at room temperature and normal pressure.
  • solvents are n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, n-octane, iso-octane (2,2,4-trimethylpentane), ethanol, propane 1-ol, propan-2-ol, butan-1-ol, butan-2-ol, tert-butanol, pentan-1-ol, pentan-2-ol, pentan-3-ol, 2-methyl-2 butanol, hexane-1-ol, toluene, 1, 2-dimethylbenzene, 1, 3-dimethylbenzene, 1, 4-dimethylbenzene, THF (tetrahydrofuran), 2-methyltetrahydrofuran, MTBE (2-mehoxy-2-methylpropane) or TBME (tert-butyl methyl ether), tert-amyl ether, DCM (dichlor
  • the most preferred solvents are pentane, isooctane (2,2,4-trimethylpentane), toluene, THF (tetrahydrofuran), MTBE (2-methoxy-2-methylpropane) or TBME (tert-butyl methyl ether), DCM (dichloromethane) or Chloroform (trichloromethane).
  • the application of one or a mixture of a plurality of hydrophobic cationic electrolytes and / or polyelectrolytes or a mixture with one or more carboxylic acids may be carried out by methods known in the art. Preference is given to a dip-coating in which the substrate to be coated is placed in a bath of the hydrophobic cationic electrolytes and / or polyelectrolytes and optionally carboxylic acids or immersed in a holding device in this. Preference is given to exposure over 10 seconds to 24 hours, more preferably between 20 seconds and 10 hours and more preferably between 30 seconds and 5 hours. Further preferred wetting methods are, for example, a spray coating or a spin coating.
  • the order procedure can be repeated or combined with another.
  • the completeness of the coating can be tested by prior art techniques, such as ellipsometry or confocal laser microscopy.
  • step b) material surfaces are freed in step c) of herein / hereby / adhering residues of solvents.
  • steps of the prior art can be used. Preference is given to vacuum drying, which preferably takes place over a period of 10 minutes to 24 hours, more preferably between 20 minutes and 10 hours. The drying was successful when no residues of the solvents used can be detected by analytical methods, otherwise the drying period is to be extended.
  • the resulting coated material is stored in an anhydrous atmosphere until the next treatment step. Preferably, the storage is in a vacuum or in an inert gas.
  • the application of one or more different carboxylic acid (s) is preferably carried out under protective gas conditions using prior art methods.
  • the one or more carboxylic acid (s) are completely dissolved in a suitable solvent.
  • a suitable solvent Preference is given, for example, to low-polar solvents, such as methanol or acetone.
  • the materials to be coated are then preferably coated with a dipping process. This is preferably carried out over a period of 1 minute and 24 hours, more preferably between 2 minutes and 1 hour and even more preferably between 3 and 10 minutes.
  • the temperature at which this takes place can be chosen freely, preferably a temperature between 5 ° and 50 ° C., more preferably between 10 ° and 30 ° C.
  • electrical contact is made with the preferably metallic coated material and a voltage is applied between the material to be coated and the coating solution or coating device.
  • a voltage is applied between the material to be coated and the coating solution or coating device.
  • an electrostatic charge of the surface is made.
  • the positively charged cationic compounds of the coated hydrophobic cationic polyelectrolytes under these conditions are preferably wetted in a bath with the dissolved carboxylic acids.
  • the electrostatically bound carboxylic acids are preferably present as a monolayer with a longitudinal axis of the carboxylic acid aligned perpendicular to the substrate plane.
  • the applied layer preferably has a height which corresponds to a molecular length of the coating-related carboxylic acid.
  • the carboxylic acids are applied in more than one layer.
  • the 2nd, 4th, 6th, etc. coating can be carried out with carboxylic acids from an aqueous medium.
  • the 3rd, 5th, 7th, etc. coating layer is then made of an anhydrous solvent phase.
  • the application of the second and further layers can be carried out by the methods described herein.
  • the successful surface coating can be done with prior art methods.
  • the determination of the water contact angle is preferred.
  • a successful coating is when the HPC> 80 °, more preferably> 90 °, more preferably> 100 °, more preferably> 1 10 ° and even more preferably> 120 °.
  • the data refer to a measurement at 20 ° C and normal pressure conditions.
  • the anhydrous wetting of the surface with at least one carboxylic acid is carried out using an organic solvent such as ethanol, methanol or acetone.
  • step e) The material surfaces coated with carboxylic acid in step d) are removed in this process step by adsorptively adhering carboxylic acids which are not electrostatically associated with the cationic electrolytes or polyelectrolytes.
  • the coated materials are preferably inserted or rinsed in a bath.
  • this is done with an alcoholic solution, preferably a mixture of water and methanol, further preferred are nonpolar organic solvents, such as ethyl acetate or acetone.
  • the rinsing or washing step can be repeated. Subsequently, a careful removal of solvent residues, which is preferably carried out by a vacuum drying.
  • the surfaces produced according to the invention are hydrophobic and have a water contact angle of> 80 ° or> 80 °, more preferably> 90 ° or> 90 °, more preferably> 100 ° or> 100 °, more preferably> 1 10 ° or> 1 10 ° and most preferably> 120 ° or> 120 °.
  • the surfaces have degradation stability in an aqueous medium at 37 ° C over 4 weeks, with a change in the water contact angle of ⁇ 10 ° during this period. Furthermore, contact with living cells with the surfaces coated according to the invention results in adhesion and the adhering cells have a significantly lower proliferation rate with respect to the adherent cell on a native (uncoated) material surface, with a low rate of apoptosis or necrosis.
  • a surface coating according to the invention can be applied to all solid medical instruments, implants and wound materials.
  • a surface coating according to the invention is particularly suitable for those implants whose structuring materials have decomposed in the course of time, dissolve and or dismantled or dissolved.
  • the time to onset of degradation / corrosion may be significantly delayed.
  • degradable materials retain their shape and functional properties for longer.
  • coatings according to the invention are suitable for suppressing corrosion processes and thereby eliminating a detachment of degardation products.
  • a surface coating according to the invention is particularly suitable for controlling active ingredients and / or supportive compounds and indicating them to the surrounding tissue over a relatively long period of time. This may be particularly advantageous, for example, in very extensive wound areas or wounds with a high inflammatory activity, such as combustion.
  • a coating of wound care materials is advantageous.
  • the coating process is particularly suitable for binding hydrophobic compounds and release them in a controlled manner. Therefore, a coating method according to the invention is also particularly suitable for the local release of hydrophobic active substances for reducing or suppressing a reunification of the vessels, in particular taxols and rapamycin as well as their derivatives.
  • a method according to the invention is suitable for forming tissue structures on artificial moldings or for producing endothelized vessel structures.
  • a coating according to the invention on implants is particularly advantageous when a rapid adhesion of cells is desired, such as in ophthalmic lenses.
  • a coating according to the invention is suitable for inhibiting the attachment of coagulation factors and platelets, as for example in catheters of venous ports or blood tubing systems as well as vascular implants.
  • FIG. 1 shows Table 1 containing the numerical results from Example 1.
  • FIG. 2 shows Table 2 containing the numerical results from Example 3.
  • FIG. 3 shows Table 3 containing the numerical results from Example 9 Examples
  • the content of phosphorus, calcium, magnesium and iron in the water phases was determined by ICP OES (iCAP 7400, Thermo-Fisher, Scientific, Germany). Values in ppm (or in mg / kg).
  • Water contact angle measurements were made with an automated contact angle meter (DAS 30, Krüss, Germany). The measurements were made by the sessile drop method, after a second contact time, at 20 ° C.
  • a surgical mesh made of PLLA (M1), a vascular scaffold (Resoloy, MeKo, Germany) (M2) and a template of osteosynthesis material (316L stainless steel) (M3) were used.
  • the pieces of material were connected at least 2 places with a platinum wire, which was attached by solder or thermomodulation. These had the task of fixing the pieces of material during the coating procedure, so that there was no contact of the material surfaces to a support surface in a container.
  • measurements were made of the insulation resistance of the coated material surfaces (M2 and M3).
  • the materials were cleaned in DCM in an ultrasonic bath for 20 minutes. This was followed by drying in a nitrogen stream and subsequent storage in an inert atmosphere.
  • the M2 preparations were placed in methanol in which L-dopamine was dissolved at a concentration of 10% by weight over 6 hours. Then rinse with THF and dry in vacuo.
  • the M3 preparations were pretreated with an oxygen plasma and then with toluene in the ODTMS (n-octadecyltrimethoxysilane C21 H52O3S1) was dissolved in a concentration of 5% by weight, stored for 6 hours. Ansch manend rinsing the material with ethanol and drying at 120 ° C for 3 hours.
  • the prepared substrates were further treated according to the following series of coatings: 1 a) oleic acid, 1 b) nitroolic acid with 25vol% ethanol additive, 2a) polyethyleneimine (MW 20,000 Da) with 25 vol% methanol addition, 2b) polyalkylenepolyamine (MW 50,000 Da) with 20 vol% - Addition of toluene.
  • the surface wetting was carried out by immersion in the solutions at 25 ° C for 3 hours. Then rinse the surfaces with ethanol. Thereafter, drying in a vacuum drying oven for 10 hours.
  • Substrates obtained from the coating steps 2a) and 2b) were coated with oleic acid in the 3a series of coating and in the 3b series with nitroolic acid by immersing them in the solutions as in the experimental series 1, followed by rinsing and drying ,
  • the substrates of the individual test series were immersed to determine the electrical insulation resistance in a 0.9% NaCl solution so far that the connection points to the platinum electrodes above the water surface remained, the determination was carried out under a 12V DC voltage. Subsequently, completely immerse the substrates in the solution and leave for 4 weeks. The determination of the electrical insulation resistance was repeated at intervals of 1 week under the identical conditions. Finally drying of the substrate surfaces.
  • the substrate surfaces were examined by SEM, EDX and confocal laser microscopy. For carrying out confocal laser microscopy, the surfaces were immersed in a solution containing Sudan for one hour and then rinsed with an ethanolic solution. Furthermore, the water contact angles (HPC) were determined before and after a coating and after the long-term examination. Results:
  • the insulation resistance to the untreated surface was increased by 26 +/- 16 ohms and 62 +/- 14 ohms, respectively.
  • the insulation resistances were between 400 to 480 and 500 to 620 ohms, whereby the resistances were higher by 80 to 120 ohms when using nitrofatty acids.
  • the insulation resistance for the coating 3a was. by 36 to 68 ohms lower than at the time of manufacture (to), while in coatings according to 3b. There was a reduction of the insulation resistance, which was less than 10% of the achieved at the time tO insulation resistance. It was for the coatings according to 3a. and 3b.
  • hydrophobic cationic electrolytes For the preparation of hydrophobic cationic electrolytes, the following compounds were used: Polyethyleneimine or poly (2-aminoethyl methacrylate) in each case reacted with 1-iodododecane.
  • Compound 1 Reaction of PEI with 1-aldodecane to PEI-C12 (100%)
  • the commercially available PEI has an average molar mass of 10,000 g / mol.
  • the molar mass of the monomer unit is 43.07 g / mol (empirical formula C2H 5 N2). This gives an estimate of the number of monomer units per PEI molecule (232.18 monomer units per PEI molecule). per PEI Mo tekiu
  • the PEI has a composition of 33.8% primary (RNH 2 ), 40.5% secondary (R 2 NH) and 25.7% tertiary amino groups (R3N).
  • the degree of alkylation is based on the amount of primary amino groups present.
  • reaction is carried out analogously to the preparation of compound 1, using 2.03 ml (8.25 mmol) of 1-alddecane.
  • the product PEI-C12 (50%) is obtained in a yield of 67%.
  • a hydrophobic treatment was carried out in coating step B1 by immersing the preparations in a solution of toluene with ODTMS (5% by weight) contained therein for 6 hours and then drying at 110 ° C. in a drying oven for 4 hours.
  • the preparations stored as in Example 1 were immersed in ethanol with 50% by weight dissolved PEI (MW 25,000 Da, highly branched) over 3 hours.
  • coating step B3 wetting with compound 1 according to Example 2 (PEI-C12 (100%)) was carried out as a 5% strength solution in pentane. Then rinse the preparations with ethanol and dry in a vacuum oven at 60 ° C for 12 hours.
  • the coating steps B2a or B3a and B2b or B3b was an occupancy of the preparations with oleic acid and nitroolic acid, as described in Example 1.
  • the coated substrates were immersed in a serial bath of an aqueous solution with one of the following additives in series of experiments performed at each coating step: V1) Type I collagen (50 g / ml) in sodium bicarbonate buffer for 20 minutes , V2) platelet-rich blood plasma for 24 hours, and V3) PBS with a pH of 7.4 for 4 weeks.
  • Platelet occupancy + little to no; ++ light; +++ middle occupancy; ++++ strong occupancy.
  • Magnesium alloy (M1) and Teflon (M2) wafers were treated by the following coating method: 1. 2. Submerge in a 1: 1 (wt%) mixture of THF and hydrophobized PEI (100,000Da weakly branched, hydrophobing prepared according to instructions for compound 7 according to Example 2) for 6 hours, then rinsing with Methanol and 2 repetitions of the procedure after drying for 24 hours at 60 ° C, 3. spray coating with a. Oleic acid or b. Nitrooleic acid diluted to 10% by volume with diethyl ether. Then rinse the surfaces with ethanol and dry in a vacuum oven at 40 ° C for 24 hours. For quality control, a HPC measurement is performed. Native as well as after 3a.
  • the influenceability of the degradation stability of the coating according to the invention was investigated.
  • the effect of reservoir formation for carboxylic acids introduced into the coating was investigated by subjecting D1 to a 1-layer coating of A) PEI 25,000Da with a degree of alkylation of 50% with a C12 alkyl radical (hydrophobed with a C12 alkyl radical) or with B) PEI 25,000D, at which degree of alkylation of 90% of 90% according to Example 2 was present.
  • the solution was in a mixture of pentane.
  • a two-layer coating development was investigated, in which in series D2) first a single-layer application of the hydrophobic cationic polyelectrolyte was carried out and after drying a coating with the respective carboxylic acid, analogous to the test series D1 c and D1 d was carried out and in the test series D3 a reverse order of D2 coating took place.
  • the water contact angles determined after coating with one of the hydrophobic cationic polyelectrolytes A) or B) were between 65 and 72 ° for D1 a, and between 85 and 96 ° for D1 b and D1 c, D3 and D3b.
  • the contact angle was 82 to 90 ° and for D2b 92 to 98 °.
  • the water contact angle first decreased by more than 5% at D1 a at time t14.
  • Example 1 Surface hydrophobing with dopamine (as in Example 1), 2. 4-layer application of a mixture of compound 4 (PEI-C12 (50%)) according to Example 2) branched with the dye Nile-red (0.1% by weight) or a Mixture of Nile-red together with nitroolic acid 0.2% by weight, in each case dissolved in pentane, which were applied at a temperature of 40 ° C. by means of a spray-coating process, vacuum drying between the coatings at 60 ° C. for 12 hours , 3. The final layer was a separation of nitroolic acid from a methanol phase. Then rinse with methanol and dry the preparations.
  • PEI-C12 50%)
  • the cell lysate was shaken out with hexane and then the content of Nile-red in the solvent phase was determined spectroscopically.
  • the platelet surfaces were cleaned after removal of the cells with an ethanolic solution in an ultrasonic bath and then dried. This was followed by water contact angle measurements.
  • the contact angles were between 104 and 100 °: In test series 1, there was no change in color over the course of 10 days, which indicates a hydrolysis, thus the coated substrates were electrically isolated defect-free. The subsequently determined contact angles were virtually unchanged.
  • the fibroblasts grown on the coated platelets had a reddish color, and cytoplasmic light microscopy revealed numerous red fluorescent vesicles. After conversion of the hydrophobic compounds into the solvent phase, Nile-red could be detected here.
  • the vesicles were larger and the Nil-red content in the cell lysate was higher when coated with a mixture of Nile Red and nitrofatty acid than when the dye alone was added to the hydrophobic cationic polyelectrolyte.
  • the contact angles, which were determined after detachment of the cells were between 1 10 ° and 1 15 ° after 4 weeks and between 85 ° and 99 ° after 8 weeks.
  • a release of hydrophobic compounds, which have been introduced in a layer structure, consisting of hydrophobic cationic polyelectrolyte, which is / can be controlled by a solution mediation with nitrofatty acids. The release can take place independently of the degradation of the coating.
  • Coatings were made using the following arrangements, using hydrophobic cationic electrolytes and polyelectrolytes of Example 2 (corresponding test number): 1) PEI-C8, 90% degree of alkylation (prepared according to Example 2, compound 6), 1 time application of 5% solution (pentane), 2) PEI-C12, degree of alkylation 50% (compound 5), 2 times a 5% solution, the compound for the first coating in the test series a) oleic acid and in the series b) nitroolic acid in an amount in which the molar mass ratio between cationic groups and carboxyl groups was 1: 1.5; 3) PEI-C12 (compound 2), degree of alkylation 90%, 4 times, 5.
  • PEI-C8 degree of alkylation 80% (compound 7), the compound being mixed in the test series a) oleic acid and in series b) nitroolic acid was, in an amount in which the molar mass ratio between cationic groups and carboxyl groups 1: 1, 2 was present; 4.
  • PEI-C12 degree of alkylation 90% (compound 2), wherein the substances were applied in total 6 times in turn.
  • the materials were each coated only with oleic acid (K1) or nitrooleic acid (K2). Further, as a reference sample, pieces of material without a surface treatment were similarly examined (Ref).
  • the coatings / wetting were carried out in each case by means of dip-coating for a period of 3 to 5 minutes. Subsequently, the materials were rinsed with ethanol. For each series of experiments or each test period 5 pieces of material were examined. These were individually placed in a water bath with a buffer solution (citrate / sodium carbonate, pH 7.4) for a duration of 2 (t2), 4 (t4) 6 (t6) and 8 (T8) weeks. In addition, 5 scaffolds each were mounted on a balloon catheter and hereby expanded in a silicone tube to the nominal diameter, so that the expanded scaffold remained tightly in the silicone tube, which was then filled with the buffer solution without air and with this at a flow rate of 6 liters / hour for 2 weeks was perfused.
  • a buffer solution citrate / sodium carbonate, pH 7.4
  • Sequential image recording of the expanded scaffold was performed, allowing visual analysis for arcing / fracturing of scaffold struts.
  • a daily determination of the magnesium content the solutions were replaced every 3 days.
  • the conductivity and the pH were continuously measured. The pieces of material were examined at the end of each experiment by light and scanning electron microscopy. The suture was tested for tensile strength at 7 and 14 days.
  • the reference samples showed a steadily increasing concentration of magnesium in the storage medium after just a few hours.
  • K1 the increase was delayed by 14 hours and in K2 by 26 hours and had a lower slope steepness.
  • the onset of measurable magnesium leaching was (for a) / b)): 72/95; 152/206 and 325/478 hours.
  • the respective steepness of slope was lower than that of K1 and K2 and the increase in steepness of the coatings 1) - 3) among each other was lower with increasing test number.
  • a coating was used, with PEI-C12 with an alkylation degree of 60% according to Example 2 (compound 4) .
  • the application was carried out by means of a micropipetting method After drying, a methanolic solution of a) oleic acid or b) nitroolic acid was subsequently applied by the same procedure, in a volume amount corresponding to one application of the respective carboxylic acid in a ratio of 2: 1 of the molar concentration of the carboxyl groups to that of the cationic groups of the applied polyelectrolyte corresponded.
  • This coating sequence was repeated 4 times.
  • the coating sequence was completed with a coating of the carboxylic acid, each previously added to the compound. This was followed by extensive rinsing of the material surfaces with an ethanolic solution. Then dry the materials, which were then stored sterile.
  • a bacterial culture (Staphylococcus aureus and Escheria coli) was set. Samples of the batch were diluted, so that about 1 000 pathogens / ml were available. The coated pieces of material and uncoated reference samples were placed therein for 12 hours. Subsequently, the pieces of material were rinsed with sterile NaCl solution and placed in sterile NaCl solution for 6 Leave hours. This process was repeated 3 times. This was followed by cell fixation and staining of the material surfaces. The storage solutions were analyzed for the presence of cells by means of a cell analyzer (Coulter Counter, Z1, Beckman, Germany) and the number of cells was determined.
  • a cell analyzer Coulter Counter, Z1, Beckman, Germany
  • VK indwelling cannulas
  • PTFE tubing flow model in which a human blood serum was circulated for 5 hours.
  • the serum was then tested for thrombin-antithombin complex (TAT) content.
  • TAT thrombin-antithombin complex
  • the CVs were then rinsed with NaCl solution and placed again in the same flow model in which a diluted platelet concentrate was then circulated for 5 hours. Then rinsing off the CVs, which were then subjected to fluorescence staining. Fluorescence microscopy quantified adherent platelets. The experiments were also carried out with uncoated VK (VK ref).
  • the reference samples had extensive bacterial lawns on all surfaces.
  • cells (bacteria) in a number of> 200 / ml were present at all times.
  • no adherent bacteria could be detected.
  • cells (bacteria) in the first storage solution There were no cells in the following storage fluids.
  • PEI Polyethyleneimine
  • PEI 25kD, average degree of branching with an alkylation of 90% of the cationic groups, 3. PEI 75kD low degree of branching with an alkylation of 80% of the cationic groups,
  • PEI 25kD, average degree of branching with an alkylation of 50% of cationic groups containing nitrooleic acid in a ratio of molar concentrations of carboxyl groups to non-alkylated cationic groups of 2: 1.
  • Each half of the samples was stored in different containers containing a PBS solution at 35 ° C, which was agitated lightly continuously.
  • the samples were taken once a day from one of the containers, which were dried in a stream of nitrogen. Thereafter, contact angle measurement (20 ° C) at predefined locations of the samples. Then re-insert into the buffer solution of the container. On the following day, the samples of the second container were taken and analyzed in an identical manner. The experiment was carried out over 80 days. The time (day) at which the initial contact angle was determined to be> 5% to 10% ( ⁇ 5),> 10 to 20% ( ⁇ 10),> 20-50% ( ⁇ 20) and> 50% was determined. ( ⁇ 50) had decreased in more than half of the samples tested.
  • Surgical mesh made of polyurethane (PU) and polylactate (PLA) was used for the study.
  • 5 ⁇ 5 mm pieces of solid and porous materials were cleaned and then coated with the compound 1 according to Example 2, according to the method B according to Example 9 with a 4-time application.
  • carboxylic acid on the one hand linolenic acid (LA) and on the other hand nitrolinolenic acid (NLA) was used.
  • pieces of material were coated with nitrolinolenic acid without prior application of a hydrophobic cationic polyelectrolyte by means of dip-coating (Ref-NFA).
  • the materials were stored for 4 weeks in a NaCl solution. After re-drying, the pieces of material were fixed in a Teflon vessel at 2 places in a drooping position.
  • the sample vessels were filled with the following solutions: 1. 0.9% NaCl solution, 2. human albumin 2% by weight, 3. human albumin 2% by weight with the addition of fibronectin or laminin, 4. human plasma.
  • the preparations were left here for 12 hours and then gently rinsed with a NaCl solution.
  • a sample set was examined for the protein adsorption by means of an immunofluorescence method and the degree of coverage quantified.
  • the cell geometry was assessed by light microscopy. It showed that cells adhering to the Ref-NLA samples had a flattened shape after 36 hours, provided that the material consisted of PU and had a predominantly dendritic shape in PLA materials. Cells adhering to Ref-NLA samples that had been conditioned with albumin or serum were predominantly dendritic in shape and exclusively dendritic in shape when conditioned with fibronectin or elastin. For samples coated with the hydrophobic cationic polyelectrolyte along with LA, the adherent cells had a globular shape except after incubation with laminin or fibronectin (here flattened to dentitic forms were present). For samples coated with the hydrophobic cationic polyelectrolyte along with NLA, there was a spherical cell shape at all times.
  • the TGF- ⁇ concentration in the respective storage medium in the Ref-NLA samples generally correlated with the number of adherent fibroblasts. However, significantly higher levels were recorded when PLA material was used or incubated with fibronectin or laminin.
  • the TGF- ⁇ levels measured on the samples coated with the hydrophobic cationic polyelectrolyte along with LA were significantly below those measured on the Ref-NLA samples at all times. The highest values were measured on samples which had been incubated with fibronectin or laminin.
  • TGF- ⁇ levels were significantly lower than for the samples coated with the hydrophobic cationic polyelectrolyte along with LA TGF- ⁇ concentration versus the other experimental conditions when the samples were incubated with fibronectin or laminin.
  • the preparations are stored in a PBS solution at 25 ° C for 3 weeks. After that, abundant rinsing and drying of the preparations. Two sets of preparations were placed individually in microreaction tubes and incubated with human serum for 1 hour at 37 ° C. Two more sets were incubated with a NaCl solution. After removal from the incubation solutions, one set of the samples was placed in a NaCl solution for 5 minutes and then rinsed off with it. Then, remove and flush the samples from the incubation solutions, which were then placed in separate reaction vessels. Human mononuclear cells obtained from healthy individuals' blood were suspended in a nutrient medium and added to the reaction vessels. There was an incubation for 3 days under standard culture conditions. Subsequently, the supernatant was analyzed for the content of IL-1 beta, IL-6, IL-8, and chemoattractant protein-1 (MCP-1).
  • MCP-1 chemoattractant protein-1
  • the reference samples showed extensive protein adsorption. With the preparations 2-4 no adherent proteins could be proven. A basically identical result was found for the detection of fibrinogen. Detection of monocyte-adhesion complexes C5b-9 succeeded only in the reference samples.
  • a 1 mm diameter thread material was extruded from a polypropylene granulate (Mat. 1). Further, the granules were further mechanically crushed and a coarse powder was obtained. It was mixed with a hydrophobic cationic electrolyte (Compound 1, according to Example 2) and 13-nitro-cis-13-docosenoic acid (nitro-erucic acid, NE). The order was carried out with continuous mixing 2 times. After evaporation of the solvent phase, a yellow-brown granules had formed, 3% by weight of the compound mixture had been introduced into the polypropylene starting material. A thread of the same kind was then extruded (Mat. 2). Furthermore, threads of Mat.1 were surface-coated with hydrophobic cationic polyelectrolytes: Compound 1 according to Example 2, Compound 2 according to Example 2. This thread material is referred to as Mat. -3.
  • the thread materials were stored after drying in an inert gas atmosphere.
  • the threads were in a flat-bottomed culture vessel, on whose base plate a clamping device made of PTFE was attached, which allowed a fixation at the thread ends and tension of the threads, so that they in an extended form and without touching the bottom of the container, submitted.
  • Human umbilical venous endothelial cells (HUVEC), human vascular smooth muscle cells (SMC) and mouse fibroblasts (MF) were cultured and suspended in a nutrient medium (FCS 5%).
  • FCS 5% a nutrient medium
  • the culture vessels were each with one of the cell suspensions, so that the filaments were completely covered even during the agitation of the medium, which was carried out during the further cultivation, which was carried out under standard cultivation conditions.
  • the studies were carried out in a 6-fold parallel experimental setup over the duration of 2 (T2), 4 (t4), 6 (t6) and 8 weeks (t8).
  • the extracted threads were gently rinsed and incubated with methylene blue for incident light in situ microscopy, and also with calcein AM and a propidium iodide solution. This was followed by fluorescence microscopy. Furthermore, filaments were subjected to scanning electron microscopy. In one set of samples, the preparations were placed in a trypsin solution and finally in an ultrasonic bath. Then REM.
  • hydrophobic cationic polyelectrolytes were prepared according to Example 2 with the following experimental numbers:
  • Solvent mixtures having a 5 and 10% concentration of the respective compounds or compound mixtures were used.
  • A) Dipping coating carried out by immersing the sample in the solvent mixture for 10 to 60 seconds
  • the contact angles of the starting material were 12 ° for S 1 and 42 ° for E.
  • To the coatings were the contact angle between 82 and 98 °.
  • Reaction 2 Reaction of PEI-C12 (100% or 80%) and PEI-C8 (80%) from Example 2 with oleic acid.
  • the solution must be concentrated to such an extent that it can be transferred by means of a pipette into a 50 mL centrifuge tube.
  • the residual solvent is carefully removed in vacuo.
  • the viscous mass is washed three times with methanol to remove excess oleic acid.
  • the remaining methanol is first in vacuo for 12 h at RT and then for 12 h at 70 ° C. In this case, a tough amber-colored mass is obtained.
  • PEI-C8 (80%) is well soluble in THF but poorly soluble in pentane.
  • PEI-C12 (100%) is very soluble in pentane.
  • an occupancy of a material surface with PEI 25 kD / average degree of separation
  • 80% alkylation was carried out with a C-8 alkane, which dissolved well in THF but poorly in pentane and as 5 % solution by means of dip coating over 30 min.

Abstract

La présente invention concerne un revêtement de surface biodégradable pour la ligature/le retardement d'une érosion/corrosion ou d'une dégradation de matériaux solides pour des applications médico-techniques et son intégration dans des pansements cellulaires.
EP18738314.6A 2017-07-07 2018-07-09 Revêtement de surface biorésorbable pour le retardement de dégradation Withdrawn EP3648806A1 (fr)

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