Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
  • A61L29/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/04—Macromolecular materials
  • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
  • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
  • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
  • A61L2300/104—Silver, e.g. silver sulfadiazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
  • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
  • A61L2300/624—Nanocapsules

Definitions

• the invention relates to processes for producing metal-containing antimicrobial plastic products and to products obtainable by the process, in particular products for medical needs.
• Plastic objects are used very frequently in the medical field and for a wide variety of purposes.
• the problem with the use of plastic products for medical purposes is that the plastics can be easily colonized with germs. The germs settle on the plastic surface and form a "biofilm".
• the consequence of the use of micro-org a n i s me n b e s i ed plastic objects are often infections.
• It is known that the use of plastic catheters and cannulas can easily lead to infection by bacterial immigration. Such infections are particularly serious and common. in central venous short, medium and long-term catheters as well as in the urological area, where urethral and ureteral catheters are routinely used, and in diverting valve systems. In the Federal Republic of Germany alone, around 12 to 15 patients die every day as a result of infections that can be attributed to the use of microbially contaminated catheters.
• WO87 / 03495 and WO89 / 04682 describe the impregnation of medical devices or implants with antibiotics.
• the problem with impregnation with antibiotics is the formation and selection of resistant microorganisms.
• Another approach to reducing infections when using plastic products is the use of metals or metal alloys, for example in the case of catheters (DE 40 41 721, DE 27 20 776 and DE 33 02 567).
• the antimicrobial property of silver is of particular importance. Traces of silver and its salts already show a bacteriostatic and bactericidal effect.
• US 4,054,139 discloses a catheter in which a silver-containing, oligodynamic material has been applied to inner and outer surfaces for prophylaxis against infection.
• the approaches described have so far not been able to achieve satisfactory results with regard to sterility with the impregnation of plastic products in every respect, in particular at the start of use.
• the object of the present invention is therefore to provide a method for producing plastic products which have a satisfactory antimicrobial activity.
• the combination of an antimicrobial metal colloid and a soluble, preferably sparingly soluble, salt of an antimicrobial metal gives a satisfactory antimicrobial activity.
• the plastic products according to the invention also achieve a significantly improved immediate effect against microorganisms.
• the antimicrobial activity is significantly improved at the beginning compared to a plastic product of the prior art, as described, for example, in WO 01/09229.
• a significantly higher antimicrobial effectiveness of the plastic products according to the invention can be shown (cf. Table 1).
• the plastic products according to the present invention also have no increased cytotoxicity compared to products of the prior art, a further advantage is that no thrombogenicity is observed when using the plastic products according to the invention.
• Antimicrobial plastic products in the sense of the invention are products which have activity against microorganisms, in particular against bacteria and / or fungi. This can be both a bacteriostatic action and a bactericidal action.
• any antimicrobial plastic product can be produced by the method according to the invention; products are preferably produced which are used in the medical field. It may, for example, catheters, tubing, tubes, especially endotracheal tubes. Objects used in urology, bone cement, preferably bone cement consisting of methyl acrylate, Goretex tissue, toothbrushes, silicone plastics, plastic foils, textiles, for example for the manufacture of work clothing, diapers and / or parts thereof. In a particularly preferred embodiment of the method according to the invention, catheters are produced.
• any polymeric compounds which are usually used in the medical field can be used as starting materials for the production of the antimicrobial plastic products according to the invention.
• Preferred polymers are e.g. Polyurethanes, polyethylene, polypropylene, cross-linked polysiloxanes, (meth) acrylate-based polymers, cellulose and cellulose derivatives, polycarbonates, ABS, tetrafluoroethylene polymers, polyethylene terephthalates and the corresponding copolymers.
• Polyurethane, polyethylene and polypropylene and polyethylene / polypropylene copolymers are particularly preferably used, most preferred being polyurethane.
• the preliminary product can comprise further additives.
• Additives can be, for example, inorganic or organic substances.
• the precursor can include all inorganic and organic substances that are inert and medicinal are harmless, such as barium sulfate, calcium sulfate, strontium sulfate, titanium dioxide, aluminum oxide, silicon dioxide, zeolites, calcium fluoride (CaF 2 ), mica, talc, pyrogenic silica, calcium hydroxylapatite, kaolin, zirconium and / or microcellulose.
• Preferred inorganic substances are barium sulfate, which can also be used as an X-ray contrast medium for special application forms, and zircon.
• one or more constituents of the preliminary product are treated with a metal colloid.
• One or more polymeric materials and / or one or more inorganic or organic particles can be treated with the metal colloid.
• the carrier materials for the metal colloid can be present in the preliminary product in an amount of about 5 to 50% by weight.
• barium sulfate is used as the carrier material, it is usually present in an amount of about 5 to 30% by weight, particularly preferably in an amount of about 20% by weight.
• silicon dioxide is used as the carrier material, it is present in an amount of approximately 30 to 50% by weight, preferably approximately 40% by weight.
• the metal colloid with which one or more constituents of the preliminary product are treated is suitably produced by reducing metal salt solutions.
• reducing metal salt solutions When using silver, this is mixed with a reducing agent, for example as an ammoniacal silver nitrate solution.
• a reducing agent for example as an ammoniacal silver nitrate solution.
• protective substances such as gelatin, silica, starch, dextrin, gum arabic, polyvinyl alcohol or complexing agents such as ethylenediaminetetraacetic acid can optionally be used. It is preferable to work without protective substances.
• Suitable reducing agents are, for example, aldehydes (for example acetaldehyde), aldoses (for example glucose), quinones (for example hydroquinone), inorganic complex hydrides (sodium or potassium borate), reducers Nitrogen compounds (e.g. hydrazine, polyethyleneimine), ascorbic acid, tartaric acid and citric acid.
• aldehydes for example acetaldehyde
• aldoses for example glucose
• quinones for example hydroquinone
• inorganic complex hydrides sodium or potassium borate
• Nitrogen compounds e.g. hydrazine, polyethyleneimine
• ascorbic acid tartaric acid and citric acid.
• the color of the coated carrier material can also be controlled by varying the reducing agents and varying or omitting the stabilizers.
• antimicrobial metals such as, for example, silver, copper, gold, zinc, zirconium, bismuth (bismuth) or cerium, and mixtures thereof, are suitable for the process according to the invention.
• Silver which has a high antimicrobial activity, is particularly preferred.
• copper is preferably used, which advantageously also has an activity against fungi.
• the amount of the metal colloid is advantageously about 0.1 to 10, preferably about 0.5 to 5% by weight.
• the application of the metal colloid to one or more components of the preliminary product can either be carried out in one step or can be followed by drying and repeated several times.
• a very high metal concentration can be achieved with both methods.
• the particle size of the metal can be controlled by varying the reducing agents and varying or omitting the stabilizers. If silver is used as the metal colloid, the preferred particle size is in the range from 10 to 50 nm. Silver of this particle size is referred to as nanosilver.
• silver remaining in the solution is precipitated by adding phosphoric acid as silver phosphate, which is referred to below as "silver phosphate in statu nascendi" and is characterized by particularly rapid onset of the antimicrobial effect.
• the amount of the metal colloid is chosen so that a sufficient part of the surface of the plastic product consists of metal particles in order to achieve an antimicrobial effectiveness.
• a soluble or sparingly soluble salt of an antimicrobial metal is further added to the preliminary product.
• This is preferably a silver salt, zinc salt, copper salt, cerium salt, platinum salt, zirconium salt, bismuth salt and / or gold salt and mixtures thereof.
• all soluble or sparingly soluble salts of antimicrobially active metals are suitable which are resistant to the action of light and are physiologically harmless.
• the amount of the metal salt used can be from 0.1 to 5% by weight, based on the total weight of the preliminary product, preferably from 0.5 to 1% by weight.
• the mixture obtained is processed further in order to obtain a plastic product.
• This can be done, for example, by extrusion, injection molding, mixing, kneading or (hot) pressing.
• Preferred molding processes are extrusion and injection molding.
• plastic products which can be obtained by the process according to the invention. It is preferably plastic products that are used in the medical field.
• the method according to the invention produces catheters.
• the preferred medical products are venous catheters for short-term implantation, in which both the outside of the catheter and each lumen inside, the Luer lock and the distributor consist of the material obtained according to the invention. Experiments have shown that an inoculum size of 10 9 germs with which the surface has been contaminated is completely eliminated in less than 9 hours.
• peripheral venous cannulas peripheral venous cannulas, Sheldon catheters for implantation over 6 weeks for hemodialysis, Hickman-type catheters for long-term implantation with a cuff made of material according to the invention (antimicrobial activity determined for at least 1 year), port catheters, with at least the port chamber made of material produced according to the invention consists, expediently, also of all other components of the same, ventricular drainage catheter (minimum duration of effectiveness 3 years), bladder catheter, cystostomy, nephrostomy catheter, urether stent (e.g.
• polyurethane pellets with a size of approximately 1 mm 3 are used as the polymeric material.
• Another component of the preliminary product is barium sulfate, which as
• the barium sulfate contains about 3 to 10% by weight, possibly also deposited more nanosilver.
• the intermediate product comprises about 0.5 to 1% by weight of silver sulfate or silver phosphate, especially in statu nascendi.
• the components of the preliminary product are mixed, the further processing can be done by extrusion.
• a combination of silver and copper in a silver / copper ratio of approximately 2: 1 is used as the metal salt.
• This combination advantageously also has a satisfactory microbial activity against fungi.
• a combination of a metal colloid, particularly preferably nanosilver, and zirconium silicate is used. Weight ratios of silver to zirconium silicate of 1: 1 -10 are particularly suitable.
• Figures 1 to 3 show results of tests for antimicrobial activity. Staphylococcus epidermidis ATCC 14 990 with an initial bacterial count of 5 ⁇ 10 7 CFU / ml was used as the microorganism.
• Figure 3 shows an experimental approach in which 0.8% nanosilver and no additional silver sulfate was used. Examples:
• Comparative Example 1 Commercial plastic according to WO 01/09299 A: Production of a silver colloid
• Example 2 10 minutes after the end of the dropwise addition, as described in Example 1, about 50 g of polyurethane pellets made from Tecothane TT-1085A are added and, for coating with colloidal silver, are stirred vigorously at 40 ° C. for 2 hours and then at room temperature for 3 hours.
• the silver colloid is separated by rapid filtration through a pleated filter with a suitable pore size, the pellets are washed again with the filtrate and the still moist pellets are transferred to an evaporation tray. After removing excess silver colloid solution not adhering to the polymer, drying takes place at 70 ° C. for 10 hours.
• Example 2 Plastic with improved antimicrobial activity.
• A Adsorption of colloidal silver on barium sulfate. In 360 ml of distilled water are successively dissolved at 50 ° C: 0.6 g gelatin and 6.0 g AgNO 3 . 7.8 ml of 25% aqueous ammonia solution are added to the solution. A solution of 3.18 g of anhydrous glucose, dissolved in 120 ml of distilled water, is slowly metered in with vigorous stirring at 50.degree. When about half the amount of glucose has been added dropwise, 100 g of barium sulfate are introduced into the already formed silver colloid with vigorous stirring, and the metering of glucose is continued. After the end of the glucose addition the suspension is turbinated for a further 2 hours at 50 ° C. and then for 3 hours at 70 ° C.
• the solid is then separated from the liquid by filtration or centrifugation.
• the solid is washed several times with ultrapure water until it is free of electrolytes, filtered, dried at 70 ° C to 80 ° C and finely ground.
• step B If 2.5% by weight of silver sulfate is added in step B, the plastic listed in Table 1 under A is obtained; if 5% by weight of silver sulfate is added in step B, the plastic listed in Table 1 under B is obtained.
• Example 3 Plastic with improved antimicrobial activity A: Adsorption of colloidal silver on barium sulfate
• Silver sulfate is added in the same way as in Example 2 B.
• samples of the corresponding plastics were incubated at 37 ° C. with a trypcase soy broth nutrient solution containing various germs.
• Staphylococcus epidermidis ATCC 14 990,
• Staphylococcus aureus ATCC 25923, Escherichia coli (E. coli), fresh clinical isolate from one
• Pseudomonas aeruginosa P. aeruginosa
• fresh clinical isolate from a patient with catheter-associated sepsis.
• the bacterial count was either 5 x 10 7 colony forming units (CFU) / ml (corresponds to an OD of 0.30 at 457 nm for staphylococci, an OD of 0.65 for P. aeruginosa and E. coli) or 10 9 CFU / ml (OD 0.65 for Staphylococci at 475 nm, 1, 2 for P. aeruginosa and E. coli) adjusted in the photometer.
• CFU / ml was determined by serial dilution on agar plates and the bacterial count determined by photometric measurement was confirmed.
• Polyurethane (Tecoflex) was used, a material from which practically all implantable central venous catheters are made. This was with nanosilver (particle size 3 to 5 nm) in an amount of 0.8 or 1, 3 wt .-% and different concentrations of silver sulfate (0.25, 0.5, 0.75 and 1, 0%) coextruded. Strands with an outside diameter of 1.6 mm were produced. Pellets of 1 mm length were cut from each, 10 pellets give a surface area of about 1 cm 2 or 50 pellets give a surface area of 5 cm 2 .
• the plastic pieces (either with a surface area of 1 cm 2 or 5 cm 5 ) were placed in a suspension with either 5 x 10 7 CFU / ml or 10 9 CFU / ml of the germs described above in physiological saline.
• the test tubes were shaken at a speed of 120 rotations / minute.
• 1 eyelet (2 ⁇ ⁇ ) was removed and streaked onto an agar plate (Müller Hinton Agar). The plates were incubated at 37 ° C for 24 hours. The bacterial count on the agar plate was then determined by counting the colonies.
• the wild strain of S. epidermidis, S. aureus ATCC 25923 and E. coli and P. aeruginosa also showed a corresponding growth behavior.
• the test experiments showed that the addition of silver sulfate significantly increases the immediate antimicrobial effectiveness (comparison of A or B against C).
• the increase in effectiveness through the addition of silver sulfate is dose-dependent, however, effectiveness can already be observed with the addition of 0.5% silver sulfate.
• the plastic according to the invention shows a significantly improved antimicrobial effectiveness compared to a plastic which only contains nanosilver (approach C).
• the carrier material barium sulfate is mixed with 20% by weight of zirconium silicate in a first test series and with 20% by weight of nanosilver and 20% by weight of zirconium silicate in a second series of tests.
• the mixtures thus obtained are mixed with different amounts of germs and the germ growth is then recorded over 48 hours.
• the solid obtained is washed several times with ultrapure water until it is free of electrolytes and finally dried in a drying cabinet at 70 to 80 ° C. and, if appropriate, comminuted after drying.
• the product produced in this way is white-gray in color and has the composition 3.6% nanosilver, 5% silver phosphate on BaSO 4 .
• the bacterial count at a concentration of 1% or 0.1% was determined according to Example 4:
• A Adsorption of colloidal silver on barium sulfate. 9 g of silver nitrate are dissolved in 360 ml of distilled water heated to 50 ° C. and 100 g of barium sulfate are stirred vigorously entered. After stirring for 20 minutes, 12 ml of a 25% ammonia solution are added.
• a solution of 5.25 g of glucose monohydrate in 182 ml of distilled water is then slowly metered in at a constant temperature. After the glucose metering has ended, the suspension is stirred for a further 2 to 4 hours at 50 ° C. and then for a further 1 to 3 hours at 70 ° C.
• the solid is separated from the aqueous phase and washed several times with ultrapure water or distilled water until it is free of electrolytes.
• the washed solid is dried in a drying cabinet at 70 to 80 ° C. and then comminuted to the primary grain size.
• Example 7 The desired amount (1 to 5% by weight) of the purest silver phosphate is added to the solid obtained according to A and mixed intensively. The examination as described in Example 4 gave equally good results as shown in Example 7.

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• 2003
  • 2003-09-10 DK DK03750507T patent/DK1536848T3/da active
  • 2003-09-10 CN CNB038233320A patent/CN100342925C/zh not_active Expired - Fee Related
  • 2003-09-10 ES ES03750507T patent/ES2297196T3/es not_active Expired - Lifetime
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  • 2003-09-10 JP JP2004535474A patent/JP5128757B2/ja not_active Expired - Fee Related
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