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WO2005110485A1 - Agents de couplage polymeres et polymeres pharmaceutiquement actifs obtenus a partir desdits agents - Google Patents

Agents de couplage polymeres et polymeres pharmaceutiquement actifs obtenus a partir desdits agents Download PDF

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Publication number
WO2005110485A1
WO2005110485A1 PCT/CA2005/000742 CA2005000742W WO2005110485A1 WO 2005110485 A1 WO2005110485 A1 WO 2005110485A1 CA 2005000742 W CA2005000742 W CA 2005000742W WO 2005110485 A1 WO2005110485 A1 WO 2005110485A1
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link
compound
agent
bio
molecular weight
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PCT/CA2005/000742
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English (en)
Inventor
Paul J. Santerre
Frank J. Laronde
Mei Li
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Interface Biologics Inc.
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Priority claimed from CA002467321A external-priority patent/CA2467321A1/fr
Application filed by Interface Biologics Inc. filed Critical Interface Biologics Inc.
Priority to EP15163241.1A priority Critical patent/EP2939695B1/fr
Priority to NZ550739A priority patent/NZ550739A/en
Priority to EP05746912A priority patent/EP1744787A4/fr
Priority to CN2005800154687A priority patent/CN1968715B/zh
Priority to CA2571320A priority patent/CA2571320C/fr
Priority to KR1020067026253A priority patent/KR20070032951A/ko
Priority to AU2005244037A priority patent/AU2005244037A1/en
Priority to JP2007511817A priority patent/JP5247144B2/ja
Publication of WO2005110485A1 publication Critical patent/WO2005110485A1/fr
Priority to HK07110293.6A priority patent/HK1105135A1/xx

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    • 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
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • C08G18/4277—Caprolactone and/or substituted caprolactone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • C08G18/70—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation

Definitions

  • POLYMERIC COUPLING AGENTS AND PHARMACEUTICALLY-ACTIVE POLYMERS MADE THEREFROM FIELD OF THE INVENTION This invention relates to polymeric coupling agents as intermediates, pharmaceutically-active polymers made therefrom, composition comprising said polymers and shaped articles made therefrom.
  • BACKGROUND TO THE INVENTION It has become common to utilize implantable medical devices for a wide variety of medical conditions, e.g., drug infusion and haemodialysis access. However, medical device implantation often comes along with the risk of infections (1), inflammation (2), hyperplasia (3), coagulation (4). It is therefore important to design such materials to provide enhanced biocompatibility.
  • Biocompatibility is defined as the ability of a material to perform with an appropriate host response in a specific application.
  • the host relates to the environment in which the biomaterial is placed and will vary from being blood, bone,, cartilage, heart, brain, etc.
  • the materials themselves, once incorporated into the biomedical device may be inherently limited in their performance because of their inability to satisfy all the critical biocompatibility issues associated with the specific application intended. For instance while one material may have certain anticoagulant features related to platelets it may not address key features of the coagulation cascade, nor be able to resist the colonization of bacteria. Another material may exhibit anti-microbial function but may not be biostable for longterm applications.
  • Bioactive agents containing polymer coatings have been developed to improve the biocompatibility of medical device surfaces.
  • Patnaik et al. (5) described a method of attaching bioactive agents, such as heparin (an anti-coagulant) to polymeric substrates via a hydrophilic, isocyanate/amine-terminated spacer in order to provide a coating of the bio-active material on the medical device.
  • bioactive agent's activity was achieved when the spacer group had a molecular weight of about 100-10,000 daltons. But most preferably that is of 4000 daltons.
  • biomaterial design relates to infection control.
  • a number of strategies have been used in attempts to solve problems such as those associated with medical device infection.
  • One approach is to provide a more biocompatible implantable device to reduce the adhesion of bacteria.
  • Silver coated catheters have been used to prevent exit site infections associated with chronic venous access (6) and peritoneal dialysis (7).
  • longterm studies have failed to demonstrate a significant reduction in the number or severity of exit site infections.
  • bacteria resistance to silver can develop over time and carries with it the risk of multiple antibiotic resistances (8). Since bacteria adhesion is a very complex process, complete prevention of bacteria adhesion is difficult to achieve with only a passive approach. There remains a need for local controlled drug delivery.
  • the advantages for the latter approach include 1) a high and sustained local drug concentration can be achieved without the systemic toxicity or side effects which would be experienced from systemic doses sufficient to obtain similar local drug concentration; 2) high local drug concentration can be attained, even for agents that are rapidly metabolized or unstable when employed systemically; 3) some forms of site-specific delivery have the potential to establish and maintain local drug action, either by preventing its efflux from the arterial wall or by using vehicles or agents that have a prolonged duration of action; 4) it gives the potential for designing a smart drug delivery system, which can be triggered to start the release and/or modulate the rate of release according to the infection status.
  • Methods for obtaining compositions which contain drugs and polymers in a composite form to yield bioactive agent release coatings are known.
  • Chudzik et al. (9) formulated a coating composite that contained a bioactive agent (e.g. a drug) and two polymers, i.e., poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate).
  • a bioactive agent e.g. a drug
  • two polymers i.e., poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate
  • norfloxacin could be released from a drug/polymer conjugate by enzyme media and in vivo studies, the drug/polymer conjugate was effective against Mycobacterium tuberculosis residing in liver (20).
  • norfloxacin was attached pendant to sequences of amino- acids which permitted its cleavage by the lysosomal enzyme, cathepsin B.
  • Santerre (13a) describes the synthesis and use of novel materials to which when added to polymers converts the surface to have bioactive properties, while leaving the bulk properties of the polymer virtually intact. Applications are targeted for the biomedical field.
  • These materials are oligomeric fluorinated additives with pendant drugs that are delivered to the surface of bulk polymers during processing by the migration of the fluorine groups to the air/polymer interface.
  • These materials can deliver a large array of drugs, including anti-microbials, anti-coagulants and anti-inflammatory agents, to the surface.
  • modification is limited to the surface. This becomes a limitation in a biodegradable polymer which may require sustained activity throughout the bio-erosion process ofthe polymer.
  • Santerre and Mittleman (14) teach the synthesis of polymeric materials using pharmacologically-active agents as one of the co-monomers for polymers.
  • 1 ,6- diisocynatohexane and/or 1,12-diisocyanatododecane monomers or their oligomeric molecules are reacted with the antimicrobial agent, ciprofloxacin, to form drug polymers.
  • the pharmacologically-active compounds provide enhanced long term anti- inflammatory, anti-bacterial, anti-microbial and/or anti-fungal activity.
  • the reaction kinetics become challenging.
  • formulations must be selective in order to minimize strong van der Waals interactions between the drug components and hydrogen bonding moieties of the polymer chains since this can delay the effective release of drug.
  • an improvement over the latter system are biomonomers made up of the drugs and agents which, without being bound by theory, would ensure a less restricted access ofthe drug during hydrolysis ofthe polymer, as well as providing more uniform chemical function for reaction with the isocyanate groups or other monomer reagents.
  • the current invention represents a group of novel diamine or diol monomers that simultaneously incorporate the following features: 1) they are synthesized under mild conditions for coupling biological or pharmaceuticals or biocompatible components together via a hydrolysable bond; 2) they contain selectively reactive groups (di-functional or greater) (including amines (secondary or primary) and hydroxyls) that could be used for subsequent polymerization of polyesters, polyamides, polyurethanes, polysulfonamides and many other classical step growth polymers; 3) they contain selectively hydrolysable groups that permit the release of defined degradation products consisting of biological, pharmaceutical or biocompatible components; 4) their molecular weights may vary depending on the molecular weight of the pharmaceutical or biocompatible reagents to be as high as 4000, but typically the molecular weights of the molecules will be preferably less than 2000 in order for them to have good mobility of the molecular segment once incorporated within the polymer, and have good reactivity in the reaction polymerization solution; 5) they provide a strategy for enhancing
  • This invention describes the unique synthesis pathways for the biomonomers, provides examples of their use in the synthesis of polymers and defines methods of processing said polymers for applications as biodegradable materials ranging from biomedical to environmental related products. It is an object of the present invention to provide synthetic pathways of biological coupling agents/biomonomers comprising, such as, anti-inflammatory, anti-bacterial, anti-microbial and/or anti-fungal pharmaceuticals as biomonomer precursors with good reactivity for step growth polymer synthesis. It is a further object of the present invention to provide biological polymers comprising said biological coupling compounds/monomers with pharmaceutically active properties.
  • the invention generally, provides the unique synthesis pathways for covalently coupling biologicals or pharmaceuticals or biocompatible components to both sides of a flexible diol or diamine, such as but not limited to triethylene glycol or any other kind of linear diol or diamine under mild conditions.
  • Bioactive agents must possess a reactive group such as a carboxylic acid, sulfonate or phosphate group which can be conjugated to the flexible diols or diamines by using a carbodiimide-mediated reaction.
  • Bioactive agents used in the coupling reaction must also contain selectively reactive multifunctional and preferably di-functional groups (including amines (secondary or primary) and hydroxyls) that could be used later on for subsequent polymerization of polyesters, polyamides, polyurethanes, polysulfonamides and any other classical step growth polymer pharmaceutic contai ing coupling agents/monomers.
  • the invention provides in one aspect, a biological coupling agent (biomonomer) having a central portion comprising of flexible i.e.
  • the invention provides a biological coupling agent of the general formula (III) PBio-LLNK A-PBio (III) wherein PBio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond and having at least one functional group to permit step growth polymerization; and LINK A is a coupled central flexible linear first segment of ⁇ 2000 theoretical molecular weight linked to each of said PBio fragments.
  • biomonomers in this specification and claims, is meant compounds of the formulae (111) used in the synthesis of the compounds of formula (I) through the use ofthe functional group for step growth polymerization. Most preferably each ofthe PBio fragments is limited to a single functional group for use in step growth polymerization.
  • the invention provides a pharmaceutically-active polymeric compound ofthe general formula (I), Y - [Yêt - LINK B - X] m - LINK B (I) wherein (i) X is a coupled biological coupling agent ofthe general formula (II) Bio - LINK A - Bio (II) wherein Bio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond; and LINK A is a coupled central flexible linear first segment of ⁇ 2000 theoretical molecular weight linked to each of said Bio fragments; (ii) Y is LINK B-OLIGO; wherein (a) LINK B is a coupled second segment linking one OLIGO to another OLIGO and an OLIGO to X or precursor thereof; and (b) OLIGO is a short length of polymer segment having a molecular weight of less than 5,000 and comprising less than 100 monomeric repeating units; (iii) m is 1- 40 ; and (i
  • the invention provides in another aspect, a pharmaceutically-active polymeric material having a backbone made from said biomonomer.
  • Such polymers comprise oligomeric segments of ⁇ 5,000 theoretical molecular weight and optional link segments, herein denoted [link B] covalently coupled to the oligomeric segment denoted herein [oligo] and the said biomonomer.
  • link B link segment
  • oligomeric segment is meant a relatively short length of a repeating unit or units, generally less than about 50 monomeric units and molecular weights less than 10,000 but preferably ⁇ 5000.
  • [oligo] is selected from the group consisting of polyurethane, polyurea, polyamides, polyalkylene oxide, polycarbonate, polyester, polylactone, polysilicone, polyethersulfone, polyolefin, polyvinyl, polypeptide, polysaccharide; and ether and amine linked segments thereof.
  • LINK A molecule is meant a molecule covalently coupling bioactive agents together in said biomonomer.
  • LINK A molecules can have molecular weights ranging from 60 to 2000 and preferably between 60 to 700, and have multi-functionality but preferably di-functionality to permit coupling of two bioactive agents.
  • the LINK A molecules are synthesized from the groups of precursor monomers selected from diols, diamines and/or compounds containing both amine and hydroxyl groups, with or without water solubility. Examples of typical LINK A precursors are given in Table 1 but they are not limited to this list. Table 1
  • LINK B molecule is meant a molecule covalently coupling oligo units together to form the second coupling segments within the central portion.
  • LINK B molecules can have molecular weights ranging from 60 to 2000 and preferably 60-700, and have difunctionality to permit coupling of two oligo units.
  • the LINK B molecules are synthesized from diamines, diisocyanates, disulfonic acids, dicarboxylic acids, diacid chlorides and dialdehydes.
  • Terminal hydroxyls, amines or carboxylic acids on the oligo molecules can react with diamines to form oligo-amides; react with diisocyanates to form oligo-urethanes, oligo-ureas, oligo- amides; react with disulfonic acids to form oligo-sulfonates, oligo-sulfonamides; react with dicarboxylic acids to form oligo-esters, oligo-amides; react with diacid chlorides to form oligo-esters, oligo-amides; and react with dialdehydes to form oligo-acetal, oligo- imines.
  • the term “pharmaceutical or biologically active agent”, or precursor thereof, is meant a molecule that can be coupled to LINK A segment via hydrolysable covalent bonding.
  • the molecule must have some specific and intended pharmaceutical or biological action.
  • the [Bio] unit has a molecular weight ranging from 40 to 2000 for pharmaceuticals but may be higher for biopharmaceuticals depending on the structure of the molecule.
  • the Bio unit is selected from the group of anti- inflammatory, anti-oxidant, anti-coagulant, anti-microbial (including fluoroquinolones), cell receptor ligands and bio-adhesive molecules, specifically oligo-peptides and oligo- saccharides, oligonucleic acid sequences for DNA and gene sequence bonding, and phospholipid head groups to provide cell membrane mimics.
  • the Bio component must have difunctional groups selected from hydroxyl, amine, carboxylic acid or sulfonic acid so that after coupling with Link A molecule, said biomonomer can react with the secondary groups of oligomeric segment to form LINK B linkage. The said secondary group may be protected during the reaction of primary groups with the LINK A.
  • Table 2 Typical Pharmaceutical Molecules Used For The Synthesis Of BiomonomerCoupling Agents
  • This invention is of particular value to those pharmacologically active compounds which are bioresponsive as hereinabove defined to provide in vivo a pharmacological active ingredient which has at least two functional groups but one of the functional groups has low reactivity with diisocyanates to form oligo-urethanes, or oligo-ureas, oligo-amides; react with disulfonic acids to form oligo-sulfonates, oligo-sulfonamides; react with dicarboxylic acids to form oligo-esters, oligo-amides; react with diacid chlorides to form oligo-esters, oligo-amides; and react with dialdehydes to form oligo- acetal, oligo-imines.
  • Such a pharmacological agent would include the fluoroquinolone family of antibiotics, or anti-coagulants, anti-inflammatory or anti-proliferative agents of the type listed in Table 2 above.
  • the present invention is of particular use wherein the pharmacologically-active fragment is formed from the antibacterial 7-amino-l-cyclopropyl-4-oxo-l,4- dihydroquinoline and naphthyridine-3 -carboxylic acids described in U.S. Pat. No. 4,670,444.
  • the most preferred antibacterial members of these classes of compounds is 1- cyclopropyl-6-fluoro-l,4-dihyro-4-oxo-7-piperazine-quinoline-3-carboxylic acid and 1- ethyl-6-fluoro-l,4-dihyro-4-oxo-7-piperazine-quinoline-3 -carboxylic acid having the generic name ciprofloxacin and norfloxacin, respectively.
  • Others of this class include sparfloxacin and trovafloxacin.
  • LINK A offers a range of hydrolysis rates by reason of chain length variation and possibly, also, due to steric and conformational variations resulting from the variations in chain length.
  • Prior art compounds not having LINK A chain length variations but having LINK B chain lengths between the two biological entities cannot provide this advantageous variations in hydrolysis rates.
  • the present invention is of particular use wherein the pharmacologically-active fragment is formed from the anti-inflammatory (2S,3S)-l-Acetyl-4-hydroxy-pyrrolidine- 2-carboxylic acid having generic name Oxaceprol and
  • the present invention is of particular use wherein the pharmacologically-active fragment is formed from the anti-thrombic (S)-2-(butane-l-sulfonylamino)-3-[4-(4- piperidin-4-yl-butoxy)phenyl]-propionic acid having the generic name Tirofibanc and [(S)-7-([4,4']bi ⁇ i ⁇ eridinyl-l-carbonyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- benzo[e][l, 4] diazepin-2-yl] -acetic acid having the generic name Lotrafiban.
  • the present invention is of particular use wherein the pharmacologically-active fragment is formed from the anti-neuplastic ( ⁇ S, 5S)- ⁇ -amino-3-chloro-2- isoxazoleacetic-5-acetic acid having the generic name Acivicin and 4-[Bis(2- chloroethyl)amino-]-L-phenylalanine having the generic name Alkeren.
  • the oligomeric polymeric segment preferably has a molecular weight of ⁇ 10,000; and more preferably, ⁇ 5,000.
  • the term "theoretical molecular weight" in this specification is the term given to the absolute molecular weight that would result from the reaction ofthe reagents utilized to synthesize any given bioactive polymers.
  • the actual measurement of the absolute molecular weight is complicated by physical limitations in the molecular weight analysis of polymers using gel permeation chromatography methods.
  • a polystyrene equivalent molecular weight is reported for gel permeation chromatography measurements. Since many pharmaceutically active compounds absorb light in the UV region, the gel permeation chromatography technique also provides a method to detect the distribution of pharmaceutically active compound coupled within polymer chains.
  • the polymeric materials of use in the practice of the invention have polystyrene equivalent molecular weights of chains ranging from 2xl0 3 to lxlO 6 , and preferably in the range of 2 10 3 to 2xl0 5 .
  • the invention provides compositions of polymers containing biomonomers alone or a base polymer in admixture with polymers containing biomonomers, as hereinabove defined, preferably in the form of a shaped article.
  • typical base polymers of use in admixture with aforesaid bioactive polymers according to the invention includes polyurethanes, polysulfones, polycarbonates, polyesters, polyethylene, polypropylene, polystyrene, polysilicone, poly(acrylonitrile-butadienestyrene), polyamide, polybutadiene, polyisoprene, polymethylmethacrylate, polyvinylacetate, polyacrylonitrile, polyvinyl chloride, polyethylene terephtahate, cellulose and other polysacharides.
  • Preferred polymers include polyamides, polyurethanes, polysilicones, polysulfones, polyolefins, polyesters, polyvinyl derivatives, polypeptide derivatives and polysaccharide derivatives. More preferably, in the case of biodegradable base polymers these would include segmented polyurethanes, polyesters, polycarbonates, polysaccharides or polyamides.
  • the polymers containing said biomonomers, or the admixed compositions according to the invention may be used as a surface covering for an article, or, most preferably, where the polymers or admixtures are of a type capable of being formed into 1) a self-supporting structural body, 2) a film; or 3) a fiber, preferably woven or knit.
  • the composition may comprise a surface or in whole or in part of the article, preferably, a biomedical device or device of general biotechnological use.
  • the applications may include cardiac assist devices, tissue engineering polymeric scaffolds and related devices, cardiac replacement devices, cardiac septal patches, intra aortic balloons, percutaneous cardiac assist devices, extra-corporeal circuits, A-V fistual, dialysis components (tubing, filters, membranes, etc.), aphoresis units, membrane oxygenator, cardiac by-pass components(tubing, filters, etc.), pericardial sacs, contact lens, cochlear ear implants, sutures, sewing rings, cannulas, contraceptives, syringes, o- rings, bladders, penile implants, drug delivery systems, drainage tubes , pacemaker lead insulators, heart valves, blood bags, coatings for implantable wires, catheters, vascular stents, angioplasty balloons and devices, bandages, heart massage cups, tracheal tubes, mammary implant coatings, artificial ducts, craniofacial and maxillofacial reconstruction applications, ligaments, fallopian tubes.
  • the applications of the latter include the synthesis of bioresorbable polymers used in products that are environmentally friendly (including but not limited to garbage bags, bottles, containers, storage bags and devices, products which could release reagents into the environment to control various biological systems including control of insects, biologically active pollutants, elimination of bacterial or viral agents, promoting health related factors including enhancing the nutritional value of drinking fluids and foods, or various ointments and creams that are applied to biological systems (including humans, animals and other).
  • environmentally friendly including but not limited to garbage bags, bottles, containers, storage bags and devices, products which could release reagents into the environment to control various biological systems including control of insects, biologically active pollutants, elimination of bacterial or viral agents, promoting health related factors including enhancing the nutritional value of drinking fluids and foods, or various ointments and creams that are applied to biological systems (including humans, animals and other).
  • the invention provides an admixed composition, as hereinabove defined, comprising in admixture either a segmented polyurethane, a polyester, a polycarbonate, polysaccharide, polyamide or polysilicone with a compatible polymer containing said biomonomer.
  • the polymers containing said biomonomer are synthesized in a manner that they contain a polymer segment, i.e. the [oligo] segments and said biomonomer in the backbone of polymer containing biochemical function with either inherent anti-coagulant, anti-inflammatory, anti-proliferation, anti-oxidant, antimicrobial potential, cell receptor ligands, e.g.
  • peptide ligands and bio-adhesive molecules e.g. oligosaccharides, oligonucleic acid sequences for DNA and gene sequence bonding, or a precursor ofthe bioactive component.
  • the in vivo pharmacological activity generated may be, for example, anti- inflammatory, anti-bacterial, anti-microbial, anti-proliferation, anti-fungal, but this invention is not limited to such biological activities.
  • Figure 1 is a proton nuclear magnetic resonance spectrum of biomononer (coupling agent) NORF-TEG-NORF
  • Figure 2 is the carbon nuclear magnetic resonanece spectrum of biomonomer NOF-TEG- NORF
  • Figure 3 is a positive electrospray mass spectum of biomonomer NORF-TEG-NORF
  • Figure 4. is a proton nuclear magnetic resonance spectrum of biomononer CIPRO-TEG-
  • Figure 5 is a carbon nuclear magnetic resonanece spectrum of biomonomer of CIPRO- TEG-CIPRO
  • Figure 6. is a positive electrospray mass spectum of biomonomer CIPRO-TEG-CIPRO
  • Figure 8. is a carbon nuclear magnetic resonanece spectrum of POC
  • Figure 9. is a positive electrospray mass spectum of POC Figure 10. is a proton nuclear magnetic resonance spectrum of biomononerPOC-TEG-
  • Figure 11 is a carbon nuclear magnetic resonance spectrum of biomononerof POC-TEG-
  • Figure 12. is a positive electrospray mass spectum of POC-TEG-POC Figure 13. is a proton nuclear magnetic resonance spectrum of PAK
  • Figure 14 is a carbon nuclear magnetic resonance spectrum of PAK
  • Figure 15. is a positive electrospray mass spectum of PAK
  • Figure 16 is a proton nuclear magnetic resonance spectrum of biomononer PAK-TEG-
  • PAK Figure 17. is a proton nuclear magnetic resonance spectrum of biomononer PAK-TEG-
  • Figure 18 is a positive electrospray mass spectum of biomononer PAK-TEG-PAK
  • Figure 19 is a gel permeation chromatography analysis of THDI/PCL/NORF
  • Figure 20 is a gel permeation chromatography analysis of THDI/PCL/CIPRO Figure 21. is a cytotoxicity test of control polymer and drug polymers with mammalian cells
  • Figure 22 is a graph ofthe released norfloxacin from NF polymer in the presence and absence of cholesterol esterase;
  • Figure 23 is a graph of Bacteria Counts from Implanted Coupons . DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • linkA molecules have molecular weights ranging from 60 to 2000 and preferably 60 to 700, and must have at least di-functionality to permit coupling of at least two [Bio] units.
  • the [Bio] unit has a molecular weight ⁇ 2000 but may be higher depending on the structure ofthe molecule.
  • Preferred [Bio] components include but are not limited to the following categries and examples: Anti-inflammatory: non-steroidal- Oxaceprol, steroidal Enoxolone; antithrombotic: Tirofiban, Lotrafiban; anti-coagulant: heparin; anti-proliferation: acivicin and alkeren; anti-microbial: fluoroquinolones such as norfloxancin, ciprofloxacin, sparfloxacin and trovafloxacin and other fluoroquinolones.
  • Scheme A provides a general synthetic procedure for preparing the compounds of product D with formula (I).
  • DMAP 4-(dimethylamino)pyridine
  • EDAC l-ethyl-3-(3-dimethylamino-propyl)carbodiimide
  • DCM Dichloromethane
  • step A a pharmaceutically active drug, such as norfloxacin or ciprofloxacin (in the form of hydrochloride salt) is reacted with protecting groups such as trityl halides in the presence of triethylene amine to provide an intermediate with both amine and carboxylic acid groups protected with a trityl group.
  • protecting groups such as trityl halides in the presence of triethylene amine to provide an intermediate with both amine and carboxylic acid groups protected with a trityl group.
  • protecting groups such as trityl halides in the presence of triethylene amine to provide an intermediate with both amine and carboxylic acid groups protected with a trityl group.
  • a suitable trityl halide is reacted with norfloxacin or ciprofloxacin hydrochloride salt in a suitable solvent, such as chloroform.
  • Suitable trityl halides include trityl chloride and trityl bromide.
  • a preferred trityl halide is trityl chloride.
  • the amount of trityl halide ranges from 2 to 4 molar equivalent of norfloxacin/ciprofloxacin, a preferred amount is 2.2 molar equivalents.
  • Triethylamine is added to scavenge free HC1 which is generated as a byproduct.
  • a little excess amount of triethylamine will avoid the deprotection of the N- triethylamine group in the following selective hyrolyzation step.
  • an excess molar amount of triethylene amine such as 2 to 4 times was added into reaction mixture. A preferred amount is 3 times.
  • the reaction mixture is stirred for a period of time ranging from 2-24 hours in a temperature range of 0 °C to 60 °C. A preferred stirring time is 4 hours and a preferred temperature is 25 °C.
  • a homogenous solution is obtained.
  • product A is left in the reaction solution for the next step ofthe in-situ reaction. No isolation ofthe product A is required during processing.
  • step B the reaction product of step A, such as norfloxacin/ciprofloxacin with both amine and carboxylic acid groups protected with trityl group, is selectively deprotected to yield product B containing free carboxylic acid and N-triethylamine groups.
  • a large amount of methanol was added into the reaction mixture of step A.
  • the volume of methanol ranges from equivalent to two times that of the solvent used in step A.
  • a preferred volume is 1.5 times that of the solvent volume.
  • the reaction mixture is stirred for 1-24 hrs in a temperature range from 25 °C to 60 °C.
  • a preferred stirring time is 2 hrs and a preferred temperature is 50 °C.
  • the selectively deprotected fluroquinolone material is precipitated from the reaction solution.
  • Product B is recovered from the reaction zone by filtration after the reaction mixture is cooled down to room temperature.
  • Product B is further purified from CHCl 3 /Methanol (9:1) by standard recrystallization method.
  • step C the purified amine-protected fluroquinolone is coupled to both sides of a diol or diamine (in this example, triethylene glycol is used) containing a flexible and/or water-soluble central portion.
  • the purified amine-protected fluroquinolone (Product B) is coupled to a tri(ethylene glycol) in the presence of a suitable coupling agent such as l-ethyl-3-(3- dimethylamino-propyl)carbodiimide herein denoted as EDAC and an appropriate base such as 4-(dimethylamino)pyridine herein denoted as DMAP as a catalyst.
  • a suitable coupling agent such as l-ethyl-3-(3- dimethylamino-propyl)carbodiimide herein denoted as EDAC
  • an appropriate base such as 4-(dimethylamino)pyridine herein denoted as DMAP as a catalyst.
  • coupling reagents may include various carbodiimides such as CMC (l-cyclohexyl-3-(2- morpholinoethyl)carbodiimide), DCC (N,N'-dicyclohexyl- carbodiimide), DIC (Diisopropyl carbodiimide) etc, but are not limited to these.
  • the amount of diol ranges from 0.3 to 0.5 molar equivalent of product B.
  • a preferred amount of diol is 0.475 molar equivalent of product B.
  • the amount of coupling agent EDAC ranges from 2 to 10 times molar equivalent of product B.
  • a preferred amount of EDAC is 8 times molar equivalent.
  • the amount of base DMAP can range from 0.1 to equal molar amount of product B.
  • a preferred amount is 0.5 molar equivalents.
  • the reaction was carried out in a suitable solvent such as dichloromethane under a noble atmosphere such as nitrogen, argon. Other solvents may be appropriate depending on their solubility properties with product B and their potential reactivity with the reagents.
  • the reactants are typically stirred together for a period of time ranging from 24 hours to 2 weeks at a temperature range from 0 °C to 50 °C. A preferred stirring time is one week and a preferred temperature is 25 °C.
  • solvent is removed by rotary evaporator. The residues are washed with water several times to remove soluble reagents such as EDAC.
  • step D the N-trietylamine groups of the purified product C are deprotected to yield the corresponding desired pharmaceutical coupling agent/biomonomer.
  • the appropriate product C is reacted with a small amount of water in the presence of a small amount of weak acid, such as trifluoroacetic acid, in a suitable organic solvent such as dichloromethane.
  • the amount of water can range from 1% to 10% volume percentage and a preferred amount is 1%.
  • the amount of trifluoroacetic acid is between 1% to 10% volume percent, with a preferred amount being 2%.
  • the reaction mixture is stirred within a temperature range of 0 °C to 50 °C over a time period of 2 to 24 hours. A preferred temperature is 25 °C and a preferred time period is 4 hours.
  • Product D is precipitated from reaction solution and collected by filtration. The product is further purified by washing with CHC1 3 .
  • Biomonomers in a Polymer Synthesis The pharmaceutically active polymers are synthesized in a traditional stepwise polymerization manner as are well known in the art.
  • a multi-functional LINK B molecule and a multi-functional oligo molecule are reacted to form a prepolymer.
  • the prepolymer chain is extended with said biomonomer to yield a polymer containing the biomonomers.
  • Non- biological extenders such as an ethylene diamine, butane diol, ethylene glycol and others may also be used
  • the linkB molecule is preferably, but not so limited, to be di-functional in nature, in order to favour the formation of a linear polymer containing biomonomers.
  • Preferred linkB molecules for biomedical and biotechnology applications are diisocyanates: for example, 2,4 toluene diisocyanate; 2,6 toluene diisocyanate; methylene bis(p-phenyl)diisocyanate; lysine dusocyanato esters; 1,6 hexane diisocyanate; 1,12 dodecane diisocyanate; bis-methylene di(cyclohexyl isocyanate); trimethyl-1,6 diisocyanatohexane, dicarboxylic acids,- di-acid chlorides, disulfonyl chlorides or others.
  • diisocyanates for example, 2,4 toluene diisocyanate; 2,6 toluene diisocyanate; methylene bis(p-phenyl)diisocyanate; lysine dusocyanato esters; 1,6 hexane diisocyanate; 1,12 dodecane diisocyan
  • the oligo component is preferably, but not so limited, difunctional, in order to favor the formation of a linear polymer containing said biomonomers.
  • Preferred oligo components are terminal diamine and diol reagents of: for example, polycarbonate, polysiloxanes, polydimethylsiloxanes; polyethylene-butylene co-polymers; polybutadienes; polyesters including polycaprolactones, polylactic acid, and other polyesters; polyurethane/sulfone co-polymer; polyurethanes; polyamides; including oligopeptides (polyalanine, polyglycine or copolymers of amino-acids) and polyureas; polyalkylene oxides and specifically polypropylene oxide, polyethylene oxide and polytetramethylene oxide.
  • the molecular weights of the [oligo] groups are less than 10,000, but preferably have molecular weights of less than 5000.
  • Synthesis of the prepolymers to the bioactive polymer can be carried out by classical urethane/urea reactions using the desired combination of reagents but with the. excess amount of linkB molecules in order to end-cap the prepolymer with linkB molecule.
  • said biomonomer is added to extend the prepolymer chain giving a final bioactive polymer.
  • the biomonomers may be substituted for inclusion as the oligo groups.
  • Bioactive polymers can be synthesized with different components and stoichometry.
  • the LINK B molecules Prior to synthesis, the LINK B molecules are, preferably, vacuum distilled to remove residual moisture.
  • the biomonomers are desiccated to remove all moisture. Oligo components are degassed overnight to remove residual moisture and low molecular weight organics.
  • Typical organic solvents include, for example, dimethylacetamide, acetone, tetrahydrofuran, ether, chloroform, dimethylsulfoxide and dimethylformamide.
  • a preferred reaction solvent is dimethylsulfoxide (DMSO, Aldrich Chemical Company, Milwaukee, Wis.).
  • a catalyst is preferred for the synthesis.
  • Typical catalysts are similar to those used in the synthesis of urethane chemistry and, include, dibutyltin dilaurate, stannous octoate, N,N' diethylcyclohexylamine, N-methylmorpholine, 1,4 diazo (2,2,2) bicyclo-octane and zirconium complexes such as Zr tetrakis (2,4-pentanedionato) complex.
  • the linkB molecules are added to the oligo component and, optionally, catalyst to provide the prepolymer of the bioactive polymer.
  • the reaction mixture is stirred at a temperature of 60 °C for a suitable time period, which depends on the reaction components and the stoichiometry. Alternate temperatures can range between 25 °C to 110 °C.
  • said biomonomer is added to the prepolymer and, generally, the mixture is allowed to react overnight.
  • the reaction is terminated with methanol and the product is precipitated in ether or a mixture of distilled water with ether or other suitable solvents.
  • the precipitate is dissolved in a suitable solvent, such as acetone and precipitated in ether or a mixture of distilled water with ether again. This process was repeated 3 times in order to remove any residual catalyst compound. Following washing, the product is dried under vacuum at 40°C. •
  • a suitable solvent such as acetone and precipitated in ether or a mixture of distilled water with ether again. This process was repeated 3 times in order to remove any residual catalyst compound. Following washing, the product is dried under vacuum at 40°C.
  • the biomonomers can be used to make polyamides using classical reactions such as those described below.
  • compositions containing biomonomers are either used alone or admixed with suitable amounts of base polymers in the fabrication of article products. If admixed in a blend, then suitable polymers may include polyurethane, polyester or other base polymers.
  • Product may be formed by; 1) compounding methods for subsequent extrusion or injection molding or articles; 2) co-dissolving of base polymer with bioactive polymer into a solvent of common compatibility for subsequent casting of an article in a mold or for spinning fibers to fabricate an article; 3) wetting the surface of an article with a solution of bioactive polymer or a blend in solvent of common compatibility with a polyurethane or other polymer to which the bioactive polymer solution is being applied; or 4) in admixture with a curable polyurethane, for example, 2 part curing system such as a veneer. All of the above processes can be used with the pure polymer, containing the biomonomer groups or with blends of said polymer and common biomedical polymers.
  • the invention thus, provides the ability to synthesize a range of novel polymeric materials possessing intramolecular properties of pharmaceutical or biological nature.
  • the bioactive polymer provides the composite having better pharmaceutical function, particularly for use in medical devices, promoting cell function and regulation, tissue integration, . pro-active blood compatibility and specifically anti-coagulant/platelet function, biostability function, anti-microbial function and anti-inflammatory function, or for use in the biotechnology sector for biological activity.
  • bioresorbable polymers used in medical device products that require the delivery of biologicals, pharmaceuticals or the release of biocompatible materials upon biodegradation within or in contact with a biological body (human or animal).
  • Such product can include but are not limited to: cardiac assist devices, tissue engineering polymeric scaffolds and related devices, cardiac replacement devices, cardiac septal patches, intra aortic balloons, percutaneous cardiac assist devices, extra-corporeal circuits, A-V fistual, dialysis components (tubing, filters, membranes, etc.), aphoresis units, membrane oxygenator, cardiac by-pass components(tubing, filters, etc.), pericardial sacs, contact lens, cochlear ear implants, sutures, sewing rings, cannulas, contraceptives, syringes, o- rings, bladders, penile implants, drug delivery systems, drainage tubes , pacemaker lead insulators, heart valves, blood bags, coatings for implantable wires, catheters, vascular stents, angioplasty balloons and devices, bandages, heart massage cups, tracheal tubes, mammary implant coatings, artificial ducts, craniofacial and maxillofacial reconstruction applications, ligaments, fallopian tubes.
  • Non-medical applications may include of bioresorbable polymers used in products that are environmentally friendly (including but not limited to garbage bags, bottles, containers, storage bags and devices, products which could release reagents into the environment to control various biological systems including control of insects, biologically active pollutants, elimination of bacterial or viral agents, promoting health related factors including enhancing the nutritional value of drinking fluids and foods, or various ointments and creams that are applied to biological systems (including humans, animals and other).
  • environmentally friendly including but not limited to garbage bags, bottles, containers, storage bags and devices, products which could release reagents into the environment to control various biological systems including control of insects, biologically active pollutants, elimination of bacterial or viral agents, promoting health related factors including enhancing the nutritional value of drinking fluids and foods, or various ointments and creams that are applied to biological systems (including humans, animals and other).
  • TEG Triethylene glycol
  • HDL l,6-Hexanediol
  • TrCl (Trityl Chloride)
  • EDAC l-ethyl-3-(3-dimethylamino-propyl)carbodiimide
  • TEA Triethylene amine
  • MIC Minimum inhibitory concentration assays were used to evaluate the antimicrobial activity of incubating solutions obtained from drug polymer biodegradation studies against P. aeruginosa. Turbidity of each culture was recorded to evaluate the inhibitory properties of degradation solution of drug polymers. Sterilization stability of drug polymers was estimated after drug polymers were sterilized by ⁇ -radiation sterilization (radiation dose: 25 Kgy), a standard method in the medical device field. GPC measurements were carried on with these samples before and after they were radiated and after a time period of 1 to 4 weeks. Biocompatibility study ofthe drug polymers was also performed in order to assess the biocompatibility of control and drug polymers with mammalian cells.
  • Example 1 NORF-TEG-NORF and CIPRO-TEG-CIPRO are examples of antimicrobial drug containing biomonomers according to the invention.
  • the example shows the use of a single drug or combination of drugs.
  • the conditions of synthesis for this reaction are as follows.
  • step A of NORF(1.3g, 4 mmol) / or CIPRO hydrochloride salt (4 mmol) were reacted with trityl chloride (2.7g, 8.8 mmol) and TEA(0.6ml, 8 mmol) (Aldrich, 99%)/or 12 mmol of TEA in the case of CIPRO in 40 ml of CHC1 3 for four hours at room temperature. A clear solution was obtained.
  • step B 40 ml of methanol was added into the above clear solution.
  • the mixture was heated to 50 °C and stirred for one hour; a precipitate appeared in the solution.
  • precipitates were collected by filtration. The precipitate was further purified from CHCl 3 /methanol.
  • step C Product B (20 mmol), TEG (1.44g, 9.5 mmol), DMAP (1.24g, lOmmol) were dissolved in 100 ml DCM. EDAC (31g, 160 mmol) was then added into the reaction system. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for one week. After reaction was finished, DCM was removed by rotary evaporator. The residues were washed with de-ionized water several times to remove soluble reagents such as the by-product of urea. The solids were then dissolved in chloroform and washed with de-ionized water again.
  • step D the purified product C (5.4g, 4.4 mmol) was dissolved in chloroform containing one volume percent of water and 1 volume percent of trifluoroacetic acid. The reaction solution was stirred at room temperature for 4 hrs. White precipitates that were produced in the reaction were collected by filtration and purified by washing with chloroform. Following washing Product D, i.e.
  • Example 2 CIPRO-HDL-CIPRO is example of biomonomer according to the invention and different from example 1 by the introduction of a hydrophobic link A molecule rather than hydrophilic link A molecule.
  • the conditions of synthesis for this reaction are as follows.
  • the reaction conditions for selectively protecting amine groups of CIPRO are the same as the step A and B in Example 1.
  • step C Product B (20 mmol), HDL (9.5 mmol), DMAP (1.24g, lOmmol) were dissolved in 100 ml DCM.
  • EDAC 31 g, 160 mmol
  • the reaction mixture was stirred at room temperature under a nitrogen atmosphere for one week. After the reaction was finished, DCM was removed by rotary evaporator.
  • step D the purified product C (4 mmol) was dissolved in chloroform containing one volume percent of water and 1 volume percent of trifluoroacetic acid. The reaction solution was stirred at room temperature for 4 hrs.
  • Example 3 NORF-HDA-NORF is example of biomonomer according to the invention and different from example 1 in that a diamine is used to generate an amide rather than ester linkage in the biomonomer.
  • the conditions of synthesis for this reaction are as follows. The reaction conditions for selectively protecting amine groups of NORF are the same as the step A and B in Example 1.
  • step C Product B (20 mmol), HDA (9.5 mmol), DMAP (1.24g, lOmmol) were dissolved in 100 ml DCM.
  • EDAC (31g, 160 mmol) was then added into reaction system.
  • the reaction mixture was stirred at room temperature under a nitrogen atmosphere for one week.
  • DCM was removed by rotary evaporator.
  • the residues were washed with de-ionized water several times to remove soluble reagents such as the by-product of urea.
  • the solids were then dissolved in chloroform and washed with de-ionized water again.
  • the crude product of the reaction was recovered from the solution by extraction.
  • Product C was isolated by column chromatography using the developer of chloroform/methanol/ammonia hydroxyl aqueous solution (9.2:0.6:0.2).
  • Product C is further purified with recrystallization technique from chloroform and methanol.
  • step D the purified product C (4 mmol) was dissolved in chloroform containing one volume percent of water and 1 volume percent of trifluoroacetic acid. The reaction solution was stirred at room temperature for 4 hrs. White precipitates produced in the reaction were collected by filtration and purified by washing with chloroform. Following washing Product D, i.e. the biomonomer was dried in vacuum oven for 24 hours at a temperature of 40 °C.
  • Example 4 OC-TEG-OC is an example of anti-inflammatory drug containing biomonomer according to the invention.
  • the biomonomer was synthesized using Oxaceprol (OC), by reacting the carboxylic acid with the hydroxyl of TEG and leaving the hydroxyl for subsequent use in the polymerization.
  • the conditions of synthesis for this reaction are as follows.
  • OC 11.55 mmol
  • t-butyldimethylsilyl chloride 28.87 mmol
  • l,8-diazabicylco[5.4.0]undec-7-ene (30.03 mmol) in 4 ml of acetonitrile at 0 °C during the addition of the base and then overnight at ambient temperature.
  • a precipitate developed during the progress ofthe reaction
  • the precipitate was filtered.
  • step B the filtrate was treated with water (10 ml) and extracted with n-pentane
  • the resulting solution was cooled to 0 °C before the addition of tetra n-butyl ammonium fluoride (x ml, 1.4 mmol).
  • the resulting solution was stirred at 0 °C for 5 min before the removal of the ice bath and continued stirring for an additional 40 min at ambient temperature.
  • the solvent was removed at reduced atmosphere and the residue was treated with water and the pH of the solution was adjusted to 3 upon which a precipitate resulted.
  • the precipitate was filtered to produce the desired product.
  • TF-TEG-TF is an example of anti-thrombic drug containing biomonomer according to the invention.
  • the biomonomer is synthesized using tirofiban (TF), reacting the carboxylic acid with the hydroxyl of TEG and leaving the amines for subsequent use in the polymerization.
  • the conditions for synthesis for this reaction are as follows.
  • TF(4 mmol) is reacted with trityl chloride (8.8 mmol) and TEA (8 mmol) (Aldrich, 99%) in 40 ml of CHC1 3 for four hours at room temperature. A clear solution is obtained.
  • step B 40 ml of methanol is added into the above clear solution. The mixture is heated to 50 °C and stirred for one hour, a lot of precipitates appeared in the solution.
  • step C Product B (20 mmol), TEG (9.5 mmol), DMAP (1.24g, lOmmol) were dissolved in 100 ml DCM. EDAC (31g, 160 mmol) is added into the reaction system. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for one week. After reaction is finished, DCM was removed by rotary evaporator. The residues were washed with de-ionized water several times to remove soluble reagents such as the by-product of urea. The solids were then dissolved in chloroform and washed with de- ionized water again. The crude product of the reaction is recovered from the solution by extraction.
  • Product C was isolated by column chromatography using the developer of chloroform/methanol/ammonia hydroxide aqueous solution (9.2:0.6:0.2). Product C is further purified with recrystallization technique from chloroform and methanol.
  • step D the purified product C (4 mmol) is dissolved in chloroform containing one volume percent of water and 1 volume percent of trifluoroacetic acid. The reaction solution is stirred at room temperature for 4 hrs. White precipitates produced in the reaction were collected by filtration and purified by washing with chloroform. Following washing Product D, i.e. the biomonomer is dried in vacuum oven for 24 hours at a temperature of 40 °C.
  • AK-TEG-AK is an example of anti -proliferation drug containing biomonomer according to the invention.
  • the biomonomer was synthesized using Alkeren (AK), reacting the carboxylic acid with the hydroxyl of TEG and leaving the amines for subsequent use in the polymerization.
  • the conditions for synthesis for this reaction are as follows.
  • step A AK (0.32 mmol) was reacted with di-tert-butyl carbonate (0.5 mmol) and TEA(0.32 mmol) (Aldrich, 99%) in THF (4 ml).
  • the suspension was cooled to 0 °C before the addition of the anhydride.
  • Dimethylformamide (0.9 ml) was added to homogenize the reaction mixture.
  • the solution was stirred for 2 hours at 0 °C, and thereafter overnight at ambient temperature.
  • the solution is then evaporated under reduced pressure and the yellowish oily residue obtained is redissolved in a 5 % aqueous solution of sodium bicarbonate (3ml).
  • the solution is washed with petroleum ether ( 3 x 3 ml) and the aqueous phase was acidified to a pH of 3 with a IN hydrochloric acid solution.
  • the mixture was extracted with ethyl acetate (3 x 3 ml).
  • the organic phases were dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure.
  • step D the purified product C (2 mmol) was dissolved in chloroform containing one volume percent of water and 1 volume percent of trifluoroacetic acid. The reaction solution was stirred at room temperature for 2 hrs. White precipitates produced in the reaction were collected by filtration and purified by washing with chloroform. Following washing Product D, i.e. the biomonomer was dried in vacuum oven for 24 hours at a temperature of 40 °C.
  • THDI/PCL/NORF is an example of pharmaceutically active polyurethane containing 15% of drugs according to the invention.
  • the conditions of synthesis for this reaction are as follows. 1.5 grams of PCL are reacted with 0.27 grams of THDI in the presence of 0.06 ml of the catalyst, dibutyltin dilaurate, in a nitrogen atmosphere with in dimethylsulfoxide (DMSO) (10 mL) for one hour. The reaction temperature is maintained between 60- 70°C. 0.32 grams of NORF-TEG-NORF is dissolved in 5 ml DMSO was then added into reaction system. The reaction is keep at 60-70°C for 5 hours and then at room temperature for overnight. Reaction is finally stopped with 1 ml of methanol.
  • DMSO dimethylsulfoxide
  • Example 8 AC/CIPRO is an example of pharmaceutically active polyamide containing antimicrobial drug Ciprofloxacin according to the invention. It differs from example 1 in that it is not a polyurethane and shows the versatility for the use of the biomonomers in a range of step growth polymerizations.
  • the conditions for this synthesis are a common polyamide interfacial polycondensation reaction. They are described as follows: A solution of 3.88 g (5 mmol) of CIPRO-TEG-CIPRO and 1.06 g (10 mmol) of sodium carbonate in 30 ml of water was cooled in an ice bath for 15 min before addition of as the water phase to a 150 ml flask containing a stir bar.
  • a organic solution containing 0.915 g of adipoyl chloride (AC, 5mmol) in 20 ml of methylene chloride was added slowly into the water phase under vigorously stirring.
  • the organic solution has been previously cooled in an ice bath for 15 min.
  • an additional 5 ml of methylene chloride was used to rinse the original acid chloride container and transfer the solvent to reaction flask.
  • the polymerization medium was stirred at maximum speed for an additional 5 min.
  • the resulting polymer was collected by filtration.
  • the polymer was then washed with water for at least 3 times. It was then washed with acetone twice.
  • the product was vacuum-dried at 40 °C for 24 hours.
  • Gamma irradiation is a popular and well-established process for sterilizing polymer-based medical devices (21). It has been known, however, that this technique can lead to significant alterations in the materials being treated.
  • High-energy radiation produces ionization and excitation in polymer molecules.
  • the stabilization process ofthe irradiated polymer results in physical and chemical cross-linking or chain scission, which occurs during, immediately after, or even days, weeks after irradiation.
  • NF and CP polymers are dissolved in a suitable solvent such as chloroform at 10%.
  • the films are cast in a suitable holder such as Teflon mold and placed in a 60°C air flowing oven to dry. The dried films are sterilized by gamma radiation.
  • the dose shall be capable of achieving the pre-selected sterility assurance level (22).
  • One of two approaches shall be taken in selecting the sterilization dose: (a) selection of sterilization dose using either l)bioburden information, or 2)information obtained by incremental dosing; b) Selection of a sterilization dose of 25 Kgy following substantiation of the appropriateness of this dose.
  • the films are analyzed by GPC to detect the change in the number-averaged molecular weight (Mn), weight-averaged molecular weight (Mw), and polydispersity (Mw/Mn) of polymer chains before and after radiation.
  • Mn number-averaged molecular weight
  • Mw weight-averaged molecular weight
  • Mw/Mn polydispersity
  • Example 10 shows the in vitro cytotoxicity of a non-bioactive control polymer, NF and CP polymers with mammalian cell lines using a direct contact method.
  • 1 ml of polymer DMSO solutions containing 1 mg/ml, 3 mg/ml and 5 mg/ml, respectively, of control or drug polymer is loaded on each Millipore 0.45 ⁇ m filter that is set on top of agar in a Petri dish. These dishes are then incubated at 37 °C in a humidified atmosphere of 5% CO 2 for 24 hours. After the solvent is diffused into agar, these filters with polymers loaded on it are transferred into a new Petri dish containing solidified agar. HeLa cells are seeded onto these filters.
  • the dishes are incubated at 37°C in a humidified atmosphere of 5% CO 2 for 48 hours.
  • Cells are stained with succinic dehydrogenase staining buffer.
  • the stained areas on the filters show the cytotoxicity of materials.
  • Figure 7 show the scanned pictures of stained cells that are seeded on the filters loaded with different amounts of control, NF and CP polymers. There are no unstained areas in each filter. The results show that the control polymer and bioactive polymers have good biocompatibility with mammalian cells.
  • Example 11 NF polymer was used to evaluate the ability of a hydrolytic enzyme to degrade the material and preferentially release drug.
  • NF polymer was coated onto small glass cylinders, and then incubated in the presence and absence of hydrolytic enzyme (i.e. cholesterol esterase) for up to 10 weeks at 37 °C. At each week interval the incubation solution was removed from NF polymer and fresh enzyme solution was added. The incubation solutions were assayed via high pressure liquid chromatography (HPLC). Standard solutions of pure norfloxacin were run through an HPLC system to get calibration curve of this system. Norfloxacin concentration in the incubated solution was determined by comparison of drug peak area of incubation solution to calibration curve.
  • HPLC high pressure liquid chromatography
  • Figure 8 shows the released norfloxacin from NF polymer in the presence and absence of cholesterol esterase.
  • a biological assay A macro-dilution minimum inhibitory concentration (MIC) assay was employed to determine the concentration of antimicrobial (norfloxacin) that would inhibit the growth of a pathogen often associated with device-related infections, Pseudomonas aeruginosa.
  • MIC macro-dilution minimum inhibitory concentration
  • the MIC for this organism and norfloxacin was determined to be 0.8 mu g/mL.
  • Incubation solutions from both enzyme and buffer control treatment of NF polymer were used in a biological assay matrix that was designed to estimate the concentration of norfloxacin as a function of incubation time and treatment.
  • the data are presented in Table 4.
  • Anti-microbial activity was not detected in the NF polymer exposed to buffer (control) incubation solution after 2 weeks.
  • the enzyme-treated NF polymers released clinically significant levels (>MIC levels) of antibiotic over a 10 week incubation period.
  • Example 13 In vivo animal studies are performed on formed coupons made of control and CP polymer with a dimension of 1x2 cm 2 .
  • the coupons were implanted in the peritoneal cavity of male rats.
  • the coupons were explanted after rats were housed for 1 week.
  • the experimental conditions according to the invention are as follows: For implantation, 5 male Sprague-Dawley rats (250-300 g) were used for every group of experiment. After they were anesthetised, a 2 cm laparotomy incision was made in the abdomen. The omentum and gubernaculum tissues were resected as they tend to envelop the coupon. Then either a control coupon or a CP coupon (1x2 cm 2 ) was implanted in the abdominal cavity.
  • Example 12 Examples of biomedical articles that integrate the bioactive polymers to the polymers using described methods 1, 2, 3 below include, for example, the following articles that are in whole or in part made of polyurethane components, namely, cardiac assist devices, tissue engineering polymeric scaffolds and related devices, cardiac replacement devices, cardiac septal patches, intra aortic balloons, percutaneous cardiac assist devices, extra-corporeal circuits, A-V fistual, dialysis components (tubing, filters, membranes, etc.), aphoresis units, membrane oxygenator, cardiac by-pass components(tubing, filters, etc.), pericardial sacs, contact lens, cochlear ear implants, sutures, sewing rings, cannulas, contraceptives, syringes, o-rings, bladders, penile implants, drug delivery systems, drainage tubes , pacemaker lead insulators, heart valves, blood bags, coatings for implantable wires, catheters, vascular stents, angioplasty balloons and devices, bandages, heart
  • Non-biomedical articles fabricated by hereinbefore method 1) include, for example, extruded health care products, bio-reactor catalysis beds or affinity chromatography column packings, or a biosensor and bio-diagnostic substrates.
  • Non-medical applications that are exemplified by method 2) include fibre membranes for water purification.
  • Non-medical applications of the type exemplified by method 3) include varnishes with biological function for aseptic surfaces.

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Abstract

L'invention concerne un composé polymère pharmaceutiquement actif de formule générale (I), Y-[Yn-LINK B-X]m-LINK B (I), dans laquelle (i) X représente un agent de couplage biologique couplé, de formule générale (II), Bio-LINK A-Bio (II), dans laquelle Bio représente un fragment d'agent biologiquement actif ou un précurseur de celui-ci, lié à LINK A par une liaison covalente hydrolysable ; et LINK A représente un premier segment linéaire flexible central, couplé, de poids moléculaire théorique <2000, lié à chacun desdits fragments Bio ; (ii) Y représente LINK B-OLIGO ; dans laquelle (a) LINK B représente un deuxième segment couplé liant un OLIGO à un autre OLIGO et un OLIGO à X ou à un précurseur de celui-ci ; et (b) OLIGO représente une longueur courte d'un segment polymère présentant un poids moléculaire inférieur à 5000 et contenant moins de 100 unités récurrentes monomères ; (iii) m est compris entre 1 et 40 ; et (iv) n est choisi entre 2 et 50. Les composés selon l'invention sont utiles en tant que biomatériaux, en particulier des biomatériaux à activité antibactérienne in vivo. L'invention concerne également des agents de couplage biologiques, utiles en tant qu'intermédiaires dans la préparation de ces composés polymères pharmaceutiquement actifs.
PCT/CA2005/000742 2004-05-14 2005-05-13 Agents de couplage polymeres et polymeres pharmaceutiquement actifs obtenus a partir desdits agents WO2005110485A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP15163241.1A EP2939695B1 (fr) 2004-05-14 2005-05-13 Agents de couplage de polymères et polymères pharmaceutiquement actifs réalisés à partir de ceux-ci
NZ550739A NZ550739A (en) 2004-05-14 2005-05-13 Polymeric coupling agents and pharmaceutically-active polymers and therefrom
EP05746912A EP1744787A4 (fr) 2004-05-14 2005-05-13 Agents de couplage polymeres et polymeres pharmaceutiquement actifs obtenus a partir desdits agents
CN2005800154687A CN1968715B (zh) 2004-05-14 2005-05-13 聚合偶合剂和由其制备的具有药学活性的聚合物
CA2571320A CA2571320C (fr) 2004-05-14 2005-05-13 Agents de couplage polymeres et polymeres pharmaceutiquement actifs obtenus a partir desdits agents
KR1020067026253A KR20070032951A (ko) 2004-05-14 2005-05-13 고분자 커플링제 및 그로부터 제조된 약제학적 활성 고분자
AU2005244037A AU2005244037A1 (en) 2004-05-14 2005-05-13 Polymeric coupling agents and pharmaceutically-active polymers made therefrom
JP2007511817A JP5247144B2 (ja) 2004-05-14 2005-05-13 高分子カップリング剤およびそれらから製造された薬学的に活性のあるポリマー
HK07110293.6A HK1105135A1 (en) 2004-05-14 2007-09-21 Polymeric coupling agents and pharmaceutically-active polymers made therefrom

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CA002467321A CA2467321A1 (fr) 2004-05-14 2004-05-14 Agents de couplage polymeres et polymeres ayant une activite pharmaceutique produits a partir de ceux-ci
CA2,467,321 2004-05-14
US10/875,550 US20050255079A1 (en) 2004-05-14 2004-06-25 Polymeric coupling agents and pharmaceutically-active polymers made therefrom
US10/875,550 2004-06-25

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148230A3 (fr) * 2006-04-14 2008-06-12 Interface Biologics Inc Polymères greffés et leurs utilisations
JP2009506055A (ja) * 2005-08-22 2009-02-12 クイック−メッド テクノロジーズ、インク． 第四級アンモニウムポリマーおよびコポリマーを用いた殺菌剤
EP2040758A2 (fr) * 2006-06-30 2009-04-01 Interface Biologics Inc. Polymeres biosensibles
WO2009129630A1 (fr) * 2008-04-25 2009-10-29 Interface Biologics Inc. Polymères actifs de manière pharmaceutique, greffés de façon covalente
EP2273989A4 (fr) * 2008-04-07 2013-05-01 Interface Biologics Inc Polythérapie pour le traitement des infections bactériennes
US10588862B2 (en) 2018-02-02 2020-03-17 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US11279729B2 (en) 2020-05-01 2022-03-22 Ripple Therapeutics Corporation Heterodimer compositions and methods for the treatment of ocular disorders

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4625852A (en) 1985-09-05 1986-12-02 Coil Acceptors, Inc. Coin detection and validation means and method
DK3357522T3 (da) * 2013-03-15 2020-01-27 Ripple Therapeutics Corp Coatet medicinsk genstand til lægemiddelsfrigivelse

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5798115A (en) * 1996-02-15 1998-08-25 Santerre; Paul J. Bioresponsive pharmacologically-active polymers and articles made therefrom
US6051576A (en) * 1994-01-28 2000-04-18 University Of Kentucky Research Foundation Means to achieve sustained release of synergistic drugs by conjugation
CA2461099A1 (fr) * 2001-09-21 2003-04-10 The Administrators Of The Tulane Educational Fund Conjugues d'analogues de somatostatine ou de bombesine a vocation diagnostique ou therapeutique, et utilisations correspondantes
US6689350B2 (en) * 2000-07-27 2004-02-10 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US20040087664A1 (en) * 2002-08-14 2004-05-06 Marcus Dennis Michael Methods and compositions for treatment of macular and retinal disease

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6468519B1 (en) * 1997-09-10 2002-10-22 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
ES2296344T3 (es) * 1997-09-10 2008-04-16 Rutgers, The State University Polianhidridos con productos de degradacion terapeuticamente utiles.
AU2001279064A1 (en) * 2000-07-27 2002-02-13 Rutgers, The State University Therapeutic azo-compounds for drug delivery
US20030158598A1 (en) * 2001-09-17 2003-08-21 Control Delivery Systems, Inc. System for sustained-release delivery of anti-inflammatory agents from a coated medical device
CA2467559A1 (fr) * 2001-11-19 2003-05-30 Control Delivery Systems, Inc. Administration topique de medicaments combines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6051576A (en) * 1994-01-28 2000-04-18 University Of Kentucky Research Foundation Means to achieve sustained release of synergistic drugs by conjugation
US5798115A (en) * 1996-02-15 1998-08-25 Santerre; Paul J. Bioresponsive pharmacologically-active polymers and articles made therefrom
US6689350B2 (en) * 2000-07-27 2004-02-10 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
CA2461099A1 (fr) * 2001-09-21 2003-04-10 The Administrators Of The Tulane Educational Fund Conjugues d'analogues de somatostatine ou de bombesine a vocation diagnostique ou therapeutique, et utilisations correspondantes
US20040087664A1 (en) * 2002-08-14 2004-05-06 Marcus Dennis Michael Methods and compositions for treatment of macular and retinal disease

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
See also references of EP1744787A4 *
WOO ET AL, BIOMATERIALS, vol. 21, 2000, pages 1235 - 1246, XP004195834 *
WOO ET AL, J.BIOMAT.RES., vol. 59, no. 1, 2002, pages 35 - 45 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009506055A (ja) * 2005-08-22 2009-02-12 クイック−メッド テクノロジーズ、インク． 第四級アンモニウムポリマーおよびコポリマーを用いた殺菌剤
US8445016B2 (en) 2006-04-14 2013-05-21 Interface Biologics, Inc. Grafted polymers and uses thereof
WO2007148230A3 (fr) * 2006-04-14 2008-06-12 Interface Biologics Inc Polymères greffés et leurs utilisations
EP2040758A4 (fr) * 2006-06-30 2014-09-17 Interface Biologics Inc Polymeres biosensibles
JP2010501026A (ja) * 2006-06-30 2010-01-14 インターフェース バイオロジクス，インコーポレーテッド 生体応答性ポリマー
EP2040758A2 (fr) * 2006-06-30 2009-04-01 Interface Biologics Inc. Polymeres biosensibles
US8962697B2 (en) 2006-06-30 2015-02-24 Interface Biologics Inc. Bioreponsive polymers
EP2273989A4 (fr) * 2008-04-07 2013-05-01 Interface Biologics Inc Polythérapie pour le traitement des infections bactériennes
US8440176B2 (en) 2008-04-25 2013-05-14 Interface Biologics, Inc. Covalently grafted pharmaceutically active polymers
WO2009129630A1 (fr) * 2008-04-25 2009-10-29 Interface Biologics Inc. Polymères actifs de manière pharmaceutique, greffés de façon covalente
US10588862B2 (en) 2018-02-02 2020-03-17 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US10632075B2 (en) 2018-02-02 2020-04-28 Ripple Therapeutics Corporation Glass formulations and uses thereof
US10945958B2 (en) 2018-02-02 2021-03-16 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US10959954B2 (en) 2018-02-02 2021-03-30 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US11612567B2 (en) 2018-02-02 2023-03-28 Ripple Therapeutics Corporation Ocular inserts comprising a covalently linked steroid dimer
US11279729B2 (en) 2020-05-01 2022-03-22 Ripple Therapeutics Corporation Heterodimer compositions and methods for the treatment of ocular disorders

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EP1744787A1 (fr) 2007-01-24
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JP2007537168A (ja) 2007-12-20

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