DE19828369A1 - Coated polymeric substrate, e.g. catheter, tube, probe, glove, condom or endoscope, with coating having high degree of lubricity, biocompatibility and bacteria repellency - Google Patents

Abstract

A polymeric substrate is coated with a composition comprising a polyisocyanate, a polyol, polyvinylpyrrolidone and a solvent, the coating being bonded to the substrate through reactive groups, especially amino groups, generated by treating the substrate with an ammonia plasma. A polymeric substrate is coated with a composition comprising a polyisocyanate, a polyol, polyvinylpyrrolidone and a solvent, the coating being bonded to the substrate through reactive groups, especially amino groups, generated by treating the substrate with an ammonia plasma. An Independent claim is also included for production of the coated substrate by treating the substrate with an ammonia plasma, applying the coating composition to the substrate, optionally removing at least part of the solvent, and curing the polyisocyanate and polyol to form a polyurethane.

Description

The invention relates to hydrophilic coated polymeric substrates a very good adhesive coating that is in contact with aqueous Media has a high lubricity and is also biocompatible and is highly bacteria-resistant. The invention further relates hin a method for producing such a coated sub strats, its use in the manufacture of medical devices or instruments and these devices and instruments.

1. State of the art

Hydrophilic coatings with high lubricity (i.e. low Coefficient of friction) on the surface of medical devices or instruments such as catheters, tubes, probes and endoscopes, are desired because they facilitate their introduction into vessels and let them slide in it more easily. It is known that the surface chen of polymers from which such devices and instruments in the Usually exist, provided with hydrophilic, lubricious coatings can be made from combinations of polyurethane with polyvinyl pyrrolidone (PVP) exist. For example, a coating is disclosed in US-A-4,642,267 tion described, consisting of a mixture of a thermoplastic Polyurethane and and PVP exists. The components do not govern each other and not with the polymer substrate on which they are applied be brought. The coatings therefore adhere when used as intended Use of the devices and instruments in water or aqueous medium not firm enough, so they are not sufficiently durable.

In US-A-4,585,666 medical devices and instruments with hy drophilic coatings disclosed in a two-stage process be generated. First you bring a polyisocyanate layer, which is then covered with a PVP layer. The Coating is cured by placing it in a humid atmosphere heated, whereby a polyurea is formed from the polyisocyanate. The coatings, in turn, are not due to covalent bonds  fixed to the substrate so that they are also not the most desirable show high resistance when used in aqueous media.

Two-stage processes are equipment and in terms of time required more complex than one-step procedures, do not allow exact Adjustment of the proportions of the two layers no uniform dissolution of the two layers into each other and make it difficult to create layers with reproducible, "tailor-made" properties.

Following the proposal of U.S. patent application Serial No. 512,872, a handed over on 04/23/1990 Polyurethane coatings are produced provides that arise from polyisocyanates and polyethylene oxides. The Coatings are created by a one-step immersion process, have a low frictional resistance and are resistant to abrasion dig, described hydrophilic and lubricious.

European patent application 0 483 941 A2 discloses a flexible one. lubricious organic coating, which in turn in one step gene process arises from the fact that a mixture of a Polyisocyanate, a polyol, PVP and a carrier liquid on the applies to the surface to be coated, ent the carrier liquid distant, the remaining mixture heated and thereby reacted. The PVP does not take part in the reaction, rather it arises interpenetrating polymer network (IPN), in which the formed Polyurethane and the inserted PUP penetrate each other. In the mentioned US patent application accordingly states that the first polyurethane "complexes" the PVP using hydrogen bonds, which is "most likely" between the carbonyl oxygen of the Form the PVP and the NH hydrogen of the urethane bond. The Coating is suitable for medical instruments used in the Body inserted, shows one in water or aqueous medium significantly reduced frictional resistance and good adhesion to sub strate, especially on polymeric substrates. The liability will possibly due to "some reaction" between coating and sub strat improved (column 1. lines 35 to 37). However, none will special measures are taken to make the IPN covalent on the substrate to fix. As a result, this lack leads to the coating in terms of adhesion to the surface of medical  Instruments are not fully satisfactory. Rather, they come loose as well as the coatings according to the aforementioned U.S. patent deregistration over time, especially when the instruments sterilized after use by treatment with superheated steam Need to become.

2. Brief description of the invention

The invention relates to coated polymeric substrates with a very well adhering flexible, hydrophilic and bacteria repellent send lubricious coating that is an integrated polymer Network is, which by means of a coating agent from (a) ei nem polyisocyanate (b) a polyol (c) a polyvinylpyrrolidone and (d) a solvent was generated. The coated substrates are characterized in that the coating on the polymer Bun substrate via reactive groups, especially via amino groups is that by treating the polymeric substrate with a Ammonia plasma were generated.

Another object of the invention is a method of manufacture development of these coated polymeric substrates, in which one Coating agent from (a) a polyisocyanate (b) a polyol (c) a polyvinylpyrrolidone and (d) a solvent on the poly mers substrate, the solvent if necessary at least partially removed and the remaining components (a) and (b) too a polyurethane that hardens with component (c) polymer network forms. The process is characterized by that the polymeric substrate before coating with an ammo treated with niak plasma.

Another object of the invention is the use of the inventions coated polymeric substrates according to the invention for the production of medical devices or instruments, the entire surface of which or partially coated according to the invention, or from fiction according to coated parts of such devices or instruments.

Another object of the invention are these devices and instru elements or their coated parts themselves.  

3. Advantages of the invention

Treatment of the polymeric substrate with ammonia plasma improved the adhesion of the coating considerably, probably through the formation of covalent bonds between the polyisocyanate (and thus the poly urethane) and reactive groups, especially amino groups, which the substrate when exposed to the ammonia plasma. Devices and instruments coated according to the invention retain their ho he glide significantly longer than comparable devices and Instruments, the polymer surface of which is not treated with ammonia Had experienced plasma. With regard to the lubricity or the Rei Resistance to exercise and flexibility are available according to the invention coatings applied to polymeric substrates to those mentioned ten European patent application. Surprisingly it is the coefficient of friction of the coating on one with ammonia plas ma treated substrate even lower than the coefficient of friction on an untreated substrate under otherwise identical conditions. It is also surprising that the known IPN coating Polyvinyl pyrrolidone and polyurethane also have a pronounced bacteria shows repellent effect and that this effect under otherwise the same Conditions is stronger if the IPN coating is coated with an Ammo niak plasma pretreated substrate is applied.

4. Detailed description of the invention

The essential feature of the present invention is the pretreatment treatment of the polymeric substrate with an ammonia plasma. Regarding the coating agent and its components (a) to (d), any Auxiliaries and additives, the coating and curing process rens and the applications of the coated polymeric substrates the coated polymeric sub according to the invention differs did not or did not streak significantly from the coated substrate the teaching of European patent application 0 483 941 A2. The Be the description of these characteristics can therefore be kept short.

4.1 Polymer substrates

Suitable polymeric substrates include polyamides, such as polyca prolactam, polylaurin lactam, polyamide-6,6 and -6,12, polyether amides, Polyester amides and polyether ester amides; Polyesters such as polyethylene duck rephthalate and polybutylene terephthalate; Polyaddition polymers such as Polyether urethanes, polyester urethanes, polyureas and polyaddi  tion polymers with urethane and urea groups; vulcanized natural liche and synthetic polydienes (rubbers), such as polybutadiene, Polyisoprene and polychloroprene as well as copolymers from the monomers these rubbers, optionally also with other copolymerisable ren monomers; Polyolefins, such as polyethylene, polypropylene, polyethylene len-co-propylene and polyisobutylene; halogen-containing polymers, such as Polyvinyl chloride, polyvinylidene chloride, polytetrafluoroethylene and Polyvinylidene fluoride; Polymers and copolymers made of or with vinylaro matic monomers, such as polystyrene, polyvinyltoluene, polystyrene-co vinyl toluene, polystyrene-coacrylonitrile, polystyrene-co-butadiene-co- acrylonitrile. Poly (styrene-co-ethylene-co-1-butene); still poly (sty rol-co-ethylene-co-2-butene), polyethers, polycarbonates, polysulfones, Polyether ketones, polyacrylonitrile, polyacrylates and methacrylates so like silicones. Even blends of two or more polymers or copolyme Ren can be hydrophilized by the process, as well as combi nations made of different plastics, which by gluing, Ver welding or melting, including the transition areas.

4.2 Treatment of the polymeric substrates with ammonia plasma

Both high-frequency plasma are suitable for treatment with ammonia ma, also called radio frequency plasma (in the kilo and megahertz range) as well as microwave plasma (in the gigahertz range). They are evacuated Treatment chamber and then sets a certain ammonia pressure, for example from 10 to 500 Pa, preferably from 20 to 180 Pa. Of the Plasma generator can work in a wide range of services. e.g. B. from a few hundred watts, such as 200 watts, to a few kilowatts, like 10 kilowatts. The duration of treatment can also continue within Limits fluctuate, e.g. B. 10 seconds to 30 minutes. After At the end of the treatment, the ammonia gas is pumped out or with air displaced, and the treatment chamber is expediently ge with air rinses. Alternatively, the ammonia plasma can also be flowing ammo nia gas are generated by continuously adding and removing ammonia pulls and adjusts to a pressure in the areas mentioned. An optimal combination of frequency. Performance, duration of treatment and ammonia pressure can be used for a given coating task easily determined by orienting tests.  

The plasma treatment creates reak on the polymer surface tive groups, especially amino groups. In the presence of Sauer reactive groups containing oxygen are also formed, possibly Usually hydroxyl, carboxyl, carbonyl and / or hydroperoxy groups. For the adhesion of the later coating, however, the amino acids are likely groups are the most important, since amino groups are known to be easier to use Isocyanates react as the oxygen-containing groups mentioned. The amino groups generated can be used with nitrogen-free substrates by means of ESCA and for all substrates via secondary reactions sen, the amino group as an anchor or coupling function use (D.A. Puleo, J. Biomed. Res. 29, 951-7 [1995]).

4.3 Coating agents All components (a) to (d) are well known and large in size Variety commercially available.

The polyisocyanate (a) has an average of at least two free isocyanate groups. The polyisocyanates are advantageously used, which are generally used as starting materials for polyurethanes. Examples include 4,4'-diphenylmethane diisocyanate and its stel lung isomers, 2,4-tolylene diisocyanate and its positional isomers. 3,4-dichlorophenyl diisocyanate, 1,6-hexamethylene diisocyanate and iso called phorone diisocyanate. Instead of this or other monomeric diiso Cyanates can also advantageously be their prepolymers or adducts Use polyols.

The polyols (b) are primarily those for the production of Polyurethane generally used polyether polyols, polyester polyols, Polyester ether polyols, castor oil polyols and polyacrylate polyols in Consideration. The average OH functionality of the polyol (b) be again bears at least 2. The combination of a certain one Polyisocyanate (a) and a certain polyol (b) as well as the functio The characteristics of these components determine the properties of the Coating, e.g. B. their elasticity. These relationships are the Well known to those skilled in the art so that they can meet a particular requirement profile can name a suitable combination, if necessary after orien preliminary tests. It is advantageous to use a polyisocyanate (a) with an NCO functionality of about 2 and a polyol with an OH Functionality of 3 or higher to make a cross-linked polyurethane  produce. The polyisocyanate (a) and the polyol (b) become advantageous used in amounts such that the equivalent ratio of NCO Groups to OH groups 0.75 to 3.0 preferably from 1.0 to 1.5 be wearing. An equivalent ratio of about 1 is particularly preferred. a small excess of NCO groups the water content in the PUP (C) and in the solvent (d) as well as by the ammonia plasma treatment generated amino groups takes into account.

The polyvinyl pyrrolidone (c) should have an average molecular weight Mw have from 50,000 to 2,500,000, advantageously from about 360,000. Of the Water content should be less than 0.5 percent by weight so not excessive isocyanate groups of the polyisocyanate by reak tion with water. Since PVP is hygroscopic and there The usual PUP usually contains 3 to 5% by weight of water, a prior drying is recommended, e.g. B. by heating to 80 up to 100 ° C in a water jet pump vacuum.

The weight ratio of components (a) + (b), i.e. H. of the polyure thans, to component (c), the PVP, can fluctuate within wide limits, namely from about 0.05 to 3.0. It is advantageously between 0.2 and 1.0.

Solvent (d) should be inert to components (a) to (c) be able to solve all components. It should in particular be practically anhydrous, d. H. contain less than 100 ppm water. Suitable solvents are e.g. B. chlorinated hydrocarbons, such as dichlor methane and dibromomethane. The preferred content of components (a) to (c) in the coating composition is relatively low, it is Use of dichloromethane between 1 and 15 wt .-%, preferably 2.25 to 4 wt .-%, and is somewhat when using dibromomethane lower.

Optionally, the coating agent in addition to components (a) to (d) contain auxiliaries, such as viscosity regulators, antioxidants, Pigments, release agents and defoamers, depending on the type and amount correspond to those that are common in polyurethane chemistry.  

4.4 Coating and hardening

The polymeric substrate is coated using conventional methods coated with agent, e.g. B. by diving, spraying, flood coating tion or spin coating. It is preferred to add solvent (d) at least partially the application of the coating agent to the substrate way to remove, e.g. B. by drying in air at room temperature door. Measures should be taken to ensure the inclusion of to prevent atmospheric water through the hygroscopic PVP or decrease. You can do this e.g. B. dry the ambient air and / or increase the drying temperature, e.g. B. to 50 to 60 ° C to shorten the drying time. If the coating by spin Coating was done, there is usually no need for additional drying nung.

The curing of the coating to form the polyurethane and IPN is done by heating, advantageously at 80 to 120 ° C, for some Minutes (e.g. 5 minutes) to a few hours (e.g. 10 hours). For some applications it is advisable to pre-coat course, including treatment with the ammonia Repeat plasma to complete coverage of the polymer To achieve substrate with the hydrophilic coating.

If it is particularly important in individual cases that the coating is free of low-molecular components, you can use these extra here, for example by using the coated polymeric substrate some time, such as 10 minutes to 3 hours, in resting or flowing water from 50 to 70 ° C.

4.5 Use of the coated polymeric substrates

The coated polymeric substrates have after exposure to what water or aqueous media have a very low coefficient of friction and are therefore highly slippery. This property remains even after a very large number of drying / humidifying cycles finally obtained from superheated steam sterilizations. The coating Therefore, substrates are suitable for the manufacture of devices or Instruments that are inserted into the body and in which openings or vessels should slide well and / or be free of Bacteria should and should remain, or as parts of such devices  or instruments. Examples include catheters, tubes, medical devices called gloves, condoms and endoscopes.

The following examples are intended to illustrate the invention further, not but limit the scope of protection as it results from the patent claims chen results.

Examples Materials and methods used Table 1 - Substrates

Treatment with ammonia plasma

The samples to be treated are either placed on a glass slide glued or mounted on a glass device so that it can be used in Anle Do not change their position in the plasma chamber due to negative pressure. The pressure is then reduced to 5 to 20 Pa and ammonia dosed and suctioned off so that a pressure of 10 to 500 Pa, preferably 20 to 180 Pa, is set and maintained. After The plasma is ignited for 20 seconds of homogenization for the gas. The optimal performance per unit area of the substrate depends on the size esse the plasma chamber and can be easily through preliminary tests average. The treatment time can be 1 sec to 30 min, depending on Substrate and desired level of basic group generation. The plasma chamber is then flushed with air for about 1 min. Opp if necessary, vacuum is applied again to remove the last traces of ammonia gas remove.  

Determination of basic groups on the treated substrate The atomic composition of the surface was treated with ESCA measured and untreated polyethylene plates.

Coating solution and coating process

The coating solution had the following composition:

1.71 g (4.2 mmol) polyethylene glycol. average molecular weight 400
1.15 g (4.6 mmol) methylene di (4-phenyl isocyanate)
13.8 g polyvinylpyrrolidone (= 5 wt. 4) in 276 g dichloromethane
320 g dichloromethane

The substrates were immersed in the coating solution for 20 seconds. The solvent was then allowed to evaporate for 5 minutes at room temperature open and dry the coated substrate at 101% for 2 hours. The sub strat was rinsed with distilled water and then 30 sec watered. The substrate was fresh three times for 2 h each Water stored at room temperature to remove any residual mono remove mere. The substrate was then at 60 ° C for several hours dried.

Determination of the coefficient of friction

The coefficient of friction µ was based on the inclined plane method certainly. For this purpose, the possibly coated substrate is placed on a round Glued metal disc and in water or 0.9 wt .-% NaCl solution solution stored for 15 minutes. Then the metal disc with the Fo lay down on one coated with the uncoated polymer flat plate set, which was moistened with distilled water. The angle of the plate to the horizontal was slowly increased. Of the The angle at which the metal disc began to slide was fixed ten. Its tangent is the coefficient of friction µ.

Qualitative determination of the gliding behavior

The optionally coated substrates were placed in water for 15 minutes. There after the sliding resistance when painting over the substrates tested with the bare hand and according to the categories "blunt - slippery - very smooth "rated.  

Determination of the primary bacterial adhesion under static conditions

An overnight culture of the bacterial strain Klebstella pneumoniae in yeast extract-peptone-glucose nutrient medium (1% + 1% + 1%) is centrifuged off and in phosphate-buffered saline (= PBS: 0.05 m KH ₂ P04. PH 7.2 + 0.9% NaCl) resumed. It is diluted with PBS buffer to a cell concentration of 108 cells / ml. The suspended bacteria are brought into contact with the piece of film to be examined for 3 hours. For this purpose, double-sided coated circular pieces of film with a diameter of 1.6 cm (= 4.02 cm ² ) are placed on a preparation needle and shaken with the cell suspension. Films coated on one side are clamped in a membrane filter apparatus in the form of a round, flat disc with a diameter of 4.5 cm and a support membrane made of 2-3 cm thick soft PVC. The cell suspension is applied to the upward-facing side with the coating to be tested and shaken for 3 hours. The membrane filter apparatus must be leakproof, ie no cell suspension may leak through leaky cells.

After the contact time has elapsed, the bacterial suspension is treated with a Aspirated water jet pump, and the pieces of film are used for washing with 20 ml sterile PBS solution in a 100 ml beaker for 2 min shakes. The piece of film is again immersed in sterile PBS solution immersed and then in 10 ml of heated TRIS / EDTA (0.1M trishydroxyethyl aminomethane, 4 mM ethylenediaminetetraacetic acid, with HCl to pH 7.8 set) extracted for 2 min in a boiling water bath.

Small Eppendorf cups are filled with the extraction solution immediately until the bioluminescence determination of the extracted adenosine triphosphate (ATP) frozen at -20 ° C. The determination will be like follows as follows: In a transparent tube made of polycarbonate 100 µl reagent mix (bioluminescence test CLS II. BOEHRINGER MANNHEIM GmbH) and over a period of 10 sec a light pulse measuring device LUMAT LB9501 (Laboratories Prof. Berthold GmbH, 75323 Bad Wildbad, Germany) integrated the light impulses. Then a 100 µl sample is added and measured again. The rela tive light units (RLU) are obtained by subtracting the light pulses in the reagent mix from the number of measured light pulses in the com get complete approach. This value is related to the number  of bacteria adhering to the film. The conversion factor between The RLU value and the number of bacteria is determined by a Aliquot of 0.1 ml of the bacterial suspension with 108 cells / ml in 10 ml extracted hot TRIS / EDTA and then the ATP content is determined. In Table 3 shows the bacterial adhesion on the untreated substrate 100% (= 0% reduction in bacterial adhesion). In a similar manner and with similar results, Ver search with other bacteria, such as Staphylococcus aureus, Staphylococ cus epidermidis, Streptococcus pyogenes, Pseudomonas aeruginosa and Escherichia coli.

Test results Table 2 - Basic groups on substrate # 3 after treatment with ammonia plasma

It can be seen from the nitrogen input that nitrogen-containing groups are formed on the polymer surface both with microwave and with radio frequency plasma, in the second case more than in the first.

Claims (10)

Characterized 1. A coated polymeric substrate having a coating which is an integrated polymeric network which, (b) a polyol, (c) a polyvinyl pyrrolidone, and (d) a solvent was produced by means of a Beschich tung by means of (a) a polyisocyanate, characterized ; that the coating is bound to the 'polymeric substrate via reactive groups, in particular amino groups, which were generated by treating the polymeric substrate with an ammonia plasma. 2. Process for producing the coated polymeric substrate according to claim 1, wherein one of a coating agent from (a) Polyisocyanate (b) a polyol, (c) a polyvinylpyrrolidone and (d) applying a solvent to the polymeric substrate that dissolves if necessary, at least partially removed and the remaining benen components (a) and (b) to a polyurethane that with component (c) forms an integrated polymer network, characterized in that the polymeric substrate before Coating treated with an ammonia plasma. 3. The method according to claim 2, characterized in that the ammo niak plasma is a high-frequency plasma (in the kilo-heart range) or a Microwave plasma (in the gigahertz range) is. 4. The method according to claim 2 or 3, characterized in that the power of the plasma generator is 200 watts to 10 kilowatts. 5. The method according to any one of claims 2 to 4, characterized in net that the treatment time is 10 seconds to 30 minutes. 6. The method according to any one of claims 2 to 5, characterized in net that the ammonia pressure is 10 to 500 Pa. 7. The method according to any one of claims 2 to 5, characterized in net. that the ammonia pressure is 20 to 180 Pa. 8. Use of the coated polymeric substrates according to claim 1 for the manufacture of medical devices or instruments.  the surface thereof in whole or in part according to claims 2 to 7 is layered, or of correspondingly coated parts of such Devices or instruments. 9. Medical devices and instruments, their surface entirely or is partially coated according to claims 2 to 7, or correspond accordingly coated parts of such devices or instruments. 10. Medical devices or instruments according to claim 9, characterized characterized that they have catheters, tubing, probes, medical Gloves, condoms or endoscopes are.