DE102007025452A1 - Surface coating method for precipitating layers onto e.g., medical appliances, involves pre-treating surface with plasma process before applying micro- or nano-particles and then fixing - Google Patents

Abstract

A surface coating method in which the surface is pre-treated with by a plasma process and at the same time or later, micro- and nano-particles are applied on to the surface, and then fixed by a plasma method. Independent claims are included for the following: (1) (A) Materials with surfaces coated with micro- or nano-particles. (2) (B) Medical appliances. (3) (C) Application of a plasma coating method for reducing germs on surfaces or sterilizing surfaces.

Description

The The invention relates to the sterilization of surfaces which Deposition of layers containing micro- and nanoparticles and their immobilization using plasma techniques. Possible Areas of application are medical devices, surfaces of Utilities in contact with bacterial contaminants as well as pharmaceutically used products.

description

Medical devices and instruments must be used sterile for their intended use in certain applications. The term "sterile" connotes a lack of biological entities capable of proliferating, such as microorganisms (bacteria and fungi) or genetic material, e.g., phages, viruses, plasmids, prions or infectious agents Nucleic acids ( KH Wallhäusser, Georg Thieme Verlag, Stuttgart, New York, 1995 ).

When used as intended, the medical devices and instruments are polluted and populated with microorganisms. It is advantageous if the absence of germs or at least a germ depletion on the surface can be maintained for a longer period even when used as intended. Particularly great is the advantage of a germ reduction on the surface of implants. The infection rates for permanent implants are usually between 0.5 and 6% [ Kohnen & Jansen, 2001 ]. Prevention strategies are urgently needed.

One Another example is infection on catheters. Together with Candida Staphylococci are the most common pathogens associated with a catheter Sepsis, of which about 50% are deadly. In Germany goes one from 3000 to 4000 catheter-associated deaths out every year.

It is the object of the patent invention, the Adhesion of microorganisms to the surface of Significantly complicate or even medical devices or instruments to prevent. For medical devices for which a reprocessing is provided, a low germ leads to a clear lower burden of pyrogens.

State of science and technology

In The present invention provides plasma assisted sterilization of medical devices and instruments with the modification of surfaces combined with nanotechnology.

Therefore should be the state of the art for both steps in the Shown briefly below.

1. Plasma-assisted sterilization

For the sterilization of medical devices and materials, there are established methods such as moist heat sterilization, gas sterilization (ethylene oxide, formaldehyde), and high-energy radiation sterilization. However, each of these sterilization methods has specific shortcomings. Thus occur in the treatment with ethylene oxide or formaldehyde toxic drug residues. Sterilization with gamma rays is only possible with special shielding and often results in irreversible material degeneration (eg embrittlement). For thermolabile materials, however, a heat or steam sterilization is not possible at all. An alternative method, which circumvents the mentioned disadvantages, is the plasma sterilization. The interaction of gas discharge plasmas with biological material, in particular the germ-reducing effect, is the subject of various investigations (cf. Laroussi et al., New J. Phys., 5, (2003), 41.1 . Moreau et al., J. Appl. Phys., 88, 2 (2000), 1166 or Awakowicz and Keil, VFPREO, 5, (2001), 294) ,

• • zu methodischen Besonderheiten der Plasmasterilisation (Fraser et al. US 3,948,601 A , 1973; Jacob, US 5,087,418 A , 1990; Martens & Caputo, US 5,482,684 A , 1994; Monroe, US 5,163,458 A , 1991; Spencer & Addy, US 5,656,238 A , 1994), zur Entfernung von Endotoxinen durch Plasmasterilisation (Ranks et al., US 6,558,621 B1 , 2000),
• • zur Kombination von Plasmen und antibakteriellen Beschichtungen/Flüssigkeiten bei der Sterilisation von Oberflächen (Caputo et al., US 6,261,518 B1 , 1998) und
• • zur Oberflächensterilisation von Medizinprodukten (z. B. Moulton et al., DE 69126312 T , 1991; Pickel, DE 101 34 037 A1 , 2001).

At present, the following patent literature already exists within this subject area:

• • on methodological features of plasma sterilization (Fraser et al. US 3,948,601 A , 1973; Jacob, US 5,087,418 A , 1990; Martens & Caputo, US 5,482,684 A , 1994; Monroe, US 5,163,458 A , 1991; Spencer & Addy, US 5,656,238 A , 1994), for the removal of endotoxins by plasma sterilization (Ranks et al., US Pat. No. 6,558,621 B1 , 2000),
• • for the combination of plasmas and antibacterial coatings / liquids in the sterilization of surfaces (Caputo et al., US 6,261,518 B1 , 1998) and
• For the surface sterilization of medical devices (eg Moulton et al. DE 69126312 T , 1991; pimples, DE 101 34 037 A1 , 2001).

Latter deal with the sterilizing effect of Low-pressure plasmas on plastics (PE, PET, UHMWPE, PLL) and metal substrates (Titanium, steel). The investigations showed that with these procedures a sufficient germ reduction can be achieved. A cross-linking or embrittlement of UHMWPE materials occurred only slightly Dimensions on.

The most widespread use as a method for material-sparing plasma sterilization of thermolabile medical instruments has so far been the low-pressure STERRAD sterilization system from Johnson & Johnson (cf. US 5,785,934 A and M. Förtsch et al. Ophthalmologist 90, 1993, No. 6, pp. 754-764 ) reached. The long treatment times required in the STERRAD process are attributable on the one hand to the short-lived nature of the reactive species and the associated low degradation rates of organic material and, on the other hand, to problems of exposure of germs to clumping and irregular or cracked surfaces. A major disadvantage is the selection of the gas hydrogen peroxide. Hydrogen peroxide vapor is strongly adsorbed by cellulosic materials. Therefore, this plasma sterilization can not be used for cellulosic sterilization. All packaging materials must be cellulose-free and are only available from the operating company. Instrument containers, such as those already available for steam sterilization, are being developed for plasma sterilization units. The instruments must be completely dry before loading the sterilizer. In the case of organic contamination of the surface, the effect of the plasma sterilization is considerably limited. The product was approved for marketing by the US Food and Drug Administration (FDA). The competing product was the Abtox Plazlyte Sterilization System, which uses peracetic acid in contrast to the Sterrad system. In 1998, these devices were recalled by the FDA.

In addition to low-pressure plasma methods, the use of normal pressure-based anisothermal plasma processes for sterilization is proposed. A variety of excitation modes can be used to generate these plasmas, including corona discharge, dielectrically impeded discharge, capillary discharge, and microwave discharge. The excitation takes place via an electric field, which acts continuously or pulsed and covers the frequency range from 0 (DC) to a few GHz. An essential prerequisite for achieving an effective germicidal effect in the treatment of surfaces is the maintenance of a uniformity of the mechanisms of action over the substrate to be treated. Technical solutions include a guided gas flow that first passes through the active plasma zone before the reactive species formed in the plasma ('downstream') sweep over the region to be decontaminated. Technical solutions of this type are for a jet plasma, for example in the patent US 6,194,036 B1 ( see. HW Herrmann et al. Physics of Plasmas Vol. 6, no. 5, 1999, p. 2284-2289 ) or are described for the decontamination inside containers, partly with the addition of alcohol to the carrier gas (Crowe R et al., WO 03/063914 A2 , 2002).

2. Use of nanotechnology for modification of surfaces

• • Silbernanopartikeln
• • Titandioxidnanopartikeln zur Herstellung photokatalytischer Oberflächen
• • Diamantbeschichtungen
• • Hydroxylapatitnanopartikeln
• • Metallkeramik-Beschichtungen und Keramiken
• • Organische Nanofasern und Kompositmaterialien
• • Nanostrukturierte Aluminiumoxidoberflächen

Various materials are used to coat medical devices:

• • silver nanoparticles
• Titanium dioxide nanoparticles for the production of photocatalytic surfaces
• • Diamond coatings
• • Hydroxylapatitnanoparticles
• • Metal-ceramic coatings and ceramics
• • Organic nanofibers and composite materials
• • Nanostructured aluminum oxide surfaces

2.1. Surfaces with silver nanoparticles

Currently Silver occurs because of the increase in antibiotic-resistant germs and The development of new forms of application increasingly in the focus the research. Because silver is gram-positive on different cell structures and gram-negative bacteria, is the emergence of resistance unlikely. For the processing of silver in metallic Shape are particularly small particles of advantage. Their big one Surface secures even with small amounts of silver one adequate and even release of Silver ions for an antiseptic effect. For The use of nanoparticulate silver is numerous Examples.

Silver nanoparticles are z. B. polymers and surface coatings that are already used in medicine, for articles of domestic hygiene and care (Hanke & Guggenbichler, US 6,720,006 B1 , 2001) as well as to the hygiene in public facilities use find or still to find. Such silver particles are already commercially available (Bio-Gate GmbH). In medicine, nanoparticles are finely distributed in polymers for catheters and implants incorporated or brought as a thin coating on instruments (eg Sicuris silver catheter, Siemens AG). Studies show a significant reduction in infection rates through the use of catheters with a silver content. Furthermore, contact lenses have been developed which contain, inter alia, nanoparticulate silver (Vanderlaan et al., EP 1 355 681 A1 , 2001). For bonding components in medical technology, an adhesive with nanosilver content is available.

The Antiseptic properties of silver are also avoided or fight infections acute and chronic Used wounds. The silver comes with materials to the management of the Wundexsudates serve, combined (eg with activated carbon, Hydropolymeren or hydrocolloids). Nanocrystalline silver comes with the wound dressing Acticoat (Smith & Nephew) for use.

One Another approach to the use of nanosilver is in development antiseptic paints for interiors, the z. B. can be used in clinics. Further will be water-soluble or low-solvent paints, the Easy to apply and contain nano silver for treatment of medical devices and consumables as well as for offered the use in prosthetics (Sarastro GmbH).

Also textiles are equipped with silver particles (Padycare ^®, Tex-a-med GmbH). There are efforts from these fibers z. As workwear, especially for the medical field to produce.

One significant disadvantage of silver, especially when combined used with nitrate or sulfadiazine, is that it during treatment side effects such as allergies or trigger an inhibition of wound healing.

2.2. Titanium dioxide in photocatalytic surfaces

Titanium dioxide is the material most commonly used as a photocatalyst. The electrons of the titanium dioxide can be excited with energy from daylight or artificial light. This process leads to the formation of highly reactive radicals that destroy microorganisms and chemical substances that are located on the surface of the particles. The titanium dioxide particles used for the production of photocatalytic surfaces have a diameter of less than 100 nm, since nanoscale particles have a greater photocatalytic effect and are transparent (Sherman, J. Org. US Pat. No. 6,653,356 B1 , 2000; Yadav et al. US 6,572,672 B1 , 2002).

In order to provide surfaces of various materials with photocatalytic coatings, corresponding coatings have been developed (Akarsu, DE 102 35 803 A1 , 2002; Beling & Mehner, DE 199 62 055 A1 , 1999).

Photocatalytic Surfaces can also be modified so that they additionally antibacterial metal ions such as copper or release silver ions. In Japan are already photocatalytic Products marketed and z. B. to reduce the number of germs in operating theaters used.

2.3. Nanostructured surfaces of implants

To extend the life of joint implants, we are looking for materials with increased wear resistance, which are also easy to work with and are characterized by a low risk of breakage. One approach is to use nanostructured surface coatings. On the one hand, these lead to a reduction in wear and, on the other hand, provide structures that promote the growth of cells and thus the healing process. So z. For example, it can be shown that the adhesion of osteoblasts on nanostructured TiO ₂ surfaces is significantly stronger than on conventional TiO ₂ surfaces. An overview of the production of coatings, the materials used and the requirements of the surfaces Thull, R Biomolecular Engineering 19, 43-50 (2002) . Encyclopedia of Science and Technology, B. Erg.-Lfg., 1-7 (2003) ,

Stents are also coated with titanium materials. The resulting low wettability surfaces improve blood compatibility, reduce the growth of cells on the implant surface and reduce the risk of blood clots ( Biehl et al., J. Biomed. Mater. Res., 2002 ; Eisenbarth et al. Biomol. Closely. 19, 233-237, (2002) ,

diamond coatings

In order to improve the wear behavior of implants protective coatings of diamond are developed (Goldstein et al., 1996, US 6,709,463 B1 , 2000; Rüffer et al., 2003). The diamond layers are applied by the CVD method. In contrast to conventional diamond coatings, they have very small surface structures of only about 15 nm, are hard and tough and are characterized by a lower coefficient of friction. In laboratory and animal experiments a high biocompatibility and bio-tolerance of the diamond surfaces were shown. Thus they could not be attacked by body fluids and did not cause any allergic or pathomorphological reactions. Diamond diamond coatings are credited with the ability to extend the life of cobalt chrome and titanium implants to more than 40 years ( Catledge et al., J. Nanoscienes and Nanotechnolgy 2 (3-4), 293-312, 2002 ).

hydroxyapatite

Due to its low strength, hydroxyapatite is not suitable as a load-bearing material for implants that are under load. However, it is used to coat titanium and cobalt-chrome implants. The nanostructured surfaces have structural properties very similar to those of the apatite in bone and enamel. This improves cell adhesion as well as proliferation and mineralization of the surrounding tissue ( Catledge et al. Nanoscienes and Nanotechnolgy 2 (3-4), 293-312 (2002) ).

For For medical applications, hydroxyapatite is usually with the help of Plasma spray method applied. The grain size the coating is then at 15-25 nm. Smaller particle sizes can not be achieved with this method, as a finer starting material would evaporate completely at the high temperature. This is a major disadvantage as the grain size determining the adhesive behavior of the hydroxyapatite coating is on the surface. For this reason, currently novel coating processes such as Ion Beam Sputtering and Pulsed Laser deposition is examined. First results show that with These surfaces produced improved properties in terms of durability and abrasion. Further sets the material releases small amounts of calcium and phosphate ions, which stimulate bone growth.

In addition it should be noted that nanocrystals of hydroxyapatite and tricalcium phosphate chemically closely related also very well suited as bone replacement materials (Vitoss ^®, Ortho Vita; Ostim ^®, Osartis GmbH & Co. KG; Roessler, US 6,706,273 B1 , 2001). The large porosity of these products allows rapid ingrowth of blood vessels and bones. The materials can form-fitting be introduced into defects and degraded within a few months largely from the organism.

Cermet coatings and ceramics

As a limiting factor for the life of joint implants, the wear of the joint socket may have an effect. To reduce abrasion rod ends were provided with ceramic surfaces. Since ceramics adhere poorly to metal surfaces, nanocrystalline Cr-Ti-N coatings have been developed. These have on their inner side on the condyle a metallic character, which conveys a good bond to the substrate and decreases towards the outside. First experiments showed that in this way the wear of the socket is greatly reduced. The suitability of this material for in vivo use is still under investigation. The implant material itself may also have a nanostructured ceramic surface. This is produced in a sintering process from TiO ₂ and Al ₂ O ₃ nanopowders or with the sol-gel process and subsequent sintering. Nanostructured ceramic surfaces are characterized by a high biocompatibility and, with corresponding particle sizes, represent a suitable growth substrate for osteoblasts.

Organic nanofibers and composite materials

Carbon nanofibers have exceptional mechanical properties, such as. As a favorable ratio of tensile strength and weight and a nanoscale geometry that is similar to that of crystalline hydroxyapatite in the bone. PCU carbon nanofibers increase z. B. cell adhesion of osteoblasts. This has also been demonstrated for nanostructured PLGA-titanium composites, whose surface and chemical properties may be very similar to those of bone ( Kay et al. Tissue engineenng, 8, 753-761 2002 ).

2.4. Nanoporous surfaces

Nanoporous Surfaces are u. a. generated on stents. So was with Help of a newly developed plasma process an aluminum layer applied to the stent, which subsequently in a wet chemical Process transformed into nanoporous, amorphous alumina has been. By incorporating radioactive nuclides into the pores of the Aluminum coating whose diameter is between 10 and 100 nm can be varied, is a controlled release of radioactivity to reach and thus the risk for a renewed vascular occlusion to reduce.

The underlying the nanoporous surfaces of the stents underlying principles were transferred to Seeds. in this connection these are small sticks, which are also one have nanoporous surface. Also with seeds the surface serves as a carrier for radioactive Nuclides. To protect against a release of nuclides, the Rods encapsulated in titanium, with the radiochemical Yield reached almost 100%. Seeds can be used as implants for local radiation therapies, such. In prostate cancer, be used.

Alumina membranes have also been used as nanoporous surfaces in drug delivery systems (Brandau et al. US 6,709,379 B1 , 2001). Pore diameters in the nanometer range can be produced. These membranes have z. As regards the temperature resistance and the resistance to acids, alkalis or solvents all advantages of inorganic materials. Since the pore diameter can be freely selected between about 10 and 100 nm, membranes with different material exit kinetics can be produced.

2.5. lipid nanoparticles

Work on the coating of medical devices with lipid nanoparticles is not available according to our research. Previous patents relate to the encapsulation of active ingredients in lipid nanoparticles and their use in cosmetics, as drug delivery systems (Müller & Olbrich, DE 199 64 085 A1 , 1999) or for UV protection (Heppner et al., DE 199 52 410 A1 , 1999; Müller et al., DE 100 16 155 A1 , 2000). A sheath of lipid nanoparticles has also been developed (Bürger et al., DE 10210449A1 , 2002).

The Research also showed that the combination of plasma sterilization or plasma disinfection and lipid nanoparticles and their special Properties have not been described so far. Therefore, according to ours Not a prior art of the invention described below opposite.

3. combination of sterilization and coating

at all previously known methods, the coating is carried out first the surface and as a final operation the germ reduction (sterilization) or sterilization. For coating with sensitive materials, the surface texture achieved partly due to the energy input associated with the sterilization destroyed.

Object of the invention

outgoing From the prior art, the invention was the object of the o. g. Disadvantages of different solutions to eliminate and new, better opportunities for coating of surfaces as well as the germ reduction or sterilization provide.

invention description

The Task has been in accordance with the features of the claims solved. According to the invention succeeded a new process for coating medical devices with nano- and to develop microparticles by the intended Use a microbial avoidance or aggravated. The procedure has been designed to disinfect and coat either simultaneously or in several successive steps be performed.

• • Vorbehandlung der Oberfläche mit einem Plasmaverfahren
• • gleichzeitiges oder nachfolgendes Aufbringen der Mikro- und Nanopartikel auf der Oberfläche
• • anschließende Fixierung der Mikro- und Nanopartikel auf der Oberfläche durch ein Plasmaverfahren.

The method according to the invention for coating surfaces with microparticles and nanoparticles consists of the steps:

• • Pre-treatment of the surface with a plasma method
• • simultaneous or subsequent application of the micro- and nanoparticles on the surface
• • subsequent fixation of the micro- and nanoparticles on the surface by a plasma process.

The Pretreatment of the surface and / or fixation of the Micro- and nanoparticles on the surface are preferably carried out with a non-thermal plasma process. Through the targeted Plasma pretreatment succeeds in sterilizing the surfaces and at the same time to improve the hydrophilicity so that Example, lipid-containing nanoparticles and microparticles particularly good distribute the surface. The timely or subsequent Application of nano- or microparticles prevents recontamination the surface as well as the contamination of the surface by contact with organic material, such. B. Blood components. The inventively applied nanoparticles and microparticles are characterized by special physico-chemical properties. In the subsequent fixation of the micro and nanoparticles Covalent bonds or hydrogen bonds are formed by a plasma process or van der Waals bonding of the particles.

The Sticking of bacteria or blood components is prevented when nanoparticles are evenly spaced of 10-3000 nm, preferably 50-1000 nm, on one Surface are distributed. The optimal distance is from dependent on the size of the particles applied. The used nano- and microparticles can additionally with antimicrobial substances / natural substances, pharmaceutical or cosmetic agents, mas kierenden ingredients, such as Surfactants or PEG or polylysines, one or more minerals, Nutritional supplements, radical scavengers, vitamins, especially vitamin C or silver particles are doped.

The homogeneous distribution of nano- and microparticles on the surface Can be used both in the dipping and in the spray process or be realized in the spray drying process. feasible is also an application of the solid nanoparticles and microparticles below Action of plasmas.

Especially In this case, coatings with lipid nanoparticles are advantageous since these are sterile easy to produce in large quantities and also very suitable as a carrier of active ingredients. There are but also coatings with suitable biodegradable polymer carriers (eg lactide-glycolide, polyhydroxybutyric acid or polyorthoester) possible. Other options are that as carrier material sugar compounds are used (eg cyclodextran). As active ingredients for encapsulation can antimicrobial substances are incorporated

By Addition of further masking ingredients z. B. surface active Substances (eg surfactants or PEG, polylysines) may be additional antibacterial and masking or protein or blood repellent Properties are generated. Through targeted modification of the Surface charge and hydrophobicity may affect the surface properties be improved. This can be done, for example, by a jacket of the particles with nonylphenols (Antarox, Gafac) and / or nonionic Block copolymers (poloxamer, poloxamines) take place. In addition to the significant Lowering the hydrophobicity is also a reduction with this process connected to the particle charge. In addition, the attachment becomes of unwanted substances such as blood or proteins the process is reduced or avoided. By the angry Micro and nanoparticles will also pollute the surface prevented.

According to the invention a subsequent surface treatment with a suitable non-thermal plasma that brings the particles to the surface fixed, extremely advantageous (see embodiment). In this final process step is also a germ killing with an improvement of the coating structure connected.

This Step can be done with a particularly favorable pretreatment (functional chemical groups on the surface) by a plasma, however fall away, so that only one step is necessary.

The object of the sterilization and subsequent covalent bonding or other bonds such as hydrogen bonding or van der Waals binding of the particles according to a by a dipping, or a spray, - or a dry process or under the action of a plasma applied layer of nano- and According to the invention, microparticles are achieved by exposing the surface prepared with particles at a suitable distance (0.5-200 mm depending on the plasma process) and, for a sufficient time, to the plasma of a non-thermal discharge. The conditions are given by the specifics of the discharge arrangement used. In particular, the type of excitation, the geometry, the process pressure, the geometric arrangement and dimensions of the reactor, as well as the process gases used, their admixtures and flow rates play a role here. Another important process parameter is the fed-in power. The use of electrodeless arrangements, such. B. microwave discharges or Inductively coupled RF plasmas also prevent contamination due to removed electrode material. When using normal pressure discharges (eg dielectrically impeded discharge or HF capillary discharge), vacuum equipment is eliminated. The arrangements according to the invention can serve for the treatment and / or coating of inner and outer surfaces, ie the treatment / coating can also take place in cavities. By adjusting the plasma conditions, the adhesion of the micro- and nanoparticles can be selectively influenced. In the exemplary embodiments, it is demonstrated that the surfaces produced by the combination method with an optimized aftertreatment are stable with respect to 6 rinsing operations. Resettlement tests on rinsed surfaces showed a significant reduction in re-contamination.

The method opens up according to the invention Series of new applications:

a) coating of reprocessable medical devices and instruments

The Procedure offers the possibility of medical devices and instruments for example, to equip catheters with a coating, through appropriate washing procedures in the reprocessing of instruments again Will get removed. The coating, for example, the Sliding properties of catheters compared to new products even improved. By selecting low melting lipids for the coating with microparticles and nanoparticles become coatings according to the invention which are stable at body temperature, however after use in a chemodesinfektionswaschverfahren between 50-80 ° C can be removed again.

This Process of detachment, controllable by the nature of the particles and the performed plasma process (especially the intensity the aftertreating plasma), the process differs significantly from the already established methods such as the coating with silver nanoparticles.

• • Reinigung des gebrauchten Gerätes oder des Instruments, dabei Entfernung der bei der vorangegangenen Aufbereitung aufgebrachten Beschichtung
• • Vorbehandlung mit einem nicht thermischen Niederdruckplasma unter gleichzeitiger Inaktivierung aller eventuell noch vorhandenen Keime und Pyrogene (Vorsterilisation)
• • Beschichtung mit Mikro- und Nanopartikeln unter aseptischen Bedingungen,
• • Fixierung der Mikro- und Nanopartikeln durch Einwirkung eines Plasmas
• • Funktionskontrolle unter aseptischen Bedingungen,
• • Verpackung unter aseptischen Bedingungen,
• • Sterilisation in der Endverpackung mit einem zugelassenen Verfahren

When reprocessing a new application of the coating is possible after cleaning. The regular removal and application of the coating prevents permanent attachment of bacteria, pyrogens and blood components. For special instruments such as catheters, this can be of great advantage ... The treatment can advantageously be carried out using the invention as follows:

• • Cleaning the used device or instrument while removing the coating applied during the previous treatment
• Pretreatment with a non-thermal low-pressure plasma with simultaneous inactivation of all possibly present germs and pyrogens (pre-sterilization)
• Coating of micro- and nanoparticles under aseptic conditions,
• • Fixation of the micro- and nanoparticles by the action of a plasma
• • Functional check under aseptic conditions,
• • packaging under aseptic conditions,
• • Sterilization in the final packaging with an approved procedure

b) equipment of surfaces of switches, keyboards, handles of devices, possibly over Protectors

For this application according to the invention is a firmer, permanent application of the particles necessary. utility devices such as the input keyboards of computers, instruments and switches must be frequented by medical staff be touched by hand. In doing so, such Keyboards contaminated with dirt and pathogens. Just The keyboards of computer can thereby become the starting point of the nosocomial pathogen transmission. With the invention Procedure, it is possible to antimicrobial the surface equip and so avoid the germ transmission. In an advantageous embodiment, the antimicrobial takes place Equipment of a protective film, with the switch. handles as well as other surfaces, often by hand must be covered.

c) Improvement of corrosion protection

There Substances resulting from the metabolism of microorganisms, can attack the material surfaces. By Preventing the adhesion of microorganisms will Protection against biocorrosion achieved. In addition, through The coating also reduces the chemical corrosion.

d) Cellulose-based coating produced materials

The coating method according to the invention is also for textiles and more preferably for cover materials suitable for wound care. The coating according to the invention special advantages reached. For polyurethane-based wound dressings, adhesion will occur restricted by bacteria. So you get wound dressings, in which a carryover of the germs in previously uninfected Areas is prevented. By incorporated active ingredients, the Wound healing can be positively influenced. In support of the Wound healing can be natural and / or pharmaceutical Active ingredients, one or more minerals and / or radical scavengers and / or vitamins, quaternary ammonium salts or substances for the stimulation of leukocytes or for the activation of the reticoloendothelial Systems are incorporated into the nanoparticles. Furthermore are as layer material also lipid-containing biomasses, available from algae, cyanobacteria and / or fungi or herbal extracts usable.

The Methods a) to d) are feasible in open systems, because with the products a final sterilization after functional testing and packaging possible with conventional sterilization process is possible.

are Products required that are not sterilized by conventional methods can be, is the implementation of sterilization and coating in a closed system possible. This sterile products are achieved.

e) bonds

The Method is also for the connection of components and / or films made of different materials, preferably made of plastics but also natural substances and modified natural substances. by virtue of different thermal and mechanical properties Such compounds are difficult to produce. The connections play but both for medical devices with simultaneous Avoid contamination as well as in connection technology for drug research, biomedical in vitro diagnostics and in areas where known harmful side effects Glue or their layer thicknesses severely limits the application such as B. for food packaging. The nanoparticles themselves or their fillings serve as glue. To may be the surfaces of the materials before and / or after being brought into contact with nanoparticles after coating, to the even distribution of nanoparticles to reach the surface and reactive binding sites. The binding sites react under pressure and / or temperature influence with the nanoparticles or their fillings. The nanoparticles can from all already mentioned in the previous section Materials and additionally with multifunctional crosslinking reagents (eg, di-epoxides, triamines, polyacids, dialdehydes) be.

EXAMPLES

in the The invention is based on preferred embodiments explained in more detail with reference to the figures, without limiting the invention to the examples mentioned.

example 1

Production of lipid nanoparticles

Table 1: Formulation of the nano- and microparticles from the lipid cetyl palmitate material Quantity in g Lipid base 5.00 Emulsifier (Plantacare® 2000 ^®) 0.05 Demineralised water 45,00 homogenization 4

The lipid is heated to a temperature of 80 ° C. Separately, an aqueous emulsifier solution is heated to the appropriate temperature (80 ° C). After that, both phases are at the desired Homogenization temperature united. The mixture is then processed by means of an Ultra Turrax T25 from Janke and Kunkel GmbH & Co KG (Staufen, Germany) in an emulsification process at 8000 revolutions per minute and a duration of 30 seconds. The suspension is then homogenized four times with a piston-gap high-pressure homogenizer Micron Lab 40 (APV-Gaulin, Lübeck) at a pressure of 500 bar and a temperature of 80 ° C.

2 shows the particle size distribution of cetyl palmitate lipid nanoparticles.

Example 2

Production of the drug-loaded lipid nanoparticles

Table 1: Formulation of the nano- and microparticles from the lipid cetyl palmitate material Quantity in g Lipid base 5.00 Emulsifier (Plantacare® 2000 ^®) 0.05 Demineralised water 44,50 Active ingredient (vitamin C) 0.5 homogenization 4

The Lipid is heated to a temperature of 80 ° C. Therein the active substance is dispersed. This is separated from an aqueous Emulsifier solution to the appropriate temperature (80 ° C) heated. After that, both phases are at the desired Homogenization temperature united. Then the mixture with the help of a Ultra Turrax T25 from the company Janke and Kunkel GmbH & Co KG (Staufen, Germany) in an emulsification process at 8000 revolutions per minute and one Duration of 30 seconds processed. The suspension is then with a Micron Lab 40 piston gap high pressure homogenizer (APV-Gaulin, Lübeck) at a pressure of 500 bar and a temperature homogenized four times from 80 ° C.

Example 3

Production of nano- and microparticles from lipids for encapsulation with prednisolone from cetyl palmitate

Table 2: Formulation of lipid nanoparticles and microparticles for the encapsulation of active substances (prednisolone) material Quantity in g biomass 5.00 Pluronic F 68 0.05 Demineralised water 45,00 prednisolone 0.5 homogenization 4

In the molten lipid composition is incorporated into the prednisolone. Separated therefrom is an aqueous emulsifier solution heated to the appropriate temperature (80 ° C). Thereafter, both phases are at the desired homogenization temperature united. The mixture is using an Ultra Turrax T25 Fa. Janke and Kunkel GmbH & Co KG (Staufen, Germany) in an emulsification process at 8000 revolutions processed per minute and a duration of 30 seconds. The suspension Afterwards, use a Micron piston-gap high-pressure homogenizer Lab 40 (APV-Gaulin, Lübeck) at a pressure of 500 bar and homogenized four times at a temperature of 80 ° C.

The nanoparticles produced can be used for coating Implants are used.

Example 3 Combination Method

The investigations of the materials showed that a plasma pretreatment is necessary for a better distribution of the particles. Microscopy images showed that without plasma pretreatment there was a very uneven distribution of the lipid nanoparticles on the surface ( 2 ). In contrast, it was possible to achieve a uniform distribution on the surface with the aid of plasma pretreatment.

• 1. Die Vorbehandlung erfolgte mittels nichtthermischem Plasma. Aus dem Spektrum der möglichen Plasmaquellen wurde das Prinzip an zwei Beispielen demonstriert: 1. Wurden die Medizinprodukte über den Zeitraum von 350 s dem Plasma eines HF-Kapillarjets [ R. Foest, E. Kindl, A. Ohl, M. Stieber, and K.-D. Weltmann, Plasma Phys. Contr. Fusion 47 (2005) B525–B536 ] ausgesetzt, der mit Argon gespeist wurde und bei Normaldruckbedingungen an Umgebungsluft arbeitete.
• 2. Die Vorbehandlung konnte in einem Niederdruck-Mikrowellenplasma mit Sauerstoff als Prozessgas durchgeführt werden (O₂ 0,5 mbar, 200 W, 200 s), wobei die Prozessbedingungen üblichen Behandlungen entsprachen [ W. Besch, K. Schröder, A. Ohl, Plasma Process. Polym. 2005, 2, 97–103 ].

3 shows an SEM image of PE surfaces without plasma pretreatment.

• 1. The pretreatment was carried out by means of non-thermal plasma. From the spectrum of possible plasma sources the principle was demonstrated by two examples: 1. Were the medical devices over the period of 350 s the plasma of an HF capillary jet R. Foest, E. Kindl, A. Ohl, M. Stieber, and K.-D. World man, Plasma Phys. Contr. Fusion 47 (2005) B525-B536 ], which was fed with argon and worked at ambient pressure conditions under normal pressure conditions.
• 2. The pretreatment could be carried out in a low-pressure microwave plasma with oxygen as the process gas (O ₂ 0.5 mbar, 200 W, 200 s), the process conditions corresponding to customary treatments [ W. Besch, K. Schröder, A. Ohl, Plasma Process. Polym. 2005, 2, 97-103 ].

Both Methods led to similar results the uniform distribution of lipid nano- and Microparticles on the surface.

These improved surface properties resulted in that a much more even distribution of Nanoparticles became possible. The coating with the lipid nanoparticles and microparticles are made by dipping the materials. In addition were used the nanoparticles prepared in Example 1.

4 shows a SEM image of PE surfaces with plasma pretreatment.

According to the invention was In the next process step, a plasma post-treatment carried out. For this treatment may be the same Apparatus, as in the pre-treatment step described above used. As a process gas in this case, an inert Serve gas. In the example plasmas described became argon plasma used. The treatment times are in the period of 100-200 s. With the help of this process step succeeded, the nanoparticles to covalently bond to the polymer surface.

Resettlement tests of bacteria on the nanoparticulate surfaces

For this, the polyethylene carriers were tested for recontamination. First, 0.01 ml of bacterial suspension (MRSA North German epidemic strain, 10 ⁶ germs) was placed on the already coated carrier. Subsequently, the carriers were rinsed with 5 ml of NaCl solution (pipette) per carrier three times. The rinsing solutions were collected and then streaked onto one agar plate each. The agar plates were then incubated at 37 ° C for 24 hours. Thereafter, the colonies of the MRSA North German epidemic strain were counted. Table 4 Investigation of microbial contamination of HDPE carriers with MRSA after three rinses Experiment after plasma pretreatment and aftertreatment (normal pressure plasma) Sample Number / flushing time in seconds Number of colonies PJ01 / 1 130 0 PJ01 / 2 130 0 PJ01 / 3 130 0 PJ02 / 1 190 0 PJ02 / 2 190 0 PJ02 / 3 190 0 PJ03 / 1 260 0 PJ03 / 2 260 0 PJ03 / 3 260 0 K1 / 1 190 1048 K1 / 2 190 167 K1 / 3 190 7 Table 5: Investigation of germination of HDPE carriers with MRSA after six rinses Experiment after plasma pretreatment and after-treatment (normal pressure plasma) Sample Number / flushing Distance to the nozzle [relative units] Number of colonies PJ04 / 4 1 102 PJ04 / 5 1 81 PJ04 / 6 1 15 PJ03 / 4 3 229 PJ03 / 5 3 183 PJ03 / 6 3 99 K1 / 4 2 2800 K1 / 5 2 380 K1 / 6 2 260

To Flushing experiments showed that the nanoparticles at the plasma conditions used so firmly on the surface were bound, which in three rinsing tests sterility was given. In further rinsing experiments, however, became clear in case of renewed contamination no adhesion of the nanoparticles was present.

By a slightly modified plasma treatment, the adhesion of the nanoparticles could be improved. This proves the sterility after up to 6 rinses. Table 6: Investigation of the germination of HDPE carriers with MRSA after six rinses Experiment after plasma pretreatment and after-treatment (normal pressure plasma) Sample Number / flushing Distance to the nozzle [relative units] Number of colonies PJ06 / 4 2 0 PJ06 / 5 2 0 PJ06 / 6 2 0 K2 / 4 1 1740 K2 / 5 1 35 K2 / 6 1 20

Example 5

The Polylactide-glycolide particles applied to a HD polyethylene surface are very hydrophilic. PLG particles with modified monomer composition, in particular copolymers with high D-lactide or L-lactide content, are increasingly hydrophobic. The cause of this is crystalline Regions of the two stereoisomers that are impermeable to water are. D, promotes L-polylactic acid as an amorphous substance however, the water absorption in the matrix.

Under In the given experimental conditions, the particles are stable. Of the hydrolytic degradation begins with the polymeric carriers 4-6 weeks.

TEM found a mean number-weighted radius of 10 μm for the PLG microparticles. The particles are very polydisperse and also highly porous ( 4 ).

5 shows an SEM image of the PLG microparticles (preparation: ultrasonic nebulization).

Due to the high particle density (769.1 mg ∙ cm ^-3 ), however, only an average particle-specific total surface is available, with a constant weight (19.1 g).

Example 6

On HDPE surfaces were nanoparticles, with different Loaded active ingredients applied by plasma coating process. The rinsing tests show the advantageous properties the coatings with drug-loaded nanoparticle layers.

6 describes the plasma pretreatment, coating and post-treatment of the plasma Carrier: PE / hard Test for germ reduction after simple germination (10 ⁶ ).

Example 7

The Release of prednisolone from cholesterol nanoparticles takes about 3 weeks and stops at about 95% of the actual Drug content. Here can be a delayed release to be spoken. The active ingredient is almost complete from the particles.

7 shows the time course of the drug release from 2% prednisolone / cholesterol nanoparticles based on the actual content; N = 2).

Example 8

The zeta potential of the nanoparticles coated with Poloxamer 407, Poloxamine 908 and Antarox CO 990 was reduced as the coating layer was increased. The charge reduction effect could not be used for adsorption with Gafac RE 960. The surfactant carries a charge at the end of the EO chain. The charge is located on the outer surface of the coated nanoparticles. This new surface charge is superimposed on the charge reduction effect of the coating. The obtained zeta potentials for Gafac RE 960 are therefore close to the potentials of the uncoated nanoparticles. Tab. 7 Zeta potentials of the polymer particles coated with four different surfactants (Poloxamine 908, Poloxamer 407, Antarox CO990, Gafac RE960) in NaCl solution (50 μS) coating material PLGA without -37.5 Poloxamine 908 -2.5 Poloxamer 407 -0.8 Antarox CO 990 -7.9 Gafac RE 960 -26.5

Example 9

8th shows an SEM image of the GMA-10% microparticles (preparation: ultrasonic nebulization).

The Surface Properties of Glycol Methacrylate (GMA) Microparticles vary due to the change in monomer composition. As the GMA fraction increases, additional functional groups become available inserted into the polymer structure. As the rising hydrophilicity with a reduced adsorption tendency also affects the Adsorption of biopolymeric components on the drug carrier adsorbates.

Example 10

Two plastic films made of polyethylene and polyetheretherketone are joined together. First, the two surfaces are pretreated with normal pressure plasmas in air. This activates the surfaces. Subsequently, the materials are immersed in lipid nanoparticles. Thereafter, the polyetheretherketone is treated with a normal pressure plasma in nitrogen, the polyethylene in a normal pressure plasma in oxygen and immediately compressed at 45 ° C with 1 MN / m ² . As a result, these materials are bonded to an adhesive layer thickness of 200 nm.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - US 3948601 A [0009]
• - US 5087418 A [0009]
• - US 5482684 A [0009]
• - US 5163458 A [0009]
• US 5656238 A [0009]
• - US 6558621 B1 [0009]
• - US 6261518 B1 [0009]
• - DE 69126312 t [0009]
• - DE 10134037 A1 [0009]
• US 5785934A [0011]
• - US 6194036 B1 [0012]
• WO 03/063914 A2 [0012]
• US Pat. No. 6720006 B1 [0015]
• EP 1355681 A1 [0015]
• - US 6653356 B1 [0020]
• - US 6572672 B1 [0020]
• DE 10235803 A1 [0021]
• - DE 19962055 A1 [0021]
• US 6709463 B1 [0025]
• - US 6706273 B1 [0028]
• - US 6709379 B1 [0033]
• - DE 19964085 A1 [0034]
• DE 19952410 A1 [0034]
• - DE 10016155 A1 [0034]
• DE 10210449 A1 [0034]

Cited non-patent literature

• - KH Wallhäußer, Georg Thieme Verlag, Stuttgart, New York, 1995 [0002]
• - Kohnen & Jansen, 2001 [0003]
• Laroussi et al., New J. Phys., 5, (2003), 41.1 [0008]
• Moreau et al., J. Appl. Phys., 88, 2 (2000), 1166 [0008]
• - Awakowicz and Keil, VFPREO, 5, (2001), 294) [0008]
• M. Förtsch et al. Ophthalmologist 90, 1993, No. 6, pp. 754-764 [0011]
• - see. HW Herrmann et al. Physics of Plasmas Vol. 6, no. 5, 1999, p. 2284-2289 [0012]
• Thull, R Biomolecular Engineering 19, 43-50 (2002) [0023]
• - Enzyklopädie Naturwissenschaft und Technik, B. Erg.-Lfg., 1-7 (2003) [0023]
• Biehl et al., J. Biomed. Mater. Res., 2002 [0024]
• Eisenbarth et al. Biomol. Closely. 19, 233-237, (2002) [0024]
• Catledge et al., J. Nanoscienes and Nanotechnolgy 2 (3-4), 293-312, 2002 [0025]
• Catledge et al. Nanoscienes and Nanotechnolgy 2 (3-4), 293-312 (2002) [0026]
• Kay et al. Tissue engineenng, 8, 753-761 2002 [0030]
• R. Foest, E. Kindl, A. Ohl, M. Stieber, and K.-D. World man, Plasma Phys. Contr. Fusion 47 (2005) B525-B536 [0067]
• W. Besch, K. Schröder, A. Ohl, Plasma Process. Polym. 2005, 2, 97-103 [0067]

Claims (27)

Process for coating surfaces with microparticles and nanoparticles, characterized by the following steps: a) Pretreatment of the surface with a plasma process b) simultaneous or subsequent application of the micro- and nanoparticles on the surface c) subsequent fixation the micro- and nanoparticles on the surface through Plasma processes. Method according to claim 1, characterized in that that made the micro and nanoparticles out a) lipids and / or b) Polymers (eg, lactide-glycolide, polyhydroxybutyric acid or polyorthoesters) and / or c) dextrins or sugar compounds and or d) lipid-containing biomasses obtainable from Algae, cyanaobacteria and / or fungi. Method according to claim 1, characterized in that that micro- and nanoparticles are used according to different Methods are available such. B. crushing process High-pressure homogenization, rapidly rotating crushing process (eg Ultraturrax) Ultrasound or other procedures Emulsification Evaporation methods, emulsion-diffusion methods or solvent-displacement methods. Method according to one of claims 1 to 3, characterized in that the micro- and nanoparticles a average diameter of 10 nm-10 microns have and that in the fixation by a plasma process the micro- and nanoparticles covalently and / or by hydrogen bonding and / or by van der Waals bonding of the particles to the surface be bound. Method according to claim 1, characterized in that that the pretreatment of the surface and / or the fixation the micro- and nanoparticles on the surface with one non-thermal plasma process takes place. Method according to claim 1, characterized in that that the coating with micro and nanoparticles by a dipping process or a spray process or dry process following or under the action of a plasma. Method according to claim 1, characterized in that that the micro and nanoparticles are at a distance of 10-3000 nm, preferably 50-1000 nm, depending on the size of the particles applied, on one Surface are distributed. Method according to claim 1, characterized in that characterized in that lipids for the coatings be selected with low melting point, so that the Coatings at body temperature are stable, however in a chemodesinfektionswaschverfahren between 50-80 ° C. be removed again. Method according to claim 1, characterized in that that the micro and nanoparticles in addition to a) antimicrobial substances / natural substances and / or b) pharmaceutical or cosmetic agents and / or c) masking Ingredients such as surfactants or PEG or polylysines and / or d) one or more minerals and / or e) radical scavengers and or f) vitamins, especially vitamin C and / or G) Silver particles and / or h) lipid-containing biomasses i) reactive multifunctional linker molecules are doped. Method according to claim 1, characterized in that that the micro- and nanoparticles with nonylphenols such as Antarox or Gafac) and / or nonionic block copolymers (e.g., poloxamer, Poloxamine) are sheathed. Method according to claim 1, characterized in that that the adhesion of the micro and nanoparticles by adjustment the plasma conditions is controlled. A method according to claim 1, characterized in that the method for bonding Schich is used. Materials whose surface is covered by micro- and nanoparticles coated, available through a) Pretreatment of the surface of the materials with a plasma process b) simultaneous or subsequent application the micro- and nanoparticles on the surface of the materials c) subsequent fixation of the micro- and nanoparticles the surface of the materials by a plasma process Medical devices whose surface Materials according to claim 10. Use of the method according to one of the claims 1 to 9 for germ reduction or degermination of surfaces and / or immobilization of microparticles and nanoparticles on surfaces. Use of the method according to one of the claims 1 to 9 to protect surfaces from new growth with microorganisms. Use of medical devices and Materials according to claim 12 or 13 in the hospital sector, in the manufacture of pharmaceutical or medical products, of transplantation medicine, in the reprocessing of medical Devices. Use according to claim 13 or 14 as an antibiotic carrier. Use of the method according to one of the claims 1 to 9 for permanent antimicrobial equipment of Nutzgeräte, preferably for switches and of other surfaces and protective films that are common must be touched by hand, preferably handles for medical devices and the keyboard of devices and computers. Use of the method according to one of the claims 1 to 9 to improve the corrosion protection. Use of the method according to one of the claims 1 to 9 for the surface modification of implants or in slow-release systems to promote ingrowth as well as for the prevention of implant-associated infections. Use of the method according to one of the claims 1 to 9 in the preparation of medical instruments and Devices. Use of the method according to one of the claims 1 to 9 to reduce sliding friction or to improve the sliding properties, especially in catheters. Use of the method according to one of the claims 1 to 9 to accelerate cell growth or stimulation of leukocytes or for activation of the reticoloendothelial system. Use of the method according to one of the claims 1 to 9 for the impregnation of textile and / or cellulose-based produced materials or as covering materials for wound care. Use of the method according to one of the claims 1 to 9 for the metered release of antimicrobial agents and simultaneous immune stimulation. Use of the method according to one of the claims 1 to 9 for connecting different materials made of plastics, Natural substances and modified natural materials with adhesive layer thicknesses from 50 to 5000 nm, preferably 100 to 500 nm.