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WO2007017019A2 - Catheters antimicrobiens - Google Patents

Catheters antimicrobiens Download PDF

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Publication number
WO2007017019A2
WO2007017019A2 PCT/EP2006/006443 EP2006006443W WO2007017019A2 WO 2007017019 A2 WO2007017019 A2 WO 2007017019A2 EP 2006006443 W EP2006006443 W EP 2006006443W WO 2007017019 A2 WO2007017019 A2 WO 2007017019A2
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WO
WIPO (PCT)
Prior art keywords
metal
catheter
catheters
pigments
catheters according
Prior art date
Application number
PCT/EP2006/006443
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English (en)
Other versions
WO2007017019A3 (fr
Inventor
Herwig Buchholz
Valerie Bicard-Benhamou
Marcus Brunner
Jerzy Meduski
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Publication of WO2007017019A2 publication Critical patent/WO2007017019A2/fr
Publication of WO2007017019A3 publication Critical patent/WO2007017019A3/fr

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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
    • A61L29/02—Inorganic materials
    • 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
    • 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
    • A61L2300/40—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
    • A61L2300/406—Antibiotics

Definitions

  • the present invention relates to catheters comprising pigments obtainable by agitating a suspension comprising one or more inorganic pigments and silver acetate, in order to reduce undesirable side effects caused by microorganisms.
  • Microbial contamination is an essential concern in our daily life and has a great impact for products and formulations.
  • health care facilities such as hospitals, nursing homes or outpatient facilities are faced with microbial contamination.
  • Nosocomial infections that means infections that originate or occur in a hospital or hospital-like setting, are a big problem in health care facilities, as described for example by R. Platt in, The new England Journal of Medicine, 1982, 637-642. These infections are responsible for about 20000 deaths alone in the U.S. per year.
  • Nosocomial infections are commonly acquired through exposure of patient to hospital environment, hospital personnel and invasive devices, such as catheters.
  • catheters are tubes for insertion into canals, vessels, passageways, or body cavities to facilitate a variety of functions, such as injection or withdrawal of fluids, keeping passages open, application of an incision device or delivery of an electrical charge. They are widely used and therefore stand in the focus for attempts to prevent nosocomial infections.
  • catheters with antimicrobial activity that are suited to reduce the number or severeness of nosocomial infections. Furthermore, catheters should show an antimicrobial activity for a long period of time without reduction of the antiseptic ability.
  • the present invention relates to catheters comprising pigments obtainable by agitating a suspension comprising one or more inorganic pigments and silver acetate, in order to reduce undesirable side effects caused by microorganisms.
  • Undesirable side effects caused by microorganisms are preferably nosocomial infections.
  • Catheters according to the present invention comprising the above- mentioned antimicrobial pigments are advantageous with respect to their ability to prevent nosocomial infections, can easily be produced, show a long term antimicrobial activity and are not limited to some types of catheters. These positive effects are achieved by using antimicrobial inorganic pigments that are included in the catheters.
  • the antimicrobial pigments can be distributed uniformly or not uniformly inside the catheter. An example for a non-uniform distribution is the deposition of antimicrobial pigments on top of the outside walls of the catheter or the incorporation into the outside surface area of the base material of the catheter. Preferably an uniform distribution of the antimicrobial component in the catheter is aimed.
  • Catheters comprising uniformly distributed antimicrobial pigments can easily be prepared with existing technologies for the preparation of catheters.
  • the catheter can be for example an infusion catheter, a cardiovascular catheter, a renal catheter, a catheter for hemodynamic monitoring or a neurological catheter.
  • catheters are acorn-tipped catheter, Amplatz coronary catheter, angiographic catheter, atherectomy catheter, balloon catheter, balloon-tip catheter, bicoudate catheter, catheter bicoude, Braasch bulb catheter, Brockenbrough transseptal catheter, Broviac catheter, cardiac catheter, cardiac catheter-microphone, Castillo catheter, central venous catheter, closed end-hole catheter, conical catheter, catheter coude, Cournand catheter, DeLee catheter, catheter a clear, de Pezzer catheter, directional atherectomy catheter, double-current catheter, double- lumen catheter, Drew-Smythe catheter, elbowed catheter, electrode catheter, end-hole catheter, eustachian catheter, female catheter, filiform- tipped catheter, fluid-filled catheter, Fogarty catheter,
  • catheters of the present invention are based on polymers.
  • the polymer for catheters of the present invention is selected from the group comprising polyurethane, PET, polyethylene terephthalate, Vialon, silicones, PVC, polyamide, polyimide, polyacrylates, fluoropolymers, such as polytetrafluoroethylene, methacrylic acid esters, ethylene-vinyl acetate copolymer, polycarbonate, polybutylene, terephthalates, polyisoprene, polysiloxanes, propylene polymers, polyetherurethane, polyoxytetramethylene, polyvinylpyrollidone, polydimethylsiloxane, epoxy resins, polybutadiene, low density polyethylene, latex, polyethylene oxide, rubber, synthetic rubber and/or mixtures thereof.
  • the antimicrobial pigments obtainable by agitating a suspension comprising one or more inorganic pigments and silver acetate.
  • the inorganic pigments can have any known regular or irregular shape, for example the shape of platelets, spheres or needles, alone or in a mixture.
  • the pigments are platelet-shaped or spherical.
  • Inorganic pigments in this sense comprise (according to DIN 55944) inorganic white pigments, inorganic coloured pigments, inorganic black pigments such as for example Carbon Black, effect pigments and luminous pigments, but also magnesium carbonates, mica, SiO 2 , TiO 2 , aluminium oxide, glass, micaceous iron oxide, oxidised graphite, aluminium oxide- coated graphite, basic lead carbonate, BiOCI, bismuth subcarbonate, bismuth trioxide, barium sulphate, chromium oxide or MgO can be used in the present invention.
  • pigments selected from the group of effect pigments.
  • effect pigments are those based on substrates which can additionally be coated with one or more layers of BiOCI and/or transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials.
  • the substrate for the effect pigments is preferably platelet- shaped and is preferably selected from the group of natural or synthetic mica, SiO 2 , TiO 2 , BiOCI, aluminium oxide, glass, micaceous iron oxide, graphite, oxidised graphite, aluminium oxide-coated graphite, basic lead carbonate, barium sulphate, chromium oxide, BN, MgO, magnesium fluoride, Si 3 N 4 and/or metals.
  • metals are aluminium, titanium, silver, copper, bronze, alloys or gold, preferably aluminium or titanium.
  • the metals can be passivated by inorganic treatment. Effect pigments with natural or synthetic mica, SiO 2 , TiO 2 , iron oxide, BiOCI, aluminium oxide and/or glass are especially preferred as substrates.
  • the one or more layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials all known materials can be selected.
  • the one or more layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials can have a high refractive index (n > 1.8) or a low refractive index (n ⁇ 1.8).
  • the metal oxides or metal oxide hydrates can be selected from any known metal oxide or metal oxide hydrate, such as for example SiO 2 , AI 2 O 3 , TiO 2 , ZnO, ZrO 2 , Ce 2 O 3 , FeO, Fe 2 O 3 , Cr 2 O 3 , SnO 2 , silicon oxide hydrate, aluminium oxide hydrate, titanium oxide hydrate and/or mixtures thereof, such as for example ilmenite or pseudobrookite.
  • the metal can be selected from any known metal, such as for example chromium, molybdenum, aluminium, silver, platinum, nickel, copper, gold and/or alloys, preferably from aluminium and/or silver.
  • An example for a metal fluoride is magnesium fluoride.
  • the effect pigments can have multilayer compositions comprising materials with a high and a low refractive index, formulations according to the present invention comprising inorganic pigments based on multilayer effect pigments are characterised through an intensively lustrous appearance and an angle-dependent interference colour.
  • the one or more layers of BiOCI and/or transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials are arranged as alternating layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials or BiOCI with a refractive index n > 1.8 and transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials with a refractive index n ⁇ 1.8
  • Preferred examples for materials with a refractive index n > 1.8 are titanium oxide, iron oxide, iron titanate, iron, chromium, silver and/or nickel, preferably titanium oxide, iron oxide, iron titanate.
  • Preferred examples for materials with a refractive index n ⁇ 1.8 are silicon oxide, silicon oxide hydrate, aluminium oxide, aluminium oxide hydrate, aluminium and/or magnesium fluoride.
  • the transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials additionally may contain organic and/or inorganic colorants or elements as dopant.
  • the absorption colour of the organic or inorganic colorant is combined with interference effects of the one or more layers of metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials thus producing pigments with special colour effects.
  • organic colorants are azopigments, anthrachinonepigments, indigo- or thioindigo derivatives, diketo-pyrrolo-pyrrol pigments, perylen pigments or phthalocyanin pigments.
  • Carbon black, Prussian blue, Turnbulls blue, Rinnmanns green, Thenards Blue and coloured metal oxide are only few examples of inorganic colorants, which can be introduced into the one or more layers.
  • Yttrium or antimony can be used as dopant.
  • Combinations of the materials mentioned above, for example mica platelets coated with fine particles of barium sulphate and a thin film of titanium dioxide are within the scope of the present invention.
  • Pigments based on all these systems combine the absorption and interference colour of the pigments with an antimicrobial activity thus enhancing the applicability of the pigments in order to reduce undesirable side-effects caused by microorganisms, such as for example nosocomial infections. Additionally, the different types of catheters can individually be coloured, thus making the catheters distinguishable.
  • the outer layer of the effect pigments which can be used according to the present invention preferably comprises a transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxide, metal suboxide, metal oxide hydrate and/or mixture of these materials, most preferably a metal oxide or metal suboxide with a high refractive index.
  • This outer layer can be additionally applied to the one or more layers or can be one of them.
  • the outer layer is composed Of TiO 2 , titanium suboxides, Fe 2 O 3 , SnO 2 , ZnO, ZrO 2 , Ce 2 O 3 , CoO, Co 3 O 4 , V 2 O 5 , Cr 2 O 3 and/or mixtures thereof, such as for example ilmenite or pseudobrookite, TiO 2 is in particular preferred.
  • the mean diameter of platelet-shaped substrates and hence the resulting pigments can vary between 1 and 200 ⁇ m, preferably 10 and 150 ⁇ m. Depending on the desired application, the size of the pigments can accordingly optimised.
  • the overall thickness of the pigments is in the range between 0.05 and 6 ⁇ m, in particular between 0.1 and 4.5 ⁇ m.
  • the thickness of the one or more layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials can vary between 3 and 300 nm, preferably between 20 and 200 nm.
  • the thickness of the metal layers is preferably in the range of 4 to 50 nm. By adjusting the layer thickness the intensity of the absorption colour or the interference colours and angles can be tuned.
  • inorganic pigments with variable colour, hiding strength, lustre and angle-dependent colour impressions are obtainable.
  • the preparation of above described layers can result from wet chemical treatment, from sol gel processes or by chemical or physical vapour deposition (CVD/PVD). After deposition, the resulting pigments can be dried or calcined.
  • CVD/PVD chemical or physical vapour deposition
  • effect pigments described here comprise pigments like Iriodin ® , Candurin ® , Timiron ® , Colorstream ® and Xirallic ® pigments from Merck KGaA, Mearlin ® and Dynacolor ® pigments from Engelhard Corp., Variochrom ® and Paliochrom ® pigments from BASF or Spectraflair ® pigments from Flex Products.
  • the inorganic pigments comprise spherical particles of metal oxides, for example SiO 2 , TiO 2 , aluminium oxide, glass, MgO, iron oxide but also BiOCI, magnesium carbonates, graphite, oxidised graphite, aluminium oxide-coated graphite, basic lead carbonate, barium sulphate, chromium oxide, BN, magnesium fluoride, SJ 3 N 4 and/or metals.
  • metal oxides for example SiO 2 , TiO 2 , aluminium oxide, glass, MgO, iron oxide but also BiOCI, magnesium carbonates, graphite, oxidised graphite, aluminium oxide-coated graphite, basic lead carbonate, barium sulphate, chromium oxide, BN, magnesium fluoride, SJ 3 N 4 and/or metals.
  • the spherical particles comprise SiO 2 , TiO 2 , AI 2 O 3 , ZnO, Fe 2 O 3 , FeO and/or mixtures thereof.
  • the spherical particles can be coated with one or more layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials.
  • the materials for the one or more layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials can be selected from the ones described for the effect pigments.
  • Spherical capsules of materials described above encapsulating organic and/or inorganic compounds or materials are also suited in the sense of the definition of inorganic pigments applied here.
  • the encapsulated compound or material can for example be selected for example from antibiotics.
  • Capsules, which are to be used particularly preferably, have walls that can be obtained by a process for example described in the applications WO 00/09652, WO 00/72806 and WO 00/71084. Preference is given here to capsules whose walls are made of silica gel.
  • the spherical particles are coated with one or more layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates, metals, metal nitrides, metal oxynitrides, metal fluorides and/or mixtures of these materials.
  • Layers of transparent, semitransparent or opaque, selectively or nonselective ⁇ absorbing or nonabsorbing metal oxides, metal suboxides, metal oxide hydrates as an outer layer, are preferred.
  • Particles described above can be obtained commercially, e.g. as Ronaspheres ® from Merck KGaA, Darmstadt.
  • the mean diameter of the spherical particles or capsules can vary between 5 nm and 100 ⁇ m, preferably between 8 nm and 50 ⁇ m and most preferably from 8 nm to 5 ⁇ m.
  • Spherical metal oxides in particular metal oxides with UV-filtering activity, preferably have a mean diameter of 5 to 100 nm, especially of 8 to 50 nm and most preferably of 8 to 30 nm.
  • a large surface area characterizes these particles, which therefore can advantageously be used as inorganic pigments for catheters according to the present invention.
  • the possibility to vary the colour of the antimicrobial pigments helps to distinguish different types of catheters by simply using different colours for different types of catheters without diminishing the antimicrobial activity of the obtained catheters.
  • the inorganic pigments can additionally be further coated with a protective coating layer.
  • the protective coating layer is believed to influence the rate at which the antimicrobial component diffuses from a dispersed particle into the application matrix.
  • the small residual porosity of the silica or alumina coating for example, also allows the antimicrobial component to diffuse through at a slow controlled rate thus extending the duration of the antimicrobial activity.
  • the ability to adjust the dispersibility of the particulate compositions of this invention both increases their use efficiency and improves the quality of the product.
  • the antimicrobial particles may further comprise a tertiary coating layer of a hydrous metal oxide, which is much legs agglomerated and disperse readily in polymers.
  • a tertiary coating of hydrous alumina or magnesia will raise the isoelectric point of the composition.
  • the control of the isoelectric point between about 5.5 and about 9.5 is beneficial in facilitating the dispersion and/or flocculation at the particulate compositions during plant processing and in their end use applications. This both increases the use efficiency of the antimicrobial pigments and improves the quality in applications.
  • Enhanced dispersibility also can be impacted by micronizing the product with small levels, e.g. 0.1 to 1 % of organic dispersion aids.
  • Dispersion aids may be incorporated either with the antimicrobial pigments or in the process for incorporating them in catheters.
  • the protective coating is selected from silica, silicates, borosilicates, aluminosilicates, alumina, aluminum phosphate, or mixtures thereof.
  • the protective coating functions as a barrier between the antimicrobial outer layer and an application matrix in which it may be incorporated, minimizing interaction with the application matrix. This protective coating also is believed to influence the rate at which the antimicrobial component diffuses from a dispersed pigment into the catheter.
  • the protective protective coating layer corresponds to 0.5 to 20 % by weight based on the antimicrobial pigments, and preferably, e.g., 1 to 5 % by weight of silica or e.g., 1 to 6 % by weight of alumina in the coated antimicrobial pigment. It will be appreciated by those skilled in the art that if fine particles of a substrate are employed in carrying out the invention, the practitioner should assure total surface coverage of the first coated substrate.
  • the protective layer of silica or alumina can be quite dense although it must be sufficiently porous to permit diffusion of the antimicrobial metal ions through the coating at a slow rate, while functioning as a barrier which limits interaction between the antimicrobial layer and the application matrix in which it is distributed.
  • Silica is a preferred coating material because of the relative ease with which dense, uniform coatings can be obtained.
  • Silica-coated particles my have a low isoelectric point and may tend to be difficult to disperse in organic materials.
  • the isoelectric point represents the pH at which a particle surface carries zero electric charge. Control of the isoelectric point between 5.5 and 9.5 is beneficial in facilitating the dispersion and/or flocculation of the particulate compositions during plant processing and in their end use applications. Therefore, for particles coated with silica or related materials with a low isoelectric point, a tertiary coating of hydrous alumina or magnesia or other metal oxide may be added to raise the isoelectric point.
  • hydrous oxides of Al, Mg, Zr and the rare earths may bring the isoelectric point into the range of 5.5 to 9.5.
  • Hydrous alumina typically as a mixture of boehmite (AIOOH) and amorphous alumina (AI2O 3 H2O), is a preferred tertiary coating material. Isoelectric points in a preferred range of 5.5 to 8.8 can readily be obtained with alumina coatings. For higher isoelectric points, magnesia is preferred.
  • alumina may be selected as the protective coating and a further coating may not be needed to adjust the isoelectric point. When alumina is used as the protective coating, the isoelectric point of the resulting pigment typically will be in the preferred range.
  • the inorganic pigment is BiOCI, bismuth subcarbonate, bismuth trioxide or barium sulphate. Therefore, catheters according to the present invention preferably comprise antimicrobial BiOCI, bismuth subcarbonate, bismuth trioxide or barium sulphate, obtainable by agitating a suspension comprising BiOCI, bismuth subcarbonate, bismuth trioxide or barium sulphate and silver acetate.
  • Catheters comprising antimicrobial BiOCI, bismuth subcarbonate, bismuth trioxide or barium sulphate are especially preferred because BiOCI, bismuth subcarbonate, bismuth trioxide or barium sulphate show high radiopacity resulting in clear visibility and a sharp contrast image under X-ray or fluoroscope. This helps to pinpoint the location of the catheter or to position it.
  • BiOCI Suitable BiOCI can be prepared by hydrolysis of bismuth salts in an acidic aqueous system in the presence of excess chloride ions and is commercially available, for example as Biron ® Powders from Merck KGaA, Darmstadt.
  • the pigments, especially BiOCI, included in catheters according to the present invention can be obtained in a simple way.
  • a preferred process for the production of the pigments includes the agitation of a suspension comprising one or more inorganic pigments and silver acetate as antimicrobial component. The process is based on a process described by A. Goetz, E. C. Y. Inn in "Reversible Photolysis of Ag Sorbed on Collodial Metal Oxides” in Rev. Modern Phys. 1948, 20, 131-142.
  • the preparation can be performed in water, ethanol, methanol, 1-propanol, 2-propanol and/or mixtures thereof, preferably water is used.
  • the preparation temperature can vary between 10 and 6O 0 C, preferably between 20 and 45°C and is most preferably held at 37 0 C.
  • the suspension is agitated from 4 up to 24 hours, preferably from 7 to 20 hours, and most preferably from 17 to 18 hours.
  • Similar pigments with antimicrobial activity can be obtained by substituting silver acetate by other antimicrobial compounds, such as for example silver salts, for example silver halogenide, silver nitrate, silver sulfate, silver oxide, silver benzoate, silver carbonate, silver citrate, silver lactate, silver salicylate, but also copper oxides, copper sulfide, copper nitrate, copper carbonate, copper sulfate, copper halogenides, copper carboxylates, zinc oxide, zinc sulfide, zinc silicate, zinc acetate, zinc chloride, zinc nitrate, zinc sulfate, zinc gluconate, zinc citrate, zinc phosphate, zinc propionate, zinc salicylate, zinc lactate, zinc oxalate, zinc iodate, zinc iodide or combinations thereof.
  • Silver acetate, silver oxide, copper sulfate, zinc acetate are the most preferably used.
  • the amount of the antimicrobial compound is in the range of 0.001 to 10% by weight, preferably 0.005 to 5% by weight, preferably 0.01 to 2% by weight, and most preferably 0.5% by weight, based on the inorganic pigment.
  • the resulting pigments with antimicrobial activity can be separated using any method known for a person skilled in the art.
  • the product is filtrated or filtrated with suction and washed with water.
  • the silver treated pigments can be further washed with organic solvents, such as acetone, to remove residual water.
  • the pigments can be dried.
  • the antimicrobial pigments are dried in an oven, most preferably at a temperature below 50 0 C, or by using a vacuum pump or a continuous flash evaporator, most preferably by evaporation of the solvents in vacuum.
  • the inorganic pigments are further coated with a protective coating layer. Usable materials for the protective coating layer are mentioned above.
  • any method known for a person skilled in the art can be used to coat the pigments with the protective coating layer, preferably the coating is performed wet-chemically.
  • active silica is added to the agitated aqueous suspension heated to a temperature between 60 and 9O 0 C, while maintaining the pH of the suspension in the range of 6 to 11. The procedure is described in detail in U.S. Pat. No. 2,885,366, the teachings of which are incorporated herein by reference.
  • Active silica a low molecular weight form of silica, such as silicic acid or polysilicic acid, may be added to the suspension, or formed in situ as by the continuous reaction of an acid with an alkali silicate.
  • Potassium silicate is generally preferred since the potassium ion has little tendency to coagulate active silica.
  • the bulk commodity is also more stable, which is advantageous from the standpoint of shipping and storing.
  • the silica content of the coated composition is between 0.5 and 20 % by weight and most commonly it is between 1 and 5 % by weight.
  • the silica deposition it is desirable to maintain substantially uniform conditions in the reaction zone to minimize precipitation of free silica gel. This is preferably accomplished by maintaining good agitation and introducing the reactants in a manner that does not allow local over- concentration.
  • the pH is allowed to fall gradually to about 6 as the process is completed and the slurry is then cured to permit completion of the deposition of silica onto the surface of the antimicrobial pigments.
  • the curing step consists of holding the slurry at temperatures between 60 and 90 0 C, preferably between 75 and 90°C, for from about one-half to two hours, preferably about one hour, while maintaining the pH of the agitated slurry between 6 and 7.5.
  • the pigments may be coated with alumina. This is accomplished by the addition, to the agitated aqueous suspension of the antimicrobial particles heated to between 60 and 9O 0 C, of an alkali aluminate solution or other soluble aluminum salt, e.g., aluminate nitrate while maintaining the pH in the range 6 to 11 by the concurrent addition of acid or base, as required.
  • aluminate solution or other soluble aluminum salt e.g., aluminate nitrate
  • Sodium aluminate is preferred, because it is commercially available as a solution, such as Vining's Solution. It is desirable to increase the density of the amorphous alumina phase in the coating by the addition of polyvalent anions selected from the group consisting of sulfate, phosphate and citrate.
  • the alumina content of the coated composition is between 0.5 and 20 % by weight and preferably between 1 and 6 % by weight.
  • the concentration of polyvalent anion in the suspension is about 0.5 % by weight based on the alumina used to coat the particles.
  • the product is then recovered as a dry powder, consisting of antimicrobial pigments coated with silica, alumina or silica/alumina, by filtration or centrifugation combined with aqueous washing to remove soluble salts.
  • a vacuum rotary-type filter is particularly suitable since washing can be carried out without removing the product from the filter.
  • the thus obtained pigments can be introduced in catheters. To accomplish this, any method known to a person skilled in the art can be used.
  • a process for the preparation of catheters according to the present invention comprises the steps a) agitating a suspension comprising one or more inorganic pigments and silver acetate and b) mixing the pigment a) with further base materials suitable for catheters.
  • the amount of the so treated inorganic pigment and therefore of the antimicrobial pigment in the catheters is in the range between 0.001 and 60% by weight, preferably between 0.01 and 50% by weight and most preferably between 5 and 40% by weight, based on the catheters.
  • the antimicrobial pigments may be incorporated into the molten polymer by known extrusion methods.
  • the molten polymer may comprise further additives for processing or the additives may be introduced together with the antimicrobial pigment. Suitable additives are known to the person skilled in the art and can be selected in accordance to the desired application.
  • the resin pellets can be compounded with the antimicrobial pigment using a twin screw compounder; the starting ingredients can be pelletized together using a twin screw machine; and the resin pellets can be compounded with the antimicrobial pigment using an extruder/compounder machine.
  • Compounding the antimicrobial pigment and extruding in a single process step is preferred, because the resulting material will have a higher durometer.
  • the resin pellets, antimicrobial pigment and other ingredients can also be fed into the compounder at a suitable rate.
  • the ingredients are melted, blended and then extruded into strands.
  • the strands may be pelletized and dried prior to further processing.
  • the homogeneous pellets of polymer and antimicrobial pigment, prepared as described above, may be remelted and molded or extruded into the desired shape of the catheter.
  • Catheters according to the present invention may additionally comprise antiseptics and/or disinfectants.
  • antiseptics and/or disinfectants examples include hexachlorophene, cationic bisguanides, for example chlorhexidine, cyclohexidine, iodine and iodophores, for example povidoneiodine, para-chloro-meta-xylenol, triclosan, furan medical preparations, for example nitrofurantoin or nitrofurazone, methenamine, aldehydes, such as for example glutaraldehyde or formaldehyde and/or alcohols.
  • catheters according to the present invention may additionally comprise antibiotics.
  • Antibiotics in this sense mean all known antibiotics, for example selected from the group of Beta-lactam, Vancomycin, Macrolides, Tetracyclines, Quinolones, Fluoroquinolones, Nitrated compounds (as for instance Nitroxoline, Tilboquinol or Nitrofurantoin), Aminoglycosides, Phenicols, Lincosamids, Synergistins, Fosfomycin, Fusidic acid, oxazolidinones, Rifamycins, Polymixynes, Gramicidins, Tyrocydine, Glycopeptides, Sulfonamides or Trimethoprims.
  • Formulation comprising combinations of antimicrobial pigments and antibiotics are advantageous with respect to the resistance of several microorganisms against certain antibiotics.
  • a combination of antibiotics with antimicrobial pigments according to the present invention helps to overcome the resistance by simply decreasing the number of microorganisms that have not been affected by the antibiotics.
  • Catheters according to the present invention may additionally comprise anti-inflammatory agents.
  • Anti-inflammatory agents include steroidal and non-steroidal anti- inflammatory agents.
  • non-steroidal anti- inflammatory drugs include aminoarylcarboxylic acid derivatives such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefanamic acid, niflumic acid, talniflumate, terofenamate and tolfenamic acid; arylacetic acid derivatives such as acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, iso
  • steroidal anti-inflammatory agents include 21-acetoxyprefienolone, aalclometasone, algestone, amicinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumehtasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednidene
  • Catheters according to the present invention may additionally comprise analgesic agents.
  • Analgesic agents include narcotic, non-narcotic analgesics and local anesthetic agents.
  • Narcotic analgesic agents include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmeth
  • Non-narcotic analgesics include aceclofenac, acetaminophen, acetaminosalol, acetanilide, acetylsalicylsalicylic acid, alclofenac, alminoprofen, aloxiprin, aluminum bis(acetylsalicylate), aminochlorthenoxazin, 2-amino-4-picoline, aminopropylon, aminopyrine, ammonium salicylate, amtolmetin guacil, antipyrine, antipyrine salicylate, antrafenine, apazone, aspirin, benorylate, benoxaprofen, benzpiperylon, benzydamine, bermoprofen, brofenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bucetin, bufexamac, bumadizon, butacetin, calcium acetylsalicylate, carbamazepine, carbi
  • Local anesthetic agents include amucaine, amolanone, amylocaine hydrochloride, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butaben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine hydrochloride, cocaethylene, cocaine, cyclomethycaine, dibucaine hydrochloride, dimethisoquin, dimethocaine, diperadon hydrochloride, dyclonine, ecgonidine, ecgonine, ethyl chloride, beta-eucaine, euprocin, fenalcomine, fomocaine, hexylcaine hydrochloride, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabut
  • Catheters according to the present invention may additionally comprise antispasmodic agents.
  • Antispasmodic agents include alibendol, ambucetamide, aminopromazine, apoatropine, bevonium methyl sulfate, bietamiverine, butaverine, butropium bromide, n-butylscopolammonium bromide, caroverine, cimetropium bromide, cinnamedrine, clebopride, coniine hydrobromide, coniine hydrochloride, cyclonium iodide, difemerine, diisopromine, dioxaphetyl butyrate, diponium bromide, drofenine, emepronium bromide, ethaverine, feclemine, fenalamide, fenoverine, fenpiprane, fenpiverinium bromide, fentonium bromide, flavo
  • catheters according to the present invention can be used for the inhibition of the growth and progeny of microorganisms.
  • Microorganisms in the latter sense are for example bacteria (Eubacteria and Archae), yeasts and/or fungi.
  • microorganisms described herein are microorganisms selected for example from the family of Enterobacteriaceae like for instance Enterobacter and more especially Enterobacter cloaceae, Klebsiella and more especially Klebsiella pneumoniae , Escherichia CoIi, Serratia and more especially Serratia marcescens, Proteus and more especially Proteus mirabilis; but also Pseudomonas and especially Pseudomonas aeruginosa,
  • a method for reducing the level of micro-organisms in a zone of biological fluid in proximity to a surface of a catheter comprising incorporating pigments obtainable by agitating a suspension comprising one or more inorganic pigments and silver acetate into the catheter or depositing them on top of the catheter, and bringing the catheter into contact with said biological fluid, is also inside the scope of the present invention.
  • the antimicrobial activity of the pigments in catheters according to the present invention can be shown by tests known for a person skilled in the art, for example similar to those described by N. Gatter et al. in Zent.bl. Bakteriol. 1998, 287, 157-169 or by Steven K. Schmitt et al. in J. Clin. Microbiol., 1996, 508-511.
  • Biron ® pigments (BiOCI, Merck KGaA, Darmstadt) are homogenized with 0.5 g silver oxide. 42 ml of deionized water is added to the mixture and stirred for 16 hours at 37-40 0 C. The suspension is filtered off and washed several times with deionized water, then with acetone. The product is dried at 40 0 C under reduced pressure.
  • a mixture of 25 wt % ([Biron/ (0,5% Ag 2 O)] powder, 70 wt % High Density Poly Ethylene and 5 wt % hydrocarbon wax Licowax PE 520 is gently mixed and introduced into a single screw extruder via a hopper and is then extruded through a cylindrical die. The material is finally cooled and cut into pellets.
  • a standard procedure (given by the European Pharmacopeia 5th Edition) to measure the anti-microbial activity of substances is used.
  • a suspension of test organisms (10 5 to 10 6 germs/ml) is inoculated into a recipient containing already the substance to be tested.
  • Sterile water containing 50% w/w of treated and untreated pellets is each investigated.
  • a single-layer matrix polymer structure is formed from a mixture containing 80 wt % of Elvax® 460, an ethylene vinyl acetate copolymer having a 18 wt % vinyl acetate content available from DuPont, and 20 wt % of BiOCI according to example A as a radio- opacifying agent,
  • the BiOCI and EVA copolymer are precompounded at 177°C, for example, in a Haake twin screw extruder.
  • the resulting mixture is then compounded at 102 0 C using a Haake twin screw extruder at a reduced shear rate ( ⁇ 30% of full screw power).

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Abstract

L'invention concerne des cathéters comprenant des pigments pouvant être obtenus par agitation d'une suspension qui renferme un ou plusieurs pigment(s) inorganiques et un acétate d'argent afin de limiter les effets secondaires provoqués par des micro-organismes.
PCT/EP2006/006443 2005-07-28 2006-07-03 Catheters antimicrobiens WO2007017019A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8921365B2 (en) 2007-07-23 2014-12-30 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9629946B2 (en) 2010-09-17 2017-04-25 Nanexa Ab Polymeric protective layer
EP3603729A4 (fr) * 2017-03-30 2020-12-16 Terumo Kabushiki Kaisha Instrument médical
EP4062868A3 (fr) * 2015-03-30 2022-12-21 C. R. Bard, Inc. Application d'agents antimicrobiens sur des dispositifs médicaux

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989001793A1 (fr) * 1987-08-29 1989-03-09 Giltech Limited Appareil destine a une utilisation antimicrobienne
US5413788A (en) * 1986-07-03 1995-05-09 Johnson Matthey Public Limited Company Antimicrobial compositions
US20030044451A1 (en) * 2001-08-15 2003-03-06 Mcghee Diane Coating for use with medical devices and method of making same
WO2003047636A2 (fr) * 2001-12-03 2003-06-12 C.R. Bard, Inc. Dispositif medical resistant aux microbes, revetement resistant aux microbes et procedes permettant de les produire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5413788A (en) * 1986-07-03 1995-05-09 Johnson Matthey Public Limited Company Antimicrobial compositions
WO1989001793A1 (fr) * 1987-08-29 1989-03-09 Giltech Limited Appareil destine a une utilisation antimicrobienne
US20030044451A1 (en) * 2001-08-15 2003-03-06 Mcghee Diane Coating for use with medical devices and method of making same
WO2003047636A2 (fr) * 2001-12-03 2003-06-12 C.R. Bard, Inc. Dispositif medical resistant aux microbes, revetement resistant aux microbes et procedes permettant de les produire

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8921365B2 (en) 2007-07-23 2014-12-30 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9968710B2 (en) 2007-07-23 2018-05-15 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9629946B2 (en) 2010-09-17 2017-04-25 Nanexa Ab Polymeric protective layer
EP4062868A3 (fr) * 2015-03-30 2022-12-21 C. R. Bard, Inc. Application d'agents antimicrobiens sur des dispositifs médicaux
EP3603729A4 (fr) * 2017-03-30 2020-12-16 Terumo Kabushiki Kaisha Instrument médical

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