WO2013104916A2 - Dispositifs médicaux, revêtements et composés - Google Patents

Dispositifs médicaux, revêtements et composés Download PDF

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WO2013104916A2
WO2013104916A2 PCT/GB2013/050052 GB2013050052W WO2013104916A2 WO 2013104916 A2 WO2013104916 A2 WO 2013104916A2 GB 2013050052 W GB2013050052 W GB 2013050052W WO 2013104916 A2 WO2013104916 A2 WO 2013104916A2
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groups
alkyl
implantable medical
medical device
group
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PCT/GB2013/050052
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WO2013104916A3 (fr
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Iain John BARLOW
Nicholas Hendrik WILLIAMS
Charles James Matthew Stirling
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Camstent Limited
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Publication of WO2013104916A3 publication Critical patent/WO2013104916A3/fr

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    • 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
    • A61L29/08—Materials for coatings
    • 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
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/14—Post-treatment to improve physical properties
    • A61L17/145—Coating
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular 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
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Definitions

  • the present invention relates to implantable medical devices, such as catheters, which comprise a calixarene-derived coating that resists adhesion and/or colonisation of bacteria, to calixarene-derived coating materials, intermediates useful in their manufacture, and to processes for their preparation and coating of said devices, Background of the Invention
  • implantable medical devices are prevalent in the healthcare sector, such devices being either totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which are intended to remain after the procedure.
  • implanted devices Associated with the use of implanted devices is the problem of biofilm build up resulting in irritation, inflammation and infection.
  • Biofilms are thin layers of microorganisms, usually protozoa and bacteria, which aggregate on the surfaces of implanted devices causing the problems described.
  • Catheters are one of the most commonly utilised implantable medical devices and it is estimated that 25% of all hospital admissions use urinary catheterization to assist with bladder drainage.
  • CAUTI Catheter Acquired Urinary Tract Infections
  • Patent Application WO 97/39077 refers to a method for imparting a water repellent surface to a hydrophilic substrate using caiixarene-derived compounds.
  • United States Patent Application US 2002/0102405 refers to surfaces comprising self-assembied monolayers that resist the adsorption of biological species.
  • international Patent Application WO 2004/018402 refers to methods for changing the surface properties of a material with an oligomer or polymer comprising open-chain aldehyde-phenol condensates
  • United States Patent Application US 2005/0221072 refers to medical devices having nanofibre enhanced surfaces for the prevention of biofou!ing.
  • International Patent Application WO 02/083176 refers to vehicles for use in tissue engineering and surgical procedures comprising a melanocyte stimulating hormone, which may be associated with the vehicle by coupling with polyethylene glycol linkers or via a calixarene treated surface.
  • International Patent Application WO 2006/048649 refers to a plasma system and methods for treating substrates, including providing substrates with siloxane-based coatings using coating-forming compositions comprising silicon-containing materials.
  • Krishna et a!, Biomateria!s, 2005, 26(34), 71 15-7123 refers to a plasma polymerisation method for covalently grafting phospholipid monolayers on a silicone catheter surface for reduction in platelet aggregation.
  • Schilp et a! Langmuir, 20Q9, 25(17), 10077- 10082, relates to a study of the settlement and adhesion of algal cells to self-assembied monolayers of oligo(ethylene glycol) and poiy ⁇ ethylene glycol) on gold surfaces.
  • Herrwertb et al J. Am. Chern. Soc, 2003, 125, 9359-9366, relates to a study of the protein resistance of oligoether self-assembled monolayers on gold and silver surfaces.
  • Ferguson et al refers to a plasma oxidative process for preparing self-assembled monolayers on disordered, polymeric substrates.
  • Roth et al Langmuir, 2008, 24, 12603- 1261 1 , refers to a plasma oxidative process for preparing polydimethyisiloxane layers on silicon wafers. Rebek et al; Chem.
  • PEG hydrogel coating of medical devices refers to the coating of urinary catheters with polyethylene glycol based hydrogels in order to limit infections.
  • Non-pharmacologic avoiding drug-drug / drug-patient interactions, eliminating the need for delivery systems, dosing, and drug testing, and does not stimulate the emergence of resistant organisms.
  • the present invention accordingly provides an implantable medical device having a coating comprising a calixarene bonded to the surface of the device via one or more surface-linker groups on one rim of the calixarene,
  • the opposing rim of the calixarene is substituted by one or more polyethylene glycol, polypropylene glycol or polytrimethylene glycol groups, or a mixture thereof, said surface-linker groups may be bonded to the surface of the device via covalent bonds, ionic bonds, hydrogen bonds, or Van der Waals forces,
  • glycol groups are attached to the calixarene via (C 3 to Ci 6 )aikyiene spacer groups, said glycol groups, each independently, have from 2 to 250 repeating glycol units and may be optionally terminated by hydrogen or (C 1 to C 4 )a!kyl,
  • said (C 3 to C 16 )alkyl spacer groups may be optionally substituted by one or more fiuoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.
  • the calixarene is bonded to the surface of the device via 2 to 8 surface-linker groups as described herein below. More preferably, the calixarene is bonded to the surface of the device via 2 to 8 surface-Sinker groups. Most preferably, the calixarene is bonded to the surface of the device via 2 or 4 surface-linker groups.
  • the bonding may be via covalent bonds, ionic hydrogen-bonds, or Van der Waals bonds.
  • said surface-linker groups are bonded to the surface of the device via covalent bonds.
  • the surface-linker groups on the calixarene compounds of the invention may be selected from any of the surface linker groups defined elsewhere herein.
  • the surface linker group is selected for covalent or ionic surface attachment: such linker groups may be selected from those that comprise acid chioride, ch!oroformate or silane functional groups; or ammonium, suifonium, phosphonium, or phosphate functional groups.
  • the surface linker group is selected for hydrogen-bonding attachment to a surface; such as linker groups comprising a group selected from hydroxy!, (a!ky!, a!kenyl or alkyny!hydroxyl, (aikyl, aikenyl or alkynyl)carboxy!
  • the surface linker group is selected for Van der Waals attachment to a surface: such linker groups may be selected from those that comprise long-chain alkyi, alkenyl, alkynyl, or ester, ether or amides thereof.
  • the calixarene is covalently bonded to the surface of a device made from siiicone or having a silicone coating thereon, via 2 to 8, preferably 2 to 6, most preferably, 2 or 4 surface linker groups,
  • the implantable medical device comprises a calixarene having a rim substituted by one or more polyethylene glycol groups.
  • the glycol groups of the invention may be attached to the alkylene spacer group directly via the oxygen of the glycol or via another viable linker group.
  • Sinker groups include, for example, carbonate, glycol ether, giycolateether, carbamate, urea, ⁇ , ⁇ -amino ether, a-hydroxyacetamide ether, amide, imide, thioether, phosphate, phosphonate, sulphate, sulphonate and triazole.
  • the coating When the medical device is implanted into a patient, the coating will preferably resist adhesion and/or colonisation of bacteria onto the surface of the device.
  • Preferred embodiments of the device may provide a coating that, either as an alternative to, or in addition to resisting adhesion and/or colonisation of bacteria, has an antimicrobial effect. Said antimicrobial effect will ideally be exhibited at a surface concentration that also provides a safe pharmacological profile.
  • the present invention encompasses any implantable medical device and, in particular, covers a medical device, which is a stent, catheter, vascular graft, cardiac pacer lead, heart diaphragm, suture, needle, angioplasty device, artificial joint, heart valve, neurological stimulator, drug pump or surgical mesh implant as reinforcement or scaffolding.
  • Medical devices having a surface, in whole or in part, which comprise silicone or a layer of silicone are preferred. Other preferred surfaces are metals (such as stainless steel and/or titanium). Catheters are the most preferred medical device to which the invention is directed. 8
  • Catheters may be made of any suitable material including, for example, silicone, latex, polyurethane, such as polycarbonate or poiyether based materials, polyamides, such as nylon 1 1 and nylon 12, fluoropolymers, such as polytetrafluoroethyiene, polyolefins, such as polyethylene, PVC, polyimides, or poiyether etherketone. Most preferred are catheters made from silicone or having a silicone coating thereon.
  • the invention also encompasses caiixarene compounds for coating to a surface of a medical device; e.g. compounds of Formula (I) and/or Formula (II) as described herein below and preferred embodiments thereof.
  • the invention encompasses intermediates of the caiixarene compounds of the invention; e.g. compounds of Formula (ill) as described herein below and preferred embodiments thereof.
  • Methods of making the coated implantable medical devices of the invention, uses for / method of using the coated implantable medical devices of the invention; and methods for the synthesis of the caiixarene compounds of the invention are also encompassed within the scope of the invention. It will be appreciated that, unless otherwise stated, preferred features of one aspect of the invention may be incorporated into any other aspect of the invention and that such combinations fall within the scope of the invention.
  • Calixarenes are macrocyc!ic molecules based on the condensation product of a phenol and an aldehyde and whose general structure is that of a molecular bowl on legs with the rim of the bowl lined by hydroxy! groups and the legs consisting of long-chain aikyl groups.
  • Bohmer Angew. Chem, Int. Ed. Engl. 1995, 34, 713-745.
  • the surface properties of the calixarenes may be suitably modified to impart the desired properties by altering the substituents on either the rim or the legs.
  • caiixarene there are three main types of caiixarene that fall within the scope of the present invention, which are derived from phenols, resorcinols or pyrogailols, or mixtures thereof. Depending on the caiixarene used in accordance with the invention, it may suitably be prepared respectively from phenols, from resorcinois (resorcinarene) and from pyrogaliols by condensation with aidehydes.
  • the present invention is applicable to all these types of caiixarenes, and encompasses devices having a coating derived from any one of them. Preferably, the invention covers a device wherein the caiixarene is a resorcinarene.
  • the present invention provides an impiantable medical device having a coating comprising a caiixarene bonded to the surface of the device via one or more surface-linker groups on one rim of the caiixarene wherein said caiixarene is derived from a compound of formula (I)
  • X is H, (d-CJalkyl, NH 2 , NH(C C 4 )aikyi, N(d-d)alkyl 2 or CH 2 NH(d-d)alkyl, and Y is OH, 0(d-d)alkyl or OCH 2 C0 2 (d-d)alkyl; or
  • X is OH, 0(d-d)alkyl or OCH 2 C0 2 (d-d)alkyl
  • Y is H, (d-d)aiky!, NH 2 , NH(d- d)alkyl, N(d-d)alkyl 2 or CH 2 NH(d-d)alkyl; or
  • X and Y are each independently OH, 0(d-d)alkyl or OCH 2 C0 2 (d-d)alkyl;
  • Z is H, OH or methyl
  • n 1 , 3 or 5;
  • R is ⁇ (C 3 ⁇ ds)aikylene ⁇ L 3 -G-R 1 wherein said alky!ene may be optionally substituted by one or more fiuoro, methyl or ethyl groups and may optionaiiy contain one or more unsaturated bonds;
  • L 3 is a bond or a Sinking group;
  • G is -0(CH 2 CH 2 0) m - « -0(CH 2 CH(CH 3 )0) m -, ⁇ G(CH(CH 3 )CH 2 Q) rrr , or -0(CH 2 CH 2 CH 2 0) m -; m is 2 to 250;
  • R is H or (C C 4 )alkyl
  • each X, Y, Z, R and R 1 group may be the same or different.
  • At least one X is H and at least one Y is OH.
  • at least one X is OH and at least one Y is H.
  • at least one X is H and at least one X is OH
  • at least one Y is H and at least one Y is OH.
  • a plurality of X moieties are H, and a plurality of Y moieties are OH (or vice versa).
  • all Y moieties are OH, and H is selected from the options given herein; and in some more preferred embodiments ail X moieties are H and all Y moieties are OH.
  • both X and Y moieties may be OH
  • the calixarene of Formula (1) is bonded to the surface directly via a suitable interaction-bonding, e.g. hydrogen-bonding, Van der Waals, ionic and/or covalent attachment.
  • the calixarene is "derived from” the compound of Formula (!) simply by way of selecting a suitable X and/or Y moiety / moieties; e.g. using a hydroxyl group at an X or Y position.
  • a plurality of X and/or Y moieties are OH, which groups can hydrogen bond to a wide range of substrates.
  • the calixarene for adhering to the surface of the implantable medical device is modified by substituting one or more of the X and/or Y substituents with a 'surface linker group'.
  • the calixarene which is derived from a compound of formula (I) or preferred embodiments thereof, is bonded to the surface of the device via surface linker groups substituted for any one or more of the X or Y substituents, or a combination thereof.
  • one or more (e.g. 2, 3, 4, 8, 8 or more, such as ail) OH groups on the calixarene are modified to incorporate a specific suitable surface linker group.
  • the calixarene is bonded to the surface of the device via 2 to 8 surface-linker groups.
  • the surface inker groups at X or Y, or a combination thereof, on the calixarene are derived from one or more of the surface linker groups described herein.
  • Z is H and/or suitably n is 1
  • R is -(Cio)alkyiene-L 3 -G-R 1 ; wherein more preferably, L 3 is a linking group selected from those of Scheme A and Scheme B above. Still more preferably, L 3 is a linking group selected from carbonate, carbamate, urea, phosphate and triazole, and most preferably, L 3 is carbonate.
  • G is -G(CH 2 CH 2 Q) m ⁇ , and/or m is 3 to 150, and/or R 1 is H or methyl. More preferably, m is 8 to 50, and most preferably, m is 15 to 25.
  • the calixarene compounds and derivatives useful as coatings for implantable medical devices in accordance with the invention are suitab y able to resist biofilm formation thereon. Without being bound by any particular theory, it is believed that this biofilm resistive coating is achieved via modification of one rim of the calixarene compounds with one or more glycol-comprising substituent. Such compounds have been shown to successfully inhibit bacterial biofilm formation, as described in the Examples.
  • the claimed compounds thus provide a structural scaffold that on one rim possessing the substitution pattern required to achieve the functional (e.g. anti-microbial) benefits of the coatings, i.e. to resist adhesion and/or colonisation of bacteria and/or fungus; and on the opposing rim possess suitable substituents for use as surface attachments / surface linker groups.
  • the implantable medical device comprises a calixarene having a rim substituted by one or more polyethylene glycol groups.
  • glycol groups of the invention may be attached to the alkylene spacer group directly via the oxygen of the glycol or via another viable linker group.
  • suitable linker groups include, for example, carbonate, glycol ether, glycolateether, carbamate, urea, ⁇ , ⁇ -amino ether, a-hydroxyacetamide ether, amide, imide, thioether, phosphate, phosphonate, sulphate, sulphonate and triazole.
  • Suitable glycol linker groups include, for example, the following groups of Scheme A and Scheme B, which can be prepared using the methods shown. O-Unkers ⁇ ⁇ C 3 - C , 6 Ca I ixa re m
  • R is an appropriate aryi, aiky!, or PEG group
  • the glycol groups are linked directly via the oxygen of the glycol, or may be attached via another linker group selected from carbonate, carbamate, urea, phosphate and triazo!e. Most preferably, when an intermediate linker group is used the glycol groups are attached to the alkylene spacer group via an intermediate carbonate linker.
  • the 'surface linker groups' when used in accordance with the invention provide the function of attaching / bonding / linking / associating the calixarene compounds to a desired surface of a medical device.
  • the function can be achieved by a broad range of chemical groups, which may be selected according to the type and/or strength of interaction desired between the compound and the surface; and/or according to the surface material.
  • Calixarene compounds and derivatives, such as those of the invention can be attached to a desired surface of a medical device using any appropriate approach within the skill of a person in the art, and all such mechanisms for surface attachment and the respective surface linker groups are considered to be encompassed within the scope of the invention.
  • calsxarene compounds can be attached to a surface through covalent or non-covalent interactions.
  • Non-covalent interactions useful in accordance with the invention are ionic bonds, hydrogen bonds, or Van der Waals forces. Accordingly, there are four subsets of interaction that may be exploited for the attachment of the calixarene (preferably resorcinarene) coating to the target substrates, ionic, covalent, hydrogen- bonding and Van der Waals forces.
  • calixarene derivatives of the invention may be hydrophiiic.
  • Calixarene compounds are known to readily attach to hydrophi!ic surfaces simply by bringing them into contact with the surface.
  • WO 97/39077 and http://www.rsc.org/pdf/mcg/shefcotes.pdf provide teaching on how to coat various different surfaces with the calixarene derivatives of the invention, and such teachings are incorporated herein by reference.
  • calixarene compounds may be attached to hydrophiiic surfaces simply by applying the compounds (e.g. in a solvent or other solution) to the surface.
  • ca!ixarene compounds can be applied to a surface using a 'dip- and-dry' technique relying on relatively weak electrostatic interactions, for example, as described in Charnley et a/. (2009), which is also incorporated herein by reference. Although these interactions are relatively 'weak', they can be sufficiently strong to impart the required properties to the coated surfaces.
  • Covalent surface attachment is desirable for some aspects of the invention because the interaction is extremely strong and suitably lasts for the lifetime of the medical device.
  • Suitable linkers for covalent attachment to a surface include chloroformaie groups, acid chloride groups and/or silane groups.
  • the chioroformate and acid chloride chemistries are closely related, and are particularly suitable for use in conjunction with medical devices having functionally-modified surfaces, e.g. plasma-modified polymers in which surface-exposed carbon chains have been oxidised to form alcohols.
  • Exemplary chioroformate and acid chloride surface linkers attached to the phenyl group of a caiixarene compound of the invention are shown below.
  • Acid chloride and ch!oroformate-containing linker groups are also applicable for polymer surfaces where the side-chains contain nucleophiiic groups, e.g. polyiysine.
  • the synthesis of such linker groups attached to caiixarene compounds can be achieved using any appropriate reaction scheme, such as those exemplified for attaching linker groups of ionic and hydrogen-bonding interactions below.
  • chloroformate-containing linkers may typically be prepared via the reaction of the caiixarene phenols with phosgene solution; and acid chloride-containing linkers may typically be prepared via the reaction of the parent acid with thsonyl or oxalyl chloride.
  • the surface linker group for covIER attachment to a surface of a medical device contains a silane functional group.
  • silane function groups are especially suitable for bonding to a silicone surface of a medical device, with which they form one or more siloxane bonds.
  • they may also be used for covended attachment to other surfaces, such as metal oxides, stainless steel, and glass.
  • Suitable exemplary siiane-containing surface linker groups include trialkoxy and trichloro siianes (as shown below), which are appropriate for attachment to glass, oxidised polymers, such as silicone, metal oxides and stainless steel.
  • Such linker groups may be introduced to the caiixarene compounds via the formation of cyclic Mannsch-type structures as depicted in Scheme C below; or by formatson of resorcsnarene esters and amides as shown Scheme D below.
  • the siiane-containing surface linker groups to be substituted at one or more of X and/or Y may, in accordance with the invention, be defined by the formula L 4 -Si(R 2 ) 3 ; or X and an adjacent Y group together form
  • L 4 is a spacer group
  • R 3 is (C 2 -C 1 o)aikyiene-S! ⁇ R 2 ) 3) wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds;
  • Si(R 2 ) 3 is selected from SiCI 3 , Si[(Ci-C 4 )alkyl] 2 CI and Si[(C r C4)aiky!]Ci 2 ; and wherein
  • each alkyl and each surface linker group may be the same or different
  • L 4 is selected from 0(C 2 -Cio)alkylene, CH Z NH(C 2 -C 0 )alkylene, OCH 2 CO 2 (C 2 -C 10 )aiky ene and OCH 2 CONH(C 2 -C 10 )alkylene; wherein said alkylene may be optionally substituted by one or more fluoro, methyl Di ⁇ ethyl groups and may optionally contain one or more unsaturated bonds.
  • Ionic surfaces may be positively charged or negatively charged, and so for ionic attachment the linker group has the opposite charge.
  • a substrate e.g. of medical devices, may naturally have a surface carrying an overall negative charge.
  • substrates include glass, polymers - particularly functionally modified polymers (preferred being plasma-modified polymers), and metals, particularly those comprising native oxide (metal oxide) layers on the surface, such as stainless steel and/or titanium.
  • the calixarene compounds are desirable modified to include one or more positively charged surface linkers.
  • Suitable positively charged linker groups include ammonium and suifonium groups, such as trialkyiammoniurn and dialkylsulfonium salts as defined below.
  • Suitable linkers for ionic attachment to a surface have the general formula L 1 -X or L 2 -X, where X carries an opposite charge to that of the target surface. More suitably X carries a positive charge, such as ammonium and suifonium.
  • Preferred linker groups are those wherein X comprises alkylammonium and aiky!sulfonium salts.
  • L and L 2 are any suitable spacer group, such as alkyl, alkeny! and alkynyl (e.g.
  • L 1 and L 2 may be branched chain or linear, and are preferabiy linear; and may be saturated or unsaturated, and are preferably saturated.
  • Exemplary L 1 and L 2 spacers include CH 2 C0 2 , CH 2 CONH, C0 2 and C(0)NH, Preferred X moieties are N + (A!ky! 3 or S + (AIkyl) 2 , wherein alkyl is defined as above, or is suitable d-Ce alkyl and preferably methyl; although X moieties having one or more alkenyl and/or alkynyl group are also encompassed.
  • the alkyl, alkenyl or alkynyl may be optionally substituted by one or more (e.g. 1 , 2 or 3) of fluoro, methyl or ethyl groups.
  • Scheme C Potential reaction schemes for the synthesis of trialkylammoniurn and dia!kylsuifonium compounds.
  • L ⁇ L 2 as defined above e.g. suitably selected from CH 2 C0 2 , CHaCONH, C0 2 and C(0)NH;
  • X as defined above, e.g. selected from N + ⁇ aikyi) 3 or S + (alkyl) 2 ;
  • Q O, NH;
  • Y is any appropriate leaving group, such as OS0 2 Ar or halide.
  • the ionic surface linker group may have the formula L 1 -X, where X comprises a phosphonic acid or phosphate group, and L 1 is as defined above.
  • X may suitably be -PO(OR p ) 2 or -OPO(OR p ) 2 ; wherein R p is suitably hydrogen, or an alkyl, aikenyl or alkyny!
  • X is -PQ(OH) 2 or -OPO(OH) 2 .
  • phosphonic acid and phosphate-containing linkers may be achieved in a manner analogous to the trialkylammonium and diaikyilsulfonium salts in Scheme C above, and/or as illustrated in Scheme D below.
  • Scheme D synthetic scheme for synthesis of caSixarene compounds comprising phosphonic acid linker groups.
  • phosphate-comprising linkers it will be appreciated that the P ⁇ C bond / group of the phosphonic acid will be replaced with P-G-C group.
  • Hydrogen-bonds may be used to attach / associate a calixarene compound to an appropriate surface.
  • Suitable caiixarene compounds may be of Formulas (I) and (1). Such a system is applicable to a wide number of substrates, including silicones, plastics, metals, glass and paper (Rebek et a/, and others).
  • a most suitable example of hydrogen bond donors used for attachment of a caiixarene compound of the invention (e.g. a resorcinarene) to an appropriate surface is where at least one X and/or Y group of Formula (I) or (II) is hydroxy!.
  • the parent phenolic OH group(s) are used.
  • linker groups comprise a carboxylafe and/or amide moiety.
  • Such linker groups may be made using any appropriate method - for example, by a!kySation of a phenol group with an ⁇ -ha!o ester, and subsequent acidic hydrolysis of the resultant (resorcinarene) ester, in a manner well known to the person of skill in the art.
  • amide linker group coupling with an aikyl amine is readily achieved using reaction Scheme E, below.
  • Scheme E Exemplary reaction scheme for attachment of carboxyl and amido hydrogen- bond donors; where X is any appropriate leaving group, e.g. halide.
  • Hydrophobic interactions may be used to connect a caiixarene compound to a surface of a medical device in accordance with the invention.
  • Hydrophobic / Van der Waais forces are generally the weakest of the four attachment systems described herein, but may be applicable for some applications - particularly if it is desired that the coating of the substrate be temporary or reversible. Without being bound by any particular theory, in this attachment system it is thought that the 'tails' of the surface linker are required to penetrate the substrate to maximize the Van der Waals interactions. Such interactions may be applicable in cases where the surface comprises a hydrophobic polymer, such as polyethylene or polystyrene.
  • the surface linker group comprises a long alkyl, fiuoroalkyi ester, ether or amide, and aikenyi or alkynyl variants, which may be straight chain or branched.
  • Suitable long' alkyl groups may contain at least 18 carbon atoms, e.g. C 18 -C 10 o, C 6 -C 60> C 16 -C 0 or C 16 -C 30 .
  • the linker may contain 16 to 22 carbon atoms (C ie -C 2 2) .
  • surface linker groups for Van der Waals interactions may be attached to calixarene compounds of the invention using the method exemplified in Scheme E above, wherein the aikyl is a long alkyl, aikenyi or aikynyi as described above.
  • the deposition of the calixarene compound onto a viable surface would be primarily via Langmuir-Biodgett or Langmuir- Schaeffer deposition, although the use of inert matrices of long chain surfactants as a co-deposition is an alternative, as will be understood by the person of skill in the art.
  • the present invention provides a compound of formula (I)
  • X is H, (C r C 4 )alkyi, NH 2 , NH(d-C )alkyl, NfCi-Oalkyfe or GH 2 NH ⁇ C r C4)aikyi, and Y is OH, 0(Ci-C 4 )alkyl or OCH 2 C0 2 (C -C 4 )alkyl; or
  • X is OH, ⁇ (C C alky! or OCH 2 C0 2 (C C 4 )a!kyS, and Y is H, (C C 4 )alkyl, NH 2 .
  • X and Y are each independently OH, 0(C C 4 )alkyl or OCH 2 C0 2 (CrC 4 )a!kyS;
  • Z is H, OH or methyl
  • n 1 , 3 or 5;
  • R is -iC 3 ⁇ C 16 )aikyiene ⁇ L 3 -G ⁇ R wherein said aikyiene may be optionally substituted by one or more f!uoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds;
  • L 3 is a bond or a linking group:
  • G is ⁇ (0 ⁇ 2 0 ⁇ 2 ⁇ ) ⁇ -, -0(CH 2 CH(CH 3 )0) m -, -0(CH(CH 3 )CH 2 0) m -, or -0(CH 2 CH 2 CH 2 0) m -; m is 2 to 250;
  • R 1 is H or (Ci-C )alkyl
  • each X, Y, Z, R and R 1 group may be the same or different;
  • X is H and Y is OH; Z is H; and/or n is 1.
  • R is -(C-;o)alkylene-L 3 -G-R ! .
  • L 3 is a linking group selected from those of Scheme A and Scheme B above. More preferably, L 3 is a linking group selected from carbonate, carbamate, urea, phosphate and triazoie. More preferably, L 3 is carbonate.
  • G is -Q(CH 2 CH 2 0),, r .
  • m is 3 to 150. More preferably, m is 6 to 50. Most preferably, m is 15 to 25.
  • R 1 is H or methyl
  • the present invention provides a compound of formula (H) wherein
  • X is H, (C C 4 )aikyl, NH 2) NH(C C 4 )alkyl, U(C -C )a ⁇ ky ⁇ 2 or CH 2 NH(Ci-C 4 )alkyl, and Y is OH, 0(C C 4 )a!kyl or 0CH 2 C0 2 ⁇ C C 4 )alkyl; or
  • X is OH, 0(Ci-C )alkyl or OCH 2 C0 2 ⁇ C C 4 )a!kyi
  • Y is H, (C C 4 )alkyl, NH 2i NH(C C 4 )aikyl, N(C r C 4 )aikyi 2 or CH 2 NH(C 1 -C )alkyl; or
  • X and Y are each independently OH, 0 ⁇ C C 4 )aikyi or OCH2C02(C C 4 )aik i; and any one or more X or Y groups, individually or in combinaiion, may be subsiiiuted for a surface linker group;
  • Z is H, OH or methyl
  • n 1 , 3 or 5:
  • R is -(C 3 -C 1g )a!ky!ene-L 3 -G- R ' wherein said a!ky!ene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds;
  • L 3 is a bond or a linking group
  • G is -0(CH 2 CH 2 0) m -, -0(CH 2 CH(CH 3 )0) m -, -Q(CH(CH 3 )CH 2 0) m -, or -0 ⁇ CH 2 CH 2 CH 2 Q) m -; rn is 2 to 250;
  • R 1 is H or (d-C 4 )alkyl
  • each X, Y, Z, R and R 1 group, and each surface-linker group may be the same or different.
  • the surface-linker groups substituted at X and/or Y, or a combination thereof, on the caiixarene are selected from any of the surface linker groups defined herein.
  • the surface linker group is selected for covalent or ionic surface attachment, e.g. the moiet at the X and/or Y positions comprises a groups selected from acid chloride, chioroformate or silane functional groups; or ammonium, sulfonium, phosphonium, or phosphate.
  • the surface linker group is selected for hydrogen-bonding attachment, e.g.
  • the moiety at the X and/or Y positions comprises a group selected from (alkyl, aikenyl or alkynyi)hydroxyl, (aikyi, alkenyl or a!kynyi)carboxy! and ⁇ alkyl, alkenyl or a!kynyl)amide; or long-chain alky!, alkeny!, alkynyl, or ester, ether or amides thereof.
  • the surface-iinker groups X or Y, or a combination thereof, on the caiixarene are silane functional groups, which may form one or more siloxane bonds with a device having a silicone surface.
  • the surface-linker groups X and/or Y are L -Si(R 2 ) 3 , or
  • L 4 is a spacer group
  • R 3 is (C2-C 10 )alkylene-Si(R 2 ) 3 , wherein said a!ky!ene may be optionally substituted by one or more fiuoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds;
  • Si(R 2 ) 3 is selected from Si[0(d-d)alkyl] 3l SiCI 3> Si[(d-d)alkyl] 2 CI and Si[(d-d)alkyl]CI 2 ;
  • each aikyi and each surface-iinker group may be the same or different.
  • L 4 is selected from O(C 2 -C 10 )aikyiene ! CH 2 NH(C 2 -C 1G )aikyiene, OCH 2 C0 2 (d-do)aiky!ene and OCH 2 CONH(C 2 -do)aIkyIene, wherein said a!kySene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.
  • X is H and Y is OH.
  • Z is H.
  • n is %
  • R is ⁇ C 10 )alkylene ⁇ L 3 -G ⁇ R 1 .
  • L 3 is a linking group selected from those of Scheme A and Scheme B above. More preferably, L 3 is a linking group selected from carbonate, carbamate, urea, phosphate and triazoie. More preferably, L 3 is carbonate.
  • G is -0 ⁇ CH 2 CH 2 0) m -.
  • m is 3 to 150. More preferably, m is 6 to 50. Most preferably, m is 15 to 25.
  • R 1 is H or methyl.
  • R is -(C 10 )alkylene-OC(O)O-(CH 2 CH 2 O) m -OH; and R 3 is (C 3 )alkylene-Si(OEt) 3 or a combination thereof.
  • m is 3 to 150. More preferably, m is 8 to 50. Most preferably, rn is 15 to 25.
  • the present invention provides a compound of formula (Ml)
  • X, Y, Z and n are as defined herein including all aspects and preferred embodiments thereof.
  • R is -(C 3 -C 16 )alky!ene-OH or wherein said alkylene may be optionally substituted by one or more fiuoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds;
  • each X, Y, Z and R group may be the same or different;
  • the present invention provides a process / method for coating a surface of an implantable medical device, as defined herein.
  • Any suitable implantable medical device may be coated (or partially coated) using calixarene compounds of the invention to prevent microorganism growth, as described elsewhere.
  • the medical device is a catheter, and more particularly, a urinary tract catheter.
  • the surface of the medical device may comprise a metal (e.g. metal oxide, stainless steel, titanium), polymer or glass.
  • Preferred substrates for attachment of calixarene compounds of the invention are functionally-modified polymers, e.g. plasma-modified polymers, and more suitably, comprising silicone surfaces.
  • the coated medical devices of the invention may suitably comprise a plasma-activated silicone surface; and the methods of the invention may suitably comprises plasma activation of a silicone surface of the device, followed by reaction with a compound of formula (H) as defined herein.
  • the present invention provides an implantable medical device preparabie by a coating process as defined herein.
  • Microorganisms The coatings of the invention desirably prevent the undesirable colonisation of surfaces of implantable medical devices with microorganisms, such as bacteria and fungi.
  • the microorganism is a gram-negative or gram-positive bacteria, and most suitably, is a gram-negative bacteria.
  • microorganisms associated with infections arising from implantable medical devices include: Escherichia co!i, or uropathogenic E.
  • UPEC bacterial coli
  • CAUTI CAUTI
  • Enterococcus faecaiis a gram positive bacterium, which is also a part of the gut flora and often associated with CAUTI. It is resistant to many commonly used antibiotics.
  • Proteus mirabilis a gram negative bacterium, that most likely comes from the patient's own gut. It is a less common cause of infection than E, coli. It is particularly desirable to prevent colonisation of implantable medical devices with P. mirabilis because in the urinary tract it can raise the pH of the urine, causing crystalline biofilms on catheters. These biofilms may not only block the catheters and prevent the draining of urine, they may also cause tissue damage when the catheter is removed from the patient.
  • Pseudomonas aeruginosa a gram negative bacterium, that usually comes from the environment or the skin, it is increasingly common in hospital environments, especially in intensive care units. It is often found in catheter biofilms and is well known for its ability to form biofilms on medical devices and for its high resistance to a range of different antibiotics. Klebsiella pneumonia, a gram negative bacterium found on the skin and in the intestines and is often associated with CAUTI.
  • the bacteria is a gram negative bacteria.
  • Other relevant gram positive species include Streptococci and Staphylococci, which may also sometimes be found in CAUTI. Indeed, materials for medical devices are often tested against Staphylococcus aureus (of which MRSA is a variant), and it is a 'standard' gram positive bacterium recommended for ISO 22198 tests.
  • Staphylococcus aureus of which MRSA is a variant
  • it is a 'standard' gram positive bacterium recommended for ISO 22198 tests.
  • Candida albicans may also be involved in infections associated with implantable medical devices, and the coatings of the invention also suitably prevent colonisation of such yeast or fungus.
  • the coatings of the invention may be suitable for targeting of both gram negative and gram positive bacteria, and also fungi if some relevant applications.
  • the compounds and devices of the present invention as described herein may be prepared according to the following methods. Formation of Protected Resorcinarene 'PEG acceptors'
  • Appropriate protection sequence- representative is di-tertbuty! dicarbonate with a nucleophilic catalyst (e.g. pyridine or 4-dimethy!aminopyridine) in a suitable solvent, such as dichloromethane.
  • a nucleophilic catalyst e.g. pyridine or 4-dimethy!aminopyridine
  • suitable solvent such as dichloromethane.
  • acetyl chloride e.g. trimethyiacetyl chloride with suitable base, e.g. triethyiamine, diisopropyiethylamine in suitable solvent, e.g. dichloromethane.
  • Suitable phosphine e.g. triphenyiphosphine, halide donor such as carbon tetrabromide in dichloromethane or similar, or a sulfonyl chloride, e.g. p-toluenesu!fony! chloride, base such as triethyiamine, pyridine, 4-dimethyiaminopyridine in suitable solvent, e.g. dichloromethane.
  • halide donor such as carbon tetrabromide in dichloromethane or similar
  • a sulfonyl chloride e.g. p-toluenesu!fony! chloride
  • base such as triethyiamine, pyridine, 4-dimethyiaminopyridine in suitable solvent, e.g. dichloromethane.
  • Azide donor such as sodium azide, trirnethylsiiyl azide in suitable solvent, e.g. tetrahydrofuran.
  • suitable phosphine e.g. triphenylphosphine in appropriate solvent, e.g. dichloromethane, or hydrogen and palladium on carbon in appropriate solvent, e.g. ethanol.
  • thiolacetic acid suitable radical initiator such as azo ⁇ bisisobutyryl)nitriie, heated to 80°C or irradiated with a UV lamp in toluene or similar solvent
  • suitable thioacetate salt such as potassium thioacetate in appropriate solvent, e.g. tetrahydrofuran.
  • Suitable base such as piperidine, pyrrolidine, ammonium hydroxide.
  • reductant such as lithium aluminium hydride in suitable solvent, e.g. tetrahydrofuran.
  • N-chlorosuccinirnide hydrochloric acid, appropriate solvent such as acetonitrile.
  • Suitable phosphine e.g. triphenyiphosphine, suitabie azodicarboxyiate eg. diethyiazodicarboxylate, triphenyirnethanethiol in suitable solvent such as dichloromethane or tetrahydrofuran.
  • triphenyimethanethiol suitable base, e.g. sodium hydride or potassium tertbutoxide in suitable solvent, e.g. tetrahydrofuran.
  • phosphorus oxychloride (3 equivalents) or similar P(V) compound in suitable solvent, e.g. dichloromethane, or phosphorus trichloride (3 equivalents) or similar then suitable oxidant, e.g. ⁇ 2 , and base such as pyridine in appropriate solvent, e.g. ace onitrile.
  • suitable phosphite eg. triethylphosphite heated at 130-160°C.
  • An alkylsiiyl halide such as trimethyisilylbromide in suitable solvent, e.g. dichloromethane, followed by methanol, xvi) Appropriate halide donor, such as thionyl chloride.
  • oxidant such as meta-chloroperbenzoic acid in suita solvent, e.g. dichloromethane.
  • PEG poly(ethylene glycol) repeat unit >3, terminus ⁇ OH
  • suitable PEG ⁇ eiectropbile e.g. PEG-chloroformate, PEG-isocyanate
  • appropriate amine base e.g. triethylamine in a suitable solvent, e.g. dichioromethane, tetrahydrofuran.
  • nucieophiie-terminaied PEG such as alcohol, amine or thiol- terminated PEG, appropriate base, e.g. sodium hydride or trlethylamine in a suitable solvent, e.g. ietrahydrofuran.
  • suitable maleimide-terminated PEG appropriate solvent, e.g. dschloromethane.
  • suitable ⁇ -haloamide-terminated PEG e.g. a-bromoacetarnidyi PEG
  • suitable solvent e.g. tetrahydrofuran.
  • appropriate olefin-terminated PEG e.g. Oaily! PEG
  • suitable solvent e.g. tetrahydrofuran.
  • appropriate PEG species e.g. methoxyPEG-350, suitable base, e.g. triethylamine, pyridine, 4-dimethy!aminopyridine, suitable solvent, e.g. dichloromethane.
  • suitable PEG e.g. methoxyPEG-350
  • suitable base e.g. triethylamine
  • appropriate solvent e.g. dichioromethane.
  • aldehyde-terminated PEG e.g. PEGOCH 2 CHO
  • suitable strong base e.g. potassium tertbutoxide
  • suitable solvent e.g. N,N-dimethyliormamide.
  • Suitable olefin metathesis catalyst e.g. Grubb's 2 nd generation catalyst
  • suitable solvent e.g. toluene
  • xxxi appropriate reduction, e.g. Lindlar's catalyst, hydrogen
  • suitable alcoholic solvent e.g. ethanol.
  • Mass spectra were obtained on a Waters LCT spectrometer for electrospray (ES) experiments, and a Bruker Reflex IN for matrix-assisted laser desorption ionisation (MALD! experiments.
  • infrared (!R) spectra were obtained on either a Perkin Elmer Paragon 1000 spectrometer equipped with a Sens!R Technologies DuroSampliR ATR accessory, or a Perkin Elmer Spectrum 100 spectrometer fitted with an ATR attachment.
  • Plasma treatment of samples was performed in a home-built plasma generator, operating at a pressure of 1 x10 "1 mbar, and at a forward power of approx. 100W at 13.5MHz.
  • Ail reagents were purchased from Sigma-Aldrich, Aifa-Aesar or Fisher Scientific, Air- sensitive reactions were performed in flame-dried glassware, and under a N 2 atmosphere.
  • Anhydrous solvents were obtained from a Grubbs solvent purification system except for acetone, which was purchased from Fisher Scientific. Flash column chromatography was performed using Davisil silica gel, and visualised on precoated Merck F 26 4 silica plates using UV light or KMn0 4 dip.
  • V C (101 MHz, Acetone) 5 (ppm) 152.89, 139.92, 125.52, 125.24, 1 14.78, 103.67, 34.62, 34.43, 34.37, 30.64, 30.53, 30.41 , 29.98, 29.87, 29.1 1 .
  • IR (oil) v (cm "1 ) 3420.0 (br.w., OH stretch), 2980.3, 2927.9, 2854.0 (str., CH stretches), 1754.6 (str., OO stretch), 1494.9 (Ar ring), 1459.3 (CH deformations), 1394.3, 1369.7, 1240.6 (str.,OH bending), 1 138.8 (str., C-O stretch).
  • MS (MALDf) m/z (arb.intensity units) 1 120 ([M+Lip, 310), 1 136 ([M+Nap, : 270),
  • Sheet silicone was cut into 0x10mm squares, peeled away from the PTFE backing, rinsed briefly with ethanoi and dried under N 2 to remove dust, and stored in 30 well plates until used.
  • Sections of silicone were pumped down in the plasma chamber to a base pressure of 1 x1 Q ⁇ 2 mbar, The air inlet was then adjusted until a constant pressure of 1 x10 "1 mbar was achieved, and the signal generator gain increased until the plasma ignited. The signal was then optimised to a forward power of ca. l QG , and then maintained for 120 s. The plasma chamber was evacuated to a pressure of 1x10 "2 mbar prior to removal of the samples.
  • a 5% (w/v) stock solution of 7 was prepared in ethanol, with the solution heated under N 2 at 60°C if dissolution was difficult.
  • 0.5% (w/v) deposition solutions (5mL total volume) were prepared by diluting fresh 5% stock solution (0.50mL) with dd.H20 (0.25mL), ethanol (4.25mL) and glacial acetic acid (5pL).
  • Plasma-modified samples were immediately immersed in the freshly prepared deposition solutions, agitated briefly, and incubated for 120 min. The samples were then rinsed thrice with ethanol, sonicated for 10 min in clean ethanol, rinsed with ethanol, water, then ethanol and dried under a stream of nitrogen.
  • the coated catheter material was tested under laboratory conditions to assess effectiveness against relevant urinary tract microorganisms.
  • Coated and uncoated silicone coupons were sterilised prior to testing by exposing to 250 nm UV light for 30 min on each side and placed into sterile 6-well micropiates.
  • the inoculum of Proteus mirabilis strain NCTC 1 1938 was prepared from an overnight culture in Tryptic Soy Broth (TSB; Oxoid, UK), which was washed three times in Phosphate Buffered Saline (PBS) prior to use.
  • TLB Tryptic Soy Broth
  • PBS Phosphate Buffered Saline
  • biofilm formation was monitored by colony counts.
  • Non-attached cells were removed by incubation in PBS with shaking at 120 rpm for 20 min. Coupons were then transferred to tubes containing 10 ml PBS and 10 sterile glass beads, and biofiims were removed by vortexing for 30 seconds.
  • Bacterial cells were enumerated by serial dilution and spreading onto TSB agar plates, which were incubated at 3?°C for 18-24 hours.
  • the coating was demonstrated to modulate the adhesion and reproduction of the key organism responsible for urinary tract infections, Pr. Mirabilis: it does not appear to cause a reduction in the adherent cell number, but rather cellular attachment leads to the death of most cells in contact with the surface leading to a 90% reduction in colonization after four days.
  • coatings of the invention were found to modulate the adhesion and reproduction of £ coli.

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Abstract

L'invention concerne des dispositifs médicaux implantables, tels que des cathéters, qui comprennent un revêtement dérivé de calixarène qui résiste à l'adhésion et/ou à la colonisation de bactéries et/ou de champignons. L'invention concerne également des matériels de revêtement dérivés du calixarène, des intermédiaires utiles pour leur fabrication, des procédés pour leur préparation, et des procédés de revêtement de dispositifs médicaux implantables par les composés calixarènes.
PCT/GB2013/050052 2012-01-11 2013-01-11 Dispositifs médicaux, revêtements et composés WO2013104916A2 (fr)

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WO2017025951A1 (fr) * 2015-08-10 2017-02-16 Ramot At Tel-Aviv University Ltd. Pillararènes et utilisations de ceux-ci

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US20140276356A1 (en) * 2013-03-14 2014-09-18 Teleflex Medical Incorporated Novel Enhanced Device and Composition for Local Drug Delivery
WO2017025951A1 (fr) * 2015-08-10 2017-02-16 Ramot At Tel-Aviv University Ltd. Pillararènes et utilisations de ceux-ci
US11161801B2 (en) 2015-08-10 2021-11-02 Ramot At Tel-Aviv University Ltd. Cationic pillararenes and uses thereof

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