WO2007058539A2 - Materiaux supramoleculaires modulaires destines a une utilisation biomedicale - Google Patents

Materiaux supramoleculaires modulaires destines a une utilisation biomedicale Download PDF

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Publication number
WO2007058539A2
WO2007058539A2 PCT/NL2006/050292 NL2006050292W WO2007058539A2 WO 2007058539 A2 WO2007058539 A2 WO 2007058539A2 NL 2006050292 W NL2006050292 W NL 2006050292W WO 2007058539 A2 WO2007058539 A2 WO 2007058539A2
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component
biomedical material
supramolecular
supramolecular biomedical
material according
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PCT/NL2006/050292
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WO2007058539A3 (fr
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Patricia Yvonne Wilhelmina Dankers
Gaby Maria Leonarda Van Gemert
Henricus Marie Janssen
Egbert Willem Meijer
Anton Willem Bosman
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Suprapolix B.V.
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Publication of WO2007058539A2 publication Critical patent/WO2007058539A2/fr
Publication of WO2007058539A3 publication Critical patent/WO2007058539A3/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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
    • C08G18/3271—Hydroxyamines
    • C08G18/3293—Hydroxyamines containing heterocyclic groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
    • C08G18/751—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring
    • C08G18/752—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group
    • C08G18/753—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group
    • C08G18/755—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group and at least one isocyanate or isothiocyanate group linked to a secondary carbon atom of the cycloaliphatic ring, e.g. isophorone diisocyanate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/008—Supramolecular polymers
    • 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

Definitions

  • the invention relates to new supramolecular biomedical materials, as well as to a process to prepare biologically active biomedical materials in a modular way, in order to obtain biomedical materials that allow easy fine-tuning of the material properties, bioresorption and bioactivity by making use of reversible supramolecular interactions.
  • the new materials of this invention can be used in a variety of biomedical applications that will benefit from said properties.
  • the supramolecular biomedical materials according to the present invention are in particular suitable for use in biomedical coating compositions.
  • Biomedical materials are distinguished in bioresorbable materials and non- bioresorbable materials.
  • a wide variety of bioresorbable materials are known that are mostly based on aliphatic polyesters (Uhrich et al. Chem. Rev. 99, 3181-3198, 1999).
  • the mechanical properties of current bioresorbable materials are strongly related to their high molecular weights that are in general over 100 kDa, the presence of chemical cross-links, and the presence of crystalline domains in these polymers.
  • the crystalline domains are beneficial for the mechanical properties of the material (strength and elasticity), they do have a strong impact on the biodegradation process of the material as the biodegradation of crystalline domains is in general very slow and crystalline domains may cause immunological responses.
  • the need for high molecular weight polymers in order to get the desired material properties, usually implies that high processing temperatures are required, and these are unfavorable as thermal degradation processes become more likely, especially when biologically active species are involved.
  • biologically active species that have been covalently attached to polymers for biomedical uses.
  • oligo-peptide based cell-adhesion promoters such as RGD-sequences have had considerable attention in this respect.
  • RGD-peptides have been covalently attached to a synthetic polymer by copolymerizing RGD-containing monomers, in order to obtain biologically active polynorbornenes (Grubbs et al, J. Am. Chem. Soc. 123, 1275, 2001).
  • biomedical coatings that are used to improve the biocompatibility of medical devices.
  • stents may be coated to reduce thrombosis (cf. for example US 6.702.850, incorporated by reference) and implants may be coated to reduce the risks of rejection.
  • Biomedical coatings may further comprise biologically active agents that are released in a controlled manner. Such biomedical coatings may be prepared by mixing a biologically active agent with a polymeric coating formulation.
  • a biological active agent that has been covalently attached to several polymers for biomedical coatings are heparin-derivatives.
  • heparins have been copolymerized in polystyrene and poly(ethylene glycol) systems (Feijen et al., J. Mater. Sci. Mat. Med. 4, 353, 1997), or heparins have been covalently attached to polyurethanes as disclosed in WO98/23307.
  • These heparin-polymer conjugates are used as anti-thrombogenic coatings for structures to be introduced into living systems.
  • aromatic diisocyanates are used that are known for their toxic biodegradation profile and a relative low amount of heparin is available at the surface of the coating resulting in a low anti-thrombogenic activity.
  • WO 2002/034312 discloses polymers to which heparin is covalently attached.via functional groups.
  • non-covalently attached biological active molecules are heparins that are ionically bound to cationic coatings due to heparin's intrinsic negative charge caused by the presence of carboxylates and sulfonates in the molecule, as disclosed for example in US 4.229.838. This method is however rather limited because the bio-active compound is leached over time from the surface due to the relative low ionic binding strength.
  • hydrophobic interactions have been used to non-covalently attach heparin to polymeric surfaces by end-group functionalizing heparin with an alkyl chain (Matsuda et al, Biomacromolecules, 2, 1169, 2001).
  • the hydrophobic interactions are rather poor, resulting in a fast decrease in activity due to leakage of the heparins from the polymeric surfaces.
  • “supramolecular chemistry” is understood to be the chemistry of non- covalent, oriented, multiple (at least two), co-operative interactions.
  • a “supramolecular polymer” is an organic compound that has polymeric properties - for example with respect to its rheological behavior - due to specific and strong secondary interactions between the different molecules. These non-covalent supramolecular interactions contribute substantially to the properties of the resulting material.
  • Supramolecular polymers comprising (macro)molecules that bear hydrogen bonding units can have polymer properties in bulk and in solution, because of the H- bridges between the molecules.
  • Sijbesma et al. see WO 98/14505 and Science 278, 1601, 1997) have shown that in cases where the self-complementary quadruple hydrogen unit (4H-unit) is used, the physical interactions between the molecules become so strong that polymers with much better material properties can be prepared.
  • WO 2004/016598 incorporated by reference, discloses chemistry to acquire polymers with grafted quadruple H-bonding units. For example, polyacrylates and polymethacrylates with grafted 4H-units have been produced using different kinds of polymerization techniques.
  • WO 2004/052963 discloses polysiloxanes comprising 4H-units in the polymer backbone. More precisely, polysiloxanes are disclosed having (a) 4H-units directly incorporated in the polymer backbone, or (b) 4H-units pending from the polymer backbone, wherein the 4H-units are covalently attached via one linker through a silicon-carbon bond.
  • the disclosed polymers are not bioresorbable.
  • Non-prepublished European Patent Application No. 05103764.6 filed 4 May 2005, discloses supramolecular bioresorbable materials comprising a polymer comprising at least two 4H-units and a biologically active compound.
  • the supramolecular bioresorbable materials are useful in biomedical applications including controlled release of drugs, tissue-engineering, prostheses and implants.
  • the present invention addresses these needs by introducing a supramolecular modular approach, wherein different ingredients (or modules or components) are blended - with each module contributing its own specific characteristic (i.e. mechanical performance, bioresorption, bioactivity, etc.) - to produce a material displaying the combined characteristics.
  • This modular approach is usually not easily possible, but is enabled here, as quadruple hydrogen bonding units (4H-units) are used in at least one of the modules that are applied, resulting in contact between the modules in the final material.
  • the presented approach eliminates the need for extensive covalent synthesis, as blending experiments with the various modules can be used to fine-tune the properties of the final material. Also, every module can be prepared in a controlled way, leading to well defined structures that result in products of controllable high quality.
  • the supramolecular biomedical material is a supramolecular coating composition.
  • the present invention therefore relates to a supramolecular biomedical material comprising the following components:
  • C-X, and the C-Y, linkages each represent a single or double bond
  • n is 4 or more
  • X represent donors or acceptors that form hydrogen bridges with the H- bridge forming monomeric unit containing a corresponding general form (2) linked to them with X, representing a donor and Y, an acceptor and vice versa.
  • Component (a) is preferably bioresorbable.
  • bioresorbable encompasses cell-mediated degradation, enzymatic degradation or hydro lytic degradation of the supramolecular biomedical material, and/or elimination of the surpamolecular biomedical material from living tissue as is will be appreciated by the person skilled in the art.
  • a biologically active compound is to be understood as a biomedically relevant compound that can induce a biological or biochemical effect in a mammal but does not include biological systems such as cells and cell organelles.
  • component (a) is a polymer comprising at least two 4H-units, preferably 2 - 50, more preferably 3 - 50, even more preferably 3 - 20, and most preferably 4 - 15 4H-units that are covalently attached to the polymer chain.
  • the 4H- units may be attached at the termini of the polymer chain as well as to the backbone of the polymer chain or both.
  • the supramolecular biomedical polymer may comprise more than one of component (a), e.g. polymers of different chemical nature, of different molecular weight, and/or different numbers of 4H-units. It is also possible that component (a) is constituted from components of different chemical nature and/or of different molecular weight.
  • component (a) is a bioresorbable polymer. However, if the supramolecular biomedical material is a supramolecular biomedical coating composition, it may be more preferred that component (a) is not bioresorbable.
  • Component (a) can be any type of polymer, the polymer can be of synthetic origin or of natural origin, such as chitosan, collagen, fibrin, or proteoglycans.
  • component (a) is selected from the group consisting of polyethers, aliphatic polyesters, aromatic polyesters, polyurethanes, polyamides, polyacrylates, polymethacrylates, polyacrylamides, (hydrogenated) polyolefms, polysiloxanes, polycarbonates, polyorthoesters, polysaccharides, poly(N- vinylcapro lactam), polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer and polyvinylalcohols (preferably partly esterified), or copolymers of these polymers.
  • polyethers aliphatic polyesters, aromatic polyesters, polyurethanes, polyamides, polyacrylates, polymethacrylates, polyacrylamides, (hydrogenated) polyolefms, polysiloxanes, polycarbonates, polyorthoesters, polysaccharides, poly(N- vinylcapro lactam), polyvinylpyrrolidone, polyviny
  • component (a) is selected from the group consisting of polyethers, aliphatic polyesters, polycarbonates, polysiloxanes, polyorthoesters and polycarbonates. Even more preferably, component
  • component (a) is selected from the group consisting of polyethers, aliphatic polyesters and polycarbonates. Most preferably, component (a) is an aliphatic polyester.
  • component (a) is selected from the group consisting of polyamides, polyacrylates, polymethacrylates, polyacrylamides, N- vinylcapro lactam, or copolymers of these polymers.
  • the number average molecular weight M n of component (a) is preferably in the range from 100 to 100000, more preferably from 100 to 60000, even more preferably
  • component (a) is prepared from relatively low molecular weight polymers having two hydroxy end-groups, primary amino end-groups, or a combination thereof.
  • relatively low molecular weight polymers having two hydroxy end-groups are:
  • polyether diols having a polyoxyalkylene structure and OH end-groups
  • polyesters and copolyesters having OH end-groups
  • polymers (i) are polyetherdiols having a polyoxyalkylene structure and OH end-groups, e.g. polyethylene glycol, polypropylene glycol, poly(ethylene-co-propylene) glycol (random or block), polytetramethylene glycol.
  • polymers (ii) are polyesters and copolyesters made by polycondensation of dicarboxylic acids, e.g. adipic acid, and diols, e.g. 1,6-hexanediol, or by polycondensation of hydroxyacids, e.g. lactic acid; polyesters and copolyesters made by ringopening polymerisation of e.g.
  • polymers (iii) are polycarbonates and copolycarbonates based on e.g. 1,6- hexanediol polycarbonate, polycarbonates and copolycarbonates made by ringopening polymerization of e.g.
  • polymers (iv) is a polyorthoester based on e.g. 3,9-diethylene-2,4,8,10-tetraoxaspiro[5.5]undecane.
  • polymers (v) are OH functionalized polybutadiene and OH functionalized poly(ethylene-butylene).
  • polymers (vi) are OH functionalized block copolymers of polycapro lactone and polyethyleneglycol.
  • Examples of relatively low molecular weight polymers having two amino end- groups are are Jeffamines® (polyoxyalkylenea amines produced and marketed by Huntsman), or other polyethers, aliphatic polyamides or polysiloxanes.
  • the polymers have two hydroxyl end-groups, primary amine end- groups, or a combination thereof have a number average molecular weight M n of 500 to and 10000, more preferably of 750 to 7000.
  • the supramolecular biomedical material comprises 50.0 - 99.99 percent by weight of component (a) and 0.01 - 50.0 percent by weight of component (b) if no component (c) is present (vide infra). More preferably, the supramolecular biomedical material comprises 70.00 - 99.99 percent by weight of component (a) and 0.01 - 30.00 percent by weight of component (b).
  • the supramolecular biomedical material comprises 90.00 - 99.95 percent by weight of component (a) and 0.05 - 10 percent by weight of component (b). All these weight ranges are based on the total weight of the supramolecular biomedical material.
  • Component (a) may have all kinds of different architectures, e.g. a linear
  • the (co)polymers may have any kind of microstructure, such as a random, a block, a segmented or a randomly segmented structure, with the 4H-units attached to this co-polymer in any fashion, such as end- capped, incorporated in the polymer chain or grafted from the backbone.
  • component (a) comprises a star shaped polymer that is (partly) end-functionalized with 4H-units, or component (a) comprises a linear polymer to which several 4H-units are grafted, or component (a) comprises a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone.
  • component (a) comprises a star shaped polymer that is (partly) end-functionalized with 4H-units, or component (a) comprises a linear polymer to which several 4H-units are grafted, or component (a) comprises a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone.
  • the preferred ranges of the number of 4H-units are disclosed above.
  • component (a) comprises a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone. Most preferably, component (a) comprises a linear (co)polymer with the 4H-units attached to it in the polymer backbone.
  • components (a) with relative low number average molecular weights M n preferably in the range from 100 to 100000, more preferably from 100 to 60000, even more preferably 800 to 40000, most preferably from 2000 to 35000, in order to allow melt -processing of the supramolecular biomedical material at temperatures preferably lower than 200 0 C, more preferably lower than 150 0 C, and most preferably lower than 100 0 C, or to process them from solutions at concentrations higher than 10% by weight, preferably higher than 15% by weight.
  • ionic or ionogenic groups may be incorporated in component (a) in order to make the material more hydrophilic and thereby facilitating water-solubility or water swelling of the supramolecular biomedical material (i.e. gelling).
  • Preferred ionogenic groups are N-methyl-diethanolamine, 2,6-bis-(hydroxymethyl)-pyridine and
  • component (a) may contain one or more hydrophilic polymeric blocks in its polymer chain in order to facilitate water-solubility or water swelling of the supramolecular biomedical material (i.e. gelling).
  • hydrophilic polymeric blocks are preferably derived from polyethylene glycol polymers, preferably having a number average molecular weight M n from 200 to 50000, more preferably from 500 to 6000.
  • component (a) has an elongation at break of at least 140%.
  • component (a) contains at least three 4H-units on average to counterbalance components (b) if component (b) has less than two 4H-units, the latter optionally acting as supramolecular chain stopper.
  • n 4 so and that the 4H-unit comprises four donors or acceptors X 1111 X 4 and Y 1111 Y 4 .
  • the 4H-unit may be self- complementary (i.e. the two hydrogen bonded units have an equal array of donors and acceptors), or non self-complementary (i.e. the two hydrogen bonded units have two different arrays of donors and acceptors).
  • the 4H-unit comprises two successive donors, followed by two successive acceptors, i.e. that it is preferred that Xi and X 2 are donors and X 3 and X 4 are acceptors.
  • the donors and acceptors are O, S, and N atoms.
  • the 4H unit is in detail disclosed in WO 98/14505 and in US 6.320.018 which are expressly incorporated by reference.
  • the 4H-unit has the general formula (3) or formula (4), and tautomers thereof:
  • R is independently selected from the group consisting of hydrogen and Ci - C 6 linear or branched alkyl, n is 1 - 6 and m is 10 to 100;
  • R is selected from the group consisting of hydrogen and Ci - C 6 linear or branched alkyl; (h) polyether groups having the formula (7)
  • R 6 and R 7 are independently selected from the group consisting of hydrogen and Ci - Ce linear or branched alkyl and o is 10 - 100;
  • oligopeptide groups consisting of sequences of 1 to 50, preferably 1 to 10, amino acids; and wherein the 4H-unit is bonded to a polymer backbone via R 1 , R 2 and/or R 3 (so that R 1 , R 2 or R 3 represent a direct bond) with the other R groups representing, independently a side chain according to (a) - (i).
  • the 4H-unit is bonded to a polymer backbone via R 1 or R 3 (so that R 1 or R 3 constitutes a direct bond), while R 2 is any one of the groups (a) - (f) defined above, preferably group (a), more preferably 2-ethylpentyl or methyl and most preferably methyl.
  • R 1 is any one of the groups (a) - (f) defined above, preferably group (a), more preferably 2-ethylpentyl or methyl and most preferably methyl.
  • R 2 and R 3 are any of the groups (a) - (f) defined above, preferably group (a), more preferably 2-ethylpentyl or methyl and most preferably methyl.
  • the 4H-unit is bonded to a polymer backbone via R 1 and R 3 .
  • groups (b) - (i) defined above may be linear, branched or cyclic where appropriate.
  • the supramolecular biomedical material of the present invention comprises a biologically active compound (b).
  • the biologically active compound (b) is selected from the group consisting of biologically active compounds with at least one 4H-unit up to a maximum of ten 4H-units, preferably one to four, and most preferably two to four 4H-units. These 4H-units are covalently attached to the biologically active compound.
  • the amount of biologically active compound (b) is 0.01 to 50.00 percent by weight and the amount of component (a) is 50.00 - 99.99 percent by weight, based on the total weight of the supramolecular biomedical material, as is disclosed above.
  • the weight range of (a) is 70.00 - 99.99 percent by weight, and even more preferably 90.00 - 99.95 percent by weight
  • the preferred weight range for (b) is 0.01 - 30 percent by weight, and even more preferably 0.05 - 10.00 percent by weight. All these weight ranges are based on the total weight of the supramolecular biomedical material.
  • the biologically active compound (b) species may comprise one or more different biologically active compounds.
  • the biologically active compound can be any compound that displays bioactivity as disclosed above.
  • a 'biologically active compound' as used herein, is a compound that is biomedically relevant and includes a compound which provides a therapeutic, diagnostic, cosmetic, medicinal or prophylactic effect, a compound that effects or participates in tissue growth, cell growth, cell differentiation, cell signaling, cell homing, protein adsorption, a compound that may be able to invoke a biological action, or could play any other role in one or more biological processes.
  • Such compounds include, but are not limited to, antimicrobial agents (including antibacterial and antifungal agents), anti-viral agents, anti-tumor agents, anti-thrombogenic agents, anticoagulant agents, lubricating agents, imaging agents, drugs, medicines, hormones, immunogenic agents, growth factors, cytokines, chemokines, (fluorescent) dyes, contrast agents, nucleic acids such as for example single or double stranded DNA and single or double stranded RNA, lipids, lipopolysaccharides, (poly)saccharides, vitamins, and peptides, polypeptides and proteins in general, biotinylated compounds or other compound that target biologically relevant molecules.
  • antimicrobial agents including antibacterial and antifungal agents
  • anti-viral agents including antibacterial and antifungal agents
  • anti-tumor agents include anti-tumor agents, anti-thrombogenic agents, anticoagulant agents, lubricating agents
  • imaging agents drugs, medicines, hormones, immunogenic agents, growth
  • a non-limiting, preferred and important group of species that can be used as component (b) according to the present invention is formed by oligopeptides and polysaccharides.
  • component (b) comprises a growth factor, an antimicrobial agent, a thrombin inhibitor, or an anti-thrombogenic agent.
  • a growth factor is defined as a protein or peptide that has a beneficial effect on the growth, proliferation and/or differentiation of living cells.
  • the supramolecular bioabsorbable material is advantageously used as a scaffold for tissue engineering, wherein the growth factor is non-covalently bound to a polymer.
  • BMP Bone Morphogenetic Proteins
  • epidermal growth factors e.g. Epidermal Growth Factor (EGF)
  • fibroblast growth factors e.g. basic Fibroblast Growth Factor (bFGF), Nerve Growth Factor (NGF), Bone Derived Growth Factor (BDGF)
  • transforming growth factors e.g. Transforming Growth Factor-.beta.1 (TGF- .beta.1), and human Growth Hormone (hGH).
  • the supramolecular bioabsorbable material is advantageously used as a biomedical coating composition, wherein the anti-thrombogenic agent is non-covalently bound to a polymer.
  • Non-limiting examples of preferred anti-thrombogenic agents are heparin, heparin analogues, heparin complexes, and molecules comprising a sulfonated glycosaminoglycan moiety.
  • the anti-thrombogenic agent may also be a heparinised polymer as disclosed in WO 02/34312, incorporated by reference herein.
  • immunogenic peptides or immunogenic proteins e.g. toxins, viral surface antigens or parts of viruses, bacterial surface antigens or parts of bacteria, surface antigens of parasites causing disease or portions of parasites, immunoglobulins, anititoxins, antigens.
  • the method according to the present invention is particularly useful for preparing materials loaded with polysaccharides and peptides, it is of course also possible to load a material with a substance other than a polysaccharide or peptide.
  • biologically active agents include non-peptide, non-protein drugs and inorganic compounds. It is possible within the scope of the present invention to incorporate drugs of a polymeric nature, but also to incorporate drugs or vitamins of a relatively small molecular weight of less than 1500, or even less than 500.
  • non-peptide, non-protein drugs which may be incorporated include the following: anti-tumor agents, antimicrobial agents such as antibiotics or hemotherapeutic agents, antifungal agents, antiviral agents, anti-inflammatory agents, anti-gout agents, centrally acting analgesics, local anesthetics, centrally active muscle relaxants, hormones and hormone antagonistics, corticosteroids such as mineralocorticosteroids or glucocorticosteroids, androgents, estrogens, progestins.
  • anti-tumor agents such as antibiotics or hemotherapeutic agents
  • antifungal agents such as antibiotics or hemotherapeutic agents
  • antiviral agents anti-inflammatory agents
  • centrally active muscle relaxants hormones and hormone antagonistics
  • corticosteroids such as mineralocorticosteroids or glucocorticosteroids
  • estrogens progestins.
  • inorganic compounds which may be incorporated, include, but are not limited to reactive oxygen scavengers or bone-extracts like apatite or hydroxy apatite.
  • Component (b) can be used as such, or can be chemically modified with one or more 4H-units. This chemical modification can be done by regular organic synthesis procedures, such as coupling methods using succinimide esters, sulfhydryl reactive agents, azides, (thio)isocyanates, carbiodiimides, aldehydes, or Cu(I)-catalyzed Huisgen [2+3] dipolar cycloadditions, or solid phase synthesis procedures which are known to persons skilled in the art.
  • this chemical modification can be done using native chemical ligation with a peptide or protein containing a C-terminal thio-ester and a 4H-unit with a N-terminal cysteine, native chemical ligation is known to people skilled in the art.
  • the 4H-unit can be bound to component (b) via a (bio)degradable linker that can be cleaved in vivo.
  • a (bio)degradable linker that can be cleaved in vivo.
  • the native component (b) is gradually released from the material, for example to induce an enhanced therapeutic effect.
  • cleavable linkers are esters or oligopeptides that are cleaved by enzymatic activity, such as the cleavage of the peptide Gly-Phe-Leu-Gly by cysteineproteases.
  • two or more different components (b) may be present in the supramolecular biomedical material. This is especially beneficial when the bioactivity is based on multivalent and/or synergistic interactions.
  • a non-limiting example of such interaction is the cell adhesion advantageously mediated by a combination of RGD and
  • the supramolecular biomedical material according to the present invention preferably also comprises a third component (c), said third component (c) being a bioresorbable polymer.
  • this bioresorbable polymer comprises one up to a maximum of fifty 4H-units, preferably one to thirty, more preferably two to twenty, and most preferably four to twenty. These 4H-units are covalently attached to the polymer chain.
  • the supramolecular biomedical material can obviously comprise different types of bioresorbable polymers, wherein these polymers are for example of different chemical nature and/or of different molecular weight, and can contain different numbers of 4H- units. It is obviously also possible that these polymers are constituted from components of different chemical nature and/or of different molecular weight.
  • Component (c) may be any bioresorbable polymer. However, it is preferred that component (c) is selected from the group consisting of polyethers (preferably aliphatic), aliphatic polyesters, aromatic polyesters, polyamides (preferably aliphatic; for example polypeptides), polycarbonates (preferably aliphatic), polyorthoesters, polysaccharides, polyvinylalcohols (preferably partly esterified). It is even more preferred that component (c) is selected from the group consisting of aliphatic polyethers, aliphatic polyesters, aliphatic polyamides, aliphatic polycarbonates, aliphatic polyorthoesters, polysaccharides and partially hydrolyzed polyvinylalcohols.
  • polyethers preferably aliphatic
  • aliphatic polyesters aromatic polyesters
  • polyamides preferably aliphatic; for example polypeptides
  • polycarbonates preferably aliphatic
  • polyorthoesters polysaccharides
  • component (c) contains any combination of polymer types, for example combinations of the preferred group of polymers disclosed above.
  • the polymer backbone is selected from the group consisting of polysaccharides, polyether and copolyethers based on, for example, ethyleneoxide, propyleneoxide, or tetrahydrofuran; polyesters and copolyesters made by polycondensation, based on, for example, adipic acid and diols or hydroxyacids, such as lactic acid; polyesters and copolyesters made by ringopening polymerisation, based on, for example, ⁇ - caprolactone, glycolide, lactide, ⁇ -valerolactone, l,4-dioxane-2-one, l,5-dioxepan-2- one, oxepan-2,7-dione; polycarbonates and copolycarbonates based on, for example, 1,6-
  • the number average molecular weight M n of component (c) is preferably in the range from 100 to 100000, more preferably from 100 to 60000, even more preferably 800 to 40000, most preferably from 2000 to 35000 Dalton.
  • Component (c) can have all kinds of different architectures: a linear (co)polymer with the 4H-units attached to it as endgroups, and/or in the polymer backbone and/or grafted onto the polymer chain; a star shaped (co)polymer with the 4H-units somehow attached to it, preferably as endgroups; a dendritic structure with the 4H-units attached to it as endgroups, and/or in the dendritic arms; or a (multifunctional) branched or hyperbranched structure with the 4H-units attached to it as endgroups, and/or in the branches.
  • the co-polymers can have any kind of microstructure, such as a random, a block, a segmented or a randomly segmented structure, with the 4H-units attached to this co-polymer in any fashion, such as end-capped, incorporated in the polymer chain or grafted from the backbone.
  • component (c) comprises a star shaped polymer that is (partly) end- functionalized with 4H-units, a linear polymer to which several 4H-units are grafted, or a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone. More preferably, component (c) comprises a linear (co)polymer with the 4H- units attached to it as end groups and in the polymer backbone. Most preferably, component (c) comprises a linear (co)polymer with the 4H-units attached to it in the polymer backbone.
  • component (a) ionic or ionogenic groups may optionally be incorporated in component (c) in order to make the material more hydrophilic and thereby facilitating water-solubility or water swelling of the material (i.e. gelling). Preferred ionogenic groups are disclosed for component (a).
  • component (c) may contain one or more hydrophilic polymeric blocks in its polymer chain in order to facilitate water- solubility or water swelling of the material (i.e. gelling). These hydrophilic polymeric blocks are preferably derived from polyethylene glycol polymers, preferably having a number average molecular weight from 200 to 50000, and more preferably from 500 to 6000.
  • the present invention also provides a method of preparing the supramolecular biomedical material.
  • This method comprises blending component (a) which predominantly attributes to the mechanical strength of the supramolecular biomedical material and component (b) which predominantly attributes to the biological activity of the supramolecular biomedical material.
  • this method comprises blending component (a), component (b) and component (c), the latter predominantly attributing to the bioresorption of the supramolecular biomedical material.
  • the blending of the components (a), (b) and (c) results in supramolecular biomedical materials with the desired material properties. In particular, if all components comprise 4H-units, they will all strongly contribute to strong physical interactions between the different components.
  • all three components (a) - (c) have at least one 4H-unit.
  • the blending of all components can be done by conventional processes, i.e. solution processing or melt-processing, or a combination of both.
  • the concept of supramolecular blending of the different components also allows tuning the biodegradation behavior of the supramolecular biomedical materials, as this behavior is determined by the degradation behavior of all the added components.
  • the supramolecular biomedical material can be obtained in three different ways: method (i) comprises blending the different components (a), (b) and optionally (c) with each other in conjunction with a medium consisting of one or more solvents, in which these components are dissolved or dispersed, preferably dissolved.
  • This first method (i) is preferably followed by processes for dissolved polymers known in the art.
  • a second method (ii) comprises blending the different components (a), (b) and optionally (c) with each other in the bulk at elevated temperatures, preferably 40° to 150°C ⁇ vide infra).
  • This second method (ii) is preferably followed by solventless processes for polymers known in the art.
  • a third method (iii) comprises a combination of methods (i) and (ii).
  • method (iii) comprises for example first blending component (b) with component (c) according to method (i), followed by blending component (a) and the blend of components (b) and (c) according to method (ii).
  • method (iii) comprises first blending component (a) with component (b) according to method (i), followed by blending component (c) and the blend of components (a) and (b) according to method (ii).
  • methods (i) and (ii) comprises the in situ preparation of components (a) and/or (c).
  • Processing according to method i) can be done from organic solvents or aqueous media, depending on the solubility of different components.
  • a solvent or mixture of solvents is used that is acceptable for biomedical uses, such as water, acetone, methyl ethyl ketone, THF, DMSO, NMP, scCO2 or aliphatic alcohols.
  • the supramolecular biomedical material is preferably obtained by solvent casting, dip- coating, freeze-drying, precipitation casting, spray coating, painting, roll-coating, foaming, solvent spinning, wet spinning, electro-spinning, micro-contact printing, ink jet printing, particulate-leaching techniques, phase-separation techniques or emulsion processes.
  • solvents should be such that the desired viscosity of the solution for the coating process is obtained, preferably polar solvents should be used to reduce hydrogen bonding between the polymers.
  • the solvent has preferably a low boiling point in order to facilitate removal from the material after the coating process, and the solvent has preferably only limited toxicity. Therefore, drying of the material is required after the coating process and is preferably followed by extensive washings with water or water containing pH-buffer.
  • wettability of the substrate can be improved by liquid etching techniques, such as the use of chromic acid, aqueous sodium hydroxide and fuming sulfuric acid, or plasma etching techniques.
  • Processing according to method (ii) is done at temperatures sufficient high to allow processing of the components although temperatures should be not too high to prevent degradation of the different components, especially component (b).
  • processing temperatures are in between 40 0 C and 150 0 C, most preferably in between 50 0 C and 120 0 C.
  • the supramolecular biomedical materials are preferably obtained by extrusion, reactive extrusion, micro-extrusion, fused deposition modeling, molding, lamination, film-blowing, reaction injection molding (RIM), spinning techniques, rapid prototyping or by thermal- or photocuring of a coating.
  • the amount of component (a) in the supramolecular biomedical material is preferably 50.00 - 99.99 percent by weight if no component (c) is present. According to this embodiment, component (a) is more preferably present between 70.00 - 99.99 percent by weight, and most preferably between 90.00 - 90.95 percent by weight
  • the amount of component (b) in the supramolecular biomedical material is preferably 0.01 - 50.00 percent by weight if no component (c) is present. According to this embodiment, component (b) is more preferably present between 0.01 - 30.00 percent by weight, and most preferably between 0.05 - 10.00 percent by weight. If component (c) is present in the supramolecular biomedical material according to the invention, the weight ratios of components (a) - (c) are preferably as follows: 20 - 59.99 percent by weight of (a), 0.01 - 40.00 percent by weight of (b), and 0.01 - 40.00 percent by weight of (c).
  • the weight ratios of components (a) - (c) are 40.00 - 69.99 percent by weight of (a), 0.01 - 30.00 percent by weight of (b), and 0.01 - 30.00 percent by weight of (c). All percentages by weight enlisted here for the supramolecular biomedical material are based on the total weight of the supramolecular biomedical material.
  • Highly porous structures can be obtained by techniques known in the art, such as freeze-drying, particulate leaching using salts or sugars, and electro-spinning. Highly porous (interconnecting) structures or non-woven fabrics are beneficial towards cell- attachment or proliferation, and allow the growth of tissue inside the scaffold. These structures can, for example, be used as porous scaffolds used in tissue-engineering, as prosthesis or implants.
  • the supramolecular biomedical material can be obtained as a hydrogel, i.e. a gel in which the liquid is water.
  • Hydrogels can be obtained by persons skilled in the art by balancing the ratio of hydrophilic and hydrophobic components in components (a) and optionally (c) in the formulation. Hydrogel materials have a high water content, potentially mimicking different roles of the extracellular matrices in tissue. Consequently, hydrogels find many uses in biomedical applications such as controlled drug delivery, delivery matrices or as coatings.
  • additional ingredients other than (a), (b), or optionally (c), may be added to the material such as excipients known in the art such as for example anti-oxidants and pH-buffers.
  • the supramolecular biomedical materials according to the invention are preferably suitable for applications related to biomedical applications such as materials for tissue-engineering, materials for the manufacture of a prosthesis or an implant. More preferably, the supramolecular biomedical materials are useful for biomedical coatings with controlled release of drugs, biomedical coatings that have anti- thrombogenic or anti-microbial activity, biomedical coatings that have enhanced lubrication, or are used for medical imaging technologies (for example MRI).
  • the biomedical coating can be applied on protheses, implants, stents, catheters, or other medical devices that come in contact with living tissue. According to another more preferred application, the supramolecular biomedical material is useful as filling material for cosmetic and reconstructive plastic surgery.
  • 1,6-Hexyldiisocyanate 650 g
  • methylisocytosine or 2-amino-4-hydroxy-6- methyl-pyrimidine, 65.1 g
  • the mixture was stirred overnight at 100 0 C under an argon atmosphere.
  • a litre of pentane was added to the suspension, while stirring was continued.
  • the product was filtered, washed with several portions of pentane and dried in vacuum.
  • the resulting 2(6-isocyanatohexylaminocarbonylamino)-6-methyl-4[lH]pyrimidinone was obtained as a white powder.
  • Methyl isocytosine (5.2 g) was added to isophoronediisocyanate (IPDI, 50 mL) and subsequently stirred at 90 0 C under an argon atmosphere for 3 days. The resulting clear solution was precipitated in heptane. The white gom was collected, heated in 150 mL heptane, cooled on ice, and filtered. The same procedure was repeated once more with the white residue, resulting in a white powder consisting of ureidopyrimidinone with one IPDI unit.
  • IPDI isophoronediisocyanate
  • This product (10.22 g) was subsequently dissolved in chloroform (20 mL), and thereafter hydroxy ethyl acrylate (HEA, 3.6 mL) and 1 drop of dibutyl tin dilaurate (DBTDL) were added.
  • HOA hydroxy ethyl acrylate
  • DBTDL dibutyl tin dilaurate
  • Telechelic PEO- 1500 (5.83 g) was stripped three times with toluene and was then dissolved in toluene (30 mL). UPy2 (2.39 g) in toluene (14 mL) was added as well as a few drops of dibutyl tin dilaurate and the solution was heated overnight under argon (oil bath temperature of 120 0 C). The polymer was isolated by precipitation into diethylether. The material is white (semi-crystalline), elastic and tough.
  • 1 H NMR 300 MHz, CDCI 3 /CD 3 OD): ⁇ 4.1, 3.6, 2.8, 2.2, 1.8-1.4, 1.2-0.8.
  • SEC THF, PS-standards
  • EDC N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide
  • NHS N-hydroxysuccinimide
  • the reducing end of heparin was oxidized with iodide (0.2 g) in 20% aqueous methanol solution (25 mL) for 6h at room temperature.
  • the reaction solution was added to ethanol containing 4% by weight potassium hydroxide (50 mL).
  • the mixture was polymerized after the addition of ammoniumpersulfate (50 ⁇ L; endconcentration 0.1%) and N,N,N',N'- tetramethylethylenediamine (TEMED, 2.5 ⁇ L; endconcentration 0.1%), resulting in a 12% acrylamide gel containing functionalized with 4H-units and containing 2% by weight of bioactive component 2.
  • ammoniumpersulfate 50 ⁇ L; endconcentration 0.1%) and N,N,N',N'- tetramethylethylenediamine (TEMED, 2.5 ⁇ L; endconcentration 0.1%)

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Abstract

La présente invention concerne un matériau biomédical supramoléculaire qui comprend un polymère renfermant au moins deux unités 4H et un composé biologiquement actif. Le matériau biomédical supramoléculaire comprend éventuellement un polymère biorésorbable en tant que troisième composant. Le matériau biomédical supramoléculaire convient tout particulièrement pour les revêtements biomédicaux dotés d’une libération régulée de médicaments, pour les revêtements biomédicaux présentant une activité antithrombogénique ou antimicrobienne, pour les revêtements biomédicaux présentant une lubrification accrue ou pour les revêtements biomédicaux employés dans le cadre de technologies d’imagerie médicale (une IRM par exemple).
PCT/NL2006/050292 2005-11-21 2006-11-17 Materiaux supramoleculaires modulaires destines a une utilisation biomedicale WO2007058539A2 (fr)

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Cited By (9)

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US8247524B2 (en) 2003-11-04 2012-08-21 Suprapolix B.V. Preparation of supramolecular polymers containing quadruple hydrogen bonding units in the polymer backbone
US8268952B2 (en) * 2004-07-12 2012-09-18 Suprapolix B.V. Supramolecular ionomers
US8628789B2 (en) 2007-03-23 2014-01-14 Suprapolix, B.V. Strong reversible hydrogels
US8754213B2 (en) 2008-07-04 2014-06-17 Suprapolix B.V. High flow supramolecular compounds
US8883188B2 (en) 2005-05-04 2014-11-11 Suprapolix B.V. Modular bioresorbable or biomedical, biologically active supramolecular materials
US9006386B2 (en) 2010-11-05 2015-04-14 Suprapolix B.V. Process for the preparation of a supramolecular polymer
US9006364B2 (en) 2006-11-20 2015-04-14 Suprapolix B.V. Supramolecular polymers from low-melting, easily processable building blocks
WO2017194786A1 (fr) 2016-05-13 2017-11-16 Technische Universiteit Eindhoven Post-fonctionnalisation de matériaux supramoléculaires
KR101808961B1 (ko) 2016-10-28 2017-12-13 숭실대학교산학협력단 초분자형 공중합체 형성법을 이용한 고인성 바이오폴리머 및 이의 제조 방법

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WO2002098377A1 (fr) * 2001-06-07 2002-12-12 L'oreal Composition cosmetique formant apres application un polymere supramoleculaire
WO2004016598A1 (fr) * 2002-08-16 2004-02-26 Suprapolix, B.V. Monomeres pouvant former quatre liaisons hydrogene et polymeres supramoleculaires formes par copolymerisation de ces monomeres avec des monomeres reguliers

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WO1998014504A1 (fr) * 1996-10-04 1998-04-09 Dsm N.V. Polymere supramoleculaire
US6320018B1 (en) * 1996-10-04 2001-11-20 Dsm N.V. Supramolecular polymer
EP0877055A1 (fr) * 1997-05-08 1998-11-11 President of Japan Advanced Institute of Science and Technology, Hokuriku Matériau hémocompatible à structure supramoléculaire
WO2002046260A1 (fr) * 2000-12-05 2002-06-13 Huntsman International Llc Polymere permettant la formation d'un polymere supramoleculaire
WO2002098377A1 (fr) * 2001-06-07 2002-12-12 L'oreal Composition cosmetique formant apres application un polymere supramoleculaire
WO2004016598A1 (fr) * 2002-08-16 2004-02-26 Suprapolix, B.V. Monomeres pouvant former quatre liaisons hydrogene et polymeres supramoleculaires formes par copolymerisation de ces monomeres avec des monomeres reguliers

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8247524B2 (en) 2003-11-04 2012-08-21 Suprapolix B.V. Preparation of supramolecular polymers containing quadruple hydrogen bonding units in the polymer backbone
US8268952B2 (en) * 2004-07-12 2012-09-18 Suprapolix B.V. Supramolecular ionomers
US8883188B2 (en) 2005-05-04 2014-11-11 Suprapolix B.V. Modular bioresorbable or biomedical, biologically active supramolecular materials
US9339586B2 (en) 2005-05-04 2016-05-17 Suprapolix B.V. Modular bioresorbable or biomedical, biologically active supramolecular materials
US9907637B2 (en) 2005-05-04 2018-03-06 Suprapolix B.V. Modular bioresorbable or biomedical, biologically active supramolecular materials
US9006364B2 (en) 2006-11-20 2015-04-14 Suprapolix B.V. Supramolecular polymers from low-melting, easily processable building blocks
US8628789B2 (en) 2007-03-23 2014-01-14 Suprapolix, B.V. Strong reversible hydrogels
US10377847B2 (en) 2007-03-23 2019-08-13 Suprapolix B.V. Strong reversible hydrogels
US8754213B2 (en) 2008-07-04 2014-06-17 Suprapolix B.V. High flow supramolecular compounds
US9006386B2 (en) 2010-11-05 2015-04-14 Suprapolix B.V. Process for the preparation of a supramolecular polymer
WO2017194786A1 (fr) 2016-05-13 2017-11-16 Technische Universiteit Eindhoven Post-fonctionnalisation de matériaux supramoléculaires
KR101808961B1 (ko) 2016-10-28 2017-12-13 숭실대학교산학협력단 초분자형 공중합체 형성법을 이용한 고인성 바이오폴리머 및 이의 제조 방법

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