WO2007054232A1

WO2007054232A1 - Method of coating surfaces with hydrogels, and hydrogel-coated polymer substrates

Info

Publication number: WO2007054232A1
Application number: PCT/EP2006/010503
Authority: WO
Inventors: Stefan DRÖSCHEL
Original assignee: Fresenius Medical Care Deutschland Gmbh
Priority date: 2005-11-12
Filing date: 2006-11-02
Publication date: 2007-05-18
Also published as: DE102005054106A1

Abstract

The present invention relates to methods of coating surfaces with hydrogels, comprising the steps of applying a composition comprising at least one hydrogel-forming polymer to a surface and forming a hydrogel coating on the surface, the hydrogel-forming polymer being immobilized on the surface by thermal treatment under inert gas at a temperature in the range from 50 to 180°C and a pressure of more than 1 bar. The present invention further relates to polymer substrates which have a hydrogel coating obtainable by the present method.

Description

Process for coating surfaces with hydrogels and polymer substrates provided with hydrogel coatings

The present invention relates to methods for coating surfaces with hydrogels, hydrogel-coated polymer substrates, and medical products comprising such polymeric substrates.

Hydrogel coatings are used to improve the biocompatibility of surfaces that are brought into contact with body fluids, particularly blood. Such hydrogel coatings are intended here to reduce the occupancy of the surfaces with cells and protein, which lead to the activation of the body's own defense systems against foreign materials or promote blood clotting. In addition, such hydrogel coatings are applied to polymeric substrates to increase lubricity and improve wettability for aqueous solutions.

Known examples of the hydrogels used for this purpose are polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP), which are already incorporated in the preparation of corresponding medical products in the matrix of the respective polymer substrates. In many cases, however, the polymer substrates are made of polymers that are immiscible in molten or dissolved form with hydrogel-forming compounds. In this case, the substrate surfaces are usually subsequently coated with hydrogels.

Various methods are known for immobilizing such hydrogels on the substrate to be treated. For example, short-wave electromagnetic radiation, in particular gamma rays are used to achieve a fixation of the hydrogels. However, this generally produces reactive intermediates in the polymer substrate. Furthermore, the optical and mechanical properties of the polymer substrates may change adversely.

Furthermore, chemical immobilization methods are known. In general, less reactive substrate materials are formed by reactive reagents, such as Activated se chlorosulfonic acid to subsequently bind hydrogels on the surface to be coated. This results in particular production problems with aggressive or toxic reagents. Especially in the case of polyvinylpyrrolidone, it proves difficult to bind a corresponding hydrogel to polymer substrate surfaces, for example polypropylene (PP) or polyvinyl chloride (PVC).

Furthermore, hydrogel coatings can be bonded to polymer substrates via interlayers. For example, according to the teaching of document US Pat. No. 4,585,666, an isocyanate coating can first be formed on the polymer substrate surface, onto which polyvinylpyrrolidone is subsequently applied. The PVP layer is fixed by heating.

Furthermore, interpenetrating polymer networks (IPN) are known in order to bind polyvinylpyrrolidone hydrogels to surfaces (see WO 00/02937).

The methods set out above, however, are expensive. In addition, harmful substances are often used, so that these methods have disadvantages.

Furthermore, a method for coating polymer substrates with hydrogels is described in US Pat. No. 4,589,873. In this case, for example, polyvinylpyrrolidone is dissolved in dimethylformamide (DMF) and applied to the polymer substrate. Subsequently, the solvent is evaporated with heating. A disadvantage of this method is that temperatures are preferably in the range of 150 ° C to 250 ° C. This leads to high energy consumption, with many substrates not being dimensionally stable at this temperature. Furthermore, the adhesion of the hydrogel coating is in need of improvement.

In addition, WO 2004/026356 describes a process for the immobilization of hydrogels on polymer substrates, in which the applied hydrogel layer is fixed on polymer surfaces with a vitamin starter and irradiation with UV light. A disadvantage of this method, however, is that hydrogel coatings can not be immobilized on surfaces which are not accessible to UV light. Therefore, it is difficult to form coatings on inner surfaces of hoses or connectors.

In view of the prior art, it is an object of the present invention to provide hydrogel coatings in inaccessible locations of polymeric molding surfaces. Furthermore, it was an object of the present invention to provide O berflächen with hydrogel coatings, which include no harmful materials.

Moreover, it was therefore an object of the present invention to provide hydrogel coatings on moldings, which has a high adhesive strength on the surfaces.

Furthermore, the hydrogel coatings should be able to be produced inexpensively and on a large scale on surfaces.

These and other objects which are not explicitly mentioned, but which are readily derivable or deducible from the contexts discussed hereinbelow, are solved by methods for coating surfaces having all the features of claim 1. Advantageous modifications of the inventive methods are to those claimed in claim 1 Claims under protection.

With respect to the polymer substrates provided with hydrogel coatings, claims 24 and 25 provide a solution to the underlying problem.

The fact that the hydrogel-forming polymer is immobilized by thermal treatment under inert gas at a temperature in the range of 50-180 ° C on a surface, it is not readily predictable way to provide methods for coating surfaces with hydrogels, comprising the steps of applying to a surface a composition containing at least one hydrogel-forming polymer and forming on the surface a hydrogel coating capable of producing hydrogel coatings even in inaccessible areas of surfaces. In addition, a number of other advantages can be achieved by the method according to the invention. These include:

The processes according to the invention can be carried out easily and inexpensively.

The processes of the invention produce hydrogel coatings without the need to use or form harmful substances.

Hydrogel coatings according to the invention have a high adhesive strength on many substrates. Accordingly, these coatings are very stable on surfaces and release no harmful materials.

According to the method of the present invention, surfaces are coated with hydrogels. In this case, any surface of a substrate can be coated on which the hydrogel coatings according to the invention have sufficient adhesive strength. Preferably, polymer substrates are coated.

As polymer substrates, it is possible to use any polymers or copolymers commonly used in particular in medical technology.

Preferably, the polymers contained in the polymer substrate can be processed thermoplastically.

In general, such polymers have a weight average molecular weight in the range of 5,000-1,000,000, preferably 10,000-500,000 g / mole.

These polymers include, but are not limited to, vinyl polymers such as polyvinyl chloride, polyvinyl acetate, polyvinyl ethers; Polyolefins, for example, polyethylene, polypropylene and polybutylene; Polycarbonates, polyurethanes, polyesters, polyamides, polystyrenes, thermoplastic elastomers and polysiloxanes.

The term polyolefins in the context of the present invention refers to polymers which consist essentially of carbon and hydrogen. These are generally selected from α-olefins, especially ethylene, propylene and butylene, for example Butadiene and isoprene, and / or aromatic hydrocarbons, for example styrene. In addition to these hydrocarbons, polyolefins may have small amounts, for example up to 10% by weight, preferably at most 5% by weight and more preferably at most 1% by weight, based on the weight of the polyolefin, of units other than those set forth above Monomers are derived, consisting of carbon and hydrogen.

Thermoplastic elastomers are known in the art. These include modified polyolefin elastomers (TPE-O), in particular polypropylene elastomers such as ethylene / propylene terpolymer / propylene (PP-EPDM), crosslinked ethylene / propylene terpolymer / propylene (PP-X / EPDM), nitrile Butadiene rubber / polypropylene (PP-NBR); crosslinked polyolefin elastomers (TPE-V); Elastomers based on polyetherester or polyesterester (TPE-E), polyetherurethane elastomer and / or polyesterurethane elastomer (TPE-U); Polyetheramide elastomer (TPE-A) and / or styrene elastomer (TPE-S), in particular styrene-butadiene-styrene copolymers (SBS), styrene-ethylene-butylene-styrene copolymers (SEBS), styrene-ethylene-propylene Styrene copolymers (SEPS), styrene-isoprene-styrene copolymers (SIS).

The polymers described above can also be used as a mixture (blends) of two or more of the polymers set forth above. In addition, the substrates may also comprise copolymers. In particular, copolymers are polymers comprising two, three or more different monomer units, with preferred monomer units being derived from the monomers from which the polymers illustrated above are derived.

Preferred copolymers include polymers which in addition to vinylic monomers additionally comprise α-olefins, for example ethylene-vinyl acetate copolymers. Furthermore, these include polyolefin copolymers, for example ethylene-propylene copolymers, and also copolymers which have styrene, ethylene and / or butylene units.

The homopolymers and copolymers which can be used for the production of polymer substrates and processes for their preparation are described inter alia in Roempp Chemie Lexikon, 10th Edition and Ullmann's Encyclopedia of Industrial Chemistry 5th Ed. detailed on CD-ROM with further information. In particular, the polymer substrate to be coated may be a medical product or a part thereof. These include, in particular, dialyzers, tubes and tube systems, catheters, stents, urethra, filters, blood bags, apheresis sets and connectors.

According to the present invention, a composition containing at least one hydrogel-forming polymer is applied to a substrate surface. In this case, the hydrogel-forming polymer can be applied to the substrate in the form of a suspension, dispersion, emulsion or solution.

According to the invention, the composition comprises at least one hydrogel-forming polymer. Hydrogels are well known in the art and described for example in Roempp Chemielexikon. In general, this term refers to water-containing gels based on hydrophilic but water-insoluble polymers. Accordingly, all polymers which can be used to form these hydrogels can be used to prepare the hydrogel coatings according to the invention. These include, in particular, polymers based on polyalkylene glycol, polyvinyl alcohol, polyethyleneimine, polyvinylamine, poly (meth) acrylic acids and / or poly (meth) acrylates. Preference is given to using polymers based on polyvinylpyrrolidone, polyalkylene glycol, polyvinyl alcohol and / or polyethyleneimine.

Polymers based on polyvinylpyrrolidone are particularly preferably used for the preparation of the hydrogel coating according to the invention. Preferably, the hydrogel-forming polymer may comprise at least 90 weight percent polyvinylpyrrolidone, based on the weight of the hydrogel-forming polymer.

Polymers based on polyvinylpyrrolidone include polyvinylpyrrolidione, copolymers comprising vinylpyrrolidone units and derivatives of these polymers.

Preferred copolymers based on polyvinylpyrrolidone comprise at least 50% by weight, more preferably at least 75% by weight, of units derived from vinylpyrrolidone. Preferably, these polyvinylpyrrolidione copolymers include units which derived from vinyl esters or vinyl ethers, for example vinyl acetate, methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether and isobutyl vinyl ether.

Derivatives of polymers based on polyvinylpyrrolidone include units derived from polyvinylpyrrolidone and polyvinylpyrrolidone copolymers, respectively. In particular, it is possible to use derivatives which are capable of modifying or modulating physiological reactions. In particular, this includes compounds which may affect blood clotting or immune system functions.

As such polyvinylpyrrolidone derivatives, for example, oligosaccharide-substituted PVP polymers and peptide-substituted PVP polymers can be cited. An example of this is PVP-heparin complexes, as described, for example, in US Pat. No. 4,239,664, to which reference is explicitly made here.

The derivatives of polyvinylpyrrolidone further include polymers obtainable by polymerization of Vinylpyrrolidonderivaten. The vinylpyrrolidone derivatives include, in particular, substituted vinylpyrrolidone monomers which have in particular one or more alkyl substituents. Preferred alkyl substituents may have 1 to 10, more preferably 1 to 6, and most preferably 1 to 4 carbon atoms. These include in particular methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl groups. The alkyl substitution can be provided both on the side chain and on the pyrrolidone ring.

Polymers based on polyalkylene glycol include, for example, polyethylene glycol (PEG), polypropylene glycol and / or copolymers comprising ethylene glycol and / or propylene glycol units. Furthermore, it also covers derivatives of these polymers, which are capable of modifying or modulating physiological reactions. In particular, this includes compounds which may affect blood clotting or immune system functions, as set forth above with respect to PVP.

The molecular weight of the hydrogel-forming polymers can vary widely. Preferably, the hydrogel-forming polymers have a weight average molecular weight in the range of 1,000-10,000,000 g / mol, more preferably 10,000-1,500,000, and most preferably 100,000 g / mol to 13,000,000 g / mol. The poly- Dispersity of the hydrogel-forming polymer Mw / Mn is preferably in the range of 1-10, more preferably 1.5-5, without this being a limitation. The weight average molecular weight Mw and the number average molecular weight Mn can be determined by gel permeation chromatography (GPC).

Polymers based on polyvinylpyrrolidone preferably have a K value of at least 15. Preferably, the K value is in the range of 25-150, more preferably 90-120. Preferred polymers based on polyvinylpyrrolidone have a weight-average molecular weight of 250,000 g / mol (K60), 85,000 (K80) or 1,000,000 (K90). The K value is a measure of the molecular weight and is described, for example, in H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 to 74, and Roempp Chemielexikon, 10th edition. The K value of the polymers can be adjusted, for example, via the amount of initiator, the temperature and the pH within the polymerization conditions.

The hydrogel-forming polymers can be obtained commercially in many cases, their preparation and commercial suppliers being widely used in Ullmann's Encyclopedia of Industrial Chemistry 5th Ed. are presented on CD-ROM.

The hydrogel-forming polymer concentrations used in the hydrogel-forming composition are not specifically limited. However, the concentration should be high enough to ensure complete coating of the desired substrate surface. The viscosity of the hydrogel-forming composition should be suitable for the coating method to be used. The exact concentration can be chosen accordingly by a person skilled in the art. Preferably, the concentration of hydrogel-forming polymer is in the range of 0.5-50 wt%, more preferably 0.1-10 wt%, and most preferably about 1 wt%.

According to a particular aspect of the present invention, the composition may preferably consist of 90.0 to 99.9% by weight of solvent and 0.1% by weight to 10.0% by weight of hydrogel-forming polymer. Preferably, the composition is in the form of a solution. The term solution in this context means that the composition is essentially a homogeneous phase that has no visible inhomogeneities.

As solvents which may be contained in the composition, in particular compounds are preferred which are safe for health. In the context of the present invention, a harmless compound is understood as meaning a substance with an LD50 (rat)> 500 mg / kg, more preferably> 950 mg / kg and particularly preferably> 2,000 mg / kg. Preferably, the solvent is a safe alcohol, especially ethanol and / or isopropanol.

According to a particular aspect of the present invention, the solvent preferably has a boiling point at atmospheric pressure (1 bar) of at most 100 ° C., more preferably at most 80 ° C.

The solvent is preferably selected according to the substrate surface to achieve a homogeneous distribution of hydrogel-forming polymer.

According to the invention, a composition comprising at least one hydrogel-forming polymer is applied to a surface. This can be done by any method known to those skilled in the art. These include, in particular, spray coatings, dip coatings, roller application and flood coatings. Particularly preferably, the composition is applied to a substrate by dip coating.

Preferably, after application of the composition, the resulting solvent-containing layer is dried. Preferably, the drying is carried out using an inert gas stream, in particular a nitrogen stream. The drying temperature depends on the nature of the solvent, wherein the drying is preferably carried out at temperatures in the range of 80 ° C to 120 ° C.

The immobilization of the hydrogel-forming polymer is carried out according to the invention by thermal treatment under inert gas at a temperature in the range of 50 ° C to 180 ° C, preferably 80 ° C to 150 ° C and most preferably 80 ° C to 120 ° C. The term "immobilization" means that after this treatment, the hydrogel coating is not water-soluble, so that a hydrogel layer can be detected after treatment with water.

The detection of a hydrogel layer can be carried out in a known manner. For example, the friction of substrates that have a hydrogel coating decreases upon contact with water. Furthermore, some hydrogels lead to complex formation, which can be detected by dyes.

The thermal treatment is carried out under inert gas. For this purpose, any gas can be used which has no adverse effect on the immobilization of the hydrogel-forming polymer. An inert gas, nitrogen and / or water vapor is preferably used as the inert gas. Preferably, the gas atmosphere in the immobilization treatment comprises at most 1% by volume, more preferably at most 0.5% by volume and most preferably at most 0.1% by volume of oxygen. An inert gas, nitrogen and / or water vapor is preferably used as the inert gas. For cost reasons, nitrogen and / or steam is preferably used. The gas atmosphere in this case preferably comprises at least 99% by volume of noble gas, nitrogen and / or water vapor.

The application of pressure for immobilization is not necessary in itself. Preferably, the immobilization of the hydrogel-forming polymer is carried out at a pressure in the range of 0.5-3 bar, more preferably 0.8-2.5 bar and most preferably in the range of atmospheric pressure (0.95 bar to 1.05 bar ).

The period of immobilization treatment is not specifically limited. In general, the immobilization process is used for a time sufficient to obtain a strong, water-insoluble hydrogel coating. The exact period of time can be selected accordingly by a specialist. In general, this period is in the range of 10-60 min, without this being a restriction.

It has proved to be advantageous, after the tempering process under nitrogen, to follow a rinsing process in order to extract non-immobilized PVP. As a result, particularly biocompatible coatings are obtained, which have a particularly low friction after contact with water.

The thickness of the hydrogel coating is not particularly limited. The hydrogel coating preferably has a thickness in the range from 10 μm to 50 μm in the swollen state.

Since no substances harmful to health are used or formed during the production of the hydrogel coating according to the invention, preferred hydrogel coatings do not release any such substances. Harmful substances are compounds with an LD-50 (rat) of <2,000 mg / kg, preferably ≤ 950 mg / kg and most preferably <500 mg / kg. In particular, solvents such as dimethylformamide are among the substances of health concern.

Hereinafter, the present invention will be described with reference to an embodiment for further explanation, without this being a limitation

example

A flexible 20m-long plastic tubing is wound on a drum and rinsed at room temperature with a 1% PVP-K90 solution while rotating the drum to complete wetting of the inner surface. After this flushing process, the tubing is stored in a heated room with further rotation so that the coated surfaces dry. Subsequently, a laminar flow of nitrogen is passed through the tube at near atmospheric pressure. It is maintained at a temperature of 120 ° C for a period of 30 minutes. It has proved to be advantageous, after the annealing process under nitrogen, to follow a rinsing process in order to extract non-immobilized PVP.

To demonstrate the coating, the treated tube is rinsed with 70 ° C hot distilled water for 30 min and then treated with an acid Dragendorff see solution. Under these conditions, soluble PVP moieties should elute from the surface layer. Even browning over the entire coated surface indicates an existing PVP layer compared to the rinse cycle immobilized with isopropanol. The proof with the Dragendorff see solution can also take place before the rinsing process. The browning that occurs then remains stable during a subsequent rinsing process.

Further indications for the coating are provided by scanning electron micrographs (SEM). These were on an untreated inner tube surface (Figure 1, 'reference untreated'), on an unspulled inner surface of the tube with immobilized PVP layer (Figure 2, 'tube unrinsed') and a rinsed, sterilized inner tube surface with immobilized PVP layer (Figure 3,; rinsed ') made. FIG. 1 shows a characteristic inner surface of the tube, which comes about through the polymer used and the extrusion process. It can be seen on a smooth surface raised, isolated from each other tips. FIGS. 2 and 3 clearly show that an unspulled hose and a flushed hose have a smooth surface compared to the untreated hose. This is an indication that the raised peaks were covered with the added PVP layer and thus are no longer visible. Since the images were taken after the rinsing process, immobilization of the PVP layer is evidently proven.

Claims

claims

A method of coating surfaces with hydrogels comprising the steps

Applying a composition containing at least one hydrogel-forming polymer to a surface and

Formation of a hydrogel coating on the surface,

characterized in that the hydrogel-forming polymer is immobilized by thermal treatment under inert gas at a temperature in the range of 50 to 180 ° C.

A method according to claim 1, characterized in that the composition containing at least one hydrogel-forming polymer is a solution.

3. The method according to claim 1 or 2, characterized in that the composition comprises solvents which are safe for health.

4. The method according to claim 3, characterized in that the solvent is ethanol and / or isopropanol.

5. The method according to at least one of the preceding claims, characterized in that the composition comprises at least one solvent which boils at a temperature of at most 100 ° C at 1 bar.

6. A method according to any one of the preceding claims, characterized in that the composition consists of 90.0 to 99.9 wt .-% solvent and 0.1 wt .-% to 10.0 wt .-% hydrogel-forming polymer ,

7. The method according to any one of the preceding claims, characterized in that the composition is applied by dip coating on the surface.

8. The method according to at least one of the preceding claims, characterized in that the surface of a polymer substrate is coated.

9. The method according to claim 8, characterized in that the polymer substrate comprises thermoplastically processable polymers.

10. The method according to any one of the preceding claims, characterized in that the hydrogel-forming polymer has a weight average molecular weight in the range of 100000 to 1300000 g / mol.

11. The method according to at least one of the preceding claims, characterized in that the hydrogel-forming polymer comprises at least one polymer based on polyvinylpyrrolidone.

12. The method according to claim 11, characterized in that the hydrogel-forming polymer comprises at least 90 wt .-% polyvinylpyrrolidone, based on the weight of the hydrogel-forming polymer.

13. The method according to any one of the preceding claims, characterized in that after the application of the composition containing at least one hydrogel-forming polymer, drying takes place on the surface.

14. The method according to at least one of the preceding claims, characterized in that the inert gas comprises at most 1 vol .-% oxygen.

15. The method according to at least one of the preceding claims, characterized in that the inert gas comprises at least 99 vol .-% noble gas, nitrogen and / or water vapor.

16. The method according to any one of the preceding claims, characterized in that the immobilization of the hydrogel-forming polymer takes place at a temperature in the range of 80 to 150 ⁰ C.

17. The method according to at least one of the preceding claims, characterized in that the immobilization of the hydrogel-forming polymer is carried out over a period of 10 to 60 minutes.

18. The method according to any one of the preceding claims, characterized in that the surface of a filter, tube system, blood bag, apheresis sets and / or catheter is coated.

19. A polymer substrate whose surface at least partially comprises a hydrogel coating which is obtainable by a process according to any one of claims 1 to 18.

20. Polymer substrate according to claim 19, the surface of which at least partially comprises a hydrogel coating, characterized in that the hydrogel coating does not release harmful substances.

21. A medical product comprising at least one polymer substrate according to any one of claims 19 to 20.